CA1041483A - Process of producing novel cephalosporin derivatives - Google Patents
Process of producing novel cephalosporin derivativesInfo
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- CA1041483A CA1041483A CA222,581A CA222581A CA1041483A CA 1041483 A CA1041483 A CA 1041483A CA 222581 A CA222581 A CA 222581A CA 1041483 A CA1041483 A CA 1041483A
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Abstract
PROCESS OF PRODUCING NOVEL CEPHALOSPORIN DERIVATIVES
ABSTRACT OF THE DISCLOSUEE
A process of producing a novel cephalosporin derivative having at the 3-position of the cephem ring a heterocyclic thlo-me:thyl group having a carboxy group or a sulfo group and at the 7-position of the cephem ring an .alpha.-heterocyclic acylaminophenyl-acetamide group. The compounds of this invention have excellent antibacterial activity to Pseudomonas and Proteus strains.
ABSTRACT OF THE DISCLOSUEE
A process of producing a novel cephalosporin derivative having at the 3-position of the cephem ring a heterocyclic thlo-me:thyl group having a carboxy group or a sulfo group and at the 7-position of the cephem ring an .alpha.-heterocyclic acylaminophenyl-acetamide group. The compounds of this invention have excellent antibacterial activity to Pseudomonas and Proteus strains.
Description
The present invention relates to a process of producing novel cephalosporin derivatives. More particularly, the invention relates to a process of producing the novel cephalosporin deriva-tives represented by the formula ..
R ~ OEI-CONH ~ ~ ~ (D)m~(E)n NH N ~ CH2S- ~B ~ R
CO ~ COOH 4 ..
Rl R2 V
'' wherein R represents a hydrogen atom or a hydroxy group; (~ ;.` .
represents a 5- or 6-membered ring having 1-2 nitrogen atoms, a ~. .
quinoline ring, or a -thiopyran ring; R and R , which may be the .. :
15 same or different, each represents a hydrogen atom, a hydroxy ~ ;I
; group, a lower alkyl group, a lower alkoxy group, a lower alkyl- . -thio group, or an oxo group; ~ represents a 5-membered ring having 1-4 nitrogen atoms and/or 0-1 sulfur atom, a 6-membered .. ;
. ring having 2 nitrogen atoms, or a .:.
' 20 1,2,4-triazolo ~3,4-b~-1,3,4-thiadiazole ring, if R and R
!I can be present, which may be the same or different, each repre-~i sents a hydrogen atom, an oxo group, a lower alkyl group, or an ` . .
~' .
amino group; D represents a sulfur atom or a -NHCO- group; E
~ represents an alkylene group or a phenylene group;.G represents .
:'~ 25 a carboxy group or a sulfo group; n is 0 or 1 when m is 0; and x n is 1 when m is 1, and the non-toxic salts thereof.
f, As the compounds of this invention show antibacterial a~ti-f ;vities in a wide range of gram positive bacteria and gram negative :f: ~ .
t bacteria and show, in particular, excellent antibacte:rial ..
~ 30 activities to Pseudomonas and PrOteus strains, they can be appliecl ..
:' .
:
to human beings and animals as agents for treating various dis-eases infected with these bacteria~
Cephalosporin derivatives effective to Pseudomonas strains have not hitherto been known bu-t by the discovery of the novel cephalosporin derivatives of this invention, it becomes possible to treat the diseases caused by these strains.
Examples of the 5- or 6-membered ring having 1-2 nitrogen atoms shown by ring ~ in this invention are a pyrrole ring, an ~ ~
imidazole ring, a pyrazole ring, a pyridine ring, a pyrimidine ~ ~-...
10 ring~ a pyridiazine ring, a pyrazine ring, etc. These rings may -~
be partially saturated. Examples of the 5-membered ring having -1-4 nitrogen atoms and/or 0-1 sulfur atom .shown by ring ~ are a pyrrole ring, an imidazole ring, a pyrazole ring, a triazole ring, a tetrazole ring, a thiazole ring, an isothiazole ring, a ;~
15 1,2,4-thiadiazole ring, a 1,3,4-thiadiazole ring, etc. Also, examples of the 6-membered ring having 2 nitrogen atoms are a pyrimidine ring, a pyrazine ring, a pyridazine ring, etc. These ;
1: .
rings may be partially saturated. Example of the lower alkyl group in R -R or the lower alkyl group forming a lower alkoxy ;~
group or a lower alkylthio group in Rl-R4 are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, etc. Furthermore, examples of an alkylene group in substituent E are, ~or example, a methylene group, an ethylene group~ a ~ri- ~ -~ : .
~ methylene group, an isopropylidene group, an ethylidene group, a . ~: .. . .
propylene group, etc.
he compound~of this invention shown by general formula V
4~
can be;prepared by, for example, reacting the compound represented by general ~ormula I
R- ~ CH-COMH ~ S
R ~ OEI-CONH ~ ~ ~ (D)m~(E)n NH N ~ CH2S- ~B ~ R
CO ~ COOH 4 ..
Rl R2 V
'' wherein R represents a hydrogen atom or a hydroxy group; (~ ;.` .
represents a 5- or 6-membered ring having 1-2 nitrogen atoms, a ~. .
quinoline ring, or a -thiopyran ring; R and R , which may be the .. :
15 same or different, each represents a hydrogen atom, a hydroxy ~ ;I
; group, a lower alkyl group, a lower alkoxy group, a lower alkyl- . -thio group, or an oxo group; ~ represents a 5-membered ring having 1-4 nitrogen atoms and/or 0-1 sulfur atom, a 6-membered .. ;
. ring having 2 nitrogen atoms, or a .:.
' 20 1,2,4-triazolo ~3,4-b~-1,3,4-thiadiazole ring, if R and R
!I can be present, which may be the same or different, each repre-~i sents a hydrogen atom, an oxo group, a lower alkyl group, or an ` . .
~' .
amino group; D represents a sulfur atom or a -NHCO- group; E
~ represents an alkylene group or a phenylene group;.G represents .
:'~ 25 a carboxy group or a sulfo group; n is 0 or 1 when m is 0; and x n is 1 when m is 1, and the non-toxic salts thereof.
f, As the compounds of this invention show antibacterial a~ti-f ;vities in a wide range of gram positive bacteria and gram negative :f: ~ .
t bacteria and show, in particular, excellent antibacte:rial ..
~ 30 activities to Pseudomonas and PrOteus strains, they can be appliecl ..
:' .
:
to human beings and animals as agents for treating various dis-eases infected with these bacteria~
Cephalosporin derivatives effective to Pseudomonas strains have not hitherto been known bu-t by the discovery of the novel cephalosporin derivatives of this invention, it becomes possible to treat the diseases caused by these strains.
Examples of the 5- or 6-membered ring having 1-2 nitrogen atoms shown by ring ~ in this invention are a pyrrole ring, an ~ ~
imidazole ring, a pyrazole ring, a pyridine ring, a pyrimidine ~ ~-...
10 ring~ a pyridiazine ring, a pyrazine ring, etc. These rings may -~
be partially saturated. Examples of the 5-membered ring having -1-4 nitrogen atoms and/or 0-1 sulfur atom .shown by ring ~ are a pyrrole ring, an imidazole ring, a pyrazole ring, a triazole ring, a tetrazole ring, a thiazole ring, an isothiazole ring, a ;~
15 1,2,4-thiadiazole ring, a 1,3,4-thiadiazole ring, etc. Also, examples of the 6-membered ring having 2 nitrogen atoms are a pyrimidine ring, a pyrazine ring, a pyridazine ring, etc. These ;
1: .
rings may be partially saturated. Example of the lower alkyl group in R -R or the lower alkyl group forming a lower alkoxy ;~
group or a lower alkylthio group in Rl-R4 are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, etc. Furthermore, examples of an alkylene group in substituent E are, ~or example, a methylene group, an ethylene group~ a ~ri- ~ -~ : .
~ methylene group, an isopropylidene group, an ethylidene group, a . ~: .. . .
propylene group, etc.
he compound~of this invention shown by general formula V
4~
can be;prepared by, for example, reacting the compound represented by general ~ormula I
R- ~ CH-COMH ~ S
2 O~ ~ ~ CH2OCOCH3 COOH --: '' :
j 2 wherein R has the same meaning as in general formula V and the heterocyclic carboxylic acid represented by general formula II
Rl ~ . :
R2 II ~ ~
.
.:
. wherein ~ , R , and R have the same meani.ng as in general ~ .
~ormula V or a reactive derivative thereof to produce the com~
pound shown by general formula III
:-., ~. , R ~ CH-CONE~ S~ III . .. ;
;1 IH O N ~ CM2OCOcH3 .. ~ .
COOEI
~, and then reacting the product with the mercapto-substituted ~ ~ .
.iJ , ~ . .....
heterocyclic ring compound represented by general ~ormula IV
.3~ ~ . ...
~ (D)m-(E)n-G
:~ M-S - ~ R3 .j ~ '. .
:J ~ : wherein M represents a hydrogen atom or an alkali metal atom and R , R , ~ , D, E, G, m and n have the same meaning as in general -:~
formula V or, more precisely, a heterocyclic compound substituted by a carboxyl group or a sulfo group, and a mercapto group.
~ ~t ~,; The reaction are illustrated by the ~ollowing reaction formulae;
R ~ 7H-coNH r~
~: ~ 2 O ~ CH20COCH3 .'.'!~ ' '', : COOH . ;
~ 3 ;.
; :'. ~ '' '.' ., ~. . .
Step 1 ¦ ~ - COOH II
R-- ~ CH-CONH- r s ~
NH O N \ ~ -cH2OCOCH3 III
C~
(D)m-(E)n-G
Step 2 ~ ~R rv ~ R
R ~ CIH CONH ~ S ~(D)m-(E)n-G
~H O N ~ CH2S ~ R~3 V
.
wherein ~ ~ D, E, G, R, R , R, R , R , m and n have the same meaning as in the above formulae.
.
l~ The reaction of step 1 is carried out by reacting the com~
! `
pound of formula I and an almost equimolar or excessive amount of the compound of formula II or ~he reactive derivative thereof.
'.. :: ::
I ~ 25 When the compound of formula II is used in a free state or the salt thereof, the reaction is carried out preferably in the .: : .
presence of a condensing agent such as ~ dicyclohexylcarbodi- `,;.
imide; a phosphoric acid trialkyl ester, e.g., triethyl phosphate;
~ , a phosphorus oxyhalide, e.g., phosphorus oxychloride; a phosphorus ;
trihalide, e.g., phosphorus trichloride; a thionyl halide, e.g~
. . ', thionyl chloride; an oxa~olyl chloride; and the like Examples of the preferred reactive derivatives of the com-pounds of formula ~I are, for example, acid halides, acid azides;
acid anhydrides; mixed acid anhydrides such as an alkylcarboxylic acid mixed acid anhydride, an alkyl phosphoric acid mixed acid anhydride, a dialkyl phosphorous acid mixed acid anhydride, a sulfuric acid mixed acid anhydride, etc., as well as an active amide with imidazole, an active ester, such as a p-nitrophenyl ester, etc.
When an alkylcarboxylic acid mixed acid anhydride, an acid halide, etc., is used as the reactive derivative of the compound ;
of formula II, the reaction is ordinarily carried out in an organic solvent such as acetone, tetrahydrofuran, dimethyl for-mamide, chloroform, dichloromethane, hexamethyl phosphoramide (hexametapol~, etc., or a mixed solvent thereof in the presence of a base such as triethylamine, dimethylaniline, etc., under cooling or at room temperature.
, The compound of formula III formed is usually isolated and 'Ji purified by an ordinary chemical procedure such as extraction, j 20 recrystallization, etc., and as the case may be, the reaction mixture containing the compound of formula III is applicable ., .
for the reaction with the compound of formula rv without further ~;~ isolation or purification~
The reaction of step 2 is carried out by reacting the com-q 25 pound of formula III and an almost equimolar or excessive amounk of the compound of formula IV. The reaction is ordinarily carried `1 :
ouk in aqueous solution, in an inert organic solvent such as acetone, ether, chloroform, nitrobenzene, dimethylsulfoxide, dimethylformamide, methanol, ethanol, etc., or a miXture thereof.
I'he r~action is also carried out in a neutral state or a slightly :"
:', , , ,, ,, , , ,, . , ,' alkaline state and in the cass of using the compound of formula IV wherein M is a hydrogen atom, the reaction is carried out in the presence of a basic material such as, for example, an alkali metal hydroxide, an alkali metal carbonate, triethylamine, etc.
5 Ths reaction may be carried out at room temperature but there is no particular limitation about the reaction temperature, and ~or example, the reaction system may be heated to a boiling point of the solvent used in the reaction.
The order of the reaction of step 1 and step 2 may be rever-10 sed. The aimed product of formula V may be isolated and purified by an ordinary chemical operation such as extraction, recrystal-lization, etc. Furthermore, the compound of formula V can be converted into a pharmacologically allowable salt thereof, e.g., inorganlc salts thereof, such as an alkali metal salt, an 15 ammonium salt, etc., and organic salts thereof, such as a tri-ethylamine, diethanolamine, lysine, ornithine, et~.
i There are many compounds of formula V thus prepared but in ., .
~'~ the preferred compound of formula V, ring ~ is a pyridine ' ring; substituent R is a hydrogen atom; R' is a hydroxy group or an oxo group; ring ~ is a thiazole ring, a thiadiazole ring, J or a tetrazole ring; D is a sulfur atom; E is an alkylene group .~ .~:,, .
` having 1-2 carbon atoms; G is a carboxy group; m is 0 or 1; and .~ - .
n is 1.
In more pre~erable compound of formula V of this in~ention, I 25 ring ~ has a hydroxy group or an oxo group at the 4-position -1 thereof; the alXylene group is a methylene group, G is a carboxy group; D is a sulfur atom; the thiadiazole ring of ring ~ is -a 1~2,4-thiadiazole ring or 1,3,4-thiadiazole ring cmd m is 1.
Practical examples of the compounds of formula V are as 30 follo~s: `
:., ': ~:
7-lD-c~ -Hydroxynico-tinoylamido)~t-phenylacetamido~-3-(5- ~
carboxymethylthio)-1,3,4-thiadiazole-~-yl)thiomethyl-~ -cephem- ~ .
4-carboxylic acid, 7-~D-~-(4-Hydroxynicotinoylamido)~-phenylacetamido~-3-t3- :.
5 carboxymethylthio-1,2,4-thiadiazol-5-yl)thiomethyl-~ -cephem-4- ~.
carboxylic acid, :; .
7- LD-~-(4-Hydroxynicotinoylamido)-~-phenylacetamido~3-(4- :
methyl-5-carboxythiazol-2-yl)thiomethyl-~ -cephem-4-carboxylic .
acid, . -7- ~D-~-(4-~ydroxynicotinoylamido)-~-phenylacetamido~--3-(1-carboxymethyl-lH-tetrazol-5-yl)thiomethyl-~ -cephem-4-carboxylic acid, 7-[D-~-(4-Hydroxynicotinoylamido)-~-phenylacetamidoJ-3-(5-carboxymethyl-4-methylthiazol-2-yl)thiomethyl-~ -cephem-4-carboxylic acid, 7-~D-~-(4-Hydroxynicotinoylamido)~-phenylacetamido~-3-(5-! carboxymethylthio-4-methylthiazol-2-yl)thiomethyl-~ -cephem-4- .. carboxylic acid, ~ ::
7-~D-~-(4-Hydroxynicotinoylamido)-~-phenylacetamido~-3-(5-20 carboxymethyl-1,3,4-thiadiazo1-2-yl)thiomethy1-~3-cephem-4-;, . . .
carboxylic acid, :. :
~'~ 7-~D-~-(4-Hydroxy-3-methylpyridin-5-ylcarboxamido)-~-phenyl- .~.
acetamido~-3-(5-carboxymethylthio-1,3,4,-thiadiazol-2-yl)thio-~f~ methyl-~3-cephem-4-carboxylic acid, 7~[D-~-(4-~Iydroxy-6-methylnicot.inoylamido~-~-ph~nylacetamido~- -
j 2 wherein R has the same meaning as in general formula V and the heterocyclic carboxylic acid represented by general formula II
Rl ~ . :
R2 II ~ ~
.
.:
. wherein ~ , R , and R have the same meani.ng as in general ~ .
~ormula V or a reactive derivative thereof to produce the com~
pound shown by general formula III
:-., ~. , R ~ CH-CONE~ S~ III . .. ;
;1 IH O N ~ CM2OCOcH3 .. ~ .
COOEI
~, and then reacting the product with the mercapto-substituted ~ ~ .
.iJ , ~ . .....
heterocyclic ring compound represented by general ~ormula IV
.3~ ~ . ...
~ (D)m-(E)n-G
:~ M-S - ~ R3 .j ~ '. .
:J ~ : wherein M represents a hydrogen atom or an alkali metal atom and R , R , ~ , D, E, G, m and n have the same meaning as in general -:~
formula V or, more precisely, a heterocyclic compound substituted by a carboxyl group or a sulfo group, and a mercapto group.
~ ~t ~,; The reaction are illustrated by the ~ollowing reaction formulae;
R ~ 7H-coNH r~
~: ~ 2 O ~ CH20COCH3 .'.'!~ ' '', : COOH . ;
~ 3 ;.
; :'. ~ '' '.' ., ~. . .
Step 1 ¦ ~ - COOH II
R-- ~ CH-CONH- r s ~
NH O N \ ~ -cH2OCOCH3 III
C~
(D)m-(E)n-G
Step 2 ~ ~R rv ~ R
R ~ CIH CONH ~ S ~(D)m-(E)n-G
~H O N ~ CH2S ~ R~3 V
.
wherein ~ ~ D, E, G, R, R , R, R , R , m and n have the same meaning as in the above formulae.
.
l~ The reaction of step 1 is carried out by reacting the com~
! `
pound of formula I and an almost equimolar or excessive amount of the compound of formula II or ~he reactive derivative thereof.
'.. :: ::
I ~ 25 When the compound of formula II is used in a free state or the salt thereof, the reaction is carried out preferably in the .: : .
presence of a condensing agent such as ~ dicyclohexylcarbodi- `,;.
imide; a phosphoric acid trialkyl ester, e.g., triethyl phosphate;
~ , a phosphorus oxyhalide, e.g., phosphorus oxychloride; a phosphorus ;
trihalide, e.g., phosphorus trichloride; a thionyl halide, e.g~
. . ', thionyl chloride; an oxa~olyl chloride; and the like Examples of the preferred reactive derivatives of the com-pounds of formula ~I are, for example, acid halides, acid azides;
acid anhydrides; mixed acid anhydrides such as an alkylcarboxylic acid mixed acid anhydride, an alkyl phosphoric acid mixed acid anhydride, a dialkyl phosphorous acid mixed acid anhydride, a sulfuric acid mixed acid anhydride, etc., as well as an active amide with imidazole, an active ester, such as a p-nitrophenyl ester, etc.
When an alkylcarboxylic acid mixed acid anhydride, an acid halide, etc., is used as the reactive derivative of the compound ;
of formula II, the reaction is ordinarily carried out in an organic solvent such as acetone, tetrahydrofuran, dimethyl for-mamide, chloroform, dichloromethane, hexamethyl phosphoramide (hexametapol~, etc., or a mixed solvent thereof in the presence of a base such as triethylamine, dimethylaniline, etc., under cooling or at room temperature.
, The compound of formula III formed is usually isolated and 'Ji purified by an ordinary chemical procedure such as extraction, j 20 recrystallization, etc., and as the case may be, the reaction mixture containing the compound of formula III is applicable ., .
for the reaction with the compound of formula rv without further ~;~ isolation or purification~
The reaction of step 2 is carried out by reacting the com-q 25 pound of formula III and an almost equimolar or excessive amounk of the compound of formula IV. The reaction is ordinarily carried `1 :
ouk in aqueous solution, in an inert organic solvent such as acetone, ether, chloroform, nitrobenzene, dimethylsulfoxide, dimethylformamide, methanol, ethanol, etc., or a miXture thereof.
I'he r~action is also carried out in a neutral state or a slightly :"
:', , , ,, ,, , , ,, . , ,' alkaline state and in the cass of using the compound of formula IV wherein M is a hydrogen atom, the reaction is carried out in the presence of a basic material such as, for example, an alkali metal hydroxide, an alkali metal carbonate, triethylamine, etc.
5 Ths reaction may be carried out at room temperature but there is no particular limitation about the reaction temperature, and ~or example, the reaction system may be heated to a boiling point of the solvent used in the reaction.
The order of the reaction of step 1 and step 2 may be rever-10 sed. The aimed product of formula V may be isolated and purified by an ordinary chemical operation such as extraction, recrystal-lization, etc. Furthermore, the compound of formula V can be converted into a pharmacologically allowable salt thereof, e.g., inorganlc salts thereof, such as an alkali metal salt, an 15 ammonium salt, etc., and organic salts thereof, such as a tri-ethylamine, diethanolamine, lysine, ornithine, et~.
i There are many compounds of formula V thus prepared but in ., .
~'~ the preferred compound of formula V, ring ~ is a pyridine ' ring; substituent R is a hydrogen atom; R' is a hydroxy group or an oxo group; ring ~ is a thiazole ring, a thiadiazole ring, J or a tetrazole ring; D is a sulfur atom; E is an alkylene group .~ .~:,, .
` having 1-2 carbon atoms; G is a carboxy group; m is 0 or 1; and .~ - .
n is 1.
In more pre~erable compound of formula V of this in~ention, I 25 ring ~ has a hydroxy group or an oxo group at the 4-position -1 thereof; the alXylene group is a methylene group, G is a carboxy group; D is a sulfur atom; the thiadiazole ring of ring ~ is -a 1~2,4-thiadiazole ring or 1,3,4-thiadiazole ring cmd m is 1.
Practical examples of the compounds of formula V are as 30 follo~s: `
:., ': ~:
7-lD-c~ -Hydroxynico-tinoylamido)~t-phenylacetamido~-3-(5- ~
carboxymethylthio)-1,3,4-thiadiazole-~-yl)thiomethyl-~ -cephem- ~ .
4-carboxylic acid, 7-~D-~-(4-Hydroxynicotinoylamido)~-phenylacetamido~-3-t3- :.
5 carboxymethylthio-1,2,4-thiadiazol-5-yl)thiomethyl-~ -cephem-4- ~.
carboxylic acid, :; .
7- LD-~-(4-Hydroxynicotinoylamido)-~-phenylacetamido~3-(4- :
methyl-5-carboxythiazol-2-yl)thiomethyl-~ -cephem-4-carboxylic .
acid, . -7- ~D-~-(4-~ydroxynicotinoylamido)-~-phenylacetamido~--3-(1-carboxymethyl-lH-tetrazol-5-yl)thiomethyl-~ -cephem-4-carboxylic acid, 7-[D-~-(4-Hydroxynicotinoylamido)-~-phenylacetamidoJ-3-(5-carboxymethyl-4-methylthiazol-2-yl)thiomethyl-~ -cephem-4-carboxylic acid, 7-~D-~-(4-Hydroxynicotinoylamido)~-phenylacetamido~-3-(5-! carboxymethylthio-4-methylthiazol-2-yl)thiomethyl-~ -cephem-4- .. carboxylic acid, ~ ::
7-~D-~-(4-Hydroxynicotinoylamido)-~-phenylacetamido~-3-(5-20 carboxymethyl-1,3,4-thiadiazo1-2-yl)thiomethy1-~3-cephem-4-;, . . .
carboxylic acid, :. :
~'~ 7-~D-~-(4-Hydroxy-3-methylpyridin-5-ylcarboxamido)-~-phenyl- .~.
acetamido~-3-(5-carboxymethylthio-1,3,4,-thiadiazol-2-yl)thio-~f~ methyl-~3-cephem-4-carboxylic acid, 7~[D-~-(4-~Iydroxy-6-methylnicot.inoylamido~-~-ph~nylacetamido~- -
3-(~5-carboxymethylthio-1,3,4-thiadiazol-2-yl)thiomethyl-~3-cepham- .
~; 4-carboxylic acid, and the like.
.1~ Now, ~or illustrating the excellent pharmacological effects of the compounds of this invention, the values o:E MIC (.~/ml.) of .
i 30 the compounds against various bacteria are shown in I~able 1, in ^ .
which the compounds of -this invention used are shown by example numbers. ~ ~
~ .
.
'~. 10 , ~ ~ , "~
,~ ' " ~. .
Il 15 i' '' ~''., .:"
', ' '~ ': , ,:
.;~i ~, ' ;": `
:~ ' .': ~ ', j 20 . ~
.: ~
j ~: ~ '',"' '' " ' i 25 ~: .:
'. , :, :', ' , ~ '~ . .'' ! ;
' `' 8 ..
3 : ~
T A B_L E I
MIC (,~/ml) Bacteria Known compound Cephalexin30 30 - ~100 - - 10 3 Cephaloglycin 25 100 100 ~100 >L00 >100 100 25 Cephazolin3.13 25 6.25?100 ~100 ~100 1.56 1.56 Cephalotin - 12.5 - ~100 ~100 - 3.13 0.78 Compound of0.190.19 0.18 25 50 25 25 6.25 Ex.
~; 4-carboxylic acid, and the like.
.1~ Now, ~or illustrating the excellent pharmacological effects of the compounds of this invention, the values o:E MIC (.~/ml.) of .
i 30 the compounds against various bacteria are shown in I~able 1, in ^ .
which the compounds of -this invention used are shown by example numbers. ~ ~
~ .
.
'~. 10 , ~ ~ , "~
,~ ' " ~. .
Il 15 i' '' ~''., .:"
', ' '~ ': , ,:
.;~i ~, ' ;": `
:~ ' .': ~ ', j 20 . ~
.: ~
j ~: ~ '',"' '' " ' i 25 ~: .:
'. , :, :', ' , ~ '~ . .'' ! ;
' `' 8 ..
3 : ~
T A B_L E I
MIC (,~/ml) Bacteria Known compound Cephalexin30 30 - ~100 - - 10 3 Cephaloglycin 25 100 100 ~100 >L00 >100 100 25 Cephazolin3.13 25 6.25?100 ~100 ~100 1.56 1.56 Cephalotin - 12.5 - ~100 ~100 - 3.13 0.78 Compound of0.190.19 0.18 25 50 25 25 6.25 Ex.
4< 0.09 0.190.39 12.5 6.25 6.25 3.13 3.13
5< 0.09 0.190.78 12.5 6.25 6.25 6.25 6.25
6< 0.09 ~0.090O39 12.5 6.25 6.25 3~13 6.25 9 0.19 0.390.39 12.5 12.5 12.5 3.13 3.13 10 <0.09 <0.090.39 25 50 50 6.25 3.13 11 0.39 6.250.56 25 12.5 12.5 25 3.13 12 0.19 0.190.39 25 12.5 25 6.25 0.39 13< 0.09 0.780.39 12.5 6.25 12.5 3.13 3.13 14 0.19 0.780.19 25 12.5 25 3.13 ~.25 0.19 0.39~ 0.09 25 6.25 12.5 6.25 ~.25 16 <0.09 < 0.090.19 25 25 25 6.25 12.5 21 <0.09 0.190.39 12.5 12.5 12.5 3.13 6.25 22 0.19 1.560.39 12.5 6.25 12.5 3.13 6.25 23< 0~09 < 0.090.19 12.5 6.25 12.5 1.56 6.25 ~,~ 24 <0.09 < n.oso.ls 12.5 6.25 12.5 3.13 6.25 25< 0.09 1.560.39 12.5 6.25 12.5 3.13 6.25 ' 26 0.19 0.390.78 12.5 12~5 25 6.25 12.5 27 <0.09 0.780.78 12.5 6.25 25 3.13 1.56 23 <0.09 12.50.78 12.5 6.25 12~5 3.13 6.~5 30~< ~.09 0.780.78 25 12.5 25 6~25 1~.5 32 <0.09 3.130.78 50 25 50 3.I3 6.25 ,~ 33 <0.09 12.50.39 ~5 25 12.5 3.13 25 3; : 34 <0.09 0.780.78 25 12.5 25 12.5 12.5 ': :
~L0~ 3 T A B L E I cont'd MIC ( y/ml) Bacteria ~ ~ ~ C) ~3) Known compound Cephalexin6.25 6.25 6.256.25 0.78 Cephaloglycir 3 3 3 10 Cephazolin 1056 1.56 1.561.56 0.19 Cephalotin 1.56 0.39 6.256.25 Compound of 1.56 0.78 6.25 25 0.78 4 1.56 0.39 0.783.13 0.19 1.56 0.39 1.566.25 0.78 6 1-56 0.39 0.783.13 0.39 9 1.56 0.39 1.566.25 0.39 1.56 0.19 1.566.25 0,39 11 0.78 0.39 6.25 25 0~39 ~2 0.19 0.19 1.563 13 0 39 13 1.56 0,39 1.563.13 0.39 14 1.56 0.78 1.563.13 0,39 3.13 0.78 3.133.13 0.39 16 1.56 0.78 3~136.25 0.39 21 1.56 0.39 1.563.13 0.39 22 3.13 0.78 1.563013 0.39 23 1.56 0.39 1.563.13 0.39 24 1.56 0.78 1.563.13 0.78 0.39 0.19 1.566.25 0.39 1 26 6.25 1.56 3.136.25 0.78 f~ 27 0.78 0.39 0.783.13 0.78 f~ 29 1.56 0.78 0.783.13 0.78 f~ 30 6.25 1.56 6.2512.5 0.78 ~ 32 1.56 1.56 0.783.13 0.78 3~; ~ 33 3.13 1.56 3.13 3-13 34 6.25 1.56 6.2512.5 0.78 . i , .
ga 3~
; ~ - .:. ., ~, 4:~.483 TABLE I cont ' d .
MIC ( ~/ml) . .
Bacteria 6) Known compound Cephalexin 0.78 1.56 1.56 6.25 12.5 Cephalog lycin .
`' 0.3 0.3 1 3 3 . : .
;. Cephazolin 0.19 0.19 0.19 0.78 1.56 ; Cephalotin <0 09 - 0.19 0.39 0,39 Compound of Ex. 10.393.13 0.78 3.13 6.25 0.19 3.13 0.78 3.13 6.25 50.393.13 1.56 6.25 6.25 - 60,396.25 1.56 6.25 12.5 ; 90.393.13 0.78 3.13 6.25 ';
,~ 100.193.13 0.39 3.13 3.13 11O. 396.250.393 . 13 6.25 123.133.13 0.78 3.13 6.25 13o 396.25 0.78 6.25 6.25 140.786.25 1.56 12.5 12.5 150.39 25 3.13 12,5 25 160.193.13 0.78 6.25 6.25 ~
210.393.13 1.56 6.25 6.25 `~;
220.786.25 1.56 12.5 12.5 230.7812.5 3.13 12.5 12.5 ~ , 2~0,396.25 0.78 6.25 6.25 250.396.25 0.78 3.13 6.25 260 786.25 1.56 6.25 12.5 ;
. ~ . . .
270.786.251.566.2S 6.25 290~786.25 1.56 6.25 12.5 ~ ;~
300.7812.5 1.56 12.5 25 ; J0.78 3.13 1.56 3.13 6.25 i'.., ~
330.783.13 3.13 12.5 25 341.5612.5 3.13 12.5 25 . ~
:- ~ ~ . ,: , : j: : : :
, ~ - :
' '~ ~ . .~ . ' ' : -Proteus vulgaris OXK US
Proteus vulgaris OX l9US
Proteus mirabilis IFM OM-l9 Pseudomonas aeruyinosa ATCC 8689 Pseudomonas aeruginosa 99 ~Gentam~ycin resistant~
Pseudomonas ovalis IMA 1002 .
Escherichia coli kauffmann 0-1 Klebsiella pn~umoniae ATCC 10031 Salmonella typhi H901 W ~ :
Salmonella enteritidis Shigella ~lexneri 2a 1675 .:
Shigella sonnei II 37148 :~
Bacillus megatherium 10778 Bacillus subtilis ATCC 6633 ~;
~ . . .
~ Micrococcus ~lavus AT~C 10240 .
Staphylococcus aureus 209P ~ -Staphylococcus Shimanishi Staphylococcus 3numa ~ -... ..
.
. ... .
.: ., .: . ..
'":": '~
, ............................. . . . ..
.... . .. .
. .. .
..
3 ~ ~
Other merit of the compounds of this invention is that the salts, for example, sodium salts of these compounds are easily dissolved in water at pH o~ living bodies, which makes them suitable for injections at high concentration. The solubility -: , 5 of these compoundc~ are illustrated in Table 2 together with a ~ ;~
control example.
Table 2 ..
Test sample ~Exa~nple no.) 4 - b The disodium salt of the compound was dissolved in water in an ~nount of more than 2~/o ghowing p~ 7.4.
6 " ;
24 "
. .
26 - b .,: ' Control sample* The sodium salt of the compound was dissolved ' clearly at 0.5%, the solution of the salt I became slight turbid at 1%, became turbid at i~
i 5%, bec~ne thickly turbid at l~/o~ and was gelled at 20%. .. ;
(*): 7-~D~ 4-hydroxynicotinoylamido~ phenylacetamido~-3-t5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-~ -cephem-4-carboxylic acid.
~ Still other merit of the compounds of this invention is that `~ -,~ 25 they are resistant to ~-lactamase produced by gram negative `;~ bacteria.
For example, the relation between the ~nount (~/ml) o~ a unaltered test sample at an initial concentration of the sample `~ ;
~ 100 ~/ml against ~-lact~nase isolated from Pseudomonas aeruginosa ``~ 30 Zl at various dilutions of the enzyme were investigated.
~: .
1 1 ~: , .
; ~ , '~' ' ' ' The results of the investigation is shown in Table 3.
Table 3 Test sample Dilution (magnification) of ~-lactamase x ~ x~ x8 x 16 x 32 x 6~ x 128 x 25~
Compound o 0 29~6 61,0 100 100 100 100 100 ~ `
Example 4 - b Cephalothin O O O 0 2.6 11.8 46.8 81.6 Cefazolin O O O O 0 9.2 21.5 84.6 Table 3 (cont.
Test sample Dilution x 512 x 1024 Compound o~ 100 100 Example 4 - b ;
15 Cephalothin 100 100 Cefazolin 96.7 100 : ~ '.', " '' ' ' Other merit of the compounds of this invention is that they are not inactivated in the internal organs in bodies. For -~
.'' .: ':.,:
example, when the compounds of this invention and cephalotin are each homogenated with the internal organs, the compounds of this invention are not decomposed while cephalotin is decomposed. -;
The relation between the reaction period of time and the ~ -anti-bacterial activity (residual activity, %) when these com~
: .~:
pounds are incubated with the plasma and the liver homogenate of a male Sprague-Dowley rat is shown in Table 4. The residual antibacterial activity was measured by a thin-layer cup me-thod : ~ .
according to Bacillus subtilis ATCC 6633.
, :.,, :.
~ 3 Table 4 A*(%) B*(%~
Time(minute)rrime(minute~
Compound of 100 97.0 93.9 103.0 100 93.5 91.3 102.2 Example 4 Compound of 100 92.0 102.0 102.0 100 95.7 8~.1 91.3 ~-Example 6 Compound o~ 100 103.0 92.0 100.0 100 100.0 100.0 102.5 Example 9 '''; ~' ' Cephalothin 100 87~0 66.0 36.0 100 17.2 12.2 12.6 Cephalorid- 100 97.2 89.5 72.2 100 82.3 86.0 91.1 ine ", ' .
A*: Residual activity l%) when incubated with 9~/O plasma.
B*: Residual activity (%) when incubated with l~/o liver homo-genate. -~; The compounds of this invention are usually administered by an intravenous injection or an intramuscular injection~ the dosage is ordinarily 1 g. psr day per adult, and the amount can be increased up to 5 g. according to the condition of diseases and the patient. The dosage for a child is 20-40 mg./kg. and the amount can be increased up to 100 mg./kg. according to the con-dition of disease and the patient~
Exam~le l-a ; 25 To 100 ml. of dichloromethane were added 4,2 g. of cephalo-glycin monohydrate, 3.0 g. of anhydrous magnesium sulfate, and ~ ~ 2,1 ml. of triethylamine and af~er stirring the mixture for one ;~ ~ hour at room temperature, magnesium sul~ate was ~ilterecl off to provide a dichloromethane solution of cephaloglycin triethylamine salt. The solution was cooled to -30 C. and then 1~75 CJ. of 4-oxo-4H-thiopyran-3-carbonyl chloride and 20 1 ml. of triethylamine were added to the solution followed by stirring for one hour.
~ hen, the temperature of the mixture was returned to room temperature and after stirring for one hour, dichloromethane was - 5 distilled off under reduced pressure. Wa~er was then added to -~
the residue formed and after adjusting the pH thereo~ to 2 by ~1 adding dropwise 4~/0 phosphoric acid to the mixture, the reaction mixkure was extracted with 400 ml. of a mixture of butanol and ,~ :
ethyl acetate in 1 : 1 by volume ratio. The extract was washed with wa~er, washed twice with a saturated aqueous sodium chloride :~ :,:.:, .
! solution, and after filtering off insoluble matters, the filtrate ~ was dried over anhydrous magnesium sulfate. Then, when a butanol ~ i '! solution of 30~/0 sodium 2-ethylhexanoate, precipitates formed, `I which was recovered by filtration, washed with ethyl acetate and i 15 ether, and then re-precipitated from a mixkure of methanol and ether to provide 2.8 g. of sodium 7-D-L~-(4-oxo-4H-thiopyran-3- -~t carbonylamino)-~-phenylacetamido3cephalosporanate having a melting point of 185-195C. (decomp.) ;
.'' :,'~,, 3~ Infrared absorption spectra: ~ ~
~, . .
~K cm. : 3450 (NH~, 1770 (~-lactam), 1660 (amide), ~ 1610 (carboxylate), and 1740 (ester).
t Nuclear magnetic resonance spectra: (D6DMS0 -~ CD30D).
2.00 (3M, s, CH3C0), 3.30 (2H, q(AB type), ~ ~ ), , H ~ -;
25 4~84 (lH, d, ~ ), 4.93 (2H, q(AB type),/~CH2-0-), ~ ~ O
5.60 (lH, d, ~ ), 5.89 ~lH, s, ~ -CH
~L0~ 3 T A B L E I cont'd MIC ( y/ml) Bacteria ~ ~ ~ C) ~3) Known compound Cephalexin6.25 6.25 6.256.25 0.78 Cephaloglycir 3 3 3 10 Cephazolin 1056 1.56 1.561.56 0.19 Cephalotin 1.56 0.39 6.256.25 Compound of 1.56 0.78 6.25 25 0.78 4 1.56 0.39 0.783.13 0.19 1.56 0.39 1.566.25 0.78 6 1-56 0.39 0.783.13 0.39 9 1.56 0.39 1.566.25 0.39 1.56 0.19 1.566.25 0,39 11 0.78 0.39 6.25 25 0~39 ~2 0.19 0.19 1.563 13 0 39 13 1.56 0,39 1.563.13 0.39 14 1.56 0.78 1.563.13 0,39 3.13 0.78 3.133.13 0.39 16 1.56 0.78 3~136.25 0.39 21 1.56 0.39 1.563.13 0.39 22 3.13 0.78 1.563013 0.39 23 1.56 0.39 1.563.13 0.39 24 1.56 0.78 1.563.13 0.78 0.39 0.19 1.566.25 0.39 1 26 6.25 1.56 3.136.25 0.78 f~ 27 0.78 0.39 0.783.13 0.78 f~ 29 1.56 0.78 0.783.13 0.78 f~ 30 6.25 1.56 6.2512.5 0.78 ~ 32 1.56 1.56 0.783.13 0.78 3~; ~ 33 3.13 1.56 3.13 3-13 34 6.25 1.56 6.2512.5 0.78 . i , .
ga 3~
; ~ - .:. ., ~, 4:~.483 TABLE I cont ' d .
MIC ( ~/ml) . .
Bacteria 6) Known compound Cephalexin 0.78 1.56 1.56 6.25 12.5 Cephalog lycin .
`' 0.3 0.3 1 3 3 . : .
;. Cephazolin 0.19 0.19 0.19 0.78 1.56 ; Cephalotin <0 09 - 0.19 0.39 0,39 Compound of Ex. 10.393.13 0.78 3.13 6.25 0.19 3.13 0.78 3.13 6.25 50.393.13 1.56 6.25 6.25 - 60,396.25 1.56 6.25 12.5 ; 90.393.13 0.78 3.13 6.25 ';
,~ 100.193.13 0.39 3.13 3.13 11O. 396.250.393 . 13 6.25 123.133.13 0.78 3.13 6.25 13o 396.25 0.78 6.25 6.25 140.786.25 1.56 12.5 12.5 150.39 25 3.13 12,5 25 160.193.13 0.78 6.25 6.25 ~
210.393.13 1.56 6.25 6.25 `~;
220.786.25 1.56 12.5 12.5 230.7812.5 3.13 12.5 12.5 ~ , 2~0,396.25 0.78 6.25 6.25 250.396.25 0.78 3.13 6.25 260 786.25 1.56 6.25 12.5 ;
. ~ . . .
270.786.251.566.2S 6.25 290~786.25 1.56 6.25 12.5 ~ ;~
300.7812.5 1.56 12.5 25 ; J0.78 3.13 1.56 3.13 6.25 i'.., ~
330.783.13 3.13 12.5 25 341.5612.5 3.13 12.5 25 . ~
:- ~ ~ . ,: , : j: : : :
, ~ - :
' '~ ~ . .~ . ' ' : -Proteus vulgaris OXK US
Proteus vulgaris OX l9US
Proteus mirabilis IFM OM-l9 Pseudomonas aeruyinosa ATCC 8689 Pseudomonas aeruginosa 99 ~Gentam~ycin resistant~
Pseudomonas ovalis IMA 1002 .
Escherichia coli kauffmann 0-1 Klebsiella pn~umoniae ATCC 10031 Salmonella typhi H901 W ~ :
Salmonella enteritidis Shigella ~lexneri 2a 1675 .:
Shigella sonnei II 37148 :~
Bacillus megatherium 10778 Bacillus subtilis ATCC 6633 ~;
~ . . .
~ Micrococcus ~lavus AT~C 10240 .
Staphylococcus aureus 209P ~ -Staphylococcus Shimanishi Staphylococcus 3numa ~ -... ..
.
. ... .
.: ., .: . ..
'":": '~
, ............................. . . . ..
.... . .. .
. .. .
..
3 ~ ~
Other merit of the compounds of this invention is that the salts, for example, sodium salts of these compounds are easily dissolved in water at pH o~ living bodies, which makes them suitable for injections at high concentration. The solubility -: , 5 of these compoundc~ are illustrated in Table 2 together with a ~ ;~
control example.
Table 2 ..
Test sample ~Exa~nple no.) 4 - b The disodium salt of the compound was dissolved in water in an ~nount of more than 2~/o ghowing p~ 7.4.
6 " ;
24 "
. .
26 - b .,: ' Control sample* The sodium salt of the compound was dissolved ' clearly at 0.5%, the solution of the salt I became slight turbid at 1%, became turbid at i~
i 5%, bec~ne thickly turbid at l~/o~ and was gelled at 20%. .. ;
(*): 7-~D~ 4-hydroxynicotinoylamido~ phenylacetamido~-3-t5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-~ -cephem-4-carboxylic acid.
~ Still other merit of the compounds of this invention is that `~ -,~ 25 they are resistant to ~-lactamase produced by gram negative `;~ bacteria.
For example, the relation between the ~nount (~/ml) o~ a unaltered test sample at an initial concentration of the sample `~ ;
~ 100 ~/ml against ~-lact~nase isolated from Pseudomonas aeruginosa ``~ 30 Zl at various dilutions of the enzyme were investigated.
~: .
1 1 ~: , .
; ~ , '~' ' ' ' The results of the investigation is shown in Table 3.
Table 3 Test sample Dilution (magnification) of ~-lactamase x ~ x~ x8 x 16 x 32 x 6~ x 128 x 25~
Compound o 0 29~6 61,0 100 100 100 100 100 ~ `
Example 4 - b Cephalothin O O O 0 2.6 11.8 46.8 81.6 Cefazolin O O O O 0 9.2 21.5 84.6 Table 3 (cont.
Test sample Dilution x 512 x 1024 Compound o~ 100 100 Example 4 - b ;
15 Cephalothin 100 100 Cefazolin 96.7 100 : ~ '.', " '' ' ' Other merit of the compounds of this invention is that they are not inactivated in the internal organs in bodies. For -~
.'' .: ':.,:
example, when the compounds of this invention and cephalotin are each homogenated with the internal organs, the compounds of this invention are not decomposed while cephalotin is decomposed. -;
The relation between the reaction period of time and the ~ -anti-bacterial activity (residual activity, %) when these com~
: .~:
pounds are incubated with the plasma and the liver homogenate of a male Sprague-Dowley rat is shown in Table 4. The residual antibacterial activity was measured by a thin-layer cup me-thod : ~ .
according to Bacillus subtilis ATCC 6633.
, :.,, :.
~ 3 Table 4 A*(%) B*(%~
Time(minute)rrime(minute~
Compound of 100 97.0 93.9 103.0 100 93.5 91.3 102.2 Example 4 Compound of 100 92.0 102.0 102.0 100 95.7 8~.1 91.3 ~-Example 6 Compound o~ 100 103.0 92.0 100.0 100 100.0 100.0 102.5 Example 9 '''; ~' ' Cephalothin 100 87~0 66.0 36.0 100 17.2 12.2 12.6 Cephalorid- 100 97.2 89.5 72.2 100 82.3 86.0 91.1 ine ", ' .
A*: Residual activity l%) when incubated with 9~/O plasma.
B*: Residual activity (%) when incubated with l~/o liver homo-genate. -~; The compounds of this invention are usually administered by an intravenous injection or an intramuscular injection~ the dosage is ordinarily 1 g. psr day per adult, and the amount can be increased up to 5 g. according to the condition of diseases and the patient. The dosage for a child is 20-40 mg./kg. and the amount can be increased up to 100 mg./kg. according to the con-dition of disease and the patient~
Exam~le l-a ; 25 To 100 ml. of dichloromethane were added 4,2 g. of cephalo-glycin monohydrate, 3.0 g. of anhydrous magnesium sulfate, and ~ ~ 2,1 ml. of triethylamine and af~er stirring the mixture for one ;~ ~ hour at room temperature, magnesium sul~ate was ~ilterecl off to provide a dichloromethane solution of cephaloglycin triethylamine salt. The solution was cooled to -30 C. and then 1~75 CJ. of 4-oxo-4H-thiopyran-3-carbonyl chloride and 20 1 ml. of triethylamine were added to the solution followed by stirring for one hour.
~ hen, the temperature of the mixture was returned to room temperature and after stirring for one hour, dichloromethane was - 5 distilled off under reduced pressure. Wa~er was then added to -~
the residue formed and after adjusting the pH thereo~ to 2 by ~1 adding dropwise 4~/0 phosphoric acid to the mixture, the reaction mixkure was extracted with 400 ml. of a mixture of butanol and ,~ :
ethyl acetate in 1 : 1 by volume ratio. The extract was washed with wa~er, washed twice with a saturated aqueous sodium chloride :~ :,:.:, .
! solution, and after filtering off insoluble matters, the filtrate ~ was dried over anhydrous magnesium sulfate. Then, when a butanol ~ i '! solution of 30~/0 sodium 2-ethylhexanoate, precipitates formed, `I which was recovered by filtration, washed with ethyl acetate and i 15 ether, and then re-precipitated from a mixkure of methanol and ether to provide 2.8 g. of sodium 7-D-L~-(4-oxo-4H-thiopyran-3- -~t carbonylamino)-~-phenylacetamido3cephalosporanate having a melting point of 185-195C. (decomp.) ;
.'' :,'~,, 3~ Infrared absorption spectra: ~ ~
~, . .
~K cm. : 3450 (NH~, 1770 (~-lactam), 1660 (amide), ~ 1610 (carboxylate), and 1740 (ester).
t Nuclear magnetic resonance spectra: (D6DMS0 -~ CD30D).
2.00 (3M, s, CH3C0), 3.30 (2H, q(AB type), ~ ~ ), , H ~ -;
25 4~84 (lH, d, ~ ), 4.93 (2H, q(AB type),/~CH2-0-), ~ ~ O
5.60 (lH, d, ~ ), 5.89 ~lH, s, ~ -CH
7,40 ~6H, ~ ~ ), 8.39 ~lH, q, 9.37 (lH, d, ~ ).
,3~
Example l-b In 50 ml . of water were suspended 820 mg. of sodium 7-tD-~-(4-oxo-4H-thiopyran-3-ylcarboxamido)-~-phenylacetamidolcephalo-sporanate and 350 mg. of (5-mercapto-1,3,4-thiadiazol-2-yl)-succi -5 namic acid and then after adding 3 ml. of an aqueous 10% sodium bicarbonate to the suspension, the mixture was stirr~d for 23 hours while heating to 55 C. After the reaction was over, in soluble matters were filtered o~f from ~he reaction mixture and then the pH of the filtrate was adjusted to 2 by adding thereto 1 N hydrochloric acid. The precipitates formed were recovered by filtration, washed thoroughly with water, and then with ether, and dried over phosphorus pentoxide under reduced pressuxe. The pro-duct thus obtained was dissolved in 12 ml of dimethyl sulfoxide and aeter adding to the solution 0.9 ml of a 30/O n-butanol solu-tion of sodium 2-ethylhexanoate, the mixture was stirred for 5 minutes. ~hen, 120 ml of ethyl acetate was added to the reac~ion mixture and the resultant mixture was stirred for 10 minutes. The precipitates thus formed were recovered by filtration, washed thoroughly with ethyl acetate and then ether, and dried over phosphorus pentoxide under reduced pressure to provide 480 mg the disodium salt Oe 7-LD-~ ~4-oxo-4H-thiopyran-3-ylcarboxamido)-~-phenylacetamido~-3-[5-(3-carboxypropionylamino)-1,3,4-thiadiazol-2-yl~thiomethyl-~ -cephem-4-carboxylic acid.
Muclear magnetic resonance spectra (D2O):
~5 S: 2.66 (4~, -NHCOCH2C~ C02Na).
..
In~rared absorption spectra:
~ YmaX cm. : 1762 ~-lactam), 1660 (amide).
Exam~le 2-a To a solution of 900 mg Oe c~phaloglycin tr:Lethylamine salt and 17 ml of dichloromethane was added 550 mg of p-nikroE~henyl 3-hydroxypyridazine-4-carboxyl~te under ice-cooling and then after adding 15 ml of dimethylformamide, the resultant mixture was stirred for one hour.
Then, the mixture was further stirred for 17 hours at room temperature. After the reaction was over, 23 ml. o dichloro methane was added to the reaction mixture and the mixture was extracted thrice with 40 ml. of an aqueous 1.5% sodium bicarbonate.
The aqueous layer recovered was washed with dichloromethane, the pH of the aqueous solution was adjusted to 2 with 1 ~ hydrochloric 10 acid, and then the precipitates formed were extracted with 60 ml. ~
of a mixture of bu~anol and ethyl acetate in 1 : 1 by volume ratio. ~--The extract was washed with water and ~hen a saturatecl aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. To the solution was added 1.3 ml. of a 30/O n-butanol ~' 15 solution of sodium 2-ethylhexanoate, -the precipitates formed were ;~l recovered by filtration, washed with ethyl acetate and then ether, i~ and dried over phosphorus pentoxide under reduced pressure to provide 600 mg~ of sodium 7-[D-~-(3-hydroxypyridazin-4-ylcarbox-amido)-~-phenylacetamido]-cephalosporanate.
Nuclear magnetic resonance spectra tD6-DMSO)
,3~
Example l-b In 50 ml . of water were suspended 820 mg. of sodium 7-tD-~-(4-oxo-4H-thiopyran-3-ylcarboxamido)-~-phenylacetamidolcephalo-sporanate and 350 mg. of (5-mercapto-1,3,4-thiadiazol-2-yl)-succi -5 namic acid and then after adding 3 ml. of an aqueous 10% sodium bicarbonate to the suspension, the mixture was stirr~d for 23 hours while heating to 55 C. After the reaction was over, in soluble matters were filtered o~f from ~he reaction mixture and then the pH of the filtrate was adjusted to 2 by adding thereto 1 N hydrochloric acid. The precipitates formed were recovered by filtration, washed thoroughly with water, and then with ether, and dried over phosphorus pentoxide under reduced pressuxe. The pro-duct thus obtained was dissolved in 12 ml of dimethyl sulfoxide and aeter adding to the solution 0.9 ml of a 30/O n-butanol solu-tion of sodium 2-ethylhexanoate, the mixture was stirred for 5 minutes. ~hen, 120 ml of ethyl acetate was added to the reac~ion mixture and the resultant mixture was stirred for 10 minutes. The precipitates thus formed were recovered by filtration, washed thoroughly with ethyl acetate and then ether, and dried over phosphorus pentoxide under reduced pressure to provide 480 mg the disodium salt Oe 7-LD-~ ~4-oxo-4H-thiopyran-3-ylcarboxamido)-~-phenylacetamido~-3-[5-(3-carboxypropionylamino)-1,3,4-thiadiazol-2-yl~thiomethyl-~ -cephem-4-carboxylic acid.
Muclear magnetic resonance spectra (D2O):
~5 S: 2.66 (4~, -NHCOCH2C~ C02Na).
..
In~rared absorption spectra:
~ YmaX cm. : 1762 ~-lactam), 1660 (amide).
Exam~le 2-a To a solution of 900 mg Oe c~phaloglycin tr:Lethylamine salt and 17 ml of dichloromethane was added 550 mg of p-nikroE~henyl 3-hydroxypyridazine-4-carboxyl~te under ice-cooling and then after adding 15 ml of dimethylformamide, the resultant mixture was stirred for one hour.
Then, the mixture was further stirred for 17 hours at room temperature. After the reaction was over, 23 ml. o dichloro methane was added to the reaction mixture and the mixture was extracted thrice with 40 ml. of an aqueous 1.5% sodium bicarbonate.
The aqueous layer recovered was washed with dichloromethane, the pH of the aqueous solution was adjusted to 2 with 1 ~ hydrochloric 10 acid, and then the precipitates formed were extracted with 60 ml. ~
of a mixture of bu~anol and ethyl acetate in 1 : 1 by volume ratio. ~--The extract was washed with water and ~hen a saturatecl aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. To the solution was added 1.3 ml. of a 30/O n-butanol ~' 15 solution of sodium 2-ethylhexanoate, -the precipitates formed were ;~l recovered by filtration, washed with ethyl acetate and then ether, i~ and dried over phosphorus pentoxide under reduced pressure to provide 600 mg~ of sodium 7-[D-~-(3-hydroxypyridazin-4-ylcarbox-amido)-~-phenylacetamido]-cephalosporanate.
Nuclear magnetic resonance spectra tD6-DMSO)
8.16, 8.30 (hydrogen of the nucleus of pyridazine ring).
Infrared absorption spectra:
cm. 1 1760 (~-lactam), 1664 (amide).
Bxample 2-b In 25 ml. of water were suspended 400 mg. of sodium 7- LD-~- :
(3-hydroxypyridazine-4-ylcarboxamido)-~-phenylacetamido]cephalo- ~;
sporanate and 170 mg. of (5-mercapto-1,3,4-thiadiazol -2--yl)-~$ succinamic acid and then 1.5 ml. of an aqueous 1~/~ sodium bicar~
~; bonate solution was added to the suspension. ~he resu]tant mix-~i 30 ture wa~ stirred for 20 hours at 60C. A~ter the reaction was , ., ~ ,' ' ~ ' ':' over, insoluble matters Eormed was filtered off from the reaction mixture and the pH of the filtrate was adjusted to 2 by adding thereto 1 ~ hydrochloric acid~ The precipitates thus formed were recovered by filtration, washed thoroughly with water, 25 ml.
of a mixture o~ methanol and ether in 1 : 5 by volume ratio, and then ether, and dried over phosphorus pentoxide under reduced pressure.
The product obtained was dissolved in 4 ml. of dimethyl sulfoxide, and a~ter adding to the solution 0.5 ml. of a 30~/0 n-butanol solution of sodium 2-ethylhexanoate, the resultant mix-ture was stirred for 5 minutes. To the reaction mixture was added 50 ml. of ethyl acetate and the mixture was stirred for 10 minutes. q'he precipitates thus ~ormed were recovered by filtra-tion, washed thoroughly with ethyl acetate and then ether, and dried over phosphorus pentoxide to provide 260 mg. oE the disodium salt of 7-tD-~-(3-hydroxypyridazin-4-ylcarboxamido)-~-phenylace-tamido]-3-{5-~3-carboxypropionylamiino)-1,3,4-thiadiazol -2-yl} ;
thiomethyl-~3-cephem-4-carboxylic acid.
Nuclear magnetic resonance spectra (D20):
~: 2.60 (4H-NHCOC~I2CH2C02Na~
Infrared absorption spectra: ~ `
1 ~m cm. : 1762 (~-lactam), 1664 (amide).
Example 3 a ~¦ After cooling a solution of 1.55 g. of cephaloglycin triethyl-25 amine salt and 25 ml. of dichlorome~hane to -30 C., 0.60 gO of 2,4-dihydroxypyrimidine-5-carboxylic acid chloride and the mixture was stirred for 2 hours at temperatures of from 20 C. to -30 C.
and then for 2 hours at room temperature. After the reaction was ,; :. : .
over, the reaction mixture was concentrated under reduced press-ure and then 30 ml. of water was added to the concentrate. Then, :' ~ . .' the p~ of the solu-tion was adjusted to 2 by adding 1 N hydro-chloric acid and then the precipitates formed were extracted with 120 ml. of a mixture of butanol and ethyl acetate in 1 : 1 by volume ratio.
The extract was washed with water and a saturated aqueous sodium chloride solution successively and dried over anhydrous magnesium sulfate and ~iltered. To the filtrate was added 1.8 ~;
ml. of a 30~/0 n-butanol solution o sodium 2-ethylhexanoate and `
the precipitates formed were recovered by filtration, washed with ..
ethyl acetate and then ether, and dried over phosphorus pentoxide under reduced pressure to provide 0.72 g. of sodium 7-[D~ 2,4-' dihydroxypyrimidin-5-ylcarboxamido)-~-phenylacetamido]cephalos~
.j '' '' "
poranate.
Nuclear magnetic resonance spectra (D6-DMS0):
~ 15 J 8.28 (hydrogen of the nucleus of pyrimidine) s', Infrared absorption spectra:
~KBr cm. 1 1760 (~-lactam), 1676 (amide). ;
~ Example 3-b , ;
,~ In 25 ml. of water were suspended 400 mg. of sodium 7- ~-t~-20 (2~4-dihydroxypyrimidin-5 ylcarboxamido)-~-phenylacetamido~- ;
~ cephalosporanate and 170 mg. of (5-mercapto-1,3,4-thiadiazol-,~ 2~yl)succinamic acid and after adding 1.5 ml. of an at~ueous 10% -sodium bicarbonate solution to the suspension, the mixture was stirred for 22 hours under heating to 55 C. After the reaction ,~
was over, insoluble matters formed were filtered off from the 3;~ ~ reaction mixture and the pH of the ~iltr~te was adjusted to 2 by adding thereto 1 N hydrochloric acid~ The precipitates formed were recovered by filtration, washed thoroughly with water and ~', then ether, and dried over phosphorus pentoxide under reduced '~ 30 pressure. By treating the product as in Example 2-b, 220 mg. of .` .
18 ~
the sodium salt o~ 7-lD-~-(2,4-dihydroxypyrimidin-5-ylcarbOXamidO)-~-phenylacetamido~-3- ¦5-(3-carboxypropionylamino)-1,3,4-thiadiazol-2~yl) thiomethyl-L\3-cephem-4-carboxylic acid was obtained.
Nuclear magnetic resonance spectrum (D20) ~: 2.62 (4~, -~HCOCH C~I C0 Na) Infrared absorption spectra:
cm. 1760 (~-lactam), 1664 ~amide).
Example 4-a In 40 ml. of dichloromethane was suspended 1.4 g. o~ 4-hydroxynicotinic acid and after adding 1.4 ml. of triethylamine to the suspension, the mixture was stirred for 30 minutes at room ~-.j .' :
' temperature to form an almost transparent solution. The solution ;~ was e~ooled to 0-5 C. and 10 ml. of dichloromethane containing 0.73 ml. of thionyl chloride was added dropwise to the solution i 15 at the same temperature. Thereafter, the mixture was stirred ~or one hour at room temperature to provide a suspension o~ 4-hydroxynicotinoyl chloride.
,.~,.. ~, .
In 100 ml. o~ dichloromethane was suspended 4.25 g. o~
`l cephaloglycin monohydrate and then 2.8 ml. of triethylamine was dissolved therein. Furthermore, 5 g. of anhydrous magnesium sul~ate was added to the system and after stirring the mixture for about 10 minutes at room temperature, the mixture was filtered to provide a solution o~ cephaloglycin triethylamine salt. The solution was cooled to -20 C. and the suspension of 4-hydroxy-- -. . , 25 nicotinoyl chloride prepared above was added dropwise to the solution with stirring. Thereafter, the cooling bath was removed to raise the temperature up to room temperature and the mixture was stirred ~or about one hour at room temperature. `
The reaction mixture obtained was concentrated at low ;~ :
~` 30 temperature under reduced pressure and the solicl residue formed 19 ~ .,: .
: ~:
' ,:
was dissolved in 100 ml. of cold water. when the pH of the solu-tion was adjusted to 2 with hydrochloric acid, white crystals were precipitated, which were recovered by Eiltration~ washed with water and a small amount o~ acetone, and then dried.
The crystals thus recovered wPre dissolved in 30 ml. of .
dimethylformamide and insoluble matters formed were filtered off.
. Then, a n-butanol solution of 3~/o potassium 2-ethylhexanoate was .
.~ added to the filtrate until the precipitation ceased. Further-more, 100 ml. of ether was added to the suspension and after 10 allowing to stand the mixture for a while, the precipitates were ~ .
recovered by filtration and washed with acetone. Then, by puri- .
fying ths precipitates by dissolving them in water~containing .:
dimethylformamide followed by ~iltration and reprscipitating with ;;
the addition of acetone, 1.35 g. of potassium 7-D- ~ -(4-hydroxy- ~ .
pyridine 3-carbonylamino)-~-phenylacetamino]cephalosporanate was obtained as the yellowish brown powdery crystals. Melting point 195-202 C, (decomp.) .
.,~ ~ . ~, . . .
In~rared absorption spectra: ~ , a cm. : 3400 (NH, OH), 1760 (.~-lactam~, 1740 (acetate), 1655 (amide), 1600 (carboxylats).
Nuclear magnetic resonance spectra (CD30D ~ D6-DMSO):
1.97 (3H, CH3COO-), 3.13 (2H, ~ ), 4-8 (2H, CH20), i ~ 5.01 (1H, ~ t ), 6.6 (lH, ~ ), 5.82 (lH, :~
~: 25 : t ~S- ) :
O ~ `"
~' 6.38 (lH, ~ CH-), 7.4-7.6 (5H, ~ ), . .: ;
` ' ~ NH , .
8.SO (lH, ~ ), 7.86 (lH
l 30 -:- ~
i( ,,` : ~ " ~.:
.:
xample 4-b To 32 ml. o~ water were added 500 mg. of sodium 7- tD-~-(4-hydroxynicotinoylamido)-~-phenylacetam,ido~cephalosporanate, 209 mg. of (5-mercapto-1,3,4-thia,diazol -2-yl)thioacetic acid, and 203 mg. of sodium bicarbonate and the mixture was stirred for 22 hours at 55C. Then, the pH 0~ the reaction mixture was adjusted to about 2 by adding 1 N hydrochloric acid under ice-cooling and the white precipitates formed were recovered by filtration) washed thoroughly with water and then ether, and dried to provide 400 `
mg. of 7-CD-O,~4-hydroxynicotinoylamido)-~-phenylacetamidO]-3-(5-..... . .
carboxymethylthio-1,3,4-thiadiazol -2-yl(thiomethyl-,,~ cephem-4-carboxylic acid.
Melting point about 250 C. (decomposed gradually).
Infrared absorption spectrum:
1 15 ~ma cm. : 1775 (~-lactam).
Z Nuclear magnetic resonance spectra (D6-DMSO): !' ' ppm: 3.58 (2H), 4.13 (2H), 4.32 (2H), 5.02 (~I), 5.77 (lH), 5.79 (lH), 6.43 (lH), 7.36 (5H), 7.80 (lH), 8,.43 ~lH), and 9.42 ~lH).
1 20 Ex~mple 5 J To 44 ml. o~ water were added 700 mg. of sodium 7-~D-~-(4-hydroxynicotinoylamido)-~phenylacetamido]cephalosporanate, 312 mg. of 3-~5-mercapto-1,3,4-thiadiazol -2-ylthio)propionic acid, and 283 mg. of sodium bicarbonate and then the mixture was stirred for 2 hours at 55 C. Then, by treating the product as in Example 4-b, 52C mg. of 7-[D- * (4-hydroxynicokincylamido)-~-phenylaceta-;' ~ mid~ -3-(5-carboxyethylkhio-1,3,4-thiadiazol ~2-yl)thiomethyl~
.. . . .
cephem-4-carboxylic acid was obtained. - `~
Melting point about 250 C. (decomp.)~
Infrared absorption spectrum:
:
21 ~` ~
r cm. 1 1775 (~-lactam).
max Nuclear magnetic resonance spectra (D6-DMSO): ~
; ~ppm: 2.74 ~2H)~ 3.42 (2~I), 3.58 (2H), 4.32 (2H), 5.02 (lH), ~ -5.77 (lH), 5.79 (lH), 6.43 (1~), 7.36 (5H), 7.80 (lH), 8.43 (lH), and 9.43 (lH).
Example 6 To 40 ml. of water were added 615 mg. of sodium 7-~D~ (4-hydroxynico-tinoylamido(-~-phenylacetamido~-cephalosporanate, 235 mg. of 3-(5-mercapto-1,3,4-thiadiazol -2-yl)thiopropionic acid, and 218 mg. of sodium bicarbonate and the mixture was stirred Eor 2 hours a-t 55 C. Then, by treating the product as in Example , 4-b, 450 mg. of 7-LD-~-(4-hydroxynicotinoylamido)-~-phenylacet-amido]-3-(5-carboxyethyl-1,3,4-thiadiazol -2-yl)thiomethyl-a -cephem-4-carboxylic acid was obtained.
Melting point about 250 C. ~decomp.) In~rared absorption spectrum:
~m x cm. : 1775 (~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO) ~ppm: 2.73 (2H), 3.25 (2H), 3.58 (2H), 4.35 (2~I), 5.01 tlH~, 5~78 (lH), 5.80 (~ 6.44 (lH), 7.36 (5H), 7.81 (lH), 1 8.44 (lH), 9.43 (lH).
.~ .; . .
Example 7-a ;
' To a suspension consisting o~ 4.23 g. of cephaloglycin mono-',~ hydrate, 3.0 g. of anhydrous magnesium sulfate, and 70 ml. of 25 methylene chloride was added 3.1 ml. of triethylamine and a~ter ~ -stirring the mixture for one hour at room temperature, magnesium i~ ... .
sul~ate was filtered off to provide a triethylamine salt solution o~ cephaloglycin. To the solution was added dropwise a solution ~; . , of nicotinoyl chloride ~-oxide prepared by adding dropwise 0.73 ml.
o~ thionyl chloride to a solution consisting of :L.39 g. of : - , nicotinic acid N-oxide, 1.4 ml. of triethylamine, and 30 ml. of methylene chloride under ice-cooling followed by stirring for 1.5 hours. In this case, the pH of the reaction mixture was maintained at 8-9 by adding triethylamine.
Thereafter, the reaction mixture was stirred for 3 hours at a temperature of -20 + S C. and then allowed to stand overnight at -20 C. To the residue formed by distilling o~f n butanol from ; the reaction mixture were added ice-water and a mixture of n- -butanol and ethyl acetate in 2 : 3 by volume ratio and adjusted the p~ thereo~ to 2.0 by th~ addition of dilute hydrochloric acid.
rrhe organic layer formed was recovered, washed thrice with water, dried over anhydrous magnesium sulfate, and was mixed with a n-butanol solution of 30% sodium 2-ethylhexanoate, whereby ~ 15 precipitates formed. By recovering the precipitates by filtration I and re-precipitating them with a mixture of methanol and ether, ~ 2.7 g. of sodium 7 ~D-~-(pyridine-N oxide-2-ylcarboxamid) ~
, ... ..
phenylacetamido~cephalosporanate was obtained.
' Melting point about 263 C. (decomp.) I~rared absorption spectra:
~m cm. : 3300 (N~I), 1760 (~-lactam), 1735 lester), ;~
1665 (amide), and 1615 (carboxylate).
. .: . ,. . . .: .
Nuclear magnetic resonance spectra ~D6-DMS0)~
`~ ~ppm: 2.00 (s, 3H, -OC-CH3), 3.48 ~q, 2H, ~ H )~ ;
,~25 4.92 (d, lH, ~ ), 4.95 (q, 2H, ~ -CH2-O~
,~5.60 (q, lH, ~ 3, 5.91 (d, lH, ~ _C-CO-), ~ ;;
N ~ -~
7.42 (m, 7H, ~ ~ ~ C0_), 8.42 ~q, lH, ::. -~' , '' ' .
~0 ~ ), 8.47 (q, lH, ~ ), 9.46 (d, lH, O --NH), and 12.14 (d, lH, -NH3 Example 7-b To a solution of 400 mg. o~ sodium 7-[D~ (pyridine-M-oxide-2-ylcarboxamido)-~-phenylacetamido3cephalosporanate in 25 ml. of water was added 190 mg. of (5-mercapto-1,3,5-thiadiazol -2-yl)~
succinamic acid at room temperature and ~urther a saturated 10 aqueous sodium bicarbonate solution was added to the mixture to .
adju~t the pH of the solution to 6.8-7.2. The solution was stirred for 26 hours at 55-60 C. and the pH thereo~ was then ;.
adjusted to 2.0 with diluted hydrochloric acid to form a suspen- ,. :
sion. The product thus obtained was extracted with a mixture of 15 n-butanol and ethyl acetate in 2 : 3 by volume ratio and the ` :
organic layer formed was washed thrice with water, dried, and then mixed with a n-butanol solution of 30/0 sodium ~-ethylhexa-noate and then ether to provide an oily material. The oily material thus obtained was dissolved in methanol and ether was 20 added to the solution, whereby precipitates formed, which were .
recovered by ~iltration, washed with ether, and dried to provide ~ .
0.25 g. of sodium 7- CD-~-(pyridine-N-oxide-2-ylcarboxamido)-~
phenylacetamido-3- [5-~3-carboxypropionylamino3-1,3i4-thiadiazol-2-y ~ thiomethyl-~ -cephem-4-carboxylate.
~ Melting point about 251 C. (decomp~
: . :
,. :
Infrared absorption spectra~
K~r cm. : 3300-3400 (broad, ~H~, 1760 (~-lact~n~
1665 (amide), 1590 (carboxylate3, ~
Nuclear magnetic resonance spectra (D20)~ -30: ~ppm: 2.49 (m, 4H, -COCH2C~-I ), 3013 (q, 2H, ~ H
:: , ,: :.
~3 : :
~CH2-S_ )~ 4-80 (d, lH, ~ - r~~
5.54 (d, lH, r~ ) 5 57 ( ~ C_<
: , 7.30 (m, 7H, ~ -~ ~ H )~ 7.96 (q, lH, ~ ), O O .: ' .~' .
and 8.18 (q, lH, H ~ )-Exampla 8-a ;
After stirring 35 ml. of a methylene chloride solution con- `-i taining 2.12 g. o~ cephaloglycin monohydrate, 1.5 g. of anhydrous i~ magnesium sulfate, and l.4 ml. of triethylamine for one hour at i~, room temperature "nagnesium sulfate was filtered oPf to provide a solution of triethylamine salt of cephaloylycin. A~ter cooling ,i 15 the solution to -25c., 816 mg. of 2-imidazolidone-1-carboxylic ,lj: . ~. . .
acid chloride and urther 0.3 ml. of triethylamine were added thereto.
sj . , ~,:
The mixture thus o~tained was stirred for 3 hours at -20 +
5 C and then allowed to stand overnight at -20 C. Then, the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was dissolved in ice water.
The pH of the solution ~as ad~usted~ to 2 with diluted hydrochlori~
acid and the precipitates formed were recovered by filtration, w~ashed with wa~er, and dried to give 2.1 g. o~ the precipitates. ~ ;
~The~precipitates were dissolved in 20 ml. of dimethylformamide and then~3~m~1. of a n-butanol solution of 30/0 sodium 2-ethylhexanoate was~added to the solution. Then, ethyl acetate was added to the mlxture, whereby precipitates formed, which were recovered by filtra~ion, washed with ether, and re-precipitated ~rom a mixture 0~ o~ mothanol and;ether to provide 1.5 g. of sodium 7-LD-~- (2~
. , . .:
imidazolidon-l ylcarboxamido)-~-phenylacetamido~cephalosporanate.
Melting point about 225 C. (decomp.) Infrared absorption spectra:
~ma cm. : 3100-3500 (~H), 1700 (~-lac~am), 1720 (ester, -N-C-N-), 1660 (amide), and 1605 (carboxylate).
Nuclear magnetic resonance spectra (D6-r)MSO).
J 1.98 ~s, 3H, -OCCH3), 3.28 (q, 2H, ~ H ), 3032, 3.69 (4H, H ~ H ~, 4.88 (d, lH, ~ , 4.91 o , . ..
(9.2H, ~ ) 5.55 (c~, lH, ~ ,_~, 5.66 (d, lH, ~ ), 7.34 (m, 5H, ~ ), 7.78 (lH, -NH), 9.13 (d, lH, -NH), 9.35 (d, lH, -NH).
Example 8-b l To an aqueous solution of 800 mg. of sodium 7-LD_~_~2_0XO_ i imidazolin-l-ylcarboxamido)-Q~phenylacetamido]cephalosporanate 1 in 50 ml. of water was added 0.38 g. o~ (5-mercapto-1,3,4-thia-diazol -2-yl)succinamic acid and then the pH of the solution was adjusted to 7.2-7.5 by adding a saturated sodium bicarbonate .j . ...
solution. The solution was stirred ~or 24 hours at 55-60 C. and after cooling, the pH of the solution was adjusted to 2.0 by diluted hydrochloric acid whereby precipitates formed. Ths pre~
cipitates were recovered by filtration, washed with water, dried, and dissolved in 8 ml. of dimethylformamide. Then, 1 ml. of a n-butanol solution of 3~/o sodium 2-ethylhexanoate was added to the solution and then ethyl acetate was added thereto ~o ~orm pre-cipitates, which were recovered by Piltration, washed wil:h ether, ~ `
.,~ ;
and re-precipitat~d from a mixture o~ methanol and ether to provide . . :
. ~ ~ , , ,,, , , . , ~ :
750 mg. of disodium 7-lD-~'-(2-oxoimidazolin-1-ylcarboxamido)~
phenylacetamido~-3-l5-(3-carboxypropioIlylamino)-1,3,4-thiadiazol-2-yl)thiomethyl-~ -cephem-4-carboxylate.
Melting point: about 246 C. (decomp.) In~rared absorption spectra:
~ma cm. : 3200-3500 (NH), 1760 (~-lactam), 1720 if`
(NHCNH), 1675, 1660 (amide), 1600 (carboxylate).
Nuclear magnetic resonance spectra (D2O) ~ ppm: 2.56 (dd, 4H, -CO~H2CEI2COO-), 3.28, 3.60 (m, 4H, H I I H ), N N
~f :,. , 4.82 (d, lH, ~ ~ ), 5.36 (s, lH, ~ ), ;... ...
~5 ~4 ~d, lH, ~ 1 ~ (, 3.92 (q, 2H, ~ CH ~;
ii 15 S ~ H ~ ~`
3.13 (q, 2H, ~ H )- -'~Examp le 9 : :
To a mixture of 0.53 g. Oe sodium 7- ~D-~-(4-hydroxynicotinoyl-amido)-~-phenylacetamido~cephalosporanate and 0.3 g. o e sodium 5-mercapto-1,3,4-thiadiazol -2-yl-thioethylsulfonate were added 35 ml. of water and 0.108 g. of sodium bicarbonate and the resul-, tant mixture was stirred for 22 hours at about 57 C. Then, after I ~ removing insoluble matters by filtration, the pH of the filtrate was adjusted to about 1 with 1.5 N hydrochloric acid under ice-'Z , ., q 25 cooling and the precipitates thus formed were recovered by fil-i tration. The preclpitates were washed with water and then ether and dried to give 0.45 g. of 7-~D-~-(4-hydroxynicotinoyl~mido)~
phenylacetamido3-3-(5-sulfoethylthio-1,3,4-thiadiazol -2-yl)thio- ;
methyl-~ -cephem-4-carboxylic acid. :
Melting point: 200-220 C. (gradually decomposed).
, . . . ... .
., .~ '', ', Infrared absorption spectrum:
KBr -1 ~ cm. : 1774 (~-lactam~.
Nuclear magnetic resonance spectra (D6-DMS0):
~(ppm): 1.89 (2H), 3.47 (2H), 3.59 (2H), 4.34 (2H), 5.05 (lH), 5.79 (lH), 5.87 (lH), 6.52 (lH), 7.41 (5H), 7.89 (lH), 8.49 (lH), and 9.47 (1~3, Example 10 To 45 ml. o~ water were added 700 mg. of svdium 7- tD-~-(4-oxo-4H-thiopyran-3-ylcarboxamido~ ~-phenylacetamido~cephalospora-nate, 284 mg. of (5-mercapto-1,3,4,-thiadiazol -2-yl)thioacetic acid, and 260 mg. of sodium bicarbonate and the resultant mixture was stirred for 20 hours at 50-54 C. When the pH of the reaction mixture thus obtained was adjusted to about 2 with 1 N hydro~
chloric acid under ice-cooling and the precipitates formed were recovered by filtration, 530 mg. of the aLmed product, 7- LD-~-(4-oxo-4H-thiopyran-3-ylcarboxamido)-~-phenylacetamido]-3-(5-carbOxy-methylthio-1,3,4-thiadiazole-2-yl)thiomethyl-~3-cephem-4-carboxylic azid was obtained.
Melting point about 190 C. (decomp.) : 20 Infrared absorption spectrum:
cm. 1 1778 (~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO)~
3.58 (2H), 4.14 (2H), 4.33 (2H), 5.02 (lH) r 5.77 (2H) ~ . . :
7.35 (6H), 8.~9 ~lM), 9~34 (lH), and 9.48 ( lH) .
~xam~le 11 To 50 ml. of water were added 0.8 g. of sodium 7-~D~-(4-hydroxynicotinoylamido)-~-phenylacetamido~cephalosporanate, 0.281 ~;~ g. of 5-mercapto-1,3,4 thiadiazol -2-carboxylic acid, and 0.296 g.
of sodium bicarbonate and the resultant mixture was stirred for ,:
~ 30 20 hours at 55 C. Then, the p~ of the reaction mixture ~hus ~ . .
~ 28 ~
:., ' ',`',' ' '. ~' obtained was adjusted to 1-2 with 1 N hydrochloric acid under ice~cooling and the white precipitates formed were recovered by filtration, washed with water, and dried to provide 0.5 g. of 7-tD-~-(4-hydroxynicotinoylamido)-~-phenylacetamido~-3-(5-S carboxy-1,3,4-thiadiazol ~2-yl)thiomethyl-~3-cephem-4-carboxylic acid.
Infrared absorption spectrum:
cm. : 1770 (~-lactam). `~
max Nuclear magnetic rasonance spectra (D6-DMSO) ~ppm: 3.59 (2H, q), 4.39 (2H, q), 5.02 (lH,d), 5.72 (lH), 5.84 (lH, d), 6.44 (lH, d), 7.37 (5H), 7.82 (lH, d), 8.45 (lE~, s), 9.44 (lH, d), 11.23 (lH, d), 1220 (lH, broad).
Example 12 15To 70 ml. of water were added 700 mg. of 7- tD-~-~7-methyl- l~ -thio-4-quinolone-3-carboxamido)~d-phenylacetamido~cephalosporanic acid, 220 mg. o~ (5-mercapto-1,3,4-thiadiazol -2-yl)thioacetic acid, and 315 mg. of sodium bicarbonate, and tha resultant mixture was stirred for 20 hours at 55-60 C. After tha reaction was over, 20 the raaction mixture obtained was cooled, acidified with diluted ;;
hydrochloric acid, and the precipitates formed were recovered by ;:
filtration, washed well with water, and dried -to provide 400 mg.
of 7-~D-~-(7-methylthio-4-quinolon -3-ylcarboxamido)-~-phenyl-. ,: .
acetamido~-3-(~-carboxymethylthio-1,3,4-thiadiazol -2--yl)thio-methyl-~ -caphem-4-carboxylic acid.
Infrared absorption spectrum:
~ma cm. : 1780 (~-lactaim)~
~uclear magnetic resonance spectra (D6-DMSO):
ppm: 2.6Q (3H), 3.56 (2~I), 4.16 (2EI), 4.20 ~2~1), 5.05 (lH), 5.84 ~lH), 5~93 (lH), 7.40 (7H), 8.18 (lH) "3.70 (lH),
Infrared absorption spectra:
cm. 1 1760 (~-lactam), 1664 (amide).
Bxample 2-b In 25 ml. of water were suspended 400 mg. of sodium 7- LD-~- :
(3-hydroxypyridazine-4-ylcarboxamido)-~-phenylacetamido]cephalo- ~;
sporanate and 170 mg. of (5-mercapto-1,3,4-thiadiazol -2--yl)-~$ succinamic acid and then 1.5 ml. of an aqueous 1~/~ sodium bicar~
~; bonate solution was added to the suspension. ~he resu]tant mix-~i 30 ture wa~ stirred for 20 hours at 60C. A~ter the reaction was , ., ~ ,' ' ~ ' ':' over, insoluble matters Eormed was filtered off from the reaction mixture and the pH of the filtrate was adjusted to 2 by adding thereto 1 ~ hydrochloric acid~ The precipitates thus formed were recovered by filtration, washed thoroughly with water, 25 ml.
of a mixture o~ methanol and ether in 1 : 5 by volume ratio, and then ether, and dried over phosphorus pentoxide under reduced pressure.
The product obtained was dissolved in 4 ml. of dimethyl sulfoxide, and a~ter adding to the solution 0.5 ml. of a 30~/0 n-butanol solution of sodium 2-ethylhexanoate, the resultant mix-ture was stirred for 5 minutes. To the reaction mixture was added 50 ml. of ethyl acetate and the mixture was stirred for 10 minutes. q'he precipitates thus ~ormed were recovered by filtra-tion, washed thoroughly with ethyl acetate and then ether, and dried over phosphorus pentoxide to provide 260 mg. oE the disodium salt of 7-tD-~-(3-hydroxypyridazin-4-ylcarboxamido)-~-phenylace-tamido]-3-{5-~3-carboxypropionylamiino)-1,3,4-thiadiazol -2-yl} ;
thiomethyl-~3-cephem-4-carboxylic acid.
Nuclear magnetic resonance spectra (D20):
~: 2.60 (4H-NHCOC~I2CH2C02Na~
Infrared absorption spectra: ~ `
1 ~m cm. : 1762 (~-lactam), 1664 (amide).
Example 3 a ~¦ After cooling a solution of 1.55 g. of cephaloglycin triethyl-25 amine salt and 25 ml. of dichlorome~hane to -30 C., 0.60 gO of 2,4-dihydroxypyrimidine-5-carboxylic acid chloride and the mixture was stirred for 2 hours at temperatures of from 20 C. to -30 C.
and then for 2 hours at room temperature. After the reaction was ,; :. : .
over, the reaction mixture was concentrated under reduced press-ure and then 30 ml. of water was added to the concentrate. Then, :' ~ . .' the p~ of the solu-tion was adjusted to 2 by adding 1 N hydro-chloric acid and then the precipitates formed were extracted with 120 ml. of a mixture of butanol and ethyl acetate in 1 : 1 by volume ratio.
The extract was washed with water and a saturated aqueous sodium chloride solution successively and dried over anhydrous magnesium sulfate and ~iltered. To the filtrate was added 1.8 ~;
ml. of a 30~/0 n-butanol solution o sodium 2-ethylhexanoate and `
the precipitates formed were recovered by filtration, washed with ..
ethyl acetate and then ether, and dried over phosphorus pentoxide under reduced pressure to provide 0.72 g. of sodium 7-[D~ 2,4-' dihydroxypyrimidin-5-ylcarboxamido)-~-phenylacetamido]cephalos~
.j '' '' "
poranate.
Nuclear magnetic resonance spectra (D6-DMS0):
~ 15 J 8.28 (hydrogen of the nucleus of pyrimidine) s', Infrared absorption spectra:
~KBr cm. 1 1760 (~-lactam), 1676 (amide). ;
~ Example 3-b , ;
,~ In 25 ml. of water were suspended 400 mg. of sodium 7- ~-t~-20 (2~4-dihydroxypyrimidin-5 ylcarboxamido)-~-phenylacetamido~- ;
~ cephalosporanate and 170 mg. of (5-mercapto-1,3,4-thiadiazol-,~ 2~yl)succinamic acid and after adding 1.5 ml. of an at~ueous 10% -sodium bicarbonate solution to the suspension, the mixture was stirred for 22 hours under heating to 55 C. After the reaction ,~
was over, insoluble matters formed were filtered off from the 3;~ ~ reaction mixture and the pH of the ~iltr~te was adjusted to 2 by adding thereto 1 N hydrochloric acid~ The precipitates formed were recovered by filtration, washed thoroughly with water and ~', then ether, and dried over phosphorus pentoxide under reduced '~ 30 pressure. By treating the product as in Example 2-b, 220 mg. of .` .
18 ~
the sodium salt o~ 7-lD-~-(2,4-dihydroxypyrimidin-5-ylcarbOXamidO)-~-phenylacetamido~-3- ¦5-(3-carboxypropionylamino)-1,3,4-thiadiazol-2~yl) thiomethyl-L\3-cephem-4-carboxylic acid was obtained.
Nuclear magnetic resonance spectrum (D20) ~: 2.62 (4~, -~HCOCH C~I C0 Na) Infrared absorption spectra:
cm. 1760 (~-lactam), 1664 ~amide).
Example 4-a In 40 ml. of dichloromethane was suspended 1.4 g. o~ 4-hydroxynicotinic acid and after adding 1.4 ml. of triethylamine to the suspension, the mixture was stirred for 30 minutes at room ~-.j .' :
' temperature to form an almost transparent solution. The solution ;~ was e~ooled to 0-5 C. and 10 ml. of dichloromethane containing 0.73 ml. of thionyl chloride was added dropwise to the solution i 15 at the same temperature. Thereafter, the mixture was stirred ~or one hour at room temperature to provide a suspension o~ 4-hydroxynicotinoyl chloride.
,.~,.. ~, .
In 100 ml. o~ dichloromethane was suspended 4.25 g. o~
`l cephaloglycin monohydrate and then 2.8 ml. of triethylamine was dissolved therein. Furthermore, 5 g. of anhydrous magnesium sul~ate was added to the system and after stirring the mixture for about 10 minutes at room temperature, the mixture was filtered to provide a solution o~ cephaloglycin triethylamine salt. The solution was cooled to -20 C. and the suspension of 4-hydroxy-- -. . , 25 nicotinoyl chloride prepared above was added dropwise to the solution with stirring. Thereafter, the cooling bath was removed to raise the temperature up to room temperature and the mixture was stirred ~or about one hour at room temperature. `
The reaction mixture obtained was concentrated at low ;~ :
~` 30 temperature under reduced pressure and the solicl residue formed 19 ~ .,: .
: ~:
' ,:
was dissolved in 100 ml. of cold water. when the pH of the solu-tion was adjusted to 2 with hydrochloric acid, white crystals were precipitated, which were recovered by Eiltration~ washed with water and a small amount o~ acetone, and then dried.
The crystals thus recovered wPre dissolved in 30 ml. of .
dimethylformamide and insoluble matters formed were filtered off.
. Then, a n-butanol solution of 3~/o potassium 2-ethylhexanoate was .
.~ added to the filtrate until the precipitation ceased. Further-more, 100 ml. of ether was added to the suspension and after 10 allowing to stand the mixture for a while, the precipitates were ~ .
recovered by filtration and washed with acetone. Then, by puri- .
fying ths precipitates by dissolving them in water~containing .:
dimethylformamide followed by ~iltration and reprscipitating with ;;
the addition of acetone, 1.35 g. of potassium 7-D- ~ -(4-hydroxy- ~ .
pyridine 3-carbonylamino)-~-phenylacetamino]cephalosporanate was obtained as the yellowish brown powdery crystals. Melting point 195-202 C, (decomp.) .
.,~ ~ . ~, . . .
In~rared absorption spectra: ~ , a cm. : 3400 (NH, OH), 1760 (.~-lactam~, 1740 (acetate), 1655 (amide), 1600 (carboxylats).
Nuclear magnetic resonance spectra (CD30D ~ D6-DMSO):
1.97 (3H, CH3COO-), 3.13 (2H, ~ ), 4-8 (2H, CH20), i ~ 5.01 (1H, ~ t ), 6.6 (lH, ~ ), 5.82 (lH, :~
~: 25 : t ~S- ) :
O ~ `"
~' 6.38 (lH, ~ CH-), 7.4-7.6 (5H, ~ ), . .: ;
` ' ~ NH , .
8.SO (lH, ~ ), 7.86 (lH
l 30 -:- ~
i( ,,` : ~ " ~.:
.:
xample 4-b To 32 ml. o~ water were added 500 mg. of sodium 7- tD-~-(4-hydroxynicotinoylamido)-~-phenylacetam,ido~cephalosporanate, 209 mg. of (5-mercapto-1,3,4-thia,diazol -2-yl)thioacetic acid, and 203 mg. of sodium bicarbonate and the mixture was stirred for 22 hours at 55C. Then, the pH 0~ the reaction mixture was adjusted to about 2 by adding 1 N hydrochloric acid under ice-cooling and the white precipitates formed were recovered by filtration) washed thoroughly with water and then ether, and dried to provide 400 `
mg. of 7-CD-O,~4-hydroxynicotinoylamido)-~-phenylacetamidO]-3-(5-..... . .
carboxymethylthio-1,3,4-thiadiazol -2-yl(thiomethyl-,,~ cephem-4-carboxylic acid.
Melting point about 250 C. (decomposed gradually).
Infrared absorption spectrum:
1 15 ~ma cm. : 1775 (~-lactam).
Z Nuclear magnetic resonance spectra (D6-DMSO): !' ' ppm: 3.58 (2H), 4.13 (2H), 4.32 (2H), 5.02 (~I), 5.77 (lH), 5.79 (lH), 6.43 (lH), 7.36 (5H), 7.80 (lH), 8,.43 ~lH), and 9.42 ~lH).
1 20 Ex~mple 5 J To 44 ml. o~ water were added 700 mg. of sodium 7-~D-~-(4-hydroxynicotinoylamido)-~phenylacetamido]cephalosporanate, 312 mg. of 3-~5-mercapto-1,3,4-thiadiazol -2-ylthio)propionic acid, and 283 mg. of sodium bicarbonate and then the mixture was stirred for 2 hours at 55 C. Then, by treating the product as in Example 4-b, 52C mg. of 7-[D- * (4-hydroxynicokincylamido)-~-phenylaceta-;' ~ mid~ -3-(5-carboxyethylkhio-1,3,4-thiadiazol ~2-yl)thiomethyl~
.. . . .
cephem-4-carboxylic acid was obtained. - `~
Melting point about 250 C. (decomp.)~
Infrared absorption spectrum:
:
21 ~` ~
r cm. 1 1775 (~-lactam).
max Nuclear magnetic resonance spectra (D6-DMSO): ~
; ~ppm: 2.74 ~2H)~ 3.42 (2~I), 3.58 (2H), 4.32 (2H), 5.02 (lH), ~ -5.77 (lH), 5.79 (lH), 6.43 (1~), 7.36 (5H), 7.80 (lH), 8.43 (lH), and 9.43 (lH).
Example 6 To 40 ml. of water were added 615 mg. of sodium 7-~D~ (4-hydroxynico-tinoylamido(-~-phenylacetamido~-cephalosporanate, 235 mg. of 3-(5-mercapto-1,3,4-thiadiazol -2-yl)thiopropionic acid, and 218 mg. of sodium bicarbonate and the mixture was stirred Eor 2 hours a-t 55 C. Then, by treating the product as in Example , 4-b, 450 mg. of 7-LD-~-(4-hydroxynicotinoylamido)-~-phenylacet-amido]-3-(5-carboxyethyl-1,3,4-thiadiazol -2-yl)thiomethyl-a -cephem-4-carboxylic acid was obtained.
Melting point about 250 C. ~decomp.) In~rared absorption spectrum:
~m x cm. : 1775 (~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO) ~ppm: 2.73 (2H), 3.25 (2H), 3.58 (2H), 4.35 (2~I), 5.01 tlH~, 5~78 (lH), 5.80 (~ 6.44 (lH), 7.36 (5H), 7.81 (lH), 1 8.44 (lH), 9.43 (lH).
.~ .; . .
Example 7-a ;
' To a suspension consisting o~ 4.23 g. of cephaloglycin mono-',~ hydrate, 3.0 g. of anhydrous magnesium sulfate, and 70 ml. of 25 methylene chloride was added 3.1 ml. of triethylamine and a~ter ~ -stirring the mixture for one hour at room temperature, magnesium i~ ... .
sul~ate was filtered off to provide a triethylamine salt solution o~ cephaloglycin. To the solution was added dropwise a solution ~; . , of nicotinoyl chloride ~-oxide prepared by adding dropwise 0.73 ml.
o~ thionyl chloride to a solution consisting of :L.39 g. of : - , nicotinic acid N-oxide, 1.4 ml. of triethylamine, and 30 ml. of methylene chloride under ice-cooling followed by stirring for 1.5 hours. In this case, the pH of the reaction mixture was maintained at 8-9 by adding triethylamine.
Thereafter, the reaction mixture was stirred for 3 hours at a temperature of -20 + S C. and then allowed to stand overnight at -20 C. To the residue formed by distilling o~f n butanol from ; the reaction mixture were added ice-water and a mixture of n- -butanol and ethyl acetate in 2 : 3 by volume ratio and adjusted the p~ thereo~ to 2.0 by th~ addition of dilute hydrochloric acid.
rrhe organic layer formed was recovered, washed thrice with water, dried over anhydrous magnesium sulfate, and was mixed with a n-butanol solution of 30% sodium 2-ethylhexanoate, whereby ~ 15 precipitates formed. By recovering the precipitates by filtration I and re-precipitating them with a mixture of methanol and ether, ~ 2.7 g. of sodium 7 ~D-~-(pyridine-N oxide-2-ylcarboxamid) ~
, ... ..
phenylacetamido~cephalosporanate was obtained.
' Melting point about 263 C. (decomp.) I~rared absorption spectra:
~m cm. : 3300 (N~I), 1760 (~-lactam), 1735 lester), ;~
1665 (amide), and 1615 (carboxylate).
. .: . ,. . . .: .
Nuclear magnetic resonance spectra ~D6-DMS0)~
`~ ~ppm: 2.00 (s, 3H, -OC-CH3), 3.48 ~q, 2H, ~ H )~ ;
,~25 4.92 (d, lH, ~ ), 4.95 (q, 2H, ~ -CH2-O~
,~5.60 (q, lH, ~ 3, 5.91 (d, lH, ~ _C-CO-), ~ ;;
N ~ -~
7.42 (m, 7H, ~ ~ ~ C0_), 8.42 ~q, lH, ::. -~' , '' ' .
~0 ~ ), 8.47 (q, lH, ~ ), 9.46 (d, lH, O --NH), and 12.14 (d, lH, -NH3 Example 7-b To a solution of 400 mg. o~ sodium 7-[D~ (pyridine-M-oxide-2-ylcarboxamido)-~-phenylacetamido3cephalosporanate in 25 ml. of water was added 190 mg. of (5-mercapto-1,3,5-thiadiazol -2-yl)~
succinamic acid at room temperature and ~urther a saturated 10 aqueous sodium bicarbonate solution was added to the mixture to .
adju~t the pH of the solution to 6.8-7.2. The solution was stirred for 26 hours at 55-60 C. and the pH thereo~ was then ;.
adjusted to 2.0 with diluted hydrochloric acid to form a suspen- ,. :
sion. The product thus obtained was extracted with a mixture of 15 n-butanol and ethyl acetate in 2 : 3 by volume ratio and the ` :
organic layer formed was washed thrice with water, dried, and then mixed with a n-butanol solution of 30/0 sodium ~-ethylhexa-noate and then ether to provide an oily material. The oily material thus obtained was dissolved in methanol and ether was 20 added to the solution, whereby precipitates formed, which were .
recovered by ~iltration, washed with ether, and dried to provide ~ .
0.25 g. of sodium 7- CD-~-(pyridine-N-oxide-2-ylcarboxamido)-~
phenylacetamido-3- [5-~3-carboxypropionylamino3-1,3i4-thiadiazol-2-y ~ thiomethyl-~ -cephem-4-carboxylate.
~ Melting point about 251 C. (decomp~
: . :
,. :
Infrared absorption spectra~
K~r cm. : 3300-3400 (broad, ~H~, 1760 (~-lact~n~
1665 (amide), 1590 (carboxylate3, ~
Nuclear magnetic resonance spectra (D20)~ -30: ~ppm: 2.49 (m, 4H, -COCH2C~-I ), 3013 (q, 2H, ~ H
:: , ,: :.
~3 : :
~CH2-S_ )~ 4-80 (d, lH, ~ - r~~
5.54 (d, lH, r~ ) 5 57 ( ~ C_<
: , 7.30 (m, 7H, ~ -~ ~ H )~ 7.96 (q, lH, ~ ), O O .: ' .~' .
and 8.18 (q, lH, H ~ )-Exampla 8-a ;
After stirring 35 ml. of a methylene chloride solution con- `-i taining 2.12 g. o~ cephaloglycin monohydrate, 1.5 g. of anhydrous i~ magnesium sulfate, and l.4 ml. of triethylamine for one hour at i~, room temperature "nagnesium sulfate was filtered oPf to provide a solution of triethylamine salt of cephaloylycin. A~ter cooling ,i 15 the solution to -25c., 816 mg. of 2-imidazolidone-1-carboxylic ,lj: . ~. . .
acid chloride and urther 0.3 ml. of triethylamine were added thereto.
sj . , ~,:
The mixture thus o~tained was stirred for 3 hours at -20 +
5 C and then allowed to stand overnight at -20 C. Then, the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was dissolved in ice water.
The pH of the solution ~as ad~usted~ to 2 with diluted hydrochlori~
acid and the precipitates formed were recovered by filtration, w~ashed with wa~er, and dried to give 2.1 g. o~ the precipitates. ~ ;
~The~precipitates were dissolved in 20 ml. of dimethylformamide and then~3~m~1. of a n-butanol solution of 30/0 sodium 2-ethylhexanoate was~added to the solution. Then, ethyl acetate was added to the mlxture, whereby precipitates formed, which were recovered by filtra~ion, washed with ether, and re-precipitated ~rom a mixture 0~ o~ mothanol and;ether to provide 1.5 g. of sodium 7-LD-~- (2~
. , . .:
imidazolidon-l ylcarboxamido)-~-phenylacetamido~cephalosporanate.
Melting point about 225 C. (decomp.) Infrared absorption spectra:
~ma cm. : 3100-3500 (~H), 1700 (~-lac~am), 1720 (ester, -N-C-N-), 1660 (amide), and 1605 (carboxylate).
Nuclear magnetic resonance spectra (D6-r)MSO).
J 1.98 ~s, 3H, -OCCH3), 3.28 (q, 2H, ~ H ), 3032, 3.69 (4H, H ~ H ~, 4.88 (d, lH, ~ , 4.91 o , . ..
(9.2H, ~ ) 5.55 (c~, lH, ~ ,_~, 5.66 (d, lH, ~ ), 7.34 (m, 5H, ~ ), 7.78 (lH, -NH), 9.13 (d, lH, -NH), 9.35 (d, lH, -NH).
Example 8-b l To an aqueous solution of 800 mg. of sodium 7-LD_~_~2_0XO_ i imidazolin-l-ylcarboxamido)-Q~phenylacetamido]cephalosporanate 1 in 50 ml. of water was added 0.38 g. o~ (5-mercapto-1,3,4-thia-diazol -2-yl)succinamic acid and then the pH of the solution was adjusted to 7.2-7.5 by adding a saturated sodium bicarbonate .j . ...
solution. The solution was stirred ~or 24 hours at 55-60 C. and after cooling, the pH of the solution was adjusted to 2.0 by diluted hydrochloric acid whereby precipitates formed. Ths pre~
cipitates were recovered by filtration, washed with water, dried, and dissolved in 8 ml. of dimethylformamide. Then, 1 ml. of a n-butanol solution of 3~/o sodium 2-ethylhexanoate was added to the solution and then ethyl acetate was added thereto ~o ~orm pre-cipitates, which were recovered by Piltration, washed wil:h ether, ~ `
.,~ ;
and re-precipitat~d from a mixture o~ methanol and ether to provide . . :
. ~ ~ , , ,,, , , . , ~ :
750 mg. of disodium 7-lD-~'-(2-oxoimidazolin-1-ylcarboxamido)~
phenylacetamido~-3-l5-(3-carboxypropioIlylamino)-1,3,4-thiadiazol-2-yl)thiomethyl-~ -cephem-4-carboxylate.
Melting point: about 246 C. (decomp.) In~rared absorption spectra:
~ma cm. : 3200-3500 (NH), 1760 (~-lactam), 1720 if`
(NHCNH), 1675, 1660 (amide), 1600 (carboxylate).
Nuclear magnetic resonance spectra (D2O) ~ ppm: 2.56 (dd, 4H, -CO~H2CEI2COO-), 3.28, 3.60 (m, 4H, H I I H ), N N
~f :,. , 4.82 (d, lH, ~ ~ ), 5.36 (s, lH, ~ ), ;... ...
~5 ~4 ~d, lH, ~ 1 ~ (, 3.92 (q, 2H, ~ CH ~;
ii 15 S ~ H ~ ~`
3.13 (q, 2H, ~ H )- -'~Examp le 9 : :
To a mixture of 0.53 g. Oe sodium 7- ~D-~-(4-hydroxynicotinoyl-amido)-~-phenylacetamido~cephalosporanate and 0.3 g. o e sodium 5-mercapto-1,3,4-thiadiazol -2-yl-thioethylsulfonate were added 35 ml. of water and 0.108 g. of sodium bicarbonate and the resul-, tant mixture was stirred for 22 hours at about 57 C. Then, after I ~ removing insoluble matters by filtration, the pH of the filtrate was adjusted to about 1 with 1.5 N hydrochloric acid under ice-'Z , ., q 25 cooling and the precipitates thus formed were recovered by fil-i tration. The preclpitates were washed with water and then ether and dried to give 0.45 g. of 7-~D-~-(4-hydroxynicotinoyl~mido)~
phenylacetamido3-3-(5-sulfoethylthio-1,3,4-thiadiazol -2-yl)thio- ;
methyl-~ -cephem-4-carboxylic acid. :
Melting point: 200-220 C. (gradually decomposed).
, . . . ... .
., .~ '', ', Infrared absorption spectrum:
KBr -1 ~ cm. : 1774 (~-lactam~.
Nuclear magnetic resonance spectra (D6-DMS0):
~(ppm): 1.89 (2H), 3.47 (2H), 3.59 (2H), 4.34 (2H), 5.05 (lH), 5.79 (lH), 5.87 (lH), 6.52 (lH), 7.41 (5H), 7.89 (lH), 8.49 (lH), and 9.47 (1~3, Example 10 To 45 ml. o~ water were added 700 mg. of svdium 7- tD-~-(4-oxo-4H-thiopyran-3-ylcarboxamido~ ~-phenylacetamido~cephalospora-nate, 284 mg. of (5-mercapto-1,3,4,-thiadiazol -2-yl)thioacetic acid, and 260 mg. of sodium bicarbonate and the resultant mixture was stirred for 20 hours at 50-54 C. When the pH of the reaction mixture thus obtained was adjusted to about 2 with 1 N hydro~
chloric acid under ice-cooling and the precipitates formed were recovered by filtration, 530 mg. of the aLmed product, 7- LD-~-(4-oxo-4H-thiopyran-3-ylcarboxamido)-~-phenylacetamido]-3-(5-carbOxy-methylthio-1,3,4-thiadiazole-2-yl)thiomethyl-~3-cephem-4-carboxylic azid was obtained.
Melting point about 190 C. (decomp.) : 20 Infrared absorption spectrum:
cm. 1 1778 (~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO)~
3.58 (2H), 4.14 (2H), 4.33 (2H), 5.02 (lH) r 5.77 (2H) ~ . . :
7.35 (6H), 8.~9 ~lM), 9~34 (lH), and 9.48 ( lH) .
~xam~le 11 To 50 ml. of water were added 0.8 g. of sodium 7-~D~-(4-hydroxynicotinoylamido)-~-phenylacetamido~cephalosporanate, 0.281 ~;~ g. of 5-mercapto-1,3,4 thiadiazol -2-carboxylic acid, and 0.296 g.
of sodium bicarbonate and the resultant mixture was stirred for ,:
~ 30 20 hours at 55 C. Then, the p~ of the reaction mixture ~hus ~ . .
~ 28 ~
:., ' ',`',' ' '. ~' obtained was adjusted to 1-2 with 1 N hydrochloric acid under ice~cooling and the white precipitates formed were recovered by filtration, washed with water, and dried to provide 0.5 g. of 7-tD-~-(4-hydroxynicotinoylamido)-~-phenylacetamido~-3-(5-S carboxy-1,3,4-thiadiazol ~2-yl)thiomethyl-~3-cephem-4-carboxylic acid.
Infrared absorption spectrum:
cm. : 1770 (~-lactam). `~
max Nuclear magnetic rasonance spectra (D6-DMSO) ~ppm: 3.59 (2H, q), 4.39 (2H, q), 5.02 (lH,d), 5.72 (lH), 5.84 (lH, d), 6.44 (lH, d), 7.37 (5H), 7.82 (lH, d), 8.45 (lE~, s), 9.44 (lH, d), 11.23 (lH, d), 1220 (lH, broad).
Example 12 15To 70 ml. of water were added 700 mg. of 7- tD-~-~7-methyl- l~ -thio-4-quinolone-3-carboxamido)~d-phenylacetamido~cephalosporanic acid, 220 mg. o~ (5-mercapto-1,3,4-thiadiazol -2-yl)thioacetic acid, and 315 mg. of sodium bicarbonate, and tha resultant mixture was stirred for 20 hours at 55-60 C. After tha reaction was over, 20 the raaction mixture obtained was cooled, acidified with diluted ;;
hydrochloric acid, and the precipitates formed were recovered by ;:
filtration, washed well with water, and dried -to provide 400 mg.
of 7-~D-~-(7-methylthio-4-quinolon -3-ylcarboxamido)-~-phenyl-. ,: .
acetamido~-3-(~-carboxymethylthio-1,3,4-thiadiazol -2--yl)thio-methyl-~ -caphem-4-carboxylic acid.
Infrared absorption spectrum:
~ma cm. : 1780 (~-lactaim)~
~uclear magnetic resonance spectra (D6-DMSO):
ppm: 2.6Q (3H), 3.56 (2~I), 4.16 (2EI), 4.20 ~2~1), 5.05 (lH), 5.84 ~lH), 5~93 (lH), 7.40 (7H), 8.18 (lH) "3.70 (lH),
9.50 (lH), 11.00 (lH), and 12.60 (lH).
Example 13 In 50 ml. of water were suspended 0.80 g. o~ 7-[D-~(4-hydroxynicotinoylamido ~-~-phenylacetamido~cephalosporanic acid and 0.32 g. of (5-mercapto-1,2,4-thiadiazol -3-yl1thioacetic acid and after adding further 0.45 g. of sodium bicarbonate to the suspension, the mixture was stirred for 24 hours while heating to 55 C. After the reaction was over, insoluble matters were filtered off from the reaction mixture and the pH of the filtrate was adjusted -to 2 by adding 5% hydrochloric acid to form precipi-tates, which were recovered by filtration, washed wel:L with water and then with water, and dried over phosphorus pentoxide under : ' reduced pressure to provide 0.70 g. of the powder of 7- ~D-~-(4-hhydroxy~icotino~ylamido)-~-phenylacetamido~-3-(3-carboxymeth thio-1,2,4-thiadiaæol -5-yl)thiomethyl-~3-cephem-4-carboxylic acid.
Melting point: 189-193 C~ (decomp.) Infrared absorption spectra:
max cm. : 1770 (~-lactam) and 1650 (amide).
~ 20 Nuclear magnetic resonance spectrum (D6-DMSO~
f ; .
`~ d ppm: 4.04 (2H~ -SCH2C02H) Example 14 - ;
1~ To 50 ml. of water were added 0.8 g. of sodium 7- LD-~-(4-; hyd~o~y~icoti~oylamido)-~-phenylacetamido~cephalosporanate~
~,~ 25 0.293 g. of 2-mercapto-4-methylthiazole-5-carboxylic acid, and 0.296 g. o~ sodium bicarbonate and the resultan~ mi~ture was stirred for 22 hours at 55C. Then, the pH of the reaction mixture was adjusted to 1-2 with 1 N hydrochloric acid under ice-cooling. The white precipita-tes thus formed were recovered by . :. .
filtration, washed with water, and dried to provide 0.6 g. of ~' ,. .
7_CD_~_(4 hydroxynicotinoylamido )-~-phenylacetamido~-3~
methyl-5-carboxythiazol -2-yl) thiomethyl-L~3-cephem-4-carboxylic acid.
Infrared absorption spectrum:
~max cm. : 1770 (~~lactam~
Nuclear maynetic resonance spectra ~D6~DMS0):
Jrppm: 2.56 (3H, S~, 3.56 (2H, q) 4.37 (2H, q) 5.01 (1H, d), 5.74 (lH), 5.86 (lH, d), 6.44 (lH, d), 7.37 (5H), 7.82 (lH, d), 8.44 (lH, d), 9.44 (lH, d), 11.21 (lH, d~, and 12.21 (lH, broad~. ;
To 40 ml. of water ~ere added 600 mg. of sodium 7-~D-a-(4-hydroxynicotinoylamido)-a-phenylacetamido]cephalosporanate, '~
195 mg. of 5-mercapto-1-carboxymethyl tetrazole, and ]80 mg. of sodium bicarbonate and the resultant mixture was stirred for 22 . .
hours at 55 C. The reaction mixture thus obtained was filtered and the pH of the filtrate was adjusted to 1 with 1~ hydrochloric ~;~ acid under ice-cooling. The precipitates formed were recovered ~, . .; . . .
l; by filtration, washed with water and then with ether, and dried ~ ~
.. . . .
~, to provide 300 mg. f 7~ CD ~ ( 4~hydroxynicotinoylamido )-~-phenyl-'~ 20 acetamido~-3-(1-carboxy~ethyltetrazol -5-yl)-thiomethyl-~3-cephem-4-~carboxylic acid. ~ ;
Melting point: about 240 C. (gradually decomposed3 :.
Infrared absorption spec~rum: -max cm. : 1775 (~-lactam3.
Nuclear magnetic resonance spectra (D6-DMS0)~
ppm: 3.60 (2H), 4.36 (2H3, 5.00 (1~), 5.34 (2H), 5.84 (2H), 6.48 (lH), 7.44 (5H), 7.88 (lH), 8.50 (lH), 9.52 (lH).
Example 16 l To 30 ml. of water were added 0.45 g. o~ sodium 7- LD-~-(4-hydroxynicotinoyLamido)-~-phenylacetamido~cephalosporanate, 0.2 g.
of 6-carboxymethylthio-4~mercaptopyrimidine, and 0.14 g. o:E sodium bicar~onate and the resultant mixture was stirred for 22 hours at 55 C. Af-ter Eilteriny the reaction mixture thus obtained, the pH of the filtrate was adjusted to 1 with 1 N hydrochloric acid under ice-cooling and the precipitates thus formed were recovered by filtration, washed with water and then ether, and dried to provide 0.42 g~ of 7 ~D~-(4-hydroxynicotinoylamido)-d~phenyl-acetamidolZ-3-(6-carboxymethylthiopyr~midin -4-yl)thiomethyl-~ -cephem-4-carboxylic acid.
Infrared absorption spectrum:
~m cm. : 1775 Nuclear magnetic resonance spectra (D6-DMSO):
~ppm: 3.50 (2H), 3.98 (3H~, 4.58 (lH), 5.00 (lH), 5.74 (2H), 6.42 (lH), 7.34 (6H), 7.78 (lH), 8.42 (lH), 9.40 (lH).
Example 17 To 37 ml. of water were added 0.5 g. of 7- CD-~-t4-hydroxy- ~
nicotinoylamido)-~-phenylacetiamido~cephalosporanic acid, 0.235 g. ~- -of 6-carboxymethylthio-4-mercapto-2-methylpyrimidine, and 0.295 g.
of sodium bicarbonate and the resultant mixture was stirred for 22 hours at 50-55 C. The reaction mixture thus obtained was filtered j and the pH of the filtrate was adjusted to about 2 with 1 N
; .:
hydrochloric acid under ice-cooling. The precipitates formed were recovered by filtration, washed with water and then ether, and dried under reduced pressure to provide 0.42 g. of 7- ~D-~
(4-hydroxynicotinoylamido)-~-phenylacetamidolZ-3-(6-carboxymethyl-~ 3 J thio-2-methylpyrimidin-4-yl)thiomethyl-a -cephem-4-carboxylic ~ . . , acid.
Infrared absorption spectrum: ~
~ cm. : 1778 (~-lactam). ;;
Z~ 30 ~uclear magnetic resonance spectra (D6-DMSO):
` "'' '.' ~::: .-7~
J ppm 2.50 (3H3, 3.52 (2H), 3.82 (lH), 3.98 (2H), 4.62 (lH), 5.02 (lH), about 5.73 (lH), 5.85 (lH), 6.45 (lH), 7.~3 (lH), 7.38 (5H~, 7.82 (lH), 8.46 (~I), and 9 44 (lH)-~xample 18 TO 37 ml. of water were added 526 mg. f 7-LD d (4-hydroxy- ,~
nicotinoylamido)~-phenylacetamido~cephalosporanic acid, 220 mg.
-~ of l-carboxymethyl-3-mercapto-6(1H)-pyridaz:inone, and 300 mg. of ~- sodium bicarbonate and the resultant mixture was stirred for 22 hours at 50-55C. After the reaction was over, the reaction mixture obtained was filtered and the pH of the filtrate was then adjusted to about 2 with 1 N hydrochloric acid under ice-cooling.
The precipitates thus ~ormed were recovered by Eiltration, washed j with water and then ether, and dried under reduced pressure to provide 350 mg. of 7-LD-~-(4-hydroxynicotinoylamido(-d-phenyl-acetamido]-3-(1-carboxymethyl-6(lH)-pyridazinon -3-yl)thiomethyl-cephem-4-carboxylic acid. ~-Infrared absorption spectrum: ~
cm. : 1775 (~-Iactam)- ~ ~;
;j 20 Nuclear magnetic re~onance spect~a (D6-DMS0):
~(ppm): 3.46 ~2H), 3.8~3 tlH), 4.33 (lH), 4.66 (2H), 4.93 (1 5.74 (2H), 6.40 ~lH), 6.88 (lH), 7.34 ~6H), 7.74 (lH), ~s ;~
8.40 (lH~, and 9.41 (lH).
xample l9 ~o 30 ml. of water were added 420 mg. of 7- LD-~-(4-hydroxy- `-niootinoylamido~-~-phenylacetamido~cephalosporanic acid, 220 mg.
of 7-amino-4-carboxymethylthio 6-mercaptopyr.imidine, and 240 mg.
o~ sodium bicarbonate and by treating the resultant mixture as .. . .
. . "
;~ in Example 18, 310 mg. of 7-~D-~-(4-hydroxynicotinoylamido)J~-30~ phenylacetamido]-3-(2-amino-4-carboxymethylthiopyrimidin-6-yl)-~:
thiomethyl-~ -cephem-4-carboxylic acid was obtained.
nfrared absorption spectrum:
~KBr cm 1 1770 max Nuclear m~gnetic resonance spectra (D6-DMS0) `-~(ppm): 3.52 (2H), 3.92 (3~I), 4.46 (lH), 5.02 (lH), 5.76 (2H), 6.44 (2H), 6.68 (2H), 7~36 (5H), 7.82 (lH), 8.46 (lH), and 9.44 (lH). s Example 20-a To 20 ml. of methylene chloride were added 290 mg. oE 4-hydroxy-2-methylpyrLm:idine-5-carboxylic acid and 0.3 ml. of tri-:, . .
ethylamine and after cooling the resultant mixture to -10 C. with ~ -~
skirring, a solution of 148 mg. of ethyl chlorocarbonate in 3 ml.
of methylene chloride was added dropwise to the mixture. The resultant mixture was stirred then for one hour at -10 C. and a solukion of 500 mg. oE cephaloglycin and 0.2 ml. of triethylamine in 10 ml. of methylene chloride was added to the mixture. The resultant mixture was further stirred for one hour at 10 C. and then for one hour at room temperature.
After the reaction was over, the solvent was distilled off . . .
j 20 under reduced pressure and 5 ml. of water was added to the residue After further adding thereto 30 ml. of a 1 : 1 mixture of n-butanol and ethyl acetate, the pH of the mixture was adjusted to -~
3 with 1 N hydrochloric acid followed by stirring well. Then, an , organic solvent layer formed was recovered, washed with water and then a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The reaction mixture thus ~ obtained was concentrated at room temperature and then 20 ml. oE
i . .;~
ether was added to the xesidue. The precipitates formed were ~:
recovered by filtration, washed with water and then ether, and ,,: ... . ,,:
'~30 dried under reduced pressure to provide 300 mg. of 7-~D-d-(4 '~
~ '. , ' ':
hydroxy-2-methylpyrimidine-5-ylcarboxamide)-~-phenylacetamidol-cephalosporanic acid.
Infrared absorption spectrum:
~ cm. : 1780 ~-lactam).
Nuclear magnetic resonance spectra (D6 DMSO~:
~ppm): 2.00 (3H), 2.41 t3H), 3.41 t2H), 4.64 (lH), 4.95 (lH), 5.04 tlH), 5.80 (lH), 5.84 (lH), 7.39 (5H), 8.55 tlH). k;~
Exi~mple 20-b In 18 ml. of water were dissolved 300 mg. of 7-[D-~-t4-hydroxy-2-methylpyrimidin -5-ylcarboxamido)~-phenylacetamido~-cephalosporanic acid, 112 mg. of 2-mercapto-1,3,4-thiadiazol -5-yl-thioacetic acid, and 183 mg. of sodium bicarbonate and by treating the solution obtained as in Example 18, 240 mg. o~ 7-~D-~-(4-~ 15 hydroxy-2-methylpyrimidin -5-ylcarboxamido)-~-phenylacetamido1-3- ~ -1 (5-carboxymethylthio-1,3,4-thiadiazol -2-yl)thiomethyl-~ -cephem-~ 4-carboxylic acid was obtained.
3 Infrared absorption spectrum:
K cm. : 1780 (~-lactc~m).
Nuclear magnetic resonance spectra tD6-DMSO): `
ppm): 2.36 t3H), 3.56 t2H), 4.12 t2~1), 4.20 tlH), 4.50 tlH), 5.02 (lH), 5.72 (lH), 5.84 tlH), 7.38 ~5H), and 8.60 (lH).
~ Example 21 j 25 To a mixture of 0.5 g. of 7- LD-~-~4-hydroxynicotinoylamido)- ;
~-phenylacetamido]cephalosporanic acid and 275 mg. of 2-(1- ` ;
~ carboxyethylthio)-5-mercapto-1,3,4-thiadiazole were added 310 mg.
i ~ of sodium bicarbonate and 37 ml. of water and the resultant mixture was stirred for 22 hours at 50-55 C. Insoluble matters 30 were filtered o~ ~rom the reaction mixture thus obtained and the ~ ~
. ~ .
' .' ., '''' ' .
pH of the filtrate was adjusted to about 2 with 1 N hydrochloric acid under ice-cooling. The precipitates formed were recovered by filtration, washed with water and then e-ther, and clried under ``
reduced pressure to provide 0.4 g. of 7-[Dv~-(4-hydroxynicotinoyl-5amido)-O~phenylacetamido~-3-~5 (1-carboxyethylthio)-1,3~4-thiadiazol -2-yl~thiomethyl-~3-cephem-4-carboxylic acid. ;
Infrared absorption spectrum:
~ K cm. : 1778 (~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO):
~; 10 ~ppm): 1.54 (3~), 3.58 (2H), 4.20 (lH), 4.37 (lH), 4O45 tlH), 5002 (~ about 5.76 (lH), 5.85 (lH), 7.39 (5H), 7.82 (lH), 8.45 (lH), and 9.45 (lH).
le 22 ~ To a mixture of 500 mg. of 7-LD-d-(4-hydroxynicotinoylamido)-;, 15 ~-phenylacetamido~-cephalosporanic acid and 292 mg. of 2-(1-carboxy- `
l-methylethylthio)~5-mercapto-1,3,4-thiadiazole were added 320 i mg. of sodium bicarbonate and 37 ml. of water and by treating the .! resultant mixture as in Example 21, 370 mg. of 7-~D-~-(4-hydroxy-I nicotinoylamido)-~-phenylacetamido~-3-[5-(1-carboxy-1-methylethyl- ',~ 20 thio)-1,3,4-thiadiazol -2-yl~thiomethyl-~3-cephem-4-carboxylic ~ acid was obtained.
~,,~ .~ . . .
Infrared absorption spectrum~
,~ ~ cm. : 1777 (~-lactam).
i ~uclear magnetic resonance spectra (D6-DMS0) ,~
~ ppm): 1.57 (6H), 3.59 (2H~, 4.23 (lH), 4.45 (lH), 5.01 ~ (lH), about 5.75 (lH), 5.84 (lH), 6.43 (lH), 7.37 ;1 ~5H), 7.81 ~lH), 8.43 ~lH~, and 9.42 (lH).
Example_23 . . .
To 40 ml. of water were added 0.63 g. of 7-LD-~-(4-hydroxy-nicotinoylamido)~ phenylacetamido]cephalosporanic acicl, 0.25 g.
' ` "~ ;' of 2-mercapto-4-methylthiazole-5-acetic acid, and 0.3 g~ of sodium bicarbonate and the resultant mixture was stirred for one hour at about 55 C. The p~ of the reaction mixture thus obtained was adjusted to about 2 with 1 N hydrochloric acid under ice-cooling and the precipitates formed were recovered by filtration,washed with water, and dried to provide 0.55 g. of 7-tD~-(4-hydroxynicotinoylamido)-~-phenylacetamido]-3-(5-carboxymethyl-4-methylthiazol -2-yl)thiomethyl-d -cephem-4-carboxylic acid. ~-Infrared absorption spectrum:
~KBr cm -1 1772 (~-lactam) Nuclear magnetic resonance spectra (D6-DMSO):
ppm): 2.20 (3H), 3.53 (2H), 3.72 (2H), 4.02 (lH), 4.46 ~lH), 4.97 (lH), 5.71 (lH), 5.82 (lH), 6.42 (lH), 7.33 (5I~), 7.78 (lH)~ 8.40 (lH), 9.39 (lH), 11.15 (lH), and 12.02 (lH).
Example 24 : . ~. .. :
~ To 50 ml~ o~ water were added 0.8 g. of sodium 7- ~D-~-(4- ~
_ hydroxynicotinoylamido)-~-phenylacetamido cephalosporanate, ;`
0.386 g. of (2-mercapto-4-methylthia~ol -5-yl)thioacetic acid, and 0.295 g. o~ sodium bicarbonate and the resultant mixture was stirred for 20 minutes at about 55 C. Then, the pH of the reaction mixture thus obtained was adjusted to about 2 with 1 N
, hydrochloric acid under ice-cooling and the precipitates formed ......
were recovered by fil~ration, washed with water, and dried to provide 0.4 g. of 7- LD-~-(4-hydroxynicotinoylamido)-q-phenylace-tamido]-3-(5-carboxymethylthio-4-methylthiazol -2-yl)thiomethyl-~3-cephem-4-carboxylic acid.
~ :: . :
!: : Infrared absorption spectrum: ~
;. i .
~max cm- 1768 (~-lactam)~ 'J '~.';;'' Nuclear magnetic resonance spectra (D6-DMS0 ''- ':.''. :'.
~(ppm): 2.35 (3H), 3.50 (2H), 3.55 (2H~, 4.07 (lH), 4.52 (lH~, 4.99 (lH), 5.74 (lH), 5.84 (lH), 6.43 (lH), 7.34 (5H), 7.80 ~lH), 8.43 (lH), 9.41 (lH), 11.29 - .:
( 1H), and 12.16 (lH).
Example 25 .
To 50 ml. of water were added 0.8 g. ol- sodium 7-tD-~-(4- -hydroxynicotinoylamido)-~-phenylacetamido~cephalosporanate, 0.284 g. of 2-mercapto-1,3,4-thiadiazole-5-acetic acid, and ,.~, 0.271 g~ of sodium bicarbonate and th~ resultant mixture was stirred for 21 hours at 55 C. The pH of the reaction mixture thus obtained was adjusted to about 2 with 1 N hydrochloric acid . .
under ice-cooling and the precipitates formed were recovered by filtration, washed with water, and dried to provide 0.45 g. of 7-~D-~-(4-hydroxynicotinoylamido)-o~-phenylacetamido3-3-(5-carboxymethyl-1,3,4-thiadiazol -2-yl)thiomethyl-~ -cephem-4-carboxylic acid. ` -~
Infrared absorption spectrum: ~ -ma cm. : 1774 (~-lactam). -Nuclear magnetic resonance spectra (D6-DMS0):
'~ 20 ~(ppm): 3.58 (2H), 3.17 (2H), 4.19 (1~), 4.53 (lEI)~ 5.00 (lH), 5.71 (lH), 5.82 (lH), 6.42 (lH), 7.35 (5H), l 7.79 (lH), 8.42 (lH), 9.41 (lH), 11.19 (lH), and ~
.... . .
12.04 (lH).
,~ Example_26-a In 150 ml. of methylene chloride was suspended 7.5 g. of ~ ~ cep~aloglycin and after adding 5.0 g. Oe triethylamine and 5.0 g ;1 ~ of magnesium sul:Eate to the suspension, the resultant mixture ;~
was stirred ~or 30 minutes at room temperature. After the reac~
tion was over, the reaction mixture was riltered and while cooling ~-' 30 the :eiltrate to -30 C., 380 g. of 4-methoxynicotinic acid chloride ,~,, .. .. :
was added all at once swoop to the filtrate followed by stirring for 2 hours at temperatures from -20 C. to -30 C. The reaction mixture was allowed to stand overnight at -~ C. and then stirred for 2 hours at room temperature~ AEter the reaction was over, 5 the solvent was distilled off a-t room temperature under reduced ~;~
pressure from the reaction mixture, the residue formed was dissolved in 300 ml. of water. A small amount of insoluble matter present in the solution was filtered off and after adjusting the pH of the filtrate by adding an aqueous 5% hydrochloric acid solution, the filtrate was stirred for 30 minutes under ice-cooling~ The precipitates thus formed were recovered by filtra-tion, washed with water, an aqueous 1% hydrochloric acid solu-tion, and then water sufficient]y, and dried over phosphorus pentoxide under reduced pressure to provide 6.3 g. of the powder 15 of 7-LD-d~(4-methoxynicotinoylamido)-~-phenylacetamido~- i cephalosporanic acid.
Infrared absorption spectra: ;
m ~cm. : 1774 t~-lactam), 1660 (acid amLde), 1728 ; ~ ;
(acetate) ' Nuclear magnetic resonance spectra (D6-DMSO):
~(ppm): 3.74 (3H, -OMe), 6.42, 7.76, 8.42 (lH, lH, l~I, the proton of pyridine nucleus), 2.00 (3~, -CH2OCOCH3), Example 26-b ~ In 44 ml. of water were suspended 0.70 g. Of 7 LD-~- ( 4 -;
methoxynicotinoylamido)-d-phenylacetamido~cephalosporanic acid and 0.26 g. of 5-carboxymethylthio-2-mercapto-1~3,4-thiadiazole and after Eurther adding 0.37 g. of sodium bicarbonate to the suspension, the resultant mixture was stirred for 22 hours at , ~ . . :, 55 C. After the reaction was over~ a small amount of insoluble , - - ~ :
i 30 matters were filtered off from the reaction mixture and then the ;
~ 39 .. .. .
. .
pH of the filtrate was adjusted to 1 by adding an aqueous 5%
hydrochloric acid solution. The precipitates thus formed were recovered by filtra-tion, washed well with water and then ether, and dried over phosphorus pentoxide under a reduced pressure to provide 0.76 g. of the white powder of 7-~D-~-(4-methoxynicoti-noylamido)-~-phenylacetamido~-3-(5-carboxymethylthio-1,3,4-thiadiazole -2-yl)thiomethyl-~ -cephem-4-carboxylic acid.
Infrared absorption spectra:
cm. : 1770 (~-lactam), 1660 (acid amide).
max Nuclear magnetic resonance spectra (D6-DMSO):
ppm): 3.76 (3~, -OMe), 3~56 (2H, ~ ), and 4.14 (2H, -SCH2COOH).
Example 27-a To 18 ml. of dichloromethane were added 300 mg. of powder 15 of 4-hydroxy-5-methylnicotinic acid and 230 mg. of triethylamine and the resultant mixture was stirred overnight at room tempera- ~;
ture. To the resultant suspension was added 241 mg. of thionyl 1 chloride under ice-cooling, then stirred for 30 minutes under i ice cooling and further 1 hour at room temperature. The solvent 1 20 was distilled off from the reaction mixture under a reduced pressure. A mixture of 500mg. of cephaloglycin and 280 mg. of ~ ;
trlethylamine, and 18 ml. of dichloromethane was cooled to -20 C ~;
and was added to the white powdery residue thus formed followed by stirring for 2 hours at temperatures from -10 C. to -20 C. The 25~ mlxture was allowed to stand overnight at the same temperature as above and then stirred for 2 hours at room temperature. The ~a~ solvent was distilled off under a reduced pressure from the reac-tion mixture and then about 6 ml. of water was added to the residue formed. Insoluble precipitates (i.e., unchan~ed 4-j ~ ..
hydroxy-5-methylnicotinic acid) were filtered off from the reaction - ~
mixture and the pH of the filtrate was adjusted to about 2 wlth l N hydrochloric acid under ice-cooling. The white precipitates thus ~ormed were extracted with a 1 : l mixture of n-butanol and ethyl acetate and the extract was washed wit:h water and -then an aqueous saturated sodium chloride solution al~d dried with magne-sium sulfa-te. After filtering off magnesiurn sulfate, a slightly excessive amount of a butanol solution of sodium 2-methylhexano-ate and the precipitates formed were recovered by filtration, ~;
i washed with ethyl acetate and ether, and dried to provide 400 mg.
of 7-LD-~- (4-hydroxy-3-methylnicotinoyla~ido)-~-phenylacetamido~-cephalosporanic acid. ~
i Nuclear magnetic resonance spectra (D6-DMS0): ~ ;
~(ppm): l.91 (3H), l.99 (3H), about 3.26 (2H), 4.70 (2H), 4.98 (lH), 5.73 (lH), 6.40 (lH), 7.24 ~5H~, 7.82 ; ;
~ 15 (lH), 8.28 (lH), and 9.34 (lH3.
!~ Example 27-b ~;
, Z :: . .: :
~ To 30 ml. of water were added 400 mg. of sodium 7 ~D-ot-(4-i . .. :
hydroxy-3-methylpyridin -5-ylcarboxamido)-~-phenylacetamido~
~ cephalosporanate, 193 mg. of 2-carboxymethylthio-5-mercapto-1,3,- ~ -,,,,,,!~Z 20 4-thiadiazole, and 172 mg. of sodium bicarbonate and the resultant mixture was stirred for 22 hours at 50-53 C. Then, by treating ,~ the reaction mlxture as in Example 21, 300 mg. of 7_CD_~_(4_ -hydroxy-3-methylpyridin -5-ylcarboxamido)-~-phenylacetamZido~ 3 ~ 5-carboxymethylthio-1,3,4-thiadiazol -2-Y1)thiOmethY1-a3-CePhem- :~
;
J 25 4~carboxyIic acid.
Infrared absorption spectrum:
. :i ,~ , r cm.~J' 1778 (~-lactam).
Z Nuclear ma~netic resonance spectra (D6-DMSO):
(ppm): 1.94 (3~l) 3.55 (2~), 4.11 (2H) about. 4.25 (2H), 5.00 (1H) 5.74 (2H), 7.34 (5H) 7.73 ~lH~, 8.34 , . . . ~ ; . .
~ ~ 41 ;. ;
. . . ~.. ~.
~4~3 ~lH), and 9.38 (lH)~
Example 28-a In 20 ml. of methylene chloride was suspended 0.50 g. of 6-hydroxy-4-me-thoxynicotinic acid and after adding 0.33 g. of triethylamine to the suspension, the mixture was stirred for 10 minutes. Then, after cooling the mixture to -30 C., a solution of 0.40 g. of thionyl chloride in 6 ml. of methylene chloride was added dropwise to the mixture. Thereafter, the resultant mixture was stirred for one hour at -25 C. Separately, 1.0 g.
of cephaloglycin was suspended in 20 ml. of methylene chloride and after adding thereto 0.65 g. of triethylamine and then 1.0 g.
of magnesium sulfate, the mixture was stirred for 20 minutes at , room temperature. After the reaction was over, insoluble matters j~ were filtered off from the reaction mixture, and after cooling 15 the filtrate to -45 C., the methylene chloride solution of the ~;
acid chloride cooled prepared above was added all at once to the ll filtrate.
Then, after stirriny the mixture for 3 hours at temperatures from -20 C. to -30 C. and then for 1.5 hours at room temperature, the solvent was distilled o~f under reduced pressure and 30 ml.
of water was added to the residue thus formed. ~he pH of the mixture was adjusted to 8 by adding an aqueous 5% sodium bicar-;,: .. :
i~ bonate solution. Thereafter, the p~ of the system was further $~ adjusted to 2 by adding thereto an aqueous 5% hydrochloric acid .j~ :
solution and the precipitates formed were recovered by filtration~washed sufficiently with an aqueous 1% hydrochloric acid solution :. ~
!~ and then water~ and dried over phosphorus pentoxide under reduced ~;-.~
pressure to provide 0.80 g. of the white powder of 7-~D~ 4~
methoxy-6-hydroxynicotinoylamido)-~-phenylacetamido~cephalosporanic ~ ~ 30 acid.
,:
Infrared absorption spectra:
cm. : 1778 ~-lactam), 1662 (acid amide)~
Nuclear magnetic resonance spec-tra (D6-DMS0):
~(ppm): 2.00 (3H), 3.40 (2H, 3H), 4.82 (2H), 5.04 (1~), - 5 5~70 (lH), 5.78 (lH, lH), 7.36 (5H), 8.42 (lH), 8.98 (lH), and 9.44 (lH).
, . ~ . .
Exa~ple 28-b ~; ~
In 43 ml. oE water were suspended 0.69 g.of 7- LD~-(6- ~
hydroxy-4-methoxynicotinoylamido)-O~phenylacetamido~Gephalosporanic - ~ ;
acid and 0~28 g. of 2-carboxymethylthio-5-mercapto-1,3,4-thia-'. ~
diazole and after adding 0.37 g. of sodium bicarbonate to the ~; --: :-.
suspension, the resultant mixture was stirred for 23 hours at 55 C. Ater the reaction was over, a small amount oE insoluble ?j;!, :.: !
~ matters ormed were filtered off from the reaction mixture and .,~ ... .
the pH of the filtrate was adjusted to 2 by adding an aqueous 5%
¦ hydrochloric acid solution. The precipitates formed were ; recovered by -filtration, washed with water and then ether, and dried over phosphorus pentoxide under reduced pressure to provide i;
-.- . ~ . . .
0.51 g. of the crystalline powder of 7-LD-~-(6-hydroxy-4-methoxy- ;
n.icotinoylamido)-c~~phenylacetam:Lclo~-3-(5-carboxymethylthio-1,3,4- ~ ;
~ 3 - -i~ thiadiazol -2-yl)thiomethyl-~ -cephem-4-carboxylic acid.
Infrared absorption spectra:
3~ KBx cm. : 177~3 (~-lactam) and 1664 (acid amide).
j~ ~ Nuclear magnetic resonance spectra (D6-DMS0)_ ;;
~(ppm~: 3.44 t2E, 3~), 4.14 (2E), 4.96 ~2H), 5.04 (lH), ~ 5.66 (lH), 5.76 (lH, lM~, 7.36 (5E), 8.40 (lH~
i~ 9.00 ~lH~, and g.46 (lH).
~ Example 29-a .j . .
.,::
To 30 ml~ o~ methylene chloride were added 1 g. of cephalo-glycin and 0.62 g. o~ triethylamine with stirring and a~ter ;- . ;
~ 43 :: . :.
, .. . . .
Eurther adding 0.53 g. of 4-hydroxy-6-methylnicotinic acid chloride to the mixture at -10 C., the resultant mixture was ; stirred for 4 hours at temperatures of from -10 C. to 0 C.
Thereafter, the reaction mixture was allowecl to stand overnight 5 at -20 C. and after stirring the mixture for 3 hours at 10-15 C., the solvent was distilled off ~rom the reaction mixture under - reduced pressure. Then, 30 ml. of water was added to the residue to dissolve the residue and after adjusting the pH of the solu-tion to 1-2 by adding 1 N hydrochloric acid under ice-cooling, -~
the product was extracted with a mixture of n-butanol and ethyl acetate in 1 : 1 by volume ratio. The extract was washed with water and then an aqueous saturated sodium chloride solution, ., . ~
and dried by anhydrous magnesium sulfate. Then, magnesium sulfate was ~iltered of from the system and the filtrate was mixed w.ith 15 a slight excess of a n-butanol solution of sodium 2-methylhexano- ~;
ate with stirring. The precipitates thus formed were recovered by filtration and washed with ether to provide 0.4 g. o~ sodium -7-LD-d- (4-hydroxy-6-methylnicotinoylamido~-~-phenylacetamido]-cephalosporanate.
Nuclear magnetic resonance spectra (D6-DMS0): ;
~, (ddm): 1.91 (3H), 2.28 (3H), 3.14 tlH), 3.40 (lH), 4.71 ~ ~
-i~ (2H), 5.00 (lH), 5.76 (lH), 6.33 (lH), about 6.43 ~;;
(lH~, 7~23 (5H), 8.21 llH), and 9.32 (lH).
Example 2~-b To 20 ml. of water were added 250 mg. of 7 LD-~- (4-hydroxy-6-~ethylnicotinoylamido)-d-phenylacetamido~cephalosporanic acid, , :. . . .
120 mg. or 2-mercapto-5-carboxymethylt~io-1~3,4-thiadiazole, and 102 mg. of soalum bicarbonate and the resultant mixture was heated for 24 hours to 50-53 C. with stirring. Then, the pH of ~ ,; . , the reaction mixture was adjusted to 1-2 with 1 N hyclrochloric ~ ', s;~
acid under ice-cooling and the precipitatesZ formeZr~l were recovered by f iltration, washed with water and then e-ther, and dried to provide about 170 mg. of 7-~D-o~-(4-hydroxy-6-methylnicotinoyl-amido)-d-phenylacetamido~-3~(5-carboxymethylthio-1,3,4-thiadiazol-5 2-yl) thiomethyl-a3-cephem-4-carboxylic acid.
Infrared absorption spectrum:
`~ ma cm . : 1776 ( ~3- lactam) .
Nuclear magnetic resonance spectra (D6-DMS0):
Z,r(ppm) 2.26 (3H), 3.59 (2H), 4.15 (2H), 4.19 (lH), 4~50
Example 13 In 50 ml. of water were suspended 0.80 g. o~ 7-[D-~(4-hydroxynicotinoylamido ~-~-phenylacetamido~cephalosporanic acid and 0.32 g. of (5-mercapto-1,2,4-thiadiazol -3-yl1thioacetic acid and after adding further 0.45 g. of sodium bicarbonate to the suspension, the mixture was stirred for 24 hours while heating to 55 C. After the reaction was over, insoluble matters were filtered off from the reaction mixture and the pH of the filtrate was adjusted -to 2 by adding 5% hydrochloric acid to form precipi-tates, which were recovered by filtration, washed wel:L with water and then with water, and dried over phosphorus pentoxide under : ' reduced pressure to provide 0.70 g. of the powder of 7- ~D-~-(4-hhydroxy~icotino~ylamido)-~-phenylacetamido~-3-(3-carboxymeth thio-1,2,4-thiadiaæol -5-yl)thiomethyl-~3-cephem-4-carboxylic acid.
Melting point: 189-193 C~ (decomp.) Infrared absorption spectra:
max cm. : 1770 (~-lactam) and 1650 (amide).
~ 20 Nuclear magnetic resonance spectrum (D6-DMSO~
f ; .
`~ d ppm: 4.04 (2H~ -SCH2C02H) Example 14 - ;
1~ To 50 ml. of water were added 0.8 g. of sodium 7- LD-~-(4-; hyd~o~y~icoti~oylamido)-~-phenylacetamido~cephalosporanate~
~,~ 25 0.293 g. of 2-mercapto-4-methylthiazole-5-carboxylic acid, and 0.296 g. o~ sodium bicarbonate and the resultan~ mi~ture was stirred for 22 hours at 55C. Then, the pH of the reaction mixture was adjusted to 1-2 with 1 N hydrochloric acid under ice-cooling. The white precipita-tes thus formed were recovered by . :. .
filtration, washed with water, and dried to provide 0.6 g. of ~' ,. .
7_CD_~_(4 hydroxynicotinoylamido )-~-phenylacetamido~-3~
methyl-5-carboxythiazol -2-yl) thiomethyl-L~3-cephem-4-carboxylic acid.
Infrared absorption spectrum:
~max cm. : 1770 (~~lactam~
Nuclear maynetic resonance spectra ~D6~DMS0):
Jrppm: 2.56 (3H, S~, 3.56 (2H, q) 4.37 (2H, q) 5.01 (1H, d), 5.74 (lH), 5.86 (lH, d), 6.44 (lH, d), 7.37 (5H), 7.82 (lH, d), 8.44 (lH, d), 9.44 (lH, d), 11.21 (lH, d~, and 12.21 (lH, broad~. ;
To 40 ml. of water ~ere added 600 mg. of sodium 7-~D-a-(4-hydroxynicotinoylamido)-a-phenylacetamido]cephalosporanate, '~
195 mg. of 5-mercapto-1-carboxymethyl tetrazole, and ]80 mg. of sodium bicarbonate and the resultant mixture was stirred for 22 . .
hours at 55 C. The reaction mixture thus obtained was filtered and the pH of the filtrate was adjusted to 1 with 1~ hydrochloric ~;~ acid under ice-cooling. The precipitates formed were recovered ~, . .; . . .
l; by filtration, washed with water and then with ether, and dried ~ ~
.. . . .
~, to provide 300 mg. f 7~ CD ~ ( 4~hydroxynicotinoylamido )-~-phenyl-'~ 20 acetamido~-3-(1-carboxy~ethyltetrazol -5-yl)-thiomethyl-~3-cephem-4-~carboxylic acid. ~ ;
Melting point: about 240 C. (gradually decomposed3 :.
Infrared absorption spec~rum: -max cm. : 1775 (~-lactam3.
Nuclear magnetic resonance spectra (D6-DMS0)~
ppm: 3.60 (2H), 4.36 (2H3, 5.00 (1~), 5.34 (2H), 5.84 (2H), 6.48 (lH), 7.44 (5H), 7.88 (lH), 8.50 (lH), 9.52 (lH).
Example 16 l To 30 ml. of water were added 0.45 g. o~ sodium 7- LD-~-(4-hydroxynicotinoyLamido)-~-phenylacetamido~cephalosporanate, 0.2 g.
of 6-carboxymethylthio-4~mercaptopyrimidine, and 0.14 g. o:E sodium bicar~onate and the resultant mixture was stirred for 22 hours at 55 C. Af-ter Eilteriny the reaction mixture thus obtained, the pH of the filtrate was adjusted to 1 with 1 N hydrochloric acid under ice-cooling and the precipitates thus formed were recovered by filtration, washed with water and then ether, and dried to provide 0.42 g~ of 7 ~D~-(4-hydroxynicotinoylamido)-d~phenyl-acetamidolZ-3-(6-carboxymethylthiopyr~midin -4-yl)thiomethyl-~ -cephem-4-carboxylic acid.
Infrared absorption spectrum:
~m cm. : 1775 Nuclear magnetic resonance spectra (D6-DMSO):
~ppm: 3.50 (2H), 3.98 (3H~, 4.58 (lH), 5.00 (lH), 5.74 (2H), 6.42 (lH), 7.34 (6H), 7.78 (lH), 8.42 (lH), 9.40 (lH).
Example 17 To 37 ml. of water were added 0.5 g. of 7- CD-~-t4-hydroxy- ~
nicotinoylamido)-~-phenylacetiamido~cephalosporanic acid, 0.235 g. ~- -of 6-carboxymethylthio-4-mercapto-2-methylpyrimidine, and 0.295 g.
of sodium bicarbonate and the resultant mixture was stirred for 22 hours at 50-55 C. The reaction mixture thus obtained was filtered j and the pH of the filtrate was adjusted to about 2 with 1 N
; .:
hydrochloric acid under ice-cooling. The precipitates formed were recovered by filtration, washed with water and then ether, and dried under reduced pressure to provide 0.42 g. of 7- ~D-~
(4-hydroxynicotinoylamido)-~-phenylacetamidolZ-3-(6-carboxymethyl-~ 3 J thio-2-methylpyrimidin-4-yl)thiomethyl-a -cephem-4-carboxylic ~ . . , acid.
Infrared absorption spectrum: ~
~ cm. : 1778 (~-lactam). ;;
Z~ 30 ~uclear magnetic resonance spectra (D6-DMSO):
` "'' '.' ~::: .-7~
J ppm 2.50 (3H3, 3.52 (2H), 3.82 (lH), 3.98 (2H), 4.62 (lH), 5.02 (lH), about 5.73 (lH), 5.85 (lH), 6.45 (lH), 7.~3 (lH), 7.38 (5H~, 7.82 (lH), 8.46 (~I), and 9 44 (lH)-~xample 18 TO 37 ml. of water were added 526 mg. f 7-LD d (4-hydroxy- ,~
nicotinoylamido)~-phenylacetamido~cephalosporanic acid, 220 mg.
-~ of l-carboxymethyl-3-mercapto-6(1H)-pyridaz:inone, and 300 mg. of ~- sodium bicarbonate and the resultant mixture was stirred for 22 hours at 50-55C. After the reaction was over, the reaction mixture obtained was filtered and the pH of the filtrate was then adjusted to about 2 with 1 N hydrochloric acid under ice-cooling.
The precipitates thus ~ormed were recovered by Eiltration, washed j with water and then ether, and dried under reduced pressure to provide 350 mg. of 7-LD-~-(4-hydroxynicotinoylamido(-d-phenyl-acetamido]-3-(1-carboxymethyl-6(lH)-pyridazinon -3-yl)thiomethyl-cephem-4-carboxylic acid. ~-Infrared absorption spectrum: ~
cm. : 1775 (~-Iactam)- ~ ~;
;j 20 Nuclear magnetic re~onance spect~a (D6-DMS0):
~(ppm): 3.46 ~2H), 3.8~3 tlH), 4.33 (lH), 4.66 (2H), 4.93 (1 5.74 (2H), 6.40 ~lH), 6.88 (lH), 7.34 ~6H), 7.74 (lH), ~s ;~
8.40 (lH~, and 9.41 (lH).
xample l9 ~o 30 ml. of water were added 420 mg. of 7- LD-~-(4-hydroxy- `-niootinoylamido~-~-phenylacetamido~cephalosporanic acid, 220 mg.
of 7-amino-4-carboxymethylthio 6-mercaptopyr.imidine, and 240 mg.
o~ sodium bicarbonate and by treating the resultant mixture as .. . .
. . "
;~ in Example 18, 310 mg. of 7-~D-~-(4-hydroxynicotinoylamido)J~-30~ phenylacetamido]-3-(2-amino-4-carboxymethylthiopyrimidin-6-yl)-~:
thiomethyl-~ -cephem-4-carboxylic acid was obtained.
nfrared absorption spectrum:
~KBr cm 1 1770 max Nuclear m~gnetic resonance spectra (D6-DMS0) `-~(ppm): 3.52 (2H), 3.92 (3~I), 4.46 (lH), 5.02 (lH), 5.76 (2H), 6.44 (2H), 6.68 (2H), 7~36 (5H), 7.82 (lH), 8.46 (lH), and 9.44 (lH). s Example 20-a To 20 ml. of methylene chloride were added 290 mg. oE 4-hydroxy-2-methylpyrLm:idine-5-carboxylic acid and 0.3 ml. of tri-:, . .
ethylamine and after cooling the resultant mixture to -10 C. with ~ -~
skirring, a solution of 148 mg. of ethyl chlorocarbonate in 3 ml.
of methylene chloride was added dropwise to the mixture. The resultant mixture was stirred then for one hour at -10 C. and a solukion of 500 mg. oE cephaloglycin and 0.2 ml. of triethylamine in 10 ml. of methylene chloride was added to the mixture. The resultant mixture was further stirred for one hour at 10 C. and then for one hour at room temperature.
After the reaction was over, the solvent was distilled off . . .
j 20 under reduced pressure and 5 ml. of water was added to the residue After further adding thereto 30 ml. of a 1 : 1 mixture of n-butanol and ethyl acetate, the pH of the mixture was adjusted to -~
3 with 1 N hydrochloric acid followed by stirring well. Then, an , organic solvent layer formed was recovered, washed with water and then a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The reaction mixture thus ~ obtained was concentrated at room temperature and then 20 ml. oE
i . .;~
ether was added to the xesidue. The precipitates formed were ~:
recovered by filtration, washed with water and then ether, and ,,: ... . ,,:
'~30 dried under reduced pressure to provide 300 mg. of 7-~D-d-(4 '~
~ '. , ' ':
hydroxy-2-methylpyrimidine-5-ylcarboxamide)-~-phenylacetamidol-cephalosporanic acid.
Infrared absorption spectrum:
~ cm. : 1780 ~-lactam).
Nuclear magnetic resonance spectra (D6 DMSO~:
~ppm): 2.00 (3H), 2.41 t3H), 3.41 t2H), 4.64 (lH), 4.95 (lH), 5.04 tlH), 5.80 (lH), 5.84 (lH), 7.39 (5H), 8.55 tlH). k;~
Exi~mple 20-b In 18 ml. of water were dissolved 300 mg. of 7-[D-~-t4-hydroxy-2-methylpyrimidin -5-ylcarboxamido)~-phenylacetamido~-cephalosporanic acid, 112 mg. of 2-mercapto-1,3,4-thiadiazol -5-yl-thioacetic acid, and 183 mg. of sodium bicarbonate and by treating the solution obtained as in Example 18, 240 mg. o~ 7-~D-~-(4-~ 15 hydroxy-2-methylpyrimidin -5-ylcarboxamido)-~-phenylacetamido1-3- ~ -1 (5-carboxymethylthio-1,3,4-thiadiazol -2-yl)thiomethyl-~ -cephem-~ 4-carboxylic acid was obtained.
3 Infrared absorption spectrum:
K cm. : 1780 (~-lactc~m).
Nuclear magnetic resonance spectra tD6-DMSO): `
ppm): 2.36 t3H), 3.56 t2H), 4.12 t2~1), 4.20 tlH), 4.50 tlH), 5.02 (lH), 5.72 (lH), 5.84 tlH), 7.38 ~5H), and 8.60 (lH).
~ Example 21 j 25 To a mixture of 0.5 g. of 7- LD-~-~4-hydroxynicotinoylamido)- ;
~-phenylacetamido]cephalosporanic acid and 275 mg. of 2-(1- ` ;
~ carboxyethylthio)-5-mercapto-1,3,4-thiadiazole were added 310 mg.
i ~ of sodium bicarbonate and 37 ml. of water and the resultant mixture was stirred for 22 hours at 50-55 C. Insoluble matters 30 were filtered o~ ~rom the reaction mixture thus obtained and the ~ ~
. ~ .
' .' ., '''' ' .
pH of the filtrate was adjusted to about 2 with 1 N hydrochloric acid under ice-cooling. The precipitates formed were recovered by filtration, washed with water and then e-ther, and clried under ``
reduced pressure to provide 0.4 g. of 7-[Dv~-(4-hydroxynicotinoyl-5amido)-O~phenylacetamido~-3-~5 (1-carboxyethylthio)-1,3~4-thiadiazol -2-yl~thiomethyl-~3-cephem-4-carboxylic acid. ;
Infrared absorption spectrum:
~ K cm. : 1778 (~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO):
~; 10 ~ppm): 1.54 (3~), 3.58 (2H), 4.20 (lH), 4.37 (lH), 4O45 tlH), 5002 (~ about 5.76 (lH), 5.85 (lH), 7.39 (5H), 7.82 (lH), 8.45 (lH), and 9.45 (lH).
le 22 ~ To a mixture of 500 mg. of 7-LD-d-(4-hydroxynicotinoylamido)-;, 15 ~-phenylacetamido~-cephalosporanic acid and 292 mg. of 2-(1-carboxy- `
l-methylethylthio)~5-mercapto-1,3,4-thiadiazole were added 320 i mg. of sodium bicarbonate and 37 ml. of water and by treating the .! resultant mixture as in Example 21, 370 mg. of 7-~D-~-(4-hydroxy-I nicotinoylamido)-~-phenylacetamido~-3-[5-(1-carboxy-1-methylethyl- ',~ 20 thio)-1,3,4-thiadiazol -2-yl~thiomethyl-~3-cephem-4-carboxylic ~ acid was obtained.
~,,~ .~ . . .
Infrared absorption spectrum~
,~ ~ cm. : 1777 (~-lactam).
i ~uclear magnetic resonance spectra (D6-DMS0) ,~
~ ppm): 1.57 (6H), 3.59 (2H~, 4.23 (lH), 4.45 (lH), 5.01 ~ (lH), about 5.75 (lH), 5.84 (lH), 6.43 (lH), 7.37 ;1 ~5H), 7.81 ~lH), 8.43 ~lH~, and 9.42 (lH).
Example_23 . . .
To 40 ml. of water were added 0.63 g. of 7-LD-~-(4-hydroxy-nicotinoylamido)~ phenylacetamido]cephalosporanic acicl, 0.25 g.
' ` "~ ;' of 2-mercapto-4-methylthiazole-5-acetic acid, and 0.3 g~ of sodium bicarbonate and the resultant mixture was stirred for one hour at about 55 C. The p~ of the reaction mixture thus obtained was adjusted to about 2 with 1 N hydrochloric acid under ice-cooling and the precipitates formed were recovered by filtration,washed with water, and dried to provide 0.55 g. of 7-tD~-(4-hydroxynicotinoylamido)-~-phenylacetamido]-3-(5-carboxymethyl-4-methylthiazol -2-yl)thiomethyl-d -cephem-4-carboxylic acid. ~-Infrared absorption spectrum:
~KBr cm -1 1772 (~-lactam) Nuclear magnetic resonance spectra (D6-DMSO):
ppm): 2.20 (3H), 3.53 (2H), 3.72 (2H), 4.02 (lH), 4.46 ~lH), 4.97 (lH), 5.71 (lH), 5.82 (lH), 6.42 (lH), 7.33 (5I~), 7.78 (lH)~ 8.40 (lH), 9.39 (lH), 11.15 (lH), and 12.02 (lH).
Example 24 : . ~. .. :
~ To 50 ml~ o~ water were added 0.8 g. of sodium 7- ~D-~-(4- ~
_ hydroxynicotinoylamido)-~-phenylacetamido cephalosporanate, ;`
0.386 g. of (2-mercapto-4-methylthia~ol -5-yl)thioacetic acid, and 0.295 g. o~ sodium bicarbonate and the resultant mixture was stirred for 20 minutes at about 55 C. Then, the pH of the reaction mixture thus obtained was adjusted to about 2 with 1 N
, hydrochloric acid under ice-cooling and the precipitates formed ......
were recovered by fil~ration, washed with water, and dried to provide 0.4 g. of 7- LD-~-(4-hydroxynicotinoylamido)-q-phenylace-tamido]-3-(5-carboxymethylthio-4-methylthiazol -2-yl)thiomethyl-~3-cephem-4-carboxylic acid.
~ :: . :
!: : Infrared absorption spectrum: ~
;. i .
~max cm- 1768 (~-lactam)~ 'J '~.';;'' Nuclear magnetic resonance spectra (D6-DMS0 ''- ':.''. :'.
~(ppm): 2.35 (3H), 3.50 (2H), 3.55 (2H~, 4.07 (lH), 4.52 (lH~, 4.99 (lH), 5.74 (lH), 5.84 (lH), 6.43 (lH), 7.34 (5H), 7.80 ~lH), 8.43 (lH), 9.41 (lH), 11.29 - .:
( 1H), and 12.16 (lH).
Example 25 .
To 50 ml. of water were added 0.8 g. ol- sodium 7-tD-~-(4- -hydroxynicotinoylamido)-~-phenylacetamido~cephalosporanate, 0.284 g. of 2-mercapto-1,3,4-thiadiazole-5-acetic acid, and ,.~, 0.271 g~ of sodium bicarbonate and th~ resultant mixture was stirred for 21 hours at 55 C. The pH of the reaction mixture thus obtained was adjusted to about 2 with 1 N hydrochloric acid . .
under ice-cooling and the precipitates formed were recovered by filtration, washed with water, and dried to provide 0.45 g. of 7-~D-~-(4-hydroxynicotinoylamido)-o~-phenylacetamido3-3-(5-carboxymethyl-1,3,4-thiadiazol -2-yl)thiomethyl-~ -cephem-4-carboxylic acid. ` -~
Infrared absorption spectrum: ~ -ma cm. : 1774 (~-lactam). -Nuclear magnetic resonance spectra (D6-DMS0):
'~ 20 ~(ppm): 3.58 (2H), 3.17 (2H), 4.19 (1~), 4.53 (lEI)~ 5.00 (lH), 5.71 (lH), 5.82 (lH), 6.42 (lH), 7.35 (5H), l 7.79 (lH), 8.42 (lH), 9.41 (lH), 11.19 (lH), and ~
.... . .
12.04 (lH).
,~ Example_26-a In 150 ml. of methylene chloride was suspended 7.5 g. of ~ ~ cep~aloglycin and after adding 5.0 g. Oe triethylamine and 5.0 g ;1 ~ of magnesium sul:Eate to the suspension, the resultant mixture ;~
was stirred ~or 30 minutes at room temperature. After the reac~
tion was over, the reaction mixture was riltered and while cooling ~-' 30 the :eiltrate to -30 C., 380 g. of 4-methoxynicotinic acid chloride ,~,, .. .. :
was added all at once swoop to the filtrate followed by stirring for 2 hours at temperatures from -20 C. to -30 C. The reaction mixture was allowed to stand overnight at -~ C. and then stirred for 2 hours at room temperature~ AEter the reaction was over, 5 the solvent was distilled off a-t room temperature under reduced ~;~
pressure from the reaction mixture, the residue formed was dissolved in 300 ml. of water. A small amount of insoluble matter present in the solution was filtered off and after adjusting the pH of the filtrate by adding an aqueous 5% hydrochloric acid solution, the filtrate was stirred for 30 minutes under ice-cooling~ The precipitates thus formed were recovered by filtra-tion, washed with water, an aqueous 1% hydrochloric acid solu-tion, and then water sufficient]y, and dried over phosphorus pentoxide under reduced pressure to provide 6.3 g. of the powder 15 of 7-LD-d~(4-methoxynicotinoylamido)-~-phenylacetamido~- i cephalosporanic acid.
Infrared absorption spectra: ;
m ~cm. : 1774 t~-lactam), 1660 (acid amLde), 1728 ; ~ ;
(acetate) ' Nuclear magnetic resonance spectra (D6-DMSO):
~(ppm): 3.74 (3H, -OMe), 6.42, 7.76, 8.42 (lH, lH, l~I, the proton of pyridine nucleus), 2.00 (3~, -CH2OCOCH3), Example 26-b ~ In 44 ml. of water were suspended 0.70 g. Of 7 LD-~- ( 4 -;
methoxynicotinoylamido)-d-phenylacetamido~cephalosporanic acid and 0.26 g. of 5-carboxymethylthio-2-mercapto-1~3,4-thiadiazole and after Eurther adding 0.37 g. of sodium bicarbonate to the suspension, the resultant mixture was stirred for 22 hours at , ~ . . :, 55 C. After the reaction was over~ a small amount of insoluble , - - ~ :
i 30 matters were filtered off from the reaction mixture and then the ;
~ 39 .. .. .
. .
pH of the filtrate was adjusted to 1 by adding an aqueous 5%
hydrochloric acid solution. The precipitates thus formed were recovered by filtra-tion, washed well with water and then ether, and dried over phosphorus pentoxide under a reduced pressure to provide 0.76 g. of the white powder of 7-~D-~-(4-methoxynicoti-noylamido)-~-phenylacetamido~-3-(5-carboxymethylthio-1,3,4-thiadiazole -2-yl)thiomethyl-~ -cephem-4-carboxylic acid.
Infrared absorption spectra:
cm. : 1770 (~-lactam), 1660 (acid amide).
max Nuclear magnetic resonance spectra (D6-DMSO):
ppm): 3.76 (3~, -OMe), 3~56 (2H, ~ ), and 4.14 (2H, -SCH2COOH).
Example 27-a To 18 ml. of dichloromethane were added 300 mg. of powder 15 of 4-hydroxy-5-methylnicotinic acid and 230 mg. of triethylamine and the resultant mixture was stirred overnight at room tempera- ~;
ture. To the resultant suspension was added 241 mg. of thionyl 1 chloride under ice-cooling, then stirred for 30 minutes under i ice cooling and further 1 hour at room temperature. The solvent 1 20 was distilled off from the reaction mixture under a reduced pressure. A mixture of 500mg. of cephaloglycin and 280 mg. of ~ ;
trlethylamine, and 18 ml. of dichloromethane was cooled to -20 C ~;
and was added to the white powdery residue thus formed followed by stirring for 2 hours at temperatures from -10 C. to -20 C. The 25~ mlxture was allowed to stand overnight at the same temperature as above and then stirred for 2 hours at room temperature. The ~a~ solvent was distilled off under a reduced pressure from the reac-tion mixture and then about 6 ml. of water was added to the residue formed. Insoluble precipitates (i.e., unchan~ed 4-j ~ ..
hydroxy-5-methylnicotinic acid) were filtered off from the reaction - ~
mixture and the pH of the filtrate was adjusted to about 2 wlth l N hydrochloric acid under ice-cooling. The white precipitates thus ~ormed were extracted with a 1 : l mixture of n-butanol and ethyl acetate and the extract was washed wit:h water and -then an aqueous saturated sodium chloride solution al~d dried with magne-sium sulfa-te. After filtering off magnesiurn sulfate, a slightly excessive amount of a butanol solution of sodium 2-methylhexano-ate and the precipitates formed were recovered by filtration, ~;
i washed with ethyl acetate and ether, and dried to provide 400 mg.
of 7-LD-~- (4-hydroxy-3-methylnicotinoyla~ido)-~-phenylacetamido~-cephalosporanic acid. ~
i Nuclear magnetic resonance spectra (D6-DMS0): ~ ;
~(ppm): l.91 (3H), l.99 (3H), about 3.26 (2H), 4.70 (2H), 4.98 (lH), 5.73 (lH), 6.40 (lH), 7.24 ~5H~, 7.82 ; ;
~ 15 (lH), 8.28 (lH), and 9.34 (lH3.
!~ Example 27-b ~;
, Z :: . .: :
~ To 30 ml. of water were added 400 mg. of sodium 7 ~D-ot-(4-i . .. :
hydroxy-3-methylpyridin -5-ylcarboxamido)-~-phenylacetamido~
~ cephalosporanate, 193 mg. of 2-carboxymethylthio-5-mercapto-1,3,- ~ -,,,,,,!~Z 20 4-thiadiazole, and 172 mg. of sodium bicarbonate and the resultant mixture was stirred for 22 hours at 50-53 C. Then, by treating ,~ the reaction mlxture as in Example 21, 300 mg. of 7_CD_~_(4_ -hydroxy-3-methylpyridin -5-ylcarboxamido)-~-phenylacetamZido~ 3 ~ 5-carboxymethylthio-1,3,4-thiadiazol -2-Y1)thiOmethY1-a3-CePhem- :~
;
J 25 4~carboxyIic acid.
Infrared absorption spectrum:
. :i ,~ , r cm.~J' 1778 (~-lactam).
Z Nuclear ma~netic resonance spectra (D6-DMSO):
(ppm): 1.94 (3~l) 3.55 (2~), 4.11 (2H) about. 4.25 (2H), 5.00 (1H) 5.74 (2H), 7.34 (5H) 7.73 ~lH~, 8.34 , . . . ~ ; . .
~ ~ 41 ;. ;
. . . ~.. ~.
~4~3 ~lH), and 9.38 (lH)~
Example 28-a In 20 ml. of methylene chloride was suspended 0.50 g. of 6-hydroxy-4-me-thoxynicotinic acid and after adding 0.33 g. of triethylamine to the suspension, the mixture was stirred for 10 minutes. Then, after cooling the mixture to -30 C., a solution of 0.40 g. of thionyl chloride in 6 ml. of methylene chloride was added dropwise to the mixture. Thereafter, the resultant mixture was stirred for one hour at -25 C. Separately, 1.0 g.
of cephaloglycin was suspended in 20 ml. of methylene chloride and after adding thereto 0.65 g. of triethylamine and then 1.0 g.
of magnesium sulfate, the mixture was stirred for 20 minutes at , room temperature. After the reaction was over, insoluble matters j~ were filtered off from the reaction mixture, and after cooling 15 the filtrate to -45 C., the methylene chloride solution of the ~;
acid chloride cooled prepared above was added all at once to the ll filtrate.
Then, after stirriny the mixture for 3 hours at temperatures from -20 C. to -30 C. and then for 1.5 hours at room temperature, the solvent was distilled o~f under reduced pressure and 30 ml.
of water was added to the residue thus formed. ~he pH of the mixture was adjusted to 8 by adding an aqueous 5% sodium bicar-;,: .. :
i~ bonate solution. Thereafter, the p~ of the system was further $~ adjusted to 2 by adding thereto an aqueous 5% hydrochloric acid .j~ :
solution and the precipitates formed were recovered by filtration~washed sufficiently with an aqueous 1% hydrochloric acid solution :. ~
!~ and then water~ and dried over phosphorus pentoxide under reduced ~;-.~
pressure to provide 0.80 g. of the white powder of 7-~D~ 4~
methoxy-6-hydroxynicotinoylamido)-~-phenylacetamido~cephalosporanic ~ ~ 30 acid.
,:
Infrared absorption spectra:
cm. : 1778 ~-lactam), 1662 (acid amide)~
Nuclear magnetic resonance spec-tra (D6-DMS0):
~(ppm): 2.00 (3H), 3.40 (2H, 3H), 4.82 (2H), 5.04 (1~), - 5 5~70 (lH), 5.78 (lH, lH), 7.36 (5H), 8.42 (lH), 8.98 (lH), and 9.44 (lH).
, . ~ . .
Exa~ple 28-b ~; ~
In 43 ml. oE water were suspended 0.69 g.of 7- LD~-(6- ~
hydroxy-4-methoxynicotinoylamido)-O~phenylacetamido~Gephalosporanic - ~ ;
acid and 0~28 g. of 2-carboxymethylthio-5-mercapto-1,3,4-thia-'. ~
diazole and after adding 0.37 g. of sodium bicarbonate to the ~; --: :-.
suspension, the resultant mixture was stirred for 23 hours at 55 C. Ater the reaction was over, a small amount oE insoluble ?j;!, :.: !
~ matters ormed were filtered off from the reaction mixture and .,~ ... .
the pH of the filtrate was adjusted to 2 by adding an aqueous 5%
¦ hydrochloric acid solution. The precipitates formed were ; recovered by -filtration, washed with water and then ether, and dried over phosphorus pentoxide under reduced pressure to provide i;
-.- . ~ . . .
0.51 g. of the crystalline powder of 7-LD-~-(6-hydroxy-4-methoxy- ;
n.icotinoylamido)-c~~phenylacetam:Lclo~-3-(5-carboxymethylthio-1,3,4- ~ ;
~ 3 - -i~ thiadiazol -2-yl)thiomethyl-~ -cephem-4-carboxylic acid.
Infrared absorption spectra:
3~ KBx cm. : 177~3 (~-lactam) and 1664 (acid amide).
j~ ~ Nuclear magnetic resonance spectra (D6-DMS0)_ ;;
~(ppm~: 3.44 t2E, 3~), 4.14 (2E), 4.96 ~2H), 5.04 (lH), ~ 5.66 (lH), 5.76 (lH, lM~, 7.36 (5E), 8.40 (lH~
i~ 9.00 ~lH~, and g.46 (lH).
~ Example 29-a .j . .
.,::
To 30 ml~ o~ methylene chloride were added 1 g. of cephalo-glycin and 0.62 g. o~ triethylamine with stirring and a~ter ;- . ;
~ 43 :: . :.
, .. . . .
Eurther adding 0.53 g. of 4-hydroxy-6-methylnicotinic acid chloride to the mixture at -10 C., the resultant mixture was ; stirred for 4 hours at temperatures of from -10 C. to 0 C.
Thereafter, the reaction mixture was allowecl to stand overnight 5 at -20 C. and after stirring the mixture for 3 hours at 10-15 C., the solvent was distilled off ~rom the reaction mixture under - reduced pressure. Then, 30 ml. of water was added to the residue to dissolve the residue and after adjusting the pH of the solu-tion to 1-2 by adding 1 N hydrochloric acid under ice-cooling, -~
the product was extracted with a mixture of n-butanol and ethyl acetate in 1 : 1 by volume ratio. The extract was washed with water and then an aqueous saturated sodium chloride solution, ., . ~
and dried by anhydrous magnesium sulfate. Then, magnesium sulfate was ~iltered of from the system and the filtrate was mixed w.ith 15 a slight excess of a n-butanol solution of sodium 2-methylhexano- ~;
ate with stirring. The precipitates thus formed were recovered by filtration and washed with ether to provide 0.4 g. o~ sodium -7-LD-d- (4-hydroxy-6-methylnicotinoylamido~-~-phenylacetamido]-cephalosporanate.
Nuclear magnetic resonance spectra (D6-DMS0): ;
~, (ddm): 1.91 (3H), 2.28 (3H), 3.14 tlH), 3.40 (lH), 4.71 ~ ~
-i~ (2H), 5.00 (lH), 5.76 (lH), 6.33 (lH), about 6.43 ~;;
(lH~, 7~23 (5H), 8.21 llH), and 9.32 (lH).
Example 2~-b To 20 ml. of water were added 250 mg. of 7 LD-~- (4-hydroxy-6-~ethylnicotinoylamido)-d-phenylacetamido~cephalosporanic acid, , :. . . .
120 mg. or 2-mercapto-5-carboxymethylt~io-1~3,4-thiadiazole, and 102 mg. of soalum bicarbonate and the resultant mixture was heated for 24 hours to 50-53 C. with stirring. Then, the pH of ~ ,; . , the reaction mixture was adjusted to 1-2 with 1 N hyclrochloric ~ ', s;~
acid under ice-cooling and the precipitatesZ formeZr~l were recovered by f iltration, washed with water and then e-ther, and dried to provide about 170 mg. of 7-~D-o~-(4-hydroxy-6-methylnicotinoyl-amido)-d-phenylacetamido~-3~(5-carboxymethylthio-1,3,4-thiadiazol-5 2-yl) thiomethyl-a3-cephem-4-carboxylic acid.
Infrared absorption spectrum:
`~ ma cm . : 1776 ( ~3- lactam) .
Nuclear magnetic resonance spectra (D6-DMS0):
Z,r(ppm) 2.26 (3H), 3.59 (2H), 4.15 (2H), 4.19 (lH), 4~50
10 (lH), 5.03 (lH), 5.79 (2H), 6.30 (lH), 7.39 (5H), 8.32 (lH) and 9.47 (lH).
Example 30 In 47 ml. O.e water were suspended 0.75 g. of sodium 7- tD~-(4-hydroxynicotinoylaZmido) ~-phenylacetamido] cephalosporanate and ~;
0.29 g. of 1-amino-2-carboxymethylthio-5-mercapto-1,3,4-tria~ole and after adding further 0.29 g . of sodium bicarbonate to the suspension, the resultant mixture was stirred for 22 hours at 55 C. After the reaction was over, a small amount of insoluble matters in the mixture were filterèd off and then the pH oE the filtrate was adjusted to 2 by aclding an aqueous 5% hydrochloric acid solution to the mixture. The precipitates thus formed were recovered by filtration, washed sufficiently with water and then ether, and dried over phosphorus pentoxide under reduced pressure to provide 0.62 g. of the crystalline powder of 7-CD~ 4-hydroxy-nicotinoylaZmido3 -c~-phenylacetamido~-3- (1-amino-5-carboxymethyl-thio-1,3,4-triazol -2-yl~thiomethyl-~ -cephem~4-carboxylic acidu ~ ;
Z Infrared absorption spectra:
Z ~ax cm. : 1772 (~i-lactam~ and 1660 (acid amiZde).
Nuclear magnetic resonance spectra (D6-DMS0~.
30 J~ppm); 3.58 (2H), 3.98 (2H), 5.04 (2H), 5.40 (2H), 5.70 ;-. .. . , , , , , ,, ,,,, , , ,:
t1H), S.78 (lH), 5.82 (lH), 6.46 (lH), 7.36 (5H), 7.78 (lH), 8.46 (lH), 9.40 (lH), and 11.16 (lH).
Example 31-a To 10 ml. of chloroform were added 500 mg. of 7~(D~-amino~
~-p-hydroxyphenylacetamido) cephalosporanic acid trifluoroacetate and 190 mg~ of triethylamine and after cool:ing the resultant mixture to -20 C., 163 mg. of 4-thiopyrone-3-carboxylic acid chloride was added to the mixture with stirring. rrhen, aftPr stirring the mixture for one hour at the same temperature as 10 above and for 2 hours at room temperature, the solvent was dis- `
.
' tilled off from the reaction mixture under reduced pressure. To . -'j the residue thus formed was added 10 ml. of water and after l acidifying the solution with 1 N hydrochloric acid, the product ;1 was extracted twice with 25 ml. of a 1 : 1 solution of n-butanol 15 and ethyl acetate. The extract was washed with water and then -dried and the solvent was distilled off under reduced pressure.
i~ Thereafter, ether was added to the residue thus ~ormed and the ~,' precipitates formed were recovered by filtration to provide 380 mg. of 7_LD_~ (4-thiopyrone-3-carboxamido)-~-p-hydroxyphenyl-~ s ~
acetamido]cephalosporanic acid.
` Infrared a~sorption spectrum: :
: ~m cm. : 1780 (~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO):
ppm): 2.00 (3H), 3.40 ~2H), 4.80 (2H), 5.02 (lH), 5.68 (2H), 6~70 (2H), 7.20 (2E), 7.22 (lH), 8.40 (lH), and 9.30 (1~
1: :
Example 31-b To 10 ml. of water were added 150 mg, of 7-~D~ (4-thio-pyrone-3-carboxamido)-~-p-hydroxyphenylacetamido~cephalo~poranic : . . .
30 acid, 61.5 mg. of 2-carboxymethylthio-5-mercapto-1,3,4--thiadia- `~
~6 ` ~ ~
'' `" '.,.,~ :`' '.:
.
. .. ... . . .... ,.. ,. ,., . .. ~ . .. , ... , , . " ~ . . " , . , . . ., , " .. . ... .
~ 3 zole, and 81.0 mg. of sodium bicarbonate and the mixture was stirred for 20 hours at 50-55 C.
After the reaction was over, the reaction mixture thus obtained was acidified by adding 1 N hydrochloric acid under ice-cooling and the precipi-tates formed were recovered by filtration to provide 120 mg. of 7 CD ~ (4-thiopyrone~3-carboxamido3-~-p-hydroxyphenylacetamido~-3- ~5~carboxymethylthio-1,3,4-tl~iadiazol -2-yl~thiomethyl-~3-cephem-4-carboxylic acid.
Infrared absorption spectrum: ;
~m cm. : 1770 ~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO):
~ (ppm): 3.56 (2~), 4.12 (2~I), 4.30 (2H), .00 (lE[), 5.64 ~ (2H), 6.70 (2H), 7.10 (lH), 7.20 (2H), 8.36 (lH), I and 9.30 (lH).
! 15 Exa ple 32 - ~. ,, , - , .
To 12 ml. of water were added 170 mg. of 7-~D-~-(4-thio~
pyrone-3-carboxamido)-~-p-hydroxyphenylacetamido~cepha~osporanic acid, 87 mg. of 2-carboxymethyl-5-mercapto-1,3,~-thiadizole, and ,, ~ .
92 mg. of sodium bicarbonate and the ~ixture was stirred for 15 ' hours at 50-55 C. Then, by treating the mixture as in Example , 31-b, 120 mg. O~ 7-LD-~-(4-thiopyrone-3-carboxamido)-~-p-hydroxy-! phenylacetamido~-3-t5-carboxymethyl-1,3,4-thiadiazol -2-yl~thio-i,~ methyI-~ -cephem-4-carboxylic acid was obtained.
,~ Infrared absorption spectru~:
, 25 ~mKBr cm. 1 1775 (~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO):
ppm)1 3.58 (2H), 4.16 (2H), 4.36 (2H), 5,00 (lH), 5.64 ~2H~, 6.70 (2H),7~20 (2H), 7.22 (lH), 8.38 (lH), ;;
and 9.10 (lH).
.................................................................................. : ,; :- .
Example 33 ~7 '..
To 10 ml. of water were added 150 mg. of 7- ~D~ (4-hydroxy-nicotinoylamido)-~-p~hydroxyphenylacetamido~cephalosporanic acid, 63 mg. of 2-carboxymethylthio-5-mercapto-1,3,4-thiadiazole, and 83.3 mg. of sodium bicarbonat0 and the mixture was stirred for 20 hours at 50-52C. After ~he reaction was over, the reaction mix-ture was acidified by adding 1 M hydrochloric acid under ice-cooling and the precipitates formed were recovered by filtration to provide 60 mg. of 7 [D-~-(4-hydxoxynicotinoylamido)-~p- ~:
hydroxyphenylacetamido~-3- ~-carboxymethylthio-1,3,4-~3-thiadiazol-2-yl~thiomethyl-cephem-4-carboxylic acid.
Infrared absorption spec-trum: ~ .
m cm. : 1770 (~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO)~
~(ppm): 3.52 (2H), 4.08 (2H), 4.28 (2H), 4.64 (2H), 4.97 (lH), 6.36 (lH), 6.68 (2Hl, 7.20 (2H), 7.74 (lH), ' 8.39 (lH).
Example 34 ; .
. . .
In 23 ml. of water were suspended 0.36 g. of sodium 7-[D-~ :
(4~hydroxynicotinoylamido)-~-phenylacetamido~cephalosporanate 20 and 0.17 g. of 5-carboxymethylthio-~-mercap-to-[1,2, ~ triazolo-' C3,4-b~ ~t3,4~-thiadiazole and after adding 0.15 g. of sodium ! bicarbonate to the suspension, the resultant mixture was stirred for 26 hours at 55 C. After the reaction was over, insoluble ~
matters formed were filtered off from the reaction mixture and ~
25 then the pH of the filtrate was adjusted to 2 by adding aqueous . .
5% hydrochloric acid solution. Then, the pxecipitates thus formed -'7 were recovered by $iltration, washed sufficiently with water and ~
' ~ then ether, and dried over phosphorus pentoxide to provide 0~27 gO .~ .
,~ of the crystallins powder of 7-~D-~-(4-hydroxynicotinoylamido)~
`~ 30 phenylacetamido~-3-(5-carboxymethylth:io- [1,2,4~--triazolo¦3,4-b3-.
48 ~`~
.
~1,3,4I-thiadiazol -2-yl)thiomethyl-~ -cephem-4-carbo~ylic acid.
Infrared absorption spec-tra:
cm. : 1776 (~-lactam) and 1660 ~acid amide).
Nuclear magnetlc resonance spectra (D6 DMS0):
~(ppm): 3.56 (2H), 4.20 (2H), 4.96 ~2H), 5.60 (lH), 5.76 (lH), 5.84 (lH), 6.42 (lH), 7.36 (5H), 7.80 (lH3, 9.42 (lH), 9.40 (lH), and 11.14 (lH).
Example 35 In 150 ml~ of water were dissolved 2.4 g. of sodium 7-D-C~ -~4-hydroxynicotinoylamido)-~-phenylacetamido~cephalosporanate and 1.1 g. of 2-mercapto-5-(3-carboxypropionylamino)-1,3,4-thia-diazol, and after adling 9 ml. of 10~/o aqueous sodium bicarbona-te `~'! solution to the solution, the mixture was stirred for 22 hours ~ `
j while heating to 55 C. After the reaction was over, insoluble , ' , ` 15 matters were filtered off from the reaction mixture and the pH - ~ -3 of the filtrate was adjusted to 2 with 2N hydrochloric acid. The precipitates thus formed were recovered by filtration, washed ~ well with water, twice each with 45 ml. of a methanol-ether '~ mixture in a 1:5 volume ratio and then ether respectively and dried over phosphorus pentoxide under reduced pressure to give 1.5 g. of the light yellow powder oE 7-D-~ -(4-hydroxynicotinoyl-! amido)-~-phenylacetamido~-3-~5-(3-carboxypropionylamino)-1,3,4-, ,~ thiadiazol~2-y ~ thiomethyl-~ -cephem-4-carboxylic acid.
Melting point 218-221C (decomp.) . ` .
Infrared absorption spectra:
~ ma cm~ : 1772 (~-lactam), 1660 ;' Nuclear magnetic resonance. spectrum (D2O-NaOD):
~: 2.54 (4H, -NHCOCH2CH2COONa) ', ---- , ,, :.
-i Example 36 -: ! , .
In 50 ml. of water were dissolved 0.8 g. of sodiurn 7-D-~ - -.. .. ~ .. .. . .. , . , ., , , , " , . . . .. .. . .. . . . ..
~43~
(4-hydroxynicotinoylamido)-~-phenylacetamidoJcephalosporanate and 0.41 g. of 2-mercapto-5-o-carboxybenzoylamino-1,3,4-thiadiazol and after adding 3 ml~ of l~/o a~ueous sodium bicarbonate solution .
to the solution, the mixture was stirred for 21 hours while heating to 55 C~
After -the reaction was over, insoluble matters were filtered of~ from the reac-tion mixture and the pH of the filtrate was adjusted to 2 with 2 N hydrochloric acid. The precipitates thus .
formed were recovered by filtration, washed well with water~
twice each with 15 ml. of a methanol-ether mixture in a 1:5 volume ratio and then ether respectively and dried over phosphorus pentoxide under reduced pressure to give 0.54 g. of the light yellow of 7-D- ~ -(4-hydroxynicotinoylamido)-~-phenylacetamido~-3-(5-o-carboxybenzoylamino-1,3,4-thiadiazol-2-yl)thiomethyl.-~
15 cephem-4-carboxylic acid. ~ -Melting point 207 - 211C
, Infrared absorption spectrum: .. ..
~i ~max cm. 1770 (~-lactam), 1658 Example 37 In 50 ml. oE water were dissolved 0.8 g. o~ sodium 7-D-~
(4-hydroxynicotinoylamido)-~-phenylacetamido3cephalosporanate ..
.: .
71 and 0.27 g. of 2-mercapto-5-carboxymethyl-1,3,4-triazole, and .~ .. .
,';~ after adding 3 ml. of loo/O aqueous sodium bicarbonate solution ..
1 : to the solution, the mixture was stirred for 22 hours while !~ 25 heating to 55 C. `.... -.
By treating the reaction mixture thus ob-tained as in Example ~ .-36, 0.28 g. of the li~ht yellow powder of 7-D-r~ (4-hydroxy~
nicvtinoylamido~ -phenylacetamido~-3-(5~carboxylmethyl-1,3,4- ..
~ triazol-2-yl)thiomethyl-d -cephem-4-carhoxylic acid.
: 30 Melting point 210 - 213 C .
50 -~ :
~: :
- Nuclear magnetic resonance spec-trum (DMSO): 3.32 (2~,-CH2-COOH) Infrared absorption spectra: -~ max cm. : 1775 (~3-lactam~, 1658 Example 33 To 20 ml. of water were added 300 mg . of sodium 7- LD-C~- (4- :
. .
hydroxynicotinoylamido~-~-phenylacetamido~cephalosporanate, 140 : -mg. of 4-(5-mercapto-1,3,ar-thiadiazol -2-yl'?butyric acid, and 120 !'`: :,...:.;, ':,...
mg. of sodium bicarbonate and tha resultant mi~ture was stirred 10 for 24 hours at 50-52 C. Then, the pH of the reaction mixture was adjusted to about 2 with 1 N hydrochloric acid and the white precipiates thus Eormed were recovered and washed with water and :-, !. ' ' then ether and dried to provide 200 mg. oE 7-CD-~-(4-hYdrOXY_ ', n ico t inoy lamido ) -o~-pheny lace tamido l- 3- L5 (3-carboxypropy l) - 1,3,4-:J' 15 thiadiazol -2-yllthiomethyl-~ -cephem-4-carboxylic acid. -l : .....
, Infrared absorption spectrum:
m cm. : 1780 (~-lactam).
Nuclear magnetic resonance spec-tra ( D6-DMSO):
~ppm: 1.91 (2H), 2.32 (2H), 3.06 (2H), 3.58 (2E), 4.17 (lH), 4.51 (lH), 5~01 (lH), 5.01 (lH), about 5.76 (lH), 5.84 (lH), 6.44 (lH), 7.38 (5H), 7.82 (lH), 1 8.45 ( lH), and 9.47 (1~) .
.~ ~; Example 39 ~,}~ ~o 20ml. of water were added 300 mg, of 7- ~ (4-hydroxy-25 6-methylnicotinoylamido)-clrphenylaceti~nido~cephalosporanic acid, ?~ ', ' ' 142 mg. o~ 4-(5-mercapto-1,3,4-thiia;zol -2-yl~butyric acid, and 169 mg. of sodium bicarbonate and the mixture was stirred Eor 24 hours at 50~52 C. ~hen, the pH o E the reaction mixture was adjus-- ~ ~ ted to about 2 with 1 N hydrochloric acid under ice-cool:ing and 30 the precipitates formed were recovered by filtration, ~ashed with ~ 51 ~;
,:, ~ ~,. ~ .
- .
4~83 ~ Y D15~5~
water and then ether, and dried to provide 200 mg. of 7-[D-a-(4-hydroxy-6~methylnicotinoylamido)-a-phenylacetamido]-3-[5-(3-carboxypropyl)-1,3,4-thiadiazol-2-yl]thiomethyl--cephem-4-carboxylic acid.
Infrared absorption spectrum:
~ KB cmv : 1778 (~-lactam).
Nuclear magnetic resonancespectra (D6-DMS0):
ppm: l.91 (2H), 2.25 (3H), 2.32 (2H), 3.06 (2H), 3.58 (2H~, 4.18 (lH), 4.51 (lH), 5.00 (lH), about 5.75 (lH), ;~ lO 5.83 (lH), 6.29 (lH), 7.38 (5H), 8.32 (lH3, and ~9__OS(A Y ~
Example 40 ~, a)In 30 ml. o methylene chloride were added S00 mq. o 4-methoxy-6-methyl-nicotinic acid and 360 mg. of triethylamine and the mixture was cooled to -20 C with stirring. Then, ~
~! 280 mg. of ethyl chlorocarbonate was added to the mixture and -the resultant mixture was stirred to conduct a reaction ~or .`1 :
2.5 hours at the same temperature.
After the reaction was over, the solution which was l 20 prepared by dissolving lg. o cephaloglycin and 27S mg. of } ~ triethylamine in 20 ml. o methylene chloride was added to the ~ reaction mixture~ and then the resultant mixture was stirred 1 ~
~ for 2 hours at th~ temperature o _20U C. The reaction , :, mixture was allowed to stand overni~ht at the same temperature and then stirred ~or one hour at the temperature o~ 0 C.
f~er~tn~ reaction was Gve~ the solvent of the rsaction~mixture was distillea of~ under reduced pressure and ths residue thus obtained was dissolved by addin~ about 40 ml.
of~water. The pH of the solution was adjusted with 1 N
.~ ~ ' - .
~ ` ' ~ f~
hydrochloric acid to 2 under ice-cooling, whereby precipitates were formed. The precipitates thus formed were recovered by . ........ ..
filtration, washed with water and dried over, whereby 850 mg. `
. .~
of 7- [D-~- (4-methoxy-i~-methyl-nicotinoylamido)-a-phenylacetamido]-cephalosporanic acid was obtained. ~ -Infrared absorption spectra ~ KBr cm- 1 1778 (~-lactam)-Nuclear magnetic resonance spectra (D6-dimethylsulfoxide) p.p.m.: 2.01 (3~), 2.32 ~3~), 3.45 (2H), 3.72 (3~), 4.67 (lH), 4.99 (lH), 5.03 (lH), 5.81 (2H), 6.42 (lH), 7.38 (5H), 8.50 (lH), 9.50 ~lH) b) in 23 ml. of water were added 300 mg. 7-[D~-(4-j methoxy-6-methylnicotinoylamido)-a-phenylacetamido]-cephalo- - i ~ sporanic acid, 140 mg. of 2-carboxymethylthio-5-mercapto-1,3, Jl 4-thiadiazole and 1~3 mg. o~ sodium bicarbonate, and the f resultant mixture was conducted to react ~or 24 hours at the :
f temperature of 50 C.
3i~ After the reaction was over, the pH of the reaction `
mixture was adjusted to about 2 with 1 ~ hydrochloric acid 20 under ice-cooling, whereby precipitates were formed. The precipitates thus formed were recovered by filtration~ washed `~:
with water~nd then with ether and dried over~ whereby 250 mg. ~ ;
of 7-[D-~-(4-methoxy-6-methylnicotinoylamido)-a-phenylacetamido]-'~: :., ':, 3-(5-carboxymethylbhio-1,3,4,thladiazole-2-yl)-thiomethyl- ~ -Q -cephem-4-carboxylic acid was obtained. :;
Infrared absorption spectra i`
maX cm- : 1778 (~-lactam) ~;
,1 ~ h~
~ Nuclear magnetic resonance spectra (D6-dimethylsulfoxide) ; ~ p.p.m.: 2.54 (3H), 3.60 (2H), 3.74 (3H), 4.18 (2H), 4.21 (lH), 4.52 (lH), 5.05 (lH), 5.83 (2H), - 6.45 (lH), 7.43 (5H), 8.52 (lH), 9.53 (lH) Example 41 In 20 ml. of water were added 300 mg. of 7-[D-a-(4-hydroxy-6-methylnicotinoylamido)_a-phenylacetamido]-cephalo-sporanic acid, 127 mg. of 2-carboxymethyl-5-mercapto-1,3,4-thiadlazole and 174 mg. of sodium bicarbonate, and the resultant 10 mixture was conducted to react for 22 hours at the temperature - -of 50 C.
.. . .
Ater the reaction was over, the insoluble matter in the reaction mixture was filtered of~ and the pH of the fil-trate was adjusted to ~bout 2 with 1 N hydrochloric acid under ice-cooling and then the product was extracted with a mixture , of n-butanol and ethyl acetate (1 : 1 in volume ratio). The ~;~
extract was washed with saturated aqueous solution of sodium ~;
;, ~ . .
1~ chloride and then dried over anhydrous magnesium sulfate.
: ~ .
Then, slightly excessive amount of sodium 2-methylhexanate was added to the solution, whereby precipitates were formed. The ,5 ~ ' . '; .
precipitates thus formed were recovered by filtration, washed with~water and then with ether and dried over, whereby 250 mg.
of sodiUm salt of 7-[D-a-(4-hydroxy-6-methylnicotinoylamido)-a-phenylacetamido]-3-(5-carboxymethyl-1,3,4-thiadiazole-2-yl)- ;
thiomethyl-~ -cephem-~-carboxylic acid was obtained.
Infrared absorption spectra KBr cm -1 1765 (~-lactam) i ! :
~ - 54 ~ ; ~
Example 30 In 47 ml. O.e water were suspended 0.75 g. of sodium 7- tD~-(4-hydroxynicotinoylaZmido) ~-phenylacetamido] cephalosporanate and ~;
0.29 g. of 1-amino-2-carboxymethylthio-5-mercapto-1,3,4-tria~ole and after adding further 0.29 g . of sodium bicarbonate to the suspension, the resultant mixture was stirred for 22 hours at 55 C. After the reaction was over, a small amount of insoluble matters in the mixture were filterèd off and then the pH oE the filtrate was adjusted to 2 by aclding an aqueous 5% hydrochloric acid solution to the mixture. The precipitates thus formed were recovered by filtration, washed sufficiently with water and then ether, and dried over phosphorus pentoxide under reduced pressure to provide 0.62 g. of the crystalline powder of 7-CD~ 4-hydroxy-nicotinoylaZmido3 -c~-phenylacetamido~-3- (1-amino-5-carboxymethyl-thio-1,3,4-triazol -2-yl~thiomethyl-~ -cephem~4-carboxylic acidu ~ ;
Z Infrared absorption spectra:
Z ~ax cm. : 1772 (~i-lactam~ and 1660 (acid amiZde).
Nuclear magnetic resonance spectra (D6-DMS0~.
30 J~ppm); 3.58 (2H), 3.98 (2H), 5.04 (2H), 5.40 (2H), 5.70 ;-. .. . , , , , , ,, ,,,, , , ,:
t1H), S.78 (lH), 5.82 (lH), 6.46 (lH), 7.36 (5H), 7.78 (lH), 8.46 (lH), 9.40 (lH), and 11.16 (lH).
Example 31-a To 10 ml. of chloroform were added 500 mg. of 7~(D~-amino~
~-p-hydroxyphenylacetamido) cephalosporanic acid trifluoroacetate and 190 mg~ of triethylamine and after cool:ing the resultant mixture to -20 C., 163 mg. of 4-thiopyrone-3-carboxylic acid chloride was added to the mixture with stirring. rrhen, aftPr stirring the mixture for one hour at the same temperature as 10 above and for 2 hours at room temperature, the solvent was dis- `
.
' tilled off from the reaction mixture under reduced pressure. To . -'j the residue thus formed was added 10 ml. of water and after l acidifying the solution with 1 N hydrochloric acid, the product ;1 was extracted twice with 25 ml. of a 1 : 1 solution of n-butanol 15 and ethyl acetate. The extract was washed with water and then -dried and the solvent was distilled off under reduced pressure.
i~ Thereafter, ether was added to the residue thus ~ormed and the ~,' precipitates formed were recovered by filtration to provide 380 mg. of 7_LD_~ (4-thiopyrone-3-carboxamido)-~-p-hydroxyphenyl-~ s ~
acetamido]cephalosporanic acid.
` Infrared a~sorption spectrum: :
: ~m cm. : 1780 (~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO):
ppm): 2.00 (3H), 3.40 ~2H), 4.80 (2H), 5.02 (lH), 5.68 (2H), 6~70 (2H), 7.20 (2E), 7.22 (lH), 8.40 (lH), and 9.30 (1~
1: :
Example 31-b To 10 ml. of water were added 150 mg, of 7-~D~ (4-thio-pyrone-3-carboxamido)-~-p-hydroxyphenylacetamido~cephalo~poranic : . . .
30 acid, 61.5 mg. of 2-carboxymethylthio-5-mercapto-1,3,4--thiadia- `~
~6 ` ~ ~
'' `" '.,.,~ :`' '.:
.
. .. ... . . .... ,.. ,. ,., . .. ~ . .. , ... , , . " ~ . . " , . , . . ., , " .. . ... .
~ 3 zole, and 81.0 mg. of sodium bicarbonate and the mixture was stirred for 20 hours at 50-55 C.
After the reaction was over, the reaction mixture thus obtained was acidified by adding 1 N hydrochloric acid under ice-cooling and the precipi-tates formed were recovered by filtration to provide 120 mg. of 7 CD ~ (4-thiopyrone~3-carboxamido3-~-p-hydroxyphenylacetamido~-3- ~5~carboxymethylthio-1,3,4-tl~iadiazol -2-yl~thiomethyl-~3-cephem-4-carboxylic acid.
Infrared absorption spectrum: ;
~m cm. : 1770 ~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO):
~ (ppm): 3.56 (2~), 4.12 (2~I), 4.30 (2H), .00 (lE[), 5.64 ~ (2H), 6.70 (2H), 7.10 (lH), 7.20 (2H), 8.36 (lH), I and 9.30 (lH).
! 15 Exa ple 32 - ~. ,, , - , .
To 12 ml. of water were added 170 mg. of 7-~D-~-(4-thio~
pyrone-3-carboxamido)-~-p-hydroxyphenylacetamido~cepha~osporanic acid, 87 mg. of 2-carboxymethyl-5-mercapto-1,3,~-thiadizole, and ,, ~ .
92 mg. of sodium bicarbonate and the ~ixture was stirred for 15 ' hours at 50-55 C. Then, by treating the mixture as in Example , 31-b, 120 mg. O~ 7-LD-~-(4-thiopyrone-3-carboxamido)-~-p-hydroxy-! phenylacetamido~-3-t5-carboxymethyl-1,3,4-thiadiazol -2-yl~thio-i,~ methyI-~ -cephem-4-carboxylic acid was obtained.
,~ Infrared absorption spectru~:
, 25 ~mKBr cm. 1 1775 (~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO):
ppm)1 3.58 (2H), 4.16 (2H), 4.36 (2H), 5,00 (lH), 5.64 ~2H~, 6.70 (2H),7~20 (2H), 7.22 (lH), 8.38 (lH), ;;
and 9.10 (lH).
.................................................................................. : ,; :- .
Example 33 ~7 '..
To 10 ml. of water were added 150 mg. of 7- ~D~ (4-hydroxy-nicotinoylamido)-~-p~hydroxyphenylacetamido~cephalosporanic acid, 63 mg. of 2-carboxymethylthio-5-mercapto-1,3,4-thiadiazole, and 83.3 mg. of sodium bicarbonat0 and the mixture was stirred for 20 hours at 50-52C. After ~he reaction was over, the reaction mix-ture was acidified by adding 1 M hydrochloric acid under ice-cooling and the precipitates formed were recovered by filtration to provide 60 mg. of 7 [D-~-(4-hydxoxynicotinoylamido)-~p- ~:
hydroxyphenylacetamido~-3- ~-carboxymethylthio-1,3,4-~3-thiadiazol-2-yl~thiomethyl-cephem-4-carboxylic acid.
Infrared absorption spec-trum: ~ .
m cm. : 1770 (~-lactam).
Nuclear magnetic resonance spectra (D6-DMSO)~
~(ppm): 3.52 (2H), 4.08 (2H), 4.28 (2H), 4.64 (2H), 4.97 (lH), 6.36 (lH), 6.68 (2Hl, 7.20 (2H), 7.74 (lH), ' 8.39 (lH).
Example 34 ; .
. . .
In 23 ml. of water were suspended 0.36 g. of sodium 7-[D-~ :
(4~hydroxynicotinoylamido)-~-phenylacetamido~cephalosporanate 20 and 0.17 g. of 5-carboxymethylthio-~-mercap-to-[1,2, ~ triazolo-' C3,4-b~ ~t3,4~-thiadiazole and after adding 0.15 g. of sodium ! bicarbonate to the suspension, the resultant mixture was stirred for 26 hours at 55 C. After the reaction was over, insoluble ~
matters formed were filtered off from the reaction mixture and ~
25 then the pH of the filtrate was adjusted to 2 by adding aqueous . .
5% hydrochloric acid solution. Then, the pxecipitates thus formed -'7 were recovered by $iltration, washed sufficiently with water and ~
' ~ then ether, and dried over phosphorus pentoxide to provide 0~27 gO .~ .
,~ of the crystallins powder of 7-~D-~-(4-hydroxynicotinoylamido)~
`~ 30 phenylacetamido~-3-(5-carboxymethylth:io- [1,2,4~--triazolo¦3,4-b3-.
48 ~`~
.
~1,3,4I-thiadiazol -2-yl)thiomethyl-~ -cephem-4-carbo~ylic acid.
Infrared absorption spec-tra:
cm. : 1776 (~-lactam) and 1660 ~acid amide).
Nuclear magnetlc resonance spectra (D6 DMS0):
~(ppm): 3.56 (2H), 4.20 (2H), 4.96 ~2H), 5.60 (lH), 5.76 (lH), 5.84 (lH), 6.42 (lH), 7.36 (5H), 7.80 (lH3, 9.42 (lH), 9.40 (lH), and 11.14 (lH).
Example 35 In 150 ml~ of water were dissolved 2.4 g. of sodium 7-D-C~ -~4-hydroxynicotinoylamido)-~-phenylacetamido~cephalosporanate and 1.1 g. of 2-mercapto-5-(3-carboxypropionylamino)-1,3,4-thia-diazol, and after adling 9 ml. of 10~/o aqueous sodium bicarbona-te `~'! solution to the solution, the mixture was stirred for 22 hours ~ `
j while heating to 55 C. After the reaction was over, insoluble , ' , ` 15 matters were filtered off from the reaction mixture and the pH - ~ -3 of the filtrate was adjusted to 2 with 2N hydrochloric acid. The precipitates thus formed were recovered by filtration, washed ~ well with water, twice each with 45 ml. of a methanol-ether '~ mixture in a 1:5 volume ratio and then ether respectively and dried over phosphorus pentoxide under reduced pressure to give 1.5 g. of the light yellow powder oE 7-D-~ -(4-hydroxynicotinoyl-! amido)-~-phenylacetamido~-3-~5-(3-carboxypropionylamino)-1,3,4-, ,~ thiadiazol~2-y ~ thiomethyl-~ -cephem-4-carboxylic acid.
Melting point 218-221C (decomp.) . ` .
Infrared absorption spectra:
~ ma cm~ : 1772 (~-lactam), 1660 ;' Nuclear magnetic resonance. spectrum (D2O-NaOD):
~: 2.54 (4H, -NHCOCH2CH2COONa) ', ---- , ,, :.
-i Example 36 -: ! , .
In 50 ml. of water were dissolved 0.8 g. of sodiurn 7-D-~ - -.. .. ~ .. .. . .. , . , ., , , , " , . . . .. .. . .. . . . ..
~43~
(4-hydroxynicotinoylamido)-~-phenylacetamidoJcephalosporanate and 0.41 g. of 2-mercapto-5-o-carboxybenzoylamino-1,3,4-thiadiazol and after adding 3 ml~ of l~/o a~ueous sodium bicarbonate solution .
to the solution, the mixture was stirred for 21 hours while heating to 55 C~
After -the reaction was over, insoluble matters were filtered of~ from the reac-tion mixture and the pH of the filtrate was adjusted to 2 with 2 N hydrochloric acid. The precipitates thus .
formed were recovered by filtration, washed well with water~
twice each with 15 ml. of a methanol-ether mixture in a 1:5 volume ratio and then ether respectively and dried over phosphorus pentoxide under reduced pressure to give 0.54 g. of the light yellow of 7-D- ~ -(4-hydroxynicotinoylamido)-~-phenylacetamido~-3-(5-o-carboxybenzoylamino-1,3,4-thiadiazol-2-yl)thiomethyl.-~
15 cephem-4-carboxylic acid. ~ -Melting point 207 - 211C
, Infrared absorption spectrum: .. ..
~i ~max cm. 1770 (~-lactam), 1658 Example 37 In 50 ml. oE water were dissolved 0.8 g. o~ sodium 7-D-~
(4-hydroxynicotinoylamido)-~-phenylacetamido3cephalosporanate ..
.: .
71 and 0.27 g. of 2-mercapto-5-carboxymethyl-1,3,4-triazole, and .~ .. .
,';~ after adding 3 ml. of loo/O aqueous sodium bicarbonate solution ..
1 : to the solution, the mixture was stirred for 22 hours while !~ 25 heating to 55 C. `.... -.
By treating the reaction mixture thus ob-tained as in Example ~ .-36, 0.28 g. of the li~ht yellow powder of 7-D-r~ (4-hydroxy~
nicvtinoylamido~ -phenylacetamido~-3-(5~carboxylmethyl-1,3,4- ..
~ triazol-2-yl)thiomethyl-d -cephem-4-carhoxylic acid.
: 30 Melting point 210 - 213 C .
50 -~ :
~: :
- Nuclear magnetic resonance spec-trum (DMSO): 3.32 (2~,-CH2-COOH) Infrared absorption spectra: -~ max cm. : 1775 (~3-lactam~, 1658 Example 33 To 20 ml. of water were added 300 mg . of sodium 7- LD-C~- (4- :
. .
hydroxynicotinoylamido~-~-phenylacetamido~cephalosporanate, 140 : -mg. of 4-(5-mercapto-1,3,ar-thiadiazol -2-yl'?butyric acid, and 120 !'`: :,...:.;, ':,...
mg. of sodium bicarbonate and tha resultant mi~ture was stirred 10 for 24 hours at 50-52 C. Then, the pH of the reaction mixture was adjusted to about 2 with 1 N hydrochloric acid and the white precipiates thus Eormed were recovered and washed with water and :-, !. ' ' then ether and dried to provide 200 mg. oE 7-CD-~-(4-hYdrOXY_ ', n ico t inoy lamido ) -o~-pheny lace tamido l- 3- L5 (3-carboxypropy l) - 1,3,4-:J' 15 thiadiazol -2-yllthiomethyl-~ -cephem-4-carboxylic acid. -l : .....
, Infrared absorption spectrum:
m cm. : 1780 (~-lactam).
Nuclear magnetic resonance spec-tra ( D6-DMSO):
~ppm: 1.91 (2H), 2.32 (2H), 3.06 (2H), 3.58 (2E), 4.17 (lH), 4.51 (lH), 5~01 (lH), 5.01 (lH), about 5.76 (lH), 5.84 (lH), 6.44 (lH), 7.38 (5H), 7.82 (lH), 1 8.45 ( lH), and 9.47 (1~) .
.~ ~; Example 39 ~,}~ ~o 20ml. of water were added 300 mg, of 7- ~ (4-hydroxy-25 6-methylnicotinoylamido)-clrphenylaceti~nido~cephalosporanic acid, ?~ ', ' ' 142 mg. o~ 4-(5-mercapto-1,3,4-thiia;zol -2-yl~butyric acid, and 169 mg. of sodium bicarbonate and the mixture was stirred Eor 24 hours at 50~52 C. ~hen, the pH o E the reaction mixture was adjus-- ~ ~ ted to about 2 with 1 N hydrochloric acid under ice-cool:ing and 30 the precipitates formed were recovered by filtration, ~ashed with ~ 51 ~;
,:, ~ ~,. ~ .
- .
4~83 ~ Y D15~5~
water and then ether, and dried to provide 200 mg. of 7-[D-a-(4-hydroxy-6~methylnicotinoylamido)-a-phenylacetamido]-3-[5-(3-carboxypropyl)-1,3,4-thiadiazol-2-yl]thiomethyl--cephem-4-carboxylic acid.
Infrared absorption spectrum:
~ KB cmv : 1778 (~-lactam).
Nuclear magnetic resonancespectra (D6-DMS0):
ppm: l.91 (2H), 2.25 (3H), 2.32 (2H), 3.06 (2H), 3.58 (2H~, 4.18 (lH), 4.51 (lH), 5.00 (lH), about 5.75 (lH), ;~ lO 5.83 (lH), 6.29 (lH), 7.38 (5H), 8.32 (lH3, and ~9__OS(A Y ~
Example 40 ~, a)In 30 ml. o methylene chloride were added S00 mq. o 4-methoxy-6-methyl-nicotinic acid and 360 mg. of triethylamine and the mixture was cooled to -20 C with stirring. Then, ~
~! 280 mg. of ethyl chlorocarbonate was added to the mixture and -the resultant mixture was stirred to conduct a reaction ~or .`1 :
2.5 hours at the same temperature.
After the reaction was over, the solution which was l 20 prepared by dissolving lg. o cephaloglycin and 27S mg. of } ~ triethylamine in 20 ml. o methylene chloride was added to the ~ reaction mixture~ and then the resultant mixture was stirred 1 ~
~ for 2 hours at th~ temperature o _20U C. The reaction , :, mixture was allowed to stand overni~ht at the same temperature and then stirred ~or one hour at the temperature o~ 0 C.
f~er~tn~ reaction was Gve~ the solvent of the rsaction~mixture was distillea of~ under reduced pressure and ths residue thus obtained was dissolved by addin~ about 40 ml.
of~water. The pH of the solution was adjusted with 1 N
.~ ~ ' - .
~ ` ' ~ f~
hydrochloric acid to 2 under ice-cooling, whereby precipitates were formed. The precipitates thus formed were recovered by . ........ ..
filtration, washed with water and dried over, whereby 850 mg. `
. .~
of 7- [D-~- (4-methoxy-i~-methyl-nicotinoylamido)-a-phenylacetamido]-cephalosporanic acid was obtained. ~ -Infrared absorption spectra ~ KBr cm- 1 1778 (~-lactam)-Nuclear magnetic resonance spectra (D6-dimethylsulfoxide) p.p.m.: 2.01 (3~), 2.32 ~3~), 3.45 (2H), 3.72 (3~), 4.67 (lH), 4.99 (lH), 5.03 (lH), 5.81 (2H), 6.42 (lH), 7.38 (5H), 8.50 (lH), 9.50 ~lH) b) in 23 ml. of water were added 300 mg. 7-[D~-(4-j methoxy-6-methylnicotinoylamido)-a-phenylacetamido]-cephalo- - i ~ sporanic acid, 140 mg. of 2-carboxymethylthio-5-mercapto-1,3, Jl 4-thiadiazole and 1~3 mg. o~ sodium bicarbonate, and the f resultant mixture was conducted to react ~or 24 hours at the :
f temperature of 50 C.
3i~ After the reaction was over, the pH of the reaction `
mixture was adjusted to about 2 with 1 ~ hydrochloric acid 20 under ice-cooling, whereby precipitates were formed. The precipitates thus formed were recovered by filtration~ washed `~:
with water~nd then with ether and dried over~ whereby 250 mg. ~ ;
of 7-[D-~-(4-methoxy-6-methylnicotinoylamido)-a-phenylacetamido]-'~: :., ':, 3-(5-carboxymethylbhio-1,3,4,thladiazole-2-yl)-thiomethyl- ~ -Q -cephem-4-carboxylic acid was obtained. :;
Infrared absorption spectra i`
maX cm- : 1778 (~-lactam) ~;
,1 ~ h~
~ Nuclear magnetic resonance spectra (D6-dimethylsulfoxide) ; ~ p.p.m.: 2.54 (3H), 3.60 (2H), 3.74 (3H), 4.18 (2H), 4.21 (lH), 4.52 (lH), 5.05 (lH), 5.83 (2H), - 6.45 (lH), 7.43 (5H), 8.52 (lH), 9.53 (lH) Example 41 In 20 ml. of water were added 300 mg. of 7-[D-a-(4-hydroxy-6-methylnicotinoylamido)_a-phenylacetamido]-cephalo-sporanic acid, 127 mg. of 2-carboxymethyl-5-mercapto-1,3,4-thiadlazole and 174 mg. of sodium bicarbonate, and the resultant 10 mixture was conducted to react for 22 hours at the temperature - -of 50 C.
.. . .
Ater the reaction was over, the insoluble matter in the reaction mixture was filtered of~ and the pH of the fil-trate was adjusted to ~bout 2 with 1 N hydrochloric acid under ice-cooling and then the product was extracted with a mixture , of n-butanol and ethyl acetate (1 : 1 in volume ratio). The ~;~
extract was washed with saturated aqueous solution of sodium ~;
;, ~ . .
1~ chloride and then dried over anhydrous magnesium sulfate.
: ~ .
Then, slightly excessive amount of sodium 2-methylhexanate was added to the solution, whereby precipitates were formed. The ,5 ~ ' . '; .
precipitates thus formed were recovered by filtration, washed with~water and then with ether and dried over, whereby 250 mg.
of sodiUm salt of 7-[D-a-(4-hydroxy-6-methylnicotinoylamido)-a-phenylacetamido]-3-(5-carboxymethyl-1,3,4-thiadiazole-2-yl)- ;
thiomethyl-~ -cephem-~-carboxylic acid was obtained.
Infrared absorption spectra KBr cm -1 1765 (~-lactam) i ! :
~ - 54 ~ ; ~
Claims (2)
1. A process of producing cephalosporin derivative represented by the formula wherein R represents a hydrogen atom or a hydroxy group, ?
represents a 5- or 6-membered ring having 1-2 nitrogen atoms, a quinoline ring, or a thiopyran ring; R1 and R2, which may he the same or different, each represents a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a lower alkyl-thio group, or an oxo group; ? represents a 5-membered ring having 1-4 nitrogen atoms and/or 0-1 sulfur atom, a 6-membered ring having 2 nitrogen atoms, or a 1,2,4-thiazolo [3,4-b]-1,3,4-thiadiazole ring, R3 and R4, when they are present, which may be the same or different, each represents a hydrogen atom, an oxo group, a lower alkyl group, or an amino group; D represents a sulfur atom or a -NH-CO- group; E represents an alkylene group or a phenylene group; G represents a carboxy group or a sulfo group; n is 0 or 1 when m is 0; and n is 1 when m is 1; and the pharmacologically allowable salts of the derivative, which comprises reacting the compound represented by the formula nuclear magnetic resonance spectra (D6-dimethylsulfoxide) ? p.p.m.: 2.28 (3H), 3.47 (2H), 3.66 (2H), 4.14 (1H), 4.50 (1H), 4.93 (1H), 5.65 (1H), 6116 (1H), 6.28 (1H), 7.27 (5H), 8.27 (1H), 9.34 (1H) wherein R has the same meaning as above and the heterocyclic carbocylic acid represented by the formula wherein ?, R1, and R2 have the same meaning as above or a reactive derivative thereof to produce the compound shown by the formula wherein ?, R, R1, and R2 have the same meaning as above and then reacting the product with the mercapto-substituted hetero-cyclic ring compound represented by the formula wherein M represents a hydrogen atom or an alkaline metal atom and R3, R4, ? , D, E, G, m and n have the same meaning as above.
represents a 5- or 6-membered ring having 1-2 nitrogen atoms, a quinoline ring, or a thiopyran ring; R1 and R2, which may he the same or different, each represents a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a lower alkyl-thio group, or an oxo group; ? represents a 5-membered ring having 1-4 nitrogen atoms and/or 0-1 sulfur atom, a 6-membered ring having 2 nitrogen atoms, or a 1,2,4-thiazolo [3,4-b]-1,3,4-thiadiazole ring, R3 and R4, when they are present, which may be the same or different, each represents a hydrogen atom, an oxo group, a lower alkyl group, or an amino group; D represents a sulfur atom or a -NH-CO- group; E represents an alkylene group or a phenylene group; G represents a carboxy group or a sulfo group; n is 0 or 1 when m is 0; and n is 1 when m is 1; and the pharmacologically allowable salts of the derivative, which comprises reacting the compound represented by the formula nuclear magnetic resonance spectra (D6-dimethylsulfoxide) ? p.p.m.: 2.28 (3H), 3.47 (2H), 3.66 (2H), 4.14 (1H), 4.50 (1H), 4.93 (1H), 5.65 (1H), 6116 (1H), 6.28 (1H), 7.27 (5H), 8.27 (1H), 9.34 (1H) wherein R has the same meaning as above and the heterocyclic carbocylic acid represented by the formula wherein ?, R1, and R2 have the same meaning as above or a reactive derivative thereof to produce the compound shown by the formula wherein ?, R, R1, and R2 have the same meaning as above and then reacting the product with the mercapto-substituted hetero-cyclic ring compound represented by the formula wherein M represents a hydrogen atom or an alkaline metal atom and R3, R4, ? , D, E, G, m and n have the same meaning as above.
2. Cephalosporin derivative represented by the formula wherein R, R1, R2, R3, R3, ? , ? , D, E, G, m and n have the same meaning as in claim 1, when prepared by the process of claim 1.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6477473A JPS5321582B2 (en) | 1973-06-11 | 1973-06-11 | |
| JP49038545A JPS5953276B2 (en) | 1974-04-05 | 1974-04-05 | Method for producing new cephalosporin derivatives |
| JP4188474A JPS50140480A (en) | 1974-04-15 | 1974-04-15 | |
| JP6312474A JPS50154282A (en) | 1974-06-04 | 1974-06-04 | |
| JP49116976A JPS5143785A (en) | 1974-10-11 | 1974-10-11 | Shinsefuarosuhorinkanrenkagobutsuno goseiho |
| JP11963874A JPS5148686A (en) | 1974-10-17 | 1974-10-17 | SHINSEFUAROSUHORINKANRENKAGOBUTSUNO GOSEIHOHO |
| JP50013200A JPS5188988A (en) | 1975-01-31 | 1975-01-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1041483A true CA1041483A (en) | 1978-10-31 |
Family
ID=27563644
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA222,581A Expired CA1041483A (en) | 1973-06-11 | 1975-03-19 | Process of producing novel cephalosporin derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1041483A (en) |
-
1975
- 1975-03-19 CA CA222,581A patent/CA1041483A/en not_active Expired
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