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GB2068959A - 7-(2-amino-4-thiazolyl) Acetamido Cephalosporins - Google Patents

7-(2-amino-4-thiazolyl) Acetamido Cephalosporins Download PDF

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GB2068959A
GB2068959A GB8104117A GB8104117A GB2068959A GB 2068959 A GB2068959 A GB 2068959A GB 8104117 A GB8104117 A GB 8104117A GB 8104117 A GB8104117 A GB 8104117A GB 2068959 A GB2068959 A GB 2068959A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom

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  • Cephalosporin Compounds (AREA)

Abstract

Compounds of the formula <IMAGE> wherein R is hydrogen, alkali metal, <IMAGE> O-CO-lower alkyl, or <IMAGE> Si(CH3)3, p-methoxybenzyl, diphenylmethyl, benzyl, trichloroethyl or lower alkyl R1 and R2 are independently selected from hydrogen and methyl; <IMAGE> or <IMAGE> R4 is hydrogen, -OCONH2, R5 and R6 are independently selected from hydrogen, lower alkyl, lower alkanoyl, or phenyl; R5 and R6 form a heterocycle of 5 to 6 members: R7 is lower alkyl; R8 is hydrogen or CONH2; R9 is hydrogen, lower alkyl, <IMAGE> or (CH2)p-N-(lower alkyl)2; R10 is hydrogen or lower alkyl; R11 is hydrogen, sodium or potassium; R12 is hydrogen or lower alkyl; n is 1, 2, 3 or 4; m is 0, 1 or 2; p is 1, 2, 3 or 4; and Z<6> is halogen.

Description

SPECIFICATION 7-(2-Amino-4-thiazolyl) Acetamido Cephalosporins This invention is directed to cephalosporins of the formula
wherein R is hydrogen, alkali metal,
Si(CH3)3, p-methoxybenzyl, diphenylmethyl, benzyl, trichloroethyl,
or lower alkyl:: R1 and R2 are independently selected from hydrogen and methyl; R3 is
R4 is hydrogen, -OCONH2,
or
R5 and R6 are independently selected from hydrogen, lower alkyl, lower alkanoyl, or phenyl; R5 and R6 may form a heterocycie of 5 to 6 members such as pyrrolidine piperidine or morpholine; R7 is lower alkyl; R8 is hydrogen or CONH2; R9 is hydrogen, lower alkyl,
or (CH2)p-N-(lower alkyl)2; R10 is hydrogen or lower alkyl; R11 is hydrogen, sodium or potassium; R12 is hydrogen or lower alkyl; n is 1,2,3 or 4; m is 0, 1 or 2; p is 1,2,3 or 4; Ze is halogen.
The inventon also provides an antibacterial pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds of the invention.
The lower alkyl groups referred to throughout this specification include straight or branched chain hydrocarbon groups containing 1 to 4 carbons, e.g., methyl, ethyl, i-propyl, t-butyl, etc.
The compounds of formula I and their intermediates that are described below that have the 2amino 4-thiazolyl group as part of their structure are, of course, tautomeric and can also be structurally represented as containing a 2-imino group. Thus, the compounds of formula I can be represented as
The intermediates and final products are being structurally represented and named throughout this specification as 2-amino-4-thiazoles though both forms are within the scope of the invention.
The compounds of formula I and the intermediates described below having the oximino substituent
can be obtained as the syn or anti isomer or as a mixture of isomers. All of these isomeric forms are within the scope of this invention. However, in general, it is preferred to obtain the final products in the syn form since that isomeric form has the greatest activity.
The symbol
is being used to represent sulfide alone or bonded to either one or two oxygens. When the sulfide is bonded to only one oxygen the sulfoxides of formula I and in the various intermediates described below can be in either the - or ss-configuration. When the sulfoxide is only in the ss-configuration it will be represented as
and when it is only in the -configuration it will be represented as
The cephalosporins of formula I can be prepared by various methods.For example, the compounds of formula I wherein R4 is --OCONH,, 0 --OO-C-lower alkyl,
and wherein F9 and R10 are as defined above can be obtained by acylating an ester of the formula
wherein R4, and m are as defined above and R is an ester protecting group such as benzyl, diphenylmethyl, t-butyl, p-methoxybenzyl or trichloroethyl, with a compound of the formula
wherein Ri, R2, R3 and n are as defined above, to yield an intermediate of the formula
The acylation reaction is carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide.
The intermediate of formula V is then treated to remove the ester protecting group and yield the compounds of formula I in the acid form. Preferably, in the above reactions, R is diphenylmethyl and the intermediate of formula V is treated with trifluoroacetic acid and anisole to remove the diphenylmethyl group.
The compounds of formula IV are obtained by reacting 2-amino-4-thiazole glyoxylic acid of the formula
with a compound of the formula
The compound of formula Vll can be prepared by treating N-hydroxyphthalimide with a compound of the formula
to yield the compound of the formula
Treatment of IX with hydrochloric acid yields the reactant of formula VII.
The 7-amino cephalosporanic acid ester ,- and ss-sulfoxides of formula Ill (m is one) are prepared by converting the 7-amino cephalosporanic acid starting material (m is zero) to the Schiff base ester of the formula
which is then oxidized with a percarboxylic acid such as m-chloroperbenzoic acid to yield a mixture of a- and ss-sulfoxide Schiff base cephalosporin esters. The Schiff base sidechain is cleaved by treatment with toluenesulfonic acid and the a- and ss-sulfoxide 7-amino cephalosporanic acid esters are separated chromatographically. Further oxidation of the a-sulfoxide yields the corresponding sulfone (m is two) of formula Ill.
The compounds of formula la can be prepared by reacting a compound of formula I wherein R is hydrogen and R4 is
with pyridine or carbamoyl substituted pyridine in a polar solvent such as water and in the presence of a catalyst such as an alkali metal thiocyanate according to the procedures taught in U.S. Patent 3,792,047 and German Offenlegungsschrift 2,234,280.
Also, the compounds of formula I wherein R4 is heterothio (i.e.
can be prepared by reacting the compound of formula I wherein R is hydrogen and R4 is
with a mercaptan of the formula hetero-S-H or an alkali metal (preferabiy sodium) mercaptan salt of the formula hetero-S-alkali metal Such methods of introducing a heterothio group in the 3-position are disclosed in various U.S. Patents including 3,955,213,4,066,762, etc.
The ss-sulfoxide compounds of formula I (m is one) can also be prepared by the direct oxidation of the corresponding sulfide compound (m is zero). Suitable oxidizing agents are percarboxyiic acids such as m-chloroperbenzoic acid, peracetic acid, etc., and this reaction can be performed at from about OOC to about 25cC.
Also, the sulfone compounds of formula I (m is two) can be prepared by the direct oxidation of the corresponding a-sulfoxide compound (m is one). Again percarboxylic acids such as m-chloroperbenzoic acid and peracetic acid are the preferred oxidizing agents.
The compounds of formula I wherein R is sodium or potassium are prepared by reacting the corresponding compound of formula I wherein R is hydrogen with the appropriate salt forming ion.
The compounds of formula I wherein R is
can be obtained by treating the corresponding free acid of formula I with a compound of the formula
wherein halo is chlorine or bromine in an inert solvent such as dimethylformamide at or below ambient temperature.
Similarly, the compounds of formula I wherein R is
are prepared by treating free acid compound of formula I with a compound of the formula
wherein L is hydroxy or Br as taught in U.S. Patents 3,860,579, 3,951,954, and 4,072,677.
Preferred compounds of this invention are those of formula I wherein the oximino group is in the syn configuration: n is one or two R is hydrogen, sodium or potassium; m is zero or one provided that when m is one the sulfoxide is in the p-configuration; R1 is hydrogen or lower alkyl; R2 is hydrogen or lower alkyl; R3 is
R4 is
R5 and R6 are hydrogen or lower alkyl; R7 is lower alkyl; R8 is hydrogen or
R9 is hydrogen, methyl,
or-(CH2)-N(CH3)2 and R" is hydrogen, sodium or potassium, p is 1 or 2, and Z is halogen.
Most preferred are the above compounds wherein R7 is
or The compounds of formula I are antibacterial agents possessing activity against various gram negative organisms including Klebsiella, Proteus, and Enterobacter species. These compounds are also active against strains of Escherichia coli, Serratia marcescens, Shigella sonnei, Cftrobacterfreundll, etc.
They may be used as antibacterial agents to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to other gram-negative antibacterial agents.
For example, a compound of formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 1 to 100 mg of formula I compound per kilogram of body weight, daily in parenteral form in single or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mg/kg in mice.
Up to about 600 mg of an acid compound of formula I or a physiologically acceptable salt or ester thereof may be incorporated in an injectable form prepared according to conventional pharmaceutical practice.
Illustrative process details are in the examples for the various reactions. Ail temperatures are on the centigrade scale. E-isomer or (E) represent the Anti-isomeric form of the molecule. Z-isomer or (Z) represent the syn-isomeric form of the molecule.
Example 1 [6R-[6a,7(Z)ii-3-[(Acetyloxy) methyl]-7-[[2-amino-4-thiazolyl) [[2-(dimethylamino)ethoxy] iminojacetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4 .2. O]oct-2-ene-2-carboxylic acid, sodium salt a) [2-[(1 ,3-Dihydro-1 ,3-dioxo-2H-isoindol-2-yl)- oxy]-ethyl]-di methylamine To a solution of 38.3 g 2-dimethylamino-1 -hydroxyethane, 70 g N-hydroxyphthalimide, 112.8 g triphenyiphosphine in 1000 ml of dry tetrahydrofurane is added dropwise 83 g diethylazodicarboxylate while stirring at OOC. The solution is stirred at room temperature over night. The solvent is removed in vacua. The oily residue is extracted with 1.5 1 of 600C water.The water is distilled off and the residue crystallized with acetonitrile, to yield, 95 g of [2-[(1 ,3-dihydro-1 ,3-dioxo-2H-isoindol-2-yl)oxy]ethylj- dimethylamine with a melting point of 130-1 320C.
b) [2-(Aminoxy)ethyl]dimethylamine, hydrochloride 4.2 g of [2-[( 1 ,3-dihydro-1 ,3-dioxo-2H-isoindol-2-yl)-oxyjethyljdimethyiamine are refluxed in 30 ml 17.5% hydrochloric acid (aqueous) for 3 hours. After this time, the mixture is evaporated to dryness, 50 ml of water are added to the residue and the precipitated phthalic acid is filtered off. The mother liquor is evaporated to dryness and the crystalline residue recrystallized from methanol/ether to yield 3 g [2-(aminoxy)ethyl]dimethylamine, hydrochloride with a melting point of 160-1 620C (dec.).
c) 2-Amino-a-[[2-(dimethylamino)ethoxy]imino]-4thiazolecarboxylic acid, potassium salt (Z) 1 5 g of 2-formylamino-4-thiazolyl-glyoxylic acid, potassium salt and 11.2 g [2 (aminoxy)ethyl]dimethylamine, hydrochloride are heated together in 50 ml water for 12 hours. After cooling 1 OOC, the insoluble material is filtered off and recrystallized from methanol to yield the Eisomer of the product compound with a melting point of 149-1 500C. The mother liquor is evaporated to dryness and the residue recrystallized from methanol to yield 11.5 g of 2-Amino a-[[2- (dimethylamino)ethoxy]imino]-4-thiazoZecarboxylic acid, potassium salt (Z) with a melting point of 153-1550C.
d) [6R-[6a,7(Z)i]-3-[(Acetyloxy)methyli-7-[[(2-amino-4-thiazolyl) [[2- (dimethylamino)ethoxy] imino]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo [4.2. O]oct-2-ene-2carboxylic acid, diphenylmethyl ester 2 g of 2-amino-&alpha;-[[2-(dimethylamino)ethoxylimino]-4-thiazolecarboxylic acid, potassium salt (Z) and 3.2 g 7-ACA-benzhydryl ester are dissolved in 200 ml dimethylformamide and the solution is cooled to OOC. At this temperature, a solution of 2 g dicyclohexylcarbodiimide in 20 ml methylene chloride is added dropwise with stirring. Stirring is continued for 48 hours. The solution is poured into ice water and 50 ml of saturated aqueous sodium bicarbonate are added. The solution is extracted 3 times with 100 ml portions of ethyl acetate.The combined organic layers are shaken 3 times with 30 ml portions of 2N H3PO4 at OOC. The combined aqueous layers are washed with 50 ml of ethyl acetate.
The organic layers are discarded. The acidic solution is now poured with stirring into a mixture of saturated aqueous sodium bicarbonate and 200 ml of ethyl acetate at OOC. Ethyl acetate extract is washed with sodium hydrochloride solution, dried over magnesium sulfate and evaporated to about 15 ml. This solution is added with stirring into 150 ml of petroleum ether. The precipitate is filtered off to yield 1.8 g of [6F-[6a,7/3(Z)j]-3-[(acetyloxy)methylj-7-[[(2-amino-4-thiazolyl)[[2- (di methylamino)ethoxy] imino]acetyl]am inoj-8-oxo-5-thia- 1 -azabicyclo[4 .2. O]oct-2-ene-2-ca rboxylic acid, diphenylmethyl ester with a melting point of 70-750C.
e) [6R-[6&alpha;,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2- (dimethylamino)ethoxy]imino]acetyl]aminoi-8-oxo-5-thia-1 azabicyclo[4 .2. O]oct-2-ene-2- carboxylic acid, trifluoroacetate salt (1:1) 1.8 g of [6R-[6,7fi(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2- (dimethylamino)ethoxylimino]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, diphenylmethyl ester and 4 g anisole are stirred at OOC. At this temperature, 8 g of trifluoroacetic acid (TFA) are added slowly. Stirring at 0 C is continued for 30 min.The solution is added to 200 ml of ether and the precipitated compound is filtered off and washed several times with ether to yield 1.2 g of [6R-[6a,7p(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2- (dimethylamino)ethoxylimino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt (1:1) with a melting point of 118-1 200C.
f) [6R-[6a,7f\(Z)]]-3-[(Acetyloxy)methyl-7-[[(2-a m ino-4-thiazolyl) [[2- (dimethylamino)ethoxy] imino]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4 .2. O]oct-2-ene-2- carboxylic acid, sodium salt 1.1 9 of [6F-[sa,7(Z)j]-3-[(aceloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2 (dimethylamino)ethoxy]imino] [acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4. 2. 0] oct-2-ene-2carboxylic acid, trifluoroacetate salt (1 :1) is dissolved in 5 ml of an acetonitrileXmethanol mixture and 0.87 g sodium ethyl hexanoate in 10 ml butanol is added.The solution is stirred for 5 min., 50 ml of ether is added and the precipitate is filtered off to yield 1.1 g of [6R-[6&alpha;,7ss(Z)]]-3-[(acetyloxy)methyl]- 7-[[(2-amino-4-thiazolyl)[[2-(dimethylamino)ethoxylimino]acetyl]amino]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt with a melting point of 130-1 350C (dec.).
Example 2 [6R-[6&alpha;,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[2-(dimethylamino)ethoxy]imino]acetyl]amino]-3-[[(1- methyl H-tetrazol-5-yl)thio] methyl]-8-oxo-5-thia-1 -azabicyclo[4 .2. O]-oct-2-ene-2-carboxylic acid, sodium salt a) [6R-[6a,7(Z)]]-7-[[(2-Amino-4-thiazolyl) [[2-(dimethylamino)ethoxy]imino]acetyl]amino]-3- [[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2carboxylic acid, diphenylmethyl ester When 2-amino-&alpha;;-[[2-(dimethylamino)ethoxy]imino]-4-thiazolecarboxylic acid, potassium salt (Zisomer) made as in Example 1 (c) is coupled with 7-ACA-3-mercaptomethyl-tetrazolyl-benzhydryl ester analogous to the procedure given in Example 1 (d), [6R-[6cr,7p(Z)]]-7-[[(2-amino-4-thiazoXyl)[[2- (dimethylamino)ethoxylimino]-acetyl]amino]3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1 azabicyclo[4 .2. O]oct-2-ene-2-carboxylic acid, diphenylmethyl ester is formed having a melting point of 1 10-1200C.
b) [6R-[6&alpha;,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[[2-(dimethylamino)ethoxy]imino]acetyl]amino]-3- [[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2carboxylic acid, sodium salt When [6R-[6&alpha;,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[[-2-9dimethylamino)ethoxy]imino]acetyl]amino]- 3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.]oct-2-ene-2-carboxylic acid, diphenylmethyl ester is processed as described in Example 1 (e), i.e. cleavage of the protecting benzhydryl ester with TFA/a nisole:: [6-R-[6&alpha;,7ss(Z)]]-7 [[(2-amino-4-thiazolyl)[[2-(dimethylamino)- ethoxylimino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1 azabicyclo[4. 2. O]oct-2-ene-2-carboxylic acid, trifluoroacetate salt is formed. By treatment of this trifluoroacetate salt with sodium ethyl hexanoate analogous to the procedure of Example 1(f), [6R- [6&alpha;,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[[2-(dimethylamino)ethoxy]imino]acetyl]amino]-3-[[(1-methyl- 1 H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2. O]oct-2-ene-2-carboxylic acid, sodium salt is formed having a melting point of 155-1 570C (dec.).
Example 3 [6R-[6a7,(Z)]j-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2- (trimethylammonio)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, sodium salt, iodide a) [2-[(1,3-Dihydro-1,3-dioxo-2-H-isoindol-2-yl)oxy]-ethyl]trimethylammonium iodide 4 g of [2-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]ethyl]dimethylamine made as in Example 1 (a) are dissolved in 20 ml dimethylformamide at 1000C. After cooling to 400C, 4 g methyl iodide is added and the mixture is stirred at room temperature for 30 min. The precipitated compound is filtered off to yield 3.2 g of [2-[( 1 ,3-d ihydro-l ,3-dioxo-2H-isoindol-2-yl)oxy]ethyl]-tri ethylam moniu m iodide having a melting point of 250-2550C (dec.).
b) [2-(Aminoxy)ethys]trimethylammonium iodide, hydrochloride 9.2 g of [2-[( 1,3-dihydro-l ,3-dioxo-2H-isoindol-2-yl)oxy]-ethyl]tri ethylam monium iodide is refluxed in 50 ml of conc. HCI with stirring for 1 hour. The mixture is evaporated to dryness and 50 ml of water are added. The isoluble phthalic acid is filtered off and the mother liquor evaporated. The remaining residue is purified by dissolving in methanol and precipitating by addition of ether to yield 4.3 g [2-(aminoxy)ethyl]trimethylammonium iodide, hydrochloride having a melting point of 11 3- 1 140C.
c) 2-Amino-a[[2-(trimethylammonio)ethoxy] im ino]-4-thiazolecarboxylic acid, iodide (Z-iso mer) 4.3 g of 2-imino-4-thiazole-glyoxylic acid, hydrochloride is suspended in 50 ml of water. The pH is adjusted with potassium carbonate to 5.5. 3.2 g of [2-(aminoxy)ethyl]trimethylammonium iodide, hydrochloride is added and the pH maintained at 5.5 while stirring for 24 hours. By addition of dilute HCl, the pH is brought to 2 and the solution evaporated in vacuo. The residue is extracted with 100 ml of hot methanol. The methanol is distilled off to a volume of 1 5 ml. After addition of ether, 2.6 g of 2 amino-&alpha;-[[2-(trimethylammonio)ethoxy]imino]-4-thiazolecarboxylic acid, iodide crystallizes.
d) [6R[6&alpha;,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2- (trimethylammonio)ethoxyjiminojacetyl]amino]-8-oxo-5-thia-I -azabicyclo[4 .2. 0]oct-2-ene-2- carboxylic acid, diphenylmethyl ester, iodide 1.7 g of 2-amino-&alpha;[[2-(trimethylammonio)ethoxy]-imino]-4-thiazolecarboxylic acid, iodide (Zisomer) and 2.3 g 7-ACA-benzhydryl ester are dissolved in 100 ml dimethylformamide. 1.9 g dicyclohexylcarbodiimide in 20 ml acetonitrile are added and the mixture is stirred for 48 hours at OOC.
The precipitated urea is filtered off and the mother liquor evaporated in vacuo. The remaining residue is dissolved in 10 ml of methanol and the solution added to 100 ml of ether with vigorous stirring. The precipitate is filtered off to yield 1.9 g of [6R-[6&alpha;,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4- thiazolyl)[[2-(trimethylammonio)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4. 2. O]oct-2ene-2-carboxylic acid, ciiphenylmethyl ester, iodide having a melting point of 155-1 570C (dec.).
e) [6R-[6oe7,B(z)]]-3-[(AcetyloxyYmethyl]-7-[[(2-a mino-4-thiazolyl) [[2- (trimethylam monio)ethoxyjiminojacetyl]amino]-8-oxo-5-thia-I -azabicyclo[4 .2. O]oct-2-ene-2- carboxylic acid, sodium salt, iodide 1 g of [6R-[6a7p(Z)]j-3-[(acewloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2- [trimethylammonio)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azablcyclo[4.2.0]oct-2-ene-2carboxlic acid, diphenylmethyl ester, iodide is suspended in 2 g anisole and the mixture is cooled to 00.
At this temperature, 4 g trifluoroacetic acid is added and stirring is continued for 1 hour. After addition of 100 ml ether, [6F-[6a,7- (Z)]j-3-[(acetyloxy)m ethylj-7- [[(2-a mino-4-thiazolyl) [[2- (trimethylammonio)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid iodide, trifluoroacetate (1:1) precipitates and is filtered off (m.p. 120-122 C. dec.) and dissolved in 10 ml methanol. An equivalent amount of sodium ethyl hexanoate is added and the solution poured into 100 ml ether.The sodium salt crystallizes, is filtered off and washed several times with ether to yield 0.6 g of [6R-[6&alpha;,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2- (trimethylammonio)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, sodium salt, iodide having a melting point of 1 50-1 550C (dec.).
Example 4 [6R-[6a,7(Z) ]-7-[[(2-Amino-4-thiazolyl) [[2-trimethylam monio )ethoxy]imino]acetyl]a mino]-3 [[(1-methyl-1 H-tetrazol-5-yl)thio] methyl]-8-oxo-5-thia-1 -azabicyclo [4. 2. O]-oct-2-ene-2- carboxylic acid iodide, sodium salt a) [6R-[6&alpha;,7ss(Z)]]-7-[(2-Amino-4-thiazolyl)[[2-(trimethylammonio)ethoxy]imino]acetyl]amino]- 3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid iodide, diphenylmethyl ester 1.8 g of [6R-[6,7/3(Z)]]-7-[[(2-amino-4-thiazolyl)-[[2- (dimethylammonio)ethoxy]imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia 1-azabicyclo[4. 2. O]oct-2-ene-2-carboxylic acid, diphenylmethyl ester from Example 2(a) are dissolved in 20 ml of ethyl acetate. At room temperature, 1.8 g methyl iodide are added and the solution is stirred for 2 hours. After this time 1.7 g of [6R-[6&alpha;,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[[2- (trimethylammonio)ethoxy]imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid iodide, diphenylmethyl ester having a melting point of 1 54-1 560C is filtered off.
b) [6R-[6.S,7/3(Z)]]-7-[[(2-Amino-4-thiazolyl)[[2-(trimethylammonio)ethoxy]imino]acetyl]amino]- 3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid iodide, sodium salt When [6R-[6ct,7,B(Z)]]-7-[[(2-amino-4-thiazolyl)[[2- (trimethylammonio)ethoxy]imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5 thia-1-azabicyclo[4 .2. O]oct-2-ene-2-carboxylic acid iodide, diphenylmethyl ester is treated with trifluoroacetic acid and anisole as described in Example 1(e), [6R-[6&alpha;,7ss(Z)]]-7-[[(2-amino-4- thiazolyl)[[2-(trimethylammonio)ethoxy]imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.O]oct-2-ene-2-carboxylic acid iodide is obtained (melting point 11 5-11 70C). This compound is dissolved in methanol, and sodium ethyl hexanoate is added as in Example 1(f), and [6R-[6cr,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[[2- (trimethylammonio)ethoxy]imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5 thia-1 -azabicyclo[4 .2. O]oct-2-ene-2-carboxylic acid iodide, sodium salt is obtained having melting point of 175-1 770C (dec.).
Example 5 [5S-[5&alpha;,6ss,7&alpha;(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino4-thiazolyl)[2 (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-i -azabicyclo[4 .2. O]oct-2-ene-2- carboxylic acid, 5,5 dioxide, sodium salt a) [5S-[5&alpha;,6ss,7&alpha;]-3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., p-sulfoxide) and [5R-[5&alpha;,6&alpha;,7ss]]-3- [(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5oxide, diphenylmethyl ester (i.e., a-sulfoxide) A slurry of 50 g of 7-aminocephalosporanic acid (7-ACA) in 1 liter of water is stirred magnetically while t-octyl amine is added dropwise, thereby maintaining the pH between 7 and 8.After one hour the undissolved solid is filtered (celite) and the filtrate is treated with a solution prepared by adjusting a mixture of 10 ml of t-octylamine and 20 ml of water to pH 8.0 with 6N hydrochloric acid. The resulting solution is then treated with 10 ml of salicylaldehyde. After 2 minutes a solid forms and after 5 minutes an additional 10 ml of salicylaldehyde is added. The slurry is stirred for an additional 10 minutes, cooled to 0 for 4.5 hours and filtered. The filter cake is slurried twice with 300 ml of cold water and filtered. The wet cake is dried at 600 in vacuo over large amounts of P205 to give 66 g of tan solid 7salicyaldiminocephalosporanic acid, t-octyl amine salt.
A slurry of 25.25 g (0.05 mole) of the above t-octyl amine salt (powdered with a mortar and pestle in 250 ml of dry acetonitrile is treated with 9.5 g (0.05 mole) of p-toluenesulfonic acid monohydrate. After 10 minutes, a solution of 9.7 g (0.05 mole) of diphenyldiazomethane in 50 ml of acetonitrile is added over the course of 1 5 minutes. After one hour, the slurry is filtered, the solid is washed with acetonitrile, and the combined filtrate and washings are evaporated in vacuo. The resulting oil is chromatographed on a 300 g silica gel column eluted with methylene chloride.Fractions (500 ml) 2-3 contain 7.5 g of the desired diphenylmethyl ester produced plus some higher Rf impurity (monitored by silica gel TLC with 3:1 chloroform-ethyl acetate development):fractions 4-11 contain 12.3 g of pure 7-salicylaldiminocephalosporanic acid, diphenylmethyl ester; NMR (CDCI3)S 1.97 (s, 3H, CH3CO); 3.23 and 3.60 (AB q, J=1 9 Hz, 2H, C-2); 4.67 and 5.01 (AB q, J=1 4 Hz, 2H, C3'); 4.99 (d, J=5 Hz, 1 H, C-6); 5.20 (broadened d, J=5 Hz, 1 H, C-7); 6.62-7.60 (m, about 15H); 9.07 (broad s, 1 H, -CH=N-).
A solution of 12.3 g (0.023 mole) of the above diphenylmethyl ester product in 125 ml of methylene chloride is cooled to 0 and a solution of 4.6 g (0.023 mole) of 85% m-chloroperbenzoic acid in 70 ml of methylene chloride is added over the course of 15 minutes. After one hour, the slurry is washed with a mixture of 100 ml of 5% sodium bicarbonate and 50 ml of 6% sodium sulfite solution.
The organic layer is dried and evaporated in vacuo. The resulting oil crystallizes from 70 ml of ethyl acetate giving 8.7 g of a mixture of a- and p-sulfoxides. A second crop of 1.5 g of a mixture of a- and p-sulfoxides is also obtained. The major (a-) isomer has a lower field acetate methyl (2.02 ppm) and C2 quartet (3.57 and 4.10 ppm) when compared to those of the minor (p isomer (1.97, 3.26 and 3.94 ppm, respectively).
A slurry of 10 g (0.018 mole) of the above 7-salicyladiminocephalosporanic acid, diphenylmethyl ester a- and p-sulfoxide mixture in 100 ml of ethyl acetate is treated with 3.42 g (0.018 mole) of ptoluenesulfonic acid monohydrate. After 5.5 hours, 300 ml of ether is added and the gummy solid is triturated, filtered, and washed twice with ether. The moist solid is dissolved in 200 ml of ethyl acetate and the solution is washed with 100 ml of 5% sodium bicarbonate solution, dried, and evaporated to give 8.0 g of residue. Chromatography on a 300 g silica gel column eluted with 3:1 chloroformethyl acetate gives (500 ml fractions):fraction 3, 1.0 g of recovered 7-salicylaldimino-cephalosporanic acid, diphenylmethyl ester; fractions 6-1 6, 4.5 g of [5R-[5&alpha;,6&alpha;,7ss]]-3-[(acetyloxy)methyl]-7-amino-8-oxo- 5-thia-1-azabicyclo[4. 2. 0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., asulfoxide isomer):NMR (CDCl3) b 2.00 (CH3COO-); 3.43 and 4.06 ppm (AB q, C-2); fractions 22-30 (eluant is changed to ethyl acetate after fraction 16) 1.5 g of [5S-[5&alpha;,6ss,7&alpha;]]-3-[(acetyloxy)methyl] 7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., ss-sulfoxide isomer):NMR (CDCl3) a 2.10 (CH3C00-); 2.97 and 3.54 ppm (AB q, C-2).
b) [6R-[6a,7j]-3-[(Acetyloxy) methyl]-7-amino-8-oxo-5-thia-i -azabicyclo[4.2.0] oct-2-ene-2carboxylic acid, 5,5-dioxide, diphenyimethyl ester [5R-[5&alpha;,6&alpha;,7ss]]-3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxlic acid, 5-oxide, diphenylmethyl ester from Example 5(a) is added to methylene chloride and cooled to Oc. An equimoiar amount of m-chloroperbenzoic acid in methylene chloride is added. After the reaction is completed, the slurry is treated with 5% sodium bicarbonate and 5% sodium sulfite. The organic layer is dried and evaporated In vacuo.Preparative thin layer chromatography of the residue yields [6R-[6&alpha;,7ss]]-3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid, 5,5-dioxide, diphenylmethyl ester.
c) [6R-[6&alpha;,7ss(Z)]]03-[(Acetyloxy) methyl]-7-[[(2-amino-4-thiazolyl [[2 (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 5,5-dioxide, diphenylmethyl ester Following the procedure of Example 1 (d) but substituting [6R-[6a.7B]1-3-[(acetyloxyfmethyl]-7- amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester for 7-ACA-diphenylmethyl ester then [6R-[6&alpha;,7ss(Z)]]-3-[(acetyloxy)-methyl]-7-[[(2-amino-4- thiazolyl)[[2-(dimethylamino)-ethoxy]iminojacel]amino}-8-oxo-5-thia- 1 -azabicyclo-[4. 2. O]oct-2ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester is formed.
d) [6 R-[6&alpha;,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-am ino-4-thiazolyl) [[29dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 5,5-dioxide, trifluoroacetate salt ( Following the procedure of Example 1(e) but substituting [6R-[6cz,7,e(Z)]]-3-[(acetyloxy)methyi]- 7-[[(2-amino-4-thiazolyl)[[2-(dimethylamino)ethoxy)imino]acetyl]amino]-8-oxo-5-thia-1azabicyclo[4.2. Ojoct-2-ene-2-carboxylic acid 5,5-dioxide diphenylmethyl ester for [6R-[6&alpha;;,7ss(Z)]]-3- [(caetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5thia-1-azabicyclo[4.2. Ojoct-2-ene-2-carboxylic acid 5,5-dioxide diphenylmethyl ester for [6R [6&alpha;,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-dimethylamino)ethoxy]- imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester then [6R-[6&alpha;,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4- thiazolyl)[[2(dimethylamino)ethoxy]imino]acetyl]aminoj-8-oxo-5-thia-1 -azabicyclo[4 .2. O]oct-2-ene2-carboxylic acid, 5,5 dioxide, trifluoroacetate salt is formed.
e) [6R-[6a,7(Z)j]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl [[2 (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 5,5 dioxide, sodium salt Following the procedure of Example 1 (f) but substituting [6R-[6&alpha;,7ss(Z)]]-3-[(acetyloxy)methyl]-7- [[(2-amino-4-thiazolyl)[[2-(dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1azabicyclo[4 .2.O]oct-2-ene-2-carboxylic acid, 5,5 dioxide for [6R-[6&alpha;,7ss(Z)]]-3-[(acetyloxy)methyl]- 7-[[(2-amino-4-thiazolyl)[[2-(dimethylamino)-ethoxyjimino]acetyl]amino]-8-oxo-5-thia-1 azabicyclo[4. 2. O]oct-2-ene-2-carboxylic acid trifluoroacetate salt (1:1) to form [6R-[6&alpha;,7ss(Z)]]-3- [(acetyloxy)methylj-7-[[(2-amino-4-thiazolyl) [[2-(dimethylamino)ethoxy]imino]aceWl]amino]-8-oxo-5- thia-1-azabicyclo[4. 2. oloct-2-ene-2-carboxylic acid, 5,5 dioxide, sodium salt.
Example 6 [5S-[5a,6,7a(Z)]j-3-[(Acetyloxy)methyl]-7-[[2-amino-4thiazolyl) Ct2- (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 carboxylic acid, 5-oxide sodium salt a) [5S-[6&alpha;,6ss,7&alpha;(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl]]2- (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 5-oxide diphenylmethyl ester Following the procedure of Example 1 (d) bLt substituting [5S-(5&alpha;,6ss,7&alpha;)]-3-[(acetyloxy)methyl]- 7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide diphenylmethyl ester (made as in Example 5(a) for 7-ACA diphenylmethyl ester then [5S-[5&alpha;,6ss,7&alpha;;(Z)-3- [(acetyloxy)methyl-7-[[(2-amino-4-thiazolyl[[2-(dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5 thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide diphenylmethyl ester is found.
b) [5S-[5&alpha;,6ss,7&alpha;)]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2- (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 5-oxide, trifluoroacetate salt (1 :1) Following the procedure of Example 1 (e) but substituting [5S-[5&alpha;,6ss,&alpha;(Z)]]-3- [(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5- thia-1-azabicyclo[4 .2. O]oct-2-ene-2-carboxylic acid, 5-oxide diphenylmethyl ester for [6R [6&alpha;;,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)-[[2- (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester then [5S-(5a,6ss,7(t)]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2- (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trifluoroacetate salt (1 :1) is formed.
c) [5S-[5,6ss,7a(Z)]]-3-(Acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl) [[2 (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-i -azabicyclo[4 .2. 0]oct-2-ene-2- carboxylic acid, 5-oxide, sodium salt Following the procedure of Example 1 (f) but substituting [5S-[5&alpha;,6ss,7&alpha;]]-3-[(acetyloxy)methyl]- 7-f[(2-amino-4-thiazolyl)[[2-dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1 azabicyclo[4.2.O]oct-2-ene-2-carboxylic acid, 5-oxide, trifluoroacetate salt (1:1) for [6R-[6a,7ss(Z)]- 3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(dimethylamino)ethoxy]imino]acetyl]amino]-8-oXo- 5-thia-1-azabicyclo[4 .2. O]oct-2-ene-2-carboxylic acid, to form [5S-[5&alpha;,6ss,7&alpha;(Z)]]-3- [(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)]]2-(dimethylamino)ethoxy]imino]-acetyl]amino]-8-oXo-5- thia010azabicyclo[4.2. O]oct-2-ene-2-carboxylic acid, 5-oxide, sodium salt.
Example 7 [5R-[5&alpha;,6&alpha;,7ss]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[2 (di methylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-i -azabicyclo[4 .2. O]oct-2-ene-2- carboxylic acid, 5-oxide sodium salt Following the procedure of Example 6(a), 6(b) and 6(c) but substituting [5R-[5&alpha;,6&alpha;,7ss]]-3- [(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e. a-sulfoxide) made as in Example 5(a) for [5S-[5&alpha;,6ss,7&alpha;]]-3- [(acetyloxy)methyl]-7-amino-8-oxo-5-thia -azabicyclo[4 . 2 . O]oct-2-ene-2-carboxylic acid, 5-oxide diphenylmethyl ester then [5R-[5&alpha;,6&alpha; ;,7ss]]-3-[(acetyloxy)methyl-7-[[(2-amino-4-thiazolyl)[2- (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 5-oxide, sodium salt is formed.
Examples 8-33 Following the procedure of Examples 1 to 7 but employing the ester shown in Col. I and the acid shown in Col. II one obtains the ester shown in Col. Ill. Removai of the ester protecting group yields the acid product shown in Col. IV.
Example R R R1 R2 R3 m n 8 O-0-CH3 -CH < ) 2 -H -H -NH2 one two 9 -C-C-CH3 -C(CH3)3 -H -CH3 -N / zero one 10 -O-C-CH3 -CH2OCH3 -CH3 -CH3 ~CH3 -N(CH3)2 zero one 11 -O-C-CH3 -CH 4 ) 2 -H -H -NH2 zero one 12 -0-C-CH3 ~CH 4 )2 -H -H -NH2 two one 13 -O-C-CH3 -CH 4 )2 -CH3 -CH3 -NH2 zero one 0 14 SO-C-C2H5 -CH 2 )2 -H -H -N(CH3)2 zero one 15 -cu+Oo 2 -H -H -NH2 zero one 16 -0-C2Hg -CH 4 )2 -CH3 -H -NH2 zero one 17 -O-C-NH2 -CH4) )2 -N(CH3)2 zero zero 18 -O-0-pH2 -CH p )2 N (CH3)2 Zero zero 19 -O-0-NH2 -CH < )2 -H -H (CH3)2 one one 20 O Pc NH -CH 4 )2 -H -H (CH3)2 two one 21 'NH2 -cH)2 )2 -CH3 -CH3 -N(CH3) 2 zero one 22 sJQLcH3 -CH 4 ) 2 -H -H ( 3) 2 one 23 sT)cH3 -CH e ) 2 -CH3 -H -N(CH3)2 zero one 24 -S-H3 -CH 2 -H -H -NH2 zero one 25 -SXr;;CH3 CH 4 ) 2 -H -CH3 -NH2 one one 26 -S 4 I N -CH- )2 -H -H -NH2 zero one CH3
Example R4 R R1 R2 R3 m 27 -S X IN -CH 2 -H -CH3 -NH2 zero one 1H 28 - 2 -cH3 -CHO -NH2 one CH3 29 -S4yN -CH 4 -CH3 -CH3 -N(CH3)2 zero one H3 30 CPI -cH)2 -H -H -NH2 zero one H2COOH N-N H 31 -cHO 2 -H -H -N-CH3 zero one CH2COOH 32 N - N -CH2 -H -H -N(cH3)2 one one H 33 -CH ) 2 -H -H -N(CH3)2 zero one ( H2)2N(CH3)2
The acid products of Examples 8 to 33 can be converted to the sodium or potassium according to known procedures.
the products of Examples 8 to 33 are obtained as the syn or anti isomer depending upon the configuration of the acid shown in Col. II. Also, when R1 and R2 are not the same. the products are obtained in the D-, L- or D,L-form depending upon the optical activity of the acid shown in Col. II.
Example 34 [6R-[6a,7(Z)]]-3-[[4-(Aminocarbonyl)pyridino] methyl]-7-[[(2-amino-4-thiazolyl) [[2- (dimethylamino)ethoxy] imino]acetyl]amino]-8-oxo-5-thia-I -azabicyclo[4 .2. O]oct-2-ene-2- carboxylic acid, (syn isomer) A mixture of 0.005 mole of the sodium salt product of Example 1(f), 0.0075 mole of 4pyridinecarboximide, 12 g of potassium thiocyanate, and 7.5 ml of water are heated at SOC for 24 hours. The resulting solution is passed through a chromatography column filled with the ion exchange Amberlite XAD-2. The column is washed with water and the titled compound is eluted with a mixture of water:methanol (8:2). The methanol is evaporated from the eluate and the aqueous solution is lyophilized.The amorphous residue is triturated with ether and filtered under suction to yield [6R [6a,7(Z)J]-3-[[4-(aminocarbonyl)pyridino]methyl]-7-[[(2-amino-4-thiazolyl) [[2- (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Examples 35-42 Following the procedure of Example 34 but employing the cephalosporanic acid sodium salt shown in Col. I and the pyridine compound shown in Col. II, one obtains the product shown in Col. Ill.
Example R1 R2 R3 m n Rg 3.5 -N(CH3)2 one zero -CNH2 (4) 36 -N(CH3)2 two zero gNH2 (3) 37 -H -H -N(CH3)2 zero one -H 38 -NH2 zero zero -H 39 -NH2 two zero -CNH2 (4) 40 -NH2 zero zero -0NH2 (2) 41 -NH2 zero zero -H 42 -NH2 zero zero UNH2 (4)
The products of Examples 35 to 42 are obtained in the syn or anti configuration depending upon the configuration of the 3-acetoxymethyl starting material shown in Col. I. Similarly, when m is one the compounds are obtained as the a- or P-sulfoxide depending upon the orientation of the 3acetoxymethyl sulfoxide starting material. Also, when R1 and R2 are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col. I.
Example 43 [6R-[6&alpha;,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)-[[2-(dimethylamino)ethoxy]imino]-3-[[(5- methyl-1,3,4-thiadiazolyl]thio]methyl]8-oxo-5-thiaz-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt 0.002 mole of the sodium salt product of Example 1 is brought into solution in 100 ml of a phosphate buffer at a pH of 6.4. Then 0.0024 mole of 5-methyl-l ,3,4-thiadiazolyl-2-thiol is added. The solution is heated at 60C for six hours. After cooling, the pH is adjusted to 7.0 and the solution is chromatographed on the ion exchange resin Amberlite XAD-2.The fraction containing the desired product is freeze dried to yield [6R-[6sg,7,B-(Z)]]-7-[[(2-amino-4-thiazolyl[[2- (dimethylamino)ethoxy]imino]acetyl]amino]-3-[[(5-methyl- 1 ,3,4-thiadiazolyl)thio]methyl]-8-oxo-5- thia-1-azabicyclo[4. 2. O]oct-2-ene-2-carboxylic acid, sodium salt.
Examples 44--49 Following the procedure of Example 43 but employing the cephalosporanic acid sodium salt shown in Col. I and the thiol shown in Col. II, one obtains the product shown in Col. Ill.
Example R1 R2 R3 m n hetero 44 -NH2 zero zero 45 -NH2 two zero 46 -NH2 one zero C2H5 47 -H -H -NH2 zero one CH2SO3Na 48 -NH2 one zero 'fN 49 -NH2 two zero ( H2)2N(CH3)2 The products of Examples 44 to 49 are obtained in the syn or anti configuration depending upon the configuration of the 3-acetoxymethyl starting material shown in Col. I. Similarly, when m is one the compounds are obtained as the &alpha;- or ss-sulfoxide depending upon the orientation of the 3 acetoxymethyl fulfoxide starting material.Also, when R1 and R2 are not the same. the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col.
Example 50 [5S-[5&alpha;,6ss,7&alpha;(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2- (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 5-oxide, sodi7um salt (ss-sulfoxide, syn isomer) The product of Example 6 can also be prepared by the following procedures.
1 g of [6R-[6&alpha;,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)-[[2- (dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, from Example 1 is dissolved in 10 ml of trifluoroacetic acid at 0 , 0.39 g ofm-chloroperbenzoic acid, are added, and the solution is stirred at 0 for 1.5 hours. Then 500 ml of diethyl ether are added and the precipitated product is filtered off to yield [5S-[5&alpha;,6ss,7&alpha;(Z)]]-3-[(acetyloxy)methyl]-7-[[(2- amino-4-thiazolyl)[[2-(dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia1 azabicyclo[4. 2. O]oct-2-ene-2-carboxylic acid.
This acid can be converted to its sodium salt by the procedure in Example 1(f).
Examples 51-59 Following the procedure of Example 50 the sulfides shown in Col. I can be oxidized to the ss- sulfoxide shown in Col. II.
Example n R1 R2 R3 4 51 one -H -H -NH2 -O-CH3 N 52 one -H -H -N(CH3)2 -S H3 one on -H -H -NH2 3 54 one -CH3 -CH3 -N(CH2)2 -O--CH3 55 zero -NH2 -0-C-CH3 56 one -CH3 -H -NH2
Example n R1 R2 R3 R7 57 one 'T -H -NH2 -O- NH2 58 one -H -CH -N, -0-0-NH2 3 2 2 59 one -CH3 -CH3 -NH2 o-(}-CH3 The products of Examples 51 to 59 are obtained in the syn or anti configuration depending upon the configuration of the sulfide starting material shown in Col. I. Also, when R, and R2 are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col. I.
The acid products of Examples 1 to 59 can also be converted to various ester forms (i.e., R is
etc.) according to known procedures.

Claims (15)

Claims
1. A compound of the formula
wherein R is hydrogen, alkali metal,
Si(CH3)3, p-methoxybenzyl, diphenylmethyl, benzyl, trichloroethyl or lower alkyl R, and R2 are independently selected from hydrogen and methyl; R3 is
R4 is hydrogen, -OCONH2,
or
R5 and Re are independently selected from hydrogen, lower alkyl, lower alkanoyl, or phenyl; R5 and Re may form a heterocycle of 5 to 6 members; R7 is lower alkyl; R8 is hydrogen or CONH2; R9 is hydrogen, lower alkyl,
or (CH2)p-N-(lower alkyl)2; F10 is hydrogen or lower alkyl; R1@ is hydrogen, sodium or potassium; R12 is hydrogen or lower alkyl; n is 1,2,3 or 4; m is 0, 1 or 2; p is 1,2,3 or 4; and Zs is halogen.
2. The compound of Claim 1 wherein the
group is in the syn configuration; R11 and R are hydrogen, sodium or potassium; R1 and R2 are hydrogen or lower alkyl R3 is
R4 is
H5 is hydrogen or lower alkyl; R8 is hydrogen or lower alkyl; R7 is lower alkyl; R8 is hydrogen or
R9 is hydrogen, methyl,
or (CH2)-N-(CH3)2; n is 1 or2; m is O or 1 provided that when m is one the sulfoxide is in the p-configuration; p is 1 or 2; Z is halogen.
3. The compound of Claim 2 wherein R4 is
4. The compound of Claim 2 wherein R4 is
5. The compound of Claim 2 wherein R4 is
and R9 is hydrogen or methyl.
6. The compound of Claim 2 wherein R4 is
7. The compound of Claim 6, [6R-[6&alpha;,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)-[[2- (dimethylamino)ethoxy]imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl[]-8-oxo-5thjia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid iodide, sodium salt.
8. The compound of Claim 6, [6R-[6&alpha;,7ss(Z)]]-7-[[2-amino-4-thiazolyl)[[ (dimethylamino)ethoxy]imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)-thio]methyl]-8-oxo-5thiaz-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt.
9. The compound of Claim 2 wherein R4 is
10.The compound of Calim 9, [6R-[6&alpha;,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4- thiazoyl)[[2-(dimethylamino)ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene-2-carboxylic acid, sodium salt.
11. The compound of claim 9, [6R-[6,7p(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4- thiazolyl)[[2-(trimethylammonio)ethoxy]imino]acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4 .2. O]oct-2ene-2-carboxylic acid, sodium salt iodide.
12. An antibacterial pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds as defined in any preceding claim.
1 3. The method of treating antibacterial infections in a mammalian specie which comprises internally administering an effective amount of the composition of claim 12.
14. The compound of Calim 1 as named or shown in any of the Examples.
15. The compound of any one of Claims 1-11 and 14 for use as an antibacterial agent.
GB8104117A 1980-02-11 1981-02-10 7-(2-amino-4-thiazolyl) acetamido cephalosporins Expired GB2068959B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2571056A1 (en) * 1984-10-01 1986-04-04 Glaxo Group Ltd CEPHALOSPORINE DERIVATIVES AND PROCESS FOR PREPARING THE SAME

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2571056A1 (en) * 1984-10-01 1986-04-04 Glaxo Group Ltd CEPHALOSPORINE DERIVATIVES AND PROCESS FOR PREPARING THE SAME

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JPS56127390A (en) 1981-10-06
DE3104697A1 (en) 1981-12-24
IT8119671A0 (en) 1981-02-11
GB2068959B (en) 1984-02-22
FR2475555A1 (en) 1981-08-14

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