BE898348A - PROCESS FOR THE PREPARATION OF CEPHEM COMPOUNDS, NOVEL PRODUCTS THUS OBTAINED AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. - Google Patents

Abstract

Cephem compounds having the formula: where R1 is the amino group or an acylamino group and R9 is a group of the formula: where R2 is an organic group, X is CH or N, Z is an acid residue, Y is CH or H and n is O, or Y is N + R2 is as defined above and n is 1, or a group of formula: -A-N + (R10) 3 or R10 is a lower alkyl group and A is a lower alkylene group, and their pharmaceutically acceptable salts are compounds useful as antimicrobial agents for the treatment of infectious diseases in humans and animals.

Description

       

    <Desc / Clms Page number 1>
 



  PATENT OF INVENTION in the name of: FUJISAWA PHARMACEUTICAL CO., LTD for: PROCESS FOR THE PREPARATION OF CEPHEM COMPOUNDS, NEW PRODUCTS THUS OBTAINED AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM Priority: Patent applications filed in Great Britain on December 6, 1982 under number 8234755 on January 5, 1983 under the n 8300122 on June 28, 1983 under the n 8'317496 on November 8, 1983 spus the n 8329768 Inventors: Takao TAKAYA, Takashi MASUGI, Takashi OGINO,
Hisashi TAKASUGI, Hideaki YAMANAKA

  <Desc / Clms Page number 2>

 
The present invention relates to new cephem compounds and their pharmaceutically acceptable salts.

   More particularly, it relates to new cephem compounds and their pharmaceutically acceptable salts, which have antimicrobial activities, to processes for their preparation, to pharmaceutical compositions comprising them and to a process for their therapeutic use for the treatment of infectious diseases in humans and animals.



   Consequently, an object of the present invention is to provide new cephem compounds and their pharmaceutically acceptable salts, which are highly active against a certain number of pathogenic microorganisms,
Another object of the present invention is to provide methods for the preparation of new cephem compounds and their pharmaceutically acceptable salts.

  <Desc / Clms Page number 3>

 



   Another object of the present invention is to provide pharmaceutical compositions comprising, as active ingredients, these new cephem compounds and their pharmaceutically acceptable salts.



   Yet another object of the present invention is to provide a method for the treatment of infectious diseases caused by pathogenic bacteria in humans and animals.



   The new cephem compounds sought are new and can be represented by the following general formula (I)
 EMI3.1
 
 EMI3.2
 where R is the amino group or an acylamino group, and 9 R is a group having the formula:
 EMI3.3
 
 EMI3.4
 where R is an organic group, X is CH or N, Z is an acid residue
 EMI3.5
 Y is CH or N and n is 0; or Y is N-RonR is as defined above and n is 1 / or a group having the formula.

  <Desc / Clms Page number 4>

 
 EMI4.1
 



  -A-N A-NS (R) 10 where RIO is a lower alkyl group and A is a lower alkylene group.



  According to the present invention, the new cephem compounds (I) can be prepared by various methods which are illustrated in the following diagrams.



  Method 1
 EMI4.2
 tf \ - - pi J L. CH = CH-S-R Acylation J LcH = CH-S-R COO 1 Or Co08 co00 (la) (Ib) or its reactive derivative on the amino group or its salt Process 2 l S Eliintna. tion of the group of R-j--) -! 1 K /: CH = CH-S-RII protection of 1 - 9 -L, n ù K carho group -N-CH-CH-SR R 0 1 coo (II) (1) or its salt or its salt Method 3 Pre reaction, paration of the salt R of ammonium cua; - ,, ternary 1 Dl- N CHCH-S-R12 "ODCHCH-S-R9 o T o T COOH COO (III) (1) or its salt or its salt

  <Desc / Clms Page number 5>

 
 EMI5.1
 Method 4 Elimination l S of the group of lg b TI? - 9 protection of c. 9 c 9 J, '-CH = CH-S-R amino group J M. L.

   CH = CH-SR "O l O C008 C000 (le) (Id) or its salt or its salt Process 5 Process 5 d p- u 9 Alkylation eD. 9 d CH = CH-S- Alkylaticn H = cH-S- 0 1 coo "coo coo coo (Ie) (If) or its salt or its salt Method 6 Elimination asz of the group of asz protection of gT'9 JLN. -CH = CH-S-R e carby J-CH = CH-S-R 0 '0' N 0 0 coo coo (Ig) (Ih) or its salt or its salt Proceed 7 s.

   K Pl RIp Sì RTI:? o N C =: CH + HS-Rll - 0 N h CH = CH-S-R9 '' COOL COOL (VIII) (XIVa) (I) or its salt or its salt or its salt

  <Desc / Clms Page number 6>

 
 EMI6.1
 Method 8
 EMI6.2
 
 EMI6.3
 (VIe) (XIVa) (1) or its salt or its salt or its salt 1 9 In these different formulas, R and R9 are each as defined above, Ra is an acylamino group, a RE is an acylamino group having a protected amino group b R1 is an acylamino group having an amino group; c R3 is a protected carboxy group; R is a group which may be substituted by a group of formula: -S-R or R is as defined above;

   R is a group of formula:
 EMI6.4
 
 EMI6.5
 0 where R., X, Z, yet n are each as defined above, or a group having the formula; - AN (RiO. 20 where A, R and Z are ch.acunconvnedéfinisci above, R is a group having the, formula;

  <Desc / Clms Page number 7>

 
 EMI7.1
 where X is as defined above iet
Ya is CH or N, or a group having the formula: 10-A-N- (R10) 2 where A and R are each as defined above;
 EMI7.2
 R. is an acylamino group having a lower imino pyridylalkoxy group; R is an acylamino group having a lower alkyl group and lower pyridinioalkoxy imino;

   Rf is an acylamino group having a lower alkoxy imino protected carboxy group, a lower alkenyl oxyimino protected carboxy group or a lower imino cycloalkoxy protected carboxy group, and
 EMI7.3
 R is an acylamino group having a lower imino carboxyalkoxy group 9, a lower carboxyalkenyl oxyimino group or a lower imino carboxycycloalkoxy group.



   Among the starting compounds of the present invention, the compound (II) is new and can be prepared by the methods which are illustrated in the following schemes.

  <Desc / Clms Page number 8>

 
 EMI8.1
 Process A- (l)
 EMI8.2
 0. s s R-12 Ri t u JL-NCHH-R HS-R--. JL i CH = CH-SR o 1} 0 R3 R3 aaaa (VI) (XIV) (iule) or its salt or its salt or its salt Reduction p S 12 ii) JL CH = CH-SR OR (IIIb) or its salt Process A- (2) Pl1 x HN x Rg-T - j HN -.- RXHNX JN CH = CH-R Dès-acylation J.

   J- CH = CH-R o r 0 N 3 R3 (V) (Va) or its salt or its salt

  <Desc / Clms Page number 9>

 
 EMI9.1
 Method A- (3)
 EMI9.2
 H2Np l HN x1 R1 1 1 ') 16 Acylation "t! J 16 16 CH = CH-R o NH = CH-R16 3 R R3 aa (Va) (V) or its reactive derivative or its salt on the amino group or its salt Method A- (4) Elimination of the R group protecting the RI) ji) -g carboxy group) j û <CH = CH-R C> ûS Nt CH = CHR15 N-CH-CH-R "-" ---------> -N'-CH = CH-R "" R3 COOH (Vb) ( Vc) or its salt or its salt Method B- (l) Reaction of prepa-rat-ion of salt - 1S. d'Hm i, S R-T-- quaternary P-T - "t N N CH = CH-S 0 CR3 R3 (IIIb) (II) or its salt or its salt

  <Desc / Clms Page number 10>

 
 EMI10.1
 Method B- (2)
 EMI10.2
 R-yS TT ") JNC = CH HS-R N CH = CH-SR o r- NC = CH> R3 R (VIlla) (XIVa) (II) or its salt or its salt or its salt Process B- (3 ) --- .- HS-Rll -fp; -. + HS-Rll J-.

   N. -CH = CH-R J -CH = CH-SR "o T o TR" R (VIb) (XIVa) (IIb) or its salt or its salt or its salt Process B- (4) 0 0 t R1 ì- 12 R1J1: t- 12 "Tt) 4 + HR! 'rrH c-1 JN - CH = CH-R" "" - JN --- Ch-CH-SR o 3 R3 R (VIa) (XIV ) (IIId) or its salt or its salt or its salt

  <Desc / Clms Page number 11>

 
 EMI11.1
 Method B- (5)
 EMI11.2
 Elimination of the protection group of the amino group p p, oS N ss CH = CH-R T 0.

   N h- CH = CH-R R3 R3 (IV) (IVa) or its salt or its salt Process B- (6) 0 tt R! -) t 15 Reduction r- = CH-R -NCH = CH-R -------- J, CH = CH-R o 0 3 R3 R Ra a (IVb) (IVc) or its salt or its salt Process C- (1) Salt preparation reaction)! 13 ammonium qua-j j] ce-i? - r \ - LL-S-R ternary n-R (IX) Ra R Rl4 a or its salt (X) or its salt Elimination of the protection group z 8> - N "ii) E \ R14 (XI) or its salt

  <Desc / Clms Page number 12>

 
 EMI12.1
 Method C- (2)
 EMI12.2
 Preparation reaction of 8. sH o --- f-s-4. ,, (3 N z - scu -, rm l (du14! 14 0'14 '14 R R R.



  (XI) (XII) 'or its salt or its salt S-S 2Z (D> ii) N N iii) (Di 14 (D 1 11; - R-.



  (XIIa) or its rSH salt. zo N el R14 b (XIa) or its salt Process C- (3) Reaction for the preparation of airmnium salt r) t r quaternary)))) H. 1 S-Sl; o 14 e 14 (xill) R R '(XIIa) or its salt or its salt

  <Desc / Clms Page number 13>

 
 EMI13.1
 l 1 l 1 3 11 12 In these formulas, R, R, Rb, R, R, R, R and Z are each as defined above, Ra is a carboxy group or a protected carboxy group; a R13 is a protection group of the mercapto group; 14 R is a lower aminoalkyl group; 14 R4 is a protected lower alkyl amino group; has a lower N, N-dialkyl aminoalkyl group; 4 R4 is a group which may be substituted by a group of 12 12 formul-S-R where R is as defined above; 4 R: is a group which may be substituted by a group of 11 11 formula'-S-R where R is as defined above; 10 X is -8- or t;

   - S- "" '0 R is a group of formula: R and-S-R where R and R are each as defined above; and R is a group of formula: -RetS-RoùR and R are each as defined above,
As regards the desired compounds (I), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih), and the starting compounds (II), (IIa ), (Irb), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc), (V), (Va), (Vb), (Vc), (VI), (VIa), (VIb) and (VIc), it should be understood that the recharged and starting compounds include the cis isomer, the trans isomer and their mixtures.

   For example, with regard to the desired compound (I), the cis isomer means a geometric isomer having the partial structure represented by the following formula:
 EMI13.2
 (where R- is as defined above) and the trans isomer
 EMI13.3
 presents the other isomer, geometric having the partial structure, represented by the following formula:

   

  <Desc / Clms Page number 14>

 
 EMI14.1
 (where Ru is as defined above)
Suitable pharmaceutically acceptable salts of the desired compounds (I) are conventional non-toxic salts and include an organic acid salt (for example acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), a mineral acid salt (e.g. hydrochloride, hydrobromide, iodhydrate, sulfate, phosphate, etc.), a salt with an amino acid (e.g. arginine, l aspartic acid, glutamic acid, etc.) and the like,
In the above and subsequent descriptions of the present invention,

   suitable illustrative examples of the various definitions which the present invention includes within its scope of protection are explained in detail as follows.



   The term "lower" is intended to mean 1 to 6 carbon atoms, unless otherwise indicated.



   The term "higher" is intended to mean 7 to 20 carbon atoms, unless otherwise indicated.



   The term "suitable acyl" and the "suitable acyl part" in the expression "acylamino" as mentioned above may include the carbamoyl group, an aliphatic acyl group and an acyl group containing an aromatic ring designated under the name of aromatic acyl, or a heterocyclic ring which is designated under the name of heterocyclic acyl,
A suitable example of this acyl group can be illustrated as follows;

   an aliphatic acyl group such as a lower or higher alkanoyl group (for example the formyl, acetyl, succinyl, hexanoyl, heptanoyl, stearoyl groups, etc.);

  <Desc / Clms Page number 15>

 a group al. lower or higher carbonyl carbonyl (for example methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); a lower or higher sulfonyl alkane group (for example methanesulfonyl, ethanesulfonyl, etc.); or the like; an aromatic acyl group such as an aroyl group (for example benzoyl, toluoyl, naphthoyl groups, etc.);

   a lower aralkanoyl group such as a lower phenylalkanoyl group (for example phenylacetyl, phenylpropionyl groups, etc.); an aryloxycarbonyl group (for example phenoxycarbonyl, naphthyloxycarbonyl, etc.); a lower aryloxyalkanoyl group (for example phenoxyacetyl, phenoxypropionyl, etc.); an arylglyoxyloyl group (for example phenyl-
 EMI15.1
 glyoxyloyl, naphthylglyoxyloyl, etc.); an arenesulfonyl group (eg benzenesulfonyl, p-toluenesulfonyl, etc.) or the like; a heterocyclic acyl group such as a heterocyclic carbonyl group (for example thenoyl, furoyie, nicotinoyl groups, etc.);

   a heterocyclic lower alkanoyl group (for example thienylacetyl, thiazolylacetyl, thiadiazolylacetyl, tetrazolylacetyl, etc. groups); a heterocyclic lower thioalkanoyl group (for example thienylthioacetyl, thiazolylthioacety-
 EMI15.2
 , isothiazolylthioacetyl, thiadiazolylthioacetyl, tetrazolylthioacetyl, etc.); a heterocyclic glyoxyloyl group (for example, thiazolyiglyoxyloye, thienylglyoxyloyl, etc.); or the like;

   where the part, heterocyclic suitable in the expression "heterocyclic carbonyl" "lower alkanoyl

  <Desc / Clms Page number 16>

 
 EMI16.1
 heterocyclic "" thioalkanoyie. heterocyclic lower "and" heterocyclic glyoxyloyie "as mentioned above mean in greater detail a saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one heteroatom such as oxygen, sulfur, nitrogen and the like.



  A specially preferable heterocyclic group can be a heterocyclic group such as a triangular to octagonal unsaturated heterocyclic group preferably pentagonal or hexagonal containing 1 to 4 nitrogen atoms, for example pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N -oxide, dihydropyridyl, pyrimidyl,
 EMI16.2
 pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1, 2, 4triazolyl, li-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, etc.), tetrazolyl (e.g. lHetrazolyl, 2H-tetrazolyl, etc., etc. ; a saturated triangular to octagonal (preferably still pentagonal or hexagonal) heteromonocyclic group containing 1 to 4 nitrogen atoms) for example the pyrrolidinyl, imidazolidinyl, piperidin, piperazinyl groups, etc. ;

   an unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atoms, for example the indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl groups, etc. ; a triangular to octagonal unsaturated heteromonocyclic group (preferably still pentagonal or hexagonal) containing 1 to 2 oxygen atoms and 1 to 3 nitrogen terminals, for example
 EMI16.3
 oxazolyl, isoxazolyl, oxadiazolyl groups (for example 1, 2, 4-oxadiazolyle, 1, 3, 4-oxadiazolyle, 1, 2, 5-oxadiazolyl, etc.), etc. ;

   a saturated triangular to octagonal (preferably still pentagonal or hexagonal) heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example the morpholinyl, sydnonyl groups, etc; an unsaturated condensed heterocyclic group containing 1 to 2

  <Desc / Clms Page number 17>

 oxygen atoms and 1 to 3 nitrogen atoms, for example benzoxazolyl, benzoxadiazolyl, etc. ;

   a triangular to oc- heteromonocyclic unsaturated group
 EMI17.1
 togonal (preferably still pentagonal or hexagonal) containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms 1 for example the thiazolyl, isothiazolyl, thiadiazolyl groups (for example 1, 2, 3-thiadiazolyl, 1, 2 , 4-thiadiazolyle, 1, 3, 4-thiadiazolyle, 1, 2, 5-thiadiazolyle, etc.), the dihydrothiazinyl group, etc .; a saturated triangular to octagonal (preferably still pentagonal or hexagonal) heteromonocyclic group containing
 EMI17.2
 with 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example the thiazolidinyl group, etc. ;

   a triangular to octagonal unsaturated heteromonocyclic group (preferably still pentagonal or hexagonal)
 EMI17.3
 having 1 to 2 sulfur atoms / for example thienyl, dihydrodithiinyl, dihydrodithionyl groups, etc. ; an unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example benzothiazolyl, benzothiadiazolyl groups, etc. ; a triangular to octagonal unsaturated heteromonocyclic group (preferably still pentagonal to hexagonal) containing 1 oxygen atom for example the furyl group, etc;

   a triangular to octagonal unsaturated heteromonocyclic group (preferably still pentagonal or hexagonal) containing 1 oxygen atom and 1 to 2 sulfur atoms, for example the dihydrooxathiinyl group, etc. a condensed heterocyclic unsaturated group containing 1 to 2 sulfur atoms , for example benzothienyl, benzodithiinyl, etc. ; an unsaturated condensed heterocyclic group containing one oxygen atom and 1 to 2 sulfur atoms., for example the benzoxathiinyl group, etc. and the like,
Regarding the heterocyclic group like

  <Desc / Clms Page number 18>

 mentioned above, the following points should be noted.

   Thus, in the case where the heterocyclic group is specifically the thiazolyl or thiadiazolyl group having an amino group or an amino group protected as a substituent in its molecule, this thiazolyl or thiadiazolyl group comprises tautomeric isomers which are caused by the specific behavior of the thiazole or thiadiazole nucleus.

   Thus, for example, the thiazolyl or thiadiazolyl protected amino or amino group is represented by the formula:
 EMI18.1
 (where R is the amino group or a protected amino group and Ya is CH or N), and. in the case where the group of formula (A) has the formula:
 EMI18.2
   (where rozet Ya are each as defined above), this group of formula (A ') can also be represented by a variant by its tautomer formula:
 EMI18.3
 (where Ya is as defined, above and zest the group
 EMI18.4
 imino or a protected imino group)
Thus, the two groups of formulas (A ') and (A ") are in a state of tautomeric equilibrium which can be represented by the following equilibrium;

   

  <Desc / Clms Page number 19>

 
 EMI19.1
   (where R, YaetR are each as defined above).



   These types of tautomerism between the 2-aminothiazole or thiadiazole compounds and the 2-iminothiazoline or thiadiazoline compounds as indicated above are well known in the art and it is obvious to a person skilled in the art that the two tautomeric isomers are in equilibrium and are in a mutually transformable state, tt / accordingly, it should be understood that these isomers are included in the same category of compound per se. Consequently, the two tautomeric forms are clearly included in the scope of protection of the present invention.

   In the present description, the desired and starting compounds comprising the group of these tautomeric isomers are represented using one of the expressions, that is to say the 2amino (or protected amino) thiazolyl or thiadiazolyl group and the formula:
 EMI19.2
 for convenience only.



   The acyl part as indicated above may have 1 to 10 suitable substituents, which are the same or different such as a lower alkyl group (eg methyl, ethyl, etc.); lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.); lower alkyl thio (e.g. methylthio, ethylthio, etc.);

  <Desc / Clms Page number 20>

 lower alkyl amino (for example methylamino, etc.) i lower cycloalkyl (for example cyclopentyle, cyclohe-
 EMI20.1
 xyle, etc.); lower cycloalkenyl (e.g. cyclohexenyl, cyclohexadienyl, etc.); halogen; an amino group; a protected amino group; a hydroxy group; a protected hydroxy group; a cyano group, a nitro group; a carboxy group;

   a protected carboxy group; a sulfo group; a sulfamoyl group, an imino group; an oxo group; a lower aminoalkyl group (for example aminomethyl, aminoethyl, etc.); the carbamoyloxy group;
 EMI20.2
 7 7 a group of formula: = N-OR where R is hydrogen, a lower alkyl group (for example methyl, ethyl, propyl, etc.), lower alkenyl (for example vinyl, allyl, 2-butenyl groups, etc.), lower alkynyl (e.g. ethynyl, 2-
 EMI20.3
 propynylei etc.), lower cycloalkyl (for example cyclopropyl, cyclohexyl, etc.), lower aralkyl such as a lower phenylalkyl group (for example benzyl, phenethyl groups, etc.), lower carboxyalkyl (for example carboxymethyl groups ,

     l-carboxyethyl, carboxypropyl, carboxybutyl, etc.), protected carboxy lower alkyl, lower hydroxyalkyl (e.g. hydroxymethyl, hydroxyethyl groups, etc.), lower carboxyalkenyl (e.g. carboxyvinyl, carboxyallyl, carboxy2-butenyl groups, etc.) , carboxy protected lower alkenyl, pyridyl lower alkyl (by
 EMI20.4
 example (2-pyridyl) methyl, (3-pyridyl) methyl, etc,), and an lower alkyl group. ur pyridinio lower alkyl (e.g. (.l-methyl-2-pyridinio) methyl, (l-methyl-3-pyridinio) methyl, etc,), or the like,
Under this. report, when the party, acyle has a group

  <Desc / Clms Page number 21>

 
 EMI21.1
 7 7 pe of formula;

   = N-OR, whereR. is as defined above, L as one or more substituents, there are geometric isomers (syn and anti isomers) due to the presence of double bonds. For example, the syn isomer signifies
 EMI21.2
 fie a geometric isomer having the group of formula: - C-CO-)) -N-On and the corresponding anti-isomer means the other geometric isomer having the group of formula: - C-CO-
 EMI21.3
 "- 0-N
The suitable "protected amino" group can comprise an acylamino group, where the "acyl" part can be designated as being one of those as mentioned above, phosphonoamino, amino protected phosphono, lower aralkyl amino such as the benzylamino group, phenethylamino, tritylamino; and the like.



   The suitable "protected phosphono group" can include an esterified phosphono group where the ester can be one of those such as the lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, ester isopropyl, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hydroxy ester, etc.) or the like.



     The suitable "protected hydroxy group" can include an acyloxy group where the "acyl" part can be designated as one of those as mentioned above.



   The suitable "protected carboxy group" and the suitable "protected carboxy part" in the expression "lower alkyl protected carboxy" and "lower alkenyl protected carboxy" may include the esterified carboxy group where the "esterified carboxy" may be designated as being one of those as mentioned above,
Suitable examples of the ester part

  <Desc / Clms Page number 22>

 of an esterified carboxy group can be one of those such as a lower alkyl ester (for example methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester ,
 EMI22.1
 t-butyl ester, pentyl ester, hexyl ester, l-cyclopropylethyl ester, etc.), which may have at least one suitable substituent,

   for example a lower alkyoyl oxyalkyl ester [for example acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, ester 1 (or 2) - acetoxyethanyl, ester l (or 2 or 3) -acetoxypropyl, ester l (or 2 or 3 or 4) -acetoxybutyl, ester l (or 2) propionyloxyethyl, ester l (or 2 or 3) -propionyloxypropylic, ester l (or 2) -butyryloxyethyl, ester l (or 2) - isobutyryloxyethyl, ester l (or 2) -pivaloyloxyethyl, ester l (or 2) -hexanoyloxyethyl, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, ester 3,

     3 dimethyl- butyryloxymethyl, the l (or 2) -pentanoyloxyethyl ester, etc.], a lower sulfonylalkyl ester lower alkane (for example 2 mesylethyl ester, etc.), a lower mono (or di or tri) -haloalkyl ester (for example 2-iodoethyl ester, ester 2, 2, 2-trichloroethyl, etc.), a lower carbonyloxyalkyl lower alkoxy ester (for example methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, ester
 EMI22.2
 2-methoxycarbonyloxyethyl, l-ethoxycarbonyl xyethyl ester, l-isopropoxycarbonyloxyethyl ester, etc.), a lower phthalidylidenealkyl ester, or a (5-lower alkyl-2-oxo-l, 3-dioxol-4-yl ester ) lower alkyl [e.g. ester (5-methyl-2-Qxo-1,3-dio-xol-4-yl)

   methyl, (5-ethyl-2-oxo-1,3-dioxo-4yl) methyl ester, (5-propyl-2-oxo-1,3-diox-4-yl) ethyl ester, etc, ; a lower alkenyl ester (by

  <Desc / Clms Page number 23>

 example vinyl ester, allyl ester, etc.); a lower alkynyl ester (e.g. ethyl ester, propynyl ester, etc.); a lower aralkyl ester which may have at least one suitable substituent (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester , bis (methoxyphenyl) methyl ester, 3, 4-dimethoxybenzyl ester, 4 - hydroxy-3, 5-di-t-butylbenzyl ester, etc.);

   an aryl ester which may have at least one suitable substituent (for example phenyl ester, chlorophenyl ester 4, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, l 'cumenyl ester, etc.); a phthalidyl ester; and the like.



   Preferable examples of the esterified carboxy group as mentioned above may include a lower carbonyl alkoxy group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl,
 EMI23.1
 pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, l-cyclopropylethoxycarbonyl, etc.), and lower phenylalkoxy carbonyl (e.g. benzyloxycarbonyl, benzhydryloxycarbonyl, etc.), which may have a nitro group.



  A suitable "organic group" may include a lower alkyl group which may have one or more suitable substituents, A suitable "lower alkyl group" may include a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or the like.



   The above-mentioned "lower alkyl group" may have 1 to 3 suitable substituents such as amino, hydroxy, lower dialkyl amino (eg dimethylamino, detethylamino, etc.), morpholino,

  <Desc / Clms Page number 24>

   piperazinyl substituted by a lower alkyl group (e.g. methylpiperazinyl, etc.), piperazinylcarbonyl substituted by lower alkyl (e.g. methylpiperazinylcarbonyl, etc.), formimidoylamino or the like.



   The suitable "mercapto group protecting group" may include an aromatic acyl group such as an aroyl group (e.g. benzoyl, toluoyl, etc.) and the like.



     Suitable "lower aminoalkyl group" may include aminomethyl, aminoethyl, aminopropyl, and the like,
The suitable "lower alkyl protected amino group" may include a phthalimidoethyl, phthalimidopropyl, and the like,
Suitable "N, N-lower dialkyl lower aminoalkyl" group may include N, N dimethylaminoethyl, N, N-dimethylaminopropyl, and the like.



   Suitable "halogen" can include chlorine, bromine, fluorine and iodine.



   Suitable "acid residue" may include an acyloxy group, azido, halogen and the like, where the acyl part in the term "acyloxy" and the halogen can be referred to as one of those as shown above by way of example.



     A suitable "lower alkylene group" may include a straight or branched chain alkylene group having 1 to 6 carbon atoms, such as a methylene, ethylene, trimethylene, propylene, butylene group or the like,
 EMI24.1
 444 Suitable R, Ra and R. groups may b include the acid residues mentioned above, etc.



   A group "lower carboxyalkyl", "lower pyridylalkoxy imino", "lower alkyl pyridinio lower alkoxy imino" "carboxy protected lower alkoxy imi-

  <Desc / Clms Page number 25>

   no "." carboxy protected lower alkenyl oxyimino "," lower carboxyalkoxy i. suitable "mino" and "lower carboxyalkenyl oxyimino" can be designated as one of those as mentioned above.



   Preferred exemplary embodiments of the compounds
 EMI25.1
 sought (I) are as follows,
The preferred embodiment of R is the amino group; amino lower aminothiazolylalkanoyl having an imino lower alkoxy group; amino lower aminothiazolylalkanoyl having a lower alkenyl oxyimino group; an amino lower aminothiazolylalkanoyl group having an oxyimino lower alkynyl group; amino lower aminothiazolylalkanoyl having an imino lower carboxyalkoxy group; amino lower aminothiazolylalkanoyl having an imino lower alkoxy protected carboxy group; more preferably lower alkoxy lower carbonylalkoxy imino-2aminothiazolylacetamido and lower aralkoxy lower carbonylalkoxy imino-27aminothiazolylacetamido;

   amino lower aminothiazolylalkanoyl having an imino lower hydroxyalkoxy group; amino lower aminothiazolylalkanoyl having a lower carboxyalkenyl oxyimino group; amino lower aminothiazolylalkanoyl having a carboxy-protected lower alkenyl oxyimino group, more preferably amino amino-lower alkanoyl having a lower aralkoxy carbonylalkenyl lower oxyimino group; amino lower aminothiazolylalkanoyl having an imino lower pyridylalkoxy group; amino lower aminothiazolylalkanoyl having a 1- (lower alkyl) pyridinioalkoxy lower imino group;

   amino protected lower thiazolylalcacanoyl amino

  <Desc / Clms Page number 26>

 having an imino lower alkoxy-group, preferably amino lower acylaminothiazolylalkanoyl having an imino lower alkoxy group, or lower aralkyl amino-thiazolylalkanoyl lower amino having an alkoxy-lower group i. ino; amino protected thiazolylalkanoyl lower amino having a lower alkynyl oxyimino group, preferably aralkyl lower aminothiazolylalkanoyl lower amino having a lower alkynyl oxyimino group;

   amino protected lower thiazolylalkanoyl amino having a carboxy group protected lower alkoxy imino, preferably acylaminothiazolylalkanoyl lower amino having a lower alkoxy group lower carbonylalkoxy imino, or lower aralkyl aminothiazolylalkanoyl lower amino having a lower aralkoxy group lower carbonylalkoxy imino; amino protected lower thiazolylalkanoyl amino having a carboxy protected lower alkenyl oxyimino group, preferably aralkyl-lower aminothiazolylalkanoyl lower amino having a lower aralkoxy group carbonyl-lower alkenyl oxyimino;

   a lower amino thiazolylalkanoyl protected amino group having a lower imino pyridyl alkoxy group, preferably a lower amino aminothiazolylalkanoyl lower alkanoyl group having a lower imino pyridylalkoxy group; amino lower aminothiadiazolylalkanoyl having an imino lower alkoxy group; amino lower aminothiadiazolylalkanoyl having a lower alkenyl oxyimino group; amino lower aminothiadiazolylalkanoyl having an oxyimino lower alkynyl group; aminothiadiazolylalkanoyl lower amino having
 EMI26.1
 an imino hydroxyalkoxy-lower group; aminothia, lower diazolylalkanoyl aminq having

  <Desc / Clms Page number 27>

 an imino lower alkoxy carboxy group;

   amino protected thiadiazolylalkanoyl lower amino having an imino lower alkoxy group, more preferably phosphonoaminothiadiazolylalkanoyl lower amino having an imino lower alkoxy group; amino lower thiazolylalkanoyl having an imino lower carboxyalkoxy group; amino lower thiadiazolylalkanoyl having an imino lower alkoxy group; lower amino isothiazolylthioalkanoyl substituted by hydrogen and a carboxy group; an amino-substituted alkanoyl group substituted by aminothiazolyihydroxy; amino dihydrooxathiinylalkanoyl having an imino lower alkoxy group; amino lower hydroxyaralkanoyl having an imino lower alkoxy group; amino lower aminopyrimidinylalkanoyl having an oxyimino lower alkenyl group;

   amino lower aminopyridylalkanoyl having an imino lower alkoxy group; amino protected lower pyridylalkanoyl amino having a lower imino alkoxy group, preferably a lower alkanoyl aminopyridylalkanoyl lower amino group having a lower alkoxy imino group; amino lower aminothiazolylalkanoyl having an imino lower carboxycycloalkoxy group;

   amino protected lower thiazolylalkanoyl amino having a carboxy group protected lower cycloalkoxy imino, preferably aralkyl lower aminothiazolylalkanoyl lower amino having a lower alkoxy group carbonyl-
 EMI27.1
 irqïno lower cycloalkoxy, and 9R, is a group with the formula

  <Desc / Clms Page number 28>

 
 EMI28.1
 
 EMI28.2
 2 where R2 is lower alkyl, lower aminoalkyl, lower hydroxyalkyl lower carboxyalkyl, lower dialkyl lower aminoalkyl, morpholinoalkyl, lower alkyl lower piperazinylalkyl, lower alkyl lower piperazinylcarbonylalkyl lower or formimidoylaminoalkyl; X is CH or N;

   Z is halogen; and
 EMI28.3
 Y is CH or N and n is 0; or (2 Y is N - R and n is 1, or a group having the formula: - AO (R), where R10 is a lower alkyl group and A is a lower alkylene group.



   The methods for preparing the desired compounds of the present invention are explained in detail in the following.



  Method 1:
The desired compound (Ib) or its salt can be prepared by subjecting the compound (Ia) or its reactive derivative on the amino group or its salt to an acylation reaction.



   A suitable reactive derivative of the amino group of the compound (Ia) may comprise an imino derivative of the Schiff base type or its tautomeric isomer of the enamine type formed by the reaction of the compound (Ia) with a carbonyl compound such as an aldehyde, a ketone or the like; a silyl derivative formed by the reaction of the compound (la) with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide or the like; a derivative formed by reaction of the compound (la) with trichloride

  <Desc / Clms Page number 29>

 phosphorus or phosgene and the like.



   A suitable acylating agent for use in the present acylating reaction may include a conventional agent and may be represented by the formula; R5-OH (VII) (where R5 is an acyl group) or its reactive derivative or its salt.



   A suitable salt of the compounds (Ia) and (VII) can comprise an addition salt with acids such as an organic acid salt (for example acetate, maleate, tartrate, 111 ethanesulfonate, benzenesulfonate, toluenesulfonate, etc.) or a mineral acid salt (for example hydrochloride, hydrobromide, sulfate, phosphate, etc.);

   a metal salt (for example the sodium salt, the potassium salt, the calcium salt, the magnesium salt, etc.); an ammonium salt, an organic amine salt (for example the triethylamine salt, the dicyochehexylamine salt, etc.) and the like,
A suitable reactive derivative of the compound (VII) can include an acid halide, an acid anhydride, an activated amide, an activated ester and the like.

   The suitable example can be an acid chloride, an acid azothhydride, an acid anhydride mixed with an acid such as a substituted phosphoric acid (for example a dialkylphosphoric acid, phenylphosphoric acid, diphenylphospboric acid , dibenzylphosphoric acid, a halogenated phosphoric acid, etc.), a dialkylphophorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, an alkylcarbonic acid, a carboxylic acid ali-
 EMI29.1
 phatic (eg pivalic acid, pentanolic acid, isopentanoic acid, 2ethylbutyric acid or trichloroacetic acid, etc.) or a? aromatic carboxylic acid (for example benzoic acid etc.), a symetic acid anhydride, an amide activated with imidazole,

   4-substituted imidazole, dimethylpyrazole, triazole, or tetrazole on an activated ester (e.g.

  <Desc / Clms Page number 30>

 
 EMI30.1
 cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester [CH) N = CH-], glycerol ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, l trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester,
 EMI30.2
 p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8quinolyl thioester, etc.), or an ester with an N-hydroxylated compound (for example N, N-dimethylhydroxylamine,

   hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, Nhydroxyphthalimide, l-hydroxy- & -chloro-1Henzotriazole, etc.), and the like. These reactive derivatives can
 EMI30.3
 re optional be chosen from among them according to the kind of compound (VII) to be used,
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvents can also be used following a mixture with water.



   When the compound (VII) is used in the form of free acid or in its salt form in the reaction, the reaction is preferably carried out in the presence of an agent
 EMI30.4
 conventional condensation such as N, N'-dicyclohexylcar bodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'- (4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide; the ; N-.ethyl-N'-.

   (. 3-. Diir, ethylam. Rnopropyl) carbodiimide, N, N-carbonylbis- (2-methylimidazole); la, pentamethylenetene-N-cyclohexylimi. born   ; diphenylketene-N-cyclohexylimine ethoxyacetylene; 1-alkoxy-1-chloroethylene; a

  <Desc / Clms Page number 31>

 trialkyl phosphite, ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphorylated chlorine); phosphorus trichloride; chloride
 EMI31.1
 thionyl, oxalyl chloride; triphenylphosphine; a 2-ethyl-7-hydroxybenzisoxazolum salt; the intramolecular salt of 2-ethyl-5- (m-sulfophenyl) isoxazo-hydroxide; lel- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole;

   a so-called Vilsmeier reagent prepared by the reaction of ladimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc. ; or the like.



   The reaction can also be carried out in the presence of an organic or inorganic base such as an alkali metal bicarbonate, a lower trialkyl amine, pyridine, an N-lower alkyl morpholine, an N, N-dialkyl lower benzylamine or the like. The reaction temperature is not critical, and the reaction is usually carried out with cooling or. Room temperature.



   In the present reaction, a syn isomer of the desired compound (Ib) can preferably be obtained by carrying out the present reaction of the compound (Ia) with the corresponding syn isomer of the starting compound (VII).



  Method 2:
The desired compound (I) or its salt can be prepared by subjecting the compound (II) or its salt to a reaction for removing the protecting group from the carboxy group.



   A suitable salt of the compound (II) can be designated as being the salt indicated by way of example for the compound (I).



   In the present elimination reaction. all the conventional methods used in the reaction for removing the protecting group from the carboxy group, for example hydrolysis, reduction, elimination using a Lewis acid, etc., are applicable. When the carboxy group protection group is an ester, it can be

  <Desc / Clms Page number 32>

 eliminated by hydrolysis or elimination using a Lewis acid. The hydrolysis is preferably carried out in the presence of a base or an acid. A suitable base can include a conventional mineral base and an organic base.



   A suitable acid can include an organic acid (e.g. formic acid, acetic acid, propionic acid, etc.) and a mineral acid (e.g. hydrochloric acid, hydrobromic acid, acid sulfuric, etc.).



   The present hydrolysis is usually carried out in an organic solvent) in water or in a mixed solvent.



   The reaction temperature is not critical, and can be suitably selected depending on the kind of carboxy protecting group and the removal process.



   Removal using a Lewis acid is preferable for removing a substituted or unsubstituted lower aralkyl ester and is accomplished by reacting the compound (II) or its salt with a Lewis acid such as a boron trihalide ( for example boron trichloride, boron trifluoride, etc.), a titanium tetrahalide (for example titanium tetrachloride, titanium tetrabromide, etc.), a tin tetrahalide (for example tin tetrachloride, tin tetrabromide, etc.), an aluminum halide (eg aluminum chloride, aluminum bromide, etc.), a trihaloacetic acid (eg trichlor- acetic, trifluoroacetic acid, etc.) or the like.



   This elimination reaction is preferably carried out in the presence of cation capture agents (for example anisol, phenol, etc.) and is usually carried out in a solvent such as a nitroalkane (for example ni-. tromethane, nitoethane, etc.), an alkyl halide-

  <Desc / Clms Page number 33>

 ne (for example methylene chloride, ethylene chloride, etc.), diethyl ether: that, carbon sulfide or any other solvent which does not adversely affect the reaction. These solvents can be used in the form of a mixture.



   Reductive removal may preferably be applied to remove the protecting group from a lower haloalkyl ester (e.g. 2-iodoethyl, 2,2,2-trichloroethyl, etc.), a lower aralkyl ester (e.g. benzyl , etc.) or the like.

   The reduction method applicable for the elimination reaction may include, for example) reduction using a combination of a metal (eg zinc, zinc amalgam, etc.), or a compound salt chromium (for example chromous chloride, chromous acetate, etc.), and an organic or mineral acid (for example acetic acid, propionic acid hydrochloric acid etc,); a conventional catalytic reduction in the presence of a conventional metallic catalyst (for example palladium-carbon, Raney nickel, etc.).



   The reaction temperature is not critical, and the reaction is usually carried out by cooling, at room temperature or by heating.



   The present carboxy group protecting group removal reaction includes, within its protection domain, cases where another protected carboxy group, acylamino and / or protected amino groups are transformed into corresponding free and / or free amino groups during the reaction or the post-processing step of the present process.



  Method 3;
The desired compound (I) or its salt can be prepared by subjecting the compound (III) or its salt to a preparative reaction. one of quaternary ammonium salt,
Salt was suitable. b. the compound (III) can be de-.

  <Desc / Clms Page number 34>

 
 EMI34.1
 signed as one of those as provided by way of examples for compound (P).



   The agent to be used in the present reaction for the preparation of quaternary ammonium salt may comprise a conventional agent such as a mono (or di) lower alkyl sulphate (for example dimethyl sulphate, etc.), a lower alkane lower alkyl sulfonate (e.g. methyl methanesulfonate, etc.), lower haloalkane (e.g. bromomethane, iodomethane, iodoethane, etc.), protected lower alkyl carboxy halide (e.g. bromoacetate benzhydryl, etc.), lower aminoalkyl halide (e.g., aminoethyl bromide, aminoethyl iodide, aminopropyl bromide, aminopropyl iodide, etc.), halide lower hydroxyalkyl (for example 2-hydroxyethyl bromide, 2-hydroxyethyl iodide, etc.),

   a lower aminoalkyl lower dialkyl halide (e.g. 2-N bromide, N-dime thylaminoethyl, 2-N iodide, N-dimethylaminoethyl, 3-N bromide, N-dimethylaminopropyl, iodide 3N, N-dimethylaminopropyl, etc.), a lower morpholinoalkyl halide (e.g. 2-morpholinoethyl bromide, 2-morpholinoethyl iodide, etc.), a halogen-
 EMI34.2
 lower alkyl piperazinyl lower alkyl nure (e.g. 3- (4-methyl-piperazinyl) propyl bromide, 3- (4-methyl-1-piperazinyl) propyl iodide, etc.);

   a lower alkyl piperazinylcarbonylalkyl halide (e.g. 1-methyl-4-piperazinylcarbonylmethyl bromide, 1-methyl-4-piperazinylcar- iodide
 EMI34.3
 bonylmêthyle, etc,), trifluoromëth. at. (2,2-dimethyl-1,3-dioxolan-. 4-yl) methyl nesulfonate or the like, When the lower alkyl ester of an acid is used as the agent, the reaction is usually carried out in a solvent such as water , acetone, tetrahydrofura, ne, ethanol, ether, din) ethylfQrmamrde or all-

  <Desc / Clms Page number 35>

 be a solvent which does not adversely influence the reaction.



   The present reaction is preferably carried out in the presence of a conventional base such as an inorganic base or an organic base.



   The reaction temperature is not critical and the reaction is usually carried out at a temperature from cooling to heating at about the boiling point of the solvent.



   Method 4:
The desired compound (l'd) or its salt can be prepared by subjecting the compound (le) or its salt to a reaction for removing the protecting group from the amino group.



   A suitable salt of the compound (1c) can be indicated as the example salt for the compound (I).



   The elimination reaction is carried out according to a conventional method such as hydrolysis, reduction, a method of treating the compound (Ic) where the protected amino part is an acylamino group with an iminohalogenation agent, an agent for iminoetherrification and then, if necessary, by hydrolyzing the resulting product; or the like. The hydrolysis may include a process using an acid or a base or hydrazine and the like.

   These processes can be chosen according to the kind of protection groups to be eliminated,
Among these methods, hydrolysis using an acid is one of the most common and preferable methods for removing protective groups such as an unsubstituted Qu-substituted alkoxycarbonyl group e.g. t-pentyloxycarbonyl, a lower alkanoyl group (e.g. formyl , acetyl, etc.,), cycloalkoxycarbonyl, unsubstituted aralkoxycarbonyl Qu unsubstituted, aralkyl (e.g. trityl), substituted phenylthio, aralkylidene substi-

  <Desc / Clms Page number 36>

 killed, substituted alkylidene, cycloalkyli. substituted dene or the like.

   A suitable acid includes an organic or mineral acid, such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and the very suitable acid is an acid which can easily be removed from the reaction mixture in a conventional manner such as distillation under reduced pressure, for example formic acid, trifluoroacetic acid, hydrochloric acid etc. The acids can be chosen according to the kind of protection group to be eliminated. When the elimination reaction is carried out with an acid, it can be carried out in the presence or in the absence of a solvent. A suitable solvent includes water, a conventional organic solvent or a mixture thereof.



   The elimination reaction using trifluoroacetic acid can be carried out in the presence of anisol.



  Hydrolysis using hydrazine is commonly applied to remove a protective group from the phthaloyl or succinyl amino group.



   Base removal is used to remove an acyl group such as the trifluoroacetyl group.



  A suitable base can include a mineral base and an organic base.



   Reduction removal is generally applied to remove the protecting group, for example a haloalkoxycarbonyl group (for example trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (for example benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc. .

   A suitable reduction may include, for example, a reduction with an alkali metal borohydride (for example sodium borohydride, etc.), a reduction with a combination of a metal (for example tin, zinc, iron , etc, or this metal with a metal salt compound (e.g. chloru-

  <Desc / Clms Page number 37>

 re chromous, chromous acetate etc.) and an organic or mineral acid (for example acetic acid, proionic acid, hydrochloric acid, etc.); and catalytic reduction. A suitable catalyst includes a conventional catalyst. for example, Raney nickel, platinum oxide, palladium-carbon and the like,
Among the protecting groups, the acyl group can generally be removed by hydrolysis.

   Special-
 EMI37.1
 a halogen-substituted alkoxycarbonyl group, enee and the 8-quinolyloxycarbonyl group are usually removed by treatment with a heavy metal such as copper, zinc or the like.



   Among the protecting groups, the acyl group can also be removed by treatment with an iminohalogenating agent (for example phosphorus oxychloride, etc.) and an iminoetherification agent such as a lower alkanol (for example methanol , ethanol, etc.) if that is the case. necessary, followed by hydrolysis.



   The reaction temperature is not critical, and may conveniently be selected depending on the kind of amino group protecting group and the removal method as mentioned above and the reaction is preferably carried out under moderate conditions such as while cooling or at a slightly high temperature,
The present invention includes, in its field of protection, the cases where another protected amino group, protected hydroxy and / or protected carboxy are transformed into corresponding free amino, free hydroxy and / or carboxy groups during the reaction or the post-processing step of the present process.



  Method 5;
The desired compound (tuff) or its salt can be prepared by reacting the compound (le) or its salt with a lower alkylating agent.



   A suitable salt of the compound (le) can be

  <Desc / Clms Page number 38>

 indicated as one of those as provided by way of examples for compound (j).



   The lower alkylating agent to be used in the present alkylation reaction may include a conventional agent such as mono (or di) lower alkyl sulfate (e.g. dimethyl sulfate etc.), a lower alkane sulfonate d lower alkyl (e.g. methyl methanesulfonate, etc.), lower haloalkane (e.g. bromomethane, iodomethane, iodoethane, etc.) or the like.



   When a lower alkyl ester of an acid is used as the lower alkylating agent, the reaction is usually carried out in a solvent such as water, acetone, tetrahydrofuran, ethanol, ether, dimethylformamide or any other solvent which does not adversely influence the reaction.



   The present reaction is preferably carried out in the presence of a conventional base such as an inorganic base or an organic base.



   The reaction temperature is not critical and the reaction is usually carried out at a temperature from cooling to heating approximately around the boiling point of the solvent.



  Method 6:
The compound (Ih) or its salt can be prepared by subjecting the compound (Ig) or its salt to a reaction for removing the protecting group from the carboxy group.



   The present reaction can be carried out in a similar manner to that of method 2 mentioned above.



   The present carboxy group protecting group elimination reaction includes, in its protection domain, cases where the protected acylamino and / or amino groups are transformed into corresponding amino groups during the reaction or step, post -treatment of

  <Desc / Clms Page number 39>

 
 EMI39.1
 present process.



  Method 7:
The desired compound (I) or its salt can be prepared by reacting the compound (VIII) or its salt with the compound (XIVa) or its salt,
A suitable salt of the compound (VIII) may be indicated as one of those provided as examples for the compound (I).



   The present reaction can be carried out in a similar manner to that of process A-, (1) -1) as mentioned below.



  Method 8:
The desired compound (I) or its salt can be prepared by reacting the compound (etc) or its salt with the compound (XIVa) or its salt.



   A suitable salt of the compound (VIc) can be indicated as being one of those provided by way of examples for the compound (1),
The present reaction can be carried out in a similar manner to that of process A- (1) -i) as mentioned below.



   The present reaction includes within its protective domain the case where the lower aminoalkyl group resulting for R is transformed into the formimidoyiamino-lower alkyl group, in a conventional manner.



   The present invention includes, in its field of protection, the cases where one type of tautomeric isomer is transformed into another type of isomer during the reaction and / or the post-treatment stage of each process.



   The desired compound (I) can be transformed into its pharmaceutically acceptable salt as mentioned previously by a conventional method.



     The processes for preparing the starting compounds of the present invention are explained in detail in the following,

  <Desc / Clms Page number 40>

 
 EMI40.1
 Process A- (1) i): (VI) + (XIV) (IrIc) The desired compound (IIIC) or its salt can be prepared by reacting the compound (VI) or its salt with the compound (XIV) or its salt.



   A suitable salt of the compound (VI) can be indicated as being one of those provided by way of examples for the compound (I),
A suitable salt of the compound (XIV) can include an alkali metal salt (e.g. sodium salt, potassium salt, etc.).



   The present reaction can be carried out in a solvent such as water, a phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethylsulfoxide, or any other organic solvent which does not adversely affect the reaction, preferably in solvents having strong polarities.



  Among the solvents, hydrophilic solvents can be used in admixture with water. The reaction is preferably carried out in an approximately neutral medium. When the compound (VI) is used in free form, the reaction is preferably carried out in the presence of a base, for example an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate, a alkali metal bicarbonate, an organic base such as trialkylamine and the like, The reaction temperature is not critical and the reaction is usually carried out at room temperature, warming slightly or strongly.

   The present reaction is preferably carried out in the presence of an alkali metal halide (for example the iodide of its dium, potassium iodide, etc.). an alkali metal thiocyanate (for example sodium thiocyanate, potassium thiocyanate, etc.), etc.,

  <Desc / Clms Page number 41>

   ii): (IIIc) # (IIIb)
The compound (rib) or its salt can be prepaid by reducing the compound (IIIc) or its salt.



   This reduction can be achieved by
 EMI41.1
 a conventional method which is applied to the transformation ot of-S-into-S-, for example, using phosphorus trichloride, a combination of stannous chloride and acetyl chloride, a combination of an alkali metal iodide (e.g. sodium iodide, etc.) and trihaloacetic anhydride, (e.g. trifluoroacetic anhydride, etc.) and the like.



   This reduction is usually made
 EMI41.2
 s in a solvent such as acetone, dioxane, acetonitrile, dimethylformamide, benzene, hexane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, acetate d ethyl or any other solvent which does not adversely influence the reaction.



   The reaction temperature is not critical and the reaction is usually carried out with cooling or at room temperature.
 EMI41.3
 



  Process A- (2) (V) (Va)
Compound (Va) or its salt can be prepared by subjecting compound (V) or its salt to a deacylation reaction.



   The present deacylation reaction is carried out according to a conventional process such as hydrolysis, reduction, deacylation using a Lewis acid the deacylation process by reacting the compound (V) with an iminohalogenation agent and then with a iminoetherrification agent and / if necessary, subjecting the resulting compound to hydrolysis, or the like,
Among these processes, "the deacylation process

  <Desc / Clms Page number 42>

 by reacting the compound (V) with an iminohalogenation agent and then with an iminoetherification agent and. if necessary, subjecting the resulting compound to hydrolysis "is a preferable process.



   A suitable iminohalogenating agent can include a phosphorus halide (e.g. phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, etc.), phosphorus oxychloride, thionyl chloride, phosgene and the like. The reaction temperature is not critical, and the reaction is usually carried out with cooling or at room temperature,
In the case where the compound (V) has a free carboxy group at position 4, this reaction is preferably carried out by protecting the free carboxy group with a silylating agent (for example trimethylsilyl chloride, trimethylsilylacetamide, bis ( trimethylsilyl) acetamide, etc.) before this reaction.



   A suitable iminoetherification agent reacted with the reaction product thus obtained may include an alcohol, a metal alkylate and the like.



  A suitable alcohol can include an alkanol (e.g. methanol, ethanol, propanol, isopropanol, butanol, t-butanol, 1, 3-butandiol, etc.) which can be substituted by an alkoxy group (e.g. methoxy, methoxy, propoxy, isopropoxy, butoxy, etc.). A suitable metal alkylate can include an alkali metal alkylate (e.g. sodium alkylate, potassium alkylate, etc.), alkaline earth metal alkylate (e.g. calcium alkylate, barium alkylate etc,) , and the like.

   The reaction temperature is not critical and the reaction is usually carried out with cooling or at room temperature,
The product thus obtained is, if necessary, subjected to: a. hydrolysis, hydrolysis can easily

  <Desc / Clms Page number 43>

 be carried out by pouring the reaction mixture obtained above into water, but a hydrophilic solvent (for example methanol, ethanol, etc.), a base (for example an alca metal bicarbonate) can be added beforehand -
 EMI43.1
 flax, trialkylamine, etc.) or an acid (eg. Z ar exeriplilute hydrochloric acid, acetic acid, etc.), in water.



   The reaction temperature is not critical and can be suitably selected depending on the kind of amino group protecting group and the removal method as mentioned above, and the present reaction is preferably carried out under moderate conditions such as '' while cooling, at room temperature or a slightly higher temperature,
The present invention includes, in its field of protection / the case where the protected carboxy group is transformed into a free carboxy group according to the reaction conditions and the kinds of protection groups during the reaction or in the post-treatment. Hydrolysis can include a process using an acid or a base and the like. These methods can be chosen according to the kind of acyl groups to be eliminated.



   A suitable acid can include an organic or inorganic acid, for example formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like.



  The acid suitable for the reaction can be chosen according to the kind of acid group to be eliminated. When the deacylation reaction is carried out with the acid, it can be carried out in the presence or in the absence of a solvent, A suitable solvent can comprise an organic solvent, water or a mixed solvent, When the acid trifluoroacetic is used, the deacylation reaction can preferably be carried out in the presence of anisol.



   A suitable base may include, for example

  <Desc / Clms Page number 44>

 a mineral base such as an alkali metal hydroxide (for example sodium hydroxide, potash, etc.), an alkaline earth metal hydroxide (for example magnesia, lime, etc.), an alkali metal carbonate ( for example sodium carbonate, potassium carbonate, etc.), an alkaline earth metal carbonate (for example magnesium carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (for example bicarbonate sodium, potassium bicarbonate, etc.), an alkali metal acetate (e.g. sodium acetate, potassium acetate), etc.), an alkali metal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.),

     an alkali metal acid phosphate (for example disodium acid phosphate, dipotassium acid phosphate, etc.) or the like, and an organic base such as a trialkylamine (for example trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1, 5diazabicyclo [4, 3, 0] non-5-ene, 1, 4-diazabicyclo [2, 2, 2] octane, 1, 5-diazabicyclo [5, 4, 0] undêcëne-5 or the like. Hydrolysis using a base is often carried out in water or in a hydrophilic organic solvent or in a mixed solvent.



   The reduction may include, for example, reduction with an alkali metal borohydride (eg sodium borohydride, etc.), catalytic reduction and analogues.



   The reaction temperature is not critical and the reaction is usually carried out at a temperature from cooling to heating, Process A- (3) (Va) -7 (V)
The compound (yob) or its salt can be prepared by subjecting the compound (Va) or its reactive derivative to the amino group or its salt to an acylation reaction.



   The present reaction can be carried out in a

  <Desc / Clms Page number 45>

 
 EMI45.1
 similar to that of process 1 mentioned above, process A "": '(4) (Vb) (Vc)
The compound (Vc) or its salt can be prepared by subjecting the compound (Vb) or its salt to a reaction for removing the protecting group from the carboxy group.



   The present reaction can be carried out in a similar manner to that of process 2 mentioned above.



  Process B- (l) (IIIb) (II)
The desired compound (II) or its salt can be prepared by subjecting the compound (IIIb) or its salt to a reaction for preparing the quaternary ammonium salt,
The suitable salt of the compound (II) or (IIIb) can be indicated as being one of those provided as examples for the compound (I).



   The present reaction can be carried out in a similar manner to that of method 3 mentioned above, Method B- (2)
The desired compound (II) or its salt can be prepared by reacting the compound (VIIIa) or its salt with the compound (XIVa) or its salt.



   A suitable salt of the compound (Villa) can be indicated as being one of those provided as examples for the compound (I),
The present reaction can be carried out in a similar manner to that of process I) mentioned above.



    Method B- (3)
The desired compound (IIb) or its salt can be prepared in fa. is. ant react the compound (. Vtb) or its salt with the compound (XIVa) or its gel,
A suitable salt of the compound (VIb) can be
 EMI45.2
 indicated as, being one of those provided as examples for the compound CI S

  <Desc / Clms Page number 46>

 
The present reaction can be carried out in a similar manner to that of method A- (l) -i) mentioned above, Method B- (4)
The desired compound (IIId) or its salt can be prepared by reacting the compound (VIa) or its salt with the compound (XIV) or its salt,
A suitable salt of the compound (VIa)

   may be designated as one of those provided as examples for the compound (I).



   The present reaction can be carried out in a similar manner to that of the process mentioned above.



  Method B- (5):
The desired compound (IVa) or its salt can be prepared by subjecting the compound (IV) or its salt to a reaction for removing the protecting group from the amino group.



   The present reaction can be carried out in a similar manner to that of process 4 mentioned above,
 EMI46.1
 Method B (6):
The desired compound (IVc) or its salt can be prepared by subjecting the compound (IVb) or its salt to a reduction reaction,
The present reaction can be carried out in a similar manner to that of the method A- (l) -ii) mentioned above.



  Method C- (l) -i):
The desired compound (X) or its salt can be prepared by subjecting the compound (IX) or its salt to a reaction for preparing a quaternary ammonium salt,
The agent a. use in the present quaternary ammonium salt preparation reaction may include a conventional agent, such as an N- [2-lower haloalkyl]

  <Desc / Clms Page number 47>

 phthalimide (e.g. N-, (2-bromoethyl) phthalimide, N- (2-bromopropyl) phthalimide, etc.) or the like.



   The present reaction can be carried out in a similar manner to that of method 3 mentioned above.



    Method C- (l) -ii):
The desired compound (XI) or its salt can be prepared by subjecting the compound (X) or its salt to a reaction for removing the protecting group.



   The present reaction can be carried out in a similar manner to that of process 4 mentioned above.
 EMI47.1
 



  Method C-- (2) -i)
The desired compound (XII) or its salt can be prepared by subjecting the compound (XI) or its salt to a reaction for preparing the disulfide,
The present reaction can be carried out in a conventional manner.
 EMI47.2
 



  Method C- (2) ii):
The desired compound (XIIa) or its salt can be prepared by subjecting the compound (XII) or its salt to an alkylation reaction of the amino part.



   The agent to be used in the present reaction can comprise a conventional agent such as a combination of formaldehyde and formic acid or the like, Method C- (2) -iii):
The desired compound (XIa) or its salt can be prepared by subjecting the compound (XIla) or its salt to a thiol preparation reaction.



   The agent to be used in the present reaction may include a conventional agent such as triphenylphosphine., Method C- (3)
The desired compound (XIIa) or its salt can be prepared by subjecting the compound (XII) or its salt to a

  <Desc / Clms Page number 48>

   reaction for preparing quaternary ammonium salt, The present reaction can be carried out in a similar manner to a. that of method 3 mentioned above.



  The desired compounds (I) and their pharmaceutically acceptable salts of the present invention are new compounds which exhibit high antibacterial activity and inhibit the growth of a large number of pathogenic microorganisms including Gram-positive and Gram-negative bacteria and are useful as antimicrobial agents. For therapeutic purposes, the compounds of the present invention can be used in the form of conventional pharmaceutical preparations which contain these compounds, as active ingredient, mixed with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient. suitable for oral, parenteral or external administration.



  The pharmaceutical preparations can be in solid form such as capsules, tablets, dragees, ointments or suppositories, or in liquid form such as solutions, suspensions or emulsions. If desired, auxiliary preparations, stabilizers, wetting or emulating, buzzing agents, buffers and other commonly used additives such as lactose, fumaric acid, may be included in the above preparations. citric acid, tartaric acid, stearic acid, maleic acid, succinic acid, malic acid, magnesium stearate, terra alba, sucrose, corn starch, talc , gelatin, agar-agar, pectin, peanut oil, olive oil, Cocoa Butter, leneglycol and the like, A, when the dose of the compounds will vary with age and the patient's condition,

   an average single dose of approx.

  <Desc / Clms Page number 49>

 The 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg compounds of the present invention have been found to be effective in treating infectious diseases caused by pathogenic bacteria. In general, daily amounts between 1 mg / organism and about 6000 mg / organism or even more can be administered,
To illustrate the usefulness of the compounds sought, the antimicrobial activities of representative compounds of the present invention are presented below.



  Minimum inhibition concentration (A) Experimental procedures
Antibacterial activity in vitro was determined by the double dilution method on agar plate.
 EMI49.1
 agar as described below.



  -gal The content of a culture loop, carried out overnight. of each experimental strain in a bouillQ Ion of trypticase-soybean (108 viable cells per ml) was caused to develop in streaks or bands on agar-agar infusion of heart (agar-agar HI) containing gradual concentrations of the representative experimental compound and the minimum inhibition concentration (MIC)
 EMI49.2
 was expressed in pg / ml after incubation at 370C for 20 hours, (B) Experimental compound (1) 7- [2-ethoxyimino-2- (5-amino-1,2,4-th. iadiazol-. 3 -yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem- 4-carboxylate (syn-isomer) (trans-isomer), (2) 7- [2- hydrochloride allyloxyimino-2- (5-amino - 1,2,4-thiadìazol-3-yl) acetamido] -3- {2- [1- (3-aminopropyl) -3-.

   pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn isomer) (cis isomer).



  (3) 7- [2-allyloxyimino-2- (2-aminothia-) hydrochloride
 EMI49.3
 zol-4-yl) acét.m.m, ido] -3- {2- [1- (3-N, N-dimethylaminopropyl) - 3-pyridinio] thiovinyl} -3-cephem-. 4-carboxylate (syn isomer) (cis isomer)

  <Desc / Clms Page number 50>

 
 EMI50.1
 (4) 7 -. [2-allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] hydrochloride] -3- {2- [1- (3-N, N -dimethylaminopropyl) -3-pyridinio] thiovinyl} 3-cephem-4-carboxylate (syn isomer) (cis isomer).



  (C) Experimental results
 EMI50.2
 C. I. H, (pg / ml)
 EMI50.3
 
 <tb>
 <tb> Compounds <SEP> experimental
 <tb> strain <SEP> experimental
 <tb> (1) <SEP> (2) <SEP> (3) <SEP> 1 <SEP> (4)
 <tb> Escherichia <SEP> coli <SEP> 31 <SEP> <0.025 <SEP> 0.050 <SEP> < <SEP> 0.025 <SEP> 0.100
 <tb> Klebsiella <SEP> pneumoniae <SEP> 20 <SEP> 0.050 <SEP> 0.200 <SEP> 0.100 <SEP> 0.100
 <tb> Staphylococcus <SEP> aureus <SEP> 0.390 <SEP> 0.200 <SEP> 0.200 <SEP> 0.200
 <tb> 209P <SEP> JC-1
 <tb>
 
The following preparations and examples are given by way of illustration of the present invention in more detail.



  Preparation of the starting compounds of the present invention
 EMI50.4
 tion.



  - ----. - Preparation 1 1) A mixture of 7-t-butoxycarbonylamino-3- (2-tosyloxyvinyl) -3-cephem-4-carboxylate benzhydryl oxide (trans isomer) (7g) and 3-mecaptopy-

  <Desc / Clms Page number 51>

 curtain (1.33 g) in dimethylformamide 50 ml) containing diisopropylethylamine (4.5 g) was stirred at room temperature for 2 hours. The resulting solution was poured into a mixture of ice-cold water (200 ml) and ethyl acetate (200 ml). The separated organic layer was washed in turn with water, a 10% aqueous hydrochloric acid solution and a saturated aqueous solution of sodium bicarbonate and brine.

   The solvent was evaporated in vacuo to give 7-t-butoxycarbonylamino-3- [2- (3-pyridyl) thiovinyl] -3-cephem-4-carboxylate (trans isomer) (5, 2) g).
 EMI51.1
 



  IR (Nujol): 3400-3200 (wide), 1780, 1710, 1490 cm NMR (DMSO-dg) <S: 1.42 (9H, s), 3.65 and 4.57 (2K, ABq, J = 20Hz), 5.05 (1H, d, J = 5Hz), 5.78 (il, dd, J = 5.8Hz), 7.33 (1H, d, J, 78 (IHÎ
J == 8Hz), 6, 93 (1H, s), 7, 0-8, 8 (14H, m).



  2) The following compounds were obtained in a manner similar to that of preparation 1-1).



  (1) 7-t-butoxycarbonylamino-3- [2- (2-pyridyl) thiovinyl] -3-cephem-4-carboxylate benzhydryl l-oxide (trans isomer).



   IR (Nujol): 3400-3200, 1780, 1710, 1700,
1550 cm '
 EMI51.2
 NMR (CDC1 m'lN (CDC13) ô: 1.50 (9H, sì, 3, 30, 4, 23 (2H, ABq, J = 18Hz), 4.50 (1H, d, J = 5Hz), 5 , 7- 5, 87 (2H, m), 6, 97 (1H, s), 7, 0-7, 67 (16H,
 EMI51.3
 m), 8, 43 (1H, d, J = 5 Hz) r (2) 7-t-butoxycarbonylamino-3-r2- (2pyrimidinyl) thiovinyl] -3- l-oxide. benzhydryl cephem-4-carboxylate (trans isomer) IR (Nujol); 340Q-3300, 1785, 1710, 1650, 15QO cm RMN '(-C DC 1 1, 5o - C9H, NMR (CDCl) 1, 5.0 .. OH, s.)., 3, 28 and 4, 23 (2H,

  <Desc / Clms Page number 52>

 
ABq, J = 18Hz) 5, 53 (1H, d, J = 5Hz), 5, 7-5, 85 (2H, m), 7, 03 (ho, s), 7, 1-7, 67 (14H , m),
8.57 (2H, d, J = 5Hz) (3) 7-t-butoxycarbonylamino-3- [2- (2pyrazinyl) thiovinyl] -3-cephem-4-carboxylate benzhydryl 1-oxide (trans isomer) .



   IR (Nujol): 3400, 1788, 1710, 1500 cm
NMR (DHSO-d6) cS: 1.50 (9H, s), 3.78 and 4.65 (2H,
ABq, J = 18Hz), 5, 10 (1H, d, J = 5Hz),
5, 85 (1H, dd, J = 5, 10Hz), 6, 43 (1H, d, J =
 EMI52.1
 10Hz), 7.03 (1H, s), 7.0-7.8 (12H, m), 8.53 (2H, m), 8.77 (1H, m).



  (4) 70tbutoxycabonylamino-3- [2- (3-pyridyl) thiovinyl] -3-cephem-4-carboxylate benzhydryl 1-oxide (cis isomer),
 EMI52.2
 IR (Nujol): 3400-3200 (large), 1780, 17QO, 14 9-0 cm NMR (CDC1 6: 1, 48 (9H, s), 3.72 (2H, dd, J '= 18Hz), 4 , 50 (1H, d, J = 5Hz), 5, 67-6, 00 (2H, m), 6, 27 (1H, d, J = 10Hz), 6, 88 (1H, d, J = 10Hz) , 7, 1-7, 83 (12H, m), 8, 45-8, 73 (2H, m), (5) 7-t-butoxycarbonylamino-3- [2- (2pyridyl) thiovinyl l-oxide ] -3-cephem-4-benzhydryl carboxylate (cis isomer).



   IR (Nujol): 3350, 1780, 1710, 1570 cm-1-
NMR (CDCl3) #: 1.55 (9H, s), 3, 50 and 4.35 (2H,
 EMI52.3
 ABq, J = 18Hz), 5, 83 (2H, m), 6, 50 (1H, bs), 7.00 (1H, s), 7, 05-8, 50 (15H, m) (6) le 7- [2-ethoxyim 1-oxide. ino-2- (5-amino - 1,2, 4thiadiazol-3-yl) acetamidoj-3-. [2- (5-nitro-2-pyridyl) thio Vi, nyl,] - 3- <:

   benzhydryl m-4-carhoxylate (syn-isomer) (trans-isomer) Preparation 2 1) To a solution of 1-oxide of 7-, t-butoxycarbQnyl-

  <Desc / Clms Page number 53>

 phosphoric acid trichloride (5) , 5 g) at -40 ° C. After stirring at the same temperature for 30 minutes, the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (100 ml). The separated organic layer was washed in turn with a 5% aqueous solution of sodium bicarbonate, water and brine.

   The solvent has been
 EMI53.1
 evaporated in vacuo to give 7-t-butoxycarbonylamino-3- [2- (3-pyridyl) thiovinyl] 3 cephem-4-benzhydryl carboxylate (trans isomer) (11.1 g).



  IR (Nujol); 3200, 1775, 1710, 1700, 1510 cm NMR (DMSO-d): 1.45 (9H, s), 3, 64 and 4.08 (2H, ABq, J == 18Hz), 3.18, (1H , d, J = 5Hz),
3.50 (1H, dd, J = 5.8Hz), 6.95 (1H, s), 7.0-
8, 8 (2 p.m., m).



  2) The following compounds were obtained in a manner similar to that of preparation 2-1).



  (1) benzhydryl 7-t-butoxycarbonylamino-3- [2- (2-pyridyl) thiovinyl] -3-cephem-4-carboxylate (trans isomer).
 EMI53.2
 



  IR (Nujol): 3300, 1770, 1700, 1670 cm NMR (CDC1. J 6; 1, 53 (9R, s), 3, 65, 41, (2H,
ABq, J = 16Rz), 5.07 (1H, d, J = 5Hz), 5.50 (1H, dd, J = 5Hz, 8Hz), 7.00 (1H, s), 7, 1-8, 0 (15H, m), 8.50 (1H, d, J = 4Hz) (2) 7-t-butoxycarbonylamino-3- [2- (2-pyrazinyl) thiovinyl] -3-cephem-4-carboxylate benzhydryl (trans isomer)
 EMI53.3
 IR (Nujol): 328Q, 1772, 1703, 1500 cm NMR (DMSO-d, -); 1, 43 (9JH, s), 3 ,. 67 and 4, 07 CL '(2HL, ABq, J18Hz), 5, 18 (1H, d, J5Hz), 5.57 (1H, d, J = 5, 8H-2), 7.00 (1H, p ), 7, 0-7, 7 C12H, m), 8.02 (1H, d, J = 8Hz),

  <Desc / Clms Page number 54>

 
8.50 (2H, m), 8.70 (1H, m), (3) benz-7-t-butoxycarbonylamino-3- [2- (3-pyridyl) thiovinyl] -3-cephem-4-carboxylate (cis isomer)
 EMI54.1
 IR (Nujol): 3300, 3200, 1785, 1710, 1525 cm RMN N (CDC 13) Åa:

   1, 47 (? H, s), 3, 82 (2H, bs), 3 5, 04 (1H, d, J = 5Hz), 5, 32-5, 72 (2H, m), 6, 25 and 6, 78 (1H, dx2, J = 10Hz), 7, 11-7, 85 (2H, m), 8, 33 ", 8, 78 (2H, m) (4) 7-t-butoxycarbonylamino-- Benzhydryl 3- [2- (2-pyridyl) thiovinyl] -3-cephem-4-carboxylate (cis isomer).
 EMI54.2
 



  IR (Nujol): 3300, 17g5, 1715, 1670 cm "RMN (CDC1: 1, 45 (9H-, s), 378 (2H, bs), 5, 00 (1H, d, J = 5Hz), 5, 50 (1H, dd, J == 5Hz, 8Hz), 6, 93 (1H, s), 6, 83 (1H, d, J = 103z), 7, 10-8, 50 (15H, m)
 EMI54.3
 (5) on 7- [2-. ethoxyimino-2- (5-. mino-1,2,4-thiadiazol-3-yl) acetamido] 3 [2- (2-drmethylaminoethyl) thiovinyl] 3-. benzhydryl cephem-4-carboxylate (syn isomer) (trans isomer).



  (6) 7- [2-ethoxyimino-2- (5-amino-1, 2, 4-thiadiazol- 3-yl) acetamido] -3- [2- (5-nitro-2-pyridyl) thiovinyl] - Benzhydryl 3-cephem- 4-carboxylate (syn isomer) (trans isomer)
 EMI54.4
 IR (Nujol): 3300, 1780, 1680, 1620, 1595, 1570, 1520 cm NMR (DMSO-d6) 6: 1, 32 (3H, t, J = 7Hz), 3.92 (2H, bs), 4 , 25 (2H, q, J = 7Hz), 5.34 (1H, d, J = 4Hz), 6.00 (1H, d-. D, J = 4, 8Hz), 7.01 (1H, s ), 7, 20-7, 91 (12H, m), 8, 42 (1H, d, J = 5Hz), 8, 57 (1H, d, J3Hz), 9, 26 (1H, d, J = 3Hz ),, 6. 8 (1H, d, J-8Hz).



  9 Preparation 3 1) A. a. cooled solution of 7-t-butoxycarbonylamino-3- [2- (3-pyridyl) thiovinyl] -3-cephem-4-carboxylate

  <Desc / Clms Page number 55>

 benzhydryl (trans isomer? (4.7 g) in acetonitrile (100 ml) p-toluenesulfonic acid (5.3 g) was added. The reaction mixture was stirred at room temperature for 2 hours After removing the solvent, the residue was dissolved in ethyl acetate and a 5% aqueous solution of sodium bicarbonate. The separated organic layer was washed in turn with water and brine. , dried over magnesium sulfate. The solvent was evaporated in vacuo to give 7-amino-3- [2-
 EMI55.1
 (3-pyridyl) thiovinyl] -3-cephem-4-benzhydryl carboxylate (trans isomer) (3.2 g).



  IR (Nujol): 3200 (wide), 1770, 1710, 1650 cm NMR (DMSO-d6) #: 3, 60 and 4, 10 (2H, ABq, J = 18Hz),
4.85 (la, d, J = 4Hz), 5.08 (1H, d, J = 4Hz),
6, 83 (1H, d, J = 16Hz), 7, 10 (1H, s), 7, 1-8, 8 (16H, m).



  2) The following compound was obtained in a manner similar to that of preparation 3-1).
 EMI55.2
 7-amino - 3- [2- (2-pyridyl) thiovinyl] -3-cephem- benzhydryl 4-carboxylate (trans isomer) IR Nujol): 1760-1770, 1710, 1650 cm "NMR (CDCl) $ : 3, 43-3, 80 (2H, m), 4, 73 (1H, d, J = 4Hz), 5.00 (1H, d, J = 4Hz), 7.00 (1H, s), 7 , 1-. 7, 75 (15H, m), 8, 45 (1H, d, J = 4Hz), Preparation 4
To a solution of 7-t-butoxycarbonylamino-3- [2- oxide. (2-pyrimidinyl) thiovinyl] -3-cephem-4-benzhydryl carboxylate (trans isomer) (4.8 g) in N, N-. dimethylformamide (25 ml) phosphorus trichloride (0.8 ml) was added at -30 C.

   After stirring for one hour at -30 ° C., the reaction mixture was poured into a mixture of ethyl acetate (300 ml) and water (300 ml). The separated organic layer was washed in turn with a 5% aqueous solution of sodium bicarbonate, water and brine. The solvent was evaporated in vacuo to

  <Desc / Clms Page number 56>

 give benzhydryl 7-t-butoxycarbonylamino-3- [2- (2-pyrimidinyl) thiovinyl] -3-cephem-4-carboxylate (trans isomer) and acetonitrile (100 ml) and l p-toluenesulfonic acid (3.5 g). The mixture was stirred for 2 hours at 35 C. After removal of the solvent, the residue was dissolved in ethyl acetate and a 5% aqueous solution of sodium bicarbonate.



  The separated organic layer was washed in turn with water and brine, dried over magnesium sulfate. The solvent was evaporated in vacuo to give benzhydryl 7-amino-3- [2- (2-pyrimidinyl) thiovinyl] -3-cephem-4-carboxylate (2.5 g).



   IR (Nujol): 3300 ,, 3400, 1770, 1720, 1560,
1550 cm
NMR (DMSO-d): 3, 65, 4, 04 (2H, ABq, J = 18Hz),
4, 8-5, 2 (2H, m), 6, 90 (1H, d, J = 18Hz), 7.00 (1H, s), 7, 17-7, 67 (13H, m), 8, 68 (2H, d J = 5Hz), Preparation 5 1) To a solution of benzhydryl 7-amino-3- [2- (3-pyridyl) thiovinyl] -3-cephem-4-carboxylate (trans isomer) (3 g) in tetrahydrofuran (30 ml) containing monotrimethylsilylacetamide (5 g) was added 2-ethoxyimino-2- (5-amino-1,2, 4thiadiazol-3-yl) chloride hydrochloride acetyl (syn isomer ) (1.8 g) with stirring between -10 and OOC, The reaction mixture was stirred at the same temperature for 30 minutes.

   After addition of ethyl acetate (150 ml) and a small amount of water, the separated organic layer was washed in turn with a saturated aqueous solution of sodium bicarbonate and brine and dried over sulfate magnesium. The solvent was evaporated in vacuo to give 7- [2-ethoxyimino-2- (5-amino-1,2,4,4-thiadiazol-3-yl) acetamido] -3- [2- (3-pyridyl) thiovinyl ] -3-cephem4-benzhydryl carboxylate (syn-isomer) (trans-isomer) (3, 1 g),

  <Desc / Clms Page number 57>

 
 EMI57.1
 TR (Nujol); 3300, 3150, 1780, 1720, 1680, 1610, 1520 cm NMR (DMSO-d6) 6: 1, 2 (3H, t, J7Hz), 3, 6-4, 2 L2H ,. m) ,, 40 (2H, q, J = 7Hz), 5.25 (1H, d,
J = 5Hz), 5.85 (1H, dd, J = 5.8Hz), 6.82 (1H, d, J = 16Hz), 6.70 (1H, s), 7.0-7.7 ( llH, m),
7, 5-8, 8 (6H, m), 9, 61 (1H, d, J = 8Hz).



  2) The following compounds were obtained in a manner similar to that of preparation 5-1).
 EMI57.2
 



  (1) benzhydryl 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- [2- (3-pyridyl) thiovinyU3-cephem-4-carboxylate (syn isomer) (trans isomer)
IR (Nujol): 3300, 1780, 1700, 1650, 1550 cm
NMR (DMSO-d6) #: 3.92 (3H, s), 3.70 and 4.15 (2H, ABq, J = 17Hz), 5.27 (1H, d, J = 4Hz),
5.88 (1H, d J = 4.8Hz), 6.86 (1H, d, J = 16Hz),
 EMI57.3
 692 (1H, s), 7, 2-8, 8 (16H, m), 9, 7 (1H, d, J = 8Hz), 11, 6 (1H s) (2) on 7- [2-ethoxyimino -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3 [2- (2-pyridyl) thiovinyl] -3 cephem- benzhydryl 4-carboxylate (syn isomer) (trans isomer)
IR (Nujol): 3390, 3250, 1760, 1715, 1660,
1620 cm
 EMI57.4
 NMR (DMSO-d6) 6;

   9, 62 (1H, d, J = 8Hz), 8, 48 (1H, d, J = 4Hz), 8, 12 (2H, b - s), 7, 17-7, 78 (14H, m) , 7.00 (1H, d, J = 16Hz), 6.97 (1H, s),
5, 93 (1H, dd, J = 8Hz, 5Hz), 5, 30 (1H, d,
J = 5Hz), 4.22 (2H, q., J = 7Hz), 3.93 (2H, ABq, J = 18Hz), 1.32 (3H, t, J = 7Hz) (3) on 7- Benzhydryl benzhydryl [2- (2-pyrimidinyl) thiovinyl-3-cephem-4carboxylate (syn-isomer) (trans isomer).
 EMI57.5
 p, f. : 164-167 C (decomposition) IR (Nujol); 330Q 3150, 1770, 1720, 1670, 1 & 1Q cm

  <Desc / Clms Page number 58>

   ID1N (DMSO-d6) #:

   1.27 (3H, t, J = 5Hz), 3.87 (2H, ABq, J = 18Hz), 4.20 (2H, q, J = 7Hz),
5, 28 (1H, d, J = 5Hz), 5, 88 (1H, dd, J = 8Hz,
5Hz), 6.23 (1H, s, J = 16Hz), 6.93 (1H, s),
7, 2-7, 6 (11H, m), 8.07 (2H, b-s), 8, 65 (2H, d, J = 5Hz), 9.58 (1H, d, J = 8Hz)
 EMI58.1
 (4) 7- [2- (2-tritylaminothiazol-4-yl) glyoxylamìdo] -3- [2-. (3-pyridyl) thiovinyl] -3-cephem-. Benzhydryl 4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 1780, 1710, 1660 cm NMR (mISa-d6) 6: 3, 674 {02 (2H, m) T 5, 27 (1H, d, J = 5Hz), 5, E8 (1H, dd , J = 8Hz, 5Hz), 6, 93 (1H, s), 7, 06-7, 7 (27H, m), 7, 87 (1H, s),
7, 85-8, 83 (4H, m), 9.75 (1H, d, J = 8Hz) (5) 7- [2-carboxymethoxyimino-2- (5-amino-1,2,4) acid - thiadiazol-3-yl) acêtamido] -3-- [2- (3-pyridyl) thiovinyl] '- 3- cephem-4-carboxylic (syn isomer) (trans isomer).



   IR (Nujol): 3300, 1760, 1600, 1400, 1160,
1050 cm "
 EMI58.2
 NMR (DMSO-dG): 3, 403, 70 (2H m), 4.37 (2H, s), 5.03 (1H, d, J = 5Hz), 5.67 (1H, dd, J = 8Hz , 5Hz), 6.50 (1H, d, J = l & Hz), 7.37 (1H, d,
J = 16Hz), 7, 30-8, 57 (4H, m), 11, 17 (1H, d, J = 8Hz) (6) le 7- [2- (3-benzhydryloxycarbonylpropoxyimino) - 2- (5- amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [2- (3-pyridyl) thiovinyl] -3-benzhydryl cephem-4-carboxylate (syn isomer) (trans isomer).
 EMI58.3
 



  (7) 7- [2- (1-methyl-'l-benzhydryloxycarbonylethoxyimino) -2- (5-amino-1, 2, 4-, thadiazol-3-yl) acetamido] -3-. [2-. (3-pyridyl) thiovinyl] -3-cephem-4-benzhydryl carboxylate r (syn isomer) (trans isomer), Preparation 6 1) A. a solution of 7- [2-methoxyimino-2- (2-formamidothiazol-4- yl) acetamido] -3- [2- (3-pyridyl) thiovinyl] -3-

  <Desc / Clms Page number 59>

   cephem4-henzhydryl carhoxyate (syn isomer) (trans isomer) (2 g) in methanol (20 ml), concentrated hydrochloric acid (0.85 ml) was added at room temperature and the resulting mixture was stirred at 25-30 C for 2 hours.

   Water and ethyl acetate were added to the reaction mixture, and the resulting mixture was adjusted to pH 7.0 with saturated aqueous sodium bicarbonate solution. The separated organic layer was evaporated in vacuo to give a yellowish residue. A mixture of this residue and trifluoroacetic acid (5 ml) containing anisol (1 ml) in dichloromethane (10 ml) was stirred at 5-10 ° C for one hour. The mixture was poured into diisopropyl ether (100 ml) to give a precipitate which was collected by filtration and dissolved in a 5% aqueous solution of sodium bicarbonate at a pH of 5.5.

   The resulting solution was chromatographed on a macroporous non-ionic resin called "Diaion-HP-20" and eluted with a 20% aqueous solution of isopropyl alcohol.



  The fractions containing the desired compound were concentrated and acidified to a pH of 2.2 with concentrated hydrochloric acid to give 7- [2-mehoxyimino-2- (2-aminothiazol-4-yl) acetamido acid. ] -3- [2- (3-pyridyl) thiovinyl] -3-cephem-4-carboxylic (syn-isomer) (trans-isomer) (0.07 g).
 EMI59.1
 



  IR (Nujol): 3300, 1770, 1670, 1540 cm NMR (DMSO-d6) ô: 3.60 and 4.00 (2H, ABq, J = 18Hz), 3.82 (3H, s), 5.15 (1H, d, J = 5Hz), 5, 68 (li, dd, J = 5, 8 Hz), 6, 73 (1H, s), 6, 90, 7, 17 (2H, 2xd, J = 16Hz ), 7, 0., .. 8, 8 (4H, m),
9.58 (1H, d, J = 8Hz.



  2) The following compounds were obtained in a manner similar to that of preparation 6L-1).



  (1) 7- [2-ethoxyimino-2- (5-amino-1, 2, 4 - thia-diazol-3-yl) acetamido acid] -3- [2- (3-pyridyl) thiovinyl] -3-cephem-

  <Desc / Clms Page number 60>

 4-carboxylic (syn isomer) (trans isomer).



   IR (Nujol): 3300, 1770, 1670, 1620, 1530 cm
 EMI60.1
 NMR (DMSO-d6) 6: 1, 25 (3H, t, J = 7Hz), 3.80 (2H, b ABq, J = 18Hz), 4.20 (2H, q, J = 7Hz), 5, 15 (1H, d, J = 5Hz), 5, 73 (1H, dd, J = 5, 8Hz), 6, 88 and 7, 14 (2H, 2xd, J = 16Hz), 7, 3-8, 8 (4H, + 2H m), 9.52 (1H, d, J = 8Hz)
 EMI60.2
 (2) acid (2) acid 7- [2-ethoxyinino2 (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [2- (2-pyridyl) thiovinyl] -3-cephem-4-carboxylic (syn isomer) (trans isomer). p. f. : 180 - 1840C (decomposition).



   IR (Nujol): 3450, 3300, 3200, 2400-2600, 1775,
1680, 1655, 1615 cm '
NMR (DMSO-d6) 6: 1, 23 (3H, t, J = 7Hz), 3.83 (2H,
 EMI60.3
 ABq, J = 18Hz), 4.17 (3H, q, J = 7Hz), 5.18 (1H, d, J = 5Hz), 5.77 (li, dd, J = 8Hz, 5Hz), 7, 03 (1H, d, J = lrjHz), 7, 1-7, 83 (4H, m), 8.07 (2H, bs), 8, 48 (1H, d, J = 4Hz), 9, 55 ( 1H, d, J = 8Hz).



  (3) 7- [2-ethoxyiino-2- (5 amino- 1,2,4,4-thiadiazol-3-y1) acetamido] 3- [2- (2-pyrimidinyl) thiovinyl] -3 cepheD-4-carboxylic acid (syn isomer) (trans isomer). p. f. : 194 - 1960C (decomposition).



  IR (Nujol): 3250, 3150, 2450-2550, 1760, 1670,
1655,1620cm-1
NMR (DMSO d6) Ò: 1.32 (3H, t, J-7Hz), 3.72 (2H,
ABq, 18Hz), 4,17 (2H, q, J = 7Hz), 5, 28 (1H, d, J = 5Hz), 7, 48 (1H, d, J = 16Hz), 7, 33 (1H, m),
8, 15 (2H, b-s), 8, 70 (2H, d, J = 5Hz),
9.62 (1H, d, J = 8Hz).



  (4) 7- [2-ethoxyimino-2- (5-amino-1, 2, 4-thia-diazol-3-yl) acetamido acid] -3- [2- (5-nitro-2-pyridyl ) thiovinyl] -
 EMI60.4
 3-cephem-4-carboxylic (syn isomer) (trans isomer), IR (Nujol; l780, 1690, l600, 1580, 1520 cm NMR (DMO-d) ù: 1.35 C3H, t, J = 7Hz), 3, 7-4, 45 6 1

  <Desc / Clms Page number 61>

 
 EMI61.1
 (4HL, m), 5, 30 (. Lu, d, J = 4Hz), 5, 90 (IH, dd, 4, 8Hz), 7, zu 3 (3H, m), 9, 71 (1H, d , J = 8Hz) (5) 7- [2- (3-carboxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [2 - (3-pyridyl) thiovinyl] -3-cephem-4-carboxylic (syn isomer) (trans isomer).



   IR (Nujol): 3300, 1770, 1670, 1620, 1530 cm
 EMI61.2
 NMR (DHSO-d6) 0: 1, 62, 7 (4H, m), 3, 8-4, 3 (4H, m), 5.23 (1H, d, J = 4Hz), 5.82 (1H , dd, J = 1, 8Hz), 7.06 (2H, s), 7, 2-8, 8 (4H, m), 9.62 (1H, d, J = 8Hz).



  (6) 7- [2- (1-methyl-1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido acid] -3- [2- (3 -pyridyl) thiovinyl] -3-cephem-4-carboxylic (syn isomer) (trans isomer).



   IR (Nujol): 3300, 1770, 1670, 1610, 1520 cm-1
NMR (DMSO-d6) #: 1, 48 (6H, s), 3, 5-4, 2 (2H, m),
5, 15 (1H, d, J = 5Hz), 5, 85 (1H, dd, J = 5, 8Hz),
7, 0 (2H, s), 7, 2-8, 8 (4H, m), 9.45 (1H, d, J = 8Hz).



  Preparation 7 1) A mixture of benzhydryl 7-t-butoxycarbonylamino-3- [2- (2pyridyl) thiovinyl] -3-cephem-4-carboxylate (5.0 g) and N, N-dimethylformamide (25 ml) and methyl iodide (5 ml) was left to stand for 9 days at room temperature. The reaction mixture was poured into diisopropyl ether and the resulting oily residue was triturated with ethyl acetate and combined by filtration to give 7-t-bu-toxycarbonylamino-3- [2- (1 -methyl-2-pyridinio) thiovinyl] -3- benzhydryl cephem-4-carboxylate in the form of iodide (trans isomer) (5.2 g).



   IR (Nujol): 3400, 1775, 1705-1695, 1650,
 EMI61.3
 1 1600 cm 'NMR (DMSO-d6) #: 1.38 (9H, bs), 4.00 (2H, ABq, J = 18Rz) r 4.23 (3H, s), 5.23 (1H, d , J = 5Hz),

  <Desc / Clms Page number 62>

 
5, 65 (LE, dd, J =. 8H. Z, 5Hz), 7, 00 (1H, s),
7, 17-7, 55 (11H, m), 7, 8-8, 5 (4H, m),
9, 2 (1H, d, J = 5Hz).



  2) The following compounds were obtained in a manner similar to that of preparation 7-1).



  (1) 7-t-butoxycarbonylamino-3- [2- (1methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylated benzhydryl iodide (trans isomer).



   IR (Nujol): 3350-3450, 1775, 1710, 1660,
1620 cm '
NMR (DMSO-d6) 5: 1, 4 (9H, s), 3, 5-4, 1 (2H, m),
4, 35 (3H, s), 5, 22 (1H, d, J = 5Hz), 5.58 (1H, dd, J = 5Hz, 8Hz), 6.97 (1H, s), 7, 1- 7, 6 (12H, m), 8, 0-8, 3 (1LH, m), 9, 1 (1H, large s) (2) 7-t-butoxycarbonylamino-3- iodide [2- ( 4-
 EMI62.1
 methyl2-pyrazinio) thioviny1] 3v Benzhydryl cephem-4-carboxylate (trans isomer).



  IR (Nujol): 3350, 1785, 1717 cm 'RMN (DMSO-d6) 5: 1, 47 (9H, s), 3, 70 and 4, 17 (2H, ABq), J = 17Hz), 4, 33 (3H, s), 5, 23 (1H, d,
J = 5Hz), 5.60 (1H, dd, J = 5Hz, 8Hz), 7.00 (1H, s), 7, 2-7, 6 (12H, m), 8.05 (1H, d, J = 8Hz),
8, 87 (1H, d, J = 4Hz), 9, 30 (1H, d; J = 4Hz),
9, 33 (1H, s) (3) 7-t-butoxycarbonylamino-3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate iodide (cis isomer ).
 EMI62.2
 



  IR (Nujol): 3400-3200 (large), 1770, 1710, 1660, 1620, 1520 cm'RMN (DMSO-D 1, 40 (9H, s), 3, 65 and 3, 95 6 (2H, ABq, J = 18Hz) 4, 3 (. 3H s), 5, 18 (1H, d, J = 5Hz), 5.56 (1H, dd, J = 5Hz, 8Hz), 6.85 (1H., D, J = 8Hz), 6, 88 (lez s), 7, 03 -, ... 7, 73 (1OH, m), 7, 75-9, 15 (4H m)

  <Desc / Clms Page number 63>

 
 EMI63.1
 (4) i. 7-t-butoxycarb odor. onylamino-3-, [2- (methyl-2-pyridiniothiovinyl-3-ephem-4-carboxylate, benzhydryl (cis isomer).



   IR (Nujol): 3300, 1780, 1720, 1680, 1615,
1565 cm
 EMI63.2
 NMR (DMSO-d6) 6; 1.47 (9H, s), 3, 5-4, 20 (2H, m), 4.15 (3H, s), 5.25 (1H, d, J = 5Hz), 5.67 (1H, dd, J = 5Hz, 8Hz), 6, 73 (1H, d, J = 10Hz), 7, 03 (1H, d, J = 10Ifz), 6, 93 (1H, s), 7, 3-9, 10 (15H, m) (5) iodide of 7 -. [2-hydroxy-2- (2-tritylaminothiazol-4-yl) acetamido] -3- (2- (1-methyl-3-pyridinio) thiovi - nyl] -3-cephem-4-benzhydryl carboxylate (trans isomer).
 EMI63.3
 



  NMR (DMSO-d) <S: 3, 5-4, 1 (2H, m), 4.33 (3H, s), 4, 9 (li, s), 5.23 (1H, d, J = 5Hz), 5.77 (1H, dd, J = 8Hz, 5Hz), 6, 53 (1H, s), 6, 94 (1H, s),
7, 02-7, 67 (27H-, m), 7, 68-9, 3 (4H, m).



  (6) 7- [2-ethoxyimino-2- (5-amino-1, 2, 4-) bromide
 EMI63.4
 thiadiazol-3-yl) acêtamido] -3- [2- (1-benzhydryloxycarbonylmethyl-3-pyridinio) thiovinyl] -3-benzophryl-4-carboxylate (syn isomer) (trans isomer).



   IR (Nujol): 3250-3400, 1780, 1750, 1720, 1660,
1620 Cm
NMR (DMSO-d6) ô: 1.13 (3H, t, J = 6Hz), 3.45 (2H,
 EMI63.5
 m), 4, 2 (2H, q, J = 7Hz), 5, 33 (1H, ò., J == 5Hz), 5, 75-6, 10 (3H, m), 6, 95 (1H, s), 7, 03 (1H, s), 7.00 (1H, d, J = 16Hz), 7, 2-7, 7 (21H, m) 8, 0-9, 33 (3H, m).



    Preparation 8
In a solution of 7- [2- (2-tritylaminothiazol-4-yl) glyoxylamido] -3- [2- (3-pyridyl) thiovinyl] -3-cephem-4-carboxylate (syn isomer) ( trans isomer) (3.1 g) in a mixture of methanol (16 ml) and tetrahydrofuran (16 ml), borohydride was added

  <Desc / Clms Page number 64>

 sodium (0.033 g) cooling with ice and the mixture was stirred for 10 minutes. The reaction mixture was adjusted to pH 7.0 with acid
 EMI64.1
 10% hydrochloric acid and extracted with ethyl acetate.



  The separated organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 7- [2- (2-tritylaminothiazol-4-yl) -2-hydroxyacetamido] -3 - [2- (3-pyridyl) thiovinyl] -3-benzhydryl cephem-4-carboxylate (trans isomer) (2.84 g).



   IR (Nujol): 3300, 1780, 1720, 1680 cm NMR (DMSO-d) 6: 3, 56-4, 02 (2H, m), 4, 9 (1H, s), 5, 22 (1H, d , J = 5Hz), 5.77 (1H, dd, J = 8Hz,
5Hz), 6.45 (1H, s), 6, 93 (1H, s), 7-7, 67 (27H, m), 7, 6-8, 7 (4H-, m) Preparation 9-1)
In an ice-cooled solution
 EMI64.2
 7- acid. [2-ethoxyimino-2- (5-amino-1,24-thiadiazol-3-yl) acetamido] -3- [2- (5-nitro-2-pyridyl) thiovinyl] -3 - cephem-4-carboxylic (syn isomer) (trans isomer) (1.35 g) in aqueous sodium bicarbonate solution (30 ml) was added sodium hydrosulfite (4.05 g) with stirring. The mixture was stirred for 30 minutes at room temperature and cooled in an ice bath and acidified to a pH of 3.5 with 10% hydrochloric acid.

   The precipitate was collected, washed and dried
 EMI64.3
 to give 1.05 g of 7- [2-ethoxyimino-2- (5-amino- 1, 2, 4-thiadiazol-3-yl) acetamidoj-3- [2- (5-amino-2-pyridyl) acid ) thiovinyl] -3-cephem-4-carboxylic (syn isomer) (trans isomer), IR (Nujol): 330Q, 1770, 1670, 1620, 1530 cm "NMR (DMQdg) 5: 1, 27 (3H, t, J = 6Hz), 3.85 (2H, B s, 4.20 C2H, q, J = 6Hz), 5.17 (us, d, J = 5Hz), 5.77 (lH, dd, J5, 8Hz ), 7, 0-7, 5 (4H, m), 8, 10 (1H, s), 9, 52 (1H., D, J = 8Hz).

  <Desc / Clms Page number 65>

 



  Preparation 9-2)
To a suspension of phosphorus pentachloride in toluene was added 2ethoxyimino72 (5-amino-1, 2, 4-thiadiazol-3-yl) acetic acid (syn isomer) by cooling to OC and stirring, which was continued for 45 minutes between 4 and 8 C. The reaction mixture was poured into ice-cold water with stirring. The organic layer was separated, washed with cold water and brine, dried over magnesium sulfate and evaporated to dryness.

   The residue was triturated in diisopropyl ether and the mixture was stirred for 10 min 30C. The resulting precipitate was filtered, washed with cold diisopropyl ether and dried
 EMI65.1
 to give 2-ethoxyimino-2- (5-dichloro phosphorylamino-1,2,4-thiadiazol-3-yl) acetyl chloride (syn isomer). p. f. : 115 C.



   IR (Nujol): 1780, 1590, 1550, 1220, 1050,
960, 910 cm
NMR (acetone-d 1.37 (3H, t, J = 7Hz), 4.45 (2H, q, J = 7Hz)
 EMI65.2
 Analysis for CH. N. OPSCI: b b 4-3-3 C H N Cl P Calculated: 20, 48 1, 71 15, 93 30, 33 8, 82
Found: 20, 79 1, 78 16, 22 30, 63 8, 98 Preparation 10
The following compound was obtained in a similar manner to that of preparation 1-1), 7- [2-allyloxyimino-2- (5-amino- 1,2,4-thiadiazol-3-) l-oxide yl) acetamido] -3- [2- (3,4-tetramethylenepyridazin-6-yl) thiovinyl] -3-cephem-4-carboxylate ben-
 EMI65.3
 zhydryl (syn isomer) (trans isomer), IR (Nujol);

   1780, 1710, 1660, 1610, 1520 cm NMR (DMSO-d-) <5 1.76- (4H, m), 2.90 (4H, m), 3.84 C2H, ABq, J = 18Hz), 4.68 (2H, d, J = 5Hz), 5.17 UR , d, J = 5H. z), 5.28 (2H, m) 5.96 (1H,

  <Desc / Clms Page number 66>

 
 EMI66.1
 dd, J = 5Hz, 8Hz), 6.05 (1H, m), 6.96 (IH, s), 7, 17, 7 (13H, m) 1 S, 06 (2H, large s), 9, 08 (1H, d, J = 8Hz) Preparation11
The following compounds were obtained in a manner similar to that of preparation 2-1)
 EMI66.2
 1) 2- [2allyloxyimino-2-.

   (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [2- (1, 3, 4-thiadiazol-2-yl) thiovinylJ-3-cephem4-carboxylate (syn isomer ), (trans isomer)
IR (Nujol): 3300 (wide), 1790, 1740, 1690,
1640 cm-1 NMR (DMSO-d6) #: 3.40 (2H, S), 4.57-4.90 (2H, m),
4, 93-5, 67 (4H, m), 5, 67-6, 13 (2H, m), 6, 13-
6.90 (2H, m), 6-.97 (1H, s), 7.0-7.57 (10H, m),
9.60 (1H, s)
 EMI66.3
 2) on 7-. t-butoxycarbonylamino-3- {2- [1- (2-N, N-dimethylaminoethyl) -1H-tetrazol-5-yl] thiovinyl} -3 - benzhydryl cephem-4-carboxylate (trans isomer)
IR (Nujol): 3300, 3350, 1780, 1710, 1600 cm
 EMI66.4
 NMR (CDC13) 6:

   1.50 (9H, m), 2.50 (6R, s), 3.05 (2H, m), 3.67 (2H, m), 4.50 (2H, m),
5, 03 (1H, d, J = 5H'z), 5, 60 (1H, m), 6, 95 (1H, s), 7, 33 (10H, m), 3) on 7- [2- allyloxyimino-2- (5-amino-1,2,4-thiadia-. zol-3-yl) acetamido] -3- [2- (3,4-tetramethylenepyridazin-6yl) thiovinyl] -3-cephem-4- benzhydryl carboxylate (syn isomer) (trans isomer).



  * IR (Nujol): 1770, 1710, 1670, 1610, 1520 cm
 EMI66.5
 NMR (DMSO-d-); 1.80 (4H,), 2.8Q (4H, m), b 3.86 (2H; ABq, J =. 18Hz), 4.66 (2H, d, J = 5Hz)), 4.6: 6, (2H, d, J = 5H. Z), 5, 27 (1H, d, J =, 5H .. z), 5, 30 (1HL, m), 5, 88 (1H, dd, J = 5Hz, 8H: z), 5.90 (1H, m), 6.96 (1H, s), 6-rS-7, 7 (13Hr m) r 9.64 (Ui, d, J = 8Hz)

  <Desc / Clms Page number 67>

 
 EMI67.1
 4) 7 - [2-allyloxYimino-2- (2-formamidothiazol-4-yl) acetamido] hydrochloride hydrochloride 3- 3- 2- (1- (3-N, N-dimethylaminopropyl) - 3-pyridinio] thiovinyl } -3-cêphejn-4z-1 benzhydryl carboxylate (syn isomer) (cis isomer)
NMR (DMSO-d6) #:

   2.5 (2H, m), 3.45 (2H, m),
3, 8 (2H, m), 4, 6-4, 7 (4H, m), 5.28 (1H, d,
J = 5Hz), 5, 3 (2H, m), 5, 95 (2H, m), 6, 50 (1H, d, J = 10Hz), 6, 90 (1H, s), 7, 2-7 , 6 (14H, m), 8, 5 (1H, s), '8, 2-9, 8 (5H, m) 5) 7- [2-ethoxyimino-2- (5-amino-1, 2 , 4-thiadiazol-3-yl) acetamido] -3- (2-tosyloxyvinyl) -3-benzhydryl cephem-4-carboxylate (syn isomer) (cis isomer).



   IR (Nujol): 3300, 1770, 1720, 1670, 1530 cm-1
 EMI67.2
 NMR (DMSO-d) ô; 1.30 (3H, t, J = 7Hz), 2.43b (3H, s), 3.60 (2H, m), 4.23 (2H, q, J = 7Hz), 5.23 (1H , d, J = 5Hz), 5.91 (1H, m), 6.00 (1H, d, J = 7Hz), 6.62 (il, d, J = 7Hz), 6.84 (1H, s ), 7, 33 (12H, m), 7, 82 (2H, d, J = 8Hz), 8, 12 (2H,
 EMI67.3
 the. s), 9 ', 58 (1H, d, J = 9Hz) 6) 7- [2-ethoxyimino-2- (5-amino - 1,2,4-thiadiazol- 3-yl) acetamido] -3 - (2-tosyloxyvinyl) -3-cephem-4-carboxylate of benzhydryl (syn isomer) (trans isomer)
IR (Nujol): 3300, 1780, 1720, 1670, 1530 cm - l
 EMI67.4
 NMR (DMSO-d,) 6:

   1, 26 (3H, t, J = 7Hz), 2.40 (3H, bs), 3.70 (2H, m), 4.20 (2H, q, J = 7Hz), 5.21 (1H, d, J = 5Hz), 5.90 (1H, dd, J = 5Hz, 9Hz), 6.50 (1H, d, J = 12Hz), 6.88 (1H, s), 7, 32 (13H, m), 7.80 (2H, d, J = 8Hz), 8.10 (2H, la. s), 9.57 (1H, d, J = 9Hz)
 EMI67.5
 7) 7-N [2-allyloxyim. ino-2-- (5-sa. mino-1, 2, 4.thiadia-. zol-3-yl) acêtainido] -3- (2-tosyloxyvinyl) -3-cephem-4-carboxylate benzhydryl (syn isomer ) (cis isomer) IR Nujol); 3300, 3200, 1770, 1720, 1680, 1530 cmRMN (DMSO-d6 '), 3, - m),

  <Desc / Clms Page number 68>

 
 EMI68.1
 4.65 (2H:, d, J = 5H. Z), 5.04-5.57 (2H, m), 5.18 (1H, d, J = 5Rz), 5.67-6, 10 ( 2H, m), 5, 95 (1H, d, J = 7Hz), 6.60 (1H, d, J = 7Hz), 6.80 (ur, s), 7, 32 (12R, m), 7.80 (2H, d, J = 8Hz), 8.09.

   (2H broad s), 9, 59 (1H, d, J = 9Hz) 8) 7- [2-allyloxyimino-2- (5-amino-1,2,4 - thiadiazol-3-yl) acetamido] Benzhydryl 3 (2-tosyloxyvinyl) -3-cephem-4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 1770, 1715, 1670, 1620, 1520 cm NMR (DMSO-d6) 6: 2, 40 (3HJ s), 3, 55 and 3, 93 (2H, ABq, J = 17Hz), 4.70 (2H, J = 4, 5Hz), 5, 1 ,, 5, 6 (2H, m), 5 , 23 (1H, d, J = 5Hz), 5, 7-6, 2 (1H, m), 5, 95 (IH, dd, J = 5Hz, 8Hz), 6.53 (1H, d, J = llHz), 6, 90 (1H, s), 7, 1-7, 6 (11H, m), 7, 47 (2H, d, J = 9Hz), 7, 86 (2H, d, J = 9Hz) , 9, 67 (1H, d, J = 8Hz) 9) 7-2-t-butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (2-tosyloxyvinyl) -3cephem-4- benzhydryl carboxylate (syn isomer) (cis isomer) IR (Nujol): 3250, 1780, 1720, 1672 cm NMR (DMSO-d6) 6:

   1, 43 (9H, s), 2, 36 (3H, s), 3, 8 (2H, m), 4, 6 (2H, large s), 5, 23 (1H, d, J = 5Hz), 6, 0 (1H, m), 6, 0 (1H, d, J = 7Hz), 6.60 (1H, d, J = 7Hz), 6.83 (1H, s), 7, 3-8, 0 (15H, m), 8.52 (1H, s), 9, 60 (1H, d, J = 8Hz).



  10) 7- [2-ni. ethoxyimino--. 2- (5-amino-1,2,4-thiadia-zol-3-yl) acetamido] -3- (2-tosyloxyvinyl) -3- <; benzhydryl ephem-4-carboxylate (syn isomer) (trans isomer) p. f. : 115, 120oC (decomposition) IR (Nujol): 3300, 3200, 1770, 172Q, 1680, 1630, 1595, 1525! 1495 cm NMR (DMSO-d6): 2f40 (3H s), 3.35 (2H, large s), 3, 9: 3 (3H, s), 5, 22 (lit, d, J = 5Hz), 5 , 90 (IR1H, dd J = 5Hz, 8Hz), 6, 52 (1H, d, J = 12H. Z),

  <Desc / Clms Page number 69>

 
 EMI69.1
 6, 88 (1H., S), 7, 23 (1H, d, J = 12Hz), 7, 33 (10H, large s), 7, 47 (2H, d, J = 8Hz), 7.82 ( 2H, d, J = 8Hz),
8, 10 (2H, large s), 9., 60 (1H, d, J = 8Hz).



  Preparation 12
The following compounds were obtained in a manner similar to that of preparation 3-1)
 EMI69.2
 1) benzhydryl 7-amino-3- [2- (3-pyridyl) thiovinyl] -3 cephem-4-carboxylate (cis isomer) NMR (DMSO-d6) 6: 3.80 (2H, s), 4, 87 (1H, d, J = 4Hz), 5, 12 (1H, d, J = 4Hz), 6, 60 (2H, dd, J = 10Hz, 16Hz), 6, 92 (1H, s), 7, 04--7, 84 (lah, m), 8, 12-8, 72 (3H, large) 2) 7-amino-3- (2-toxyloxyvinyl) -3- cephem-4-carboxylate l-oxide benzhydryl (trans isomer)
IR (Nujol): 3400, 1765, 1715, 1620, 1580 cm
NMR (DMSO-d6) 6 ': 3, 45 and 4, 28 (2H, ABq, J = 18Hz),
4, 82 (hui, dd, J = 8Hz, 5Hz), 6, 63 and 7, 20 (2H, dd, J = 12Hz), 6, 87 (1H, s), 7, 10-7, 57 (lOH , m)
 EMI69.3
 3) 7-amino-3- {2- [l-.

   (2-N, N-dimethylaminoethyl) 1H-tetrazol-5-yl] thiovinyl} -3-cephem-4-benzhydryl carboxylate (trans isomer) Preparation 13
The following compounds were obtained in a manner similar to that of preparation 5-1) 1) 7- [2-allyloxyimino-2- (5-amino-1,2,4-thiadiazol) l-oxide -3-yl) acetamido] -3- (2-tosyloxyvinyl) -3-cephem-
 EMI69.4
 Benzhydryl 4-carboxylate (syn isomer) (trans isomer) R1v1N (DHSO-d6'0:

   2, 43 (3H, s), 3, 60 and 4, 15 b (2H, ABq, J = 18Hz), 4, 71 (2H, d, J = 5Hz), 5.07 (1H, d, J = 5Hz), 5, 10-5, 60 (2H, m), 5, 98 (1H, dd, J5Hz, 8Hz), 5, 80-6, 3 (1H, m),
6.76 (1H, d, J = 12Hz), 6.95 (1H, s), 7, 1-7, 7 (13H, m), 7.91 (2H, d, J = 9Hz), 9, 10 (1H, d, J = 9Hz) 2) 7- [2-allyloxyimino-2- (5-amino-1,2,4-thiadia-

  <Desc / Clms Page number 70>

 zol-3-yl) acetamido] -3- [2- (3-pyridyl) thiovinyl] -3-cephem- 4-benzhydryl carboxylate (syn isomer) (cis isomer)
 EMI70.1
 NMR (DMSOD 3.85 (2H, large), 4.70 (2H, d, J = 5Hz), 5.30 (1H, d, J = 5Hz), 5, 10-5, 57 (2H, m) , 5, 80-6, 13 (2H, m), 6, 63 (2H, s), 6, 93 (1H, s), 7, 17-7, 67 (10H, m), 7, 67- 8 , 67 (4H, m), 9, 70 (1H, d, J = 8Hz) 3) 7- [3-hydroxy-2- (2-tritylaminothiazol-4-yl) propionamido] -3- [2- ( 3-pyridyl) thiovinyl] -3 - cephem'-4-carbo- benzylryl xylate (trans isomer)
IR (Nujol):

   3350, 1770, 1710, 1670, 1650, 1620,
1570, 1520 cm-1
NMR (DMSO-d6) 6-: 3, 30-4, 05 (5H, m), 4.95 (1H, d, J = 5Hz), 5.85 (1H, m), 6.20 (1H, s), 6, 53 (1H, d, J = 16Hz), 7.00 (1H, s), 7, 15-7.50 (26H, m), 7, 70-8.65 (5H, m)
 EMI70.2
 4) on 7-. [2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-, [2- (3-pyridyl) thiovinyl] -3-cephem-4-carboxylate benzhydryl (syn isomer) (cis isomer)
IR (Nujol): 3300, 3150, 1780, 1730, 1680, 1620,
1530 cm "
 EMI70.3
 NMR (DHSO - d6) cS:

   3.83 (2H, m), 3.92 (3H, s), 5.28 (1H, d, J = 5Hz), 5.95 (1H, dd, J = 5Hz, 8Hz),
7, 32 (1H, d, J = 10Hz), 6.68 (1H, d, J = 10Hz),
6, 90 (1H, s), 7, 15-7, 60 (10H, m), 7, 65-8, 70 (6H, m), 9, 60 (1H, d, J = 8Hz) 5) le Benzhydryl- 7- [2-allyloxyimino-2- (5-amino-1,2,4,4-thiadiazol-3-yl) acetamido] -3- [2- (3-pyridyl) thiovinyl] -3-cephem-4carboxylate ( syn isomer) (trans isomer)
 EMI70.4
 NMR (DMSO-d6) 6; 3, 95, 4, 19 (2H, ABq, J = 18Hz) 4, 66- 12H, d, J = 5Hz), 5, 1-5, 6 (2H, m), 5, 23 (1H, d, J =; 5Rz ', 5, 91 (1H, ddr J = 5Hz, 8Hz), 6, 8-7, 7 (13H, m), 6, 92 GlH, s), 7, 87 (lR, dd, J = 2lfz, 8Hz), 8, 11 (2H, large s), 8, 55 (2H, m), 9, 65 (1H, d, J = 8Hz)

  <Desc / Clms Page number 71>

 
 EMI71.1
 6) 7 -. [2 - ethoxyimino-2- l-oxide.

   (5-amino-1,2,2thiadiazol-3-yl) acetamidoj-3- (2-tosyloxyvinyl) - benzhydryl 3-cephem- 4-carboxylate (syn isomer) (cis isomer)
IR (Nujol): 3320, 3150, 1800, 1720, 1660,
1520 cm
 EMI71.2
 NMR (DMSO-d6): 1.30 (3H, t, J = 7Hz), 2.39 (3H, bs), 3.83 (2H, m), 4.23 (2H, q, J = 7Hz) , 5.05 (1H, d, J = 5Hz), 6.06 (1H, m), 6.16 (1H, d,
J = 7Hz), 6.67 (1H, d, J = 7Hz), 6.86 (1H, s),
7, 33 (12H, m), 7, 85 (2H, d, J = 8Hz), 8, 95 (1H, d, J = 9Hz) 7) 7- [2-ethoxyimino-2- l-oxide (5-amino-1,2, 4thiadiazol-3-yl) acetamido] -3- (benzhydryl 2-tosyloxyvinyl0-3-cephem- 4-carboxylate (syn isomer) (trans isomer)
 EMI71.3
 NMR (DMSO-d):

   1.33 (3H, t, J = 7Hz), 3.67 (2H, m), 4.26 (2H, q, J = 7Hz), 5.10 (1H, d, J = 5Hz),
6.07 (1H, dd, J = 5Rz, 9Hz), 6.77 (1H, d,
J = 12Hz), 6, 95 (lEI, s), 7, 38 (13H, m), 7, 88 (2H, d, J = 7Hz), 9.05 (1H, d, J = 9Hz) 8) 7- [2-allyloxyimino-2- (5-amino-1,2,2-l-oxide)
 EMI71.4
 4-thiadiazol-3-yl) acêtamido] -3- (2-tosyloxyvinyl) -3-cêphem- 4-benzhydryl carboxylate (syn-isomer) (cis-isomer) NMR (DMSO-d.-) 6:

   2.36 (3H, s), 3.80 (2H, m),
4, 68 (2H, d, J = 5Hz), 4, 95-5.53 (3H, m),
5, 70-6, 30 (2H, m), 6, 15 (1H, d, J = 7Hz),
6, 65 (1H, d, J = 7Hz), 6, 84 (1H, s), 7, 34 (12H, m), 7, 83 (2H, d, J = 8Hz), 9.02 (1H, d, J = 8Hz) 9) 7- [2-allyloxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (2-tosyloxyvinyl) l-oxide - Benzhydryl 3-cephem-4-carboxylate (syn isomer) (trans isomer)
NMR (DMSO-d) 4;

     2, 43 (3H, s), 3, 60 and 4, 15
 EMI71.5
 (2H, ABq, J = 19Hz), 4.71 (2H, d, J = 5Hz), 5.07 (1K, d, J = 5Hz), 5 / 1-5, 6 (2H, m), 5 , 99 (1H, dd, J = 5Hz, 8Rz), 5, 8-. 63 (1H, m), 6.76 (1H, d,

  <Desc / Clms Page number 72>

 
 EMI72.1
 J = 12 fiz), 6, 9. 5 (l fi, s), 7, 1-7, 7 (13H, m), 7, 91 (2H, d, J = 9Hz), 9, 10 (lH, d, J = 9Hz) 10) 7- [2-allyloxyimino-2- (5-amino-1,2,2,4-thiadiazol-3-yl) acêtamido] -3- {2- [l- (2-N , N-dimethylaminoethyl) -lHtetrazol-5-yl] thiovinyl} -3-cephem-4-benzhydryl carboxylate (syn isomer) (trans isomer) IR (Nujol):

   3250, 170, 1715, 1640, 1520 cm NMR (DMSO-, d 2, 20 (6H, s), 3, 30 "7. 4, 00 (4H, m), 6
4, 67 (2H, d, J = 5Hz), 5, 15-5, 50 (3H, m),
5, 70-6, 15 (1H, m), 6, 70-7, 10 (3H, m), 7, 33 (lOH, m), 9, 67 (1H, d, J = 8Hz) 11) le Benzhydryl 7- [2-methoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (2-tosyloxyvinyl) -3-cephem- 4-carboxylate (syn isomer) (trans isomer) p. f. : 135-140 C (decomposition)
IR (Nujol): 3300, 3150, 3050, 1790, 1720, 1675,
1625, 1595, 1520, 1495 cm-1
NMR (DMSO-d6) <5:

     2.40 (3H, s), 3.72 and 4.35 (2H,
ABq, J = 15Hz), 3.93 (3H, s), 5.07 (1H, d,
J = 5Hz), 6.05 (1H, dd, J = 5Hz, 8Hz), 6.80 (1H d, J = 12Hz), 6.93 (1H, s), 7.27 (1H, d, J = 12Hz
 EMI72.2
 (2H, d, J = 8Hz), 7, 20-7, 60 (10H + 2H), 7, 50 (2H, d, J = 8Hz),
7, 85 (2H, d, J = 8Hz), 9, 10 (1H, d, J = 8Hz), 12) 7- [2-t-butoxycarbonylmethoxyimino- 2- (2-formamidothiazol-4) l-oxide -yl) acetamido] -3- (2-tosyloxyvinyl) -3 cephem-4-benzhydryl carboxylate (syn-isomer) (cis-isomer).



   IR (Nujol): 3300, 1790, 1720, 1675 cm-1
NMR (DMSO-d6) 6: 1, 43 (9H, s), 2.38 (3H, s),
3, 8 (2H, m), 4, 67 (2H, large s), 5, 12 (1H, d,
 EMI72.3
 J =; 5Hz), 6 ,, 1 (1H, m), 6, 1-6, 8 (2H, m)
6, 90 (1H, s), 7, 6-8, 0 (15H, m), 8.55 (1H, s), 8, 9 (1H, d, J = 8Hz).



  Preparation 14
The following compounds were obtained from a ma-

  <Desc / Clms Page number 73>

 similar to that of preparation 6--1).



  1) 7- [2-allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido acid -3- 2- (1, 3, 4-thiadiazol-2-yl ) tbiovinyl] 3éphemr 4-carboxylic (syn isomer) (trans isomer)
IR (Nujol): 3300, 1760, 1670, 1620, 1520 cm
 EMI73.1
 NMR (DMSO-d6) 6-: 2, 0 (1H, s), 3, 6-4, 16 (2H, bm), 4.72 (2H, s), 5.22 (1H, d, J = 5Hz), 4, 84-5, 56 (3H, m), 5, 84 (1H, dd, J = 8Hz, 5Hz), 7, 22 (2H, s), 9, 6 (1H, s)
 EMI73.2
 2) acid 7- [2-. allyloxyimino-2- (5-amino-1,2,2thiadiazol-3-yl) acetamido] -3- [2- (3-pyridyl) thiovinyl] -3 cephem-4carboxylic (syn isomer) (cis isomer) IR (Nujol) : 3300, 1770, 1670, 1610, 1525 cm RHN (DNSO-d6) 6:

   3, 92 (2H s), 4, 73 (2H, d, J = 5Hz), 5, 27 (1H, d, J = 5Hz), 5, 10-5, 60 (2H, m), 5, 77 -6.07 C2H, m), 6.75 (2H, ABq, J = 10Hz, 14Hz), 7.30-8.73 (2H, m), 9.65 (1H, d,
J = 8Hz) 3) acid 7-. 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido-3- [2- (3-pyridyl) thiovinyl] -3-cephem-4-carboxylic acid (syn isomer) ( cis isomer)
IR (Nujol): 3300, 3170, 1770, 1670, 1615,
1520 cm RHN (DMSO - d6) 6:

   3.93 (2H, ABq, J = 18Hz), 3.96
 EMI73.3
 (3H, s), 5.27 (1H, d, J = 5Hz), 5.87 (1H, dd, J = 5Hz, 8Hz), 6.63 (1H, d, J = llHz), 6.85 (1H, d, J = llHz), 7, 33-7, 67 (4H, m), 8, 13 (2H, large s), 9, 67 (1H, d, J = 8Hz)
 EMI73.4
 4) 7- [2-allyloxyimino-2- (5-amino-1,2,4,4-thiadiazol-3-ylacetamido] -33 {2- l- (2, N, N-dimethylaminoethyl) 1H-tetrazol acid -5-yl] thiovinyl} -3-cephem-4-carboxylic (isomer-. Re syn) (trans isomer) IR (Nujol):. 3300, 3150, 2650, 2400, 1765, 1695, 1670, 1600, 1520 cm "RM.

   N (Dd-020):. 3.05 (6H, m), 3.50-. 4, 2Q (4R, m),

  <Desc / Clms Page number 74>

 
 EMI74.1
 4, 70-5, 05 (4H, m), 5, 20-5, 70 (2H, m), 6, 15 (1H, d, J = 16Hz), 7, 23 (1H, d, J = 16Hz ) 5) 7- [2-allyloxyimino-2- (5-amino-1,2,2, 4thiadiazol-3-yl) acêtantido] -3- [2- (3, 4-tetramethylenepyridazin-6-yl) thiovinyl acid ] -3 cephem-4carboxylic (syn isomer) (trans isomer).



  IR (Nujol): 3200, 1770, 1670, 1620, 1560, 1520 cm NMR (Dr-1S0-d6) 6: 1, 78 (4H, m), 2, 50-3, 20 (4H, bm), 3 , 83 (2H, ABq, J = 18Hz), 4.67 (2H, d, J = 5Hz), 5.25 (1H, d, J = 5Hz), 5.28 (2H, m), 5.80 (1H, dd, J = 5Hz, 8Hz), 5.87 (1H, m), 7.25 (1H, dd, J = 15Hz), 7.48 (1H, s), 8, 10 (2H-, large s), 9, 60 (1H, d, J = 8Hz) 6) 7- [2allyloxyimino-2- (5-amino-l, 2, 4thiadiazol-3-yl) acetamido acid] -3-- [ 2 (3-pyridyl) thiovinyl] -. 3 cephem-4-carbxylic (syn isomer) (trans isomer) IR (Nujol): 3150, 1765, 1670, 1520 cm "NMR (DMSO-. Dg):

   3.85 (2H, m), 4.70 (2H, d, J = 5Hz), 5.20 (1H, d, J = 5Hz), 5, 2-5, 6 (2H, m), 5, 83 (1H, dd, J = 5Hz, 8Hz), 5, 8, 6, 3 (1H, m), 7, 43 (1H, dd, J = 5Hz, 8Hz), 7, 93 (1H, dd, J = 2Hz, 8Hz), 8, 13 (2H, large s), 8, 60 (2H, m), 9, 61 (1H, d, J = 8Hz) 7) 7- [2-ethoxyimino-2 acid - (5-amin. Ol, 2, 4-thiadiazol-3-y1acétamido] -3- (2tosyloxyviny1) -3céphem-4-carboxylic (syn isomer) (cis isomer) IR (Nujol): 3300, 3200, 1770, 1760, 1620, 1520 cm NMR (DSO-d) 6: 1, 27 (3H, t, J;

   = 7Hz), 2.43 (3H, s), 3.59 (2H, m), 4.18 (2H, q, J = 7Hz), 5.13 (1H, d, J = 5Hz), 5, 81 (1H, dd, J = 5Hz, 8Hz), 6.07 (1K, d, J = 7Hz), 6.67 (1H, d, J == 7Hz), 7.48 (2H, d, J = 9Hz), 7.87 (2H d, J = 9Hz), 8.06 (2H arge s), 9.48 (IH, d, JSHz)

  <Desc / Clms Page number 75>

 8) 7- [2-ethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- (2-tosyloxyvinyl) -3-cephem-4carboxylic acid (syn isomer ) (trans isomer)
IR (Nujol): 3300, 3200, 1770, 1670, 1620,
1520 cm '
 EMI75.1
 NMR (DMSO-d6) 6:

   1, 22 (3H, t, J = 7Hz), 2.40b (3H, s), 3.65 (2H, m), 4.15 (2H, q, J = 7Hz), 5.12 (1H , d, J = 5Hz), 5.77 (1H, dd, J = 5Hz, 9Hz), 6.60 (1H, d, J = 12Hz), 7.15 (1H, d, J = 12Hz), 7 , 45 (2H, d, J = 8Hz), 7.82 (2H, d, J = 8Hz), 8.04 (2H, large s), 9.49 (1H, d, J = 9Hz)
 EMI75.2
 9) 7--2-allyloxyimino-2- (5-amino-1,2,2, 4thiadiazol-3-yl) acetamido] -3- (2 - tosyloxyvinyl) - 3-cephem- 4-carboxylic acid ( syn) isomer (trans isomer) IR (Nujol):

   3300, 3200, 1770, 1670, 1620, 1590, 1520 cm NMR (DMSO-d 2, 41 (3H, s), 3, 66 (2H, m), 4, 67 (2H, d, J = 4Hz), 5, 15 (1H, d, J = 5Hz), 5, 2 .., -5, 6- (2H, m), 5.80 (1H, dd, J = 5Hz, 8Hz),
6, 60 (1H, d, J = llHz), 7, 20 (1H, d, J = llHz),
7.47 (2H, d, J = 8Hz), 7.87 (2H, d, J = 8Hz),
8, 10 (2H, large s), 9, 55 (1H, d, J == 8Hz) 10) 7- [3-hydroxy-2- (2-aminothiazol-4-yl) propionamido-3- acid [2- (3-pyridyl) thiovinyl] -3-cephem-4carboxylic (trans isomer)
IR (Nujol): 3250, 3150, 1770, 1660, 1600,
1520 cm '
NMR (DMSO-d6) #:

   3.3O4, OO (5H, m), 5.03 (IH, d,
 EMI75.3
 J = 5Hz), 5.60 (1H, dd, J = 5Hz, 8Hz), 6.30 (1H, large s), 6.33 (1H, d, J = 16Hz), 6.90 (2H, s ), 7, 2O-8.85 (6H, m), 11) 7- [2-carboxymethoxyimino-2- (2-aminothia-) acid
 EMI75.4
 zol-4-yl) acetamido] -. 3- (2-tosyloxyvinyl) -3-cephem-4-carbo-. xyliqua (. syn isomer) (cis isomer)

  <Desc / Clms Page number 76>

 
 EMI76.1
 IR (Nujol): 3300, 1775, 1705, 1650 (large) NMR (DMSO-d) 5-: 2, 46 (3H, s), 3.70 (2H, m), 6
4, 66 (2H, large s), 5, 20 (1H, d, J = 5Hz),
5, 85 (1H, m), 6, 15 (1H, d, J == 7Hz), 6, 70 (1H, d, J = 7Hz), 7, 56, 7, 93 (2H, ABq, J = 8Hz),
9, 52 (1H, d, J = 8Hz) 12) 7- [2-methoxyimino-2- (5-antino-1, 2, 4-thiadiazol-3-yl) acetamido acid] -3- (2 -toxyloxyvinyl) -3-cephem-4carboxylic (syn isomer) (trans isomer) p. f. :

   145-150 C (decomposition)
IR (Nujol): 3400, 3300, 3190, 2550, 1770, 1670,
1525, 1595, 1525 cm '
NMR (DMSO - d6) 6: 2, 43 (3H, s), 3.60 and 3.80 (2H, ABq, J = 18Hz), 3.93 (3H, s), 5.17 (1H,
 EMI76.2
 d, J = 5Ez), 5, 83 (1K, dd, J = 5Hz, 8Hz), 6, 65 (1H, d, J = 12Hz), 7, 18 (1H, d, J = 12Hz), 7, 52 (li, d, J = 8Rz), 7, 88 (1H, d, J = 8Hz), 8, 12 (2H, large s), 9, 58 (1H, d, J = 8Hz).



    Preparation 15
The following compounds were obtained in a manner similar to that of preparation 7-1).



  1) 7- [3-hydroxy-2- (2-tritylaminothiazol-4-yl) propionamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem- iodide Benzhydryl 4-carboxylate (betrayed isomer)
IR (Nujol): 3300, 3150, 1770, 1710, 1670, 1620,
1570, 1530 cm
NMR (DMSO-d6) #: 3, 30-3, 90 (5H, m), 4, 30 (3H, s),
5, 20 (1H, d, J = 5Hz), 5, 80 (1H, m), 6, 33 (1H, s), 6, 62 (1H, d, J = 16Hz), 7, 10-7, 67 (2H, m),
8, Qu-9, QO (3H, m), 9, 17 (1H, broad s) 2) iodide of 7- [2-allyloxyimino-2- (5-amino-1, 2, 4-
 EMI76.3
 thiadiazol-3-yl) acêtamido] -3- {2- [l- (4-methylpiperazin-lylcarbonylmethyl) -. 3-pyridiniot'iovinyl} -3-.cephem-4-carbo- xylated benzhydryl (syn isomer) (isomer trans)
IR (Nujol);

   3350 (large), 178Q, 1710, 1670,

  <Desc / Clms Page number 77>

 
 EMI77.1
 1620 cm RMN (DNSO-d6'Ó: 2, 70-2, 87 (8H, m-3, 23-3, 63? -3, 23-3, 63 (7H, m), 4, 67 (2H, d, J = 5Hz), 5.07-5.53 (4H, m), 5.70-6.20 (3H, m), 6.77 (1H, s), 07.07-7.57 ( lOH, m), 7, 90-9, 43 (4H, m), 9, 67 (1H, d, J = 8Hz)
 EMI77.2
 3) 7- [2allyloxyimino-2- (5-amino-1,2,2, 4thiadiazol-3-yl) acetamido iodide] -3- [2- {l- [3- (4-methylpiperazinl-yl) propyl ] -3-pyridinio} thiovinyl] -3-benzhydryl cephem-4-carboxylate (syn isomer) (trans isomer) Preparation 16 To a solution of 7- [2-ethoxyimino-2- (5-amino- 1, 2, 4-thiadiazol-3) yl) acetamido] -3-ethynyl-3-cephem-4-benzhydryl carboxylate (syn isomer) (294 mg) in a mixture of acetonitrile (2 ml) and water (1 ml)

   3-mercapto-1-methylpyridinium chloride (97 mg) was added at room temperature. The reaction mixture was stirred for one hour at the same temperature and then evaporated to dryness under vacuum to give 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl chloride) ) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-benzhydryl cephem-4-carboxylate (syn isomer) (cis isomer) (360 mg). p. f. : 140-145 C (decomposition)
IR (Nujol):

   3350, 1780, 1720, 1675, 1525 cm "Preparation 17 1) In a mixture of 1- (3-aminopropyl) -3-mercaptopyridinium chloride hydrochloride (2.8 g) and diisopropylethylamine (0.5 ml) in N, N-dimethylformamide (30 ml) was added 7- [2-allyloxyimino-2- (2-formamido-
 EMI77.3
 thiazol-4-yl) acetamido] -3- (2-tosyloxyvinyl) -3-benzhydryl-cephem-4carboxylate (syn-isomer) (trans-isomer) (3.0 g).

   The reaction mixture was stirred at room temperature for 4 hours and poured into ethyl acetate (250 ml) The resulting precipitates were collected by filtration, washed with ethyl acetate 1

  <Desc / Clms Page number 78>

 and dry under reduced pressure to give 7- [2-allyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] hydrochloride chloride -3- {2- [1- (3-aminopropyl) -3-pyridinio ] benzhydryl thiovinyl} -3-cephem-4-carboxylate (syn iso-mother) (trans isomer) (3.5 g).



   IR (ujol): 1770, 1705, 1660, 1610 cm NMR (DMSO-d6) #: 2.50 (2H, m), 3.0 (2H, m),
 EMI78.1
 3.98 (2zarge s), 4.80 (2H, m), 5.33 (IH, d, J = 5Hz), 5.30 (2H, m), 5.95 (1H, dd, J = 5Hz , 8Hz), 7.0 (1H, s), 7, 2-7, 7 (1H, m), 8.5 (1H, s), 8, 9-9, 6 (5H, (m) 2) The following compound was obtained in a manner similar to that of preparation 17-1) the hydrochloride of 7- [2-
 EMI78.2
 allyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- {2- [l- (3-N, N-dimethylam. inopropyl) -3-pyridinio] thiovinyl} 3- cephem-4-carboxylate benzhydryl (syn isomer) (cis isomer)
IR (Nujol):

   1780, 1710, 1660, 1630 cm
NMR (DMSO-d6) #: 2, 7 (2H, m), 2.90 (6H, s),
3, 1 (2H, m), 4, 2 (2H, m), 4, 8 (4H, m), 5, 2 (1H, d, J = 5Hz), 5, 3 (2H / m), 6 , 0 (2H, m),
6, 95 (1H, s), 7, 0-7, 6 (13H, m), 8, 0-9, 4 (5H, m) Preparation 18 1) With a hydrochloride solution of
 EMI78.3
 7 - '[2-allyloxyimino-2- (2-formamidothiazol-4-yl) acetamJ. do] -3- {2- [1- (3-aminopropyl) -3-pyridinio] thiovinyl} benzhydryl 3-cephem-4-carboxylate (syn isomer) (trans isomer) (3.5 g) in methanol ( 70 ml) concentrated hydrochloric acid (1.90 ml) was added.

   The mixture was stirred at room temperature for 3.5 hours and poured into ethyl acetate. The resulting precipitates were collected by filtration and washed with ethyl acetate to give hydrochloride hydrochloride.

  <Desc / Clms Page number 79>

 
 EMI79.1
 7- [2-allyloxyimi. no-. 2- (2 - friend. Nothiazol-4-yl) a. ketamido] -3- 2- [1- (3-aminopropyl) -3-pyridinio] thiovinyl} -3-cephem-4-benzhydryl carboxylate (syn-isomer) (trans-isomer), (1, 4 g).
 EMI79.2
 



  NMR (DMSO-d) 8: 2.50 (2H, m), 2.9 (2H, m), 3.45 (2H, m), 4.85 (2H, m), 5.26 (1H, d, J == 5Hz), 5, 2 (2H, m), 5, 9 (2H, m), 6, 95 (1H, s) ,. 7, 4 (12H, m), 7, 6 (1H, s), 8, 1-8, 7 (3H, m), 8, 9-9.6 (3H, m) 2) The following compound was obtained in a manner similar to that of preparation 18-1)
 EMI79.3
 7- [2t-butoxycarbonylmethoxyirnino-2- (2 aminothiazol-4-yl) acetamido] 73- (2-tosyloxyvinyl) -3Ïcephephem-4-carboxylate (syn isomer) (cis isomer)
IR (Nujol): 33QO, 1780, 1718, 1672, 1630 cm RMN (DMSO-d6) #:

   1, 43 (9H, s), 2.40 (3H, s),
3.65 (2H, m), 4.60 (2H, large s), 5.23 (1H, d,
J = 5Hz), 6.0 (1H, m), 6.04 (1H, d, J = 7Hz),
6, 67 (1H, d, J = 7Hz), 6.85 (1H, s), 7.3-8, 0 (15H, m), 9, 52 (1H, d, J = 8Hz) Preparation 19
 EMI79.4
 A suspension of 7-ethoxyimino-2- (5-amino-1, 2, 4-thiadiazol3-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyH-3-cephem - 4- carboxylate (syn isomer) (trans isomer) (5.5 g) in water (300 ml) was adjusted to pH 6.5 with saturated aqueous sodium bicarbonate solution.

   µm while cooling to O-5 ° C and then sodium borohydride (800 mg) was added in parts, simultaneously adjusting to pH -7.0 with IN hydrochloric acid, The reaction mixture was stirred for one hour at O-5 C and then adjusted to a pH of 3.0 with 6N hydrochloric acid. A small amount of insoluble matter was removed by filtration. The filtrate was subjected to column chromatography on a resin

  <Desc / Clms Page number 80>

 non-ionic adsorption known as Diaion HP-20 (II).

   After washing the column with water and a 30% aqueous methanol solution subsequently, the fractions which were eluted with a 50% aqueous methanol solution were evaporated and lyophilized to give acid 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [2- (1-methyl-1, 2, 5, 6-tetrahydropyrid-3-yl ) thiovinyl] -3-cephem-4-carboxylic (syn isomer) (trans isomer) (30 g). p. f. : 160-165 C (decomposition).



   IR (Nujol): 3300, 1760, 1600, 1520 cm
 EMI80.1
 NMR (DMSO-d) 6: 1, 33 (3H, t, J = 7H), 2.60 (3H, s), 3, 1-2, 8 (2H, m), 3.47 (4H, large s),
3.77 (2H, large s), 4.27 (2H, q, J = 7Hz),
5, 17 (1H, d, J = 5Hz), 5.80 (1H, 2d, J = 8Hz,
J = 5Hz)), 6.13 (1H, large s), 6.57 (1H, d,
J = 15Hz), 7, 10 (1H, d, J = 15Hz),
8, 17 (2H, large s), g, 56 (1H, d, J = 8Hz) Preparation 20 1) (1) A mixture of 3-benzoylthiopyridine (8,6 g) and N- (2-bromoethyl) phthalimide (12.2 g) was heated for 8 hours at 95-100 ° C and triturated in chloroform (100 ml) for 30 minutes at room temperature. The resulting precipitates were collected by filtration, washed with chloroform and dried to give 1- (2-phthalimidoethyl) -3-benzoythiopyridinium bromide (8.3 g).



   IR (Nujol): 1770, 1710, 1690, 1620, 1590,
1580 cm (2) The following compound was obtained in a similar manner to that of preparation 20-1) - (1), 1- (3-phthalimidopropyl) -3-benzoylthiopyridinium bromide.
 EMI80.2
 



  IR (Nujol) 1760, 1695, 1610, 1440, 1390 cm "2)

  <Desc / Clms Page number 81>

 (1) A suspension of 1- (2 - phthalimidoethyl) -3-benzoylthiopyridinium bromide (40 g) in 6N hydrochloric acid (510 ml) was heated at reflux for 10 hours and cooled to Room temperature.



  The resulting precipitates were separated by filtration and washed with water. The filtrate and washes were combined and washed with chloroform. The separated aqueous layer was evaporated to dryness under reduced pressure. The residue was triturated in acetone, and the resulting precipitates were collected by filtration and dried in vacuo to give 1- (2-
 EMI81.1
 aminoethyl) -3-mercaptopyridinium (18.1 g). p. f,: 180-1820C IR (Nujol):

   2300-. 2200, 1610, 1560, 1450,
1315 cm '
NMR (DO) 6: 3.73 (2H, t, J = 7Hz), 4.93 (2fi, t, J = 7Hz), 7.91 (1H, dd, J = 5Hz, 8Hz),
8, 51 (1H, dd, J = 2Hz, 8Hz), 8, 67 (1H, dd,
J = 2Hz), 5Hz), 8, 87 (1H, s) (2) The following compound was obtained in a manner similar to that of preparation 20-2) - (1) l- chloride chloride hydrochloride (3 - aminopropyl) - 3-mercaptopyridinium
NMR (D20) 6:

   2.47 (2H, m), 3.23 (2H, t, J = 7Hz),
4.71 (2H, t, J = 7Hz), 8.00 (1H, m), 8.50 (1H, dd, J = 2Hz), 8Hz), 8.70 (1H, dd, J = 2Hz, 5Hz),
8, 91 (1H, s) 3) To a solution of 1- (2 aminoethyl) -3-mercaptopyridinium chloride hydrochloride (9.0 g) in water (45 ml) was added an iodine solution (4, 1 g) in etha. - noi (90 ml) at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was triturated in ethanol. The resulting precipitates were combined by filtration, washed with ethanol and dried in vacuo to give dichlorhydra-

  <Desc / Clms Page number 82>

 
 EMI82.1
 te of desulfide of 3, 3'-:, [chloride of 1, l '- di (2-aminoethyl) pyridinium] (10.0 g).



   NMR (DO): 3.77 (4H, t, J = 7Hz), 5.03 (4H, t,
J = 7Hz), 8, 17 (2H. Dd, J = 5Hz, 8Hz), 8, 75-
9.05 (4H, m), 9.27 (2H, large)
4) A mixture of disulphide dihydrochloride
3, 3 '- [1,1'-di (2-aminoethyl pyridinium chloride) (9,75 g), sodium bicarbonate (3,62 g), formic acid (9,91' g), 35% aqueous formaldehyde solution (8.13 g) and water (4.3 ml) was heated for 1.5 hours at 100 ° C. and cooled. To the mixture acid was added. 6N hydrochloric acid (7.0 ml) and the formic acid and any excess formaldehyde were evaporated The residue was diluted with water (50 ml) and subjected to column chromatography on a resin. non-ionic adsorption known as "HP-20" (320 ml).

   The elution was carried out with water.



   The fractions containing the desired compound were combined and evaporated to dryness to give 3.3 '- [1,1'-di (2-N, N-dimethylaminoethyl) pyridinium disulphide dihydrochloride] (8.7 g ) as an oil
NMR (D2O) #: 3, 03 (12H, s), 3.95 (4H, t, J = 7Hz),
5, 15 (4H, t, J = 7Hz), 8, 13 (2H, m), 8, 70-8, 93 (4H, m), 9, 27 (2H, large s).



   5) (1) To a solution of disulfide dihydrochloride of 3, 3 '- [1,1'-di (3-N, N-dimethylaminopropyl) pyridiniun chloride] (16.0 g) in water (80 ml) and methanol (160 ml) triphenylphosphine (7.84 g) was added at room temperature. The mixture was stirred at the same temperature for one hour and concentrated under reduced pressure to remove the methanol. The residual aqueous solution was washed with chloroform twice and evaporated in vacuo. To the residue was added ethanol and the ethanolic solution was concentrated to give 1- (3-N, N-dimethylamino) hydrochloride

  <Desc / Clms Page number 83>

 propyl) -3-mercaptopyridinium (16.0 g).



   NMR (D20) 5: 2.60 (2H, m), 3.0 (6H, s), 3.35 (2H, m), 3.70 (2H, m), 7.86 (1H, m) , 8, 60 (2H, m),
8, 93 (1H, large s) (2) The following compound was obtained in a similar manner to that of preparation 20-5) - (1)
 EMI83.1
 1 (2-N, N-dimethylaminoethyl) -3-mercaptopyridinium IR hydrochloride chloride (Nujol): 2680-2550, 1620, 1555, 1440, 1405 cm "NMR (D O):

   3.07 (6H, s), 3.93 (2H, t, J = 7Hz), 5.13 (2H, t, J = 7Hz), 8.08 (1H, dd, J = 5Hz,
8Hz), 8.72 (1H, dd, J = 2Hz, 8Hz), 8.90 (1H, dd, J = 2Hz, 5Hz), 9.07 (1H, large s), 6) Disulfide of 3, 3'-dipyridyl (7.0g) and 3 - N, N - chloride hydrochloride. dimethylaminopropyl (10.05 g) were stirred between 130 and 140 for 4 hours to give 3,3'-disulfide dihydrochloride [1', l'-di (3-N, N-dimethylaminopropyl) pyridinium] (17, 0 g)
NMR (D20) 6: 2, 6 (4H, m), 2.93 (12H, s), 3.33 (4H, m), 4.76 (4H, t, J = 7Hz), 8.08 ( 2H, m),
8, 80 (4H, m), 9, 20 (2H, large s) Preparation 21 1) A. a stirred mixture of triphenylphosphine (40.7 g) and zinc powder (18.5 g) in chloride methylene (250 ml) carbon tetrabromide (45 g) was added between 20 and 30 C.

   Benzhydryl benzhydryl 7-phenylacetamido-3-formyl-2-cephem-4carboxylate (10 g) was added in portions to the above reaction mixture and the mixture was stirred for 30 minutes at room temperature. The triphenylphosphine oxide was solidified by additions of ethyl acetate to the reaction mixture and removed by filtration. The residue left by the removal. nt of the solvents was chromatographed on silica gel, elution with chloroform containing ethyl acetate (10%) was

  <Desc / Clms Page number 84>

 
 EMI84.1
 given 7-phenylacetamido-3- (2,2-dibromovinyl) -2 cephem-. Benzhydryl 4carboxylate (4.4g).



  IR (Nujol); 3200, 1730, 1730, 1650, 1520 cm NMR (DMSO-dJ 6: 3, 55 (2H, s), 5, 13 (1H, d, b J = 5Hz), 5.45 (1H, dd, J = 5.8Hz), 5.65 (1H, s), 6.90 (1H, s), 7.1 (1H, s), 7, 2-7, 7 (16H), 9.2, (1H, d , J = 8 Hz) 2) To a suspension of phosphorus pentachloride (13.74 g) in dichloromethane (150 ml), pyridine (5.34 ml) was added dropwise between -15 and -10 ° C. stirring and stirring was continued at the same temperature for 30 minutes. To the above mixture was added 7-phenylacetamido-3- (2,2-dibromovinyl) -2 cephem-4-benzhydryl carboxylate (29.4 g) at -5 C.



  After the reaction mixture was stirred at -50 ° C for 1.5 hours, drop a. drop the methanol reaction mixture (26.62 ml) while cooling to -20 ° C and the mixture was stirred cooling to -20 ° C to -5 ° C for 1.5 hours. Then, water (30 ml) was added to the reaction mixture while cooling with ice.

   After the reaction mixture was stirred for 1 hour at the same temperature, diisopropyl ether (100 ml) was added to the reaction mixture at 0 ° C. The resulting precipitates were collected by filtration and washed in turn with water and diisopropyl ether to give 7-amino-3- (2,2-dibromovinyl) -2-cephem-4-carboxylate hydrochloride (25, 23 g).
 EMI84.2
 



  IR (Nujol); 1775, 1730, 1580 cm NMR (DMSO-d6, 6):. 5, 03 (1H, d, J4Hz), 5, 20 o (1H, d, J = 4Hz), 5.70 (1H, s), 7, 83 (1H, s),
7, 08 (1H, s), 7, 13-7, 63 (10H, m) 3) To a mixture of water (100 ml), ethyl acetate (100 ml) and tetrahydrofuran (100 ml ) 7-amino-3- (2,2-dibromovinyl) -2-cephem-4- hydrochloride was added

  <Desc / Clms Page number 85>

 benzhydryl carboxylate (5 g) and the mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with brine, dried over magnesium sulfate. The solution was evaporated in vacuo and the residue was dissolved in dichloromethane (50 ml). On the other hand, acetic anhydride (3.2 ml) and formic acid (1.29 ml) were stirred at 40 to 45 ° C for 30 minutes.



   This solution was added to the dichloromethane solution obtained above while cooling with ice and the resulting mixture was stirred at the same temperature for 1 hour. After water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate.



   The solution was evaporated in vacuo to give
 EMI85.1
 7-formamido-3- (2,2-dibromovinyl) -2-cephem-4-carboxylate ner of benzhydryl (4.20 g).



  IR (Nujol): 1780, 1725, 1655 cm NMR (DMSO-d): 5, 20 (1H, d, J = 4Hz), 5, 70 (1H, dd, J = 8Hz, 4Hz), 7, 70 ( 1H, s), 6, 90 (1H, s), 7, 12 (1H, s), 7, 23-7, 73 (10H, m), 8, 20 (1H, s), 9, 17 (! Hi, d, J = 8Hz) 4) To a solution of benzhydryl 7-formamido-3- (2,2-dibromovinyl) -2-cephem-4-carboxylate (4.2 g) in acetate ethyl (42 ml) a solution was added
 EMI85.2
 m-chloroperhenzoìque acid (1.72 g) in ethyl m-chloroi acid acetate between - 20 and 71 (DOC and the resulting mixture was stirred at -10 for 45 minutes, The precipitates were combined by filtration to give 7-formamido3- (2,2di.

   benzhydryl bromovinyl) -3-cephem-4-carboxylate as l-oxide (1, 9 9) IR (Nujol) 3270, 1790, 17] 0., 1655 cm-1

  <Desc / Clms Page number 86>

 
 EMI86.1
 R. MN (DMSO-dJ <S-: 3, 6: 7-4, 17 (2H, m), 5.05 .1H, d, J = 5Hz), 6, 12 (1H, dd, J = 8Hz, 5Hz), 6, 98 (lff, s), 7, 2-7, 77 (10H, m),
8, 20 (1H, s), 8, 47 (1H, d, J = 8Hz) 5) To a solution of 7-formamido-3- (2, 2-dibromovinyl) -3-cephem-4-oxide -benzhydryl carboxylate (1.8 g) n-butyllithium (7.27 ml of a 1.65 M solution in hexane) was added between -65 and -60 ° C. under a nitrogen atmosphere. After the resulting mixture was stirred at the same temperature for 30 minutes, ethyl acetate (50 ml) was added to the reaction mixture.

   The reaction mixture was heated to -20 ° C and hydrolyzed with 10% hydrochloric acid. The organic layer was separated and washed with water and brine and dried over magnesium sulfate. The solution was evaporated in vacuo to give l-oxy-
 EMI86.2
 of 7 - fornamido-3-ethynyl-. Benzhydryl 3-cephem-4-carboxylate (1.30 g) IR (Nujol): 17g0, 1720, 1660 cm NMR (DMSO-d6) 6:

   3.67-4.08 (2H, m), 4.72 (1H, s), 5.02 (1H, d, J = 5Hz), 6.03 (1H, dd, J = 8Hz, 5Hz), 6, 97 (1H, s), 7, 12-7, 78 (10H, m), 8, 15 (1H, s), 8, 48 (1H, d,
J = 8Hz) 6) To a solution of the oxide of 7-formamido-3-
 EMI86.3
 benzhydryl ethynyl-3-cephem "4-carboxylate (12 g) in N, N-dimethylformamide (96 ml) phosphorus trichloride (0.48 ml) was added at -20oe and the resulting mixture a was stirred at -20 ° C. to -10 ° C. for 10 minutes.



  After water and ethyl acetate were added to the reaction mixture, the separated organic layer was washed with water and brine, dried over magnesium sulfate, The solution was was evaporated in vacuo to give 7-formamido-3-ethynyl-3-cephem-4-carboxylated with henzhydryl (1.15 g).

  <Desc / Clms Page number 87>

 
 EMI87.1
 IR (Nujolj - l IR (Nujol: 1780, 1720, 1670 cm 'RMN (DMSO-d6) #:

   3, 58-4, 12 (2H, m), 4, 73 (1H, s), 5, 25 (1H, d, J = 5Hz), 5, 92 (1H, dd, J = 8Hz,
5Hz), 6, 97 (1H, s), 7, 08-7, 75 (10H, m),
8, 17 (1H, s), 9, 13 (1H, d, J = 8Hz) 7) To a solution of benzhydryl 7-formamido-3-ethynyl-3-cephem-4-carboxylate (3 g) in a mixture of methanol (30 ml) and tetrahydrofuran (15 ml), phosphorus oxychloride (2.75 g) was added while cooling with ice. After the resulting mixture was stirred at room temperature for 30 minutes, the reaction mixture was added to diisopropyl ether (300 ml), and the precipitates were collected by filtration.



  The precipitates were added to a mixture of water (50 ml) and ethyl acetate (50 ml) with stirring, and the mixture was adjusted to pH 7.0 with a saturated aqueous solution of bicarbonate. sodium, To the separated aqueous layer was added ethyl acetate (50 ml), and the mixture was acidified to a pH of 3.0 with 10% hydrochloric acid and the resulting precipitates were combined by filtration to give 7 amino-3-ethynyl-3-cephem-4carboxylate benzhydryl (2.03 g)
 EMI87.2
 -: -. 1 IR (Nujol): 1775, 1720 cm NMR (DMSO-d) 6:

   3, 5-3 ,. 9 (2H, m), 4.60 (1H, s), 4.88 (1H, d, J = 5Hz), 5.08 (1H, d, J = 5Hz), 6.92 (1H, s) , 7! 08-7t73 (1OH, m) 8) 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol- 3-yl) acetamido] -3-ethynyl-3-cephem-4- benz carboxylate. ydryl (syn-isomer) (2.0 g) was obtained by reacting benzhydryl benzhydryl 7-amino-3-ethyl-3-cephem-4-carboxylate (1.50 g) with 2- [2-chloride hydrochloride 2-ethoxy-
 EMI87.3
 imino-2- (5-amino-1,2,4-thiadiazQl-. 3-yl) Ja. cetyl (syn isomer) (1.25 g) in a conventional manner.



  IR (Nujol); 1780, 1720, 1650 cm NMR (DM! Q-1, 25 hard, t, J = 7Hz), 3.33-3.95

  <Desc / Clms Page number 88>

 (2H, m), 4.18 (2H, q, J = 7Hz), 4.65 (1H, s), 5.23 (1H, d, J = 5Hz), 6.97 (1H, dd, J = 8Hz, 5Hz), 6, 93 (1H, s), 7, 07-7, 70 (10H, m), 9, 60 (1H, d, J = 8Hz)
 EMI88.1
 9) 7- [2-ethoxyimino-2- (5-amino-1,2,2, 4thiadiazol-3-yl) acetamido] -3-ethynyl-3-cephem-4-carboxylic acid (syn isomer) (0.35 g) was obtained by submitting 7-2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido -3-ethynyl-3-cephem-4-carboxylate of benzhydryl (1.9 g) to a reaction for removing the protecting group from the carboxy group in a conventional manner.



   IR (Nujol): 3260, 1775, 1670
NMR (DMSO-d6) #: 1, 25 (3H, t, J = 7Hz), 3.38-
3.88 (2H, m), 4.18 (2hui q, J = 7Hz), 4.45 (1H, s), 4.85 (1H, dd, J = 8Hz, 5Hz), 5.18 (1H , d, J = 5Hz), 8, 10 (2H, large s),
9, 55 (1H, d, J = 8Hz) Preparation of the desired compounds of the present invention
EXAMPLE 1
 EMI88.2
 To an acid solution 7-- [2-ethoxyimino-'2- (5 amino-l, 2, 4-thiadiazol-3-yl) acetamido] -3- [2- (3-pyridyl) thiovinyl] -3- cephem-4-carboxy (syn isomer) (trans isomer) (1.2 g) in a mixture of water (5 ml), tetrahydrofuran (70 ml) and dimethylformamide (10 ml) was added 'methyl iodide (0.7 ml).

   After stirring at the Emulating temperature for 15-20 hours, the mixture was concentrated and poured into ethyl acetate (300 ml).



  The resulting precipitates were collected by filtration and washed with diisopropyl ether. These precipitates were chromatographed on a macroporous nonionic resin called "Diaion-HP-20" and eluted with a 20% aqueous solution of isopropyl alcohol. The fractions containing the desired compound were concentrated and lyophilized to give 7- [ 2-ethoxyimino-2-

  <Desc / Clms Page number 89>

 (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [2- (l-methyl- 3-pyridinio-thiovinyl] -3-cephem-4-carboxylate (syn isomer) (isomer trans) (0.45 g
 EMI89.1
 IR (Nujol); 3300 (large), 1760, 1660, 1600, 1520 cm "NMR (DHSO-d6) 0:

   1, 30 (2H, t, J = 7Hz), 3, 1-3, 8 (2H, m), 4.28 (3H, q, J = 7Hz), 4.40 (3H, s),
5, 12 (1H, d, J = 4Hz), 5, 71 (1H, dd, J = 4,
8Hz), 6, 53 and 7, 50 (2H, 2xd, J = 16Hz), 7, 8-
9, 20 (5H, m), 9, 50 (1H, d, J = 8Hz)
EXAMPLE 2 1) A mixture of 7- [2-ethoxyimino-2- (5-amino- 1, 2, 4-thiadiazol - 3-yl) acetamido] -3- [2- (2-pyridyl) thiovinyl acid ] -3-cephem-4-carboxylic (syn-isomer) (trans-isomer)
 EMI89.2
 (1.5 g), dimethylformamide (15 ml) and methyl iodide (1.5 ml) was stirred for six days at room temperature in a stainless steel bomb. The reaction mixture was poured into ethyl acetate.

   The resulting precipitate was collected by filtration and washed with ethyl acetate and dried to give 7- [2-ethoxyimino-2- (5-amino-
 EMI89.3
 1, 2, 4-thiadiazol-3-yl) acêtamido '] - 3- [2- (1-methyl-2-. Pyridinio) thiovinyl] -3-cephem-4carboxylate (syn isomer) (trans isomer) (2, 0 g) IR (Nujol): 3400, 3250, 1780, 1650-1680, 1620 cm NMR (DMSO-d) 6: 1, 38 (3H, t, J = 7Hz), 3.87 (2H, ABq, J = 18Hz), 4, 23 (3EI, s), 4, 3 (2H.,:

   rn), 5.3 (1H, d, J = 5Hz), 5.88 (1H, dd, J = 8Hz, 5HZ), 7.07 (1H, J = 16Hz), 7.48 (1H, d, J = 16Hz), 7, 8-. 8, 7 (3H, m), 9.0 (1H, d, J = 5Hz),
9, 67 (1H, d, J = 8Hz) 2) 7- [2-ethoxyimino-2- (5-amino- 1,2,4-thiadiazol-3-ylacetamido] -3- [2-iodhydrate] - (1-methyl-2-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn-isomer) (iso-

  <Desc / Clms Page number 90>

 trans mother) (2.0 g) was dissolved in a saturated aqueous solution of sodium bicarbonate. After adjusting to a pH of 5.5 with a 10% aqueous hydrochloric acid solution, the solution was filtered to remove the undissolved compound. The filtrate was purified by column chromatography on a non-ionic macroporous adsorption resin called "Diaion HP-2O" and eluted with a 30% aqueous solution of isopropyl alcohol.

   The fractions containing the desired compound were combined, concentrated in vacuo and lyophilized to give 7-
 EMI90.1
 [2-ethoxyimino-2- (5-aminol, 2,4-thiadiazol3-yl) acetamido] - 3) [2- (1-methyl-2-pyridinio-thiovinyl] -3-cephem-4-carboxylate (syn isomer ) (trans isomer) (0.8 g).



  IR (Nujol): 3300, 3200, 1760, 1650, 1600 cm NMR (DMSO-D 6: 1, 28 (3H, m), 3.55 (2H, ABq, J = 18Hz), 4, 20 (3H, s), 4.15 (2H, m), 5.15 (1H, d, J = 5Hz), 5.70 (1H, dd, J = 8Hz, 5Hz), 6.65 (1H, d, J = 16Hz), 7.80 (1H, d, J = 16Hz), 8.00-8.50 (5H, m), 8.90 (1H, bs), 9.55 (1H, d J = 8Hz
EXAMPLE 3
The following compounds were obtained in a manner similar to that of Example 1 or of Example 2.



  1) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1-methyl-3-pyridinio-thiovinyl] -3-cephem- 4-carboxylate (isomer syn) (trans isomer)
IR (Nujol): 3400-3100 (large), 1760, 1660,
1600, 1520 cm '
NMR (DO-DCl): 3.90 (2H, d), 4.12 (3H, s),
4.50 (3H, s), 5.32 (1H, d, J = 4Hz), 5.80 (1H, d, J = 4Hz), 7.05 and 7.40 (2H, 2xd,
J = 16Hz), 7.18 (1H, s), 7, 8-9, 0 (4H, m) 2) the trifluoroacetic acid salt of iodhydrate
 EMI90.2
 7-amino-3- [2- (1 - methyl-2-? yridinio) thiovinyl] -3-cephem- 4-carboxylate (trans isomer) (3,9 g)

  <Desc / Clms Page number 91>

 
 EMI91.1
 IR (Nujol): 2550-. 2450, 1760, 1660, 1640, 1600 cm 'NMR (DMSO-d) 0:

   3, 75-4, 3 (2H, m), 4, 21 (3H, s), 5, 0-5, 47 (2H, m), 7, 13 (1H, d, J = 16Hz),
7, 3-8, 3 (6H, m), 9.0 (1H, d, J = 5Hz) 3) the trifluoroacetic acid salt of 7-amino-3- [2- (1-methyl -3-pyridinio-thiovinyl] -3-cephem-4-carboxylate (trans isomer)
IR (Nujol): 3350, 2500-2600, 1780, 1670,
1620 cm
 EMI91.2
 NMR (DMSO-d6) 6: 3.95 (2H, ABq, J = 18Hz), 4.30 b (3H, s), 5, 1-5, 3 (2H, m), 6, 5-7, 3 (2H, m),
8, 0-8, 9 (5H, m), 9, 13 (1H, large s) 4) the trifluoroacetic acid salt of 7-amino-3- [2- (4-methyl-2- pyrazinio) thiovinyl] -3-cephem-4-carboxylate (trans isomer)
 EMI91.3
 IR (Nujol): 3300, 1800, 1670 cm IR (Nujol):

   3300, 1800, 1670 cm 5) 7- [2-methoxyimino-2- (2-amothothol-4-yl) acetamido] -3- 2- (1-methyl-2-pyridinio) thiovinyl -3-cephem-4 -carboxylate (syn isomer) (trans isomer) IR (Nujol): 3300, 1765, 1670, 1611, 1562,
1533 cm
 EMI91.4
 6) 7- [2-methoxyimìno-2- (2-aminothiazol-4-yl) acetamìdo] -3- [2- (4-methyl-2-pyrazinìo) thiovinyl] 3-cephem-4-carboxylate ( syn isomer) (trans isomer)
IR (Nujol): 3300, 1765 (wide), 1660, 1600 cm
 EMI91.5
 7) 7- [2-methoxyimino-2- (2-tritylaminot. Hiazol-4yl) acetamido] -3- [2- (1-methyl-2-pyridinio) thiovinyl] -3 cephem-4-carboxylate (syn isomer ) (trans isomer)
IR (Nujol): 3250, 1780, 1672, 1595 cm
 EMI91.6
 8) 7- [2-methoxyimino-2- (2-t-pentyloxycarbonylaminothiazol-4-yl) acetamido] -3-:

   - [2- (4-methyl-2-pyrazini0) thiovinyl] -3-céphern-4-carboxyla te (syn isomer) (trans isomer)

  <Desc / Clms Page number 92>

 
 EMI92.1
 9) 7- [2-ethoxyimino-2- (5-amino-1,2,2, 4thiadiazol-3-yl) acetamido] -3- [2- (1,3-dimethyl-2-pyrimidinio iodide) ) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer)
IR (Nujol): 3350, 1770, 1663, 1605 cm
 EMI92.2
 NMR (D20) 6:

   1.40 (3H, t, J = 7Hz), 3.80 (2H, large s), 3.91 (3Hi s), 4.14 (3H, s), 4.50 (2H, q, J = 7Hz), 5.30 (1H, d, J = 5Hz), 5.80 (le, d, J = 5Hz), o, 73, 7, 27 (2H, ABq, J = 16Hz), 7.77 ( 1H, m), 9.03 (2H, m)
 EMI92.3
 10) 7- [2-étfioxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acêtamido] -. 3-- [2- (4-methyl-'2-pyrazinio) thiovinyl - 3-cephem-4-carboxylate (syn-isomer) (trans-isomer)
IR (Nujol): 3350, 1760 (wide), 1665, 1607 cm-1
NMR (DMSO-d6) 6-:

   1, 20 (3H t, J = 7Hz), 3.90 (2H, o large s), 4, 13 (2H, q, J = 7Hz), 4.26 (3HR s),
5, 17 (1H, d, J = 5Hz), 5.77 (1H, dd, J = 5Hz,
8Hz), 7, 22 (2H, wide s), 8, 03 (2H, wide s)
 EMI92.4
 8, 80 (1H, large s), 9, 20 (2H, large s), 9, 50 (1H, d, J = 8Hz) 11) le 7- [2-methoxyimino-2- (5-amino-1 , 2, 4-thiadiazol-3-yl) acetamido] -3- [2- (1-methyl-2-. Pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer) Il 3250- 3350, 1770, 1660, 1620, 1560,
1530 cm 12) the trifluoroacetic acid salt of iodhydrate
 EMI92.5
 7-amino-3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (cis isomer)
IR (Nujol):

   3400 (wide), 2350 (wide), 1800
1670, 1620, 1540-1520 cm "- 13) 7- [2-ethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [2- (1- ethyl-3-pyridinio) thiovinyl] - 3-cephem-4-carboxylate (syn-isomer) (trans-isomer)
IR (Nujol): 3300 (wide), 1770, 1675, 1600,
 EMI92.6
 l 1520 cm

  <Desc / Clms Page number 93>

 
 EMI93.1
 NMR (DMSO-d6) 6: 1, 05-1, 80 (4H, m, J = -7Hz), b 3, 13-3, 8 (2H, m), 4.23 (3H, q, J = 7Hz), 4.68 (3H, q, J = 7Hz), 5.12 (1H, d, J = 5Hz), 5.68 (IH, dd, J = 5, 8Hz), 6.64 (1H, due J = 16Hz), 7.49 (1H, d, J = 16Hz), 7.80-9.30 (6H, m), 9.50 (1H, d, J = 8Hz) 14) on 7- [ 2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [2- (1-methyl-. 3-pyridinio) thiovinyl] - 3-cephem-4- carboxylic (syn isomer) (cis isomer) IR (Nujol):

   3300 (large), 1760, 1665, 1600, 1520 cm '15) le 7- [2carboxymethoxyimino-2- (5-amino-l, 2, 4-thiadiazol-3-yl) acetamido] -3- [2- ( 1-methyl-3-pyridinio) thiovinyl] - 3-cephem-4-carboxyla te (syn isomer) (trans isomer) IR (Nujol): 3300 (large), 1765, 1670, lus15, 1560, 1525 cm 16) le 7- [2-allyloxyimino-2- (5 "amino-1,2,4-thiadiazol-3-yl) aceamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3 cephem-4- carboxylate (syn isomer) (isomerretrans) IR (Nujol): 3300, 1760, 1670, 1620, 1600, 1530 cmT 17) on 7-. [2-.

   (t-butoxycarbonylmethoxyimino) - '2- (2-amino "thiazol-4-yl) acetamido] -3- (l-methyl-3-pyridinio) thiovi. nyl] - 3-cephem-4carboxyla te (syn isomer) ( trans) IR isomer (Nujol): 3200-3300, 2400-2600, 1770, 1715, 16. 80, 1630 cm NMR (DMSOd) Ò: 1.50 (9R, s), 3, 20-4, 10 (2H , m), 4.43 (3H, s), 4.70 (2H, s), 5.30 (1H, d, J = 5Hz) 5, 83 (1H, dd, J = 5Hz, 8Hz), 7 , 00 (1H, s), 7, 30 (2Hì wide s), 8. -9.00 (6H, m), 9, 2'7 (IH, large s), 9, 77 ('H, d, J = 8Hz 18) le 7- [2carboxyméthoxyimino-2- (2-aminothiazol-4-. Yl) acëtamido] -3-. 2- (. L-methyl-3-pyri, dinio) thiovinyl] -3-cê-

  <Desc / Clms Page number 94>

 phem-4-carboxylate (syn isomer) (trans isomer)
IR (Nujol): 3300, 1765, 1670, 1620 cm '
 EMI94.1
 NMR (DMSO-d-) 6:

   3, 50-4, 10 (2H, m), 4, 30 b (3H, s), 4, 63 (2H, large s), 5, 23 (1H, d, J = 5Hz), 5, 90 ( 1H, dd, J = 5Hz, 8Hz), 6.87 (1H, s), 6.95 (1H, d, J = 15Hz), 7.15 (2H, large s), 7.47 (1H, d , J = 15Hz), 7, 90-8, 90 (3H, m), 9, 13 (1H, large s), 9, 80 (1H, d, J = 8Hz)
 EMI94.2
 19) 7- [2- (3-carboxy - 2-propenyloxyimino) -2-. (2 aminothiazol-4-yl) acetamido] -3- [2. ".

   (1-methyl-3 "-pyridinio) thiovinyl] -3-cephem-4-carboxy1a te (syn isomer) (trans isomer) IR (Nujol): 3300, 1760, 1660, 1600, 1535 cm NMR (DMSO-d6 / D20) 6: 3, 57. 4, 20 (2H, m), 4.37 (3H, s), 4, 57-4, 93 (2H, m), 5, 10 (1H, d,
J = 5Hz), 5, & o (1H, dd, J = 5Hz, 8Hz), 5, 98 (1H, d, J = 16Hz), 6.51 (lE, d, J = 16Hz),
7.48 (1H, d, J = 16Hz), 6.78 (hui, s),
7, 76-9, 17 (4H, m), 9, 67 (1H, d, J = 8Hz)
 EMI94.3
 20) on 7- [2-. (1-methyl-2-pyridiniomethoxyimino) - 2-.



  (2-amintohiazol-4-yl) acetamido] - '3- [2- (1-methyl-3-pyri dinio) thiovinyl] -3-cephem-4-carboxylate as iodide (syn isomer) (trans isomer )
IR (Nujol): 3250, 1760, 1665, 1615 cm-1 NMR (D20) 6: 7, 0-9, 00 (8H, m), 7, 17 (1H, d,
J = 16Hz), 7, 10 (1H, s), 6, 67 (1H, d, J = 16Hz),
5.90 (1H, d, J = 5Hz), 5.75 (2H, s), 5.34 (1H,
 EMI94.4
 d, J = 5Hz), 4.45 (6H, s), 3, 5-4, 25 (2H, m), 21) on 7- [2- (2-pyridy1methoxyimino) -2- (2-aminothia zo 1- 4-yl) acetamido] -3- f2- (1-methyl-3-pyridinio) thiovinyl] - 3-cephem-4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 3300, 1760, 1660 , 1620, 1590 cm NMR (DMSO-dJ 6:

   3, 7-4, 20 (2H, m), 4, 47 (3H, s), 5, 15 (1H, d, J = 5Hz), 5, 25 (2H, s), 5, 72

  <Desc / Clms Page number 95>

 (1H, dd, J = 5Hz, 8Hz), 6.48 (1H, d, J = 14Hz),
6, 80 (1h, s), 7, 1-9, 0 (11H, m), 9, 90 (1H, d,
J = 8Hz) 22) 7- [2- (3-carboxypropoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3 -céphem-4-carboxylate (syn isomer) (trans isomer)
 EMI95.1
 IR (Nujol): 3300, 1760, 1660, 1600, 1535 cm 'RMN (DMSO-d6 / D20) 6: 1, 5-2, 73 (4H, m), 3, 3- 4, 27 (4H, m ), 4.37 (3H, s), 5.08 (1H, d, J = 5Hz), 5.63 (1H, dd, J = 5Hz, 8Hz), 6.60 (1H, d, J = 16Hz ), 7, 48 (1H, d, J = 16Hz), 6, 74 (1H, s), 7, 76-9, 13 (4H, m), 9, 55 (li, d, J = 8Hz)
 EMI95.2
 23) 7- [2- (1-carboxypropoxyimino) -2-.

   (2-: -. Aminothiazol-4-yl) acetamido-3-b- (1-methyl-. 3-. Pyridinio) thiovinyl] - 3-cephem-4-carboxylate (syn isomer) (trans isomer)
IR (Nujol): 3300, 1760, 1660, 1590 cm
NMR (DMSO-d6) 8: 1.08 (3H, t, J = 7Hz), 1.62-
2, 24 (2H, m), 3, 2-3, 9 (2H, m), 4.42 (3H, s), 4.47 (1H, t, J = 6Hz), 5.15 (1H, d,
 EMI95.3
 j = 5Hz), 5.77 (lis, dd, J = 8Hz, 5Hz), 6.47 (1H, d, J = 16Hz), 6.87 (1H, s), 7.0 (1H, d, J = 16Hz), 7, 02-, 3 (4H, m) 24) le 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1-methyl- 3-pyridinio) thiovinyl] -3-c-. phem-4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 3300, 1760, 1660, 1600, 1530 cm NMR (DMSO-d6 / D20) 6 ':

   3, 33-3, 87 (4H, m), 4, 37 (3H, s), 4, 62 (2H, d, J = 5Hz), 6, 50 (1H, d,
J = 16Hz), 7.47 (1H, d, J = 16Hz), 6.73 (1H, s), 7, 83-9, 03 (4H, m), 9., 57 (1H, d, J = 8Hz)
 EMI95.4
 25) 7- [2- (2-hydroxyethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1-methyl3-. Pyridinio) thiovinyl] -3-cephem-4- carboxylate (syn isomer) (trans isomer)
IR (Nujol); 3300, 1760, 1660, 1600, 1535,

  <Desc / Clms Page number 96>

 
 EMI96.1
 1500 cm NMR (DMSO-d6 / D20) 6 3, 20-3, 83 (2H, m), 4.35 (3H, s), 26) 7- [2-ethoyimino-2- (2-aminothiazol- 4-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3- cephem-4-carboxylate (syn isomer) (trans isomer)
IR (Nujol). :

     3300, 1760, 1665, 1600, 1535 cm-1
NMR (DMSO-d6 / D2O) #: 1, 25 (3H, t, J = 7Hz),
4, 13 (2H, ABq, J = 7Hz), 4, 37 (3H, s), 5, 08 (1H, d, J = 5Hz), 5, 65 (1H, dd, J = 5Hz, 8Hz),
6.48 (1H, d, J = 16Hz), 7.48 (1H, d, J = 16Hz),
7, 73-7, 93 (4H, m), 9, 52 (1H, d, J = 8Hz),
6, 73 (they, s)
 EMI96.2
 27) 7- [2- (2-propynyloxyiminc) -2- (2-aminothiazol-4-yl) acetamìdo] -3- [2- (1-methyl-3-pyìrìdìnio) thiovì- nyl] -3-cephem -4-carboxylate (syn isomer) (trans isomer)
IR (Nujol): 3250, 1760, 1660, 1600, 1530 cm
 EMI96.3
 NMR (DMSO-d6 / D20): 3, 3-3, 8 (3H, m), 4.37 (3H, s-);

   4, 7 (2H, s), 5.09 (1H, d, J = 5Hz), 5.63 (1H, dd, J = 5Hz, 8Hz), 6.53 (1H, d, J = 16Hz), 6, 78 (1H, s), 7, 50 (1H, d, J = 16Hz), 7, 73-. 7, 93 (4H, m), 9.05 (1H, s), 9.52 (1H, d, J == 8Hz) 28) 7- [2-t-butoxycarbonylmethoxyimino) -2- (2formamìdothiazol-- 4-y1) acêtamido] -3'-2- (1-methyl--. 3-pyri-dinio) thiovinyl] -3-cephem4-carboxylate (syn isomer) (trans isomer)
 EMI96.4
 IR (Nujol): 3200-3400, 1760, 1720-1730, 1690, 1670 cm 'RMN (DMSO-d) 6:

   1.50 (9H, s), 3, 50-4, 20 (2H, m), 4.37 (3H, s), 4.63 (2H, s), 5.27 (1H, d, J = 5Hz), 5.87 H1 (dd, J = 5Hz, 8Hz), 7.00 (1H, d, J = 16Hz), 7.40 (1H, d, J = 16Hz), 7.45 (1H, s ), 7, 95-9, 10 (4H, m), 8, 53 (1H, s), 9, 67

  <Desc / Clms Page number 97>

 
 EMI97.1
 (1H, d, J = 8Hz), 12, 70 (1H, large s) 29) 7- {2- (lt-butoxycarbonyl) propoxyimino] -2- (2-formamidothiazol-4-yl) acetamido}] - 3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer)
IR (Nujol): 3250, 1760, 1720, 1680 cm
NMR (DMSO-d6) #:

   0, 98 (3H, t, J = 7Hz), 1.45 (9H, s), 1.52-2.06 (2H, m), 3.67-4, 17 (2H, m), 4, 37 (3hot s), 4, 5 (1H, t, J = 6Hz)
5, 28 (1H, d, J = 5Hz), 5, 93 (1H, dd, J = 8Hz,
5Hz), 6.43 (1H, d, J = 16Hz), 7.22 (1H, s),
7, 63 (1H, d, J = 16Hz), 7, 83-9, 33 (4H, m),
8.52 (1H, s), 9.6 (1H, d, J = 8Hz)
 EMI97.2
 30) 7- [2- (2-pyridylmethoxyimino) --27 (2-formamidothiazol-4-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) - thiovinyl] -3-cephem- 4-carboxylate (syn isomer) (trans isomer)
 EMI97.3
 NMR (DMSO-d) 6:

   3, 3-4, 00 (2H, m), 4, 33 (3H, bone), 5, 13 (1H, d, J = 5Hz), 5, 30 (2H, large s), 5, 83 (1H , dd, J = 5Hz, 8Hz), 6.50 (1H, d, J = 15Hz), 7, 20-9, 00 (9H, m), 7.43 (1H, s), 8.50 (1H , s), 9.95 (1H, d, J = 8Hz)
 EMI97.4
 31) 7- [2 '- (3 - benzhydryloxycarbonyl-2-propenyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3- 2-- (1methyl-3-pyridinio) thiovinyl -3- cephem-4-carboxylate (syn isomer) (trans isomer)
IR (Nujol): 3300, 1780, 1720, 1680, 1600, 1530,
1500 cm-1
NMR (DMSO-d / DO) o:

   3, 7-4, 35 (2H, m), 4.40 (3H, s), 4, 67-5, 00 (2H, m), 5.27 (1H, d, J = 5Hz), 5, 83 (1H, m), 6.25 (1H, d, J = 16Hz),
6, 67-7, 00 (3H, m), 7, 33 (26H, m), 8, 00-
9, 20 (5H, m), 9, 80 (1H, d, J = 8Hz)
 EMI97.5
 32) 7- [2-ethoxyimino-2- (2-tritylaminothiazol-4yl) acetamido] -3- [2- (I-methyl-3-pyridinio) thiovinyl] -3-ce-

  <Desc / Clms Page number 98>

   phem-4-carboxylate (syn isomer) (trans isomer)
NMR (DMSO-d6 / D20) 0:

   1, 20 (3H, t, J = 7Hz), 3, 6-4, 0 (2H, m), 4, 06 (2H, ABq, J = 7Hz), 4.37 (3H, s),
5, 15 (1H, d, J = 5Hz), 5, 67 (IH, dd, J = 5Hz,
8Hs), 6, 72 (1H, s), 7, 17-7, 50 (15H, m), 8, 43-
 EMI98.1
 7 9, 17 (4H, m), 9, 51 (1H, d, J = 5Ez) 33) 7- [2- (2-propynyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] - 3- [2- (I-methyl-3-pyridinio) - thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer)
 EMI98.2
 NMR (DMSO-d6 / D20) 6: 3, 4-3, 7 (3H, m), 4.37 (3H, s), 5.21 (1H, d, J = 5Hz), 5.73 (1H , dd, J = 5Hz, 8Hz), 6, 78 (1H, s), 7, 13-7, 50 (15H, m) 9, 65 (LH, d, J = 8Hz) 34) on 7- [2 - (3-benzydryloxycarbonylpr3poxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (l-methyl-3pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer )
IR (Nujol):

     3350, 1770, 1720, 1665, 1590,
 EMI98.3
 - -1 1520 cm NMR (DHSO-, d6 / D20) Q: 1, 53-, -2, 10 (4H, m ', 3, 50- 0 Z 3, 70 (2H, m), 3, 83- 4.27 (2H, m), 4.35 (3H, s), 5.17 (1H, d, J = 8Hz), 5.63 (1H, m), 6.78 (1H, s), 6 , 87 (1H, d, J = 15Hz), 6, 90 (IRI s), 7, 10-, 7, 50 (26H, m), 7, 80-9, 17 (4H, m), 9, 60 (1H, d, J = 8Hz)
 EMI98.4
 35) 7- [2-carboxymethoxyimino-2- (thiazol-4-yl) -. acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] - 3-cephem-4-carboxylate (syn isomer) (trans isomer)
IR (Nujol): 3350, 1760, 1660, 1600 cm
NMR (D2O-NaHCO3) #:

   3.73 (2H, s), 4.35 (3H, s),
 EMI98.5
 4, 50-4, 87 (2H, m), 5, 32 (1H, d, J = 5Hz), 5, 83 (1H, dd, J = 5Hz, 8Hz), 6, 63 (1H, d, J16Hz ), 7, 17 (1H, d, J = 16Hz), 7, 80-8, 80 (6R, m)

  <Desc / Clms Page number 99>

 36) 7- [2-hydroxy-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4carboxylate (trans isomer)
 EMI99.1
 IR (Nujol): 3300, 1760, 1670, 1600 cm NMR (DMSO-d6) 6: 3, 42-4, 04 (2H, m), 4, 43 (3H, s), 5, 00 (1H, s ), 5, 15 (1H, d, J = 5Hz),
5.70 (1H, dd, J = 8Hz, 5Hz), 6.54 (1H, s),
6, 6 (1H, d, J = 16Hz), 7, 02 (2H, large s),
7, 53 (1H, d, J = 16Hz), 7, 73--9, 17 (4H, m) 37) le 7- [2- (1-carboxy) ethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer)
IR (Nujol):

   3300, 1770, 1665, 1600, 1520 cm "
NMR (DMSO-d6 / D @ O) #: 1.51 (3H, d, J = 6Rz), 3.80 (2H broad s), 4.31 (3H, s), 4.75 (1H, d ,
J = 6Hz), 5.25 (1H, d, J = 4Hz), 5, 83 (1H, d, J = 4Hz ', 6.83 (1H, d, J = 16Hz), 7.50 (1H, d, J = 16Hz), 7, 6-9, 4 (4H, m) 38) 7- [2- (1-methyl-1-carboxyethoxyimino) -2- (5 amino-l, 2, 4-thiadiazol- 3-yl) acetamido] -3- [2- (1-methyl-3pyridinio) thiovinyl -3-cephem-4-carboxylate (syn-isomer) (trans-isomer)
IR (Nujol): 3300, 1770, 1670, 1610, 1520 cm
 EMI99.2
 NMR (DO-NaHCO) 6:

   1.60 (6H, s), 3.82 (2H, s),
4.42 (3H, s), 5.35 (1H, d, J = 4Hz), 5.90 (1H d, J = 4Hz), 6.70 (1H, d, J = 16Hz), 7.20 (1H, d, J = 16Hz), 7, 5-8, 9 (3H, m) 39) Le 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl ) acetamido] -3- [2- (1-carboxymethyl-3-pyridiniothiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer)
IR (Nujol): 3300, 1760, 1640-1680, 1610,
1520 cm-1 NMR (DMSO-d6) #: 1, 30 (3H, t, J5Hz), 3.33-

  <Desc / Clms Page number 100>

 
3.90 (2H, m), 4.25 (2H, q, J = 7Hz), 4.95-5, 20 (3H, m), 5.75 (1H, m), 6.60 (1H, d, J = 16Hz), 7.50 (1H, d, J = 16Hz), 8.00-9.00 (4H, m), 9.55 (1H, d, J = 8Hz) 40) on 7- [2-ethoxyimino-2- (5-amino-1, 2, 4-thiadiazol- 3-yl) acetamido] -3- [2- (2-trimethylammonioethyl) thiovinyl] -3-cephem-4-carboxylate (syn isomem ) (trans isomer)
 EMI100.1
 IR (Nujol):

   3300, 1760, 1670, 1600, 1520 cm "NMR (DMSO-d4): 1, 25 (3H, t, J = 5Hz), 3, 10-4, 00 (6H, m), 4, 20 (2H, q, J = 7Hz), 5.05 (1H, d, J = 5Hz), 5.60 (1H, m), 6.60 (1H, d, J = 16Hz), 7.03 (1H, d, J = 16Hz), 8.06 (2H, large s), 9.50 (1H, d, J = 8Hz)

  <Desc / Clms Page number 101>

 
 EMI101.1
 41) 7- [(4-carboxy-3-hydroxyisothiazol-5-yl) thioacetaniido] -3- [2- (lm ethyl-3-pyridinio) thiovinyl] -3cephem-4-carboxylate (trans isomer) IR (Nujol ): 3300, 1760, 1670 cm-1 NMR (DMSO-d) 6: 3, 93 (2H, s), 3. 83-4. 00 (2H, m), 4.47 (3H, s), 5; 27 (1H, d, J = 5Hz), 5.70 (1H, dd, J = 8Hz, 5Hz), 7, 30 (6H, m), 9, 50 (1H, d, J = SHz) 42) le 7- [2-methoxyinino-2- (5, 6-dihydro-1,4-oxathiin- 2-yl) acetaido '! -3- [2- (lT. Ethyl-3-pyridinio) thiovinyl] -3cephen-4 -carboxylatc (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1760, 1660, 1600, 1500 cmRMN (D 1 0) Ï: 3. 0-3. 23 (2H, m), 3. 73 (2H, s), 4. 33 (3H, s), 5. 22 (1H, d, J == 5Hz), 5. 71 (1H, d, J = 5Hz ); 5. 97 (1H, s), 6.58 (1H, d, J = 16Hz), 7. 12 (1H, d, J = 16Hz) / 3) le 7- [2-rnethoxyimino-2- (1, 2, 3-thiarliazol-4-yl) aceta. nido] -3- [2- (1-ethyl-3-pyridinio) thiovinyl] -3-c'ephem- 4 - c2. rboxy1a te (syn isomer) (trans isomer).



  IR (Nujol): 3200-3350, 1760, 1660, 1600, 1555 cm-1 NMR (DMSO-d6 / D9O) g: 3.67 (2H, s), 4, 02 (3H, s), 437 (3H / s), 513 (1H, d, J = SHz), 5.80 (1H, 4 * 37 (3H 5 ,, 13 dd, J = 5Hz, SHz), 6, 50 (1H, d, J = 16Hz ), 750 (1H, d, J = 16Hz), 7, 83-9. 10 (4H, m), 9 /, 40 (1H, s), 9, 78 (il, d, J = 8Hz) // 44) 7- [2-methoxyinino-2- (3-hydroxyphenyl) acetaido] - 1 carboxylate (isomer svn) (isomer trann) IR (Nujol): 1770, 1650, 1600, 1570, 1500 cm 'NMR (DMSO- d / DO) 6: 3, 50-4, 17 (5H, m), 4, 17-4, 67 NMR SO-d 6 / D,? O) 6:. 7 (3H, m), 5.17 (1H, d, J = 5Hz), 5.77 (1H, dd, J = 5Hz, 8Hz), 6.60 (1H, d, J = 16Hz), 7. 53 (1H, d, 4 J = 16Hz), 683-740 (4H, m), 773-8. 93 (4H, m) J = 16Pz), 6f. 9 7 f

  <Desc / Clms Page number 102>

 
 EMI102.1
 45) The trifluoroacetic acid salt of 7 amin9-3- [2- (1-methyl-2-pyridinio) thiovinylj-3-cephem-4-carboxylic iodhydrate IR (Nujol):

   2300-2500, 17S0, 1670, 1610, 1560 cm-1 NMR (DMSO-d6) 6: 3; 85 (2H, ABq, J = 17Hz), 4; 20 (3H, s), 5; 35 (2H, 8), 6i67 (1H, d, J = 10Hz), 6 f 95-850 (4H,), 9.10 (1H, large s), 9, 67 broad s) 46) on 7- [ 2-n'ethoxyiino-2- (2-ariinothiazol-4-yl) acets. mido] -3- [2- (1-nthyl-2-pyridinio) thiovinyl) -3-cepheni- 4-carboxy1ate. (syn somer) (cis isomer).



  IR (Nujol): 3400-3100, 1765, 1660, 1610, 1560, 1550 cm "RMN (DMSO-d6) 6: 3, 67 (2H, ABq, J = 16Hz), 3. 83 (3H, s), 417 (3H, s), 5.12 (1H, d, J = 5Hz), 5.63 (1H, dd, J = 5Hz, 3Hz), 6.42 (1H, d, J = 14Hz), 6, 73 (1H, s), 7, 25 (2H,] rge. S), 763 (1H, d, J = 14Hz), 79-900 (4H, m), 9.57 (1H, d, J = 8Hz ) on 7--, m. and, oxy r. in o-: ij 47) on 7- [(2-j-nethoxyiino-2- (2-air'othiazol-4-yl) - 1 1 acetaido] - 3- [2- (1-methyl-3-pyridínio) thiovinyl-3- / ce-ptlen-carbo: e '(syn isomer) (cis isomer) IR (Nujol): 3300, 1760, 1660, 1600, 1530 cm -1 NMR (DMSO-d6) g:

   372 (2H, ABq, J = 16Hz), 3.82 (3H, s), 4 ,. 33 (3H, s), S, lO (lH, d, J = SHz), 5) 65 (1H, dd, J = 5Hz, 8Hz), 6, 33 (1H, d, J = 10Hz), 6. 73 (1H, s), 7, 22 (1H, d, J = 10Hz), 7. 13 (2H, large 5), 7. 85 - 8. 90 (3H, m), 9 ,. 17 (hui, large 5), 9, 50 (1H, d, J = 8Hz) 1 48) le 7- [2-metÌloxyimino-2- (2-tritylahlinothiazol-4-y1) acetanido] -3- [2- (l-ethyl-3-pyridinio) thioviyl] -3cephem-4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 3300-3400, 1770, 1675, 1620, 1600 cm-1

  <Desc / Clms Page number 103>

 
 EMI103.1
 NMR (DMSO-d) g: 3.77 (3H, s), 3.80 (2H, m), 4732 (3H, s), 5 .. 17 (1H, d, J = 5Hz), 567 (1H , dd, J = SHz, 8Hz), 6. 70 (1H, s), 6. 85-767 (17H, 1 s), 8. 00-9. 03 (4H, m), 9. 55 (1H, d, J = 8Hz) 1 49) 7- [2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- ( l-ethyl-2-pyridinio) thiovinyl] -3cephen-4-carboxylate '(syn isorere) (isoë-re cis) IR (ujol):

   3300-3200, 1775, 1680, 1660, 1615, 1600, 1570 Cm NMR (DMSC-dJ 6: 3, 67-3. 95 (2H, m), 3.78 (3H, s), 4720 (3H, s ), 5, 17 (1H, d, J = 5Hz), 51'70 (1H, dd, J = 5Hz, 8Hz), 6 70 (1H, s), 6: 7S (1H, d, J = 10Hz) , 7; 00-7, 50 (15H, El), 7, 67-9, 05 (4H, m), 9. 52 (1H, d, J = SHz) 1 SO) 7- (2-methoxvimino- 2- (2-trity1aElinoLhiazol-4-yl) acetaido] -3- [2- (l-methyl-3-pyridinio) thiovinyl] -3-cephen- 4-carboxvlate (svn isomer) '(cis isomer) IR (Xujo1 ): 3350-3250, 1770, 1670, 1620, l-zo RMN (DMSO-d.) 5:

   3.70-4 ,. 00 (SH, m), 380 (5H, s), S. 70 ud, 4.30 (3H, s), 5, 20 (1H, d, J = 5Hz), 5, 70 (1H, dd, T -H'7 8Hz 670 (1H, s), 6, 73 (1H, d, J = llHz), 7. 00 (1H, d, J = llHz), 7, 15-7.50 (15H, m) , 800-9, 10 (5H, m), 9. 50 (1H, d, J = 8Hz) 51) 7- [2- (3- arboxypropoxyimioJ-2- (5-amino-1, 2, 4- / thiodiazol-3-yl) acetanido] -3- [2- (1-ethyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) 1. 1-L y (trans isomer) IR C .; ujol): 3300, 1765, 1665, 1600, 1530 cru-1 NMR (D:.! SO-d.) <5:

   16-27 (4H, m), 3.75 (2H, large s), 6 Ip. $ iyi 4jO-4 .. 4 (2H, m), 4, 4 0 (3'il, s), 510 (1H, d, J = 4Hz), 5, 72 (1H, dd, J = 4, 8Hz ), 6, 75 (1H, d, J = 16Hz), 7, 44 (1H, d, J = 16Hz), 77-9. 1 (4H, n), 9, 60 (1H, d, J = 8Hz)

  <Desc / Clms Page number 104>

 
 EMI104.1
 52) 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-5yl) acetamido] -3- [2- (l-methyl-2-pyridinio) thio ''. 'Inyl ] -3L cephem-4-carboxylate (syn isomer) (cis isomer) IR (Nujol): 3300, 1765, 1670, 1610, 1560 cm-l NMR (DMSO-dJ 6: 1.27 (5H, t, J = 5Hz), 5.65-4.55 1 6 1 1) (4H, m), 5. 10 (1H, J = 5Hz), 5.68 (1H, dd, J == 5Hz, 8Hz), 6, . 42 (1H, d, J = 14Hz), 7. 67 (1H, d, J = 14Hz), 6.95-900 (6H, m),. 50 (1H, d, J = 8Hz) gr-¯O 00 r6, j 55) le 7- [2-ethoxyimino-2- (5-phosphonoanino-l, 2, 4thiadi ol-3-yl) acetaido1-3- [2- (l-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer).



   IR (Nujol): 3200-3400 (broad), 1760, 1672, 1520 cm-1
 EMI104.2
 NMR (NaHCO - D20): 1.35 (5H, t, J = 7Hz), 5. 77 (2H, 2 large s), 4., 55 (5H, s), 4.33 (2H, q, J = 7Hz), 5.30 (1H, d, J = SHz), 5, 82 (IH , d, J = 5Hz), 6.60 (1H, d, J = 15Hz), 7. 17 (1H, d, J == 15Hz), 7. 85-3, 80 (4H, m) 54) 7- [2-ethoxyiino-2- (5-phosphonoagino-I, 2,4L i. Thiadiazol-3-yl) acetamido] -3- [2- (1-methyl-2-pyridinio) - 1 thiovinyl] -5 -cephem-4-carbcxylate (syn isomer) (trans isomer).



   IR (Nujol): 3200, 1768, 1673, 1610, 1560, 1508,
1269, 1230 cm-1
NMR (NaHCO3-D20) g: 1.33 (3H, t, J = 7Hz), 3.83 (2H, large s), 4.23 (3H, s), 4.38 (2H, a,
J = 7Hz), 5.30 (1H, d, J = SHz), 5.80 (they, d,
J = 5Hz), 61. 60 (1H, d, J = 14Hz), 7. 38 (1H, d,
J = 14Hz), 74-8, 8 (4H, m)

  <Desc / Clms Page number 105>

 
EXAMPLE 4
To an ice-cold solution of 7-t-butoxycarbonylamino-3- [2- (1-methyl-2-pyridinio) thiovinyl] -3-cephem-4-carboxylate iodide iodide (trans isomer) (5 , 0 g) in methylene chloride (15 ml), and anisole (20 ml) was added dropwise trifluoroacetic acid (40 ml). The mixture was stirred under the same conditions for 2 hours.

   The reaction mixture was poured into diisopropyl ether and the resulting precipitate was collected by filtration to give the salt of trifluoroacetic acid 7-amino-3- [2- (1-methyl-2-iodide). -pyridinio) thiovinyl) -3- cephem-4-carboxylate (trans isomer) (3, 9 g).



   IR (Nujol): 2550-. 2450, 1760, 1660, 1640,
 EMI105.1
 - 1 1600 Cm -
NMR (DMSO-d) o: 3.75-4.3 (2H, m), 4.21 (3H, s), 5.0-0-5.47 (2H, m), 7.13 (1H, d , 7, 3-8, 3 (6H, m), 9.0 (1H, d, J = 5Hz).



   EXAMPLE 5
The following compounds were obtained in a manner similar to that of Example 4.
 EMI105.2
 



  1) 7- [2-ethoxyimino-2- (5-amino-1,2,4,4-thiadiazol-3-yl) acetamido] -3-. [2- (1-methyl-3-pyridinio) thiovinyll-3 cephem-4-carboxyla te (syn isomer) (trans isomer)

  <Desc / Clms Page number 106>

 
 EMI106.1
 IR (Nujol): 3300 (large), 1760, 1660, 1600,1520cn ', 1 2) le 7- [2-meihox'imino-2- (2-aRinoihia2ol-4-yl) acetE. niidcj- '-z- (syn isomer) (trans isomer) cp arboxylate (syn isomer) (trans isomer) - R co, 0 1) - (' O ¯100 (1) '- 60 "f," 0'600 1520 cm "3) 7- [2-et. Hoxyimino-2- (S-amino-1,2,2-4thiadiazol-3-yl) acetamido] -3- [2- (l-methyl-2-pyridinio) iodhydrate ) thiovinyl] - 3-cephem-4-carbcxylate (syn isomer) '(trans isomer).



  IR (Nujcl): 3400, 32SO, 1780, 1650-16S0, 1620 c '4) le 7- [2-ethcxyimino-2- (5-aino-l, 2, 4-thiadiaol-3-yl) le aceiaido] '5-LZ- (l-nethyl-2-? Yridinic) lhicYinyl] -3cephe-4-carbcxylate (syn isomer) (trans isomer) IR (Nujol): 3500, 3200, 1760, 1650, 1600 cm' 5) le trifluoro2cetic acid salt of 7 amino-3 hydroiodide - [2- (1-methyl-3-pyri2inio) thiovinyl] -3-cephem-4carboxylate (trans isomer) IR (Nujol): 33SO, 2500-2600, 1780 , 1670, 1620 ci 'R (DMSO-d) 6: 39S (2H, ABq, J-lSHz), 430 (3H, s), 5 1-53 (2H, n0, 65-73 (2H, n), 80-8; 9 (5H, m), Q ria broad s) 6) the trifluoroacetic acid salt of 7-amino-3- [2- (4-methyl-2-pyrazinio) thiovinyl] -3 hydroiodide cephem-4carboxylate (trans isomer) IR (N uj 01): 3300, 1800, 1670 cn 'NMR (D 6:

   393 (2H, br. S), 443 (3H, s), 5J18 (1H, d, J = SH =), 540 (1H, d, J = 5H), 8 (1H, d, 7, 42 (2H , s), S. 59 (1H, d, J = 4H), 9 i 0 (1H, br. s), 9) 13 (1H, br. s).

  <Desc / Clms Page number 107>

 
 EMI107.1
 



  7) le7- [2-niethoxyimino) -2- (2-aminothiazol-4-yl) acetamidoJ- 5- [2- (1-methyl-2-pYTidinio) hiovinyl) -5-cephem-4c2. rboxyla. te (syn isomer) (trans isomer) IR (Hujol): 3300, 1765, 1670, 1611, 1562, 1535 c '8) le7- [2-n2thoxyiBd. no-2- (2-a = u. nothiazcl-4-yl) acetaEiidoj- 3- [2- (4-ethYI-2-PYTazinio) thiovinyl) -3-ce? hes-4carbo) -lâLe (-jre syn) (trans isomer). il (Nujol): 3300, 1765 (br.), 1660, 1600 cm "9) le [2-methoxyimino-2- (2-tritylainothiaiol" 4-yl) acetaido] -3- [2- (l-methyl- 2-? Yridiniothicviyl] -3cephe'm.-4-cs. Rboxyla. Te (syn isomer) (trans isomer) -R (Nujol): '3250, 1780, 1672, 1595 cni "1 10) le7-. [2 -ethoxyim. ino-2- (2-tert-pentyloxycarbonylamin. otiazol-4-y1) actamido] -3- [2- (4-methyl-Z-FYTa. zinio) thioviyl) -3-cephem "4-carboxylate ( syn isomer) (trans isomer).



  IR (Nujol: 3350, 1762, 1700, 1660, 1530 cm 'H) iodide of 7 [2-ethoxyimino-2- (5-amino-l,?, 4¯thia4izol- - 3-yl) acëtamido] - 3- [2- (1,3-dimethyl-7-rii. Inio) thi-o \ '- in -'. L] 3-cephen4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 3350, 1770, 1663, 1605 cm '12) le7- [2-ethoxyiEino-2- (5-amino "l, 2, 4-thiadiaol-3-yl) acetsL! 7!. Ido] -3- [2- (4-nethyl-2-pyTS. In. Io) thiovinyl] -3cephen-4-carboxylale '(syn isomer) (trans isomer) IR (Nujol): 3350, 1760 (br.), 1665, 1607 cm' 13) le7- [2-mthoxyimino-2- (5-amino-1,2,4,4-thiadiazol-3-yljacéaidoJ-3- (2- (1-methyl-2-PYTidi: 1io) thiovinyl) -3cephe-4-carbcxylate (syn isomer) (isomer, trans) IR (Nujo1):

   3250-3350, 1770, 1660, 1620, 1560, 1550 cm '

  <Desc / Clms Page number 108>

 
 EMI108.1
 L 14) trifluoroacetic acid lesiod of hydroiodide e '' amino - 3 -.! 2 -. (L -.] T) thl-3-'yrJrdinio) -thiovinyli-? -Che '.- 4-carboxylate (cis isomer) IR (Nujol): 3400 (large), 2350 (brcad), 1800, 1670, 1620, 1540-1520 c8-1 R) -! ! \ (DM50-d) o: 394 (2H, b), 438 (3H, s), 7, 90-9, 23 (4H, 1: 1).



  790-925 (4H, n).



  15) le7- [2-ethylcino-2- (5-aino-1,2,4-thidiazol-3-yl) acetamido1-5- [2- (l-ethyl-3-pyridiiojhicvinyl] -3cephe-4-carbcxylare (syn isomer) (trans isomer) IR. (Nujol): 3300 (large).,. '1770, 1675, 1600, 1520cm "16) le7- [2-ethGxyimino-2- (5-mino-132, 4- thiadia: 01-3- 1. l - [(1 '"L 1 ......) h ...] 3-cephem-4-crboxylate' (syn isomer) (cis isomer) IR (Nujol): 3300 Clarge), 1760, 1665, 1600, 7 le 7-2L 1520 cm (i-so, o, ere-trans) thiadiazol-3-yl) aceiar. idc-3-2- (l-'Re'thyl-3-pyridinio) - "L ... -... 1" \ 1 "] oz r 2 (''" h 1 .... d .. ) (trans isomer) IR (Nujol): 3300 (large), 1765, 1670, 1615, 1560 1525 cm-1 18) le7- [2-c!. llyloxyiin. o-2- (5-s. mino-1,2,4-thiadi2. 2. ol-3yl) acaido] -3- [2- (l-ethyl-3-pyridinio) thiovinyl] -3cehem-4-carboxylate (syn isomer) (trans isomer) c-hem-4-cp-rbox-lIR (Nujcl):

   3300, 1760, 1670, 1620, 1600, 1530 cm

  <Desc / Clms Page number 109>

 
 EMI109.1
 19) 7- [2- (tr-butoxycarbonylmethoxyimino) -2- (2aninothiazol-4-yl) acetaniido] -3 [2- (1-methyl-3-pyridinio) thiovinyl] -3-cepheni-4-carboxylate ( syn) isomer (trans isomer) thiov -'-. -. yi 3-cer, 'D-e- ,. u- 4-ca-rh ox, ate IR (Nujol): 3200-3300, 2400-2600, 1770, 1715, 1680, 1630 NMR col (DMSO-d6) 6: 1, 50 (9H, s), 320- 410 (2H, m), 443 (3H, s), 470 (2H, s), 530 (1H, d, J-5Hz), 5, 83 (1H, dd, J = 5H =, 8Hz), 700 ( 1H, s), 730 (2H, large s), 8-900 (6H, m), 927 (1H, large - s), 9} 77 (IH, Åa, J = 8Hz) 20) on 7- [2 -carboxymethoxyimino-2- (2-aminothiazol-4yl) acëtaido] -3- [2- (l-methyl-3-pyridinio) thiovinyl] -3cephei-4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 3300, 1765, 1670, 1620 cn 'Rt.'N (DMSO-d) <S: 350-410 (2H, m), 430 (3H, s), 4763 CZH, large s), 5;

   23 (1H, d, J == 5Hz), 590 (1H, dd, J = 5Hz, 8Hz), 6, 87 (1H, s), 695 (1H, d, J = 15Hz), 715 (2H, large s), 747 (1H, d, J = 15Hz), 790-890 (3H,), 9 13 wide s), 9; 80 (1H, d, J = SHz) 21) 7- [2- (5-carboxy-2-propenyloxyiino) -2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1- methyl-3-pyridinio) thiovinyl] -3-cephen-4-carboxylate. (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1760, 1660, 1600, 1535 cm 'RMN (DMSO-d / DO) 6: 357-4 20 (2H, m), 437 (3H, s), 457-493 (2H, m ), 510 (1H, d, J = SH3), 5/60 (1H, dd, J = 5Hz, 8Hz), 5, 98 (IH, d,! 716Hz), 651 (1H, d, J-loHz) , 748 (1H, d, J = 16Hz), 6) 78 (li, s), 7} 76-9) 17 (4H, m), 9, 67 (1H, d, J = SPz) 22) 7- [2- (1-methyl-2-pyridiniomethoxyimino-2-2-) iodide

  <Desc / Clms Page number 110>

 
 EMI110.1
 'aminothiazol-4-11) acetamido] -3-2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn-isomer) trans-isomer) IR (Nuiol "3-ZSO, 1760, 1665, 1615 NMR (D0) 6: 79-9) 00 (8H, m), 717 (1H, d, J = 16Hz), 7 10 (1H, s), 667 (1H, d, J = 16Hz), 590 (1H. D, J = 5Hz), 5) 75 (2E, s), 5):

   34 (1H, d, J = 5Hz), 4 45 (6H, s), 35-4, 25 (2H,) 23) 7- [2- (2-Pyridyl! T'ethoxyiniino) -2- (2 -aninothiazol- 4-yl) acets. nido] -3- [2- (l-methyl-5-pyridin. io) thiovinyl] -5cephe-4-carDoxylate (syn isomer) (trans isomer) IR (Nujol): 5500, 1760, 1660, 1620, 159O cn -1 RM, DMSO-d6) 6: 57-4, 20 (2H, m), 447 (2H, s), 5) 15 (1H, d, J = 5H), 525 (2H, s), 572 ( 1H, dd, J = 5Hs, 8Hz), 648 (1H, d, J-14Hz), 680 (1H, s), 7; 1-90 (11Hs m), 990 (1H, d, J == 8Hz) 24) 7- [2- (5-crboxypropoxyiino) -2- (2-aninothiazol- 4-yl) 3. c. etanido] -5- [2- (l-methyl-5-pyridin. io) thiovinyl] -5cephen.-4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 3300, 1760, 1660, 1600, 1555 cn "NMR (DMSO-d./DO) 6:

   1, 5-2, 73 (4H, m)} 3) 3-4) 27 (4H, m) ,. 4 37 (3H, s), 508 (1H, d, J = 5Hz), 5} 63 (1H, dd, J = 5Hz, 8Hz), 650 (1H, d, J = 16Hz), 7 48 (li, d, J = 16Hz), 6) 74 (1H, s), 7) 76-913 (4H, m), 9 55 (1H, d, J = 8Hz) 25) on 7- [2- (l-crboxypropoxyimino ) -2- (2-aminothiazol- 4-yl) acetamido] -3- [2- (l-methyl-3-pyridinio) thiovinyl] -3cephem-4-carboxylate.

   (syn isomer) (trans isomer) IR (Nujol): 3300, 1760, 1660, 1590 cn-1 RE (DMSO-d) g: 1, 08 (3H, t, J = 7Hz), l, ó2-2 / 24 (2H, m), 3) 2-3 / 9 C2H, m), 4; 42 (3H, 5),

  <Desc / Clms Page number 111>

 
 EMI111.1
 447 (li, t, J = 6Hz), 5, 15 (1H, ci, J = SHz), 577 (1H, dd, J = 8Hz, 5Hz), 647 (1H, d, J = 16Hz), 6) 87 (1H, s), 70 (1H, d, J = 16Hz), 702-93 (4H, n) 26) le 7- [2-ally1oxyiino-2- (2-aminothiazol-4-yl) acetamido] - 3- [Z- (1-methyl-5-pyridinio) thiovinyl] -3-cephe- 4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 3300, 1760, 1660, 1600, 1530 cu "RM ( DMSO-d6 / D 0) o:

   352-387 (4H, m), 437 (3H, s), 6 2 4) 62 (ZE, d, J = 5Hz), 650 (1H, d, J = 16Hz), 7.47 (1H, d. , J = 16Hz), 6773 (IH, s), 7 733-903 (4H, m), 9} 57 (IH, d, J = 8Hz) 27) on 7- [2- (2-hydroxye'thoxyimino) -2- (2-amin. Othiazol- 4-yl) acdanido] -3- [2- (l-methyl-3-pyridinio) thiovinyl] -3ce'pher.-4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 3300, 1760, 1660, 1600, 1535, 1500 cm 'RMN (DMSO-d / D 0) 6: 320-3 83 (2H, m), 435 (3H, s) 6 g) on 7 -r2-ethoxyinino-2- (2 "aninothiazol-4-yl) - 28 acdtamido] -3- [2- (1-dthyl-3-pyridinio) thiovinyl] -3cephen-4-carboxylaie" (syn isomer) (isomer trans) p-1 IR (Nujol): 3300, 1760, 1665, 1600, 1535 cm 'NMR (DMSO-d./DO) g: 1; 25 (3H, t, J = 7f {z), 413 (2H, ABq, J = 7Hz), 4.37 (3H, s), 5708 (UI, d, J = 5Hz), 5/65 (1H, dd, J = SHz, 8ho), 6/48 (ex, d, J = 16Hz), 7, 48 (1H, d, J = 16Hz), ï, 73-7, 93 (4H, m), 9, 52 (1H, d, J = 8Ez), 6 J 73 (1H, s).



  29) 7- [2- (2-opynyloxyinino) -2- (2-a2inothiazol-4- 1 y1) acetamio] -3- {Z- (1-methyl-3-pyridinio) thiovinyl] 3cephem.-4- carboxylate '(syn isomer) (trans isomer).



  IR (Nujol): 3250, 1760, 1660, 1600, 1530 cni '-

  <Desc / Clms Page number 112>

 
 EMI112.1
 NMR. (DMSO-dó / DO) o: 3. 3-38 (3H, m), 437 (3H, s), 7 (2H, s), 509 (1H, d, J = 5Hz), 563 (1H, dd , J = SHz, 8Hz), 6, 53 (1H, d, J = 16Hz), 678 (1H, s), 750 (1H, d, J = 16Hz), 773-793 (4H, m), 905 ( 1H, s), 952 (1H, d, J = 8Hz) 30) on 7- [2- (t-butoxyc2rbonylmethoxyimino) -2- (2L forai2. Midothiazol-4-yl) acetamido1-3- [2- (l -methyl-3pyridinio) thiovinyl] -3-cephem-4-cs. rbcxylate (syn isomer) P (trans isomer) IR (Nujol): 3200-3400, 1760, 1720-1730, 1690, 1670 cn. ' RRIN'-;

   SO-4120 NMR (DMSO-dJ o: 150 (9H, s), 350-420 (2H, n), 4; 37 (SH, s), 4, 63 (2H, s), 5, 27 (1H, d, J = 5i1z), 5JS7 (lH, dd, J = 5Hz, 8Hz), 7} 00 (IH, d, J = 16Hz), 740 (1H, d, J = 16Hz), 745 (1H, s) , 795-910 (4H, m), 8. 53 (1H, s), 967 (1H, d, J = 8Hz), 12) 70 (lH, large s) ie-t 31) on 7 - f2- (l- -butoxyc2. rbonyl) pro? oxyinir Oj-2- (2f .. h. 1, ") 1. - II - [7 (1 1 ..... pyridinio) thic'vinyl] -3-cephen-4-ca. rboxylate (syn isomer) (trans isomer) py (isom --- re transl / IR (Nujol): 3250, 1760, 1720, 1680 cm 'NMR (DMSO-d). 6:

   OJ98 (SB, t, J = 7Hz), L45 (9H, s), 1.52-2 "G6 (ZR, m), 3) 67-4, 17 (2Hf m), 4.37 (3H, s ), 45 (1H, t, J = 6Hz), 528 (1H, d, î28 (1H, d, J = 5Hz), 593 (1H, dd, J = 8Hz, 5Hz), 6, 43 (1H, d , J = 16Hz), 722 (1H, s), 763 (1H, d, J = 16Hz), 7, 33-933 (4H, n), 852 (1H, s), 9 6 (li, d, 32 Le 1 thi3. Zol-4-yl) s. Cetamido] -3- [2- (1-m. Ethyl-3-pyridinio) thioviayl] -3-csphem-4-carboxy1ate (syn isomer) syn isomer) (isomer trans).

  <Desc / Clms Page number 113>

 
 EMI113.1
 



  MN (DMSO-dJ6: 33-400 (2H, m), 4) 33 (3H, s), 5, 12 (1H, d, J = 5Hz), 5, 30 (2H, large s), 5, 83 (1H, dd, J = 5Hz) 8Hz), 6. 50 (1H, d, J = 15Hz), 7, 20-9, 00 (9H, m), 743 (1H, s), 850 (1H, s ), 9) 95 (1H, d, J = 8Hz) 33) 7- [2- (3-enzhydryloxycarbonyl-2-pTOpenyloxyimino) am- (2-tritylaminothia. Zol-4-yl) acetanido] -3- [ 2- (l-inethyl-3pyridinio) thiovinyl] -3-cephem-4-carboxylaie (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1780, 1720, 1680, 1600, 1530, 1500 cn 'Ï (DMSO-d6 / D2O) 6: 37-435 (2H, n), 440 (3H, s), 4. 00 " (2H, m), 527 (1H, d, J = 5Hz), 583 (1H, m), 6.25 (1H, d, J = 16Hzj, 657-700 (3H,), 733 (26H, m) , 800-920 (SH, m), 980 (1H, d, J = 8Hz) 34) 7- [2-ethoxyimino-2- (2-tritylam. Inothiazol-4-yl) - 1acetanido] -3- [ 2- (l-methyl-3-pyridinio) thiovinyl] -3 "cephem-4-carbcxylate (syn isomer) '(trans isomer) RUN (DMSO-d./DO) g: 120 (3H, t, J = 7Hz ), 36-4 0 6 2. 0 1 (2H, m), 4.06 (2H, ABq, J = 7Hz), 437 (3H, s), 15 (1H, d, J = 5Hz), 567 ( 1H, dd, J = 5Hz, 8Hs), 6, 72 (1H, s), 7, 17-7, 50 (15H, n), 8, 43-9) 17 (4H, n), 951 (1H, d, J = 5Hz) on 35) 7- [2- (2-propynyloxyimino) -2- (2-tritylamincthiazol-4- ', acetamido] -3- [2- (l-methyl-3-pyridinio) thioviny1 ] - 3-cc'phes-4-carboxy1a te (syn isomer) - (trans isomer).



  NMR (DMSO-d6 / DO) 6: 3, 4-3; 7 (3H, m), 4.37 (3H, s), 6 2 1 tjy 5.21 (1H, d, J = 5Hz), 573 (1H, dd, J = 5Hz, 8Hz), 678 (1H, s), 713-750 (15H, m), 9; 65 (IH, d, J = 8Hz)

  <Desc / Clms Page number 114>

 
 EMI114.1
 36) 7- [2- (3-benzhyryloxycarbony1propoxyimino) -2- (2-tritylain. Othiazol-4-yl) acetaniido] -3- [2- (l-methyl-3pyridinio) thioviyl] -3-cephem-4 -carboxy1ate (syn isomer) (trans isomer).



  IR (Nujol): 3ju 1770, 1720, 1665, 1590: 1520 cm-l RE0 (DMSO-d6 / DO) o: 153-210 (4H, m), 350-3, 70 (2H, m), 3) 83-4, 27 (2H, m), 4d35 (3H, s), '517 (1H, d, J-SHz), 563 (1H, m), 678 (1H, s), 687 (17.d, J = 15Hz690 (1H, s), 710-750 (26H, n), SO-917 (4H, m), 960 (IH, d, J = 8Hz) JJ 37) on 7- (2-carboxynethoxyimino-2- (thiazol-4-y1) acetanido] -3- [2- (1-erhyl-3-pyridinio) thiovinyl] -3- 10 cepheni-4-carboxyls. te (syn isomer) (trans isomer) IR (Nujol): 3330, 1760, 1660, 1600 cm 'CD NMR 0-NaP% -O'13RMN (DO-NaHCOj6: 3. 73 (2H, s), 4. 35 (3H, s), 4; 50-4; 87 ( 2H, m), 532 (1H, d, J = 5Hz), 5} 83 (IH, dd, J = SHz, 8Hz), 663 (1H, d, J = 16Hz), 717 (1H, d, J = 16Hz), 780-8) 80 (6H, m) / 3g) on 7- [2-h. ydroxy-2- (2-aininothiazol-4-yl) acetanidoj- - [7 rI / h 1 ..,. "d" ") '"' 1] - 1 T 1 b.



  (trans isomer) IR (Nujol): 3300, 1760, 1670, 1600 cm "R (DMSO-d). 0: 3, 42-404 (2H, n), 443 (3H, s) 5 ,, 00 (1H , 5), 5; 15 (1H, d, J = 5Hz), 5; 70 (1H, dd, --SOT SHZ), 654 (1H, s), 66 (1H, d, J-16Hz), 702 (2H, large s), 753 (1H, d, J = 16Hz), 7 73 917 (4H, m) /.- 39) on 7- [2- (I-carboxy) ethoxyicino-Z- (5-amino -1, 2, 4thiadiazol-3-yl) acetaido] -3-2- (l-ethyl-3-pyridinio) thiovinyl] -3-cephe-4-carboxylate '(syn-isomer) (trans-isomer) IR (Nujol) : 3300, 1770, 1665, 1600, 1520 cm '

  <Desc / Clms Page number 115>

 
 EMI115.1
 NMR (DMSO-d6 / D2O) s:

   1 51 (3H, d, J = 6Hz), 3.80 (2H, broads), 44 31 (3H, s), 475 (1H, d, J = 6Hz), 5.25 (1H, d, J = 4Hz), 585 (1H, d, J = 4Hz), 6. 83 (1H, d, J = 16Hz), 7} 50 (1H, d, J = 16Hz), 76-9 4H, 40) on 7 - [2- (l-methyl-l-carboxyethoxyinino) -2- (5-amino- 1 1, 2, 4-thiadiazol-3-yl) ace aido] -3- [2- (l-methyl-3pyridin. io) thiovinyl] -3-cephem-4-carboxylate (syn isomer) {trans isomer) IR (Nujol): 3300, 1770, 1670, 1610, 1520 cn 'R (D20-NaHCO) 6: 1 60 (6H, s ), 3. 82 (2H, s), 442 (3H, s), 535 (1H, d, J = 4Hz), 590 (1H, d, J = 4Hz), 6.70 (IH, d, J = 16Hz), 7) 20 (IH, è., J = 16Hz), 75-89 (3H, m) 4D le 7- [Z-ethoxyimio-2- (5-ar (ino-l, 2, + -thiadiazo1 - 3-yl) acetamido] -3- [2- (l-carboxymethyl-3-pyridinio) thiovinyl] - 3-cephem- 4-c2. Rboxyla te syn isomer (trans isomer).



  IR (Nuiol): 3300, 1760, 1640-1680, 1610, 1520 cm '-z3- 3. 90 MN (DMSO-d6) 6: 130 (3H, t, J = 5Hz), 333-390 (2H, m ), 4ï25 (ZH, q, J = 7Hz), 4 95-5 20 (3H, 575 (1H, n), 660 (1H, d, J = 16Hz), 7J50 (1H, d, J = 16Hz), 800-900 (4H, m), 955 (1H, d, J = 8Hz) 2) le7- [2-ethoxyiin.o-2- (5-a. Ino-l, 2, 4 thiadiazol-3yl) acetamido] -3- [2- (2-trimethylamonioethyl) thiovinyl] -3ce'phem-4 -carboxyla te (syn isomer) (trans isomer) IR (Nujol): 3300, 1760, 1670, 1600, 1520 cm-1 MN (DMSO -d6) .o 1. 1 25 (3H, t, J = 5Hz), 310-400 (6H, m), 4;

   ZO (ZH, q, J = 7 Hz), 5; 05 (1H, d, J = 5Hz), 560 (1H, n), 660 (1H, d, J-16Hz, 7 03 (1H, d, J = 16Hz), 8; 06 (ZH, large s), 9 J 50 (IH, d, J = 8 Hz)

  <Desc / Clms Page number 116>

 
 EMI116.1
 43) 7- [(4-carboxy-3-hydroxyisothiazo1-S-yl) thioacetamido] -3-2- (1-niehyl-3-pyridinio) th. iovinyl] -3ce / phem- -carbo-yl cte (trans isomer) IR (Nujol): 5500, 1760, 1670 cm 'NMR (DMSO-d6) ô: 393 (2H, s), 383-4, 00 (2H , m), 6d 7 1 1 447 (3H, s), 527 (1H, d, J = 5Hz), 570 (1H, dd, J = SHz, 5Hz), 7, 30 (6H, m), 9, 50 (1H, d, J = 8Hz) 44) le 7- [2-methc yiino-2- (5j, ô-dihydro-1, 4-oxat. H. Iin- 2-11) actmido] -3- ( 2- (1-2thyl-3-PYTidnio) tioviny1] -3cehem-4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 3300, 1760, 1660, 1600, 1500 cm-1 NMR (DO) 6:

   30-323 (2H, m), 373 (2H, s), 433 (3H, s), 522 (1H, d, J = 5Hz), 18 (1-ii, 571 (1H, d, J = 5Hz) , 597 (1H, s), 658 (1H, d, J = 16Hz), 712 (1H, d, J = 16) / 45) le 7- [2-methoxyiino-2- (l, 2, 3-thiadia = ol-4-yl) P-ce acetanido] -3- [2- (l-Rethyl-3-pyridinio) thiovinyl] -3-ceDhem- 4-carboxylate (syn isomer) (trans isomer) IR Nujol): 3200 -3350, 1760, 1660, 1600, 1555 CL NMR (DMSO-d6 / DO) c: 367 (2H s), 402 (3H, s), 6 2 f 437 (3H, s), 513 (1H, d, J = 5Hz), 580 (1H, dd, J = 5Hz, SH :), 6. 50 (1H, d, J = 16Hz), 7. lso (1H, d, J = 16Hz), 783-9 10 ( 4H, n), 940 (1H, s), 9 J 78 (1H, d, J = 8Hz) 46) on .. [2 (1 1 hM ... d ..), .. Il - 1 h 4 3- [2- (1-niethyl-3-? Yridinio) thlovinyl] -3-cepheni-4carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 1770, 1650, 1600, 1570, 1500 con 1 RMS (DMSO-d6! DZO) 6: 3, 50-4, 17 (SH,), 4, 17-4167 2 yf (3H, m) , 517 (1H, d, J-5Hz), 577 (1H, dd, J == 5Hz, 8Hz), 6. 60 (1H, d, J = 16Hz), 7.53 (1H, d, J = 16Hz ), 6, 83-7; 40 (4H, m), 773-8 / 93 (4H, m) J = 16 "z), 6 i f-

  <Desc / Clms Page number 117>

 
 EMI117.1
 47) the trifluoroacetic acid salt of 7-amino iodide 1 nO-3- [2- (1-methyl-2-pyridinio) thiovinyl] -3-cephem-4-carboxylic (cis isomer) IR (Nujol ): 2500-2500, 1730, 1670, 1610, 1560 cm 'NMR (DMSO-d.) 6: 3 85 (2H, ABq, J = 17Hz), 420 (3H, s), S35 (2H, m), 667 (1H, d, J = 10Hz), 6, 95-350 (H, m), 910 (1H, large s), 9, 67 (2H, large s) 48) on 7- [2-methoxyinino-2 - (2-ainothiazol-4-yl) acetanidc] -3- [2- (l-niethyl-2-pyrid. In. Io) thiovinyl) -3-cephe- 4-cs. Taoxyla. T. e (syn isomer) (cis isomer).



  IR (Nujol): 3400-3100, 1765, 1660, 1610, 1560, 1550 cm 'RMN (DMSO-d6) g: 367 (2H, ABq, J = lcHz), 383 (3H, s), 417 (3H, s), 512 (1H, d, lj '= SHz), S} 63 (1H, dd, J = 5Hz, 8Hz), 6) 42 (IH, d, J = 14Hz), 673 (1H, s), 725 (2H, large s), 7) 63 (IH, d, J = 14Hz), 7, 9-9, 00 (4H, ira), 9, 57 (IH, d, J = 8Hz) on 49) on 7- [(2-ethoxyinino-2- (2-aninorhiazol-4 "yl) - 1 J cepheu-4-ca. Rboxylate (syn-isomer) (c-isomer).



  IR (Nujol): 3300, 1760, 1660, 1600, 1530 Cree, NMR (DMSO-d6). 6: 3172 (2H, ABq, J = 16Hz), 3} 82 (3H, s), 433 (3H, s), 510 (1H, d, J = 5Hz), 5) 65 (1H, dd, J = 5Hz, 8Hz), 638 (1H, cl, J = IOHz), 6, 73 (1H, s), 7, 22 (El, d, J-10Hz), 7 13 (2H, large s), 785-890 (3H, m), 917 (1H, large s), 9) 50 (1H, d, J = 8 Hz) 1 50) 7- [2-methoxyiino-2- (2-tritylainothiazol-4-yl) - 1 1 cephem-4-carboxylate (syn isomer) (trans isomer) p IR (Nujol): 3300-3400, 1770, 1675, 1620, 1600 cm '

  <Desc / Clms Page number 118>

 
 EMI118.1
 NMR (DMSO-d) g: 3) 77 (3R, 5), 3.80 (2H, m), 4.32 (3H, s), 5.17 (IH, d, J = 5Hz), 5, 67 (1H, dd, J = 5Hz, 8Hz), 6. 70 (IH, s), 6j8S-7) 67 (17H, r.) ,, 800-903 (4H, m), 9 55 (1H, d , J = 8Hz) /) 51) 7-r2-methoxyinin. o-2- (2-T: ritylaminothiazol-4-yl) acetamido] -3- [2- (l-nithyl-2-pyridinic) thiovinyl] -3L cphem.-4-ca. rbc yla. te (syn isomer) (cis isomer).



  IR (Nujol): 3300-32CO, 1775, 1680, 1660, 1615, 1600, 1570 cm 'M' (DMSO-d) 6: 367-3 95 (2H, m), 78 (3H, s), 6d i 420 (3H, s), 517 (1H, d, J = 5Hz), 570 (1H, dd, J = 5Hz, 8Hz), 6) 70 (IH, s), 675 (1H, d, Ly J = 10Hz ), 7, 00-7, 50 (15H, n), 767-9J05 (4H, m), 952 (1H, d, J = 8Hz) 1 52) 7- [2-msthoxyiino-2- (2- tritylaninothiazol-4-yl) actamido] -3- [2- (1-sthyl-3-pyridinio) thiovinyl] -3-cëphenacetaml'o - j- - - -etny - -,) -PYTJ. QlillO t. J. 10VlilY - - cep. E:: f. ! - 4-carboxylate (syn isomer) (cis isomer).



  IR (Nujol): 3550-5250, 1770, 1670, 1620, 1590 cm 'NMR (MSO-d) 6: 370-4. 00 (5H, m), 5. 80 (3H, s), go A 430 (3H s), 520 (1H, d, J = 5Hz), 570 (1H, dd, J = 5Hz, 8Hz), 670 ( 1H, s), 673 (1H, d, J = llHz), 7) 00 (IH, d, J = llHz), 715-750 (15H, m), 00-9 10 (5H, m), 950 ( 1H, d, j = Sqz) 5 le 53) le 7- [2- (3-ca. Rboxypropoxyinino) -2- (5-amino-l, 2, 4- .... 1 - 1) / "] - [2 (1 1, 1 -'dO ') th. Iovinyl] -3-cephe-4-ca. Rboxylate (syn isomer) (trar. Isomer), IR (Nujol): 3300, 1765, 1665, 1600 , 1530 cm 1 NMR (DMSO-dJû: 16-27 (4H, n), 3.75 (2H, large s), -2 7 1 6d 4 0 t 40-44 (2H, n), 440 (3H, s), 510 (1H, d, J = 4Hz),; 72 (1H, dd, J = 4, 8Hz), 6 (1H, 'd, J = 16Hz), 744 (1H, d, J = 16Hz) , 77-91 (4H, m), 9;

   60 (IH, d, J = 8Hz)

  <Desc / Clms Page number 119>

 
 EMI119.1
 54) 54) 7- [2-ethoxyimino-2'- (5-amino-1,2,4-thiadiazol-3yl) acetamido] -3- [2- (l-methvl-2-pYridinio) thiovin. yl] -3cephem-4-carboxylate (syn isomer) (cis isomer).



  IR (Nujoi): 3300, 1765, 1670, 1610, 1560 cn-l NMR (DMSO-d) 6: 127 (3H, t, J = 5Hz), 3, 65-4 ,, 35 (4H, m), 5710 (1H, J = 5Hz), 568 (1H, dd, J = 5Hz, 8HZ), 642 (1H, d, J = 14Hz), 767 (1H, d, J = 14Hz), 6 95-9û0 (6H , m), 950 (1H, d, J = 8Hz) 55) 7- [2-ethoxyinino-2- (5-phosphonoa. niino-1, 2, 4thiadiazol-3-y1) acetaido] -3- [2 - (l-methyl-3-pyridinio) thioviyl] -3-cephen-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3200-3400 (broad), 1760, 1672, 1520 cm 1 NMR (NaHCO - DO) o: 1J33 (3R, t, J7Hz), 3} 77 (2H, 3 2 large s), 435 (3H, s), 433 (2H, q, J = 7Hz), 530 (1H, d, J = 5Hz), 582 (1H, d, J = 5Hz), 6.60 (IR, d, J = 15rIz ), 7; 17 (1H, ci, J = 15 Hz), 7 J 8:; - 8; 80 (4H, m) 56) 7- [2-ethoxyi. in. o-2- (5-phosphonoami? io-l, 2, 4thiadiazol-3-yl) acetanido] -3- [2- (l - niethyl-2-pyridin. io) thicviyl] -3-cephem-4- carboxylate (syn isomer) (trans isomer), IR (Nujol):. 3200, 1763, 1673, 1610, 1560, 1508, 1269, 1230 cm 'NMR (NaHCO¯-DzO) 6:

  -133 (3H, t, J = 7Hz), 383 (2H, large s), 423 (3H, s), 438 (2H, q, J == 7Hz), 5) 30 (lH, d, J = 5Hz ), SJ80 (1H, ci, J = 5Hz), 660 (1H, d, J = 14Hz), 7) 38 (H, ci, J = 14Hz), 74-88 (4H, m)

  <Desc / Clms Page number 120>

 
EXAMPLE 6
To a solution of trifluoroacetic acid salt of 7-amino-3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate hydroiodide (trans isomer) (17, 5 g) in tetrahydrofuran (300 ml) containing monotrimethylsilylacetamide (27 g) was added 2-ethoxyimino-2- (5-amino-1,2, - 4-thiadiazol-3-yl) hydrochloride hydrochloride acetyl (syn isomer) (10.5 g) with stirring between -10 and -5 C. The mixture was stirred for an hour and a half under the same conditions.

   After removal of the solvent, to the residue was added
 EMI120.1
 ethyl acetate (11) and a 5% aqueous solution of sodium bicarbonate (300 ml). The separated aqueous layer was concentrated in vacuo at 30oC. The resulting aqueous solution was adjusted to a pH of 4.5 with 10% hydrochloric acid, cooled with ice and subjected to column chromatography on a macroporous non-ionic adsorption resin called "Diaion HP- 2O "and eluted with a 5% aqueous solution of isopropyl alcohol.

   The fractions containing the desired compound were combined, concentrated in vacuo and lyophilized to give 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acêtamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn-isomer) (trans-isomer) (6.0 g).
 EMI120.2
 



  IR NUJol) '; 3300 (large), 1760, 1660, 1600, 1520 cm "m. M (DSO-d6) ô: 1, 30 (2, t, J = 7Hz), 3, 1-3, 8 (2H, m), 4, 28 (3H ', q, J = 7Hz), 4, 40 (3H, s), 5, 12 (lH, d, J = 4Hz), 5, 71 (lit, dd, J = 4, 8Hz) , 6, 53 and 7, 50 (2H, 2xd, J = 16Hz), 7, 8-9, 20 (5H, m), 9, 50 (1H, d, J3Hz), EY7at? H: 7 EXAMPLE 7
The following compounds were obtained in a manner similar to that of Example 6, 1) 7-, [2-ethoxyimino2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] - 3- [2- (1-methyl-2-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer),

  <Desc / Clms Page number 121>

 
 EMI121.1
 IR (Nujol): 3300, 3200, 1760, 1650, 1600 cm 'NMR (DMSO-dJ 6:

   128 (3H, m), 3) 55 (2H, ABq, RMi, '6 17 J = 18Hz), 420 (3H, s), 415 (2H, s), 5 ClH, S 70 5. 15 (1H, d, J = 5Hz), 570 (1H, dd, J = SHz, 5H), 6.65 (1H, d, J = 16Hz), 780 (1H, d, J = 16Hz), 8.00-850 ( 5H, n), 890 (1H, broad s), 955 (1H, d, J = 8H =).



  2) 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadia zol "-3-yl) acetanido] -3- [2- (1-methyl-2-pyridinio) thiovinyl liiodhydate ] - 3-cêphein-4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 3400, 3250, 1780, lëSO-1680, 1620 c '-. 1 "..? (i "T"., A.,)) "., -2- (1-methyl-3-pyridinio) thiovinyl] -3-ce'phes-4cs. rboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3400-3100 (large), 1760, 1660, 1600, 1520 cn '4) le7- [2-methcxyimino-2- (2-ainohiacl-4-yl) acetaido- - [2- (l- in. ethyl-2-pyridin. ic) thiovin. yl) -3-cephe-4L carbcxylate (syn isomer) (trans isomer).



  IR (Kujol): 3300, 1765, 1670, 1611, 1562, 1533 c '5) le7- [2-methcxyiuino-2- (2-ainothiazol-4-yl) acetamido] - 3- [2- (4-nethyl -2-pyrazinio) thiovinyl-3-cephem-4L carboxylate (syn isomer) (trams isomer) IR (Nujol): 3300, 1765 (bT.), 1660, 1600 cl 6) le7- [2-me hoxyimino-2- (2-tritylaincthiaol-4-yl) acetamidoj-3- [2- (1-methyl-2-pyridinio) hiovinyl] -3cepheni-4-ca. synbox fisomer rboxylate (trans isomer), IR (ujol): 3250, 1780, 1672, 1595 c 'NMR (DMSO-d) 6: 377 (3H, s), 380 (2H, m), 6'y ze ( 3H, s), 5) 20 (lE, d, J-5Hz), 5J77 (1H, de. R and 8Hz), 6) 70 (lH, s),

  <Desc / Clms Page number 122>

 
 EMI122.1
 68-7) 7 (18E, m), 7, 7-9105 (4H, El), 957 (1H, d, J = 8Hz) i) le7- [2-meihoxyimino-2- (2-tert-pentylcxycarbonylaminothiazol- 4-yl) acetaido] -3- [2- (4-methyl-2-pyrazinio) thiovinyl) -3-cephem-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3350, 1762, 1700, 1660, 1530 cmRMN (DMSO-d) 6: 086 (3H, t, J = 7Hz), 143 (6H, s), 6 88 S) -173 (2H, q , J = 7H =), 385 (2H, s), 388 (3H, s), zo (3H, s), 525 (1H, d, J = 5H), 583 (1H, dd, J = 5H and SHx ), 726 (1H, s), 730 (2H, br. S), 887 (1H, m), 930 (2H, n), 9) 73 (1H, d, J = 8Hz).



  8) 7- [2-ethoxyimino-2- (5-amino-1,2,4,4-thiadiazol-3-yl) acetamido iodide] -3- [2- (1,3-dimethyl-2-pyrimidinio ) thio- 1 vinyl] 3-cephem-4-carbolate (syn isomer) (trans isomer) IR (Nujol): 3350, 1770, 1663, 1605 cm-l 9) leï- [2-ethoxyiminio-2- (5- aino-1, 2, 4-thiadiazol3yl) acetanido] -3- [2- (4-methyl-2-pyrazinio) thiovinylj-3cdphem-4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 3350, 1760 (br.), 1665, 1607 cm-1 NMR (DMSO-d6) 6: 1 20 (3H, t, J = 7H), 390 (2H, br. s), 413 (2H, q, J-7Hz) , 426 (3H, s), 517 (1H, d, J-SHz), 577 (1H, dd, J = 5Hz, 8H =). 7) 22 (2H, br. S), 03 (2H, br.s), 8) 80 (1Hp br. S), 9. 20 (2H, br. S), 9, 50 (1H, d, J8Hz ).



  1 10) 7- [2-me thoxyimino-2- (5-aniino-1,2,4-thiadiazol-3- 1 1 3-cephem-4 "carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3250-3350, 1770, 1660, 1620, 1560, 1530 cm 'mIN (DMSO-d6) 6: 35-41' (2H ,, m), 390 (3H, s), 4} 17 ( 3R, s),

  <Desc / Clms Page number 123>

 
 EMI123.1
 510 (1H, d, J = 5H2), 5; 87 (1H, d-d, J = 5Hz, and 8Hz), 650 (1H, d, J = 16Hz), 767 (1H, d, J = 16Hz), 8; 00-8, 3 (5H, m), 8; 97 ClH, d, J = 5Hz), 9, 55 (1H, d, J = 8Hz) Il) leï- [2-ethoxyimino-2- (5-mino-l, 2, 4-thiadiazol-3yl) aceranidoj- 3- [2- (1-ethyl-3-pyTidinio) thiovinyl] -3ce cephe-4-carboxylate (.-Syn isomer) (trans isomer) IR (Nujol): 3300 (large), 1770, 1675, 1600, 1520 cm- 12) le7- [2-etoxyimino-2- (5-amino-1,2,4-thiadiazol-3yl) acetanido] -3- [2- (l-nthyl-3-pyridinio) thiovinylj-5 "cephe -4-carboxylate isomer syn) (cis isomer).



  IR (Nujol): 3300 (wide), 1760, 1665, 1600, 1520 cm NMR (DMSO-d) 6: 1.25 (3H, tJ-7H), 4.06 (2H, ABq, 6 Li> J = 7Hz), 4. 35 (3H, s), 5.04 (1H, d, J = 5Hz), 5. 65 (1H, dd, J = 5Hz, 8Hz), '6. 38 (1H, d, J = 10Hz), 7.25 (1H, d, J10Hz), 7. 87-9. 30 (6H, m), 9.43 (1H, d, J = 8nz).



  13) Ie7- [2-carbcxymelhcxyiino-2- (5-ainc-12, 4- "-" Il - [2. {,., 2 (. 1 2 4 thiovinyl] -3-cephen-4-carboxylate (isomer syn) (trans isomer).



  IR (Nujol): 3300 (large), 1765, 1670, 1615, 1S6C, 1525 cm 'l4SQ, i¯25 cm.



  NMR (DMSO-d) 5: 4; 27 (2H, ABq, J-18Hz), - 433 (3H, s), 4. 63 (2H, s), 502 (1H, d, J = 5H =), 576 (1H, dd, J = 5, 8Hz), 663 (1H, d, J = 14Hz), 7) 35 (El, d, J14Hz), 7) 67-9) 10 (6H, n), 10; 03 (lE, d, J = 8H :).



  L of y 14) 7- [2-allyloxyiniino-2- (5-aniino-1,2,4-thiadia: ol-3 "yl) acetaido] -3- [2- (l-nethyl-3- pyridinio) thiovinyl] -3cerhc-4-carboxylateisomer syn) (isomerretrans).



  IR (Nujol): 3300, 1760; 1670, 1620, 1600, 1530 is ""

  <Desc / Clms Page number 124>

 
 EMI124.1
 (DILSO-d Pun (DMSO-d) 6: 3j70 (2H, b. S), 440 (5H, s), 10 (2H, d, J = 3H), 515-95 (4H,), 653 (1H , d, J = 16H), 745 (1H, d, J = 16H), 1 800-9) 10 (6H, n), 957 (1H, d, J = 8Hz)

  <Desc / Clms Page number 125>

 
 EMI125.1
 15) 7- [2- (. T-butoxycarbonylmethoxyinino) -2- (2 aminothiazol-4-yl) acetaido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cepheni-4- carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3200-2500, 2400-2600, 1770, 1715, 1680, 1630 cm 'RMN (DMSO-d6) 6:50 (9H, s), 320-410 (2H, m), 43 (3H, s), 4 70 (2H, s), 530 (1H, d, J = 5Hz), 533 (1H, dd, J = 5H1, 8Hz), 700 (1H, s), S3 f 0 0 (1 S) y 7, 30 (ZH, large s), 8-9) 00 (6H,; n), 9; 27 (1H, large s), 977 (1H, d, J = 8Hz) 16) le 7- [2-carboxymethoxyimino-2- (2-amiiiothiazol-4L yl) acetaido] -3- [2- (l-methyl -3-? YTidinio) thicvinyl] -3ceDhem-4-carboxylate (Syn-isomer) (trans-isomer).



  IR (Nujo1): 3300, 1765, 1670, 1620 cm-l NMR (DMSO-d) <S: 350-410 (2H, m), 430 (3H, s), 6 y 1 4, 63 (gold, large s), 523 (1H, d, J = 5Hz), 87 (1H, 590 (1H , dd, J = 5Hz, 8Hz), 687 (1H, s), 6 995 (1H, d, J-15Hz), 715 (2H, large s), 747 (1H, d, J = 1SHz), 790- 890 (3H, m), 913 (1H, large s), 980 (1H, d, J = 8Hz) 17) le 7- [2- (3-carboxy-2-propenyloxyiJìlino) -2- (2-aminothiazol- 4-yl) acetamidoj-3- [2- (1-methyl-3-pyridini. O) thiovinyl] -3-ce? he-4-carboxylate (syn isomer) (trans isomer), IR (Nujol): 3300, 1760, 1660, 1600, 1535 cm "NMR (DMSO-d / DO) o:

   357-4, 20 (2H, m), 437 (3H, s), 6 2 1 1 457-493 (2H, m), 5, 10 (1H, d, J = 5H :), 5) 60 (1H , dd, J = 5Hz, 8Hz), 598 (1H, d, J = 16Hz), 651 (1H, d, J = 16Hz), 748 (1H, d, J = 16Hz), 6 78 (IH, s) , 7,678 (1H, s), 776-917 (4H, m), 967 (1H, d, J = 8Hz) 18) 7- [2- (1-methyl-2-pridiniomethoxymino) iodide) -

  <Desc / Clms Page number 126>

 
 EMI126.1
 2- (2-aminothiazol-4-yl) acetamido] -3- [2- (l-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer) IR (Xujol) : 3250, 1760, 1665, 1615 cm'1 NMR (D0) 6: 79-900 (8H, m), 7, 17 (1H, d, J = 16Hz), 710 (lH, s), 6) 67 ( 1H, d, J = 16Hz), 5 90 d, J = SHz), 5.75 (2H, s), 5.34 (1H, d, J = 5Hz), 445 (6H, s), 35-425 (2H, m) 1 and 19) 7- [2- (2-pyridylinethoxyimino) -2- (2-aninothiazol- 'p 4-y1) acaDido] -3- [2- (1-8thyl-3-PYTidinio ) thiovinyl] -3ceptem-4-carboxylate (syn isomer) (trans isomer) IR (\ jol):

   3300, 1760, 1660, 1620, 1590 cm-1 MN (DMSO-d6) g: 37-420 (2H, m), 447 (3H, s), 5J15 (EI, d, J = 5Hz), 5) 25 (ZH, s), 5/72 (1H, dd, J = SEz, 8Hz), 6) 48 (1H, ci, J = 14Hz), 630 (1H, s), 71-90 (11H, m), 990 (1H, d, J = SHZ) 20) 7- [2- (3-carboxypropoxyimino) -2- (2-ainothiazolL 4-yl) acetamido] -3- [2- (l-nethyl-3-pyridinio ) thiovinylj-3c ceDher-carboxyiate (syn isomer) (t isomer: rarAs).



  IR (Nujo1):. 3300, 1760, 1660, 1600, 1535 cm-1 NMR (DMSO-d 6 / D O) o: 15-2 73 (4H, m), 33-427. or),. 437 (3H, s), 508 (1H, d, J = 5Hz), 563 (1H, dd, J = 5Hz, 8Hz), 650 (1H, d, J = 16Hz), 7) 48 (IH, d, J = 16Hz), 6 74 (IH, s), t) 76-9 J13 (4H, m), 955 (1H, d, J = 8Hz) 21) on 7- [Z- (1-Carboxypropoxyimino} -2 - (Z-amnothiazo1- 4-yl) aceiamidoj-3- [2- (l-niethyl-3-pyridinio) thiovin. Yl] -3cephem-4-carboxylate '(syn isomer) (trans isomer).



  IR (Nujol): 3300, 1760, 1660, 1590 cill-1 NMR (DMSO-d6) 6: 1.08 (3H, t, J = 7Hz), 162-224 (2H, m). 32-3, 9 (2H, m), 442 (3H, s),

  <Desc / Clms Page number 127>

 
 EMI127.1
 4} 47 (il, t, J = 6Hz), 5, 15 (lH, d, J = 5Hz), 5, 77 (lH, dd, J = 8Hz, 5Hz), 6, 47 (lH, d, J = 16Hz), 6i87 (IH, s), 7, 0 (1H, d, J = 16Hz), ï, 02-9, 3 (4H, m) 22) 7- [2-allyloxyimino-2- (2 -s. minothia. sol-4-yi) acetamido] -3-f2- (1-methyl-3-pyridinio) thiovinyl] -3-cephemp 4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1760, 1660, 1600, 1530 cm 'MN (DMSO-d6 / D 0) g: 333-387 (4H, s), 437 (3H, s), 462 (2H, d, J = 5Hz), 6., 50 (1H, d, J = 16Hz), 7. 47 (1H, d, J = 16Hz), 673 (1H, s), m 783-903 (4H, m), 957 ( 1H, d, J8Hz) 23) 7- [2- (2-ydroxyethoxyimino) -2- (2-aminoihiazol- 4-yl) acetanido] -3- [2- (1-methyl-3-pyridinio) thiovin. yl] -3cdphem-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1760, 1660, 1600, 1535, 1500 cm-1 M (DMSO-d / D 0) 6: 3 20-3 83 (2H, m) 435 (3H, s) 24) on 7 - [2-ethoxyimino-2- (2-aninothia. Zol-4-yl) acetamido] -3- [2- (l-ethyl-3-pyTidinio) thiovinylj-3e do cephem-4-cs. rbcxylate (syn isomer) (trans isomer).



  IR (Kujol): 3300, 1760, 1665, 1600, 1535 c '1665, 1600, 1535 NMR (DMSO-d / DO) g: 1, 25 (3H, t, J = 7Hz), 6 2 1) y 413 (2H, ABq, J = 7Hz), 437 (3H, s), 508 (1H, d, J = 5Hz), 565 (1H, dd, J = 5Hz, 8Hz), 6. 48 (IH, d, J = 16Hz), 748 (1H, d, J = 16Hz), 773-793 (4H, m), 9 52 (1H, d, J = 8Hz), 6 3 S) 25) on 7- [2- (Z -propynyloxyinino) -2- (2-aminothiazol-4yi acetaido] -3- [2- (1-ethyl-3-pyridinio) thiovinyl] -3cephem-4-carboxyla te (syn isomer) (trans isomer).



  IR (Nujol): 3250, 1760, 1660, 1600, 1530 cm-l

  <Desc / Clms Page number 128>

 
 EMI128.1
 NMR (DMSO-d / DO) g: 3 3-38 (3H, m), 437 (3H, s), (DMSO-D 6 / D 247 (2H, s), 5.09 (1H, d, J = 5Hz), 5.63 (1H, dd, J = 5Hz, 8Hz), 6J53 (lH, d, J = 16Hz), 6.78 (IH, s), 7J50 (lH, d, J = 16Hz) , 7) 73-7, 93 (4H, m), 9.05 (Ei, s), 9jS2 (1H, d, J = 8Hz) 26) on 7- [2- (t-butox) 'carbonylmethoxyiniino-2 '- (2forjn. Amidothiazol-4-yl) ace'iamido] -3- [2- (1-ethyl-3pyridinio) thiovinyl] -3-cephen-4-carboxylale (syn-isomer) (trans-isomer).



  IR (Nujol): 3200-3400, 1760, 1720-1730, 1690, 1670 c 'RMN DMSO-d6) 6: 150 (9H, s), 350-42û (2H, m), 4, 37 (3H, s ), 4; 63 (2H, s), 5, 27 (IH, d, J = 5Hz), 587 (1H, dd, J = 5Hz, 8Hz), 700 (1H, d, J = 16Hz), 7) 40 (1H, d, J = 16Hz), 745 (1H, s), 795-910 (4H, m), 853 (1H, s), 9) é7 (lE, d, J = 8Hz), 12) 70 (lH, large s) 27) 7-- (- t-butoxycarbonyl) propoxyiino] -2- (2fOTawidothiazol-4-yl) actaido]} -3- [2- (1-Rdthyl-3py-ridiiiio) thiovinyl] -3-ceDhen -4-c. arbcxylate (syn isomer) (trans isomer) IR (Nujol): 3250, 1760, 1720, 1680 cm 'RHN (DMSO-d.). 6: 098 (3H, t, J = 7Hz), 1) 45 (9H, s), 1) 52-2, 06 (2H, m), 3J67-4, 17 (2H, m), 4) 37 ( 3H, s), 45 (1H, t, J = 6Hz), 5.28 (1H, d, J = 5Hz), 593 (1H, dd, J = 8Hz, 5Hz), 6.43 (1H, d, J = 16Hz), 722 (1H, s), 7) 63 (1H, d, J = 16Hz), 7;

   83-9 33 (4H, m), 852 (1H, s), 96 (1H, d, J = 8Hz) 1 28) 7- [2- (2-pyridylmethoxyimino) -2- (2-formaidothiazol-4 -yl) acetainido] -3- [2- (l-methyl-3-pyridinio) 'thiovinyl] -3-cepheni-4-carboxylate (syn isomer) - (trans isomer).

  <Desc / Clms Page number 129>

 
 EMI129.1
 



  NMR (DMSO-d.) G: 33-4, 00 (2H, m), 4.33 (3H, s), 5.13 (1H, d, J = 5Hz), 530 (2H, large s), 5, 83 (1H, dd, J = 5Hz, 8Hz), 6, 50 (1H, d, J = 15Hz), 20-9 00 (9H, m), 7. 43 (1H, s), 850 (1H , s), 9. 95 (1H, d, J = 8Hz) J 29) 7- [2- (3-benzhydryloxycsrbonyl-2-propenyloxyimino) L 2- (2-tTity1aminothiazol-4-yl) acetamido] -3 - [Z- (1-methyl-3- ... ") L '. 1] 3 I} .. 1. -) (trans isomer) IR (Nujol): 3300, 1780, 1720, 1680, 1600, 1530 , 1500 cry RN (DMSO-d6 / D 0) 6: 37-4> 35 (2H, mj, 4) 40 (3H, s), 4. 67-5) 00 (2H, m), 527 (1H, d, J = 5Hz), 583 (1H, m), 625 (1H, d, J = 16Hz), 6) 67-700 (3H, m), 7 (26H, m), 800-9, 20 (5H , m), 9) 80 (1H, el, J = 8Hz) 30) 7- (Z-ethoxyimino-Z- (Z-tritylaminothiazol-4-yl) do 1-3- [2- (1-rethyl- 3 - paceranidoj-3- [2- (l-methyl-3-pyridinio) thiovinyl] -3cephe-4-carboxylate (syn isomer) (hrans isomer).



  NMR (DMSO-d./DO) ô: 1. 20 (3H, t, J = 7Hz), 36-40 (2H, m), 406 (2H, ABq, J = 7Hz), 437 (3H, s) , 5, 15 (1H, d, J = 5Hz), 5; 67 (1H, dd, J = 5Hz, SHs), 672 (1H ,. s), 7) 17-7, 50 (15H, m), 843-917 (4H, m), 951 (1H, d, J = SHz) 3l) 7- [2- (2-propynyloxyimino) -2- (2-tritylainothiazol-4-yl) acetamido] -3- [2- (l-melhyl-3-pyridinio) thiovinyl] -3- cephem-4-carboxylate (syn isomer) (trans isomer).



  NMR (DMSO-d / DO) 6: 34-37 (3H, m), 437 (3H, s), 6 2 521 (1H, d, J = 5Hz), 573 (1H, dd, J = 5Hz, 8Hz ), 678 (1H, s), 713-750 (15H, m), 965 (1H, d, J = 8Hs)

  <Desc / Clms Page number 130>

 
 EMI130.1
 32) 7- [2- (3-benzhydryloxycarbony1propoxyimino) -2- "-hy! (2-tritylaminothiazol-4-yl) acéttaIT. IdoJ-3- [2- (1-methyl-3pyridinio) thiovii-Lyl] - 3-ce? Heni-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3350, 1770, 1720, 1665, 1590, 1520 cm 'RMX (DMSO-d / DO) 6: 153-210 (4H, m), 350-370 U 2 (ZH, niL 3, 83- 427 (2H, m), 4) 35 (3H, s), '517 (1H, d, J = 8Hz), 563 (1H, m), 6; 78 (1H, s), 87 (1H, d, J = 15Hz), 690 (1H, s), 77.10-7 50 (26H,), 780-917 (4H, ni), 960 (iH, d , J = 8Hz) 33) 7- [2-carboxymethoxyiminc-2- (thiazol-4-yl) acetaido] -3- [2- (l-ethyl-3-pyridiio) thiovinyl] -3a e du 1 e cepher .-4-carboxyla-ce (syn isomer) (tran isomer) IR (Nujol): 3350, 1760, 1660, 1600 cn "1 D (DO-NaHCO): 73 (2H, s), 4 35 (3H, s ), -4-z) 450-487 (2H, m), 532 (1H, d, J = 5Hz), 1: 83 (IH, dd, J = 5Hz, 8Hz), 6, 63 (IH, d, J = 16Hz), 717 (1H, d, J = 16Hz), 730-880 (6H, m) / 3 zo [2-hydroxy-2- (2-a ii. Othiazol-4 "yl) aceta; ; tido] - 3- [2- (1-ethyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (trans isomer).



  IR (Nujol): 3300, 1760, 1670, 1600 cni 'RN (DMSO-d) -o: 342-404 (2H, m), 443 (3H, s), 500 (1H, s), 515 (1H, d, J = 5Hz), 570 (1H, dd, H 5Hz), 654 (1H, s), 6 6 (1H, d, J = 16Hz), 702 (2H, large s), 753 (1H, d, J = 16Hz), 773-917 (4H, m) 35) 7-r2- (1-carboxy) ethoxyimin. o-2- (5-aino-l; 2, 4thiadiazol-3-yl) acetaido] -3-2- (l-methyl-3-pyridiio) thiovinyl] -3-cephe-4-carboxylate (syn isomer) ( trans isomer).



  IR (Nujol): 3300, 1770, 1665, 1600, 1520 cm '

  <Desc / Clms Page number 131>

 
 EMI131.1
 NMR DMSO-d / DO) g: 1 51 d, J = '6 Hz), 3; 80 (2H, large s), 4J31 (3H, s), 475 (1H, d, J = 6Hz), 1 lir = il F 7-) 1 525 (1H, d, J = 4Hz), 585 (1H, d, J = 4Hz), e 683 (In, d, J = 16Hz), 750 (1H, d, J = 16Hz), rn) 76-94 (4H, mj 1 l, 2, 4-thiadis. zol- 3-yl) acetamido] -2- [2- (l-nethyl-3pyTidinio) thicvinylj "5-cephem-4-carboxylate (syn isomer CisoD, notch era).



  IR (Nujol): 3300, 1770, 1670, 1610, 1520 cm "CD (DO-NaHCO-) 6: 160 (6H, s), 582 (2H, s), 4 (H, s), 555 (1H, d, J = 4H =), 5 90 (1H, d, J = 4H2), 670 (1H, d, J = 16Hz), 720 (1H, d, J = lôHs), 75-89 (3H, m) 37) 7- [2-2, -LL 37) le 7- [2-ë-c: hoxyiEiin. O-2- (5-anino-12 4-thia. Diazol-, ..., ... 1 "] 3 [7 r 1 T- 1 ..., .. -. -.) H - - 1 J 3-cephen-4-ca. rboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1760, 1640-1680. 1610, 1520 cni NMR (DMSO-dJ g: 1, 30 (3H, t, J = 5Hz), 323-390 (2H, n), 425 (2H, q, J = 7Hz), 495-520 (3H, m), i (1H, m), 660 (1H, d, J = 15Hz), 750 (1H, ci, J = 16Ez), 8) 00-9, 00 (4H, m), 9) 55 (1H , d, J = 8Hz) 38) 7- (2-ethcxyimino-2- (S-amino-1, 2, 4-thiadiazol-3- '' / y acetamlQO - - w-trlmetnyatiOnloetJyl tllovlnyl -.) cephem-4-caTboxylae '(syn isomer) (trs isomer).



  IR (ujo1): 5300,1760,1670,1600,1520 c 'NMR (DMSO-d.) 6: 1: 25 (3H, t, J = 5Hz), 3, 10-4, 00 (6H, m) , 420 (2H, q, J = 7Hz), 5.05 (1H, d, J == 5Hz), 560 (1H, n), 660 (1H, d, J = 16Hz), 703 (1H, d, J = 16Hz), 306 (2H, large s), 9 50 (1H, d, J = 8Hz)

  <Desc / Clms Page number 132>

 
 EMI132.1
 39) le [(4-carboxy-3-hydroxyisothiazol-5-yl) -. "1" ci]; - r7 (1 "¯do 0) h" "1]; thio2. cetajnido] -3-2- (l-nieth. yl-3-pyridinio) thiovinyl] -3- 1 IR (Nujol) -: 3300, 1760 , 167G cm Rf'1ì, (DMSO-dJ g: 393 (2H, s), 333-400 (2H, m), 447 (3H, s), 527 (1H, d, J = 5Hz), 570 (1H , dd, J = 8Hz, 5Hz), 750 (6H, m), 9750 (1H, d, J = 8Ez) - 0 ie 7- [2-met: hoxyinino-2- (5, 6-dihydro-14- cxathiin.e 2-v-3--3i L syn) (isomer - trcins) 2-yl) s. ceia. mido] -3- [2- (1-eihyl-5-pyridin. io) thiovin. yl] -J) - 1 IR (Nujci): 5500, 1760, 1660, 1800, 1500 "RMX (DO) 6:

   3 0-525 (2H, ni), 375 (2H, s), 2 1 455 (3H, s), 322 (1H, d, J = 5Hz), cry (1H, d, JSHz), 597 (1H, s), 653 (1H, d, J = 16Hz), 712 (1H, d, J = 16Hz) 41) le 7- [2-n-ethcxyiniino-2- (l, 2., 3-thiadiazol-4- yl) acctanido] -5- [2- (i-methyl-5-pyridiio) thiovinyl] -5-cephe- 41) le-7- [-z-lce '4-cs. rbcxyls-te (syn isomer) (trans isomer).



  -rbo- ate (isomr c IR (Nujol): 3200-3550, 1760, 1660, 1600, 1555 c 1 NMR (DMSO-d / DO) 5: 367 (2H, s), 402 (3H, s), 4 , 37 (3H, s), 5, 13 (lH, d, J = SHz), 580 (1H, dd, J = 5Hz, SHz), 650 (1H, d, J = 16Hz), 750 C d, J -16Hz), 7 83-9 10 (4H, n), 940 (1H, s), 9, 78 (IH, d, J = 8Bz) 1 1 1 42) 7- [2-methoxyiino-2- ( 3-hydToxyphenyl) acetaido] - 1 1 3- [2- (1-ethyl-3-pyridinio) thiovinyl] -3-cephern-4c 2-roo a4L. it. rbcxylate e (syn isomer) (trans isomer).



  IR (Nujol): 1770, 1650, 1600, 1570, 1500 cm-1 RMX (DMSO-d6 / DO) a: 350-417 (5H, m), 4 17-zut 67 6 2 (3H, m), 517 (1H, d, J = 5Hz), 577 (1H, dd, J = 5Hz, 8HZ), 660 (1H, d, J = 16Hz), 753 (1H, d, J = 16Hz), 6, 83-Î , 40 (4H, m), 7) 73-8) 93 (4H, ri1)

  <Desc / Clms Page number 133>

 
 EMI133.1
 43) le7- [2-) ethoxyiin.o-2- (2-a.ninothiazol-4-yl) - 4, 3) 1 e 7- [2-ni hox --...- z aceiamidc] -3 - [2- (1-melhyl-2-pyridijiio) thiovinyl) -3-cepheni- 4-carboxylate (syn isomer) (cis isomer).



  1K (Nujol): 5400-510C, 1765, 1660, 1510, 1560, - -1 R: IN (DMSO-d.) O: 5, 67 (2H, ABq, J = 16Hz), 5S5- (3H, s ), 417 (5H, s), 512 (1H, d, J = 5Hz), 563 (IH, dd, J = 5H, SHz), 642 (1H, d, J = 14Hz), 675 (1H, s) , 7, 25 (2, large s), 765 (IH d, J = 14Hz), 79-900 (4H,), 9 57 (1H, d, J = 8Hz) e 7-m -to X, r 0 -ai 4L.-r-0 tz 0 1 v 1 L 4) le7-f (2-nthoxyiino-2- (2-ainohiaol-4-yl) s. cets. idcj-3- [2- (l-merhyl -5-pyridin. Io) thiovin. Yl-5ce? Heni-4-ca. Rboxyla. Te'Usomer syn) (cis isomer).



  'IR (ujol): 2500, 1760, 1660, 1600, l550 c' R:. (DMSO-d). c: 3.72 (2H, ABq, J = 16Hz), 582 (5H, 6 s), 455 (5H, s), 510 (1H, d, J = 5H =), 565 ci-ri dd, J = 5H, SHz), 638 (1H, d, J = 10Hz), '18 6 73 (1H, s), 722 (1H, d, J = 10Hz), 7, 18 (2H,' -large s), 735 -890 (5H, ill), 9) 17 (1H, large s), So 50 r rIs ds J = SEHZ) 45) le 7-2-mth. oxyiino-2- (2-tritylaminothia. zol-4-yl) L -do 3-idi-p-io'j (i-soni-, re syn) (trans isomer) cephem.-4-carboxylate (syn isorere) (trans isomer).



  IR (Nu-: 3300-3400, 1770, 1675, 1620, 1600 i

  <Desc / Clms Page number 134>

 
 EMI134.1
 NMR- (DMSO-d6) g: 77 (3H, s), 380 (2H, m), 4J32 (3H, s), 5717 (IH, d, J = SHz), 5.67 (IH, dd, J = 5Hz, 8Hz), 670 (1H, s), 685-767 (17H, m), 8.00-9, 03 (4H, m), 9d55 (IH, d, J = 8Hz) 46-) on 7 - [2-methoxyimin. o-Z- (2-tTitylaminothia. zol-4-yl.) acetamido] -3- [2- (l-methyl-2-pyridinio) thiovinyl] -3cephem-4-ca. rbcxylate (s n isomer) (cis isomer).



  1 1.615 IR (Nujol): 3300-3200, 1775, 1680 1660, 1615, 1600, 157J cm NMR (DMSO-dJ 6: 367-395 (2H, m), 373 (3H, s), "O s ), 517 (1H, d, J = 5Hz), 570 (1H, dd, J = 5Hz, SHz), 670 (1H, s), 675 (1H, d, J = 10Hz), 700-750 (15H, m), 767-905 (4H, n), 9q52 (1H, d, J = 8Hz) 47) 7- [2-methoxyimino-2- (2-tritylainin. othiazol - 4-yl) aceta. mido] -3- [2- (l-methyl-3-pyridinio) thiovinyl] -3-cephen- 4-carboxylate (syn isomer) (cis isomer).



  IR (Nujol): 3350-3250, 1770; 1670, 1620, 1590 cm "NMR (DMSO-dJ 6: 370-400 (5H, m), 3.80 (3H, s), 430 (3H, s), 5, 20 (1H, d, J = 5Hz ), 570 (1H, dd, J = SHizX 8Hz), 670 (1H, s), 673 (1H, d, J = llHz), 1. <: 0 (-H) 5 Z Or l ri J - U), .. 7 0 (ï H ', 700 (1H, d, J = llHz), 715-750 (1SH, m), 8, 00- 9, 10. (SH, m), 9150 (IH, d, J == 8Hz) 48) 7- [2- (3-carboxypropoxyinino) -2- (5-amino-l, 2, 4thiodiazol-3- yl) acetaido] -3- [2- (l-ethyl-3-pyridinio) thiovinylj-3-ce? hem.-4-carboxylate syn isomer) (trans isomer).



  IR (Nujol): 3300, 1765, 1665, 1600, 153Åa cm 'RMN (DMSO-d.) Û: 16-27 (4H, m), 375 (2H, large s), 6 1 40-44 (2H, m), 440 (3H, s), 510 (1H, d, J = 4Hz), 572 (1H, dd, J = 4, 8Hz), 675 (1H / d, J = 16H =), 744 (1H, d, J = 16Hz), 77-91 (4H, n), 9 J 60 C IH, d, J = 8Hz)

  <Desc / Clms Page number 135>

 
 EMI135.1
 49) 7- [2-ethoxyiinino-2- (5-anino-1,2,4-thiadiazol-3yl) acetamido] -3- [2- (1-methyl-2-pyridinio) thiovinyl] -3e cepheni- Syn-isomer 4-carboxylate (cis isomer).



  IR (Nujol): 3300, 1765, 1670, 1610, 1560 cn-l RHN (DMSO-d) 6: 1: 27 (3H, t, J = 5Hz), 565-4. 33 6 1>. 1 (4H, m), 5) 10 (1H, J = 5Hz), SJ63 (1H, dd, J = SHz, 8Hz), 642 (1H, d, J = 14Hz), 767 (1H, d, J- 14Hz), 6, 95-900 (6H, L), 950 (1H, d, J = 3 z) 50) 7- [2-ethoxyimino-2- (5-? HosphoRoaio-1, 2, 4this. Diazol -3-yl) s. cetamido] -3- [2- (l-n. ethyl-5-pyridinio) thiovin. yl] -3-cephem-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3200-3400 (wide), 1760, 1672, 1520 cm-l NMR (NaHCO-DO) 6: 133 (3H, t, J = 7Hz), 377 (2H, large s), 435 (3H , s), 33 (2H, q, J = 7Hz), 530 (1H, d, J = SHz), 582 (1H, d, J = 5Hz), 660 (1H, d, J = 15Hz), 7 17 (1H, d, J = 15Hz), 85-8 80 (4H, m) L 51) 7-2-ethoxyimino-2- (5-phosphonoaminc-l, 2, 4- .. d- 1 ... 1) 1 ",] .., [2 (1 JT 1? '.." 1 thiovinyï-3-cephen-4-ca. Rboxyla. Te (syn isomer) (trans isomer), IR (Nujol):. 3200 , 1768, 1673, 1610, 1560, 1508, 1269, 1230 cm 'RHN (NaHCO3-DO) o: 133 (3H, t, J = 7Hz), 383 (2H, large s), 4) 23 (3H, s ), 4 J 38 (2H, q, J = 7Hz), 530 (1H, d, J = 5Hz), 580 (1H, d, J === 5Hz), 6/60 (lH, d, J = 14Hz ), 38 (1H, d, J = 14Hz), 7;

   4-8 / 8 (4H, m)

  <Desc / Clms Page number 136>

 
EXAMPLE 8 To a suspension of 7- [2-methoxyimino-2- (2-t-
 EMI136.1
 pentyloxycarbonylaminothiazol-4-yl) acetamido] -3- [2- (4methyl-2-pyrazinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer) (1.0 g) in anisole (2 ml) trifluoroacetic acid (6 ml) was added while cooling with ice with stirring. The mixture was stirred at room temperature for 2 hours.



  The resulting solution was poured into diisopropyl ether (200 ml). The precipitates were collected by filtration and dissolved water (100 ml) was added at a pH of 4.5. The aqueous solution was subjected to column chromatography of a non-ionic macroporous resin called "Diaion HP -2O "and eluted with a 20% aqueous solution of isopropyl alcohol. The fractions containing the desired compound were concentrated and lyophilized to give 7 [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methyl-2-pyrazinio) thiovinyl] 3-cephem-4-carboxylate (syn isomer) (trans isomer) (0.12 g).



   IR (Nujol): 3300, 1765 (wide), 1660, 1600 cm "RMN (D2O) @: 3.80 (2H, large s), 4.00 (3H, s),
4.40 (3H, s), 5.30 (1H, d, J = 5Hz), 5.85 (1H, d, J = 5Hz), 7.0 (2H, large s), 7.13 (1H , s), 8, 53 (1H, d, J = 4Hz), 8, 90 (1H, large s), 9, 10 (1H, m).



   EXAMPLE 9
The following compounds were obtained in a manner similar to that of Example 8.
 EMI136.2
 



  1) 7- [2-methoxyimino-2- (2-aminothiazol-4yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-

  <Desc / Clms Page number 137>

 
 EMI137.1
 carboxylate (syn isomer) (trans isomer) IR (Nujol): 3400-3100 (large), 1760, 1660, 1600, 1520 ca '2) le7- [2-me'thoxyiïni'no-2- (2-aEiin. othiazol-4-yl) acetamido-3- [2- (l-nethyl-2-pyridinio) thiovinyl) -3-cephem-4carDoxylate (syn-isomer) (trans-isomer) IR (Nujol): 3500, 1765, 1670, 1611 , 1562, 1533 cnT Ri (DO-DCl) 6: 400 (2H, la, s), 413 (3H, s), 4 30 (3H, s), 537 (1H, d, J = 5Hz), 583 ' (1H, d, 7 CO r-, w rl ,. I, s) J = 5H), 700 (1H, d, J = 16Hz), 717 (1H, s), 763 (1H, d, J = 15H =), 76-82 (2H, n), 8 33 (1H, dd, J = 8Hz), 873 (1H, d, J = 8H =).



  3) le7-2-ethoxyiino-2- (5-ino-l, 24-thiadiazol-3-yl) acetamido] -3- [- l ethyl-3-pyridinio) thiovinyl] -3a L cephen.-4-c . at. rbcxylate (syn isomer) (trans isomer) IR (Nujo1): 3300 (large), 1760, 1660, 1600, 1520 CB-1 4) lG7- [2-CihoxyiE. ino-2- (5-s. uino-l, 2, 4-thiadiE-ol-3-yl) acetaido] -3- [2- (lr.ethyl-2-pyridin.io) thiovin.yl] "- 3cephen-4-carbcxylate (syn isomer) (trans isomer) IR (Nujol): 3300, 3200, 1760, 1650, 1600 cm '5) iodide ce 7- [2-ethoxyimino-2- (5-amino-l , 2, 4-thiadiadiazol-3-yl) acêtamido] -3- [2- (1,3-dimethyl-2-pyrimidinio) thiovinyU-3-cr-err - carboxylate (syn isomer) (train isomer = :) .



  IR lI \ ilJol): 3350, 1770, 1663, 1605 cm-l 6) Le7- [2-êhoxyiio-2- (5-aino-l, 2, 4-thiadiazol-3-, "., - [., (J. 1'J ..) h ". 1] ccDhe-4-carboxylate ((syn isomer) (trans isomer).



  IR (Nujol): 3350, 1760 (la.), 1665, 1607 en y l'icdhycratEde 7- [2-ethoxyimino-2- (5-amino-l, 2, 4-thia-

  <Desc / Clms Page number 138>

 
 EMI138.1
 diazol-3-yl) acêtamido] -3- [2- (1-methyl-2-pyridinio) thiovinyl] -3-c phem - carboxylate (syn isomer) (tra- isomer =). IR (Nujo1): 3400, 3250, 1í80, 1650-1680, 1620 CD-l 8) 1 - [2 J h .. 2 (. 1 - 4 .. .., yl) acetanido] -3- [2- (l-methyl-2-pyridinio) thiovinyl] - 5-cepher.-4-carboxyla. te (syn isomer) (trans isomer) IR (Kujol): 5250-3350, 1770, 1660, 1620, 1560, 1530 cm- -Q) "- e 7- 9) le [2-ëthoxyiino-2- (5- s. riino-1,2,4-thiadiazol-3-yl) acGtaidc] -3- [2- (l- & thyl-3-pyridinio) thiovinyl] -3cephen-4-carboxylate (syn isomer) (trans isomer) .



  IR (Nujol): 3300 (wide), 1770, 1675, 1600.



  10) le7- 10) le7- [2-ethoxyinino-2- (5-anino-1,2,4-lhiadiazol-3yl) acetamidoj-3- [2 "(l-merhyl-3-pyridinio) thiovinyl- 1 3 -cephem-4-carboxylate (isowre syn) (cis isomer) IR (Nujol): 3300 (large), 1760, 1665, 1600, 1520 cn '; Il) 1e7- [2-carbcxY2ethoxyiino2- (5-amino-l, 24thiadia2ol-3-yl) acetaido] -3- [2- (1-'B. Ethyl-3-pyridinio) "thiovinyl] -3-cephen-4-carboxylate (syn isomer) (trans isomer).



  IR (Kujol): 33CO (large), 1765, 1670, 1615, 1560, 15 25 cm 1 12) le7- [2-allyloxyimino-2- (5-ami-n. Ol, 2, 4-thiadiazol-3y1) ectaido] -3- [2- (1-thyl-3-pyridinio) thiovinyl] -3cdpheD-4-c8. rboxylate (syn isomer) (trans isomer) IR (Kujol): 3300, 1760, 1670, 1620, 1600, 1530 cm '

  <Desc / Clms Page number 139>

 
 EMI139.1
 4-bonylme /, 13) le7- [2- (t - butoxycarbonylniethoxyimino) -2- (2-.,. 1)} "] - [7 (1'1 ..., .. ci ..) thiovinyl ] -3-cephem-4-cTboxy1ate (syn isomer) (trans isomer).



  IR (Nujol): 3200-3300, 2400-2600, 1770, 1715, 1680, 1630 cm NMR (DMSO-dJ 6: 150 (9H, s), 320-4, 10 (2H) 4-, 43 (3H, s), 4.70 (ZH, s), 5.30 (1H, d, J = SHz), 4. 43 H.



  5, 83 (El, dd, J = 5Hz, 8Hz), 7.00 (1H, s), 730 (2H, large s), 8-900 (6H, m), 927 (1H, large s), 977 (IH, d, J = 8Hz) 1. 4) 7- [2-carboxynethoxvimino-2- (2-aminothiazol-4yl) acetaniido] -3- [2- (l - methyl-3-pyTi in. Io ) thiovinyl] -3cphem-4 - caTboxylate (syn-isomer) (trans-isomer).



  IR (Nujol): 3300, 1765, 1670, 1620 c 'R. K (DMSO-d) 6: 3, 50-4, 10 (2H, -), 430 (3H, s), 4, 63 (2H, large s), 5) 23 (lE, ci, J = 5Hz), 5. 90 (1H, dd, J = SHz, 8Hz), 6) 87 (IH, s), 6, 95 (IH, d, J = 15Hz), 7.15 (2H, broad s), 7.47 (1H, d, J = 15Hz), 7; 90-8, 90 (. SH, m), 913 (1H, large s), 9J80 (IH, ci, J = 8Hz) <15) 7- [2- (3-earboxy-2-propenyloxyimino) -2- (2-ainothiazol-4-yl) acetamido] -3- [2- (l-ethyl-3-pyridinio) thiovinyl] - 3-cephen-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1760, 1660, 1600, 1535 c "Ru-'N (DMSO-d / DO) 6: 357-420 (2H, m), 437 (3H, s), 4, 57-4 , 93 (2H, n), 5f10 (1H, d, J = 5Hz), 560 (1H, dd, J = 5Hz, 8Hz), 598 (1H, d, J = 16Hz), 6, 51 (IH, d , J = 16Hz), 7 J 48 (lE, d, J = 16Hz), 678 (1H, s), 776-9, 17 (4H, n), 967 (1H, d, J = 8Hz) 16) l '7- [2- (1-methyl-2-pyridiniomethoxyimino) -2- iodide

  <Desc / Clms Page number 140>

 
 EMI140.1
 (2-aminothiazol-4-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer).



  IR (Xujol): 3250, 1760, 1665, 1615 cw-l NMR (D. 0) 6: 7 9-9 00 (8H, m), 717 (1H, d, J = 16Hz), z 1 r-. y 7) 10 (1H, s), 667 (1H, d, J = -16Hz), S} 90 (1H, d, J = 5Hz), 575 (2H, s), 5; 34 (1H, d, J == 5Hz), 4, 4.5 (6H, s), 3, 5-4, 25 (2H "m) 17) on 7- [2- (2" Pyridylmethoxyiino) -2 - (2-aminothiazolL azoi- 4-yl) acetamido] -3- [2- (l-methyl-3-pyridinio) thiovinyl] -3ceDhem.-4-ca. rboxyls. te (syn isomer) (trans isomer).



  IR (Xujol): 3300, 1760, 1660, 1620, 1590 cn-1 NMR (DMSO-d.) 6: 37-420 (2H, n), 447 (3H, s), 5, 15 (1H, d, J = 5Hz), 525 (2H, s), 5 72 (1H, dd, J = SHZ, 8liz) ,. 6 dd, J = 5Hz, 8Hz), 643 (1H, d, J = 14Hz), 6) 80 (lH, s), 71-90 (11H, m), 990 (1H, d, J = 8Hz) 13 7- [2- (3-carboxypropoxyimio) -2- (2-aninothiaol-4-yl) acetamidoj-3- [2- (1-niethyl-3-pyridinio) thiovin. yl] -5cephem-4-carboxylate (syn isomer) (i somer tran) IR (Nujol): 3300, 1760, 1660, 16OO, 1535 c "RN (DMSO-d6 / D 0) 6: 1 5-2 75 ( 4H, m), 33-427 A (4H, m),. 4 37 (3H, s), 508 (1H, d, J = 5Hz), 563 (1H, dd, J = SHz, SHz), 6) 50 (1H, d, J = 16H), 748 (1H, d, J = 16Hz), 674 (1H, s), 7) 76-913 (4H,! Il), 9) 55 (1H, d, J = 8 Hz) 19) 7- [2- (l-carboxypropoxyiino) -2- (2-aminothiazol- 4-yl) acetaido] -3- [2- (l-methyl-3-pyridinio) thiovinyl] -3L cephem -4-carboxylate Cisomer syn) (trans isomer).



  (trans isomer).



  IR (Nujol): 3300, 1760, 1660, 1590 cm-1 R (DMSO-d6) 6: 1, 08 (3H, t, J = 7Hz), 1.62-2) 24 (2H, m), 32 -39 (2H, n), 442 (3H, s),

  <Desc / Clms Page number 141>

 
 EMI141.1
 4, 47 (1H, t, J = 6Hz), 5, 15 (1H, d, J = 5Hz), 5177 (1H, dd, j = 8Hz, 5Hz), 6J47 (1H, d, J = 16Hz), 687 (1H, s), 70 (1H, d, J = 16Hz), r A 702-93 (4H, a) 20) 7- [2-allyloxyiniino-2- (2-amin. Othiazol-4-yl ) acetamido] -3- [2- (1-thyl-5-pYridinio) thiovinyl -5-cepnem- 4-CS. Tboxylate (syn iscner) (trans isomer).



  IR (Nujo1): 3300 1760, 1660, 1600, 1530 cm-1 NMR (DMSO-d./D. O) 6: 553-3 87 (4H, m), 437 (3H, s), 6 4 7> 462 (2H, d, J = 5Hz), 650 (1H, d, J = 16Hz), 747 (1L, d, J = lônz 673 (1H, s), 7) 83-9. 03 (4H, s), 9.57 (1H, ci, J = 8Hz) 21) 7- [2- (2-ydroxyethoxyimino) -2- (2-amiothiazolY. L 1 4-yl) aceta. midoj-3- [2- (l-m. ethyl-3-pyridinio) thiovin. ylj-5T cephen-4-carboxylate (syn isomer) (isometer 1-rans).



  IR (Nujol): 3300, 1760, 1660, 16001 1535, 1500 cm-1 RN (DMSO-d / DO) 6: 3) 20-3. 83 (2H, m), 35 (3H, s) 22) 7- [2-cthoxyiEir. o-2- (2-amin. othiazol-4-yl) acets. mido] -3- [2- (l-methyl-3-pyTidinio) thiovinylj-3p -.- air cephem-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1760, 1665, 1600, 1535 cnT1 L, (DMSO-d6 / D 0) g: 125 (3H, t, J = 7Hz), 413 (2H, ABq, J = 7Hz), 437 (3H, s), 503 (1H, d, j = 5Hz), 565 (1H, dd, J = 5Hz, 8Hz), 648 (1H, d, J = 16Hz), 748 (1H, d, J = 16Hz ), 7, 73-7193 C. + H, m), 9) 52 (1H, d, J = 8Hz), 6 J 73 (1H, 5) 23) on 7-2- (2-p ropvnyio-, , - 23) 7- [2- (2-? Ropyn. Yloxyimino) -2- (2-aminothiazol-4yl) acetaniido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3cephem -4-carboxylate (syn isomer) (trans isomer).



  1 L-rans).



  IR (Nujol): 3250, 1760, 1660, 1600, 1530 ci "

  <Desc / Clms Page number 142>

 
 EMI142.1
 0) 3 3-3 8 4 37 (3H, RN (DMSO-d6 / DO) g: 3d3-38 (3H, m), 437 (3H, s) -, 47 (2H, s), 509 (1H, d, J = 5Hz), 563 (1H, il dd, J = 5H =, 8ho), 653 (lH, d, J = 16Hz), d ,, j. = 7 3-7 9 3 678 (1H, 3 \ 7, 5G (1H, d, J = 16H =), 7, 73-7, 93 (H,), 905 (1H, s), 952 (1H, d, J = 8Hz) 24) on 7- [ 2-hydroxy-2- (2-aninothiazol-4-yl) acetamidc] J 24d on 7- 3- [2- (l-methyl-3-pyridin. Io) thiovin. Yl] -3-ce? Hem-4 -ca'rboxyl2. te (tran isomer) IR (Nujol): 3300, 1760, 1670, 1600 cm-1 NMR (DMSO-d.) '6:

   3 2-404 (2H, m), 443 (3H, s), 500 (1H, s), 515 (1H, d, J = 5Hz), 570 (1H, d J = 3H =, 5Hz), 654 ( 1H, s), 66 (1H, 'd, J = 16Hx), 702 (2H, large s), 753 (1H, d, J = 16H =), 773-917 (4H, m) 1 L 25) le 7- [2- (l-carboxy) ethoxyiino-2- (S-amino-1,2,2, 4thiadiazol-3-yl) acetamido-3-2- (im. Etnyl-3-pyridin. Io) LJ e thiovinyï] -3-cephem-4-ca. rboxyl. 3-te (syn isomer) 1600, (trans isomer).



  -'1 (Nujol): 3300, 1 70, 1665, 1600, 1520 c "RM (DMSO-d / D 0) g: 151 (3H, d, J = 6H), '380 (' H, large s) , 4. 31 (3H, s), 475 (1H, d, J6Hz), 5) 25 (1H, d, J = 4Hz), 5785 (1H, d, J = 4Hz), 683 (1H, d, J = 16Hz), 750 (1H, d, J = 16Hz), 7, 6 - 9} 4 (4E, m) 26) on 7- [2- (l-mehyl-l-carboxyehoxyiino) -2- (S- aino- 1 1 l, 2, 4-thiadiazol-3-yl) acetaido] -3- [2- (l-nethyl-3pyriciinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1770, 1670, 1610, 1520 cn RMN (DO-NaHCO) o: 160 (6H, s), 3, 32 (2H, s), 442 (3H, s), 535 (1H, d, J = 4H =), 5 90 (1H, d, J = Hz), 670 (1H, d, J == 16H :), 7) 20 (li, d, J == 16Hz), 7) 5 -8; 9 (3H, m)

  <Desc / Clms Page number 143>

 
 EMI143.1
 27) 7- [2-ethoxyiic-2- (5-aniino-1,2,4-thiadiazol- 3-Yl) actamirlo] -3- [Z- (1-carboxymthyl-3-PYTidinic) thiovinyl] - 5 -cephe-4-carboxylate ('' syn isomer) (trans isomer).



  ', - 610, IS20 IR (xujoJ: 330û, 1760, 1640-1680, 1610, 1520 CL RMN (DMSO-dJ 6: 150 (5H, t, J = 5Hz), 555-5, 90 (2H, n ), 425 (2H, a, J = 7Hz), 495-5, 20 (5H, m), 575 (1H,), 660 (1H, d, J = 16Hz), 7.50 (1H, d, J = 16Hz), 8.00-900 (4H, m), 955 (1H, d, J = 8Hz) 28) 7- [2-ethoxyiino-2- (5-anino-l, 2, 4-thiadiazol- 5L yl) acstamidc] -3- [2- (2-triethylamonioethyl) thiovinyl] -5cephe-4-carboxylate (syn isomer) (trac isomer).



  IR (Nujol): 5500, 1760, 1670, 1600, 1520 cn 'RriN (DMSO-d.). 6: 1; 25 (5H, t, J = 5H), 510-400 (6H,), 420 (2H, q, J = 7Hz), 505 (1H, d, J = 5Hz), 5.60 (1H, m), 660 (1H, d, J = 16Hz), 7 03 (1H, d, J = 16Hz), 306 (2H, large s), n 9. SO (1H, d, J = 8Hz) 29) on 7- [ 2-methoxYinino-2- (2-aminothiazol-4-yl) - </ 3. mido] -3- [2- (l-melhyl-2-? Yridinio) thiovin. yl) -5 "cephenT.- 4-carboxylate (syn isomer) (cis isomer).



  IR (Nujol): 3400-3100, 1765, 1660, 1610, 1560, 1 530 cm 1 NMR (DMSO-d.) G: 5, 67 (2H, ABq, J = 16Hz), 585 (5H, s), 4, 17 (5H, s), 5, 12 (1i, d, J = 5Hz), 563 (1H, dd, J = 5H =, 3Hz), 6, 42 (1H, d, J = 14Hz), ( lH, dd, 6,675 (1H, s), 725 (2H, large s), 7163 (IH, d, J = 14Hz), 7 9-900 (4H, m), 97 (1H, d, J = 8Hz ) 0 f 30) 7- [(2-methoxyii o-2- (2-aiTiin. Othiazol-4-yl) -,. 1 "c]] .., [2 (1 h 'd'") " "" '"IR (Nujol): 5500, 1760, 1660, 1600, 15s0 cm 1

  <Desc / Clms Page number 144>

 
 EMI144.1
 NMR (CMSO-dJ-6: 3:

   72 (2H, ABq, J = 16Hz), 3, 82 (3H, s), 4733 (3H, s), 510 (1H, d, J = 5Hz), 5 63 (1H, dd, J = 5Hz, 8Hz ), 638 (1H, d, J = 10Hz), j = 'C-eez, 7 673 (1H, s), 722 (1H, d, J = lCHz), 713 (2H, large s), 785-890 (3H, m), 917 (1H, large s), 950 (1H, d, J = 8Hz) on 31 on 7-2- (3-caTboxypropcxyiino) -2- (3-âinG-l, 2, 4thiodiaol- 3-yl) actamido] -3- [2- (1-ethyl-3-? Yridinio) thio -.- inyï] -3-cephent-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1765, 1665, 1600, 150 cn '' (DMSO-d) o: 16-27 (4H, m), 375 (2H, large, s), 40-44 (2H,), 440 (3H, s), 510 (1H, d, -z) 75 d, S 72 (lH, dd, J = 4Hz), 572 (1H, dd, J = 4, 8Hz, 675 (1H / d, J = 16Hx), 744 (1H, d, J = 16Hz), 77-91 (4H, m), 9) 60 (IH, d, J = 8Hz)? 2'1 '[....'. '., (' 1 7 l'L'1 "yl) acets. Mido] -3- [2- (l-! Nethyl-2-pyridinio) thiovin. Yl] -3cephe-4-carcoxylate (isomèresyn) (isomèrecis).



  IR (Nujol): 3300, 1765, 1670, 1610, 1560 c 'R (DMSO-d) s: 1, 27 (3H, t, J = 5Hz), 365-435 n), mj, 510 (1H, J = 5Hz), 568 (1H, dd, J-SHx, 8Hz), 642 (1H, d, J = 14Hz), 767 (1H, d, 6 42 (1-q, d, J = 14Hz), 6; 95-9) 00 (6H, m), 950 (1H, d, J = 8Hz)

  <Desc / Clms Page number 145>

 
EXAMPLE 10
In a mixture of anisole (10 ml) and trifluoroacetic acid (8 μl), 7- [2-
 EMI145.1
 (t-butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- [2- (l-methyl-3-pyridinio) thiovinyj] -3-cephem-4carboxylate as hydrochloride (syn isomer) (trans isomer) (1.2 g). The mixture was stirred at 25 ° C for one hour and added to diisopropyl ether to provide a precipitate. The precipitate was collected by filtration and dissolved in water at a pH of 5.0.



  The solution was subjected to column chromatography on a macroporous nonionic resin called "Diaison HP-20" and eluted with an aqueous solution of 7% isopropyl alcohol. The fractions containing the desired compound were concentrated in vacuo and lyophilized to give 7- [2-carboxymethoxyimino-2- (2-aminothizol-4-yl) acetamido] -3- [2- (1-methyl-3-pyridinio ) thiovinyl] -3-cephem-4-carboxylate (syn simer) (trans isomer) (0.55 g).



   IR (Nujol): 3300, 1765, 1670, 1620 cm 'RMN (DMSO-d6) #: 3.50-4.10 (2H, m), 4, 30 (3H, s-), 4, 62- ( 2H, large s), 5, 23 (1H, d,
J = 5Hz), 5.90 (1H, dd, J = 5Hz, 8Hz), 6.87 (1H, s), 6.95 (1H, d, J = 15Hz), 7.15 (2H, large s ), 7, 47 (1H, d, J = 15Hz), 7, gO-.



   8, 90 (3H, m), 9, 13 (1H, large s), 9, 80 (1H, d, J = 8Hz).
 EMI145.2
 



  EXAMPLE 11
The following compounds were obtained in a manner similar to that of Example 10 1) dz [2- (3-carboxy-2-propenyloxyimino) -3- (2-
 EMI145.3
 aminothiazol-4-yl) acêtamido] -3-2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn-isomer) (trans-isomer).



   IR (Nujol): 3300, 1760, 1660, 1600, 1535 cm "

  <Desc / Clms Page number 146>

 
 EMI146.1
 2) 7- [2- (3-carboxypropoxyimino) -2- (2-aminothiaL zol-4-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinylj - 3-cephem-4 -carboxylate (syn isomer) (trans isomer) IR (Nujol): 3300, 1760, 1660, 160-J, 1535 cm 3) on 7- [2- (1-carboxypropoxyimino) -2-.

   (2-aminothiazol-4-yl) acetamido] -3-12- (1-methyl3-pyridinio) thiovinyl] -3-cephem-4-carboxy1ate (syn isomer) (trans isomer) IR (Nujol): 300, 1760, 1660, 1590 cm '4) le 7- [2-carb3xymêthoxyimìno-2- (thiazol-4-yl) acêtamido] -3- [2- (l-rcthyl-3-pyridinio) thiovinyl] -3cêphem-4-carboxylate ( is mother syn) (trans isomer) I? (r \ ujol): 3350, 1760, 1660, 1680 cm-1 5) 7- [2- (1-carboxy) ethoxyimino-2- (5-anino-l, 2, 4thiadiazol-3-yl) acëtamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephen-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1770, 1665, 1600, 1520 cm-1 6) 7- [2 (1-methyl-1-carboxyethoxyimino) -2- (5 amino- 1,2,4-thiadiazol-3-. yl) acêtamido] -3- [2-- (1-methyl-3-. pyridinio) thiovinyl] -3-ephem-4-carboxyate (syn-isomer) (trans-isomer).



  * IR (Nujol): 3300, 1770, 1670, 1610, 1520 cm 7) 7- [2- (3-carboxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido ] -3-2-. (l - methyl-3-pyridinio) thiovinyl] -3-cephem-4-caroxy1ate (ìsomÀre syn) (trans isomer) IR (Nujo1): 3300, 1765, l665, 1600, 1550 cm-l 8) on 7- [2-carboxymethoxyimino-2- (5-aminol, 2, 4 thiadiazol-3-yl) acetamido] -3- [2 -. (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate ( syn isomer) (trans isomer).



  IR (Nujol): 3300 (wide), 1765, 1670, 1615, 1525 cm EXEMPEL 12 A mixture of 7- [2- (2-pyridylmethoxyimino) -2 (2-

  <Desc / Clms Page number 147>

 formamidothiazol-4-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn-isomer) (trans-isomer) (1.5 g) and Methyl iodide (2 ml) in a mixture of N. N-dimnthylformamide (25 ml) and water (10 ml) was stirred at room temperature for 3 days.



    After having the reaction mixture containing iodide of 7- [2- (1-methyl-2-pyridiniomethoxyimino) -2- (2-formamido-
 EMI147.1
 thiazol-4-yl) acêtamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn-isomer) (trans-isomer) was evaporated to dryness in vacuo methanol (50 ml) of the acid. concentrated hydrochloric acid (2 ml) was added to the residue. The mixture was stirred for 4 hours at room temperature and evaporated to dryness in vacuo.

   The residue was dissolved in water and subjected to column chromatography on a non-ionic adsorption resin "macroporeusedite" DiaionHP-20 "usually
 EMI147.2
 re to give 7- [2- (1-methyl-2-pyridiniomethoxyimìno) re to- L-- 2- (2-aminothiazol - 4-yl) acetamido] -3- [2- (1-methyl-3 "-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer) (0.5 g)
IR (Nujol): 3250, 1760, 1665, 1615 cm NMR (D2O) #: 7, 9-9.00 (8H, m), 7.17 (1H, d, J = 16Hz), 7, 10 (1H , s), 6.67 (1H, d, J = 16Hz), 5.90 (1F, d, J = 5Hz), 5.75 (2H, s), 5.34 (1H, d, J = 5Hz ), 4, 45 (6H, s), 3, 5-4, 25 (2H, m).



   EXAMPLE 13
In a mixture of 7- [2-ethoxyimiDo- bromide
 EMI147.3
 2- (5-a "tino-1,2,4-thiadiazol-3-yl) acetamido] -3- [2- (l-benzhydryloxycarbonylmethyl-3-pyridinio) thiovinyl] -3-cephem- - iz 4-carboxylate benzhydryl (syn isomer) (trans isomer) (1 g) in a mixture of CH2Cl2 (3 ml) and anisole (5 ml) 2 2 3 ml) and anisole (5 ml) were added dropwise trifluoroacetic acid at 5 ° C. with stirring. The reaction mixture was stirred for 2 hours at room temperature and poured out.

  <Desc / Clms Page number 148>

 in diisopropyl ether to give a precipitate.

   Purification by column chromatography on a macroporous nonionic adsorption resin known as "Diaion-HP-20" in the ordinary manner provided - [2-
 EMI148.1
 ethoxy imino- 2- (S-amino-1,2,4-thiadiazol-3-yl) acetamidoj- 3- [2- (l-carboxymethyl-3-pyridinio) thiovinyl] -3-cephem- 4-carboxylate (isomer syn) (trans isomer) (0.35 g), IR (Nujol): 3300, 1760, 1640-1680, 1610,
1520 cm-1 NMR (DMSO-d6) 6: 1, 30 (3H, t, J = 5Hz), 3.33-3, 90, (2H, m), 4.25 (2H, 9, J = 7Hz ), 4, 95-5, 20 (3H.
 EMI148.2
 



  T ilm), 5.75 (lE, m), 6.60 (1H, d, J = lGHz), 7.50 (lu, d, J = 16Hz), 8.0-0-9.00 (4H m) , 9, 55 (1H, d, J = 8Hz) EXAMPLE 14
To a solution of 7- [2-ethoxyimino-2- (5 amino-l, 2,4-thiadiazol-3-yl) acetamido-3-ethynyl-3-cephem- acid solution
 EMI148.3
 4-carboxylic acid (syn isomer) (200 mg) in a 1- mixture of Getonitrile (2 ml) and water (1 ml), 3-mercapto-1-methylpyridinium chloride (97 mg) was added to room temperature by adjusting to a pH of 3.0 with a saturated aqueous solution of sodium bicarbonate. The reaction mixture was stirred for 2 hours and demi, then ethyl acetate (10 ml) and water (10 ml) were added.

   The separated aqueous layer was evaporated to remove the organic solvents and subjected to column chromatography on a non-ionic resin called "HP-20" (50 ml). After washing with water, the column was eluted with a 30% aqueous solution of methanol and the eluate was evaporated to remove the methanol and the remaining aqueous solution was lyophilized to give 7- [2 -ethoxyimino-2- (5-amino-1, 2, 4- thiadiazol-3-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate ( syn isomer) (trans isomer) (110 mg).

  <Desc / Clms Page number 149>

 



    150-1550C (decomposition) IR (Nujol): 3300, 1760 ,. 1670, 1600, 1520 cm-1 NMR (DMSO-d) 6: 1, 32 (3H, t, J = 7Hz), 3.75 (2H, large s), 4.23 (2H, q, J = 7Hz ), 4, 38 (3H, s),
 EMI149.1
 5.08 (1H, d, J = 5Hz), 5.67 (1H, 2d, J = 5Hz, 8Hz), 6.35 (d, J = 10HZ) .7.30 (d.J-10Hz).



  6.35 (d, J == 15Hz) -'7.50 (d, J == 15Hz) J, 8.20 (2H, large s), 8.00 (1H, m), 8.50 (1H , d), 8, 80 (1H, d), 900 (s). 9, 40 (d, J = 8Hz) -.



  9, 13 (s) 9, 13 (s) '9, 50 (d, J == 8Hz) 1
EXAMPLE 15
To a mixture of 1- (3N, N-dimethylaminopropyl) -3-mercaptopyridinium chloride hydrochloride (1.08 g) and diisopropylethylamine (0.5 ml) in N, N-dimethylformamide (11 ml) acid 7- {2-
 EMI149.2
 ethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido} - 3- (2-tosyloxyvinyl) -3-cephem-4-carboxylic (syn-isomer) (cis-isomer) (1, 18 g) at room temperature.



  After stirring for 2 hours 45 minutes, the reaction mixture was poured into ethyl acetate (ISO ml). The resulting precipitates were collected by filtration and washed with ethyl acetate. The wet residue was dissolved in water and evaporated to remove the ethyl acetate. The aqueous solution was adjusted to a pH of 3.5 with an aqueous solution of sodium bicarbonate, subjected to column chromatography on a nonionic resin called "Diaion HP- 20", and eluted with an aqueous solution of methanol at 25%. The fractions containing the desired compound were combined and IN hydrochloric acid (1.2 ml) therein.
 EMI149.3
 has been added.

   The acid solution was concentrated and lyophilized to give 7- hydrochloride. [2-ethoxyimino- 2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- {2-fl- (3- N, N-dimethylaminopropyl) -3-pyridinio] thiovinyl} -3-cephem- 4-carboxylate (syn isomer) (cis isomer). (0.75 g).



   IR (Nujol): 1770, 1665, 1620, 1520 cm

  <Desc / Clms Page number 150>

 
 EMI150.1
 1 NMR (DQ): 1.35 (3H, t, J = 5 Hz), 2.57 (2H, m), 2.95 (6H, s), 3.30 (2H, m), 3.80 (2H, large s), 4.37 (2H, q, J = 7Hz), 5.30 (1H, d, J = 5Hz), 5.88 (1H, d, J = 5Hz), 6.60 ( 1H, d, J = 1OHz), 6.97 (IH, d, J = 10Hz), 8/00 (lH, c1d, J = 5Hzl 8Hz), 8.47 (1H, d, J = 8Hz), 8 , 93 1H, d, J = 5Hz), 8, 86 (IH, large s)
 EMI150.2
 EXAMPLE 16 The following compounds were obtained in a manner similar to that of Example 15.



  1) 7- [2-allyloxyimino-2- (2 aminothiazol-4-yl) Qcetamido] hydrochloride -3-2- [1- (3-aminopropyl) -3a- (3-ar ,, i- r, op ro; Dv 1) -3- pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn isomer) (cis isomer).



   IR (Nujol): 3300, 1768, 1663, 1619 cm
 EMI150.3
 RM. N (DO) 6 ': 2.50 (2H, m), 3.20 (2H, m), 3.72 (2H, large s), 4.80 (2H, m), 5.23 (1H, d, J = 5Hz), 5.43 (2H, m), 5.78 (1H, d, J = 5Hz), 5.8 (Hi, m), 6, 46, 6, 86 (2i- \ 1 ABq, Ir
J = 1OHz), 7.03 (1H, s), 7.95 (1H, dd,
J = 6Hz, 8Hz), 8.46 (1H, d, J = 8Hz), 8.68 (1H, d, J = 6Hz), 8.80 (1H, large s).



  2) 7- [2-methoxyimino-2- (2-amino-) hydrochloride
 EMI150.4
 thiazol-4-yl) acetamido] -3- {2- [1- (3-aminopropyl) -3-pyridiniojthiovinyl} -3-cephem-4-carboxylate (syn isomer) (cis isomer).



     NMR (D2O) #: 2.58 (2H, m), 3.23 (2H, m), 3.80 (2H, large s), 4.08 (3H, s), 4.83 (2H, m ),
5, 27 (1H, d, J = 5Hz), 5.80 (1H, d, J = 5Hz),
6, 80 (2H, ABq, J = 10Hz), 7.15 (1H, s), 8.0 (1H, dd, J = 6Hz, 8Hz), 8.47 (1H, d, J = 8Hz),
8, 77 (1H, d, J = 6Hz), 8, 87 (1H, large s) 3) 7- [2-ethoxyimino-2- (5-amino- 1, 2, 4-thiadiazol-3) hydrochloride -yl) acetamido] - {2- [1- (2-aminoethyl) -

  <Desc / Clms Page number 151>

 3-pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn isomer) (cis isomer). p. f. : 115-124 C (decomposition).



   IR (Nujol): 1770, 1670, 1620, 1520 cm-1
NMR (D2O) #: 1.34 (3H, t, J = 7Hz), 3.60-3.90 (4H, m), 4.38 (2H, q, J = 7Hz), 4.98 (2H , t, J = 7Hz), 5.30 (1H, d, J = 5Hz), 5.87 (1H,
 EMI151.1
 d, J = 5z), 6, 63 (1H, d, J = lOHz), 6, 93 (1H, d, J = lOHz) 1 8, 03 (1H, dd, J = 9Hz, 6Hz), 8, 53 (1H, d, J = gHz), 8, 78 (1H, d, J = 6Hz), 8, 90 (1H, large s).
 EMI151.2
 



  4) 7- [2-ethoxyimino hydrochloride - 2- (5 amino-l, 2, 4-thiadiazol-3-yl) acetamido] - 3-t2- [1- (2-aminoethyl) -3 -pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn isomer) (trans isomer). p. f. : 113-1220C (decompositio) IR (Nujol): 3320, 1765, 1660, 1620, 1520 cm "RUN (D20) 6;: 1, 33 (3H .. t, J = 7Hz), 3, 60-3, 96 (4H, m), 4.35 (2H, q, J = 7Hz), 5.00 (2H, t, J = 7Hz), 5.28 (1H, d, J = 5Hz), 5.82 ( 1H, d,
J = 5Hz), 6.87 (1H, d, J = 15Hz), 7.30 (1H, d, J = 15Hz), 8.03 (1F, dd, J = 9Hz, 6Hz),
8.55 (1H, d, J = 9Hz), 8.79 (1H, d, J = 6Hz),
8, 94 (hui, large s) 5) 7- [2-ethoxyimino-2- (5-amino-) hydrochloride
 EMI151.3
 1, 2, 4-thiadiazol-3-yl) acêtamido] -3- {2- [l- (2-N, N-dimethylaminoethyl) -3 "pyridinio] thiovinyl} -3-oêphem-4-carboxylate ( syn isomer) (cis isomer).



   IR (Nujol): 3300, 1760, 1670, 1610, 1520 cm-
NMR (D2O) #: 1.35 (3H, t, J = 7Hz), 3.04 (6H, s),
3.67-4.07 (4H, m), 4.38 (2H, q, J = 7Hz),
4.97 (2H, t, J = 7Hz), 5.28 (IH, d, J = 5Hz),
5.85 (1H, d, J = 5Hz), 6.53 (1H, d, J = 10Hz),
 EMI151.4
 6.92 (1H, d, J = 10Hz), 8.00 (1H, m), 8.38-8.96 (m, 3H).

  <Desc / Clms Page number 152>

 
 EMI152.1
 



  6) 7-r2-methoxyimino-2- (2-aminotDiazol-4-yl) acetamido hydrochloride] -3 {2- [1- (3-N, N-dimethylaminopr0pyl) -3-pyridinio] thiovinyl} -3 -céphem-4-carboxylate (s1'n isomer) (trans isomer).



  NMR (D2O) 6: 2.55 (2H, m), 2.92 (6H, s), 3.30 (2H, m), 3.77 (2H, large s), 4.07 (3H, s ), 3, 85 (2H, m), 5, 27 (1H, d, J = 5Hz), 5, 77 (hui, d, J = 5Hz), 6, 95 (2H, ABq, J = 15Hz), 7, 12 (1H, s), 8, 0 (1H, dd, J = 6Hz, 8Hz), 8, 50 (IH, d, J = 8Rz), 8, 73 (1H, d, J = 6Hz), 8.85 (1H, large s).



  7) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamidoj-3- {2- [1- (2-aminoethyl) -3-pyridinio] thiovinyl} -3-cephem- hydrochloride 4-carboxylate (syn isomer) (trans isomer) Rr-1 (DO): 3.72 (2H, t, J = 7Hz), 3.75 (2H, broad s), 4.30 (3H, s), 4, 97 (2H, t, J = 7Hz), 5.27 (1H, d, J = 5Hz), 5.77 (hui, d, J = 5Hz), 6.87 (2H, ABq, J = 15Hz ), 7.05 (1H, s), 8.0 (1H, dd, J = & Hz, 8Hz), 8.52 (1H, d, J = 8Hz) / 8.72 (Hf, d, J = 6Ez), 8, 85 (1H, large s) 8) 7 [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] chlorh1'drate -3- {2- [l- (3- N, N-dimethylaminopropyl) -3-pyridinioJthiovinyl} -3-cephem4-carboxylate (syn isomer) (cis isomer) NMR (DO):

   2.50 (2H, m), 3.33 (2H, m), 3.73 (2H, broad s), 4.0 (3H, s), 4.50-4.77 (2H, m), 5, 25 (1H, d, J = 5Hz), 5, 78 (1H, dd, J = 5Hz), 6, 67 (2H,} \ Bq, J = 10Hz), 6, 95 (1H, s), 7, 92 (lEo, dd, J = 6Hz, 8Hz), 8, 43 (1H, d, J = 8Hz), T 8, 68 (1H, d, J = 6Hz), 8, 82 (1H, large s ) 9) 7- [2-methoxyimino-2- (2-aminotiazol-4-1'l) acetamido] -3- {2- [1- (3-aminopropyl) -3-pyridinio] thiovinyl} hydrochloride - 3-cephem-4-carboxylate (syn isomer) (trans isomer)

  <Desc / Clms Page number 153>

 
 EMI153.1
 IR (Nujol): 1770, 1670, 1620, 1560 cm NMR (D20) 6:

   2.53 (2H, m), 3.18 (2H, m),
3.80 (2H, large s), 4.07 (3H, s), 4.82 (2H, m), 5.27 (1H, d, J = 5Hz), 5.77 (1H, d, J = 5Hz), 7.05 (1H, dd, J = 15Hz), 8.0, (1H, dd,
J = 6Hz, 8Hz), 8.50 (1H, d, J = 8Hz), 8.73 (1H, d, J = 6Hz), 8.87 (1H, large s) 10 hydrochloride 7- [2 -al1yloxyimino-2- (2-ami-
 EMI153.2
 nothiazol-4-yl) acëtamido] -3- {2- [l-. (2-a. Minoethyl) -3-pyridinio] tiovinyl} -3-cephem-4-carboxylate (syn isomer) (cis isomer).



   IR (Nujol): 3350, 1770, 1660, 1620 cm
NMR (D2O): 3.70 (2H, broad s), 3.72 (2H, t,
J = 7Hz), 4.80 (2H, m), 4.97 (2H, t, J = 7Hz),
5, 23 (1H, d, J = 5Hz), 5.45 (2H, m), 5.80
 EMI153.3
 (1H, d, J = 5Hz), 5.90 (1H, m), 6.46 and 6.88 (2H Bq, J-10Hz), 7.02 (1H, s), 7.98 (1H, dd, J = 6Hz, 8Hz), 8,? 0 (1H, d, J = 8Hz), 8, 74 (1H, d, J = 6Hz), 8, 83 (1H, large s).



  11) 7- [2-allyloxyimino-2-- (2 aminothiazol-4-yl) acetamido] -3- {2- [l-. (3-N, N-dimethylaminopropyl) -3-pyridinio] thiovinyl} - 3-cephem - 4-. carboxylate isomer syn) (trans isomer).



  IR (Nujol): 3350, 177Q, 1660, 1613 cm "RMN DD20) o: 3.50 (2H, m), 2.93 (6H, s), 3.30 (2H, m), 3.77 ( 2H; Large s) 1 4, 83 (2H, m), 5.27 (1H, d, J = 5Hz), 5, 4 (2H, m), 5.80 (1H, d, J = 5Hz), 5, 9 (1H, m), 6, 63 (7, 10 (2H, ABq,
J = 15Hz), 7, 10 (,! H, s), 7, 98 (1H, dd, J = 6Hz,
8Hz), 8.50 (1H, d, J = 8Hz), 8.70 (1H, d,
J = 6Hz), 8.84 (1H, large s).



  12) 7- [2-allyloxyimino-2- (2-amino-) hydrochloride
 EMI153.4
 thiazol-4-yl) acêtamido] -3- {2- [1- (2-amin06thyl -3-pyridiniojthiovinyl-3 - cephem-4-carboxylate (syn isomer) (trans isomer)).

  <Desc / Clms Page number 154>

 
 EMI154.1
 



  IR (Nujol): 3350, 1768, 1660, 1627 cm 1 NMR (D20) 6: 3.75 (2H, t, J = 7Hz), 3.80 (2H, large s), 4, 8 (2H, m ), 5, 00 (2Er t, J = 7Hz), 5, 30 (1H ,. d, J == 5Hz), 5, 45 (2H, rr.), 5, 82 (lE, d, J = 5Hz ), 5, 9 (lES, m), 6, 72 and 7, 18 (2H, ABq, J = 16Hz), 7, 15 (lH, s), 8.05 (1H, dd, J = 6Hz), 8Hz), 8, 60 (1H, d, J = 8Hz), 8, 80 (1H, d, J = GHz), 8, 93 (1H, large s) 13) hydrochloride I 7- [2-methoxyimino- 2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- {2- [l- (3-aminopropyl) 3-pyridiniojthiovinyl} -3-cephem-4-carboxylate (syn isomer ) (trans isomer). p. f. : 185-l90nC (decomposition) IR (Nujol): 3350, 3150, 1765, 1670, 1615, 1595 ,.



  "765, 16" 0, 1615, 1595, 1560, 1525, 1490 cm (2 "I) (DO) 6-: 2, 40-2, 70 (2H, m), 3, 0-3, 40 (2H , m), 3.72 (2H wide s), 4.05 (3H, s), 4.40-4.9'0 (2H, m), 5.23 (1H, c1, J = 5Hz), 5, 82 (lE, d, J = 5Hz), 6, 68 (1H, d, J = loHz), 7, 15 (1H, d, J == 16Hz) 1 7, 77-8, 10 (lE, ml, 8, 23-8, 50 (1H, IT '.), 8, 57-. 8, 87 (2H, m).



  14 7- [2-carboxymethoxyimino-2- 2-amlnothiazol-4-yl) acaido] -3- {2- [1- (3-aminopropyl) - 3-pyridinio] thiovinyl} -3-cephem-4 hydrochloride -. carboxylate (syn isomer) (cis isomer).



  IR (Nujol): 3350, 1780, 1710, 1673, 1627 cm "MN (D2O) 6: 2, 30 (2H, m), 3, 14 (2H, m), 3.80 (2H, m), 4 , 7 (2H, large s), 4, 86 (2H, m), 5, 10 (1H, d, J = 5Hz), 6.05 (1H, d, J = 5Hz), 6, 57, 6, 85 (2H, ABq, J = 10Hz), 7, 20 (1H, s), 7, 91 (1H, dd, J == 6Hz, 8Hz), 8.45 (1H, d, J = 8Hz), 8 , 65 (1H, d, J = 6Hz), 8, 80 (1H, large s).



  EXAMPLE 17 A mixture of 7 [2-allyloxyimino-2- (5-amino-

  <Desc / Clms Page number 155>

 1, 2, 4thiadiazol-3-yl) acetamido] -3- (2-tosyloxyvinyl) -3- benzhydryl cephem-4-carboxylate (syn-isomer) (trans-isomer) (5.0 g), chloride chloride hydrochloride 1- (3aminopropyl) -3-mercaptopyridinium (4.0 g) and diisopropylethylamine (0.6 ml) in N, N-dimethylformamide (40 ml) was stirred for 5 hours at room temperature. re ambient. The reaction mixture was diluted with ethyl acetate (250 ml) and decanted. The residual oil was washed with methylene chloride (100 ml) and dried in vacuo.

   To the residue was added anisole (15 ml) and trifluoroacetic acid (20 ml) was added thereto while cooling in an ice bath. After stirring for 40 minutes, the reaction mixture was poured into ethyl acetate (200 ml). The resulting precipitates were collected by filtration, washed with ethyl acetate, dissolved in water and evaporated to remove the ethyl acetate under reduced pressure. The aqueous solution was adjusted to a pH of 1 with an aqueous solution of sodium bicarbonate, subjected to column chromatography on a nonionic resin called "Diaion HP-2O" and eluted with a 30% aqueous solution of methanol.

   The fractions containing the desired compound were combined and 1N hydrochloric acid (3 ml) was added thereto. The acid solution was concentrated and lyophilized to give 7- [2-allylo- dihydrochloride
 EMI155.1
 xyimino-2- (5-arnino-1,2,4-thiadiazol-3-yl) acetamido] -3- {2- [l- (3-aminopropyl) -3-pyridinio] thiovinyl} -3-cephBm- 4 -carboxylate (syn isomer) (trans isomer (1.48 g). yp, f .: 164-168 "C (decomposition) IR (Nujol):

   3400-3100, 1770, 1710, 16. 7Q,
1620, 1530 cm R M (D20) 6 ': 2.53 (2H, m), 3.21 (2H, m),
3.80 (2H, m), 5.29 (1H, cl, J = SHZ)
5, 3-5, 7 (2H, m), 5, 87 (1H, d, J = 5Hz),
5, 7-6, 3 (1H, m), 6, 90 (1H, d, J = 15Hz),

  <Desc / Clms Page number 156>

 
7, 31 (1H, d, J = 15Hz), 8, 1 (1H, d, J = 6Hz),
8.50 (1H, m), 8.80 (1H, d, J = 6Hz),
8.93 (1H, s)
EXAMPLE 18
The following compounds were obtained in a manner similar to that of Example 17.



  1) 7- [2-allyloxyimino-2- (5 amino- 1,2,4-thiadiazol-3-yl) acetamido hydrochloride] -3- [2- [1- (3-N, Ndimethylaminopropyl) -3- pyridinio] -thiovinyl} -3-cephem- 4-carboxylate (syn isomer) (trans isomer) p. f. : 70-75 C (decomposition)
IR (Nujol): 3300, 2700, 1760, 1660, 1610,
1520 cm "
NMR (DMSO-d6) #: 2.20-2.60 (2H, m), 2.73 (3H, s), 2.80 (3H, s), 2.90-3.30 (2FT, P . 1), 3, 70-
 EMI156.1
 3.90 (2H), 4.0-5-5, 0 (4H, m), 5.0-5.53 (3H, m), 5.87 (1H, dd, J = 5Hz, 8Hz), 5, 70-6, 20 (1H, m), 7, 23 (2H, s), 7, 87-: cB, 27 (JH, m), 8, 50-8, 80 (1H, m), 8, 97 -9.20 (1H, m), 9.30 9, 43 (1H, large s), 9, 63 (1H, d, J = 8Hz).
 EMI156.2
 



  2) 7- [2-'allyloxyimino- dihydrochloride. 2- (5-. Friend no-1, 2, 4-thiadiazol-3-yl) acêtamidoj-3- {2- [l-- (2-). mino-ethyl) -3-pyridinio] thiovinyl) -3-cephem'-4-. carboxylate (syn isomer) (cis isomer) p. f. : 125-130 C (decomposition)
 EMI156.3
 IR (Nujol): 1765, 1670, 1605, 1510 cm 'R1l': (D 20) 0: 3, 77 (4H, m), 4, 97 (2H, t, J = 7Hz) 5, 28 (1H, d, J = 5Hz), 5, 2-5, 7 (2H, m), 5, 83 (1H, d, J = 5Hz), 5, 3 (lu-, m), 6, 60 (lH, d , J = 10Hz), 6.93 (1H, d, J = 10Hz),
8.05 (1H, m), 8.50 (1H, m), 8.78 (1H, d, J = 6Hz), 8.87 (1H, large s).



  3) 7- [2-allyloxyimino- hydrochloride. 2- (5-
 EMI156.4
 amino-1,2,4-thiadiazol-3-yl) acetamidoj-3- {2- [l- (3-N, N-dimethylaminopropyl) -3-pyridinio] thiovinyl} -3-cephem-4-

  <Desc / Clms Page number 157>

 
 EMI157.1
 carboxylate (syn isomer) (cis isomer) p. f. : 65-70 C (decomposition) IR (Nujol): 3350, 2700, 1765, 1670, 1600, 1525 cm 'NMR (D20) ppm: 2, 30-2, 80 (2H, ha), 2, 97 (6E , s), 3, 13-3, 53 (2H, m), 3.77 (2H, large s), 4, 60-5, 0 (4H), 5, 10-5, 60 (3, 2) , 5, 80- 6/40 (2If, m), 6, 53 (lE, d, LJ = lOEz), 6/93 (1H, d, J = lOHz;, 7, 83-8, 15 (1H, n), 8, 30- 8, 60 (1H, m), 3, 60-8, 98 (2H, fi).



  4) 7- [2-allyloxyimino-2- (5-amino-1/2, 4-thiadiazol-3-yl) acetamido] -3- {2- [1-- (J-aminopropyl) -3 hydrochloride -pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn isomer) (cis isomer) p. f. : 65-70 C (decomposition) IR (Nujol): 3350, 3150, 1770, 1710, 1670, 1620, 1525 cm "'RMN (D20) 0: 2, 20-2, 70 (2H, m), 2, 90-3, 40 (2H, m), 3.77 (2H, large s), 4, 40-5, 0 (4H), 5, 10- 5, 60 (3H, m), 5, 60 "70 , 30 (2H, m), 6, 60 (1H, d, J-10Hz), r 92 (1H, d, J = 1-Hz), '7, 77-8, 17 (1H, m), 8 , 20-8, 53 (1H, m), 8, 63-8, 92 (2H, m) 5) 7- [2-allyloxyimir dihydrochloride. o-2- (5-. amino-1,2,4-thiadiazol-3-yl) acetamido] -3-2- [1- (2-aminoethyl) no-1, 2-L t 3-pyridinio] thiovinyl } -3-cephem - 4-. carboxylate (syn isomer) (trans isomer) p. f. : 170-175 C (decomposition) IR (Nujol): 1760, 1670, 1620 cm NMR (D20) 6:

   3.71 (4H, m), 4.95 (2H, t, J = 7Hz), 5.36 (lE, d, J = 5Hz), 5, 3-5, 6 (2H, m), 5, 82 (lR, dl J = 5Hz), 5, 7-6, 2 (lH, m), 6, 811 (1H, d, J = 15Hz), 7, 29 (lH, d, J = 15Bz), 8 , 01 (lEI, m), 8, 50 (1H, m), 8, 77 (1H, d, J = 6Hz), 8, 91 (1H, s) le 7- [2'-ethoxyin hydrochloride. ino-2- (5-amino-

  <Desc / Clms Page number 158>

 1, 2, 4-thiadiazol-3-yl) -acetamido] -3- {2- [1- (3-aminopropyl) - 3-pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn isomer) (isomer cis),
 EMI158.1
 p. f. : 116-1260C (decomposition) -COD .. Poslrion) IR (Nujol): 1770, 1670, 1610, 1510 cm RMN (D20) 6: 1, 31 (3H, t, J = 7Hz), 2, 00-2 , 80 (2H, m), 2.98-3.33 (2H, m), 3.73 (2H, large s), 4.33 (2H, q, J = 7Hz), 5.25 (1H, d, J = 5Hz), 5.83 (1H, d, J = 5Hz), 6.53 (1H, d ,.

   J = 10Hz), 6.87 (1H, d, J = 10Hz), 7.77-8, 15 (1H, m), 8, 33-8, 90 (3H, m)
 EMI158.2
 7) 7- [2-ethoxyimino-2- (5 amino- 1, 2, 4-thiadiazol-3-yl) acetamido hydrochloride] -3- {2-. [1- (3-aminopropyl) - 3-pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn isomer) (trans isomer). p. f,: 148-157 C (decomposition) IR (Nujol): 1770, 1670, 1620, 1530 cm NMR (D2O) #: 1, 33 (3H, t, J = 7Hz), 2, 17-2, 80 ( 2H, m), 3.03-3.40 (2H, m), 3.83 (2H, wide), 4.35 (2H, q, J = 7Hz), 5.28 (1H, d ,
 EMI158.3
 J = 5Hz), 5, 83 (lé, d, J = 5:

   -Iz), 6, 92 (1H, d, J = 16Hz), 7, 28 (1H, d, J = 16Hz), 8.01 (1H, dd, J = 9Hz, 6Hz), 8, 53 (1H , due J = 9Hz), 8, 86 (1H, d, J = üHz), 8, 92 (1H, large s) 8) hydrochloride of 7- [2-ethoxyimino-2- (5-amino- 1, 2, 4-thiadiazol-3-yl) acetamido] -3- {2- {1- (3-N, N-dimethylaminopropyl) -3-pyridinio] -thiovinyl} -3-cephem-4-carboxylate (syn isomer) (trans isomer)
 EMI158.4
 p. f. : 121-130 C (decomposition) IR (Nujol): 3350, 2700, 1770, 1670, 1620, 1530 cm NMR (DO) 6: 1, 31 (3H, t, J = 7Hz), 2, 26-, 2 , 83 (2H, m), 2.90 (6H, s), 3, 13-3, 50 (2H, m), 3.78 (2H, large s), 4.33 (2H, q, J = 7Hz), 5, 26 (: i.

   H, d, J = 5Hz), 5.78 (1H, d, J = 5Hz),

  <Desc / Clms Page number 159>

 
6, 80 (1H, d, J = 16Hz), 7, 17 (1H, d, J = 16Hz),
7, 98 (1H, dd, J = 8Hz, 6Hz), 8, 50 (1H, d, J = 8Hz),
8, 72 (1H, d, J = 6Hz), 8, 86 (1H, large s).



    EXAMPLE 19
The following compound was obtained in a manner similar to that of Example 10.
 EMI159.1
 



  7- [2- (1-carboxy-1-cyclopentyloxyimino) -2- (2-aminothiazol-4-yl) ac6tamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer).



   IR (Nujol): 3300, 1760, 1650, 1590 cm-1 NMR (DMSO-d6) #: 1.73-2, 3 (8H, m), 3, 8 (2H, large) 4, 3 (3H, s), 5, 3 (2H, d, J = 5Hz),
5, 7 (1H, d), J = 5Hz), 6, 6 (1H, d, J = 16Hz),
6.95 (1H, s), 7, 2 (1H, d, J = 16Hz), 7, 6-8, 7 (4H, m).



   EXAMPLE 20
A solution of 7- [2-allyloxy- hydrochloride
 EMI159.2
 imino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- {2i nD L --- t [1- (3-aminopropyl) -3-pyridinio] thiovinyl} - 3-cephem-4carboxylate (syn isomer) (trans isomer) in a phosphate buffer at pH 7.0 (6.5 ml) was treated with NaOH-1N to adjust to pH 8.0 by cooling with ice . Ethyl formimidate hydrochloride (1.01 g) was added in parts to the mixture and the pH of the mixture
 EMI159.3
 was maintained at 7.70.5 by adding NaOH-1N. After stirring for 40 minutes, the insoluble material was removed by filtration and the pH of the filtrate was adjusted to 4.6.

   The solution was subjected to column chromatography on the product known as Diaion HP-2O using water and an aqueous solution of methanol at 20'Yü (cn volume / volume) as eluent. The fractions eluted with a 20% aqueous solution of methanol are lyophilized to give 7- [2-allyloxyimino-2- (5-amino-1, 2, 4thiadiazol-3-yl) acetamido] -3- {2 - [1- (3-formamidoylamino-

  <Desc / Clms Page number 160>

 propyl) -3-pyridinio] thiovinyl-3-cephem-4-carboxylate (syn isomer) (trans isomer)
IR (Nujol): 3250, 1760, 1710, 1660, 1590,
1530 cm
 EMI160.1
 NMR (D2O) o:

   2, 13-2, 68 (2H, m), 3.48 (2H, t,
J = 7Hz), 3.73 (2H, m), 5.26 (1H, d, J = 5Hz),
5, 79 (1H, d, J = 5Hz), 5, 15-6, 08 (3H, m),
6.62 (1H, d, J = 14Hz), 7.08 (1H, d, J = 14Hz),
7, 83 (1H, s), 7, 95 (1H, m), 8, 43 (1H, d,
J = 8Hz), 8.69 (1H, d, J = 6Hz), 8.79 (1H, s).



     EXAMPLE 21 The following compounds were obtained from a
 EMI160.2
 similar to that of Example 1, Example 4, Example 6 and Example 8.



  1) 7- [2-allyloxyimino-2- (5-amino-1,2,4,4-thiadiazol-3-yl) acetamido] -3 {2- [1- (2-hydroxyethyl) -3 - pyridinio ] thiovinyl} - 3-cephem-4-carbox \ late (syn isomer) (trans isomer) p. f,: 160-165 C (decomposition) IR (Nujol): 1770, 1660, 1610, 16OO, 1560, 1520 CD.



  NMR (D2O + DMSO-d6) #: 4.67 (4H, m), 5.08 (1H, d, J = 5Hz), 5, 1-5.5 (2H, m), 5.70 (1H , d,
J = 5Hz), 5.6-6, 2 (1H, m), 5, 6-6, 2 (1H, d,
 EMI160.3
 J = 15Hz), 7.36 (1H, d, J = 15Hz), 7.99 (1H, 7.99 (1H, m), 8.50 (lEI, d, J = 9Hz), 8.75 ( lH, d, J =
7Hz), 8.92 (1H, s) 2) 7-f2-allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] hydrochloride] -3 {2- [ 1- (2-morpholinoethyl) -3-pyridinio]

  <Desc / Clms Page number 161>

 
 EMI161.1
 thiovinyl -3-cephem-4-carboxylate (syn isomer) (trans isomer). p. f. : 75-80 C (dec.) IR (Nujol): 3300, 3200, 2650, 25501 2450, 2350, 1770, 1710, 1670, 1630, 1560, 1550, 1525, 1490 cm "M (D20) 6:

   3, 30-3) 67 (4H, m), 367-420 (8H, m), 450-4 90 (4-, n), 50-553 (3H, m), 5 83 (1H, d, J = 5Hz), 5.90-6) 40 (1H, m), 66 90 (1H, d, J = 16Hz), 720 (1H, d, J = 16Hz), 790-820 (1H, m), 8 4Q- q 0'1'H m) 3) 7-2 3) 7- [2-aliyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) - 1 thiovinyl} -3- cephem-4-carboxylate (syn-isomer) (trans-isomer).



  'p. f. : 195-200 C (dec.) IR (Nujo1): 17601 1665, 1600, 1560, 1520 cm-l NMR (DMSO-d) 6: 32-43 (7H, m), 469 (4H, m), 510 (1H, d, J = 5H2), 51-56 (2H, m), 5778 (1H, dd, J = 5Hz, 8Hz), 57-62 (1H, m), 656 (1H, d, J = 15Hz ), 735 (1H, d, J = 15H), 8, 16 (3H, m), 857 (1E, m), 884 (1H, m), 907 (1H, la. S), 955 (1H, d , J = 8Hz) 4) 7- [2-allyloxyimino-2- (S-amino-1,2,4-thiadiazol-3-yl) acëtari.iido] -3- {2- [1- (4- . ethylpi? erazin-l-ylcarbcnylir. ethyi) - 3-pyridinioJtiovinyl} -3-cephem-4-carbcxylate (gvn isomer (trans isomer).) trans) IR (Nujol): 3250-3400 (large), 1760, 1660, 1600, 1510 cm. ' NMR (DMSO-dg) 6:

   228-234 (SH, m), 356 (2H, m), 4} 16-4) 56 (3H, m), 4) 68 (2H, s), 5) 08-5) 48 (3H, m) , 552-6 0 (4H, m), 684 (1H, d, J = 16Hz), n 16 7 6 (li d, J = 16Hz), 7J88-8f16 (4E, m), fi-8 8 56 ( 1H, d, J = 8Hz)

  <Desc / Clms Page number 162>

 
 EMI162.1
 5) 7- [2-ethoxyimino-2- (S-amino-I, 2,4-thiadiazol-3-yl) acetamido] -3- [2- (l-methyl-3-pyridinio) thiovinyl] -3 - cephem-4-carboxylate (syn isomer) (cis isomer). ' p. f. : 152-157 C (dec.)
IR (Nujol): 3300, 1760, 1670, 1600, 1520 cm NMR (DMSO-d6) #:

   1.26 (3H, t, J = 7Hz), 3.78 (2H, la. S), 4.17 (2H, q, J = 7Hz), 4.32 (3H, s),
5.20 (1H, d, J = 5Hz), 5.83 (1H, 2d, J = 8Hz,
J = 5Hz), 6.67 (il, d, J = 10Hz), 6.95 (1H, d, J = 10Hz), 8.08 (2H, la. S, NH2), 8.0 (1H, m), 8. 50 (1H, d),
8777 (1H, d), 9.00 (1H, s), 9.50 (1H, d, J = 8Hz) 6) 7- [2-allyloxyimino-2- (2-aminothia-) hydrochloride
 EMI162.2
 zol-4-yl) acetamìdoJ-3- {2 [1- (3-aminopropyl) -3-pyiridin0] t. hìovinyl} -1-cephem = -4-carboxylate (syn isomer) (trans isomer).



   IR (Nujol): 3350, 1770, 1665, 1618 cm
 EMI162.3
 R (D20) 6: 250 (2H, m), 3) 15 (2H, m), 3) 78 (2H, la. S), 478 (2H, m), 5717 (li, d, J = 5Hz) , 5, 45 (2R, m), 5, 83 (1H, d, J = 5Hz), 60 (1H, m), 6) 70 and 7) 06 (2H, ABq, J = 16Hz), 7} 14 (lH, s), 8, 0 (il, dd, J = 6Hz, 8Hz), 853 (1H, d, J = 8Hz), 8775 (li, d, J = 6Hz), 8J90 (iH, la. s ) 7) 7- (2-11yloxyimino-2- (S-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [2- {l- [3- (4-methylpiperazin-1 -yl) propyH-3pyridinio} thiovinyl] -3-cephe-4-carboxylate. mp: 168-170 C IR (Nujol): 3300, 1760, 1660, 1610 cm
NMR (DMSO-d6) #:

   2-3 (2H, m), 3.1 (3H, s),
3.3-4.2 (12H, m), 4.5-4.7 (4H, m), 5.1-6.2 (5H, m), 6.73 (1H, d, J = 16Hz ), 7137 (1xi, d,
J = 16Hz), 8.0-8.3 (2H, m), 8, 4-8) 8 (IH, m),
8.8-9.3 (2H, m) 8) le7- [3-hydroxy-2- (2-aminothiazol-4-yl) propionamido] -3-

  <Desc / Clms Page number 163>

 
 EMI163.1
 [2- (l-ir. Ethyl-3-pyridinio) thiovinyl) -3-cephem-4-carboxylate (trans isomer) IR (Nujol): 3300, 3200, 1780, 1660, 1600, 1520 cm NMR (DMSO-dJ 6: 3. ze 05 (5H, m), 4.30 (3H, s), 0 5103 (il, d, J = 5Hz), 560 (1H, dd, J = 5Hz, 8Hz), 6, 33 ( 1H, br. s), 6) 53 (li, d, J = 16Hz), 6, 93 (2n, la. s), 7) 50 (1H, d, J = 16Hz), 7;

   90-890 (3H, m), 9.06 (1H, br. S) 9) 7- [2-allyloxyimino-2- (2-aminothiazol- 4-yl) acetamido] hydrochloride -3-'f2- [1- (3-N, N-dimethylaminopropyl) -3-pyridinioJthiovinyl} -3-cephem-4-carboxylate (syn isomer) (cis isomer).



  IR (Nujol): 3300, 1775, 1660, 1610 cm "RJ. (DO) c: 250 (2H, m), 2, 9 0 (6 H, s), 3 .. DO 2 1 (2R, m) , 3 J 73 (2E, br. S), 4) 80 (2H, m), 4. 82 (2H, m), 5/22 (1H, d, J = 5Hz), 5J43 (2H, m), 76 (li, d, J = 5Hz), 590 (1H, m), 6, 55 and 5) 92 (22, ABq, J = 10Hz), 7.07 (1H, s), .93 (1H, dd , J = 6Hz, 8Hz), 8 40 (1H, d, J = 8Hz), 8) 70 (1H, d, J = 6Hz), 882 (1H, La. S) 1 10) le7- (2-ITethoxyimino -2- (6-amino-2-pyridyl) actamido] - 3- [2- (l-methyl-3-pyridinio) thiovinyl] -3-cephem-4- carboxylate (syn isomer) (trans isomer) pf: 165 -170oC (d2C.) IR (Nujol): 3300, 3170, 1760, 1660, 1600, 1560, 1540, 1490 cm "NMR (D20 + DCl) 6: 388 (2H, la. S), 4, 22 (3H , s), 4, 46 (3R, s), 5, 22 (1H, d, J = 5Hz), 5; 82 (1H, d, J = 5Hz), 6; 90 (il, d, J = 8Hz ), 7) 12 (li, d, J = 16Hz), 7) 16 (li, d, J = 8Hz), 7J32 (lH, d, J = 16Hz), .96 (1H, tri, J = 8Hz) , 7 80--816 (1H, m), 8} 40-8) 6 (IR, m), 8) 64-8;

   84 (IR, m), 892 (li, s)

  <Desc / Clms Page number 164>

 
 EMI164.1
 1 ll) le7- [2- (l-carboxy-l-methylpropoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- [2- (l-methyl-3-pyridinio) thiovinyl] -3 -cphem-4-carboxylate (svn isomer); - (trans isomer); IR (Nujol): 3300, 1760, 1660, 1595 cm NMR (DMSO-d6 / D2O) 6: 0) 67-1, 17 (3H, m), 1) 33-163 (2H, m), 347-423 (5H, m), 4) 37 (3E, s), 5113 (1H, d, J = 5Hz), 575 (1H, dd, J = 8Hz, 5Hz), 6.53 (lH, d, J = 16Hz ), 677 (1H, s), 7, 30 (1H, d, J = 16Hz), 7) 70-923 (4H, m) 12) on 7- [2-a. llyloxyiTilino-2- (4-amino-2-pyrimidinyl) - 1 / <=. cetaiaido] -3- [2- (l-methyl-3-pyridinio) thiovinyl] -3-cephe- 4-carboxylate (syn isomer) (trans isomer), p. f. : 160-165 C (dec.) NMR (DMSO-d6) 6:

   3172 and 3, 88 (2H, ABq, J = 18Hz), 4} 38 (3H, s), t50-4) 86 (2H, m), 5, 10 (1H, d, 5Hz), 5. 20- 5. 52 (2H, m), 5. 74 (1H, dd, J = 5Hz, 8Hz), 5r72-616 (1H, m), 650 (1H, d, J = 6H), 660 (1H, d, J = 16Hz), 7.12 (2R, la. s), 7.50 (1H, d, J = 16Hz),; 7; 84-8) 20 (1H, m), 8, 14 (1H, d, J = 6Hz), 832-860 (1H, m) 13) e7- [2-methoxyiTilino-2- (6-formamido-2- pyridyl) acetamido] - 3- [2- (l-methyl-3-pyridinio) thiovinyl] -3-cephem-4p carboxylate (syn isomer) (trans isomer). p. f. : 145-150 C (dec.) IR (Nujol): 3500, 3350, 3230, 3030, 1770, 1690, 1670, 1662, 1622, 1602, 1575, 1560, 1490 cm 'RMN (DHSO-d6) ô: 3 , 50-3, 83 (2H), 3 98 (3H, s), 4735 (3H, s), 5 10 (li, d, J = 5Hz), 5, 72 (lH, dd, J = 5Hz, 8Hz ), 6; 52 (lE, d, J = 16Hz), 697 (1H, d, J = 8Hz), 7, 43 (lH, d, J = 16Hz), 7 50 (1H, d, J = SHz), 783 (lH , d, J = 8 Hz), 793-817 (1H, m), 8, 33-863 (1H, m), 8;

   70-8} 90 (1H, m), 9710 (il, la. S), 9, 50 (il, d, J = 8Rz), 1057-10; 90 (1H)

  <Desc / Clms Page number 165>

 
 EMI165.1
 14) le7- [2- (1-tert-butoxycarbonyl-1-cyclopentyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3- [2- (1-methyl-3pyridinio) thiovinyl] -3- cephem-4-carboxylate (syn-isomer) (trans-isomer) IR (Nujol): 1780, 1720, 1680, 1600 ci 15) le7- [2-allyloxyimino-2- (5-amino-1,2,4-oxadiazol- 3-vl) - // acetar '. ido] -3-2- (l-methyl-3-pyridinio) thiovinyl] -3-cephem- 4-carboxylate '(syn isomer) (trans isomer).



  IR (Nujol): 3200-3300, 1760, 1660, 1600 cm-l i RMN (DMSO-d6) 6: 3, 97 (2H, s), 4, 37 (3H, s), b 4, 72 (2H , d, J = 5Hz), 50-593 (5H, m), 657 (1H, d, J = 16Hz), 7 J47 (1H, d, J = 16Hz), 7J77-8, 13 (4H, m) , 9. 70 (1H, d, J = 8Hz) 16) le7- [2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1-methy1- 3-pyridinio) thiovinyl] -3 -cephe-4-carboxylate (svn isomer) (trans isomer).



  IR (Nujol): 3300, 1760, 1660, 1600 cT RÌ'1N (D20) 6: 365 (2H, d), 4; 37 (3R, s), 517 (1H, d, J = 5Hz), 5} 67 (lE, d, J = 3Hz), 6} 50 (2H, s), 6760 (li, d, J = 16Hz) , 7; 13 (1H, d, J = 16Hz), 7 77-8. 07 (1H, m), 8J30-8) 77 (3H, m) 17) le7- [2-mthoxyirnio-2- (5-amino-1,2, 4-oxadiazol-3-yl) i acdtamido] -3 - [2- (1-rn'thyl-3-pyridinio) thioviny1] -3cphem-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1760, 1660, 1600 cm R (DMSO-d6 / D20) 6: 3753 (2H, s), 3.97 (3E, s), 4737 (3H, s), 5; 07 (lE, d, J = 5Hz), 5.67 (1H, dd, J = 8Hz, 5Hz), 6JS3 (lE, d, J = 16Hz), 7; 47 (IR, d, J = 16Hz), 7.83-823 (1H, m), 8) 33-9; 10 (3H, m), 967 (1H, d, J = 8Hz) 18) le7- [2-ethoxyiino-2- (5-aDino-1,2,4-thiadiazol-3-yl) -

  <Desc / Clms Page number 166>

 to ketamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3- cephem-4-carboxyate (syn-isomer) (cis-trans isomer). p. f. : 150-155 C (decomposition)
IR (Nujol): 3300, 1750, 1670, 1600, 1520 cm 19) 7- [2-ethoxyimino-2- (5-amino-1,2,4-) hydrochloride
 EMI166.1
 thiadiazol-3-yl) acetamido] -3- {2- [(1- (3-N, N-dimethy1aminopropy1) -3-pyridinio] thioviny1} -3-cephem-4-carboxylate (syn isomer) (cis isomer) .



   IR (Nujol): 1770, 1665, 1620, 1520 cm 20) 7- [2-allyloxyimino-2- (2 aminothiazol-4-yl) acetamido] hydrochloride -3- {2- [1- (3-aminopropyl) -3- pyiridnioJthioviny1} thiovinyl} -3-cephem-4-carboxylate (syn isomer) (cis isomer)
 EMI166.2
 1 IR (Nujol): 3300, 1768, 1663, leu19 cm 7 [2-methoxyìmino-2- (2-aminothiazol-4-yl) acetamìdo] hydrochloride -3- {2- [1- (3-aminopropyl) -3-pyridinio] tiovinyl} -3-cephem-4-car6oxylate (syn isomer) (cis isomer).



  22) 7- [2-ethoxyimino-2- (5-amino) hydrochloride
 EMI166.3
 1, 2, 4-hiadiazol-3-yl) acetamido] -3- {2- [1- (2-aminoethyl) -3pyridinio] thiovinyl} -3-cephem-4carboxylate (syn isomer) (cis isomer) p. f. : 115-124 C (decomposition).



   IR (Nujol): 1770, 1670, 1620, 1520 cm 23) 7- [2-ethoxyimino-2- (5-amino-) hydrochloride
 EMI166.4
 1, 2, 4-thiadiazol-3-yl) acetamido] -3- {2- [1- (2-aminoethyl) - 3-pyiri-diniolthiovinyll-3-cephem - 4-carboxylate (syn isomer) (trans isomer ). p. f. : 113-122 C (decomposition)
IR (Nujol): 3320, 1765, 1660, 1620, 1520 cm

  <Desc / Clms Page number 167>

 
 EMI167.1
 24) 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido hydrochloride] -3- {2- [1- (2-N, N-dimethylaminoethyl) ) -3-pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn isomer) (cis isomer) IR (Nujol): 3300, 1760, 1670, 1610, 1520 cm 25) 7 [2-methoxyiminio- hydrochloride 2- (2 aminothiazol-4-yl) acetamido] -3- {2- [1- (3-N, N-dimethylaminopro? Yl) -3-pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn isomer) (trans isomer).



  26) 7- [2methoxyimino-2- (2-aminothiazol-4-yl) acetamido] hydrochloride -3- {2 [1- (2-aminoethyl) -3-pyridinio] thiovinyl '} - 3-cephem-- 4-carboxylate (syn isomer) (iso-. Z y trans mother).



  27) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- {2- [l-- (3-N, N-dimethylaminopropyl) -3-pyridinìo] hydrochloride hydrochloride } -3 cephem-4-carboxylate (isomer- (cis isomer).



  28) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido hydrochloride] -3- {2- [1-. (3-aminopropyl) 3-pyiridinio] thiovinyl) -3-cephem-4-carboxylate (syn isomer) (trans isomer) IR (Nujol): 1770, 1670, 1620, 1560 cm-1 29) 7-2 hydrochloride -allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- {2-. [1 (2-aminoethyl) -3-'pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn isomer) (cis isomer) IR (Nujol): 3350, 1770, 1660, 1620 cm 30) the hydrochloride of 7 - [2-allyloxyimino-2- (2 aminothiazol-4-yl) acetamido] -3- {2- [l-- (3-N, N-dimethylaminopro? Yl) -3-pyridinio] thioviny1} -3-cephem- 4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3350, 1770, 1660, 1613 cm 31) 7- [2-al1yloxyimino-2- (2-aminothiazol-4-y1) acetamido hydrochloride] -3- {2- [1- (2 aminoethyl) -3-pyridir. io] thiovinyl} -3-cephem-4-carboxylate (syn-isomer) (isomer-

  <Desc / Clms Page number 168>

 
 EMI168.1
 trans) IR (Nujol): 3350, 1768, 1660, 1627 cm '32) 7- [2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido hydrochloride] -3- {2- [1- (3-aminopropyl) -3-pyridinio] thiovinyl] -3-cephem-4-carbxoylate (syn isomer) (trans isomer) p, f. : 185-190 C decomposition)
IR (Nujol):

   3350, 3150, 1765, 1670, 1615,
1595, 1560, 1525, 1490 cm '33) 7- [2-carboxymethoxyimino hydrochloride -
 EMI168.2
 2- (2-aminothiazol-4-yl) acetamido] 3- {2- [1- (3-aminopropyl) - 3-pyiridinio] thiovinyl} - 3-cephem-4 - carboxylate (syn isomer) (cis isomer )
IR (Nujol): 3350, 1780, 1710, 1673, 1627 cm 34) 7- [2-allyloxyimino-2- dihydrochloride
 EMI168.3
 amino-1,2,4-Lhiadiazol-3-yl) acetamido] -3- {2- [l-.

   (3-amino-propyl) -3-pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn-isomer) (trans-isomer) m.p .: 164-168 C (decomposition)
IR (Nujol): 3400-3100, 1770, 1710, 1670,
1620, 1530 cm * 35) 7- [2-allyloxyimino-2- (5-ami) hydrochloride
 EMI168.4
 no-1, 2, 4-thiadiazol-3-yl) -acetamido] -3- {2- [l- (3-N, N-dimethylaminopropyl) -3-pyridinio] thìovinyl} -3-cephal-4-carbo - xylate (syn isomer) (trans isomer) p. f. : 70-75 C (decomposition)
IR (Nujol): 3300, 2700, 1760, 1660, 1610,
1520 cm 36) 7 [2-allyloxyimino-2- (5-. Amino-1,2,4-thiadiazol-3-yl) acetamido] dihydrochloride -3- {2- [1- (2-aminoethyl) ) -3-pyridinio] thiovinyl] -3-cephem-4-carbxoylate (syn isomer) (cis isomer). p. f. : 125-130 C (decomposition)
IR (Nujol):

   1765, 1670, 1605, 1510 cm 37) 7- [2-allyloxyimino-2- dihydrochloride (5-

  <Desc / Clms Page number 169>

 
 EMI169.1
 amino-1,2,4-thiadiazol-3-yl) acetami-do] -3-12- [I- (3-N, N-dimethylaminopropyl) -3-pyridinio] thiovinyl} -3-cephem-4-carboxylate (isomer syn) (cis isomer) p. f. : 65-70 C (decomposition)
IR (Nujol): 3350, 2700, 1765, 1670, 1600,
1525 cm "
 EMI169.2
 38) 7- [2-a11y10xyimino-2- hydrochloride 2- (5 amino-l, 2, 4-thiadiazol-3-yl) acêtamido] -3- {2- [l- (3-aminopropy1) -3-pyridinio ] thiovinyl} -3-cephem-4carboxylate (syn isomer) (cis isomer) p. f. : 65-70 C (decomposition)
IR (Nujol):

   3350, 3150, 1770, 1710, 1670, 1620,
 EMI169.3
 1525 cm "39) 7- [2-allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido dihydrochloride] -3- {2- [1- (2-amino- ethyl) -3-pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn isomer) (trans isomer). mp: 170-175 C (decomposition)
IR (Nujol): 1760, 1670, 1620 cm 4O) 7- [2-ethoxyimino-2- (5-amino-) hydrochloride
 EMI169.4
 1, 2, 4-thiadiazol-3-yl) acêtamido] -3- {2- [l (-3-aminopropyl) - 3-pyridinio] thiovinyl} -3-ce? hem-. 4-carboxylate (syn isomer) (cis isomer) p. f,: 116-126 C (decomposition)
IR (Nujol):

   1770, 1670, 1610, 1510 cm 41) 7- [2-ethoxyimino-2- (5-amino-) hydrochloride
 EMI169.5
 1, 2, 4-thiadiazol-3-yl) acêtamido] - 3-. {2- [1- (3-aminopropyl) - 3-pyridinio] thiovinyl} -3-cephem-4carboxylate (syn isomer) (trans isomer). p. f. : 148-1570C (decomposition) IR (Nujol): 1770, 1670, 1620, 1530 cm '42) 7- [2-ethoxyimino-2- (5-amino- 1, 2, 4-thiadiazol-3-) hydrochloride yl) acetamido] -3- {2- [l- (3-N, N-dimethyl-
 EMI169.6
 aminopropyl) -3-pyridinio] thiovinyl} -3-cephem-4-carboxyla- -nio] thiovinyl., te (syn isomer) (trans isomer).

  <Desc / Clms Page number 170>

 p. f. : 121-130 C (decomposition)
IR (Nujol):

   3350, 2700, 1770, 1670, 1620, 1530 cm 43) 7- [2- (l-carboxy-l-cyclopentyloxyimino) -2- (2 aminothiazol-4-yl) acetamido] -3- [2- (1- methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer)
IR (Nujol): 3300, 1760, 1650, 1590 cm
EXAMPLE 22
The following compounds were obtained in a manner similar to that of Examples 14 and 15.
 EMI170.1
 



  1) 7- [2-ethoxyimino-2- (5-aDino-1,2,4-thiadiazol-3-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thioviny1] -3e cephem-4-carboxyla te (syn isomer) (trans isomer) IR (Nujol): 3300 (large), 1760, 1660, 1600,
1520 cm '2) 7- [2-ethoxyimino-2- (5-amino- 1, 2, 4-thiadiazol-3-yl) acetamido] -3- [2- (1-methyl-2- pyridinio) thiovìnyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer).



   IR (Nujol): 3400, 3250, 1780, 1650-1680, 1620 cm
 EMI170.2
 3) 7- [2-ethoxyimino-2- (5-amino-1,2,4,4-thiadiazol-3-yl) acetamido] -3- [2- (1-methyl-2-pyridinio) thiovinyl] -3-cephem-4-carbxoyalte (syn isomer) (trans isomer).



   IR (Nujol): 3300, 3200, 1760, 1650, 1600 cm
 EMI170.3
 4) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem- 4-carboxylate (isomer syn) (trans isomer)
IR (Nujol): 3400-3100 (large), 1760, 1660,
1600, 1520 cm
NMR (DO-DCl) û: 3.90 (2H, d), 4.12 (3H, s), 4.50 (3H, s), 5.32 (1H, d, J = 4Hz), 5, 80

  <Desc / Clms Page number 171>

 (1H, d, J = 4Hz), 7.05 and 7.40 (2H, 2xd,
J = 16Hz), 7.18 (1H, s), 7, 8-9, 0 (4H, m) 5) the trifluoroacetic acid salt of 7-amino-3- [2- (1- methyl-2-pyridinion) thiovinyl] -3-cephem-4-carboxylate (trans isomer).



   IR (Nujol): 2550-2450, 1760, 1660, 1640,
1600 cm
 EMI171.1
 NMR (DMSO-d): 3.75-4.4, 3 (2H, m), 4.21 (3H, s), 5.0-0-5.47 (2E .. m), 7.13 (1H, d , J = 16Hz), 7, 3-8, 3 (6H, m), 9.0 (1H, d, J = 5Hz).



  6) the trifluoroacetic acid salt of 7-amino-3- [2- (1-methyl-3-pyridinio) thiovinyl1- 3-cephem-4-carboxylate hydroiodide (trans isomer).



   IR (Nujol): 3350, 2500-2600, 1780, 1670, 1620 cm "
 EMI171.2
 NMR (DMSO-d6): 3.95 (2E, ABq, J = 18Hz), 4.30 (3il, s), 5, 1-5, 3 (2H, m), 6, 5-7, 3 ( 2H, m), 8, 0 -. 8, 9 (5H, m), 9, 13 (1H, large) 7) the trifluoroacetic acid salt of 7-amino-3- [2- (4-methyl-2-pyrazinio) thiovinyl] iodide -3 3-cephem-4-carboxylate (trans isomer)
IR (Nujol): 3300, 1800, 1670 cm-1

  <Desc / Clms Page number 172>

 
 EMI172.1
 / 1 - 8) le7- [2-m2thoxyimino-2- (2-ainolhiazol-4-yl) acetaido] - 5- [2- (l-methyl-2-pyridin. Io) thiovinyl] -5-cepheEi-4carboxylate . (syn isomer). (JL trans trans.) ..



  IR (Nujol): 5500, 1765, 1670, 1611, 1562, 1555 c '9) le7- [2-methoxyinino-2- (2-amiTiothiaol-4-yl) acetamidp] - - [7 (A) ... , 1 7 "-) h". 1, - 1. A 'carboxylate (isorr.èresyn) (isomer tra-Ts) IR (Nujol): 5500, 1765 (la.), 1660, 1600 c' -a 1 Ls7-2-methoxyinino-2- (2 -tritylaminothiazol-4-yl) acé anidc] -5- [2- (l-nethyl-2-pyridinio) lhicvinyl] -5cepher-i-4-carboxylate. (syn isomer) (tra. ns isomer).



  IR (Nujol): 5250, 1780, 1672, 1535 cs. ' lle7-2 "methoxyiino-2- (2-teTt-pentylcxycarbQnylainotiazol-4-yl) acaido] -3- [Z- (4-Rthyl-2-pYTa = inio) - 1 (trans isomer).



  IR (ujol): 5550, 1762, 1700, 1660, 15 0 c '10 iodide of 7- [2-ethoxyimino2- (5-amino-1,2,4,4-thiadiazol-3-yl) acëtamido] -3 - [2- (13-dimëLhyl-2-pyrimidinio) thiovinyl] -3-cphen-4-carbolate (syn isomer) (trans ison)



  IR (Nujol): 5550, 1770, 1663, 1605 ci 'RN (DO) 6: 140 (3H, t, J-7Hz), 380 (2H, la. S), 591 (5H, s), 414 (3H , s), 4y50 (2H, q, J = 7H =), 550 (1H, d, J = 5Hz), 580 (IH, d, J = 5H =), 675, 727 (2H, 77 (1H, 9 ABq, J = 16H =), 777 (1H, m), 903 (2H, n) - 3-nyll-3- 13) ie7-2-ethoxyinin. o-2- (5-aniino-l, 2, 4-thiadiazol-5-yl) - 3330, 1 1760 (la. ce-sheYR-4-carboxylate (isomersyn) (isomeretrans).



  IR (Nuj 01): 5550, 1760 (la.), 1665, 1607 c "

  <Desc / Clms Page number 173>

 
 EMI173.1
 NMR (DMSO-d6) 6: 120 (5H, t, J = 7Hz), 3.90 (ZH, la. S), 4 113 CZH, q, J = 7Hz), 426 (5H, s), 517 ( 1H, d, J = 5Hz), 577 (1H, dd, J = 5R2, 8H), 722 (2H, la. S), 8.05 (2H, bT. S), 8 ,, 80 (1H, la . S), 9,; 20 (2E, la. S), 9, 50 (1H, d, J = 8Hz).



  14) le7- [2-methoxyimino-2- (5-aino-1,2,4-thiadiazol-3-yl) - 2- (1 aceiaido] -5- [2- (l-neThyl-2-pyridinio) thiovinyl] -3phe-4-carboxylate (isomeresyn) (trans isomer).



  -60, IR (Nujol): 3250-5550, 1770, 1660, 1620, 1560, 1 "'- 0 -1 the trifluoroacetic acid salt of 7aino-3- [2- (1-methyl-5) iodide -pyridinio) thiovinyl] -3-cephem-4carboxylate (cis isomer).



  (Nujol): 3400 (wide), 2350 (wide), 1800, 1670, 1620, 1540-1520 Cr - 16) ie7- [2-ethoxyimino-2- (5-anio-l, 2y4-thiadiaol-5-yl ) acetaido] -3- [2- (1-ethyl-5-pyridinio) thiovinyl] -5ce? he: -4-cs. rbcxylate (syn isomer) (trans isomer).



  IR (Nujol): 5500 (large), 1770, 1675, 1600, 152Q c '' R (DMSO-d) 6: 105-180. (4H, m, J = 7H),.) 71.). "8 (7 nsm 3 ae Z 2 J (9 C> J / -Z) S 515-58 (2H, m), 425 (5H, c , 'J = 7Hz), - 1- - 8 (".) A - (-'. T -T) 4 y68 C3T-4., Q, J = 7;; iz) 5. 712 (lH2 a. Yi = 5,568 (1H, dd, J = 5.8Hz), 664 (1H, d, J-16Hz), 49 (1H, d, J = 16Hz), 7) 80-9130 (61m), 9/50 (in, d, J = 8Hz) 17) 7- [Z-ethoxyimino-2- (5-amino-l, 2, 4-thiadiazcl-3-yl) actaido] -5- [2- (l-merhyl- 5-pyTidinio) thiovinyl] -5- 1 7) 12 7 [2 e ¯ .. OX yi 2 i 2 o 2 (D 2 zi AX 0 1 S 2 X x G ¯ ¯ ai ¯ & zc 1 D y ¯) c C é ido] D [2 (1 R ç 1 P, I iino) t Ä X ¯ O vi ny 1] 3 cephen-4-carbolate (syn isomer) (isorr. cis era).



  IR (Nujol): 3300 (large), 1760, 1665, 1600, 1520 c: n -

  <Desc / Clms Page number 174>

 
 EMI174.1
 1 18'1 - r- 0, - 0 - (. 1? 'Thioviyl1-5-cehem-4-carboxylte (isomeresyn) 1 P C -some --- e syn (trans isomer).



  TR (Nujoi: 3300 (laroe '), 1765. 1670, 1615, 1560, 1SH f 19) le7- [2-allyloxyiiD. o-2- (5-s-mio-l, 2, 4-thiE. c. is. ol-3ce ccphe .-- ca. (-som; -, re svn) trans) IR (Nujol): 5300 , 1760, 1670, 1620, 1600, 1550 c-. ' 3 30 0,

  <Desc / Clms Page number 175>

 
 EMI175.1
 20) 7- [2- (t-butoxycarbonylmethoxyiino) -2- (2- 3. minothiazol-4-yl) acetamido] -3- [2- (l-methyl-3-pyridinio) thioviny1] -3-cephem -4-carboxyate "Ctsomer syn) (trans isomer).



  -P IR (Nujol): 3200-3300, 2400-2600, 1770, 1715, 1680, 1630 cm NMR (DMSO-d) ô: 1) 50 (9H, s), 3, 20-4, 10 (2H, , m), 4.43 (3H, s), 4.70 (2H, s), 5; 30 (1H, d, J = 5Hz), 5 83 (1H, dd, J = 5Hz, 8Hz), 700 (1H, s), 750 (2H, large s), 8-900 (6H,), 927 ( 1H, large 5), 9.77 (1H, d, J = 8Hz) 21) 7- [2-carboxymethoxyimino-2- (2-anin. Othiazol-4yl) actamido] -3- [2- (I- methyl-3-pyridinio) thioviny1J-3ephem-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1765, 1670, 1620 cm 'CD, (DMSO-d) 6: 550-410 (2H, m), 450 (5H, s), 4, 63 (2H, large s), 5 ) 2-D (1H, d, J = 5Hz), 5, 90 (1H, dd, J = 5Hz, 8Hz), 687 (1H, s), 6, 95 (IH, d, J = 15Hz), 7 ) 15 wide 747 (1H, d, J = 15Hz), 7) 90-8, 90 (3H, m), 9, 13 (1H, wide 5), 9) 80 (IH, d, J = SHz) 22 ) 7- [2- (5-carboxy-2-propenyloxyimiuo) -2- (2-aminoEhiazol-4-yl) acetamido] -3- [Z- (1-methyl-5-pyridinio) thiovinyl] -3- cephem-4-carboxylatc.

   (syn isomer) (trans isomer) IR (Nujol): 5500, 1760, 1660, 1600, 1535 cm-1 NMR (DMSO-d6 / DZO) 0: 3 / 57-4 / 20 (ZH, m), 4; 37 (SB, 5), 4. 57-4, 95 (2H, m), 510 (1H, d, J = 5Hz), 5/60 (1H, dd, J = 5Hz, 8Hz), 5J98 (1H, d, J = 16Hz), 6751 (1H, d, J = 16Hz), 7.48 (1H, d, J = 16Hz), 678 (1H, s), 776-917 (4H, m), 9267 (1su d, J = 8Hz) 23) Ze iodide [2-- (1-methyl-2-pyridiniomé thoxyimino)

  <Desc / Clms Page number 176>

 
 EMI176.1
 2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1-methyl-3-pyridiio) thiovinyl] -3-cephem-4-carboxylate (sn isomer y trans isomer) 1 IR (Nujol ): 3250, 1760, 1665, 1515 cm "RMN (D0) 6: 79-9, 00 (SH,, 7717 (1H, d, J = 16Hz), 2 1; 7 r 7, 10 (1H, 5) , 6; 67 (1H, d, J = 16Hz), 5, 90 (1H, d, J = 5Hz), 575 (2H, s), 5.34 (1H, d, J =:

   Hz), 445 (6H, s), 35-425 (2H,) rl. 7'n L 24) le 7- (2-pyridyliethoxyimin. Oj-2- (2-aninothiazolL vri-dili io) to ,, '-yl) aceanido] -3- [2- (l-ethyl-3-pyridinio ) thiovinyl] -2h r ceDhen-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 5500, 1760, 1660, 1520, 1590 c ') -7-4 & -17 (-, H, s) RM (DMSO-d6) o: 37-420 (2H, n), 447 ( 3H, s), 515 (1H, d, J = SHz), 525 (2H, s), 572 (1H, dd, J = 5Hz, 8Hz), 64S (1H, d, J = 14H), 6 J 8 a (1H, s), 71-90 (11H,, 990 (1H, d, J = 8Hz) 25) 7- [2- (5-carboxypropoxyimio) -2- (2-ainothisol- 4-yl) acetaniido ] -3- [2- (l-methyl-3-pyridinio) 'chiovinYl] -5nio) ovi ephe-4-carbcxylate (syn isomer) (trans isomer).



  IR (Xujol): 5500, 1760, 1660, 1600, 1555 c "1 1 r¯ 3 NMR (DMSO-d 6 / DO) a: 1 5-275 (4H, 3), 35-4 27 (4H, m ), 4, 37 (SH, s), 5, 08 (IH, d, J = 5Hz), 563 (1H, dd, J = 5Hz, 8Hz), 650 (1H, d, J = 16Hz), 7, 48 (1H, d, J = 16Hz), 674 (1H, s), 7, 76-913 (4H, m), 955 (1H, d, J = 8Hz) 26) on 7- [2- (l- carboxypropoxyimino) -2- (2-aniothiazol- -7-pyri dirio) thiov n, 1 3t-yl) acetamido] -3- [2- (l-elhyl-3-pyridinio) thiovinyl] -3- 1 zephem-4 -carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3500, 1760, 1660, 1590 cm-1 i NMR (DMSO-d) 6: lOS (3H, t, J = 7Hz), 162-224 (2H, m), 3) 2-3) 9 (2H, D), 4; 42 (3H, 5),

  <Desc / Clms Page number 177>

 
 EMI177.1
 4147 (1H, t, J = 6Hz), 5/15 (1H, d, J = 5Hz), 5.77 (lH, dd, J = 8Hz, 5Hz), 6.47 (IH, d, J = lHz ), 687 (1H, s), 7 r 0 (1H, d, J = 16Hz), 1 7, 02-9) 3 (4H, m) 27) le 7- [2-a11yloxyimino-2- (Z- aminothi2. z01-4-yl) acetaido] -3- [2- (1-inethyl-3-pyridinio) thiovinyl] -3-cephem- 4-carbcxylate. (pvn isomer), (trans isomer).



  1-- (tra-ns' isomer ?.



  IR (ujol): 5500, 1760, 1660, 1600, 1530 cm-1 NMR (DMSO-d./D. O) g: 555-587 (4H, m), 457 (5H, s), 6; 3 3-3 11 87 4, 62 (2H, d, J = 5Hz), 6; 50 (1H, d, J = 16Hz), 71- + 7 (1H, d, J = 16Hz), 673 (1H, s), 7183-9, 03 (4H, m), 9.57 (1H, d , J = 8Hz) ale 7- [2- (2-hydroxyethoxyimino) -2- (2-ainothiazol- 4-yl) ac tanido] -3- [2- (1-methyl-3-pyridinic) rhiovinyl] -5c e-Dri cephe-4-carboxylate (syn isomer) (trac isomer) ''.



  3300, 1760, 1660, 1600, lS35 150G IR (Nujol): 5500, 1760, 1660, 1600, 1555, 1500 c 'RMN (DMSO-d6 / D20) 6: 3, 20-3, SS (2H,), 455 (5H, s) 29) 7- [2-ethoxyiino-2- (2-ainothia ol-4-yl) ace'ranido'j-5- [2- (l-iethyl-3-pyridirLic) thiQ ' .'in. yl] -5ceDhen-4-carhoxylate (syn isomer) (trans isomer). ' IR (Xujol): 3300, 1760, 1665, 1600, 1533 cl C. 71 NMR (DMSO-d / DO) g: 1.25 (3H, t, J = 7H), LJ 2 4, 13 (2H, ABq , J = 7Hz), 4.57 (5H, s), 5.08 (1H, d, J = 5Hz), 5.65 (1H, dd, J = 5H =, SHz), 648 (1H, d, J = 16Hz), 7) 48 (1E, d, J = SHz), 7.75-793 (4H, m), 9; 52 (1H, d, J = 8Hz), 6) 73 (1H, s) 30) 7- [2- (2-propyn. Yloxyimino) -2- (2-ar. Inothiazol-4yl) acetaido] -5 - [2- (l-methyl-5-pyridinio) thiovinyl] -5cephem-4-carboxylate (syn isomer) (trans isomer).



  (trans isomer) IR (Nujol): 3250, 1760, 1660, 1600, 1550 cm '

  <Desc / Clms Page number 178>

 
 EMI178.1
 RN (DMSO-d6 / DO) o: 3, 3-3, 8 (3H, m), 437 (3H, s), 47 (2H, s), 509 (1H, d, J = 5Hz), 563 ( 1H, dd, J = 5Hz, SH :), 6) 53 (1H, d, J = 16Hz), I 6; 78 (1H, s), 750 (1H, d, J = 16Hz), 7) 73-7, 93 (4H, m), 9.05 (1H, s), 9} 52 (1H, d, J = 8Hz) 31) 7- [2- (t-butoxycarbonylethoxyimino) -2- (2formamidothiazol-4-yl) acetanido] -3- [2- (1-methyl-3- 1 (veryJ5 isomer).



  IR (Nujol): 3200-3400, 1760, 1720-1730, 1690, 1670 RMN cru (DMSO-d6) 6: 1 50 (9H, s), 3, 50-420 (2H, n), 4} 37 ( 3E, s), 4, 63 (2R, s), 5, 27 (1H, d, J = 5Hz), 5, 87 (1H, dd, J = 5Hz, 8Hz), 7.00 (1H, d, J = 16Hz), 7240 (il, d, J = 16Hz), 7.45 (1H, s), 795-9, 10 (4H, m), 853 (1H, s), 9.67 (1H, d , J = 8Hz), 12, iO (1H, large s) 32) on 7-2- (1- -butoxycarbonyl) propoxyiino] -2- (2foraidothiazol-4-yl) acetaidoj} -3- [2- (l -ethyl-3- (syn isomer) pyridinio) thioviiiyl] -3-cephe - carbcxyla. t. e (syn isomer) (trance isomer.



  IR (Nujol): 3250, 1760, 1720, 1680 cm. ' NMR (DMSO-d6) 6: 0.98 (3B, t, J = Hz), 1.45 (9E, s), 1.52-206 (2H, n), 3.67-4, 17 (2H , m), 437 (SH, s), 4, 5 C1H, t, J = 6Hz), 5) 28 (lH, d, J = 5Hz), 593 (lH, dd, J = SHz, S: -iz ), 6J43 (1H, d, J = 16Hz), 722 (1H, s), 7) 63 (1H, d, J = 16Hz), 783-933 (4H, m), 3J52 (1H, s), 6 (1H, d, J = 8Hz) 33) 7- [2- (2-pyridylmethoxyiino) -2- (2-formaidothiazol-4-yl) acetamido] -3- [2- (1-methyl-3-pyridinio ) L e - j thiovinyl] -3-cephem-4-carboxylate (syn isomer) (ip trans isomer).

  <Desc / Clms Page number 179>

 
 EMI179.1
 



  MN (DMSO-dJ: 33 3-4, 00 (2H, m), 4; 33 (3H, s), 513 (1H, d, J = 5Hz), 530 (2H, large s), Sj83 (1H, dd, J = SHz, 8Hz), 650 (1H, d, J = 1.5Hz), 720-9, 00 (9H, m), 7.43 (IH, s), 8 50 (1H, s), 995 (1H, d, J = 8Hz) 3Ll) 7- [2- (3-benzhydryloxycarbonyl-2-propen. Yloxyimino) nc) L- (2-tritylaninothiazol-4-yl) acetaido] -3- [2- (1-ethyl-5p pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn syn isomer) (trans isomer).



  IR (Nujol): 3300, 1780, 1720, 1680, 1600, 1530, 1500 cm 'r (DMSO-d / D 0) 6: 37-4) 35 (2H, n), 4 40 (3H, s), -L- = SHZ), S 83 467-500 (2H, n), 527 (1H, d, J = 5Hz), 583 (1H, m), 6/25 (1H, d, J = 16Hz), 667 -700 (3H, m), 7; 33 (26H, m), 800-920 (5H, n), 980 (1H, d, J = 8Hz) 35) le 7- [2-Gthoxyinio-2- (2-tritylainothiazol-4-yl) acetamido] - 3- [2- (l-methyl-3-pyridinio) thiovinyl] -3cephe-4-carboxylate (syn isomer) (trans isomer).



  NMR (DMSO-d6 / D20) g: 120 (3H, t, J = 7Hz), 36-40 (2H, m), 406 (2H, ABq, J = 7Hz), 4.37 (3H, s), 5 15 (1H, d, J-Hz), 5 67 (1H, dd, J = 5Hz, SHs), -7 6, 72 (1H, s), 7) 17-7, 50 (15H,), 8J43 -917 (4H, m), 9, 51 (1H, ci, J = 5Hz) 36) 7- [2- (2-propynyloxyirnino) -2- (2-tritylainothiazol-4-yl) 3Lcetamido] -3- [2- (l-methyl-3-pyridin. Io) thiovinyl] -3-cephem-4-ca. rboxylate (syn isomer) (trans isomer).



  NMR (EMSO-dg / D2O) o: 34-37 (3H, m), 4.37 (3H, 5): 521 (1H, d, J = 5Hz), 5.73 (1H cid, J = 5Hz, 8Hz), f "l F-7-, m 6, 78 (1H, s), 7) 13-7, 50 (ISH, Iìl), 9 65 (1H, d, J = 8Hz)

  <Desc / Clms Page number 180>

 
 EMI180.1
 37) 7- [Z- (3-ben7-r 37) 7- [2- (3-benzhydryloxycarboaylpropoxyimino) -2- (2-tritylamiiiothiazol-4-yl) acetamido] -3- [2- (l- methyl-3e e pyridinio) thiovinyl] -3-cepheni-4-carboxylate, (syn-isomer) (trans-isomer).



  IR (Nujol): 3350, 1770, 1720, 1665, 1590, 1520 cmRMN (DMSC-d / DO) g: 153-2, 10 (4H, m), 350-370 6 2 1 1 (2H, m), 383-427 (2H, m), 435 (3H, s), 517 (1H, d, J = SHz), 563 (1H, m), 678 (1H, s), 1 1687 (1H, d, j = 15Hz), 690 (1H, s), 710-750 (26H, m), 7S80-9 17 (4H, m), 960 (1H, d, J = 8Hz) 33) on 7- [2-carboxymethoxyiinc- 2- (thiazol-4-yl) t aceta. mido] -3- [2- (1-ethyl-3-pyridinio) thiovinyl] -3ceDhe! - & -cnrboxylate ((syn isomer) (trans isomer).



  -L 6 0 0 ci-Il IR (Nujo1): 3350, 1760, 1660, 1600 cm - (D (DO-NaHCO) 6: 373 (2H, s), 435 (3H, s), 4} 50-4 , S7 (2H, m), 5; 32 (1H, d, J = SHz), 583 (1H, dd, J = 5Hz, 8Hz), 663 (1H, d, J = 16Hz), 7, 17 (1H , d, J = 16Hz), 780-880 (6H, n) 39) le 7- [2-hydroxy-2- (2-anioh. ia. zol-4-yl) acetamido] - 3- [2- ( l-methyl-3-pyTidinio) thioviyl] -3-cephe-4-carbcxylate (trans isomer).



  IR (Nujol): 3300, 1760, 1670, 1600 c '(DMSO-d) 6: 342-404 (2H, ni), 443 (3H, s), 5.00 (1H, s), 5) 15 ( IR, d, J = 5Hz), 5) 70 (1H, dd, J = SHz, 5Hz), 6) 54 (IH, 5), 6) 6 (IH, d, J = 16Hz), 702 (2H, large s), 7) 53 (li, d, J = 16Hz), 7} 73-9; 17 (4H, m) J 40) 7- [2- (l-carboxy) ethoxyi in. o-2- (5-amin.no-l, 2, 4L thiadiazol-3-yl) acetamido] -3-i'2- (l-methyl-3-pyridin. io) - .., 1] - 1 , A'1 (0 -) (trans isomer).



  IR (Nujol): 3300, 1770, 1665, 1600, 1520 cm '

  <Desc / Clms Page number 181>

 
 EMI181.1
 NMR (DMSO-d / D20) o: 1) 51 (3H, d, J = 6Hz), 3) 80 (2H, large s), 4, 51 (3H, s), 475 (1H, d, J = 6Hz), 5.25 (1H, d, J = 4Hz), 5785 (1H, d, J = 4Hz), 6; 83 (1H, d, J = 16Hz), 7; 50 (1H, d, J = 16Hz), 76-94 (4H, m) 41) 7- [2- (lnethyl-l-carboxyethoxyinino) -2- (5-amino- 7 ..... 1 - 1) 1.,].,. [2 (1 1 h 1.,. Pyridinic) th. iovin. yl j-5-cephem-4-carboxylae (yn isomer) (trans isomer).



  TR (Nujol): 3300, 1770, 1070, 1610, 1520 cm 1 NMR (DO-NaHCO) 6: 160 (6H, s), 582 (2H, s), 442 -, s), 535 (1H, d, J = 4Hz), 590 (1H, d, J == 4Hz), 6; 70 (1H, d, J = 16Hz), 7} 20 (1H, d, J = 16Hz), 7; 5-8J9 (3H, m) 42) 7- [2-hoxyinino-2- (5-amino-1,2,2,4-thiadiazol- / J 5-cephe-4-carboxylate syn isomer) (trans isomer).



  IR (Nujol): 5500, 1760, 1640-1680, 1610, 1520 cm "1 NMR (DMSO-d.) 6: 1: 50 (5H, t, J = 5Hz), 353-590 2 - (21 (2H , m), 425 (2H, q, J7Hz), 495-5. 20 (3H,), L 5} 75 (LH m), 660 (1H, d, J = 16Hz), 750 (1H, d, J = 16Hz), 800-900 (4H, m), 955 (1H, d, M) J = 8Hz) 43) 7- [2-ethoxyimino-2- (5-amino-1,2,4,4-thiadiazol- 5yl) acetaniido] -3- [2- (2-triniethylanunonioethyl) thiovinyl] -5cephe-4-carboxylate (syn isomer) (trans isomer).



  Il 3300, 1760, 1670, 1600, 1520 cm-1 RM (DMSO-dJ o: 125 (3H, t, J = 5Hz), 3, 10-400 (6H, m), 4, 20 (2H, q, J = 7Hz), 505 (1H, d, J = 5Hz), 5) 60 (1H, "1), 6, 60 (1H, d, J = 16Hz), 7) 03 (1H, d, J = 16Hz ), 806 (2H, large 5), 9} N / A (1H, d, J = 8Hz) 9

  <Desc / Clms Page number 182>

 
 EMI182.1
 44) 7- [(4-carboxy-3-hydroxyisothiazol-5-yl) - 1 1 cephen-4-carboxylate (trans isomer).



  IR (Nujol): 3300, 1760, 1670 cm 'p (DMSO-d6) 6: 393 (2H, s), 3, 83-4, 00 (ZH,), 447 (SH, s), 527 (1H, d, J = SHz), 5.70 (1H, dd, J = 8Hz, 5Hz), 7D30 (6H, m), 9D50 (1H, ci, J = 8Hz) / 45) on 7- [2-methoxyinin. o-2- (5,6-dihydro-1,4-oxathiirL-2-yl) acetaido] -3- [2- (l-ethyl-3-pyridinio) rhiovinyl] -3cephe-4-carboxyls. te (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1760, 1660, 1600, 1500 cm - -3 (1'- H CD (DO) 6: 30-3, 23 (2H, m), 373 (2H, s), 433 (3H , s), 522 (1H, d, J = 5Hz), S, 71 (IH, d, J = 5Hz), 5; 97 (1H, s), 653 (1H, d, J = 16Hz), 7 i 12 (IH, el, J = J. 6Hz) 46) on 7- [2-n '. ethoxyiino-2- (l, 2, 3-thia. dis. zol-4-yl) - 1 .., - '"(1 1 ... 1., .. d ..) h'. -] - /.



  4-carbcxYlate (syn isomer) (trans isomer).



  R (Xujol): 3200-3350,1760,166, 600, 155 'cn' (nN (DSO-d./DO) 6: 3767 (2H, s), 402 (3H, s), A 0 437 (3H , s), 513 (1H, d, J = 5Hz), 5, SO (1H, dd, J = 5Hz, 8Hz), 6J50 (IH, d, J = 16Hz), Î) 50 (1H, d, J = 16Hz), 7 83-9. 10 (4H, m), 10 (lu, s), 9 i 78 C 1H, d, J = 8 Hz) 47) 7- [2-methoxyain. o-2- (3-hydroxyphen. yl) acetamido] - 3- [2- (l-ethyl-3-pyridinio) thiovinyl] -3-cëphen-4a-rboxylate (isomeresyn) (trans isomer) IR (Nujol): 1770, 1650, 1600, 1570, 1500 cm 'J ..: -1 1 CTR Rl! N (DMSO-d6 / DO) 6: 350-417 (SH, m), 417-467 (3H, m), 5117 (lE, d, J = 5Hz), S, 77 (lH, cid, J = 5Hz , SHz), 660 (1H, d, J = 16Hz), 753 (1H, d, J = 16Hz), 6 83-7, 40 (4H, m), 773-893 (4H,)

  <Desc / Clms Page number 183>

 
 EMI183.1
 48) the trifluoroacetic acid salt of 7-amino-3-- [2- (1-methyl-2-pyridinio) thiovinyl] -3-cephem-4-carboxylic iodide (cis isomer).



  IR (Nujol): 2300-2500, 1780, 1670, 1610, 1560 cm "RMN (DMSO-d.) 6: 3785 (2H, ABq, J = 17Hz), 420 (3H, s), 535 (2H, n ), 667 (1H, d, J = 10Hz), 695-850 (4H, m), 9, 10 (1H, broad s), 967 (ZH, broad s), 49) on 7- [2-methoxyimino- 2- (2-amin. Othiazol-4-yl) aceta. Id. O-3- [2- (l-nielhyl-2-pyridin. Io) thiovinyl) -5-cephem- 4-carboxylate (syn isomer) ( isomer ùis).



  IR (ujol): 3400-3100, 1765, 1660, 1610, 1560, 1530 -1 RMX (DMSO-d.) G: 367 (2H, ABq, J = 16H), 333 (3H, 6) s), 417 (3H, s), 512 (1H, d, J = 5Hz), 563 (1H, dd, J = 5H =, 8H2 :), 642 (1H, d, J = 14Hz), 673 (1H, s), 725 (2H, large s), 763 (1H, d,. Zi J = 14Hz), 79-900 (4H,), 957 (1H, d, J = 3H) / 50) on 7- [(2-methoxyiino -2- (2-ainothia = ol-4-yl) - 1 .... - [7 (1, .. 1 - .., ... at the .. 1cephe-4-cs. Rboxylate isomer svn ) (isomer <is). ' IR (Nujol): 3300, 1760, 1660, 1600, 1530 cm 'v-3--) (3H, (Di'SO-d 6: 3 72 6.

   ABq, 'li7 3 RE (DMSO-d) 6: 3: 72 (2H, A3q, J = 16Hz), 3S2 (3H, s), 433 (3H, s), 510 (1H, d, J = 5Hz) , 565 (1H, dd, J = 5Hz, 8Hz), 638 (1H, d, J = 10Hz), 6J73 (1H, s), 7J22 (lE, d, J = 10Hz), ï) 18 (2H, large s), 7, 85-8 / 90 (SH, m), 9, 17 (1H, large 5), 9 50 (1H, d, J = SHz) 1 4 51) 7- [2-methoxyiio-2 - (2-tritylaminQthiaol-4-yl) p acetaido] -3- [2- (l-methyl-3-? Yridinio) thiovinylj-3cepheJil-4-carboxy1ate (syn isomer) (trans isomer).



  - 1

  <Desc / Clms Page number 184>

 
 EMI184.1
 NMR (DMSO-d6) 6: 5. 77 (3H, s), 3.80 C2H, m), 4} 32 (3H, s), 5J17 (1H, d, J = SHz), 5.67 (1H , dd, J = Sqz il SH7) -7-H, dd, J = SHz, 8Hz), 70 (1H, s), 6J85-7 (17H, m), 8) 00-9, 03 (4H, m ), 9 ,, 55 (1H, d, J = 8Hz) J 52) 7- [2-methcxyinino-2- (2-tritylaminothiazol-4-yl) acetaido] -3- [2- (l-methyl- 2-pyTidin.io) thiov-Tiyl] -3cepilem-4-carboxylate (syn isomer) (Cree isomer, F IR (Nujol): 5500-320C, 1775, 1680, 1660, 1615, 1600, 1573 con 1 Ri '( DMSO-d) 6: 367-595 (2H, ir.), 5, 78 (3H, s), 4120 (3H, s), 5) 17 (1H, d, J = 5Hz), 5 70 (1H, dd, J = 5Hz, 8Hz), 6, 70 (1H, 5), 6) 75 (1H, d, J = 10Hz), 700-750 (15H, m), 767-905 (4H, rr.), 9 J 52 CIH, d, J = 8Hz) 53) le7- [2-methoxyiino-2- (2-tritylaminothiazol-4-yl) acetamido] -5- [2- (l-methyl-3-pyridinio) thiovin. yl] -5-cephen.- 4-carboxylaie (syn isomer) (cis isomer).



  IR (Nujol): 3350-3250, 1770, 1670, 1620, 1590 c 'ç -, - Od 3 7 0- "T 0 0 F, 1) 8 0 R (EM. -D.) O: 5 0- 400 (H,), 3 0 (H, s), 430 (3H, s), 520 (iH, d, J = 5Hz), 570 (1H, dd, t: y = S'HZ S 8, L. Z) s 6 s I (lH S s) 6J 7X (1Ha d JR J = 5Hz, 8Hz), 670 (1H, s), 673 (1H, d, J = llHz), 700 (1H, d, J = llHz), 7. 15-750 (15H, n), 8 00-9 10 (5-, i, M) 9 50 (1711-, de j = SF, -7) 54) on 7- [2- ( 3-carboxypropoxyinin. O) -2- (5-a'min. Ol, 2, 4thiodiazol-3-yl) acetanido] -3- [2- (l-eihyl-3-pyridinio) thiovin.yl] -3- cephem-4-carboxylate (isomeresyn) (trans isomer).



  IR (Nujol): 3300, 1765, 1665, 1600, 1530 cm 'mm (DMSO-d6) 6: 16-27 (4H, m), 375 (2H, large), 40-44 (2H, m), 440 (3H, s), 510 (1H, d, J = 4H), 572 (1H, dd, J = 4, 8Hz), 675 (1H, d, A 4 J = 16Hz), 744 (1H, d, J = 16Hz), 77-9, 1 (4H,), 9, 60 (1H, d, J = 8 Hz)

  <Desc / Clms Page number 185>

 
 EMI185.1
 55) 55) 7- [2-eth. oxyimin. o-2- (5-amino-1,2,4-th. iadiazol-3- / 1 cepheni-4-carboxylate (syn isomer) (cis isomer). <IR (Nujoi): 3300, 1765, 1670, 1610, 1500 ca 1 m1N (DMSO-d6) 6: 1) 27 (3H, t, J == 5Hz), 3, 65-4, 35 (4H, m ), 510 (1H, J = 5Hz), 563 (1H, dd, J = .- 5Hz, 8Hz), 6J42 (1H, d, J == 14Hz), 7, 67 (IH, ci, J = 14Hz) , 695-900 (6H, m), 950 (1H, d, J = 8Hz) 56) le 7- [2-ethoxyimino-2- (5-phosphoncamino-1, 2, 4thiadiazol-3-yl) acetamido] - 3- [2- (l-methyl-5-pyridinio) thiovinyl] -3-cephe-4-carboxylate Jisomer syn) (trans isomer).



  IR (Nujol): 3200-3400 (broad) 1760, 1672Y 1520 NMR NaHCO-D20) 6: 1, 33 (3H, t, J = 7Hz), 377 (2H, large s), 435 (3H, s), 433 (2H, q, J = 7Hz), 5} 30 (lH, d, J = 5Hz), 5, 82 (lH, d, J = SHz), 6 60 (li, d, J = lSHz), 7 ) 17 (1H, d, J = 15H :), 735-380 (4H, m) 57) L 57) 7- [2-ethoxyinino-2- (5-phos? Honoaino-l, 2, 4- . 1 e 1-¯-etnoxYllno - l-phosp2onoa8lno-, -, thiovinyll-J-ceprert -; .- carDoxn l <. e (syn isomer) (trans isomer).



  IR (Nujol): 3200, 1768, 1673, 1610, 15ÓO, 1508, 1269, 1230 cni 'RMN (NaHCO3-D20) 6: 1) 33 (3H, t, J = 7Hz), 3, 83 (2H, large s), 423 (3H, s), 4.38 (2H, q, J = 7Hz), 5D30 (1H, d, J = 5Hz), 530 (1H, d, J = SHz), 6; 60 (1H, d, J = 14Hz), 7} 33 (1H, d, J = 14Hz), 74-83 (4H, m)

  <Desc / Clms Page number 186>

 
 EMI186.1
 58) 7 [2-a1ly1oxyimino-2- (2 aminothiazol-4-y1) acetamido hydrochloride -3- {2- [1- (3-a8inopropyl) -3pyridinio) thiovinyl} -3-cephem-4-carboxylate ( syn isomer) (trans isomer).



   IR (Nujol): 3350, 1770, 1665, 1618 cm- 59) 7- [2-allyloxyimino-2- (2-ami-) hydrochloride
 EMI186.2
 nothiazol-4-yl) acëtamido] -3- {2- [l-. (3-N, N-dimethylaminopropyl) -3pyridinio] thiovinyl} -3-cephem-4-carboxylate (syn isomer) (cis isomer).



   IR (Nujol): 3300, 1775, 1660, 1610 cm-1 EXAMPLE 23
The following compounds were obtained in a manner
 EMI186.3
 re similar to that of Examples 1, 4, 6, 8, 14 and 15.



  1) 7-- [2-ethoxyii "tino-2- (2-aminothiazol-4-yl) acetamido] hydrochloride -3- {2 - [1- (3-N, N-dimethylaminopropyl) -3- pyridinio] -thìovinyl} -3céphem-4-carboxylate (syn isomer) (trans isomer).



   IR (Nujol): 3250, 1770, 1670, 1630, 1550 cm 'RMN (D2O) #: 1, 33 (3H, t, J = 7Hz), 2.51 (2H, m),
2.92 (6H, s), 3.32 (2H, m), 3.79 (2H, wide), 4.34 (2H, q, J = 7Hz), 4.79 (2H, m ),
5, 26 (1H, d, J = 5Hz), 5, 79 (1H, d, J = 5Hz),
6, 93 (2H, ABq, J = 16Hz), 7, 08 (1H, s), 7, 97 (1H, dd, J = 6Hz, 8Hz), 8.48 (1H, d, J = 8Hz),
 EMI186.4
 6, 87 (1H, d, J == 6Hz), 8, 80 (1H, large s) 2) hydrochloride of 7- [2 - et.'jxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- {2- [1- (3-aminopropyl) -3-pyri-dinio] thiovinyl} -3-cephem-4-carbxoylate (syn isomer) (trans isomer)
IR (Nujol): 3250, 1770, 1670, 1630, 1550 cm
NMR (D2O):

   1.34 (3H, t, J = 7Hz), 2.42 (2H, m),
3, 17 (2H, m), 3, 81 (2H, large s), 4, 32 (2H, q, J = 7Hz), 4, 79 (2H, m), 5.28 (1H, d, J -5Hz), 5.75 (1H, d, J = 5Hz), 7.03 (2H,
ABq, J = 16Hz), 7.08 (1H, s), 7.97 (1H, dd,

  <Desc / Clms Page number 187>

 
J = 7Hz, 8Hz), 8.48 (1H, d, J = 8Hz), 8.68 (1H, d, J = 6Hz), 8.85 (1H, large s).



  3) 7- [2-methoxyimino-2- hydrochloride
 EMI187.1
 (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-t2-1- (3dimethylaminopropyl) -3-pyridinio] tiovinyl} -3-cephem-4-carboxylate (syn isomer) (isomer trans), p. f. : 140-145 C (decomposition).



   IR (Nujol): 3350.2650,1770,1670,1610,
1550, 1525, 1490 cm 'RMN (D0) 6: 2, 30-2, 72 (2H, m), 2.92 (6H, s), 3, 15-3, 50 (2H, m), 3, 77 (2H, large), 4.07 (3H, s), 4.50-4.85 (2H, m),
5, 27 (1H, d, J = 5Hz), 5, 82 (1H, d, J = 5Hz),
6, 80 (1H, d, J = 16Hz), 7, 20 (1H, d, J = 16Hz),
7, 90-8, 17 (li, m), 8, 38-8, 58 (1H, m),
8, 67-8, 80 (1H, m), 8, 88 (1H, s) EXAMPLE 24
The following compound was obtained in a manner similar to that of Example 20
 EMI187.2
 7- [2-allyloxyimino-2- (5-amino-1,2,4,4-thiadiazol-3-yl) acetamido] -3-- {2- [l- (3-formimidoylairdnopropyl) - 3-pyridinio] tiovìnyl } -3-cephem-4-carboxy1ate (syn isomer) (trans isomer).



   IR (Nujol): 3250, 1760, 1710, 1660, 1590,
 EMI187.3
 -1 1530 cm NMR (D20) ó: 2, 13-2, 68 (2H, m), 3.48 (2H, t, J = 7Hz), 3.73 (2H, m), 5.26 (1H , d, J = 5Hz), 5.79 (1H, d, J = 5Hz), 5.15-6.08 (3H, m), 6.62 (1H, d, J = 14Hz), 7.08 (lI., d, J = 14Hz), 7, 83 (1H, s), 7, 95 (1H, m),
8, 43 (1H, d, J = 8Hz), 8, 69 (1H, d, J = 6Hz),
8.79 (1H, s)
EXAMPLE 25
The following compound was obtained in a manner similar to that of Examples 1, 4, 6, 8, 14 and 15.

  <Desc / Clms Page number 188>

 
 EMI188.1
 7- [2propargyloxyimino-2- {2 amLno--aminothiazol-4-yl) acetamido] -3- {2- [1- (3-aminopropyl) -3pyridinio] thiovinyl} -3-cephem-4-carboxylate hydrochloride ( syn isomer, (trans isomer).



  IR (Nujol): 1760, 1650, 1580, 1520 cm '
The present invention is not limited to the exemplary embodiments which have just been described, it is on the contrary liable to modifications and variants which will appear to those skilled in the art,


    

Claims (1)

 CLAIMS 1-New cephem compounds characterized in that they have the formula:  EMI189.1    EMI189.2  where-D1 or is the amino group or an acylamino group; and 9 R is a group having the formula:  EMI189.3  where R2 is an organic group, X is CH or N, Z is an acid residue,  EMI189.4  Y is CH or N and n is 0; or (2 2 Y is N-R where R is as defined above and n is 1 or a group having the formula:  AnS (R), where R is a lower alkyl group and A is a lower alkylene group, and its pharmaceutically acceptable salts, 2-Compound according to claim 1, characterized  <Desc / Clms Page number 190>    EMI190.1  in that R is an amino group; amino lower aminothiazolylalkanoyl having an imino lower alkoxy group; amino lower aminothiazolylalkanoyl having a lower alkenyl oxyimino group; amino lower aminothiazolylalkanoyl having an oxyimino lower alkynyl group; amino lower aminothiazolylalkanoyl having an imino lower carboxyalkoxy group; amino lower aminothiazolylalkanoyl having an imino lower carbonylalkoxy lower alkoxy group; lower amino thiazolylalkanoyl having a lower aralkoxy amino group lower carbonylalkoxy imino;  amino lower aminothiazolylalkanoyl having a lower hydroxyalkoxy group; amino lower aminothiazolylalkanoyl having a lower carboxyalkenyl oxyimino group; amino lower aminothiazolylalkanoyl having a lower aralkoxy group lower carbonylalkenyl oxyimino; amino lower aminothiazolylalkanoyl having an imino lower pyridylalkoxy group; amino lower aminothiazolylalkanoyl having a lower 1-alkyl group pyridinioalkoxy lower imino; lower alkanoyl aminothiazolyl lower alkanoyl amino having an imino lower alkoxy group; lower aralkyl amino lower aminothiazolylalkanoyl having an imino lower alkoxy group; lower aralkyl amino lower aminothiazolylalkanoyl having an oxyimino lower alkynyl group;  lower alkanoyl aminothiazolyl lower alkanoyl amino having a lower alkoxy group carbonylalkoxy lower imino; lower aralkyl amino lower aminothiazolylalkanoyl having a lower aralkoxy group lower carbonylalkoxy imino;  <Desc / Clms Page number 191>  lower aralkyl amino lower aminothiazolylalkanoyl having a lower carbonylalkenyl lower aralkoxy oxyimino group; lower alkanoyl aminothiazolyl lower alkanoyl amino  EMI191.1  having an imino lower pyridylalkoxy group; amino lower aminothiadiazolylalkanoyl having an imino lower alkoxy group; amino lower aminothiadiazolylalkanoyl having a lower alkenyl oxyimino group;  amino lower aminothiadiazolylalkanoyl having an oxyimino lower alkynyl group; amino lower aminothiadiazolylalkanoyl having an imino lower hydroxyalkoxy group; amino lower aminothiadiazolylalkanoyl having an imino lower carboxyalkoxy group; amino phosphonoaminothiadiazolylalkanoyl having an imino lower alkoxy group; amino lower thiazolylalkanoyl having an imino lower carboxyalkoxy group; amino lower thiadiazolylalkanoyl having an imino lower alkoxy group;  EMI191.2  hydrogen-substituted amino carboxy lower isothiazolylthioalkanoyl; amino alkanoyl substituted by aminothiazolyl hydroxy; lower amino dihydrooxathiinyla1canoy1 having an imino lower alkoxy group;    lower hydroxyaralcanoyl. an amino having an imino lower alkoxy group; amino lower aminopyrimidinylalkanoyl having an oxyimino lower alkenyl group; amino lower aminopyridylalkanoyl having an imino lower alkoxy group; lower amino alkanoyl aminopyridyl lower alkanoyl having an imino lower alkoxy group;  <Desc / Clms Page number 192>  amino lower aminothiazolylalkanoyl having an imino lower carboxycycloalkoxy group; or lower aralkyl amino lower aminothiazolylalkanoyl having a lower alkoxy group carbonylcycloalco- xy lower imino; and 9 R is a group of formula:    EMI192.1    EMI192.2  or is a lower alkyl group, lower aminoalkyl or R is a lower group, lower amlfioa¯Ky, lower hydroxyalkyl, lower carboxyalkyl, lower dialkyl lower aminoalkyl, lower morpholinoalkyl, lower alkyl piperazinyl lower alkyl, lower alkyl piperazinylcarbonylalkyl  EMI192.3  laughing or lower formimidoylaminoalkyl; X is CH or N; Z is halogen, and Y is CH or N and B is 0; or (f) 2 Y is N -R and n is 1, or a group of formula A-N (R), or R is a lower alkyl group and A is a lower alkylene group.  3 - Syn isomer of a compound of claim 2, characterized in that R1 is the group 2-metho-  EMI192.4  xyimino-2- (2-aminothiazol-4-y]) ketair) ido, 2-ethoxyiminoz 2- (2-aminothiazol-4-yl) acet'3Lmido, 2-carboxynethoxyimino- 2- (2-aminothiazol-4-yl ) acetamid, 2-allyloxyimino-2- (2 aminothiazol-4-yl) acetamido, 2- (2-propynyloxyimino) -2- (2-aminothiazol-4-yl) acetamido, 2-methoxyimino-2- (5 amino-l, 2, 4-thiadiazol-3-yl) acetamido, 2-ethoxyiminc- 2- (5-amino-1,2,4, thiadiazol-3-yl) acetamido, or 2-allylo-  <Desc / Clms Page number 193>    EMI193.1  xyimino-2- (5-amino-1,2,4-thìadiazol-3-yl) acetamido and 9 R is a group having the formula:    EMI193.2    EMI193.3  1 where R ″ is methyl, ethyl, 3-aminopropyl, 2-aminoethyl, 3-N, N-dimethylaminopropyl or 2-, N-- dimethylaminoethyl and Y is CE or J and n is 0.4 7 Compound according to claim 2, character-  EMI193.4  laughed at in that it is selected from the group consisting of the trifluoroacetic acid salt of 7-amino-3- [2- (1-methyl-3-pyridinio) thivinylj-3-ce-phem-4-carboxylate ( cis isomer or trans isomer) or its iodhydrate and the trifluoroacetic acid salt of 7-amino-3- [2- (1-methyl-2pyridinio) thiovinyl] -3-cephem-4-carboxylate (cis isomer, trans isomer ) or its iodhydrate.  5-Compound according to claim 3, caracos-- risé in that it is chosen from the group consisting of: 7- [. -ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) - acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-cephem-4-carboxylate (syn isomer) (cis isomer or trans isomer);  EMI193.5  7- [2-allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) thiovinyl] -3-- cephem-4-carboxylate (syn isomer) (cis isomer or trans isomer), of 7- [2-allyloxyimino2- (5-amino-1, 2, 4-thiadiazol-3-yl)  EMI193.6  acetamid-3 2- [1- (3-aminopropyl) -3-pyridinio] -thiovinyl} -3-cephem-4-carboxylate (syn isomer) (cis isomer or trans isomer) or its hydrochloride;  7- [2-allyloxyimino-2- (5-amino-1,2,4,4-thiadiazol-3-yl)  <Desc / Clms Page number 194>    EMI194.1  acetamido] -3- {2- [1- (3, N, N-dimethylaminopropyl) -3pyridìnio] thìovinyl} -3-cephem-4carboxylate (syn isomer) (cis isomer or trans isomer) or hydrochloride, 7- [2 -ethoxyimino-2- (5-amino-1, 2, 4-thiadiazol-3-yl) acetamido] -3- {2- [1- (3-aminopropyl) -3-? yridinio] thiovinylJ-3-cephem-4-carboxylate (syn-isomer) (cis-isomer or trans-isomer) or its hydrochloride, of 7- [2-ethoxyimio-2- (S-amno-1,2,4-thiadiazol-3 -yl) acetamidoj-3- {2- [l- (3-N, N-dimethylaminopropyl) -3-pyridinio] thiovinylJ-3-cephern-4-carboxylate (syn isomer) (cis isomer or trans isomer) or its hydrochloride , 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] - 3- {2- [1- (3-aminopropyl) -3-pyridinio] thiovinyl} -3-cephem- 4-carboxylate (syn isomer) (cis isomer or trans isomer) or its hydrochloride and 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido ] - 3- {2- [1- (3-LN-dimethyl71aminopropyl) -3-? yridinio] thiovinyl} -3-cephem-4carboxylae (syn isomer) (cis isomer or trans isomer) or its hydrochloride, 6 - Process for the preparation of new cephem compounds having the formula:  EMI194.2    EMI194.3  or.  R is the amino or acylamino group; and q R is a group of formula:  EMI194.4    <Desc / Clms Page number 195>    EMI195.1  2 where R is an organic group, X is CH or N, Z is an acid residue y is CH or N and n is 0; or Y is N '- R whereRR is as defined above and n is 1, or a group of formula:  EMI195.2  G la - AN (R or R is a lower alkyl group and A is a lower alkylene group, or its pharmaceutically acceptable salts. Character. If - this consists in that it consists in subjecting a compound having the formula:  EMI195.3    9 or R is as defined above, or its reactive derivative on the amino group, or its salt, in an acylation reaction, to give a compound having the formula:    EMI195.4    EMI195.5  on R is as defined: above and Ra is an acylamino group, or its salt.    7 - Process for preparing a cephem compound as indicated in claim 6 or their pharmaceutically acceptable salts, characterized in that  <Desc / Clms Page number 196>  that it consists in submitting a compound having the formula:  EMI196.1  where R is as defined in claim 6, R is a protected carboxy group, and R is a group of formula:  EMI196.2  2  EMI196.3  'cini. where R2! X, Z, Y and n are each as defined. in claim 6, or a group of formula; 1O-A-N # (R1O) 3.Z # or A, R and Z are each as defined in claim 6, or its salt, in a reaction to remove the protecting group from the carboxy group to give  EMI196.4  a compound of formula:    EMI196.5    EMI196.6  1 9 or R and R are each as defined in the res  <Desc / Clms Page number 197>  dication 6 or its salt.  8 - Process for preparing a cephem compound or their pharmaceutically acceptable salts, characterized in that it consists in subjecting a compound having the formula:  EMI197.1    EMI197.2  where R "is as defined in claim 6, and 12 R is a group of formula:  EMI197.3  where X is as defined in claim 6, and Ya is CH or N, or a group of formula:  EMI197.4  10 - A-N (R where A and R are each as defined in claim 6, or its salt, in a reaction for the preparation of a quaternary ammonium salt, to give a compound of  EMI197.5  formula :  EMI197.6    EMI197.7  1 9 or R and R are each as defined in claim 6 or its salt.  <Desc / Clms Page number 198>    9-A process for preparing a cephem compound having the formula as indicated in claim 6 or their pharmaceutically acceptable salts, characterized in that it consists in subjecting a compound having the formula:  EMI198.1    EMI198.2  9 1 or 9 is defined in claim 6 and R is where R is come eni ans a reven lcaLlon eL'b eSL an acylamino group having a protected amino group, or its salt, to a protective group elimination reaction  EMI198.3  from the amino group, to give a compound having the formula;  EMI198.4    EMI198.5  9 1 or R is as defined in claim 6, and R is c an acylamino group having an amino group, or its salt.    10-Process for preparing a cephem compound having the formula indicated in claim 6, and their pharmaceutically acceptable salts, characterized in that it consists in reacting a compound having the formula:  <Desc / Clms Page number 199>    EMI199.1    EMI199.2  g where 8. is as defined in claim 6, and Rd1 is an acylamino group having a lower pyridylalkoxy group imino or its salt, with an alkyla-  EMI199.3  tion to give a compound having the formula:    EMI199.4    EMI199.5  9 1 where R is retort defined in claim 6 and Re is an acylamino group having a lower alkyl group pyridinio lower alkoxy imino, or its salt. il-Process for the preparation of cephem compound indicated in claim 6 or their pharmaceutically acceptable salts, characterized in that it consists in subjecting a compound having the formula:  EMI199.6    <Desc / Clms Page number 200>    9 where R is as defined in claim 6 and  EMI200.1  l Rf is an acylamino group having a carboxy group protected lower alkoxy imino, a carboxy group protected il, lower alkenyl oxyimino or a carboxy group protected cycloalkoxy lower imino or its salt a reaction 1 of elimination of the group protecting the carboxy group, tIZ to give a compound having the formula:    EMI200.2    9 1 where R is as defined in claim 6 and R  EMI200.3  g is an acylamino group having a lower imino carboxy alkoxy group, a lower alkenyl carboxy oxyimino group or a lower cycloalkoxy carboxy group or its salt.  12 - Process for preparing a cephem compound having the formula indicated in claim 6 or their pharmaceutically acceptable salts, characterized in that it consists in reacting a compound of formula  EMI200.4    EMI200.5  whereR is as defined in claim 6, or its ion salt 6, or its s. l  <Desc / Clms Page number 201>  with a compound of formula: Ho-rill where R11 is as defined in claim 7 or its salt, to give a compound of formula:  EMI201.1    EMI201.2  1 9 where R tR are each as defined in claim 6 or its salt.    13-A process for preparing a cephem compound having the formula indicated in claim 6 or their pharmaceutically acceptable salts, characterized in that it consists in reacting a compound having the  EMI201.3  formula : . Cor-rr., Ul-e:  EMI201.4    EMI201.5  1 where 1 is as defined in claim 6 and R 'is a group which may be substituted by a group of formula; 9 9 - S-R or R is as defined in claim 6, or its salt with a compound of formula: Ho-rill 11 where R is as defined in claim 7 or its salt, to give a compound of formula:  <Desc / Clms Page number 202>    EMI202.1    EMI202.2  1 9 or R and R are each as defined in claim 6 or its salt.   14 - Pharmaceutical composition characterized in that it comprises an effective amount of a compound of claim 1 or its pharmaceutically acceptable salt in association with a pharmaceutically acceptable carrier or etc-li pient, substantially non-toxic. process for producing a pharmaceutical composition, characterized in that it consists in mixing a compound of claim 1 or its salt  EMI202.3  pharmaceutically acceptable as an active ingredient with an inert carrier. 16. Use of the compound of claim 1 or of its pharmaceutically acceptable salt, characterized in that these compounds are used for the treatment of infectious diseases in humans and animals.  17-As a new industrial product, composed of formula:  EMI202.4    <Desc / Clms Page number 203>    EMI203.1  where R is the amino group or an acylamino group; R3 is a carboxy protecting group and R is a group of formula:  EMI203.2    EMI203.3  2 where R is an organic group, X is CH or H Z is an acid residue,  EMI203.4  Y is CH or and n is 0; or, F) Y is defined as above and Y is NR where R es n is 1, or a group of formula: -AN # (R1O) 3 where R is a lower alkyl group and A is a lower alkylene group and its salt, 18-Process for the preparation of a cephem compound having the formula:  EMI203.5  or R1 is the amino group or an acylamino group;    R is a carboxy protecting group, and R is a group of formula:  <Desc / Clms Page number 204>    EMI204.1    EMI204.2  2 or R is an organic group, X is CH or N Z is an acid residue, Y is CH or N and n is O; or Y is K -R where R is as defined above and ny is-R is 1, or a group oe formula: - AN (R), ù, R is a lower alkyl group, and A is a lower alkylene group , or its salt, characterized in that it consists in subjecting a compound having the formula:  EMI204.3    EMI204.4  where R and R are as defined above and 1 R is a group of formula:  EMI204.5    EMI204.6  where X is as defined above and Ya is CH or N, or a group of formula:  10 - A-N (R)  <Desc / Clms Page number 205>  where A and R are each as defined above, or its salt, to a reaction for preparing a quaternary ammonium salt, to give a compound of formula:  EMI205.1    EMI205.2  - l 3 II t h'f "'or R 1 R and R are each as defined above, or its salt.  19-Process for the preparation of a cephem compound having the formula indicated in claim 18 or of its salt, characterized in that it consists in reacting a compound having the formula:  EMI205.3    EMI205.4  RI t R3 t h d, "f" "d l. Where à and R are each as defined in claim 18 or its salt, with a compound of formula: HS-R or R11 is as defined in claim 18, or its salt, to give a compound of formula:  EMI205.5    <Desc / Clms Page number 206>    EMI206.1  where R, RetR are each c. as defined in reOÙ R R e-t R sonl .-- vendication 18, or its salt.  20 - Process for the preparation of a cephem compound indicated in claim 18, or its salt  EMI206.2  characterized in that it consists in reacting a compound having the formula;  EMI206.3    EMI206.4  uRet are each con defined in the claim. 1 is 18, and R is a group which may be substituted by b a group of formula: il -S-R where R is as defined in claim 18, or its salt with a compound of formula:  HS - Rll ùR is as defined in claim 18, or its salt, to give a compound of formula:  EMI206.5    1 3 11 where R, R and R are each as defined in claim 18, or its salt, 21 - Process for the preparation of cepher compound. indicated in claim 18, or their  <Desc / Clms Page number 207>  salts characterized in that it consists in subjecting a compound having the formula:  EMI207.1    1 3 1 1 where R, R @ and R @ are each as defined in the re-  EMI207.2  vendication 18, or its salt, to a reduction reaction, v to give a compound of formula:  EMI207.3    EMI207.4  1-3 il or R, R and R are each as defined in claim 18, or its salt.