DE2905656A1 - 3,7-DISUBSTITUTED-3-CEPHEM-4CARBONIC ACID COMPOUNDS, PROCEDURE FOR THEIR MANUFACTURING AND PHARMACEUTICAL PRODUCTS CONTAINING THEM - Google Patents

Description

T-51765

3,7-di & substituted-3-cephem-4-carboxylic acid compounds, Process for their preparation and pharmaceutical compositions containing them

The invention relates to new 3,7-disubstituted- "3-Cephcm ~ 4- carboxylic acid compounds and their salts, in particular their pharmaceuticals compatible salts, it relates specifically to new 3,7-disubstituted ~ 3 ~ cephem-4-carboxylic acid compounds and their Salts, especially their pharmaceutically acceptable salts, which have antibacterial activities, processes for their preparation and pharmaceutical agents containing them and their therapeutic use for the treatment of infectious diseases in humans and animals.

It is an object of the invention to provide new 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and salts, in particular pharmaceutically acceptable salts thereof, to indicate the opposite a number of pathogenic bacteria have a high level of activity (effectiveness). The aim of the invention is also to provide methods for the preparation of the S ^ -disubstituted-S-cephem - ^ - carboxylic acid compounds and their salts, in particular their pharmaceutically acceptable salts. The aim of the invention is also

909834/0751

ORIGINAL XSP ¹ ECTED

indicate pharmaceutical agents that are used as active ingredients (active Component) at least one of the 3,7 ~ disubstituted-3 ~ Cephcni-4-carboxylic acid compounds and / or pharmaceutically acceptable salts thereof. Finally, the aim of the invention is Use of the compounds mentioned for the treatment of those caused by pathogenic bacteria in humans and animals Infectious diseases.

The 3,7-disubstituted-3-cephem-4 "carboxylic acid compounds which are an object of the invention are new and they can be represented by the general formula:

where mean:

R amino or protected amino,

R carboxy or protected carboxy,

2 4

R isobutyl and R acetoxy or

R cyclo (lower; alkyl or lower alkynyl and R lower

Alkanoyloxy or
R is lower alkyl and R (C, _{-C A} ) alkanoyloxy or

Λ DO

R (C_-C,) alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R hydrogen, carbamoyloxy, thiadiazolylthio, which may have a lower alky ^ or triazolylthio or

R (C2 ~ C,) alkyl, cyclo (lower) alkyl or lower alkynyl and R tetrazolylthio with a methyl or

909834/0751

ORiGiNAL Ihil

λ,

i '' J UD b h 6

R lower; Alkyl, lower alkenyl, cyclo (lower) alkyl or

4th
Lower alkynyl and R aroyloxy, which can have nitro or amino, cyclo (lower) aJkancarbonyloxy, carbanoyloxy with an aryl which can be substituted by ifalogen, ar (nicdrig) -alknoyloxy, aryloxy (lower) alkanoyloxy with loweryl alkoxy, thcnooyloxy , Teirazolyltliio with a (C - C.) Alkyl or ßenzotliiazolyltliio.

The compounds of the formula (i) which have been found according to the invention New connections can be established as described below Process I to IV are prepared.

Procedure 1

(ID

or a reactive derivative on the amino group or a salt of it

S N

k ²

or a reactive derivative on the
Carboxy group or a
Salt from it

or a salt thereof

Procedure 2

OR

Elimination of the amino protection group _ ■

or a salt thereof 909834/0751 ORIGINAL INSPECTED

~ -. "21. 0 5 6

C-CONH-20

or a salt thereof

Procedure 3

K ¹ - /! - - \ C-CONH- ₁ -

^ s ^ HJ>! J ~ cii -R ⁴

V - ' ^ i 2 Elimination of the carboxy protective

OR ²

de)

Jt I'Λ- ^ "4

N ^ - N -

^0R 'COOII

or a salt of it

Procedure 4

N  J- Nv ^ - CHrR ^4a reduction

^ ^2a0 T ²

or a salt thereof

909834/0751 OWGLAL INSPECTED

-S-

CH ₂ -R ^4b

or a salt thereof

wherein R, R, R and R each have the meanings given above

to have,

R protected amino,

R protected carboxy,

R lower alkyl, lower alkenyl, cyclo (lower) alkyl or

lower alkynyl,

4a
R aroyloxy with one or more nitro groups and

4b
R is aroyloxy with one or more amino groups.

Among the starting compounds are some of the compounds (III) new, and they can be made by processes supported by the

the following reaction schemes are shown: (1)

CH ₃ -CO-CZ> CH ₃ -CO-JZ

i \ 2

OH QR Halo gen ation ^

' P

(IV) (V)

V-CH ₂ CO-CZ _i> H ₂ NO N

N OR

* 2
OR ^

(VI) (VII)

909834/0751

% / \ i: JD b:> 6

N-TT-C-COOH N-v-C-COOH

^s έκ ² ' ^s k ²

Amino-detergent (Ilia) (IIIa ')

IrO-NH _{2 N}

cocoon ^ L ^R H>

or exn salt oavon

_{2 N}

· C ι · SN exn salt oavon ^ ^

(VIII) ("D

where R, R and R each have the meanings given above, Z is protected carboxy and
Y signify halogen.

Some of the other starting compounds (II) are also new and can be manufactured using processes that are explained below:

^CS 2

(X)

or a salt thereof

909834/0751

INSPECTED

X-N

CAL "Ν !! CS-SR '1.5

- ^; "j" j 5 p

(X] I) ^C 6 ^H 13

or a So3 ζ of it

η, Ki — r ^ i κ ^ - ^CH ? - ^R 1

.3 N-N

(XiV) CXV)

the one SnI / - of it or a salt thereof

»2 ^K

R '

or a salt thereof

la / ο

N ^ -CH ₂ OH R ³

1-CH ₂ OR

(XVI)

909834/0751

ORIGINAL INSPECTED

,.: i Ο

R - S ^s ^ Il I

Oxidation - *, ν ' /} πι κ

0 ϊ ^l

reduction

(XVIII)

CII ₂ -O-U '

Elimination of amino protecting group

IJ.N ^ -

J-CH ₇ -O- ^ c

(XIX)

1 O

wherein R and R each have the meanings given above,

Y ¹ a Sciurarest,
5
R lower alkyl,

X is an alkali metal

R is a group which can be substituted by a group of the formula

N-N

_n >

R ⁷ (C -C) alkyl and

4c
R is carbamoyl with an aryl which can be substituted by halogen, aryloxy (lower) alkanoyl with lower alkoxy, thenoyl, cyclo (lower) alkanecarbonyl or aroyl with nitro.

With regard to the compounds according to the invention of the formulas (i), (Ib), (Id) and (If) and the starting compounds of the formulas (Ia), (Ic), (Ie), (ill), (purple), (purple ¹ ) , (VIl) and (VIII), these compounds according to the invention and these starting compounds

909834/0751 ORIGINAL INSPECTED

also include a'ic tautoir.ercn isor.eren with regard to their thiazole groups. Dae knows if the group of the formula j, ~ Λ

(in which R has the meanings given above) in the formula of these inventive compounds and these starting compounds the formula (A) N given below

I ».

v / orin R has the meanings given above), this can Group of formula,

alternatively also by their tautomeric formula (B) .. / * \ T

(where R is imino or protected imino) will. That is, both group (A) and group (ß) lie in the state of equilibrium as so-called tautor.iore forms which can be represented by the following reaction equilibrium:

(where R and R each have the meanings given above).

These types of tautomerism between 2 ~ aminothiazole compounds and 2-Iminothiazoline compounds, as noted above, are disclosed in US Pat Literature is known per se and it is for those skilled in the art on this Area readily apparent that both tautomeric isomers exist in equilibrium with one another and are easily reciprocated are convertible into each other and it is therefore a matter of course

909834/0751

ORIGINAL INSPECTED

VO -

that these Ic, orv: rcn also fall into the same category of connection. Both automatic forms of the compounds according to the invention and the output compounds are clearly dated within the scope of the present invention. For Ver be a fpchuny liier compounds of the invention and the Au, .gnrmrvoj bindunrcn which comprise the group of these toutonieren isomers represented by using only one of the two prints Dafur, ie the foriiol u>

For the orfindunr ^ gerriäßon compounds (i), (Ib), (ld) and (Ii) and the Au;, rjoncj & verbinc. ^! ungen (lc), (lc), (le), (ill), (lilac), (lilac ¹ ) and (1V) biü (VI ) also applies that these inventive connections to and these external connections also the syn- Ir. (> I: "! Crc _/ anti-isoiners and a mixture thereof encompass. So katiii at tpi elsweir.c in the inventive compound (i) the syn-Icowcre dargnoi-cllt are due to the partial structure of the formula

in their molecule, while the corresponding anti-isomer by the

Partial structure. Formula, ,, \\

Rl- H- W- C-CCs

R ² ON can be represented in its molecule, and when it is expedient for the explanation of the invention, also ίο bring both the syn-isomers and anti isomer by a general formula expressed, so this is represented by the partial structure ocr formula vi. .

, 2

909834/0751 ORIGINAL INSPECTED

-M- ".

JO b " J

With regard to the other above-mentioned inventive compounds and starting compounds, the syn isomer and the dos anti isomer can also refer to the same geometric isomers have been obtained, v / i e they have been explained for the compound (l) are.

Suitable salts, in particular pharmaceutically acceptable salts, which he finciungcyctiicßen 3,7-disubstituted-3-Cepheti! "4 - = - carboxylic acid compounds (j) are conventional salts, especially conventional non-toxic salts, and may include inorganic salts such as metal salts, for example alkali metal salts (such as sodium, "Kaliuinsalz and the like") νηό alkaline earth metal salts (such as CaJciuti ", magnesium salt and the like.), ammonium salts and the like., organic salts, e.g., B. organic amine salts (such as triethylamine, triethylamine, ethanolamine, diethanolamine *, pyridine, picoline, dicyclohexylarcin *,! '«!, N'-dibenzylethylenediamine salt and the like) and the like, organic acid salts (e.g. acetate , Maleate, Tartrate, Kothansulfonot, Dsnzenesulfonat, Toluenesulfonat and the like.), Inorganic acid salts (eg. and the like

In the preceding and following description of the invention Suitable examples and illustrations of the various definitions which the present invention comprises are as follows:

The term “lower” or “lower” stands, unless otherwise indicated, for radicals or groups which have 1 to 6 carbon atoms contain.

90983A / 0751

ORIGINAL INSPECTED

,: . '■' ¹ JD ύ ϋ <3

The term "(C -C,)" means that the following group a b

α to b contains carbon atoms, for example, '(C ₂ -C,) alkyl "means alkyl of 2 to 6 carbon atoms. Suitable protected amino can include an acylamino and amino group which is substituted by a conventional protecting group other than the acyl group, such as ar (lower) alkyl (such as benzyl, trityl and the like.) and the like.

A suitable protected imino may include an acylitnino- and imino group substituted with another conventional one Protecting group as the acyl group, v / ie e.g. ar (lower) alkyl (such as benzyl, trityl, etc.) and the like.

A suitable acyl radical in the terms "acylamino", "acylirnino" and "acyloxy" may include carbamoyl, an aliphatic acyl group, and an acyl group that is aromatic or heterocyclic Includes ring. Suitable examples of the acyl can be lower Alkanoyl (such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, hexanoyl and dg].); Cyclo (lower) alkanecarbonyl with 4 to 7 carbon atoms (e.g. cyclopropanecarbonyl, cyclohexanecarbonyl, and the like), preferably one having 6 to 7 carbon atoms; lower alkoxycarbonyl with 2 to 7 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, I-cyclopropylethoxycarbonyl, Isopropoxycarbonyl, butoxycarbonyl, t-ßutoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl and the like); lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, Isopropanesulfonyl, butanesulfonyl and the like); Arenesulfonyl (e.g. benzenesulfonyl, tosyl, and the like); Aroyl (e.g. benzoyl, toluoyl, Naphthoyl, phthaloyl, indanecarbonyl and the like); Ar (lower) alkonoyl (e.g., phenylacetyl, pfienylpropionyl, and the like);

909834/0751 INSPECTED

Ar (lower) alkoxycarbonyl (e.g. ßenzyloxycarbonyl, phenethyloxycarbonyl and the like); Aryloxy (lower) alkanoyl (e.g. phenoxyacetyl, Phenoxypropionyl, phenoxyhexanoyl and the like); heterocyclic Carbonyl (e.g. thenoyl, furoyl, nicotinoyl, and the like); and the like

The acyl radical raised above can have 1 to 3 suitable substituents such as halogen (such as chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, aliino, lower alkoxy (such as methoxy, ethoxy, Propoxy, isopropoxy and the like), preferably one with 1 up to 2 carbon atoms, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, and the like), lower alkenyl (e.g. Vinyl, allyl and the like), aryl (e.g. phenyl, tolyl and the like), which may be substituted by halogen, or the like.

Preferred examples of acyl having one or more of these substituents can be halogen (lower) alkanoyl (especially trihalogen (lower) alkanoyl), N-aryl- or N-halogen-substituted Arylcarbamoyl, aryloxy (lower) alkanoyl with lower alkoxy or aroyl with nitro or amino.

Preferred examples of acylamino can be lower alkanoylamino, Ar (lower) alkanoylamino (especially phenyl (lower) alkanoylamino) or halogen (lower) alkanoylamino (especially trihalogen (lower) alkanoylamino).

Suitable protected carboxy may include an esterified carboxy in which the ester residue is, for example, one of the following esters can be: lower alkyl ester (such as methyl, ethyl, propyl · · ^ Isopropyl, butyl, isobutyl, t-butyl, pentyl, t-pentyl, Hexyl, 1-Cyclopropyläthylester and the like.), Wherein the lower

909834/0751

ORIGINAL / NSPECTED

-H-

Alkyl radical preferably one with 1 to 4 carbon atoms can be; a lower alkenyl ester (like vinyl ester, allyl ester and the like); a lower alkynyl ester (such as ethynyl, propynyl ester and the like); a mono (oc! er di- or tri) halogen (lower) alkyl ester (v / ie 2 ~ iodoethyl, 2,2,2-trichloroethyl ester and the like.); a lower one Alkenoyloxy (lower) alkyl esters (such as acetoxymethyl, propionyloxymethyl, Butyryloxymethyl], valeryloxymethyl, pivaloyloxymethyl, Haxanoyloxyethyl, 2 - / \ cetoxyethyl, 2-propionyloxyethyl, and like); a lower alkanesulfonyl (lower) ulkylester (v / ie hecylmetltyl-, 2-! 1esy] ethyleeter and the like); an Ar (low) cl!: ylestsr, e.g. a mono- or di- or triphosnyl (niGch: ig) alkyl ester, of which one or can have several suitable substituents (e.g. a benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, benzhydryl, Bis (roothoxyphenyl) methyl, 3,4-dimethoxybenzyl, 4-llydroxy-3, 5-di-tert-butylbenzyl ecter and the like); an aryl ester, which may have one or more suitable substituents (such as a Phenyl, tolyi, tert-butylphsnyl, xylyl, mesityl, curnenyl esters and the like.) and the like.

Preferred examples of protected carboxy may be lower alkoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycorbonyl and the like) having 2 to 7 carbon atoms, preferably those having 2 to 5 carbon atoms; lower alkanoyloxy (lower) alkoxycarbonyl having 3 to 13 carbon atoms (such as acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, hexanoyloxymethoxycGibonyl and the like), preferably one having 6 to 8 carbon atoms; or Ar (lower) alkoxycarbonyl with 8 to 20 carbon atoms (such as benzyloxycarbonyl, phenäthyloxycarbonyl,

909834/0751

ORIGINAL INSPECTED

j b b b

Benzhydry.loxycarboriyl, trityloxycarbonyl and the like *), preferably one with 12 to 14 carbon atoms.

A suitable cyclo (low) ci.l! Cyl is one with 3 to Carbon atoms and it can unfosscn cyclopropyl, cyclobuty.t, Cyclopeniyl, cyclohexyl and o'nl., And preferably one with 5 to 6 carbon atoms,

A suitable lower alkynyl is one with 2 to 6 Carbon atoms and it may include ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3-moxynyl and the like]., And preferably one with 2 to 4 carbon atoms, in particular one those with 2 to 3 carbon atoms.

A suitable lower alkanoyloxy is one with a lower alkanoyl group as mentioned above, and it may include for example formyloxy, acetoxy, propionyloxy, üutyryloxy, Isobutyryloxy, valeryloxy, succinyloxy, pivaloyloxy, hexanoyloxy and the like, preferably one having 2 to 6 carbon atoms.

Suitable lower alkyl may include one that may be branched, such as methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.

Suitable lower alkenyl is one having 2 to 6 carbon atoms and it may include, for example, vinyl, AjLIyI, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl and the like., and preferably one having 2 to 4 carbon atoms.

909834/0751

- γ ν / -

2005656

Suitable tliadiazolylthio may include, for example 1,2,4 - thiadiazolylthio, 1,3,4-thiadiazolylthio, 1,2,5 ~ thiadiazolyl ~ thio and the like. This thiadiazolylthio group may be a lower alkyl group as mentioned above.

Suitable triazolylthio may include, for example, 4H-1,2,4-triazo.lyltliio, 1 H-1,2,3-triazolylthio, 211-1,2,3-triazolylthio and like

Suitable tetrazoy.lthio may include 1H-tetrazolylthio or 2H-tetrazolylthio.

A suitable aroyloxy can include, for example, benzoyloxy, Toluoyloxy, naphthoyloxy, phthaloyloxy, indancarbony.loxy and the like, which can have 1 to 3 nitro groups or amino groups.

A suitable cyclo (low) alkonecarbony.! Oxy is one with 4 to 7 carbon atoms and it can include, for example, cyclopropanecarbonyloxy, Cyclohexanecarbonyloxy and the like, preferably one having 6 to 7 carbon atoms.

Suitable aryl which is the substituent of carbamoyloxy may include phenyl, tolyl, and the like, denoted by 1 to 3 halogen atoms (e.g. chlorine, bromine and the like) can be substituted.

Suitable ar (lower) alkanoyloxy may preferably be phenyl (lower) alkanoyloxy and it may include phenylacetoxy, Phenylpropionyloxy and the like.

Suitable aryloxy (lower) alkanoyloxy may preferably be

909834/0751

ORIGINAL INSPECTED

- 17 -

/ .j ο υ b S

Phenoxy (lower) alkanoy] oxy and it may include phenoxyacetoxy, Phinoxypropionyloxy, phenoxyhexanoyloxy and the like, 1 to 3 lower alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy and the like), preferably one having 1 to 3 carbon atoms.

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

Suitable acid residue may include the above-mentioned halogen, lower alkanesulfonyloxy (e.g., mesyloxy, athenesulfonyloxy, and the like), arenesulfonyloxy (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, and the like), and the like.

Suitable alkali metal may include sodium, potassium, and the like.

A suitable group which may be substituted by a group of Formula Ν — Ν

-S-J ^

■ "ί

may include azido, the above halogen, acyloxy (preferably lower alkanoyloxy) and the like.

A suitable carbamoyl with an aryl which may be substituted by halogen, aryloxy (lower) alkanoyl with lower alkoxy, cyclo (lower) alkanecarbonyl and aroyl with nitro can such as exemplified above for acyl.

Among the appropriate examples for each of the groups of the invention sgomäßei

909834/0751

ORIGINAL INSPECTED

- 16 -

', η. J O Ü D

Connections as explained and explained above, the preferred Boispic.le are the following:

The preferred expression for R can be; UUO the preferred example of R may be carboxy or ar (nicdrig) aJ.koxycarbonyl (especially Dipbenyl (lower) alkoxycarbonyl) can.

The processes for making the compounds of the invention are explained in more detail below.

Ver go n 1

The invention compound (i) or a salt thereof can be produced are by reacting the compound (il) or one reaction: .capable derivative at the amino group or a salt thereof with the compound (III) or a reactive derivative of the carboxy group or a salt thereof.

Suitable reactive Deri vest at the amino group of the compound (II) may be an imino isomer Schiff's base type or its isomer, tautomeric enamine type _f is prepared by reacting the compound (Il) with a carbonyl compound such as acetoacetic acid or like; a silyl derivative prepared by reacting the compound (II) with a silyl compound such as trimethylsilylacetamide, bis (trimethylsilyl) acetanide or the like; a derivative is prepared which comprises by reacting the compound (Il) with phosphorus trichloride or phosphine and the like, _v.

909834/0751 ORIGINAL INSPECTED

A suitable salt of the compounds (II) and (III) may include an acid addition salt, such as an organic acid salt (v / ie an acetate, maleate, tartrate, benzene sulfonate, toluene sulfonate and the like) / or an inorganic acid salt (such as a hydrochloride, Hydrobroüiid, sulfate, phosphate and the like.); a metal salt (e.g. a sodium, potassium, calcium, magnesium sulphate and the like); a Ammonium salt; an organic amine salt (e.g. a triethylamine, Dicyclohxylominsalz and the like.) And the like.

A suitable reactive derivative on the carboxy group of Compound (ill) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. The appropriate one Example can be an acid chloride, an acid azide; a mixed one Acid anhydride with an acid such as substituted phosphoric acid (such as dialkylphosphoric acid, phenylphosphoric acid, diphenyl * = phosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid and the like), dialkylphosphorous acid, sulphurous acid, thio * sulfuric acid, sulfuric acid, alkyl carbonic acid, an aliphatic Carboxylic acid (such as pivalic acid, PentGnsöuro, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid and the like) or an aromatic carboxylic acid (such as benzoic acid and the like); a symmetrical one Acid anhydride; an activated Ar.iid with imidazole, 4-substituted Imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g. a cyanomethyl, mothoxymethyl, Di met hyli rni η omethyl [(CI-L ^ N = CH -] -, vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, Mesylphenyl, phenylazophenyl, phenylthio, p-nitrophenylthio, p-cresylthio, carboxymethylthio, pyranyl, pyridyl, piperidyl, 8-quinolyl thioester and the like) or an ester with an N-hydroxy

909834/0751
ORIGINAL INSPECTED

- 20 -

l _iA 2005656

compound (such as N, N-dimethylhydroxy] amine, 1-hydroxy-2- (iH) pyridcn, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H ~ benzotriazole and the like) and the like. These reactive derivatives can depending on the type of compound used (III) can be selected at will.

The reaction is usually carried out in a conventional solvent, for example in water, acetone, dioxane, acetonitrile, chloroform, methylone chloride, ethylene chloride, tetrahydrofuran, Ethyl acetate, Ν, Ν-DiiTiethylforniamid, pyridine or any other organic solvent which does not adversely affect the reaction. These conventional solvents can also used in Fon ;, a mixture thereof.

When the compound (III) is used in the reaction in the form of the free acid or in the form of its salt, the reaction is preferably carried out in the presence of a conventional condensing agent such as N ^ N'-dicycloliexylcarbodiimide, N-cyclohexyl-N ¹ -morpholinoäthylcarbodiir: iid , N-Cyclohexyl-N '- (4-diethylaniinocyclohexyl) carbodiimide, Ν, Ν'-diethylcarbodiimide, Ν, Ν'-diisopropylcarbodiimide, N-ethyl-N' - (S-dimethyluminopropyl-carbodiimide, N, N-carbonylimidazole-2 ), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, Äthoxyacetylen, l-alkoxy-1-chloroethylene, trialkyl phosphite, Äthylpolyphosphat, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, Triρhen y! phosphine, 2-ethyl-7-hydroxybenzisoxazolium , the intramolecular 2-ethyl-5- (n-sulfophenyl) isoxazolium hydroxide salt, 1- (p-chlorobenzenesulfonyloxy) -o-chloro-1H-benzotriazole, the so-called Vilsmoier reagent, which is produced by reaction

909834/0751

ORIGINAL INSPECTED

. 6? · ^N bb5ö

of dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride and the like., Or the like. Performed.

The reaction can also be carried out in the presence of an inorganic or organic base, such as, for example, an alkali metal bicarbonate, a tri (lower) alkylamine, pyridine, N- (Nicdrig) alkylmorpholine, N, K'-di (lower) alkylbenzylamine or the like _; be performed. The reaction temperature is not critical and the reaction is usually carried out with cooling or at ambient temperature.

In the reaction according to the invention, a syn ison> eres can Invention compound (i) are preferably obtained by you implement the compound (il) with the appropriate syn isomers of the starting compound (Hl), for example in Presence of a Vilsnieier Reagon as mentioned above and below approximately neutral conditions.

procedure 7th

The compound (ib) according to the invention or a salt thereof can can be prepared by subjecting the compound (Ia) or a salt thereof to a reaction for eliminating the amino protective group.

Suitable salt of the compound (Ia) may include a metal salt, an ammonium salt, an organic amine salt and the like mentioned above.

The elimination reaction of the present invention is applied

909834/0751

- 2h -

/ -. / ν ¹ '^ GS6

a conventional method, e.g. hydrolysis, Reduction, of a process in which one uses the compound (la), wherein the protecting group is an acyl group with an amino halogenating agent and then reacted with an imino etherification agent and 'if necessary, the compound obtained in this way from a hydrolysis subject, or the like. Performed.

The hydrolysis can be a process in which an acid or a base or hydrazine and the like is used.

These procedures may vary depending on the type of to be eliminated Schui ^ groups are selected.

Among these methods, hydrolysis carried out using an acid is one of the common and preferred methods for eliminating protective groups such as substituted or unsubstituted alkoxycarbonyl (such as t-pentyloxycarbonyl and the like), alkanoyl (such as Fcrmyl and the like). ), Cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (such as ßenzyloxyccrbonyl, substituted benzyloxycarbonyl and the like.) Or the like. A suitable acid may include an organic or an inorganic acid such as formic acid, trifluoroacetic acid, hydrochloric acid, hydrochloric acid, p-toluene ., and a preferred acid is, for example, formic acid, trifluoroacetic acid, hydrochloric acid and the like. The acid suitable for the reaction can be selected depending on the kind of the protecting group to be eliminated. When the elimination reaction is conducted with the acid, it can be carried out in the presence or absence of a solvent. Suitable solvents can be an organic solvent,

909834/0751
ORIGINAL INSPECTED

- 23 -

ObüSö

Water or a mixture thereof. When using trifluoroacetic acid the elimination reaction can preferentially / gently in the presence be carried out by anisole.

The hydrolysis, which is carried out using hydrazine, is usually used to eliminate a protecting group such as succinyl or phthaloyl.

When the hydrolysis is carried out with a base, it is preferred to eliminate an acyl group, for example of haloalkanoyl (such as trifluorocotyl and the like) and the like. Applied. Suitable bases include an inorganic base or an organic base. The hydrolysis, which is carried out using a base, is often carried out in water or in a hydrophilic organic solvent or a mixture thereof carried out.

Among the protecting groups, the acyl group can generally be obtained by hydrolysis as mentioned above or using another conventional hydrolysis can be eliminated. If the acyl group is halogen-substituted alkoxycarbonyl or 8-quinolyloxycarbonyl, it can be eliminated by graze Treatment with a heavy metal such as copper, zinc or the like.

Reductive elimination is generally used to eliminate a protecting group such as halo-alkoxycarbonyl (e.g. Trichlorothoxycarbonyl and the like.), Substituted or unsubstituted Aralkoxycarbonyl (e.g. benzyloxycarbonyl, substituted benzyloxycarbonyl, and the like), 2-pyridylmethoxycarbonyl, and the like.

909834/0751

ORIGINAL INSPECTED

- 24 -

A suitable reduction may include reduction, for example with an alkali metal borohydride (such as sodium borohydride and the like) and like

Under the protection group !! the acyl group can be eliminated by treatment with an irininohalogenating agent (e.g. Phosphroxychloride, phosphorus trichloride, phosphorus pentachloride and the like) and an imino cithering agent such as a lower one Alkanols (such as methanol, ethanol and the like.) What if necessary followed by hydrolysis. The reaction temperature is not critical and they can be zv / eckrcüßig depending on the type of Amino protecting group and the elimination process used, v / ie described above, can be selected and the reaction according to the invention is preferably carried out under mild conditions, for example carried out under cooling, at ambient temperature or at a slightly elevated temperature.

The present invention also includes the case that the protected Carboxy group under the reaction conditions in the course of the reaction or is converted into the free carboxy group in the aftertreatment.

Ed Ahren 3

The compound (Id) of the present invention or a salt thereof can be prepared by subjecting the compound (ic) to a reaction to eliminate the carboxy protective group.

The elimination reaction of the present invention is carried out using a

309834/0751

ORIGINAL INSPECTED

conventional process, for example by hydrolysis or Like., carried out. Hydrolysis can be a process act using an acid or a base and the like. These procedures may vary depending on the type of to be eliminated Protection groups can be selected.

The hydrolysis carried out using an acid is one of the most common and preferred methods of elimination of protecting groups such as ar (lower) alkyl [v / ie mono (or di ~ or tri) phenyl (lower) alkyl, substituted phenyl (lower) alkyl and The like], lower alkyl, substituted lower alkyl or the like. A suitable acid may, for example, be an inorganic one or organic acid, such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like. The reaction according to the invention can be carried out in the presence of anisole. The acid suitable for the reaction may vary depending be selected by the protecting group to be eliminated and other factors.

The hydrolysis carried out using an acid can be carried out in In the presence of a solvent, for example an organic solvent, water or a mixture thereof will. The reaction temperature is not critical and it can depend on the nature of the protecting group and the one used Elimination method is suitably selected and the reaction according to the invention is preferably carried out under mild Conditions carried out, for example, with cooling, at ambient temperature or with slight heating.

The present invention also includes the case that the protected

90983W0751

Amino group is converted into the free amino group during the reaction or aftertreatment in the process according to the invention.

Traverse en A-

The compound (if) or a salt thereof according to the invention can be prepared by subjecting the compound (Ie) or a salt thereof to reduction.

Suitable salt of the compound (Ie) may be one, as indicated above exemplifies the compound (Ia). The reduction of the present invention is carried out using a conventional method such as catolytic reduction or the like. Suitable catalysts may include plcitin (IV) oxide, palladium on charcoal, and the like. Suitable solvents may include an alcohol (such as methanol, ethanol, and the like), tetrahydrofuran, or any other solvent that does not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually carried out with cooling, at ambient temperature or with heating .

The processes for the preparation of the starting compound (lib) are explained in more detail below.

1.) The compound (XVIl) can be prepared by reacting the compound (XVl) with an acylating agent.

909834/0751

ORiGiNAL INSPECTED

- 27 -

2G05656

Suitable acylating agents may include a compound of the formula R -OH (XXl), in which R represents aryloxy (lower) alkanoyl, may have lower alkoxy, thenoyl, cyclo (ni edr j g) al!: anccirbanyl or aroyl with nitro, or a reactive one Derivative thereof, and a compound of the formula

R ⁸ -NrX = 0 (XXII)

wherein R is aryl which can be substituted by halogen.

Suitable reactive derivatives of the compound (XXI / include those as exemplified above for the compound (Hl) have been specified.

A suitable aryl for R can be phenyl, tolyl, xylyl, mesityl, Curienyl, naphthyl and c'gl., Where, the aryl group by 1 to 3 halogenatoriie (e.g. chlorine, bromine, iodine or fluorine) substituted can be.

The inventive reaction is carried out in a manner similar to that in Procedure 1 stated carried out.

In the formula of the compound (X \ / Il), the structure of the following formula means f *

a mixture of 3- and 2-cephern compounds.

2.) The compound (XVIIl) can be prepared by oxidizing the compound (XVIl).

Suitable oxidizing agents can include conventional ones

909834/0751

,.: J ο ο b

Oxidizing agents such as those used for the oxidation of sulfur atoms used in the first position of cephaloj.porin compounds be, such as a Persuure (such as perbenzoic acid, 3-Cli.lorperbenzoecüuro), V / oeec rstoffperoxid / sodium tungstate or dcjl.

The reaction according to the invention is usually carried out in a solvent such as ethyl acetate, tetrahydrofuran or any other solvent which does not adversely affect the reaction, carried out and ir, usually it is carried out under cooling or at ambient temperature.

3.) The connection (XIX) can be established by reducing the compound (XVIIl).

Suitable reducing agents can include conventional reducing agents such as those used for the reduction of S-oxide e.g. a phosphorus halide (such as phosphorus trichloride, Phosphorus tribromide and the like.) Or the like.

The reaction is preferably carried out in a solvent such as dimethyl * formamide or the like, and it is preferably carried out under cooling or at ambient temperature.

4.) The connection (lib) can be established by using the Subjecting compound (XIX) to a reaction to eliminate the amino protecting group.

The elimination reaction of the present invention is carried out in a similar manner carried out as indicated in method 2.

909834/0751

ORIGINAL INSPECTED

- 29 -

05656 Ml

In the above standardized reactions and / or in the follow-up treatment of the reactions according to the invention can include the tautomers mentioned Isomers occasionally converted into the other tautomeric isomers and this case is also within the scope of the present invention.

If the inventive compound (I) is in the form of the free acid is obtained in the · Ί position and / or when the invention Compound (l) has a free amino group, it can under Using a conventional procedure in a salt, preferably a pharmaceutically acceptable salt thereof as indicated above can be transferred.

The compound (i) according to the invention and its salts, in particular their pharmaceutically acceptable salts are all new compounds that have a high antibacterial activity (effectiveness) exhibit the growth of a wide variety of pathogenic microorganisms including gram positive and gram negative Inhibit or prevent bacteria and represent verbose antibacterial agents.

To demonstrate the usefulness or advantageous properties of the compound (i) according to the invention are below for some representative compounds according to the invention the data given in tests to determine the antibacterial in vitro activity were obtained.

909834/0751

ORIGINAL INSPECTED

-ae-

Testv or bi inventions

(1) 7- [2- (2-Propi.nyloxj ^r ird.no) ~ 2 "(2-arainothiasol ~ -'i-yl) - acetamido] cephalosporan acid (syn-I somer _e s).

(2) 7- [2- (2-propinyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] - 3-carbamoyloxymethyl • 3-cephem-4-cai'bo nsöure (syn-I soine res).

(3) 7- [2- (2-propynyloxyimiiio) -2- (2-aminoth.ia7.ol-4-yl) acetamido] -3- (IH-1, 2,3-triazol-5-yl ) thiomethyl-3-cep] iCia-4 "carbonic acid '(syn isomer).

(4) 7 - [2 -h th oxy imino - 2 · · (2 - ami no thi a zol - 4 - yl) ace t amido 3- (1,3.4 "thiadia7.ol-2-yl) thio ] ethyl "3-cep] icm-4-carboxylic acid (syn-i some.r _es ).

(5) 7- [2- (2-Propinyloxyimino) -2- (2-aminothiazolyl-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cep} icm-4 -carbo nsöure (syn-isomercs).

(6) '] · ■ \ 2-Al] yloxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3- (1,3,4-thiadiar.ol-2-yl) thiomethyl-5- ccplie] ii-4 -carboxylic acid (syn-I someres).

(7) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thio-methy1-3-cep] iC! U- 4-carbonic acid (syn_i somer _es ),

(8) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-111-tetra2ol-5-yl) thiorethyl-3-cephcm-4-carboxylic acid . ' (syn-I someres).

Test form

The in vitro anti bacterial activity was applied the two-fold agar plate dilution procedure described below certainly.

One-stop filling of an overnight culture of each test strain in trypticase

909834/0751

ORIGINAL INSPECTED

USüöö

Soy broth (10 living cells per ml) was spread on a heart infusion agar (! II-Agor) containing graduated concentrations of the test compounds and the minimum Hsmm concentration (MIC), expressed in μ ₉ / η1, ηαοη 20 hours

Incubation determined at 37 ° C.

Testerqebnir.se

Test bacteria

Pr, vulgaris I.

0.78

Test connections ■ (2) (3)

0.20

0.39

(4) (S) • MIC (uss / ml) (8th) Test bacteria 0.78 0.39 Test connections 0.78 (6) (7) B. subtilis 0.78 0.78 ATCC 6653

909834/0751

ORIGINAL INSPECTED

- 2Si -

2C05656

For therapeutic administration, the he invention are gcmcißen Compounds (i) and / or their pharmaceutically acceptable salts in the form of conventional pharmaceutical preparations (drugs) used, which represent a further object of the invention and which as active ingredient (active component) i,; indestenc one of these compounds, optionally mixed with a pharmaceutically acceptable carrier, such as e.g. an organic or inorganic solid or liquid auxiliary material, which is used for the earth, parenteral or excernal administration is suitable.

The pharmaceutical preparations can be in solid form, for example in the form of capsules, tablets, coated tablets, ointments or suppositories, or in liquid form for injection, e.g. in the form of solutions, Suspensions or emulsions. If necessary, can the above mentioned preparation © also auxiliary substances, stabilizers, Contain wetting agents or emulsifiers, buffers and other commonly used additives.

Although the dosage of the compounds can vary and also depends on the age, condition of the patient, the nature of the Disease, the type of compound (i) administered and the like, has an average single dose of about 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg as effective for the treatment of infectious diseases caused by pathogenic bacteria proven. In general, a daily dose can be between 1 and about 6000 mg per body or even more Administered to patients.

The invention is illustrated by the preparation examples described below and examples are explained in more detail, but without being restricted thereto.

909834/07 5 1

INSPECTED

5 f.

Manufacturing game 1

1.) 71.2 g of ethyl 2- (2-propinyloxyimino) -3-oxobuyrate (syn isomer)

were obtained by reacting 56.7 g of ethyl 2-hydroxyimirio-3-oxobutyrate with 43 g of 2-propynyl bronze in the presence of 72.3 g of potassium carbonate and 280 ml of N, N-diiriethylformamide. IR (PiIm): 3280, 3220, 2120, 1735, 1G70 cm " ¹

2.) 61.6 g of ethyl 2- (2'propinyloxyimino) ~ 3-oxo-4 ~ chlorobutyrate (syn isomer) were obtained by reacting 71.2 g of ethyl 2- (2 ~ propinyloxyimino) -3- oxobutyrate (syn isomer) with 50.2 g of sulfuryl chloride in 81 ml of acetic acid.
IR (film): 3300, 2130, 17Ί5, 1720, 1675 cm " ¹ 3.) 35.6 g ethyl ~ 2- (2-propinyloxyimino) -2- (2-ominothiazol-4-yl) ~

acetate (syn isomer) were obtained by reacting 61 g of ethyl 2- (2-propinyloxyimir! o) -3-oxo-4-chlorobutyrate with 20 g Thiourea in the presence of 35.8 g sodium acetate trihydrate,

150 ml of water and 180 ml of ethanol,
IJl. (Nujol): 3290, 2220, 1729 to " ¹

4.) 1.924 g 2- (2 ~ propinyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid

sbure (syn-Isoineres) were obtained by hydrolysis of 2.8 g of ethyl 2- (2-propinyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn-Isomeres) in the presence of 22.17 ml of a aqueous 1 η sodium hydroxide solution, 23 ml of methanol and 20 ml of tetrahydrofuran. IR (Nujol): 2190, 1740cm " ¹
Production example 2

107 g of formic acid were converted into 239 g of acetic anhydride with ice cooling was added and the mixture was stirred for 1 hour at 50.degree

90983A / 0751

ORIGINAL INSPECTED

-M-

(j3

stirred and then cooled to 20 C. 135 g of 2- (2 »propinyloxyimino) -2 ~ (2-αηΰ nothiazol-4-yl) acetic acid were added to the mixture (syn-isomeres) was added and the mixture was left for 3 hours stirred at ambient temperature. To the mixture, 400 ml of diisopropyl ether was added, and then the precipitated ones became Crystals collected by filtration, washed with diisopropyl ether and then dried, 118.4 g of 2- (2-propinyloxyimino) -2- (2-formamidothiuzo1-4 ~ yl) acetic acid (syn-Isomerec) was obtained.

IR (Nujol): 32S0, 2130, 1685, 1600, 1560 cm ' ¹ NMR Cd ₆ -DMSO, O): 3.53 (UI, m), 4.87 (2H ₁ d, J = 2Hz), 7.63 (IH, s) , 8.61 (111, s), 12.7 (IH, broad O

Manufacture llyηαεbei game 3

To a solution of 30 g of 2- (2-formamidothiazol-4-yl) glyoxylscure and 12.6 g of sodium bicarbonate in 1300 ml of water became 19.8 g Allyloxyaru n hydrochloride was added and the mixture was 7 Stirred for hours at ambient temperature at pH 6. To the Reaction ε me. 500 ml of ethyl acetate were added c hu ng. After this the mixture with 10 points hydrochloric acid to pH 1.9 was adjusted, the ethyl acetate layer was separated. The ethyl acetate layer was washed with an aqueous sodium chloride solution washed, dried over magnesium sulfate and then the solution was distilled off. The residue was dissolved in diisopropyl ether pulverized, collected by filtration and then dried to give 25.3 g of 2-allyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-Isonieres) received.

909834/0751

ORiGiNAL INSPECTED

- 3.5 -

/. '. U you

Γ ' ' M.

n " ¹

I.R. (NujoJ): 3110, 1730, 1660, 1540 cn

NMR (Cl ₆ -DMSO, δ): 4.70 (2IJ, m), 5.13-5.60 (2H,

> n), 5.73-6.27 (IM ₁ m), 7.57 (IH, s),

8-35 (111, _s )

Hc rs. tj ^ JLlu n / j rJx · ■ * · iiEi

1.) 35.2 g of sulfuryl chloride were added all at once to a stirred solution of 40.9 g of ethyl 2-cc
was continued at the same temperature for 1 hour. After adding dor do to 200 ml of water with the solution obtained, the solution was extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, with a
neutralized aqueous sodium bicarbonate solution and washed with water. The solution was dried over magnesium sulfate and concentrated under reduced pressure, giving 53.8 g of ethyl 2-thoxyirfiino-3-oxo-4-chlorobutyrate (syn-Isorr.eres) in the form of a pale yellow oil.

2.) A mixture of 38.7 g of ethyl-2-ethoxyirni no ~ 3-oxo-4-chloro

butyrct, 13.2 g thiourea, 14.3 g sodium acetate, 95 ml
Methanol and 95 ml of water were stirred at 48 ° C. for 40 minutes. After the resulting solution had been adjusted to pH 6.5 with an aqueous sodium bicarbonate solution, the precipitates which occurred were collected by filtration and washed with diisopropyl ether, 14.7 g of ethyl 2-cithoxyinino-2- (2-ninothiazole- 4-yl) acetate (syn-Isomercs), m.p. 130 to 131 ° C.

IR (Nujol): 3450, 3275, 312S, 1715, 1620 era " ¹

90983W07B1

ORIGINAL INSPECTED

- 36 -

. j -.- i . 2Ü05656

3.) 5 g of ethyl-2-uthoxyiniino-2- (2-aniinothiozol- ^/ ! -Yl) cicetate

(syn-Isomeres) \ / urdcn was added to a mixture of 45.9 ml of 1 η sodium hydroxide and 30 μl of ethanol and the mixture was stirred for 5 hours at room temperature. After removing the ethanol from the resulting solution under reduced pressure, the residue was dissolved in 60 ml of water and mixed with. 10 / Siger Clilorvasser & toffsüure adjusted to pH 2.0. The solution was subjected to 1 to yl and the precipitates were collected by filtration and dried to give 2.9 o 2-Athoxyirnino-2- (2-ainothiazoJ-4-yl) acetic acid (syn - isomer).

I.R. (Nujol): 3625, 3225 (shoulder). 3100,

1650, 1615 cm " ¹
N ₁ .MR Cd ₆ -DMSO ₁ δ): 1.20 (3H, t, J = 7Hz), 4.09 (211, q, J-7Hz), 6.82 (IH, s), 7.24 (2H, broad s)

4.) 100 g of 2-Äthoxyirnino-2- (2 "arninothiazol'-4-yl) acetic acid (syn-isomeres), 85.5 g formic acid and 190.1 g acetic anhydride were in the same way as in preparation example 2 beliande.lt, 99.1 g of 2-athoxyimirio-2- (2-formamidothiazole ~ 4-yl) acetic acid (syn isomer) was obtained.

IR (Nujol): 3200, 3140, 3050, 1700 an " ¹ NMR Cd ₆ -DMSO ₁ S): .1.18 (3H, t, J = 6Hz), 4.22 (2H, q, J = (SIIz) ₁ 7.56 ( III, s), 8.56 (IH, s), 12.62 (III, br _e it s) ',

Manufacturing example 5

In a similar manner as in Preparation Examples 1 to 4 were made made the following connections:

90983A / 0751

ORIGINAL INSPECTED

.- '■■ Ubbbo

(1) 2-Isopropoxyimino> 2- (2-forinnmidothiazol-4-yl) -acetic acid (Csyn. Isomeres), F ₀ 168-16i) ° C (dec.).

IR (Nujol): 3200, 3130, 1710, 1600, 1560 to ^"1 (2) 2-Üutoxyimino-2- (2-formamidüthiazol-4-yl) _oss igsäure (syn-isomer.")
IR, (Nujol): 3350 ₁ 3160, 3050, 1700, 1680,

1570 cm " ¹ ...

(3) 2-Hexyloxyimino-2 - (2-JformamidotJiiazol-4 -yl) acetic acid (syn-isomeres) ^. ^{115-116 C} C (dec.) • IR (Nujol): 3170, 3070, 1720, 1700, 1660 cm " ¹ NMR ((I ₆ -DMSO, 6): 0.6-2.1 (1111, m), 4.15

(2) 1, t, J = C) Hz), 7.53 (IH, s), 8.56 (III,

s), 12-69 (IU, s)

(4) 2-pentylo; iyinjino-2 - (^ ~ aminothia2ol-4-yl) acetic acid (syn -I: .omer _es ) _# M.P. 176 ° C (dec.)
Ϊ R (Nujol)

3160, 1655, 1620, 1460 cm " ¹ NM R.Cd ₆ -DMSO, δ)

7.20 (2H ₁ s), 6.82 (111, s), 4.07 (211, t, • J = 6Hz) ,. 0.6-2 *. 2 (9H, m)

C 5) 2-propoxyimino-2- (2-formamidothiazol-4-yl) _{acetic acid} . '(syn »isomeres), m.p. 164 ⁰ C (decomp.).

IR (Nujol): 3200, "3120, 3050, 1700, 1550 cm" ¹

(6) 2-Pentyloxyimino ^ -2- C2-formamidothiazol-4-yl) acetic acid (syn-Isomeres), m.p. 125 ⁰ C CZers.).

■. IR (Nujol): 3200, 3140, 1700, 1565 era * ¹ '

• ·

(7) 2-Allyloxyiraino-2- (2-arainothiazol "4-yl). _Essi g _S a _ure (syn Lisomer _es ) _r f .187 ⁰ C ( _{Zers #} ) _#

IR (Nujol): 3350. "> 30, 1580, 1460 cm" ¹ (β) 2-Hexyloxyiinino-2- (2-aminothiazol-4-yl) acetic acid (syn-isomer _es ), F. 174 ° C (dec.). IR (Nujol): 1660, 1625, 1425 cm " ¹ (9) 2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syji-isomeres), mp 51 ° C (dec.).
. (10) 2-Isobutoxyiraino-2- (2-aminothiazol-4-yl) acetic acid

909834/0751

. 65-

) ^. 122 - IPA ⁰ C.

(11) 2-Cyclohexyloxyimino -? "- (2 ~ aminolhiazol-4 ~ yl) essigsciure Osyn-isomer), mp 148 ⁰ C (ZCRS)..

(12) 2-Propoxyiraino-2- (2-aiuinothiazol-4-yl) acetic acid (syn -isomeres), ^{m.p. 161 0} C (decomp.) «

(13) 2 ~ lGobuloxyirnino-2 ~ (2 - forrnaniidothifisol ~ 4 "yl) - acetic acid Ifjyn- _J l.soiner _e s) _/ F.1G3 ⁰ C (dec.).

Herste 1 lunar, example _6_

1.) 500 in]. Water was added to 490.0 g of hexyluirin and taken under

Ice-cooling and with stirring, a solution of 193.6 g of sodium hydroxide in 700 ml of water was added. Over a period of 2 hours at 2 to 10 ° C. 367.1 g of carbon disulfide were added dropwise and then over a period of 1 hour at 0 to 5 ° C. 687.3 g of methyl iodide were added dropwise. The resulting mixture was stirred for 30 minutes at the same temperature and 2 hours at ambient temperature. The reaction mixture was extracted with 1.5 l of diethyl ether. The extract was washed with 30 ml of a saturated aqueous sodium dichloride solution, dried over magnesium sulfate and concentrated to give 825.5 g of methylene-N-hexyldithiocurbamate in the form of an oil.

IH (film): 3225, 2960, 2935, 2860 cm " ¹ NMR (CDCJl ₃ , O): 0.86 (3H, t, J-5.0Hz),

1.10 * 1.90 (811, m), 2.58 (3H, s),

3.72 (2H ₁ m)

2.) 155.9 g of sodium oxide and 0.8 l of water are added with stirring

a solution of 430 g of methyl N-hexyldithiocorbaiate in 1.7 Ethanol was added and the resulting mixture was 3.5 Heated under reflux at 90 ° C. for a long time. The ethanol was distilled off from the coacting mixture and the residue became washed with 1 1 diethyl ether, with concentrated hydrogen chloride

909834/0751

iOii-JAL INSPECTED

'905656

- 89 -

Go

acid adjusted to pH 2.0 and extracted with 1 l of diethyl ether. The extract was washed with water over magnesium sulfate dried and concentrated, 431.3 g of 1-hexyl-IH-tetrazole-5-thiol received in the form of an oil.

IR (film): 3110, 2960, 2930, 2860 cm " ¹

NMR (CDCJl _3. O : 0.91 (3H, t, JS.pHz),

. 1.1 (class 65 (6H, m), 1.97 (2H, ra),

4.33 (2H, t, J-7.0HZ).

3.) To 150.0 g of 7-aminocephalosporanic acid, 3 l of a 0.2 M

Phosphate buffer solution added, which by dissolving 62.1 g Sodium biphosphate dihydrate and 25.5 g of disodium hydrogen phosphate in 3 l of water had been prepared, and the mixture obtained in this way was adjusted to pH 6.5 with an aqueous 2 η sodium carbonate solution. To the mixture was 154.6 g of 1-hexyl-IH-tetrazole-5-thiol added and the resulting mixture was 2 hours at 60 to 65 C and at a pH of 6.0 stirred to 6.5 while passing in nitrogen gas. The reaction mixture was treated with concentrated hydrochloric acid Ice cooling adjusted to pH 3.5. The precipitates were collected by filtration and washed with water, and it became 4 liters Methanol and 400 ml of concentrated hydrochloric acid were added. The mixture was stirred for 2 hours and an insoluble matter was filtered off. The filtrate was coated with activated charcoal treated and with a 28 / Sigen aqueous ammonia solution to pH 3.5 set. The precipitates were collected by filtration, washed successively with water, acetone and diethyl ether and dried to give 116.38 g of 7-amino-3- (i-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid in form of

909834/0751

ORIGINAL INSPECTED

/ '■ Ü56S6

. 61

Powder received.

IR (Nujol): 1803, 1620, 1350 cm " ¹ NMR Cd ₆ -DMSO, δ): 0.95 (3H, t, J = 6.5Hz),

1.26 (6H, m) ", 1.80 (2H, m), 3.65 (2H, AB, J = 18Hz)., 4.00 ^ 4.50 (4H, m), 4.79 (IH, d, J »= 6.0Hz), 4.95 (IH, d, J = 6.0Hz)

Production example 7

283.0 g of 7-aminocephalosporanic acid and 225.0 g of 1-propyl-IH-tetrazole-5-thiol were treated in a manner similar to Preparation Example 6 (3) in 5.5 liters of 0.2 M phosphate buffer solution, v / obei man 125.0 g of 7-amino-3- (1-propyl-1H-tetrazol-5-yl) thioiethyl-3-cephem-4-carboxylic acid received.

IR (Nujol): 3300, 1795 ,. 1610 cm " ¹

NMR (d ₆ -DMS0, δ): 0.91 '(3H, t, J = 7.SHz),

1.60 ^ 2.28 (2H, m), 3.63 (2H, AB _q , J = 18.0Hz), 3-.9 8 ~ 4.58 (4H, m), 5.08 (IH, d, J = 5. OHz), 5.49 ( IH, .d, J = 5

Production example 8

1 ·) 3.7 g of 3-chlorophenyl isocyanate were added at ambient temperature to a solution of 10.3 g of benzhydryl 7- (2-phenylacetamide) -S-hydroxymethyl-S-cephem - ^ - carboxylate added in a mixture of 200 ml of tetrahydrofuran and 2.4 g of triethylamine and the mixture was stirred for 1 hour. The reaction mixture was taking

90983 4/0751

ORIGINAL INSFECTED

05656

CS

concentrated under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate dissolved and the solution was successively with 10 J ^ iger Washed hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, a solution was obtained which was a mixture of benzhydryl 7- (2-phenylacetamide) -3 ~ [N- (3-chlorophenyl) carbamoyloxymethylj-3-cephem-4-carboxylate and benzhydryl 7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -2-cephem-4-carboxylate contained.

2.) The ethyl acetate solution obtained above was added at 7 to 10 ° C

a solution of 5.2 g of 3-chloroperbenzoic acid in ethyl acetate was added dropwise and the mixture was stirred for 1 hour at the same temperature. The precipitates were collected by filtration, washed with diethyl ether and dried, giving 7.7 g of benzhydryl-7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) -carbamoyloxymethylD-S-cephem - ^ - carboxylate- i-oxide received.

IR (Nujol): 3280, 1790, 1700, _1650/1600, 1530 to ^"1

3.) 3.2 g of phosphorus trichloride were stirred at -40 ° C

Solution of 7.6 g of benzhydryl 7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4-carboxylate-1-oxide in 50 ml of dimethylformamide was added and the mixture was stirred at -20 to -40 C for 1 hour. The reaction mixture was poured into chilled water. The precipitates were collected by filtration, washed with water and dried, whereby 5.0 g of benzhydryl 7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) -carbamoyloxymethylj-S-cephem ^ -carboxylate received.

909834/0751

ORIGINAL INSPECTED

G3.

I.R. (Nujol): 3280, 3190, 1780, 1730, 1710,

1660, 1620, 1600, 1540 cm " ¹

NMR (d ₆ -DMSO, δ): 3.56 (2H, s), 3.64 (2H, s),

4.86 (2Η, AB, J = 12Hz), 5.14 (IH ₁ d, J * 5Hz), 5.76 (IH, d, d, J = S ind CHz), 6.95 (IH, s), 7.00 * 7.70 (19ΪΙ, m), 9.10 (IH, d, 'J = 8Hz), 10.00 (IH, s)

4.) 1.9 g of pyridine were added to a solution of 4.93 g of phosphorus penta-

chloride in 50 ml of methylene chloride was added at 5 C and the Suspension was stirred for 30 minutes at ambient temperature. To the reaction mixture was added 5.0 g of benzhydryl 7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4-carboxylate at 5 ° C. and stirring was carried out for 1.5 hours at 5 to 7 ° C. to form a homogeneous solution. To the one above obtained solution, which had been cooled to -30 ° C., 8 ml of methanol were added. After the solution for 1 hour at -10 to After stirring at -20.degree. C., 5 ml of water were added and stirring was continued at 0-5.degree. C. for 30 minutes. After Removal of the solvent under reduced pressure, 80 ml of water and 100 ml of diethyl ether were added to the residue and the an aqueous layer containing oil was separated. The aqueous solution containing the oil was mixed with a 20% aqueous solution Sodium carbonate solution adjusted to pH 8.0 and extracted with ethyl acetate. The extracts were with a saturated aqueous Washed sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was pulverized with diisopropyl ether, 2.2 g of benzhydryl-7-omino-3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4-carboxylate received.

909834/0751

w J y

- 4a -

. C4

I.R. (Nujol): 3410, 3360, 1760, 1700, 1650,

1595, 1520 cm " ¹

NMR (d _c -DMSO, 6) : 3.60 (2H, br _e it s),

4.80 (IH, d, J-SHz), 4.83 (2H, AB _q , J-13HZ), 5.05 (IH, d, J = SHz), 6.93 (IH, s), 6.90 ^ 7.70 (14H, m), 9.97 (IH, s)

Prod el .l ungs at s p e l 9

1.) 1O ₇ 3 g benzhydryl- = 7-2-phenylacetamido) ~ 3-hydroxymethyl-3-cephem-

4-carboxylate and 7.4 g of 2- (4-methoxyphenoxy) acetyl chloride were added in a manner similar to Production Example 8 (l) with each other reacted to form a solution containing a mixture of benzhydryl 7- (2-phenylacetamido) -3- [2- (4-methoxyphynoxy) acetoxymethyl] -3-cephem-4-carbxylate and benzhydryl 7- (2-phenylacetamido) -3- [2- (4-methoxyphenoxy) acetoxymethyl] -2-cephem-4-carboxylate contained.

2.) The solution obtained above was treated with 4.7 g of 3-chloroperbenzoic acid

in a similar manner to Preparation Example 8 (2) 7.1 g of benzhydryl 7- (2-phenylacetamido) -3- [2- (4-methoxyphenox ^ Oacetoxymethyl ^ -S-cephem ^ -carboxylate-i-oxide received.

I.R. (Nujol): 3270, 1780, 1760, 1720, 1650,

1520, 1500 cmT ¹ NMR (d ₆ -DMSO, 6): 3.63 (2H, s), 3.67 (3H, s),

3.75 (2H, AB _q , J = 19Hz), 4.65 (2H, s),

4.90 (IH, d, J = SHz),

4.97 (2H, AB _q , J = 13Hz), 5.93 (IH, d, d, J = 5 υ-nd SHz), 6.85 (4H, s), 6.96 (IH, s) ,. 7.00 ^ 7.70 (15H, m), 8.41 (IH, d, J »8Hz). '"

90983A / 0751

ORIGINAL INSPECTED

/ Γϋ5656

• 6S-

3.) 6.9 g of benzhydryl-7 "(2-phenylacetamido) -3- [2- (4-methoxyphenoxy) -acetoxymethylJ-S-cephernic-carboxylate-i-oxide and 2.7 g of phosphorus trichloride were prepared in a manner similar to the preparation example 8 (3) reacted with one another to form 6.1 g of benzhydryl 7- (2-phenylacetar> iido) -3- [2- (4-methoxyphenoxy) acetoxymethyl] -3-cephem-4-carboxylate.

IR (Nujol): 3300, 1775, 1740, 1730, 1650 cm " ¹

NMR Cd ₆ -DMSO, 6); 3:50 (AH _{1 eit} br s),

3.63 (3H, s), 4.62 (2H, s), 4.83 (2H, AB _q , J-13Hz), 5.07 (IH, d, J-SHz), 5.72 (IH, d, d, J-5 uid 8Hz ), 6.77 (411, s), 6.85 (IH, s), 6.70 ^ 7.60 (ISH, m), 9.00 (IH, d, J-SHz)

4.) 6.0 g Benzhydryl-7- (2 ~ phenylacotamido) -3 ~ [2- (4-methoxyphenoxy) -

acetoxymethyl] -3-cephem-4-carboxylate, 5.65 g phosphorus pentachloride, 2.2 g of pyridine and 7.3 ml of methanol were reacted with each other in a similar manner to Production Example 8 (4) Formation of 4.6 g benzhydryl 7-amino-3- [2- (4-methoxyphenoxy) acetoxymethyl] -3-cephem-4-carboxylate.

NMR (J ₆ -DMSO, δ): 3.52 (2H, br _e it s), • 3.68 (3H, s), 4.69 (2H, s),

4.60 ^ 5.10 (4H, m), 6.89 (4H, s), 6.96 (IH, s), 7.00-V7.70 (1OH, m)

Preparation example 10

The compounds listed below were made in a similar manner prepared as indicated in preparation example 8:

909834/0751

ORIGINAL INSPECTED

29U5656

(1) Benzhydryl-7-amino-3- (2-thenoyl) oxymethyl-3-ccphcm-

4-carboxylate,

I.R. (Nujol): 3400-V3300, 1770, 1710, 1610,

1520 cm " ¹
NMR Cd ₆ -DMSO, δ): 3.68 (2H, br s _ince)

4.90 (IH, d ", J = 5Hz), 5.03 (2H, · AB, J = 13Hz), 5 .. 12 (IH, d, J = 5Hz), 6.97 (IH, s), 7.17 ^ 7.67 (HH, m), 7.73 ^ 8.1 (2H, m) ■ *

(2) Benzhydryl - 7-amino-3-cyclohexane-carbonyloxymethyl-S-c'ephcm - ^ - carboxylate, · '.

• IR (Nujol): 3200, 1800, 1730, 1620 cm " ¹ NMR (d ₆ -DMSO, 6) : 0.83 ^ 2.0 (1OH, m),

3.07 ^ 3.40 (IH, m), 3.58 (2H, br _e it s), 4.66 ^ 5.33 (4H, m), 6.93 (IH, s), 7.0 ^ 7.58. (1OH, m)

(3) Benzhydryl-J-aminö-3- (N-phenylcarbamoyloxymethyl) -3-cephem-4-carboxylate,

I.R. (Nujol): 3420, 3380, 1770, 1725, 1660,

1600, 1530 cm " ¹

NMR (d ₆ -DMSO, δ); 3.65 (2H, br _e it s),

4.83 (2H, AB, J »13Hz), 4.90 (IH, .d, J = SHz), 5.10 (IH, d, J» 5Hz), 7.00 (IH, s), 6.83 ^ 7.73 (15H ₁ m), 9.78 (IH, s)

(4) Benzhydryl-7-amino-3- (4-nitrobenzoyloxymethyl) -3-ccphem-4-carboxylate hydrochloride,

I.R. (Nujol): 3400, 3350, 1770, 1720, 1630,

1600, 1540 cm " ¹ .

NMR (d ₆ -DMSO, δ): 3.74 (2H, br _e it s),

4.72 ^ 5.32 (4H, m), 6.92. (IH, s), 7.0 ^ 7.64 (1OH, m), 8.12 (2H, d, J «= 9Hz), 8.32 (2H, d, J = 9Hz)

90983A / 0751

.: Γ ü 5 6 5

• G7 ·

example 1

3.0 g of 2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) and 40 ml of dry ethyl acetate were added at 0 to 5 C with stirring to a suspension of a ViIsmeier reagent based on conventional Manner was prepared from 1.0 g of dry dimethylformamide and 2.1 g of phosphorus oxychloride in 4.0 ml of dry ethyl acetate, and the resulting mixture was stirred for minutes at the same temperature. The solution was at -10 C with stirring to a solution of 3.7 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, 10.3 g Trimethylsilylacetamide and 6.8 g of ßis (trimethylsilyl) acetamide in 80 ml of dry ethyl acetate were added and the mixture was stirred for 1.5 hours at the same temperature. After adding 50 ml of water to the reaction mixture, an insoluble matter was filtered off, the ethyl acetate layer in the filtrate was separated and extracted with 50 ml of an aqueous solution of sodium bicarbonate. The aqueous extract was washed with ethyl acetate and acidified to pH 2.0 with concentrated hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 2.3 g of 7- [2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained in the form of a powder.

IR (Nujol): 3250, 1780, 1680 cm " ¹

NMR Cd ₆ -DMSO.6 ) : 1.31 (3H, t, J-7.0IU),

3.77 (2H, m), 4.28 (2H, q, J = 7.0Hz), 4.43 (2H, AB _q , J = 13.0Hz), 5.18

(IH, d, J = SUHz), 5.84 (IH, d, d, J «5.4 aid 9.8Hz), 7.42 (IH, _s ), 8.53 (IH, s), 9.57 (IH, s), 9.66 (IH , d, J = 9.8Hz) 909834/0751

ORIGINAL INSPLo ί ^ j

- 47 -

• ω-

Example 2

0.96 g of phosphorus oxychloride became a suspension at one time of 1.13 g of 2- (2-propynyloxyimino) -2- (2-aminothiazoi-4-yl) acetic acid (syn-J.someres) in 10 ml of dry tetrahydrofuran was added at 2 ° C. and the mixture was stirred at 2 to 4 ° C. for 15 minutes. 1.0 g of trimethylsilylaeetamide were added dropwise and the same The resulting mixture was stirred at 2 to 6 ° C. for 20 minutes. 0.96 g of phosphorus oxychloride was added and the mixture was stirred for 20 minutes. Εε v / urden 0.45 g of dry dimethylformamide was added all at once at 4 to 6 C and the mixture was stirred for 1 hour to give a clear solution. on the other hand 4.6 g of trimethylsilylaeetamide were added to a stirred suspension of 1.65 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in 20 ml of dry ethyl acetate was added and the solution was stirred at 40 ° C. for 30 minutes. To this To the solution, the tetrahydrofuran solution obtained above was added all at once at -30 ° C. and the obtained mixture became 1 hour stirred at -5 to -20 C. To the reaction mixture, 30 ml of water and 20 ml of ethyl acetate were added. An organic layer was separated and extracted with an aqueous sodium bicarbonate solution. The extract was acidified with 10% hydrochloric acid adjusted to pH 3.0. The precipitates were collected by filtration, washed with water, whereby 1.4 g of 7- [2- (2-propynyl) oxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (i, 3 , 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres) received.

909834/0751

. t9.

IR (Nujol): 3300, 1780, 1680 cm " ¹ NMR Cd ₆ -DMSO, δ): 3.43 (IH, m), 3.67 (2Η,

broad -s), 4.42 (2Η, .ΛΒ, J = 13Hz), 4.68 (2H, broad s), 5.13 (IH, d, J = 5Hz), 5.77 (IH, d, d, J = 5 and 8Hz) , 6.77 (IH, s), 7.1θ (2H, br _e it s), 9.50 (IH, s), 9.60 (IH, d, J = 8Hz)

Example 3

Conventionally, 1.0 g of dry dimethylformamide, 4 ml of dry ethyl acetate and 2.1 g of phosphorus oxychloride prepared the Vilsineier reagent. Then 45 ml of dry Ethyl acetate and 2.85 g of 2-methoxyimino-2- (2-formamidothiozol-4-yl) acetic acid (syn isomer) added. This solution was added at -10 C to a stirred solution that had been prepared was obtained by stirring a mixture of 4.5 g at 40 ° C. for 1 hour 7-Amino-3- (l -hexyl-1H-tetrazol-S-ylJthiomethyl-S-cephem ^ -carboxylic acid, 10.4 g trimethylsilylacetcinide and 90 ml dry ethyl acetate, and the resulting mixture was stirred at -5 to -10 C for 1.5 hours. To the reaction mixture, 50 ml V / water was added and the ethyl acetate layer was separated. 40 ml of water were added and the mixture was mixed with a saturated aqueous sodium bicarbonate solution adjusted to pH 7.0, The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 2.5 with 10% strength hydrochloric acid. The precipitates were collected by filtration, washed with water and dried under reduced pressure to thereby 6.18 g of 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) obtained in the form of a powder.

909834/0751

- £ O υ b 6 5

IR ". (Nujol): 3250, 1777, 1680 cm" ¹

NMR Cd ₆ -DMSO, δ): 0.85 (3H, t, J = 5.SlIz),

1.65 (6H, m), 2.78 (2H, m),. 3.72 (2H ₁ m), 3.93 (3H _r s),

.4.07M. 59 (4H, m), 5.17 (IH, d, J-S.OHz), 5.83 (IH, d, d, J = S.0;, 8.2Hz) i 7.46 (IH, s), 9.56 (IH, s), 9.70 (IH, d, J = 8.2Hz)

Example 4

0.92 g of phosphorus oxychloride were added over a period of 3 minutes at -5 to -10 C to a solution of 0.44 g of dimethylformamide in 2 ml of ethyl acetate was added dropwise. 20 ml of ethyl acetate were added and after 10 minutes 1.29 g of 2-isopropoxyimino-2- (2-formamido ~ 1,3-thiazol-4-yl) acetic acid (syn-isomeres) added at -5 to -10 C, The mixture was stirred for 10 minutes to give a clear solution. On the other hand, 1.37 g of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid became with stirring in a solution of 1.68 g of sodium bicarbonate dissolved in 30 ml of water and then 20 ml Acetone added. The ethyl acetate solution obtained above was added to the solution with stirring at 0 to 5 ° C. and at a pH of 6.5 to 7.5 were added dropwise. After stirring for 20 minutes at the same temperature, the aqueous layer was separated and the acetone was distilled off. The remaining aqueous layer was with 10 show hydrochloric acid while cooling with ice and stirring adjusted to pH 3.0. The precipitates were collected by filtration, washed with water and dried, whereby 1.5 g 7- [2-Isopropoxyimino-2- (2-formamido-1, S-thiazol ^ -yl ^ cetamidou-S-carbamoyloxymethyl-S-cephem ^ -carboxylic acid (syn-isomeres) received.

909834/0751

ORIGINAL INSPECTED

- JBO -

I R (Nujol)

3450, 3250, 1780, 1710, 1690, 1650 cm

NMR Cd ₆ -DMSO.6 )

9.63 (IH, d, J = 8Hz), 8.53- "(IH, s), 7.43 (IH, s), 6.60 (IH, s), 5.83 (IH, dd, J = 5, 8Hz), 5.20 (IH, d, J = 5Hz), 4.77 (2H, ABq, J = 14Hz), 4.40 (IH, m), 3.57 (2H,

wide s), 1.27 (6H, d, J = 6Hz) Example 5

0.05 g of water was added to a suspension of 1.0 g of 2-allyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn-Isoneres) in 10 ml of tetrahydrofuran was added. At 0 to 5 C, 0.84 g were obtained Phosphorus oxychloride was added and the mixture was left for 20 minutes stirred for a long time at the same temperature. There were 0.66 g of trimethylsilylacetamide was added and the mixture was stirred for 20 minutes at the same temperature, then 0.84 g Phosphorus oxychloride was added, the resulting mixture was stirred for 20 minutes at 0 to 5 ° C., then 0.45 g of dimethylformamide were added was added and the resulting mixture was stirred for 1 hour at the same temperature. The received Solution was added dropwise at -5 to 5 C and at pH 7.0 to 8.0 to a solution which had been prepared by addition of 15 ml of acetone and 15 ml of tetrahydrofuran to a solution of 1.45 g of 7-amino-3- (1,3,4-thiadiazol-2-yi) thiomethyl-3-cephem-4-carboxylic acid in a mixture of 0.42 g of sodium bicarbonate and 10 ml of water. The resulting mixture was stirred for 2 hours under ice-cooling, the pH of the mixture being 7.0 until 8.0 and then the pH was adjusted to 7.5.

909834/0751

" ⁵¹ I" 2005656

The insoluble matter was filtered off and the filtrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 6.0 and the organic solvent in the aqueous layer was distilled off under reduced pressure. The one left behind aqueous layer was adjusted to pH 4.0 and an insoluble matter was filtered off. The filtrate was adjusted to pH 3.0 and the precipitates were collected by filtration and dried, giving 1.5 g of 7- [2-allyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] ~ 3- (1 , 3,4-thiadiazol-2-yl) -

thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres). I R (Nujol) ';

33S0, 1780, 1680, 1630 cm " ¹ NMR Cd ₆ -DMSO, 6)

9.63 (IH, d, J = 8Hz), 9.57 (IH, 's), 7.23 (2H, m), 6.77 (IH, s), 6.10 (IH, m), 5.83 (IH, dd, J = S, 8Hz), 5.43 (IH, m), 5.25 (IH, m), 5.17 (IH, d, J = 5Hz), 4.61 (2H, m), 4.47

(2H, ABq, J = 14Hz), 3.72 (2H, m) Example 6

0.1 ml of water was added to a suspension of 2.0 g of 2-hexyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn-Isomeres) in 20 ml of tetrahydrofuran was added. At 0 to 5 C, 1.4 g of phosphorus oxychloride were added and the mixture was allowed to last for 20 minutes stirred for a long time at the same temperature. There were 1.3 g of trimethylsilylacetamide was added and the mixture was stirred for 20 minutes at the same temperature, then 1.4 g

909834/0751

ORIGINAL INSPECTED

• Γ J '

Phosphorus oxychloride was added, the resulting mixture was stirred for 20 minutes at 0 to 5 ° C., 0.75 g were obtained Dimethylformamide was added and the resulting mixture was stirred for 1 hour at the same temperature. The received The solution became a solution of 3.3 g of 7-amino-3- (iH-1, 2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid all at once at -20.degree in a mixture of 30 ml of tetrahydrofuran and 6.8 g of trimethylsilylacetamide admitted. The obtained mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was aftertreated in a manner similar to the above examples, 1.5 g of 7- [2-hexyloxyimino ~ 2- (2-amino- !, S-thiazol ^ -ylJacetamidol-S-iTH-i ^^ - triazol-S-ylJthiomethyl-3-cephem-4-carboxylic acid (syn-isomeres) received.

I R (Nujol) »■

310Oi 1780, 1630 cm " ¹ NMR Cd ₆ -DMSO, 6)

• 10.17 (IH, d, J = 8Hz), 8.17 (2H, m),

7.97 (IH, s), 7.25 (IH, m), 6.70 (IH, s), . 5.73 (IH, dd, J = S, 8Hz), 5.13 (IH, d,

J = 5Hz), 3.97 (2H, m), 3.60 (2H, m),

1.25 (8H, m), 0.83 (3H, m)

Example 7

1.2 g of 2- (2-propynyl) oxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn-isomeres) were suspended in 15 ml of tetrahydrofuran. 1.0 g of phosphorus oxychloride were added at 0 to 5 ° C. and the mixture was stirred for 20 minutes at the same temperature. 0.5 g of trimethylsilylacetamide were added and the

909834/0751

'** " 23üöb56

Mixture was stirred for 20 minutes at the same temperature, then 1.0 g of phosphorus oxychloride was added to obtain the obtained Mixture was stirred at 0-5 ° C for 20 minutes, then 0.5 g of dimethylformamide was added and the resulting mixture was stirred for 1 hour at the same temperature. The received Solution was added dropwise at -5 to 5 C and at pH 6.5 to 8.5 to a solution which had been prepared by adding 10 ml of acetone and 10 ml of tetrahydrofuran to a solution of 1.9 g of Z-amino-S-carbamoyloxymethyl-G-cephem - ^ - carboxylic acid in a mixture of 0.4 g of sodium bicarbonate and 15 ml of water. The obtained mixture was stirred for 2 hours under ice-cooling, keeping the pH of the mixture at 7.0 to 8.0, then the pH was adjusted to 7.5. An insoluble material was filtered off and the filtrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 6.0 and the organic Solvent in the aqueous layer was distilled off under reduced pressure. The remaining aqueous layer became on Adjusted to pH 4.0 and an insoluble matter was filtered off. The filtrate was adjusted to pH 3.0 and the precipitates were collected by filtration and dried to give 2.2 g 7- [2- (2-propynyl) oxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -S-carbamoyloxymethyl-S-cephem ^ -carboxylic acid (syn-isomeres) received. I R

3300, 1770, 1720, 1640 at "· NMR Cd ₆ -DMSO, 6)

9.63 (IH, d, J = 8Hz), 7.27 (2H, m), 6.80 (IH, s), 6.58 (2H, m), 5.77 (IH, dd, J = 5.8Hz), 5; 15 (IH , d, J = SHz), 4.76 (2H, ABq, J = 12Hz), 4 .'73 (2H, s), 3.50 (2H, m), 3.45 (IH, m) 90983A / 07 51

ORIGINAL INSPECTED

- 54 -

Game 8

0.92 g of phosphorus oxychloride were added dropwise over a period of 3 minutes at -5 to -10 C to a solution of 0.44 g of dimethylformamide in 2 ml of ethyl acetate. 20 ml of ethyl acetate were added and after 10 minutes 1.29 g of 2-isopropoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetic acid (syn-isomer) at -5 to -10 ° C. were added . The mixture was stirred for 10 minutes to give a clear solution. On the other hand, 1.64 g of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid was dissolved in a solution of 1.68 g of sodium bicarbonate in 30 ml of water with stirring and then 20 ml of acetone was added. The ethyl acetate solution obtained above was added dropwise to the solution with stirring at 0 to 5 ° C. and at a pH of 6.5 to 7.5. After stirring for 20 minutes at the same temperature, the aqueous layer was separated and acetone was distilled off. The remaining aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and with stirring. The precipitates are collected by filtration, washed with water and dried to give 1.7 g of 7- [2-isopropoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3 - (i-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I R (Nujol)

3500, 3300, 1780, 1730, 1680 cm " ¹ · NMR Cd ₆ -DMSO, 6)

9.62 (IH, d, J = 8Hz), 8.53 (IH, s) -7.40 (IH, s), p.83 (IH, dd, 'j = 5, 8Hz), 5.17 (IH, d, J = 5Hz), 4.17 (2H, m), 3.97 (3H, s), 3.73 (2H,. Br eit. S), 1.27 (6H, d, J = 6Hz)

909834/0751 ORIGINAL INSPECTED

- 55 -

I J Ü b 6 5 • 76 ·

Example 9

0.51 g of phosphorus oxychloride were added over a period of 5 minutes at 5 C to a solution of 0.24 g of dimethylformamide in 1 ml of dry ethyl acetate was added dropwise. After the precipitation of crystals the mixture was stirred at 10 C for 30 minutes, then were 9 ml of dry ethyl acetate and 0.89 g of 2-methoxyimino-2- [2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl] essi all at once Acid (syn isomer) was added at -10 ° C. The resulting mixture turned 30 Stirred at -10 to -5 C for minutes. The resulting solution became a solution of at -15 ° C. over a period of 5 minutes 1.0 g of Z-amino-S-benzoyloxymethyl-S-cephem ^ -carboxylic acid and 3.2 g Trimethylsilylacetamide in 10 ml of dry ethyl acetate was added dropwise, then the mixture obtained was kept at -10 to -15 ° C. for 1 hour touched. 10 ml of water was added to the reaction mixture and the ethyl acetate layer was separated. The aqueous layer was extracted with an additional 10 ml of ethyl acetate. The ethyl acetate layers were combined and 20 ml of water was added. The resulting mixture was made up with sodium bicarbonate adjusted to about pH 6. The aqueous layer was separated and 25 ml of ethyl acetate was added. The mixture was cooled with ice and while stirring with 10 7 »strength hydrochloric acid pH adjusted to 2.5. The ethyl acetate layer was separated and the aqueous layer was further added with 15 ml and 10 ml of ethyl acetate extracted. The ethyl acetate layers were combined with each other, washed with a saturated aqueous sodium chloride solution, Dried over magnesium sulfate, treated with activated charcoal and evaporated under reduced pressure to give crystals, which have been dried under reduced pressure to give

909834/0751
ORIGINAL INSPECTED

*? ~,: Ο 0 S b S

T τ '

1.1 5 g of 7- [2-l1ethoxyimino-2-l2- (2,2,2-trifluoroacetamido) -1,3 ~ thiazol-4-yl} acetamido] -3-benzoyloxyriethyl-3-cephem-4- carboxylic acid (syn isomer).

IR (Nujol)

3250, 1790, 1730, 1650 cm " ¹

Example 10

NMR (dg-DMSO,

9.95 (IH, d, J = 8Hz), 7.92-8.16 (2H, in),

7.4 -7.84 (311, m), 7.6 (IH, 's).,

5.92 (IH, dd, J-5, 8Hz), 5.26 (IH, d, J = SKz),

5.18 (2H, ABq, J = 13Hz), 3.96 (3H, s),

3.76 (2H, br _e £ _t s)

0.56 g of phosphorus oxychloride became one at a time below 5 ° C Mixture of 0.6 g of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn-isomeres) and 6 ml of dry ethyl acetate were added and the mixture was stirred at 4 to 6 ° C for 20 minutes. At the same temperature, 0.3 g of bis (trimethylsilyl) acetamide was added all at once was added and the mixture was stirred for 10 minutes at the same temperature. To the mixture obtained 0.56 g of phosphorus oxychloride was added all at once and the mixture was stirred for 30 minutes at the same temperature, then 0.24 g of dimethylformamide were added dropwise and the resulting mixture was stirred at 4 to 6 ° C. for 30 minutes. The received Solution suddenly became a solution of at -15 ° C. with stirring 1.1 g of 7-amino-3- (4-nitrobenzoyl) oxymethyl-3-cephem-4-carboxylic acid and 3.5 g of trimethylsilylacetamide in 20 ml of dry ethyl acetate were added and the resulting mixture was for 2 hours at -5 Stirred to -10 C. The reaction mixture was below 0 C with a

909834/0751 ORIGINAL INSPECTED

saturated aqueous sodium bicarbonate solution adjusted to pH 7 to 7.5, Stirred for 1 hour at pH 7 below 5 C, adjusted to pH 2.5 and filtered. The organic layer in the filtrate was separated and 20 ml of water were added. The mixture was adjusted to pH 6.5 with sodium bicarbonate. The aqueous layer was separated and washed with diethyl ether. The solvent remaining in the aqueous layer was removed by bubbling Nitrogen gas was removed and the aqueous layer was washed with 10 / Siger Hydrochloric acid adjusted to pH 2.5 with ice cooling. the Precipitates were collected by filtration, washed with water and dried, giving 0.7 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (4-nitrobenzoyl) oxyniethyl-3-cephem-4 -carboxylic acid (syn-Isomeres), m.p. 151 to 163 C (dec.), in the form of a pale yellow powder.

IR (Mujol)

3250 - 3350, 2500 - 2G00, 1780, 1725, 1680,

1650, 1600, 1535, 1350 cm * " ¹
NMR (dg-DMSO, ξ)

9.68 (IH, d, J = 8Hz), 8.5 (4H, m), 7.28 (2Ii, s), 6.80 (IH, s), 5.88 (IH, dd, J = 5, 8Hz), 5.24 (IH, d, J = 5Hz), 5.20 (2H, A3q, J = 13Hz), 3.82 (3H, s), 3.72 (2H, ABq, J = 18Hz),

909834/0751

ORIGINAL INSPECTED

- ** "/ :: 05656

Example 11.

In a similar manner in Examples 1 to 10, the following prebindings were made:

(1) 7-f2-Isopropoxyiinino-2- (2-formamidothiazol-4-yl) -acetamido] -3- ( _l, 3,4-thi «Tdiazol-2-yl) thiomothyl-3-ccphem-4-carbo . _acid (syn_jsomeres).

. ..1.R. (Nu; oil): 3300, 3050, 1777, 1727, 1072 cm " ¹ " • NMR Cd ₆ -DMSO, <5): 1.28 (611, d, J = OHz),

3.75 (2H, broad s), 4.4 3 (3H ₁ in), 4.8 ^ 5.6 (IH), 5.90 (IH-, d, d, J = S · '■... Nd-CHzj, 7.4 5 (IH, s), 8.58 (IH,

br s), 9.60 (III, s), 9.77 (IH, d, J-ClIz), 12.80 (IH, br _eit s)

'(2) 7- [2-Pentyloxyimino-2- (2-formamidothiazol-4-yl) -acctamido] -3- (1,3,4-thiadiazol-2-yl) thioracthyl-3-ccphem-4-carboxylic acid (.syn_2somer _es ).

IR (Nujol): 3300, 3250, 1785, 1680 cm " ¹ NMR (d ₆ -DMS0, ΰ): 0.6 ^ 1.9 (9H, m), 3.72 (2H,

wide s), 4.11 (2H, t, J = 6Hz), 4.47 (2H, AB, J «13Hz), 5.18 (IH, d, J = SJU), 5.82 (IH, d, d, J = S and 8IJz ), 7.41 (IH, s), 8.53 (IH, s), 9.57 (IH, -s), 9.64 (lii, d, J = 8Hz), 12.65 (IH, s) 7- [2-butoxyimino-2- (2-formamidothiazol.-4-yl) acetamido] -3- (1-methyl-IH-tetrazol-5-yl) thiomethyl-3-cephem-4-carbonic acid (syn _isomer _es ) _#

I.R. (Nujol): 3300, 2550 ^ 2600, 1775, 1710,

1690, 1670, 1645 era " ¹ NMR (d ₆ -DMSO, 6): 0.90 (3H, m),

909834/0751

ORIGINAL INSPECTED

"*" 2 ^ 05656

'.1.2 * 1.8 (4H,' m), 3.70 (211, AB,

J = ISHz), 3. * 94 (3H, s), 4.12 · ' · · (2H, m), 4.32 (2H, AB, J = 13Hz),

5.1g (IH, d, J-SHA), 5. '8O. (IH, S d ......, d, JS _nd 8 Hz), 7:37 (IH ₁ s) ,.

8.50 (IH, s), -9.62 (IH, d, J = 8Hz) _f 12.G (IH, s) · ·

(4) 7- [2- (2-Propynyloxyimino) -2- (2-formainidothiazol-4-yl) acctamido] -3- (1-methyl ~ 1H-tetrazol-5-yl) thiomethyl • 3-ceplicm-4 -carbo nsbure (syn_isomer _es ) _#

■ IR ₁ (Kujol): 3240, 2110, 1770, 16G5 cm " ¹

NMR, · Cd ₆ -DMSO, C) : 3.49 (IH, m), 3.70 (2H, m), ■ · ■ · .. · 3.96 (3H, ε), 4.33 (2H, ΛΒ,

■ J «15. OHz) ₁ 4.76 (2H, n), p.14

.-. ·; .. (Ill, d _f J «5.0Hz), 5.80 (IH, d, d,

J »5.0 and 8.0Hz), 7.44 (IH, s), 8.53 (IH, s), 9.74 (IM, d,

. J »8.0Hz) '·. .

'(5) 7- [2-Methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-propyl-1H-tctrazol-S-yl) thiomethyl-

3-ccphcin-4-carboxylic acid (S) Ti-I somer _es ).

'IR (Nujol): 3180, 1775, 1665 cm " ¹ · NMR (d _c -DMSO, 6): 0.85 (3H, t, J = 8.0Hz),

1.82 (2H ₁ m), 3.69 (2H, m),

'25 3.88 (3H, s), 4.06M.66 (4H, m),

5.13 (111, d, J = S.OHz), 5.81 (IH, d, d, J = S.0 and 8.0 Hz), 7.42 (IH, S), 8.52 '(IH, s), 9.65 (IH, d, J «= 8.0Hz)

(6) 7- [2-Allyloxyimino-2- (2-formamidothiazol-4-yl] facetamido] -3- (1-propyl-IH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn_isomer _e s).

IR (Nujol): 3180, 1775, 1670 cm " ¹ NMR (d ₆ -DMSO, 6): 0.87 (3H, t, J = 8.0Hz), 1.65 (2H ₁ in), 3.73 (2H, AB _q ,

"· · 909834/0751

ORIGINAL INSPECTED

- ίΓό -

. ... $ Λ ^ 0 56

J «16. OHz), 4.0 0 * 4. S3 {M \ _t m), 4.69 (2H ₁ d, J = 5.0Hz), 5.00 * 5.68. (3H, m), 5.68 * 6.36 (2H, m), 7.4S. (III, s) _t 8.56 (IH, s), 9.72 (IH, 5 'd, J «8.0Hz) ·

(7) 7- [2- (2-Propjmyloxyimino) -2- (2 "- £ ormaraidothiazol-4- - yl) acetamido] -3- (1-propyl-1H-tetrazol - 5-yl) thiomethyl-

3-ccphem-4-carboxylic acid (syn isomer).

'IR (Kujol): 3270, 2125, 1780,' 1680 cm " ¹ -Ή.MR Cd ₆ -DMSO, 6) : 0.87 (3H, 't,' J» 8 .0Hz),

1.B4 (2H, re), 3.50 (IH, m), . P.73 (2H, broad s), 4.03 ^ 4.59 • (4Π, η), 4.78 (2Η, m), 5.17 (IH, d, J-S.OHz),

5.84 IS '. (1 H, d, d, J ^ 5.0 _nd 8.0 Hz),

7.47 (IH ₁ s), 8.56 (IH, s),

"'· 9.76 · (IH, d, J = 8.0Hz)

(8) 7- [2-Isopropoxyiiuino-2- (2-formamidot] iiazol-4-yl) - · acetamido] -3- (1-hydroxy-1H-tetrazol-5-yl) thiomethyl-3-. ccp] ieni-4-cai "bo nsöure (syn-isomeres).

IR (Nujol): 3175, 1780, 1670 cm " ¹ 'NMR Cd ₆ -DMSO, δ): 0.66 (3Η, t, J-5.0Hz), • ... 1.05M..S7 (OH, m), 1.92 (2H,

in), 3.77 (2H, m), 4.1OM.

· · .- '(SH, m), 5.24 (IH, d, J = S.OHz),

5.90 (IH, d, d, J = 5.0 and 8.4Hz), 7.43 (IH, s), 8.56 (IH ,. s), 9.64 (IH, d, J = 8.4Hzj

(9) 7- [2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) - • 30 acetamido] -3- (l-hexyl-1H-tctrazol-5-yl) thiomethyl-3-

cep] iein-4-carbonic acid Csyi ^ -Isomcres).

IR (Nujol): 3175, 1785, 1642 cm " ¹ NMR C ^ ₆ -DMSO, 6): 0.86 (6H, m), 1.0 <Kl.S7 (12H, m), 1.57 <v2.07 (4H, m ), 3.75 (2H, m), 3.97 * 4.60 (8H, m),

90983A / 0751

ORiGiNAL INSPECTED

2305656

5.18 (IH, el, J = S.2Hz), 5.85 (IH, did, J-5.2 and 8.4Hz), 7.41 (IH, ε), 8.56 (IH, s), 9.65 (IH, d,

'■ ·· "■■ ·' · · '■ ·· ■' 'J * 8.4Hz) ·

'5 (IQ) 7- [2-Allyloxyimino-2- (2-formamidothiazol-4-yl) -. '

. ^ .acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-. 3-cephem-4-carboxylic acid (syn isomer _e s).

'lR (Nujol): 3180, 1780 ,. 1680 cm " ¹ ·. NMR (d ^ -DMSO, δ) : 0.64 ^ 1.-97 (HH, m), 3.68 (2Η, AB, J-18Hz), 4.30

(4M, m), 4.64 (2Η, η) , 5.00 ~

. '. .5.46 (3Η, ηι), 5.56 ^ 6.24 (2Η, m),

7.37 (IH, s), 8.48 (IH, s), 9 ^ 67. (IH, d, J = 8Hz) (11) Ben% hydryl 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cyclolicxane-carbonyloxymethyl-3-cephcm-4-carboxylate (syn-I some res). . * · ■ _: '

IR (KBr): 3300, 1780, 1730, 1690, 1630 cm " ¹ NMR (d ₆ -DMSO, 6) ': 1.0 ^ 2.10 (1OH, m),

■ 20 ·. 3.13 (IH, m), 3.60 (2H, br _e its),

• '3.93 (3H ₁ -S) ₁ 4.93 (2H, AB _q ,

5.22 ". (1H, d, '- J« = 5Hz), 5.83 (IH, d, d, J = 5 and 8Hz), 6.87 (IH, s), 6.96 (IH, s), 7.17 ^ 7.67 (1OH, m), 9.70 (IH, d,

. 'J »8Hz)

(12) Benzhydryl 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methoxyphenoxy) acetoxymethyl] -3-cephem-4-carboxylate (syn isomer). · L.R. (Nujol): 3300, 1780, 1725, 1680, 1620 ,.

1530, 1510 cm " ¹

NMR (d ₆ -DMSO, δ): 3.58 (211, broad s), 3.70 (3H, s), 3.87 (3H, s), 4.70 (2H, s), 4.91 (2H, AB _q , J = 14Hz) , 5.22 (IH, d, J = SHz),

909834/07 51

BATH ORIGINAL

... 2üJÜ56b6

5.92 (IH, d, d, J «5 and 8Hz), 6. * 78 ClH, s), 6.88 (4H, s), 6.95 ClH, s), 7.04V / .64 (1011 ,. m), 9.64 (IH, d, J = 8H :;)

. Benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-pivaloyloxymethyl-3-cphem-4- - carb'oxylate (syn-I scmeres). \.

. I.R. (Kujol): '3300, 1780, 1725, 1680, .162O,

1530 cm " ¹

KMR (d _c -DMSO, δ): 1.13 (9H, s), 3.62 (2H,

■ ... broad s), 3.88 (3H ₁ s), 4.86

· ,, (2H, AB, J «14Hz) ', - 5.26 (IH, d,

"■ '. J» 5Hz) ₁ 5.96 (IH ₁ d, d _f J = 5 _and nd

8Hz.), 6.80 (IH, s), 6.98 (IH, s),

'■ ■■ 7.12 ^ 7.68 (1OH, m), 9.73 (IH,

■ .. '■■ · ■' d, J "8Hz)

(14) Benzhydryl 7- [2-methoxyiinino-2- (2-aminothiazol-4-yl) acetamido] -3- (2-thcnoyl) oxymethyl "3-cephem-4-carboxylate (syn -isomeres).
.20 · IR (Nujol): 3300, 1780, 1710, 1670, 1610,

•. 1510 cm " ¹

• NMR "'(O ₆ -DMSQ, δ): 3.V3 (2Η, b ^ it s),

P.87 (3H, s), 5.03 (2H, AB _q , J ° 13Hz), 5.27 (IH, d, J = 5Hz), p.93 (IH, d, d, J = S and 8Hz),

. 6.77 (IH ₁ s), 6.97 (IH, s), 7.1 ^ 7.67 (11H, m), 7.77 ^ 8.1 (2H, m), '9.67 (IH, d, J = 8IIz)

• (15) Benzhydryl-7- [2-ynethoxyinlino-2- (2-aminothiazol-4-yl) acetamido] -3- [N- (3-chlorophenyl) carbamoyloxy-

methyl] -3-cephem-4-carboxylate (syn-isomeres). I.R. (Nujol): 3300, 1770, 1720, 1670, 1600,

1530 cm " ¹

NM R. (d ₆ -DMSO, δ): 3.70 (2H, broad s), ' 3.90 (3H, s), 4.90 (2H, AB _fl , J = 13! U),

90983A / 0751

QRiGJNAL INSPECTED

^ 5.27 (IH, .d, J = 5Hz), 5.93 (IH, d, d, '■■ J »5 and 8Hz), 6.80 (IH, s), 6.97 (IH, s), 6.87 ^ 7.77 (14H , m),! 9.60 (IH, d, J <= 8Hz), 10.00 (IH, s) • 5 '._ (16) Benzhydryl ~ 7- [2-mctlioxyimino-2- (2-aminothiazole-4-

. \ yl ^ acetamido] -3- (N-phenylcarbamoyl'oxymethyl) -3- ■ ... ·· "ccphcra-4-caxboxylate (syn_ isomer _es ).
"· .. '-IR (Nujol): 3300, 1780, 1720, 1675, 1600,

'\ 1530, 1500 cmT ¹ · ...' ■ ·. '

ΙΟ 'NMR (d ₆ -DMS0, C): 3.63 (2H, br s i _{t s),} 3.80

(3H ₁ s), 4.80 (2H, AB. J = 13Hz), p.20. (1H, d, J «5Hz), 5.86 (IH, d, d, 'J» 5 dad 8Hz), 6.73 (IH , s) _t 6.93 (IH, s), 6.83% 7.67 (ISH, m),. 9.57 (IH, d, J-8Hz), 9.73 (111, s)

•. * '(17) 7- [2- (2-r ⁱ ropinyloxyimino) -2- (2-'formamidothiazol-4. ■ yl) acetami.do] -3- ₍₁ I S ^ -th
(syn> isomer _es ) _#

IR (Nujol): 3250, 1780, 1690, 1660, 1620, '. 1550, 1530 cm " ¹

NMR (d ₆ -DMSO, 6): 3.44 (IH, m), 3 ^ 68 (2H _{,. AB q} , J-18HZ), 4.44 (2H, AB _q ,

J »13Hz), 4.74 (2H, m), 5.16 (IH, d, J = SHz), 5.80 (IH, d, d, J-S and'8Hz), 7.44 (IH, s),

8.50 (IH, s), 9.76 (IH, d, J «8Hz) i 12.66 (IH, br _e it s)

(18) 7- [2- Ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-ccphem-4-

carboxylic acid (syn_ isomer _es ).

IR (Nujol): 3300, 1775, 1660 cm " ¹

909834/0751

ORIGINAL INSFECTED

(19) 7 - ^ - Isopropoxyimino ^ - (2-aminothiazol-4-yl) -. acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carbo acid (syn isomer).

IR (Nujol): 3325, 1774, 1656 cm " ¹ • (20) 7- [2 _t -I'entyloxyimino-2- (2-aminothinzol-4-yl) -. Acetamido] -3- (1,3, 4-thiadiazol-2-yl) thiomethyl-3-

cephem-4-carboxylic acid (syn ~ isomer _e s).

, 15. · 'LR (Nujol): 3350, 3200, 1775, 1675 .cm " ¹

•. * '(21) 7- [2-Butoxyimino-2- (2-aminothiazol-4-yl) acctamido] -

3- (1-methyl-1H-tetrazol.-5-yl) thiomethyl-3-cephem-4- _i- carboxylic acid (syn-I somcr es).

lR (Nujol): 3350, 3250, 2550 ^ 2600, 1780 ,. .20 ■ 1700, 1670, 1630 cm " ¹

• ('22 ") 7- [2- · (2-Propinyloxyimino) -2- (2-aminothiazol-4-yl) -acetamido] -3- (1-methyl-1H-te'trazol-5-yl) .thiomethyl-3-cephem-4-carboxylic acid (syn-I somcres).

I, R. (Nujol): 3280, 2130, 1765, 1690, 1630 cm " ¹

• 25 (23) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acctamido] -

3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carbo acid (syn isomer es).

IR (Nujol): 3350, 1780, 1670, 1630 cm " ¹

(24) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] - • 30 3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-.cephcm-4-

carboxylic acid (syn isomer _e s).

IR (Nujol): 3340, 3230, 1780, 1680, 1630 cm " ¹

(25) 7- [2- (2-Propinyloxyimino) -2- (2-aminothiazol-4-yl) -acetamido] -3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-

cephein-4-carboxylic acid (syn-Isomeifes).

909834/0751 ORIGINAL INSPECTED

Dr «: C O 5 6 S

IR (Nujol): 3330, 2150, 1770, 1677, 1635 cm " ¹ (26) 7- [2-methoxyimino-2- (2-aminothiazol.-4-yl) -acetamido] -3- (l-hxyl- lH-tetrazol-5-yl) thiomethyl-.3-

.cephem-4-carboxylic acid (syn isomer _e s).

. '. IR (Nujol): 3350, 3230, "'1777, 1675, 1627 cm" ¹ ' (27) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) - ■ -acetamido] -3- ( 1-hexyl-1H-tetrazpl-5-yl) thiomethyl-3-Cphem-4-carbonic acid (syn-isomer) '.

: ■ IR (Nujol): 3320, 1780, '1675, 1630 cm " ¹
(28) 7- [2-Hcxyloxyimino-2- (2-aminothiazol-4-yl) -. acetamido] -3- (1-hexyl-1H-tetrazol-S-yl) thiomethyl-

5-; cephem-4-carboxylic acid (syn isomer).

• IR (Nujol): 3350, 3230, 1765, 1670, 1615 cm " ¹ (29") 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) - ./.
acetamido] -3- (1-hexyl-1H-tctrazol-S-ylJthiomethyl-S-ccphem-4-carboxylic acid hydrochloride (syn-Isomcres). 'IR (Nujol): 3240, 1780, 1720,. 1675 cm' ¹

* (30) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -

3- [N- (3-chlorophenyl) carbamoyloxymethyl] -S-cephem ^ -

carboxylic acid (syn isomer).

I.R. (Nujol): 3320, 1780, 1710, 1680, 1600,.

1540 cm " ¹

• (31) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acctamido] -

S-cyclohexanecarbonyloxymethyl-S-cephem - ^ - carbonic acid (syn isomer).

909834/0751

ORIGINAL'INSPECTED

· "IR (Nujol): 3300, 1780,. 1730, 1670 cm" ¹ · (32) 7- [2-Methoxyimino-2-C2-aminothiazol-4-yl) acetaraido] ■ • 3- [2 - ^ - methoxyphcnoxy ^ cctoxymethylJ-S-cephem ^ - ·

carbonic acid (syn_isomer es). ·. ·

"5 ·, 1st row (Nujol): 3300, 1780, 1730, 1680, 1635 cm" ¹ ·. '

'(33) 7- [2-Methoxyimino-2-C2-aminothiazol-4-yl) acetamido] · ■ 3-pivaloyloxymethyl-3-cephem-4-carboxylic acid

(syn isomer it). \ '. . . ·

'' lR (Nujol): 3300, 1780, 1720, 1670, 1540 cm " ¹ (34) 7- [2-MetlioxyiminO" 2- (2-aminothiazol-4-yl) acetamido] ·

3- (2-thnoyl) oxymethyl 1-3-CCpHCm-4-carbonic acid ._ (syn-isomer). . . ''

'"IR (Nujol): 3250, 1780, 1710, 1680, 1635, _{.... ·;} " -15301 cm " ¹

• 15 (55) Benzhydryl-7- [2-ynethoxyimino-2- (2-amin'othiazol-4-

yl) acetamido] -3- (4-HItTObCnZOyIoX) TnCtIIyI) -3-ccphem-4 "carboxylate (syn isomer). . · '

IR (Nujol): 3300, 1780, 1720, 1670, 1600 ■ ·. 1520- cm " ¹

• 20 NMR (d ₆ -DMSO, O): 3.43 (2H, broad s),

3.92 (3H, s), 5.08 (2H ₁ AB _q , J = 13 Hz) ₁ 5.2 (IH, d, J «5Hr), 6.00 (IH, d, d, J« 5 Lnd 8Hz), 6.83 (IH, s), 7.00 (IH, s), 7.10 ^ 7.80 (1OH, m),. · 8.15 (2H, d, J = 9Hz), 8.38

(2H, d, J = 9Hz), 9.73 (IH, d, J = 8Hz)

(56) Benzhydryl 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-aminobenzoyloxymethyl) -3-cephem-4-carboxylate (syn-isomer).
* IR (Nujol): 3280, 1780, 1710, 1670, 1605 ,.

1520 cm " ¹

) 7- [2-Methoxyimino-2- (2-aminothiazol-4ryl) acctamido] 3- (4-aminobenzoyloxymethyl) -3-cephem-4-carboxylic acid (syn isomer es).
3S IR (Nujol): 3350, 1780, 1680, 1605, 1540 cm " ¹ x

909834/0751

ORIGINAL INSPFCTFO

7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] - ' 3- (M-phenylcarbamoyloxymethyl) -3-CCpIiCm-4-carboxylic acid

(syn -isomeres). · '· ·. · ". · · IR (Nujol): 3300, 1780, 1710, 1670, IGOO cm" ¹

(39) 7 - [2-Isobutoxyimino-2- (2-amino-1,3-th5.azol-4-yl) acetamido] cephalosporanic acid (syn isomer).

. I R (Nujol)

3400-3200, 1780, 1740, 1660, 1630, 1540 cm " ¹
NMR Cd ₆ -DMSO, 6) '

9.56 (IH, d, J = 8Hz), 6.72 (IH, s), 5.78 (IH, dd, J = 5, BHz), 5.14 (IH, d, J »5Hz), 4.83 (2H, ABq, J = 14Hz), 3.82 (2H, d, .J = 7Hz), 3.54 (2H, ABq, J-r / Hz), 2.02 (3H, s), 1.98 (IH, m), • 0.88 (6H, d, J = 7Hz) '.; ..

(40) 7- [2-Cyclohexyloxyinino-2- (2-amino-1,3-thiazol-4-yl) acetamido] cephalosporanic acid (syn isomer).

R CNujol)

. 3400-3200, 1780, 1740, 1670, 1630, 1530 cm " ¹

NMR Cd ₆ -DMSO, δ).

9.46 (IH, d, J = 8Hz), 6.72 (IH, s), 5.76 (IH, dd, J = 5,: -. 8Hz), 5.10 (IH, d, J = 5Hz), 4.84 (2H, ABq , J = 13Hz), 4.00 (IH, m), 3.50 (2H ₁ wide s), 2.00 (3H ₁ s), 1.00-2.00 (10H, m)

909834/0751

ORIGINAL. INSPECTED

. $ 3, ^: j05656

(41) 7- [2- (2-propynyl) oxyimino-2- (2-amino-.l, 3-thiazol-4-yl) acetamido] cephalosporanic äure _S isomer).

R (Nujol)

3310, 1780, 1740, 1670 cm " ¹

NMR Cd ₆ -DMSO.6)

9.72 (IH, d, J-SHz), 7.3 (2H, m), 6.83 (IH, s), 5. € 3 (IH, dd, J-5, 8Hi), 5.20 (IH, d, J = 5Hz), 4.87 (2H-, · ·

ABq, J = UHz), 4.77 (2H, d, J = 2Hz), 3.60 (2H, m), 3.50 (IH, m),? .Ll (3H, s)

(42) 7- [2-'Propoxyimino-2- (2-amino-1,3-thiazol-4-yl) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carbic acid (syn isomer).

IR (Kuj ol)

3400-3200, 1780, '1670, 1630, 1535 cm " ¹ NMR (d ₆ -DMSO, δ)

9.57 (IH, d, J = 8Hz), 6.72 (IH, s), 5.77 (IH, dd, J = S, 8Hz), 5.13 (IH, d, J «5Hz), 4.30 (211, ABq, J = 14Hz), 4.02 (2H, t, J = 7Hz), 3.93 (3H, s),. 3.69 (2H, ABq, J = 18Hz), 1.64 (2H, m), 0.90 (3H ₁ t, J = 7Hz)

909834/0751

ORIGINAL INSPECTED

So·

CO) 7- [2-pentyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) t>' thiomethyl-3 -cephem-4-carboxylic acid - (syn-Isomeifes). R (Nujol)

3300, 1770, 1660, 1630 cm " ¹ NMR Cd ₆ -DMSO, δ)

9.52 (IH, d, J = 8Hz), 7.20 (2H, m), 6.68 ClH, s), 5.74 ClH, dd, J = 4, 8Hz), 5.10 (IH, d, J = 4Hz), 4.30 C2H, ABq, J = 13Hz), 4.02 C2H, t, J = 6Hz), 3.90 (3H ₁ S) ₁ 3.66 (2H, ABq, J = 18Hz) \ ' 1.60 C2H, m), 1.30 C * H, m), 0.82 C3H, t, J = 6Hz)
(44) 7- [2-Hexyloxyimino-2-C2-amino-1,3-thiazol-4-yl] -

90983A / 0751

INSPECTED

acetamido] -3- (1-methyl-IH-tetrazol-5-yl) thioniethyl.r _Ί , - -. , ,,

/, -JDbDO

3 »cephem-4-carboxylic acid (syn-isomeres).

Ί R (Nujol) '

3350, 3250, 1780, 167θ \ 1630 cm " ¹ .

.NMR Cd ₆ -DMSO, δ) '_ \

, 10.25 (IH, d, J = 5Hz), 7.25 (2Η, m),

6.73 (IH, ε), 5.77 (IH, dd, J = 5, 8Hz), 5.13 (IH, d, J = SHz), 4.17 (2H, m), ■ '" _v 3.91 (3H ₁ s)., 3.67 (2H, -m), 1.33 (SH, .0 n), 0.83 (3H, m)

(45) 7- [2-Ethoxyimino * 2- ^ -formamido-1- ^ -thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephcm-4-carboxylic acid (syn isomer).

. I R (Nujol)

IS '... 3500, 3300, 1780, 1710, 1660 cm " ¹

NMR (O ₆ -DMSO, δ)

9.67 (IH, d, J = 8Hz), 8.53 (IH, s), 7.43 (IH, s), 6.58. (1H, s), 5.87 (IH, dd, J = S, 8Hz), 5.23 (IH, d, J = SHz), 4.80 (2H, ABq, J = 13Hz), 4.23 (2H, q,

• J = 7Hz), 3.57 (2H, br _e it s), 1.3 (3H, t, J = 7Hz)

(46) 7- [2-Ethoxyimino-2- (2-amino-1 ", 3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-

^ ⁵ carboxylic acid (syn isomer).

R (Nujol)

3300, 3200, 1780, 1720, 1660 cm " ¹ NMR (d ₆ -DMSO, 6)

9.58 (IH, d., J = 8Hz), 7.33 (III, broad s), 6.77 (IH ₁ s), 6.58 (IH, s),

9098 * 4/0751

ad original

5.83 (IH, dd _t J = 4, GHz), 5.2CC

d, JMHz), 4.77 (2H, ABq, J = 12Hz), ^J ° ^Q 4.16 (2H, q, J = 7Hz), 3.53 (2H, broad.s), .1-23 (311, t, J- 7Hz)

S. (47) 7- [2-propoxyimino-2- (2-formamido-1,3-thiazole-

. "" 4-yl) acetamido] -3-carbamoyloxyjneihyl-3 ~ cephem-4-carbo acid tert. • (syn ~ _e Isomei- s). / · ■

'I R (Nujol)'. . ·. ·. ·

_v . 3250, 3200, 1780, 1700, 1660, 1525 cm " ¹ NMR Cd ₆ -BMSO, 6)

■ .9.62 (IH, d, J «8Hz), 8.50 (IH, s), 7.43 (IH, s), 6.57 (2H, br _e it s),

5.84 (IH, dd, J = 5.8Hz) ₁ "5.18 (IH, d, J = 5Hz), 4.58 (2H, ABq, J = 13Hz), 4.08

5-5 (2H ₁ t, J = 7Hz), 3.54 (2H, ABq, J-18Hz),

1.68 (2H, in), 0.92 (3H, t, J = 7Hz)

(48) 7- [Z-Isobutoxyiiriino ^ - (2-for> namido-l, 3-

tlii a zo 1-4 -yl) acetamido] - S-carbamoyloxymethyl-S-cephem-4-carboxylic acid (syn isomer it).

IR (Nujol) '

3450, 3300, 1780, 1710, 1680, 1610 cm " ¹ NMR (d ₆ -DMSO, δ)

9.6 (IH, d, J = 8Hz), 8.5 (IH, s), 7.18 (IH, s), 6.6 (2H, br _e it ^s ) »p.8 (IH, dd, J = 5, 8Hz), 5.15 (IH, d,

J = 5Hz), 4.76 (2H, ABq, J = 13Hz), 3.84 (2H, d, J = 6Hz), 3.5 (2H, ABq, j = 18Hz), 2.04 (IH, m), 0.88 (6H, d, J = 6Hz)

(49) 7- [2-Isobutoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-

909834/0751

<* ■ ■

BATH ORIGINAL

. - 93-

'carboxylic acid (syn isomer).

IR (Nujol). .

3300, 1770, 1730, 1660 cm " ¹ N .MR (d ₆ -DMSO, δ)

P.SS (IH, d, J = 9Hz), .7.27 (2H, br _e it

s), 6.73 (IH, s), 6.60 (IH, br _e it s),

5.83 (IH, dd, J = S, 9! Iz), 5.20 (IH, d,

•. J = SHz), 4.'80 (2H, ABq, J = - 12Hz), 3.87 ·

(2H, d, J = 7IIz), 3.53 (2H,. ABq, 'J = 18Hz), LO. 0.90 (GH, d, J = 7Hz)

(50) • 7- [2-A13yloxyimino • 2- (2-amino-1,3-thiazol-4-yl) acetamido] -S-carbarAoyloxymethyl-S-cephem - ^ - carbonic acid (syn isomer es).

"_; IR (Nujol) .. · ■" ·

3300, 1770, 1720, 1660, 1030 cm " ¹

NMR Cd ₆ -DMSO, δ), .. · .. ' .9.82 " (IH, d, J-BHz), 7.20. (2H, m), 6.92 (IH, s), 6.7 (2H, m), 6.0 (IH, m), 5.80 (IH, dd, J = 5, "8Hz), 5.40 (111, πι), 5.22 (IH, m), 5.13 (IH, d, J = 5Hz),

4.70 (2H ₁ ABq, J = MHz), 4.65 (2H, m), 3.50 (211, ABq, J = 16Hz)

(51) 7- [2-propoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazbl-2-yl) thiomethyl-3-

cephem-4-carboxylic acid (syn -isomeres) ..

R (Nujol)

3400-3200, 1780, 1670, 1625, 1540 cm " ^1. NMR Cd ₆ -DMSO, δ).

9.50 (IH, .s), 9.50 (IH, d, · J = 8Hz), ■ 6 ".68" (IH, s), 5.74 '(IH, dd, J = 5,

90983A / 07 51
^f ORIGINAL INSPECTED

-73 -

5.12 (IH ,: d, J »5Hz), 4.40 (? .H, ABq, rj cg ·· g J« = 14Hz), 3.98 (2H, t, 'J = 7Hz), 3.66 (2H, ■ ABq, J = 17Hz), 1.62. (2H, m), 0.87 (3H _f

t, J ° 7Hz)

(52) 7- [2-Ethoxyimino-2- (2- £ ormamido-1,3-thiazol- 4-yl) acetamido] -3- (IH-1,2,3-triazol-5-yl) thiomethyl-

3-ceph \ 2m-4-carboxylic acid (syn isomer).

j R (Nujol)

'^ · 3500, 3200, 1780, 1670/1620 cm " ¹

NMR (d ₆ -DMSO, δ) "· ■ '.'.- ■

9.64 (IH, d, J «8Hz), 8.5 (IH, s), 7.9 (IH, s), 7.4 (IH, s), 5.76 (IH, dd, J-4, 8Hz), 5.14 (IH, d, J = 4Hz), 4.1 (2H, q, J-7Hz), 3.92 (2H, ABq, -

I ⁵ 'J »13Hz), 3.58 (2H, ABq, J = 18Hz),

1.26 (6H, t, J = 7Hz)

(53) 7- [2-Ethoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (IH-1,2,3-triazol-5-yl) thiomethyl- 3-cephem-4-carboxylic acid (syn isomer).

I R (Nujol)

3350, 3150, 1770, 1670 cm " ¹ NMR (d ₆ -DMSO, δ)

9.56 (IH ₁ d, J = 9Hz), 7.92 (IH, s), 7.28 (IH, m), 6.75 (IH, s), 5.75 (IH, dd, J = 5, 9Hz), 5.06 (IH, d , J = 5Hz),

4.05 (2H, q, J * = 7Hz), 3.9 (2H _1. M), 3.64 (2H, ABq, J = 17Hz), 1.24 (3H, 't, J = 7Hz)

(54) 7-i2-propoxyimino-2- (2- £ ormamido-1,3-thiazol-4-yl) acetamido] -3- (IH-1,2,3-triazol-5-yl) thiomethyl-

90983A / 075.1

ORIGINAL INSPECTED

% 5

3-ccphcrn-4-carboxylic acid (syiv isomeres). : ..

■ · .. · ■ ■. . ■ j: ubbbS

3300-3100, 1780, 1680, 1650, "1550 cm" ¹ NMR Cd ₆ -DMSO, 6)

S 9.62 (IH, d, J = EHz), 8.50 (IH, s), "

7.92 (IH, ε), 7.38 (IH, s), 5.78 (IH, 'dd, J = S, EIIz), 5.15 * (IH, d, J = SHz), .4.20-3.70 (4H, m), 3.65 (2H, ABq, J = 17Hz), . .1.66 (IH, in), 0.90 (SH, t, J = 7Hz)

(55) 7- [2-Propoxyimino-2- (2-amino-1,3-thia'zol-4-yl) -acetamido] -3- (IH-1,2,3-triazol-5-yl) thiomethyl-3-cephcm-4-cai'boxylic acid (syn isomer).

■■ I.R (Mujol)

3400-3100, 1770, 1670, 1.630, 1530 cm " ¹ IS NMR Cd ₆ -DMSO, 6)

9.58 (IH ₁ d, J = 8HO, 7.97 (IH, ε), 6.77 (IH, s) ", 5.78 (IH, dd, J = S, 8Hz), 5.18 (IH, d, J = SHz), 4.23 -3.76 (4H, m),

■ ·

3.67 (2H, broad s), 1.67 (2H, m), 0.93 (3H, t ", J = 7Hz)

(56) 7- [2-Isopropoxyimino-2- (2-amino-1,3-thiazol · 4-yl) acetamido) -3- (1H-1,2,3-triazol-5-yl) thiomethyl- 3-cephem-4-carbonic acid (syn isomer _e s).

R (Nujol)

3300, 3150, 1780, 1670, 1640 cm " ¹

NMR (d ₆ -DMSO, 6)

9.50 (III, d, J = 9Hz), 7.97 (IH, s), 6.73 (IH, s) ,: 5.77 (IH, dd, J. = 5, - 9Hz), 5.17 (IH, d, J = 5Hz), 4.33 (IH, m), 4.0 (2H, ABq, J = 13Hz), 3.67 (2H, ABq,

J-IBHz), 1.23 (6H, d, J = 6Hz) 90983A / 0751

ORIGINAL INSPECTED

-75-

7 "[2-Isobutoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1 H-l ', 2,3-triazol-5-yl) thioin-ethyl" 3-ccphem -4-carboxylic acid (syn .. isomer _es ). "'■' ■ _;

3470, 3320, 3200, 3160, 1770, 1660 cm " ¹

NMRC ^ ₆ -DMSO, 6) ■. . ·. . '■ -. . ,

9.57 (IH, d, J = PHz) -, 7.97 (IH, s),

• *. ■

7.22 (2H, 'broad s), 6.75 (IH, - s),' 5.77 (IH, dd, JS, 9Hz), - 5.18 (IH, 'd _f J «5Hz), 4.03 (2H, ABq, J = 12Hz), 3.88

(ZH, d, J = 6Hz), 3.70 (2H, ABq, J = ISHz), ZO (IH ₁ in), 0.92 (6H, d, J = GHz) (5 ^) 7- [2 '(2- Propynyl) oxyimino "2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1H-'l ', 2,3-triazol ~ 5-yl) -j5 thiomethyl-3- ccphera-4-carbonic acid (syn-isomeres),

IR (Nujol)

3320, 3150, 1770, 1670, 1630 cm " ¹ NMR (d ₆ -DMSO, 6) ■ '

9.67 (IH, d, J "8Hz), 7.98 (IH, s), 6.83 (IH, s), 5.75 (IH, .dd, J = 4, 8Hz),

5.18 (IH, d, J = 4Hz), 4.77 (2H, m), 4.0 (2H, ABq, J = I3Hz), 3.70 (2H, ABq, J = ISHz), 3.48 (IH, m) '

909834/0751

ORIGINAL INSPECTED

(59) 7- [2-Icopropoxyimino - 2- (2-aminothiazol ~ 4-yl) acetainido] J-carbaraoyloxyraethyl- ^ - cephem ^ -carbo nsciure (syn-

Ioomeres).

-1

I.R. (Nuj oil): 3300, 3200, 1700, 1720, 1640 cm

(60) 7 ~ [2-Propoxyimino-2- (2-aminothiazol-4-yl) acetamido] ~ 3-carbaraoyloxy methyl-3-cephem-4-carbo nsciure hydrochloride (syn -isomeres).

I.R. (Nujol): 3350, 3200, 1770, 1720, 1665, 1630, 1550 cm"

(61) 7- [2-Isopropoxyimino-2 ~ (2-aminot) iiazol "4-yl) acetanido] -3- (1-methyl-1H-tetra2ol ~ 5 ~ yi) thiomethyl ~ 3-cephem-4-carboxylic acid (syn-l'joaeres).

IR (Nujol): 3330, 3250, 1780, 1680 cm " ¹

(62) 7- l2-Methoxyimino-2-i2- (2, 2, 2-trifluoroacetamiäo) -1,3 ~ thiazol-4-ylT acetamido] -3- (4-nitrobenzoyl) oxymethyl-3-cephein- ·

909834/0751

4-carboxylic acid (syn-I someres), pale yellow powder. · «- ^ 56.56

.. IR - '(NuJOl). '9 ^'

3200, 2500 - 2600, 1785, 1720, 1680, 1G50, 1600,. 1525, 1355 cm " ¹
NMR (dg-DMSO, S)

.9.80 (IH, d, J = BHz), 8.4 (4H, m), 7.60 "(IH, s), 5.78 (IH, dd, j» 5, 8Hz), 5.25 (IH, d, J = 5Hz), 5.15 (2H, ABq, J = 13Hz), 3.94 (3H, s), 3.75 (2H, ABq, J = 18Hz)

C55) 7- [2-methoxyimino-2- (2-amino-1,3-thiazoi-4-yl) acetamido] -3-benzoyloxymethyl-3-cephem-4-carbo acid (syn-I someres). IR (Nujol).

3300, 1780, 1720, 1680 cm * " ¹ '' \ ■

NMR (d ₆ -DMSO, .S) '

9.63 (IH, d, J = 8Hz)., "7.87 - 8.1 (2H, m), 7.48 - 7.75 (3H, m), 6 * .75 (IH, s), 5.83 (IH, dd, J = 5, 8Hz), 5.19 (IH, d, J = 5Hz), 5.15 (2H, ABq, J = 13Hz), 3.83 (3H, s),

3.72 (2H, broad s) ·.

{54) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-phenylacetoxymethyl-3-cephem-4-carbo nsöure (syn isomer). IR (Nujol)

3350, 3300, 1780, 1710, 1660, 1542, 1535, 1460, 1400, 1380, 1320, 1280, 1260, 1240, 1130, 1115, 1065, 1042, 965, 720 cm " ¹ NMR. (Dg-DMSO, ζ )

7.33 (511, s), 7.23 (2H, br _e it ^s ) ' ^{6 78} ( ^1H * ^s >' 5.81 (IH, dd, J = 4, 8Hz), 5.16 (IH, d, J = 4Hz), 4.78 md 5.06 (2H, ABq, J = 8Hz), 3.9 (3H, s),

3.73 (2H, s), 3.5 (2H, br _e it s)

909834/0751

Original inspected

- 78 -

. 99

(65) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido]: ~ 3 · hexanoyloxyinethyl-3-cephera-4 ~ carbo nsäuro (syη-isomeres). ·

• -

IR (Nujol).

, .3350 ,. 3300, 1780, 1700, 1660, 1535, '.

1460, 1400 ·, 1375, 1340, 1315, 1280, 1255, ■

.1045 cm " ¹
Nl-IR (dg-DMSO, S)

■ 9.63 (IH, d, J = 8Hz), 7.24 (2K, br _e it s), 6.76 (IH, s), 5.01 (III, dd, J = 4, 8Hz), 5.17 (IH, d, J = 4Hz), 4.75 and 5.03 (2H, ABq, J = 12IIz), 3.84 (3H, s), 3.45 and 3.67 (2H, ABq, J = 18Hz) , 2.32 (2H, t, J = 8Hz), 1 - 1.7 (GH, m), 0.85 (3Ii, t, J = 3Hz)

(66) 7- [2-Methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) -acetamido] -3- (2-benzothiazolyl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR (Nujol)

3200, 1780, 1680, 1620, 1545, 1460, 1435, 1385, 1040, 1000 era " ¹

NMR (d, -DMSO, S)
ο

9.7 (IH, d, J = 8Hz), 8.53 (IH, s), 7.66 - 8.16 (2H, m), 7.16 - 7.66 (3H, m), • 5.83 (IH, dd, J = 5, 8Hz), 5.18 (IH, d, J = 5Hz) , 4.23 and 4.81 (2H, ABq, J = 15Hz), 3.93 (3H, s), 3.73 (2H ₁ broad s)

909834/0751

BATH ORIGINAL

(67) 7- ^ -Propoxyimino ^ - (2-forniamidothiazol-4-yl) acetamido] - 3-methyl-3-cephem-4-carboxylic acid (syn -isomeres).

I.R. (Nujol): 3450, 3300, 1775, 1725, 1680,

1055, 1620, 1590, 1555 cm " ¹

NMR Cd ₆ -DMSO.6): 0.88 (311, t, J = 7Hz),

1.67 (2H, m), 2.00 (3H, s), 3.43 (211, AB, J = UHz), 4.03 (2H ₁ t, J = 7Hz), 5.10 (IH, d, J = SHz), 5.75 (IH , d, d, J = 5 and 8 Hz), 7.40 (IH, s), 8.53 (IH, ε), 9.60 (IH, d, J = 8Hz), 12.7 (IH, wide s)

(68) 7- [2-Hexyloxyimino-2- (2- £ ormamidothiazol-4-yl) acetamido] - 3-ethyl- 3-cephem-4-carbonic acid (syn_ Isomer).

• I.R. (Nujol): 3310, 3230, 3080, 1780, 1690,

1660 cm " ¹
NMR (d ₆ -DMSO.6): 0.6-2.2 (HH, m),

2.05 (311, s), 3.64 (2H, AB, J = 19Hz), 4.12 (2H, t, J = 6Hz), 5.13 (IH, d, J-SHz), 5.74 (IH, d, d, J-S and 8Hz), 7.41 (IH, s), 8.52 (IH, s), 9.57 (IH, d, J = SHz), 12.69 (IH, broad s)

(69) 7- [2-Propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-methyl-3-cephem-4-carbo acid (syn -isomer).

IR (Nujol): 3300, 1775, 1655, 1635, 1545 cm " ¹

(70) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] ■ 3-methyl-3-cephem-4-carbonic acid (syn -isomeres).

I.R. (Nujol): 3420, 3170, 3070, 1765, 1720,

1670, 1630 cm " ¹

909834/0751

> ORIGINAL INSPECTED

2 over 6 56

- 96 -, AOA

Example T2

0.85 g of concentrated hydrochloric acid was added under ice-cooling to a stirred solution of 2.3 g of 7- [2-ethoxyimino-2- (2-formamidothiazol ~ 4 ~ yl) acetamido] -3-0 , 3,4-thiadiazol-2-yl) thiomethyl-S-cephem ^ -carboxylic acid (syn-Isomeres) in a mixture of 23 ml of methanol and 23 ml of tetrahydrofuran was added and the mixture was Stirred for 2.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous sodium bicarbonate solution (pH 7.0). The aqueous solution was washed with ethyl acetate and adjusted to pH 3.5 with concentrated hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 1.865 g of 7- [2-ethoxyimino-2- (2-gminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2 -yl) thiomethyl-3-cephcm-4-carboxylic acid (syn-isomer) received in the form of a powder,

IR (Nujol): 3300, 1775, 16C0 cm " ¹ NMR Cd ₆ -DMSO, δ): 1.67 (3H, t, J = 7.6 Hz),

3.75 (? .H, to), 4.16 (2H, q, J = 7.6Hz), 4.48 (2H, ΛΒ, J = 13.6Hz), 5.18 (IH, d, .J = S.2Hz), 5.83 (IH , d, d, J- = 5.2- and 8.0Hz), 6.79 (IH, s), 7.38 (2H, br _o it s) ,. 9.63 (IH, s), 9.63 (IH, d, J = 8.0Hz)

909834/0751

ORlGlNAt INSPECTED

B EISP iel 13

2.1 g of concentrated hydrochloric acid was added under ice cooling and with stirring to a solution of 6.0 g of 7- [2-l-ethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (i-hexyl-l H-tetrazol-5-yl) thiomethyl-S-cephem - ^ - carboxylic acid (syn-isomeres) in 60 ml of methanol was added and the mixture was allowed to stir for 4 hours at ambient temperature touched. The solvent was removed from the reaction mixture and 50 g of ethyl acetate was added. The mixture was taking Stirring adjusted to pH 7.0 with a saturated aqueous sodium bicorbonate solution. The aqueous layer was separated with ethyl acetate washed and adjusted to pH 3.5 with concentrated hydrochloric acid. The precipitates were collected by filtration, washed with water and dried under reduced pressure, giving 4.62 g of 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamidoJ-3- (i-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres) received.

IR (Nujol): 3350, 3230, '1777, 1675, 1627 cm' ¹ NMR Cd ₆ -DMSO, 6): 0.82 (3H, t, J = 5.0Hz) ,.

1.23 (6H, _m ) _f i _{# 80 (2H> m) f}

3.69. (2H, m), 3.85 (3H, s), 4.05M.63 (4H, m), 5.12 (IH, d, J-5.0HZ), 5.75 (HI, d, d, J = S.0, 8.6Hz), 6.76 ClH, s), 7.23 C2H, wide s), 9.59 ClH, d, J = 8.6Hz)

Example 14

1 ml of concentrated hydrochloric acid was added to a solution of 1.3 g of 7- [2-isopropoxyimino-2- (2-formamido-l _/ 3-thiazol-4-yl) -acet-

90983A / 0751

f. ■ ■

ORIGINAL INSPECTED

i 8 ü 5 6 5 6

ami do] -3-carbamoyloxymet hy l-3-cephein-4-carboxylic acid (syn-Isorneres) was added in a mixture of 10 ml of tetrahydrofuran and 10 ml of methanol. The mixture was stirred at ambient temperature for 3.5 hours and then concentrated to dryness. Water was added to the residue and sodium bicarbonate was added to the mixture to form a solution. The solution was adjusted to pH 3.0 with concentrated hydrochloric acid under ice-cooling. The precipitates were collected by filtration, washed with water and dried to give 0.25 g of 7- [2-isopropoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl- 3-cephem-4-c.arbon-

acid (syn isomer).
IR (Nuj oil)

3300, 3200, 1780, 1720, 1640 cm "

NMR Cd ₆ -DMSO, δ)

9.48 (IH, d, J = 8Hz), 7.24 (2H, broad s),. 6.7 (IH, s), 6.54 (IH, s), 5.75 (IH, dd, J = 5 _t 8Hz), 5.16 (IH, d, J = SHz), 4.72 (2H, ABq, J = 13Hz), 4.3 (Him),

3.5 (2H, broad s), 1.22 (6H, d, J = 6Hz) Example 15

0.5 g of 7- [2-propoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamide] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-Isomeres) were in 15 ml of methanol suspended. To the suspension was added 0.2 ml of concentrated hydrochloric acid and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated and the residue was washed with tetrahydrofuran, collected by filtration and dried to give 0.4 g of 7- [2-propoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] ~

909834/0751

- 05656

S-carbamoyloxyi.iethyl-S-cephem - ^ - carboxylic acid hydrochloride (syn-Isomeres) received, j _{R (Nujol)}

3350, 3200, 1770, 1720, 1665, 1630, 1550 cm " ¹

Beis p iel Io

NMR Cd ₆ -DMSO, <S)

9.82 (IH, d, J = SHz), 6.98 (IH, s), 5.80 (IH, dd, J = 5, 8Hz), 5.22 (IH, d, J = SHz), 4.80 (2H, ABq, J = 14Hz), 4.15 (2H, t, J = 7Hz), 3:58 (211, broad s), 1.72 (2H, m), 0.92 (3H, t, J = 7Hz)

1 ml of concentrated hydrochloric acid became a solution of 1.5 g of 7- [2-isopropoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- (1-methy1-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomeres) in a mixture of 12 ml of tetrahydrofuran and 12 ml of methanol are added. The mixture was stirred at ambient temperature for 3.5 hours and then concentrated to dryness, Water was added to the residue and sodium bicarbonate was added to the mixture to form a solution. the Solution was taken with concentrated hydrochloric acid Ice cooling adjusted to pH 3.0. The precipitates were collected by filtration, washed with water and dried, whereby 0.8 g of 7- [2 ~ isopropoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (i-met hy1-1H-tctrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres) received.

909834/0751

ORIGINAL

-JM-

I R (Nujol)

3330, 3250, 1780, .1680 cm " ¹ NMR ((I ₆ -DMSO, 6)

9.50 ClH, d, J = 8Hz), 6.70 ClH, s), 5.83 ClH, dd, J = 5.8Hz), 5.17 (IH / d, J «5Hz), 4.33. (2H, br _e it s), 3.97 (3H, s), 3.71 (ZH, br _e .it s), 1.25 (6H, d, J = 6Hz)

Example 17

A solution of 1.1 g of 7- [2-methoxyimirio-2- | 2- (2,2,2-trifluoroacetamido) r1,3-thiazol-4-yl \ acetamidou-S-benzoyloxymethyl-S-cephem-4-carboxylic acid (syn-isomeres) in 4 ml of acetone was added at ambient temperature to a solution of 2.4 g of sodium acetate trihydrate in 10 ml Water was added and the mixture was left to stand for 3 hours at ambient temperature ditched. The acetone was distilled off under reduced pressure and 10 ml v / water was added. The received Mixture was made with 10% hydrochloric acid while cooling with ice adjusted to pH 2.5. The precipitates were collected by filtration, washed with water and reduced under reduced pressure Pressure dried, whereupon 0.62 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomeres) received.

IR (Nujol)

3300, 1780, 1720, '1680 cm " ¹ KMR (d ₆ -DKSO, J)

9.63 (IH, d, J = BHz), 7.87 - 8.1 (2H, m),

7.48 - 7.75 (3H, m), 6.75 (IH, s),

5.83 (III, dd, J = 5, 8Hz), 5.19 (IH, d, J = 5Hz),

5.15 (211, ABq, J = 13Hz), 3.83 "(3H, s),

3.72 (2H, broad s)

909834/0751

ORiGiMAL INSPECTED

ubbbö

Example 18

The compounds listed below were based on similar Way prepared as in Examples 12 to 17:

(L) 7- [2-Isopropoxyimino-2- (2-aminotl) iazbl-4-yl) - • "acetamido] ^ - (1,3,4-thiadiazol-2-yl) thiomethyl-3-

cephem-4-carboxylic acid (syn-I some res).

IR (Nujol): 332S, 1774, 1656 cm * ¹ NMR- (d ₆ -DMSO, J): 1.22 (6H, d, J = 6Hz),

3.70 (2H, broad s), 4.37 (3H, m),

• ... · "· 5.15 ClH, d, J = SHz), 5.77 ClH, d, d,

- ...'.-; · J ^C 5 and 8Hz), '6.70 (IH, s), 7.20

.. {2H, m), 9.50 ClH, d, J = 8Hz), 9.55 ClH, s) ''

(2) 7- [2-pentyloxyimino-2- (2-aminothiazol-4-yl) -

acctamido] -3-Cl | 3,4-thiadiazol-2-yl) thiomethyl-3-phern-4-carboxylic acid C ^s y ⁿ -I ^somcr es).

IR / (Nujol): 3350, 3200, 1775, 1675 cm " ¹ NMR Cd ₆ -DMSO, 6) : 0.62 ^ 2.0 (9H, m), 3.72

(2H ₁ broad s), 4.06 C2H, t, J = 6Hz), 4.4S * (2H, AB, J = 13Hz), · 5.17 ClH, d, J »5Hz), 5.78 ClH, d, d, J« 5 and 8Hz) -, 6.73 ClH, s), 7.2 (211, s) _r 9.5 (IH, d, J-8Hz), 9.55 (IH, s)

O) 7- [2-Butoxyimino-2-C2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tctrazol-5-yl) thiomethyl-3-ccphcm-4-carboxylic acid (syn-Isomeres ),

I.R. (Nujol): 3350, 3250, 2550 ^ 2600, .1780,

1700, 1670, 1630 cm ' ¹

909834/0751

ORIGINAL INSPtCVtD

IZ Ü bb 5

NMR (Cl ₆ -DMSO ₁ 6): 1.0 (311,. M), 1.2 * 1.7 (4Η,

in), 3.77 (2H, AB. J-19Hz), 3.95 (3Η, s), 4.15 (2H, in), 4.33 (2H ₁ ΛΒ ·, Jp13Hz), 5.20 (IH, d, J = 5Hz) »

5.82 (IH, d, d, J = 5 _; 8Hz), 6.73 (IH, s), 9.56 (IH ₁ d, J = -8Hz)

Φ) 7- [2- (2-Propinyloxyimino) -2- (2-arainothiazol-4-yl) - • acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-

3-cephem-4-carboxylic acid (syn isomer).

'iR (Nujol): 3280, 2130, 1765, 1690, 1630 cm "NMR (d ₆ -DMSO, S) : 3.45 (IH, m), 3.70 (2H ₁ m),

3.96 (311, s), 4.33 (2H, AB _q , J-16Hz),

4.71 (211, .κι), 5.14 (IH, d, J-5.0Hz) / 5.79 (IH, d, d, J-5.0 _y nd 8.0Hz), 6.79 (IH, s), 7.65 (2H, br _e it s), 9.33 (IH, d, J = 8.OHz)

(5) 7- [2-MCtIiOXyImIHO-Z- (2-aminothiazol-4-yl) acetamido] 3- (l ~ propyl - lH-tctrazol ~ 5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

• IR (Nujol): 3350, 1780, 1670, 1630 cm " ¹ NMR Cd ₆ -DMSO, 6): 0.07 (3H, t, J = 7.0Hz),

1.84 (2H, m), 3.73 (2H, broad s), 3.89 (3H ₁ s), 4.06- ^ 4.72 (4H, m), p.14 (IH, d, J = S.OHz), 5.80 (IH ₁ d, d, J «5.0 and 8.0Hz), 6.78 (IH,. S), · 7.23 (2H, broad s), 9.59 (IH, d, J« 8.0Hz)

(6) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acet «imido] -. 3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-ccphem-4-

carboxylic acid (syn isomer).

IR (Nujol): 3340, 3230, 1780, 1680, 1630 cm " ¹ NMR (d _c -DMSO, 6) : 0.86 (3H, t, J = 7.0Hz), ·

1.83 (2H ,. m), 3.71 (211, br _e it s) ,. 4.05M. 80 (GH, m), 5/01 * 5.53 (3H, m), 5.63 ^ 6.42 (2H, m), 6.75 (IH, s), 7.20 (2H, broad s), 9.59 (IH, d, Je8

909834/0751

ORIGINAL INSPECTS ©

(D 'V- [2- (2-propinyloxyimino) ·?, - (2-aminothiazol-4-yl) -acetamido] -3- (1-propyl-1H-tetrazol-5-yl) thioethyl-3-cephein -4-carbo nsciure (syn isomer).

IR (Nujol): 3330, 21S0, 1770, 1677, 1635 cm " ¹ KMR Cd ₆ -DMSO, δ): 0.86 (3H ₁ t, J«?. 0Hz) _f

1.84 (211, τη), 3.4 9 (IH, m), 3.73 (211, τη), 3.91 ^ 4.60 (411, m), 4.75 (211, m), 5.17 (IH, d, J = 5.0 Wv.) , 5.80 (IH d, d, J = 5.0 _{a nd} 8.0Hz), 6.86 (IH, s), 9.72 ₍₁ UI d, J = O.OHz) ·

(. 8) '/ ■ · [2- Isopropoxyimino-2 "(? _2-; minothiazol-4-yl) -, ncet.am5.r3o] -3- (1-hcxyllH-tetrazol-5-yl) thioncthyl- 3-cojihem- ¹ '; -carboxylic acid (syn.-I.sdincrbs). ·'. "

^: iR (Nujol): 3320, 1780, 1675, 1630 cm " ¹ .KMR (d ₆ -DMSO, 6): 0.84 (3H, t, .J = COHz),

1.00 * from left D0 (12H, m), 1.80 (2H, m), 3.72 (2H, AB, J-I7.OHz), 4.10 ^ 4.60 (511, in), 5.15 (IH, d, J = 5.0 Hz ), 5.81 (IHj d, d, J = S.0, 8.0Hz), • 6.77 (IH, s), 9.59 (IH, d, J-8.0 Hz)

(9) 7- [2-llexyloxyimino-2- (2-aminothiaz61-4-yl) acct: am5.do] 3- (L-hexyl-1H-tctrazol-5-yl) thiomethyl-3-ccphcni-4-carbo acid (syn-I.'s.omGi'es). . · ■

IR (Nujol): 3350, 3230, 1765, 1670, 1615 cm " ¹ NMR Cd ₆ -DMSO, 6): 0.84 (CH, m), 1.26 (12H,

in), 1.70 (4H, m), 3.2OM.60 (8H, jn), 5.40 (IH, d, JS.OHz), p.68. (IH, d, d, J ° 5.0, 8.0Hz), 6.72 (IH ,. s), 7.23 (2H, broad s), P.49 (UI _1. D, J-8.0HZ) (10) 7- [2-allyloxyimino-2- (2-aminothiazole-4 ^# - yl) -ncctamido] -3- (l-licxyl-lH-tctrazol-5-yl) thibmct3iyl-3-ccplicm-4-carbonic acid hydrochloride (syn ~ isomer _es ) _#

90983 ^ / 0751

lNAL! ^ SFECTED

ι ύ U ο bb

IR (Nujol): 3240, 1780, 17? -0, 1675 cm ' ¹ NMR Cd ₆ -DMSO,' A): 0.63'v2 .13 (111!, In),

3.73 (211, AB _q , J-IKHz), 4.08-1 4.90 (611, in), 5.1 (KG. 30 (511, τη), 6.94 (IH, s), 7.93 (211, broad s), 9.80 pH , d, J-SHz)

(ll) 7- [2-Metho>: yim.no-2- (2-ainino-l, B-thiazol-4-yl) acetamido] -3- (4-nitrobenzoyl) oxy-methyl-3-cephc: m - <l-cafboxylic acid

(syn -Isomores), pale yellow powder, F, 151 - 16 3 ⁰ C (Ztrs *) ·. IR (Nujol)

3250 - 3350, 2500 - 2600, 1700, 1725, 1680, 1650 *, 1600, 1535, 1350 cm " ¹
KUR (d ^ -DMSO, $)

9.60 (IH, d, J = 8Hb) / 0.5 (4H, '. M),.' 7.28 (211, s), 6.80 (IH, ο), 5.80 (IH, ad, J = 5, 8Hz), 5.24 (IH, d, J = 5Hz), 5.20

(2H, ^ Bq, J = 13Hz), 3.02 (3H, s), 3.72 (2H, ABq, J.

(12) 7- [2-methoxyimino-! 2- (2-amino-1,3-thia? .Ol-4-yl) acetamido] 3-pheny lace toxyme thy 1-3-cephem-4-carboxylic acid (cyn-LsoiTieres)

IR (Nujol)

3350, 3300, 1780, 1710, 1660, 1542, . 1535, 1460, 1400, 1380, 1320, 1280, 1260,

1240, 1130, 1115, 1065, 1042, 965/720 era " ¹ HMR (dg-DMSO, S)

7.33 (5H, s), 7.23 (2H, broad s), 6.78 (IH, s), ' 5.81 (IH, dd, J = 4, OHz), 5.16 (III, d, J = - 4Hz), 4.78 and 5.06 (2H, ADq, J = OHz), 3.9 (3H, s), 3.73 (2H, s), .3.5 (2H, broad s)

909834/0751

ORIGINAL INbrciüTED

06Ö56

0.3) ⁷ -I2-Methoxyi _m ino-2- (2-amino-l _/ 3 ~ thia _X ol-4-yl) acetajnido).

3-hexanoyloxymethyl-3-c _e phein-4-carboxylic acid (syn -isomeres). IR (Nujol)

3350, 3300, 1700, 1700, 1660, 1535, 1460, 1400, 1375, 1340, 1315, 1280, 1255, 1045 cm " ¹

KMR (d, -DMSO,
■ - b

9.63 (III, d, J = 8Hz), 7.24 <2H, br _e it ε), 6.76 (IH, s), 5.81 (IK, dd, J = 4, 8Hz), • 5.17. (IH, d, J - 4IIZ), 4.75 and 5.03 (2H, 7vBg, J = 12Hz), 3.84 (3K, s), 3.45 and 3.67 (2H, ABq, J = IOiIz),. 2.32 (211, t, J = 8Hz), 'i -'.'Ί .-. 7; <6H,:. M), D.85 (3H, t ', J = 3Hz)

In addition, in a manner similar to Examples 12 to 17 the compounds of Examples 2 and 5 to 7 and the compounds of Examples 11 (11) to 11 (16), 11 (30) to (44), 11 (46), 11 (49) to 11 (51), 11 (53), 11 (55) to 11 (58) and 11 (69) through 11 (70).

Example 19

10.1 g of trifluoroacetic acid were stirred with ice-cooling Solution of 3.1 g of benzhydryl-7- [2-methoxyimino-2- (2-aminothiazol ^ -ylJacetamidoj-S-iN-phonylcarbamoyloxymethyl) -3-cephem ~ 4-carboxylate (syn-isomeres) and 3.8 g anisole in 30 ml

909834/0751

ORIGINAL INSPECTED

.: 'J (J b 6 b - £ 0 -

Methylene chloride was added and the mixture was stirred at ambient temperature for 30 minutes. After removing the Diethylene chloride from the reaction mixture became diethyl ether admitted. The precipitates were collected by filtration. Water and ethyl acetate were added to the precipitates and the mixture was washed with an aqueous sodium bicarbonate solution The separated aqueous solution is adjusted to pH 7.5 adjusted to pH 6.0 with 10% hydrochloric acid, with Washed ethyl acetate and removed to remove the organic solvent evaporated. The aqueous solution was 10 / oiger Hydrochloric acid adjusted to pH 3.0 with ice cooling and the precipitates were collected by filtration and dried, 1.35 g of 7 ~ [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] ~ 3- (N-phenylcarbamoyloxyrriethyl) -3-cephem-4-carboxylic acid (syn-isomeres) received.

IR (Nujol): 3300, 178 ?, 1710, 1670, 1600 cm " ¹ NMR Cd ₆ -DMSO, δ): 3.67 (2H, br _e it s),

3.91 (3Ii, s), 4.98 (2H, AB, J = 13Hz), 5.23 (IH, d, J = SHz), 5.83 (IH, d, d, J = 5 and 8Hz), 6.83 (IH, s), 6.97 ^ 7.67 (511, m), 9.67 (IH, d, J = 8Hz), 9.8 (IH, s)

Example 20

The following compounds were prepared in a manner similar to Example 19:

909834/0751

ORIGINAL

Ü5656

(1) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] 3- [N- (S-chlorophenyl / carbamoyloxymethyl] -3-ccphcm-4-carbo nsöure (syn ~ I someres).

I.R. (Hujol): 3320, 1780, 1710, 1680, 1600,

1540 cm " ¹

NMR ((J ₆ -DMSO, fi): 3.67 (211, br _e jt s),

3.90 (3H, s), 4.95 (2H, ΛΒ ₍ , J «= 13Hz), 5.20 (IH, d, J = SHz), r» .P> l (111, d, d, J = 5 uid 8Hz) , 6.78 (IH, s), 6.83 ^ 7.76 (4H, m), 9.63 (IH, d, J = 81Iz), 10.1 (IH, s)

(2) 7- [2-Methoxyimiiio-2- (2-aininothiazol-4-yl) acetamido] 3-cyelohxane-carbonyloxymethyl-3-cephem-4-carbon ». acid (syn isomer).

IR (Nujol): 3300, 1780, 1730, 1670 cm ^"1 NMR Cd _{1 6} -DMSO 6):. L (K2.03 (1011, m),

3.53 (211, broad s), 3.83 (IH, in), 3.87 (3H, ₁ s), 4.88 (2H, AB, J = 13 Hz), 5.18 (IH, d, J = 5Hz), 5.82 (IH, d , d, J = 5 and 8Hz), 6.77 (IH, s), 7.28 (2H, broad s), 9.62 (IH, d, J = SHz)

(3) 7- [2-Met.hoxyimino-2- (2-aminotliiazol-4-yl) acetamido] - 3- [2- (4-methoxy ph en oxy) ac.ctoxymethyl] - 3-cephem-4-carboxylic acid (syn isomer it).

IR (Nujol): 3300, 1780, 1730, 1680, 1635 cm " ¹ NMR Cd ₆ -DMSO, 6): 3.52 (2H, AB, J = 17Hz),

3.68 (3H, s), 3.93 (3H, s), 4.74 (2H, s), 4.96 (2H, AB, J-13HZ), 5.14 (IH, d, J = 5Hz), p.78 (IH, d, d, J = 5 and 8Hz), 6.90 (IH, s), 6.86 (4H, s),

909834/0751
ORIGINAL INSPECTED

ⁿ u bbb 6

./(13·

IO

15th

25th

30th

9. ftU (IH, d, J

(4) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3-pivaloyloxymethyl-3-cphcm-4-carboxylic acid (syn. isomer).

IR (Nujol): 3300, 1780, 1720, 1670, 1540 cm NMR Cd ₆ -DMSO, 6): 1.06 (911, S), 3.50 (211,

broad ε), '3.80 (3Η, s), 4.83 (2Η, ΛΒ, J = 13Hz), 5.13 (IH, d, J «- 5Hz),

5.76 (III, d, d, J = 5 and 8Uz), 6.75 (III, s), 9.58 (IH, d, J = 8Hz)

(5) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (2-tlienoy] ) oxymethyl- 3-cepliem- 4-carboxylic acid (syn-Isoineres).

I.R. (Nujol): 3250, 1780, 1710, 1680, 1635,

1530 cm "" ¹

NMR (d ₆ -DMSO, 6): 3.70 (211, br _s i _t s),

3.92 (311, s), 5.15 (211, AB, J-131Iz), 5.22 (IH, d, J = SHz), 5.83 (IH, d, d, J = 5 and 8Hz), 6.85 (IH, s) , 7.27 (IH, m),
7.83 ^ 8.12 (211, m), 9.72 (IH, d, J «8Hz)

(6) 7- [2-methoxyimino · 2- (2-aminothiazol-4-yl) acetamido] - 3- (4-aminobenzoyloxyir.ethyl) - 3-cephem-4-carboxylic acid · (Syn isomer es).

IR (Nujol): 3350, 1780, 1680, 1605, 1540 cm NMR '(d ₆ -DMSO, δ): 3.72 (2H, broad s),

3.87 (311, s), 5.08 (211, AB, J-13HZ), 5.20 (IH, d, J = 5Hz), 5.83 (IH, d, d, J-5 and 8Hz),

6.77 (IH, s), 6.88 (2H, d,
J = 9Hz), 7.80 (211, d, J = 9Hz), 9.67 (IH, d, J = 8Hz)

909834/0751

ORIGINAL INSPECTED

- 98 -

In addition, in a manner similar to Example 19, the compounds of Examples 1 to 10 and the compounds of Examples 11 (i) to 11 (1O), 11 (17) to 11 (34) and 11 (37) to 11 (70).

Example 21

To a solution of 4.3 g of Genzhydryl-7- [2-methoxyimino-2- (2-aminothiazo.1 "4-yl) acetariiido] -3- (4-nitrobenzoyloxymethyl) -3-cepheri] -4-carboxylate (syn-Isomeres) in a mixture of 50 ml of ethanol and 50 ml of tetrahydrofuran was added 0.4 g of platinum (IV) oxide and the The suspension was subjected to catalytic reduction at ambient temperature under normal pressure for hours. After Removal of the catalyst from the resulting mixture by filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a saturated aqueous sodium chloride solution over Magnesium sulfate dried and evaporated in vacuo. The residue was pulverized in diethyl ether, 3.0 g of benzhydryl-7-r2-metlioxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-aminobenzoyloxymethyl) -3-cephem-4-carboxylate (syn-isomeres) received. I.R. (Nujol): 3280, 1780, 1710, 1670, 1605,

1520 cm ' ¹

NMR Cd ₆ -DMSO, 6): 3.76 ■ (211, bv _eit s),

³ · 88 (3H, s), 5.02 (2H, _A B, J = 13Hz), p.26 (IH, d, J = SHz), 5.96 (IH, d, d, J = 5 and 8Hz), 6.82 (IH, s), 6.90 (2H, d, J = 9Hz), 6.98 (IH, s), 7.04% 7.66 (1OH, m), 7.82 (2H, d, J = 9Hz), 9.72 (IH, d, J = 8Hz)

90983 4/0 7 51

Claims (1)

... ■ :: ■ ü:> ti T 51 765 Claims 1 * 3, Z-Üisi'bstituiorte'-S-Ccphcni ^ -carboniiäuro-VerbincJungGn, characterized by the general formula 1 ^N -
^R ~ t ~ "TfC-CON ¹ Il oir R '
where mean: R amino or protected amino, 3
R carboxy or protected carboxy, 2 4 R isobutyl and R acetoxy or R "is cyclo (lower ricj) alkyl or lower alkynyl and R is lower Alkanoyloxy or 2 4 R is lower alkyl and R (C _r ~ C,) alkcnoyloxy or R (C - C.) Alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R hydrogen, carbamoyloxy, thiadiazolylthio, which may have a lower alkyl, or Triazolylthio or
2
R (C ₉ -C) alkyl, cyclo (lower) alkyl or lower alkynyl and 4 ^Z ° R tetrarolylthio with a methyl or 2
R lower alkyl, lower alkenyl, cyclo (lower) alkyl or 4th
lower alkynyl and R aroyloxy, which may have nitro or 90983A / 07 5 1 Amino, cyclo (low) alkanecarbonyloxy, carbamoyloxy with an aryl which can be substituted by halogen, ar- (lower) alkanoyloxy, aryloxy (lower) alkanoyloxy with lower Alkoxy, thenoyloxy, tetrazolylthio with a (C,. ~ C,) alkyl or Benzothiazolylthio, as well as the salts, especially the pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, characterized in that it is the syn isomer of a compound of the general Formula (i) is. 3. A compound according to claim 2, characterized in that it is a compound of the general formula -C-CONM— j / ^s \ R ³ and their salts, in particular their pharmaceutically acceptable salts. 4. A compound according to claim 3, characterized in that in the general formula R Amii
mean esterified carboxy. 1 3 of the general formula R amino or acylamino and R carboxy or 5. A compound according to claim 4, characterized in that : R is amino, lower alkanoylamino or halogen (lower) alkanoyl R carboxy or Ar (lower) alkoxycarbonyl, 909834/0751 I. , ϋ ο α b ö 2 4 R isobutyl and R acetoxy or R Cyclü (niec! Rig) aJkyl or lower alkynyl and R lower alkanoyloxy or R is lower alkyl and R (C ^ -C,) alkanoyloxy or R (C «-C,) alkyl, lower alkenyl or lower alkynyl and R is hydrogen, carbamoyloxy, thiadiazolylthio or triazolylthio or R (C ₀ -C,) alkyl or lower Alkynyl and R tetrazolylthio with a methyl or 2 4 R is lower alkyl, lower alkenyl or lower alkynyl and R Aroyloxy, which can have nitro or amino, cyclo (n.low) -alkanecarbonyoxy, Carbamoyloxy with an aryl which can be substituted by halogen, Ar (lower) alkanoyloxy, aryloxy (lower) alkcmoyloxy with lower alkoxy, thenoyloxy, tetrazolylthio with a (C, -C,) Al! iyl or benzothiazolylthio. 6. A compound according to claim 5, characterized by the formula 7- [2 ~ isobutoxyimino-2- (2-aminothiazol-4-yl) acetamidojcephalosporanic acid (syn-Isorncres). 7. A compound according to claim 5, characterized in that R 3 2 Amino, R carboxy, R cyclo (lower) alkyl or lower alkynyl 4th
and R is lower alkanoyloxy. 8. A compound according to claim 7, characterized in that R 4th
Cyclohexyl or 2 ~ propynyl and R is acetoxy. 9. A compound according to claim 8, characterized by the formula 7- [2 ~ cyclohexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -cephalosporansö'ure (syn isomer). 909834/0751 ORIGINAL 10. A compound according to claim 8, characterized by the formula 7- [2- (2-Propinyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] ~ cephalosporanic acid (syn isomer). 11. A compound according to claim 5, characterized in that R 3 2 Amino, R is carboxy or Ar (lower) a.lkoxycarbonyl, R is lower alkyl and R (C _r -0-alkanoyloxy. 12. A compound according to claim 11, characterized in that R Means carboxy or diphenyl (lower) alkoxycarbonyl. 13. A compound according to claim 12, characterized in that R 2 4 Carboxy or benzhydryloxycarbonyl, R is methyl and R is pivaloyloxy or hexanoyloxy. 14. A compound according to claim 13, characterized by the formula 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-pivaloyloxymethyl-3-cepheni-4-carboxylic acid (syn isomer). 15. A compound according to claim 13, characterized by the formula 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-hexanoyloxymethyl-S-cephem ^ -carboxylic acid (syn isomer). 16. A compound according to claim 5, characterized in that R 3 2 Amino or lower alkanoylamino, R carboxy, R (C ₀ -C,) alkyl, 4 is lower alkenyl or lower alkynyl and R is hydrogen, carbamoyloxy, thiadiazolylthio or triazolylthio. 17. A compound according to claim 16, characterized in that R 909834/0751 r, 05656 (C_-C,) alkyl and R denotes hydrogen. 18. A compound according to claim 17, characterized in that R 2
Amino or Formalnmido and R is propyl or hexyl. 19. A compound according to claim 18, characterized by the formula 7- [2-4 ⁵ TOpOXyI mi no-2- (2-ami not hiazol-4-yl) a ce tamido] -3 ~ methyl-3-cephem-4- carbonic acid (syn isomer). 20. A compound according to claim 18, characterized by the formula 7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-methyl-3-cephem-4-carboxylic acid (syn isomer). 21. A compound according to claim 16, characterized in that R Means carbamoyloxy. 22. A compound according to claim 21, characterized in that R 2 ··
Amino or formamido and R AtI Mean allyl or 2-propynyl, 2 ··
Amino or formamido and R ethyl, propyl, isopropyl, isobutyl, 23. A compound according to claim 22, characterized by the formula 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer). 24. A compound according to claim 22, characterized by the formula 7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-carbamoyloxymethyl-S-cephem ^ -carboxylic acid and its hydrochloride (syn isomer). 909834/0751 ORIGINAL INSPECTED 2 9 0 56 25. A compound according to claim 22, characterized by the formula 7- [2-isopropoxyimino-2 = (2-aminothiazol-4 ~ yl) acetamido] -3-carbamoyl oxymethyl-3-cephem-4-carboxylic acid (syn-isomeres). 26. A compound according to claim 22, characterized by the formula 7- [2-isobutoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer). 27. A compound according to claim 22, characterized by the formula 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer). 28. A compound according to claim 22, characterized by the formula 7- [2- (2-propynyloxyimino) -2- (2-ominothiazol-4-yl) acetamido] -3-carbamoyloxymethyl-S-cephem - ^ - carboxylic acid (syn isomer). 29. A compound according to claim 16, characterized in that R Means thiadiazolylthio. 30. A compound according to claim 29, characterized in that R 2
Amino or formamido, R ethyl, propyl, isopropyl, pentyl, allyl 4th
or 2-propynyl and R l, 3,4-thiadiazol-2-ylthio. 31. A compound according to claim 30, characterized by the formula 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (i, 3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 32. Compound according to claim 30, characterized by the formula 7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (i, 3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 909834/0751 ORIGINAL INSPECTED 2C05656 33. Compound according to claim 30, characterized by the formula 7- [2-isopropoxyimino-2- (2-aminothiazol ~ 4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 34. Compound according to claim 30, characterized by the formula 7- [2-pentyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (i, 3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 35. A compound according to claim 30, characterized by the formula 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-S-cephem - ^ - carboxylic acid (syn isomer). 36. A compound according to claim 30, characterized by the formula 7- [2- (2-propinyloxyirnino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl ) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 37. A compound according to claim 16, characterized in that R (C «-C,) alkyl or lower alkynyl and R denotes triazolylthio. 38. A compound according to claim 37, characterized in that R 2 ··
Amino or formamido, R ethyl, propyl, isopropyl, isobutyl, 4th
Hexyl or 2-propynyl and R are IH-I, 2,3-triazol-5-ylthio. 39. A compound according to claim 38, characterized by the formula 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (iH-1,2,3-triazol ~ 5-yl) thiomethyl -3-cephem-4-carboxylic acid (syn isomer). 40. A compound according to claim 38, characterized by the formula 908834/07 51 ORIGINAL INSPECTED 7- [2-Propoxyimino-2- (2-anunothiazol- ^/ i-yl) acetamido] -3- (iH-1, 2,3-triazol "5-yl) thiomethyl-3-cephern-4-carboxylic acid ( syn isomer). 41. A compound according to claim 38, characterized by the formula 7- [2-isopropoxyimi.no-2- (2-aminothiazol-4-yl) acetamido] -3- (iH-1, 2,3-triazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid (syn-Isomerec.). 42. Compound according to claim 38, characterized by the formula 7- [2-isobutoxyimino-2- (2-aniinothiazol-4-yl) acetomido] -3- (iH-I, 2, 3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-Isorneres). 43. A compound according to claim 38, characterized by the Formula 7- [2-Hexyloxyimino-2- (2-aiiiinothiazol-4-yl) acetamido] -3- (i.d. H-1, 2, S-triazol-S-y ^ thiomethyl-S-cephem ^ -carbonic acid (syn ~ Isomer). 44. Compound according to claim 38, characterized by the formula 7- [2- (2-propinyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1H-1, 2,3-triazole-5 -yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 45. A compound according to claim 5, characterized in that R 3 2 Amino or lower alkanoylamino, R carboxy, R (C ^ -C or lower alkynyl and R denotes tetrazolylthio with a methyl. 909834/0751 I UbbSö 46. A compound according to claim 45, characterized in that 1 . 2 R amino or formamido, R propyl, isopropyl, butyl, pentyl, Hexyl or 2-propynyl and R is 1-methyl-1H-tetrazol-5-ylthio. 47. Compound according to claim 46, characterized by the formula 7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetatenido] -3- (i-methyl-1 H-tetrazol ~ 5-yl) thiomethyl-S-cephem - ^ - carboxylic acid (syn isomer). 48. Compound according to claim 46, characterized by the formula 7- [2-isopropoxyimino-2 ~ (2-aminothiazol "4-yl) acetamido] ~ 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 49. Compound according to claim 46, characterized by the formula 7- [2-butoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-met hy 1-1 H-tetrazol-5-yl) t hi omethyl-S-cephetn - ^ - carbon acid (syn isomer). 50. A compound according to claim 46, characterized by the formula 7- [2-pentyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (i-methyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 51. A compound according to claim 46, characterized by the Formula 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (i-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 90983A / 0751 ORIGINAL INSPECTED 29üb656 52. Compound according to claim 46, characterized by the formula 7- [2- (2-propinyloxyiniino) -2- (2-arainothiazol-4-yl) acetamido] -3 "(i-methyl-1H-tetrazol-5-yl ) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 53. A compound according to claim 5, characterized in that R lower alkyl, lower alkenyl or lower alkynyl and R aroyloxy, which can be converted into nitro or amino, cyclo (lower) alkanecarbonyloxy, Carbamoyloxy with an aryl which can be substituted by halogen, Ar (lower) alkanoyloxy, aryloxy (lower) alkanoyloxy with lower alkoxy, thenoyloxy, tetrazolylthio with a (C "-C,) alkyl or benzothiazolylthio. 54. A compound according to claim 53, characterized in that 1 2 R amino or halogen (lower) alkanoylamino, R lower alkyl 4th
and R is aroyloxy, which may have nitro or amino. 55. A compound according to claim 54, characterized in that 1 3 R amino or 2,2,2-trifluoroacetamido, R carboxy or benzhydryl 2 4 oxycarbonyl, R methyl and R benzoyloxy, 4-nitrobenzoyloxy or Mean 4-aminobenzoyloxy. 56. A compound according to claim 55, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -S-benzoyloxymethyl-S-cephem ^ -carboxylic acid (syn isomer). 57. A compound according to claim 55, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-nitrobenzoyl) oxymethyl-3-cephem-4-carboxylic acid (syn isomer). 909834/0751 58. A compound according to claim 55, characterized by the
Formula 7 - [2-Methoxyimino-2- (2-aminothiool ~ 4-yl) acetarnido] -3- (4-aminobosnzoyl) oxymethyl-3-cephem-4-carboxylic acid (syn-isomeres). 59. A compound according to claim 53, characterized in that 1 O A. R is amino, R is lower alkyl and R is cyclo (lower) alkanecarbonyloxy. 60. A compound according to claim 59, characterized in that 3
R carboxy or benzhydry. ' mean hexane carbonyloxy. 3 2 4 R carboxy or benzhydryloxycarbonyl, R methyl and R cyclo- 61. Compound still claim 60, characterized by the formula 7- [2-methoxyimino ~ 2- (2-aminothiazol-4-yl) acetamido] -3 ~ cyclohexanecarbonyloxymethyl-S-cephem - ^ - carboxylic acid (syn-Icorneres). 62. A compound according to claim 53, characterized in that 1 2 4 R amino, R lower alkyl and R carbamoyloxy with an aryl, which may be substituted by halogen, mean. 63. A compound according to claim 62, characterized in that 3 2 4 R is carboxy or benzhydryloxycarbonyl, R is methyl and R is N-phen) carbamoyloxy or N- (3-chlorophenyl) carbamoyloxy. 64. A compound according to claim 63, characterized by the formula 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (N-phenylcarbamoyloxymethyl) -3-cephem-4-carboxylic acid (syn isomer). 65. Compound according to claim 63, characterized by the formula 909834/075 1
ORIGINAL INSPECTED I J Db56 7- [2-Hethoxyimino-2- (2-aminothiazoJ-4-yl) acetamido] -3- [N- (3-chlorophenyJ.) Carbamoyjoxymethyl] -3-cephem-4-carboxylic acid (syn-isomereo). 66. A compound according to claim 53, characterized in that R is amino, R is carboxy, R is lower alkyl and R is Ar (lower) alkanoyloxy. 67. Compound according to claim 66, characterized by the formula 7-L2-methoxyimino-2- (2-aminothici £ ol-4-yl) acetamido] -3 ~ phenylacetoxymethyl-3-ccphem-4-carboxylic acid (syn isomer). 68. A compound according to claim 53, characterized in that R O A. Amino, R is lower alkyl and R is aryloxy (lower) alkanoyloxy with lower alkoxy. 69. A compound according to claim 68, characterized in that R 2 4 Carboxy or benzhydryloxycarbonyl, R methyl and R 4-methoxyphenoxyacetoxy mean. 70. A compound according to claim 69, characterized by the formula 7r [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-methoxyphenoxyJacetoxymethyl-S-cephem ^ -carboxylic acid (syn isomer). 71. A compound according to claim 53, characterized in that 1 2 4 R is amino, R is lower alkyl and R is thenoyloxy. 72. A compound according to claim 71, characterized in that R carboxy oc
oxy mean 3 2 4 R carboxy or benzhydryloxycarbonyl, R methyl and R 2-thenoyl- 909834/0751 ORIGINAL INSPECTED . Ij Ό U 6 73. Compound according to claim 72, characterized by the formula 7- [2-methoxyiriiino-2- (2 ~ aminothiazol-4-yl) acctamido] -3- (2-thenoyl) -oxymethyl-S-cephcm ^ -carboxylic acid (syn-isomerec). 74. A compound according to claim 53, characterized in that R amino or lower alkanoylamino, R carboxy and R tetrazoly.lthio with a (C_-C,) alkyl. ο Ο 75. A compound according to claim 74, characterized in that 1 2 R amino or formamido, R methyl, isopropyl, hexyl, allyl or 4th
2-propynyl and R are 1-propyl-1H-tetrazol-5-ylthio or 1-hexylH-tetrazol-5-ylthio. 76. Compound according to claim 75, characterized by the formula 7- [2-MGthoxyimino-2- (2-aminothiazol-4-yl) acctamido] -3- (i-propylH-tetrazol-5-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer). 77. Compound according to claim 75, characterized by the formula 7- [2 «allyloxyirriino-2- (2-a-minothiazol-4-yl) acetamido] -3- (ipropyl-1H-tetrazo l-5-yl) thiomethyl-3 -cephem-4-carbon acid (syn-isomeres). 78. Compound according to claim 75, characterized by the formula 7- [2- (2-propinyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (i-propyl-1H-tetrazol-5-yl ) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 79. A compound according to claim 75, characterized by the formula 909834/0751
ORIGINAL INSPECTED ά. 'J ':> bb 6 7- [2-Mathoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) t hi omethyl-S-cephem - ^ - carbon acid (syn-isomeres). 80. Compound according to claim 75, characterized by the formula 7- [2-isopropoxyimino ~ 2- (2-aminothiazol-4-yl) acetamido] -3- (1hexyl ~ 1H-tetrazol-5-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer). 81. Compound according to claim 75, characterized by the formula 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexylH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 82. Compound according to claim 75, characterized by the formula 7- [2-allyloxyimino-2- (2-aminothiazol ~ 4-yl) acetamido] ~ 3- (1-hexyl-1H ~ tetrazol-5-yl) thiomethyl-S -cephem - ^ - carboxylic acid (syn isomer). 83. Preliminary binding according to claim 53, characterized in that R is lower alkanoylainino, R is carboxy, R is lower alkyl and R is benzothiazolylthio. 909834/0751 ORIGINAL INSPECTED ; Ub656 84. Process for the preparation of 3,7-disubstituted-3-Cephsm-4-carbonic acid compounds the general formula ^ \ S " ⁿ -C-COa'Ht — f"' II _n , "4 M ^ // —LIl.-, - i \. where mean: OR ² R ³ R amino or protected anino, R carboxy or protected carboxy, 2 4 R isobutyl and R acetoxy or 2 R is cyclo (lower) alkyl or lower alkynyl and R is lower Alkanoyloxy or R "lower alkyl and R (C ₅ -C,) alkanoyloxy or R ″ (C ₉ -C) alkyl, lower alkenyl, cyclo (lower) alkyl or 4 lower alkynyl and R hydrogen, carbamoyloxy, thiadiazolylthio, which may have a lower alkyl, or triazolylthio or
2
R (C_-C,) alkyl, cyclo (lower) alkyl or lower alkynyl and R tetrazolylthio with a methyl or 2
R lower alkyl, lower alkenyl, cyclo (lower) alkyl or 4 lower alkynyl and R aroyloxy, which may have nitro or amino, cyclo (lower) alkanecarbonyloxy, carbamoyloxy with one Aryl, which can be substituted by halogen, Ar (lower) alkanoyloxy, Aryloxy (lower) alkanoyloxy with lower alkoxy, thcnoyloxy, tetrazolylthio with a (C "-C,) alkyl or benzothiazolylthio or the salts, in particular the pharmaceutically acceptable salts of that, 909834/0751 ORIGINAL INSPECTED A -0b656 characterized in that non a connection of the general formula ; S. , 4 (H) H ₂ N γ / "CH ₂ -R , 3 3 4
wherein R and R each have the meanings given above, or a reactive derivative of the amino group or a salt with a compound of the general formula ^Rl "t3" S " ^C00H you) N ^s 2 oir 1 2 wherein R and R each have the meanings given above, or a reactive derivative on the carboxy group or a salt of it converts. 05. Process for the preparation of a compound of the general formula : -coN'Hr- ~ r, .... ₄ (Ib) x-CONH ι N , J S 2 oir where mean: 3
R carboxy or protected carboxy, 2 4 R isobutyl and R acetoxy or R cyclo (lower) alkyl or lower alkynyl and R lower alkanoyloxy or 909834/0751 ORIGINAL INSPECTED '■ ·, ;, 6b6 O A. R is lower alkyl and R (C_-C,) alkanoyloxy or R (C ₉ -Cx) AIky.I, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R is hydrogen, carbanoyloxy, thiadiazolylthio, which may have a lower alkyl, or Triazolylthio or
2
R (C ^ C,) A.Jkyl, cyclo (nicü'rig) alkyl or lower alkynyl and R tetrazolylthio with a methyl or R lower alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R aroyloxy, which may have nitro or amino, cyclo (lower) alkanecarbonyloxy, carbamoyloxy with an aryl which can be substituted by halogen, ar- (lower) alkanoyloxy, Aryloxy (low) alkanoyloxy with lower alkoxy, thenoyloxy, tetrazolylthio with a (Cj-C,) alkyl or Benzothiazolylthio or the salts, in particular the pharmaceutically acceptable salts of that, characterized in that one connects the general Formol wherein R is protected amino and R, R and R are each have the meanings given above, or a salt thereof is subjected to an elimination reaction to remove the amino protective group. 86. Process for the preparation of a compound of the general formula 909834/0751 ORIGINAL INSPECTED 2 '. '' ■ ϋ ο 6 S ö ok ² COOII where mean: R amino or protected amino, 2 4 R isobutyl and R acetoxy or R cyclo (lower) alkyl or lower alkynyl and R lower alkanoyloxy or R is lower alkyl and R (C ₅ -C,) - alkanoyloxy or R (C ₉ "C,) alkyl _/ lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R hydrogen, carbamoyloxy, thiadiazolylthio, which may have a lower alkyl, or triazolylthio or 9 A R (C -C,) alkyl, cycloC-lower alkyl or lower alkynyl and R Totrazolylthio with a methyl or
2 R lower alkyl, lower alkenyl, cyclo (lower) alkyl or lower alkynyl and R aroyloxy, which may have nitro or amino, cyclo (lower) alkanecarbonyloxy, carbamoyloxy with an aryl which can be substituted by halogen, ar (lower) alkanoyloxy, Aryloxy (lower) alkanoyloxy with lower alkoxy, thenoyloxy, tetrazolylthio with a (C "-C,) alkyl or benzothiazolylthio or the salts, in particular the pharmaceutically acceptable salts of that, characterized in that a compound of the general formula ^N ~ \ ^v 'ü LLJ ^{(Ic) 0R} 90983A / 07 5 1 ORIGINAL INSPECTED . . J b Ö b b wherein R is protected carboxy and R, R and R each have the meanings given above, an elimination reaction to remove the carboxy protecting group subject. 87. Process for the preparation of a compound of the general formula., pi - // - A-C-CONIi- .3
K where mean: R Amino or protected amino, R lower alkyl, lower alkenyl, cyclo (lower) alkyl or R carboxy or protected carboxy,
lower alkyl, lower lower alkynyl and 4b
R aroyloxy with one or more amino groups, or the salts, in particular the pharmaceutically acceptable salts thereof, characterized in that a compound of the general formula 1 ⁿ \ S ^J ' ^fr " ^V "' ^ -CH ₂ -R ⁴⁸¹ 1 ο 2fj
wherein R, R and R each have the meanings given above 4a
and R is aroyloxy with one or more nitro groups, or a salt thereof is subjected to a reduction. 909834/0751 ORIGINAL INSPECTED 88. Compound characterized by the general formula H ₂ N pS
J JN ^ CII -S
0 T 2 R ³ 3 7 where R is carboxy or protected carboxy and R is (C ~-C,) alkyl mean, as well as their salts. 89. A compound according to claim 88, characterized in that doß 3 7 in the general formula R carboxy and R propyl or hexyl mean. 90. Compound characterized by the general formula y N γι CH ₂ -O- I>' ^1c R ³ 3 4c wherein R is carboxy or protected carboxy and R is carbamoyl with an aryl which may be substituted by halogen, aryloxy (lower) alkanoyl with lower alkoxy, thenoyl, cyclo (lower) alkanecarbonyl or mean aroyl with nitro, as well as their salts. 91. Pharmaceutical agent with antibacterial activity, characterized in that there is at least one S ^ -disubstituted-S-Cephem ^ -carboxylic acid compound as the active ingredient (active component) according to one of claims 1 to 83, optionally in combination with at least one pharmaceutically acceptable, contains essentially non-toxic carrier and / or auxiliary substance. 92. Process for the preparation of a pharmaceutical agent with 909834/0751 ORIGINAL INSPECTEO - ²¹ - ι v> υ b 6 antibacterial effectiveness, characterized in that one at least one 3,7-disubstituted-3-cephem-4-carboxylic acid compound according to any one of claims 1 to 83 as an active ingredient (active component) with at least one inert carrier and / or Mixes excipient. 909834/0751