THE 7ALPHA-TO-[...] DERIVATIVES AND PROCESSES FOR THEIR PREPARATION.

(1)

méthoxycéphalosporine

of formula according to claim 1 as an ingredient

acUL

the present invention relates to derivatives of the

7améthoxycéphalosporine

and salts thereof acceptable pharmaceutical, which are novel compounds having l0 a high antibacterial activity, as well as methods for the preparation of these derivatives.The compounds of the cephalosporin have antibacterial activity, and numerous derivatives thereof have been produced so far. Some of these derivatives (e.g.

eéphalexine

and

céphalotine

) are used in therapeutics as showing excellent

antibactéñens

. As a result of recent studies on the compounds of type cephamycin which have a methoxy group at the Ta of the core

céphaIosporine

(e.g. cefoxitin), many derivatives belonging to this type have been described. However, very few of the traditional type cephalosporin compounds exhibit antibacterial activity against both satisfactory to tA gram positive and gram negative.Following the new search limited to

7améthoxycéphalosporine

derivatives having high antibacterial activity, it was now found that 2s novel

eomposésantibaetérienne

high which have activity can not be replaced by any of the conventional derivatives 7a-to-

méthoxycéphalosporine

. The novel compounds are represented by the general formula (I-) following:The I "r2 o4 - - '" - H 2 IR coor4 wherein r1 represents a heterocyclic ring or a fused

Shétérocyclique

; r2 represents a hydrogen atom, a carboxyl group or a group - Coor, where RS is a lower alkyl group, an alkyl group or a lower alkylamino group - c-O ER, I-Y where RS is a lower alkyl group, a lower acyl group is a lower alkoxycarbonyl group and Y is a hydrogen atom or a lower alkyl group; r3 represents a hydrogen atom, a group or a lower acyl group

earbamoyle

; r4 represents a hydrogen atom, a lower alkyl group, an alkyl group or a lower alkylamino group - ch-O-remarked, these recommendations are ori and RS and Y are as defined above; a and b, the same or different, each represent a straight-chain alkylene group having from 1 to branched or 5 carbon atoms; X is 0 or 1, or the salts thereof pharmaceutically-acceptable.The compounds of formula (I-) may exist in the form of a inner when Rz of LEL, Ra and r4 are each hydrogen and, in other cases, these compounds may exist advantageously in the form of their pharmaceutically acceptable salts of the pharmaceutical. If Rz is a carboxyl group or a group - Coor, the compounds of formula (I-) 643,851 may take the form of a d-stereoisomer or an L-stereoisomer, both isomers are within the scope of this invention. The D form typically has antibacterial activity greater than the L-form, except the amino substituent.The heterocyclic ring of 5 to r1 is heterocycle or 6 members containing 1 to 4 nitrogen atoms as heteroatom.The heterocyclic ring may also contain one or two sulfur atoms as hetero atom other than nitrogen atoms. Of

préîérence

, the heterocyclic ring is a heterocyclic 5 or 6 members containing 1 to 4 nitrogen atoms as heteroatom.The group

acile

lower r3

aeyle

group is a straight or branched chain aliphatic containing I to 6 carbon atoms which may be substituted with a halogen atom or an amino group. The group preferred

acile

Ra is an acetyl group aliphatic linear or branched chain containing from 1 to 4 carbon atoms, such as a formyl group, a group

aeétyle

, a trifluoroacetyl group, a glycyl, alanyl and a propionyl group.The lower alkyl group of r4 and RS is a straight chain alkyl or branched alkyl having 1 to 6 atoms of carbon, of

préférenee

I to 4 carbon atoms.The group of lower dialkylamino alkyl r4 and RS, each core alkyl is a branched or straight chain alkyl having from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.The allyl group is

Ró

lower chain alkyl or branched alkyl having 1 to 6 of carbon atoms, preferably 1 to 4 carbon atoms.The acyl group is an acyl group of RS straight chain or branched aliphatic having from I to 6 carbon atoms.In the alkoxycarbonyl group re, the core is an allyl alkyl straight or branched chain having from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.The lower alkyl group of Y is a straight-chain alkyl group or branched] to 4 carbon atoms.The alkylene group of a and b is a straight chain alkylene group having from 1 to branched or 5 carbon atoms, preferably 1 to 3 carbon atoms.Preferably X is 0.More particularly, the derivative of the 7u-to-

méthoxycéphalosporine

is represented by the following formulae:An í r2 01 hr3 q) ch. 3 i Ch 2s Ch

CONHS

- 2 (I-) n-COOH wherein ODs ch2 ri01 r1 ol is the following groups:9 conh2, n-n-n-n-n-, hindered n -, I-I-n-n-n-n-ch3 ch2

COOIt

643,851 n n - s - I-n-n - s ch2so3h? , N-n-n-I-ctt2ch2-to-so3it - if it - ch2 COOH i HT or n ' - n-n-I-ch-COOH->if 3 n/n - oh I-ch3 r20i represents a hydrogen atom is a carboxy group; and r3 represents a hydrogen atom, a carbamoyl group or a lower acyl group; (j-I-X-Osh o1 h2 a CB -

sCAB

-to-kno J-to-a-

çs

"] I-ob-n-COOH-ch2 ri0135 r101

COOI

-I where a and b are identical or different, each represents a straight-chain alkylene group having from 1 to branched or 5 carbon atoms; X is 0 or 1; X-och3 C. h2 (),, 1 -

ccù2

-Y

sccù2

CONE - - -: 11 I-(-c) 01 coor4 Coor i ch3 wherein R, and R the O *, same or different, each represent a hydrogen atom, a lower alkyl group, an allyl group or a lower alkylamino group - - c-O-to-

Ró

, I-Y wherein Ro represents a lower alkyl group, an acyl group or an alkoxycarbonyl group

inféfleurinféñeur

and Y represents a hydrogen atom or a lower alkyl group; X is 0 or 1; Y and Z, which are identical or different, each represents an integer of L to 5; the R, O-and RS are not simultaneously a hydrogen atom; LEL of these compounds or a pharmaceutically acceptable pharmaceutical.In the formula (I-), r3 represents a hydrogen atom, a carbamoyl group or a lower acyl group. The acyl group of r3

inféñeur

aliphatic acyl group is a straight or branched chain containing I to 6 carbon atoms which may be substituted with a halogen atom or with an amino group. Preferred acyls

inféñeurs

include a formyl group, an acetyl group, a trifluoroacetyl group, a propionyl group, a glycyl and alanyl.The following heterocyclic rings containing illustrate substituents in position 3:the 5 - (l-methyl-I-H

tétrazoIyl

) thiomethyl, from 5 - (1 a-

carboxyméthyl1H

-to-tetrazolyl) thiomethyl, from 5 - (1 - sulfomethyl (or sulfoethyl) 1:00 - tetrazolyl) thiomethyl, and 5 - (2 a-

carboxyméthyl1H

thereof the present invention provides triazolyl) thiomethyl, from 5 - (2-carboxymethyl-1-methyl 1 hr-present invention provides triazolyl) thiomethyl, 3lo (4 methyl-5 oxo-6 hydroxy-4.5 to-

dihydro1,

2.4-to-or triazinyl) thiomethyl,

pyridiniumméthyle

and P-

carbamoylpyridiniumméthyle

.The compounds of formula (I-) are illustrated by the following examples:Acid 7p-to-

aminométhylthioacétamido

-to-

ToE

-methoxy-3 - (1 a-

méthyl151H

-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.Acid 7p-to-

uréidoéthylthioacétamido

-a gnat tct-methoxy-3 - (1 a-methyl1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.Acid 71 - (2d-a 2-amino 2 carboxyl)

éthylthioacétamido

-to-

Tctméthoxy

and 3 - (l-methyl H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylique.

7p

acid - (2dl-to-2-amino 2 carboxy)

étbylthioacétamido

-to-

7ctméthoxy

and 3 - (l-methyl-1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylique.Supplying Drop Acid - (2l-To-2-Amino 2 Carboxy)

Éthylthioacétamido

-To-7ct-Methoxy-3 - (L-Methyl-Lh-Tetrazol-5 Yl) Thiomethyl-A 3 A-Cephem-To-4-Carboxylic Acid.71 -

aminoéthylthioacét

acid amido 7u-methoxy-3 - (1-carboxymethyl-I-H-tetrazole-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.713 to-

uréidoéthylthioac

&acid amido 7ct-methoxy-3 - (L-- carboxymethyl-lH-tetrazole-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.Supplying drop acid - (2d-a 2-amino 2 carboxy)

éthylthioacétamido

-to-7a-methoxy-3 - (] - carboxymethyl-lH-tetrazole-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylique.Acid 71 -

aminoéthylthioacétamido

-to-7ct-methoxy-3 - (1 -

sulfométhyl1

1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.Acid

71Laminoéthylthioacétamido

-To-7ct-Methoxy-3 - (L

sulfoéthyl1H

-Tetrazol-5 Yl) Thiomethyl-A 3 A-Cephem-To-4-Carboxylic Acid.Acid 7p-to-

uréidoéthylthioacétamido

-to-7ct-methoxy-3 - (1 a-

sulfométhyl1

1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.Supplying drop acid - (2d-a 2-amino 2 carboxy)

éthylthioacét

amido 7tz-methoxy-3 - (1 a-sulfomethyl lH-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylique.Supplying Drop Acid - (2d-A 2-Amino 2 Carboxy)

Éthylthioacétamido

-To-7a-Methoxy-3 - (1 A-

sulfoéthyl1H

-Tetrazol-5 Yl) Thiomethyl-A 3 A-Cephem-To-4-Carboxylic Acid.Acid 7p-to-

trifluoroacétamidoéthylthioacétamido

-to-7ct-methoxy-3 - (1 - methyl1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.Acid 71 -

formamidoéthylthioacétamido

-to-7ct-methoxy-3 - (

lméthyl1H

-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.Acid 7p-to-

acétamidoétbylthioacétamido

-to-7a-methoxy-3 - (1 a-methyl1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.Acid 7

[Laminoéthylthioacétamido

-To-7ct-Methoxy-3 - (2 A-

carboxyméthyl1

H

triazoI

-To-5 Yl) Thiomethyl-A 3 A-Cephem-To-4-Carboxylic Acid.Acid 7ç D-

alanylaminoéthylthioacétamido

-To-7a-Methoxy-3 - (

lméthyl1H

-Tetrazol-5 Yl) Thiomethyl-A 3 A-Cephem-To-4-Carboxylic Acid.Supplying drop acid - (2l-to-2-ureido-2 carboxy)

éthylthioacétamido

-to-7ct-methoxy-3 - (1 - methyl1 H

tétrazòl

-to-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.Acid 7ç-To-

aminoéthylthioacétamido

-To-7a-Methoxy-3 - (P

carboxyamidopyridinium

) Methyl-3 A-Cephem-To-4-Carboxylic Acid.

7p

acid - (2d-a 2-amino 2 carboxy)

éthylthioacétamido

Ta-methoxy-3 - (P

carboxyamidopyñdinium

) methyl-3 a-cephem-to-4-carboxylic acid.

7p

acid - (2d-a 2-amino 2 carboxy)

éthylthioacétamido

-to-

7améthoxy

and 3 a-

pyridiniumméthyl

and 3 a-cephem-to-4-carboxylic acid.Acid 71] - (2d-A 2-Amino 2 Carboxy)

Éthylthioacétamido

-To-

7améthoxy

And 3 - (2-Carboxymethyl-L-Methyl-Lh-Triazole-To-5 Yl) Thiomethyl-3 A-Cephem-A 4 A-

earboxylique

.643,851 acid 71 - (2d-a 2-amino 2 carboxy)

éthylthioacétamido

-to-7ctm6thoxy and 3 - (4 methyl-5 oxo-6 hydroxy-4.5 dihydro-L-, 2.4 and triazine-to-3yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.In the formula (I-b), examples of the substituent in position 3 comprising a heterocyclic ring are the same as those discussed above for formula (I-).The compounds of formula (I-d) may be illustrated by the following examples.Acid 7 [3 - (3d And 3-Amino 3 Carboxy)

propylthioacétamido

-To-

7ctméthoxy

And 3 - (L-Methyl-Lh-Tetrazol-5 Yl) Thiomethyl-A 3 A-Cephem-To-4carboxylique.Supplying drop acid - (3d and 3-amino 3 carboxy)

propylsulfinylacét

amido 7" - methoxy-3 - (1 a-methyl1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylique.Acid - 71 (3d and 3-amino 3 a-

earboxy

)

propylthioacétamido

-a 7" - methoxy-3 - (2-carboxymethyl-1 1H-triazole-to-5 yl) thiomethyl-a 3 a-

céphem4

-carboxylic acid.Acid 7 [3 - (3d and 3-amino 3 carboxy)

propylthioacétamido

-a 7" - methoxy-3 - (P

carbamoylpyridinium

) methyl-3 a-cephem-to-4-carboxylic acid.Acid 71] - (3dl-To-3-Amino 3 Carboxy)

propylthioacétamido

-To-

7ctméthoxy

And 3 - (1 Methyl-Lh-Tetrazol-5 Yl) Thiomethyl-A 3 A-Cephem-To-4earboxylique.Acid 7 [3 - (2d-a 2-amino 2 carboxy) -

éthylthiopropionamido

-to-7c

mëthoxy

and 3 - (1 methyl-1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylique.

7ç

acid - (3d and 3 a-Amin to O 3 carboxy)

propylthiopropionamido

-to-

7améthoxy

and 3 - (1 a-methyl1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylique.Supplying drop acid - (4d and 4-amino 4 a-

carboxybutylthioacétamido

) - 7ct-methoxy-3 - (1 - methyl1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.Supplying drop acid - (2d-a 2-amino 2 a-

carboxy1,

1 - dimethyl)

éthylthioacétamido

-a 7" - methoxy-3 - (1 - methyl-1 1H-tetrazol-5 yl) thiomethyl-to-

3céphem

-to-4-carboxylic acid.Examples of pharmaceutically acceptable salts of the compounds of formulae pharmaceutical (I-) and (I-b) are alkali metal salts

tcls

that the LEL of sodium salts and basic amino acids such as L-lysine-LEL. The terminal amino acid at position 7 in the formulae (I-), (I-b) and (L-C-) can either be comprised by a d-stereoisomer by either an L-CD + Reo-isomer, the two kinds of isomers are within the scope of this invention. The D form typically has a bacterial activity greater than that of the L-form, except the amino substituents.The derivative of the 7" -

méthoxycéphalosporine

of formula (L-C-) has a high antibacterial activity for administration orally or parenterally, preferably orally.The compounds of formula (I-c) may be used in the form of a free base when two carboxylic groups are esterified, but it is more advantageous to use them in the form of an acid addition salt pharmaceutically acceptable pharmaceutical, with for example hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, maleic acid, succinic acid, glutamic acid or aspartic acid or an internal LEL. These acid addition salts or inner salts are not only highly stable, but they are also very soluble in water and therefore suitable for their administration. Further, their ability to form a uniform dispersion results in an increased therapeutic effect.With reference now to the formula (I-c), r4 rs01 and feel each a hydrogen atom, a lower alkyl group (such as methyl, ethyl, isopropyl or tert-butyl) and dimethylaminoethyl, methoxymethyl, ethoxymethyl, L ethoxyethyl (- CH2CH2 - (warp) and OEt), acetoxymethyl, an L-acetoxyethyl,

propionyloxyméthyle

, L

propionyloxyéthyle

, pivaloyloxymethyl, 1 a-

pivaloyloxyéthyle

,

méthoxycarbonyloxym

&

hyle

, 1 m-&

hoxycarbonyloxyéthyle

,

éthoxycarbonyloxyméthyle

, L ethoxycarbonyloxyethyl, andc.The terminal amino acid at position 7 can be a donation a

Lstéréo

-isomer, the two isomers and their racemic form being included in the scope of the invention. The D form generally has a superior antibacterial activity in vivo in the L-form.The compounds of formula (I-c) are illustrated by the examples below.Supplying drop acid - (2d-a 2-amino 2-methoxycarbonyl)

éthylthioacétamidol

0 7ct-methoxy-3 - (1 methyl-I-i-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylique.Acid 71] - (2d-a 2-amino 2-ethoxycarbonyl)

éthylthioacétamido

-a 7" - methoxy-3 - (L-methyl-lh-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylique.e acid 7 [3 - (2dl-to-2-amino 2-ethoxycarbonyl)

éthylthioacétamido7ct

-methoxy-3 - (1 methyl-1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylique.Acid 7 - (3d and 3-amino 3-ethoxycarbonyl)

propylthioacétamido7

" - methoxy-3 - (L--

méthyl1H

-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylique.Supplying drop - (2d-a 2-amino 2-methoxycarbonyl)

éthylthioacétamido

-a 7" - methoxy-3 - (1 a-methyl1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate methoxymethyl.Supplying drop - (3d and 3-amino 3-ethoxycarbonyl)

propylthioacétamido

-a 7" - 2s methoxy-3 - (1 methyl-I-H-tetrazole-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate methoxymethyl.7 [3 - (2d-a 2-amino 2-ethoxycarbonyl)

éthylthiopropionamido

-a 7" - methoxy-3 - (l-methyl-Li I-a tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate of 1 a-ethoxyethyl.Supplying drop - (2d-a 2-amino 2-ethoxycarbonyl)

éthylthioacétamido

-a 7" - methoxy-3 - (1 methyl-lh-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate of 1 a-ethoxyethyl.71 - (2d-a 2-amino 2-methoxycarbonyl)

éthylthioacétamido

-a 7" - methoxy-3 - (L-methyl-lh-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate dimethylaminoethyl.71 - (2d and 2 a-Amin to O 2-ethoxycarbonyl)

éthylthioacétamino

-to-

7ctméthoxy

and 3 - (1 -

m6thyl1

1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate dimethylaminoethyl.Supplying drop - (2d-a 2-amino 2 carboxy)

éthylthioacétamido

-a 7" - methoxy-3 - (1 m-&hly-I-H-tetrazole-5 yl) thiomethyl-a 3 a-cephem-a 4 a-

carboxy]ate

of

lacétoxyéthyle

.Supplying drop - (2d-a 2-amino 2-methoxycarbonyl)

éthylthioacétamido

-a 7" - methoxy-3 - (L-methyl-lh-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate acetoxymethyl.71] - (2d-a 2-amino 2-ethoxycarbonyl)

éthylthioacétamido

-a 7" - methoxy-3 - (1 methyl-lH-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate of 1-acetoxyethyl.71] - (2d and 2 a-

Aminoéthoxycarbonyl

)

éthylsulfoxydeaeétamido

-to-

7améthoxy

and 3 - (1 methyl-1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4s0 carboxylate 1-acetoxyethyl.71] - (3d and 3 a-

Aminoéthoxycarbonyl

)

propylthioacétamido

-to-

7ctméthoxy

and 3 - (1 methyl-I-H-tetrazole-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate of] - acetoxyethyl.71] - (2d-a 2-amino 2-methoxycarbonyl)

éthylthioacétamido

-to-

7ctméthoxy

and 3 - (1 methyl-lh-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate pivaloyloxymethyl.7 [3 - (2d-a 2-amino 2-ethoxycarbonyl)

éthylthioacétamido

-a 7" - methoxy-3 - (l-methyl-1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate of 1 a-

pivaloyloxyéthyle

.7 [3 - (2d-a 2-amino 2-methoxycarbonyl)

éthylthioacétamido

-a 7" - methoxy-3 - (1 methyl-1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate of

méthoxycarbonyloxyméthyle

.71 - (2d-a 2-amino 2-ethoxycarbonyl)

éthylthioaçétamido

-a 7" - methoxy-3 - (L-methyl-lh-tetrazol-5 yl) methylthio-3 a-cephem-to-46s carboxylate 1 a-ethoxycarbonyloxyethyl.Supplying drop - (2d-a 2-amino 2 a-

acétoxyéthoxycarbonyl

)

éthylthioacétamido7

" - methoxy-3 - (1 a-

rnéthyl

-a 1 H

t6trazol

-to-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate L-acetoxyethyl.643,851 71 - (2d-a 2-amino 2 a-

pivaloyloxyéthoxycarbonyl

)

éthylthioacétamido

-a 7" - methoxy-3 - (1 methyl-1 1H-tetrazol-5 yl)

thiométhyl3

-to-cephem-to-4-carboxylate 1 a-

pivaloyloxyéthyle

.71 - (2d-a 2-amino 2 a-

méthoxyméthoxycarbonyl

)

éthylthioacétamido

-to-7ct-methoxy-3 - (1 methyl-lh-tetrazol-5 yl) thiomethyl-to-

3céphem

-to-4-carboxylate methoxymethyl.The compounds of formulae (I-) and (I-b) high

antibactéñenne

have activity against a broad spectrum of pathogenic

baetéries

. The compounds of formulae (I-) and (I-b) have such an antibacterial activity not only in-

vitto

, but also in-vivo.The activity of the compounds according to the invention against several bacterial species in table 1 which shows the efficacy of these compounds in comparison with cefoxitin (product manufactured by

Merk

and O.) used as a control.Table I microorganism methicillin 209p

Baeillus

anthracisgenome no. 119 Escherichiacoli 255 Citrobacter Klebsiella Proteus mirábilis

morganü

Serratia no. 1 or Pseudomonas aeruginosa IFO 8371 3080 compound g. 1 1.56 0.39 6.25 1.56 3.13 6.25 3.13 compound g. 2 3.13 0.78 12.5 1.56 3.13 3.13 compound g. 3 6.25 0.78 12.5 0.78 0.39 1.56 PCM * (MCG pattern/ml.) compound g. 11 3.13 0.20 0.78 1.56 3.i3 0.78 100 compound g. 12 6.25 1.56 3.13 6.25 12.5 12.5 6.25 compound g. 13 12.5 1.56 3.13 6.25 12.5 100 cefoxitin 1.56 3.13 3.13 6.25 3.13 100 * the bacteria were preincubated in soya broth

Tripticase

(manufactured by BBL) to 37° C for one night, and is diluted up to 100 times with the same broth as above to provide the solution to inoculate. Agar (DIFCO's)

nutñtif

as the medium for measuring mica been inoculated with the solution to inoculate obtained above and incubated at 20 C. for 37° H to determine the MIC (minimal

inhibitory

concentration of=minimum inhibitory concentration).The compounds of formula (I-c) exhibit a low antibacterial activity in vitro but, when administered in vivo, the ester bond readily breaks that they can thus have a potent antibacterial activity. The antibacterial activity in-vivo (

EDso

) of several compounds according to the invention which have been administered orally to mice is mentioned in table 2 to determine whether the efficacy of these compounds in comparison with the

céphaléxine

and the

eéfoxitine

used as controls.Table 2 compound of the example 17 compound of the example 18 compound of the example 19 cephalexin cefoxitin pathway for oral administration subcutaneously oral subcutaneous oral subcutaneous oral subcutaneous oral subcutaneous

EDso

(mgs/mouse)* with Escherichia coli no. 29, 0.86 of O, male

ddY

mice 046, 0.36 0.24 0.25 0.17 1.60>5.0 0.43 (5 mouse per group, each mouse weighing g in average) were treated intraperitoneally with a suspension of 7.9 × 10 (31.9

LDso

) of Escherichia coli no. 29 of the

macine

preincubated in aqueous 2.5%. Immediately after inoculation, the test compounds and the control compounds dissolved or suspended in 0.2 LTA of physiological saline solution was administered to that were then fed during 1 week to observe their fate.

EDso

values have been computed by the "integrity".The compounds of formula (I-) according to the invention have a value of about 6 to 8

LDso

gms/kg per intravenous injection in mice and thus are substantially non-toxic.Accordingly, these compounds are advantageously employed as medicament for the treatment of diseases caused by bacteria. For this purpose, the compounds of formulae (I-) and (I-b) can be administered either parenterally as an intravenous injection is muscle, or suppository, or

oraiement

tablet form, powder, capsule, syrup, and so on. and the compounds of formula (I-c) may preferably be administered orally in the form of tablet, powder, capsule, syrup, and so on if an addition salt of the compound of formula (L-C-) is soluble in the ADC, it may be administered parenterally in the form of a muscular or intravenous injection or suppository.It is obvious that the preferred dosage of the active compound of the formula (1) varies according to the particular composition formulated for administration, according to the mode of administration and according to the particularities of the disease being treated. Many factors which modify the action of the drug will be considered by the skilled person, for example age, weight, sex, diet, time of administration, route of administration, the level of secretion, the drug combinations, the sensitivity reaction and disease severity. Generally, in the case of intravenous or intramuscular administration of the compounds of formulae (L-a-) and (I-b), 1 g of the active compound is given per day to an adult person and, when a patient is suffering from a serious disease, 2 to 4 g of the active compound are administered per day to an adult person. In the case of the oral administration of the compounds of formula (I-c), 0.5 g to 1 g of the active compound is administered per day to an adult person.The derivatives of the 7" -

méthoxycéphalosporinereprësentés

by the general formula (I-) can be prepared by one of the following methods.i) by reacting a compound of formula (III):the X - oca3 (

A'

-to-TOC has'] ",)

O'JL'

-a-n-ch2 or7 COON 11,643 851 in which X represents a halogen atom (e.g. chlorine, bromine OH-iodine), r7 represents an acetyl group, a group

carhamoyle

, a group" - methoxy-p-

su]foxydnnamoylephydroxycinnamoyle

or group, and a represents

alky

] ene straight or branched chain having from I to 5 carbon atoms, with a compound of formula (II):(B.) hr3 cms - - shush I-r201 wherein r20 I represents a hydrogen atom or a carboxy group, r3 represents a hydrogen atom, a carbamoyl group or a lower acyl group, and b represents a straight-chain alkylene group having from 1 to branched or 5 carbon atoms, by using an inert solvent (e.g. water, methanol, aqueous acetone, and so on), in the presence of a base such as trap acid (e.g. an alkali metal hydrogen carbonate, a

tñalky

] amino, pyridine, and so forth), at room temperature or at a lower temperature and for about I to 5 hr, to obtain a compound of formula (VI):Ch - (β) - O - {has) - CONE e " (VI)

'I

r201 rz0 I-COOH wherein the Ra, ri, a and b are as defined above, followed by reaction of the compound of formula (VI) above with a reagent

nuc

]

éophile

(for example pyridine derivatives, p

carbamoylpyridine

, 5 a-mercapto-L-methyl-lH-tetrazol, acid 5 a-mercapto lH-tetrazol-

1acétique

, acid 5 a-mercapto lH tetrazol L-methanesulfonic, acid 5 a-mercapto 1h-tetrazol L-ethanesulfonic, acid 5 mercapto-

lHtriazol

-to-2-acetic, acid 5 a-mercapto lH triazole-to-2-carboxylic, 3mercapto-to-4-methyl 5 oxo-6 hydroxy-4.5 above 2.4

dihydro1,

-triazine derivatives), using a solvent (e.g. water) under nearly neutral conditions (e.g. at pH 6.0 - 7.5) at a temperature of between 40 and 70 °c during 7 to 20 hr and.ii) by reacting a compound of formula (IV):3 - X-ch-theS @ (has)- CONE, ch2 RT-O-COOH wherein Rl represents a heterocyclic ring or an s-heterocyclic core, a is an alkylene chain or branched having from I to 5 carbon atoms and X represents a halogen atom, with a compound of formula (ii1):(B.) hr3 - HM - shush (lll)I-r201 wherein b, r3 r20 and are as defined above, using a solvent (e.g. water, methanol, aqueous acetone, and the like), in the presence of a trap acid (e.g. an alkali metal hydrogen carbonate, a trialkylamine, pyridine, 6s etc) in nearly neutral conditions (e.g. at pH 6.5 - 7.5), to ambient temperature or lower and for about 30

tempèrature

min. to 5 Tl.iii) by reacting a compound of formula (VIII):Osh, 3 (VIII)

coozI

(lll) LO in which ri represents a heterocyclic ring or an s-heterocyclic and z1 represents a carboxyl protecting group removable, with a compound of formula (VIII-):(D)- CH2 - O - (has)- TOC (VIII.) I-

COOZ

3 wherein a and b, the same or different, each represents an alkylene chain or branched alkyl having I to carbon atoms, HilbertZZ represents an amino protecting group removable, z3 represents a carboxyl-protecting group

éliminab

] W, X is 0 or I and T is a hydroxide group or an atom or group required to form an active derivative of carboxylic acid such as an acid halide, a mixed acid anhydride, or ester

suecinimide

a p

nitrophény]e

. The reaction is carried out in a solvent (for example dichloromethane, chloroform, benzene, dimethylformamide, and so on) in the presence of an acid trap (e.g. a trialkylamine, pyridine derivatives, for n-n-dimethylaniline, etc) or a dehydration condensation agent (e.g. n, not-to-

dicyc]ohexylcarbodiimide

) at room temperature or at a temperature below 5 to 1 and during the H, followed by removal of the Z protecting groups,, HilbertZZ z3 and, if necessary.In the above preparation method, the starting compound of formula (III) can be obtained in a conventional manner, for example using the method

décñte

in "of Chemical and Pharmaceutical ballot", LIU. 24, 2629 (1976) p, and made by the method described in "

Tetrahedron

Letters and", n° l6, e. 1307 (1976). The starting compound of formula (IV) can be also obtained in conventional manner, for example using the method described in US Patent no. 4115645. As to the starting compound of the formula (binding of), it can also be obtained in a conventional manner, for example using the method described in "Journal

Antibiotics

", LIU.29, e. 554 (I-976), the method described in "

Tetrahedron

Letters and", P (1975) 2705 or the method described in "Journal of the American (IV) use of Chemical Society in", LIU. 99, e. 5505 (1977).The preparation of the compounds of formula (I-) according to the invention will be described hereinafter in more detail.The compounds of formula (I-) can be prepared by reacting a compound of formula (II-):Eyelash 3' O K ch2conh-to-a-f - - "7 (II-) 04" " n - ch2 r7 COOH wherein X represents a halogen atom, and R represents

ûn

acetyl group, a carbamoyl group, a CT-methoxy-

psulfoxycinnamoyle

group or a P-hydroxycinnamoyl, with a compound of formula (III-):Hr3 H ch shush (III-) r201 643,851 12 wherein r201 r3 carboxy and represents a hydrogen atom, a carbamoyl group or an acyl group

inféñeur

, to obtain a compound of formula (IV-):Hr3 och3 ch ch2 s-ch2conh e ", the I (IV-) jr201 r20 I-COOH wherein, RT and r3 are as defined above, followed by reaction of the compound of formula (IV-) with a nucleophilic agent (e.g. pyridine derivatives, p

carbamoylpyridine

, 5 a-mercapto1-to-

méthy

!- lH tetrazol, acid 5 a-mercapto lH-tetrazol-i-acetic, acid 5 a-mercapto lH tetrazol L-methanesulfonic, acid 5mercapto I-H

tétrazol1

- ethanesulfonic, acid 5 a-

mercapto1Htriazol

-to-2-acetic, acid 5 mercapto-I-H

triiol

-to-2-carboxylic, 3mercapto-to-4-methyl 5 oxo-6 hydroxy-4.5 to-

dihydroxy1,

2 and 4 triazine) LEL or an alkali metal thereof.The

eomposés

of formula (II-) used as starting material may be obtained by a conventional method, for example by the method

decnte

in "

Chemlcal

and

Pharmaceutlcal

ballot", LIU. 24, p (1976) and in 2629 "

Tetrahedron

Letters and">, no. 16, P (1976) 1307.From halogen atoms for X in the formula (II-), chlorine, bromine and iodine are usable, bromine being preferred.The reaction for producing the compound of formula (IV-) from the compound of formula (II-) and the compound of formula (III) is generally carried out using an appropriate inert solvent, in the presence of an acid trap, and in a molar ratio of about 1 to 1.5 for the

réaetifs

. Any solvent can be used in this reaction without particular limitation, provided that it does not occur in the reaction, and the suitable examples of such a solvent are the ADC and methanol. Examples of the trap acid are the bases suchre uests that alkali metal hydrogencarbonate, trialkylamine and pyridine. The compounds of formula (II-) react with the compound of formula (III-) in the presence of such a trap acid, at room temperature or a lower temperature, to obtain the compound of formula (IV-). The reaction time mainly depends on the type of halogen, trap acid and solvent used, and it is generally between 1 and 5 hours.The compounds of formula (IV-) thus prepared can be recovered from the reaction mixture by a conventional method

réaetionnel

, if necessary. For example, the reaction mixture diluted with water, absorbed onto an absorbent resin (e.g.

DiaionHP20

, and so on) or on activated carbon, and eluted with an organic solvent containing water to be purified. If necessary, the compounds obtained can be subjected to column chromatography comprising different types of absorbents (e.g. of DIAION HP and 20, and so on) to be

puriñés

. The compounds of formula (IV-) thus obtained can be e.g.

7ç

acid - {2 amino (or carbamoylated or

aminoacétylé

)

éthylthioacétamido

} - 7ct-to-

méthoxy3

-to-acetoxymethyl and 3 a-cephem-to-4-carboxylic acid and supplying drop - {2 amino (or carbamoylated or

aminoacétylé

) - 2 a-

carboxyéthylthioacétamido

} - 7." - methoxy-3 a-acetoxymethyl and 3 a-cephem-to-4-carboxylic acid.The obtained compounds of formula (IV-) are further reacted with a nucleophilic reagent (for example pyridine derivatives,

pcarbamoylpyridine

, 5 a-mercapto-L-methyl-lH-tetrazol, acid 5 mercapto-I-H-tetrazol L-acetic, acid 5 mercapto-lH-tetrazole-

1méthanesulfonique

, acid 5 mercapto-lH tetrazol L-ethanesulfonic, acid 5 a-mercapto lH triazole-a 2 a-

aeétique

, acid 5 mercapto-hr-triazole and 2 a-

earboxylique

, 3 mercapto-4-methyl 5 oxo-6 a-

hydroxy4,

5 dihydro-L-, 2.4-triazine derivatives) or LEL alkali metal thereof such that the LEL of sodium or potassium LEL, using a solvent.Any solvent can be used without limitation insofar as it can be does not participate in the reaction, water being the preferred solvent. The reaction is carried out preferably under conditions substantially neutral (pH 6.0 - 7.5) and, if the nucleophilic reagent described above is very slightly soluble in water, the reaction is preferably carried out in an aqueous solution in the presence of a base

teile

as an alkali hydroxide or an alkali phosphate, to convert the compound into an LEL a

teile

basis. There is not particular limitation with regard to the reaction temperature, but a temperature of about 40 to 70 °c is advantageously used. The substitution reaction described above is lo and somewhat longer than the reaction for the preparation of a cephalosporin not having 7a-methoxy group, and it is generally about 7 to 20 hr, when the reaction temperature is 70 °c.According to a modified method for preparing the compound of the formula Si (I-), a compound of formula (III-):Ch ch2sh hr3 (III-) 20201 wherein r20 r3 carboxy and represents a hydrogen atom, a carbamoyl group or a lower acyl group, or a LEL thereof, is reacted with a compound of formula (VI-):Xch2conh 9ch3 cents Oj is n-B

_CH2

r101

eOOH

wherein R O represents:B. means CONH2, n-n-n-"' n-n-, - hindered n - e // n-n-I-I-ch3 ch2 - COOH-n-n-n-n - s n - s lg, OS n-n-I-I-ch2so3h ch2 ch2 - so3 H-n-n-it - ch2 COOH, n-I or H - V-caarying ." OH-I-(I-n-n-n - s>2113 COON 12tt3 and X represents a halogen atom, or LEL thereof.13,643 851 the compound of formula (VI-) is obtained by a conventional method, for example by runway described in US no. 4115645.The halogen atom X in formula (VI-) is chlorine, bromine or iodine, chlorine and bromine being preferred.The reaction for preparing the compound of formula (I-) from the compound of formula (VI-) is generally carried out by reacting the compound of formula 011 a-a) with the compound of formula (VI-) in an inert solvent and in the presence of an acid trap. Any solvent can be used without particular limitation l0 this reaction, on condition of not to take part in the reaction, and suitable examples are water, methanol and acetone. Examples of trap acid are bases suchre uests that alkali metal hydrogencarbonate, trialkylamine and pyridine. The compound of formula (VI-) reacts with the compound of formula (III-) in the presence of such a trap acid at room temperature or a lower temperature, at about neutral pH (pH of 6.5 to 7.5) to form the compound of formula (I-). The reaction time mainly depends on the activity of the halogen, type of trap acid and solvent, and is typically between about 30 min and 5 hr.The reaction product can be recovered from the product mixture

réaetionnel

in a conventional manner. For example, the reaction mixture is made acidic to precipitate the reaction product which is then recovered. Alternatively, the reaction product is adsorbed on activated carbon or on an adsorbent resin (e.g. of DIAION HP and 20, and so on), eluted with a solvent containing water and subjected to column chromatography of sephadex lH 20 or g-10 (manufactured by Pharmacia, Sweden) to purify it.A compound of formula (I-), wherein r3 is carbamoyl or a group

acile

, can also be obtained by reacting a compound of formula (I-) obtained by the above described method (when r3 is hydrogen) with a carbamoylating reagent, such as an alkali metal cyanate or a carbamoyl chloride or an acylating agent such as S-

éthyltrifluorothioacétate

, trifluoroacetic anhydride, formic acid anhydride/carbonic acid or acetic anhydride. The reaction may be performed in a solvent that does not participate in the reaction (e.g. water, pyridine or dimethylformamide) and is completed in several hours (of 5 to 30 hr) at room temperature is at a lower temperature, and under neutral conditions to slightly alkaline (pH of 7.5 to 8). After the reaction, the final compound of formula (L-a-) where r3 is carbamoyl or a group can be purified

acile

suitably and recovered by adsorption on activated carbon or resin absorbent, by

éIution

and column chromatography of sephadex lH 20 or g-10.The compounds of formula (I-b) can be prepared by reacting a compound of formula (ii1-to-1):H2 HM - (β) - shush 0li L) I-

COOIt

wherein b is a straight chain alkylene group having from 1 to branched or 5 carbon atoms, is a LEL thereof, with a

composédermule

(VI B):The X - 3 Osh (has)- n-

CONHdi

ch2 ri01-COOH(VI B) in which a is a straight chain alkylene group having from 1 to branched or 5 carbon atoms,

Rxox

is as defined with respect to formula (I-) and X such as a halogen atom, or a compound of formula (IX-):the T!Z2 HM - (β) - shush ooz3 LEL thereof. The compound of formula (VI B) is obtained by a conventional method, for example by that described in US Patent no. 4115645.The halogen atom X in formula (VI B) is chlorine, bromine or iodine, chlorine and bromine being preferred.The reaction for the preparation of a compound of formula (I-b) from a compound of formula (VI B) is generally performed when acted upon by the compound of formula (III-I) on the compound of formula (VI B) in an inert solvent and in the presence of an acid trap.Any solvent may be

utiIisé

in this reaction without particular limitation as long as the solvent does not participate in the reaction, and suitable examples are water, methanol and acetone. Examples of trap acid are bases suchre uests that alkali metal hydrogencarbonate, an

tñalkylamine

la and pyridine derivatives. The compound of formula (VI B) reacts with the compound of formula (III 1) in the presence of such a trap acid, at room temperature or lower temperature and under conditions approximately neutral (pH of 6.5 - 7.5), to form the compound of formula (I-d). The reaction time mainly depends on the activity of the halogen and type of trap acid and solvent, and is typically between about 30 min and 5 the.According to a modified method for the preparation of compounds of formula (I-d), a compound of formula (binding of a-b):Och3 ' theS # ITs 2 d, I-(VII-b) the O " c [12 ri01 cooz1 wherein R, 1 O-z1 is as defined above and is a carboxy protecting group removable, is reacted PREA process a compound of formula (

Vili

):HM - (β) - - (has)- TOC (

vIu

) I-

COOZ

3 wherein z2 is an amino protecting group removable, z3 is a carboxyl-protecting group removable, a and b are each

alkyIène

straight or branched chain having from 1 to carbon atoms, X is 0 is 1, T is a hydroxyl group or an atom or group required to form an active derivative of carboxylic acid (such as an acid halide, a mixed anhydride, a succinimide and p-nitrophenyl ester), by Za, and z2 z3 being removed if necessary of the reaction product.The compounds of formula (binding of b) used as starting materials are obtained in a conventional manner, for example using the method described in<<Journal

Antibiotics

", flight. 29, p (1976) 554, described in "

Tetrahedron

Letters and", P (1975) 2705 or that described in "Journal of the American of Chemical Society in", flight. 99, p (1977) 5504.The compounds of formula (

Vili

) are obtained by reaction of a (IX.) wherein z2, Za and b are as defined above, with a compound of formula (X-):- X-COOH or - (has) (the X) wherein X is a halogen atom and a is a straight chain alkylene group having from 1 to branched or 5 carbon atoms, by reacting 643,851 14 followed

éventuellernent

DCs agent forming a

sulfoxydc

as hydrogen peroxide on the reaction product of, followed by reaction of an agent capable of forming an acid halide such as thionyl chloride or an agent DCs

anhydñde

forming a mixed such as ethyl chlorocarbonate on.The symbol z2 of formula (IX-) represents an amino protecting group such as tert-butoxycarbonyl-cents or trichloroethoxycarbonyl, the symbol by Za of formula (IX-) and the symbol z1 of formula (binding of b) represent a protecting group such as a group carl0

boxyletrichloroéthylc

or diphenylmethyl, and are

introdnits

and is removed in a conventional manner. In formula (X-), the halogen atom is chlorine, bromine or

lode

, bromine being preferred.The

composês

DCs formula (I-b) are obtained from the

compoi

5

sés

of formula (VII-b), and the reaction to the

préparaüon

of these compounds (I-C) may generally be carried out by reacting the compound (

Vili

) to compound (VII-b) in an inert solvent and under conditions suchre uests to allowing the formation of an amide bond. Any solvent can be used in this reaction, without particular limitation, as long as the solvent does not occur in the reaction. Suitable solvents are, for example, organic solvents such as dichloromethane, chloroform, benzene and dimethylformamide. When the compound of formula (

Vili

) nozzles is an acid halide, the compounds of formula (VII-b) and (VIII-) react with each other in the presence of an acid scavenger, for example a base

teile

that the trialkylamine, N, N-dimethylaniline or pyridine, at room temperature or a lower temperature. The removal of protecting groups amino and carboxyl leads to the formation of the compounds of formula (I-b). The reaction time varies primarily with the activity of the carboxylic acid derivative is generally between 1 and and 5:00.If the symbol T in the formula (VIII.) is a hydroxide group, the compound of formula (H-b) can be obtained by reacting the compound of formula (VIII-) with the compound of formula (binding of a-b) in the presence of a dehydration and condensation agent such as n, n-' - dicyclohexyl carbodiimide.The compounds of formula (I-C) thus prepared can be recovered from the reaction mixture by a conventional method. For example, the mixture

réactìonnel

is diluted with water, adsorbed onto an adsorbent resin or on activated carbon, and eluted with an organic solvent containing water for purification. If necessary, a new

puññcation

/isolation can be by lower alkoxycarbonyl group,

c'est

to say an alkoxyalkyl halide or an

alcoxycarbouyloxyalkyle

, but only the

lode

is chosen if

inféñeur

Ro is an acyl group,

c'est

to say an acyloxyalkyl halide. Examples of amino protecting groups are removable t-butoxycarbonyl,

adamantyloxycarbonyle

, p-nitrobenxyloxycarbonyl,

benzhydryloxycarbonyle

and 2.2.2-to-

trichloroêthoxycarbonyle

.The reaction is performed Gen&

esterificatoalcment

by reaction of a compound of formula (IX) with a compound of formula (i3 in an appropriate inert solvent and in the presence of a base used to trap acid, the molar ratio of 1 to

réactiîs

is about 1.5.Any solvent can be used in this reaction without particular limitation insofar as it does not occur in the reaction, and suitable examples of solvent are n,

Ndiméthylformamide

, acetonitrile, acetone, n, n

diméthylatamide

, the

diehlorométhane

, liquid sulfur dioxide, dioxane and tetrahydrofuran.Examples of trap acid are organic amines suchre uests that trialkyl amine, pyridine derivatives, ethyl aniline, dicyclohexyl amine, morpholine and N-methylmorpholine, as well as inorganic bases suchre uests that

hydrogéuocarbonate

sodium, potassium hydrogen carbonate and lithium carbonate. In the presence of an acid such trap, and with a halide or a halide of acyloxyalkyl alkoxycarbonyloxyalkyl used as esterification agent, the reaction easily proceeds at a temperature of between -30 et + 15 °c and, if an alkoxyalkyl having generally a high activity is used, the reaction proceeds readily at a temperature between -50 et + 10 °c. The duration of the

rëaction

depends primarily on the type of halogen, trap Acme and solvent, and is generally between 1 and 5 hours.The compounds of formula 0 a-c) can also be prepared by reacting a compound of formula (IV '):9cri3:

xCci

O, Z-)

zcoùH

-a-th - - - cents " n I-II-II-n-it (IV ') n-co011 IREM 3 wherein X is a halogen atom and Z is an integer of 1 to 5, with a compound of formula (IX):X-AH-or6 (XL)Y-column chromatography of sephadex lH 20 or g-10 (45 product to form a compound of formula (XIII):by Pharmacia, Sweden) or DC of DIAION HP-to-20 (manufactured by Mitsubishi Chemical in of).The compounds of formula (I-c) can be prepared by reacting a compound of formula (IX):Xh-to-or6 (XL in) wherein R " is a lower alkyl group, an acyl group or a lower alkoxycarbonyl group

inféñeur

, Y is a hydrogen atom or a lower alkyl group and X is a halogen atom, with a compound of formula (I-') DCs:Nh2s Osh.the L - " O X Cit - (supra,) - O - (eyelash,)/

CONltBf

"n-ΔBL l - r"=- - I-I when it COON 0# _ Z-n-Gil hindered n haw (R.)'s cool cii3 wherein ze is hydrogen or an amino protecting group and Y and Z are each an integer of 1 to 5, this compound has been synthesized as previously described.The halogen atom of the formula (IX) may be chlorine, bromine or

lode

when

Ró

is a lower alkyl group or a VCO "" I-e X - (

GIIz

)

EON1iBÆ

" Z-L-n-n-hr||-II, I-500 * n (XIII).

COOCH

NJwhere OR6 or I-I-gli2 - s. cu3 Y in which X, the Z, Y and r6 are

coramedèfinls

previously, pulse by reacting the resulting compound of formula (XIII) with a compound of formula (wire '): nh2 HM - (cri2) Y-SH(wire') Color of the m wherein R '2 is hydrogen is a lower alkyl group, and Y is an integer from I to the compound of formula (IV') is conventionally obtained, for example using the method described in US Patent no. 4007177. The reaction between the compound of formula (IV ') and the compound of formula (IX) to form

Fester

of formula (XIII) is carried out under conditions identical to those provided for the reaction between the compound of formula (I-') and the compound (XII) mentioned previously.The resultant compound of formula (XIII) is then reacted with cysteine or a homolog thereof or with an ester s by lower alkyl thereof, in a solvent, to form the compound of formula (I-c). Any solvent can be used in this reaction without particular limitation as long as it does not occur in the reaction. Suitable solvents include water, the

rnéthanol

,

réthanol

, acetone, dioxane, the t0

tétrahydroîuranne

and n, n-dimethylformamide, which can be used alone or in admixture. The reaction is preferably carried out under conditions substantially neutral and an acid or an alkali can be optionally added to maintain the pH of the reaction mixture between 6.5 and 7.5. The reaction occurs at a temperature between the s - 10 °c - and ambient temperature. The reaction time varies according to the activity of the halogen and the type of solvent, and usually ranges from 30 min to 5 hr.A modification of the process

décñt

above comprises the reaction of a compound (IX)

formnle

with a compound of formula (R-'):2 hr

OCII

combat money "

Iù

",, "" "-COOR2" n-CTC-Z-is 9 "/" I-n/n/2s (the R ')'s cool I-cry 3 wherein R " 2 is a lower alkyl group, and Y and Z are each an integer of 1 to 5, this compound being obtained by reacting a compound of formula (IV') with a compound of formula (1119. The reaction may be carried out under conditions identical to those described above.A dialkyl amino lower alkyl ester derivative of the compound of formula (I-c) can be readily prepared by reacting a reactive ester of the N-t-

butoxyearbonyle

of formula (I-') or (I-' 9 (e.g. an active ester formed using an anhydride of mixed acid, an ester of P-nitrophenyl and carbodiimide or carbonyldiimidazole in) with an alcohol, the n, n-lower alkylamino alkyl in an organic solvent (such as dichloromethane, chloroform, tetrahydrofuran, n-, n-dimethylformamide or dioxane), then using trifluoroacetic acid to remove a tert-butoxycarbonyl group of the reaction product.The compound of formula (I-c) can also be prepared by reacting a compound represented by the following formula:"O" - 0ch5 enjoying

Lí

'0, 0, '

_S

ch2 n-n-I-I-

COOCH

-to-or6 cri3 SSs therein wherein R " and Y are as defined above in formula (I-c), with a compound of formula (

Vili

'):(0) I-IX.

NHZ

, O-CH2 - O - (cri2) - (cri2) - TOC (VIII. ') I-W Y Z Color of wherein R " 2 is a lower alkyl group, the X, Y and Z are as defined above in formula (I-a LC Z is hydrogen or an amino protecting group removable, T is a hydroxyl group or an atom or group of atoms forming a 643,851 active derivative of carboxylic acid, then by removing the amino protecting group of the resulting product. Examples of amino protecting groups are those which show

ëté

mentioned in the definition of formula (I-'). examples of active derivatives of carboxylic acid are those that are typically employed in the formation of amide bond, for example an acid halide such as acid chloride or acid bromide, a mixed acid anhydride as a product

éthoxycarbonyloxylé

, a succinimide and p-nitrophenyl ester.The reaction just discussed using a condensing agent such as dicyclohexyl carbodiimide dehydrating and if T in the formula (

Vili

') is a hydroxide group. Any solvent which does not participate in the reaction can be used, such as for example dichloromethane, chloroform, tetrahydrofuran, dioxane, diethyl ether and n, n-dimethylformamide. The reaction takes place at ambient temperature or a lower temperature.The reaction time varies according to the activity of the carboxylic acid derivative, the type of solvent and temperature, and is generally between about 1 and 10 hr. The ease with which the amino protecting group is removed depends on the type of protecting group chosen and this

élirnination

generally occurs readily in the presence of trifluoroacetic acid, acid or acid

zincacétiqueforinique

, or by catalytic reduction.After the reaction, the reaction product or the final product of

formnle

(I-) can be purified efficiently and recovered by solvent extraction using a weak alkali or by extraction with acid water if the compound is a diester, and by extraction with alcohol, acetone, and the like, if the compound is a monoester.If necessary, further purification may be carried out by chromatography on sephadex lH 20, and the like, conventionally

teile

in the previously described.The present invention will be now illustrated and described in detail with reference to the following examples.Example 1:l-g acid 713 bromoacetamido-to-7ct-to-

méthoxycéphalosporanique

was suspended in 20 ml of water, and the

NaHCOa

was added to adjust the pH of the slurry to 7.0 to form an aqueous solution of acid. Then, 300 mg of mercaptoethylamine hydrochloride were added to the solution, and the reaction was carried out at room temperature for a period of 2 hours, the pH being maintained at 7.0. After the reaction, the reaction mixture was diluted 3

foís

with water, passed through a column filled with 500 ml of of DIAION HP-to-20 (trademark for a high porous polymer manufactured by Mitsubishi Chemical in of), washed with water and eluted with 10% aqueous acetone. The fractions containing the product were concentrated and dried to give 620 mg cold acid 713 to-

aminoéthylthioaeétamido

-to-7ct-to-

méthoxycéphalosporanique

. 500 mg of the product was dissolved in 10 ml of water, and 155 mg of 5 a-mercapto 1-methyl-1h-tetrazol were added to the solution, which has then been adjusted to a pH of between 6.5 and 7.0 and subjected to reaction in 600 C. for 7 hr. After the reaction, the reaction mixture was diluted 3 times with water, pH adjusted to 6.5, and the mixture was passed through a column of

DiaionHP20

, and eluted with 10% aqueous acetone. The fractions containing the final compound were concentrated and dried to give 250 mg cold acid 713 to-

aminoéthylthioacétamido

-to-7ct-methoxy-3 - (

1méthyl1

1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid having the following characteristics:RF value of thin layer chromatography of

Silieageh

0.49 (or n-butanol/acetic acid/water=2/1/1) MRT (in heavy water, values in ppm from TMS as standard external) 5.16 (IH-, e), 4.16 (2:00, Q-), 4.05 (3:00, e), 3.6 (2:00, Q-), 3.55 (3:00, e), 3.5 (2:00, Q-), 3.3 (2:00, T-), 3.0 (2:00, T-) example 2:mg acid 713 to-

aminoéthylthioacétarnido

-to-7ct-methoxy-3 - (

1méthyl

over 1 hr-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic 643,851 16 obtained in the example 1 were dissolved in 3 ml of water, and 30 mg of potassium cyanate was added Å in the solution, which has then been adjusted to a pH of between 7.5 and 8.0, and then subjected to the reaction at room temperature for a period of 6 hours. After the reaction, 7 mi of water were added to the reaction mixture, the pH was adjusted to 6.5 and the mixture was passed over a column of DIAION HP-a 20, the fractions eluted with water and containing the final product is then concentrated and dried to give 20 mg of cold acid 713 to-

uréidoéthylthioacétamido

-to-7th-methoxy-3 - (1 a-

méthyI1Htétrazol

-to-5 yl)

thiòméthyl

and 3 a-cephem-to-4-carboxylic, an Rf value by thin-layer chromatography on silica gel of 0.73 (

nbutanol

/acetic acid/water=2/1/1).Example 3:425 g acid 713 bromoacetamido-to-7th-to-

méthoxycéphalosporanique

were suspended in 10 LTA of water, and then the suspension was adjusted to pH 7.0 to form an aqueous solution of acid, and 200 mg of d-cysteine hydrochloride were added to this solution which was re-adjusted to pH 7.0 and subjected to reaction at room temperature for a period of 2 hr. After the reaction, the reaction mixture was treated in the same manner as in the example 1, to give 270 mg of acid

7ç

- (2-amino 2carboxy)

éthylthioacétamido

-a 7" -

méthoxycéphalosporanique

. 210 mg of the product were reacted with 5 mercapto-l-methyl-

lHtétrazol

, and the mixture was treated by column chromatography of DIAION HP-a 20 to give 120 mg of the final product, supplying drop acid - (2d-a 2-amino 2 carboxy)

éthylthioacétamido

-a 7" - methoxy-3 - (1 -

méthyl1H

-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic, an Rf value by thin layer chromatography silica gel of 0.41 (or n-butanol/acetic

aeide

!water=2/1/1).Example 4:9.2 g acid 713 to-

bromoacétamido

-to-7ct-methoxy-3 - (1 -

méthyl1Htétrazol

-to-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid were suspended in 100 LTA water, and a saturated solution of aqueous sodium bicarbonate was added to the suspension while cooling to adjust its pH to 7.2 to form an aqueous solution of this acid. With this solution were added, while cooling, 4.63 g of d-cysteine hydrochloride, and the mixture was stirred at room temperature for a period of 30 to 40 min during which the pH has been adjusted to a level between 7.1 and 7.2. The reaction mixture was then passed through a column (5 x 70 cm) filled with 800 mi of of DIAION HP and 20 and eluted with water. From fractions eluted with water, 5.25 g of a LEL acid sodium supplying drop - (2d-a 2-amino 2carboxy)

éthylthioacétamido

-to-7th-methoxy-3 - (1 methyl-lh-

tétrazol5

yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid were obtained. The column of DIAION HP-to-20 was washed with 5% aqueous acetone to recover an additional amount of 1.45 g of the final compound.

éthylthioacétamido

-to-7ct-methoxy-3 - (1 - sulfoethyl-to-1 i-tetrazol-5 yl) - thiomethyl-a 3 a-cephem-a 4 a-

earboxylique

.Example 5:100 mg acid 713 to-

aminoéthylthioacétamido

-to-7th-to-

méthoxycéphalosporanique

were dissolved in 10 ml of water, and 61 mg acid 5mercapto lH-tetrazol L-ethanesulfonic acid were added to the solution, and then aqueous sodium bicarbonate was added to this solution to adjust its pH to 6.8, and the mixture is heated to 60 °c for 12 hr.After the reaction, the reaction mixture was treated with hydrochloric acid in-bring its pH to 1.9, washed with 10 mi example 6:230 mg of a mixture comprising supplying drop acid - (2d-a 2-amino in Mino -. 2 carboxy)

éthylthioacétamido

-to-7ct-to-

méthoxycéphalosporanique

and mg of acid 5 a-mercapto lH tetrazol L-methanesulfonic was dissolved in 10 ml of water, and aqueous sodium bicarbonate was added to the solution to adjust its pH to 7.1, the reaction being carried out at 60 °c for 20 hr. After the reaction, the reaction mixture was treated in the same manner as in the example 5 to give mg of a LEL acid sodium supplying drop - (2d-a 2-amino 2 a-

earboxy

)

éthylthioacétamido

-to-7a-methoxy-3 - (1 a-

sulfométhyl1H

-tetrazol-5 yl) - thiomethyl-a 3 a-cephem-to-4-carboxylic acid.Example 7:The same procedure as in example 3 was repeated, except that acid 713 bromoacetamido-to-7th-to-

méthoxyeéphalosporanique

(1.42 grams) was dissolved in 60 LTA of water, and that d-cysteine has been replaced by 640 mg of L-cysteine. 240 mg of a LEL acid sodium 7 [3 - (2l-to-2-amino 2 carboxy)

éthylthioacétamido

-to-7n-methoxy-3 - (1 methyl-1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid were obtained.Example 8:The same procedure as that of the example 3 was repeated, except that 0.71 g acid 713 bromoacetamido-to-7ct-to-

méthoxycéphalosporanique

30 was dissolved in water and the LTA

Dcystéine

has been replaced with 320 mg of dl-cysteine. 130 mg of an LEL acid sodium supplying drop - (2dl-to-2-amino 2 a-

earboxy

)

éthylthioaeétamido

and 7 - methoxy-3 - (1 methyl-1 H-tetrazol-5 yl) thiomethyl-to-

3céphem

-to-4-carboxylic acid were obtained.Example 9:78 mg of the sodium salt obtained in the example 7 were dissolved in 10 ml of water, and 50 mg of potassium cyanate was added to the solution, which was allowed to stand at room temperature for 2 d-. After the reaction, the reaction mixture was adjusted to pH 6.7, passed through a column (1, 5 x 40 cm) of of DIAION HP and 20 and eluted with water. The fractions containing the final compound were combined and dry to give 64 mg

coneentrées

an LEL acid sodium supplying drop - (2l-a 2 a-

carbamoylamino

and 2 carboxy)

éthylthioacétamido

-to-7a-methoxy-3 - (L methyl1 1H-tetrazol-5 yl) thiomethyl-3 a-cephem-to-4-carboxylic acid.Example 10:200 mg of the LEL sodium obtained in the example 4 were dissolved in 2 ml of water, then the solution was treated with hydrochloric acid 1n to adjust its Pt I between 2.5 and 2.6, passed through a column filled with 100 ml of of DIAION HP-a 20, washed with water, eluted in 20% aqueous acetone, to give 184 mg of the free acid.140 mg of the free acid were dissolved in 5 ml of water and to this solution was added a solution of 40 mg of L-lysine in 0.8 ml of water, the resulting mixture (PRP=8, 05) is then dried to give 180 mg of cold LEL a L-lysine acid 71] - (2d and 2 a-amino2 carboxy)

éthylthioacétamido

-to-7ct-methoxy-3 - (1 a-methyl1 H

tétrazol5

yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid.ethyl acetate twice, and then treated with hydrochloric acid " 1n O to bring its pH to 1.0, passed over a column (2 × 50 cm) of of DIAION HP and 20, and eluted with water and 5% aqueous acetone.The fractions with a ninhydrin-positive reaction were combined and processed with sodium bicarbonate to adjust the PL - - [to 7.0. The eluate was concentrated, passed through a column of sephadex lH 20, washed with water and eluted with 50% methanol. The fractions containing the final compound were concentrated and dried to give 50 mg cold of a sodium salt of the acid 713 to-

aminoExemple

11:960 mg of acid 713 bromoacetamido-to-7ct-methoxy-3 - (1 a-

méthyl1H

-tetrazol-5 a-yj) thiomethyl-a 3 a-cephem-to-4-carboxylic acid were suspended in 20 ml of water, and sodium hydrogen carbonate was added to adjust the pH of the slurry to 7.0, to form an aqueous solution of the acid. 300 mg of d-homocysteine DCs were added to the solution and the reaction was carried out at room temperature for a period of 1.5 hours, the pH being maintained between 7 and 7.5. After the reaction, the reaction mixture was adjusted to a pH between 5.5 and 6.0, concentrated to a small volume, passed through a column (2 x 68 cm) filled with 150 ml of of DIAION HP and 20, and eluted with water. The fractions containing the final compound were combined, dried and

eoncentrées

to give 390 mg of cold 7 [3 - (3d and 3-amino 3 carboxy)

propylthioaeétamido

-to-7ct-methoxy-3 - (

lméthylI

1H-tetrazol-5 yl)

thiomëthyl

and 3 a-cephem-to-4 carboxylate sodium, having a value

Rfpar

thin-layer chromatography on silica gel of 0.39 (or n-butanol/acetic acid/water=2/1/1).Example 12: lo and 1.45 g of the 7

[

3 bromoacetamido-to-7ct-methoxy-3 - (P

carbamoylpyridinium

) methyl-3 a-cephem-to-4-carboxylic LTA was dissolved in water, and then 450 mg dl-homocysteine were added to this solution and the reaction was carried out at room temperature for 2 hr, the pH of the solution is maintained at 7.0. After the t5 reaction, the procedure of the example 11 was repeated to give 600 mg of acid supplying drop - (3dl-a 3 amino-carboxyl)

propylthioacétamido

-to-

7ctméthoxy

and 3 - (P

carbamoy[pyridinium

) methyl-3 a-

eéphem

-a 4 a-

earboxylique

having a value

Rfpar

thin-layer chromatography on silica gel of 0.25 (or n-butanol/acetic acid/water=2/1/1).Example 13." 1.25 g of the 713 bromoacetamido-to-7ct-methoxy-3 - (1 a-

méthyl1H

-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid was suspended in 20 ml of water, and then sodium hydrogen carbonate was added to form an aqueous solution of acid, and 530 mg of hydrochloride of d-penicillamine were added, whereupon the reaction carried out at 10 °c during 1.5 hr, and by maintaining the pH of the mixture between 7.0 and 7.5

réaetionnel

. After the reaction, the reaction mixture was treated in the same manner as in the example 11 to give 680 mg of 713 - (2d-a 2-amino 2-carboxy-L, L--dimethyl) -

thioacét

amido 7a-methoxy-3 - (1 - methyl1 H-T-stored characteristics

razol

-to-5 yl) thiomethyl-a 3 a-

eéphem

-to-4 carboxylate sodium, having a value

Rfpar

"

chromatographìe

thinly on silica gel of 0.45 (n

butanoliacide

acetic acid/water=2/1/1).Example 14:500 mg acid 7ç and 2 a-

bromopropionamido

-a 7 - tert-methoxy-3 (

1méthyl1H

-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid were suspended in 10 ml of water, and then sodium hydrogen carbonate was added to adjust the pH of the slurry to 7.0 and forming an aqueous solution of acid, and 210 mg of d-cysteine hydrochloride were added to the solution, whereupon the reaction carried out at room temperature for a period of 2 hr, and by maintaining the pH of the reaction between 7.0 and 7.5. After the reaction, the reaction mixture was adjusted to pH 6.0, concentrate

jusquä

a small volume and treated in the same manner as in the example 11 to give 230 mg of

7p

- {substituted 2 - (2d-amino 2 carboxy)

éthylthiopropionamido

} - 7." - methoxy-3 - (l-methyl-I-H

tétrazoI

-to-5 yl) thiomethyl-a 3 a-cephem-to-4 carboxylate sodium, an Rf value by thin-layer chromatography on silica gel of 0.4 (n

butanolo

acetic acid/water=2/1/1).Example 15:980 mg of acid 713 to-

bromopropionamido

-to-7ct-methoxy-3 - (

lméthyl1H

-tetrazol-5 yl) thiomethyl-a 3 a-cephem-a 4 a-

earboxylique

were suspended in 20 ml of water, and sodium hydrogen carbonate was added to adjust the pH to 7.0 and forming an aqueous solution of this acid. 325 mg of d-cysteine were added to this solution and the reaction was carried out for a period of 2 hr by maintaining the pH of the mixture between 7.0 and 7.5. The reaction mixture was treated in the same manner as in the example 11 to give 410 mg of 713 - (3d and 3-amino 3 carboxy)

propylthiopropionamido

-a 7" - methoxy-3 - (1 methyl-1 1H-tetrazol-5 yl) thiomethyl-to-

3céphem

-to-4 carboxylate sodium, an Rf value by thin-layer chromatography on silica gel of 0.43 (n-butane and/acetic acid/water=2/1/1).17,643 851 example 16:1.05 g of 7

[

3-amino 7ct-methoxy-3 - (1 methyl-1h-tetrazol-5 yl) - thiomethyl-a 3 a-cephem-to-4-carboxylate diphenylmethyl LTA 20 was dissolved in dichloromethane, 0.35 ml of dimethylaniline was added cooling to -20 °c, LTA 5 and then a solution of 1.2 g of chloride 3d and 3 T-butoxycarbonylamino 3 a-

diphénylmthoxycarbonylpropylsulñnylacétyle

in dichloromethane were added dropwise to the solution, and the reaction was carried out for a period of 3 hours. After the reaction, the reaction mixture was mixed with 100 LTA of dichloromethane, washed sequentially with aqueous sodium hydrogen sulfate to 5 degrees/

'o

, with saturated aqueous sodium chloride and sodium hydrogen carbonate aqueous 5%, then washed with water, dried using anhydrous sodium sulfate and concentrated to dry. The residue was dissolved in 8 ml anisole, then 10 LTA

triñuoroacétique

acid were added to the solution while cooling to 0 °c, and the reaction was carried out for a period of 40 minutes. After the reaction, the reaction mixture was concentrated to remove trifluoroacetic acid.100 lTA of ethyl acetate were added to the residue which was then extracted with 150 LTA aqueous sodium hydrogencarbonate to 5%.The extract was washed with ethyl acetate and its pH adjusted to 6.0

étæ

, then was concentrated to a small volume and treated in the same manner as in the example 11 to give 430 mg of 713 - (3d-to-3amino-to-3 carboxy)

propylsulfinylacétamido

-to-7u-methoxy-3 - (1 a-

méthyl1H

-tetrazol-5 yl) thiomethyl-a 3 a-

eéphem

-to-4 carboxylate sodium, an Rf value by thin-layer chromatography on silica gel of 0.35 (or n-butanol/acetic acid/water=2/1/1).Example 17:480 mg of acid 7

[

3 a-

bromoaeétamido

-to-7n-methoxy-3 - (1 a-

méthyliH

-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid were suspended in 15 water LTA, and sodium bicarbonate was added to the suspension to adjust its pH to 7.0 and forming an aqueous solution of acid. 170 mg of hydrochloride ethyl

Fester

D-cysteine was added to the solution whose pH has been maintained at 7.0 batches of the reaction was done 80A. 5 °c during 2 hours. The reaction mixture was adjusted to pH 6.0, passed through a column filled with 70 LTA XAD-to-2, washed with water and eluted with 50% aqueous acetone. The

fraetions

containing the final compound were concentrated and dried to give 450 mg cold white powder acid 7 [3 - (2d-a 2-amino 2-ethoxycarbonyl) -

éthylthioaeét

amido 7ct-methoxy-3 - (1 - methyl1 H

tëtrazol

-to-5 yl) - thiomethyl-a 3 a-cephem-to-4-carboxylic acid. This powder leads to greater commercial value corresponding to a single RF 0.6 by thin-layer chromatography on

Silieagel

(

aeétone

/methanol=2/1).310 mg of the acid obtained above were dissolved in 5 ml of water, and the solution was treated with sodium hydroxide 0 °c IN to adjust its pH to 9.5, and then was immediately

séchëe

cold. The dry product was suspended in 6 ml of n, n

diméthyls0

of formamide, and 3 ml of a solution of 220 mg of pivaloyloxymethyl iodide in n, n-dimethylformamide were added dropwise to the suspension for a period of 10 min at -20 °C, and then the reaction was performed for 1 H at 0 °c with agitation.The reaction mixture was diluted with 30 water LTA, washed with 30 mi s5 ethyl acetate at pH 3.0, treated with sodium bicarbonate to bring the pH to 8.0 and LTA 100 extracted with ethyl acetate. The extract was washed twice with 30 LTA of water, dried with anhydrous sodium sulfate and filtered. The

ñltrat

was mixed with 0.3 ml of trifluoroacetic acid, and immediately dry concentrate to give 340 mg of a powder of a trifluoroacetate

bianche7ç

- (2d-a 2-amino 2-ethoxycarbonyl)

éthylthioaeétamido

-to-7a-to-

méthoxy3

- (1 methyl-lh-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylate pivaloyloxymethyl,

ayant.une

rf value by thin layer chromatography on silica gel of 0.75 (acetate/acetone=5/1

dëthyle

).Example 18:960 mg of acid 7

[

3 bromoacetamido-to-7ct-methoxy-3 - (L-I-

Htétrazol

-to-5 yl) thiomethyl-a 3 a-

eéphem

-to-4-carboxylic acid were dissolved in 10 ml 643,851 18 n, n-dimethylformamide, and 0.28 ml of triethylamine were added to this solution to -20 °C, then 5 ml of a solution of 500 mg of iodide 1-acetoxyethyl in n, n-dimethylformamide were added dropwise to the mixture over a period of minutes, followed by stirring for 1 hr at 0 °c. The reaction mixture was diluted with 50 LTA of water, and extracted with 100 mi of ethyl acetate at a pH of 6.0. The extract was washed with 5õ ml water, dried with anhydrous sodium sulfate, filtered and concentrated to dry. The residue was washed with 30 LTA of petroleum ether and the insoluble residue was dried over phosphorus pentoxide to give 1080 g of a white powder of 7

[

3 a-

bromoaeétamido

-to-7c-methoxy-3 - (1 a-

méthyllH

-tetrazol-5 yl) thiomethyl-a 3 a-cephem-a 4 a-

earboxylate

L-acetoxyethyl, having a value IR " by thin-layer chromatography on silica gel of 0.85 (acetone/methanol=2/1).A portion of 565 mg of the powder was dissolved in 8 ml of dioxane, and 15 ml of water were added to this solution which has then been treated with sodium bicarbonate to adjust its pH to 7.0, and 180 mg of hydrochloride rampage methyl d-cysteine was added to the solution, and the reaction was carried out at a temperature between 0 and 5 °c during 2.5 hr, the pH being maintained between 6.5 and 6.8. The reaction mixture was diluted with 50 mi of water, extracted with 100 ml of ethyl acetate at pH 8.0, and then transferred to 50 ml of diluted hydrochloric acid. The extract was treated with bicarbonate

sodiurn

to adjust its pH to 8.0, re-extracted with 100 ml of ethyl acetate and dried with anhydrous sodium sulfate, then concentrated to dry to give 470 mg of a white powder of 713 - (2d-a 2-amino 2-methoxycarbonyl)&

hylthioacétamido

-to-7c-methoxy-3 - (1 methyl-lh-tetrazol-5 yl)

thiométhyl3

-to-cephem-to-4-carboxylate 1-acetoxyethyl, an Rf value by thin-layer chromatography on silica gel of 0.70 (acetate/acetone=5/1

dëthyle

).Example 19:620 mg of the ester 1 a-

pivaloyloxyéthyle

acid 7 -

bromo3s

acetamido-7ct-methoxy-3 - (L

méthyl1H

-tetrazol-5 yl)

thiométhyl3

-to-cephem-to-4-carboxylic acid obtained by the method of example 18, were dissolved in tetrahydrofurane 10 OLAP, OLAP 20 and water have&e added to the solution which was then treated with aqueous sodium bicarbonate to adjust its pH to 7.0, and 190 mg of

chlorqo

hydrate D-cysteine was added to the solution, the reaction being carried out at a temperature between 0 by 5° and C for 2 hr

péñode

of, and the pH maintained between 6.5 and 6.8. The reaction mixture was adjusted to pH 5.5, and then cold dried immediately, and the residue was extracted with 20 mi of acetone. The solvent was evaporated to dry, and the solid obtained was dissolved in 50 LTA of water, and washed with 50 ml of ethyl acetate at a pH of 2.0. The aqueous layer was adjusted to pH 5.5 again, saturated with sodium chloride and extracted with 100 LTA of ethyl acetate three times. The extracts were combined and dried with anhydrous sodium sulfite O, and then concentrated to dry to give 380 g of a powder of 7 [3 -

bianche

(2d-a 2-amino 2 carboxy)

éthylthioacétamido7

" - methoxy-3 - (l-methyl-1 1H-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4carboxylate L-

pivaloyloxyéthyle

, an Rf value by thin-layer chromatography on silica gel of 0.2 (acetone/methanol 20 g.:1.25 g acid

7ç

- (2d-a 2 T-butoxycarbonylamino 2 a-

earboxy

)

éthylthioacétamido

-to-7c-methoxy-3 - (1 -

méthyl1H

-to-

tétmzol

-to-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylic acid were dissolved in 20 ml of n,

Ndiméthylformamide

, and 0.66 ml of triethylamine was added to the solo with cooling to - 15 °c

lution

, then a solution of 1.2 g of pivaloyloxymethyl iodide in n, n-dimethylformamide was added dropwise to the mixture over a period of 20 minutes, followed by the reaction for 1 hr with agitation. The reaction mixture was poured into 100 mi of ice water, and extracted with 100 mi 1 ethyl acetate twice. The extracts were combined, washed three times with ml of water, dried with anhydrous sodium sulfate and concentrated to dry. The residue was washed with petroleum ether 2õ mid to give 1.02 g of a pale yellow syrup of 7 - (2d and 2 a-

tbutoxycarbonylamino

and 2 a-

pivaloyloxyméthoxycarbonyl

)

éthylthioacétamido

-to-7c-methoxy-3 - (1 a-

méthyl1H

-tetrazol-5 yl)

thiométhyl3

-to-cephem-to-4-carboxylate pivaloyloxymethyl.A portion of 450 mg syrup above was dissolved in trifluoroacetic acid to LTA 4 - 10 °c and left at rest for minutes. The trifluoroacetic acid was removed by the

évaporaUon

, and the reaction mixture was passed through a column filled with 100 sephadex LTA-lH 20 and eluted with acetone. The fractions containing le final compound were combined and concentrated to give 260 mg of dry powder of 7 [3 -

bianche

(2d-a 2-amino

2pivaloyloxyméthoxycarbonyl

)

éthylthioacétamido

-to-7c-methoxy-3 - (1 methyl-lH-tetrazole-5 yl) thiomethyl-a 3 a-cephem-to-4-carboxylate pivaloyloxymethyl, an Rf value by thin-layer chromatography on silica gel of 0.33 (

achate

ethyl/acetone=5/1).Example 21:250 mg of acid 7 - (3dl-to-3-amino 3 carboxy)

propylthioacétamido

-to-7c-methoxy-3 - (1 methyl-lh-tetrazol-5 yl) thiomethyl-to-

3céphem

-a 4 a-

earboxylique

were dissolved in a mixture of 4.0 ml of n, n-dimethylformamide and 1.5 LTA of dichloromethane, and 0,135 mi of

tri6thylamine

were added to the obtained solution.Then, 3 ml of a solution of dichloromethane containing 80 1 I-methoxymethyl chloride were added dropwise to 35° - c on a period of 30 minutes, followed by a reaction of 3 H at -35 °c with agitation. The reaction mixture was poured into ml of water ice, and then extracted three times with ethyl acetate 50 to LTA.a pH of 8.0. The extracts were then combined,, washed with water, dried with anhydrous sodium sulfate and concentrated to dry. The residue was washed with 10 ml of hexane, dissolved in 3 ml of dioxane and dried to give 80 mg of cold powder

bianche

of 7l - (3dl-to-3-amino

mëthoxyméthoxyearbonyl

)

propylthioacétamido

-to-7c-methoxy-3 - (1 methyl-I-H-tetrazole-5 yl) thiomethyl-to-

3céphem

-to-4-carboxylate methoxymethyl, an Rf value by thin-layer chromatography on

Silieagel

of 0.19 (ethyl acetate/acetone=5/1).