CA1078380A

CA1078380A - Cephalosporin analogues

Info

Publication number: CA1078380A
Application number: CA283,811A
Authority: CA
Inventors: Yoshio Hamashima; Wataru Nagata
Original assignee: Shionogi and Co Ltd
Current assignee: Shionogi and Co Ltd
Priority date: 1976-08-09
Filing date: 1977-07-29
Publication date: 1980-05-27
Also published as: NL7708793A; JPS5321188A; GB1552100A; FR2361399B1; JPS609515B2; CH644382A5; DE2735888A1; FR2361399A1; BE857621A

Abstract

CEPHALOSPORIN ANALOGUES
ABSTRACT
1-Oxa-cephalosporin analogues of the formula:
[wherein X is hydrogen or methoxy; Y is hydrogen, halogen, lower alkoxy, sulfonyloxy, arylthio or monocyclic heterocycle-thio; Z
is acyl; R is hydrogen or carboxy protecting group]
exhibiting potent antimicrobial actions, and preparations thereof.

Description

- 1~7838(~

This invention relates to l-oxadethia-3-cephem compounds and , derivatives thereof. Particularly, this invention relates to 3-substituted or -unsubstituted-7-acylamino-1-oxa-1-dethia-3-cephem-4-carboxylic acids or derivatives thereof. Compounds of this in-5 vention are represented by the formula: ;-Z~ O~ , N ~
COOR (I) (wherein X is hydrogen or methoxy; Y is hydrogen, halogen, lower alkoxy, sulfonyloxy, arylthio or monocyclic heterocycle-thio; Z
is acyl; R is hydrogen or carboxy protecting group).
Acyl groups z in the above-mentioned formula (I) are, in particular, acyl groups represented by the formula :
Z'-CO-wherein Z' is 1) thenyls such as 2-thenyl; 2) substituted or un-substituted benzyloxy, such as benzyloxy, p-nitrobenzyloxy, p-aminobenzyloxy, p-hydroxybenzyloxy and p-methoxybenzyloxy; or 3) groups represented by the formula:

Z"-CH-W

[wherein Z" is thienyl or substituted or unsubstituted phenyl; W
is hydroxy, protected hydroxy (e.g. formyloxy, acetoxy), amino, protected amino (e.g. acetylamino, benzyloxycarbonylamino, p-nitro-benzyloxycarbonylamino, p-methoxybenzyloxycarbonylamino, t-butyl-oxycarbonylamino, 4-ethyl-2,3-dioxopiperazinylcarbonylamino, phthalimino), carboxy or protected carboxy (e.g. methyl ester, ethyl ester, benzyl ester, p-nitrobenzyl ester, diphenylmethyl ester, t-butyl ester, p-chlorobenzyl ester)].
Halogen atoms represented by Y are fluorine, chlorine, bromine :. .

:" 10783~0 - and iodine. Lower alkoxy means an Cl - C5 alkoxy such as methoxy, ethoxy, n-propoxy, i-propoxy, and n-butoxy. Sulfonyloxy means Cl -C5 alkylsulfonyloxy such as methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, i-propylsulfonyloxy, and n-butylsulfonyloxy, or C6 - C8 arylsulfonyloxy such as benzenesulfonyloxy and toluene-sulfonyloxy. Arylthio means substituted or unsubstituted C6 - C10 arylthio such as phenylthio, tolylthio, methoxyphenylthio and dimethoxyphenylthio. Monocyclic heterocycle-thio groups are five-membered ones containing 1 - 4 hetero atoms (N, 0 or S), which may be represented by the formula:
-S ~ .
Wherein Q is five-membered heterocyclic group containing aza, oxa, thia, diaza, dithia, triaza, trioxa, trithia, tetraza, oxaza, oxa-thia, thiaza, oxadiaza and thiadiaza in the ring, for example, furan, tetrahydrofuran, pyrrole, pyrrolidine, thiophene, tetra-~, hydrothiophene, oxazole, oxazoline, thiazole, thiazoline, isoxa-zole, isothiazole, pyrazole, imidazole, oxathiole, dioxole, dith- ;
iole, trizole, thiadiazole, oxadiazole, dithiazole, dioxazole, oxathiazole, tetrazole, oxatriazole, thiatriazole, dithiadiazole and the like, The S group connected to the heterocycle may be located at any possible position of the heterocycle. The hetero-cycle may involve 1 - 4 substituents such as Cl - C5 alkyl, hydroxy, ~ Cl - C5 alkoxy, halogen, nitro and amino at an optional possible 1 position or positions.
Carboxy protecting groups represented by R mean ester forma-tive groups which are ordinarily utilized in the field of penici-llin or cephalosporin chemistry. The symbol R includes Cl - C5 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl), Cl - C5 halogenated alkyl (e.g. chloromethyl, dichloromethyl, 2,2-30 dichloroethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl), C7 -_ 2 , . .

`` ~0783~(~

C20 arylmethyl (e.g. benzyl, diphenylmethyl (benzhydryl), triphenyl- ; ;
methyl (trityl), p-methoxybenzyl, 3,4,5-trimethoxybenzyl, p-nitro- -benzyl, p-chlorobenzyl), C8 - C12 acylmethyl (e.g. phenacyl), sub-stituted silyl (e.g. dimethylsilyl, trimethylsilyl, triphenylsilyl), substituted stannyl (e.g. trimethylstannyl), adamantyl, ~-methyl, a-selenonaphthyl, piperidyl, ~-methylthioethyl, 4-methylthiophenyl,

2-benzyloxyphenyl, tetrahydropyran-2-yl, 2-cyanoethyl and the like.
In the compounds represented by the formula (I), when R is hydrogen or when the acylamino at the 7 position involves a free carboxy group -COOH or amino, they may form salts with pharmacologi-cally acceptable inorganic or organic acids or bases.
The compounds in this invention represented by the formula (I) may be prepared on acylation of the corresponding 7-amino deriva- ~ ;
tives represented by the following formula (II). The reaction se-quence is represented as follows:
Reaction Scheme 1 X X
o ZNH ~ o~

C~OOR > O N
COOR
(II) (I) (wherein X, Y, Z and R are the same as mentioned above).
The starting materials represented by the general formula (II) may be prepared from well-known compounds of the formula (a) (Japanese Unexamined Patent Publication ~o. 51-41385) in a manner as shown in Reaction Scheme 2. In Reaction Scheme 2, Z" is amino protecting group; L is halogen atom or sulfonyloxy, Y' is hydrogen, arylthio or monocyclic heterocyclethio; R' is lower alkyl; and X, Y and R are the same as mentioned above.

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Each reaction step illustrated in Reaction Scheme 2 is briefly explained as follows.
The reaction of the starting materials (a) to (b) is halogena- -tion or sulonylation of the 3-hydroxy group (enolic hydroxy group), by which a halogen atom or sulfonyloxy group is introduced into the

3-position. Removal of the amino protecting group Z' from the intermediates (b) yields the starting materials (II), wherein X is hydrogen and Y is halogen or sulfonyloxy.
The intermediates (b) are subjected to reduction (preferably by means of zinc and acetic acid) to yield another intermediates (c), wherein Y is hydrogen (Y'=H), while (b) is subjected to sub-stitution reaction with arylthiols or monocyclic heterocyclethiols to yield alternative intermediates (c), wherein Y is arylthio or - monocyclic heterocyclethio (Y'=arylthio or monocyclic heterocycle-thio). Removal of the amino protecting group Z' from the interme-diates (c) yields the starting materials (II), wherein X is hydro-gen and Y is arylthio or monocyclic heterocyclethio.
The starting materials (a) are subjected to alkylation (pre-ferably by means of diazoalkane) to yield the intermediates (d), wherein Y is lower alkoxy (R =lower alkoxy). Removal of the amino protecting group as mentioned above yields other starting materials (II) of this invention, wherein X is hydrogen and Y is lower alkoxy.
Introduction of methoxy group into the starting materials (II)(X=H) in a well-known manner, for example, in a manner as des-cribed in Japanese Unexamined Patent Publication No. 50-50394, yields the other starting materials (II)(X=OCH3).
Acylation at the 7-amino as shown in Reaction Scheme 2 may be carried out in accordance with acylation procedure ordinarily used in the field of penicillin and cephalosporin chemistry. Represen--1(~783~(~
tative of acylating agents are the carboxylic acids (i.e. Z'COOH) corresponding to desired acyl group Z (i.e. Z'-CO) or their reac-tive derivatives such as acid halides, acid anhydrides (mixed acid anhydrides are included), esters, azides, imidazolides, pyrazolides, triazolides and the like. A11 of the above-mentioned acylating agents may be employed in acylation in well-known manners. The following exemplifies the particularly preferred acylation with free carboxylic acids and acid halides. -The acylation at the 7-amino with free carboxilic acids, Z'-COOH, as acylating agents is preferably carried out in the pre-sence of carbodiimides such as DCC (N,~-dicyclohexylcarbodiimide) in a solvent such as methylene chloride, acetonitrile, dimethyl~
formamide, pyridine, tetrahydrofuran and the like at room tempera-ture or below.
When acid halides, in particular, acid chlorides or acid bromides are employed, the acylation is preferably carried out in an inert solvent under cooling at low temperature. Preferred inert solvents are aprotic solvents such as benzene, ethers, methyl-ene chloride, chloroform, and the like.
In carrying out these reactions, it is appropriate ~o properly protect easily attacked groups, for example, when R=H in the start-ing compounds (II), when (II) have easily acylable functional groups (e.g. amino, hydroxy) at other positions, or when the acyl-ating agents have amino, hydroxy, carboxy group or the like.
Introduction and elimination of the protecting groups may be carried out in a conventional procedure.
It has been confirmed by the inventors that the objective compounds (I) in this invention exhibit much more potent antimic-robial action than the well-known cephalosporin antibiotics posses-sing normal cephalosporin nucleus (i.e. l-thia cephalosporin ` 1~78380 nucleus). Particularly, they exhibit potent antimicrobial action against gram positive and negative bacteria and may be applied in prevention and treatment of various infections caused by those bacteria. For example, these compounds may be administered to human intravenously at a dose of 10 mg - 5 g a day or by other suitable manners (e.g. oral administration, external application), for purpose of prevention and treatment of infections. The follow-ing examples are provided to further illustrate this invention, but not intended to limit the scope of the invention. In the examples and tables, P~B means p-nitrobenzyl and BOC, t-butyloxycarbonyl, respectively.
ExamPle 1 7~-(2-thienyl)acetamido-l-oxa-l-dethia-3-cephem-4-carboxylic acid (I: z= ~S~CH2CO-To a suspension of 55 mg (0.25 mmole) of 7,~-amino-l-oxa-l-dethia-3-cephem-4-carboxylic acid (II: X=Y=R=H) in 3 ml of aceto-nitrile is added 100111 (l equivalent) of bis(trimethylsilyl)aceta-mide. The mixture is mixed with 35 ~1 (1 equivalent) of triethyl-amine under ice-cooling, stirred at room temperature for 1.5 hours, cooled to -20~C, then mixed with 41 ,ul (1.5 equivalents) of ~-methylmorpholine and 60 ,ul (1.5 equivalents) of thienylacetyl chloride, then warmed up to room temperature, and stirred for 1 hour. The mixture is cooled with ice, poured into 5% phosphoric acid aqueous solution and extracted with ethyl acetate. The extract is washed with water, dried and evaporated under reduced pressure. The residue (116 mg) is chromatographed on a column of 12 g of silica gel, and eluted with ethyl acetate-acetic acid (100: 1 - 50: 1). The eluate is washed with petroleum ether to yield 7 mg of the title compound as powder (9.0 % yield).
IR: y 3 1790, 1680, 1515 cm max 1~7838~
~MR : (CDC13+CD30D) : ~ 4.53(s,2H), 5.09(d, lH, j=4.0Hz), 5.49(d, lH, J=4.0Hz), 6.52(m, lH), 7.05~7.32(m3H)ppm The compounds described in Table 1 are prepared from the cor- `
responding 7-amino compounds in the same manners as mentioned above.

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Example 2 1) p-nitrobenzyl 7~-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-l-oxa-l-dethia-3-cephem-4-carboxylate (I : X=Y=H ;
CO
6 5 ~ COOCH(C6H5)2 2 6 4 2) To a solution of 76 mg (0.238mmole) of p-nitrobenzyl 7~-amino-l-oxa-l-dethia-3-cephem-4-carboxylate (II : R=CH2C6H4NO2-p ; X=Y=H) in 8 ml of methylene chloride is added 39 Jul (1.5 equivalents) of N-methylmorpholine under cooling at -20C, and the mixture mixed ;
with a methylene chloride solution of acid chloride prepared from 10 124 mg of diphenylmethyl 2-phenylmalonate, 50 ~ul (1.5 equivalents) of triethylamine and 30 lul of oxalyl chloride, and stirred at -20C
for 30 minutes. The mixture is poured into ice water and extracted with methylene chloride. The extract is washed with water, dried and evaporated under reduced pressure. The residue (244 mg) is chromatographed on a column of 6 g of silica gel, eluted with ben-zene-ethyl acetate (5 : 1) to yield 116 mg of title compound as foamy material (75.3 % yield).
IR : ~ ma 3 1800, 1730, 1680, 1640, 1610, 1520, 1350 cm NMR : (CDC13) : ~ 4.47(m,2H), 4.77(s,1 H), 5.03(d,1H,J=4.0Hz), 20 5.39(s,2H), 5.73(dd,1H,J=4.0;9.0Hz), 6.57(m,1H), 6.94(s,1H), 7.64-8.27 (A2B2q,4H,J=9-0Hz)ppm-2) 7~-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid (I : Z=C6H5CH < ; R--X=Y--H) ( 6 5)2 To a solution of 109 mg (0.168 mmole) of the product in Example 2-1) in a mixture of 5 ml of methylene chloride and 5 ml of acetic acid is added 100 mg of active zinc powder under ice-cooling, the mixture stirred for 60 minutes, and then additional 50 mg of zinc powder added. After 70 minutes, the mixture is fil-tered and the filtrate diluted with methylene chloride, washed with ~7~31~0 water, dried and evaporated under reduced pressure. The residue is dissolved in chloroform and the insoluble material is filtered off. The filtrate is chromatographed on a column of 2.5 g of sili-ca gel and eluted with ethyl acetate - chloroform - acetic acid (50 : 5 : 1). The eluate is washed with petroleum ether to yield 53 mg of the title compound (61.6 % yield).
IR : ~ 3 1800, 1730, 1680, 1640, 1520 cm NMR: (CDC13+CD30D): ~ 4.29(b,2H), 4.78(s,lH), 5.07(d,1H,J=4.0Hz), 5.68(d,lH,J=4.0Hz), 6.51(m,lH), 6.95(s,lH)ppm.
10 Specific Rotation : [a] D ~ 5.9+1.9 (c=0.239, CHC13).
The compounds described in Tables 2 and 3 are prepared in the same manner as mentioned above.
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Example 3 , :~
1) p-nitrobenzyl 3-chloro-7a-methoxy-7~-(2-phenyl-2-benzhydryloxy-carbonyl)acetamido-l-oxa-l-dethia-3-cephem-4-carboxYlate To a solution of 35 mg (0.091 mmole) of p-nitrobenzyl 3-chloro-7a-methoxy-7~-amino-1-oxa-1-dethia-3-cephem-4-carboxylate dissolved in 3 ml of methylene chloride at -20C are added 15 jul (1.5 equiva-lents) of N-methylmorpholine and 1.5 equivalents of 2-phenyl-2-benzhydryloxycarbonylacetyl chloride, and the mixture stirred at the same temperature for 1 hour, poured into 5% phosphoric acid aqueous solution under ice cooling and extracted with ethyl acetate.
The extract is washed with water, dried and evaporated under redu-ced pressure. The residue (93 mg) is chromatographed on a column of 5 g of silica gel and eluted with a mixture of benzene and ethyl acetate (10 : 1) to yield 54 mg of the title compound (83.2 % yield).
15 TLC : Rf=0.30 (benzene : ethyl acetate = 5 : 1) IR-: v H 3 1795, 1740,~1730,~ 1695, 1350 cm NMR :i(CDC13)-~ ~$~3.40j 3.44(1:1,3H),-4i33t-bs,2H~), 4.44(s,1H), 5.13 ts,lH), 5.43(AB~,2H), 6.97(s,lH), 7.68(d,J=9Hz,2H),8.29(d,J=9Hz,2H)ppm.
2) 3-chloro-7a-methoxy-7~-(2-phenyl-2-benzhydryloxycarbonvl)-acetamido-1-oxa-1-dethia-3-cephem-4-carboxYlic acid To a solution of 53 mg of the product in Example 3-1) in a mixture of 2.5 ml of methylene chloride and 2.5 ml of acetic acid is added 50 mg of active zinc powder under ice cooling and the mix-ture stirred for 50 minutes and then filtered. The filtrate is diluted with methylene chloride, washed with water~ dried and eva-porated under reduced pressure. The residue (50 mg) is chromato-graphed on a column of 2.5 g of silica gel containing 10% water and eluted with chloroformmethanol (95 : 5) to yield 35 mg of the title compound as powder (81.6% yield).
30 TLC : Rf=0.32 (ethyl acetate : acetic acid : water = 18 : 1 : 1) IR :~ 1757, 1702 cm 11 ~ 7 8 3 80 max ~' ~MR : (CDC13-CD30D) : ~ 3.42(s,3H), 5.09(bs,lH), 6.94(s,1H). ~
3) 3-chloro-7a-methoxy-7~-(2-phenyl-2-carboxy)acetamido-1-oxa-1- ~-dethia-3-cephem-4-carboxylic acid To a solution of 33 mg of the product in 1.5 ml of methylene chloride are added 0.2 ml of anisole and 0.2 ml of trifluoroacetic acid, and the mixture stirred for 30 minutes. Then, 5 ml of tolu-ene is added, and the mixture evaporated under reduced pressure.
The residue is washed with petroleum ether to yield 24 mg of the title compound as powder.
TLC : Rf=0.52 (ethyl acetate : acetic acid : water = 5 : 1 : 1) IR :~ 1782, 1705(sh), 1675 cm .

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing compounds of the formula:
wherein X is hydrogen or methoxy; Y is hydrogen, halogen, lower alkoxy, sulfonyloxy, C6 to C10 arylthio, or five membered monocyclic heterocycle-thio containing 1 to 4 hetero atoms; Z
is acyl; R is hydrogen or carboxy-protecting group selected from the group consisting of C1 to C5 alkyl, C1 to C5 haloge-nated alkyl, C7 to C20 arylmethyl, C8 to C12 acylmethyl, dimethylsilyl, trimethylsilyl, triphenylsilyl, trimethylstannyl, adamantyl, .alpha.-methyl, .alpha.-selenonaphthyl, piperidyl, .beta.-methyl-thioethyl, 4-methylthiophenyl, 2-benzyloxyphenyl, tetra-hydropyran-2-yl, or 2-cyanoethyl;and therapeutically acceptable salts thereof, comprising acylating compounds of the formula:
wherein X, Y and R are as defined above with an acylating agent, selected from carboxylic acids corresponding to the desired acyl group Z or reactive derivatives thereof, including acid halides, acid anhydrides, esters, azides, imidazolides, pyrazolides or triazolides.

2. A process according to claim 1, wherein the acyl group Z
is represented by the formula Z'-CO- and the acylating agent is represented by the formula Z'-COOH (wherein Z' is:
1) thenyl;
2) benzyloxy, p-nitrobenzyloxy, p-aminobenzyloxy, p-hydroxybenzyloxy or p-methoxybenzyloxy; or 3) groups represented by the formula:

wherein Z" is thienyl or phenyl; W is hydroxy, formyloxy, acetoxy, amino, acetylamino, benzyloxy-carbonylamino, p-nitrobenzyloxycarbonylamino, p-methoxybenzyloxycarbonylamino, t-butyloxycarbonyl-amino, 4-ethyl-2,3-dioxopiperazinylcarbonylamino, phthalimino, carboxy, methyl ester, ethyl ester, benzyl ester, p-nitrobenzyl ester, diphenylmethyl ester, t-butyl ester, or p-chlorobenzyl ester), or the reactive derivatives thereof, including acid halides, acid anhydrides, esters, azides, imidazolides, pyrazolides or triazolides.

3. A process according to claim 2, wherein Z' is thenyl.

4. A process according to claim 2, wherein Z' is benzyloxy, p-nitrobenzyloxy, p-aminobenzyloxy, p-hydroxybenzyloxy or p-methoxybenzyloxy.

5. A process according to claim 2, wherein Z' is represented by the group:
wherein Z" and W are as defined in claim 2.

6. A process according to claim 1, wherein Y is a five-membered heterocycle-thio having the heterocycle selected from the group consisting of furan, tetrahydrofuran, pyrrole, pyrrolidine, thiophene, tetrahydrothiophene, oxazole, oxazoline, thiazole, thiazoline, isoxazole, isothiazole, pyrazole, imi-dazole, oxathiole, dioxole, dithiole, trizole, thiadiazole, oxadiazole, dithiazole, diaoxazole, oxathiazole, tetrazole, oxatriazole, thiatriazole, and dithiadiazole.

7. A process according to claim 1, wherein the acylation is carried out with free carboxylic acids of the formula Z"-COOH in the presence of carbodimides, wherein Z' is as defined in claim 2.

8. A process according to claim 1, wherein the acylation is carried out with acid halides derived from the free carboxylic acids of the formula Z'-COOH wherein Z' is as defined in claim 2.

9. A process according to claim 2 for the preparation 7.beta.-(2-thienyl)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, Y is hydrogen, R is hydrogen and Z' is thenyl.

10. A process according to claim 2 for the preparation of 7.beta.-(2-thienyl)acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogen, Y
is methoxy and Z' is thenyl.

11. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-formyloxy)acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogen, Y is methoxy, Z" is phenyl and W is formyloxy.

12. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-tert-butoxycarbonylamino)acetamido-3-methoxy-1-oxa-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogen, Y is methoxy, Z" is phenyl and W is tert-butoxy-carbonylamino.

13. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-amino)acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogen, Y is methoxy, Z" is phenyl and W is amino.

14. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-p-nitrobenzyloxycarbonyl)acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogen, Y is methoxy, Z" is phenyl and W
is p-nitrobenzyloxycarbonyl.

15. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-carboxy)acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogenl Y is methoxy, Z" is phenyl and W is carboxy.

16. A process according to claim 5 for the preparation of 7.beta.-(2-carboxy-2-thienyl)acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogen, Y is methoxy, Z" is thienyl and W is carboxy.

17. A process according to claim 3 for the preparation of 7.beta.-(2-thienyl)acetamido-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogen and Y is chlorine.

18. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-formyloxy)acetamido-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogen, Y is chlorine, Z" is phenyl and W is formyloxy.

19. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-tert-butyxocarbonylamino)acetamido-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogen, Y is chlorine, Z" is phenyl and W is tert-butoxycarbonylamino.

20. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-amino)acetamido-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogen, Y is chlorine, Z" is phenyl and W is amino.

21. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogen, Y is chlorine, Z" is phenyl and W is benzhydry-loxycarbonyl.

22. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-carboxy)acetamido-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is hydrogen, R is hydrogen, Y is chlorine, Z" is phenyl and W is carboxy.

23. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-tert-butoxycarbonylamino)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X, R and Y are hydrogen, Z" is phenyl and W is tert-butoxycarbonylamino.

24. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-amino)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X, R and Y are hydrogen, Z" is phenyl and W is amino.

25. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-hydroxy)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X, R and Y are hydrogen, Z" is phenyl and W is hydroxy.

26. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-tert-butoxycarbonylamino)acetamido-3-(1-methyl-tetrazol-l-yl)thio-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X and R are hydrogen, Y is (1-methyltetrazol-1-yl)thio, Z" is phenyl and W is tert-butoxycarbonylamino.

27. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-amino)acetamido-3-(1-methyltetrazol-1-yl)thio-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X and R
are hydrogen, Y is (1-methyltetrazol-1-yl)thio, Z" is phenyl and W is amino.

28. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-3-(1-methyl-tetrazol-1-yl)thio-1-oxa-1- dethia-3-cephem-4-carboxylic acid, wherein X and R are hydrogen, Y is (1-methyltetrazol-1-yl)thio, Z" is phenyl and W is benzhydryloxycarbonyl.

29. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-carboxy)acetamido-3-(1-methyltetrazol-1-yl)thio-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X and R
are hydrogen, Y is (1-methyltetrazol-1-yl)thio, Z" is phenyl and W is carboxy.

30. A process according to claim 5 for the preparation of 7.beta.-[2-phenyl-2-(2,3-dioxo-4-ethylpiperazinylcarbonyl)amino]-acetamido-3-(1-methyltetrazol-1-yl)thio-1-oxa-1-dethia-3-cephem-3-carboxylic acid, wherein X and R are hydrogen, Y
is (1-methyltetrazol-1-yl)thio, Z" is phenyl and W is (2,3-dioxo-4-ethylpiperazinylcarbonyl)amino.

31. A process according to claim 5 for the preparation of p-nitrobenzyl 7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylate, wherein X and Y are hydrogen, R is p-nitrobenzyl, Z" is phenyl and W is benzhydryloxycarbonyl.

32. A process according to claim 5 for the preparation of 7.beta.(2-phenyl-2-benzhydryloxycarbonyl)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein R, X and Y are hydrogen, Z" is phenyl and W is benzhydryloxycarbonyl.

33. A process according to claim 5 for the preparation of p-nitrobenzyl 7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-3-methylsulfonyloxy-1-oxa-1-dethia-3-cephem-4-carboxylate, wherein X is hydrogen, Y is methylsulfonyloxy, R is p-nitro-benzyl, Z" is phenyl and W is benzhydryloxycarbonyl.

34. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-carboxy)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein R, Y and X are hydrogen, Z" is phenyl and W is carboxy.

35. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-3-methylsul-fonyloxy-l-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein R and X are hydrogen, Y is methylsulfonyloxy, Z" is phenyl and W is carboxy.

36. A process according to claim 5 for the preparation of 7.beta.-(2-phenyl-2-carboxy)acetamido-3-methylsulfonyloxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein R and X are hydrogen, Y is methylsulfonyloxy, Z" is phenyl and W is carboxy.

37. A process according to claim 5 for the preparation of p-nitrobenzyl-3-chloro-7.alpha.-methoxy-7.beta.-(2-phenyl-2-benzhydryloxy-carbonyl)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylate, wherein X is methoxy, Y is chlorine, R is p-nitrobenzyl, Z"
is phenyl and W is benzhydryloxycarbonyl.

38. A process according to claim 5 for the preparation of 3-chloro-7.alpha.-methoxy-7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)-acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein X is methoxy, Y is chlorine, R is hydrogen, Z" is phenyl and W is benzhydryloxycarbonyl.

39. A process according to claim 5 for the preparation of 3-chloro-7.alpha.-methoxy-7.beta.-(2-phenyl-2-carboxy)acetamido-1-oxa-1-dethia-3-cephen-4-carboxylic acid, wherein R is hydrogen, X is methoxy, Y is chlorine, Z" is phenyl and W is carboxy.

40. A compound represented by the formula:
wherein X is hydrogen or methoxy; Y is hydrogen, halogen, lower alkoxy, sylfonyloxy, C6 to C10 arylthio, or five-membered monocyclic heterocycle-thio containing 1 to 4 hereto atoms; Z

is acyl; R is hydrogen or carboxy-protecting group selected from the group consisting of C1 to C5 alkyl, C1 to C5 haloge-nated alkyl, C7 to C20 arylmethyl, C8 to C12 acylmethyl, dimethylsilyl, trimethylsilyl, triphenylsilyl, trimethylstannyl, adamantyl, .alpha.-methyl, .alpha.-selenonaphthyl, piperidyl, .beta.-methyl-thioethyl, 4-methylthiophenyl, 2-benzyloxyphenyl, tetra-hydropyran-2-yl, or 2-cyanoethyl and the therapeutically acceptable salts thereof, when prepared by the process of claim 1.

41. Compounds claimed in claim 40, wherein Z is an acyl group represented by the formula Z'-CO- (wherein Z' is thenyl), when prepared by the process of claim 3.

42. Compounds claimed in claim 40, wherein Z is an acyl group represented by the formula Z'-CO- (wherein Z' is benzyloxy, p-nitrobenzyloxy, p-aminobenzyloxy, p-hydroxybenzyl-oxy or m-methoxybenzyloxy), when prepared by the process of claim 4.

43. Compounds claimed in claim 40, wherein Z is an acyl group represented by the formula Z'-CO-, wherein Z' is represented by the formula:

(wherein Z" is thienyl or phenyl; W is hydroxy, formyloxy or acetoxy, amino, acetylamino, benzyloxycarbonylamino, p-nitro-benzyloxycarbonylamino, p-methoxybenzyloxycarbonylamino, t-butyloxycarbonylamino, 4-ethyl-2,3-dioxopiperazinylcarbonyl-amino and phthalimino, carboxy, or protected carboxy selected from the group methyl ester, ethyl ester, benzyl ester, p-nitrobenzyl ester, diphenylmethyl ester, t-butyl ester, and p-chlorobenzyl ester, when prepared by the process of claim 5.

44. A compound claimed in claim 40, namely 7.beta.-(2-thienyl)-acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 9.

45. A compound claimed in claim 40, namely 7.beta.-(2-thienyl)-acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 10.

46. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-formyloxy)acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 11.

47. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-tert-butoxycarbonylamino)acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 12.

48. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-amino)acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 13.

49. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-nitrobenzyloxycarbonyl)acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 14.

50. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-carboxy)acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 15.

51. A compound claimed in claim 40, namely 7.beta.-(2-carboxy-2-thienyl)acetamido-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 16.

52. A compound claimed in claim 40, namely 7.beta.-(2-thienyl)-acetamido-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 17.

53. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-formyloxy)acetamido-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 18.

54. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-tert-butoxycarbonylamino)acetamido-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 19.

55. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-amino)acetamido-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 20.

56. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 21.

57. A compound as claimed in claim 40, namely 7.beta.-(2-phenyl-2-carboxy)acetamido-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 22.

58. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-tert-butoxycarbonylamino)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 23.

59. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-amino)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 24.

60. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-hydroxy)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 25.

61. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-tert-butoxycarbonylamino)acetamido-3-(1-methyltetrazol-1-yl)-thio-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 26.

62. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-amino)acetamido-3-(1-methyltetrazol-1-yl)thio-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 27.

63. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-3-(1-methyltetrazol-1-yl)thio-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 28.

64. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-carboxy)acetamido-3-(1-methyltetrazol-1-yl)thio-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 29.

65. A compound claimed in claim 40, namely 7.beta.-[2-phenyl-2-( 2,3-dioxo-4-ethylpiperazinylcarbonyl)amino]acetamido-3-(1-methyltetrazol-1-yl)thio-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 30.

66. A compound claimed in claim 40, namely p-nitrobenzyl 7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylate, when prepared by the process of claim 31.

67. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 32.

68. A compound claimed in claim 40, namely p-nitrobenzyl 7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-3-methylsul-fonyloxy-1-oxa-1-dethia-3-cephem-4-carboxylate, when prepared by the process of claim 33.

69. A compound claimed in claim 40, namely 7.beta.-(2-pheynyl-2-carboxy)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 34.

70. A compound claimed in claim 40, naemly 7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-3-methylsulfonyloxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 35.

71. A compound claimed in claim 40, namely 7.beta.-(2-phenyl-2-carboxy)acetamido-3-methylsulfonyloxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 36.

72. A compound claimed in claim 40, namely p-nitrobenzyl-3-chloro-7.alpha.-methoxy-7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)aceta-mido-1-oxa-1-dethia-3-cephem-4-carboxylate, when prepared by the process of claim 37.

73. A compound claimed in claim 40, namely 3-chloro-7.alpha.-methoxy-7.beta.-(2-phenyl-2-benzhydryloxycarbonyl)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, whèn prepared by the process of claim 38.

74. A compound claimed in claim 40, namely 3-chloro-7.alpha.-methoxy-7.beta.-(2-phenyl-2-carboxy)acetamido-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of

claim 39.