AU614723B2 - 3-propenylcephem derivative - Google Patents

Description

COMMONWEALTH OF AUSTRALIA CL O M N ELHO A COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 Form COMPLETE SPECIFICATION FOR OFFICE USE Short Title: Int. Cl: 614723 Application Number: Lodged:

C..

Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: Related Art: ;uud .10j 130-U00 Adq sUTWU03 JUp'X1zI: qLL_ TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: EISAI CO., LTD.

6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo, Japan TAKASHI KAMIYA; TOSHIHIKO NAITO; SHIGETO NEGI; YUUKI KOMATU; YASUNOBU KAI; TAKAHARU NAKAMURA; ISAO SUGIYAMA; YOSHIMASA MACHIDA; SEIICHIRO NOMOTO; KYOSUKE KITOH; KANEMASA KATSU and HIROSHI

YAMAUCHI

GRIFFITH HASSEL FRAZER 71 YORK STREET SYDNEY NSW 2000

AUSTRALIA

Complete Specification for the invention entitled: "3-PROPENYLCEPHEM DERIVATIVE" The following statement is a full description of this invention, including the best method of performing it known to us:- 3513A/bm '4

SPECIFICATION

TITLE OF THE INVENTION 3-Propenylcephem derivative BACKGROUND OF THE INVENTION Field of the invention: The present invention relates to novel cephem derivative useful for anti-bacterial agents. More particularly, the present invention relates to 3propenylcephem derivative. The present invention also provides process for the preparation of the 3propenylcephem derivative, anti-bacterial agents, intermediate for the 3-propenylcephem derivative, and process for the preparation of the intermediate.

Description of the prior art: Cephem detivatives having ammonio group have been conventionally known from Japanese Patent Appli- 0* 0 cation Laid-open Nos. 174,387/83; 198,490/83; 130,295/84; o. 172,493/84; 219,292/84; 97,983/85; 197,693/85, 5,084/86, etc.

Particularly, cephem derivative having an ammoniopropenyl group at the 3-position thereof, similar to the compound of the present invention, have been disclosed in Japanese Patent Application Laid-open Nos. 1 ,493/84 and 5,084/86.

IA

*I

l I

U

SUMMARY OF THE INVENTION The present inventors have found that cephem derivative having an ammoniopropenyl group at the 3-position thereof and a fluoro-substituted lower alkoxyimino group or a cyano-substituted lower alkoxyimino group in a side chain at the 7-position thereof have excellent anti-bacterial activities, leading to completion of the present invention.

An object of the present invention is therefore to provide novel cephem compounds useful as antibacterial agents; a process for the preparation thereof; pharmaceutical composition containing the same; intermediates for the derivatives; and a process for the preparation of the intermediates.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERED EMBODIMENTS The present invention relates to 3-propenylcephem derivative of the following formula N-C-CONH -S I: H 2 N ST -H H=CHCH2-A (I)

R

O

wherein R I represents a fluoro-substituted lower alkyl group or a cyano-substituted lower alkyl group, and A I represents a cyclic or acyclic ammonio group, and a pharmaceutically acceptable salt thereof.

2 ^1 As illustrative examples of the fluorosubstituted lower alkyl group represented by R 1 in the formula may be mentioned fluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoroethyl, 2-fluoropropyl, l-(fluoromethyl)-2-fluoroethyl, 3-fluoropropyl and the like with fluoromethyl being particularly preferred.

Regarding the cyano-substituted lower alkyl.

group represented by R 1 in the formula there may be enumerated cyanomethyl, 2-cyanoethyl, 3cyanopropyl, and the like.

As illustrative examples of the acyclic ammonio group represented by A in the formula may be mentioned a group of the following formula:

R

12 N -R 1• R 4

R

R

3 in which R 2

R

3 and R4 are the same or different and mean individually a group selected from the group consisting of lower *3 3 alkyl, hydroxyl-substituted lower alkyl, catbamo ~1-substituted lower alkyl, cyanosubstituted lower alkyl, amino, (l~ywer alkyl)carbonylamino-substituted lower alkyl, aminosulfonylaminocarbonyl--substituted lower alkyl, (lower alkyl) sulfonylaminocarbonylsubstituted lower alkyl, (lower alkyl)aminocarbonyl-substituted lower alkyl, hydroxyland carbamoyl-substituted lower alkyl, hydroxyl- and hydroxy(lower alkyl)aininosee carbonyl-substituted lower alkyl, (lower alkyloxy)aminocarbonyl-substituted lower alkyl, hydroxyaminocarbonyl-substituted lower alkyl, carbonyl(lower alkyJ.)aminocarbonylsubstituted lower alkyl, hydroxy~lower alkyl)aminocarbonyl-substituted lower alkyl, 0 as (lower alkyl)amino-substituted lower alkyl, carboxylate (lower alkyl )di Clower alkyl) amxnonio-substituted lower alkyl, (lower alkyl)amino-substituted lower alkyl, (lower :alkyl)amino- and hydroxyl-substituted low~er alkyl, ureido, hydroxyl, carboxyl-substituted lower alkyl, hydioxyl- and carbamoylsubstituted lower alkyl, lower alkyloxysubstituted lower alkyl, di(lower alkyi)arnino-

L

I

lo e a k l dcarbdyl-substituted lower alkyl, bis~hydroxy(lower alkyl) laminocarbonylsubstituted lower alkyl, dihydroxylsubstituted lower alkyl, trihydroxylsubstituted lower alkyl, bislhydroxy(lower alkyl)amino-substituted lower alkyl, amino-substituted lower alkyl, oxosubstituted lower alkyl, di-lower alkyl- ***substituted lower alkyl, heterocycle-substituted lower alkyl wherein said heterocycle stands for pyrazolyl, imidazolyl, oxadiazolyl or tetrazolyl.

Further, illustrative of a cyclic amrbonio group S. represented by A in the formula may include, for example, a group of the following formulae:

J

:1.I i 4*

N/N

-N NH -N NH R0

R

/-N

~N'

4.3

C.

C

R 0 S No R5

N

N

H

T-

N /N

N

N R Rg in which R 5means a group selected from lower alkyl, carbamoyl-substituted lower 6

B!

LL

V:

i alkyl, amino-substituted lower alkyl, hydroxyl-substituted lower alkyl, carboxylsubstituted lower alkyl, cyano-substituted lower alkyl, dihydroxyl-substituted lower alkyl and ureido-substituted lower alkyl groups, said cyclic ammonio group optionally containing on the ring thereof one or more substituents selected from hydroxyl-substituted lower alkyl, hydroxyl, formyl, sulfonic, carboxyl-substituted lower alkyl, carbamoyl, sulfamoyl, carboxyl, hydroxyimino-substituted lower alkyl, imino-substituted lower alkyl, bis[hydroxy(lower alkyl)laminocarbamoyl, hydroxy(lower alkyl)aminocarbamoyl, amino, morpholinocarbonyl, carboxy(lower alkyloxy)-substituted lower alkyl, carboxy lower alkylthio ctitutzti 1 t 1el. and lower alkyl groups.

.Illustrative of the lower alkyl group in the definition for A (R 2

R

5 in the formula (I) 7 1F i;

_I

may include alkyl groups having 1 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, secrbutyl and t-butyl.

As non-toxic salts of the compounds of the formula may be mentioned their pharmaceutically acceptable salts, for example, alkali metal salts such as sodium salts and potassium salts; ammonium salts; quaternary ammonium such as tetraethylammonium salts and betaine salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, carbonates and bicarbonates; organic carboxylates such as acetates, maleates, lactates and tartrates; organic sulfonates such as methanesulfonates, hydroxymethanesulfonates, hydroxyethanesulfonates, taurine salts, benzenesulfonates and tolienesulfonates; amino acid salts such as argin3.ne salts, lysine salts, serine salts, aspartates and glutamates; amine salts such as trimethylamine salts, triethylamine salts, pyridine salts, procaine salts, picoline salts, dicyclohexylamine S salts, N,N'-dibenzylethylenediamine salts, N-methylglucamine salts, diethanolamine salts, triethanolamine salts, tris(hydroxymethylamino)methane salts and phenethylbenzylamine salts; etc.

8 1 Each of the compounds of the formula which pertain to the present invention, has its syn-isomer and anti-isomer with respect to its stereoscopic configuration at the following moiety:

-C-

II

N

O-R,

Although both isomers are included in the present invention, the syn-isomers are desired owing to their antibacterial activities.

The compounds of this invention can be produced by the following process.

i. Namely, the compounds of the formula and their pharmaceutically acceptable salts can individually be obtained by reacting a compound, which is represented by the formula (II): O COOH wherein R 1 means a fluoro-substituted lower alkyl group or a cyano-substituted lower alkyl group, by the formula (III): A* *(III) wherein A' means an amine corresponding to A, a compound wherein the functional group(s) are protected with protecting group(s), or a salt thereof; followed, by optionally removing the protecting group(s).

As halogen atoms represented by X in the above formula may be mentioned iodine atom, bromine atom and chlorine atom., The above reaction may be carried out at a reaction temperature of -10°C 60 0 C,preferably, 0 C 40 0 C. As a reaction solvent, an.anhydrous organic solvent is desired. As usable organic solvents, may be 4* mentioned lower alkylnitriles such as acetonitrile and propionitrile; halogenated lower alkanes such as chloromethane, dichloromethane and chloroform; ethers 6* such as tetrahydrofuran, dioxane and ethyl ether; amides such as dimethylformamide; esters such as ethyl acetate; ketones such as acetone; hydrocarbons such as benzene; alcohols such as methanol and ethanol; and sulfoxides such as dimethylsulfoxide; as well as mixed solvents thereof.

The removal of the protecting group(s) may be S" carried out by a fmethod known per se in the art in accordance with the kind(s) of the protecting group(s) used, such as hydrolysis or reduction.

As the salts of the compounds of the formulae (II) and (III) and the protecting groups for alkyl)amino- and hydroxyl-substituted lower alkyl, ureido, hydroxyl, carboxyl-substituted lower alkyl, hydroxyl- and carbamoyl- ./3

J:

the compounds, those employed routinely may also be used so long as they do not impair the above reaction.

Exemplary protecting groups for the amino group may include formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, phenylacetyl group, thienylacetyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, trityl group, p-methoxybenzyl group, diphenylmethyl group, benzylidene group, p-nitrobenzylidene group and m-chlorobenzylidene group. As illustrative protecting groups for the carboxyl group, may be mentioned p-methoxybenzyl group, p-nitrobenzyl group, t-butyl group, methyl group, 2,2,2-trichloroethyl group, diphenylmethyl group and pivaloyloxymethyl group. Here, use of a silylating agent such as N,0bis(trimethylsilyl)acetamide, N-methyl-N-(trimethylsiiyl)acetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide or N-(trimethylsilyl)acetamide is convenient because such a silylating agent can protect both amino and carboxyl groups at the same time.

As salts of the compounds of the a formulae (II) and (III), suitable selection may be made Sfrom their salts such as alkali metal salts such as q i sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; quaternary ammonium salts such as triethylammonium salts and betaine salts; inorganic 11 I i I acid salts such as hydrochlorides, hydrobromides, sulfates, carbonates, hydroiodides and bicarbonates; organic carboxylates such as acetates, trifluoroacetates, maleates, lactates and tartrates; organic sulfonates such as methanesulfonates, hydroxymethanesulfonates, hydroxyethanesulfonates, taurine salts, benzenesulfonates and toluenesulfonates; amine salts such as trimethylamine salts, triethylamine salts, pyridine salts, procaine salts, picoline salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, N-methylglucamine salts, diethanolamine salts, triethanolamine salts, tris(hydroxymethylamino)methane salts and phenethylbenzylamine salts; amino acid salts such as arginine salts, aspartates, lysine salts, S. glutamates, serine salts and glycine salts; etc.

The compounds of this invention show strong *antibacterial activities against both gram-positive and *i gram-negative bacteria and are hence useful as antibacterial agents. The compounds are used for treating a disease caused by bacteria.

When using the compounds of this invention as injections, they may be administered generally at a daily dose of 100 mg 10 g in 1 4 portions either intravenously or intramuscularly. Needless to say, the dose may be increased or decreased depending on the age and conditions of disease.

Their injections may be produced by a method 12 I known per se in the art. For example, each compound of this invention may be formulated into an injection by dissolving same in distilled water, if necessary, in the presence of an isotonic agent, solubilizer and/or the like. They may each be filled as powder in a vial or the like, thereby providing injections which require dissolution before use. These injections are hence dissolved in distilled water for injection, physiological saline, glucose injection, amino acid infusion or the like upon administration.

o*.

S. A compound of the above-mentioned formula (II) i.e. an intermediate; a compound wherein the amino S. and/or carboxyl group(s) are protected with a protective group; or salts of these compounds are all novel compounds.

These compounds can be prepared by the following process.

That is to say, the compounds can be prepared by reacting .o a compound of the formula: S" N C COOH N (IV) H N SN N O

R

2 1 Swherein R1 has the same meanings as mentioned above, a reactive acid derivative thereof, a compound wherein an amino group is protected with a protective group, or a salt of the compound with a compound of the formula: I i i

H

2

N

S(v) 0 CH CHCH 2

X

COOH

wherein X has the same meanings as defined above, a compound wherein a carboxyl group is protected with a protective group, or a salt thereof, followed by optionally removing the protective group, and/or converting a halogen atom represented by the symbol X into the other halogen atom.

The above-mentioned reaction can be conducted in Saccordance with a conventional reaction condition for an N-acylation. For example, the reaction can be carried out at a temperature from -50 0 C to 50 0 C in an inert solvent such for example as tetrahydrofuran, ethyl acetate, acetone, N,N-dimethyl formamide, acetnitrile, dioxane or a mixed solvent thereof.

As for a reactive acid detivative of the compound of the formula there may be exemplified an acid halide such as acid chloride, acid bromide, etc.

symmetrical acid anhydride, a mixed acid anhydride, 0 an active ester, an active acid amide, and the like.

When a free carboxylic acid of the formula (IV) or a salt thereof is used in the reaction, it is preferable to conduct the reaction in the presence of a conventional condensing agent such as N,N'- 14 i I 77-. n_ dicyclohexylcarbodiimide, p-tuluene sulfonic acid, and the like, for e,.ample.

The conversion of a halogen atom represented by X into the other halogen atom is carried out in a conventional manner. For example, there can be prepared a compound of the formula (II) wherein X' represents iodine atom, when a compound of the formul'a, (II) wherein X represents chlorine atom is reacted with an alkali metal iodide.

Further, the intermediates of the under-mentioned formula (VI) are also novel compounds, such as a compound of the formula: N C HNN N

H

2 N S OCH 2

F

(VI)

-wherein R 6 represents carboxyl group, a halogenocarbonyl group, carbamoyl group, or cyano group, a compound wherein amino and/or carboxyl group(s) are protected with a protective group, or a salt thereof.

Illustrative of protective groups for the amino group and the carboxyl group may include a similar group as exemplified in the compound of the formula (II).

The above-mentioned compounds can be prepared by the following exemplary process.

t" Not NC C -CONH 2 OH

(VII)

NC C -CONH 2 N- OCH 2F

(I

N 11- C -COOIH 11 N H N S, N \(XIV) *.e

S

S

S.

*5.

S.

S.

S

5555 S* 555 5* 0 S S

SSSSSS

S

NC C -CN 11

N

'OCH 2 F N C Cox H2NS \OCH 2F

(IX)

halogen N -n-C COOH 2 (XIII) 2 OCH 2F atom)

HN

C -CN 11

N

NOCH 2F N -C CONH 11 N 1 1 2

HNN

H2 NOCH 2

F

(XII)

2 N S N "1C 2

F

(XI)

I,

i i i 3 1 *0 o 0 *09* 0** The compound of the formula (VIII) can be prepared by reacting a compound of the formula (VII) with a halogeno fluoromethane in an inert solvent.

As the halogeno fluoromethane, there may be exemplified bromo fluoromethane, iodo fluoromethane, and the like.

The reaction is carried out at a temperature ranging from -300C to 100 0

C.

The compound of the formula (IX) can be prepared by reacting a compound of the formula (VIII) with a dehydrating agent in an inert solvent. As the reaction temperature, it is preferable to use room temperature or above. A dehydrating agent may include oxyphosphorus chloride, thionyl chloride, etc.

The compound of the formula can be prepared by reacting the compound of the formula (IX) with ammonia and/or ammonium salt in an inert solvent sucn as water, a lower alcohol, acetone, chloroform, etc.

Suitable reacLion temperature may range from -20 0 C to room temperature. Ammonium salt may include ammonium chloride, ammonium acetate, ammonium sulfate, and the like.

The compound of the formula (XI) can be prepared by reacting the compound of the formula with a halogenatina agent such as gaseous bromine, gaseous chlorine, etc. to effect the halogenation, followed 17

I

I

K:~

_.i f by reacting it with an alkali metal thiocyanate, preferably in the presence of a base. Suitable reaction temperature may range from -20 C to room temperature. As an alkali metal thiocyanate, there may be used potassium thiocyanate, sodium thiocyanate, and the like.

A compound of the formula (XII), a compound-wherein amino group is protected with a protective group, or a salt thereof can be prepared by hydrolyzing a compound of the formula a compound where n amino group is protected with a protective group, or a salt thereof in the presence of an oxydizing agent and a base, followed by optionally removing the protective group.

The reaction can be carried out at a reaction temperature of from 0 0 C to 70 0 C in water, a buffer solution or a mixed solvent of the former with a lower alcohol.

"There may be used hydrogen peroxide, oxygen, etc.

as an oxydizing agent; and sodium hydroxide, potassium hydroxide, etc. as base.

A compound of the formula (XIII), a compound wherein amino group is protected with a protective group, or a salt thereof can be prepared by hydrolyzing a compound of the formula (XII), a compound wherein amino group is protected with a protective group, or a salt thereof in the presence of a base, followed by optionally removing the protective group.

18 .HI I I h.l~ i a.

a a.

a The types of the base, solvents, the reaction temperatures, etc. may be the same as those described in the.reaction sequence from the compound of the formula (XI) to that of the formula (XII).

Furthermore, a compound of the formula (XIII), a compound wherein amino group is protected with a protective group, or a salt thereof can be also prepared by reacting a compound of the formula' (XIV) wherein amino and/or carboxyl group(s) are protected by a protected group, with a halogeno fluoromethane, followed by optionally removing the protective group.

The halogeno fluoromethane may indlude bromo fluoromethane, iodo fluoromethane, chloro fluoromethane.

The reaction can be carried out in an inert solvent at a reaction temperature ranging from -30°C to 100 0

C.

Illustrative examples of the inert solvent to be used may include sulfoxides such as dimethyl sulfoxide, etc., amides such as N,N-dimethylacetamide, formamide, hexamethylphosphoryl triamide, etc., ketones such as acetone, etc., or a mixed solvent thereof.

i 1 19 L A compound of the formula a compound wherein amino group is protected with a protective group, or a salt thereof can be prepared by reacting a compound of the formula (XIII), a compound wherein amino group is protected with a protective group, or a salt thereof with a halogenating agent.

Illustrative examples of the halogenating agent may include phosphorus pentaoxide, thionyl chloride, thionyl bromide, oxyphospho u chloride, and the like The above reaction can be carried out in an inert esolvent such for example as dichloromethane, tetrahydrofuran, ethyl acetate, chloroform or a mixed solvent thereof at a reaction temperature of from C to 50 0

C.

The present invention will next be described in further detail by the followina Experiments and Examples.

S* I Experiment 1 (Synthesis of the raw material compound) Ethyl 2-(5-tritylamino-l,2,4-thiadiazol-3-yl)-(Z)- 2-fluoromethoxyimino acetate O-L NCN COOC2

H

CHN r\T S'N-OCH 2

F

Ethyl 2-(5-tritylamino-l,2,4-thiadiazol--3-yl)-(Z)-2hydroxyimino acetate (60.4 g) was dissolved in dimethyl sulfoxide (210 ml), and then potassium carbonate (96.48g) 'as added thereto under ice-cooling. The solution was stirred for 10 minutes.

Thereafter, bromofluoromethane (19 g) was added thereto, and the solution was stirred for 3 hours at room temperature.

Ethyl acetate (1 liter) was added to the reaction solution and the solution was washed with water and then with a saturated brine, followed by drying with addition of anhydrous magnesium sulfate. The solvent was distilled off, and ethanol (120 ml) was added to the residue. Crystals deposited were collected by filtration, and washed with ethanol to obtain the object o. 9 9 9 S product (58.2 g).

9 Experiment 2 (Synthesis of the raw material compound) 2-(5-Tritylamino-l,2,4-thiadiazol-3-yl)-(Z)-2fluoromethoxyimino acetic acid I i %R7 S -Ty--C-COOIl -coo04 0 H N

F

6

OCHF

Into a mixed solution containing sodium hydroxide (2.04 g), ethanol (146 ml) and water (29 ml) was added the compound (17.87 g) prepared in Experiment 1, and the solution was stirred for 20 minutes under reflux. After the solution was concentrated under reduced pressure, ethyl acetate (200 ml) and 1N hydrochloric acid (77 ml) were added thereto. The ethyl acetate layer was separated to collect and washed with a saturated brine, followed by drying with addition of anhydrous magnesium sulfate. The solvent was distilled off to obtain crystals. The crystals were crushed with addition of petroleum ether, and then recoveredby filtration to obtain the object product (16.55 g).

Experiment 3 (Synthesis of the raw material compound) p-Methoxybenzyl 7p-[2-(5-tritylamino-l,2,4-thiadiazol- 3-yl)-(Z)-2-fluoromethoxyiminoacetamido]-3- C(Z)-3-chloro- 1-propen-l-yl l-3-cephem-4-carboxylate i.

_C CONH S C1 O HN N CH OOCH

OCH

3 22 t, i 4 9* 9 9 *9 9* 99 9 9 9 99999 9 99 9 0 9 9 Dimethylformamide (348 Al) and tetrahydrofuran (4.1 ml) were cooled to -10 0 C, and phosphorus oxychloride (418/1) was added thereto,,and stirred for 90 minutes under ice-cooling.

To this solution was added a solution of the compound (1.73 g) prepared in Experiment 2 in tetrahydrofuran (5.5 ml) with cooling to -10 0 C, and the resulting solution was stirred for minutes under ice-cooling. The reaction solution was cooled to -20 C, and a mixed solution containing p-methoxybenzyl 7p-amino-3-[(Z)-3-chloro-l-propen-l-yl]-3-cephem-4-carboxylate hydrochloride (1.78 N-(trimethylsilyl)acetamide (2.95 g), ethyl acetate (18 ml) and tetrahydrofuran (5.5 ml) was added thereto, and the resulting solution was stirred for one hour at -10 0 C. To the reaction solution was added ethyl acetate (100 ml), and the resulting solution was washed succesively with water, a saturated aqueous sodium hydrogencarbonate and a saturated brine, followed by drying with addition of anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the object product (2.65 g).

Experiment 4 (Synthesis of the raw material compound) p-Methoxybenzyl 70-[2-(5-tritylamino-l,2,4-thiadiazol- 3-yl)-(Z)-2-fluoromethoxyiminoacetamido]-3- [(E)-3-iodol-propen-l-yl]-3-cephem4-carboxylate i i HN r-C-CONH 0 IN^N o 1 N OCHF OOCH 2

-OCH,

The compound (10.11 g) prepared in Experiment 3 was dissolved in acetone (212 ml), and sodium iodide (9.03 g) was added thereto under ice-cooling. The resulting solution was stirred for minutes under ice-cooling and for additional 90 minutes at a room temperature. The solvent was distilled off, and the S residue was extracted with ethyl acetate (500 ml). The extract was washed with a saturated aqueous sodium thiosulfate solution e*j and with a saturated brine, followed by drying with addition of anhydrous magnesium sulfate. The dried extract was concentrated under reduced pressure and n-hexane was added thereto. The resulting precipitates were collected by filtration to obtain the object product (10.92 g).

Experiment 5 (Synthesis of the raw material compound) p-Methoxybenzyl 7P-[2-(5-tritylami.-o-1,2,4-thiadiazol- 3-yl)-(Z)-difluoromethoxyiminoacetamido]-3- ((Z)-3-chlorol-propen-l-yl]-3-cephem-4-carboxylate NT--C-CONH-S C1 CHN N \OCHF, OOCH 2

,--OCH,

In the same manner as described in Experiment 3, tritylamino-l 2, -thiadiazol-3-Yl -2-dif luoromethox yiminoacetic acid (2,00 g) was reacted with p-methoxybenzyl 7,P-amino-3.

[(Z)-3-chloro-l-propen-l-yl--3-cephem-)4-carboxylate hydr.)chloride (1.795 g) to obtain the object product (3.17 g).

Experiment 6 (Synthesis of the raw material compound) p-Methoxybenzyl 7P-[2-(5-.tritylamino-l,2,4-thiadiazo- Z)-2-difluoromethoxyiminoacetamido)-3- iodo-l-propen-l--yi]-3-cephem-)4-carboxylate 4.

4.

*4, 4 4

S..

S S 4** .4 4 b* *444 £9 4 4 a

S.

S*

S

p

OCH,

lc=( i~n the same manner as described in Experiment 4, the compound (3.00 g) preapred in Experiment 5 was reacted with sodium iodide (2.62 g) to obtain the object product (2.92 g).

Example 1 fluoromethoxyiminoacetamido3-3- ((E)-3-(carbai~ylmethylethylmethylammonio )-l-propen--l-yl]-3-cephem-.4-carboxylate

I.

12

HCONHCCH

3

H

2 N N' .CONH,

\O-CH

2 F COO- CH The compound (550 mg) prepared in Experiment 4 was dissolved in a mixed solution containing ethyl acetate (20 ml) and ethyl ether (10 ml), and then ethylmethylaminoacetamide (117 mg) was added thereto. The resulting solution was stirred at room temperature for 4 hours and 30 minutes. Isopropyl ether was added to the reaction solution, and the resulting precipitates were collected by filtration and dried to obtain the yellowish brown powder (400 mg).

The powder was stirred in a mixed solution of trifluoroacetic acid (4.5 ml) anisole (4 ml) for one hour under icecooling, and ethyl ether was added thereto. The resulting precipitates were collected by filtration and washed with ethyl ether. The precipitates were suspended in water (5 ml). The

S

suspension was adjusted to pH 5.5 6.5 with sodium acetate.

0. Insolubles were removed by filtration, and the filtrate was purified by reversed phase chromatography to obtain the object product (49 mg).

Example 2 70-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2fluoromethoxyiminoacetamido-3- (E)-31-(2-hydroxyethyl)- 4-carbamoyl-l-piperidinio]-l-propen-l-yl]-3-cephem-4carboxylate -v

_AVLY

/V V\26.

13

OH

HzN C-CONCO S H N17 1 N N DCoN 2

\O-CH

2 F COO- O-CHiF The compound (700 mg) prepared in the Experiment 4 was dissolved in dimethylformamide (3 ml), and a solution of l.- (2-hydroxyethyl)isonipecotamide (194 mg) in dimethylformamide ml) was added thereto. The solution was stirred overnight.

The reaction solution was added to ethyl ether (120 ml), and the resulting precipitates were collected by filtration to obtain yellow powder (680 mg).

S To this powder was added anisole (4.5 ml), and trifluoroacetic acid (5.3 ml) was added drop by drop over 30 minutes with stirring under ice-cooling. After the dropping was completed, the mixture was stirred for additional one hour and 30 minutes.

To the reaction solution was added isopropyl ether (50 ml), and

*O

the resulting precipitates were collected by filtration.

The precipitates were suspended in water (30 ml), and the suspension was adjusted to pH 7.0 with sodium acetate. The i S* resulting insolubles were removed by filtration, and the filtrate was purified by reversed phase silica gel column Schromatography to obtain the following two types of isomers of the subject compound: Isomer 21 mg Isomer 20 mg 1:1 Mixture of the two isomers 50 mg 27 i 9 1-4 Example 3 fluoromethox yiminoacetamido] (lS-carbamoylethyl) dime thy lammoniol-l-propel-l-yl) -3-cephem-4-carboxy'late (3-1) acetamido]-3- [(E)-3-[(lR-carbamoylethyl )dimethylarnmonio]- 1-rpn1YJ3cpe--abxlt (3-2)

S@@

S

S*@

S

SS

S S

S

*SS S 0SO* S S

S

S..

S

S.

555 0S S 0

S

*5 *555** ~C CONH TS CH 3

CH-

3

H

2 N4: ST Nz N kCONH 2

\OCH

2 F COO- The compound (600 mg) prepared in Experiment Lj was dissolved in a mixed solution containing ethyl acetate (20 ml) and ethyl ether (10 ml), and then 2-dimethylaminopropylamide (150 mg) was added thereto. The resulting solution was stirred for 3 hours at room temperature. Isopropyl ether was added to the reaction solution, and the resulting precipitates were collected by filtration, followed by drying to obtain yellowish brown powder (50 mg).

28 This powder was stirred in a mixed solution containing trifluoroacetic acid (5.5 ml) and anisole (5 ml) for one hour under ice-cooling and, thereafter, ethyl ether was added thereto.

The resulting precipitates were collected by filtration and washed with ethyl ether. The precipitates were suspended in water (5 ml), and the suspension was adjusted to pH 5.5 with sodium acetate. The insolubles were removed by filtration, and the filtrate was purified by reversed phase silica qel column chromatography to obtain the object products of 8 ng of the 7 mg of the and 4 mg of the mixture of the and the Example 4 7(-C2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2fluoromethoxyiminoacetamido)-3- C(2-hydroxypropyl) dimethylammonio]-l-propen-l-yll-3-cephem-4-carboxylate

S

S. S

S

S.

S

S

S

S

S

5555

S

CH

3 S. S

S

S S

S

The compound (550 mg) prepared in Experiment 4 was dissolved in a mixed solution containing ethyl acetate (20 ml) and ethyl ether (10 ml), and then 3-dimethylamino-2-propanol (0.124 ml) was added thereto. The resulting solution was stirred at room temperature for one hour and 30 minutes. Isopropanol was 29 added to the reaction solution. The resulting precipitates were collected by filtration and dried to obtain yellowish brown powder (530 mg).

This powder was stirred in a mixed solution containing trifluoroacetic acid (5.5 ml) and anisole (5 ml) for one hour under ice-cooling. Thereafter, ethyl ether was added thereto.

The resulting precipitates were collected by filtration and washed with ethyl ether. 'The precipitates were suspended in water (5 ml). The suspension was adjusted to pH 5.5 with sodium acetate. Insolubles were removed by filtration and the filtrate was purified by reversed phase silica gel column chromatography to obtain the object product (70 mg).

Example S7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2fluoromethoxyiminoacetamido)-3- ((1R-carbamoyl- 2-hydroxyethyl)dimethylammonio]-l-propen-l-yl]-3-cephem- 4-carboxylate

*CH

-co-C-CONH S- C OH3 S N

H

o \OCH 2 F CONI- 2 The compound (1.00 g) prepared in Experiment 4 was dissolved r ;i 0 00 1't :0.

0 0 0 *5

S

S

55

S

4, in dimethylformaide (2 ml). A solution of N,N-dimethyl-Dserinamide was prepared by dissolving N,N-dimethyl-D-serinamide trifluoroacetAte (590 mg) in methanol (5 ml), adding IN-aqueous sodium hydroxide solution (2.4 ml) thereto, followed by distilling off the solvent under reduced pressure, .and extracting the residue with acetonitrile (2 ml). The N,N-dimethyl-D-serinamide solution was added to the solution of the compound prepared in Experiment 4 in dimethylformamide under ice-cooling. The resulting solution was stirred for 30 minutes. The reaction-solution was added to ethyl ether, and the resulting precipitates were collected by filtration to obtain yellow powder (1.1 g).

To this powder was added anisole (8 ml), and trifluoroacetic acid (9 ml) was dropped over 30 minutes with stirring under ice-cooling, followed by stirring for additional one hour and minutes. Ethyl ether was added to the reaction solution, and the resulting precipitates were collected by filtration.

The pr'ecipitates were suspended in water (10 ml). The suspension was then adjusted to pH 7 with sodium acetate.

The isolubles were removed by filtration, and the filtrate was purified by reversed phase silica gel column chromatography to obtain the object product (30 mg).

Example 6 7g-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2fluoromethoxyiminoacetamidoo]-3- (E)-3-(4R-hydroxy-2Rhydroxymethyl-l-methyl-l-pyrrolidinio)-l-propen-1-yl]- 3-cephem- 4 -carboxylate 31 -i-i

CH

3

.OH

HC-CONH

S

\OCH

2 F COO- C CHzOH The compound (700 mg) prepared in Experiment 4 was dissolved in acetone (4 ml), and a solution of N-methyl-cis-4-hydroxy- D-prolinol (89 mg) in acetone (2 ml) was added thereto. The resulting solution was stirred overnight. The reaction solution was added to ethyl ether (100 ml), and the resulting precipitates were collected by filtration to obtain yellow powder (700 mg).

To this powder was added anisole (4.5 ml), and trifluoroacetic acid (5.3 ml) was dropped over 30 minutes with stirring under ice-cooling, and stirred for additional one hour and minutes. To the reaction solution was added isopropyl ether S (50 The resulting precipitates were collected by filtration.

The precipitates w-re suspended in water (30 ml), and the suspension was adjusted to pH 7 with sodium acetate. The insolubles were removed by filtration, and the filtrate was purified by reversed phase silica gel column chromatography to obtain the following two types of isomers (relating to a nitrogen atom of pyrrolidine): Isomer 27 mg Isomer 100 mg 32 I F 19 Example 7 7 -[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2fluoromethoxyiminoacetamido)-3- 4R-hydroxy-1- (2-hydroxyethyl)-2S-hydroxymethyl-l-pyrrolidinio]-lpropen-l-yl]-3-cephem-4-carboxylate

OH

C-CONH-

OH

H NNISI N N \OCHF COO-

CH

2

OH

The compound (2.0 g) prepared in Experiment 4 was added to S a solution containing (R)-4-hydroxy-l-(2-hydroxyethyl)-(S)- 2-hydroxymethylpyrrolidine (450 mg) in dimethylformamide ml). The resulting solution was stirred overnight. The reaction solution was added to ethyl acetate. The resulting precipitates were collected by filtration to obtain yellow powder (1.65 g).

To the powder was added anisole (10 ml), and then S" trifluoroacetic acid (11.7 mi) was dropped over 30 minutes with stirring under ice-cooling, and further stirred for additional one hour and 30 minutes. Isopropyl ether was added to the reaction solution, and the resulting precipitates were collected by filtration. The precipitates were suspended in water ml), and the suspension was adjusted to pH 7 with sodium acetate. The insolubles were removed by filtration, and the filtrate was purified bysilica gel column chromatography to I i A 33 obtain two types of the isomers (relating to a nitrogen atom of pyrrolidine) of the subject compound as follows: Isomer 96 mg Isomer 207 mg Example 8 7p-[.2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2fluoromethoxyiminoacetamido)-3- (E)-3-(4R-hydroxy-2S-hydroxymethyl-l-methyl-l-pyrrolidinio)-l-propen-l-yll-3-cephem- 4-carboxylate

CH

3

.OH

C-CONH S N

N-

\OCH

2 F COO- CHOH The compound (700 mg) prepared in Experiment 4 was dissolved in ace-tone (4 ml), and a solution of N-methyl-trans-4-hydroxy- L-prolinol (89 mg) in acetone (2 ml) was added thereto, and the resulting solution was stirred overnight. The reaction solution was added to ethyl ether (100 ml), and the resulting precipitates were collected by filtration to obtain yellow powder (700 mg).

To the powder was added anisole (4.5 ml), and trifluoroacetic acid (5.3 ml) was dropped with stirring under ice-cooling over 30 minutes, and then the mixture was stirred for additional one hour and 30 minutes. To the reaction solution was added isopropyl a'ther (50 ml), and the resulting precipitates were collected by filtration. The precipitates were then suspended L. -ii in water (30 ml). The suspension was adjusted to pH 7 with sodium acetate. The insolubles were removed by filtration, and the filtrate was purified by reversed phase silica gel column chromatography to obtain the object compound (92 mg).

Example 9 7C-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2fluoromethoxyiminoacetamido)-3- C(E)-3-(l-carbamoylmethyl-3hydroxy-l-pyrrolidinio)-l-propen-l-yl]-3-cephem-4carboxylate

/CONH

SN -C-CON

SOH

OCHF COO- The compound (1.0 g) prepared in Experiment 4 was dissolved in dimethylformamide (4 ml), and a solution of N-carbamoyl- *5 methyl-3-hydroxypyrrolidine (186 mg) in dimethylformamide (2 ml) was added thereto. The resulting solution was stirred overnight.

The reaction solution was added to ethyl ether (200 ml). The resulting precipitates were collected by filtration to obtain yellow powder (970 mg).

5 To the powder was added anisole (9.0 ml), and then trifulooroacetic acid (10.6 ml) was dropped over 30 minutes with stirring under ice-cooling. The mixture was further stirred for additional one hour and 30 minutes. To the reaction solution 22 i4.

*1 was added isopropyl ether (80 ml), and the resulting precipitates were collectdd by filtration. The precipitates were suspended in water (50 The suspension was adjusted to pH 7 with sodium acetate. The insolubles were removed by filtration, and the filtrate was purified by reversed phase silica gel column chromatography to obtain the respective types of isomers (relating to a nitrogen atom, and carbon atom on the 3-position of pyrrolidine, and there are four types on high pressure liquid chromatography) of the subject compound as follows: Isomer 71 mg (mixture of two types) Isomer 70 mg (sihgle material) Isomer 54 mg (single material) Example o 7 -[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2fluoromethoxyiminoacetamido)-3-((E)-3-(l-methyl-4sulfo-l-piperazinio)-l-propen-l-yll-3-cephem-4carboxylate

CH

S- C-CONH'-- S HNS N N- SOH S" \OCH F OO- The compound (2.0 g) prepared in Experiment 4 was added to a mixed solution containing 4-methylpiperazinosulfonic acid sulfate (718 mg), N-methyl-N-(trimethylsilyl) trifluoroacetamide (2 ml) and dimethylformamide (6 ml), and the resulting solution 36 it was stirred overnight. To the reaction solution was added methanol (2 ml), and the insolubles were removed by filtration.

The filtrate was added to a mixed solution containing ethyl acetate (50 ml) and ethyl ether (50 ml), and the resulting precipitates were collected by filtration to obtain yellow powder (1.79 g).

To this powder was added anisole (10.9 ml), and 'trifluoroacetic acid (12.7 ml) was dropped over 30 minutes with sti'r'ing under ice-cooling. The resulting solution was further stirred for additional one hour and 30 minutes. To the reaction solution was added isopropyl ether (100 ml), and the resulting precipitates were collected by filtration. The precipitates were susp.-, :d in water (4.5 ml), and the suspension was adjusted to pH 7 with sodium acetate. Insolubles were removed by filtration and the filtrate was purified by reversed phase silica gel column chromatography to obtain the object product (50 mg).

Example 11 7 6-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2fluoromethoxyiminoacetamido)-3- (E)-3-(l-carbamoylmethyl- 4-hydroxy-l-piperidinio)-l-propen-1-yl]-3-cephem-4carboxylate

/COCONH

2 N C-CON-

OH

\OCH

2 F COO- 37 The compound (1.0 g) prepared in Experiment 4 was dissolved in acetone (9 ml), and N-carbamoylmethyl-4-hydroxypiperidine (206 mq) was added thereto. The solution was stirred overnihgt. The reaction solution was added to a mixed solution (100 ml) containing ethyl ether and isopropyl ether and the resulting precipitates were collected by filtration to obtain yellow powder (1.0 g).

To this powder was added anisole (9.0 ml), and trifluoroacetic acid (10.6 ml) was'dropped over 30 minutes with stirring under ice-cooling, and the resulting solution was further stirred for additional one hour and 30 minutes. To the reaction solution was added isopropyl ether (80 ml), and the resulting precipitates were collected by filtration. The precipitates were suspended in water (5 ml), and the suspension was adjusted to pH with sodium acetate. Insolubles were removed by fil'ration, and the filtrate was purified by reversed phase silica gel column chromatography to obtain the object product (166 mg).

Example 12 7P-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2fluoromethoxyiminoacetamidol-3- 2,8-dioxabicycloC33.3.1]nona-5-io)-l-propen--yl)-3cephem-4-carboxylate N -C-CONH S ^-O ,N S' N O NCH \OCH,F I r 0 Ii.

L The compound prepared in Experiment 4 was dissolved in dimethylformamide (10 ml), 5-aza-l-methyl-2,8-dioxabicyclo [3.3.1]nonane (800 mg) was added thereto at- room temperature.

The resulting solution was stirred for 20 minutes. The reaction solution was diluted with ethyl acetate (25 ml) and the solution was added to ethyl ether to obtain brown precipitates (3.85 g).

The precipitates were dissolved in anisole (23 ml), and trifluoroacetic acid (26 ml) was added thereto under ice-cooling.

The solution was stirred for 30 minutes at the same temperature.

Ethyl ether was added to the reaction solution, and resulting Sprecipitates were collected by filtration. The precipitates were suspended in water (40 ml), and the suspension was adjusted to pH 7.0 with sodium a-cetate. Insolubles were removed by filtration, and the filtrate was purified by reversed phase silica gel column chromatography to obtain the object product (408 mg).

In the same manner as described in the Examples 1 12,

*SS*

the following compounds in Examples 13 113 were preapred:

C-CONH

S' N OCH2F COOCH F OCH, (compound in Experiment 4) A' (amine corresponding to A) C-CONH Si

H

2 N1 S N NA

\OCH

2 F COO- 39 carboxylate 4.:

I.

Plural isomers may be formed due to the portion of ammonio group on A. When these isomers were separated, the respective yields were shown for the respective isomers individually..

The following abbreviations were used: Boc: t-butoxy carbonyl group tBu: t-butyl group Bh: benzhydryl group Tr: trityl group a a.

a.

*aa.

9 a.

9a 9 a 9 9 i;: it i

E;

k

I

C

C. C C

S

*SC

C S S 9 9 9 5 2 S *9 9 S S SO S 9 5 S S 9 5 5* S C C Exml Use amount of the starting compound Yield of the No. A' aieCmon f objective product' Experiment 4 CH3COH2Isomer. (13- 1) 29mg 13 183 Mg 800 mag Isomer (13- 2) 33mg -N Mixture of both isomers .14mg 14 10 7mg 600 Mg 8 mg

-N

9n H

OH

-N

r 169 mg 1.0 g Isomer! (15- 1) isomer, (15- 2) 23mag I I i

OH

2

O

2+O 187 mg 1.0 g 114 mg 1 4 3 33 333* ExapleA se mont of the starting compound Yield of the Ex mp eUs.ao Compound of objective product A' (amine Experiment4 17+NCH 2 0H 203 ag33g

\CONH

2

CH

2 .OH1.g

CH

2 OH

CONH

2 N As by-products 18 -N 23 mg ofExample 17)

COGH

19

CONH

2 247 mg 600 mg 85 xg

OH

100 Mg 500mXg 90 Mg

OHOH

21136 nig 1.0 g 6m a a be 4 C *C 4 C C C C C S C C C C C C C C C C eCC C C a eta C..

C CC. C C CC C *C C C C S CS C C C. S C AUse amount of the starting compound Yield of the A' (amine )Compound of objective product Experiment 41

NH

2 345 mg BOC-HNNo 1.0 g 40 mg OHIsom'er (23- 1 13mg H.131 mg 700 Tag isomer (23- 2 13mag

-N

CH

3 544 mg 2.0 g 226 mg -N -CHO

CH

3 N344 ag 1.0 g 17 Mg N N."VSO 3 Na

CH

3 229 ig N 1.0 g 112 mg -N NHC1 (Hydrochloride)

CH

3

II

U U U US 999 U U*r **b PU 99 S U* S UU U* S S U 9 U S U U S U p U U U p U U S U U US UU S U U 5 4 S S U S U U C U U U SUU ECU 5*9 ft 9 U 54 9 5 U a S. 6 9 9 OW 9 6 9 S S S 555 a4.) 595 S e~ 9. 5 5~ a a a 555 0 *SP *OS SS~ S S 5 S S 0 C S 55 5 S b40~ S S 4.

*m C 0

S

~~0a *dC a 0 00 S 0S 00 S C *05 0 .0O *5 0

C

S.

a 09S 0 600 @06 ma..

S C S a 8 0 @0 Os S S S 4. .005 0 mm 4. a ~J ExampleA use amount of the starting compound A amine) Compound of A' _I Experiment 4 Yield of the objective product

OH

150 Mg 500 ing 22 mg F 4 1 38

OH

HO-

-NO

180 iMg 1lg 20 mg I4 I~ i

-CH

3 H O 4

N\J-O

160 mg 1lg 35 mgL 4 <CONH2 -YD-CONH 2 298 mg Ilg 218 mng 4- 4 4-

CH

3

-NDN-OH

159 7ng 800 Mg -20 mg 1

S

S S S S .55 *SS S 00. 0, S S S 5. S. S S S S 5 S. 5 A Use amount of the starting compound Yield of the A' amneCompound of objective product A' (.amie )Experiment 4

OH

C= OH260 mg 800 Mg 6mg

OH

274 mg. 1 g 80 M9 +ND CONH2 +1100 Mg 550 mg 89 mag

CR

3

XCH

3 CN160 Tag 550 mfg 16 mg

C

3

I

semi .55 S S S a t

S

Use amount of the starting compound Yield of the objective product IA' amn Compound of

CH

3

LCONH,

CH

3 I I.

\OH

LCOGH

Exreriment 4 j -t 220 ing 26 m 1g., (As by-product 19 Mg \of Example 46/ i i I

CH

3 -N -"'CONH 2 L cONH,

OH

~~Nz'NCONH 2

,OH

608 7ag 3 g 145 mg I 4 913 mg (Hydrochloride) 2 g 3 mg 200 Mig I g 23 M 'OHI a IUse starting compound Yield of the Compound of objective product Example

NO.

amount of the

A'X

atmine)

I

4

~OH

-N^,,,NHCOCH

3 InOH 200 Tag 1lg 13 ing I- i OH

O

,OH

OH

194 mng 500 mg 46 mg J 7 1 1

CH

3 -N-NHCONH 2

CH

3 166 mng I g 8 ag

CH

3 S1 54 -N-OH 2.5m 1a g U±1 3 15 mng

CR

3

CONHCH

3 381 7ag 31mng2 g 250 mg I- *e C C C C C C C C C C C C C C CC. CC* C C C

C

C C

C

CCC C *CC CCC C C C C C C C *C C C C. C C *C C C C C C CC C C

I

Example AUEse amount of the starting compound yield of the No IA'( mieA Compound of objective product Experiment 4 C3

-CONH

2 61 -N H 445m 2 g 268 mg C CONH2

OH

3 I

OH

62 N milH 3.39 g 23.8 9 1.42 g

H

3

CONH

2

OH

3 41

OH

63 -N H 20 0mg 500m7g 14 mg I CONHCH 2 0H UkH 3

OH

3 64 -N--'NzOH 81 ,a1 500 mg 101 Mg

OH

3 OH3H3

-NO

3 150 Mg 750 mg 127 mg H3 OH Use amuto h trig opudYedo h Copudo betv rdc A -a in Ex pe im n 4 U U UU 15 7a 75 mg 12 xg r

CH

3 310 mg 75 mg 120 mg -3 H O OH300 vg 1 g 126 ag 3

CH

3 400 mg 1 g 3 5 7F

-OH

-OH

361 Mg 1.5 g -15 mg

-OH

a a a a A Use amount of the starting compound Yield of the A' (amine Compound of objective product Experiment 4

-N~COHQH

3 71 ing 500 Mg 6 mg

CH

3 301 mg -N-CONHOH CH3K 80g2 m I H3--N-CNO Tr 0 a a

CR

3 1

'CNH

2 150 Mg 800 Mg 52 mg

CR

3 110 mg 500 mg 74mIg

H

CR

3 N CNzZH260 mg 500 mag 48 mg

CR

3 9 o C Il- 0 0 4 S S S S S S S S S *5 C a S S S AUse amount of the starting compound Yield of the A' amine )Compound of objective product A' Experiment 4

OH

3

OH

3 373 mg I tI C OH CH 3

OH

3 Br

OH

3 Ol' N--H 3 158 Tl~ 800 Tag 8 n

OH

3 OH3

H

N~ N(OH 3 18Tg800 g 36 img OHt 3

OH

N

NIN-N115 mg 500mTg 92 mg

OH

-N 70m7g 500mg 4mTg C 4* 4 44 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 44 4 4 4 4 4 4 4 4 4 4 44 4 4 4 4 4 4 4 4 4 S 4 4 4 4 4 4 444 4 4 a 4 44 4 4 4

S

I

S

P

S S S S S S

I

se

S..

S

S. S S S S

S

S S *5e S

S

S S S

S

Example AUse amount of the starting compound Yield of the No. A' amine )Compound of ojtieproduct Experiment 4 86 NXD300 Mg 1.5 g 97m7g

CH

3 3 26 7mg +1 87 -N'V--NHCH 3

CH

3 Boc 1 g 130 mg CjH 3 CHN CH)

CH

3 88 OH 192mg191 3 6mg

CH

3 0OH Isomer (89- 1 28mg 89 N 250 mg 1.59g Isomer (89- 2 62mg

CH

2 0H

CIT

3 -NOH 156 mag 1.05 g 107 mag a a a. a a a.

a 9.* C C a a a C a S a a S as S *5 S a a a a Example AUeaon ftesatn opud Yedo h No. Experiment 4

OH

91 HN0 187 Mg 1 g 56 mg

CH

3 1 92 COH-O 350 iag 1.2 g 67 mng

IH

CH

3 93 -Ni~/N\.7CONH 2 150m7g 1 g 97 mg

CH

3

CH

3 94 N -CNH 203 7ag 100 Mg 25 mg

CH

3 +1O -N 180 mg 1.2 g 50 mg I OH

CH

3 Example No.

t a *.a a a a t a a a.

a sat a..

a a C a S S S S 5* r S S a *4 S S C 00 Examplei Use amount of the starting compound j Yield of the NQ A' (amine )Compound of__ objective product

CH

3 96 -N-"'CONH, 420 mg 2 g 98 7g 0113 1 97 -N.-N\CONHCH 3 90 xg 600 Mg7 xg CH1 3

CH

3 I ,CH 98 \CN C390 Mg 600 mg 7 Mg

OH

3 99 N1 z\ OCH3 132 lg 1 g 19m7g

OHOH

100 N 470 Mg 2 g -40 mg

OH

3

CONH,

of ob ec iv product*** compound of becieprdc N.A' (amine xperimet4 11 -N N-CONH 2 391 mg 1 g 62 mg 0113 10.N1 130 mg 500 Mg 35 mg I N- \J-L011C 3

H

'0

NH

2 103 -NZ 150 mg 500 mg 30 mg 1-1 a. 0 0 0

C

*ee b 9 0 ~O* *0 S S 0 6 3 0 OS 0 S a a 000 *OS 0 egg S S a 0 OS S a @5 S eS. 0 *r S Example NaA Ulse amount of the starting compound IA' (amine Compound of Yield of the objective product 106 107 108 109

CH

3 C3

H

120 mg1 500 1Mg 30 Mg

-N-NH

2

OH

-ND-C-

I

I

200 11 400m 720 719 800 17g Ilg

M

21

M

43 mg1 t .1 110 S"'\COOH 545 Tg1 -33 Mg Vt .1 r Example A Use amount of the starting compound Yield of the Nq A' amn Compound of objective product amine I Experiment 4 670 aig 111 -NCOOH I g6m COO--:Bu) 112 CO 3 g50M (Hydrochi-oridie) 50 g31 Mg 113 -NT jH207L 500 Mg 28 mg (Hydrochloride) 9 Exmaple 114 7p-12-(5-Amino-,2, -thiediiazol-3-yl)-(Z)-2-difluoromethoxyiminoacetamidoj-3-,(El)-3-(dimethylcarbamoylmethylammonio)-1propen-1-yl -3-cephem-4-carboxylate

CH

3 N- C-CONH- S- N NNSN N o HN s OCHF, 00- CH3 The compound (500 mg) of Experiment 6 was dissolved in a mixed solution of ethyl acetate (10 ml) and ethyl ether (10 ml). To the solution was added dimethylglycine amide (160 mg), followed by stirring for 30 minutes at a room temperature. To the reaction solution was added iso-propyl ether. The resulting precipitate was recovered by filtration, and dried to obtain yellowish brown powder (400 mg).

This powder was stirred under an ice-cooling in a mixed solution of trifluoroacetic acid (5 ml) and anisole (4.5 ml) for one hour. To the reaction solution was added ethyl ether, and the resulting S precipitate was recovered by filtration, followed by washing with ethyl ether. This precipitate was suspended in water (5 ml), followed by adjusting its pH to 5.5 6.5 with sodium acetate. The insolubles were removed by filtration, and the filtrate was purified through a reversed phase silica gel chromatography to obtain the object product (55 mg).

In the same manner as described in Example 14, there were produced the compounds of the following Examples 115 117.

.i 6 I~ (Compound of Experiment 6) (The corresponding amine to A) 0 0. a 0 0 0 0 63 Us amun of th statin comoun yil of. the Useamont f te sartncompound if o NomleAA'.amn Exoeriment_ 6 115 -N )-COOH 389 Mg 1 4 4mg 116 ,N120 mg 600 mg 78 mg C 117 OH 220 mg 700 Mg 30 mg

~OH

sac 77 C~jv g N N.

C. C C

S

*.C

S

C

C C C C List of phiisical data Experi- Infrared absorptionNMR Spcrm ment s&6 7uNMRSpectrum Na cMr 1 Nujoil) 1735, 1530 (DMSO-d 6 1.19 (3H, t, J=7Hz), 4.21 (2H, q, J=7Hz), 5.79 d, 7.30 (15KH, s) 10 .03 (1 H, s).

2 17 20, 15 85 (DMSO-d 6 5.78 (2K, d, J=5KHz), 7.31 (15H, 10.06 (1H, s) 1765, 17 72 5 (DMSO-d 6 3.45 (1H, d, J=l8Kz), 3.63 (1K, d, J=18Hz),, 3.75 (3K, s), 1680, 1 6 10 3.95 (1H, dd, J=8Kz, 12Hz), 4.12 (1K, dd, J=8Hz, 12Hz), 5.07 (1K, d, J=12Hz), 3 5.14 (1K, d, J=l2Hz),' 5.24 (1H, d, J=5Hz), 5.70 O1H, mn), 5.78 (2K, d, 5.85 (1H, mn), 6.26 (1H, d, J=12Kz), 6.92 (2K, d, J=9Hz), 7.25-7.4 (17H, mn), 9.74 (1 H, d, J=8Hz), 10.08 (1KH, s) 1770, 17 15, (ODd 3 3.51 (1K, d, J=l8Kz), 3.60 (1K, d, J=18Kz), 3.81 (3K, s), 1685, 16 1 0 3.98 (2H, d, J=8Hz), 5.04 (1K, d, J=5Kz),. 5.19 (1K, d, J=12Hz),, 4 5.24 (iH, d, J=12Kz), 5.82 (2K, d, J=55Hz), 5.90 (1K, mn), 6.14 (1K, dt, J=8Kz, 16Hz), 6.77 (1K, d, J=9Kz), 6.90 (2K, d, J9Kz), 7.00 (1K, d, J=16Hz), 7.2-7.4 (17K, in), 7.83 (1K, s) ~77i~7T~7T.7 L_ M W a a S a a a..

a a. a a a a a Experi- jInfrared absorption ment spectrum IN M R spectrum Na (cm't, Nujol) 1775, 1725, 1690, 16 10 (ODd 3 3.75 (1 H, 5.10 (1H, 5.92 (1lH, 6.81 (1lH, 7.29 (2H, 3.34 (1H, d, J1l8.5Hz), 3.52 (1H, d, J=18.5Hz), dd, J=1.l.Hz, 8.Hz), 3.80 O3H, 3.93 O1H, dd, J=8.5Hz, 12.1Hz), d. J=5.OHz), 5.14 (2H. 5.74 (1H, cit, J=8.5Hz, 11.0Hz), dd, J=5.OHz, 8.Hz), 6.25 (1H, dd, J=11.OHz), 6.79 (1H, ci, J=8.8Hz5, t, J=71.2Hz), 6.87 (2H, di, J=8.7Hz), 7.15-725 (6H, in), di, J=8.7Hz), -7.25- 7.40 (9H, mn), 7.67 (1H, brs) 1780, 17 20, (CDCI,) 3.51 (1H, d, J=17.6Hz), 3.61 (1H, di, J=17.6Hz),, 3.81 (3H, s), 1690, 16 10 3.98 (2H, di, J=8.OHz), 5.05(1H, di, J=5.OHz), 5.21 (2H, brs), 5.89 (1H, dci, J=4.8Hz, 8.8Hz), 6.14 (1H, cit, J=8.OHz, 16.0Hz), 6.78 (1H, d, J8.8Hz), 6.81 (1H, t, J=71.2Hz), 6.90 (2H, di, J=8.8Hz), 7.00 (1H, di, J=16.0Hz), 7.15-7.45 (17H, in), 7.63 (1Hi, brs) k

K

9 .4 S 4.*

S

S

d4 SS* 5 555 5*S S S 4 .4 5 4 *4 4 a 4 Expe catrum abopinN M R Spectrum (cnr', Nujol) 1760, 167 5, (DMSO-d,) 1.26 (3H, t, J=7.2Hz), 3.08 a.nd.- 3.09 (totalI 3H, S), 90, 15 20 3.4-3.6 (2H, mn), 3.47 (1H, d, J=16.8Hz), 3.65 (1H, d, UT-16.8Hz), 4.01 (2H, s), 1 4.05-4.2 (2H, in), 5.06 (1H, d, J=4.8Hz), 5.6-575 (2H, mn), 5.79 (2H, brd, J=55.3Hz), 7.17 (1H, d, J=15.8Hz), 7.66 (1K, 8.23 (2H, 8.33 O1H, 9.71 (1H, d, J=8.4Hz) 1750, 16 50, (D 2 0) 2.18 -2.30(4K, n) 2.78 -2.83 (11H, mn), 3.48 -3.54 (4 H, m) 1590, 1520 3.73--84 (4H, in), 4.15-4.18(2H. in), 4.32 (2K, in), 5.38 (1H, d, 2-1 5.94--600 (1H, mn), 5.96 (211, d, J=54.2z), 5.97 (1K, d, 7.07 (1KH, d, J=16.8 Hz) 1750, 1 650, (D 2 0) 2.19 2.26 (4KH, in), 2.76 2.81 (lIM, mn), 3.42 -3.54 (2K H.n), 1590, 15 20 3.65--366 (2K, in), 3.73--83 (4H, 4.14--16 (2H, in), 4.24-4-27 (2H, in), 2- 2 5.39 (1KH, d, J =5.1lHz), 5.96 (2KH, d, J =54.6 Hz) 5.97 (1KH, d, J =5.1Hz), 6.07 (1 H, in), 7.02 (1KH, d, J =15.8KHz) k 4 0 S 4* a S 0 0 S S S *5* S S 00 a S. S SS* 550 S 0* S S S Se S S S S S S 5 9 Example- Infrared absorption spec-trum N M R? Spectrum No. (CMr', Nujol) 1760, 1 670, (DMSO-de) 1.48(3OH, d, J=7.OHz), 3.05 (3H, 3.08(3OH, s), 1590, 1 5 1 5 3.48 H.i, J=16.7Hz), 3.65 (1H1, d, J16.7Hz), 3.97-4.15 OH-, in), 3-1 5.07 (1 H, di, J=5.0Hz), 5.66 (1H1, dd, J=5.Hz, 8.4Hz), 5.65--5.75 (111, m), 5.78 (2H, brd, J=55.5Hz), 7.15 (111, d, J=15.8Hz), 7.70 (11H, 8.12 (2H, s),i 8.26 (11, 9.70 (111, d, J=8.4Hz) 1 760, 1 6 70, (DMSO-d§) 1.46 (31, ci, J=7.OHz), 3.04 (3H, 3.06 (3H, s), 1590, 1520 3.49 (11H, d, J =17.2 Hz), 3.64 (11H. d, J =17.2 Hz), 4.05 (1 H, in), 4.15 -4.30 (211, in), 3-2 5.09(111, ci, J=5.OHz), 5.67 O1H, dci, J=5.014z, 8.0Hz), 5.5-5.8 (1H1, m), 5.79 (2H, brd, J=55.511z), 7.18 (1H, d, J15.41z), 7.67 (1H1, 8.21 (2H, s), 8.64 (1H1, 9.70 (1H1, d, J=8.oHz) 1765, 1 660, (DMSO-db) 1.11 (31, ci, J=6.211z), 3.01 (3H, 3.04 (31, s), 1600, 1525 3.22 (2H1, brci, J=7.OHz), 3.46 (1H, d, J=17.OHz), 4 3.63 a n d 3.65 (t t a il1H, di, J=17.OHz), 4.06 (2H1, brd, J=6.2Hz), 4.26 (1H1, brs), 5.06 (1H, d, J=5.OHz), 5.6-5.75 (211, in), 5.79 (2H, brd, J=55.3Hz), 7M6 (1H, ci, J1l5.8Hz), 8.27 (2H1, 9.71 (1H1, d, J=8.lHz)

V.

pro- 6 6 6 *6r 6 6 6 ~6* 6 6* 6 *66* 6 6 6 6 *66 6 6 6e 6 6 6* 6 6 Examiple IInfrared absorption jspectrum N M R Spectrum a) 1765, 16 70, (DMSO-d 0 3.08 (3 H. 3.14 (31H, 3.49(11H, d, J =17.2 Hz), 1 600, 1 530 3.6 2(11H, d, J =17.2 Hz) 3.87 (11H, dd, J =5.5 Hz, 12.5 Hz) 4.06 (11H, dd, J 5.5 Hz, 12.5 Hz) 4.1 -4.2 0IH. mn), 4.19 (2 H, d, J =7.3 Hz) 5.08 (1H1, d, J=5.OHz), 5.67 (111, dd, J=4.Hz, 8.4Hz), 5.70-5.85 (1H, in), 5.79 (2H. d, J=55.0Hz), 7.11 (1H, d. J=154Hz), 7-76 (1H, 8.22 (2H, s), 8.52 01H, s) 9.73 (1 H. d, J =8.4 Hz) 17 50, 165 0, (DMSOU') 1.73 1.78 (1 H, in), 2.54- 2.60 (111, in), 3.04 (31H, s), 1590, 15 1 0 3.44 -3.86 (511, in), 3.46(1H, d. J=17.211z), 3.62(1H, d,-J=17.2Hz), 6- 1 4.0 0 -4.23 211, mn), 4.43(OH, in), 5.06 (1H1, d, 5.65 (1H1, dd, J=5.11z, 8.4Hz), 5.71-586 (3H, mn), 7.13 (1H. d, J=15.4Hz), 8.22 (21H, 9.70 (11H, d, J=8.4 Hz) 1750, 16 50, 90, 151 0 6 -2 (DMSO-d,) 1.77 -1.83 (111, mn), 2.53 -2.59 (111,.in), 3.04 (311, s), 3.32 -3.94 (511, mn), 3.46 (111. d, J =16.9 Hz), 3.65 -3.71 (111, in), 3.91- 4.19 (2H, in), 4.45 (111,.im), 5.07 (1 H. d, J=5.1Hz), 5.64 (111, dd, J=5. Hz, 8.4 Hz), 5.71 -5.86 (311, in), 7.14 (1IH. d, J =15.7 Hz), 8.24 (211. 9.70 (lH. d, J=8.4Hz) 9 S 9 *9 9c a 4.b 9 9 V 9 9 *9 9 U 9 5 .9 a a a S 4 .99 V 9 9 *t9 99* 055 9 ha. 9 9 9*99 9 .j a S S 9 9 S a qa a 9 7~* Examnple- Infrared absorption Pi spec~rum N M R Spectrum aQ (air', Nujol) g 1760, 1 665i (DMSO-d,) 2.0 5 (1H, in) 2.31 (iH,mi), 3.4-3.9 (1111,Mi), 4.01 (1H,mi), 1590, 1 52 5 4.13(01K, mn), 4.31 01K, brs), 4.42 (1KH, brs), 5.07 (1K, d, J=4.8Hz), 7-i 5.65 (1K,dd, J=4.8PZ, 8.4Hz), 5.76 (1H,mi), 5.78 (2H, d, J56.6Hz), 7.14 (1K, d, J=15.4Hz), 8.22 (2K, 9.70 (1K, d, J=8.4Hz) 1760, 166 5, (DMSO-d,) 2.05(1H,Mi), 2.29(1H,Mi), 3.4-3.9(11K,Mi), 3.90--35(3H,mi), 7-2 15 90, 1530 j4.44 (IH, brs), 5.07 (1K,d, J=4.8Hz), 5.65 (1H, dd, J4.8Kz, 8.1Hz), 5.78 (2K, d, J55.6Hz), 5.79 (1H,mi), 7.11 (ii, d, J15.4Hz), 8.21 (2K, s), 9.71 (1K, d, J =8.1z) 1750, 1660, (IDMSO-d,) 1.95-2-07 (1K, 2.17-2-35(OH, mn), 1590, 15 10 2.92 and 3.14(t o t a13K,s), 3.22-4.03(5K,mi), 3.45-3.66(2H,mi), 84.03--22(2K,Mi), 4.42 (1K,mi), 5.07 (1K,d, J4.8Kz), 5.65 (1K,dd, J4.8Kz, 8.1Hz), 5.71-5.86(3K,mi), 7.11'-7.18(1H,mi), .8.22 (2KH, 9.70 (1KH, d, J=8.1 Hz) 4 S S S V S 56 V 5 96 S 0 a 0 6 0~ *g 0a 3*0 0* S S OS S S 5* SE S a 0 Example- Inraed absorptionNM Spcrm Na (C27r', Nujol) 1590, 15 10 3.59-3.82 (5H, mn), 4.19(OH, 4.24 (2H, mn), 4.50(OH, mn), 9-1 5.06 (1H, d, J=4.8Hz), 5.65 (1H, dd, J=8.lHz, 4.8Hz), 5.69-5.75.(1H, in), 5.79 (2H, d, J=55.OHz), 7.10 (1H, d, J=15.8Hz), 7.66 (1H1, s), 8.10 a n d' 8.12 o t a I- IH, 8.22 (2H, 9.70 (1H, d, J=8.lHz) 1750, 16 60, (DMSO-d,) 1.97-1.99 (1H, in), 2.40-2.42 (1H, in), 3.45 (1H, d, J16.9Hz), 1590, 15 10 3.60--85 (5H, mn), 4.06 (2H, 4.18-4.32 (2H, in), 4.51 (1H, mn), 9-2 5.06 (1H, d, J=4.8Hz), 5.65 (1H1, dd, J=S.lHz. 4.8Hz), 5.70'-5.85 (1H, mn), 5.79 (2H. d, J=55.3Hz), 7.10 (1H, d, J=15.4Hz), 7.66 (1H, 8.15 (1H, s), 8.22 (2H1, 9.70 (1H, d, J=8.lHz) 1750, 16 60, (DMSO-da) 1.95-1.98-(1H, in), 2.37-2.42 O1H, mn), 3.46 (1H, d, J=16.9Hz), 1590, 15 10 3.60 -3.83 (5 H, mn), 4.06 (2 H, 4.26 (21, in), 4.52 (1 H, in), 9 -3 5.06 (1H, d, J=4.8Hz), 5.65 (11, dd, J=8.lHz, 4.8Hz), 5.72-5.84 O1H, in), 5.79 d, J=55.OHz), 7.10 (1H, d, J=15.8Hz), 7.65 (1H, 8.18 O1H, s), 8.22 (2H1, 9.70 (1H1, d, J=8.IHz) -Example Infrared absorption spectrum N M R Spectrum No. Nujol) 1765, 1670, (DMSO-d 6 2.95 (2H, 3.0- 3.5 (8H, mn), 3.52 (1H, d, J=16.9Hz), 1595, 15 25 3.76 U1H, d, J=16.9Hz), 4.08 (2H. in), 5.12 (1H, d, J=4.8Hz), 5.71~-5.85 (3H, in), 7.14 (1 H, d, J=15.8Hz), 7.16 (1H, brs), 8.21 (2H, 9.74 (1H, d. J=8.lHz) 1760, 1 650, (1JMSO-d,) 1.74 (2H, brs), 2.01 (2H, brs), 3.2-3.8 (6H, in), 3.81 O1H, s), 1590, 1530 4.02 (2H, 4.28 (21H, 5.05 a n d 5.06 t o t a 1 11H, d, J=5.1lHz), 11 5.6 -5.8 (1 R, in), 5.64 (1 H, dd, J=5.1Hz, 8.1 Hz), 5.78 (2H1, d, J=55.3 Hz), 7.14(1OH, d, J=15.8Hz), 7.71 (1H, 8.22 (3H, 9.69(1OH, d, J=8.lHz) 1750, 1660, (DMSO-d,) 1.35 (3 H. 3.1- 4.0 (12 H, in), 4.1- 4.3(01H, in), 12 1610, 15 90 4.50 (2H, d, J=3.6Hz), 5.07(111, di, J=4.8Hz), 5.6-5.8 (211, m), 5.76 (211, d, J=52.OHz), 7.15 (1H1, d, J=15.711z), 8.22 (2H, 9.70 (1H1, d, J=8.OHz) 1 76 0, 1 67 0, (DMSO-d,,) 1.50 d, J=6.61Z), 2.00 (4H, brs), 3.47 (1 H, ci, J=17.OHz), 1590, 15 20 3.45-3-70 (31, in), 3.63 (OH, d, J=17.OHz), 3.85--3.95 (11, in), 4.07 (2H, in), 13-1 4.15 4.25 (11H, in), 5.07 (1H, d, J=4.8Hz), 5.65 (111 dci, J=4.81z, 575.8 (1H, in), 5.78 (2H1, d, J=55.OHz), 7.16 (1H, d, J=15.8Hz), 7.69(1OH, S), 8.36 (1H, 9.71 (1H1, d, J=8.oHz) V V V *V V V V V V

V

V V V V V *V *.V V Ve *V*V V V V V V V V VVV C V V CV V V Example lInfrared absorption spectrum NMRsetu Nba- Nujol) N R setu 1765, 1680, (DMSO-d,) 1.49 (3H, d, J=6.6Hz), 2.00 (411, brs), 3.47 (11, d, J=17.11z), 1600, 1525 3.5 3.70 (3 H. mn), 3.59 O1H. d, J=17.OHz), 3.8-3.9 (111, mn), 4.07 (2H. mn), 13-2 4.25 -4.35 (11H, mn), 5.07 (1 H, d, J =5.O0Hz) 5.66 (1 H. dd, J 5. 0Hz, 8.-4 Hz) 5.70-585 (1H, mr), 5.78 (211. d. J=55.OHz), 7.16 (1H, d. J=15.4Hz), 7.69 (1H. s), 8.22 (2 H. 8.50(11H, 9.70 (1 H, d. J=8.4 Hz) 1765, 1665, D,0) 2.35 -2.45 (21H, in), 3.75 -4.0 (6 H. in), 4.3 -4.4 (2 H. m), 14' 1595, 1520 4.73 (2H. 5.40 (1H1, d, J=4.8Hz), 5.96 (2H, d, J=54.5Hz), 5.98 (11H. d, J=4.8Hz), 6-09 (11H, dt, J=8.Hz. 15.8Hz), 7.15 O1H, d, J=15.8Hz) 1750, 1650. (DMSO-d,) 1.91 -1.96 (1 H. in), 2-32 -2.41 (1 H, in), 3.31 -3.99 (1011, in), 151 1590, 15 10 3.99- 4.24 (2H1, in), 4.50 (1H, in), 5.06 (1H, d, J=4.BHz), 5.65 (1H1, dd, J=4.8Hz, 8.1Hz), 5.66--72 mn), 5.79 (2H1. d, J=55.3Hz), 7.16 (1 H. d, J=15.8 Hz), 8.21 (2 H, 9.70 (1 H, d, J =8.1lHz) 1750, 1650, (DMSO-d,) 1.93- 1.970(H, in), 2.35-2.42 (lH, in), 3.34-3-82 (1011, i), 1590, 15 10 4.09 -4.23 (211, in), 4.51 (111,.in), 5.07 (1 H, d, J =4.8 Hz), 15'-2 5.65(1OH, dd, J=4.8Hz, 8.1Hz), 5.72-5.82 (1H, in), 5.79 (2H1, d, J=53.9Hz), 7.15 (1 H. d, J =15.8 Hz), 8.21 (2 H, 9.70 (1 H. d, J=8.1 Hz) ZI~i~ a.

S S 55. e S S S Example Infrared absorption spb~ctrm N M Spectrum Na Nujol) 1740, 1640, (DMSO-d 6 1.8-2.3 (4H, 3.4-4.2 (111, 3.97-4.13 (2K H m), 1580 5.07 (1H, d, J=5.1Hz), 5.64 (1K, dc, J=5.1z, 8.4Hz), 5.71 -5.78 (1K, i), 16 5.79 (211, d, J5=5.3Hz), 7.15 a n. d 7.16 (t o t a I.1H, d, J=15.8Kz), 8.22 (2H, s), 9.70 (1H, d, J8.4 Hz) 1750, 1660, (DMSO-d,) 1.8-'2.3 (4K, 3.3-4.4 (9K, 4.01- 4.29 (2H, MI), 1590 5.07 (1H, d, J=4.8Hz), 5.66 (1K, dc, J=4.8Hz, 8.1Hz), 5.76 (1H, m), 17 5.78 (1K, d, J=57.5Kz), 7.14 d, J15.4Hz), 7.61 (1K, 8.21 (1K, s), 8.24 (2H, 9.72 (1H, c, J=8.l1z) 1760, 1650, (DMSO-d,) 1.92- 2.20 (4K, 3.40 -3.75 (4KH, 3.43-3.75 (2KH, m), 16*00, 1520 3.86(111, 4.08(1Hm), 4.66(1H, 5.05(1, d, J=4.8Kz), .18 5.63 (1K, di, J=8.4Hz, 4.8Hz), 5.68-5-76 (1K, 5.79 (2H, d, J=55.3Hz), 7.12 (1K, c, J=15.8Hz), 8.22 (2K, 9.71 1, c, J=8.4Hz) (DMSO-d,) 2.06 (4K, brs), 3.45(1, c, J=17.2Hz), 3.5-3.7(5K, i), 4.05 4.13(2K, brs), 5.06(1K ci, J=4.8Kz), 5.65(1KH, d, J4.8Kz, 19 5.65 5.8 (1 H, 5.78(211, brd, J55.Hz)., 7.12 (1K, c, J16.2Hz), 7.66 (1H, 8.23 (3K, 9.70 (1 H, c, J=8.0 z) -3l

U

C

S

C..

55.

C C C C. a S. S S S C C S S *SS S S C xample No.

Infrared absorption spec~trum (cm'1, Nujol) N M R Spectrum (DMSO-d,) 2.05 (AW, brs), 3.44 (1H1, d, J=16.8Wz), 3.50 (6H, brs), 3.63 (1WH, d, J =16.8 Hz), 4.8 -4.9 (2WH, in), 4.01 H. J=7.3WHz), 5.06 (1WH, d, J 5.0Wz), '5.64 (1W, dci, J=5.0Wz, 8.Hz), 5.7-5.8 (111, m), 5.78 (2H, brd, J=56.0Wz), 7.17 (11H, d, J=15.8Wz), 8.23 (2H1, s), 9.70 (1W, d, J=8.OHz) (DMSO-d,) 1.75-225 (411, in), 2.88 (1H. 3.06 (2H, 3.2-4.3 (9H, mn), 3.45 (1 H, ci, J='l6.9Wz), 3.680(1, d, J16.911z), 5.050H 1 ci, J=4.8Wz), 21 5.6 -5.8 (11H, mn), 5.63 (11H, cid, J=4.8Hz, 8.4Wz), 5.78 (2H, ci, J=58.6Wz), 7.15 a n d 7.18 o t a I 1H, d, J15.4Wz), 8.23 (2H1, 9.69 (1H, ci, J=8.4Hz) 2.34 (4H, 3.5-3.9 (OWH, in), 4.17 (2H1, d, J=7.7Wz), 22 5.39 (11, di, J=4.8Wz), 5.97 (111, d, J=4.8Hz), 5.97 (2H1, d, J=54.6Hz), 6.00--15 (1W, mn), 7.07 (11, di, ,L=15.8Wz) 1750, 1650, (DMSO-do) 2.06~- 2.08 (3H, in), 3.21- 3.63 (1211, mn), 4.02- 4.08 (2H1,i) 1580 5.08 (1 H, d, J=5.1lHz), 5.66 (1WH, dci, J=5.1 Hz, 8.1 Hz), 5.71 -5.76 (11H, in), 23-.1 5.79 (2H1, d, J=55.311z), 7.13(11H, di, J=15.811z), 8.21 (2H1, s), 9.71 (11H, d, J =8.1Hz) C C C C C *C C C.

C

Exaple Infrared absorptionI spe'ctrum N M R Spectrum Na Nujol) 1750, 1650, (1JMSO-d,) 2.08 (31H, in), 2.98 3.07 (21H, 3.36-3.80 (9 H, 1580 3.98--020(11, Mn), 4.07-412 (2H, in), 5.06(1H, d, J=4.8Hz), 23- 2 5.66 (11H, dd, J=4.81z, 8.1Hz), 5.71--5.85 (3H, mn), 7.06 (1H1, d, J=15.811z), 8.20 (21H, 9.75 (1 H, d, J=8.1Hz) 1765, 1650, (DMSO-d 0 3.06 (31H, s) 3.3 -3.5 (4 1, in), 3.46 (11H, d, J =16.9 Hz) 1595, 152 5 3.5- 4.0 (4H1, in), 3.64 (111, d, J=16.91z), 4.15 (2H, in), 5.06 (1H, d, J=4.8Hz), 24 5.6 -5.8 (1 H, mn), 5.64 (11H, dd, J =4.8 Hz, 8.4 Hz), 5.79 (2 H, d, J =57.2 Hz), 7.22 (1 H, d, J=15.8 Hz), 8.08 01H, 8.23 (211, 9.70 (1 H, d, J =8.4 Hz) 1750, 1650, (DMvSO-d 0 2-55~- 2.90 (1011, 2.97(3OH, 3.1-35(1,i) 1620, 1580 3.48 (1 H, d, J=17.6Hz), 3.75 (1H1, d, J=17.611z), 4.0-4.2 (211, in), 5.12 (111, d, J=5.lHz), 5.65-5.80 (111, in), 5.80-5.90 (111, mn), 5.79 (2H1, d, J=55.3Hz), 7.11 (11, d, J1l5.8Hz), 8.21 (211, s), {9.73 (1 H, d, J=8.111z)

'C-

OWN

S S S 55 S S S S S S S S S S S S S S S 55 SS* S S* *S5S *S*5 **S5 S S S S 5 9 5 S S S S C. *S S Example No.

Infrared absorption spectrum (cMr', Nujol) N M 1 R Spectrum I I 1765, 1670.

1 5 90, 1 53 0 (DMSO-d,) 3.6 -4.1 8H, 5.6 -5.8 (11H, 7.22 (1 H, d. J 2.28 (3 H, 3.10 (311. 3.46 (11H. d, J =16.9 Hz), mn), 3.64 (1H. d. J=169Hz), 4.16 (2H, mn), 5.07 (111, d. J=4.8Hz), in), 5.79 (2H. d, J=57.2Hz), 5.66 (11H, dd, J=4.8Hz, 7.7Hz), =15.4Hz), 8.23 (2H, 9.70 (111, d, J=7.7Hz) 1760, 1660, (DMSO-d,) 2.49 -3.85 (161H. mn), 3.42 -3.51 0IH. mn), 3.66 (1 H, d. J =17.2 Hz), 1590, 1520 4.17 (211, d, J=6.6Hz), 5.06 (1H, d, J=4.8Hz), 5.6-5.9 (11H, mn), 27 5.64 (1H, dd, J=4.8Hz, 8.lHz),* 5.79 (2H. d, J=55.3Hz), 7.17 (11H, ci. J=15-8Hz), 8.24 (211, s) 9.70 (1 H, d, J =8.1Hz) 1750, 1 650, (D 2 0) 3.6-3-85 (8H1, in), 3.85-3.97 (411, mn), 4.19 (2H, t, J=4.8Hz), .28 1580 4.39 (2H, mn), 5.39 (1H, di, J=4.8Hz), 5.96 (2H1, d, J=54.2Hz), 5.97 (1H1, d, J=4.8Hz), 6.0 -6 .08 (1H, mn), 7.06 (1 H, d, J =15.7 Hz) 1750, 1660, (DMSO-d,) 3.2- 3.7 (12H, mn), 3.8 (2H. in), 4.22 (2H, d, J=7.3Hz), 29 1580 5.08 (11H. d, J =5.1Hz), 5.6 -5.8 (2 H, mn), 5.79 (21H. d. J =55.7 Hz), 7.13 (21H, s) 7.18 (11H, d, J=15.811z), 8.22 (2H, 9.70 (111 H. d J=8.OHz) 3.5 4.0 (1411, in), 4.35 -4.55 (311, in), 5.38 (11H, d, J=4.7 Hz), 5.95 (21H, di, J =54.2 Hz), 5.97 (1 H. d, J=4.7 Hz), 6.0 -6.5 (1H. in), 7.06 (11H, d. J =15.4 Hz)

I

Al *e S S I S I. U S S 5 5** S S S S S S S S S US U S 55 55 S S S S S .5 S S S S S S S S *S S Ispectrum p Ifrre asoptonN M R Spectrum NQL (CMi1, Nujo.l) .1750. 1650, (D 2 0) 3.75- 4.00 (10H, in), 4.23(111, d, J=16.411z), 311580 4.30(111, d, J=16.411z), 4.53(2H1, d, J=8.lHz), 5.39 (1H, d, J=4.8Hz), 5.95 (2H, d, J=54.2Hz), 5.97 (1 H, d, J=4.8Hz), 6.0- 6.05 (11H, mn), 7. 05 (111. d, J =15.8 Hz) 1750, 1 640, (DO0) 3.55-4.0 (1411, in), 4.25-4.40 (2H1, in), 5.39 (1H, d, J=4.7Hz), 32 1580 5.97 (11H, d, J=4.71z), 5.98 (2H, d, J=53.41z), 6.04 (1H1, in), 7.08 01H, d. J =15.7 Hz) 1750, 1 660, (DMSO-d,) 2.8-3.4 (00H, in), 2.970(H, 3.46(111. d, J1l7.2Hz), 33 1620, 1580 3.63 (1 H. d, J=17.2Hz), 4.07 (2H, in), 5.06 (11, d, J=5.Hz), 5.6- 5.9 (4H, in), 7.20 (1 H. d, J=15.8Hz), 8.24 (211, 9.70 (111, brs) 1750, 1 660, (DMSO-d,) 2.3-3.4 (12H, Mn), 2.97 (OH, 3.44 (111, d, J=17.2Hz), 1620, 1580 3.62 (11H, d, J=17.2Hz), 4.07 (2H1, brs), 5.05 (1H1, d, J=4.81z), 5.63 (2H, in), 34 5.78 (2H1, d, J=55.51z), 7.20 (IH, d. J=15.411z), 8.21 (2H1, s), 9.69 (11H, d. J=8.8Hz) 18 ris S. S S S a C S S S S a

S

S S S.

S

*S

I

1 Example Infrared absorption spectrum I N M R spectrum a) NaL t'JUJU±J 1750, 1660, (DMSO-d,) 3.4- 3.8 (6H, 3.9- 4.05 (411, 4.15 d, J=16.Hz), 51620, 1590 4.20 d, J=16.lHz), 4.37 (1H, d, J=7.3Hz), 5.08(1, d, J=4.7Hz) 5.65-5.8 (21, 5.79 d, J=55.3z), 7.13 (1H, d, J15.7Hz), 8.21 (3H, s), 8.24(1, 9.70 (1H, d, -J=8.lHz) 1750, 1 650, (DMSO-d.) 3.2 3.6 (10H, 3.8- 4.0 (411, 4.1- 4.3 (21, m), 36 1610, 1 590 5.11 (1H, d, J4.7Hz), 5.80 (21, d, J=62.01z), 5.80-595 (21, i), 7.12 d, J=16.OHz), 8.21 (21, s)

(D

2 0) 3.65-3.82 (811, 4.20-4.35(6H, 4.38--4.50 (211, I), 37 5.41 (1H, d, J=4.8Hz), 5.98(2H, d, J=54.6Hz), 5.99(111, d, J=4.8Hz), 6.00-6.10 (111, 7.08 (111, d, J15.8Hz)

(D

2 0) 3.55'-3.90 (1011, 4.14- 4.24 (411, 4.35- 4.55 (311, m), 38 5.38(1H, d, J4.8Hz), 5.97(1, d, J4.8Hz), 5.96(2H, d, J=54.22Hz), 5.95 -6.05 (111, 7.07(11, d, J=15.3 z) (DMSO-d,) 1.14 -a n d 1.16 (t o t a 1 31, d, J=6.6Hz), 3.2- 3.7 (811, m), 3.85 -4.00 (411, 4.2-4.45 (311, 5.05 a n d 5.06 (t o t a 11H, d, J4.8Hz), 39 5.6 5.7 (211, 5.75 (211, d, J55.3Hz), 7.18 a n d 7.20 (t o t a 111H, d, J=15.8 Hz), 8.23(2H, 9.67(1H, d, J=8.4Hz)

L

ExpE ment

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S

a a S tExample Infrared absorption spectrum N M R spectrum NO. Nujol) 1 7 6 0, 1 6 6 0, (DMSO-d,) 1.95- 2.03 (411, rn), 2.40 (1 H, 3.4- 4.8 (411, m), 1 5 90, 1 5 20 4.00- 4.05 (2H, 4.25 (2H, 5.05 (1H, d, J4.8Hz), 5.6- 5.8 (2H, i), 5.79 (2H, d, J=55.3Hz), 6.99-8.29 (4H, 7.14(11, d, J=16.OHz), 8.22 (2H, s), 9.70 (1H, d, J=8.lHz) 17 50, A 660, (DMSO-d 8 1.73 (3 1.95 (6H, ni), 3.41 (6H, 3.47 (1H, d, J16.9Hz), 1580 3.64 (11H, d, J=16.9Hz), 3.89 (2H, brs), 5.08 (iH, d, J=4.8Sz), 41 5.66 (1H, dd, J4.8Hz, 8.4Hz), 5.70(1H, 5.79 (2H, d, 7.14 d, J=15.8Hz), 8.21 (2H, 9.70(1, d, J8.4Hz), 10.73(111, s) 1750, 1650, (DMSO-d,) 2.61 (211, brs), 3.2--3.65 (41, 3.47(1, d, J17.2Hz), 1580 3.69 (1H, d, J=17.2Hz), 3.87 (2H, t, J=4.8Hz), 4.0-4.2 (4H, m), 42 5.07 (1H, d, J=51.Hz), 5.60-- 5.85 (1H, 5.66 (1H, dd, J=5.1 Hz, 8.1Hz), 5.79 (21H, d, J=53.lHz), 6.08 (111, 7.18(1H, d, J=15.8Hz), 7.85 (1H, s), 8.21 (211, 9.70(1H, d, J=8.1Hz) i r

I

0 9 OS V 0 @9 S 0 9 9* 6 00~ 0 00 0 0.0 S S 9 6 0 @00 b S a 5 6 *ee* *o 9060 *0~0 0095 09 09 0 S S E 9 9 009 I 0 9 0* 5 9 0 6~ -4 9 9 9.

Examiple Infrared absorption 1580 ~3.67 0IH, d, J=17.6 Hz), 3.87 (2 H, in), 4.08 (4 H, Mn), 5.06 (1IH, d. J =5.1Hz), 43 ~5.40 -5.90 (2 H, in), 5.66 0IH. dd, J=5.1Hz, 8.1 Hz), 5.79 (2 H, d, J=58-6 Hz), 6.48 (1 H, 7.19 01H. J=18.0Hz), 7.21 (1 H. s), 7.61 a n d 7.67 (t o t a I 1H. 8.22 (2H. s), 9.69 and 9.71 (to tal i1H, d. J8.lHz) 1760, 1660, (DMSO-d 8 1.24 (3H. t, J=7.2Hz), 2.94 (3H, 3.29 (4H, brs), 441600, 1 52 0 3.4 5 (1 H. d. J=16.9Hz), 3.65 (1H. d, J=16.9Hz), 3.83 brs), 4.00 (2H, brs), 5.06 (1H. d. J=4.8Hz), 5.6--75 (2H, in), 5.78 (2H, brd, J=55.5Hz), 7.17(10-H. d, J=15.8Hz), 8.24 (2H, 9.70 (1H, d, J=8.OHz) 1 760, 1 660, (D 2 0) 1.55 (OH, t, J=7.3Hz), 3.32 (311, 3.71 (2H, q, J=7.3Hz), 1600. 1520 3.78 (1H, d, J=17.2Hz), 3.83 (IH, d. J=17.2Hz), 4.32 (2H, brd, J=7.3Hz), 4.72 (2H.1 5.41 (1H. d, J=4.8Hz), 5.97 (2H, d, J=54.5Hz), 5.99 (IH, d, J=4.8Hz), 6.0-6.1 (1H, in), 7.14 (1H, 4, J1l5.4Hz) Ppp- .9*

S

S S S S S *5 55 5 .1 Example Inf rared absorption spectrum N M R Spectrum 1 750, 1 660, (DMSO-d,) 3.10-3.87 (4 H, in), 3.17 (3 H. s) 3.4 9 (1 H, d, J =17.2 Hz), 1590. 15 20 3.68 (1H. d, J=17.2Hz), 4.09 (2H. 4.26 d, J=7.OHz), 5.08 (1 H. d. J=4.8Hz), 465.6-5.9 (3H, in), 5.67 (1H, dd, J'=4.8Hz. 8.4Hz), 7.14 (1H, d, J=15.3Hz), 1750, 1650, (DMSO-d 8 3.10 a n d 3.12 t o t a I 3H. 3.53-3.92 (8H, in), 4.33 (2H, in), 47 1600, 1 5 1 0 5.18 (1IH. d, J =4.8 Hz) 5.79 (2H, d. J=57.2Hz), 5.80 (1K, dd, J=4.8Hz, 8.4Hz), 6.03 (1 H. 7.01 (1 H, d, J=15.8 Hz), 8.22 (2 H, 9.79 (1 H, d, J=8.4 Hz) 1765, 1680, (DMSO-d 8 3.27 (3H. 3.50 (1H, d. J17.6Hz), 3.69 (1K. d. J=17.6Hz), 48 1595, 15 25 4.28 4H. s) 4.37 2H. mn), 5.09 (1KH. d. J=4.8Hz), 5.68 (1KH, dd. J=4.8Hz, 8.4Hz), 5.74 (1 H. Wn, 5.79 (2 H, d, J =55.3KHz), 7.14 (1 H. d, J=154 Hz), 7.66 (2 H, s), 8. 11 (1KH. 8.14 (1KH. 8.22 (2KH, 9.72 (1IK, d. J=8.4 Hz) 1765, 1670, 1595, 15 10 (DMSO-d,) 3.84 (4H, s), 2.63 (2H, mn), 3.2-.3.7 (4H, mn), 3.73 (1K, d, J=16.9Hz), 4.07 (2 H, in), 5.07 (1 H. d. J=4.8 5.43 (1K H.n), 5.60 (1K, dd. J=4.8Hz, 8.1Hz), 5.73 (1K. in), 5.80 (2H, d. J=54.6Hz), 7.06 7.20 (1 H, d. J =15.8 Hz), 7.89 (1 H. 8.21 (2H. s) 9.52 (1 H, d, J =8.1 Hz)

'S.

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S S S S SOS *S S S* S S S S S S 0 Example Infrared absorption NMR Setu Na (cnr', Nujol) 1750, 1650, (D 2 0) 1.33 a,n d 1.35 (t 0 t a 1 3H, d, J=6.2Hz), 3.50- 3.65 (211, mn), 16 10, 1580 3.65 -3.85 (611, in), 4.1 -4.2 (411, mn), 4.3 -4.55 (2 H, in), 4.55 (11H, mn), 5.38 (1H1, d, J=4.71z), 5.95 (211, d, J=54.lHz), 5.97 (1H1, d, J=4.71z), 6.02 (1 H, in), 7.02 (1 H, d, J=15.81z) 2.09 (3H, 3.55- 3.85 (1011, mn), 4.15(4OH, brs), 51 4.32 (2H, d, J=7.71z), 5.38 (1H, di, J=r4.711z), 5.95 (2R1 d, J=5 5 .011z), 5.97 (1H, J=4.71z), 6.05 (1H. in), 7.05 (1H1, d, J=15.7Hz) 17 50, 17 20, (DMSO-d,) 2.5 -3.5 (211H, in), 3.64 (111, ci, J =16.9 Hz), 4.11 (211, ci, J=6.6 Hz), 52 1650, 1580 5.07 (1 H, d, J=5.lHz), 5.6- 5.9 O3H, mn), 5.65 (11, dci, J=5.lHz, 8.4Hz), 7.16 H, di, J=15.8Hz),- 8.21 (2H1, 9.74 (1H1, d, J=8.41z) 1750, 1660, (D 2 0O) 3.46 (31H, 3.50 (31H, 3.63 (2 H, 4.2 -4.6 (211, mn), 53 16 10, 1580 5.21 (1H, ci, J=6.OHz), 5.78 (1H1, d, J=6.OHz), 5.78 (211, d, 5.80 (1 H, in), 6.85 (111, ci, J17.0Hz) 54. 4.44 (211, in), 5. 15(111.,ci, J=4.6 Hz), 5.7 -6.0 (311, in), 7.16 (111, di, J =15.4 Hz), 8.21 (211, 9.76 (111, ci, J=8.81z) k

N,

MAN

0. Example- In.frared absorption NMR Setu Na (cvA, Nujol) 17 60, 1'6 7 0, 1(DMSO-d 8 2.64 O3H, d. J=4.4Hz), 3.13 O3H, 3.1i O3H, s), 1640, 15 90, 3.48 (1 H. d, J=17.2Hz), 3.65 OIH, d, J=17.2Hz),- 4.03-418 (4H, in), 1 520 5 .07 (1 H, d. J =4.8 Hz) 5 5.84 (1 H, n) 5.66 (1 H, dd, J 8Hz, 8.4 Hz), 5.78 (2 H. d, J=56.4Hz), 7.17 (1 H, d, J1l5.4Hz), 8.23 (2H,s) 9. t9 (I H. d, J=4.4Hz), '9.71 O1H, d. J=8.4Hz) 1760, 1650, (DI 90-d,) 2.88 (3 H. 2.94 (3 H, 3.15 (6 H, 3.45 (1 H. d. J =16.9 Hz), 561600, 1 520 3.63 (1 H. d, J=16.9Hz), 4.20 (2H1, d, J=7.7Hz), 4.34 s), 5.05 (11H, d, J=5.lHz), 5.6--5.7 (1H, in), 5.63 (1H, dd, J=5:1lHz, 8.1Hz), 5.71-5.85 (2H1, 7.140(H. d, J15.81z), 8.24(2H,. 9.70 (IH, d, J=8.1Hz) 1765, 1670, 1.87(6H, 3.18(6H1, 3.78(1H, d, J~17.5Hz), 1600, 1520 3.84(111, d, J=17.5Hz), 4.26(2H1, d, J=7.311z), 5.40(111, d, J=4.8Hz), 57 5.97 (2H, d, J=54.21z), 5.98(1H, d, J=4.811z), 6.08 (1H, dd, J=15.8Hz, M.Hz), 7.03(111, d, J=15.8Hz) 2 T7~ I -qp- apl t, 4 *46 *6* 4 6 J 4 66. *r S p 4 6 C CC C C P 4 6 6 Example Infrared absorption spectrum; N MR Spectrum Na. (cm-1, Nujol) 1765, 1665, 1 (DMSO-d 6 Y) 1.46 (3H, J=6.6Hz), 2.64 (3H, d. J4.8Hz), 3.04 (3H, s), 1600, 152 5 3.08 (3H, 3.50 (1H, d, J=17.OHz), 3.65 (1H, i, J=17OHz), 4.0-4.2,(2H, m), 58 4.25-4-35 5.08 (1H, d, 5.66 (1H, cd, J=5.OHz, 5.7- 5.8 (111, 5.78 (2H, d, J55.OHz), 7.17 (1H, d, J15.4Hz), 8.22 9.13 (1H, brs), 9.73 (1H, d, 1765, 1670, (DMSO-d,) 1.44(3O, d, J=7.0Hz), 2.65 (3H, d, J=4.51z), 3.00(311, s), 1600, 15 25 3.06(3H, 3.50(1H, d, J=17.OHz), 3.68 (1H, d, J=17.OHz), 3.9-4.0(1H, m), 59 4.3-4.5 (2H, 5.11 (1H, c, J=4.8Hz), 5.65->5.80 (211, m), 5.78 (2H, d, J=55.OHz), 7.26(1H, d, J=15.4Hz), 8.21 (2H, s), 9.71 (1H, d, J=8.OHz), 9.79(1 brs) 1760, 1670, (DMSO-d,) 2.77(21, 3.03(611, 3.48(111, d, J=16.9Hz), 95, 15 15 3.66(11. d, J=16.9Hz), '4.10 (21, 4.26 (1H, d. J=7.7Hz), 5.08 (1H, d, J=4.8Hz), 5.66 (1H, dd, J=4.8Hz, 8.4Hz), 5.76(1, n), 5.79 (2H, d, J=55.OHz), 7.14(1, 7.20 0H, d, J=158Hz), 7.82 (2H, s), 8.22(2 H, 8.27 (1H, 9.72(1H, d, J=8.4Hz) "El I Ir~~ L I r

S.

S S S S S S S C S *S *SS* S S S S *55 S S S S S *5 55 5 N M R Spectrum a~

.CM-

1 Nujol) 1765. 1675, (DMSO-d,) 2.77 2 H. Wn, 3.02 (38. 3.03 (3H, 3.49 (11H, d, J 16.9 Hz), 1595, 15'25 3.62 (1 H. d. J=16.9 Hz), 4.10 (2 H, mn), 4.32 (18H. d. J=7.7 Hz), 5.09 (18H, d. J=5.1 Hz), 5.66 (18H, dd, J=5.1 Hz. 8.1 Hz), 5.75 (18H. m), 5.79 (2H, d, J=56.8Hz), 7.16 (1H, d. J=15.OHz), 7.18 (1 H, 7.71 (18H, s), 7.83(18. 8.22 (2H. 8.33(1H, 9.72(1H, d, J=8.lHz) 1765, 1680, 1590, 1525 (DMSO-d,) 3.07 (3H, 3.14 (3H. 3.47 (1H, d, J=16.98z), 3.67 (1H, d, J=16.9Hz), 3.86 dd, J=5.9z, 12.1Hz), 4.01 (18, t, J=5.9Hz), 4.08 (18, dd. J=5.9Hz, 12.1Hz), 4.18 (2H, mn), 5.07(18, d, -J=5.1Hz), 5.67(18, dd, J=5.lHz. 8.1Hz), 5.76(18, in), 5.78 d, J=55.2Hz), 7.13 (18H. d, J=15.8Hz), .776(18H, 8.22 (2H, 8.33 (18H, S), 9.70 (18, d, J=8.lHz) (DMSO-d 6 3.17 3.18 (38, 3.47 (118, d, T=17.OHz), 3.67 (18H. d, J =17.0Hz) 3.85 3.95 (18H. in), 3.95 -4.10 (28H, in), 4.10 -4.25 (28H, mn), 4.35--4.45 (18H, mn), 4.75 -4.85 (18H, in), 5.08 (18H, d, J =4.8 Hz), 5.67 (18H. dd, J=4.88Hz, 8 .0 Hz), 5.70 -5.85 (18H, in), 5.79 (2H, d, J=55z), 7.05 d. J=15Hz), 8.21 (2H. 9.31 (1H. brs), 9.71 (1H, d, J=8.oHz)

'I-

I-

spctu N M RC Spectrum* *C (CM* 1, S (DS*a 3.0 (6 H. s) 3. 3 -5C (2 HM,346( .d 69H) 9.7 (1re Hu.j= .1Hz 175,160, (DMSO-d 8 3.01 O6H, d, 3=.2Hz)3. (21 O, 3.46 304 d, Js),9z) 1600, 1525 3.224(12H, d J16.1z), 3.846 brs), 3d6 .Oz) 64 5.06 (2H,1 bd, 5.0. (1H, 5.(111, dJ=.Hz. .1z) 56 578(75 716(111, J55.8z), .2 s),8H) .2 2H 9.71 (111, d, J=8.1 Hz) 1765, 1 660, (DMSO-d,) 1.11 (311 d. J=6.2z), 3.01 (OH. 3.04 (3H, s), 1600, 1525 3.22 (2H, brd, J=7.OHz), 3.46(1OH, d, J=17.OHz), 3.65 (1H. d, J=~17.0Hz), 4.06 (2H. brd. 4.26(1OH, brs), 5.065(1H, d, 5.6-575 (211. 5.79 (2H. brd, J=55.311z), 7.16(1H. d. J=15.811z), 8.27 (2H1, s), 9.71 (111. d, J=8.1 Hz) *00 00. 6% 9 Examl

NC

Infrared absorption spectrum N M R Spectrum (6) 1765, 1670, (DMSO-d 8 1.32 (31H, d, J =6.6 Hz), 2.93 (3 H. 2.98 (3H, s), 1600, 1530 3.4 -3.5 (1 H, mn), 3.46 (1 H. d, J =17.0 Hz), 3.64 (11H. d, J=17.OHz), 3.65-3.85(2H. mn), 4.04 (2H. d, J=7.3Hz). 5.06(111. d, 5.6-5.8 (2H, mn), 5.79(2H., d. J=55.OHz), 7.18(111. d. J=15.811z), '8.23 (2H1. s), 9.70 (1H, d, J=8.OHz) 1765. 1670, (DMSO-d,) 1.32(3OH, d, J=6.611z), 2.93(3OH, 2.96 (3 H. s), 1600, 1525 3.4 -3.5 01H, in), 3.45 (1 H. d. J17.2 Hz), 3.65(11H, d, J 17.2 Hz) 3.7 -3.8 (211. Mn), 4.07 (2 H. in), 5.06 (11H. d, J =5.0 Hz), 5.6 -5.75 (2 H. mn), 5.78 (2H1, d. J=55.OHz), 7.16 (1H1, d, J=15.8Hz), 8.24 (2H, s), 9.70 (1H. d. J=8.411z) 1760. 1660, (DMSO-d 8 1.36 (6H1 2.88 (6H1, 3.47 (1H. d, J=17.011z), 1595, 1520 3.63 (11H, d, J=17.OHz), 3.70 (2H1, 4.00 d, J=7.311z), 5.06 (11H. d, J=5.0OHz), 5.64 (11H, dd. J=5.0Hz, 8.4 Hz), 5.65 -5.75 (111H.in), 5.79 (211, brd, J=55.OHz), 7.14 (1 H. d, =15.4Hz), 8.22 (211, s), 9.70 (11H. d. J=8.4 Hz) 71 Li U a S S S Example Infrared absorption Na spectrum N M R Spectrum a (CM'1, Nujol) 1760, 1670, (DMSO-d,) 3.12 O61, 3.91 (6H, 3.49 (1H1, d, J=17.211z), 1595, 1525 3.67(1OH, d, J=t7.2Hz), 4.35 (2H, in), 5.08 (1H, d, 5.66 (1H, dd, J=5.lHz, 8.Hz), 5.7- 6.0 (1Hrn), 5.79 (2H1, d, 7.09 (111, d, J=158Hz), 8.21 (211, 9.71 (OH, d, J=8.4Hz) 1750, 16 60, (D 2 0) 3.16 (6H, 3.62 (2H1, 3.68 (3H1, 3.81 (2H1, 4.15 (2H1, m), 71 15 590 5.19 (1H, d, J=5.5Hz), 5.76 (211, d, J=60.011z), 5.78 (1H, d, 5.90 (11H, mn), 6.84 (11H, d, J=17.0Hz) 1750, 1 660, (DMSO-d 6 3.15 (3H, 3.21 (3H, 3.47 (lE, d, J=17.2Hz), 1580 3.68(11, d, J=17.2Hz), 3.77(11, d,J=14.311z), 3.93(11, d,J=14.3Hz), 72 4.12(211,mi), 5.08 (1H.d, J4.81z), 5.68 (1H, dd, J=4.811z, 8.1Hz), 5.75 (1H,mi), 5.79 (211, d, J=55.3 Hz), 7.03 (1H1, d, J=15.81z), 8.21 (211, s), 9.72 (1H1, d, J=8.41z), 11.4(1OH, brs) f *ee 0. 0 0 *0

.P

EmpeInfrared absorption spectrum Nuol NMR Spectrum 1750, 165 0. (DMSO-d.) 3-1A(3H, 3.15 O3H, 3.48 (OH, d, !=16.9Hz), 1580 3.66 (1 H. d, J=16.9Hz), 3.71 (2H, d, J=5.9Hz), 4.08 (2H, in), 4.15 (2H, in), 73 5.07 (11H. d, J=5.1 Hz), 5.67 (IH, dd, J=5.1Hz, 8.1 Hz), 5.70 0IH, mn), 5.78 (2H1, d, J =53.8 Hz), 7.07 (11H, 7.15 (1 H. d. J =15.8 Hz). 7.54 (1 H, 8.21 (211, 9.15 (iH. brs), 9.71 (1H, d, J=8.lHz) 1 760, 1 6 50, (DMSO-d,) 3.10 (311, 3.1 3.7 (8 H, in), 3.22 (3 H. 3.41 (0 H, d. J 17.2 Hz), 1620, 1590, 3.67 (1H, d, J1l7.2Hz), 4.06 (2H. in), 4.35 (2H, d. J='6.2Hz), 74 1520 5.05 (1 H. d, J=5.Hz), 5.6-:5.9 (1H, in), 5.66 (18, dd. J=-5.iHz. 8.Hz), 5.78 (2H1, d, J=55.311z), 6.92 (1H1, d, J=15.811z), 8.20 (2H1, s), 9.78 (11H, d, J =8.4 Hz), 1580, 1520 3.48 (111, d, J=16.9 Hz), 3.64 (1 H. d, J=16.9 Hz), 4.00 (2 H. s), 5.66 (1 H. dd, J=5.1Hz, 8. 1Hz), 5.78 (2 H, d. J =55.3 Hz), 7. 10 (1iH, d. J=15 .4 Hz), 8.22 (2H, 8.96(11H, d, J=5.1Hz), 9.71 (18H, d, J=8.1 Hz)

U

S

C

S S

S

S S CSS

S

055 *S* S S C *5 5 Example rcatrared absorptionNMR Spcrm (8) Na Nujoil) 1750, 1650, (DMSO-d,) 3.06 (6 H, 3.14 -3.48 (2 H, mn), 3.19 (31H, 3.22 (31H, s), 701590, 15 10 3.66 -3.75 (41H, mn), 4.09 (2 H, in), 4.11 -4.30 (211, mn), 5.07 (11H, d, J=48 Hz), 5.67 (1H, dd, J=4.8Hz, 8.1Hz), 5.71-5.77 (1H, mn), 5.79 (2H1, d, J=55.OHz), 7.19 (1H, d, J=15.411z), 8.23 (2H1, 9.73(1OH, d, J=8.lHz) 1 750, 16 660, (DMSO-d,,) 1.98 (2H1, brs), 2.57 (6H, 2.72 (2H1, brs), 3-.0H, s), 1580 3.11 (3H, 3.20 (2H1, 3.54(1OH, d, J=17.6Hz), 3.82 (11, d, J=17Sifz), 77 4.03 (2H, mn), 5.15 (11, d, J=4.8Hz), 5.78 (OH, dd, J=4.8Hz, 8.1Hz), 5.79 (2H1, d, J=54.11z), 5.91 (111, in), 7.09 (1H, d, J=15.4Hz), 8.22 (2H, s), 9.72 (1H1, d, J=8.lHz) 1750, 1660, (DMSO-d,) 2.48 (6H1, 2.60 (-I11, in), 3.07(3OH, 3.08(311, S), 1580 3.24 (2 H, in), 3.54 and 3.59jo t al 1-'1H, c, J=17.6Hz), 3.82 and 3.88 (jota I, 1H,dJl17.6Hz), 4.15 (2H, in), 4.38(111, mn), 78 5.17 and 5.18 (to tal.' JH, d, J=4.8Hz), 5.79 (111, mn), 5.79 (2H1, d, J=57.1 Hz), 6.00(11H, Wn, 7.0)3 and 7.07 (t o taL 'I1, di, J =15.8 Hz), 8.22 (21H, s), 9.74 and 9-77( total. 11H, d, J .4 26

-J

-J

'.0

H

L

29

N

I, a a a a a a a a .a* a a a a a a. a a a 4 Example Infrared absorption Na spectrum N M R Spectrum (6) Na (Cijr, Nujol) 1750, 1650, (DMSO-d,) 3.5 0 d, J =16.9 Hz) 3.68 (1 H, d, J =16.9KHz), 1 580, 15 1 0 4.45--511 (14H, in), 5.07 (1H, d, 5.63-5.71 O1H, mn), 79 5.65 (1K, dd, J=5.1Hz, 8.1Hz), 5.78 (2H, d, J=58.3Hz), 7.17 J=15.8Hz), 8.27 (2H, 9.72 (1KH, d, J=8.1Hz) 3.69 3.74 (2H, mn), 5.13 (2H, d, J=4.8Hz), 5.37 (1H, d, J=4.8Hz), 5.96 (1H, d, J=4.8Kz), 5.96 (2H, d, J=54.2Hz), 6.18 (1 H, in), 6.92 (1 H, d, J -15.8 Hz), 7.54 -7.56(01H, in), 7.63 -7.661KH, in), 7.87 7.89 (2 H, m) 1750, 1 650, (DMSO-d,) 2.41 (3H, 3.02 (2H, t, J=5.5Hz), 3.42 (1K, d, J=17Hz), 811580, 15 10 3.52 (1H, d, J=17Kz), 3.62-3-66 (2H, mn), 5.03 (1K, d, J=4.8Hz), 5.21 (2K, d, J=5.lHz), 5.63 (1H, dd, J=4.8 Hz, 8.4Hz), 5.71-5.84 (1K, mn), 6.67 (1KH, d, J=16.lHz), 8.24 (2K, 9.68 (1K, d, J=8.4Hz), 10.1 (1H, s) (DMSO-do) 3.39 (1H. d, J=16.9H&), 3.49 01H, d, J=16.9Hz), 4.2 -4.35 (2KH, mn), 5.04 (1KH, J- 5.O0 5.15 -5.40 (2 H, in), 82 5.65 (1H, dd, J=5.O~z, 8MHz), 5.75-5.90 (1H. in), 5.77 (2H, d, J=56.4Hz), 7.11 (1K, d, J=15.8Hz), 7.45 (1K, 8.0-8-15 (2H, in), 8.22 (2H, s), 8.30 (1H, 8.54 (1KH, in), 9.03 (1KH, d, J=5.5 Hz), 9.68 (1H, dI J=8.2KHz) S. S S S C

S

S. S S C S S S S Example Infrared absorption spectrum N MR Spectrum Na (cm-1, blujoi) 1760, 1670, (DMSO-d,) (10OH, n) 5.-01 (1 H, di, J=4.8Hz), 5.37 (2H, d, 1620, 15 20 5.62 (1H, dci, J=4.8Hz, 8.Hz), 5.78 (2H, ci, J=56.4Hz), 83 5.98 (1H, dt, J=4.5Hz, 16.5Hz), 6.29 (iH, di, J=16.5Hz), 8.17 (2H. di, J=7.OHz), 8.21 (2H, 9.06 (2H, ci, J=7.OHz), 9.69 (1H, d, J=8.2Hz) 1765, 16 60, (DMSO-d,) 3.30- 3.60 (8H, mn), 5.04 (1H, ci, J=4.8Hz), 5.35 (2H, d, J=6.6Hz), 1600, 15 520 5.64 (1H, cid, J=4.8Hz, 8.4Hz), 5.78 (2H, di, J=56.oHz), 5.80- -5.95 (1 H, Mn), 84 7.20 (1H, di, J=15.8Hz), 8.23 (2H. 8.46 (2H, ci, J=:6.6Hz), 9.18 (2H, d, J=6.6Hz), 9.56 (1H, t, J=5.OHz), 9.71 O1H, d, J=8.4Hz)F 1760, 1 665, (IDMSO-d, 9 3.41 (1 H, di, J =17.O0Hz), 3.48 (1 H, d, J =17 -O0Hz), 3.74 (2 H, s), 1590, 1 520 5.04 (1 H, ci, J=5.OHz), 5.30 (2H, ci, J=7.3Hz), 5.63 (1H, dci, J=5.oHz, 8.4Hz), 5.77 (2 H, di, J=54.2Hz), 5.80-5.90 O1H, 7.19 OHi, 7.24 (1H, di, J=15.8Hz), 7.82 (1 H, 8.09 (1 H, dci, J =6.2 Hz, 8. 0Hz), 8.23 (2 H, 8.46 (1 H, ci, J 8.93 (1H, di, J=6.2Hz), 8.98 O1H, 9.71 (1H, ci, J=8.4Hz) Exan

N

37

A,-

0 S S *SS S

S

S S 5 0

S

*Se S 550 S S S S S S S a S S *5 S Esamie' 6trudm abopinN M R Spectrum Na (cnr', Nujoil) 1765, 167 0, (DMSO-d 8 3.42 (I1H, d, J=16.9Hz), 3.56 (1H, d, J=16.9Hz), 4.19 (2H in), 1595, 1525 4.41 (2 H, mn), 4.98 5.04 (1H, d, J=4.8Hz), 5.18 (2H, d, J=6.6Hz), 86 5.63 (1H, dd, J=4.8Hz, 8.4Hz), 5.77 (1H, mn), 5.78 (2H, d, J=52.0Kz), 6.77 01H, d, J =2.9 Hz), 7.06 (1KH, d, J =15.8 Hz), 8 .21 (2 H, s), 8.48 01H, d, J=2.9Hz), 9.69 (1KH, d, J=8.4Hz)

(D

2 0) 2.93 (3H, 3.26 (6H, 3.6-3.9 (6H, in), 4.22 (2H, d, J=7.3Hz), 87 5.40 (OH, d, J=4.8Hz), 5.97 (2H, d, J=54.2Hz), 5.98 (1H, d, J=4.8Kz), 6.00 -6.15-(1 H, in), 7.07 (1KH, d, J=15.4 Hz) 1750, 1650, (DMSO-d,) 3.02, 3.04, 3.06 and' 3.08 .total 16H, 3.20--3.50 (6H, mn), 1590, 15 25 3.61 -and 3.70(.totaU 1K, d,.J=16.9Hz), 4.06'-4.13(3H, mn), 5.05'-575(1H, and 5.07(total 1H, d, J=4.8Hz), 88 5.65 (1H, dd. J=4.8Hz, 8.1Hz), 5.78 (2H, d, J=55.3Hz), 7.09'and 7.14(totai- 1H, d, J=15.8Hz), 8.21 (2H, s), 9.71 and 9.74(t otal 1H, d, J=8.4Kz) Examp Na 4C -7 Pr-

S

S S S V .55 5 S 5 5 S S S. S S Example I Na Infrared absorption spe'ctrum (cml1, Nujo].] 1755, 1650, 1590, 15 25 N M R Spectrum a (DMSO-d 6 a) 4.03 (1 H, mn) 5.63 (1 H, dd, 8.21 (2H, s), 1.75 01H. in), 2.51 (1 H, in), 3.04 (3 H, 3.2 -3.9 (7 H), 4.19 (1H. in) 4.46 (1 H, s) 5.0 5 (1 H, d, J =4.8 Hz) 5.6 -5.8 (1 H, in), J=4.SHz, 8.1Hz)., 5.78 (2H, d, J=58.6Hz), 7.15 J=15.8Hz), 9.69 (1 H, d, J=8.1Hz) 1xap 43 1755, 1650, (DMSO-de) 1.80 (1H, in), 2.60 (1H. mn), 3.03(3H, 3.48 (1H, d, J=16.9Hz), 90, 1525 3.62 (1H, d, J=16.9Hz), 3.65-4-00 (6H, in), 4.16(OH, mn), 4.46 (1H, s), 5.07 (1H, d, J=5.lHz), 5.6-5.8 (1H, mn), 5.65 (1H, dcl, J=5.lHz, 8.1Hz), 5.78 (2H, d, J=57.5Hz),, 7.17 (1H, d, J=15.8Hz), 8.22 (2H, s), 9.70 (1 H, d, J =8.1Hz) 1760, 1650, 1590, 153 0 (DMSO-d,) 1.71 (2H. brs), 1.97 (2H, brs), 2.94 and 2.96 (total -3H, 3.1-3.5 (6H, in), 3.61 and 3.62(totai 1H, d. J=17.2Hz), 3.77(1H, brs), 4.02 (2H,mi), 5.04 and 5.05(totati1H, d, J =17.2 Hz), 5.6 -5.8 (1 H, m) 5.63 (lH, dcl, J=5.lHz, 8.4Hz), 5.79 (1H, d, J=58.6Hz), 7.19 and 7.20 tot a 1H, d, J=15.4Hz), 8.24 (2Hi.- 9.69 OHi d, J=8.4Hz) 1

-I-

0-

L

0. 0 0. 0. Example Infrared absorption NQ ujoliN M R Spectrum (8) -1 760, 16 50, (DMSO-d,) 1.72 (2H, brs), 1.99 (2H. brs), 3.2-3.8 (8H, mn), 3.84 O3H. m), 911590, 15 30 4.10 (2H. in), 5.05 and 5.06totai 1H, d, J=4.BHz), 5.6--5.8 (iH. mn), 5.64 (i1R, dd. J =4.8 Hz. 8.1 Hz) 5.78 2H. d, J =55. 1Hz), 7.18 J =14.3 Hz) 8.21 (2 H. 9.69 (1lH. d, J=8.1Hz) 1760, 1665, (DMSO-d 8 3.15 (3 H. 3.20 O3H, 3.47 (IH, d, J= 16.9 Hz), 1590. 1520 3.66 (OH, d. J=16.9Hz), 4.05-4.25 (4H. mn), 4.45-4.55(OH. in), 92 4.60-4.70 (IH, in), 5.06 (1H, d, J=4.8Hz), 5.66 (iN, dd, J=4.8Hz, S. 1Hz), 5.7-5.8 0iH. mn), 5.78 (2H, d. J=54.0.Hz), 7.09 d. J=15-4 Hz), 8.22 (2 H, s) %0 ~9.20 01H. brs), 9-71 (1IN, d, J=8.1Hz) 1760, 1 660, (DMSO-d.) 2.61 (2 H, in), 2.96 O3R, 2.97 (3 H, 3.3 -3.6 (2 H, mn), 1595 3.45 (1 H. d, J=16.9Hz), 3.68 (1iN, d. J=16.9Hz, 3.96 (2H, d, J=7.3Hz), 93 5.07 (1iN. d, J=4.8Hz), 5.8 (1 H. 5.65 01H, dd, J=4.8Hz. 8.1 Hz), 5.78 (2H, d. J=58.3Hz), 7.08 (iH, 7.18 (1H. d. J=15.8Hz), 7.82 (1H, s), 8.21 (2 H. 9.70 (iNH, d, J=8.1Hz) 7

C

a a a

C

a a a S C a 0 9 S 0 a C S C. C C C 9 C CC C

I.

Example No.

Infrared absorption spec~dtrum (CMr', Nujo2l) N M R Spectrum 1760, 1660, (DMSO-db) 2.08 (2 H, 2.98 (3 H. 3.2 -3.8 (1OH. mn), 4.09 (2 H, in), 1590, 1520 5 .07 (1 H, d, J=4.8Hz), 5.6-5.9 (1H, in), 5.65 (1H, dd, J=4.SHz, 8.1Hz), 94 5.79 (2H, d, J=55.3Hz), '6.05 (2H, 7.19 O1H, d, J=15.8Hz), 8.21," (2H, s), 9.70 (1 H, d, J =8.1Hz) 1760, 1660, (DMSO-d,) 3.02 O3H, 3.04 (3H, 3.45 (1H, d, J=17.2Hz), 1595, 1520 3.67 (1 H, d, J=17.2Hz),. 3.7 -4.0 (4 H, mn), 4.15 (2 H, in), 5.07 (1 H. d, J =5.1lHz), 5.65--80 (1H, mn), 5.66 (1H, dd, J=5.lHz, 8.1Hz), 5.79 (2H, d, 7.15 (1H, d, J=15.8Hz), 8.21 (2H, 9.70 O1H, d, J=8.4Hz) 17 60, 1665, (DMSO-d,) 1.24 (6H, t, J=7.oHz), 3.2-3.6 (6H, mn), 3.68 (1H, d, J=17.2Hz), 1595, 1520 3.90 (2H, 4.09 (2H, mn), 5.07 (1H, d, J=4.8Hz), 5.6-5.8 (2H, in), 96 5.79 (2H, d, J=58.6Hz), 7.16 (1H, d, J=16.OHz), 7.69 (1H, 8.08 (1H, s), 8.21 (2H. 9.70 (2H, d, J=8.lHz) 1 76 0, 1 6 60, (DMSO-d,) 2.5 2.7 (2 H, mn), 2.57 (3 H, d, J=4.4 Hz), 2.97 (3 H, s), 971600 2.98 (3H, 3.2-3.6 (2H, mn), 3.45 (1H, d, J=16.5Hz), 3.71 (1H, d, J=16.5Hz), 3.97 (2H, 5.08 (1H, d, J=5.lHz), 5.65-5.80 (2H, in), 5.78 (2H, d, 7.19 (1H, d, J=154Hz), 8.21 (2H, 8.42 O1H. brs), -9.72 O1H, d, J=8.4Hz)

S

S a* C S S St S C S C 5 4 S S 5. 5 Example Infrared absorption specdtrum N M R Spectrum NCa Nujol) 1 1760, 1660, (DMSO-d,) 2.84 (311:' 2.87 (21H, in), 2.97 (61H, 3.02 (3 H, 3.46 (2 H, mn), 1600 3.46 (11H, di, J=17.2Hz), 3.65 (11H,.Cd, J=17.211z), 3.99 (211, d, J=7.311z), 98 5.07 (11H, d, J 8 Hz), 5.6 -5.8 (1 H, n) 5.64(11H. dd, J =4.8 Hz, 8.4 Hz) 5.78 (2H1, d, J=58.6Hz), 7.19 (111, d, J=1541z), 8.21 (211, s), 9.70 (111, d, J =8.4 Hz) 1760, 1660, (DIVSO-d 6 2.99 (6H1, 3.32 (3H, 3.47 (2H1, brs), 3.48(111, d, J=17.2Hz), 95, 1525 3.65 (11H, d, J=17.211z), 3.76 (2-H1, brs), 4.02 (211, d, J=7.11z), 99 5.07 (11H, d, J=5.lHz), 5.6-5.7 (1H, in), 5.65(111, dci, J=5.lHz, 8.4Hz), 5.79 (211, d, J=55.71z), 7.17(111, di, J=15.4Hz), 8.21 (211, s), 9.71 (11H, d, J =8.4 Hz) 1760, 1670, (DMSO-d,) 1.20(311, di, J=6.21z), 3.06(3OH, 3.22(3OH, 1590, 1520 3.48 (111, di, J=:17.OHz), 3.61 (111. d, J=17.OHz), 3.95 (111, d, J=9.21z), 100 4.15- 4.45(3OH, mn), 5.07(111, di, J=4.g11z), 5.66 (111, dci, J=4.8Hz, 8.4Hz), 5.79 (211, d, J=55.OHz), .5.8-5.9 (1H, in), 7.01 (111, di, J=15.411z), 7.83 (1H1, 8.21 (211, 8.71 O1H, 9.71 (1H1, d, J=8.4Hz) ls&du N M R Spectrum 16 0 159 5.0 0 5. (1H M) 5.6 (1H .d z H .78 (2H. da J=86H) 6.0 (2H S) 7.1 (1H d, J,8.2(H 9N7 (1r' Hujol)~z 1760, 1650, (DMO-d§ 2.10 (6H, 3.3073 (1 in5.), .84.5 1630 150 4.06 (21H, J=5.lHz), 4.605. (1K s, 5n 1 .5 (1H, dd.8H) J5.97z 8.1H,dJ5.H 102~ 5.78 (2 .d dt, J58.6Hz), 6.04 7.17 (1H, d, J=15.8Hz),8.2(Hs) (1KH, d, J81.Hz),79 H CJ2Sz 1760, 1 660, (1DMS0)o 3.12-3. (1K3 (1d, J5.z), 3.85 J=.Hz), 1,1590 4.11 (1H, d, J.lHz, .60H 5.40 (1K. d, T3H48z), 5.05.9 ),56H 102 5.98 (2H, d) .OC, J4.1 (1K, d, J7.57 z, 15.4.Hz), .66 7, (1H mK), 7.04-8(15 d2, .3(KJ28z 1750, 1660, (DMO-d 3.436 (2K 3n), 5. d,7 (1.Hzd, 5=.0 d 1620, 1590 3.64 (1K, d, J=7.lHz, .Hz)2, 5.7)2K 4 d,2H) n) 103 3.40 (1H, d, J17.OHz), .94 (2H, s, J=4.4 5.9 6.0-6.1 (1H, in), 7.03 (1K, d, J=15.7Kz) 2' a..

a. a a a a a a a.

a a a a a a a a

S

a. a a Example Infrared absorption -a NO. (CM-1 Nujol) N R Setu 1760, 1660, (D 2 0) 3.19 (3H, 3.30 (3H, 3.32 (3H, 3.80 (1H, d. J=17.2Hz), 1590 3.86 (1H1, d, J=17.2Hz), 3.98 4.3-4.4 (2H, mn), 5.39 (1H, d, 105 5.97 (2H1, d, J=54.2Hz), 5.98 (1H, d, J=5.lHz), 6.0'-6.1 (1H, mn), 7.04 (1H, d, J15.4Rz) 1760, 1650, (D 2 0) 3.06 (6H1, 3.75 (1H1, d, J=17.2Hz), 3.83 (1H, d, J=17.2Hz), 1590 4.05 (2H1, 4, J=7.3Hz), 4.47 (2H1, 5.38 (1H, 4, J=4.8Hz), 5.95 (2H1, d, J=62.21z), 106 i 5.95 (1H1, d, J=4.8Hz), 6.07 O1H, dt, J=73Hz, 15.8Hz), 7.02 (1H1, d, J=15.8Hz), 7.55 (1 H, 7.92 (11H, s)

(D

2 0O) 3.7- 3.9 (611, mn), 4.15- 4.25 (4H1, mn), 4.43 (211, d, J=7.31z), 107 5.38 (1H1, d, J=4.7Hz), 5.95 (11K, 4, J=54.2Hz), 5.97(1OH, d, J=4.7Hz), 6.1 (11, in), 7.06 (1H, 4, J=15.71z) 1765, 1 670, (DMSO-d,) 3.27 (211, brs),- 3.42 (1K, d, J=17.OHz), 3.48 (1K, C1, J=17.oHz), 1630, 1 525 3-56(211, brs), 3.65 (2H, brs), 3.69 (211, brs), 5.04 (1K, 4, J=4.8K4z)., 108 5.33 (211, d, 5.63 (1K, 44, J=8.41z, 4.8Hz), 5.78 (2H, d, J=55.31z), 5.85-5-95 O1H, in), 7.21 (1H, d, J=1581z), 8.20 (2K. d, .J=6.6Kz), 8.22 (2H1. s), 9.14 (2H, d, J=6.6Hz), 9.70 (1H, d, J=8.4Hz) Exa 63 q. ai* 4, It

S

S

S **S S S S S S S. S S* S S S S *5 S S Exampile Infrared absorption sp'c trum N MR Spectrum Na (CM-1' Nujo2l) 1760, 1660, (D 2 0O) 3.75 (21, 4.20 (2 H, 5.01l(2 H, 5.35 -5.45 (3 H, in), 109 1 610, 1575, 5.96 (2H, d, J=54.6Hz), .5.97 (1H. d. J=4.8Hz), 6.20 (1H, dt, J=15.-8Hz, 7.5Hz), 2 0 7.03 (1 H, d, J=15.8Hz), 8.14 (2H, d, J=6.2Hz), 8.88 (2H, d, J=6.2Hz) 1760, 1660, (DMSO-d,) 3.44 (1H, d, J=16.9Hz), 3.53 (111, d, J=16.9Hz), 3.89 (2H, s), 16 1 5, 1 590 5.07 (1 H, d. J=4.8Hz), 5.12 (2H, brd, J=6.0Hz), 5.68 (1H, dd, J=4.8Hz, 8.Hz), 110 5.78 (2H, d, J=55.7Hz), 5.92 (1H, dt, J=15.8Hz, 6.0Hz), 7.03 (1H, d, J=15.8Hz), 7.35 O1H, brs), 7.85 (2H, d, J=7.OHz), 8.22 (2H, 8.60 (2H, d, 0 9.73 (1H, d, J=8.4Hz) (DMSO-d,-- D, 0) 2.66 (2H, t, J=7.OHz), 3.08 (2H, t, J=7.OHz), 3.40 O1H, d, J=17.OHz), 3.48 OHi, d, J=17.0OHz), 5.00 O1H, d, 111 5.18 (2H, d, J=7.OHz), 5.63 (OH, d, J=5.0Hz), 5.75 (2H, d, J=55.7Hz), 5.88 (1H, dd, J=7.OHz, 16.0Hz), 7.10 (1H, d, J=16.oHz), 7.59 (2H, d. J=6.6Hz), 8.81 (2H, d, J=6.6Hz) -17 60, 165 5, (DMSO-d,) 2.01 (4H, brs), 3.1- 3.9 (8H, in), 4-25- 4.4 (2H. mn), 112 16 10, 152 0 5.10 01H, d, J=4.8Hz), 5.7-5.9 (2H, in), 5.79 (2H, d, J=55.oHz) 4 7.04 (l H, d, J=15.7Hz), 7.39 (1H, brs), 8.22 (2H, 9.74 (1H, d, FExanp 64P CD 66 2T m 4 4 4 4 4 4 4 4 4 444 4 4 4 4 4 4 4* 4 4 *4 4 4 4 4 *4 4 Example* Infrared absorption specdtrum N MR Spectrum Na (cm-1, Nujol) 1760, 1655, (DMSO-d,) 3.41 (1H, d, J=169Hz), 3.48 (1H, d, J=16.911z), 3.59 (2H1, s), 1575 5.04 (OH, d, J=5.lHz), 5.28 (2H, brs), 5.63 (1H1, brs), 5.78 (2H1, d, J=55.7Hz), 113 5.8- 5.95 O1H, in), 7.17 O1H, d, J=16.0Hz), 8.02 (1H1, dd, J=6.211z, 7.7Hz), 8.22 (21H, 8.42 (11H, d, J=7.7 Hz), 8.83 (11H, d, J=6.2 Hz), 8.96 (1 H, s), 9.72 (11H, brs) 1770, 1 690, (DMSO-d, 8 3.14 (3H, 3.15 (3H, 3.48 (OH, d, J=16.8iHz), 1630, 1600 3.66 (1H1, d, J1l6.8Hz), 4.03 (1H, d, J=15.5Hz), 4.06 (1H, d. J=15.5Hz), 114 4.17 (2H1, brd, J=7.711z), 5.07 (1H1. d, J=4.8Hz), 5.65 (1H1, dd, J=4.8Hz, 5.70 (1H1, dt, J=7.7Hz, 15.4Hz), 7.17 (1H1, d, J=15.4Hz), 7.22 (1H1, t, J=70.5Hz), 7.64 (1H1, 8.29 (31, 9.83 (111, d, J=8.OHz) (3)20) 3.75 (2H1. 5.39 (1H1, d, J=4.711z), 5.44 (2H1, d, J=8.oHz), 115 5.97 (1H, d, J=4.7Hz), 6.21 O11, dt, J=8.1z, 15.0Hz), 7.07(1OH, d, 7.09(1OH, t, J=70.0Hz), 8.37 (2H1, d, J=6.71z), 9.01 (211, d, J=6.71z) 1770, 1675, (DMSO-d,) 2.95-3-05 (6H, in), 3.20--30 (611, in), 3.46 (1H1, d, J=17.oHz), 1630, 1 605 3.62(1OH, d, J=17.OHz), 3.92 (2H1, d, J=7.31z), 5.07(1OH, d, 116 5.50--70 (2H, in), 7.17 (1H1, d, J=15.8Hz), 7.22 (1H, t, J=70.7H1z), (2H1, 9-83 (1H, J=7.9Hz) 1~ :00 Example Irared absorption specztrum N NMR Spectrum8) 1770, 167 5, (DMSO-d.) 3.40- 3.50 (7 H, in), 3.70 (11H, ci, J 18.2 Hz), 3.85 (6 H, brs),- 1605 4.10- 4.25 (2H, in), 5.08.(1H, d, J=5.Hz), 5.66 (11, cid, J=5.Hz, 8.Hz), 11775 (111 dt, J=78SH 15.8Hz), 7.19 (111 d, J15.81z), 7.22 (111, t, J=70.711z):- (2H1, 9.83 (11, d, J=8.41z) Experiment 7 (Synthesis of Raw Material Compound): p,-methoxybenzyl 73- 2-(5-tritylamino-1,2,4-thiadiazol- 3-yl)-(Z)-2-(2,2,2-trifluoroethyl)oxyiminoacetdmido)- 3- (Z)-3-chloro-1-propen-l-ylD3-cephem-4-carboxylate: N N7C\-C-CON S NI' 2 CH9

N

OCH2 CF 3 -OCH3 A mixture solution comprising dimethylformamide (0.247 ml) and tetrahydrofuran (3 ml) was cooled to -10 0

C,

Sand phosphorus oxychloride (0.297 ml) was added thereto and S stirred for 40 minutes with ice-cooling. To the resulting solution was added the tetrahydrofuran solution (4 ml) of 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)- trifluoroethyl)oxyiminoacetic acid (1.36 followed by Sstirring for further one hour at the said temperature.

The resulting reaction solution was added to a mixture solution comprising p-methoxybenzyl 7B-amino-3- (Z)-3-chlorol -propen-1-yl -3-cephem-4-carboxylate hydrochloride (1.145 g), S N-(trimethylsilyl)acetamide (2.09 g) and ethyl acetate ml), with cooling at -20 0 C, followed by elevating the temperature up to 0 0 C with stirring for one hour. After ethyl acetate was added to the reaction solution, this was washed with water and dried with anhydrous sodium sulfate 101

'I

a i c~ The solvent was evaporated out and the residue was purified by silicagel column chromatography to obtain the desired product (1.43 g).

Example 118 7B- 2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido] (E)-3-(carbamoylmethyldimethylammonio)-l-propen-l-yl]-3-cephem-4-carboxylate:

S.

S

S.

*SSS

S

9O

S

The compound (500 mg) obtained in Experiment 4 was dissolved in a mixture solution comprising methanol (3 ml) and diemthylformamide (1 ml), and N,Ndimethylglycinamide (71.3 mg) was added thereto with icecooling and then stirred overnight at room temperature.

The resulting reaction solution was added to a mixture solution comprising ethyl acetate (50 ml) and ethyl ether (50 ml) and the precipitate formed was collected by filtration and dried to obtain an yellow powder (382 mg).

This powder was added to a mixture solution comprising trifluoroacetic acid (2.7 ml) and anisole (2.3 ml), followed by stirring for 2 hours with ice-cooling. The C 1 o co o

O

92 reaction solution was added to a mixture solution comprLing ethyl ether (25 ml) and isopropyl ether (25 ml), and the precipitate formed was collected by filtration and washed with ethyl ether. The thus-obtained precipitate was suspended in water (4.5 ml), followed by adjusting the pH of the Example 119 7 i- w2- (5-Amino-, 2,4-thiadiazol-3-yl) -2-fluoromethoxyiminoacetamido] (l-methyl-4-sulfamoyll-piperazinio) -propen- -yl -3-cephem-4-carboxy late: I I H NN N-SONT1 vOCH 2

F

fore wcoo- The compound (500 mg) obtained in Experiment 4 was dissolved in a mixture solution comprising methanol (3 ml) and dimethylformamide (1 ml), and Nsulfamoyl-N'-methylpiperazine (116 mg) was added thereto with ice-cooling and then stirred overnight at room temperature.

1: 106 (94 mg) Sco 00 93 The reaction solution was added to a mixture solution comprising ethyl acetate (50 ml) and ethyl ether (50 ml), and the precipitate formed was collected by filtration and dried to obtain an yellow powder (402 mg).

The powder was added to a mixture solution comprising trifluoroacetic acid (2.8 ml) and anisole (2.5 ml) and stirred for 2 hours with ice-cooling. The reaction solution was added to a mixture solution comprising ethyl ether (25 ml) and isopropyl ether (25 ml), and the precipitate formed was collected by filtration and washed with ethyl ether. The resulting precipitate was suspended in water h Sml), followed by adjusting the pH of the resulting suspension S to the range of from 5.5 to 6.5 with sodium acetate, and the insoluble substances were removed by filtration. The filtrate was purified by reversed phase-silicagel column chromatography to obtain the desired product (58 mg).

Example 120 78- \-(5-Amino-l,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido -3 [(1,3,4-oxadiazol-2yl)methyldimethylammonio) -l-propen-l-yl -3-cephem- 4-carboxylate: i CH3 H N-SC-CONH

-S

COO

CH

3 107 't r methoxyimlnoacetamido'-- 4-xdazl2 ;i s NI l 1 1 S00 i 00o oo acetate solution (1 ml) of 2-dimethylaminomethyl-1,3,4- The compound 1500 mg) obtained in Experiment 4 was dissolved in a mixture solution comprising methanol (I ml) and ethyl acetate (4.8 ml), and the ethyl acetate solution (1 ml) of 2-dimethylaminomethyl-l,3,4oxadiazole (88.8 mg) was added thereto with ice-cooling and then stirred overnight at room temperature. The resulting reaction solution was added to a mixture solution comprisihg ethyl acetate (50 ml) and ethyl ether (50 ml), and''the precipitate formed was collected by filtration and dried to obtain an yellow powder (443 mg).

a b The powder was added to a mixture solution comprising trifluoroacetic acid (3.1 ml) and anisole (2.7 ml) and stirred for 2 hours with ice-cooling. The resulting reaction solution was added to a mixture solution comprising ethyl ether (25 ml) and isopropyl ether (25 ml), and the S precipitate formed was collected by filtration and washed with ethyl ether. The thus-obtained precipitate was suspended in water (4.5 ml), followed by adjusting the pH of the resulting suspension to the range of from 5.5 to 6.5 with S, sodium acetate, and the insoluble substances were removed by L filtration. The filtrate was purified by reversed phasesilicagel column chromatography to obtain the desired product S(92 mg).

Example 121 7B- [2-(5-Amino-l,2,4-thiadiazol-3-yl)- (Z)-2-fluoro- 108 i -m I methoxyiminoacetamido-3- [(E)-3-(l-methyl-4-carbamoyl- 1-piperazinio)-l-propen-l-yl-3-cephem-4-carboxylate: N C-CONHTS CH3 H,N 5 CHzF

COO

The compound (500 mg) obtained in Experiment 4 was dissolved in a mixture solution comprising f* methanol (3 ml) and dimethylformamide (1 ml), and N-methyl- N'-carbamoylpiperazine (100 mg) was added thereto with ice-cooling and then stirred overnight at room temperature.

e The reaction solution was added to a mixture solution comprising ethyl acetate (50 ml) and ethyl ether (30 ml), and the precipitate formed was collected by filtration and dried to a obtain an yellow powder (425 mg).

The powder was added to a mixture solution comprising trifluoroacetic acid (3.0 ml) and anisole (2.6 ml) and stirred for 2 hours with ice-cooling. The reaction solution was I added to a mixture solution comprising ethyl ether (25 ml) and isopropyl ether (25 ml), and the precipitate formed was collected by filtration and washed with ethyl ether. The precipitate was suspended in water (4.5 ml), followed by adjusting the pH of the resulting suspension to the range of from 5.5 to with sodium acetate, and the insoluble substances were 109 96 i removed by filtration. The filtrate was purified by reversed phase-silicagel column chromatography to obtain the desired product (107 mg).

Example 122 7B- 2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamidoj-3- 2-dimethyl-l-pyrazolidinio) 1-propen-l-yl -3-cephe'f-4-carboxylate (Isomers: A.and B): SCH 3 COO CH, The compound (783 mg) obtained in Experiment 4 was dissolved in a mixture solution comprising methanol (1.5 ml) and ethyl acetate (7.1 ml), and the ethyl acetate solution (1.5 ml) of N,N'-dimethylpyrazolidine S a (103 mg) was added thereto with ice-cooling and then stirred *5 overnight at room temperature. The reaction solution was added to a mixture solution comprising ethyl acetate (50 ml)

S

and ethyl ether (50 ml), and the precipitate formed was collected by filtration and dried to obtain an yellow powder (631 mg). i The powder was added to a mixture solution comprising trifluoroacetic acid (4.5 ml) and anisole (3.8 ml) and stirred for 2 hours with ice-cooling. The reaction solution was 110 added to a mixture solution comprising ethyl ether (25 ml) and isopropyl ether (25 ml), and the precipitate formed was collected by filtration and washed with ethyl ether. The precipitate was suspended in water (4.5 ml), followed by adjusting the pH of the resulting suspension to the range of from 5.5 to 6.5 with sodium acetate, and the insoluble substances were removed by filtration. The filtrate was purified by reversed phase-silicagel column chromatography to obtain the desired isomer A (37 mg) and isomer B (27 mg).

Example 123 7B-[2-(5-Amino-l,2,4-thiadiazol-3-yl)-(Z)-2-fluoro- .methoxyiminoacetamido-3- (E)-3-(l-methyl-4-formimidoyl- 1-piperazinio)-l-propen-l-yl -3-cephem-4-carboxylate S hydrochloride:

HC

S. The compound (750 mg) obtained in Experiment 4 was dissolved in a mixture solution comprising methanol (4.5 ml) and dimethylformamide (1.5 ml), and Nmethyl-N'-formimidoylpiperazine hydrochloride (158 mg) was added thereto with ice-cooling and then stirred overnight at 111

-I

98 room temperature. The reaction solution was added to a mixture soluti9p comprising ethyl acetate (50 ml) and ethyl ether (30 ml), and the precipitate formed was collected by filtration and dried to obtain an yellow powder (485 mg).

The powder was added to a mixture solution comprising trifluoroacetic acid (3.4 ml) and anisole (3.0 ml) and stirred for 2 hours with ice-cooling; The reaction solution was added to a mixture solution comprising ethyl ether (25 ml) and isopropyl ether (25 ml), and the precipitate formed was collected by filtration and, washed with ethyl ether.

The precipitate was suspended in water (4.0 ml), and the insoluble substances were removed by filtration. The filtrate was purified by reversed phase-silicagel column chromatography to obtain the desired product (58 mg).

In the same manner as Examples 118 to 123, the compounds of the following Examples 124 to 140 were synthesized.

Example 124 7B [2-(5-Amino-l,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido]-3-[(E)-3-(l-methyl-l-piperazinio)-1propen-l-yl -3-cephem-4-carboxylate: *9 coo *1 CH N -C O N H S HN S, N

N.

COO

112 I LL 99 The compound (750 mg) obtained in Experiment 4 was reacted with N-methylpiperazine (116 )1l), followed by removing the protective group, to obtain the desired product (16 mg).

Example 125 7B- [2-(5--Amino--,2,4-thiadiazol-3-yl)-(Z)--2-fluotomethoxyiminoacetamido-3- 13E)-3- (4-carboxypyridinio)-, 1-pope-l-ll-3-cephem-4-carboxylate: HN 7 A CONH 6 N NSCo V.

OO

V. ~The compound (750 mg) obtained in Experiment', 4 was reacted with isonLootinic acid (198 mg) followed by r emoving the protective group, to obtain the desired product (143 mg).

Example 126 78- L2- (5-Amino-l, 2, 4-thiadiazol-3-yl) -2-fluoromethoxyiminoacetamidoj (l-methylpyrrolidinio) -1o. propen-1-yi), -3-cephem-4-carboxylate: N T\C-CONH S C 3 2 S N~

OCH

2 F0~ coo- 113 The compound (500 mg) obtained in Experiment 4 was reacted with N-methylpyrrolidine (55.8 pi), followed by removing the protective group, to obtain the desired product (21mig).

Example 127 7B- [2-(5-Amino-l,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetami'oJ [(in (4-carbamoylpyridinio)l-propen-l-y1i3-3--cephem-4-carboxylate: N-TCCONi

-S

As{ COOH

C...H

The compound (500 mg) obtained in Experiment 4 was reacted with 4 -carbamoylpyridine (131 Mg), followed by removing the protective group, to obtain the desired product (42 mg).

Example 128 7B- C2- (5-Amino-, 2,4-thiadiazo-3yl) 2fluoromethoxyiminoacetamido)-3- [SE) -3--(trimethylammonio) l-propen-l-yl] -3-cephem-4-carboxylate: NV-C-CONH, CH3

H

2 S NouF -l COOCClF 1114 The compound (500 mng) obtained in Experiment 4 was reacted with trimethylamile (whereupon trimethylamine hydrochloride (57 mg), as neutralized, was used), followed by removing the protective group, to obtain the desired product (79 mg).

Example 129 methoxyiminoacetamido}-3- (1,4-diazabicyclo- [2,2,i octan-l-io)-l-propen-l-yl]-3-cephem-4-carboxylate: Ij N-7C-CONH~

NI

The compound (500 mg) obtained in Experiment 4 was reacted with 1,4-diazabicyclo(2,2,2)octale (72 mng) followed by removing the protective group, to obtain the desired product (61 mg).

Example 130 7B- -(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido] [kE) 5-diazabicyclo p3,3, Oj1octan- 1-io)-l-propen-1-yl]-3-cephem-4-carboxyla.e: 7 CCONH

S

H2N N, N J2NNg

LOT

The compound (500 mg) obtained in Experiment, 4 was reacted with l,5-diazabicyclo C,3,0I octane (120mg), followed by removing the protective group, to obtain the desired product (32 mg).

Example 131 713- 2- (5-Amino-i, 2, 4-thiadiazol-3-yl) -2-fluoromethoxyiminoacetamidbj-3- r(E)-3-(4-methy,,th1iomorpholine- 1,1-dioxid-4-io) -l-propen--ylJ-3-cephem-4-carboxyalte:

H

2 NSNOCH,F

H

0400 The compound (250 mg) obtained in Experiment.

4- was reacted with 4-methylthiomorpholine-1,1-dioxide (52 mg) followed by removing the protective group, to obtain the desired product (17 mg).

Example 132 73-U 2-(5-Amino-l,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido3-3- [(E)-3-(1,4-dimethyl-1l-piperazinio)- I -propen-l-y 1)-3-cephem-4-carboxylate: S N, HN OCK 2 F 0 coo 4 wasThe compound (500 mg) obtained in Experiment, 4 was reacted with 1,4-dimethylpiperazine (94 Jal), followed by removing the protective group, to obtain the desired product (35 mg).

Example 133 methoxyiminoacetamidoj-3- Q7E) [k2-aminoethyl) dimethyl"amxnonio] -l-propen-l-ylJ -3-cephem-4-carboxylate: N vCN S CH 3

H

2 NSN \/AA\NH,

NOCLIFCH

3 The compound (750 mg) obtained in Experiment, *4was reacted with N,N-dimethylethylenediamine (115 pl) followed by removing- the protective group, to obtain the desired product (15 mg).

Example 134 7B-C2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoro- 3- Ctetrazol-5-yl) methylulmetAIylammonloj-1-propen-1-yij -3-cephem-4-carboxylate: C-C0NH S OH

H

2 SNS~c.

2 Y+k\ HN' HF0 H O '00CH 117 The compound (500 mg) obtained in Experiment A was reacted with (150 mg) 1 followed by removing the protective group, to~obtain the desired product (37 mg).

~t Example 135 7B-112- (5-Amiino-i, 2, 4-thiadiazol-3-yl) -(Z)-flomethoxyiminoacetamido-3- UE)-3- (3-sulfopyridinio)- 1-propen--yi i-3-cephem-4-carboxylate: N--w-C-CONH SH .0

H

2

OCH

2 F N The compound (750 mg) obtained in Experiment :4 was reacted with 3-pyridinesulfonic acid (384 mg), followed by removing the protective group, to ob)tain the de~ired product (68 mg).

Example 136 9.3 9*methoxyiminoacetamido3-3-[CE)-3-B[2-dimethylaminoethyl)diehlmmno -roe--i-3-cephem-4--carboxy late: N C-CONH I CH 3

CH

3 IN N

N

CH

3 118 The compound (500 mg) obtained in Experiment 4 was reacted with N,N,N',N'-tetramethylethylenediarine (105 Pa1), followed by removing the protective group, to obtain the desired product (22 mg).

Example 137 methoxyiminoacetamido]-3- f32-oxopropyl) dimethyLa mmonio]-l-propen-1--yl] -3-cephem-4--carboxylate:

CH

3 N \C-CONHTr S HIN OQCH 9 ,FdC The deie rdcmon (600 mgmgtie i xermn was reacted with (diimethylamino) acetone (80 Ptl), Example 138 78-[2--(5-Amino-l,2,4-thiadiazol-3-yl)-(Z)-2-fluoro-- B methoxyiminoacetamido-3- L(E)-3-(-abmyqiuldno) 0* l1-propen--y§J -3--cephem-4--carboxylate: N *-ON S

NN

-~H

2 NI SN\ N 119 il.

The compound (500 mg) obtained in Experiment 4 was reacted with 4-carbamoylquinuclidine (107.6 mg), followed by removing the protective group, to obtain the, desired product (77 mg).

Example 139 7B-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido-3- 13E) [l-methyl-2- (2-hydroxyethyl) pyrrolidinio]-l-propen-1-yJ 1- 3-cephem-4-carboxy late (Isomers: A and B): es..

*5* *9 S S *5 *5*

S

*5 *5 S S *5

S

HN-

The compound (500 mg) obtained in Experiment 4 was reacted with 1-methyl-2-(2-hydroxyethyl)pyrrolidine (83.3 mg) followed by removing the protective group, to obtain the desired isomer A (24 mg) and isomer B (26 mg).

Example 140 7B-L2-(5-Amino-1,2,4-thiadiazol.-3-yl)-(Z)-2-fluoromethoxyiminoacetamidol B(E) (4-carboxymethylpyridinio) l-propen-1-yl] -3-cephem-4-carboxylate: AN ~CQNH

E(S

N4 N

CH

2 000H H72N S NCAF0 coo 120

I

107 The compound (500 mg) obtained in Experiment.

4 was reacted with 4-pyridyl acetic acid hydrochloride (280 mg), followed by removing the protective group, to obtain the desired product (5 mg).

Example 141 7B- 2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido]-3- [(E)-3-(1,4,4-trimethyl-lpiperazinio)-l-propen-l-yl~-3-cephem-4-carboxylate iodide:

CH,

SN-C-CONH o o S N* ON

*T

4 was suspended in ethyl ether (100 ml), and the ethyl acetate solution (40 ml) of 1,4-dimethylpiperazine (189 pl) was dropwise added thereto and stirred overnight.

"OCH

The precipitate formed was collected by filtration, and this S. was further re-precipitated in tetrahydrofuran/ethyl acetate S and then washed with ethyl acetate to obtain an yellow powder (492 mg). This was dissolved in dichloromethane (2 ml), and methyl iodide (4 ml) was added thereto with ice-cooling and then stirred overnight at the same temperature. The reaction 121 solution was put into ethyl acetate, and the precipitate formed 1i 121 was collected by filtration to obtain an yellowish brown powder (190 mg).

This powder was added to a mixture solution comprising trifluoroacetic acid (1.35 ml) and anisole (1.16 ml) and stirred for 2 hours with ice-stirring. The reaction solution was added to a mixture solution comprising ethyl ether (25 ml) and isopropyl ether (25 ml), and the precipitate formed was collected by filtration and washed with ethyl ether. The resulting precipitate was suspended in water (4.5 ml), and the insoluble substances was removed by filtration. The filtrate was purified by reversed phasesilicagel column chromatography to obtain the desired product (23 mg).

Example 142 7B-C2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-(2,2,2trifluoroethyl)oxyiminoacetamidoj-3- [(E)-3-(carbamoylmethyldimethylammonio)-1-propen-l-yl -3-cephem-4carboxylate: 0 (S CH 3 /N I NC A

ONH

2 /N ,y N I.

H

2 N NOCHCFc C 3 2 3 COO The compound (1.43 g) obtained in Experiment 122 i i log 7 was dissolved in acetone (20 ml), and sodium iodide (0.927 q) was added thereto with ice-cooling and stirred for 10 minutes at the same temperature and successively for 1 hour and 30 minutes at room temperature. The solvent was evaporated out, and after ethyl acetate was added to the resulting residue, this was washed with a diluted sodium thiosulfate solution and saturated brine and then dried with sodium sulfate as added. The brine was evaporated out, and the residue was dissolved in ethyl acetate (40 ml).

Afterwards, dimethylgycinamide (237 mg) was added to the resulting solution and stirred for one hour at room temperature.

To the resulting solution was added isopropyl ether, and the precipitate formed was collected by filtration, to obtain an 6 yellowish brown powder (1 07 g) The powder was added to a mixture solution comprrsing trifluoroacetic acid (8 me) and anisole (6 m and stirred for one hour with ice-cooling. Ethyl ether was added to the resulting reaction solution, and the precipitate formed was collected by filtration. This precipitate was suspended in water (10 ml), followed by adjusting the pH of the resulting esuspension to the range of from 5.5 to 6.5 with sodium acetate, and the insoluble substances were removed by filtration. The filtrate was purified by reversed phase-silicagel column chromatography to obtain the desired product (268 mg). 123 1 MMMMMMMwwM~ j-' U U a a *a S. U a U C U U S U S S S *S U C**S at UseS S.*S 55.5 S S S S t U S U U.S a U S C U S a. a List of physical data )eri- I nfrared absorption it spectrum IN M R spectrum No. (Cm-1, Nujol) (CDC9 3 3.22 1I1, d, J=17.Olz) 3.50 (1H. d, J=17.0fHz) 3.55-3.95 (2H. mn) 3.74 311, a) 4.62 (211, q. J=8.3Hz) 5.01 1IH, d, J=4.7Hz 5.08 2H, a) 7 5.66( (11, dt, J=11.Oliz, 7.8H1z), 5.85 iN.dd, J=8.5Hz, 4.7Hz), 6.18 (1H, d,J=11.O11z), 6.61 (1H, d, J=8.511z). 6.78 (2H, d, J=8.5Hz), 7.0-7.4 (17H,mi), 7.48 H, bra)

I-

N ~7

S

SB. S

S

S

S

S

.5S 5 O*5 *SS S S S S S S S S S* S S* S S B S *5 S B Infrared absorption spectrum N M R Spectrum (cnr', Nujol) 1 7 6 0 1 6. 7 0, (DMSO-d, 3.14(31, 3.15(31,S), 3.47(11, d, JI7Hz), 3.65(111, d, J17Hz), 1 5 9 0 4.02 (211,8), 4.16 d,J=8Hz), 5.06 (11, d, J=5Hz), 5.65 (11, dd, J511z, 8Hz), 5.70 11,mi), 5.80 (211, d, J=55Hz), 7.16 H, d, J=l5Hz), 7.64 H, 8.19 8.22 (2H, 9.70 (11, d, J=81z) 1 7 6 5 1 6. 7 0 DMSO d, 3.01 3H, s 3.2-3.6 9H, mn), 3.65 (1IH, d, J=1711z), 4.12(2H1, d, J=7Hz), 1 6 0 0 5.06 (if, d, J=5H-z). 5.65 11,dd, J=5Hz, 8Hz), 5.7 (1H,mi), 5.78 (2H, d, 7.14 (2H, 7.21 (111, d, J16H1z), 8.22 (21, 9.70 H, d, J8Hz 1 7 6 0, 1 6 6 5, (DMSO-d~ 3.09(61,s), 3.48(11,d,JI17Hz), 3.67(1H,d,J71{z), 1 5 9 5 4.15 (2H, d, J=8H2-), 4.97 (211, 5.07 (11, d, J5Hz), 5.65 (11, dd, J5Hz. 8Hz), 5.70 (111;m), 5.78 (211, d, j'=35Hz), 7.22 (11, d, J=161z), 8,22 (211, 8) 9.47(111, 8), 9.71 (111, d, J=8Hz) 1 76 5, 16 50,' (DlvSO-d, .8.01 3.15-3.4 3.

4 -3.55(3H,in), 3.67( 1H,d,J=18H&), 1 5 9 0 3.7-3.8 (211,mi), 4.11 (211,mi), 5.07 (11, d, J5Hz), 5.66 11,dd, J=5HZ, 8Hz), 5.70 11. 5.78 (21, d, J=55Hz), 6.27 (211,s), 7.19 (111, 1,J=16Hz 8.20 (211, 9.70 (111, d, J=811z) 1 7 6 5, 1 6 6 0, DMSO -2.15(2H, 2.66 3.0 (2H1,im), 3.02(2H, m) 1 5 9 5 3.45 (1H, d, J=7Hz), 3.58 (111, d, J=7Hz), 3.55-.3.75 (211,mi), 4.03(111, dd, J=8z,31z), 4.19 11,dd, J=8Hz, 13Hz), 5.06 11,d, J=51{z), 5.64 11,dd,J=5Hz, 8Hz), 5.65(1H,mi), 5.78 (21, d, J55Hz), 7.19 1, d, J=16Hz), 8.21 (211,8), 9.70 11,d, J=811z) Exapl Inrae absorption a a a SpzrmN M R Spectrum 1 7 6 0, 1 6 6 5, (DMSO-d, 2.16 (211, in), 2.66 (311, 3.0 (2H1, mn), 3-.01(3H, 3.45(1H, d, J=17H.z), 1 5 9 0 3.58 (111, d, J=l7H1z), 3.6-3.8 (211, mn), 4.01 (111, dd, J=7Hz, 13Hz), 4.21(1H, dd, J=7Hz,13H1z),.

122-B 5.06 (IH1, d, J=511z), 5.64 (ill, dd, J=5H 2 8Hz), 5.65 (1H1, mn), 5.78 (2H, d, 7.19 (1H,d, J=l6Iz), 8.21 (2H, 9.69 (1H, d, J=8Hz) 1 7 6 0, 1 6 6 0, (DMSO-d, 3.12 (311,sa), 3.50 (1H,d, J=I1z), 3.55 (4H,mi), 3.72 (1H, d, JI8Hz)' 1 5 9 0 3.85-4.15 (4H, 4.20 (211,mi), 5.11 (1H,d, J=5Iz), 5.71 (IH, dd, J=5Hz, 8Hz), 123 5.79 (2H, d, J=55Hz), 5.80 (111,Mi), 7.19 (IH, d,J=l5Hz), 8.08 (11, 8.22 (2Hf,a), 9.71 (1H1, d, J=8Hz), 9.70 (1H, br) 1 7 6 5, 1 6 7 0, (DMSO d, 3.05 (3H1, 3.17 (411, in), 3.35 (411, mn), 3.60 (11H, d, J=l8H1z), ro1 6 2 5 3.95 (1H1, d, J=18Hz), 4.14 (11H, dd, J=7Hz, 13Hz), 4.21 (1H, dd, J=7Hz, 13Hz), 124 5.21 (1H1, d, J=5Hz), 5.79 (211, d, J=5Hz), 5.85 (1H1, dd, J=5Hz, 8Hz), 6.12 (111, mn), 7.07 (111, d, J=IS11z), 8.21 (211, 9.78 (111, d, J=8Hz) 1 7 6 5, 1 6 6 0, (DIVSO-4~) 3.49 (IH, d, J17f~z), 3.63 (1H, d, J=l7Hz), 5.12 (1H, d, 1 6 0 5 5.31 (2H, d,J=7Hz), 5.74 (1H, dd, J=5Hz, 8Hz), 5.78(211, 156.07 (1H, dd, J8Hz,1Hz), 7.07 (1H, d, J=16Hz), 7.20 (1H, br), 8.19 (2H, d, J=71{z), 8.20 (2H, 8.89 (211, d, J=7IHz), 9.75 (1H,d, J=8Hz) 1 7 5 5, 1 6 5 0 (DMSO-d 8 2.07 (411, br), 2.95 (3H, 3.3-3.4 3.45 (1H, d,J=17Hz), 1 5 9 0 3.61 (IH, d, J=l7Hz), 3.99 (211, d, J=71Iz), 5.06 (1H, d, J=5Hz), 5.63 (1H, dd J=5Hz, 8Hz), 126 (IH,mi), 5.78 (2H, d, J=5511z), 7.18 (11, dJ=16Hz), 8.22 (2H, 9.69 (111, d, J8HZ) .9 9 9 9~

C

99* 9 9 4* 09* 9 999 C 9 9 9 9 9 99 9 9 9 4 9 4 1 7 6 5, 1 5. 9 5, (DMSO-cb 2.99 (911, 3=1.46 d. J=17.0Kz), 3.3 1K,, 5J.0 ),J481 3.98 553(2K, d, J7.Hz), 5.05 (1K, d, J=4.OHz, 560-..5.70(K n) .8(2H, d, J=:55.3Hz), 7 .18 (1K,d, J=15.8Hz), 8.25 (2H, 9.84 (1H,d, J=68H4z),.7(HdJ85z 1 7 6 0, 1 5 9 5 (DMSO-7d) .15- .5 6K 3.6(H,d, J1.9z), 36(HdJ6.1z,3.92 (2K, dJ=7.3z), 5.05 (1K, dJ=5.IHz), 5.50--5.70(2~) (2K, 52 .79 (2H,d, J55.Kz), 7.17 (1K,sd, ),97(KdJ8O 1 7 6 0, 1 5 9 5. (DMSO-d, 2.15-.137(4H,in), 3.00.--3.15 3.20-.-3.35 (1 in), 3.44 (1H, d,J=16.9Hz), 3.54 (1K,d, J=16.9Hz), 3.60-3.82 (4K,mi), 4.08 (2H, d, J6.61kz), 130 5.05 (111, d, J5.lHz), 5.60-5.70 (2K,mi). 5.79 (2K, d,J=55.3Hz), 7.19(1K, d, J=15.8Hz), 8.24 (2H, 9.70 (111, d, 1 7 6 5, 1 6 7 0, (DMSO-d 8 3.16 (311,sa), 3.47 (1K,d, J=I7KZ), 3.65-375 (511,m), 3.80-3.90(4H,mi), 11 1 6 0 0 4.27 (ITI,dd, J=7Hz, 13Hz), 4:33 (1K,(Id, J=7z,13Hz), 5.09 (111, dJ=Hz), 5.67 (1H,dd, J=5Hz, 8Hz), 5.7-5.8 (1K,mi), 5.79 (2H, d, J55z), 7.26 (1K,d, 8.21 (2H, 9.71 (111, d, J=8Kz) Mir 0 0 0* 0 00 0 0 0 0* 0 0 0 0 0 0 .0e 0o0 *00 0* 040 0 *00 *0* 0 0 0 0 0 0 0 0. 0 *0 0 0 0 0 0 0 0 *0 0 0 Example Infrared absorption NMR Setu Ma (cm-1, Nujol) 1 7 6 5, 1 6 7 0, (DMSO d, 2.27 (311, 2.60 (2H1, in), 2.75 (2H, in), 2.97 (311, 3.3 (4H, mn), 1 5 9 5 3.45 (111, d, J=7Hz), 3.63 (1H, d, J=171Hz), 4.07 (2H1, d, J=811z), 5.05 (111, d, 132 5.64 (1H1, dd, J=5Hz, 8Hz), 5.69 (111, mn), 5.78 (2H1, d, J=55Hz), 7.20 (1H1, d, J=16Hz), 8.22 (211, 9.70 (1H, d, J=81z) 1 7 6 5, 1 6 7 0, (DMSO d, 3.27 (611, 3.65 (2H1, mn), 3.72 (211, in), 3.78 (1H1, d, J=17Hz), 1 6 0 0 3.84 (1H1, d, J=17{z), 4.22 (211, d, J=8Hz), 5.40 (111, d, J=5Hz), 5.97 (2H1, d, 133 ~~5.98 (11, d,J=5Hz), 6.09 (11, dt, J=8Hz, 16Hz), 7.07.(1H, d, J=l6Hz) 1 7 6 0, 1 6 6 5, (DMSO-d, 2.89(311, 2.90(311, 3.50(11, d,J=17Hz), 3.67(11, d, J=17Hz), 1 5 9 5 3.96 (111, d, J=7Hz), 4.61(211,sa), 5.08 (1H,d, J=SHz), 5.66 (1H, dd, J5Hi 8Hz), 134 5~~.79 (21, d, J=6Hz), 5.82 (IH, dt,J=7Hz, 15Hz), 7.20 (11, d, J=l5Hz), 8.21.(2H, s), 9.72 (1H1, d, J=8z) 1 7 6 5, 1 6 7 0, (DMSO-d 3.46(11, d, J=l7.2fz), 3.55 (111, d, J=17.2Hz), 5.09(11, d, J=4.81Hz), 1 6 2 1 5 9 0, 5.39 (21. bra), 5.70 (11, bra), 5.78 (2H, d, J=55.311z), 5.98 (11, dt, J=15.811z, 6.5H1z), 151 5 3 0, 1 2 4 0, 7.20 (111. d,J=15.81z). 8.13 (IH, dd, J=8.OHz, 6.0Hz), 8.20(2H, 8.69 (1H, d, J=8.O11z), 1 2 1 5 8.98 (11, d, J=6.0[lz), 9.24 (11, 9.73 (1H, d, 1 7 6 5, 1 6 7 0, (DMSO-dd 2.26 (6H, 2.74 (2H, 3.04 (6H,4s), 3.42(211,mi), 1 6 0 0 3.62 (11, d, J=18Hz), 3.98 (111, d, J=1811z), 4.11 (211,d, J=8Hz), 5.23 (1H1,'d. J=Hz), 1-65.79 (2H, d, J56Hz), 5.86 (111,m), 6.13 (li, dt, J8Hz, 15Hz), 7.02 (11, d, 8.21 (2H, 9.79 (IH, d, J=811z) 1S 5~ *5 5 3.3l U,=71) 45 021d,=~) 5 5 5=Hz 175.64 (1H, dd, J=51z, 8Hz), 5.68 (11, dt, J=8z, 16Hz), 5.79 (2H, d, J=551{z), 7.12 (1H, d,J=1611z), 8.22 (2H, 9.70 (11, d, J=8Hz) 1 7 6 0, 1 6 5 5, (DMSO-d 8 3.25-3.45 (1211, 3.45(11, d, J171z), 3.61 (111, d, J171z), 1 5 9 0 3.88 (21, d, J=71z), 5.06 (111, d, J=511z), 5.62 (111,min, 5.63 (11, dd,J=5Hz, 8Hz), 138 5.78 (21, d, J55Hlz), 7.11(111, 7.15 (1H,d,JI16Hz), 7.34(111, 8.23 (211, a), 9.70 (1H1, d, J8BHz) 1 7 6 0, 1 6 5 0, DMSO- 1.6-2.4 (6H, 3.00(31, 3.2-3.7 (511,mi), 3.44 (11, d, J17HIz), 1 5 9 0 -3.66 (11, d, J=I7Hz), 3.69 (211,d, J8Hz), 5.06 (11, d, J=511z), 5.64 (11, dd, J=5Hz, 8Hz), 139-A 5.67 (11,mi), 5.78 (211, d,J=55Hz), 7.18 (1H,d,J=15Hz), 8.24 (211, 9.69(11, d, J=811z) 1 7 6 0, 1 6 5 0, (DMSO-d, 1.6-2.4 (611,mi), 3.00(311, 3.2-3.7 (5H,mi), 3.46(11, d,J=17Hz), 1 5 9 0 3.63 (11, d, JI7Hz), 3.75 (2H, d, J=7Hz), 5.06 (111, d, J=5Hz), 5.64 (1H, dd, J5Hz,811z), 139-B 5.67 (111,m), 5.79 (2H, d, J5511z). 7.16 (11, d,J=16Hz), 8.21 (211,sa), 9.70 (11, d, J811z) (DMSO d, 5.02 (111, d, J=4.811z), 5.22 (211, d, J6.6l1z), 5.61 (1H, dd, J=4.811z,8.4HZ), 5.77 (2H, d, j=551LZ), 5.8-5.9-(111, in), 7.31 (1H1, d, J=15.O11z), 7.97 (2H1, d, J=6.211z), 140 8.20 (2H1, 8.86 (211, d, J=6.211z), 9.70 (111, d, J=8.41z) 9 9 9 *4 9 9 .9 t S 4 9 49 9 4* 9 9 999 0'9 S r69 49 ft. 9 9 99* Sn 9 9 9 9 9 9* t' a ft b§ a S A 9* 94 9 5. 9 9 a PaleInfrared absorption fla specNtrIA N R spectrum I 1 ~7 6 0, 1 6, 7 (DAMSO-d 4 ".09 (6H, aJ. 3.18 3.51 (11,d, J=171Hz), 3.74 (il, d, J17Hz), 1~ 59 5 3.83 br), 4,34 (211, mn), 5.12 Gil, d, J=5H2;, E6.73 (ill, 5.78 (2H1, d, 2.15.8,(MH, mn), 7.24 (Ii, d, J=15Hz), 8.21 (2H1, 9.92 (111, d, J=8Hz) I 1 7 6 2, 1 6. 8 0, t MO- 0 .0(1,s,3.3-3.7 (211,mi), 3.9-4.3 (4H,mr), 4.71 (21, q, J9.Ollz), 1 5 9 0 4.98 (111. d, Jr5.OHz), 7.13 (IHI, d, J=15.5Hz), 7.55 (111, brs), 142 8.17 (2H, brsj, 8.40 (11H,brs), 9.57 (111, d,,J=8.OHz) Example 143 7P-[2-(5-Amino-1,2,4-thia !iazol-3-yl)-(Z)-2 fluoromethoxyiminoacetamidol-3- tris(2hydroxyethyl)ammonio]-l-propen-1-yll-3-cephem-4carboxylate 'C C-CONH-,, S--C-CONH

OH

'O-CHF I OO

OH',

400 Mg of the compound prepared in the Experiment 4 was dissolved in 1 4 m) of ethyl acetate, and 96 mg of triethanolamine solution in 4 mI of ethyl acetate was added thereto. The resulting solution was stirred for 6 hours oa..

at the room temperature. To the reaction solution was added i aa 24 mH of diisopropyl ether, and the resulting precipitates were collected by filtration. This precipitates were added a" to 4.5 mi of a mixed solution containing trifluoro acetic acid and anisole under ice-cooling. The mixture was stirred for one hour and 30 minutes a.t the room temperature. To the reaction solution was added 18 mi of a diisopropyl ether. The resulting precipitates were collected by filtration, and washed with diisopropyl ether. This precipitates were suspended, iz 3 mi of water, and sodium acetate was added thereto to adjust the resulting solution to pH 6. Insolubles were removed by filtration, and the filtrate was purified by a reversed-phase silica gel column i 131 chromatography to obtain 17 mg of the objective product.

Example 144 fluoromethoxyiminoacetamidoj C(E)-3-Cbis(2hydroxyethy.)methylammonio]-l-propen-l-ylI-3cephem-.4-carboxylate NC -CONH--

O

N ii sN

N-CH

3 H2 S N 03

Q-CH

2 F coo- \OH 0 4f 43 :94 0 In the same manner as the Example 3. 500 mg of the compound prepared in the Experiemnt 14 was reac ted with 150 mg of N-methyldiethanolamine, and the protecting group was eliminated to obtain 15 m- of' the objective product.

*mow *:too

IL

ow..

132 a

J

go. a..i a *c a a.

a a.

Sao a a.r r S 0 0e S xamp Infrared absorption Etle spectrum N M R Spectrum 1 aa (Cm-1, Nujoi3 (DMSO-d,) 3.43(6H, bra), 3A7 (1H, d, J=1711z), 3.69 (11, d, J=17Hz), 384 (6H, brs), 4.16 (2H, d, J=7Hz), 5.07 d. J=5H), 5.67 (1H, dd, J=8Hz, 5H1z), 1.43 5t7-5.8 5.78 (211, brd, J=56Hz), 7.15 (111, d, J=1Hz), 8.21 (2H, s), 9.70 (1H, d, J=BHz) (D 0) 3.23 (311, 3.60- 3.70 (4H, 3.77 (1H, d, J=17.61), 1760, 1670, 144 1600 3.83(111, d, J=17.61Wz, 4.1-4.2 (41, 4.27 (2H, d, J=7AHz), H 539 d. J=4.8Hz), 5.96 d. J54.6z), 5.98 (1H, d, J=4.BH 2 _6.0-6.1 (111. 7.03 (IIH. d, J15.7Hz) i Experiment 8 (Synthesis of the raw material compound) 2-(5-Tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-cyanomethoxyiminoacetic acid N-r -COOH CHNI

N

V O-CHCN 8.00 g of N-cyanomethoxyphthalimide was suspended in ml of ethanol and 1.93 ml of hydrazine monohydride was added thereto at room temperature. The resulting mixture was stirred for 1 hour and 45 minutes. Then a saturated brine and ethyl ether were added thereto. The mixture was made basic with conc. aqueous ammonia and then extracted with ethyl ether. The ethyl ether layer was washed with a S" saturated brine solution and dried over anhydrous sodium sulfate. Subsequently the solvent was distilled off.

To the residue, 350 ml of methanol and 6,50 g of 2-(5-tritylamino-1,2,4-thidiazol-3-yl)glyoxylic acid were 0 added and the resulting mixtuire was stirred at room temperature for one hour. After distilling off the solvent, the residue was dissolved in ethyl acetate and then washed with 0.1 N hydrochloric acid followed by with a saturated brine solution. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off.

Thus 7.64 g of the objective compound was obtained.

Experiment 9 (Synthesis of the raw material compound) p-Methoxybenzyl 7P-[2-(5-tritylamino-1,2,4-thiadiazol-3- 134

L~

V..

V.

V.

V

5 yl)-(Z)-2-cyanomethoxyiminoacetamido]-3-[ (Z)-3-chloro-1 propen-1-yl] -3-cephem-4-carboxylate 0 -CO 1

SO-CHZCN

II COOCH(rr-OCH, 1.51 ml of dimethylformamide and 18 ml of tetrahydrofuran were cooled to -10 C and 1.82 ml of phosphoryl chloride was added thereto. The resulting mixture was stirred for 40 minutes under ice-cooling. Then a solution of 7.64 g of the compound of Experiment 8 in 24 ml of tetrahydrofuran was added thereto and the resulting mixture was stirred at the same temperature for additional one hour.

A solution comprising 6.00 g of p-methuxybenzyl 76amino-3-[(Z)-3-chloro-1-propen-l-yl]-3-cephem-4carboxylate hydrochloride, 12.8 g of N-trimethylsilylacetamide and 60 ml of ethyl acetate was cooled to -25 Then the above-mentioned reaction mixture was added thereto and the resulting mixture was stirred for 40 minutes while raising the temperature to 0 C. This reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated bride solution and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified with silica gel column 135 r chromatography, Thus 7.80 g of the objective compound was obtained.

Experiment 10 (Synthesis of the raw material compound) p-Methoxybenzyl 7(-[2-(5-tritYlamino-1 r2,4-thiadiazol-3yl)-(Z)-2-cyanomethoxyiminoacetamido-3-(E)-3-iodo-1 propen-1-yl]-3-cephem-4-carboxylate Y N-nF-C-CO"Tf Qc-CNOCN _CHN N

I"

COOQrFVOM3

C

*9 To a solution of. 7.80 g of the compound of Experiment 9 in 120 ml of acetone, 6.9 g of sodium iodide was added under ice-cooling. The resulting mixture was stirred for minutes and then for additional 1 hour and 30 minutes at room temperature. The solvent was distilled off and the residue was extracted with ethyl acetate. The extract was ~washed with a dilute aqueous soltuion of sodium thiosulfate 9.99 followed by with a saturated brine solution and then dried over anhydous sodium sulfate. The solution was concentrated .9 and added dropwise to a mixture of isopropyl ether and ethyl 9999$9 ether. The precipitate thus formed was filterd out to thereby give 6.50 g of the objective compound.

Example 145 7p-(2-(5-Amino-1 ,2,4-thiadiazol-3-yl)-(Z)-2-cyanomethoxy- 136 -1 -~IP -WUII~- I~FUI LI iminoacetamid o (1 S-carbamoyl-2-hydroxyethyl) dimethylammonio l-1 -propen-1 -yl ]-3-cephem-4-carboxylate N C-CON S. CH 3

H

H H I CONH 2 OCH,CN CH 3 g of the compound of Experimentl0 was dissolved in 2 ml of dimethylformamide and 210 mg of (1S-carbamoyl-2hydroxyethyl)dimethylamine was added thereto at room temperature. The resulting mixture was stirred for one hour and then diluted by adding 10 ml of ethyl acetate thereto.

The resulting solution was added dropwise to 100 ml of ethyl ether to thereby give 710 mg of a brown precipitate.

This precipitate was stirred in a mixture of 6 ml of anisole and 6.5 ml of trifluoroacetic acid under ice-cooing 00.. for one hour. Then ethyl ether was added to the reaction mixture to thereby give 430 mg of a brown precipitate. This precipitate was suspended in 10 ml of water and the pH value of the obtained suspension was adjusted to 7.0 with sodium acetate. After filtering off the ins\,luble matters, the filtrate was purified with reverse phase silica gel column chromatography to thereby give 50 mg of the objective compound.

Example 146 7 2-(5-ino-1 2,4-thiadiazol-3-yl) (Z)-2-cyanomethoxy- 137 I-~-u iminoacetamido]-3-[(E)-3-(1-methyl-2R-hydroxymethyl-4Rhydroxy-l-pyrrolidinio)-'I-propen-1-yl -3-cephem-4carboxylate

SOH

HN N g+o Nth

'O

C H

CN-

00

CH

1

OH

g of the compound of Experimentl0 was dissolved in a mixture of 10 ml of ethyl acetate and 8 ml of ethyl ether.

Then 167 mg of N-methyl-4R-hydroxy-D-prolinol was added I thereto and the resulting mixture was stirred overnight.

The reaction mixture was added to 100 ml of ethyl ether and the precipitate thus formed was filtered out to thereby give 840 mg of a yellow powder.

To this powder, 6 ml of anisole was added and 8 ml of trifluoroacetic acid was added dropwise to the resulting mixture under ice-cooling for 30 minutes. Then the mixture was stirred for additional 1 hour and 30 minutes. 100 ml of ethyl ether was added to the reaction mixture and the precipitate thus formed was filtered out and suspended in 4 S' ml of water. The pH value of the resulting suspension was adjusted to 7.0 with sodium acetate. After filtering off the insoluble matters, the filtrate was purified with reverse phase silica gel column chromatography to thereby give 24 mg of the objective compound.

138 The following compzunds of Examples 147 154 were obtained in the same manner as those deccribed in Examples 145 and 146 (compound of Experimentio) (amine corresponding to A)

I

19

I.

p *9 a p 9p** p p

I,

p p9 a

H

2

N

In a case where plural isomers were formed depending on the ammonio group Qf A, the yield of each isomer, if isolated, was given.

139 a a C *at a *aa.

a. a a. a a a a a a a a a a a a a a. a Use arnou.

Example Na nt of the startinq comDound I Yield of the objective product amine) *Compound of *Experiment

OH

147' 9 60 mg 3.0 g 3 7 g

-\OH

CHI CRs 148 -N a~aH 5 00 Mg 1.0 9 5 0 iq-<

OH

OHS

149 OH"' 0. 19 i 1-0 1 13 E9 1,mixtur I

C

CH, R (racemate) a. a S

C

C

S P

C

CS C* a C a4* La.. S. aceS Seca abe.

S C S C a P C C C ea, C C C C C Sc S. C

T

£cxample Na use amount of the starting compoun-d Yield of the objective product A~(amine Compound of I L- I 0CH,

CH,

OH

5

ONH,

11 CH

CONH,

2 50 ia9 4 3 my

H

5 C CONH, (racema te)~ 1. 0 9 2 4 xq

H

152 1_ :O 20 =9 8 0 0 z9

CHZOH

C 1 011H 153 J-Th 4r 1 47 0 2.0 3 1 CH., ONHZ

CH,

0 0- 3 2 nt 2- 0 S? 1 20 r.9 .1 list of~ Physical Data:..

5 5

S

S

S..

S S

S

S*S S 555 eSS S S 5* S S 5* SS S S Excer-. f rared absorption !men; spectrua R Setu

(CDCL

3 4.86 (2H1, 7.29 (15H., 8.10 (1H1, brs) a 5.02 (1Hi, d, J=5.OHz), 5.08 (2H1, 5.66 (1H1, dt, J=ll.31z, 7.7Hz)., 5.82 (1H1, d, J=9.011z, 5.5Hz), 6.18 (1H, d, Jz41.311z), 6.79 (2H1, d, J=8.6Hz,), 6.95 (111,cd.J=9OHz), 7.0-735 (1711.brs). '7.59(11, brs) 1 7 70, 1 7 1 5, 4.95 (111,.J=5.OHz), 5.13 (211, 5.7-6.35 (311,mi), 6.5-7.4 (20H,mi), 7.66(11, brs) 167 5, 1 605

S

C. S S

S

*S.

S

S* S S

C

S C

S

S S

C

S S

S

S. ra* S C 55 C Example Tnfrared spectrum Ca (caz.

absorptioa2 Nujol)I N M1 R Spectrum.

a f-MOd) 30 31,a,31 31 3.48 (1H1, d, J=17.OHz), 3.67 (1H1, d, J=17.OHz), I 1 7 7 0. 1 6 8 S. 3.87 (11, dd, J8.lHz, 14.3Hz) 4.05~--4.15 (2H, 4.1S-4.25 (2H, mn), 5.07 (1H1, d, J=4.8Hz), 145 1 6 Pi 0, 11 5 -3 -0 5.10 (211, 5.66 (111, dcL. J=4.81Lz, 8.1Hz)', 5.75-5,85 (11L, 7.14 (111, di, J=15.81-zj.

7.75 (111, 8.24 (2H1, t8.38 (lE, 9.73 (111, J=8.lllz) CDMSO-4a) 1.78 (111,mi), 2-55 (11, mn), 3.04 (3H. 3.47 (1H, d, J46.9H-z), 1.61 7 6 5, 1 6 6 0. 3.6-4.0 3.665(1H1, d, J16.911z), .4.18 (211, in), 4.45 (1H1, bra), 5.05 (111, 4, 1 5 9 S. 1 53 0 5.10 (2H1, 5.6-5.8k(111, 5.63 (1H, dd, J=51lHz, 8.1Hz), 7.13 'and -7.17 total 111, 4, J=159Hz), 8.24 (2H1, 9.71 a, J=8.11-z) DMSO-d,) 3.40-3.50 (711, in), 3.67 (111, d, J=17.2Hz), 3.85 (611,bra).

171 7 6 5, 1 6-7,0, 4.10--4.25 (21, 5.06 (11, 4, J=5.01z). 5.10 5.65 (11,dd, J=5.0Hz, 8.3Hz), 147G 5-75 (111, dt, J=7.0H~z, 15.8Hz), 7.14 (111, J=15.8ffz), 8.24 (211, 9.71 (111, d, J=8.3Hz) (DMSO-d,) 1.32(311,d, J=6.6Hz), 2.94 (311, 2.98 (311, 3.40-3.50 (11, i), 1t7 6 0. 1 6 6 0, 3.47(11,4 J=16.:9Hz), 3.65 (11, i, J=16.9Hz), 3.65-2-..75 (1111,mi), 3.80-3.90 (1Hm i), 1 5 93, 15 20 4.04(2H,brd,J=7.7Hz), 5.05(111,dJ=4.8Hz), 5.10(,211, 5.63 (11,dd, J=4.8Hz, 8.4Hz), 5.65-I5.75 (111, 7.18 (111,415.8Hz),, 8.26 (2H1,9), 9.71 (11, d, J=8.Hz) t Sc a S

S

a S-

P

.nr 4*

S*

S S Ce S Cr *4S P .95 SCS SAC S S S C S *5 C. SI S C S S o SC C S Example Infrared absorption spectrum NMR Spectrum Ell N% hiuoll (DMSO-) 1.11 (3H, d, J=6.2Hz), 3.01 3.04 (1H, 3.22 (7 bra), 1 7 6 5, 1 6 7 0, 3A7 (11L d, J=172Hz), 3.63 and 3.66 total 1H1, J=t7.2Hz), 4.05 (2H, bra), 1 6 0 0, 15 3 0 4.26 (1H hrsa). 5.05 (1H, d, J=4.8H), 5.10 (2H, 5.63 (1Hdd, J=4.8Hz, 8.4Hz), 5.65-5.75 (11H, 7.16 (1H, d, J15.4 Hz), 827 (2H, 9.71 (1H, J=8.4H) (DMSO-d). 1.47 (3H, d, =6.61z), 3.06 3.08 (3H, 3.49 (1H, d, .J17.OHz), 17 6 5, 1 6 7 5, 364 (lII, d, J=17.Hz), 4.0-4.2 (3H. ra), 5.06 (1H, 4, J=4.81z), 5.10 (21, a), 150 1 5 9 5, 1 5 3 0 5.65 (1H, dd, J=4.8Hz, 8.4Hz), 5.65-5.80 (111 7.16 (111, d J=15.8Hz), 7.68 (11, 8.25 (2H, 8.41 (11, 9.73 (1H, d, J=8.4Hz) C(DMSO-d,) 1.45 (3H, d, J=6.6Hz), 3.02 (3H, 3.07 (31, 3.51 (1H, d, J=16.9gz), 176 5, 168 0, 3.65 (1H, 4 J=16.9Hz), 4.0-4.1 4.35-4.45 (21, 5.08 (11, d, J=4.811-Z) 151 9 5, 153 0 5.10(2H, 5.66(11,dd,J=4.8H;, 8.1Hz), 570-.85(Hin), 7.26(1H. J=15.4Hz), 7.64(lHs), 8.24 8.5(1, 9.72(lid, J=8.lHz) DMSQ-d 8 1.95-2.10 (1H, 2.15-2.40 (1HI, 2.93 (21, 3.14 (11, a), 1 7 6 5, 1 6 6 0, 3.40-3.65 (31, 3.48 (1H, d, J=16.911z), 3.64 (1H1, d, J=16.911z), 3.65-3.90 (21, n), 152 1 6 3 0, 1 6 0 0, 3.95-4.10 (1H, 4-10-4.25 (11, 4.40 (11, bra), 5.06 (111, d, J4.8Hz), 5.10 (21, a), 9 0, 15 4 0 5.64 (1H1, 44, J-4.81z, 8.4Hz), 5.70-5.85 (1H, m), j 7.13 and 7-16 total '1H, d, J=154Hz), 8.24 (21, 9.72 (1H1, d, J=8.41z) 1k c p- ~I 1 ft~ ft ft

U

ft ft ft** *93 ft ft. ft ft ft.

ft ft .*ft ft 09 .*9 ft. a ft *ft* *ftft fts.

ft* ft ft ft ft ft ft 9 eft 1 ft ft ft, ft ft ft ft ft ft ft ft ft 99 ft ft ft Example Infrared absorption spectrumi N MR Spectrum No. (CnII,1 Nujol) (DMSO-d,) 1.20 (3H1, d, J=6.2Hz), 3.06 (3H, 3.22 (3H, 3.49 (1H1, d, J=17.2HZ), 1 7 6 0, 1 6 6 5. 3.62 (1Hi, d. J=17.21z), 3.96 (111, dl, J=9.2Hz), 4.15-4.45 (3H1, 5.07 (1H, J=5.2Hz), 153 1 5 9 0, 1 S 2 0 5.10 (21H, 5.66 (111 dd. J=5.2Hz, 8.4H-z), 5.8-5.9 (1H1, mn), 7.02 (111, d, J=15 .8Hz) 7.83 (1H, 8.24 (211, 8.71 (1H1, 9.72 (111H, d, J=8.4Hz) C DMSO-da) 2.16 (3H, 3.09 (311. 3.10 (3H1, 3.46 (1H, d, J=17.11z), 1 7 6 0, 1 6 6 3.63 (111. d, J=17.OHZ), 4.12 (211, d, J=7.3Hz), 4.51 (2H1, 5.05 (111, d, 154 1 5 0, 5 0 510 211,a),5.63 (1H, ddJ5.lHz, 8.1Hz). 5.65- 5.75 (111, 7.13 (111 d, J=15.4H) 8.26 (2H1, 9.71 (111, d, J=8.Hz) 'a- ~.2 Example 155 me thoxyiminoacetoaido-3-[E)-3-arbamfoyl me thyldimethylamnionio)-l-propen-l-ylJ 3 -caphem-4-carboxylate N--C CONH- S CR 3 I +1 N N N~CNi H2NO-CT{ 2 CN

COCF

Dime thyiglyci namide (64 rug) was added to a solution of the compound (390 mug) of Experiment 10 in ethyl acetate (15 MI), and this mixture was stirred at a room temperature for I hour.

E~thyl ether was added to the reaction solution and the produced precipitate was filtered and dried, thus providing a yellowish too brown powder (260 mg).

A mixture of toifuloroacetic ao~i' (2 mV~' and anisole m- was added to this powder and stirred for 1 hour under *a an ice-cooling condition. Ethyl ether was added to the rel',lting solution, and the produced precipitate was filtered and washed with ethyl ether. This precipitate was suspended into water, ad and pH of the suspension was adjusted to 5.5 to P* a4 a following which the insoluble material was filtered off. The filtrate was refined in a reversed phase chromatography, thus providing the desired material (37 mug), 1)46 _R4 Example 156 methoxyimnoacetoamido-3-[(E)-3-(l-methyl-4-sulfamoyll-piperazinio)-l-propen---.,il) 3-cephem-4--carboxyl ate N-a--C-CONH SCs ~'O-cH-ICN +Z soN- GCo The compound (500 mg) of Exper'imentj.0 was dissolved into a mixture of dichloromethane (5 m2O) and methanol (1 and N-sulfamoyl-N'..methylpiperazine (.145 mg) was added thereto, and the whole was stirred at a room temperature for 4 hours.

The resulting solution was concentrated, and ethyl eth~r was a. added thereto. The produced precipitate was filtered and dried, thus providing a yellowish brown powder ('450 mg).

A mixture of trifluoroacetic acid (3.5 mg) and ani~ole (3 M.2) was added to this powder; and the whole was stirred *fee for 1 hour. Ethyl ether was add~ed to the resulting solution, and the produced precipitate was filtered and washed with ethyl ether. The precipitate was suspended into water (5 mJ-) and a the pH- of the suspension was adjusted to 5.5 to 6.51 following which the insoluble material yjas filtered off. The filtrate was refined in a reversed phase chromatographyo thus providing the desired material (39 mg)., Example 157 7P-C2-(5-Amino-1,2,4 me thoxyiminace toami octane-l-io)-l-prope -thiadiazol-3-yl)-(Z)-2-cyano do]-3-[(E)-3-(1,4-diazabicyclo[2,2,2] n-1-yl) -3-cephem-4-carboxylate .9 a 99.

9* 9 999 9 9 .9

S.

9 .9 99 N- CONH----

S

H2N S O-CH CN 6

CO(T

The compound (500 mg) of Experiment 10 was dissolved into a mixture of ethylacetate (6 mi) and methanol (0.5 my), and 1,4-diazabicycloC2,2,2]octane (90 mg) was added thereto and stirred at a room temeprature for 20 minutes. Ethyl ether was added to the resulting solution, and the produced precipitate was filtered and dried, thus providing a yellowish brown powder (330 mg).

A mixture of trifluoroacetic acid (3 mf) and anisole (2.5 m) was added to this powder, and the whole uas stirred for 1 hour under a ice-cooling condition. Ethyl ether was added to the resulting solution, and the produced precipitate was filtered and washed with ethyl ether. The precipitate was suspended into water (5 mj) and the pH of the suopension was adjusted to 5.5 to 6.5, following which the insoluble material was filttered off. The filtrate was refined in a reversed phase chromatography, thus providing the desired material (4 mg).

Compounds of the following Examples 158 to 161 were provided in the same manner as in Examples 155 to 157.

148 Example 158 methoxyi-mnodtomido-3ha-(E)0-3-Y--caolyidoi-propen-1-yiJ-3-cephem-4-carboxylate HzN S~ N dN ~~CN

O-GH

2 CN Too The compound (600 mg) of Experiment 10 was reacted with 1 -carbamoylpyridine (235 mg,, and the protective group was removed to provide the desired material (37 mg).

Example 159 methoxyiminoacetoamido]-3.4(E)-3-(l,3,4-oxadiazo.-2yl )methyldimethylammonioll-1-propen -l-yl -3-cephem-4carboxylate

OH

3 N--C-CONH N 1

O--CH

2 CN CO: CHi3 The compound (600 mg) of Experiment 10 was reacted with 2-diethlamnomthyl1,34-oadizol(163 mg), and the protective group was removed 'to provide the desired material 54 mg).

149 Example 160 79[-5Aio124tidizl3Y)()2cao methoxyimiroacetoamidoj-3-[(E)-3-(1,2-dimethyl-1pi perazin io)-1 -prop en 3-cpe-4croxl (isomers-. A and B) NrG CONH-,~ s

FH

H

2 N "O-CH 2

ON+

0o Cu The compound (510 mg) of Experimerio was reacted with 12 *0 dime thylpyrazolidine (0.4l mk), and the protective group was removed to provide the desired isomer A (20 mg) and the .0::..desired isomer B (20 mg) Example 161 7p-[2-(5-Amino-1,2,LI-thiadiazol-3-Yl)-(Z)-2-cyabomethoxyiminoacetoamido-3.[(E)-3.(1,5-diazabicyelo 4. 0 3.3. Oloctane-l-.io propen--J,.y1) -3-cephem--.carboxylate 0 00 02 NI U The compound (600 mg) of Experiment 10 was reacted with l,5-.diazabioyclo[3,3,0Jootane (220 mg) and the protective group was removed to provide the desired material (39 mg).

150 ;77a S. S S a a S S S 5*5 S

S

a S a S S C S S S a S S *5 U S Example Infrared absorption Z £ecrm N spectrum NMR -pcrm Ild el Nujol) (DMSO-d.) 3-10- (611, 3.4-3.7 (211. in), 3.9-4.3 (411, mn), 155 160, 670,15905.00 (11H, d, J=5.Ollz), 5.05 (2H1.. 5.5-5.9 (2H, mn), 7.18 (111, d. J=15.3 11z), 7.56 (111 brs), 8.18 brs), 8.27 (1h1, brs), 9.61 (1H1. d. J=8.311Z) (DMSO-do) 3.00 (311, 3.2-3.7 (1011, in), 3.95-4.25 (2H. in), 156 765,15985.00 (2H1, d, J=4.711z), 5.05 (2H1, 5.45-5.8 (211, in), 7.09 (211, brs), 7.15 (1 H. d, J=15.11z), 8.18 brs), 9.60 (1H1, d, J=8.21-1z) (DMSO-d.) 2.75-3.3 (12H1, 2.35-3.75 (211, 3.75-4.1 (211, mn), 157 1765, 1598 4.§9 (11H, d. J=4.8H-z), 5.05 (211, 5.35-5.8 (211. mn), 7.10 (11, d, J=15.51fz), 8.20 (211. brs), 9.62 (11-1 d, J=8.3Hz) (DMSO-do) 3.2-3.4 (211, in), 4.99 (1H, d, J=5.oHz), 5.10 (21, 8), 158 760 160, 5955.15-5.45 (2H, mn), 5.5-6.05 (2H, mn), 7.20 d. J=15.5 Hz), 8.19(3OH, brs), 9.63 (11, d. J=8.OHz)

I

0 0e aC 0 S *A.

cc 0e s C 0 0 C

SO*

C C .e C Oc 0060 0-C 0666 SO C CC r. C 6 CC U CCC S. 0 0 0O C 6 0 9 r a v Example] Infrared absortion spectrum N M R spectrum (a) No (cm-l. Nujol) (DMSO-de) 3.06-(11. 3.35-3.65 (2H. 4.15 (2H. bra), 4-99 (1H, d. J=5.211z), 5-05 (21. 5.4-5.85 (2H, 7.15 (1H, d, J=157H), 8.18 (2H, brs), 9.36 9.61 (1H. d, J=8.01z) (DMSO-do) 1.95-2.35 (211. 2.63 3.00 (3H, a), 160-A 1765, 1595 2.85-3-75 (611, 3.85-4.35 (211. 4.98(1. d J=5.1Hz), 5.04 (2H. a).

5.25-5.75(2H, 7.13 (IHd, J=15.5Hz) 8.18(2, brs), 9.60 (1H, d. J=8.OHz) (DMSO-d) 1-95-2.35 (211, im), 2.63 (3H. 3.00 3, 2.9-3.75 m), 3.85-4.35 (2H, 4.98 (111, d, J=5.0Hz), 5.04 5.3-5.75 (2H1 n), 16-B 1760-, 1590 7.13 (iH, d. J=15.511z), 8.19 tirs), 9.60 d, J=8.Hz) (DMSO-da) 2.1-2.45 (411. 2.9-3.9 (101, 3.95-4.2 (2H, m), 5-04(1OH. d. J=5.OHz), 5.10 (211. 5.5-5.8 (2H, 7.21 (1H, d, J=16.OHz), 161 1765, 1600 8.30 bra), 9.70 (111, d, J=8.0 z) c E- C~ i Experiment 11 (Synthesis of the raw material compound) methoxyiminoacetyl chloride hydrocblorid-, ,N HC1 Phosphorous pentachlor-tde (395 mg) was dissolved In dichlorornethane (2.9 rn9) and to aof to -5 C. To the solution was dde -th copoun (67 mg ofqw-4+4- 2,and agitated for 2 andhal hors t 'he ametemperature as described above. The and -oca-n (94 m) .Theresultiniu crystalline substance was colectd b f 1-ta in, ndwashed with n-octane to obtain the obijective product (325 mg).

0 .*Melting point: 139 140 0 C (decomposition) Mass spectrumi (mle): M+ 480 9 A,482 37

CA)

o. Infrared absorption spectrum (cm" NuJol): 1795, 1780, 1740, 1630 NMR spectrum DMSO-d 6 5.79(2H, d, J=54Hz), 7.31(15H, s), 10.09(IH, s) ii 133 Kd Experiment 12 (Synthesis of the raw material compound) 2-(5-AmIno-1,2,4-thiad iazol-3-yl)-(Z)-2-fluoromethoxyiminoacetic acid ethyl ester N T C C COOCzHs N OCIiF The compound (2,00 g) of Experiment 1 was agitated in trifluoroacetic acid at room temperature for 30 mIInutes. The solvent was dLftilIed offI and the residue was purified by s osilica gel column chromatography to obtain tho objective product (405 mg).

Meltlnc point: 172 173 0

C

InfPared absorption spectrum (cm 1 NuJol): 1730, 1615 NMR spectrum DNSQ-d 6 1.28(311, t, J 7. H) 4.34(21, q, J=7,l-1z), 5.83(2H, d, J=545Hz) 8,27 (2H, brs) Experiment 13 (Synthesis of the raw material compound) 2-(5-Amino-l,2,4-thiadiazol-3-yl )-(Z)-2uooehx.

iminoacetic acid N- COGH

H

2 Nk NN

N~OCH.:F

The compound (200 mg) of Experiment 12 was suspended in mixture of ethanol (6 mA) and water (2 mA), IN aqueous sodium hydroxide solution (1,75 mSA) was added -thereto, and stirred at Cfor 1 hour. Ethanol was distilled off from the reaction j solution, and the solution was adjusted to pH- 2 with the use ui IN hydrochloric acid. The resulting solution was purified by ::~.means of "Dia-lon SF207' (trade mark for noniooic adsorption resin manufactured by Mitsubishi Chemical Industriest Ltd.) to :...obtain the objective product 30 mg).- Infrared absorption spectrum (cm ,NuJol)': 1720, 1620 '.NMR spectrum DMSO-d 6 5474(2H, d, J= 55 Hz), 8.24(2H-, br) Experiment 14 (Synthesis of the raw material compound) P-Methoxybenzyl 72-C2-(5-tritylamino-i ,2,4-thiadiazol-3- Yl)-(Z)-2-fluorc;r-!-ethoxyiminoacetamidoJ-3-~CZ)-3-.chloro- Propen -1-yJ -3-cephem-4-carboxylate 0 N-TC-CONH--7 HN S- N 0 ~COOCH

OCH

3 fo To a, miXtUre of ethyl acetate (37 rA), tetrahydrofuran mg), and dichloromethane (15.7 mAJ Were added N-I trimethylsilyl)acetamide (8.17 g)-and p-methoXYbenyl 7M-aiino-s- CZ)- 3-hoQ1poe-I-jI--ehm4croy t hydrochloride (3.33 g) to dissolve the latter materials. The solution was Cooled to -20QC, then the com~pound of 4*omp4-e i2( ,80 g) was added thereto, and agitated at too C for I hour. After~ the addition of ethyl acetate (500 m9Q.) to the reaction~ solutton, the *mixture was washed successively with water#, a saturated aqueous sodium bicarbonate solution, IN hydr'ochloric acid, and a saturated brine solution, and then anhydrous magnesium sulfate was added ther'eto to dry the same, The solvent was distilled of f, and the ro Idue wjas pur If Ied by sIcI a gel col umn chromatography to obtain the objective product (4.33 g) The infrared absorption spectrum and the NIMR spectrum of 'the resulttnt product coinicided with those of Experiment 3, 1 6 Experiment 15 (Synthesis of the raw material comqor<'I 2-Cyano-2-fluoromethoxyiminoacetamide NC C CONHI 2I

N

'OCH

2

F

2-~Cyano-2-hydroxyiminoacetamide (22.6 g) was dissovled ii dimethyl sulfoxide (100 ml), and then potassium carbonate (55,2 g) was added thereto with stirring at room temperature, and the sol~ution was further stirred for additional 20 minutes Fluorobromomethane (27 g) dissolved in dime thylf ormamide (20 ml) was then added to the solution, and the solution was stirred for 20 hours at room temperature and then allowed to cool. The

J'

1 ;*:~reaction solution was added to Iced water (1 liter)) and extracte!d *:~twice with ethyl acetate (150 ml), The organic layer was washed twice with a saturated brine, and dried with addition of anhyctroiis magnesium sulfate, followed by distilling off the solvent, The reiu was washed with ethyl ether, and dried to obtain the 'c'objective product (14,4 q), Melting point: 124 125 0 c, ft 9 Infrared absoprtion spectrum (cm- 1 Nujol): 3410, 329O, 3150, 1690~ 1590 NMR spctrum L. M$0-d) 5M4 MZ, d, JTh54.Q liz) 7.85 -9.40 b) 157 Experiment 16 (Synthesis of the raw material compound) 2-Fluoromethoxyiminopropanedinitrile

NC-C-GN

II

N

d -OCH 2

F

A mixture containing the compound (14.0 g) prepared in Experiment 15, acetonitrile (15 ml), sodium chloride (15 g) and phosphoryl chloride (14 ml) was reacted under reflux for 2 hours, To the mixture was added phospho'yl chloride (5 ml}, and the whole was reacted for 2 hours. The reaction solution was, aftrr cooling, added to iced water (200 ml) and stirred at room temperature for e one hour. The solution was extracted twice with methylene chloride (50 ml). The extract was washed with 5% aqueous solution of sodium bicarbonate, and with a saturated brine, and then drid with addition of anhydrous magnesium sulfate. The solvent was distilled off. The resulting oily product was subjected to distillation Under reduced pressure to obtain a colorless oily objective product (9.1 g).

Boiling point: 69 70°C/25 mmHg NMR spectrum CDCI 1 5.85 (2H, J=52.0 Hz) 1 Be

S

t 145 i i; Experiment 17 (Synthesis of the raw material compound) 2-Cyano-2-fluoromethoxy..iinoacetamidine

H

2

N

C C-CN

HN

N

OCH

2

F

A mixed solution containing 28% aqueous ammonia (50 ml), ammonium chloride (8 g) and ethanol (50 ml) was cooled to and the compound (9.1 g) prepared in Experiment 16 was added thereto with stirring, and Lnen further stirred at the s me temperature for additional 3 hours. Water (100 ml) was added to the reaction solution. The solution was extracted thrice Swith methylene chloride (50 ml). After drying the extract with addition of anhydrous magnesium sulfate, the solvent was distilled off, The residue was washed with ethyl ether and dried to obtain the obejctive product (3.4 g).

A portion of the product was dissolved in ethanol, and 0 glacial acetic acid was dropped thereto with stirring. The resultant precipitates were recovered by filtration and washed Swith ethanol, followed by drying to obtain an acetate of the subject compound. The following data of physical properties are those of the acetate.

Melting point: 125 127 0

C

Infrared absorption tpectrum (cm Nujol); 3200, 1670, 1570 NMR spectrum DMSO-d 6 1.90 (3H, 5.95 (2H, d, J=54.0 Hz), 7.40 (3H, b) -59 I i Experiment 18 (Synthesis of the raw material compound) 2-(5-Amino-l,2,4-thiadiazol-3-yl)-(E)-2-fluorometoxyiminoacetonitrilq N- C CN N N

H

2 N S OCH2F The compound (3.0 g) prepared in Experiment 17 was dissolved in methanol (50 ml), and triethylamine (4.2 g) was added thereto, After cooling the solution to -5 0 C, bromine (3.5 g) was dropped to the solution. A solution of potassium thiocyanate (2.1 g) in methanol was then dropped thereto at a temperature from -3 °C to -5 0 C, and the solution was stirred at the same temperature :for 2 hours. The resulting precipitates were recovered by filtration and washed with water and with methanol. The precipitates were then recrystallized from acetone to obtain the objective product (3.4 g).

Melting point: 236 238 0

C.

Infrared absorption spectrum (cm Nujol) 3450, 3250, 3075, 1610, 1520 NMR spectrum DMSO-d 6 6,02 (2H, d, J=54.0 Hz), 8.32 (2H,b) *160 160 Experiment 19 (Synthesis of the raw material compound) 2-(5-Amino-l,2,4-thiadiazol-3-yl)-(- Z)-2fluoromethoxyiminoacetamdde

N

N-I- C CONH2

H

2 N S/

OCH

2

F

To a solution of sodium hydroxide (0.23 g) in water (18 ml) was added 35% aqueous hydrogen peroxide (7.4 ml). And, the compound g) prepared in Experiment 18 was added thereto with stirring at room temperature. The solution was further stirred at a temperature from 25QC to 300C for additional 8 hours. The *6 precipitates deposited were recovered by filtration, and washed with water and with acetone, followed by drying to obtain the

S

c. objective product (1.3 g).

Melting point: 210 21l 0

C.

-1 Infrared absorption spectrum (cm Nujol): *3450, 3260, 3180, 1690, 1610

S.

MNR spectrum DMSO-d 6 .5.73 (2H, d, J=55.0 Hz), 7.69 (2H, br), 7.98 (1H, br), 8.10 1H, br) 161 Experiment 2- (5-Amino-1,2, 4-thiadiazo'L-3-yl)- fluoromethoxyi'minoacetic acid N COOH N N Sz I-IOCH 2

F

H

2

N

A mixture containing the compound (1.1 g) prepared in Experiment 19 and 2N aqueous sodium hydroxide solution (10 ml) was stirred at 50 0 C for 5 hours. The reaction mixture was cooled, and adjusted to pH 1.0 with concentrated hydrochloric acid, *-ollowed by extraction thrice with ethyl acetate (20 ml). After *Iddition of anhydrous magnesium sulfate to the extract, followed bdryinogthe solvent was ditilled off. The residue was washed with isopropyl ether to obtain a crude product (0.8 The crude product was purified by reversed phase silica gel column -hromatography to obtain the objective product (0.4 g) The infrared absorption spectrum and NMR spectrum were identical with those of Experiment 13.

162 Example 162 (Preparation of an injection) The compound (10 g) prepared in Example 1 was dissolved in distilled water (50' ml). The solution was divided and infused, so that the respective vial may contain 5 ml of the solution.

This solution was lyophilized to give an injection.

Example 163 (Preparation of an injection) The compound (10 g) prepared in Example 151 was dissolved in distilled water (50 ml). The solution was divided and infused, so as to contain 5 ml per one vial. This solution was lyophilized S to give an injection.

*49 The acute toxicity and the anti-bacterial activity of the compounds according to this invention were determined as follows: l Acute toxicity in mouse: The compounds according to this invention dissolved in a physiological saline solution were intravenously dosed to five ICR male 6 weeks-old mouse. As the result, the values of acute toxicity of the compounds prepared in the following Examples were all in excess of 2g/kg, Example Numbers: 1, 2-1, 2-2, 3-1, 3-2, 5, 6-1, 6-2, 7-1, 7-2, 9-1, 9-2, 9-3, 10, 11, 12, 13-1, 13-2, 96, 121, I 137, 145, 146, 15.0, 151, 154 and 155 Anti-bacterial activity (MIC): MIC (Ayg/ml) were determined by an agar dilution method (Chemotherapy (Japan), 29, 76 79, 19811. Overnight cultures of the bacterial strains in Mueller-Hinton broth were diluted to 163 i ;1 final concentration of about 106CFU/ml, and 5 A1l of each bacterial suspension was spotted onto Mueller-Hinton agar plates that contained twofold serial dilutions of antibiotics. MICs were measured after incubation for 18 hours at 37 0

C.

As the controls, CAZ (Cefatazidime) and CTM (Cefotiam) were selected.

*9 9 4.6 9.

9 4 *9* PS 9 *00* 0* 4. 4.

0 *99 .9 *4 @94 *4 44 *4 a 44.4 4 04*9*9 0 4. 4 4 S *4 *4 4 0 164

H

I to o: .0 0 t to* too* S List of anti-bacterial activity S*SS *S SSS* 5.55 SSS* S S S S S S

S

S S 55 *5 rn~-ftAS4~ 'bacterium Trest compoufli Example 1 2-1 2-2 3 -1 3-2.

4 MA L C C uig aL I T Staph. aureus 9-P 0.2 0-4 0.4 0.2 0-2 0.4 0.2 Escher .coli NI EU Kleb pneumofliae EK-6 Sermarcescens ES-75 M~organella morgaflii EP-14 Pseud aerugifosa EP- 01 Example Na 155 156 I 0.025 0.05 0-025 S0.025 0-025 0.05 ;5 0-025 0-025 0.05 ;S 0.025 iK 0-025 :0-025 ;S 0.025 ;K 0-025 0.1 0.05 K0.025 0.05 0.1 0.1 Kg 0.025 0.025 0.05 0-025 0.025 !i 0-025 0.05 0-025 0.8 1.56 1.56 0.8 1.56 0.8 0.8 I 158

IN

I.

S SOS S 55 S S S S S S S S S S S S a *SS *5 **SS S S S S S 0.

S -I S S bactern~ m c C ft Lni Test- Staph,aureus Escher-coli Kleb- Ser- Morganella Pseud.

pneumofliae .marcescens morqanii aerugiflosa Trest 20- I-JEK-6 ES-75 EP-14 EP-01 FExample 6-1 6-2 7-1 7-2 9-2 9-3 0.2 0.1 0.2 0.2 0.2 0.4 0A4 0.4 0.05 :70-025 0-025 0.025 0.025 0-025 0.025 0.025 0-025 S0.025 0-025 0-025 S0,025 0.025 0-025 0-025 0.025 0.025 0-025 0.025 0-025 0.025 0.025 0-02 5 0.025 0-025 0.025 0.025 0.025 0-025 0.02 5 0.025 0.8 0.8 0.8 0.8 0-8 0.8 0.8 0.8 J a *a*a a. a. a a a. S a a a a a a a a a a a a S 555 5 a a. a a a a. a *55 a a S a a a a a a a S S a a a a a a. .55 a a a a. a. a 0 NL r S S..

S. S Sb S. S S S S S S S S S S S S S S S S S S 555 5 5 5 S S S S S S S S S C S S S S 55 555 5 5 0 a S. S S S S S S S S S S C C 55 S *SC* .55 S 0 aTet 1 M I cg Staohaureus Eschercoli Keb- Ser- organella Pseudpneumfofllae mnarcescens morganji aerugiflosa 209P IH EK-6 ES-75 EP-14 -EP-01 Compound Example 24 26 27 28 29 31 32 0.2 0.2 0-4 0.4 0A4 0-4 0-4 0-2 ;9 0.-025 0.

0.05 0.05 0-025 0.05 0.05 0,025 0-025 0.1 0-025 0.05 ~0-025 0.05 0-025 0,025 0-025 0A4 0.1 0.2, 0.1 0,2 0.1 0.05 0-025 0.1 0.05 0.05 0.025 0.05 0-025 0.025 1.56 0.8 1.56 1-56 0.8 1-56 1-56 1.56 S. SS *S 5r 5r 5rl 5 S* Si 55 555 5 S Test bacterma~n Tes r ccAmpourd Zxample 36 37 39 42 43 M I g nL Staph-aureus 209-P 0A 0.2 0.2 0,2 0-2 0.4 0.2 0.2 _I .1 I Escher-coli

NIHJ

0,05 0,05 0.05 0.025 0.025 Kleb.

pneumonlae £K-6 Ser, .marcescens ES-75 morganella morganii EP-14 Pseud.

aerugiOSa

EP-O

4- i 0,025 0.025 0-025 0.05 0 025 0.025 0.05 s 0-025 0-1 0.1 0.1 0-2 0.1 0 025 0M025 0025 0.05 0-05 0-05 0.1 0.05 0-025 0.025 0-025 0-8 1.56 1.56 1-56 1.56 0-8 1.56 0.8 L. .3

A

S. e .3 3 .3.3 .5 33* S. S S 55 55 3 3 S 3 3 5 S S S 3 3 3 3 3 6 5 635 5 5 S 3 3 S .35 S S S S S S S 3 3 S 53 3 5 3S 53 C Test bacterim.

Test ccaipcundt Ex amp' e 44 53 56 57 M I C jg -ML Staph .aureus -r r Zscher-.coli

NIHJ

pneutuoflae Ser.marcesc ens ES-75 Lmorganella xnorganlii EP -14 Pseud aerugiflosa EP-01 t 1 t 0.:05 S0-025 0-05 0.05 0.05 0~ 0.02 5 0-05 0,05 5Z0.0125 0-025 0.05 0-05 0.05 0.05 0.1 0.1 0-2 0.05 0M 0. 025 0.1 ,0-2 0.05 0-025 0-05 0.l05 0.05 0.025 0.05 0-025 1-56 0-8 1-56 J-.56 0.8 0.4 1-56 0.8 S S S 555 55 *S*5 4S 50 S S 55 5 5 5 S S S S 5 5 S S S S 555 5 S S S S S S S S *SS S S S S S S S S S S S S S *S S S St 55 5 5 k

S

I

S S S .5 54.S *9R@ 5* *O 55 46 S S S S S S S S S S S S S S S 555 5 5* S S S S S S S S S S SeQ S S S S S 555 5 5* 5.5 S S 55 5 5

F-

'0

N'

f~ a tqa a. a a a. .a a a a p a a a a. a a *0 a a a a a a asas sea. a a S a a a a U a p a a a a a. p a 0 bacterium TEest compoudI'n Excample 77 78 81 82 83 84 M I C ,xg niL Staph. aureus 209-P Esch er -coli NI E-J i 0-4 0)-A 0.4 0-2 0.4 0.8 0-4 0.2 0.05 0.2 0,2 ;E 0. 02 5 S0.025 0.05 0-05 0-025 Klebpneumofllae EK- 6 0.05 0-2 0.2 0-025 0.025 0.025 0-025 0,025 Ser.

marcescens ES-75 morganella morganji EP-14 0.2 0-2 0.2 0-025 0.05 0.1 0.1 0.025 Pseud.

aerugilosa.

I EP-01 0.05 0.4 0.2 :0.025 0.025 0.025 0.05 0.025 1.56 3.13 3.13 J.56 1.56 3-13 1.56 1.56 1~ a ate at a S. .5 tO S a. S S 5 4 5 5 5 S S C C a a S 4S* a a C S S a a S S s~t S S S C a *5 555 a a t a. a a 'bactermum Trest cmound M I C oig niL Example 88 89- 1 89-2 91 92 93 94 Staphaureus Escher.coli 209-P NIH-J 0.2 ;9 0.025 0.2 9 0.025 0.2 0,025 0,2 0.05 0-2 0-05 0-2 ;5 0-025 0.2 0.025 0.2 0,025 KietDpnelflofiae E K- 6 rnarcescens ES-75 Morganella morgaflii EP-14 Ser.

Pseud aeru-glOs I EP-01 ;5 0-025 0-025 0.025 0.025 0.025 0.025 0-025 0.025 0-025 0.025 0.025 0.025 5 0-.02 5 0.025 0-025 0. 02 5 0 002 5 0.025 0.025 0.05 ;5 0.025 0-025 ;5 0-025 0.025 0.8 0.8 0.8 0.8 ~56 0.8 0.8 0.8 r 0 bacterium S S C Staph-aures Escher-olx Kleb- Ser- Morganella S *eud5 pne'imoniae -Marcescens Imrai aeruginosa, 209-P 1~ H Testt, E:K-6 ES-75 EP-14 EP-01 ompoundu Example 0-2 005 -025 0.025 0 025 0.8 96S 0.2 O S 025 0.025 0. 0*25 0 02 50.8 97u 0.2 I0-025<0-025 0-02C5 0-025 0.8 98 20-4 0 -05 K-0.05 4 .05 0.025 E3.13 ri a a. *.aa S S S a C S a C CS C C S S 059 a S 0 9 C a S C C 550 S S *5 S Test bacteriumM 1 C(g/n pneumoniae .marcescens Mrael s1ds 209-P NI14J E- S7 P Test EK6E-5E-4EP-01 Example 103 0A 1 0-025 0-025 0.025 0.025 3.13 106 0.4 0.025 0.05 0.1 0.05 3.13 107 0.2 0.05 0.02 0.05 0.025 1.56 080-4 0.05 ;25 0-025 0.1 0.05 31 114 0.2 0-05 0.025 0.05 0.025 0.8 115 0.8 0-025 L 0-025 0.05 0-025 3.13 116 0,2 0-025 0.025 0.025 0.025 1.56 117 0-4 0.05 0-05 0.2 0.025 1.56

I'

a a a a a a a a a -4 Tet bacterium 1 Test compound Example 118 119 120 121 122-A 12 2-B 123 124 125 126 127 128 129 M I C j4g MI Ser.

Stapht aureus 209-P Escher .coli

NIH-J

Kleb.

pneumlofliae EK-6 marcescens ES-75 .Morganella morganii EP-14 Pseud aerugiflosa EP -01 -t 1 t 0.2 0.2 0-.2 0.-2 0..2 0. 1 0-4 0.2 0.4 0. 1 0. 1 0-2 0.2 0. 02 5 :0.02 5 0-025 0.025 0.025 0.02,5 0.0 5 0.0 5 0.025 ;5 0.025 0.025 0-0 5 0-02 5 0. 0 2 5 0-025 0.02 5 0.025 0.02 5 0-025 0.0 5 0.0 25 0-025 0-025 :0.02 5 0.0 5 :0.02 5 0. 1 0.0 5 0.0 5 0. 1 0.025 0.0 5 0.-2 0. 1 0.025 0.0 5 0.0 5 0. 1 0.0 5 10 02 5 0: 002 5 0 2 5 0.025 0.0 25 0.02 5 0.05 0.05 0.02 5 0-025 0.025 0.05 0-025 0. 4 0.-8 0-8 0.-8 0.-8 0. 8 1.56 0.-8 1.56 0. 8 0. 8 0. 8 0.-8 I I i I L 4, S. S S S S S S S S S S

*.S

S S 55.. aS.. S S C S S S S S S S S S *5 5. Test bacterium M I C(~/L Staph.aureus Escher-cli Kleb. Ser. ognlaPed Testo ia marc sceJ morgan i aeruginosa Te t2 59-P NI J K-6 ES-75 EP-14EP 0 compondi 0.02 143 144 0.05 0.925 0-025 005 0.025

V-;

IL a a a a a. a. rr r r rr r rrr r r rr r r r r r r rr rr r r

L

Test "acterium Test compoif Example 145 146 147 148 149 150 151 152 1P3 154 M I C up mt Staph-aureus 209-P Escher-coli

NIHJ

Klebpneumoniae EK-6.

Ser- .marcesCens ES- '5 Morganella morganii EP-14 Pseud.

aeruginosa

EP-O

1 -t 0.4 0.4 0.2 0-4 0-2 04 0.4 0.2 0.4 0-4 0. 2 0. 1 0.1 0. 1 0. 1 0-2 0.1 0. 1 0.2 0.1 0. 1 0.05 0.05 0.05 0.05 0.1 0. 05 0. C 5 0. 1 0. 1 0. 1 0-0,5 0. 2 0. 0 5 0-0 5 0. 1 0. 0 5 0 05 0.1 0. 1 0.1 0-05 0. 05 0. 1 0. 05 0-1 0.0 5 0 05 0. 1 0.1 1. 56 1. 56 1.56 1-56 1- 56 1.56 1. 56 1. 56 1.56 0. 8 L _I t S *O 55 5 5 5 S S S S S S S 5 5 5 5 4 S S S S S S S S S S S S 555 S S S S S S S *5S 555 5 5 55 5*

I

01 Test bacteriumI-i

-M

Staph-aureus Escher-coli Kieb- Ser. Morgane2lla Pseudpneumofliae mar-cescens rnorganii aeruginosa Test 209-P N114J EK-6 ES-75 EP-14 \opournd Example 155 0-.4 0. 1 0-05 0. 2 0. 1 1.5 6 156 0-4 0. 1 0- 1 0. 1 0. 1 0. 8 157 "4 0.1 0.1 0.2 0- 1 1.5 6 020.025 ~0-0 25 0. 1 0. 1 1.5 6 1904 00 5 00 5 0. 1 0. 1 1. 56 160-A 0. 1 0-025 0. 0 25 0. 1 0. 05 0. 8 160-B 0. 1 0. 05 0. 05 0-2 0. 05 0. 8 161 0-2 0.0 5 0. 05 0. 2 0. 1 1.5 6

I

I a. a t as a.

a a p 58 S a a a C 5.5 USa p..

C S U a a so S a 5 5*a* 5, 5590 abs. *Sts *8 as a 5 5 5 t a asa a *0 U a t Us a. 5 a

I

WI

I.

3. Anti-bacterial activity (MIC): Comparison tests of the anti-bacterial activities were conducted between the compounds of the following formula according to the present invention and the corresponding control compounds wherein R 1 represents methyl group. Measurements of MIC are the same as described in the above item 2. The results are shown in the following table.

N C CONH S H 0~ CR

I

H=CHCH

2

-A

o- R coo

S

C

*CIC

SC

183 ~2X a a W~e a. a a a. a. a a a a a a a a £8 a 0** r a a a a*-a an.

S S a p 8 a 088 a S S C S a. at S C 0 M IC (A/nli bacteria Staph. Enterobacter Proteus IXantornonas aureus cloacae vulgaris rnaltophilia RIE 31106 E-74 E 08042 E 04004 CH C1 F1 56 0 05 0.05 12

-N

(Example 126)1 -CH3 (Control) 6-25 j 0.1 1-56 100 -CH 2

F

+3-13 0-025 0.025 6.25 -N 2 JExample, 127) -CR3j 6-25 0-4 3-13 (control) C Coof (Example 125) 6,25 0,4 0-2

-CR

3 12-5 3.13 12.5 (Control) CH3 ~-CHi 2 F3.301012 (Examnple 128) 31301012 -C6 25-2 0-2 6-25 >100 Cf! 3 (Control)

,L-

Claims (14)

1. A 3-propenylcephem derivative of the following formula: N -w7CCON~H y.S H 2 N-AS;) C=CCH wherein R represents a fluoro-substituted lower alkyl LI group or a cyan.susiue lower alkyl group, and A roresents a cyclic or an acylic ammonio group or a pharmaceutically acceptable salt thereof.

2. The 3 -pro ponylIcephem derivative ~.a V pharmaceutically acceptable salt thereof as claimed in b claim 1, wherein N. retpresents an acylic ammonjo group *of the following formula: R 3 inwhc;RR n ~n hih R~ 3 and are the same or different. and mean individually a group So-s selectod from the group co'nsistinrg of lower alkyl,. hydroxyl-substltuted lower alkyl, carbaraoyl-substituted lower, alkyl, cyano- substituted lower alkyl, amino, (lower alky))carbonylamino-subatituted lower alkyl, arinosulfonylaminocarbonyl -substituted lower 00 C\4 cy') 4) x alkyl, (lower alkyl)sulfonylaminocarY. nyl- substituted lower alkyl, (lower alkyl)amino- carborlyl-substituted lower alkyl, hydroxyl- and carbanoyl-substituted lowet alkyl, hydroxyl- and hydroxy(lower alkyljamino- carbonyl-substituted lower alkyl, (lower alkyloxy)axninocarbonyl-substituted lower alkyl, hydroxyami nocarbonyl- subs ti tuted lower ~1 alkyl, -Gabemy(lower alkyl)amino- carbonyl-substituted lower aj.kyl, hydroxy- (lower alkyl )arinocarbonyl-substituted lower alkyl, (lower alkyl)amino-substituted lower alky".f carboxylate (lower alkyl)di(lower o v 6 &alkyl)aminonio-substitutedAlower alkyl, (lower alkyl ami no-s ubs ti tutedA lower alkyl, (lower alkyl)amino- and hydroxyl-substituted lower alkyl, ureirlo, hydroxyl, carboxyl-substituted lower alkyl, hydroxyl- and carbamoyl- au~iue loetoko owrakyoy substituted lower alkyl, dlower alyl emino 0ecab-substituted lower alkyl, lwraklmno dcarbnyl-substituted lower alkyl, siaby-ubstitued lower alkyl,rx- substituted lower alkyl, tihydroxyl- substituted lower alkyl, brihydroxyloe alkyl )amjino-subsLtituted lower alkyl, 186 ti: i- -I amino-substituted lower alkyl, oxo-substituted lower alkyl, di-lower aikylamino-substituted lower alkyl, 5-membered heterocycle-substituted lower alkyl wherein said heterocycle stands for pyrazolyl, imidazolyl, oxadiazolyl or tetrazolyl, or A represeht a cyclic ammonio group of one of the following formulae: a. S S.. a S a *Sa S S S.. Rs R 5 R 5 -NH ~J© Rs Rs ;N a 2NA%-N> SSS a SW., 5055r a SO *I~ a S S R H N N 0 RN RR +K N in which Rmeans a group selected from lower alkyl, carbamoyl-substituted lower alkyl, amino-substituted lower alkyl, hydroxyl-substituted lower alkyl, carboxyl- substituted lower alkyl, cyano-substituted lower alkyl, dihydroxyl-subs~ttuted lower alkyl and ureido-substituted lower alkyl groups, said cyclic ammonio group optionally containing on the ring thereof one or more substituents select~ed from hydroxyl -subs ti tuted lower alkyl, hydroxyl, iormyl, sulfonic, carboxyl-substituted lower alkyl, carbamoyl, gulfamoyl, carboxyl, hydroxyimino-substituted lower alkyl., imino-substituted lower alkyl, bis[hydroxy(lower alkyl) )arinocarbony( hydroxy(lower alkyl)amino- carboni( 4tmino, morpholi nccarbonyl, carboxy (lower V. alkyloxy) -substituted lower alkyl, carboxy lower alkylthio chiucdlewer al~ky!-, and lower alkyl groups. $Olt

3. The 3-propenylcephem derivative as claimed in claim I or 2 wherein R 1 represents fluoromethyl grou~p, or a pharmaceutically acceptable salt thereof T E 188

4. The 3-propenylcephem derivative as claimed in claim 1 or 2 wherein R 1 represents cyanomethyl group, or a pharmacetically acceptable salt thereof. S. The compound as claimed in claim 3, which is methoxyimi noacetamido 1-3- -3 -(carbamoylmethyl ethyl- methylamxnonio 71-propen-l-yl I 3-cephem- 4-carboxyla te.

6. Thecompound as claimed in Claim 3, wihi 2- (5-amino- 2 4-thiadiazol-3-yl Z)-2-fluoro- methoxyiminoacetamidol,-3-f (E)-3-(l-(2-hydroxyethyl)-4- carbamoyl-l-piperidinib -l-propen-l-yl 21-3-cephem-4- carboxylate. The compound as claimed in Claim 3, which is 7 9 methoxyiminoace.tamido3 C~lS-carbamoylethyl) 0 dimethylammonio 0-l-properi-1-yl)- 3-cephem-4-carboxylate.

8. The compound as claimed in Claim 3, which is 70,-t2-(5-amino-1,2,4-thiadiazol--3-yl)-(Z)-2-fluoromethoxy- i a 4, iminoacetamido (E)-3-f(lIR-carbamoylethyl)dimethyl- ammonio I1 -1-propen-1-yl 21 -3 -cephem-4 qcarboxyla~e. B 9. The compound as claimed in Claim 3, which is .9 methoxyiminoacetamidolj-3-C (lR-carbanoyl-2- hydroxyethyl )dimethylammonio 21-l-propen-l-yl 21-3-cephem- 4-carboxylate. l8g The compound as claimed in claim 3, which is methoxyiminoacetamido) C(E)-3-(5-aza-l-methyl-2,8- dioxabicyclo(3,3,l) nona-l-io)--l-propen-l-yl -3-cbphem- 4-carboxylate.

11. The compound as claimed in claim 3, which is 7 1 -(2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2.fluoro. metho~yiminoacetamido3 r(E-3-(carbamoylmethy.- diethylammonilo) -l-propen-l-ylJ -3-cephem-4-carboxy1ate.

12. The compound as claimed in claim 3, which is :11. 7p-(2-(5-amino-1,2,4-thiadiazol-3-yl)Z2luoro. methoxyiminoacetamidoj C r)-2-oxopropyl~dimethylN ammoi 1propn-1yl)-3-cephem-4-carboxylate. 3.The compound as claimed in claim 4, which is 7p- j2-(5-amino-l ,2 ,4-thiaciazol-3-yl )-(Z)-2-cyano- methoxyiminoacetamidoj f(F8-3 ((2-oxopropyI )dimethyl- ammonioj -l-propen-l-ylJ -3-cephem-4-carboxylate.

14. The compound as claimed in claim 4, which is methoxyiminoacetamido) -3-C(E)-3-(I(lS-carbamoylethyl) dimethylarnmonio) -l-propen-l-yl" -3-cephem-4-carboxylate. The compound as claimed in claim 4, which is 7p3-C2- (5-amino-., 2, 4-tlhiadiazol..3-yl )-2-cyano- 190 140 a) 1- n t0 0 N N C N N N C14 4 J 3. E -4 H N N H H H H H jfj methoxyiminoace tam ido C(E)-3-((lR-carbamoylethyl) dimethylammonio) -1-propen-l-ylJ -3-cephem-4-carboxylate.

16. A process for the preparation of a 3- propenylcephem derivative of the formula: HZN~SY!C -OONH~ S N r S CII=CH CLI 2 -A \0 6 00-' wherein R 1 represents a fluoro-substituted lower alkyl group or a cyano-substituted lower alkyl group, and A Vo represents a cyclic or an acyclic ammonio group, or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the following formula: H 2 N~QC -CONH S *\Q-R 1 go wherein R.1has the same meaning as defined above and X represents a halogen atom, a compound whereiii said amino and/or carboxyl groups are protected with p rotecting groups, or a salt thereof with a compound ofthe following formula: At wherein A' represents an amine corresponding to A, 191 I a compound wherein the functional groups are protected with protecting groups, or a salt thereof, followed by optionally removing the protecting groups.

17. A pharmaceutical' composition which comprises an effective amount of a 3-propenylcephem derivative of the formula: N C -CONH S H 2 S ON 0 0 N -CH.-=HCH---A 1 R COO wherein R 1 represents a fluoro-substituted lower alkyl group or a cyano-substituted lower alkyl group, and A represents a cyclic or an acyclic ammonio group, or a pharmaceutically acceptable salt thereof, nd optionally a pharmacologically acceptable carrier.

18. A method for treating a disease caused by 4a iAo?+ <\eqec or 4cA -/rt7emeAS bacteria with the administration 4 of a compound of the formula: N' CONH -c"coo S0 wherein R 1 represents a fluoro-substituted lower alkyl group or a cyano-substituted lower alkyl group, and A represents a cyclic or an acylic ammonio group, or a pharmaceutically acceptable salt thereof, having an A7' 192 antibacterial activities.

19. A compound of the formula: N CONH H N S NN-r('NCH CHCHX O-R 1 COOH wherein R 1 represents a fluoro-substituted lower alkyl group or a cyano-substituted lower alky2. group, and~ X represents a halogen atom, a compound wherein said amino group and/or carboxyl groups are protected with a protective group, or salts of their compounds. A process for the preparation of a compound of the formula: H2 N rwherein represents a fluQro.-substituted lower alkyl 69 group or a Qyano-substituted lower al1kyl. group, and X represents a halogen atom, a compou.nd wherein said amino grouAp and/or carboXyJ. groups are protected with a protective group, or salts of their compounds, which 193 1 1 ~k sri I I I 0@ L~ 4 I S S.. I @555 S S S. j I 5 comprises reacting a compound of the formula: N C COOH -7 11 N N 2 S wherein R1has the same meanings as defined above, a reactive acid derivative thereof, a compound wherein said amino group is protected with a protective group, or a .salt thereof with a compound of the formula: H 2 N S ===CHCH 2 x CQOH wherein X haa the same meanings as defined above, a compound wherein said carboxyl group is protected with a protective group, or a salt thereof, followed by optionally removing the protective group and/or conver~ting the halogen atom into the other halogen atom. 194 4:6.0 195

21. A 3-propenylcephem derivative substantially as herein described with reference to any one of the Examples. DATED this 19th day of November 1990 EISAI-CO.. LTD. By their Patent Attorn~eys GRIFFITH HACK CO. as. Q,981s/SMcL