CH643849A5 - 3,7-Disubstituted 3-cephem-4-carboxylic acid compounds, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

The present invention also includes the cases in which solvents which do not adversely affect the reaction

the protected carboxy group for R3 flows into the free carb flow, and it is usually transferred with cooling oxy group and the protected amino group or carried out at ambient temperature.

is converted into the free amino group during the reaction. 3.) l-Hexyl-1H-tetrazole-5-thiol or a salt thereof can be prepared in the re-process according to the invention by reaction of the compound (XV)

action. 30 with compound (XVI).

The reaction according to the invention is generally carried out in

Method 4 a solvent such as an alcohol (e.g. methanol,

The compound of the present invention (If) or a salt (ethanol and the like), an aqueous alcohol or any

von can be prepared by reacting the compounds with other solvents which do not adversely affect the reaction of manure (Ie) or a salt thereof with the compound (XVIII) 35, and preferably it or its metal salt on the mercapto group. To be carried out under appropriate heating or heating.

Salts for the compound (Ie) include those as 4.) The compound (IIa) or a salt thereof can be

exemplified above for the compound (II) are made by reacting 1-hexyl-1 H-tetrazole-5-

are. Suitable metal salts on the mercapto group of the thiol or a salt thereof with the compound (XVII) or bond (XVIII) are e.g. an alkali metal salt (such as a sodium salt of a salt thereof. Suitable salts of the compound um-, potassium salt and the like) or the like (XVII) include those exemplified above for the

The reaction according to the invention can be specified in a solution compound (Ia). A suitable salt medium, such as water, in a phosphate buffer, acetone, chloro-of 1-hexyl-1 H-tetrazole-5-thiol may comprise a metal form, nitrobenzene, methylene chloride, ethylene chloride, di-salt, such as e.g. an alkali metal salt (such as a sodium, potassium methylformamide, methanol, ethanol, ether, tetrahydrofu salt, and the like) or the like.

ran, Dimethylsulfoxid or in any other organ- The reaction according to the invention can in a solvent solvent which does not adversely affect the reaction medium, such as water, acetone, chloroform, nitrobenzene, meth, preferably in those with strong polarities, ylene chloride, ethylene chloride , Dimethylformamide, methanol. Among the solvents, the ethanol, ether, tetrahydrofuran, dimethyl sulfoxide can be used in a hydrophilic solvent mixed with water, or in any other solvent. The reaction is preferably carried out in a preferably neutral medium which does not adversely affect the reaction. If the compound (Ie) is wise in those with strong polarities, who or the compound (XVIII) used in a free form. Among the solvents, the hydrophilic solvent, the reaction is preferably used in the presence of a solvent mixed with water. The base, e.g. an inorganic base, such as an alkali metal reaction, is preferably carried out under weakly basic or hydroxide, an alkali metal carbonate, an alkali metal or about neutral conditions. When the verbin carbonate, an organic base such as a trialkylamine manure (XVII) and / or l-hexyl-1H-tetrazole-5-thiol in free and the like, is carried out. The reaction temperature is not in the form used, the reaction becomes critical and the reaction is usually carried out in the presence of a base, e.g. an inorganic base, exercise temperature, with heating or under weak Er-60 such as an alkali metal hydroxide, an alkali metal carbohydrate. nates, an alkali metal bicarbonate, an organic base. The reaction according to the invention also includes the case, such as a trialkylamine, of pyridine and the like, that protected amino R'R "N- is converted into free amino. The reaction temperature is not critical and the conversion Depending on the type of protective group and / or tongue, it is generally carried out at ambient temperature or under the reaction conditions used .. 65. The reaction product can be isolated from the reaction mixture after the reaction of the compound (VIII) by the conventional method from the reaction mixture - Manure (IX) is usually washed in a solvent such as.

water, alcohol, a mixture thereof or the like. In the above reactions and / or in the

13

643 849

After-treatment of the reactions according to the invention, the above-mentioned tautomeric isomers can occasionally be converted into the other tautomeric isomers and such a case also falls within the scope of the present invention.

If the compound (I) according to the invention is obtained in the form of the free acid in the 4-position and / or if the compound (I) according to the invention has a free amino group, it can be converted into a salt, in particular into a pharmaceutically acceptable one, using a conventional method Salt thereof, as stated above, are transferred.

The compound (I) according to the invention and its salts, in particular its pharmaceutically acceptable salts, are all new compounds which have high antibacterial activity (activity), inhibit the growth of a wide variety of pathogenic microorganisms, including gram-positive and gram-negative bacteria, and are valuable antibacterial agents .

In order to demonstrate the usability of the compound (I) according to the invention on the basis of some representative compounds according to the invention, some test data relating to the antibacterial in vitro activity are given below.

Test connections

1.) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomeres)

2.) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetami-do] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carbon -acid (syn isomer)

3.) 7- [2- (4-aminomethylbenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid dihydrochloride (syn isomer).

Antibacterial in vitro activity test procedure

In vitro antibacterial activity was determined using the dual agar plate dilution method described below.

An eyelet fill of an overnight culture of each test strain in trypticase soy broth (108 viable cells per ml) was streaked on a cardiac infusion agar (HI agar) containing graduated concentrations of the test compounds and the minimum inhibitory concentration (MIC) was expressed in jig / ml, determined after 20 hours of incubation at 37 ° C.

Test results test bacteria

Staph.aureus 6 do. 32

MIC (ng / ml) test compounds (1) (2) (3) 1.56 0.78 0.78 1.56 0.78 1.56

For therapeutic administration, the compound (I) according to the invention or its pharmaceutically acceptable salts are used in the form of a conventional pharmaceutical preparation which contains this compound as an active ingredient (active ingredient), optionally in a mixture with pharmaceutically acceptable carriers, e.g. an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration. The pharmaceutical preparations can be in solid form, e.g. in the form of capsules, tablets, dragees, salts or suppositories, or in liquid form for injection, e.g. in the form of solutions, suspensions or emulsions. If necessary, auxiliary substances, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives can be incorporated into the above-mentioned preparations.

The dosage of the compounds may vary and it also depends on the age, the condition of the patient, the type of disease, the type of compound (I) administered and the like, an average single dose io of about 10 mg, 50 mg, However, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) according to the invention has been found to be effective in the treatment of infectious diseases caused by pathogenic bacteria.

Generally, a daily dose between 1 mg and about 6000 mg / body weight or more can be administered to a patient.

The invention is explained in more detail by the following production examples and examples, but without being restricted thereto.

Production Example 1 1.) 500 ml of water were added to 490.0 g of hexylamine and a solution of 193.6 g of sodium hydroxide in 700 ml of 25 water was added with ice cooling and with stirring. 367.8 g of carbon disulfide were added dropwise at 2 to 10 ° C. over a period of 2 hours and then 687.3 g of methyl iodide were added dropwise at 0 to 5 ° C. over a period of 1 hour. The resulting mixture was stirred at the same temperature for 30 minutes and at ambient temperature for 2 hours. The reaction mixture was extracted with 1.51 diethyl ether. The extract was washed with 300 ml of a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated to give 825.5 g of methyl N-hexyldithiocarbamate in the form of an oil.

I.R. (Film): 3225.2960.2935.2860 cm- '

N.M.R. (CDC £ 3, S): 0.86 (3H, t, J = 5.0 Hz), 1.10-1.90 (8H, m), 2.58 (3H, s), 3.72 (2H, m)

40 2.) 155.9 g of sodium azide and 0.81 of water were added with stirring to a solution of 430 g of methyl N-hexyldithiocarbamate in 1.71 of ethanol, and the resulting mixture was at 90 ° for 3.5 hours C heated under reflux. Ethanol was distilled off from the reaction mixture and the residue was washed with 11 diethyl ether, adjusted to pH 2.0 with concentrated hydrochloric acid and extracted with 11 diethyl ether. The extract was washed with water, dried over magnesium sulfate and concentrated to give 431.3 g of 1-hexyl-1H-tetra-50 zol-5-thiol in the form of an oil.

I.R. (Film): 3110.2960.2930.2860 cm "1 NMR (CDC £ 3, §): 0.91 (3H, t, J = 5.0 Hz), 1.10-1.65 (6H, m), 1.97 (2H, m), 4.33 (2H, t, J = 7.0 Hz)

3.) To 150.0 g of 7-aminocephalosporanic acid, 3 1 egg-55 ner 0.2M phosphate buffer solution, which had been prepared beforehand by dissolving 62.1 g of sodium biphosphate dihydrate and 25.5 g of disodium hydrogen phosphate in 31 water, were added and the the resulting mixture was adjusted to pH 6.5 with an aqueous 2N sodium carbonate solution. 154.6 g of 1-hexyl-1H-tetrazole-5-thiol was added to the mixture, and the resulting mixture was kept at 60 to 65 ° C for 2 hours while introducing nitrogen gas at a pH of 6.0 to 6 , 5 stirred. The reaction mixture was adjusted to pH 3.5 with concentrated hydrochloric acid with ice cooling. The precipitates were collected by filtration and washed with water, and 41 methanol and 400 ml of concentrated hydrochloric acid were added. The mixture

643 849 14

was stirred for 2 hours and an insoluble material. Production Example 4

was filtered off. The filtrate was treated with activated carbon 1.) 27.5 g of 2-bromoethyl benzoate were stirred and mixed with a 28% aqueous ammonia solution on a mixture of 15.7 g of ethyl 2-hydroxyimino-3-oxobutyrate.

pH 3.5 adjusted. The precipitates were filtered off (syn isomer), 20.7 g of potassium carbonate and 25 ml of N, N-di-

collected, successively with water, acetone and diethyl smethylformamide over a period of 10 minutes under

ether washed and dried, dropwise adding 116.38 g of 7- ice cooling and stirring for 4 hours at ambient

Amino-3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 temperature stirred. The mixture obtained was filtered

carboxylic acid was obtained in the form of a powder. trated and washed with acetone. The filtrate and the washing

I.R. (Nujol): 1803.1620.1350 cm-1 water were combined and vacuum

N.M.R. (d6-DMSO, 8): 0.95 (3H, t, J = 6.5 Hz), 1.26 (6H, xoengt. After adding 100 ml of water to the residue m), 1.80 (2H, m), 3.65 ( 2H, ABq, J = 18 Hz), 4.00-4.50 (4H, the solution was extracted 3 times with methylene chloride. The m), 4.79 (1H, d, J = 6.0 Hz), 4.95 (1H, d, J = 6.0 Hz) extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate

Preparation example 2 and concentrated in vacuo, 28 g of ethyl 2- (2-ben-

1.) 0.84 g of sodium bicarbonate were obtained as a suspension i5zoyloxyäthoxyimino) -3-oxobutyrate (syn-isomer),

of 2 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid in 120 ml of 2.) A mixture of 28 g of ethyl 2- (2-benzoyloxyeth-

Water added to make a solution. To the Lö-oxyimino) -3-oxobutyrate (syn-isomeres), 13.5 g Sulfurylchlo-

4.56 g of ethyl 2-aminooxyacetate hydrochloride were added and 30 ml of acetic acid was added at 40 ° C. for 10 minutes

and stirred at ambient temperature for 3 hours and at room temperature for 5.5 hours. After stirring, while the pH was adjusted with sodium bicarbonate to add 20 ml of water to the resulting solution. The resulting solution was extracted with the mixture was extracted with methylene chloride. The ex

Hydrochloric acid adjusted to pH 1.5, salted out and tract was with water, a saturated aqueous sodium

Extracted 3 times with ethyl acetate. The extract was over bicarbonate solution and a saturated aqueous sodium

Magnesium sulfate dried and concentrated in vacuo. The chloride solution washed successively, over magnesium sulfate

The residue was pulverized with diethyl ether and the oil was dried and then concentrated in vacuo, the residue being collected by filtration and dried. 29 g of ethyl 2- (2-benzoyloxyethoxyimino) -4-chloro-3-oxobuty-

net, giving 1.44 g2-ethoxycarbonylmethoxyimino-2- (2-rat (syn-isomer)).

formamidothiazol-4-yl) acetic acid (syn-isomer), F. 3.) A mixture of 29 g of ethyl 2- (2-benzoyloxyeth-

112 ° C (dec.). oxyimino) -4-chloro-3-oxobutyrate (syn-isomeres), 7.76 g thio-

1st row (Nujol): 3150.1740.1670.1550 cm-1 urea, 8.37 g sodium acetate, 75 ml water and 75 ml N.M.R. (DMSO-d6.5): 1.23 (3H, t, J = 7 Hz), 4.16 (2H, q, ethanol) was stirred at 40 ° C. for 1 hour.

J = 7 Hz), 4.77 (2H, s), 7.56 (1H, s), 8.54 (1H, s) solution was concentrated in vacuo and the back

2.) A mixture of 7.2 g of 2-ethoxycarbonyl methoxy was extracted twice with ethyl acetate. The extracts imino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer), were washed with a saturated aqueous sodium chloride solution-10 ml of concentrated hydrochloric acid, 70 ml of ethanol, solution over magnesium sulfate and dried in and 20 ml of tetrahydrofuran was concentrated under reverse vacuum for 2 hours. After adding 200 ml of diethyl exercise temperature. After removing the ether ether to the oily residue, the soluble substance was removed from the reaction mixture in vacuo, what was separated by decantation, and the solution was added in a vaser, and the mixture was concentrated with an aqueous vacuum. The residue was crystallized into pH 3.3 in diisopropyl ether sodium bicarbonate solution with ice cooling and the precipitates were collected by filtration. The precipitates were collected by filtering, 9 g of ethyl 2- (2-benzoyloxyethoxyimide) and drying, giving 4.6 g of 2-ethoxycarbonyl-no) -2- (2-aminothiazol-4-yl) acetate (syn-isomer). methoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isome NMR (DMSO-d6.8): 1.28 (3H, t, J = 7 Hz), 4.34 (2H, q, res). J = 7 Hz), 4.56 (4H, m), 6.44 (2H, broad s), 6.68 (1H, s),

I.R. (Nujol): 3170.1720.1660.1620 cm "1« 7.68-7.34 (3H, m), 8.06 (2H, d, d, J = 8 Hz, 2 Hz)

N.M.R. (d6-DMSO, 8): 1.27 (3H, t, J = 7 Hz), 4.25 (2H, q, 4.) A mixture of 8.5 g of ethyl 2- (2-benzoyloxyeth-

J = 7 Hz), 4.77 (2H, s), 6.96 (1H, s) oxyimino) -2- (2-aminothiazol-4-yl) acetate (syn-isomer),

35 ml of an aqueous 1N sodium hydroxide solution, 40 ml of methanol and 40 ml of tetrahydrofuran were prepared for 9 hours in preparation example 3 at 35 to 40 ° C. and for 12 hours at ambient temperature. 4.2 g of sodium bicarbonate were stirred into a suspension of tur. After the resulting Lö-10 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid in 500 ml of solution had been adjusted to pH 6.5 with concentrated hydrochloric acid, water was added to prepare a solution. 8.1 g of t-butyl-2-aminooxyacetate hydrochloride were concentrated in the solution to about 2/3 of its initial volume. The concentrate was added with concentrated chlorine and adjusted to pH 3.5 for 3 hours at ambient temperature, hydrochloric acid with ice cooling and stirred while the solution was adjusted to pH 6 with sodium bicarbonate. The precipitates were collected by filtration and adjusted. The solution obtained was washed successively with water and acetone and then adjusted to pH 1.5 over hydrochloric acid, salted out and phosphorus pentoxide dried under reduced pressure, extracted 3 times with ethyl acetate. The extract was dried over 3.3 g of 2- (2-hydroxyethoxyimino) -2- (2-aminothia magnesium sulfate) and concentrated in vacuo to give eo zoI-4-yl) acetic acid (syn-isomer).

Residue was pulverized with diethyl ether and the Nie I.R. (Nujol): 3350,3075,1680,1620 cm-1

Strips were collected by filtration and dried - N.M.R. (DMSO-d6.8): 3.64 (2H, t, J = 5 Hz), 4.10 (2H, t,

net, 11.3 g of 2-t-butoxycarbonylimethoxyimino-2-J = 5 Hz), 6.84 (1H, s), 7.16 (2H, m)

(2-formamidothiazol-4-yl) acetic acid (syn-isomer), 5.) A solution of 1.6 g of formic acid and 3.6 g of acetic acid

Mp 117 ° C (dec.). 65 acid anhydride was stirred at 50 ° C for 1 hour. To

I.R. (Nujol): 3180.3140.1750.1690.1630 cm-1 After cooling, 1 g of 2- (2-hydroxyethoxyimino) -2- (2-

N.M.R. (DMSO-d6.8): 1.46 (9H, s), 4.66 (2H, s), 7.56 aminothiazol-4-yl) acetic acid (syn isomer) to the solution

(1H, s), 8.56 (1H, s), 12.67 (1H, broad s) and added for 3 hours at ambient temperature

15

643 849

stirs. Diisopropyl ether was added to the resulting solution and the precipitates were filtered off. The filtrate was concentrated in vacuo and the residue was pulverized in diisopropyl ether. The precipitates were collected by filtration to give 0.7 g of 2- (2-formyloxyethoxyimino) -2- (2-formamidothiazol-4-yl) acetic acid (syn isomer).

I.R. (Nujol): 3200.1710.1690 cnr1

N.M.R. (DMSO-d6.8): 4.38 (4H, s), 7.58 (1H, s), 8.26 (1H, s), 8.54 (1H, s)

Production Example 5

1.) 126.4 g of ethyl-2-hydroxyimino-2- (2-aminothiazol-4-yl) acetate, 81.3 g of formic acid and 180 g of acetic anhydride were treated in a manner similar to that in Preparation 4- (5), wherein 109.6 g of ethyl 2-hydroxyimino-2- (2-formamidothiazol-4-yl) acetate (syn isomer) were obtained.

1st row (Nujol): 3320.3140.3050.1710.1555 cm "1

N.M.R. (d6-DMSO, 8): 1.30 (3H, t, J = 7 Hz), 4.33 (2H, q,

J = 7 Hz), 7.54 (1H, s), 8.54 (1H, s), 11.98 (1H, s), 12.58 (1H,

s)

2.) A mixture of 7.97 g of chloromethylthiomethane, 15.1 g of powdered potassium iodide and 79 ml of acetone was stirred for 1 hour at ambient temperature and the resulting mixture was filtered and washed with a small amount of acetone. The washings and the filtrate were combined and made into a stirred suspension of 17.5 g of ethyl-2-hydroxyimino-2- (2-formamidothi-azol-4-yl) acetate (syn isomer) and 15.5 g of powdered potassium umcarbonate in 300 ml acetone added. The mixture was stirred at ambient temperature for 3 hours and washed with acetone. The washings and the filtrate were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed twice with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The oily residue was subjected to column chromatography on silica gel and eluted with chloroform to give 2.4 g of ethyl-2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetate (syn-isomer), m.p. 130 to 131 ° C.

I.R. (Nujol): 3160.3125.3050.1740, 1695 cm- '

N.M.R. (d6-DMSO, 8): 1.32 (3H, t, J = 7 Hz), 2.22 (3H, s), 4.38 (2H, q, J = 7 Hz), 5.33 (2H, s), 7.67 (1H, s), 8.56 (1H,

s)

3.) A mixture of 2.4 g of ethyl-2-methylthiomethoxy-imino-2- (2-formamidothiazol-4-yl) acetate (syn isomer), 23.8 ml of an aqueous 1N sodium hydroxide solution and 19.8 ml Methanol was stirred at 30 ° C for 2.5 hours. The solution obtained was adjusted to pH 7 with 10% hydrochloric acid, and methanol was distilled off in vacuo. The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid with ice cooling and extracted 3 times with ethyl acetate. The extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 1.13 g of 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer), mp 157 ° C (dec.).

I.R. (Nujol): 3210.3160.3075.1700.1555 cm- '

N.M.R. (d6-DMSO, 8): 2.24 (3H, s), 5.31 (2H, s), 7.61 (1H, s), 8.57 (1H, s), 12.73 (1H, s)

Production Example 6

The following compounds were prepared in a similar manner to that in Preparation Examples 2 to 5:

(1) 2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer)

I.R. (Nujol): 3330.3200.3100.1660.1590 cm "1

(2) 2- (3-isoxazolyl) methoxyimino-2- (2-formamidothi-azol-4-yl) acetic acid (syn isomer) F. 110 ° C (dec.)

I.R. (Nujol): 3270.3130, 1680, 1540 cm "" 1 s (3) 2- (2-ethoxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer)

I.R. (Nujol): 3350.3140.1740.1700 cm "1

Production Example 7 10 A solution of 17.4 g of 4-bromo-3-hydroxybenzyloxyamine phosphate in 200 ml of water and 200 ml of ethanol were stirred at room temperature and adjusted to pH 7.0 with sodium bicarbonate. 10.0 g of 2- (2-formididiaziaz-4-yl) glyoxylic acid were added to the solution and the suspension obtained in this way was adjusted to pH 4.0 to 4.5. After stirring the solution at room temperature for 2 hours, ethanol was removed from the resulting solution in vacuo. Ethyl acetate was added to the aqueous residue and the pH was adjusted to 20-2 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate. The solution was concentrated in vacuo to give 14.8 g of 2- (2-formamidothiazol-4-yl) -2- (4-bromo-3-hydroxybenzyloxyimino-no) acetic acid (syn isomer).

25th

Nujol

I.R. v: 3350.3150.1720.1680.1570 cm "1 max

N.M.R. 8 (DMSO-d6, ppm): 5.13 (2H, m), 6.8 (1H, dd, 30 J = 8 Hz, 2 Hz), 7.02 (IH, d, J = 2 Hz), 7.5 (IH, d, J = 8 Hz), 7.58 (1H, s), 8.58 (1H, s), 10.35 (1H, broad s), 12.7 (1H, broad s).

Production Example 8

1.) A mixture of 25 g l, 4-bis (chloromethyl) benzene, 35 23.4 g N-hydroxyphthalimide and 14.5 g triethylamine in 200 ml acetonitrile was heated under reflux for 1.5 hours. The reaction mixture was poured into 11 ice water and the precipitates were collected by filtration. The precipitates were washed with ethanol and dried to give 25.5 g of N- (4-chloromethylbenzyloxy) phthalimide.

Nujol

1st row v: 1780.1740 cm-1

Max

45 N.M.R. 8 (DMSO-dfi, ppm): 4.8 (2H, s), 5.23 (2H, s), 7.22 (4H, s), 7.9 (4H, s).

2.) A mixture of 18.5 g of N- (4-chloromethylbenzyloxy) phthalimide and 15.4 g of potassium phthalimide in 180 ml of N, N-dimethylformamide was kept at 60 ° C. for 5 hours.

50 stirs. The mixture was poured into ice water and the precipitates were collected by filtration. The precipitates were washed successively with water and acetone to give 21.0 g of N- (4-phthalimidomethylbenzyloxy) phthalimide.

55 Nujol

LR. v: 1780.1760.1740.1720.1610 cm "1 max

N.M.R. 8 (DMSO-d6, ppm): 4.78 (2H, s), 5.13 (2H, s), 7.38 (4H, m), 7.83 (8H, m).

60 3.) 4.2 g of 100% hydrazine hydrate were added to a suspension of 16.4 g of N- (4-phthalimidomethylbenzyloxy) phthalimide in 160 ml of ethanol at 60 ° C. and stirred at the same temperature for 1 hour. 12 ml of 65 concentrated hydrochloric acid and 120 ml of water were added to the resulting mixture while cooling with ice. After the insoluble substance had been filtered off, the filtrate was concentrated in vacuo. The residue was adjusted to pH 7.0 with a 10% sodium hydroxide solution

643 849

16

adjusted and washed with ethyl acetate. To the aqueous solution containing 4-aminomethylbenzyloxyamine, 5.3 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid and 150 ml of ethanol were added, and the solution was stirred at pH 4.0 to 4 for 2.5 hours. 5 stirred. The precipitates were collected by filtration and washed with water. The precipitates containing 2- (2-formamidothiazol-4-yl) -2- (4-aminomethyl-benzyloxyimino) acetic acid (syn isomer) were added to a mixture of 100 ml water and 100 ml dioxane and with 10% sodium hydroxide adjusted to pH 8.0. 3.2 g of triethylamine and 4.7 g of 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile were added to the mixture and the mixture was stirred at room temperature for 6 hours. Dioxane was removed in vacuo and the aqueous residue was washed with diethyl ether. Diethyl ether was added to the aqueous solution and the pH was adjusted to 3.0 with 10% hydrochloric acid. After removing diethyl ether from the mixture, the residue was washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 3.8 g of 2- (2-formamidothiazol-4-yl) -2- (4-tert. -but-oxycarbonylaminomethylbenzyloxyimino) acetic acid (syn-isomer), received.

Nujol

I.R. v: 3300.3150.1710.1690.1620.1560 cm- 'max

N.M.R. § (DMSO-d6, ppm): 1.38 (9H, s), 4.15 (2H, d, J = 6 Hz), 5.22 (2H, s), 7.6 (1H, s), 7.68 (4H, s), 8.62 (1H, s), 12.8 (1H, broad s).

Production Example 9

1.) 40.0 g of ethyl 2-hydroxyimino-3-oxobutyrate (syn-isomeres), 43.6 g of 4-fluorobenzyl chloride, 60.0 ml of N, N-dimethylformamide, 52.0 g of potassium carbonate and 60 , 0 ml of ethyl acetate were treated in a conventional manner, using

64.4 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxobutyrate (syn isomer) was obtained.

1st row (Film): 3000.2940.1730.1690.1600 cnT1

N.M.R. (DMSO-d6.5): 1.21 (3H, t, J = 7.0 Hz), 2.34 (3H,

s), 4.26 (2H, qj = 7.0 Hz), 5j, 2 (2H, s), 6.97-7.73 (4H, m).

2.) 64.0 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxobutyrate (syn isomer) and 35.6 g of sulfuryl chloride and 70.0 ml of acetic acid were prepared in a similar manner to that in Preparation 4- (2) treated to obtain 29.55 g of ethyl 2- (4-fluoro-benzyloxyimino) -3-oxo-4-chlorobutyrate (syn isomer).

I.R. (Film): 1720.1600 cm- '

N.M.R. (DMSO-d6.8): 1.20 (3H, t, J = 7.0 Hz), 4.28 (2H, q, J = 7.0 Hz), 4.87 (2H, s), 5.36 ( 2H, s), 7.00-7.75 (4H, m).

3.) 29.0 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn isomer), 8.8 g of thiourea, 7.9 g of sodium acetate, 72.5 ml of water, 60 ml of tetrahydrofuran and

72.5 ml of ethanol were treated in a similar manner as in Preparation 4- (3), giving 28.0 g of ethyl 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn-isomer ) received.

I.R. (Nujol): 3450.3150.3100.1710.1620 cm "1

N.M.R. (DMSO-d6.8): 1.23 (3H, t, J = 7.0 Hz), 4.30 (2H, q, J = 7 Hz), 5.15 (2H, s), 6.90 (1H, s), 6.95-7.60 (4H, m)

4.) 25.5 g of ethyl 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn-isomer), 1.3 g of 1-methylimidazole,

118.3 ml of a 1N sodium hydroxide solution, 250 ml of methanol and 200 ml of tetrahydrofuran were treated in a similar manner as in Preparation 4- (4), giving 22.11 g of 2- (4-fluorobenzyloxyimino) -2- (2- aminothiazol-4-yl) acetic acid (syn-isomer).

LR. (Nujol): 3650.3450.3300.3150.1630 cm "1

N.M.R. (DMSO-d6.8): 5.16 (2H, s), 6.88 (1H, s), 7.04-7.66 (4H, m)

5.) 23.4 g2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn-isomer), 32.2 g bis (trimethylsilyl) acetamide, 49.9 g 2, 2,2-Trifluoroacetic anhydride and 234 ml of dry ethyl acetate were treated in a similar manner to that in Preparation 4- (5) to give 18.9 g of 2- (4-fluorobenzyloxyimino) -2- [2- (2.2, 2-trifluoroacetamido) thiazol-4-yl] acetic acid (syn-isomer), mp 180 to 182 ° C. I.R. (Nujol): 3200.3150, 1730 cm "1 NMR (DMSO-d6.8): 5.25 (2H, s), 7.02-7.60 (4H, m), io 7.72 (1H, s).

Production Example 10 1.) The compound given below was prepared by reacting ethyl 2-hydroxyimino-3-oxo-butyrate (syn isomer) with 3,4-dichlorobenzyl chloride in a conventional manner:

Ethyl 2- (3,4-dichlorobenzyloxyimino) -3-oxobutyrate (syn isomer), oil

1st row (Film): 1730.1690, 1600.1470.1400.1370.1310, 2o 1240.1130.1080.1010 cm "1

N.M.R. (CC14.8): 1.30 (3H, t, J = 6 Hz), 2.30 (3H, s), 4.30 (2H, q, J = 6 Hz), 4.47 (2H, s), 7.00-7.53 (3H, m)

2.) The following compound was prepared in a similar manner to Production Example 4- (2):

2S ethyl 2- (3,4-dichlorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn isomer), oil

I.R. (Film): 1740.1710.1590.1470.1400.1370.1320, 1260.1200.1130.1010 cm- '

N.M.R. (CCI4.8): 1.37 (3H, t, J = 6 Hz), 4.23 (2H, q, 30 J = 6 Hz), 4.43 (2H, s), 5.27 (2H, s), 7.10-7.60 (3H , m)

3.) The following compound was prepared in a similar manner to Production Example 4- (3):

Ethyl 2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothi-azol-4-yl) acetate (syn-isomer)

3s LR. (Nujol): 3460.1720.1600.1540.1460.1390.1260, 1180.1020.1010.880.810 cm- '

N.M.R. (DMSO-d6.8): 1.25 (3H, t, J = 7 Hz), 4.30 (2H, q, J = 7 Hz), 5.17 (2H, s), 6.93 (1H, s), 7.27-7.73 ( 3H, m)

4.) The following compound was prepared in a manner similar to that in Preparation 4- (4):

2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn isomer)

I.R. (Nujol): 3430.1660, 1590.1400.1010 cm "1 N.M.R. (DMSO-d6.8): 5.23 (2H, s), 6.93 (1H, s),« 7.30-7.77 (3H, m)

5.) The following compound was prepared in a similar manner to Production Example 4- (5):

2- (3,4-dichlorobenzyloxyimino) -2- [2- (2,2,2-trifluoroacetamido) thiazol-4-yl] acetic acid (syn isomer)

so I.R. (Nujol): 1720.1580,1300,1260,1200,1160, 1150 cm- '

N.M.R. (DMSO-d6.8): 5.40 (2H, s), 7.47-7.93 (4H, m)

55

Production Example 11 To a suspension of 21.0 g of N- (cinnamyloxy) phthalimide in 200 ml of ethanol was added 8.3 g of hydrazine hydrate at 60 ° C. and the mixture was stirred at the same temperature for 1.5 hours. To the mixture was added 22 ml of concentrated hydrochloric acid and 220 ml of 60 water, and the resulting mixture was filtered. The filtrate was concentrated to give precipitates which were filtered off. The filtrate was adjusted to pH 7.0, and to the solution containing O-cinnamylhydroxylamine, 300 ml of ethanol and 10.0 g of 2- (2-formamido-65 thiazol-4-yl) glyoxylic acid were added. The mixture was stirred at pH 4.0 to 4.5 for 2 hours. The reaction mixture was concentrated and adjusted to pH 2.0 after the addition of ethyl acetate. The organic layer was covered with

17th

643 849

an aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to give 8.6 g of 2-cinnamyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer).

I.R. (Nujol): 3400-3100.1700.1550 cm "1

N.M.R. (DMSO-d6, 8): 4.85 (2H, d, J = 5 Hz), 6.2-6.93 (2H, m), 7.2-7.72 (5H, m), 7.6 (1H, s), 8.57 (1H, s ), 12.7 (1H, broad s).

example 1

The Vilsmeier reagent was prepared from 0.139 g of dry dimethylformamide, 0.290 g of phosphorus oxychloride and 1.0 ml of dry tetrahydrofuran by the conventional method. 3.0 ml of dry tetrahydrofuran were added and then 0.4 g of 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) were added at -5 ° to 0 ° C. The mixture was stirred at the same temperature for 30 minutes. The resulting mixture was at -5 to 0 ° C to a stirred solution of 0.725 g of 7-amino-3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in a mixture 7 ml of water and 7 ml of acetone, the pH of which was kept at 7.5 to 8.5 by means of triethylamine, were added dropwise, and the mixture was stirred at the same temperature at pH 7.5 to 8.5 for 30 minutes. Acetone was removed from the reaction mixture. Ethyl acetate and water were added to the residue and the mixture was adjusted to pH 2.0 with 10% hydrochloric acid. The insoluble material was filtered off and the filtrate was extracted twice with ethyl acetate. The combined extracts were washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with diethyl ether, whereby 0.64 g of 7- [2-methylthiomethoxy-imino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4- thia-diazol-2-yl) thiomethyl -3-cephem-4-carboxylic acid (syn isomer) was obtained.

I.R. (Nujol): 3230.1780.1680.1550 cm "1

N.M.R. (d6-DMSO, 8): 2.22 (3H, s), 3.72 (2H, ABq, J = 18 Hz), 4.44 (2H, ABq, J = 14 Hz), 5.18 (1H, d, J = 5 Hz) , 5.23 (2H, s), 5.84 (1H, d, d, J = 5 and 9 Hz), 7.46 (1H, s), 8.52 (1H, s), 9.54 (1H, s), 9.74 (1H, d , J = 9 Hz), 12.64 (1H, broad s)

Example 2

2.3 g of phosphorus oxychloride were added all at once to a suspension of 3.4 g of 2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer) in 30 ml of dry tetrahydrofuran at -3 ° C and the Mixture was stirred at the same temperature for 20 minutes. 2.4 g of trimethylsilylacetamide and 5 ml of tetrahydrofuran were added dropwise, and the resulting mixture was stirred at the same temperature for 20 minutes. 2.3 g of phosphorus oxychloride was added and the mixture was stirred at 0 to 3 ° C for 30 minutes. 1.1g of dry dimethylformamide was added all at once at 0 to 3 ° C and the mixture was stirred at the same temperature for 1 hour to obtain a clear solution.

On the other hand, 12.7 g of trimethylsilylacetamide became a stirred suspension of 4.0 g of 7-amino-3- (1,3,4-thia-diazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in 60 ml of dry Ethyl acetate was added and the solution was stirred at ambient temperature for 1 hour. To this stirred solution, the tetrahydrofuran solution obtained above was then added all at once at −20 ° C. and the mixture obtained was stirred at −5 to −15 ° C. for 2 hours. To the reaction mixture was added 50 ml of a saturated aqueous sodium chloride solution. The organic layer was separated and extracted with a saturated aqueous sodium bicarbonate solution (pH 7.0). The extract was washed with ethyl acetate, treated with activated carbon and adjusted to pH 4.5 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried, giving 1.03 g of 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetami-do] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained in the form of a powder. I.R. (Nujol): 3320.3200.1770.1670.1610 cm "1 NMR (d6-DMSO, 5): 3.59 (2H, ABq, J = 18.0 Hz), 4.47 (2H, ABq, J = 12.0 Hz), 5.09 (IH, d, J-4.0 Hz), 5.15 (2H, s), 5.73 (1H, d, d, J = 4.0 and 8.0 Hz), 6.74 (1H, s), 7.36 (5H, m), 9.56 (1H, s), 9.69 (1H, d, J = 8.0 Hz)

15 Example 3

The Vilsmeier reagent was prepared from 0.667 g dry dimethylformamide, 1.40 g phosphorus oxychloride and 4 ml dry ethyl acetate by the conventional method. 16 ml of dry ethyl acetate was added and then 2 g of 2-t-butoxycarbonylmethoxy-imino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) were added at 0 ° C. The mixture was stirred at the same temperature for 30 minutes. The resulting mixture was at -15 ° C to a stirred solution of 3.01 g of 7-amino-3-25 (1,3,4-thiadiazol-2-yI) thiomethyl-3-cephem-4-carboxylic acid and 9, 6 g of trimethylsilylacetamide in 30 ml of dry ethyl acetate were added dropwise and the mixture was stirred at -15 to -5 ° C. for 50 minutes. 50 ml of water was added to the reaction mixture. An insoluble material was filtered off and the filtrate was extracted twice with ethyl acetate, the extracts were washed twice with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diethyl ether and the powder was collected by filtration and dried to give 2.67 g of 7- [2-t-butoxycarbonylmethoxyimino-2 - (- formamidothia-zol-4-yl) acetamido] -3- ( l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained.

I.R. (Nujol): 3225.1780.1725.1685.1550 cm "1 40 NMR (d6-DMSO, 8): 1.38 (9H, s), 3.64 (2H, ABq, J = 17 Hz), 4.38 (2H, ABq , J = 14 Hz), 4.56 (2H, s), 5.12 (1H, d, J = 5 Hz), 5.77 (1H, d, d, J = 5 and 9 Hz), 7.38 (1H, s), 8.47 (1H, s), 9.49 (1H, s), 9.54 (1H, d, J = 9 Hz), 12.57 (1H, broad s)

45 Example 4

The compounds listed below were prepared in a similar manner to that given in Examples 1 to 3:

(1) 7- [2-methylthiomethoxyimino-2- (2-formamidothi-

50 azol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiometh-yl-3-cephem-4-carboxylic acid (syn-isomer)

I.R. (Nujol): 3250.1780.1675.1550 cm "1 NMR (d6-DMSO, S): 2.22 (3H, s), 3.72 (2H, ABq, J = 19 Hz), 3.96 (3H, s), 4.33 (2H, ABq, J = 14 Hz), 5.17 (1H, ss d, J = 5 Hz), 5.26 (2H, s), 5.85 (1H, d, d, J = 5 and 8 Hz), 7.48 (1H , s), 8.54 (1H, s), 9.78 (1H, d, J = 8 Hz), 12.64 (1H, s)

(2) 7- [2- (2-ethoxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-ce- phem-4-carboxylic acid (syn isomer)

60 I.R. (Nujol): 3500.3200.1780.1720.1680 cm "1

N.M.R. (d6-DMSO, 5): 1.13 (3H, t, J = 7 Hz), 3.2-4.0 (6H, m), 4.30 (2H, t, J = 4 Hz), 4.50 (2H, ABq, J = 13 Hz), 5.23 (1H, d, J = 5 Hz), 5.87 (1H, d, d, J = 5 and 8 Hz), 7.48 (1H, s), 8.58 (1H, s), 9.60 (1H, s ), 9.70 (1H, d, J = 8 Hz)

(3) 7- [2- (2-formyloxyethoxy) imino-2- (2-formamidothi-azol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer)

I.R. (Nujol): 1770.1710.1670 cm "1

65

643 849

18th

N.M.R. (d6-DMSO, 5): 3.50 (2H, m), 4.10-4.60 (4H, m) 4.79 (2H, m), 5.16 (IH, d, J = 5.0 Hz), 5.81 (1H, d, d, J = 5.0 and 8.0 Hz), 6.58 (2H, broad s), 7.47 (1H, s), 8.28 (1H, s), 8.55 (1H, s)

(4) 7- [2- (2-formyloxy ethoxy) imino-2- (2-formamidothi-azol-4-yl) acetamido] -3-methyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3150.1765.1675 cm "1 NMR (d6-DMSO, 5): 2.03 (3H, s), 3.45 (2H, ABq, J = 18 Hz), 4.36 (4H, m), 5.11 (1H , d, J = 5 Hz), 5.75 (1H, d, d, J = 5 and 8 Hz), 7.46 (1H, s), 8.24 (1H, s), 8.53 (1H, s), 9.63 (1H, d , J = 8Hz)

(5) 7- [2- (2-Formyloxyethoxy) imino-2- (2-formamidothi-azol-4-yl) acetamidoj-3- (l-methyl-1H-tetrazol-5-yl) thiometh-yl-3 -cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3160.1775.1710.1670 cm "1 NMR (dg-DMSO, 8): 3.71 (2H, ABq, J = 18.0 Hz), 3.96 (3H, s), 4.00 - 4.54 (6H, m) , 5.16 (1H, d, J = 4.5 Hz), 5.84 (1H, d, d, J = 4.5 and 9.0 Hz), 7.45 (1H, s), 8.24 (1H, s), 8.53 (1H, s), 9.70 (1H, d, J = 9.0 Hz)

(6) 7- [2- (2-formyloxyethoxy) imino-2- (2-formamidothi-azol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3- cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3180.1775.1673 cm "1 NMR (d6-DMSO, 8): 3.75 (2H, m), 4.25-4.65 (6H, m), 5.22 (1H, d, J = 5.0 Hz), 5.88 (1H, d, d, J = 5.0 and 9.0 Hz), 7.49 (1H, s), 8.26 (1H, s), 8.57 (1H, s), 9.59 (1H, s), 9.71 (1H, d, J = 9.0Hz)

(7) 7- [2-ethoxycarbonylmethoxyimino -2- (2-formamido-dothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thio-methyl-3-cephem-4 -carboxylic acid (syn isomer)

I.R. (Nujol): 3250.1775.1720.1680.1540 cm "1 NMR (d6-DMSO, 8): 1.22 (3H, t, J = 7 Hz), 3.74 (2H, .s), 4.20 (2H, q , J = 7 Hz), 4.77 (2H, s), 5.22 (1H, d, J = 5 Hz), 5.88 (IH, d, d, J = 5 and 8 Hz), 7.51 (1H, s), 8.58 (1H, s), 9.63 (1H, s), 9.70 (1H, d, J = 8 Hz), 12.68 (IH, broad s)

(8) 7- [2-ethoxycarbonylmethoxyimino-2- (2-formamido-thiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thio-methyl-3-cephem- 4-carboxylic acid (syn isomer)

I.R. (Nujol): 3250.1780.1725.1680.1540 cm "1 NMR (d6-DMSO, 8): 1.22 (3H, t, J = 7 Hz), 3.73 (2H, s), 3.97 (3H, s) , 4.18 (2H, q, J = 7 Hz), 4.35 (2H, ABq, J = 14 Hz), 4.76 (2H, s), 5.18 (1H, d, J = 5 Hz), 5.86 (1H, d, d, J = 5 and 9 Hz), 7.48 (1H, s), 8.56 (1H, s), 9.67 (1H, d, J = 9 Hz), 12.69 (IH, broad s)

(9) 7- [2-t-Butoxycarbonylmethoxyimino-2- (2-formamido-dothiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) tlio-methyl-3-cephem -4-carboxylic acid (syn isomer)

I.R. (Nujol): 3180.1785.1725.1690.1550 cm "1 NMR (d6-DMSO, 8): 1.45 (9H, s), 3.72 (2H, ABq, J = 17 Hz), 3.96 (3H, s) , 4.33 (2H, ABq, J = 14 Hz), 4.64 (2H, s), 5.17 (1H, d, J = 5 Hz), 5.84 (1H, d, d, J = 5 and 9 Hz), 7.46 ( 1H, s), 8.52 (1H, s), 9.62 (1H, d, J = 9 Hz), 12.61 (IH, broad s)

(10) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l -hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer)

I.R. (Nujol): 3350.3250.1780.1680.1633 cm "1 NMR (d6-DMSO, 8): 0.86 (3H, m), 0.97-1.53 (6H, m), 1.53-2.10 (2H, m), 3.70 (2H, m),. 4.10-4.77 (4H, m), 5.00-5.50 (3H, m), 5.85 (1H, d, d, J = 5.0 and 8.0 Hz), 6.80 (1H, s), 6.98 -7.63 (7H, m), 9.71 (1H, d, J = 8.0 Hz)

(11) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-formamido-thiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3- cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3200.1775, 1675.1540 cm "1 NMR (d6-DMSO, 8): 3.72 (2H, s), 4.45 (2H, ABq, J = 13 Hz), 5.18 (1H, d, J = 5 Hz), 5.30 (2H, s), 5.96 (1H, d, d, J = 5 and 8 Hz), 6.67 (1H, d, J = 2 Hz), 7.50 (1H, s), 8.55 (1H,

s), 8.90 (1H, d, J = 2 Hz), 9.58 (1H, s) 9.79 (1H, d, J = 8 Hz), 12.69 (1H, s)

(12) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-

54-carboxylic acid (syn isomer)

I.R. (Nujol): 3340.3200.1775.1670 cm "1

(13) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-ce-phem-4- carboxylic acid (syn isomer)

io I.R. (Nujol): 3300.1770.1670.1530 cm "1

(14) 7- [2- (2-ethoxyethoxy) imino-2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer)

I.R. (Nujol): 3160.3100.1780.1670.1630 cm "1" (15) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothi-azol-4-yl) acetamido] -3- (l-methyl- lH-tetrazol-5-yl) thiometh-yl-3-cephem-4-carboxylic acid (syn-isomer)

I.R. (Nujol): 3350.3220.1780.1680.1630 cm "1 (16) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothi-2oazol-4-yl) acetamido] -3- (l, 3.4 -thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3350.3230.3100.1780.1680.1630 cm "1 (17) 7- [2-t-butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l , 3,4-thiadiazol-2-yl) thiometh-25 yl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3300.1775.1730.1675.1630 cm "1

(18) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-ce-phem-4-carboxylic acid (syn isomer)

30 I.R. (Nujol): 3340.3200.1775.1675.1630 cm "1

(19) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-ce- phem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3350.3230.3110, 1775.1675 cm "1 35 (20) 7- [2-carboxymethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l-methyl-lH- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer)

I.R. (Nujol): 3200.1780.1720.1680.1545 cm "1

(21) 7- [2-carboxymethoxyimino-2- (2-aminothiazole-4-

40 yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer)

I.R. (Nujol): 3360.3240.3100.1780.1680.1635 cm "1

(22) 7- [2- (4-t-Butoxycarbonylaminomethylbenzyl-oyimino) -2 - (2-formamidothiazol-4-yl) acetamido] -3- (l, 3,4-

45 thiadiazol -2- yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3300-3150, 1790, 1690, 1550 cm "1 NMR (DMSO-d6.8): 1.33 (9H, s), 3.6 (2H, m), 4.08 (2H, d, J = 5 Hz) , 4.4 (2H, ABq, J = 14 Hz), 5.11 (1H, d, so J = 5 Hz), 5.13 (2H, m), 5.78 (1H, dd, J = 5 and 8 Hz), 7.25 (4H , m), 7.33 (1H, s), 8.47 (1H, s), 9.5 (1H, s), 9.68 (1H, d, J = 8 Hz), 12.5 (IH, broad s)

(23) 7- [2- (t-Butoxycarbonylmethoxyimino) -2- (2-form-amidothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiometh-

55 yl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3170.1770.1720.1670 cm "1 NMR (DMSO-d (j, S): 1.44 (9H, s), 3.68 (2H, m), 4.33 (2H, ABq, J = 12.0 Hz) , 4.63 (2H, s), 5.16 (1H, d, J = 5.0 Hz), 5.82 (1H, dd, J = 5.0 and 8.0 Hz), 7.43 (1H, s), 8.51 (1H, s), 60 9.56 (1H, d, J = 8.0 Hz)

(24) 7- [2- (4-Fluorobenzyloxyimino) -2- {2- (2,2,2-tri-fluoroacetamido) thiazol-4-yl] acetamido] -3- (l-methyl-lH-tetrazole -5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

65 I.R. (Nujol): 3370.3180.1760.1710.1680.1650 cm "1 NMR (DMSO-d6.8): 3.68 (2H, m), 3.92 (3H, s), 4.32 (2H, m), 5.03- 5.35 (3H, m), 5.83 (1H, dd, J = 5 and 8 Hz), 6.99-7.70 (4H, m), 7.54 (1H, s), 9.87 (1H, d, J = 8 Hz)

19th

643 849

(25) 7- [2-ethoxycarbonylmethoxyimino -2- (2-formamido-dothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer ), Mp 112-125 ° C (dec.).

I.R. (Nujol): 3250.1770.1730.1680 cm "1 NMR (DMSO-d6.5): 1.20 (3H, t, J = 8 Hz), 3.71 (2H, m), 4.07 (2H, q, J = 8 Hz), 4.36 (2H, m), 4.77 (2H, m), 5.20 (1 H, d, J = 5 Hz), 5.88 (IH, dd, J = 5 and 8 Hz), 7.50 (IH, s ), 8.57 (IH, s), 9.67 (IH, d, J = 8 Hz), 12.38 (IH, broad s)

(26) 7- [2-Benzyloxyimino -2- (2-aminothiazol-4-yl) acetamido] -3- (1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn-isomer), mp 172-174 ° C (dec.).

I.R. (Nujol): 3250.3150.1770.1620 cm "1 NMR (DMSO-d6.5): 3.67 (2H, m), 4.33 (2H, m), 5.08-5.36 (3H, m), 5.83 (IH, dd, J = 4 and 8 Hz), 6.88 (IH, s), 7.39 (5H, s), 9.73 (IH, d, J = 8 Hz)

(27) 7- [2- (4-Fluorobenzyloxyimino) -2- - (_ 2- (2,2,2-trifluoro-oroacetamido) thiazol-4-yl} acetamido] -3- (l, 3,4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3200.1770.1720.1650 cm "1 NMR (DMSO-d6.5): 3.73 (2H, ABq, J = 18 Hz), 4.49 (2H, ABq, J = 14 Hz), 5.03-5.46 (3H, m), 5.88 (IH, dd, J = 4 and 8 Hz), 7.03-7.84 (4H, m), 7.59 (IH, s), 9.60 (IH, s), 9.88 (IH, d, J = 8 Hz)

(28) 7- [2-Cinnamyloxyimino -2- (2-formamidothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomeres)

I.R. (Nujol): 3400-3100.1780.1680.1540 cm "1 NMR (DMSO-d6.8): 3.67 (2H, m), 4.45 (2H, ABq, J = 14 Hz), 4.83 (2H, d, J = 5 Hz), 5.18 (IH, d, J = 5 Hz), 5.87 (IH, dd, J = 5 and 8 Hz), 6.65 (IH, s), 6.12-7.0 (2H, m), 7.1- 7.7 (5H, m), 8.53 (IH, s), 9.57 (IH, s), 9.73 (IH, d, J = 8 Hz), 12.6 (IH, broad s)

(29) 7- [2- (4-Fluorobenzyloxyimino) -2- £ _2- (2,2,2-tri-fluoroacetamido) thiazol-4-yl} acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3200.1780.1730.1660 cm-1

(30) 7- [2- (4-Fluorobenzyloxyimino) -2- {2- (2,2,2-trifluoro-oroacetamido) thiazol-4-yf} acetamido] cephalosporanic acid (syn isomer)

I.R. (Nujol): 3250.1780.1730.1660.1630 cm-1 N.M.R. (DMSO-d6.5): 2.07 (3H, s), 3.59 (2H, m), 4.90 (2H, ABq, J = 14 Hz), 5.13-5.46 (3H, m), 5.90 (IH, dd, J = 5 and 8 Hz), 7.30-7.77 (4H, m), 7.58 (IH, s), 9.68 (IH, d, J = 4.0Hz)

(31) 7- [2- (3,4-dichlorobenzyloxyimino) -2- {2- (2,2,2-tri-fluoroacetamido) thiazol-4-yl} acetamido] cephalosporanic acid (syn isomer)

I.R. (Nujol): 1780.1730.1650 cm "1 NMR (DMSO-d6.5): 2.03 (3H, s), 3.57 (2H, m), 4.87 (2H, ABq, J = 12 Hz), 5.17-5.23 (3H, m), 5.87 (IH, dd, J = 6 and 8 Hz), 7.33-7.73 (4H, m), 9.87 (IH, d, J = 8 Hz)

(32) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-formamidothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) thiomethyl- 3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3400-3100,1780,1680,1540 cm- 'N.M.R. (DMSO-d6.5): 3.7 (2H, broad s), 4.45 (2H, ABq, J = 13 Hz), 5.13 (IH, d, J = 5 Hz), 5.18 (2H, s), 5.82 (IH , dd, J = 5 and 8 Hz), 6.97 (IH, d, J = 2 Hz), 7.4 (IH, s), 7.45 (IH, d, J = 8 Hz), 8.5 (IH, s), 9.68 (IH, d, J = 8 Hz), 12.6 (IH, broad s)

(33) 7- [2- (4-Aminomethylbenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) thiomethyl-3-cephem -4-carboxylic acid - dihydrochloride (syn isomer)

I.R. (Nujol): 3400-3100,1770,1660,1620,1540 cm- '

(34) 7- [2- (t-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1 H-tetrazol-5-yl) thiomethyl-3-ce-phem- 4-carboxylic acid (syn isomer)

I.R. (Nujol): 3280.3200.1770.1670.1630 cm-1

(35) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer)

I.R. (Nujol): 3300,3200,1770,1660,1620,1600 cm "1 5 (36) 7- [2-ethoxycarbonylmethoxyimino -2- (2-aminothi-azol-4-yl) acetamido] -3- (lH- tetrazol-5-yl) thiomethyl-3-ce-phem-4-carboxylic acid (syn-isomer), mp 168-185 ° C (dec.)

I.R. (Nujol): 3250.1765.1670.1625 cm "1

(37) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-io 4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) thiomethyl-3-ce-

phem-4-carboxylic acid (syn isomer), mp 145-149 ° C (dec.).

I.R. (Nujol): 3250.1765.1650 cm "1

(38) 7- [2-cinnamyloxyimino -2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) thiomethyl-3-cephem-4-

i5 carboxylic acid (syn isomer)

I.R. (Nujol): 3350-3100, 1760, 1650, 1620, 1520 cm "1

(39) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomeres)

20 I.R. (Nujol): 3300.3200.1770.1660.1630.1600 cm "1

(40) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] cephalosporanic acid (syn isomer), mp 185-192 ° C (dec.).

I.R. (Nujol): 3380.3250.1780, 1700.1650 cm-1 25 (41) 7- [2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothi-azol-4-yl) acetamido] cephalosporanoic acid ( syn-isomer), mp 200-205 ° C (dec.).

I.R. (Nujol): 1730.1640.1600, 1230.1020 cm "1

(42) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2-30 (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazole -2-

yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3400-3100.1760, 1660, 1620, 1520 cm "1

(43) 7- [2-carboxymethoxyimino -2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-

35 carboxylic acid (syn isomer), mp 178-180 ° C (dec.).

I.R. (Nujol): 3300.3280.1770.1670.1630 cm "1

(44) 7- [2-t-Butoxycarbonylmethoxyimino -2- (2-form-amidothiazol-4-yl) acetamido] -3- [tetrazolo [l, 5-b] pyridazin-6-yl] thiomethyl-3- cephem-4-carboxylic acid (syn isomer).

«I.R. (Nujol): 3150.1780.1720.1670 cm ~>

N.M.R. (DMSO-d6.5): 1.42 (9H, s), 3.73 (2H, m), 4.25-4.85 (4H, m), 5.17 (IH, d, J = 4 Hz), 5.84 (IH, dd, J = 4 and 8 Hz), 7.43 (IH, s), 7.72 (IH, d, J = 10 Hz), 8.50 (IH, s), 8.56 (IH, d, J = 10 Hz), 9.56 (IH, d , J = 8 Hz) 45 (45) 7- [2- (t-butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- [tetrazolo [l, 5-b] pyridazine- 6-yl-] thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300.1770.1670.1620 cm "'

(46) 7- [2-carboxymethoxyimino -2- (2-aminothiazol-4-50 yl) acetamido] -3- [tetrazolo [1,5-b] pyridazin-6-yl] thiomethyl-3-cephem-4- carboxylic acid (syn isomer).

. I.R. (Nujol): 3270.3170.1765.1670.1620 cm- '

55

Example 5

A mixture of 0.58 g of 7- [2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer), 0.405 g of concentrated hydrochloric acid, 8.7 ml of methanol and 5 ml of tetrahydrofuran was stirred at ambient temperature for 2 hours and 10 mi-60 minutes. The solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous sodium hydroxide solution (pH 7 to 8.5). An insoluble material was filtered off and the filtrate was adjusted to pH 3.4 with 10% chloro-65 hydrochloric acid under ice cooling and stirred for 30 minutes. The precipitates were collected by filtration, washed with water and dried, giving 0.4 g of 7- [2-methylthiomethoxyimino -2- (2-ami-

643 849

20th

nothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer)

received.

I.R. (Nujol): 3340.3200.1775.1670 cm-1

N.M.R. (d6-DMSO, 8): 2.23 (3H, s), 3.74 (2H, s), 4.48 (2H, ABq, J = 13 Hz), 5.20 (IH, d, J = 5 Hz), 5.24 (2H, s), 5.83 (IH, d, d, J = 5 and 9 Hz), 6.83 (IH, s), 7.28 (2H, broad s), 9.62 (IH, s), 9.68 (lH, d, J = 9Hz )

Example 6

A mixture of 2.3 g of 7- [2-t-butoxycarbonylmethoxy-imino -2- (2-formamidothiazol-4-yl) acetamido] -3- (l, 3,4-thia-diazol -2-yl) thiomethyl -3-cephem-4-carboxylic acid (syn isomer), 3.74 g of concentrated hydrochloric acid and 35 ml of methanol were stirred at ambient temperature for 2 hours and 40 minutes. The solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous sodium hydroxide solution (pH 7 to 8). The aqueous solution was adjusted to pH 3.0 with 10% hydrochloric acid under ice cooling and stirred for 30 minutes. The precipitates were collected by filtration, washed with water and dried, yielding 1.1 g7- [2-t-butoxycarbonylmethoxyimino -2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4- thiadiazol -2-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) was obtained.

I.R. (Nujol): 3300, 1775, 1730, 1675, 1630 cm "1

N.M.R. (d6-DMSO, 5): 1.46 (9H, s), 3.67 (2H, s), 4.42 (2H, ABq, J = 14 Hz), 4.55 (2H, s), 5.16 (IH, d, J = 5 Hz) '5.78 (IH, d, d, J = 5 and 9 Hz), 6.77 (IH, s), 7.21 (2H, s), 9.43 (IH, d, J = 9 Hz), 9.52 (IH, s )

Example 7

To a stirred solution of 2.7 g of sodium acetate in 46 ml of water was added 2.3 g of 7- [2- (4-fluorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacetamido) thiazol-4-yQacetamido] -3- (l, 3,4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid was added and the mixture was stirred at ambient temperature for 20.5 hours. The reaction mixture was adjusted to pH 5.0 with 10% hydrochloric acid after the addition of ethyl acetate, and the resulting mixture was shaken. The aqueous layer was separated, washed twice with ethyl acetate and adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried, giving 1.82 g of 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3 , 4-thiadiazol -2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145 to 149 ° C (dec.).

I.R. (Nujol): 3250.1765.1650 cm "1

N.M.R. (DMSO-d6.8,): 3.73 (2H, ABq, J = 18 Hz,), 4.48 (2H, ABq, J = 14 Hz,), 5.01 - 5.39 (3H, m,), 5.85 (IH, dd , J = 4 and 8 Hz,), 6.83 (IH, s,), 7.02-7.75 (4H, m,), 9.63 (IH, s,), 9.75 (IH, d, J = 8 Hz,)

Example 8

The following compounds were prepared in a manner similar to that given in Examples 5-7.

(1) 7- [2-Benzyloxyimino -2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

LR. (Nujol): 3320.3200.1770.1670.1610 cm "1

(2) 7- [2-Benzyloxyimino -2- (2-aminothiazol-4-yl) acetamido] -3- (l-hexyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3350.3250.1780.1680.1633 cm "1

(3) 7- [2-methylthiomethoxyimino -2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-ce-phem-4- carboxylic acid (syn isomer)

I.R. (Nujol): 3300.1770, 1670.1530 cm "1 NMR (d6-DMSO, 8): 2.20 (3H, s), 3.72 (2H, s), 3.97 (3H, s), 4.36 (2H, s) , 5.17 (IH, d, J = 5 Hz), 5.22 (2H, s), 5.82 (IH, d, d, J = 5 and 8 Hz), 6.82 (IH, s), 7.28 (2H, broad s) , 9.60 s (lH, d, J = 8 Hz)

(4) 7- [2- (2-ethoxyethoxy) imino -2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer)

I.R. (Nujol): 3160.3100.1780.1670.1630 cm- 'io N.M.R. (d6-DMSO, 8): 1.08 (3H, t, J = 7 Hz), 3.45 (2H, q, J = 7 Hz), 3.5 ~ 3.90 (4H, m), 4.20 (2H, t, J = 4 Hz), 4.47 (2H, ABq, J = 13 Hz), 5.17 (IH, d, J = 5 Hz), 5.80 (IH, d, d, J = 5 and 8 Hz), 6.77 (IH, s), 9.55 (IH, s), 9.55 (IH, d, J = 8 Hz)

(5) 7- [2-ethoxycarbonylmethoxyimino -2- (2-aminothi-15 azol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiometh-

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

I.R. (Nujol): 3350.3220, 1780, 1680.1630 cm "1 NMR (d6-DMSO, 8): 1.23 (3H, t, J = 7 Hz), 3.70 (2H, s), 3.97 (3H, s) , 4.16 (2H, q, J = 7 Hz), 4.35 (2H, s), 4.69 (2H, 2o s), 5.15 (IH, d, J = 5 Hz), 5.80 (IH, d, d, J = 5 and 9 Hz), 6.81 (IH, s), 7.24 (2H, broad s), 9.54 (IH, d, J = 9 Hz)

(6) 7- [2-ethoxycarbonylmethoxyimino -2- (2-aminothi-azol-4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) thiomethyl-

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

25 LR. (Nujol): 3350.3230.3100.1780.1680.1630 cnT1 N.M.R. (d6-DMSO, 8): 1.21 (3H, t, J = 7 Hz), 3.72 (2H, ABq, J = 18 Hz), 4.18 (2H, q, J = 7 Hz), 4.70 (2H, s) , 5.20 (IH, d, J = 5 Hz), 5.84 (IH, d, d, J = 5 and 8 Hz), 6.84 (IH, s), 7.26 (2H, broad s), 9.56 (IH, d, J = 8 Hz), 9.60 (IH, s) 30 (7) 7- [2-carboxymethoxyimino -2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5 -yl) thiomethyl-3-ce-phem-4-carboxylic acid (syn-isomer)

I.R. (Nujol): 3340.3200, 1775.1675.1630 cm "1 NMR (d6-DMSO, 8): 3.68 (2H, s), 3.94 (3H, s), 4.32 35 (2H, AB ,, J = 14 Hz), 4.70 (2H, s), 5.14 (IH, d, J = 5 Hz), 5.78 (IH, d, d, J = 5 and 9 Hz), 6.81 (IH, s), 7.1 (2H, broad s), 9.59 (IH, d, J = 9 Hz)

(8) 7- [2- (3-isoxazolyl) methoxyimino -2- (2-aminothiazole-

4-yl) acetamido] -3- (l, 3,4-thiadiazole -2-yl) thiomethyl-3-ce-40 phem-4-carboxylic acid (syn-isomer)

I.R. (Nujol): 3350.3230.3110, 1775.1675 cm "1 NMR (d6-DMSO, 8): 3.71 (2H, ABq, J = 18 Hz), 4.46 (2H, ABq, J = 14 Hz), 5.17 (IH, d, J = 5 Hz), 5.27 (2H, s), 5.82 (IH, d, d, J = 5 and 8 Hz), 6.66 (IH, s), 6.83 (IH, s), 7.30 ( 2H, 45 widths), 8.87 (IH, s), 9.57 (IH, s), 9.75 (IH, d, J = 8 Hz)

(9) 7- [2-Carboxymethoxyimino -2- (2-aminothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomeres)

I.R. (Nujol): 3360.3240.3100.1780, 1680.1635 cm "1 50 (10) 7- [2-benzyloxyimino -2- (2-aminothiazol-4-yl) acetamido] -3- (1H -tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 172-174 ° C (dec.).

I.R. (Nujol): 3250.3150.1770.1620 cm "1

(11) 7- [2- (4-aminomethylbenzyloxyimino) -2- (2-amino-55 thiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) thiomethyl-

3-cephem-4-carboxylic acid dihydrochloride (syn isomer) I.R. (Nujol): 3400-3100.1770, 1660, 1620, 1540 cm "1 NMR (DMSO-d6.8): 3.68 (2H, broad), 3.97 (2H, d, J = 6 Hz), 4.43 (2H, ABq, J = 13 Hz), 5.12 (IH, d, J = 5 Hz), 60 5.12 (2H, s), 5.72 (IH, dd, J = 5 and 7 Hz), 6.88 (IH, s), 7.43 (4H, s), 9.5 (IH, s), 9.8 (IH, d, J = 7 Hz)

(12) 7- [2- (t-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1 H-tetrazol-5-yl) thiomethyl-

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

I.R. (Nujol): 3280.3200.1770.1670.1630 cm- '

(13) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazole-

4-yl) acetamido] -3- (l-methyl-lH-tetrazoI-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer)

65

Claims (24)

643849 2nd PATENT CLAIMS 1,3,7-disubstituted 3-cephem-4-carboxylic acid compounds, characterized by the general formula: R \ N— \ n - / - \ —c-cqnh—> f% R "S 11 (i) gr2 coor in which: the proviso that R2 is not carboxy (lower) alkyl, R "'OOC- R 'and R "each represent hydrogen or a protective group, 15 (lower) alkyl, where R"' represents a protective group, or R2 represents an aliphatic hydrocarbon group with a benzyl when R4 represents acetoxy and that R2 or more substituents, not benzyl, when R4 is substituted by a methyl group. R represents hydrogen or a protective group, and substituted tetrazolylthio, and the salts thereof. R4 is hydrogen, acyloxy or a heterocyclic thio 2. Syn isomer of a compound according to claim 1, group, which may be substituted by lower alkyl, characterized by 20, that the group r 'Vf r' n i N — fi— - || —one of the formula ^ B'i / R'j / S is. 3. Compound according to claim 1 or 2, characterized thereby) alkanoyl, e.g. Formyl or 2,2,2-trifluoroacetyl, R "What-records that R2 lower alkylthio (lower) alkyl, lower serum and R2 lower alkylthio (lower) alkyl, lower alkoxy (lower) alkyl, Ar (lower) alkenyl, acyloxy (lower) - alkoxy (lower) alkyl, phenyl (lower) alkenyl, lower alk-alkyl, carboxy (lower) alkyl, R "'OOC- (lower) alkyl, wherein 30 anoyloxy (lower) alkyl, carboxy (lower) alkyl , lower alk-R "'represents a protecting group, isoxazolyl (lower) alkyl or oxycarbonyl (lower) alkyl, isoxazolyl (lower) alkyl or ar (lower) alkyl, the halogen, hydroxy, amino (lower) alk-phenyl (low) alkyl, which may have 1 or 2 halogen atoms, hydroxy, yl or acylamino (lower) alkyl, R water-amino (lower) alkyl or lower alkoxycarbonyl- and R4 may have hydrogen, lower alkanoyloxy, carbamino (lower) alkyl groups, e.g. Methyl-yloxy, thiadiazolylthio, tetrazolopyridazinylthio or Te-35 thiomethyl, ethoxyethyl, cinnamyl, formyloxyethyl, carb-trazolylthio, which may have a lower alkyl group, oxymethyl, ethoxycarbonylmethyl, t-butoxycarbonylmeth-mean, with the measure, not carboxy (nied- yl, isoxazolylmethyl or benzyl, which represents 1 or 2 fluoro-, bromo-rig) -alkyl, R "'OOC- (lower) alkyl or benzyl, if atoms, hydroxy-, aminomethyl- or t-butoxycarbonyl-R4 Acetoxy means, and that R2 is not benzyl, may have aminomethyl groups. when R4 means tetrazolylthio with a methyl group. 40 10. A compound according to claim 9, consisting of 4. A compound according to claim 3, characterized in that 7- [2-methylthiomethoxyimino -2- (2-aminothiazol-4-yl) -that R 'is lower alkanoyl, R "is hydrogen, R2 is lower alkacetamido] -3- (l , 3,4-thiadiazol -2-yl) thiomethyl-3-cephem-4-anoyloxy (lower) alkyl and R4 is hydrogen or carbamoylcarboxylic acid, syn isomer, oxy mean. 7- [2-Cinnamoyloxyimino -2- (2-aminothiazol-4-yl) acet- 5. A compound according to claim 3, characterized in that 45 amido] -3- (l, 3,4-thiadiazole -2- yl) thiomethyl-3-cephem-4-that R2 ar (lower) alkyl having 1 to 2 halogen atoms and R4 carboxylic acid, syn isomer, mean lower alkanoyloxy. 7- [2-carboxymethoxyimino -2- (2-aminothiazol-4-yl) - 6. Compound according to claim 5, characterized in acetamido] -3- (l, 3,4-thiadiazole -2- yl) thiomethyl-3-cephem-4-that R 'is hydrogen or halogen (low) alkanoyl, R "What - carboxylic acid, syn isomer, and R2 and phenyl (lower) alkyl with 1 to 2 halogenato- 50 7- [2- (3-isoxazolyl) methoxyimino -2- (2-aminothiazole-men. 4-yl) acetamido] -3- (1,3 , 4-thiadiazol-2-yl) thiomethyl 7. A compound according to claim 6, characterized in that 3-cephem-4-carboxylic acid, syn isomer, that R 'is hydrogen or trihalogen (low) alkanoyl, e.g. 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] - 2,2,2-trifluoroacetyl, R "hydrogen, R2 benzyl with 1 to 2 3- (l, 3,4-thiadiazol -2-yl) thiomethyl-3-cephem-4-carbon chlorine or fluorine atoms, for example 4 -Fluorobenzyl or 3,4-di- 55 acid, syn isomer, chlorobenzyl, and R4 mean acetoxy. 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) - 8. A compound according to claim 3, characterized in acetamido] -3- (l, 3,4-thiadiazole -2- yl) thiomethyI-3-cephem-4-that R 'is hydrogen, lower alkanoyl or halocarboxylic acid, syn- Isomeres, (lower) alkanoyI, R "hydrogen, R2 lower alkylthio- 7- [2- (3-hydroxy-4-bromobenzyloxyimino) -2- (2-amino- (lower) alkyl, lower alkoxy (lower) alkyl, Ar (lower) - 60 thiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) alkenyl, lower alkanoyloxy (low ) alkyl, carboxy-thiomethyl-3-cephem-4-carboxylic acid, syn isomer and (lower) alkyl, lower alkoxycarbonyl (lower) alkyl, isox- 7- [2- (4-aminomethylbenzyloxyimino) -2- (2-aminothi- azolyl (lower) alkyl or ar (lower) alkyl, the 1 to 2 halo-azol-4-yl) acetamido] -3- (l, 3,4-thiadiazol -2-yl) thiomethyl-3-gene atoms, hydroxy- , Amino (lower) alkyl or lower alk-cephem-4-carboxylic acid, syn isomer and their dihydro-oxycarbonylamino (lower) alkyl groups, 65 chloride. and R4 is thiadiazolylthio. 11. A compound according to claim 3, characterized 9. A compound according to claim 8, characterized in that R 'is hydrogen or lower alkanoyl, e.g. Formyl that R 'is hydrogen, lower alkanoyl or trihalo (lower- R "hydrogen, R2 carboxy (lower) alkyl or lower 643849 Alkoxycarbonyl (lower) alkyl, e.g. Carboxymethyl or t-butoxycarbonylmethyl, and R4 mean tetrazolopyridazinylthio. 12. The compound of claim 11, consisting of 7- [2-carboxymethoxyimino -2- (2-aminothiazol-4-yl) - acetamido] -3- [tetrazolo [1,5-b] pyridazin-6-yl] thiomethyl-3-cephem-4-carboxylic acid, syn isomer. 13. A compound according to claim 3, characterized in that R 'is hydrogen, lower alkanoyl or halogen (lower) alkanoyl, R "hydrogen, R2 lower alkylthio- (medrig) alkyl, lower alkanoyloxy (lower) alkyl, carboxy (low ) alkyl, lower alkoxycarbonyl (lower) alkyl or phenyl (lower) alkyl, which may have a halogen atom, and R4 means tetrazolylthio, which may have a lower alkyl group, with the proviso that R2 is not benzyl when R4 is tetrazolylthio with a Means methyl group. 14. A compound according to claim 13, characterized in that R2 carboxy (lower) alkyl, lower alkoxycarbon-yl (lower) alkyl or phenyl (lower) alkyl, which may have a halogen atom, and R4 tetrazolylthio, which may have a hexyl group , mean. 15. A compound according to claim 14, characterized in that R 'is hydrogen, formyl or 2,2,2-trifluoroacetyl, R "is hydrogen, R2 is carboxymethyl, ethoxycarbonylmethyl, t-butoxycarbonylmethyl or benzyl, which may have a fluorine atom. 16. The compound of claim 15 consisting of 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] - 3- (1-hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer, 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer and 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer . 17. A compound according to claim 13, characterized in that R2 is lower alkylthio (lower) alkyl, lower alk-anoyloxy (lower) alkyl, carboxy (lower) alkyl, lower alk-oxycarbonyl (lower) alkyl or phenyl (lower) alkyl with one Halogen atom and R4 tetrazolylthio with a methyl group. 18. A compound according to claim 17, characterized in that R 'is hydrogen, formyl or 2,2,2-trifluoroacetyl, R "is hydrogen and R2 is methylthiomethyl, formyloxyethyl, carboxymethyl, ethoxycarbonylmethyl, t-butoxycarbonyl-methyl or benzyl with a fluorine atom. 19. A compound according to claim 18, consisting of 7- [2-methylthiomethoxyimino -2- (2-aminothiazol-4-yl) - acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-ce-phem-4-carboxylic acid, syn isomer. 7- [2-Carboxymethoxyimino -2- (2-aminothiazol-4-yl) acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3-ce-phem-4-carboxylic acid, syn -Isomeres and 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-ce-phem- 4-carboxylic acid, syn isomer. h2n n-t-t ^ o T CVR ai) coor in which R and R4 each have the meanings given above, or a ship see base with a carbonyl compound, a silyl derivative or a phosphorus trichloride or phosgene derivative of the amino group or a salt thereof with a carboxylic acid of the general formula: 15 R ' r " N — U- c-c00h i at) 20th <2 OR wherein R ', R "and R2 each have the meanings given above, or a reactive derivative on the carboxy group or a salt thereof. 25 21. Process for the preparation of a compound of the general formula: H- 30th c-cohh '... 11 1 '' lch2-r4 <ib> 20. A process for the preparation of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds of the formula given and defined in claim 1, and the salts thereof, characterized in that an amino compound of the general formula h ^ coor 35 wherein R2 is an aliphatic hydrocarbon group with one or more substituents, R is hydrogen or a protective group and R4 is hydrogen, acyloxy or a heterocyclic thio group, which may have lower alkyl, with the proviso that R2 is not carboxy (low) - 4o alkyl, R "'OOC- (lower) alkyl, wherein R"' represents a protecting group, or benzyl when R4 represents acetoxy and that R2 does not represent benzyl when R4 represents tetrazolylthio substituted by a methyl group, or the salts thereof , characterized in that one 45 binding the general formula: or2 0 T coor 55 wherein R2 and R4 each have the meanings given above, R'a is a protecting group and R "is hydrogen or a protecting group, or a salt thereof is subjected to an elimination reaction to remove the amino protecting group (s). 6o 22. Process for the preparation of a compound of the general formula: r ',, iML ^ -COJÄ-r-p ^ èR2b 'W coor 50 -CH2-Rm (Ia) 643 849 4 wherein R, R 'and R "each have the meanings given above, lower alkyl can be substituted, or the salts have, R2b carboxy (lower) alkyl and R4a hydrogen, carb- the same, characterized in that one is a Verbin-amoyloxy or a heterocyclic thio group which is obtained by applying the general formula: r! r ' , n- -c-conh I! ? rti_ or 2a -ch2-r 4a (Ic) coor in which R, R ', R "and R4a each have the above-mentioned meaning elimination reaction for removing the carboxy protections and R2a R"' OOC- (lower) alkyl, in which R "'subjects a grapple R"'. Represents protecting group means, or a salt thereof a 23. Process for the preparation of a compound of the general 15 my formula: \ N - \\ zn'i: s j. r "s n j— ? 2 0 OR ch2-s-r " (If) coor in which R, R 'and R "each have the meanings given above25, with the proviso that R2 is not benzyl, R2 is an aliphatic hydrocarbon group with tetrazolyl or one or more substituents and R4' substituted by a methyl group and R4 ' represents a heterocyclic group, or the salts thereof, characterized in that group which may be substituted by lower alkyl, in that a compound of the general formula: (Ie) coor in which R, R ', R "and R2 each have the meaning given above in combination with a pharmaceutically acceptable one and X' is a leaving group which contains conferred, non-toxic carriers or excipients. can be pushed by a radical of the formula R4'-S- wherein R4 'has the meanings given above, or a salt of same with a compound of the general formula: The invention relates to new 3,7-disubstituted-3-cephem- 4-carboxylic acid compounds and their salts, in particular R4'-SH (VIII) 45 their pharmaceutically acceptable salts which have antibacterial activity, process for their preparation and in which R4 'has the meanings given above, or a pharmaceutical composition containing them the treatment implements metal salt on the mercapto group thereof. of infectious diseases in humans and animals. 24. Antibacterial pharmaceutical agent, characterized in that the 3.7-disub-an object of the invention that at least one 3,7-disubstituted-3- 50 substituted-3-cephem-4-carboxylic acid compounds are new cephem -4-carboxylic acid compound according to one of the claims and they can be represented by the general formula 1 to 19, or a pharmaceutically acceptable salt: (I) coor R2 is not carboxy (lower) alkyl, R "'OOC- (lower) alkyl, wherein R"' is a protecting group, or benzyl when R4 is acetoxy, and that R2 is not benzyl when R4 is methyl substituted tetra- 65 means zolylthio. The new compounds according to the invention of the above group, which may have lower alkyl, with the general formula (I) given, are prepared by processes 1 to 4 given below. in which mean: R 'and R "are each hydrogen or a protective group, R2 is an aliphatic hydrocarbon group with one or more substituents R is hydrogen or a protective group, and R4 is hydrogen, acyloxy or a heterocyclic thio Procedure 1 643 849 h2n_ 0 s * o- ' \ ^ - ch -r "N coor (II) or certain reactive derivatives on the amino group or salts thereof > ~ o r "s "c-cooh II n * 2 OR (III) or their reactive derivative on the carboxy group or a salt thereof H \ N—, / "~ 0" R "s N or a salt thereof Method 2 c-conh or ' coor (I) R »M -N : h2-r (ia) Elimination of the amino protecting group or a salt thereof coor N -o-c0hk n o & r2 or a salt thereof Method 3 gï2 ~ r 4th coor R \ • / ^ v-SrC0NH r "s n 0R2a 0 Elimination of the carboxy protecting group in R2a (Ib) 7 -cm-R <a (lc) coor 65 or a salt of it 643849 r ' n. n ~~ tì "h} - rf, / or a salt of it • c-conh- n i or 2 B ff "n ch2-r Ma coor (Id) Method 4 r '" n- n-h-yf " s (la) or a salt thereof r: c-conh Ii n * 2 OR r »N -n 0 ch2-x '+ r -sh coor (XVIII) r " .n n -O . c-conh-ft n 5 2 OR 0 coor ch2-s-r or a metal salt on the mercapto group (If) or a salt thereof a rocyclic group which may have a lower alkyl, wherein R, R ', R ", R2 and R4 each represent the above-mentioned names, R'a have a protective group, R4a is hydrogen, carbamoyloxy or a heterocyclic R2a R "'OOC- (lower) alkyl, wherein R"' represents a protecting group - thio group, which may have lower alkyl, with the proviso that R2 is not benzyl when R4 'tetra- R2b means carboxy (lower) alkyl and zolyl with a methyl group. X 'denotes a leaving group which are displaced. Among the starting compounds are the compounds Vann by a radical of the formula R4'-S-, wherein R4 'is a hetero of the formula (III) new and they can be prepared by 35, which are illustrated by the following reaction scheme-q-j: CHç-CO-C-Z 4th :> ch „-c0-c-z -salogaihh ^ k b H II n 5 2 QIC (IV) (v) h2n-c-nh2 y ~ ch9 ~ co ~ c ~ z • z- i & r2 (vi) N-tpC-z 2nd (VII) 0R at C-COOIi R \ 4th fr ■ - c-coqh ii N s *? or * " OR amino protecting group agent (Illa) (Illa ') 643849 1 (2) 2 Rt R 0-NH2 R N-S "-jj-COCOOH (IX ^ ^ Ç-COOH .. "". -HT "! • p / \ / or a / k. J I ' R S salt thereof R "s N (VIII) (III) R- a * 2 OR ^ n \ «n f« w n "fh -ft-C-Z amino protection- N -fr -jt-C-Z> R -—W -jrC-î S ^ il grapp ^ -s> R "^ \, '" N S ^ N ! t \ OH OH OR (X) (XI) (XII) 2nd Elimination -f? a ^ -t ~ l ~ irc00h R "Ns N * 2 OR (IIIb) where R ', R'a, R "and R2 each have the meanings given above. Some of the other starting compounds (II) are also have, Z is protected carboxy and Y is halogen. C6H13K'H2 CS. if new and they can be made using the procedures outlined below: - »c6h13nhcs-se r5-y * (XIV) • (XIII) or a salt of it C, .H,, NHCS-SR "u ló (XV) X-N (XVI) 1 " A— Ir- R " (XVII) or a salt thereof n -n // HS "\ N fc6DlS or a salt of it 55 y-CH2-It6 K * ~ -N ] ^ ch2s-0 ' (/ -l'i Y <• y "3 I "C6H13 (IIa) • or a salt thereof -> 643849 wherein R3 has the meanings given above, Y 'is an acid residue, R5 lower alkyl, R6 is a group which is represented by a radical of the formula n -N _u_ JL " co-ft-or ' n — n s4 "> 5 are represented in their molecule, while the corresponding anti-isomer is represented by the partial structure of the formula vh13 may be substituted, and X is an alkali metal. With regard to the compounds of the formulas (I), (Ib), (Id) and (If) according to the invention and the starting compounds of the formulas (la), (le), (Ie), (III), (Illa), (Illa ') , (Illb), (VII), (VIII) and (X) to (XII) it should be noted that these compounds and starting compounds according to the invention also include the tautomeric isomers with respect to their thiazole groups. That is, the group of the formula -f | 20- c-co- -n can be represented in its molecule and if it is expedient for the explanation of the present invention to express both the syn isomer and the anti isomer by a general formula, this is represented by the partial structure of the formula n 1 20th c-coli £ rz R'R "N - ^ - ~ 4} - (wherein R 'and R "have the meanings given above) in the compounds and starting compounds according to the invention can alternatively also by their tautomeric form hn- A r'n are shown. This means that the two forms exist as so-called tautomers in the state of equilibrium, which can be represented by the following equation: n n. hn- r'r "n in the n r'n (a) (B) These types of tautomerism between 2-aminothiazole compounds and 2-iminothiazoline compounds, as indicated above, are known per se in the literature and it will be readily apparent to those skilled in the art that both tautomeric isomers are in equilibrium and are easily interrelated are convertible and consequently these isomers are also within the scope of the present invention, ie belong to the connection itself. Both tautomeric forms of the compounds according to the invention and of the starting compounds are clearly encompassed by the present invention. In addition, with regard to the compounds (I), (Ib), (Id) and (If) according to the invention and the starting compounds (la), (le), (Ie), (III), (Illa), (Illa '), ( Illb), (IV) to (VII) and (X) to (XII) that these compounds and starting compounds according to the invention also include the respective syn isomers, anti isomers and mixtures thereof. For example, in the compound (I) according to the invention, the syn isomer can be represented by the partial structure of the formula With regard to the other compounds and starting compounds according to the invention, as mentioned above, the syn isomers and anti isomers can also be based on the same geometric isomers as are shown for the compound (I). Suitable salts, in particular pharmaceutically acceptable salts of the 3,7-disubstituted-3-Ce-30-phem-4-carboxylic acid compounds (I) according to the invention are conventional salts, in particular conventional non-toxic salts and may include an inorganic salt, e.g. a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt and the like) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt and the like), the ammonium salt and the like, an organic salt, e.g. an organic amine salt (e.g. trimeth-ylamine salt, triethylamine salt, ethanolamine salt, diethanolamine salt, pyridine salt, picolinic salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt and the like) and the like, an or-40 ganic acid salt (e.g. an acetate, maleate Tartrate, methane sulfonate, benzenesulfonate, toluenesulfonate and the like), an inorganic acid salt (e.g. a hydrochloride, hydrobromide, sulfate, phosphate and the like) or a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid and 45 like.) and the like The various definitions as used here are explained in more detail below and suitable examples are given. The term “low” or “low” 50 used here means a group with 1 to 6 carbon atoms, unless stated otherwise. The protecting groups of the amino group (R 'and R ") are in particular the acyl group, furthermore Ar (lower) alkyl (such as benzyl, trityl and the like) or the like. 55 A suitable acyl radical in the terms "acylamino", "acylimino" and "acyloxy" may include carbamoyl, an aliphatic acyl group and an acyl group containing an aromatic or heterocyclic ring. Suitable examples of the acyl can be its lower alkanoyl (such as form-60 yl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, hexanoyl and the like), preferably one having 1 to 4 carbon atoms, in particular one with 1 to 2 carbon atoms; lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g. methoxycarbonyl, 65 ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl and the like); 9 643 849 lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, oxy-3,5-di-tert-butylbenzyl ester and the like); an aryl ester which Propanesulfonyl, isopropanesulfonyl, butanesulfonyl and the like); can have one or more suitable substituents Arenesulfonyl (e.g. benzenesulfonyl, tosyl and the like); (such as a phenyl, tolyl, tert-butylphenyl, xylyl, Aroyl (e.g. benzoyl, toluoyl, naphthoyl, phthaloyl, mesityl, cumenyl ester and the like) and the like Indancarbonyl and the like); 5 Preferred examples of protected carboxy can be Ar (lower) alkanoyl (such as phenylacetyl, phenylpropionyl and lower alkoxycarbonyl (such as methoxycarbonyl, ethoxy- Like.); carbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycar- Ar (lower) alkoxycarbonyl (such as benzyloxycarbonyl, bonyl, t-pentyloxycarbonyl, hexyloxycarbonyl and the like) Phenethyloxycarbonyl and the like); and the like. 2 to 7 carbon atoms, preferably having 2 to 5 carbon atoms The above The acyl radical can have 1 to 3 suitable substituents and 10 atoms. have, such as Halogen (such as chlorine, bromine, iodine or suitable aryl and a suitable aryl radical in the AusFluor), hydroxy, cyano, nitro, lower alkoxy (such as meth-press "arylthio" and "aryloxy" can include phenyl, oxy, ethoxy, propoxy, Isopropoxy and the like), lower alkyl tolyl, xylyl, mesityl, cumenyl, naphthyl and the like, which (such as methyl, ethyl, propyl, isopropyl, butyl and the like), lower aryl group may have 1 to 3 suitable substituents, res alkenyl (such as vinyl, allyl and the like), aryl (such as phenyl, toi-15 such as halogen (such as chlorine, bromine, iodine or fluorine), hydr-yl and the like) or the like oxy, amino (low) alkyl (such as aminomethyl, aminoethyl, a preferred example of acylamino can be lower aminopropyl, aminobutyl and the like), protected aminores alkanoylamino or mono-, di- or (lower) alkyl, wherein the protected amino is trihalo (low) as defined above alkanoylamino and a preferred example, preferably lower alkoxycarbonylamino (lower) alk game for acyloxy may be n lower alkanoyloxy or carb-20 yl (such as methoxycarbonylaminomethyl, ethoxycarbonylamoyloxy. aminomethyl, t-butoxycarbonylaminomethyl and the like.) or The aliphatic hydrocarbon group is the like. A suitable lower alkoxy can include such a clical aliphatic hydrocarbon group with 1 to 6 carbon atoms which can be branched, e.g. Methoxy, ethoxy, propoxy, and they can include lower alkyl, cyclo-isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, (lower) alkyl, lower alkenyl, lower alkynyl and the like. Hexyloxy and the like, and it may preferably be one with This aliphatic hydrocarbon group has 1 to 2 1 to 4 carbon atoms, especially one with 1 to suitable substituents, e.g. Carboxy, protected 2 carbon atoms. Carboxy, arylthio, lower alkylthio, aryl, acyloxy, lower - under a suitable heterocyclic group and a res alkoxy, aryloxy, a heterocyclic group or the like or a suitable heterocyclic radical in the expression “a A suitable lower alkyl and a lower alkyl group in heterocyclic thio group which have lower alkyl can have the terms lower alkylthio, carboxy (lower) alkyl is a saturated or unsaturated, monocyclic and R "'OOC- (lower) alkyl can include such a the or polycyclic heterocyclic group to understand the. can be branched, e.g. Methyl, ethyl, propyl, isoprop- at least one heteroatom, e.g. an oxygen, welding yl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like, 35 of which contains a free atom, a nitrogen atom and the like. A particularly lower alkyl can preferably be a preferred heterocyclic group can be a heterocyclic one with 1 to 4 carbon atoms, in particular a sol group such as an unsaturated 3 to 8-membered (preferably ches with 1 to 2 carbon atoms. 5- to 6-membered) heteromonocyclic group, the 1 to 4 A suitable cyclo (lower) alkyl is one containing 3 to nitrogen atoms, e.g. Pyrrolyl, pyrrolinyl, imida- 6 carbon atoms and it can include cyclopropyl, 40 zolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazi- Cyclobutyl, cyclopentyl, cyclohexyl and the like. Nyl, pyridazinyl, triazolyl (such as 4H-1,2,4-triazolyl, IH-1,2,3- A suitable lower alkenyl is one having 2 to 6 triazolyl, 2H, 1,2,3-triazolyl and the like), tetrazolyl (such as 1H carbon atoms and may include, for example, vin-tetrazolyl or 2H-tetrazolyl) and the like; yl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl and his 8-membered (preferably 5 to the like. "6_gi - A suitable lower alkynyl is one with 2 to 6 atoms, such as z.o. rjnuuumji, muuiuuuump, x * Carbon atoms and may include ethynyl, 2-peridino, piperazinyl and the like; pinyl, 2-butynyl, 3-pentenyl, 3-hexynyl and the like, an unsaturated condensed heterocyclic group, The carboxy group can be protected in the form of an ester containing 1 to 5 nitrogen atoms, e.g. Indolyl, isoindosein, in which the ester residue can be, for example, a lower 50 lyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, inda- Alkyl esters (such as methyl, ethyl, propyl, isopropyl, butyl, zolyl, benzotriazolyl, tetrazolopyridazinyl and the like; Isobutyl, t-butyl, pentyl, t-pentyl, hexyl, 1-cyclopropyl- an unsaturated 3- to 8-membered (preferably 5 to ethyl ester and the like), wherein the lower alkyl radical is preferably 6-membered ) heteromonocyclic group, which may be 1 to 2 acids of 1 to 4 carbon atoms; contains one nitrogen atom and 1 to 3 nitrogen atoms, e.g. Oxa-der alkenyl esters (such as vinyl, allyl esters and the like); a lower 55-zolyl, isoxazolyl, oadiazolyl (such as 1,2,4-oxadiazolyl, alkoxy ester (such as ethynyl, propynyl ester and the like); 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl and the like .) and the like; Mono (or di- or tri-halogen (lower) alkyl esters (such as a saturated 3- to 8-membered (preferably 5- to 2-iodoethyl ester, 2,2,2-trichloroethyl ester and the like); a lower 6-membered ) heteromonocyclic group which contains 1 to 2 acid alkanoyloxy (lower) alkyl esters (such as acetoxymethyl, substance atoms and 1 to 3 nitrogen atoms, such as, for example, morphopropionyloxymethyl, butyryloxymethyl, valeryloxymeth 60 pholinyl and the like; yl, pivaloyloxymethyl, hexanoyloxymethyl, 2-acetoxy ether - an unsaturated condensed heterocyclic group, yl, 2-propionyloxyethyl ester and the like.); a lower alkane which contains 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms sulfonyl (lower) alkyl esters (such as mesylmethyl, 2-mesylethyl, such as benzoxazolyl, benzoxadiazolyl and the like; esters and the like); an ar (lower) alkyl ester (such as phenyl- an unsaturated 3 to 8-membered (preferably 5 to (lower) alkyl ester containing one or more suitable substituent 65 6-membered) heteromonocyclic group containing 1 to 2 residues (such as a benzyl, 4-methoxybenzene atom and contains 1 to 3 nitrogen atoms, such as thiazo- yl, 4-nitrobenzyl, phenethyl, trityl, diphenylmethyl, lyl, thiadiazolyl (such as 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, Bis (methoxyphenyl) methyl-, 3,4-dimethoxybenzyl-, 4-hydro- 1,2,5-thiadiazolyl and the like) and the like; -s-l è, 643 849 10 a saturated 3- to 8-membered (preferably 5- to dung (II) or certain reactive derivatives on the amine 6-membered) heteromonocyclic group, which contains 1 to 2 Swiss groups or a salt thereof with the compound (III) felatoms and 1 to 3 nitrogen atoms, e.g. Thiazo or its reactive derivative on the carboxy group lidinyl and the like; or a salt of it. an unsaturated 3 to 8-membered (preferably 5 to 5-membered) The reactive derivatives mentioned on the amino-6-membered) heteromonocyclic group which is a sulfur group of the compound (II) contains the Schiff bases or tom, such as e.g. Thienyl and the like; the tautomeric enamines formed by reacting the Ver an unsaturated condensed heterocyclic group, bond (II) with a carbonyl compound such as acetoacetic acid containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, acid or the like; a silyl derivative formed by reaction such as e.g. Benzothiazolyl, benzothiadiazolyl and the like; wherein io of the compound (II) with a silyl compound, such as the heterocyclic group 1 to 2 lower alkyl substituents trimethylsilylacetamide, bis (trimethylsilyl) acetamide or (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the like; and a derivative, formed by reacting the verbin-pentyl, cyclopentyl, hexyl, cyclohexyl and the like.) Have dung (II) with phosphorus trichloride or phosgene. can. Suitable salts of the compounds (II) and (III) can be Suitable halogen may include chlorine, bromine, an acid addition salt such as e.g. an organic fluorine and iodine. Acid salt (such as an acetate, maleate, tartrate, benzenesulfonate, A suitable acid residue may include the above toluenesulfonate and the like) or an inorganic acid salt called halogen, lower alkanesulfonyloxy (such as mesyloxy (such as a hydrochloride, hydrobromide, sulfate, phosphate and ethanesulfonyloxy and the like), arenesulfonyloxy (such as benzenesulfide) .); a metal salt (such as sodium, potassium, calcium, fonyloxy, p-toluenesulfonyloxy and the like) and the like 20 magnesium salt and the like); the ammonium salt; an organic amine salt (such as a triethylamine, dicyclohexylamine salt, a suitable group represented by a group of the formula and the like) and the like. 2 ^ On suitable reactive derivatives on the carb .. oxy group of compound (III) may include an acid * 25 logenide, an acid anhydride, an activated amide, an activated r ^ H ter ester and the like. A suitable example may be an acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkyl v6 13 phosphoric acid, phenylphosphoric acid, diphenylphosphorus Acid, dibenzylphosphoric acid, halogenated phosphoric acid may include azido, which are described above and the like), dialkylphosphoric acid, sulfurous acid, named halogen, acyloxy and the like. Thiosulfuric acid, sulfuric acid, alkyl carbonic acid, one A suitable alkali metal may include sodium, potassium aliphatic carboxylic acid (such as pivalic acid, pentanoic acid, lium and the like. Isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid A suitable radical X can include azido, the above 35 un (j. The like) or an aromatic carboxylic acid (such as benzo-called halogen, acyloxy and the like. Acid and the like.); a symmetrical acid anhydride, an active Among the suitable examples of each of the fourth amide groups with imidazole, 4-substituted imidazole, di-compounds of the present invention as described above methylpyrazole, triazole or tetrazole; or an activated one, preferred examples are the following: esters (e.g. a cyanomethyl, methoxymethyl, dimethyl a preferred example for R 'is hydrogen, for R "Was- 40 iminomethyl [(CH3) 2-N + = CH -] -, vinyl, propargyl, p-Ni-serum, amino or acyl (especially lower alkanoyl trophenyl- , 2,4-dinitrophenyl, trichlorophenyl, pentachloro or halogen (lower) alkanoyl); phenyl, mesylphenyl, phenylazophenyl, phenylthio, p- a preferred example of R2 may be lower alkyl, nitrophenylthio, p-cresylthio, carboxymethylthio, thio (lower) alkyl, lower alkoxy (lower) alkyl, pyranyl, pyridyl, piperidyl, 8-quinolylthioester and the like.) Ar (lower) alkyl (especially phenyl (lower) alkyl), which can be an ester with an N-hydroxy compound (such as halogen, hydroxy, amino (lower) alkyl or N, N-dimethylhydroxylamine, l-hydroxy- 2- (lH) pyridone, N-acylamino (lower) alkyl, Ar (lower) alkenyl (especially hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-6-phenyl (lower) alkenyl), acyloxy (lower) alkyl (especially chloro- 1H-benzotriazole and the like.) and the like. These reactive lower alkanoyloxy (lower) alkyl), carboxy (lower) alkyl, gene derivatives can be selected in any manner from them-protected carboxy (lower) alkyl (especially lower 50 in Depends on the type of alkoxycarbonyl (lower) alkyl) or isoxazolyl (low) compound (III) used. alkyl; The implementation is usually carried out in a conventional a preferred example of R3 can be carboxy; ien solvents, such as water, acetone, dioxane, acetonitrile, and chloroform, methylene chloride, ethylene chloride, tetrahydro- a preferred example of R4 may be hydrogen, 55 furailj ethyl acetate, N, N-dimethylformamide, pyridine or ir-acyloxy (especially carbamoyloxy or lower alkano gene or another organic solvent which the yloxy), tetrazolylthio which may have lower alkyl, reaction not adversely affected. This thiadiazolylthio or tetrazolopyridazinylthio, with which conventional solvents can also be in the form of a Provided that R2 does not use carboxy (lower) alkyl, protected mixture. Represents carboxy (lower) alkyl or benzyl when R4 is aceto If the compound (III) is in the form of the free acid or oxy, and that R2 is not benzyl when R4 is used in the form of its salt in the reaction, tetrazolylthio with a methyl group. the reaction preferably in the presence of a conventional The processes for the preparation of the inventive condensing agents such as N, N'-dicyclohexylcarbodimide; Connections are explained in more detail below. N-cyclohexyl-N'-morpholinoethyl carbodiimide; N-cyclo- 65 hexyl-N '- (4-diethylaminocyclohexyl) carbodiimide; N, N'-Di method 1 ethyl carbodiimide, N, N'-diisopropyl carbodiimide; N-ethyl The compound (I) according to the invention or a salt thereof - N '- (3-dimethylaminopropyl) carbodiimide; N, N-carbon-von can be produced by reacting the compound ylbis (2-methylimidazole); Pentamethylene ketene-N-cyclohexyli- 11 643 849 min; Diphenylketene-N-cyclohexylimine; Ethoxyacetylene; is carried out in the presence or absence of a 1-alkoxy-1-chloroethylene; Trialkyl phosphite; Ethyl solvent to be performed. To suitable Lö polyphosphate; Isopropyl polyphosphate; Phosphorus oxychloride; solvents can include an organic solvent, Phosphorus trichloride; Thionyl chloride; Oxalyl chloride; Triphe water or a mixture of solvents thereof. If Triflu nylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-eth-s oracetic acid is used, the elimination reaction yl-5- (m-sulfophenyI) isoxazolium hydroxide intramolecularly- preferably in the presence of anisole, salt; l- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; The hydrolysis, which is carried out using hydrazine of the so-called Vilsmeier reagent, produced by reaction, is generally used to eliminate the formation of dimethylformamide with thionyl chloride, phosgene, protective groups, e.g. Succinyl or phthaloyl, Phosphorus oxychloride and the like; or the like. Used. The reaction can also be carried out in the presence of an inorganic base. alkali metal to minimize acyl groups, e.g. Haloalkanoyl (such as carbonate, a tri (lower) alkylamine, pyridine, N-trifluoroacetyl, and the like) and the like. A suitable (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine base can include an inorganic base or an or the like. The reaction temperature is ganic base. The hydrolysis, which is not critical and the reaction is usually carried out under base, is often carried out in water or in a cool or at ambient temperature. A hydrophilic organic solvent or in a loin of the reaction according to the invention can preferably be carried out in a mixture of these. A preferred syn isomer of the compound (I) receiving base according to the invention can be an alkali metal acetate. if the reaction of the compound (II) 20 can be carried out under the protective groups, the acyl group in general with the corresponding syn isomer of the starting compounds by hydrolysis, as mentioned above, or with Form (III), for example in the presence of a Vilsmeier use of another conventional hydrolysis, eliminates agent, as mentioned above, and the like, and at approximately neutral loading. If the acyl group is carried out by halogen conditions. substituted alkoxycarbonyl or 8-quinolyloxycarbonyl 25, it can be treated with a heavy metal, Method 2 such as copper, zinc or the like can be eliminated. The compound (Ib) according to the invention or a salt thereof. The reductive elimination is generally employed. of can be made by using compound (Ia) to eliminate protecting groups such as e.g. Halo- or a salt thereof of an elimination reaction to remove alkoxycarbonyl (such as trichloroethoxycarbonyl and the like), subject to the amino protective group. 30 substituted or unsubstituted aralkoxycarbonyl (such as Suitable salts of the compound (Ia) may include benzyloxycarbonyl, substituted benzyloxycarbonyl and a metal salt, the ammonium salt, an organic one), 2-pyridylmethoxycarbonyl and the like. Amine salt and the like as indicated above. . production can include, for example, the reduction with a The eliminating reaction of the present invention is carried out in an alkali metal borohydride (such as sodium borohydride and the like). performed using a conventional Ver 35 and the like. driving, for example by hydrolysis, by reduction, among the protective groups, the acyl group can be eliminated by a process by reacting the compound (Ia), by treatment with an iminohalogenation — in which the protective group is an acyl group, with an imitant (such as phosphorus oxychloride, phosphorus pentachloride and nohalogenating agent and subsequent reaction with the like.) and an imino etherification agent such as lower alk-an imino etherification agent and, if necessary, 40 anol (for example methanol, ethanol and the like), if necessary, by carrying out a hydrolysis with the resultant hydrolysis. binding; or the like. The reaction temperature is not critical and can be in The hydrolysis may include a method in which a dependence on the type of amino protecting group and the Acid or a base or hydrazine and the like is used. the elimination process used, as described above These methods can be selected in dependence on 45, be selected in a suitable manner and the invented on the type of protecting groups to be eliminated. reaction according to the invention is preferably carried out under mild These processes include hydrolysis, which is carried out under conditions, for example under cooling, at ambient temperatures. is carried out using an acid, one of the usual temperature or at a slightly elevated temperature, and preferred methods of eliminating protection. The present invention also includes the cases where groups such as substituted or unsubstituted alkene-protected carboxy into the free carboxy group, depending on the oxycarbonyl (such as t-butoxycarbonyl, t-pentyloxycarbonyl the reaction conditions, in the course of the reaction or the like), alkanoyl (for example formyl, acetyl and the like), Cycloalk- is transferred in the aftertreatment. oxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (such as benzyloxycarbonyl, substituted benzyl process 3 oxycarbonyl and the like.), substituted phenylthio, substituted-55 The compound according to the invention (Id) or a salt there- Aralkylidene, substituted alkylidene, substituted of can be prepared by using the compound (Ic) Cycloalkylidene or the like, or a salt thereof of an elimination reaction to remove Suitable acids may include subjecting the carboxy protecting group to an inorganic group. Suitable or an inorganic acid, e.g. Formic acid, trifluoride salts of the compound (Ic) include those as above acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid 60 exemplified for the compound (Ia), seric acid and the like, and a preferred acid is a die Elimination reaction according to the invention is carried out under acid, which in a conventional manner, for example by using a conventional method, for example distillation under reduced pressure, easily from the reaction by hydrolysis or the like. The hydrolysis mixture can be removed, e.g. Formic acid may include a method using an acid or trifluoroacetic acid, hydrochloric acid and the like. The base used for the 65, and the like. These methods may be suitable in reaction, depending on the kind depending on the kind of protecting groups to be eliminated the protective group to be eliminated. to be chosen. If the elimination reaction is carried out with an acid. The hydrolysis is carried out using an acid 643 849-12 is one of the most common and preferred. The reaction temperature is not critical and the implementation Processes for eliminating protective groups, such as phenylation, are generally carried out with cooling to heating. (lower) alkyl, substituted phenyl (lower) alkyl, lower. Alkyl, substituted lower alkyl or the like. A suitable The method for producing the starting compound Acid can include an inorganic or organic 5 (IIa) are explained in more detail below. Acid such as Formic acid, trifluoroacetic acid, benzenesul- 1.) The compound (XIII) or its salt can be prepared from fonic acid, p-toluenesulfonic acid, hydrochloric acid and are obtained by reacting hexylamine with carbon dioxide and the like. The reaction according to the invention can be carried out in the presence of lenstoff in the presence of a strong base. Anisole can be carried out. The suitable strong base suitable for the reaction may include an inorganic Acid, depending on the base to be eliminated, or an organic base, e.g. an alkali Protecting group and, depending on other factors, tall hydroxide (such as sodium hydroxide, potassium hydroxide and the like), an alkali metal alkylate (such as sodium methylate, sodium The hydrolysis, which is carried out using an acid through methyl acetate, potassium methylate and the like.), An alkali metal hy- is carried out in the presence of a solvent, both (such as sodium hydride and the like) or the like. for example an organic solvent, of water. The reaction according to the invention is generally carried out in a or a mixture of solvents thereof, such as water, or in any other. Solvent which does not adversely affect the reaction. The reaction temperature is not critical and it can be carried out, and is usually carried out with cooling Depending on the type of protective group and the temperature at or at ambient temperature. 20)) The compound (XV) can be prepared by choosing and the reaction according to the invention is pre-reaction of the compound (XIII) or its salt with the preferably under mild conditions, e.g. with cooling, with compound (XIV). Ambient temperature or with slight heating. The reaction according to the invention is generally carried out in a carried out. a solvent such as water or in any other