DE2514322A1 - NEW CEPHALOSPORIN DERIVATIVES - Google Patents

Description

The present invention relates to new cephalosporin derivatives. More specifically, the invention relates to novel cephalosporin derivatives having the formula

(D) - (E) -G

wherein R represents a hydrogen atom or a hydroxy group; (A) means a 5 ~ or 6-membered ring having 1 to 2 nitrogen atoms, a quinoline ring or a thiopyran;

1 2
R and R, which may be the same or different, each represent a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an oxo group; Qi) means a 5-membered ring with 1 to ^L \ nitrogen atoms and / or 0 to I sulfur atoms, a 6-membered ring with 2 nitrogen atoms, or a 1,2,4-triazolo (33 ^ -bj -! ^, ^ -thiadiasolring, if R '' and R can be present, which are the same or different

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could be; each represents a hydrogen atom _} an oxo group, a lower alkyl group or an amino group;

D represents a sulfur atom or an -NHCO group;

E represents an alkylene group or a phenylene group;

G represents a carboxy group or a sulfo group; η is 0 or 1 when m is 0; and η is I ₅ when m is 1 j

and their non-toxic salts.

Since the compounds of this invention have broad range of antibacterial activities, both gram-positive and gram-negative Bacteria have and especially excellent antibacterial activities against Pseudomonas and Proteus strains have, they can be used for the treatment of humans and animals in various diseases, which are based on infections with these bacteria.

Cephalosporin derivatives effective against Pseudomonas strains have not yet become known. However, it is now with them new cephalosporin derivatives possible to treat the diseases caused by these strains.

Examples of the 5- or 6-membered ring with 1 to 2 nitrogen atoms, represented by the ring (T) in this invention, are a pyrene ring, an imidazole ring, a pyrazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring Pyrazine ring and the like. These rings may be partially saturated. Examples of the 5-membered ring having 1 to 4 nitrogen atoms and / or 0 to 1 sulfur atom, represented by the ring Qy, are a pyrene ring, an imidazole ring, a pyrazole ring, a triazole ring, a tetrazole ring, a thiazole ring, an iso-thiazole ring, a 1,2,4-thiadiazole ring, a 1,3,4-thiadiazole ring and the like.

Examples of the 6-membered ring with 2 nitrogen atoms are a pyrimidine ring, a pyrazine ring, a pyridazine ring and the like

These rings can be partially saturated. Examples of the

1 4
lower alkyl group in R -R or the lower alkyl group,

which is a lower alkoxy group or a lower one

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1 4
Alkylthio group forms in R -R are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and the like.

Further are examples of an alkylene group in the substituent E: a methylene group, an ethylene group, a trimethylene group, an isopropylidene group, an ethylidene group, a propylene group and the like.

The compounds of this invention with the general formula V can be prepared, for example, by compounds with the general formula I.

CH ₂ OGOGH ₅

(D>

COOH

wherein R has the same meaning as in formula V, are reacted with the heterocyclic carboxylic acid with the general Formula II

COOH

(ID

1 2
R and R have the same meaning as in the

wherein [A

Formula V or one of its reactive derivatives to produce a compound of general formula III

R- ^ A-CH-GONH NH

CO

GH ₀ OGOCH

(III)

COOH

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and whereupon the compound III with the mercapto-substituted heterocyclic compound with the general formula IV

MS UBJ- R ". _(IV)

is reacted, where M is a hydrogen atom or an alkali metal atom and R, R, 0Oj ^, E, G ₅ m and η have the same meaning as in the general formula V; or more specifically, a heterocyclic compound substituted with a carboxyl group or a sulfo group and a mercapto group.

The implementation is illustrated by the following reaction sequence formulas:

50 98 A 1/1003

/ VCH-CONH

CH ₂ OCOCH ₅

COOH

step 1

A A - COOH II

// GH-CONH
NH

0 '

COOH

CO

III

Level 2

R-

H3

IV

NH

CO-f A

Ο "

CH ₂ S-

1 COOH

R-

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where (T), (β) » D, E ₃ G, R, R ¹ , R, R ^ ₃ R ₃ m and η have the same meaning as already explained in the above formulas.

Reaction step 1 is carried out by the compound with the formula I in an almost equimolar or excess amount of the compound with the formula II or its reactive Derivative is implemented.

When the compound of the formula II is used in the free state or as its salt, the reaction is preferably carried out in Carried out in the presence of a condensing agent, e.g., Ν, Ν-dicyclohexylcarbodiimide; a phosphoric acid trialkyl ester, e.g., phosphorus oxychloride; a phosphorus trihalide, e.g. Phosphorus trichloride, a thionyl halide, e.g., thionyl chloride; of an oxazclyl chloride and the like.

Examples of the preferred reactive derivatives of the compounds with the formula II are: acid halides, acid azides, Acid anhydrides j mixed acid anhydrides, such as an alkyl carboxylic acid mixed acid anhydride, an alkylphosphoric acid anhydride, a dialkylphosphoric acid anhydride, a sulfuric acid anhydride and the like. As well as an active amide with 'imidazole, an active ester such as a p-nitrophenyl ester, and the like

When a mixed alkyl carboxylic acid anhydride, an acid halide and the like. When the reactive derivative of the compound having the formula II is verx ^ ends, the reaction is usually in an organic solvent such as acetone, tetrahydrofuran, dimethylformamide j chloroform, dichloromethane, hexamethylphosphoramide (Hexametapol) and the like. Or in their solvent mixture in the presence of a base, e.g. triethylamine, Dimethylaniline and the like. With cooling or at room temperature carried out.

The compounds formed with the formula III are isolated, purified and purified by the customary chemical methods e.g. obtained by extraction, recrystallization and the like. It is also possible that the reaction mixture which the e.g., triethyl phosphate; a phosphorus oxyhalide,

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Compound of the formula III contains, for reaction with the compound of the formula IV directly, a further isolation and cleaning, can find use.

The reaction in stage 2 is carried out by reacting the compound of formula III and an almost equimolar or excess Amount of the compound with the formula IV carried out. The reaction is usually carried out in an aqueous solution all at once inert organic solvents, e.g. Acetone, ether, chloroform, nitrobenzene, dimethyl sulfoxide, dimethylformamide, Methanol, ethanol and the like. Or their mixtures. The implementation will be in the neutral state or a weak one carried out in alkaline state; and if the used Compound of the formula IV. Wherein M is a hydrogen atom, is used, the reaction is carried out in the presence of a basic material such as alkali metal hydroxide, Alkalimet all carbonate, triethylamine. The reaction can also be carried out at room temperature and it exists no particular limitation on the reaction temperature; for example, the reaction batch to the boiling point of the solvent used in the reaction are heated.

The order of implementation stage 1 and implementation stage can be reversed. The product with the formula V produced can be isolated and purified by customary chemical methods, such as extraction, recrystallization and the like Alkali metal salt, ammonium salt and the like, their organic salts, for example triethylamine, diethanolamine, lysine, ornithine salt and the like. Many compounds of the formula V can be prepared, but in the preferred compounds of the formula V, RingQw consists of a pyridine ring , the substituent R is a hydrogen atom, R 'is a hydroxy group or an oxo group, ring (β) is a thiazole ring, a thiadiazole ring or a tetrazole ring, D is a sulfur atom, E is an alkylene group ⁺ and the like.

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having 1 to 2 carbon atoms; G is a carboxy group; m is 0 or 1; and η is 1.

In the more preferred compounds of formula V of this invention, ring (h) has a hydroxy group or an oxo group in the ^ -position; the alkylene group is a methylene group; G is a carboxy group; D is a sulfur atom; the thiadiazole ring of ring (b) is a 1,2,4-thiadiazole _{ring or 1,3 a} 4-thiadiazole ring; and m is

Practical examples of the compounds with the formula V are as follows:

7 ~ [ϋ-α- (Jj-Hydroxynicotinoylamido) -a-phenylacetamidöj -3- (5 ~ carboxymethylthio) _{-1;, 3 J} 4-thiadiazol-2-yl) thiomethyl-A ^ -cephem-4-carboxylic acid,

7- [D-α - (^ - hydroxynicotinolylamidoi-a-phenylacetamido] -3 ~ (3 ~ carboxymethylthio-1,2,4-thiadiazol -5-yl) thiomethyl ~ A cephemi-carb on acid,

7-ÖD-a- (4-hydroxynicotinoylamido) -a-phenylacetamido] -3-cornet hy1-5-carboxythiazol -2-yl) thiomethyl-A ^ -cephem-4-carboxylic acid,

7- [na- (4-hydroxynicotinoylamido) -a-phenylacetamidöj -Ji- (I- carboxymethyl-1H-tetrazole -S-yDthiomethyl-A ^ -cephemifcarboxylic acid,

7- JP-aC ^ -Hydroxynicotinoylamidoi-ct-phenylacetamidoj -3- (5 ~ carboxymethy 1-4-methyIthiazol -2-yl) thiomethyl-A- ⁵ -cephem- ¹ carboxylic acid,

7- (pa- (4-Hydroxynicotinoylamido) -a-phenylacetamidöj -3 ~ (5 ~ carboxymethylthio-4-methylthiazol -2-yl) thiomethyl-A ^{: 5} -cephem-4-carboxylic acid j

7- | D-a- (4-Hydroxynicotinoylamido) -a-pheny! Acetamido] -3 ~ (5 ~ carboxymethyl-l ^ jM-thiadiazol -2- yDthiomethyl-Δ ^ - cephem-4-carboxylic acid,

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7- Epα- (4-Hydroxy-3-methylpyridin -5-ylcarboxamido) -a-phenylacetamidc] -3- (5-carboxymethylthio- 1,3, 4-thiadiazol -2-yl) thiomet hy l-Δ · ^ - cephem- 4-carb on acid,

7- [p-α- (Jj-Hydroxy-ö-methylnicotinoylamido) -a-phenylacetanido] 3- (5-carboxymethylthio-1,3j4-thiadiazol - 2-yl) thiome thy 1-Δ- ⁵ -cepham-4- carboxylic acid and the like.

Table I now shows the excellent pharmacological effects of the compounds of this invention the MIC values (γ / ml) (microbiological inhibition concentrations) of the compounds against various bacteria indicated in which the compounds used of this invention are provided with the numbers of the examples. In Table I, the numbers in a circle have the following Meaning:

Proteus vulgaris OXK US Proteus vulgnris OX 19US Proteus mirabilis IFM OM-19 Pseudomonas aeruginosa ATCC 8689

Pseudomonas aeruginosa 99 (gentamycin resist ent)

Pseudomoifas oval is ΙΗΛ 1002 Escherichia coli ATCC 10031 pneumoriiae kauffmann 0-1 Klebsiella Salmonella typhi II901 W Salmonella enteritidis (! 7) Shigella flexneri 2a Shigella sonnei 1675 37148 II Bacillus megatherium ATCC 10778 Uacillus subtilis 6G33 ^(Micrococcus flavus ATCC 10240 Staphylococcus aureufs 209P

Staphylococcus Shimanishi

Staphylococcus Onuma

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Table MIC (γ / ml)

BekarTTCe connection Bakttriun
(D © 3D - Θ .0 - Θ (ί) Θ Θ 0.2 ". S) Θ Θ © Θ © 12.3 I. ro Cephaloxin 30th inn 100 > lim - > 1OII 10 S. ., 23 «, 23 3 ,, = 3 O, 7H 0.7H 1.3 « 1.50 0.23 3 _Λ
O cn CephaloBly- 23 25th C.25 > KO > IO3 “Lon ion i3 3 3 in 1 0.3 0.3 1 3 1.5 (1st I. Cephazolin 3.13 12.3 - > 1M - 1.3 « 1.5. 1.36 1.30 0.23 1.31. ο, ιβ 0.19 O, 1'J 0.10 0.78 0.39 -F- Cephalothin - O ₁ IiJ O, 7 » > 100 > 100 23 3.13 0.7. J, 50 0.39 <■, « C, Z3 - <0.09 - 0.19 0.39 0.23 CO Connection (reniis 0.19 0.19 n, 3> 23 SU 0.23 = 5 «, Ϊ́ΐ 1.3 « 0.711 U, 7f 25th .1.7H 0.09 3.13 O, 78 3.13 0.2-> Example l ζα, ον 0.19 O, 7tt 1 =, S. 6.25 0.25 3.13 3.13 1.3 « 0.39 1.5 (1st 3.13 0.19 0.19 3.13 0.78 3.13 0.25 ro 5 <0.1) 9 <0.09 fl, 39 12, p 6.25 0.25 «, 23 0.2 » 1.30 0.39 0.76 -r ³ 0.7 « 0.39 .1,13 1, SC 0.23 12.5 0 <0.09 Ο, Γ.9 », 311 12,! I 0.25 12 _T 1 3.13 0.25 1.36 0.39 i, v. 3.13 O, 59 HyW 0.25 1.35 0.25 6.25 9 0.19 N »I ¹ » O, 3W 12, p 12.3 SO 3.13 3.13 1.36 0.39 1,.-." ") - ^p U, 39 I), 3'J 3.13 11.78 3.13 3.13 10 <, '0.0D 0.21 O, 3C 23 sa 13, » C, 23 3.13 1.3. 0 | 19th 9.21 ., 23 O, 3B O ₁ Il) 3.13 0.39 3.13 0.23 11 0.30 0.19 O.39 23 1 =, 5 25th 29 3.13 0.78 0.39 1.50 I), 3 » 0.311 «, 25 0.39 3.13 6.23 12th 0.19 U, "ι! U, 3S 23 »-T ³ IU ₁ S 6.23 0.3 » 0.1 » 0.19 ι, sr. 3.13 0.3U 3,! 3 3.13 0.78 3.13 6.23 13th <0.09 O, 7U », 19 12.5 S3 5.13 3.13 1.3. 0.39 1, SS Γ.,. 3 0.31) 0.39 0.25 O, 7B 6.2Λ 12.5 14th 0.19 0.39 (0.1.9 23 12.5 12.3 3.13 6.23 1.3 « 0.78 3.15 5.13 0.39 0.7 » U.25 1.50 12.5 2S 19th 0.1 U <To, o » Oil. 23 S, 23 23 *, S » 0.25 3.13 0.7H 3.13 =, 13 11.39 '0.3U 23 3.13. 12.5 », 25 10 <0.0U 0.18 O, 33 23 25th 12.5 "V * 15.3 1.3. 0.7 « 1.3U V ^s 0- _; 39 11.19 3.13 0.7 » «, 23 0.23 21 <0.09 1.5 « 0.3'J 12.5 12.3 12.3 3.13 6.25 1.3 « 0.39 ijsa 3.13 .1,3U 0.59 3.13 1, SO 0.23 12.3 22nd 0.19 <o, oa O, IS 12.5 t, 25 12.3 3.13 e, 23 3.13 0.78 1.53
1 tub 3.13 0.30 * O _; 7 » 0.25 1.50 12.5 12.3
0.23 23 <«; ■» Y, M O, 3 » '- • ^{5 0} I- ⁵ 12.5 1.50 6.25
f. tm 1.3 «
l.ae 0.39
• U.78 f
1.30 3.13
3.13 0.39
0.7U 0.39 12.3
0.2Λ 3.13
0.7B 12.3
0.23 6.25 24
25th <O, .I9 0.3 « 0.7 « 12.3 "I ³ 23 3.13 6, -5
0.23 1 .
0.31) ;
0.10 3.13 6.23 7th O, 39 Γ
0.23 O, 7H 3.13 12.3 SO 0.19 0.7 » 11.73 12.5 12.3 25th 0.23 ) =, 5 0.29 1.50 0.7M. U, 23 0.711 n, 7H 0.25 1.30 (,, 2Π 0.25 27 <U, 09 I =, 3 υ, 7β 12.5 e, = s li, 5 3.13 1.56 0.78 0.39 O, 7H 3.13 HyH O, 7H 0.23 ι, γ, ο 0.23 12.3 29 {0.09 0.7K .1.7 « l-, 5 «., 25 25th 3.13 k, 25 1.3 « 0 ^ 78 0.2% 3.13 0.78 Ο, 7B 0.25 I ₁ SG 6.23 25th 30th 0> 1 ^m 3.13 0.76 ". 12.5 SO L, 2S 12.5 «, 23 .ljB6 o, 7d 12.5 O, 7K o, 7a 12.3 1, = 6 12.3. 6.25 32 <0.09 12.3 ■ 0.39 5.1 25th 12.5 3.13 6.25 1.5. 1, SO 3.13 3.13 O, 7H 0.711 3.13 1.36 3.13 23 31 <0.09 0.78 11.7 » 23 25th 25th 3.13 23 3.13 1.36 U, 25 3.13 n, 78 0.78 3 ^ 13 3.13 12.5 23 31 / (1, UU 21 12.5 12.5 12.3 ., 23 1, SB 12.5. 0.7H ι, no 12.3 3.13 12.3

- li -

Other advantages of the compounds of this invention are that the salts, for example ilatriur. Salts thereof Compounds are easily soluble in water at the pH of the living body, making them suitable for injections at high concentrations are suitable. The solubility of these compounds are illustrated in Table 2 along with a control sample.

Table 2

Test sample (example no.)

4 - b The disodium salt of the compound was at least 20% by weight solution with a pH 7, ^ dissolved in water. 6th

2H "

26 - b

Control The sodium salt of the compound Q was clearly solved 5 ^ ig probe ^+. The solution of the salt became slightly cloudy at 1% , dissolved the solution was cloudy, dissolved 10%, the solution was very cloudy and the solution gelled at 20%.

Lp

(5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-A -cephem-4-carboxylic acid.

Another advantageous property of the compounds of this invention is the resistance to ß-

PTSITl J

Lactamase. produced by negative bacteria.

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An example is the relationship: between the subject

I) an unchanged test sample with an initial

concentration of the sample 100 ^ f / ml against ß-lactamase Pseudomonas aeruginosa 21 isolated, examined at various dilutions of the enzyme.

The results of the investigation are shown in Table 3 shown.

Table 3

(Enlargement) of ß-lactamase χ 16 χ 32 χ 64 χ 128 χ

test
sample dilution
χ 2 χ 4 χ 8 Connect
manure
according to
example
4 - b 0 29.6 61.0 Cephalo
thin 0 0 0 ι Cefazo-
lin 0 0 0 ι Table 3 (Forts) Test sample dilution χ 512 χ 1024 Connect
manure
according to
example
4 - b 100 100 Cephalo
thin 100 100 Cefazolin 96.7 100

100 100 100 100 100 0 2.6 11.8 46.8 81.6 0 0 9.2 21.5 84.6

Other advantageous properties of the compounds of this invention are that they are not inactivated in the internal organs in the body. When the compounds of this invention and cephalotin are homogenized individually with internal organs, the compounds are thereby

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According to this invention, not decomposed while cephalotin is decomposed. The relationship between the reaction period of time and the antibacterial activity (residual activity %) is shown in Table 4 for the case when these compounds were kept in the incubator with the plasma and liver homogenate of a male Sprague-Dowley rat. The residual antibacterial activity was measured using a thin-layer dish method with Bacillus subtilis ATCC 6633.

Table 4

Time (minutes) 0 15 30 90

Time (minutes) 15 30 90

link

game k 100 97.0 93.9 103.0 100 93.5 91.3 102.2

link
according to example 6 100 92.0 102.0 102.0 100 95.7 89.1 91.3

link
according to
game 9 100 103.0 92.0 100.0 100 100.0 100.0 102.5

Cephalothin 100 87.0 66.0 36.0 100 17.2 12.2 12.6

Cephaloridines 100 97.2 89.5 72.2 100 82.3 86.0 91.1

A ⁺ : residual activity (%) when with 90 lb. plasma in the incubator

held.
B: remaining activity (^), if with 10? Liver homogenate kept in the incubator.

The compounds of this invention are usually administered by intravenous injection or intramuscular injection. The dosage is usually 1 g per day for

S0984 1/1003

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- i4 -

Adult . The amount administered can be up to 5 g Type of disease and the patient's condition are increased. The dosage for children is 20-40 mg / kg and the amount can be increased up to 100 mg / kg according to the kind of the disease and the condition of the patient.

Example 1-a

In 100 ml of dichloromethane were added 4.2 <r cephaloglycin-Konohydrat, added 3 ₅ 0 g of anhydrous magnesium sulfate and 2.1 ml of triethylamine. After stirring the mixture for one hour at room temperature, magnesium sulfate was filtered off and a dichloromethane solution of cephaloglycine triethylamine salt was obtained. The solution was cooled to -30 ^0C. Then 1.75 g of 4-oxo-4H-thiopyran-3-carbonyl chloride and 2.1 ml of triethylamine were added to the solution and the solution was stirred for one hour. The temperature was allowed to rise to room temperature in the batch. After stirring for one hour, dichloromethane was distilled off under reduced pressure. To the resulting residue, water was _added}, and the pH was adjusted to 2 by dropwise addition of 40 $ strength phosphoric acid to the mixture. The reaction mixture was extracted with 400 ml of a mixture of butanol and ethyl acetate in a 1: 1 volume ratio. The extracts were washed with water, washed twice with saturated aqueous sodium chloride solution. After filtering off the insoluble matter, the filtrate was dried over anhydrous magnesium sulfate. Then a eutanol solution of 30% sodium 2-ethylhexanoate was added to form a precipitate. The precipitate was separated off by filtration, washed with ethyl acetate and washed with ether. It was reprecipitated from a mixture of methanol and ether. 2.8 g of sodium 7-D- jä- (4 "-oxo-

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- ⁱ m-thiopyran-3-carbonylamino) -a-phenylacetamido] cephalosporanate with a melting point of 185-195 ° C with decomposition.

Infrared absorption spectrum:

KBr -1
V cm: 3 ^ 50 (NH), 1770 (ß-lactam), 1660 (amide),

^max 1610 (carboxylates) and 1740 (esters). Nuclear magnetic resonance spectrum (D, -DMSO + CD, OD).

6: 2.00 (3H, s, CH ₃ CO), 3.30 (2H, q (AB type), '

H
4.84 (IH, d, ~ π), 4.93 (2H, q (A3 type),

N
5.60 (IH, d, ^Ν ~~ Μ-τ >> ⁵ ' ⁸ 9 ( ^1K > ^s > ^ jVcH-),

^Λ 8 ο

/ 7 \\ ^H OL / ^C0 Π / CO

7.40 (6Κ, (/ ^x y- + Yj), 8.39 (IH, q r (\ ' ),

^Ω .CO ^S

9.37 (IK, d, QT).

Example 1-b

820 mg of sodium 7- | D-a- (4-oxo-4H-thiopyran-3-ylcarboxamido) -a-phenylacetamido] were added to 50 ml of water. cephalosporanate and 350 mg (5-mercapto-1,3,4-thiadiazol-2-yl) succinic acid half-amide suspended. After adding 3 ^ l aqueous 10 ^ iger sodium bicarbonate solution to the suspension the mixture was stirred with heating at 55 ° C. for 23 hours. After completion of the reaction, they became insoluble Fractions from the reaction mixture filtered off. Then the pH of the filtrate was adjusted to 2 by adding 1 η of hydrogen chloride acid set. The precipitates formed

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were separated off by filtration, carefully washed with water, rewashed with ether and dried over phosphoipentoxide under reduced pressure. The obtained product was dissolved in 12 ml of dimethyl sulfoxide. 0.9 ml of a 30% n-butanol solution of sodium 2-ethylhexanoate was added to the solution. The mixture was stirred for 5 minutes. Then 120 ml of ethyl acetate was added to the reaction mixture. The resulting mixture was stirred for 10 minutes. The precipitates formed were separated by filtration and carefully washed with ethyl acetate and then with ether. It was dried over phosphorus pentoxide under reduced pressure. It was ΜδΟ mg of disodium salt of 7 ~ [Da- ( ⁱ l-0xo ⁱ lH-thiopyran-3-ylcarboxamido) -a-phenylacetamido] -3- [5- (3-carboxypropionylamino) lj3j ^ -thiadiazol-2-yljthiomethyl- Δ-cephem-4-carboxylic acid obtained.

Nuclear Magnetic Resonance Spectrum (D "0): δ: 2.66 (4K, -NKCOCH ₂ CH ₂ CO ₂ Na). Infrared absorption spectrum:

.KBr _Λ

• V cm: 1762 (β-lactam), 1660 (amide). Max

Example 2-a

550 mg of p-nitrophenyl-3-hydroxypyridazine-4-carboxylate were added to a solution of 900 mg of cephaloglycine triethylamine salt and 17 ml of dichloromethane while cooling with ice. After adding 15 ml of dimethylformamide, the resulting mixture was stirred for one hour. Then the mixture was further stirred for 17 hours at room temperature. After the completion of the reaction, 23 ml of dichloromethane was added to the reaction mixture. The mixture was washed three times with ¹ ml of aqueous 1.5 IO / sodium bicarbonate Üiger

5098A1 / 1003

solution extracted. The separated aqueous layer was washed with dichloromethane. The pH of the aqueous solution was adjusted to 2 with 1 η hydrochloric acid. The precipitates formed were with 60 ml of a mixture extracted from butanol and ethyl acetate in a 1: 1 volume ratio. The extract was made with water and afterwards washed with saturated sodium chloride solution. It was dried over water-free magnesium sulfate. 1.3 ml of a 30% n-butanol solution of sodium 2-ethylhexanoate were added to the solution added. The precipitates formed were separated by filtration, then with ethyl acetate washed with ether and dried over phosphorus pentoxide under reduced pressure. 600 mg of "atrium-7- [_D-a- (3 ~ hydroxypyridazin-4-ylcarboxamido) -a-phenylacetamidol -cephalosporanate obtain.

Nuclear Magnetic Resonance Spectrum (D, - DMSQ):

S: 8.16, 3.3C (hydrogen of the core of the pyridazine ring).

Infrared absorption spectrum: KBr

Q cm "' ¹ : 1770 (β-lactam), 1664 (amide). Max

Example 2-b

400 mg of matrium-7- [p-a- (3-hydroxy ~ pyridazin-4-ylcarboxamido) -a-phenylacetamido] cephalosporanate and 170 ml (5-mercapto-1,3,4-thiadiazol-2-yl) succinic acid ehalbamid suspended. Then 1.5 nil became one aqueous! Add the above sodium bicarbonate solution to the suspension added. The resulting mixture was stirred at 60 ° C. for 20 hours. The implementation was completed insoluble fractions formed from the reaction mixture filtered off. The pH of the filtrate was adjusted to 2 by addition

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adjusted from 1 η hydrochloric acid. The thereby Formed precipitates were separated by filtration, carefully mixed with water, 25 ml of a mixture Methanol and ether in a 1: 5 volume ratio and then washed with ether. It was reduced over phosphorus oxide under Print dried.

The obtained product was dissolved in 4 ml of dimethyl sulfoxide. After the addition of 0.5 ml of a 30% strength n-butanol solution of sodium 2-ethylhexanoate, the resulting mixture was stirred for 5 minutes. To the reaction mixture was added 50 ml of ethyl acetate, and then the mixture was stirred for 10 minutes. The precipitates thus formed were separated off by filtration and carefully washed with ethyl acetate and then with ether and dried over phosphorus pen oxide. 260 mg of the disodium salt of 7 ~ £ p ~ a- (3 ~ hydroxypyridasin - ^ - ylcarboxamido) -a-phenylacetamidoj -3- J5 ~ (3-carboxypropionylanino) -1 ₅ 3,4-thiadiazol-2-yl} thiomet 'hyl-Δ -cephem-Jj-carboxylic acid obtained.

Nuclear Magnetic Resonance Spectrum (DpO): δ: 2.60 (4H-NHCOCH ₂ CH ₂ CO ₂ Na) Infrared absorption spectrum:

KBr

^ cm ""' ¹ : 1762 (β-lactam), 1664 (amide), max

Example 3 ~ a

After a solution of 1.55 g of cephaloglycine triethylamine salt and 25 ml of dichloromethane had cooled to -30 ° C., 0.60 g of 2,4-dihydroxypyrimidine-5-carboxylic acid chloride was added. Da.s mixture was stirred for 2 hours at temperatures between -20 ⁰ C to -30 ° C. and then stirred after 2 hours at room temperature. After completion of the implementation

1/10

the reaction mixture was concentrated under reduced pressure. 30 ml of water was added to the concentrate. Then the pH of the solution was adjusted to 2 by adding 1N hydrogen chloride acid set.

The precipitates thereby formed became with 120 ml of one extracted from butanol and ethyl acetate in a 1: 1 volume ratio existing mixture.

The extract was washed with water and with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. 1.8 ml of a 30% n-butanol solution of sodium 2-ethylhexanoate were added to the filtrate. The precipitates formed were separated by filtration and washed with stylacetate and then with ether. It was dried over phosphorus pentoxide under reduced pressure. 0.72 g of sodium 7- [Da- (2 _i ¹ i-dihydroxypyrimidin-5-ylcarboxamido) -a-phenylacetamidoj cephalosporanate was obtained.

Nuclear Magnetic Resonance Spectrum (D ^ -DMSO): δ: 8j28 (hydrogen in the nucleus of Pyrirp.idine) Infrared absorption spectrum:

.KBr

V cm "" ¹ : 1760 (β-lactam), Ι676 (amide). Max

Example 3 ~ b

400 mg of sodium 7- [pa- (2,4-dihydroxypyrimidin-5-ylcarboxamido) -a-phenylacetanido | -cephalosporanate and 170 mg (5-mercapto-lj3 _s 4-thiadiazol-2yl) succinic acid half-amide suspended. After adding 1.5 ml of the above aqueous sodium bicarbonate solution to the suspension, the mixture was stirred for 22 hours while heating to 55 ° C. When the reaction had ended, the insoluble fractions were filtered off from the reaction mixture. The reaction mixture and

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the pH of the filtrate is adjusted to 2 by adding 1 η hydrochloric acid. The precipitates formed were separated off by filtration and carefully washed with water and then with ether. It was dried over phosphorus pentoxide under reduced pressure. By treating the product as described in Example 2-b, 220 mg of the sodium salt of 7 ~ [pa- (2, ⁱ l-dihydroxypyrimidin-5-ylcarboxamido) -a-phenyl acetamido] ~ 3 ~ p ~ (3-carboxypropionylaraino) -lj3, ⁱ l-thiadiazol-2-yll thi ^ carboxylic acid obtained.

Nuclear Magnetic Resonance Spectrum (D "0) δ: 2 ₅ 62 (4h, -NHCOCH ₂ CK ₂ CO ₂ Na). Infrared absorption spectrum:

^ KBr

ν CiTT ^: I76O (β-lactam), 1664 (amide) '. Max

Example 4-a

1.4 g of 4-hydroxynicotinic acid were suspended in 40 ml of dichloromethane. After adding 1 ₃ 4 ml of triethylamine to the suspension, the mixture was stirred for 30 minutes at room temperature. to form an almost transparent solution. The solution was cooled to 0-5 ° C. 10 ml of dichloromethane containing 0.73 ml of thionyl chloride _/ was added dropwise to the solution at the same temperature. The mixture was then stirred for one hour at room temperature, whereby a suspension of ^ -hydroxynicotinoyl chloride was obtained.

H, 25 g of cephaloglycine nohydrate and then 2.8 ml of triethylamine were dissolved in 100 ml of dichloromethane. 5 g of anhydrous magnesium sulfate was added to the batch _} and then the mixture was allowed to stand at room temperature for about 10 minutes

stirred. The mixture was filtered and a solution of cephaloglycine triethylamine salt was obtained. The solution was cooled to -20 C and the suspension of 4-hydroxynicotinoyl chloride prepared above was added dropwise to the solution with stirring. The cooling bath was then removed in order to allow the temperature in the batch to rise to room temperature. The reaction mixture was then stirred for about an hour at room temperature. The obtained reaction mixture was concentrated at low temperature under reduced pressure, and the solid residue formed was dissolved in 100 ml of cold water. The pH of the solution was adjusted to 2 by adding hydrochloric acid. White crystals were deposited, which were separated by filtration _; washed with water and a small amount of acetone and dried.

The separated crystals were dissolved in 30 ml of dimethylformamide. The insoluble matter formed was filtered off. Then an n-butanol solution of 30% potassium 2-ethylhexanoate was added to the filtrate until no more precipitation occurred.

100 ml of ether were added to the suspension. It was left standing for some time. The rainfall were separated by filtration and washed with acetone. Thereafter, the precipitates were by dissolving in water-containing Purified dimethylformamide, then subjected to filtration and reprecipitated by adding acetone. It was 1.35 g potassium 7-D-jjx- (4-hydroxypyridine-3-carbonylamino) -aphenylacetamino] cephalosporanate as yellowish brownish powdery crystals with a melting point of 195-2O2 ° C with decomposition obtain.

509841/1003

Infrared absorption spectrum:

cm " ¹ : 3400 (NH, -0H), I76O (ß-lactam), 1740 (acetate), ^max I655 (amide), I600 (carboxylate). Nuclear magnetic resonance spectrum (CD-OD + Dg-DHSO):

S / -

δ: 1.97 (3H, CH ₃ COO-), 3.13 (2H, ^J ^ f \ _H ), 4.8 (2H, -CH ₂ O),

OH H

5.01 (IH, j_ _N °), 6.6 (IH, yss-), 5.82 (IH,

0 V

6.38 (IH, ^ -CH-), 7.4-7.6 (5H,

NH
OH 'OH - ■

8.50 (IH, ([V), 7.86 (IH, ffy).

Example 4-b

500 mg of sodium 7- [pa- ( ¹ I-hydroxynicotinoylamido) -otphenylacetamido3 cephalosporanate, 209 ng (5-mercapto-1,3,4-thiadiazol-2-yl) thioacetic acid and 203 mg of sodium bicarbonate were added to 32 ml of water. The mixture was stirred at 55 ° C. for 22 hours. Then, the pH of the reaction mixture was adjusted to about 2 by adding 1 η hydrochloric acid while cooling with ice. The white precipitates formed were separated off by filtration, carefully washed with water and then with ether and dried. There are 400 mg of 7- rD-a- (4-hydroxynicotinoylamido) ~ a-phenylacetamidoJ-

3- (5-carboxymethylthio-1,3,4-thiadiazol-2-yl) thiomethyl-A -

obtained cephem-4-carboxylic acid.

Melting point about 25O ⁰ C (with partial decomposition).

Infrared absorption spectrum:

> P ^r -1

x) cm: 1775 (β-lactam).

Max

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Nuclear Magnetic Resonance Spectrum (D ^ -DMSO):

eppm: 3.58 (2H) ₃ 4.13 (2H) ₃ 4.32 (2H), 5.02 (IH) ₃ 5 ₃ 77 (IH) 5.79 (IH) ₃ 6.43 (IK) ₃ 7 ₃ 3β (5H) ₃ 7.80 (IH) ₃ 8.43 (IH) and 9.42 (IH).

Example 5

To 44 ml water / water were 700 mg: iatriun-7- [pa- (4-hydroxynicotinoylamido) -a-phenylacetar, id_oj cephalosporanat, 312 rag 3- (5-mercapto-1,3,4-thiadiazol-2-ythio ) propionic acid and 283 mg sodium bicarbonate were added. The mixture was then stirred at 55 ° C. for 2 hours. By treating the product as indicated in Example 4-b, 520 ng of 7- [pa- (4-Hydroxynicotinoylair.ido) -a-phenylacetamidecj -3- (5-carboxyethylthio-1,3,4-thiadiazol-2-yl ) thiomethyl-Δ cephem-4-carboxylic acid obtained.
Melting point about 250 ° C (with decomposition).

Infrared absorption spectrum:

cm "': 1775 (β-lactam). max

Nuclear Magnetic Resonance Spectrum (D ^ -DflSO): ippm: 2.74 (2H) ₃ 3.42 (2H), 3.58 (2K) ₃ 4.32 (2H), 5.02 (IH), 5.77 ( IH), 5.79 (IH), 6.43 (IK) ₃ 7.36 (5H) ₅ 7.80 (IH) ₃

8.43 (IH) and 9.43 (IH).

Example 6

To 40 ml of water was added 615 mg of sodium-7- £ D-a- (4-Hydroxynico-

tinoylamido) -a-phenylacetamido] -cephalosporanate, 235 mg 3 ~ (5 ~ Mercapto-l, 3,4-thiadiazol-2-yl) thiopropionic acid and 218 mg sodium bicarbonate added. The mixture was

Stirred at 55 ° C. for 2 hours. Then by treating

as indicated in Example 4-b, 450 mg of 7 -_ [pa- (4-hydroxy-

841/1003

25U322

never otinoylaF.ido) -a-pheny lac et amido] -3- (5 ~ carboxyethyl-1,3, ijthiadiazol-2-yl) thiomethyl-A -cephem-4-carboxylic acid. Melting point et v / a 250 ° C (with decomposition). Infrared absorption spectrum:

cm "\ 1775 (β-lactam). max

Nuclear Magnetic Resonance Spectrum (D / - DMSO)

fopm: 2.73 (2H), 3.25 (2H), 3.58 (2H), 4.35 (2H), 5.01 (IH), 5.78 (IH), 5.80 (IH), 6.44 (IH), 7.36 (5H), 7.81 (IH), 8.44 (IH), 9.43 (IH).

Example 7 ~ a

3.1 ml of triethylamine were added to a suspension of 4.23 g of cephaloglycine monohydrate, 3.0 g of anhydrous magnesium sulfate and 70 ml of methylene chloride. After stirring the mixture for one hour at room temperature, magnesium sulfate was filtered off. A triethylamine salt solution of cephaloglycine was obtained. To the solution was added dropwise a solution of nicotinoyl chloride N-oxide prepared by adding 0.73 nil thionyl chloride dropwise to a solution consisting of 1.39 g of nicotinic acid N-oxide, 1.4 ml of triethylamine and 30 ml of methylene chloride while cooling with ice and then stirring for 1.5 hours. The pH of the reaction mixture was kept at 8-9 by adding triethylamine. Thereafter, the reaction mixture was stirred at a temperature of -20 ° C. + -5 ° C. for 3 hours. It was left to stand at -20 ° C. overnight. After n-butanol was distilled off from the reaction mixture, ice water and a mixture of n-butanol and ethyl acetate in a 2: 3 volume ratio were added, and the pH was adjusted to 2.0 by adding dilute hydrochloric acid. The educated inflicted

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organic layer was separated, washed three times with water and dried over anhydrous magnesium sulfate. The solution was mixed with an n-butanol solution of 30% sodium 2-ethylhexanoate, whereby precipitates were formed. C-urcii burning off the precipitates by filtration and over precipitation with a mixture of methanol and ether, 2.7 g of sodium 7- [pa- (pyridin-ri-oxid-2-ylcarboxamide) -a-phenylacetamidg cephalosporanate obtained. Melting point 263 ° C (with decomposition). "^ about infrared absorption spectrum:

JCBr
S) cnT ¹ : 3300 (Uli), I76O (β-lactam), 1735 (ester), ^max 1665 (amide) and I615 (carboxylate).

Nuclear Magnetic Resonance Spectrum (IV-DMSO):

ippm: 2.00 (s, 3H, -00-CH ₃ ), 3, ^ 3 (q, 2Η, ^ bH),

4.92 (d, IH ₅

H
5.60 (q, IH, ~ t ~ T ° ^> 5.91 (d, IH ^ OJ ^ -C-CO-),

-N-

JN

Hv ^ I 7.42 (m, 7H, L ⁰ J ⁺ r ° T_cO- ^{) 3 8jl13 (q} > ^1H '

-H
0 I), 8.42 (q, IH, UO j), 9.46 (d, IH, -NH)

and 12.14 (d, IH, -NH).

5098 ^ 1/1003

Example 7 ~ b

190 mg of (5-mercapto-1,3,5-thiadiazole -2-yl) -succinic acid half-amide added at room temperature. A saturated aqueous sodium bicarbonate solution was further added to the mixture to adjust the pH of the solution to 6.8 7.2. The solution was stirred at 55-60 ° C. for 26 hours. The pH was then adjusted to 2 using dilute hydrochloric acid, forming a suspension. The product obtained was extracted with a mixture of n-butanol and ethyl acetate in a 2: 3 volume ratio. The formed organic layer was washed three times with water, dried, and then mixed with an n-butanol solution of 30% sodium 2-ethylhexanoate, and then added with ether, whereby oily matter was obtained. The obtained oily matter was dissolved in methanol, and ether was added to the solution, thereby forming precipitates, which were separated by filtration. These were washed with ether and dried. 0.25 g of sodium -? - i ~ Da- (pyridine-N-oxide-2-

-Frylcarboxamido-a-phenylacetamid_oj-3- [5- (3 "" carboxypropionyl-

amino) 1,3,4-thiadiazol-2-yl ~ | thianethyl-Δ-cephem - ^ - carboxylate

obtain.

Melting point about 251 ^° C. (decomposition).

Infrared absorption spectrum:

KBr ν) cm "" ¹ : 3300-3 ^ 00 (band, UH), 176Ο (ß-lactam),

^max - 1665 (amide), 1590 (carboxylate).

Nuclear Magnetic Resonance Spectrum (D ₀ O): _σ

. oppm: 2.49 (m, 4ll, -COOCH ₂ CH ₂ -), 3.13 (q, 2H, J ^ H),

H _sr ".-,

;, 54 (d, IH, -4-r "S), 5.57 (S, IH, [Oj),

), H , 80 CD, IH, O ^ H N - 27 ^ Hp-S-

0 '
7.30 (m, 7H, I 0.1 + Γθ "Χ _Η ), 7.96 (q, IH foX ) and

8.18 (q, IH,

Example 8-a

After passing stirring a 35 ml methylene chloride solution containing 2.12 g of cephaloglycin monohydrate, 1.5 g of anhydrous magnesium sulfate and 1, ¹ J ml of triethylamine for one hour at room temperature magnesium sulfate was filtered off. A solution of the triethylamine salt of cephaloglycine was obtained. After the solution had cooled to -25 ° C., 81.6 mg of 2-imidazolidone-1-carboxylic acid chloride and 0.3 ml of triethylamine were added. The resulting mixture xvurde 3 hours at -20 + 5 C and stirred overnight at -20 ⁰ C allowed to stand. Then, the solvent was distilled off from the reaction mixture under reduced pressure, and the residue obtained was dissolved in ice water. The pH of the solution was adjusted to 2 with dilute hydrochloric acid and the precipitates formed were washed by filtration ¹ "with water and dried. There was obtained 2.1 g of precipitates. The precipitates were dissolved in 20 ml of dimethylformamide _r and then 3 ml a n-butanol solution of 30 * sodium 2-ethylhexanoate added to the solution. Then was added fithylacetat to the mixture, which precipitates were formed. These were separated by filtration with ether overall ⁺

25U322

wash and unprecipitate with a mixture of methanol and ether. 1.5 g of sodium 7- [p-a- (2-imidazolidone-lylcarboxamido) -a-phenylacetamidoj obtained cephalosporanate.

Melting point about 225 ° C (with decomposition).

Infrared absorption spectrum:

KBr

^) cm " ¹ : 3100-3500 (NH) ₃ 17OO (ß-lactam), 1720 (ester, max"

^ N-C-N ^), 1660 (amide) and I605 (carboxylate). Nuclear Magnetic Resonance Spectrum (Dg-DMSO).

0 _ JS

Il ^

Il

δ: 1.93 (s, 3H, -OCCH ₃ ), 3.28 (α, 2H

H H

H-

-H

), 4.88 (d, IH ₃

j _}

) ₃ 3.32, 3.69

), 4 ₃ 91 (q, 2H,

) 5.55 (q, IH ₃

, 5.66 (d,

7 ₃ 34 (m, 5 H ₃ [V jj ~), 7.78 (IH ₃ -NH) ₃ 9.13 (d, IH -MH _{3) 3} 9.35 (d, IH -NH _3).

Example 8-b

To an aqueous solution of 800 mg of sodium ~ 7 ~ [p-a- (2-oxoimidazolin-1-ylcarboxamido) -a-phenylacetamide ^ J cephalosporanate in 50 ml of water was 0.38 g (5-mercapto-1,3,4-thiadiazol-2-yl) succinic acid half-amide added. The pH of the solution was increased to 7.2 - 7.5 by adding a saturated Sodium bicarbonate solution adjusted. The solution was stirred at 55-60 ° C. for 24 hours. After cooling it was the pH of the solution by adding dilute hydrogen chloride

5 0 9 3 4 1/10 0 3 '

25H322

acid adjusted to 2.0, whereby precipitates were formed. The precipitates were separated by filtration, washed with water / water, dried and dissolved in 8 ml of dimethylformamide. Then 1 ml of an n-eutanol solution of. 30 £ sodium 2-ethyl hexanoate was added to the _solution} and then ethyl acetate was added thereto to form precipitates, which were separated by filtration, washed with Sther and were reprecipitated from a mixture of methanol and ether. 750 mg of dinatrium-7-da- (2-oxoimidazolin-1-ylcarboxamido) -a-phenylacetaric; ido -3 ~ f_5- (3 ~ carboxypropionylamino) -! , 3,4-thiadiazol-2-yl-thioniethyl-Δ-cephem- ^ i-earboxylate.
Melting point about 246 C (with decomposition). Infrared absorption spectrum:

KBr

• V cm " ^q : 3200 - 3500 (NH), I76O (ß-lactam), 1720 max

(MECNH), 1675, 1660 (amide), IaOO (carboxylate). Nuclear Magnetic Resonance _{Spectrum (D 0} O) H_Ju_Jl_H

6-ppm: 2.56 (dd, 4H, -COCK ₂ CH ₂ COO-), 3.28, 3.6θ (m, 4H ^ ·),

(d, IH, ~ T ~ f J,), 3.92 (q, 2H, vjL _CH ),

4.82 (d, ΙΗ, -ρ-K ^ j), 5.36 (s, IH, [Oj),

), 3.92 (q, 2H, ^^ L_o, _ 3.13 (q, 2H, ^ J ^X H).

Example 9

To a mixture of 0.53 g of matrium-7- [p-a - ^ - hydroxynicotinoylamido) -a-phenylacetamido! cephalosporanate and 0.3 g of sodium 5-mercapto-1,3,4-thiadiazol-2-yl-thioethylsulfonate were 35 ml

509841/1003

Water and 0.108 g sodium bicarbonate added. The resulting mixture was held at about 57 ° C for 22 hours. After removing the insoluble matter by filtration, the pH of the filtrate was adjusted to about 1 with 1.5 η hydrochloric acid while cooling with ice. The precipitates thereby formed were separated by filtration. The precipitates were washed with water and then with ether and dried. There were 0.45 g of 7- [jD-a- (4-Hydroxynicotinoylamido) -a-phenylacetamido] -3- (5-sulfoäthylthio-1,3,4-thiadia3ol-2-yl) thiomethyl-A ⁵ -cephem- 4-carboxylic acid obtained.

Melting point about 200-220 ° C (partial decomposition). Infrared absorption spectrum:

-.KBr

ν cnT ¹ : 177 ¹ I (β-lactam).

ITi CL X

Nuclear Magnetic Resonance Spectrum (Dg-DMSO): δ (ppm): 1.89 (2H), 3.47 (2H), 3.59 (2H), 4.34 (2H), 5.05 (IK), 5.79 (IH), 5.37 (IH), 6.52 (IH), 7.41 (5H), 7.89 (IH), 8.49 (IH) and 9.47 (IH).

Example 10:

To 45 ml of water, 700 mg of sodium 7- [pa- (4-oxo-4H-thiopyran-3-ylcarboxamiaöj -a-pheny! Acetamido] cephalosporanate, 284 mg (5-mercapto-1,3,4-thiadiazole- 2-yl) thioacetic acid and 260 mg of sodium bicarbonate were added, the resulting mixture was kept for 20 hours at 50-54 ° C. The pH of the resulting reaction mixture was adjusted to about 2 with 1 η hydrochloric acid while cooling with ice, and the precipitates formed were separated by filtration. There were 530 mg of the product prepared, 7 ^w Ep-a- (4-Oxo-4H-thiopyran-3-ylcarboxamido) -a-phenylacetamido] -3- (5-carboxymethylthio-1,3,4-thiadiazole-2- yl) thiomethyl-A cephem-4-carboxylic acid.

509341/1003

25H322

Melting point 190 ^° C. (with decomposition). ⁺ about infrared absorption spectrum:

KBr
^) cm 1778 (ß-lactam). . Max

Nuclear magnetic resonance spectrum (D, - DMSO):

6: 3.58 (211), 4.14 (2H), 4.33 (2H), 5.02 (IH), 5.77 (2H),

7.35 (6H), 8.39 (IH), 9.34 (IH) and 9.48 (IH). Example 11 :

To 50 ml of water were 0.8 g of sodium 7- [p-CT (4-hydroxynicotinoylamidoj-a-phenylacetamidöj cephalosporanate, O, 28lg

5-Mercapto-1,3,4-thiadiazole-2-carboxylic acid and 0.296 g sodium bicarbonate were added. The resulting mixture was stirred at 55 ° C. for 20 hours. The pH of the obtained reaction mixture was adjusted to 1-2 with 1 η hydrochloric acid under ice-cooling, and the formed white precipitates were separated by filtration, washed with water and dried. There were 0.5 g of 7 ~ [θ-α- (4-Hydroxynicotinoylamido) -a-phenylacetair.idq] -3- (5-carboxy-_ 1,3,4-thiadiazol-2-yl) thiomethyl-A - obtained cephem-4-carboxylic acid.
Infrared absorption spectrum:

KBr

0 cm "': 1770 (β-lactam). Max

Nuclear Magnetic Resonance Spectrum (D ^ -DMSO)

6 ppm: 3.59 (2H, q), 4.39 (2H, q), 5.02 (IH, d), 5.72 (IH), 5.84 (IH, d), 6.44 (IH, d), 7.37 (5H), 7.82 (IH, d), 8.45 (IH, s), 9.44 (IH, d), 11.23 (IH, d), 1220 (IH, Band)

509841/1003

15Ί4322.

Example 12:

700 mg of 7- (pa- (7-methylthio-4-quinolone-3-carboxamido) -a-phenylacetarnido / cephalosporanic acid, 220 mg (5-mercapto- ^{1,3, 1} »-thiadiazole-2- yl) thioacetic acid and 315 mg of sodium bicarbonate were added The resulting mixture was stirred for 20 hours at 55-60 ° C. After the reaction had ended, the reaction mixture was cooled, acidified with dilute hydrochloric acid and the precipitates formed were separated off by filtration, washed with water and dried. There were 400 mg of 7-fD-a- (7-methylthio-'4-quinolon-3-ylcarboxamido) -a-phenylacetamidol-3- (5-carboxymethylthio-1,3,4-thiadiazol-2-yl) -thiomethyl -Δ -cephem-4-carboxylic acid. Inf rar ο tab s or pt ion s spectrum:

KBr _ ^ 1780 (β-lactam). ^ cm ■: Max

Nuclear magnetic resonance spectrum (D, - DMSO):

δ ppm: 2.60 (3H), 3.56 (2H), i |, 16 (2H), 4.20 (2H), 5.05 (IH),

5.84 (IH), 5.93 (IH), 7.40 (7H), 8.18 (IH), 8.70 (IH),

9.50 (IH), 11.00 (IH). and 12.60 (IH).

Example 13:

0.80 g of 7-C "D-a- (4-hydroxynicotinonylamido) -a-phenylacetamido]] cephalosporanic acid was added to 50 ml of water and 0.32 g of (5-mercapto-1,2,4-thiadiazol-3-yl) thioacetic acid suspended. After adding 0.45 g of sodium bicarbonate to the suspension the mixture was stirred with heating at 55 ° C. for 24 hours. After completion of the reaction, the insoluble Fractions from the reaction mixture filtered off. The pH of the filtrate was adjusted to 2 by the addition of 5% hydrochloric acid set to form precipitates. The bodices were separated by filtration, well with water

50984 1/1003

washed and dried over phosphorus pentoxide under reduced pressure. 0.70 g of powdery 7 - {_ p-a- (4-Hydroxynicotinoylamido) -a-phenylacetamidoJ-3- (3-carboxymethylthio-1,2,4-thiadiazol-5-yl) thiomethyl 1 -Δ-cephem-4-carboxylic acid obtained.

Melting point: 189-193 ° C. (Decomposition). Infrared absorption spectrum:

KBr

\) cm "" ': 1770 (ß-lactam and 165Ο (amide). Max

Nuclear Magnetic Resonance Spectrum (Dg-DMSO): δ ppm: 4.04 (2H,

Example 14:

0.8 g of sodium 7-fp-a- (4-hydroxynicotinoylamido) -a-phenylacetamidojcephalosporanate, 0.293 g of 2-mercapto-4-methylthiazole-5-carboxylic acid and 0.296 g of sodium bicarbonate were added to 50 ml of water. The resulting mixture was stirred at 55 ° C. for 22 hours. Then the pH of the reaction mixture was adjusted to 1-2 with 1 η hydrochloric acid while cooling with ice. The white precipitates thus formed were separated off by filtration, washed with water and dried. 7 ~ LD-a- (4-hydroxynicotinoylamido) -a-phenylacetanidoJ-3- (4-ynethyl-5-carboxythiasol-2-yl) -thiomethyl-Δ-cephem-4-carboxylic acid were obtained. ⁺ 0.6 g infrared absorption spectrum:

^ ^KBr cnT ¹ : 1770 (ß-lactam) max

Nuclear Magnetic Resonance Spectrum (D ^ -DMSO):

δ ppm: 2.56 (3H, s), 3.56 (2H, q), 4.37 (2H, q), 5> 01 (IK, d), 5.74 (IH), 5.86 (IH, d), 6.44 (IH, d), 7.37 (5H), 7.82 (IH, d), 8.44 (IH, d), 9.44 (IH, d), 11.21 (IH, d) and 12.21 (IH, band).

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Example 15:

600 mg of sodium 7- [Da- (4-hydroxynicotinoylamido) -a-pheny / acetamido] cephalosporanate , 195 mg of S-mercapto-1-carboxymethyltetrazole and 180 ml of sodium bicarbonate were added to 40 ml of water. The mixture obtained was stirred at 55 ° C. for 22 hours. The reaction mixture obtained is filtered voirde. The pH of the filtrate was adjusted to 1 by adding 1N hydrochloric acid under ice-cooling. The precipitates formed were separated off by filtration, washed with water and rewashed with ether. The precipitates were then dried. 300 mg of J- [Da- (4-hydroxynicotinoylamido) -aphenylacetamidoj-Sd-carboxymethyltetrazole-S-yD-thiomethyl-Δ-cephem-4-carboxylic acid were obtained.

Melting point: about 240 C (partial decomposition).

Infrared absorption spectrum: γ "" cm: 1775 (β-lactam).

Max

Nuclear Magnetic Resonance Spectrum (Dg-DMSO):

6 ppm: 3.60 (2H) ₃ 4.36 (2H), 5.00 (IC), 5.34 (2H),

5.84 (2H), 6.48 (IH), 7.44 (5H) ₃ 7.88 (IH),

8.50 (IH) ₃ 9 ₃ 52 (IH).

Example 16:

To 30 ml of water, O _3, 45 g of sodium -? - [O-a- (4-hydroxynicotinoylamido) -a-phenylacetanidjo] cephalosporanate, O ₃ 2 g of 6-carboxymethylthio-4-mercaptopyrirr.idin and 0.14 g of sodium bicarbonate were added . The resulting mixture was 22 hours

509841 Π003

the stirred at 55 ° C. After the reaction mixture obtained was filtered off, the pH of the filtrate was adjusted to 1 with 1 η hydrochloric acid while cooling with ice. The resulting sediments were separated by filtration, washed with water and then with ether and dried. 0.42 g of "J- [5-a- (4-hydroxynicotinoylamido) -α-phenylacetamido] -J> - (6-carboxymethyIthiopyrimidin-4-yl) thiomethyl-Ä-cephem-4-carboxylic acid was obtained.

KBr

on ¹ : 1775 max

Nuclear Magnetic Resonance Spectrum (Dg-DMSO):

6 ppm: 3.50 (2H), 3.98 (3H), 4.58 (IH), 5.00 (IH),

5.74 (2H), 6.42 (IH), 7.34 (6H), 7.78 (IH),

8.42 (IH), 9.40 (IH).

Example 17:

0.5 g of 7 ~ | Da- (4-hydroxynicotinoylamido) -a-phenylacetamido / cephalosporic acid, 0.235 g of 6-carboxymethylthio-4-mercapto-2-methylpyrimidine and 0.295 g of sodium bicarbonate were added to 37 ml of water and the mixture obtained was stirred at 50-55 ° C. for 22 hours. The obtained reaction mixture was filtered, and the pH of the filtrate was adjusted to about 2 with 1 η hydrochloric acid under ice-cooling. The precipitates formed were separated off by filtration, washed with water and rewashed with ether and dried under reduced pressure. There was added 0.42 g of 7- [JP-A (4-Hydroxynicotinoylamido) -a-phenylacetamido] -3 ~ (6-carboxymethylthio-2-methylpyrin ⁱ idin-4-yl) thiomethyl-A -cephem-4-carboxylic acid obtain.
Infrared absorption spectrum:

KBr) em "" ¹ : 1778 (β-lactam). Max

509841/1003

25U322

Nuclear Magnetic Resonance Spectrum (D / - DMSO):

6 ppm: 2.50 (3H) ₅ 3.52 (2H), 3.82 (IC) ₅ 3 _S 98 (2H),

4.62 (IH), 5 ₅ O2 (IH), about 5.73 (IH), 5 85 ₅ (IH) ₅

6.45 (IH), 7.23 (IH), 7.38 (5K) ₅ 7.82 (IH),

8.46 (IH) and 9.44 (IH).

Example 18:

526 mg of J- jjD-a- (4-hydroxynicotinoyl amido) -a-phenylacetamidqj cephalospcranic acid, 220 mg of 1-carboxymethyl-3-mercapto-6- (1H) -pyridazinone and 300 mg of sodium bicarbonate were added to 37 ml of water. The resulting mixture was stirred at 50-55 ° C. for 22 hours. After completion of the reaction, the resulting reaction mixture was filtered, and the pH of the filtrate was adjusted to 2 by adding 1 η hydrochloric acid under ice-cooling. The sediments thus formed were separated off by filtration, washed with water, rewashed with ether and dried under reduced pressure. 350 mg of 7 ~ | pa- (4-hydroxynicotinoylanido) -a-phenylacetamidoJ -.3- (I carboxymethyl-6 (IH) -pyridazinon-3-yl) thiomethyl-Δ-cephem 4-carboxylic acid were obtained.
Infrared absorption spectrum: -

• \) a ¹ : 1775 (ß-lactam). Max

Nuclear magnetic resonance spectrum (Dg

δ (ppm): 3.46 (2H), 3.88 (IH), 4.33 (IH), 4.66 (2H), 4.93 (IH), 5.74 (2H), 6.4o (IH), 6.88 (IH), 7.34 (6H), 7.74 (IH), 8.4C (IH) and 9.4L (IH).

Example 19:

420 mg of J- j D-α- (4-hydroxynicotinoylamido) -a-phenylacetamidoj cephalosporanic acid, 220 mg of 2-amino-4-carboxymethylthio-6-mercaptopyrimidine and 240 mg of sodium

509841/1003

bicarbonate. By treating the mixture as indicated in Example 18, 310 mg of 7- [pa- (4-Hydroxynicotinoylamiao) -a-phenylacetamidoj -3- (2-anino-4-carboxymethylthiopyrimidin-6-yl) thiomethyl-A -cephem-4 -carboxylic acid obtained, added
Infrared absorption spectrum:

KBr _ _Λ

cm: 1770
Max

Nuclear Magnetic Resonance Spectrum (D - DMSO) δ (ppm): 3.52 (2H), 3.92 (3H) ₃ 4.46 (IH), 5.02 (IH) ₃ 5.76 (2H) ₃ 6, 4l | (2H) ₃ 6.68 (2H), 7.36 (5K), 7.82 (IH) ₃ 8.46 (IH) and 9.44 (IH).

Example 20-a:

290 mg of 4-hydroxy-2-methylpyrimidine -5-carboxylic acid and 0.3 ml of triethylamine were added to 20 ml of methylene chloride. After the obtained mixture was cooled to -10 ° C. with stirring, a solution of 143 mg of ethyl chlorocarbonate in 3 ml of methylene chloride was added dropwise to the mixture. The resulting mixture was then for one hour at -10 C j stirred and a solution of 500 mg cephaloglycin and 0 ₃ 2 ml of triethylamine in 10 ml Kethylenchlorid was added to the mixture. The mixture obtained was stirred for a further hour at -10 ° C. and then stirred for a further hour at room temperature. After the completion of the reaction, the solvent was distilled off under reduced pressure and 5 ml of water was added to the residue. After adding 30 ml of a 1: 1 mixture of n-butanol and ethyl acetate, the pH of the mixture was adjusted to 3 by adding 1 η hydrochloric acid and stirred thoroughly.

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Then the organic solvent layer formed was separated, washed with water / water, rewashed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The resulting reaction mixture was concentrated at room temperature, and then 20 ml of ether was added to the residue. The formed precipitates were separated by filtration, washed with water and then with ether, and dried under reduced pressure. 300 mg of 7 ~ f ^ ~ ^a ~ (4-hydroxy ~ 2-methylpyrimidin-5-ylcarboxamide) -a-phenylacetamido [cephalosporanic acid were obtained.
Infrared absorption spectrum:

KBr

-ζ) cijj ..: 1780 (ß-lactam). Max

Nuclear Magnetic Resonance Spectrum (Dg-DMSO):

δ (ppm): 2.00 (3H), 2.41 (3H), 3 ₃ 4l (2H), 4.64 (IH), 4.95 (IH), 5.04 (IH), 5.80 (IH), 5.84 (IH) _5, 7.39 (5H), 8.55 (IH).

Example 20-b:

300 mg of ¹ J- [p-ct- (4-Hydroxy-2-methylpyrimidin-5-ylcarboxamido) -a-phenylacetamido] -cephalosporanic acid, 112 mg of 241capto-1,3 _s 4-thiadiazol-5-yl -thioacetic acid and 183 mg sodium bicarbonate dissolved. By treating the solution as indicated in Example 18, 240 mg of 7-jp-a- (4-Hydroxy-2-methylpyrimidin-5-ylcarboxamido) -aphenylacetamido] -3- (5-carboxymethylthio-1,3,4- thiadiazol-2 ~ yl) thiomethyl-A -cephem-4-carboxylic acid. Infrared absorption spectrum:

KBr

cm * "': 1780 (β-lactam). Max

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Nuclear Magnetic Resonance Spectrum. (D ^ -DMSO): δ (ppm): 2.36 (3H), 3.56 (2H), H, 12 (2H), 4.20 (IH), 4.50 (IH), 5, C2 (IH), 5.72 (IH), 5.84 (IH),

7.38 (5H) and 8.60 (IE).

Example 21:

To a mixture of 0.5 g of 7- [p-a- (4-Hydroxynicotinoylarcido) -a-phenylacetaniidoj cephalosporanic acid and 275 ng 2- (l-Carboxyäthylthio) -5-mercapto-l, 3, ^ - thiadiazole were 310 mg sodium bicarbonate and 37 n: l water were added. The mixture was stirred at 50 ~ 55 ° C for 22 hours. Insoluble matter was filtered off from the resulting reaction mixture and the pH of the filtrate was raised about 2 adjusted with 1 η hydrochloric acid with ice cooling. The precipitates formed were through Separated by filtration, washed with water and then with ether and dried under reduced pressure. It 0.4 g of 7- {p-a- (4-Hydroxynicotincylamido) -a-phenylacetamidoj -3- Jf- (l-carboxyethylthio) -! , 3, 4-thiadiazol-2-yl] obtained thiomethyl-A-cephem-4-carboxylic acid. Infrared absorption spectrum:

\ ^KBr

V cm: 1778 (β-lactam).

Max

Nuclear Magnetic Resonance Spectrum (Dg-DMSO):

δ (ppm): 1.54 (3H), 3.58 (2H), 4.20 (IH), 4.37 (IH),

4.45 (IK), 5.02 (IH), about 5.76 (IH), 5.85 (IK),

7.39 (5H), 7.82 (IH), 8.45 (IH) and 9.45 (IH).

Example 22:

To a mixture of 500 mg of 7-Q? - «- (4-Hydroxynicotinoylamido) -a-phenylacetamidoj -cephalosporanic acid and 292 mg of 2- (1-carboxy-1-methylethylthioJ-S-niercaptc-1,3, ^ - thiadiazole 320mg sodium bicarbonate and 37 ml v / water were added

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adds. By treating the mixture as indicated in Example 21, 370 mg of J- j ~ Da- (4-Kydroxynicotinoylamido) -a-phenylacetamidoj -J> - p-il-carboxy-l-raethylethylthio) - !, 3,4- thiadiazol-2-ylJ thiomethyl-Δ-cephem-4-carboxylic acid obtained, infrared absorption spectrum:

cm " ¹ : 1777 (β-lactam).
Max

Nuclear Magnetic Resonance Spectrum (D ^ -DMSO) δ (ppm): 1.57 (6H), 3.59 (2H), 4.23 (IK), 4.45

5.01 (IH), about 5.75 (IH), 5.84 (IH), 6.43 (IH), 7.37 (5H), 7.81 (IH), 8.43 (IH) and 9.42 (IH).

Example 23:

To 40 ml of water were 0 ^ 63 g of J- Q) -a- (4-hydroxynicotinoylamido) -a-phenylacetamido] cephalosporanic acid, 0.25 g of 2-mercapto-4-methylthiazo-5-acetic acid and 0.3 g of sodium bicarbonate added. The resulting mixture was held at about 55 ° C for one hour. The pH of the resulting reaction mixture was adjusted to about 2 with 1 η hydrochloric acid while cooling with ice. The educated. Precipitates were separated by filtration, washed with water and dried. 0.55 g of 7- [pa- (4-hydroxy nicotinoylamido) -a-phenylacetamidoj -3- (5-carboxymethyl-4-methylthiazol-2-yl) thiomethyl-A ' ⁵ -cephem-4-carboxylic acid were obtained.
Infrared absorption spectrum:

cm "': 1772 (β-lactam).
Max

Nuclear Magnetic Resonance Spectrum (Dg-DMSO):

δ (ppm): 2.20 (3H), 3.53 (2H), 3.72 (2H), 4.02 (IH),

4.46 (IH), 4.97 (IH), 5.71 (IH), 5.82 (IH),

6.42 (IH), 7.33 (5H), 7.78 (IH), 8.40 (IH),

9.39 (IH), 11.15 (IH) and 12.02 (IH).

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Example 24:

0.8 g of Natriura-7-jp-a- (4-hydroxynicotinoylamido) -a-phenylacetamido] cephalosporanate, 0.38-6 g (2-mercapto-4-methylthiazol-5-yl) thioacetic acid and 0.295 g sodium bicarbonate was added. The resulting mixture was stirred at about 55 ° C. for 20 minutes. Then, the pH of the reaction mixture was adjusted to about 2 by adding 1 η hydrochloric acid under ice cooling.

The formed precipitates were separated by filtration, washed with water and dried. There were obtained 0.4 g of 7 ~ [PA (4-Hydroxynicotinoylamido) -a-phenylacetamidoj ~ 3 ~ (5 ~ carboxymethylthio-4-r.ethylthiazol-2-yl) thiomethyl-A cephem-4-carboxylic acid.

Infrared absorption spectrum:

^ ^KBr

x) cm " ¹ : 1768 (β-lactam).

Max

Nuclear magnetic resonance spectrum. (D ^ -DMSO): δ (ppm): 2.35 (3H), 3.50 (2K), 3.55 (2K), 4.07 (IH), 4.52 (IH), 4.99 (IH), 5.74 (IH), 5.84 (IH), 6.43 (IK), 7.34 (5H), 7.3O (IK), 3, ^ 3 (IK), 9.41 (IH), 11.29 (IH) and 12.16 (IE).

Example 25 '

To 50 ml of water, 0.8 g of Matriuru-7-p-a- (4-hydroxynicotinoyl amido) -a-phenyiacetamidoj cephalosporanate, 0.2S4 g of 2-mercapto-1,3,4-thiadiazole-5-acetic acid and 0.271 g of matrium bicarbor.att The resulting mixture was stirred at 55 ° C. for 21 hours. The pH of the reaction chamber obtained was increased about 2 with 1 η hydrochloric acid adjusted under ice cooling, and the boilers formed were filtered off e.bge & rennt, washed with water and dried. It

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0.45 g of 7- [p-a- (4-Hydroxynicotinoylamido) -a-phenylacetamidöj -3- (5-carboxymethyl-1,3,4-thiadiazol-2-yl) thiomethyl-Δ -cephem - ^ - carboxylic acid obtained. Infrared absorption spectrum:

KBr

V cm " ¹ : 1774 (β-lactam).
Max

Nuclear Magnetic Resonance Spectrum (D ^ -DMSO): δ (ppm): 3.58 (2H) ₃ 3.17 (2H), 4.19 (IE), 4.53 (IH), 5.00 (IH), 5 .71 (IH), 5.82 (IH), 6.42 (IH), 7.35 (5H), 7.79 (IH), 8.42 (IH), 9.42 (IH), 11, 19 (IH) and 12.04 (IH).

Example 2ö-a:

7.5 g of cephaloglycine were suspended in 150 ml of methylene chloride. After adding 5.0 g of triethylamine and 5.0 g of magnesium sulfate to the suspension, the resulting mixture was stirred for 30 minutes at room temperature 4-Methoxynicotinsäurechlorid gegebenj in one portion to the filtrate and then for 2 hours at temperatures of -20 C was stirred to -30 C. the reaction mixture was stirred overnight at -8 ⁰ C allowed to stand and then stirred for 2 hours at room temperature. Mach reaction has ended,

was the solvent at room temperature under

-f-

reduces em pressure from the water dissolved. A small amount of insoluble matter in the solution was filtered off. After adjusting the pH of the filtrate by addition of an aqueous 5 / äigen hydrogen chloride was stirred, the filtrate for 30 minutes under ice-cooling, the acid solution = The precipitates thus formed were collected by filtration _s separated by V / ater, an aqueous l ^ aqueous hydrochloric acid solution and with

° the reaction mixture was distilled off _o Dsr educated residue was dissolved in 3OO ml

509841/100 3

Washed enough water and dried over phosphorus pentoxide under reduced pressure. 6.5 g of powdery 7- jp-ct- (4-kethoxynicotinoylamido) -a-phenylacetamido] -cephalosporanic acid were obtained. Infrared absorption spectrum:

- \ ^KBr

\) cm * "': 1774 (ß-lactam), 1660 (acid amide), ^max 1728 (acetate)

Nuclear Magnetic Resonance Spectrum (Dg-DMSO): θ (ppm): 3.74 (3H, -OMe), 6.42, 7.76, 8.42 (IH, IH, IH, the proton of the pyridine nucleus), 2.00 (3H, -CH ₂ OCOCH ₃ ).

Example 26-b:

0.70 g of 7- [p ~ a- (4-methoxynicotinoylamido) -a ~ phenylacetamido / cephalosporanic acid and 0.26 g of 5-carboxymethylthio-2-mercapto-1,314-thiadiazole were suspended in 44 ml of water. Then 0.37 g of sodium bicarbonate was added to the suspension. The resulting mixture was stirred at 55 ° C. for 22 hours. After the reaction had ended, a small amount of insoluble matter was filtered off from the reaction mixture. The pH of the filtrate was adjusted to 1 by adding 5% hydrochloric acid solution. The precipitates formed were separated off by filtration, washed well with water, washed with ether and dried over phosphorus pentoxide under reduced pressure. 0.76 g of white powdery 7- {Da- (4-methoxynicotinoylamido) -a-phenyIacetamido] -3- (5-carboxymethylthio-1,3,4-thiadiazol-2-yl) thiomethyl-A -cephem-4 -carboxylic acid obtained.
Infrared absorption spectrum:

cm "': I77O (β-lactam), I66O (acid amide). Max

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Nuclear Magnetic Resonance Spectrum (D, - DMSO):

δ (ppm): 3.76 (3H, -OMe), 3.56 (2H, Ss ^ i) and

4.14- (2H ₃ -SCH ₂ COOH). ^ ^H

Example 27-a:

300 mg of powdery 4-hydroxy-5-methylnicotinic acid and 230 mg of triethylamine were added to 18 ml of dichloromethane. The resulting mixture was stirred overnight at room temperature. To the suspension obtained, 241 mg of thionyl chloride was added while cooling with ice. Then, stirring was carried out for 30 minutes while cooling with ice and for one hour at room temperature. The solvent was removed from the reaction mixture under reduced pressure. A mixture of 500 mg and 280 mg cephaloglycin Triäthylarnin and 18 ml of dichloromethane was cooled to -20 C and added to the white powdery residue and stirred for 2 hours at temperatures from -10 ⁰ C to -20 ⁰ C. The mixture was left to stand over power at the above temperature and then stirred for 2 hours at room temperature. The solvent was distilled off from the reaction mixture under reduced pressure. 6 ml of water was added to the residue obtained. Insoluble precipitates (for example unreacted ^ -hydroxy-S-methy! Nicotinic acid) were filtered off from the reaction mixture and the pH of the filtrate was adjusted to about 2 with 1 η hydrochloric acid while cooling with ice. The white precipitates formed were extracted with a 1: 1 mixture of n-butanol and ethyl acetate. The extract was washed with water and washed with saturated aqueous sodium chloride solution and dried with magnesium sulfate. After filtering off the magnesium sulfate, a slightly excess amount of a butanol solution of sodium 2-methylhexanoate was added.

509841/1003

added and the Miederschl ^formed:? ge vairden separated by filtration, and thylacetat with £ 'ether and dried. 400 μg of 7 "[pa- (4-hydroxy-3-methylnicotinoylamido) -a-phenylacetamido] -cephalosporanic acid were obtained.

Nuclear Magnetic Resonance Spectrum (D ^ -DMSO):
δ (ppm): 1.91 (3H), 1.99 (3K), about 3.26 (2H), 4.70 (2H), 4.98 (IH), 5.73 (IH), 6, 40 (IH), 7.24 (5H), 7.32

(IH), 8.28 (IH) and 9.34 (IH).

Example 27-b:

To 30 ml of water, 400 ng of i; atriun: -7- [Da- (4-hydroxy-3-methylpyridin-S-ylcarboxairidoJ-a-phenylacetar.idJ] -cephalosporanate, 193 mg 2-carboxymeth: / lthio-5- mercapto-l, 3,4-thiadiazole and 172 mg sodium bicarbonate were added
The resulting mixture was stirred at 50-53 ° for 22 hours. Then, by treating the reaction mixture,
as indicated in Example 21, 300 mg of J- JD-a- (4-hydroxy-3-methylpyridin-5-ylcarboxarr.idc) -a-pher.ylacetamidoj -3- (5-carboxymethylthio _{-1,3 J} 4-thiadia2 ; ol-2-yI) thiomethyl-A ' ^5- cephera-4-carboxylic acid obtained.
Infrared absorption spectrum:

(2H),

V cz: - * : 1778 (β-lactam). Max

Nuclear magnetic resonance spectrum. (D ^ -EIISO): 6 (ppm): 1.94 (3H), 3.55 (2H), 4.11 (2K) ₅ etva 4.2

5.00 (IH), 5.7 ^ (2H), 7.34 (5K) ₅ 7.73 (IH), 3.34

(IK) - and 9.33 (IE). ■

Example 23-a:

In 20 ml of methylene chloride was 0.50 g of 6-Uydroxy - ^ - r.ethox; · - nicotinic acid suspended, "after addition of 0.33 ε Triäthyi · anin 3i! the suspension v / urda read the mixture through for 10 minutes.

509841/1003

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touched. Then, after cooling the mixture to -30 ⁰ C was added a solution of 0.40 g of thionyl chloride in 6 ml of methylene chloride was added dropwise to the mixture. The mixture obtained was then stirred at -25 ° C. for one hour. Separately, 1.0 g of cephaloglycine was suspended in 20 ml of methylene chloride. After adding 0.65 g of triethylamine and then I ₃ O g of magnesium sulfate, the mixture was stirred for minutes at room temperature. After the reaction had ended, the insoluble matter was filtered off from the reaction mixture. After the filtrate had been cooled to -4 5 ° C., the methylene chloride solution prepared above of the acid chloride prepared under cooling was added to the filtrate in one go.

Then by stirring the mixture for 3 hours at temperatures between -20 ⁰ C to -30 C ⁰ ", and then a further 1.5 hours at room temperature, the solvent was distilled off under reduced pressure and added 30 ml water to the resultant residue. The pK of The mixture was then adjusted to 8 by the addition of aqueous 5% sodium bicarbonate solution, after which the pH of the batch was adjusted to 2 by the addition of aqueous 5% hydrochloric acid solution, and the precipitates formed were separated off by filtration and diluted with a sufficient amount of an aqueous solution hydrogen chloride solution and then washed with water and dried over phosphorus pentoxide under reduced pressure. There was obtained 0 _s 80 g white powdery 7- [p-α- (4 ~ methoxy ■ -ohydrόxynicotinoylamidd) · ^s · -α- ■ phenylacetamidqj cephalosporanic acid.
Infrared absorption spectrum:

cm "* ': 1778 (β-lactam} ₃ 1662 (acid amide).

9-8Λ1 /

25U322

- H 7 -

Nuclear magnetic resonance spectrum (0, - DMSO):

6 (ppm): 2.00 (3H), 3.40 (2H, 3H), 4.82 (2H), 5, Oi: _(1H ) ₃ 5.70 (IH), 5.78 (IH, iK ), 7.36 (5H>, 8.42 (IH),

8.98 (IH) and 9.44 (IH).

Example 28-b:

0.69 g of 7- [pa- (6-hydroxy-4-methoxynicotinoylamido) -ct-phenylacetamido] cephalosporanic acid and 0.28 g of 2-carboxymethylthio-5-mercapto-1,3,4-thiadiazole were suspended in 43 ml of water . After adding 0.37 g of sodium bicarbonate to the suspension, the resulting mixture was stirred at 55 ° C. for 23 hours. After the reaction had ended, a small insoluble fraction was filtered off from the reaction mixture and the pH of the filtrate was adjusted to 2 by adding an aqueous 5% hydrochloric acid solution. The precipitates formed were separated off by filtration, washed with water, rewashed with ether and dried over phosphorus pentoxide under reduced pressure. 0.51 g of crystalline powdery 7-jp-a- (6-hydroxy-4-methoxynicotinoylamido) -a-phenylacetanidöj -3- (5-carboxymethylthio-1,3,4-thiadiazol-2-yl) thiomethyl7 Δ - obtained cephem-4-carboxylic acid.
Infrared absorption spectrum:

NKBr

V cm " ¹ : 1778 (β-lactam) and 1664 (acid amide). Max

Nuclear Magnetic Resonance Spectrum (D ^ -DMSO):

δ (ppm): 3.44 (2H, 3H), 4.14 (2H), 4.96 (2H), 5.04 (IH), 5.66 (IH), 5.76 (IH, IH), 7.36 (5H), 8.40 (IH),

9.00 (IH) and 9, ^ 6 (IH).

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Example 29-a:

1 g of cephaloglycine and 0.62 g of triethylamine were added to 50 ml of methylene chloride with stirring. After addition of 0.53 g of 4-hydroxy-6-methylnicotinsäurechlorid to the mixture at -10 ⁰ C, the mixture was stirred for 4 hours at temperatures between -10 C to 0 ⁰ C. After that, the Reaktionsgerrasch overnight at -20 ⁰ C was allowed to stand. The mixture was then stirred at 10-15 ° C. for 3 hours. The solvent was distilled off from the reaction mixture under reduced pressure. Then, 30 ml of water was added to the residue to dissolve, and the pH of the solution was adjusted to 1-2 by adding 1 η hydrogen chloride solution while cooling with ice. The product was extracted with a mixture of n-butanol and ethyl acetate in a 1: 1 volume ratio. The extract was washed with water and then with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The magnesium sulfate was then filtered off from the batch and the filtrate was mixed with stirring in a slight excess of an n-butanol solution of sodium 2-methylhexanoate. The precipitates thereby precipitated out were separated off by filtration and washed with ether. 0.4 g of sodium 7- [pa- (4-hydroxy-6-methylnicotinoylamido) -aphenylacetamide cephalosporanate was obtained. Nuclear Magnetic Resonance Spectrum (Dg-DMSO):

SCppm): 1.91 (3H), 2.28 (3H), 3.14 (IH), 3.40 (IH), 4.71 (2H), 5.00 (IH), 5.76 (IH), 6.33 (IH), about 6.43 (IH), 7.23 (5H), 8.21 (IH) and 9.32 (IH).

Example 29 ~ b:

250 mg of 7- [p-a - (- 4-Hydroxy-6-methylnicotinoylamido ) -A-phenylacetamido] cephalosporanic acid, 120 mg 2-mercapto-5-carboxymethylthio-1,3,4-thiadiazole

509841/1003

and 102 ir.g sodium bicarbonate added. The resulting mixture was heated to 50-53 ° C. with stirring for 24 hours. The pH of the reaction mixture was then adjusted to 1-2 with 1 η hydrochloric acid solution while cooling with ice. The precipitates formed were separated off by filtration, washed with water and then with ether and dried. About 170 mg of 7- [pa- (4-Hydroxy-6-methylnicotinoylamido) -a-phenylacetamido] -3- (5-carboxymethylthio-1,3j4-thiadiazol-2-yl) thiomethyl-A -cephem-4- carboxylic acid obtained.
Infrared absorption spectrum:

KBr

^) cm "': 1776 (ß-lactam).
Max

Nuclear magnetic resonance spectrum (0, - DMSO):

6 (ppm): 2.26 (3H), 3.59 (2K), 4.15 (2H), 4.19 (IH), 4.50 (IH), 5.03 (IH), 5.79 (2H), 6.30 (IH), 7.39 (5H), 8.32 (IH) and 9.47 (IH).

Example 30:

In 47 ml of water was added 0.75 g Iiatriun-7- [DA (4-Hydroxynicotincylan: ido) -a-phenylac9tamido] cephalosphoranat and 0.29 g l-Arr _i ino-2-ethylthio-5-carboxyir _I niercapto- l, 3,4-triazole suspended. After adding 0.29 g of sodium bicarbonate to the suspension, the resulting mixture was stirred for 22 hours at 55 ° C,

After the end of the reaction, a small portion became more insoluble Components filtered off from the reaction mixture and then the pH of the filtrate was adjusted to 2 by addition aqueous 5% hydrogen chloride solution to the Geirisch set. The resulting precipitations were separated by filtration, washed with sufficient water and then washed with zither and over phosphorus pentoxide

509841/1003

dried under reduced pressure. There were 0.62 g of crystalline powder of "J- [ba- (4-Hydroxynicotinoylamido) -aphenylacetamideq] -3- (l-amino-5-carboxymethylthio-1,3,4-triazol-2-yl) thiomethyl-Δ -cephem-4-carboxylic acid.

KBr

^ \ cnT ^ .1772 (ß-lactam) and ΙββΟ (acid amide). Max

Nuclear Magnetic Resonance Spectrum (D ^ -DMSO).

δ (ppm): 3.58 (2H), 3.98 (2H), 5.04 (2H), 5.40 (2H), 5.70 (IH), 5.78 (IH), 5.82 (IH), 6.46 (IH), 7.36 (5H), 7.78 (IH), 8.46 (IH), 9.40 (IH) and 11.16 (IH).

Example 31-a:

500 mg of 7- (Da-amino-ap-hydroxyphenylacetamido) cephalosporanic acid trifluoroacetate and 190 mg of triethylamine were added to 10 ml of chloroform. Mach cooling the obtained mixture at -20 ⁰ C was I63 mg of 4-Thiopyron-3- carboxylic acid chloride was added to the mixture with stirring. Then by stirring the mixture for one hour at the same above temperature and then a further 2 hours was stirred at room temperature and then the solvent under reduced pressure from the reaction mixture removed "To the residue thus formed was added 10 ml of water was _added}, and the solution was acidified with 1 η hydrochloric acid. The product was extracted twice with 25 ml each of a 1: 1 mixture of n-butanol and ethyl acetate. The extracts were washed with water and then dried. The solvent was distilled off under reduced pressure. Then, ether was added to the residue obtained, and the precipitates formed were separated by filtration. There were 38Ο mg of 7-Ba- (4-thiopyron-3-carboxamido) -ap-hydroxyphenyl-

⁵ Mh distilling off

509841/1003

acetamido] cephalosphoranic acid. ■ Infrared absorption spectrum:

KBr _Λ

T) cm: I78O (β-lactam).
Max

Nuclear Magnetic Resonance Spectrum (Ιγ-DMSO):

6 (ppm): 2.00 (3H), 3, ¹ IO (2H), 4.80 (2H), 5.02 (IH), 5.68 (2H), 6.70 (2H), 7, 20 (2H), 7 ₃ 22 (IH), 8.40 (IH) and 9.30 (IH).

Example 31-b:

^{150 mg of 1} J- [pa- (4-thiopyron-3-carboxamido) -ap-hydroxyphenylacetamido] cephalosporanic acid, 61.5 mg of 2-carboxymethylthio-5-mercapto-l, 3 _s ² J-thiadiasol, were added to 10 ml of water. and 81.0 mg sodium bicarbonate added. The mixture was held at 50-55 ° C. for 20 hours.

After the end of the reaction, the reaction mixture obtained was acidified by adding 1 η chlorine anhydrous acid while cooling with ice. The precipitates formed were separated off by filtration. 120 mg of 7-Jp-Ot - (^ - thiopyron-3-carboxamido) -ap-hydro: <yphenylacetamidq] -3-J5-carboxymethylthio-1,3, ⁱ t-thiadiazol-2-yl] thiomethyl-Δ cephem - ^ - carboxylic acid obtained.
Infrared absorption spectrum:

KBr ^ ₁

- «0 cm: I77O (β-lactam).
Max

Nuclear Magnetic Resonance Spectrum (D ^ -DMSO):

6 (ppm): 3.56 (2H), 4.12 (2H), 4.30 (2H),, 00 (IH), 5.64 (2H), 6.70 (2H), 7.10 ( IH), 7.20 (2H), 8.36 (IH) and 9.30 (IH).

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25U322

Example 32:

170 mg of 7 ~ jp-a- (4-thiopyrone-3-

carboxamido) -a-p-hydroxyphenylacetamido] cephalosporanic acid, 87 mg of 2-carboxymethyl-5-mercapto-1,3,4-thiodiazole and 92 mg of sodium bicarbonate were added. The mixture was

Stirred for 15 hours at 50-55 ° C. Then the approach

treated as indicated in Example 31 ~ b. It was 120 mg 7-Jp-a- (4-thiopyrone-3-carboxamido) -a-p-hydroxyphenylacetamido]

3- | ^ -carboxymethyl-1,3-4-thiadiazol-2-yl | thiomethyl-Δ ^ -

obtained cephem-4-carboxylic acid.

Infrared absorption spectrum:

.KBr \) era "' : 1775 (β-lactam). Max

Nuclear Magnetic Resonance Spectrum (D ^ -DMSO):

δ (ppm): 3.58 (2H), 4.16 (2H), 4.36 (2H), 5.00 (IH), 5.64 (2H), 6.70 (2H), 7.20 (2H), 7 _S 22 (IH), 8.38 (IH) and 9 ₃ 10 (IH).

Example 33 ■ "

150 mg of 7-jp-a- (4-hydroxynicotinoylamido) -ap-hydroxyphenylacetamidol cephalosporanic acid, 63 mg of 2-carboxymethylthio-5-mercapto-l, 3,4-thiadiazole and 83 i 3 mg of sodium bicarbonate were added to 10 ml of water / water. The mixture was stirred at 50-52 ° C. for 20 hours. After the reaction had ended, the reaction mixture was acidified by adding 1 η hydrochloric acid while cooling with ice. The precipitates formed were separated by filtration. 60 mg of 7-jp-a- (4-hydroxynicotinoylamido) -ce-p-hydroxyphenylacetamidOJ -

3- | 5-carboxymethylthio-1,3,4-thiadiazol-2-yil -thiomethyl-Δ-cephem-4-carboxylic acid.
Infrared absorption spectrum:

KBr

cm ~ ^Ί : 1770 (ß-lactam). Max

509841/1003

Nuclear Magnetic Resonance Spectrum (D / - DMSO):

δ (ppm): 3.52 (2H) ₃ 4.08 (2H), 4.28 (2H) ₅ 4.64 (2H), 4.97 (IH), 6.36 (IH), 6.68 (2H), 7.20 (2H), 7.74 (IH), 8.39 (IH),

Example 34:

0.36 g of sodium 7- [p-a- (4-Hydroxynieotinoylaraido) -a-phenylacetamidoj cephalosporanate and 0.17 S 5-carboxyraethylthio-2-mercapto- [1,2,4] -triazolo- £ 3,4 --- b] -Jj, 3 thiadiazole suspended. Then, after adding 0.15 g of sodium bicarbonate to the suspension, the resulting mixture became Stirred for 26 hours at 55 ° C., when the reaction has ended The insoluble matter was filtered off from the reaction mixture, and then the pH of the filtrate was adjusted by adding from aqueous 5% hydrochloric acid solution to 2 set. The resulting precipitations were

separated by filtration, washed sufficiently with water,

T> entoxidji washed with ether and dried over phosphorus. It

0.27 g of crystalline powdery 7 ~ ^ -a- (4-hydroxynicotinoylamido) -a-phenylacetamidoj-3- (5-carbxyr.iethylthio- [1,2,4] -triazole - ^, 4-bj - [l , 3,4] thiadiazol-2-yl) thiomethyl-Δ-cepheni-4-carboxylic acid.
Infrared absorption spectrum:

^KBr -1

cm: 1776 (β-lactam) and 1660 (acid amide).

Max

Nuclear Magnetic Resonance Spectrum (D ^ -DMSO);

θ (ppm): 3.56 (2H), 4.20 (2H), 4.96 (2K), 5.60 (IH) ₅ 5.76 (IH), 5.84 (IH), 6.42 (IH), 7.36 (5H), 7.80 (IH), 9.42 (IK), 9.40 (IH) and 11.14 (IH).

Example 35:

In ISO ml water was 2.4 £ Hatrium-7 ~ Df "a- (4-IIydi- oxynicotinoylanidoj ^{i-a-phenylacetarr.idq]} cephalosporanate and

509841/1003

25U322

Dissolved 1.1 g of 2-mercapto-5- (3-carboxypropionylamino) -1, 3,4-thiadiazole. After adding 9 nil 10 ^ strength aqueous sodium bicarbonate solution to the solution, the mixture was stirred for 22 hours with heating at 55.degree. After the reaction had ended, the insoluble matter was filtered off from the reaction mixture and the pH of the filtrate was adjusted to 2 with 2 η hydrochloric acid. The precipitates thus formed were separated off by filtration, washed well with water, washed twice with 45 ml each of a methanol / ether mixture in a 1: 5 volume ratio and then with ether. It was dried over phosphorus pentoxide under reduced pressure. 1.5 g of pale yellow powdery 7 ~ D- £ a- (4-hydroxynicotinoylamido) -a-phenylacetamido] ~ 3 ~) 5 ~ (3-carboxypropionylainino) - !, j5,4-thiadiazol-2-yllthiomethyl-Δ obtained cephem-4-carboxylic acid.
Melting point 218-221 ⁰ C (with decomposition). Infrared absorption spectrum .:

x ^KBr -1
• ^ cm: 1772 (β-lactan), 166O

Max

Nuclear Magnetic Resonance Spectrum (D ~ O-MaOD) ' δ: 2.54 (4h, -N

Example 36:

In 50 ml of water was 0 ₅ 8 g iIatrium-7-D-α- (4-Hydroxynicotinoylamido) -a-phenylacetar.idol cephalosporanate and 0 _s 4l g of 2-mercapto ~ 5 ~ o-c'arboxybenzoylamino-l, 3 _s 4-thiadiasol dissolved. After adding 3 ml of the above aqueous sodium bicitonate solution to the solution, the mixture was stirred for 21 hours while heating to 55 ° C. After the completion of the reaction, insolubles were filtered off from the reaction mixture, and then the pH of the filtrate became

503841/1003

25H322

- ro -

adjusted to 2 with 2η hydrochloric acid. The precipitates thus formed were separated off by filtration, washed well with water, washed twice with 15 K of a methanol-Xther mixture each time in 1: 5 voluir-enamel and then washed with Xther and dried over phosphorus pentoxide under reduced pressure. It v.'urde 0.5 J ² g light yellow 7-D- [a- ⁽ⁱ i-Hydroxyr: icotinoylamido) -a-phenyl-

acet amido "] - 3- (5-o-carboxybenzoylanino-1,3, ¹ I-thiadiazol

3 2-yl) thiomethyl-A-cephem-Ji-carboxylic acid.

Melting point: 207 - 211 ⁰ C Infrared absorption spectrum:

KBr _1

cm: 1770 (β-lactam), 1653 Max

Example 37:

In 50 ml of water was 0 g -i Matrium-7-D- [OT ^(i-f Hyclroxynicotinoylarnido) -a-phenylacetanido] cephalosporanate and 0 ₃ 27 g of 2-! Iercapto-5 ~ carboxyr.ethyl-l ₃ 3 j ^ü ~ -riazole dissolved. After adding 3 ml of aqueous sodium bicarbonate solution to the solution, the mixture was stirred for 22 hours while heating at 55 ° C.

By treating the reaction equipment thus obtained, as indicated in Example 36, 0.23 g of pale yellow powder of 7-D-Γ a- ( ⁱ t-Hydroxynicotinoylainido) -a-phenylacetamido3] -3- (5-carboxylir.efchyl-l , 3,4-triazol-2 ~ yl) thiornethyl-A -cephen ¹ -4-carboxylic acid.
Melting point: 210-213 ° C
Nuclear Magnetic Resonance Spectrum (DMSO): 3.82 (2H ₅ -CH ₂ CCOH)

Infrared absorption spectrum:

KBr

cm ~ 1; 1775 (β-lactam), 1658 Max

509841/1003

Example. 38:

300 mg Iiatrium.-7- | _p-a- (4-Hydroxynicotinoylamidoj-a-phenylacetanidojcephalosporanat, 140 mg 4- (5-mercapto-1,3,4-thiadiazol-2-yl) butyric acid and 120 mg sodium bicarbonate were added. The resulting mixture became Stirred at 50-52 ° C. for 24 hours. Then the pH of the reaction mixture to 2 with 1 η hydrochloric acid set. The white precipitates formed were separated off and washed with water and then with ether and dried. There were 200 ng of 7 ~ [p-a- (4-Hydroxynicotinoylamido) ·

ot-phenylacetamido ^ J-3 ~ [5 ~ (3 ~ carboxypropyl) -1, 3,4-thiadiazol ~ 2-ylj-thioinethyl-A -cephem-4-carboxylic acid. Infrared absorption spectrum:

KBr ^

cm: I78O (β-lactam). Max

Nuclear Magnetic Resonance Spectrum (Dg-DMSO): 6 ppm: 1.91 (2H), 2.32 (2H), 3 _s O6 (2K) ₅ 3.58 (2H), 4.17 (IH), 4.51 ( IH), 5.01 (IE), 5.01 (IH), about 5.76 (IH), 5 _S 84 (IH), 6 _S 44 (IH), 7.38 (5H), 7.82 ( IH), 8.45 (IH) and 9, ^ 7 (IH).

Example 39:

300 mg of 7-fp-a- (4-kydroxy-6-methylnicotinoylamido) -a-phenylacetamido] were added to 20 ml of water. cephalosporanic acid 142 mg 4- (5-mercapto-l, 3,4-thiazol-2-yl) butyric acid and 169 mg sodium bicarbonate added. The mixture was stirred at 50-52 ° C. for 24 hours. Then the pH of the Reaction mixture to about 2 with 1 η hydrochloric acid set under ice cooling. The precipitates formed were separated by filtration, with water and then washed with ether and dried. There were 200 mg of 7- [p-a- (4-Hydroxy-6-methylnicotinoylamido) -a-phenylacetamido] ■ 3- Q> ~ (3-carboxypropyl) -1, 3,4-thiadiazol-2-yl]] thiomethyl- ' Δ-cephem-4-carboxylic acid obtained.

5 0 9 8 41/1

25H322

Infrared absorption spectrum:

cm """ ¹ : 1778 (β-lactam).
Max

Nuclear Magnetic Resonance Spectrum (Dg-DMSO): ppm: 1.91 (2H), 2.25 (3H) _3, 2.32 (2H), 3.06 (2H), 3.58 (2H), 4.18 (IC ), 4.51 (IH), 5.00 (IH), about 5.75 (IH), 5.83 (IH), 6.29 (IH), 7.38 (5H), 8.32 (IH ) and 9.46 (IH).

509841/1003

Claims (1)

Claims wherein R represents a hydrogen atom or a hydroxy group; QQ means a 5- or 6-membered ring with 1-2 nitrogen atoms , a quinoline ring or 1 2 a thiopyran ring; R and R, which may be the same or different, each represent a hydrogen atom, a hydroxy group _} a lower alkyl group, a lower alkoxy group, a lower alkylthio group, or an oxo group; \ BJ means a 5-membered ring with 1-H nitrogen atoms and / or 0-1 sulfur atoms ₅ a 6-membered ring with 2 nitrogen atoms, or a 1,2, M-Triasolo f3 _s 4 -bl -1,3, ^ -thiadiazole ring R ^ and R j if they are present, which can be the same or different _s each denotes a hydrogen atom ₅ an oxo group, a lower alkyl group or an amino group D represents a sulfur atom or an -NH-CO group j E represents an alkylene group or a phenylene group; 6 represents a carboxy group or a sulfo group; η is 0 or lj when m is 0; and η is 1 when m is 1 and the pharmacologically acceptable salts of the derivatives. Cephalosporin derivatives and their phamafeplogiseh S 0 9 8 4 1/1 0 0 3 Allowable salts according to claim 1, wherein the R "\ ~ QQ a pyridine ring and the ring (Jp a Represents 1,3 ^ thiadiazole ring, 3. Cephalosporin derivatives and their pharmac ο logical permissible salts according to claim 1, wherein the ring nij is a pyridine ring and the ring (β) is a 1,2, ^ - thiadiazole ring 4. Cephalosporin derivatives and their pharmacologically acceptable salts according to claim 1, wherein the ring Qy is a pyridine ring and the ring Γβ) is a thiazole ring. 5 · 7 ~ | j ⁾ ~ a- (4-HydroxynicotinoylaTr.ido) -a-phenylacetairado | -3- (5 ~ carboxymethylthio-1,3, ^ - thiadiazol-2-yl) thiomethyl-Δ -cephem - ^ - carboxylic acid. 6. 7 ~ [p-a - (^ - Hydroxynicotinoylar.ido) -ci-phenylacetamido] -3- (3 ~ carboxynethylthio-1, 2, ^ i-thiadiazol-S-yl) thiomethyl-Δ -cephem - ^ - carboxylic acid. " 7. 7 ~ nb-aC ^ -Hydroxynicotinoylar.idoJ-a-phenylacetaraidoJ -3 ~ (5 ~ carboxymeth3 / lthio- ⁱ (-iriethylthiazol-2-yl) thiomethyl- Δ -cephem - ^ - carboxylic acid, 8. 7 ~ fp ~ ct- ( ⁱ -Hydroxynicotinoylaraido5-a-phenylacetainidoJ -3- (5-carboxymethyl-l _s 3j ⁱ } -thiadiazol-2-yl) thiomethyl- Δ -cephem - ^ - carboxylic acid. 9. 7 ~ (D-ou ( ⁱ i-Hydroxy-3 ~ niethylnicotinoylair _i ido) -a-phenyl- acetamido] -3- (5 ~ carboxymethylthio-1,3, ⁱ * ~ thiadiazol-2-yl) - 3
thiomethyl-Δ-cephem-4-carboxylic acid. 509841/1003 10. 7 ~ pa- ^(J Wiydroxy-6-methylnicotinoylamido) -a-phenylacetamidoj -3- (5-carboxynethylthio-l, J>, 4-thiadiazol-2-yl) thiomethyl-· Δ -oephem-JJ-carboxylic acid. 11. Process for the preparation of cephalosporin derivatives with
of Formula V CH-UOtIII NH CiT ₂ Gf- Β -} - Κ ''' ®1 2 3 4
, RjRjRjR has the meaning already explained habenj characterized in that a connection with the Formula I. ClI-COIUI NlI 2 0 COOH
with a heterocyclic carboxylic acid with the formula II ) COOH II or is reacted with a reactive derivative of the heterocyclic carboxylic acid and the compound obtained with the Formula III I-CONH NH GH ₂ OGOOH ₇ GOOH 5 0 9 8 4 1/1 Q-O 3 then with the mercapto-substituted heterocyclic ring compound with the formula IV IV is reacted and the compound of the formula IV is optionally converted into its pharmacologically acceptable salt will. 12. Use of the cephalosporin derivatives mentioned in claims 1 to 10 as an antibiotic active ingredient for Manufacture of pharmaceuticals with common carriers and common auxiliaries. 509841/1003