JPS5862181A - Cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formulaI[R1 and R2 are H or lower alkyl; R3 is H, lower alkyl, hydroxy lower alkyl, or carboxy lower alkyl; R4 is H, acetoxymethyl, carbamoyloxymethyl, or -CH2S-R5(R5 is 5-membered or 6-membered ring having 2-4 hetero-atoms); n is 0-2] or its salt. EXAMPLE:7beta-{2-[2-(Piperazine-1-yl)carbonylmethoxyimino]-2-(2-aminot hiazole- 4-yl)acetamido}-3-(1-methyl-1H-tetrazole-5-yl)thiomethyl-3-cephem-4-ca rboxylic acid(syn-isomer). USE:An antibacterial agent. PROCESS:A compound shown by the formula II(R7 is carboxylic acid-protecting group) is reacted with a compound shown by the formula III(R6 is amino-protecting group) to give a compound shown by the formula IV, which is deprotected to give a compound shown by the formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cephalosporin derivatives represented by the following general formula and salts thereof.

In the formula, the angle and - are each independently hydrogen or lower alkyl,
- is hydrogen, lower alkyl, hydroxy lower alkyl or carboxy lower alkyl, R4 is hydrogen, acetoxymethyl, carbamoyloxymethyl or bar CH25-R, (
- is a 5-membered ring or a 6-shell ring having IN4 heteroatoms, and may be substituted with lower alkyl, amino lower alkyl, minino, carbamoyl lower alkyl or carboxy lower alkyl. ), or n represents 0.1 or 2.

As a result of research on various cephalosporin derivatives, the present inventors learned that the novel compound represented by the above formula (1) exhibits high antibacterial activity against a wide range of Gram-space bacteria and positive bacteria, and completed the present invention. .

The target substance (1) of the present invention is 1, for example, the following reaction formula % formula %
) In the formula, RJ# hr Ft, R4 and n are the same as above, Rs is an amino group used in peptide synthesis represented by trityl, formyl, 8th-butoxycarbonyl, p-methoxybenzyloxycarbonyl, etc. The protecting group, Rs, is hydrogen, lower alkyl, hydroxy lower alkyl protected with trityl etc., carboxy lower alkyl protected with 8th butyl etc., furthermore trityl, formyl.

Protection of amino groups used in peptide synthesis such as 8th-butoxycarbonyl tp-methoxybenzyloxycarbonyl IR7 is a protecting group for carboxylic acids used in peptide synthesis such as benzhydryl and 8-butyl, and
indicates halogen.

In addition, 1 the compound (I) of the present invention, the raw material compounds (1), (g), and M each contain a syn isomer (
A), the anti-isomer (B) and mixtures thereof.

In the present invention, when the syn isomer and the anti isomer are conveniently explained in one expression, they are expressed by one partial structure (C) (0).

The thiazole moiety shown in the present invention is thought to have a tautomeric structure of a 2-aminothiazole form and a 2-iminothiazoline form, but in this specification, it will be described as a thiazole type.

Next, to explain the manufacturing method in more detail, the compound (1) of the present invention can be converted into compound (1) or a reactive derivative thereof at the amine 7 group, or a salt thereof.

It can be produced by reacting with compound (1) or a reactive derivative thereof at the carboxyl group and then removing the protective group.

Examples of reactive derivatives at the amino group of compound (1) include silyl derivatives obtained by reacting compound (1) with a silyl compound such as trimethylsilyl chloride or bis(trimethylsilyl)acetamide.

Further, examples of the salts of the compound (it) include organic amine salts such as triethylamine salt.

Reactive derivatives at the carboxyl group of compound (1) include active esters, acid halides, acid anhydrides, active amides, etc.1 For example, active esters include N-hydroxy compounds (1-hydroxybenzotriazur),
rI (hereinafter referred to as OBtJ), N-hydroxysuccinimide.

Examples include esters with N-hydroxyphthalimide, etc.).

When compound (1) is reacted in the form of a free acid or a salt thereof, a condensing agent such as N,N'-disicvhexylcarbodiimide (hereinafter referred to as "DCC") is used.

The above reaction can be carried out using 9 e.g. water, dimethylformamide (hereinafter "
It is called "DMF". ), Tetrahydri 7 runs (hereinafter 1'-
It is called ToyJ. ), it can be carried out in the presence of other organic solvents that do not adversely affect the progress of the reaction.

The elimination reaction of the protecting group is carried out by hydrolysis with an organic acid such as formic acid or trifluoroacetic acid or an inorganic acid such as hydrochloric acid, or by conventional catalytic reduction using a conventional catalyst such as palladium on carbon. In the case of hydrolysis, a solvent that does not adversely affect the reaction may be used, or it may be carried out in the presence of a scavenger such as anisole. In the case of catalytic reduction, empty a solvent such as TIF or alcohol that does not adversely affect the reaction.

Also, the compound of the present invention 4? I (I) can also be produced by reacting the compound (g) or its salts with an acid halide in the presence of a deoxidizing agent, and then deprotecting the compound under the conditions described above. . As the deoxidizer, an organic compound such as pyridine or an inorganic compound such as sodium carbonate is used, and as a solvent, a solvent that does not adversely affect the reaction, such as dichloromethane or DMF, is used.

On the other hand, there are various methods for synthesizing the raw material compounds, but an example of the synthesis of the raw material compounds is the reaction formula of Shimoki.

(In the formula, RI+Rsa R6, 穓 and
A product (good) is obtained by reacting with acetate in a solvent such as acetate. Furthermore, by reacting N-hydroxy 7-taliimide (1) in a solvent such as acetonitrile in the presence of a deoxidizing agent such as triethylamine, a 7-taliimide derivative (1) is obtained. Next, a hydroxyamine derivative (2) obtained by reacting the compound (2) with hydrazine hydrate in a solvent such as alcohol
thiazole-4-glyoxylic acid derivative source) in an organic solvent such as ethanol.

Raw material compound (1) can be produced.

The compound of the present invention exhibits a broad antibacterial spectrum and high antibacterial activity, but is particularly resistant to conventional cephem compounds.
Pr, vulgaris, ICnt, black crab, IC
nt, erogenes, ser, marse, sense.

It also exhibits strong antibacterial activity against Ps and Ps. aeruginosa.

The antibacterial activity of several examples of the compounds of the present invention is compared with that of cefazolin, a known representative cephem compound, as shown in the following table.

Antibacterial spectrum minimum inhibitory concentration (MIC; μ974d
, bacterial mass compound Ania β-[:2-((piperazine-1
-yl)carbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamide)-s=(1-methyl-IH-nato5zol-5-yl)thiomethyl-
8-cephem ichiban-carboxylic acid hydrochloride (syn isomer)
.

Compound B Nia β-(2-((piperazin-1-yl)carbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamide)-a-acetoxymethyl-
Sodium salt of 8-cephem-4-carboxylic acid (syn isomer) 0 Compound Cnia β-C-2-((piperazin-1-yl)
carbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamide)-3-(5-amino-1
,8,4-thiadiazol-2-yl)thiomethyl-8
- Cephem-4-carboxylic acid hydrochloride (syn isomer).

The present invention will be explained in more detail with reference to Examples below.

Example 1 7β-(2-((piperazin-1-yl)carbonylmethoxyamine thiazol-4-yl)acetamide)-8-(l-methyl-IH-tetrazol-5-yl)thiomethyl-8-
Cephem-4-carbonyl hydrochloride (syn isomer): 1-(4-methoxybenzyloxycarbonyl)piperazine 81.19 and N,N-dimethylaniline go, op
Bromoacetic acid bromide 29 was added to a seventone solution of
．． Add 5g dropwise. After stirring at the same temperature for 1 hour, the solvent was distilled off, and water was added to the residue.

Extract with ethyl acetate. The ethyl acetate layer was washed successively with 10% citric acid, 5≦hydrous sodium chloride solution, and saturated brine, and dried over anhydrous sulfuric acid. After drying with IJum, ethyl acetate was distilled off to obtain a brown oil residue 44.4%.

An acetonitrile solution of the above residue is added to an acetonitrile solution of N-hydroxyphthalimide 19.11 and triethylamine 16.8 while cooling with water and stirring. After stirring at the same temperature for 80 minutes9 and then at about 50°C for 8.5 hours, the solvent was distilled off.
Add water to the residue and extract with ethyl acetate. The ethyl acetate layer was washed with 5% aqueous hydrogen oxide solution and then with saturated brine, dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off.

The residue is washed with ether to obtain 7-taliimide 86.6F having a melting point of 164-156°C.

84.8 g of the above product obtained and hydrazine hydrate3.
Reflux 8 g of ethanol solution for 2 hours.

After cooling, insoluble matters were removed by filtration, the filtrate was dried, ethyl acetate was added to the residue, and the mixture was washed with water, 5% hydrogen sodium chloride solution, then saturated saline solution, and anhydrous sulfuric acid. harden The residue was purified by column chromatography using silica gel (solvent: mixture of chloroform and methanol) and then recrystallized from ether-petroleum ether to yield a carbonylmethoxyamine compound 20. with a melting point of 59-60°C. Get '19.

The above product obtained 4.02 and 2 = (Z-tritylaminothiazol-4-yl)glyoxyl@s, 1
After stirring gp in ethanol at room temperature for 45 hours, the solvent was distilled off! Ru. Ethyl acetate was added to the residue, washed with 10% citric acid and then with saturated saline, and the solvent was distilled off. When the residue is washed with ether, the melting point is 100-125℃ (decomposition) 17) Z
-C(4-(4-methoxybenzyloxycarbonyl)
piperazin-1-yl)carbonylmethoxyimino)i
Syn-isomer of -(2-tritylaminothiazol-4-yl)acetic acid (hereinafter referred to as "Compound Y")'1. Get Q9.

The resulting compound YO09ritoHOBt 169II9
DCo 258''9 was added to the DMF solution under cooling.

Stir at room temperature for 2 hours. Insoluble materials were removed by filtration, and 7-amino-8-(l-methyl-11-tetrazol-5-yl)thiomethyl-3-ceph JL-4-carboxylic acid (hereinafter referred to as "compound 2") was added to the filtrate under water cooling. ) 45B”9 and triethylamine 41?+ in DMF and stirred at room temperature.
Stir for an hour. After evaporating the solvent, ethyl acetate was added to the residue,
The mixture is washed with 10% citric acid and then with water, and the ethyl acetate layer is dried over anhydrous sodium sulfate and then evaporated to dryness. Ether was added to the residual liquid, and the powder (s151119) obtained by filtration was added with anisole 1, 3 m/g, and then, under water cooling, trifed 0-mouth acetic acid 50-
was added, stirred at room temperature for 2 hours, and then dried. The residue was washed with ether, 10% hydrochloric acid was added to the resulting crude product, the insoluble matter was filtered off, the residue was dried, and the residue was subjected to high performance liquid chromatography (
Purification is performed using Microbondapak Oss (carrier: Micro Bondapack Oss, solvent: 15% methanol adjusted to pH 8 by adding hydrochloric acid) to obtain the title target compound.

IFlνKBrcm-': l 780.1680■
ax FT-NMR (020,200MH2) δppm '8
．． 25-B, 50, 8.80-4.00 (total 8H.

-11 H) 8.80 (2H+ (1(1+ cephem nucleus 2nd position nometale>(02-M)) 4.10 (8H,s, tetrazole-1-CHs) 4.25 (2H,aa, - c.
%-5-)5.51 (2H,s, -0CH2GO-
)548 (LM, +1.c6-H)5.84 (
l M, +5.07-H) 749 (1M, a, thiazole-5-H) Elemental analysis (%) c41H2sN
Calculated value c for ttOsas4HCjl・21tO
84.44. H4, 26, N 21.0B actual value CB2S3. H4,09,N ZO,'1
1 Run 2 7β-(2”((4-methylbiperazin-1-yl)carbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamide)-8-(1-methyl-IM
-Tetrazol-5-yl)thiomethyl-8-cephem-4-carboxylic acid hydrochloride (syn isomer): N-(carboxymethoxy)7talimide Stir for an hour. The precipitate collected by filtration is suspended in DMF, 8.0 g of threshold-methylbiperazine is added, and the mixture is stirred for 16 hours. Insoluble materials were removed by filtration, the filtrate was dried, dilute sodium chloride water was added to the residue, extracted with chloroform, and dried over anhydrous sulfuric acid. After distilling off the solvent, the residue was washed with isopropyl ether to obtain a 7-taliimide compound 3.2 with a melting point of 105-107'C.
Get 9.

A methanol solution of 0.59% of hydrazine hydrate is added to a dichloromethane solution of 2.59% of the above product obtained, and the mixture is stirred for 8 hours. Insoluble matter is filtered off and dried, saturated brine is added to the residue, extracted with chloroform, dried over anhydrous sodium sulfate, and chloroform is distilled off. Residue (yellow oil, g5
Gm9) to Z-(2-)ditylaminothiazole-4-
The mixture was added to a suspension of 1.029 glyoxylic acid in ethanol, stirred for 50 hours, and the ethanol was distilled off. The residue was washed with ether, the resulting white powder was suspended in methanol, and the pH was adjusted to about 5 by adding hydrochloric acid and methanol.
After stirring, it was collected by filtration and had a melting point of 192-194°C! −((4
1.09 of the syn isomer of -methylbiperazin-1-yl)carbonylmethoxyimino)-1-(!-)ditylaminothiazol-4-yl)acetic acid is obtained.

D(C; 2509 was added to a DMF solution of the above product 684119 and HOBt16Z and stirred for 5 hours. Insoluble matters were removed by filtration, and the filtrate was added to a DMF solution of compound 28g81'9 and triethylamine B00I119.
Stir for an hour. After drying, saturated brine was added to the residue, and 5-
Adjust the pH to about 8 with hydrochloric acid, and extract with 9 tablespoons of HF. After drying over anhydrous sulfuric acid (IJ), the solvent is distilled off and ether is added to the residue. Filtered powder (approximately 9501193 anisole la/, then under ice cooling) IJ 71ff acetic acid 20
- and stirred at room temperature for 2 hours. After distilling off the truffle acetic acid, ether was added to the residue and filtered, and the filtered brown powder was suspended in 15≦methanol.

After stirring, it is filtered and the filtrate is dried to give a light yellow powder (500%
m9) is obtained. 16% adjusted to paIIAJs with hydrochloric acid
Dissolve in methanol, remove insoluble matter by filtration, and dry. The residual liquid was subjected to high-performance liquid chromatography (Carrier: Microbondapak + 48. Solvent: 15% adjusted to pH approximately L5 with hydrochloric acid.
Purification with methanol) gives the title compound.

IR, KBrC, -1:17'75.1625a+aX FT-NMR (D20, 200MHz) δppm '2
．． 96 (8H,s, -NN-GHs)-11no □ B, 20. a, 6g (total 8H, each ■, -N
-H) 4.08 (8H,s, tetrazole-to-c
)ls)5.26 (LH,ei, 06-H)5-8
'3 (l H2d, Ci7 H)? -28(l
H1f! , thiazole-5-H) elemental analysis (%) G
zzI (calculated value for 27NssOsm-ZHGI-14zO CB6.26. H4,29,N!1
1.15 Actual value C86,09,H4,8? , 8
20.85 Example 8 7β-[2-((4-(Z- and droxyethyl)piperazin-1-yl)carboxymethoxyimiz)-1-(
2-aminothiazol-4-yl)acetamido-8-
C1-Methyl-IH-tetrazol-5-yl)thiomethyl-8-cephem-4-carboxylic acid hydrochloride (syn isomer): 9.1 g of 1-(2-hydroxyethyl)piperazine and 11.7 g Ll of triethylamine in dichloromethane 11.0-benzyloxycarbonyl chloride was added dropwise to the chlorine solution under water cooling. After stirring at room temperature for 2 hours, water was added and separated, and the organic layer was washed with lθ% citric acid 1 and then with saturated saline, and anhydrous. After drying with IJum (sulfuric acid), 0 residue (yellow oil) is evaporated to dryness.

1 g, ag) was dissolved in dichloromethane, triethylamine l 1-7's and then 17.6 g of trityl chloride.
The mixture was stirred at room temperature for 4 hours, water was added, and the mixture was distributed. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then dried to dryness, and the residue was recrystallized from ethanol to give 1 with a melting point of 97-98°C.
-(!-)lytyloxyethyl)-4-(benzyloxycarbonyl)piperazine! We get 4.19.

The obtained product 18.4F was dissolved in a mixed solvent of ethyl acetate and ethanol, and 10% palladium on carbon was added.
Catalytic reduction is performed at room temperature and pressure, the catalyst is filtered off, and the filtrate is dried to obtain 1-(2-trityloxyethyl)piperazine 16.1- as a yellow oil.

By using the above piperazine compound in place of Example 1 (7) l-(4-methoxybenzyloxycarbonyl)piperazine and carrying out the reaction in the same manner as in Example 1, 2 with a melting point of 16z-164°C was obtained. -((4-(Z-trityloxyethyl)piperazin-1-yl)carbonylmethoxyimino)-2-(2-)ditylaminothiazol-4-yl)acetic acid (syn isomer) is obtained.

Then, the obtained above products 842WI9 and HOBt1
Add D CCZ 46"9 to a DMF solution of 75119 and stir at room temperature overnight. After removing insoluble matter by filtration, compound Z8"; 48M9 and triethylamine 0.4z-DM were added to the filtrate.
Add F solution and stir overnight. After drying, the residue was washed successively with water, ethanol, and ether.

The obtained powder (1,099) was dissolved in formic acid 11-
．． Stir for 5 hours. After removing insoluble materials by filtration, the filtrate is dried.

The powder obtained by washing the residue with ether was mixed with 10 g of water.
After adding 1-4N hydrochloric acid, insoluble matter was filtered off, and the filtrate was dried. Wash off the residue with ether (57
6”9L Diaion HP-20 column chroma dog 5
High performance liquid chromatography (carrier: Microbondapak"18
1 solvent: 15% methanol adjusted to pH approximately 2 with hydrochloric acid) to obtain the title target compound.

FT-NMR (50,200MHz) δ91. :8.1
0-8.48, 8.90-4.0! (Total 8H,
each) twI.

8.74 (2H,t, -cH2H2NOH4,10(
@H,s, tetrazole-1-CHa)5.14 (f
l, H, s, ==N-OCH2CF)5, z?
(IH, 6, +4-H) 6.8 s (l)I, a, C7-)1 )7J8
(IH,s, thiazole-5-H) elemental analysis%)
C4a) Calculated value for bsNtxoy8m4Hc748ao OB5.69. H4, 54, N 1G
, 86 actual value c 85.29. H45s, N
1186 Example 4 7β-[2-[(4-(carboxymethyl]piperazin-1-yl)carbonylmethoxyimino)-2-(2-
aminothiazol-4-yl)acetamide]-8-(1
-Methyl-IH-tetrazol-5-yl)thiomethyl-8-cephem-4-carboxylic acid sodium salt (syn isomer): 1-(4-methoxybenzyloxycarbonyl)piperazine in Example 1 instead of 1- By using (8th-butoxycarbonylmethyl)piperazine and sequentially carrying out the reaction in the same manner as in Example 1, melt A125-1
88℃ (decomposition)! The syn isomer of -((4-(8th-butoxycarbonylmethyl)piperazin-1-yl)carbonylmethoxyimino)-2-(2-)rithylaminothiazol-1-yl)acetic acid is obtained.

Next, a reaction similar to that of Example 1 was carried out using the above-obtained product and Compound 2, and the resulting crude product was dissolved in dilute sodium chloride water and subjected to high performance liquid chromatography (carrier: Microbondapak). Purification with 1° solvent: 5.% methanol gives the title compound.

I RklKBrcm-”: l 760aX FT-NMR (D20, 200MHz) δ2. ■: 2.
6-2.8.8.5-8.7 (total 8 H, -N
N-)I)B, 14 (2H,s, :>N-CH2
CQ-)4.05 (8H,s, tetrazole-1-G
) t3) 5.0 G ('B H,a, -OC%GO
-)5.11 (IH, (1, (4-)1 )5.8
? I (IH, d, c, -H) 7.10 (IH, s
, thiazole-5-H) elemental analysis (%) 02m)b
eNttOissNal-8) Calculated value for 120
C85,48,H400,N 19.76Yi measured value C
85.5g, H448,N 19.8gExample b 7β-[1-(2-((piperazin-1-yl)carbonyl)prop-2-oximino]-2-(g-aminothiazol-4-yl) a7tamidoco-8-(l-methyl-IH-tetrazol-5-yl)thiomethyl-8-
Cephem-4-carboxylic acid hydrochloride (syn isomer)-1
-Oil obtained by reacting 9.2119 of (4-methoxybenzyloxycarbonyl)piperazine and 9.749 of 2-bromo-2-methylpropionyl bromide in the same manner as in Example 1 + dimethyl sulfoxide of a99 solution.

Syn-isomer of 2-(hydroxyimino)-2-(Z-tritylaminothiazol-4-yl)ethyl acetate 4,1
To the dimethyl sulfoxide solution of No. 19 was added 1,989 g of potassium carbonate under a nitrogen stream, and then added under vigorous stirring and stirred overnight. Pour the reaction solution into water, collect the precipitate by filtration, dissolve the filtered product in ethyl acetate, wash sequentially with 10% citric acid and water, and sulfuric anhydride) After drying with IJum, dryness. do.

After washing the residue with petroleum ether and dissolving 6.9 g of the powder in 60 methanol, add ZN-NaOH and reflux. After distilling off the methanol, water is added, 20% citric acid is added to make the liquid acidic, and the mixture is extracted with ethyl acetate.

After washing the ethyl acetate layer with water, it is dried over anhydrous sulfuric acid (IJ) and the solvent is distilled off. The residue was purified by column chromatography on silica gel (solvent: mixed solvent of chloroform and methanol) to yield 2-[2-((+-(+-methoxybenzyloxycarbonyl)piperazine) with a melting point of 152-155°C (decomposition). -1-yl)carbonyl] Prob-2-o, ximinocoric 2-(Z-)ditylaminothiazol-4-yl)acetic acid syn isomer 960 .mu. is obtained.

Next, using the above-obtained product and Compound 2, reaction and purification are carried out in the same manner as in Example 1 to obtain the title target compound.

IR, KBr, -1:17?0.1680aX yT-NMR (D20.200MHz) δppm"
L, S t (8H, s, C-CH5) 1.65 (
8H,s, C1-CH5) 11J-8,4,8,6~
4. ! ! (Total 81 (, each ■.

-N N-H) 4.10 (8H,s, tetrazole-1-C)Li)
5.29 (11(, (1, (4-H)5.88 (I
H, d, c? -) 1) 7.80 (lH, s, thiazole-5-H) elemental analysis (%) C45H2sNtt
Calculated value Ci 8 for os1%4Hcl-2H20
6.82. H4, 64, N 20.26 actual value
a 86.16. H4,89,N 19.9g
Example 6? β-cz-(i-((piperazin-1-yl)carbonyl)eth-1-oxyimino]-2-(2-aminothiazol-4-yl)acetamide]-8-(1-methyl-18-tetrazole- 5-yl)thiomethyl-8-cephem-4-carboxylic acid hydrochloride (syn isomer): in the same manner as in Example 1, using 2-bromopropionyl bromide in place of bromoacetate bromide in Example 1. Upon reaction and purification.

Melting point 100-108℃ (decomposition) 17) 2-[1-((4
-(4-methoxybenzyloxycarbonyl)piperazin-1-yl)carbonyl]-1-oxyimino]
The syn isomer of -z-(z-tritylaminothiazol-4-yl)acetic acid is obtained.

Next, a reaction was carried out in the same manner as in Example 1 using the above-described product and Compound 2.

Finally, it is purified by high performance liquid chromatography (carrier: Microbondapak Negative 8, solvent: 15% methanol adjusted to pH 2.5 by adding hydrochloric acid) to obtain active form A and active form B of the title compound.

Data for active form A Melting point 145-155°C (decomposition) IRνKBrcm-': 1770.1680aX FT-NMR (D20.200MHz) δppm"
4.00 (8H,s, Tetrazole-1-C)Is)
6.28 (IH, d, (4-H) 5.88 (LH, d, C7-H) 7J@ (IH, s, thiazole-5-H) elemental analysis (
%) C42I(2yNuOsSr2HGl・8Hx
Calculated value for O 0 84.55. H4,61,
N'20.15 Actual value C34L41. )I
4.48. N 20.09 Data of Activated Form B Melting point 145-155°C (decomposition) IRνKBrCjl-”: 1780.1680D)
ILX FT-Nyn (ho, 200MH2) δppm ”1.
56 (8H, d, )OHzuj)BJ ~B, 5.8
．． 6-4.1 (Total 8H, -N N-77)H) 4
°10 (BH, s, tetrazole-1-083) 5.8
0 (IH, 5, False-H) 5.94 (IH, 6, C?-H) 7.28 (IH, a, +7zo #-5-H) Elemental Analysis Department) C42 City 7N! 1 audience・'2) Calculated value for 1cj・270 CB5.89. H4, 45, N
! 0.64 Actual value CB5.21. H468,N
20.8B Example 7 7β-(2-((Piperazin-1-yl)carbonyloxyimino)-2-C2-aminothiazol-4-yl)acetamide)-8-(1-methyl-IH-tetrazole-5 -yl)thiomethyl-8-cephem-4-carboxylic acid hydrochloride (syn isomer): Syn of 2-(hydroxyimino)-2-(2-)rithylaminothiazole/I/-4-yl)acetic acid Isomer 4.8g
is suspended in dichloromethane, isopropenyl methyl ether 4- is added, stirred with 1RrMl, and then dried. Dissolve the residue in HF.

HOBt1. +9. Next IrD (j Gt Ll
Add 9.

Stir for 5 hours and remove insoluble matter by filtration. The filtrate was converted to compound Z89.
and triethylamine 4@t in DMF, stirred for 16 hours, and then dried under reduced pressure. Water is added to the residue, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then evaporated to dryness. Isopropyl ether is added to the residual liquid to form a powder, which is filtered to obtain condensate 8.59.

The above-obtained product 8.5F was dissolved in acetone z5-, 2N hydrochloric acid 1O- was added thereto, stirred for 1 hour, and then dried.

A mixed solution of ethyl acetate and THF is added to the residual solution, and insoluble materials are filtered off, washed with saturated brine, dried over anhydrous sulfuric acid, and then evaporated to dryness.

After adding ether to the residue, the powder (2,8
9) Dissolve in ttTHF, add diethylamine 9-, and then add isopropyl ether. Filter the precipitate,
After reprecipitation with THF-isopropyl ether and washing with ether, the melting point was 140-145℃ (decomposed) Noah β-
(2-(hydroxyimino)4-(2-tritylaminothiazol-4-yl)acetamide]-8-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-
The syn isomer of the diethylamine salt of 77 em-4-carboxylic acid is 1.89 mol.

4-(4-methoxybenzyloxycarbonyl)piperazine-1-carbonyl chloride eso was added to a dichloromethane solution of the above-obtained product 1.22 and pyridine 0.4-
q (prepared from x-(4-methoxybenzyloxycarbonyl)piperazine and phosgene) was added, and after stirring for 5 hours,
Dry. Dissolve the residual liquid in ethyl acetate, add 1% water and then 1%
Wash with hydrochloric acid, dry with anhydrous sodium sulfate, and then evaporate to dryness. After adding isopropyl ether to the residue, it was collected by filtration, and the resulting powder (1, 29) was poured with ice? & lower anisole lsd, then add 20% of truffle acetic acid and stir for 1 hour. The truffle 0-mouth acetic acid was distilled off, ether was added to the residual liquid, the precipitate was collected by filtration, dissolved in 80 g of water, and Amberlite-45
was added to adjust the pH to 8, and after filtering off the resin, the pH was adjusted to pH 8 with 5% hydrochloric acid.
shall be. After drying, the residue was subjected to high performance liquid chromatography (
Carrier: Microbondapak C18, Solvent: pH with hydrochloric acid
Purification with 15° methanol (adjusted to 15°C) gives the title compound.

Il'l)""rC"-': l? 75. l
? 8 Gm KameX FT-NMR (D20.ZOOMHZ) δ29. :8.
40.8.86 (total 8H, each broad, -〆1
H) 4.10 (8H,s, Tetrazole-hcH
a) 4.24 (*H,s, 0s-CH2-8-
) 5.80 (IH, d, (4-H) 5.90 (I H, ei, 0r-H) 7.50 (
LH,s, tetrazole-5-H) elemental analysis (%)
C2o) b3NoosSs・2HGl-1,5) tzo
Calculated value for CBB, 85. H8,98,N
21.71 Actual value C8B, 80. H8,74,
N 21.81 Example 8 7β-[2-(2-((piperazin-1-yl)carbonyl)eth-1-oximino]-2-(2-aminothiazol-4-yl)acetamide]-8-( 1-Methyl-IH-tetrazol-5-yl)thiomethyl-8-77emu 4-carboxylic acid hydrochloride (syn isomer): 1-
(8-(benzyloxycarbonylaminooxy)propionyl)-+-(81st &butoxycarbonyl)piperazine 11.19 in an ice-cold 25% hydrogen bromide acetic acid solution 7
After stirring under ice-cooling for 20 minutes and at room temperature for 40 minutes, ether 100- was added under stirring under water-cooling, and the supernatant was decanted.

After repeating the operation of adding ether to the residue and decanting it, 9.1 g of white powder was obtained by drying under reduced pressure over phosphorus pentoxide.
Dissolve in ice water 8B-. Under water cooling and stirring, 84@1 KN-sodium hydroxide and then 182@1 dioxane are added. After returning to room temperature, 8.49 g of 2-(8th-butoxycarbonyloxyimino)-2-phenylacetonitrile was added.

The mixture was stirred for 2 hours, and 2.0 mm of the same acetonitrile compound was added, and the mixture was stirred for 2 hours. Dioxane is distilled off, the residue is made alkaline by adding sodium hydroxide, extracted with chloroform, dried over anhydrous sodium sulfate, and then evaporated to dryness. The residue was purified by silica gel chromatography (medium: chloroform and methanol mixture) to obtain 5.8 g of ethoxyamine as a colorless oil.The above product and z-(tritylamino)thiazole-4-glyoxyl If the reaction is carried out in the same manner as in Example 1 using an acid,
Melting point ls5-185℃ (decomposition) (1m-((4-(8th
(butoxycarbonyl)piperazin-1-yl)carbonylmethoxyiminoj-s-(z-tritylaminothiazol-4-yl)acetic acid syn isomer 1 was then carried out using the obtained product and compound 2. Reaction and purification in the same manner as in Example 1 yields the desired compound.

FT-NMR (D20, 200M) apppH: 2
．． 97 (2H, broad, -C%GO-)3.8
B, 8.88 (total 8H, each broad, -N"N
- H) 4.10 (8H,s, tetrazole-1-C
H3) 4.6 B (,Z H,broad, =OC
H2-)5J 6 (1)1. +1. C4-H)5
．． 82 (IH, (1,C?-H) 7.21 (LH,a, +7sol-5-n) Elemental analysis (%) CtuHstNssOsBs・BHGl-
Calculated value for 2Hp C85,89,)1 4.45
．． N Zo, 64 actual measurement value C85, F8. I
(4,4G, N No. 20.7 Example 9 7β-(Z-((piperazin-1-yl)carbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamide]-3-(x -(Z-dimethylaminoethyl)-LH-tetrazol-5-yl)thiomethyl-
8-se7emu-4-carboxylic acid hydrochloride (syn isomer)
: Compound Y and 7β-amino-8-(1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl)thiomethyl-8-77! The title compound is obtained by reaction and purification in the same manner as in Example 1 using mu-4-carboxylic acid.

F T -N M R (h Oe 200 MHz)
δppm ”4゜S 4 (% J 8.C3-C%S
)4,G14 (@H,t, -0HaN(CH
s)z)5.16 ('B H,s, -OC%CO-
)5.80 (IH, (1,C@H)6.86(I
H, (1,07H) 7.28 (IH,s, thiazole-5-H) Elemental analysis (%) 0z4HszNttQsSs4HG/-Zl
Calculated value for bO 0 85.67, H461,
N io, 14 actual value 0 85.88. H49
0,N 19.7B Example 10 7β-(1-((piperazin-1-yl)carbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamide)-8-(1-(carbamoylmethyl )
-1H-tetrazol-5-yl)thiomethyl-8-77emu-4-carboxylic acid hydrochloride (syn isomer): Compound Y and 7β-amino-a-(1-(cal).

pamoylmethyl)-1H-tetrazol-5-yl)thiomethyl-8-seb! The title compound is obtained by reaction and purification in the same manner as in Example 1 using mu-4-carboxylic acid.

FT-NMI'1(DzO,!, OOMI(riδppm
'8, S 6.8.86 (total 8H1 each broa
d, -N, =N-H)5.12 (2H,a,:N-
0-G &-) 5, a 6 (IH, (1, false-H) 5.86 (2H, 8, -7 groan C0NHz) 5.82
(l H, el, Gy-H)7J 6 (1B,
a, Thiazole-6-H) Elemental analysis (%) axxy
Calculated value CB4.0 for asNsxorss-SHct-m,o? , H8, 90, N 21.67 actual value C8B, 96. H410,N @1.84
Example 11 7β-(S-((piperazin-1-yl)carbonylmethoxyimino)-g-(z-aminothiazol-4-yl)acetamide]-8-(1-(carboxymethyl)-
1H-tetrazol-5-yl)thiomethyl-8-77
Emu 4-carboxylic acid hydrochloride (syn isomer): Compound Y and 7β-ami/-8-(1-(carboxymethyl)-
1H-tetrazol-5-yl)thiomethyl-8-77
The title compound is obtained by reaction and purification in the same manner as in Example 1 using emu-4-carboxylic acid.

FT-NMR(I)xo,ZOOMHz)'ppm:8
．． 86, 8.86 (total 8H, each broad, → H
-H) -11no5.14 (2H,s, -OC%GO-)5J 4
(t, H, at, >N-9COOH)648 (1m
(, a, (4-H) 6.8 6 (18, +1. G to H)? J8 (
IH,s, thiazole-5-H) elemental analysis ($) C
4z) Calculated value for I2sN1sOaE3s-suct-zm C84LO2,H4,04,N 19.8
4 Actual measurement value CB4.22. H8,98,N19
．． 45 Examples 1, 2 7β-(2-((piperazin-1-yl)carbonylmethoxyimino) to 2-(Z-aminothiazole-4-
Sodium salt (syn isomer) of yl)acetamide]-8-acetoxymethyl-8-cephem-4-carboxylic acid: Compound Y and 7β-amino-8-acetoxymethyl-8-
Sef! A reaction was carried out in the same manner as in Example 1 using Mu-4-carboxylic acid, and the resulting crude product was subjected to Diaion HP-
Column chromatography using 20 as a carrier (solvent = 5
~zO attack ethanol) 2 then high performance liquid chromatography (carrier: Microbondapak C1 Hatake, solution I: 2
Purification with 0% methanol gives the title compound.

IRνKBrcm-”:1770.1780.1685
ax FT-NMR (DzO, ZOOMHz). :2-1
0 (8H* s e −OCOCt(s ) 8.74
~8.84.8.16~8.80 (Total 8H.

5.01 (2H,a, -〇〇H2GO-)5.25
(l H, (1, C1-H)5.85 (IH, (
1,07-H)7.10 (IH,ts, thiazole-
5-H) Elemental analysis (%) C2+Hz40sNyS2
Na8) (20 Ni vs. shite calculation value G 89.19.
H47G, N 15.2B Actual value c 88.8
1. H bustling 40. N 15.18 Example 18 7β-(B-((piperazin-1-yl)carbonylmethoxyimino)l-(2-aminothiazol-4-yl)acetamido-8-cephem-4-carboxylic acid hydrochloride (syn isomer): Compound Y?20s9 and 7-ami?4
-77Emu-4-carboxylic acid p-nitrobenzyl ester 8s5II119 in THF! After adding HOBt 185"9 and Ncczoas 19 under ice-cooling and stirring, the mixture was stirred at the same temperature for 1 hour and then at room temperature overnight. After filtering off insoluble matter, it was dried and the residue was poured into silica gel. Purification by column chromatography (solvent: mixture of chloroform and methanol) yields 7β with a melting point of 180-188°C.
-[2-((4-(4-Methoxybenzyloxycarbonyl)piperazin-1-yl)carbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamidocarboxylic acid fem-4-carbon Syn isomer 800119 of p-nitrobenzyl ester of acid is obtained.

The obtained product 5oos9 was dissolved in THF and 10
% palladium on carbon 50G''9 was added and catalytic reduction was carried out under normal pressure. After filtering off the catalyst, the filtrate was dried and ether was added to the residue. Add 80@t of acetic acid and stir for 2.5 hours. After distilling off the truffle acetic acid and adding ether to the residue, add 10% hydrochloric acid to the granules obtained by filtration to remove insoluble matter. After filtration, the residue is purified by high performance liquid chromatography (carrier: Microbondapak (nll solvent: 15% methanol adjusted to pH 21.5 by adding hydrochloric acid) to obtain the title compound.

IR, KBrCmI-t: 1770.1680Ia
X F T-N M R (D20 t 200 MHz)
δppm '+3.84.8.85 (Total 8H, H of each town-N, , N-) 8.70 (2H, tr, (4
-H) 5.10 (2H, a, -Oc horse C0-) 5.2
8 (IH, (1, (4-H)) 5.92 (IH, 6, C7-1 () 6.70 (IH, m, Cs H) 7.25 (IH, s, thiazole-5-H) Elemental analysis (%) C+5H2tN7SzOs・2HC/-8)
Calculated value for 120 C8 roll 7B, H4,8? ,
8 15.75 Actual value CB5.10. H41
8,N 15.85Example 14 7β-(ffi-((piperazin-1-yl)carbonylmethoxyimino)-2-(2-aminothiazole-4
-yl)acetamide)-8-(5-amino-1,B,
Hydrochloride (syn isomer) of 4-thiadiazol-2-yl)thiomethyl-8-cephem-4-carboxylic acid: Compound Y and 7β-amino-8-(5-ami/-1,8,
The title compound is obtained by reaction and purification in the same manner as in Example 1 using 4-thiadiazol-2-yl)thiomethyl-8-cephem-4-carboxylic acid.

IRvKBrel-' :1765,1660,1
620ax 2-NMR (D20, 200MH2) δppm '8
．． 136 (4H, (1,-N,N-H)5.12
(Z H, B, -0GH2GO-)548 (IH,
a, Cs-H) 5.88 (LH, ei, Gy-H) 7.28 (L
H, s, thi'7sol-5-H) elemental analysis (%)
Calculated value for C2IH24NloOs&4HC/-15H20 c 8B, 24. H4, 12, N
18.46 Actual value C88,5S, H4,0! ,
8 18.11 Example 15 7β-(2-((piperazin-1-yl)carbonylmethoxyimino)-2-(2-aminothiazole-4-
yl)acetamide)-8-(5-1-1-ru 1,8
．． 4- +7diazole-2-yl)thiomethyl-8
-Cephem-4-carboxylic acid hydrochloride (syn isomer): Compound Y and 7β-ami/-8-(5-methyl-1,8,
The title compound is obtained by reaction and purification in the same manner as in Example 1 using 4-thiadiazol-2-yl)thiomethyl-8-cephem-4-carboxylic acid.

Claims (1)

[Claims] A cephalosborin crocodile conductor or a salt thereof represented by: However, Formula 2 Chuma and Ma are each independently hydrogen or lower alkyl, R3 is hydrogen, lower alkyl, hydroxy lower alkyl or carboxy lower alkyl, R4 is hydrogen, acetoxymethyl, carbamoyloxymethyl or is a 5-membered or 6-membered ring having 3 to 3 different atoms, and may be substituted with lower alkyl, amino lower alkyl, amino, carbamoyl lower alkyl or carboxy lower alkyl), and n is 0, Indicates 1 or 2 ◇
2) Claim 1, wherein R4 is -c)I2s-h and the island is a tetrazolyl group optionally having lower alkyl, amine lower alkyl, carbamoyl lower alkyl, or carboxy lower alkyl as a substituent. compound. 8) The compound according to claim 1, wherein & is hydrogen or a thiadiazolyl group optionally having a patent amino or lower alkyl group, which is acetoxymethyl. 5) The compound according to claim 1, wherein - is -cH2s-- and the ratio is a triacyl group which may have hydroxy as a substituent. 6) 7β-(?1-((piperazin-1-yl)carbonylmethoxyimi7)-2-Nl-aminothiazole-
4-yl)acetamide]-B-(1-methyl-IH-tetrazol-5-yl)thiomethyl-8-cephem ichiban-ka? )7β-(!-((4-methylbiperazine-1-
yl)carbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamide)-8-(1-methyl-IH-tetrazol-5-yl)thiomethyl-8-
2. The compound according to claim 1, which is a syn isomer of 778-mu-1-carboxylic acid and a salt thereof. 8) 7β-[2-(2-((piperazin-1-yl)carbonyl)prop-2-oximino)-! I-(2-
aminothiazol-4-yl)a7tamidoco-3-(l
-Methyl-IH-tetrazol-5-yl)thiomethyl-8-ce7! The compound according to claim 1, which is a syn isomer of mu-4-carboxylic acid and a salt thereof. 9) 7β-(j!-((piperazin-1-yl)carbonyloxyimino)-!1-(2-aminothiazole-
4-yl)acetamide]-8-(1-methyl-11-tetrazol-5-yl)thiomethyl-8-cephem-4
- The compound according to claim 1, which is a syn isomer of carboxylic acid and a salt thereof. 1O)7β-(1:Z-(1-((piperazin-1-yl)carbonyl)eth-1-oximino)-Z-(2
-aminothiazol-4-yl) and cetamideco-8-(
The compound according to claim 1, which is the syn isomer of 1-methyl-IH-tetrazol-5-yl)thiomethyl-8cephem-4-carboxylic acid and its salt. 11) 7β-(2-((piperazin-1-yl)carbonylmethoxyimino)-2-(!?,-aminothiazol-4-yl)acetamide]-8-acetoxymethyl-3-cephem-4-carboxylic acid 12) 7β-(!-((Piperazin-1-yl)carbonylmethoxyimino)-2-(2-aminothiazole-4- 1B) 7β-(2-((piperazin-1-yl)carbonyl methoxyimino )-1-(!-aminothiazol-4-yl)acetamide]-8-(5-amino-1,8,
2. The compound according to claim 1, which is the syn isomer of 4-thiadiazol-2-yl)thiomethiA/-8-cephemu-4-carlinic acid and salts thereof.