JPS6216487A - Novel cephalosporin derivative, salt thereof, production of said compound, and remedy for infectious disease containing said compound as active component - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {R is organic residue; Q is group of formula II [dotted line represents single or double bond; R<1> is H, alkyl or -(CH2)nR<2> (R<2> is cyano, carboxyl, alkoxycarbonyl, etc.; n is 0-5)]}. EXAMPLE:[ 6R-[ 6alpha,7beta(Z) ] ]-4-[[7-[[( 2-amino-4-thiazolyl )(metoxyim-ino)acetyl) amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4, 2, 0-]--oct-2-en-3-yl ] methyl] hexahydro-1H-pyrrolidium hydroxide intramolecular salt. USE:Antibacterial agent against Gram-positive and Gram-negative bacteria. It has low toxicity. PREPARATION:The objective compound can be produced by reacting 7- acylamino-3-acetoxymethylcephalosporin of formula III [R' is (protected) organic residue; A is carbonyl-protecting group] with a trialkylsilyl halide, and reacting the resultant 7-acylamino-3-halomethylcephalosporin of formula IV (X is halogen) with the pyrrolizidine compound of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to novel cephalosporin derivatives and salts thereof, methods for producing them, and infectious disease therapeutic agents containing the compounds as active ingredients.

(Prior art) Research on cephalosporins is carried out by Cephaloapor.
The invention originated from the fact that several antibiotics were isolated from the culture fluid of P. iuma aremonlum and named cephalosporins P1 to P5 and N. Cephalosporin C was then isolated from crude cephalosporin N.

This cephalosporin C has a wide range of antibacterial spectra (A) and inhibits the growth of Durham-positive and -negative bacteria, but has a problem in that it has weak antibacterial activity.

For this purpose, the acetoxymethyl group at the 3-position of cephaloszolin C was replaced with another group, and another acid group was introduced in place of the D-α-aminoadipic acid group bonded to the amino group at the 7-position. Various derivatives have been developed. Representative examples of these derivatives include, for example, cephalolidine, i.e., 7-(2-chenyl)acetamido-3-pyridine-
1-ylmethyl-3-cephem-4-cal xylate (U.S. Pat. No. 3,449,338), cefotaxime or -7-[2-(2-aminothiazol-4-yl)-2
-methoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-cartoxylate sodium salt (US Pat. No. 4,152,432), and the like.

(Problems to be Solved by the Invention) When compared to penicillin, various derivatives of cephalosporin C have a broader antibacterial spectrum, are effective against Gram-negative bacterial infections, have less cross-allergy with penicillin, and are hypersensitive to penicillin. Some of them, including the above-mentioned cephaloridine, have already occupied an important position in clinical practice because they can be used in humans suffering from the disease and have little cross-resistance with penicillin.

However, in order to further advance antibiotic therapy using cephalosporin compounds, compounds with a broader antibacterial spectrum and high activity against resistant bacteria, especially Durham-negative bacteria, have been clinically developed. is the current situation.

Therefore, the main objective of the present invention is to develop a novel cefurosphorin derivative that has a broad antibacterial spectrum and therefore has a wide range of application, has high activity, has strong antibacterial power, and has low toxicity and is therefore safe to use. The goal is to provide the following.

An incidental object of the present invention is to provide a method for producing such a novel Cephalos/Rif derivative and a therapeutic agent for infectious diseases containing the derivative as an active ingredient.

(Means and effects for solving the problems) Cephalosporins, like penicillins, lose their antibacterial activity when the β-lactam ring in their structural skeleton is cleaved.

Therefore, the present inventors conducted extensive research in search of a cephalosporin antibiotic that is relatively stable against β-lactamases and has a broad antibacterial spectrum, and as a result, they added a pyrrolidinium methyl group to the 3-position. We have now found a novel cephalosporin derivative having the following formula: , the dotted line means an optionally present double bond, R1 means hydrogen, an alkyl group or a group -(CH2)nR2, R is a cyano group, a carboxyl group, an alkoxy/I/thenyl group, a substituted (means an amino group that can be substituted or an aminocarbonyl group that can be substituted, and n means an integer of θ-5).

The organic residue R can be, for example, the following groups.

H OOH C2H5 NCCH2-, NCCH25CII2-.

= NoCH3 Among these groups, when it has an iminoether bond, those with syn configuration are preferred.

In the substituent R1 of Q at the 3-position of the hepphalosporin derivative in the present invention, the alkyl group can be a linear, branched or cyclic alkyl group, and the linear alkyl group has 1 to 1 carbon atoms. 1° such as methyl, ethyl, n-propyl, n-butyl, n-methyl, n-
Examples of branched alkyl groups include hexyl, n-f full groups, and isopropyl, isobutyl, 5ec
Examples of the cyclic alkyl group include those having 3 or more carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups.

Specific examples when substituent R1 means a group -(CH2)nR2 include cyano, cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, cyanopentyl, carboxy, carboxyethyl, carboxyethyl, carboxypropyl, carboxyethyl, carboxyethyl. , methoxycarbonyl, ethoxycarbnyl, probyloxycarbunyl, methyloxycargonyl, methoxycarzenylmethyl, ethoxycarbonylbutyl, propyloxycarbinylmethyl, butyloxycal is nylmethyl, methoxycal? Nylethyl, ethoxycarbonylbutyl, propyloxycarbonylethyl, methyloxycargonylethyl, methoxycarbonylglohy〃, ethoxycarbonylpropyl, methoxycargenylbutyl, ethoxycarbonylbutyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, ethyl aminomethyl,
・Dimethylaminomethyl, mol 7 orinomethyl, pyrrolidinomethyl, piperidinomethyl, piperazinomethyl, benzylaminomethyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, morpholinoethyl, pyrrolidinoethyl, piperidinoethyl, piperazinoethyl , benzylaminoethyl, formylaminomethyl, acetylaminomethyl, methoxycargenylaminomethyl, ethoxycarbonylaminomethyl, penzyloxycargenylaminomethyl, formylaminoethyl, acetylaminoethyl, methoxycargenylaminoethyl, ethoxycarb Nylaminoethyl, penzyloxycarbnylaminoethyl, aminocarbonyl, methylaminocarbyl, dimethylaminocarbyl, ethylaminoel? Nyl, diethylaminocarbonyl, morpholinocarbonyl, pipezinocartilyl, piperazinoel M-nyl, piperazinoergenyl, sulfonithylaminocarvinyl, aminocal is nylmethyl, methylaminocarbonylmethyl, dimethylaminocal is nylmethyl, methylaminocarbonylethyl, diethylaminocarbonylmethyl, morpholinocarbonylmethyl, pyrrolidinocargonylmethyl,
Piperidinocal is nylmethyl, hyherazinocarbonylmethyl, sulfonithylaminocal is nylmethyl, aminocarbonylethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, ethylaminocar? nylethyl, diethylaminocarbnylethyl, morpholinocarbonylethyl, pyrrolidinocal is nylethyl,
Biphoricinocal = /l/ I can be there.

Among the cephalosporin derivatives according to the present invention, compounds having basicity, such as compounds having an amino-substituted heterocycle in the 7-position side chain and compounds having an amino-substituted pyrrolidinium methyl group in the 3-position side chain, may be used as acid addition salts. can be formed,
Examples of acids for forming salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as hinimethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, hexamaric acid, and maleic acid. can.

According to the method of the invention, cephalosporin derivatives of formula I and salts thereof are prepared by formula (where R' is an optionally protected organic residue well known for β-lactam antibiotics) 7-acylamino-3-acetoxymefN-cephalosporin represented by the formula (wherein R' and A have the above-mentioned meanings, and X means )・logon). It can be produced by reacting with the pyrrolitidine compound shown in ), removing the protective group if present, and then converting it into a salt if necessary.

Examples of the protecting group for the organic residue R at the 7-position include trityl, alkoxycarbonyl, and allylalkoxycarbonyl groups, and examples of the carboxyl-protecting group A at the 4-position include ester functional groups that are easily removed, such as alkyl and substituted Examples include alkyl (1-methyl, 2.2.2-)lihaloethyl, etc.), benzyl and substituted benzyl (p-methoxybenzyl, p-nitrobenzyl, etc.), and trialkylsilyl groups. Protecting group for organic residue R at position 7 and 4
The car at position shares the xyl-protecting group A, thereby facilitating introduction and elimination.From this point of view, trialkylsilyl, such as trimethylsilyl, is particularly preferred as the common protecting group.

When attempting to protect by introducing trimethylsilyl groups at both the 3 and 7 positions starting from 7-acylamino-3-acetoxymethyl-3-cephem-4-carboxylic acid,
Cal, the starting material? The phosphoric acid is suspended in a halodanized hydrocarbon solvent such as methylene chloride, chloroform, chloroethane etc. or other inert organic solvent such as acetonitrile, propylnitrile etc. and is treated with a commonly used silylating agent such as mono- or bistrimethylsilylacetamide, preferably bistrimethylsilyl. This can be done by adding trifluoroacetamide and stirring.

The trialkylsilyl halide for converting the above compound (1) into compound (2) may be, for example, trimethylsilyl iodide, which contains at least 1 equivalent, preferably 2 to 3 equivalents.
It is preferable to use double equivalents.

This halodanization reaction also proceeds simply by stirring at room temperature.

The resulting 3-halomethyl derivative of formula (1) does not necessarily need to be isolated. Therefore, one reaction mixture can be concentrated to remove volatile substances, such as the solvent, dissolved in an inert solvent, such as acetonitrile, and then tetrahydrofuran is added to decompose the unreacted halogenating agent. The 3-halomethyl derivative-containing solution thus obtained is mixed with a solution of pyrrolitidine or substituted pyrrolitidine (formula ■) dissolved in a suitable solvent such as acetonitrile (if calgexyl, amino group, etc. are present in the pyrrolitidine skeleton) is preferably protected by prior treatment with a silylating agent such as bistrimethylsilyltrifluoroacetamide). The reaction between the .3-halomethyl derivative of formula (1) and the pyrrolitidine compound of formula (2) can easily occur and proceed simply by stirring at room temperature.

After the reaction is complete, if water is added to the reaction mixture, the protecting group will be removed and the desired compound will precipitate, which is poured into the bottom of the furnace.

The products obtained are generally crude and are therefore subjected to purification. This purification can be carried out, for example, by column chromatography.

As one of the starting materials, 7-acylaminocephalosporanic acid, commercially available products can be used.
Even if it is not available, it can be synthesized by a method known per se. For example, 3-[(acetyloxy)methyl)-
7-[C(,2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]8-oxo-5-thia-1
-AzobicycloC also x, o]Oct-2-ene-2-cargenic acid can be synthesized according to the method described in US Pat. No. 4,152,432. The other starting material, pyrrolitidine, is also a known compound and can be synthesized, for example, according to the method described in Miyano et al., "5 Synthesia," 1978, p. , No. 755
(1981)].

(Effects of the Invention) The cephalosporin derivatives and salts thereof according to the present invention have a broad antibacterial spectrum, inhibit the growth of many microorganisms including pathogenic Durham-positive and -negative bacteria, and have strong antibacterial activity. Furthermore, since the LD5o is Il1 or more/ki9 and has extremely low toxicity in mice, it has excellent safety when used as a therapeutic agent for infectious diseases.

In addition, the method of the present invention for producing such cephalosporin derivatives is easy to operate because the reaction can be carried out simply by stirring at room temperature, and furthermore, other treatments are also simple. It has advantages.

(Dosage form and dosage when used as a therapeutic agent for infectious diseases) There are no restrictions on the dosage form when formulating the cephalosporin derivatives and their salts according to the present invention as therapeutic agents for infectious diseases. It can be used as a dosage form, such as capsules, tablets,
It can be in solid form, such as sugar-coated tablets, ointments, herbal medicines, etc., or in liquid form, such as solutions, suspensions, or emulsions. If necessary, auxiliaries, stabilizers, wetting agents, emulsifiers, buffers, or other conventional additives may be added during formulation.

The dosage of the derivative or salt thereof according to the present invention varies depending on the type, patient's age, symptoms, etc.
0■/day is appropriate.

(Production Examples, etc.) Next, production examples, medicinal efficacy pharmacology test examples, and curing agent examples will be specifically explained.

Production Example 1 [6iR[6α,7β(Z))]-]4-CC7-1:
:(2-amino-4-thiacylyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,z,o)oct-2-ene-3- yl]-methyl]hexahydro-If
f-pyrrolidinium and droxide inner salt [6R-[
eα,yβ(Z)]3-3-[(acetyloxy)methyl]-7-[((2-amino-4-thiazolyl)(methoxyimino)acetyl]aine]-8-oxo-5-thia-1 -AzabicycloC41210) Oct-2-2-2-carbic acid 2.7311 in methylene chloride 12ml
N-Methyl-N-trimethylsilyltrifluoroacetamine vs, v4rtl was added and the solution was suspended at room temperature for 1
．． Stirred for 5 hours. Trimethylsilyl iodide 2.30 r
Add rtl.

After stirring for 0.5 hours, the mixture was concentrated under reduced pressure.

Dissolving the concentrate in acetonitrile zzrd, adding 0.492 rrtl of tetrahydrofuran and stirring for 10 minutes gives a solution of the crude silylated J-3-tomethyl derivative in acetonitrile.

2/3 of this @ solution was collected and added to a solution of 532 das of hexahydro-IH-pyrrolinone in 3.0 acetonitrile, stirred at room temperature for 3 hours, and 0.392 ml of water was added to remove the precipitated crystals. , acetonitrile and ether, and then dried to give dark brown crystals of 2.28.
! i+ obtained.

2.1817 of these crystals were collected and water zomlltclf
; After dissolving and removing insoluble matter from the furnace, Diamond Ion WA −
21 column, eluted with water, lyophilized, further subjected to silica column chromatography, leached out with acetone/water = 1071-371, and lyophilized to obtain the title compound. 781m9 of pale yellow powder is obtained as the compound and its structural isomer.

FAB-MS (m/z): 507 (M+H)
+'H-NMR (D20) δppm: 3.96
(3H,B,OMa)IR(ν)cnl, 34
00, 1760, 1605, 1530.1030
Production Example 2 (6R-1:6α,7β(Z))]-]4-1:lNear[:(2-amino-4-thiazolyl)(methoxyi
)) Acetyl]amino]-2-cal? xy-8-oxo-5-thia-1-azobicyclo[4,2,O]]oct2-dyn-3-yl]-methylhexahydro-ami-
1/2 of the acetonitrile solution of the iodomethyl derivative obtained by the same treatment as in Production Example 1 of cyano-IH-pyrrolidinium hydroxide inner salt was taken, and 490 μm of 7m-cyanohexahydro-IH-pyrrolidine in acetonitrile 2. 5- Add to the solution and stir at room temperature for 3 hours,
Add 0.0ml of water, separate the precipitated crystals, wash with acetonitrile and ether, and then dry to obtain 1.y41 yellowish brown crystals.

1.60 fi of this crystal was collected and dissolved in 5 ornl of water, and after removing the insoluble matter from the furnace, it was applied to a Diaion WA-21 column, eluted with water, freeze-dried, and further subjected to alumina column chromatography. Acetone/water = 3
/1 and lyophilization of the relevant fractions yields the title compound and its structural isomers as a yellow powder of 650
m9 is obtained.

FAB-MS (rrV/z): 532 (M+H)
+'H-NMR (D20) δppm: 3.9
7 (3H, s, OMe) 6.93 (IH, s,
Thiazolyl-H)IR(,KBr)m-': 34
00, 1775, 1605, 1535, 103
0 Production Example 3 [ga-C6α, 7βCz)]]-]]4-CCy-C
CCx-amino-thiazolyl)(methoxyimino)acetyl]amino]-2-caldexy8-oxo-5-thia-1-azobicyclo[4,Z,O]]oct2-en-3-yl]-methylhexahydro- 1/2 of the acetonitrile solution of the iodomethyl derivative obtained by the same treatment as in Preparation Example 1 of IH-pyrrolidinium hydroxide inner salt, in which the amyl-ethoxycarboxylic acid is 7a-ethoxylical? Add to a solution of 660 m9 of -IH-pyrrolidine in 2.2 d of acetonitrile,
Stir at 0-25°C for 3 hours, add 0.290 ml of water, separate the precipitated crystals, wash with acetonitrile and ether sequentially, and then dry to give 2.06 ml of yellowish brown crystals.
1! can get.

The crystals were collected at 1.90/i and dissolved in water soml, and after the insoluble materials were removed from the furnace, they were applied to a Diaion WA-21 column, eluted with water, freeze-dried, and then subjected to silica gel column chromatography. Then, acetone/water = 1
Elution at 0/1-3/1 and lyophilization of the relevant 7-lactone gives the title compound and its structural isomer 85oIn9 as a yellow powder.

FAB-MS (rrL/z): 579 (M+H
) +'H-NMR (D20) δppm: 1.35 (3H, g, J=7.OHz, CH
2CHJ) 3.98 (JH, s, OMe) 4.
37 (2H, q, J=7.OH1, -CH2CH
3) IR(νKBr)cnl-': 54oo,
176o, 1e2o, 1sto, 1o4° Production example 4 [6R-[6(1,7β(Z)co)-4-([near-[
[(2-amino-4-thiazolyl)(methoxyimino)
acetyl)amine]-2-cal? xy8-oxo~5
-thia-1-azabicyclo[4,2,0]octa-2-
En-3-yl]-methyl]hexahydro-amymethoxycar? 1/2 of the acetonitrile solution of the iodomethyl rust conductor obtained by the same treatment as in Production Example 1 of Nylmethyl-IH-pyrrolidinium hydroxide inner salt was taken to obtain 660η of 7a-methoxycargenylmethyl hexahydro-IH-pyrrolidine. Add to a 2.2M solution of acetonitrile,
Stir at 0-25°C for 3 hours, add 1 liter of water, separate the precipitated crystals, wash with acetonitrile and ether in sequence, and dry.
1I511 is obtained.

1.7011 of these crystals were collected and dissolved in water aornl, and after the insoluble materials were removed from the furnace, they were applied to a Diaion WA-21 column, eluted with water, freeze-dried, and further subjected to silica glu column chromatography. , acetone/water=
Elution with 1071'' 4/1 and lyophilization of the relevant fractions yields 627m9 of the title compound and its structural isomers as a pale yellow powder.

FAB-MS (m/z): 579 (M+H)”
'H-NMR (D20) δppm: 3.73 (3
H,s,COOMe)3.97(3H,s,
OMe) IR(j2:rx)cm-': 3400', 17
65, 1620, 1540, 1040 Example 5 (6R-(6α, 7β(z))]-4-CO-CI:
(,?-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-caloxy-8-oxo-5-thia-1-azobiccycloC4,2,o]]octa2-7-3 , (l]-Methyl]hexahythroam-cyanomethyl-IH-pyrrolidinium hydroxide inner salt production example 1/2 of the acetonitrile solution of the iodomethyl rust conductor obtained by the same treatment as in IFC was sampled to obtain 7a. −
Cyanomethylhexahydro-IH-pyrrolidine 540m
9 acetonitrile 2.5 rILI! add to the solution,
Stir at room temperature for 3 hours, add 0.29 g of water, separate the precipitated crystals, wash successively with acetonitrile and ether, and then dry to obtain 1.78 g of brown crystals.

1.631 of these crystals were collected and dissolved in 80ml of water,
After the insoluble matter was removed from the oven, it was applied to a Diaion WA-21 column, eluted with water, freeze-dried, and further subjected to alumina column chromatography, with acetone/water == 1.
Elution at 0/1-3/1 and lyophilization of the relevant fractions yields 318m9 of the title compound and its structural isomers as a pale yellow powder.

FAB-MS (m/Z): 546 (M+H)+
1H-NMS (D20) δppm:, 9.99 (jH,
s, OMQ) IR (1/,: miniconi) m-' 2
3400, 1760, 1620, 1
535, 1040 Production Example 6 [6-R-[6(1,7β(z):1]-4-((y
-[C(2-amino-4-thiazolyl)(methoxyimino)acetyl]amine)-2-carboxy-8-okyne-5-thia-1-azobicyclo[also 2. o] Octa-2
-en-3-yl]-methyl]hexahythroa 1-methylaminomethyl-IH-pyrrolidinium Hydroxide inner salt production example 1/2 of the acetonitrile solution of the iodomethyl derivative obtained by the same treatment as in JK was sampled. ,7 m
956a and acetonitrile 2.2- and 20-25°C. The mixture was stirred for 3 hours, 0-390 ml of water was added, the precipitated crystals were collected, washed successively with acetonitrile and ether, and then dried to obtain 1.831 ml of yellow crystals.

1.7077 of these crystals were collected and dissolved in 2 oml of water, and after removing the insoluble matter in a furnace, it was applied to a Diaion WA-21 column, eluted with water, freeze-dried, and subjected to silica gel preparative thin layer chromatography. Eluent: Acetone/
water = 1/1), further subjected to alumina short column chromatography, eluted with acetone/water = 1/1,
Lyophilization of the relevant fractions yields 121rng of the title compound and its structural isomers as a pale yellow powder.

FAB-MS (m/z): 550 (M+H)+
"H-NMR (D20) δppm: 3.97 (J
H, m, OMe) IR(v r) crn: 340
0,1760,1620,1540,1040ax Pharmaceutical efficacy pharmacology test example 1 (antibacterial spectrum and antibacterial activity) A dilution series was prepared in a medium using a representative example of the compound according to the present invention as a test substance and rntamicin as a control substance, and The minimum inhibitory concentration (MIC) for each bacterial species was measured according to the agar plate dilution method, which is a standard method of the Society of Chemotherapy, and the results were as shown in the table below.

R-ntamicin, which was used as a control substance, is one of the water-soluble basic antibiotics that is generally said to have a broad antibacterial spectrum and strong antibacterial activity. It clearly shows that it surpasses the

Pharmacology Test Example 2 (Acute Toxicity) ICR mice weighing 29-32 g (male) and 2 l-2611 (female) (6 weeks old) were used as experimental animals, and each test drug (Manufacturing Example 1-6) was administered in physiological saline. in water! The solution was administered orally and intraperitoneally to mice.

Immediately before administration and after administration, body weight and general symptoms were observed once a day. Dead mice were sacrificed immediately, and surviving mice were sacrificed 14 days after administration for autopsy.

LD5o by the method of Lead and Munch.
It was found that the toxicity of each drug was 11 or more/kg, indicating that each drug had extremely low toxicity.

Formulation example 1 (injection) An injection was prepared by mixing the following ingredients and using a conventional method.

Compound according to Production Example 1 o, i po・9tiNa
CL Solution Remaining 10ml/vial Preparation Example '2 (Dry Powder for Injection) 0.5y of the compound according to Production Example 2 was aseptically loaded into a glass vial and sealed.

This drug was dissolved in water for injection just before administration, and the total amount was 10
4 and ready for use.

Formulation example 3 (tablet) Tablets were manufactured by blending the following ingredients and using a conventional method.

Compound according to Production Example 3 150m9 Lactose
20 starch powder
5 Hydroxyglobil cellulose 4 Magnesium stearate
1180■/Tablet Formulation Example 4 (Granules) Granules were prepared by blending the following ingredients in a conventional manner.

Compound No. 50 lactose according to Production Example 4
2゜starch powder
5Hydroxypropyl cellulose 5J soln9/Sample Formulation Example 5 (Ointment) The following ingredients were blended to produce an ointment in a conventional manner.

Compound according to Production Example 1 o, sg petrolatum
100100.51 Formulation Example 6 (Layering agent) A layering agent was prepared by blending the following ingredients in a conventional manner.

Compound according to Production Example 4 0.2fi Witepsol H-121,6 Maleic acid 0.22.0jp
/Individual

Claims (14)

[Claims] (1) Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R means an organic residue well known for β-lactam antibiotics, and Q is a group▲There are mathematical formulas, chemical formulas, tables, etc.▼ , the dotted line indicates an optional double bond, and R^1 is hydrogen, an alkyl group, or a group -(CH_2)_n
R^2 means a cyano group, a carboxyl group,
(means an alkoxycarbonyl group, an optionally substituted amino group, an optionally substituted aminocarbonyl group, and n represents an integer of 0-5), a novel cephalosporin derivative represented by and its salt. (2) The derivative and salt thereof according to claim 1, wherein R is an organic residue having a phenyl group which may be substituted. (3) R is an atom selected from nitrogen, oxygen and sulfur, and 1-
The derivative and its salt according to claim 1, which is an organic residue having four 4- to 6-membered heterocyclic residues. (4) The derivative and salt thereof according to claim 1, wherein R is an organic residue having an alkyl or alicyclic hydrocarbon which may be substituted. (5) R is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^3 means hydrogen, alkyl groups, or groups ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and a and b are hydrogen or alkyl The derivative and its salt according to claim 1, characterized in that it is an organic residue represented by a group (R^4 means a hydroxy or carboxyl group). (6) [6R-[6α,7β(Z)]]-4-[[7-
[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-
5-thia-1-azabicyclo[4,2,0]octa-2
The derivative and its acid addition salt according to claim 1 or 5, which are -en-3-yl]methyl]hexahydro-1H-pyrrolidinium hydroxide inner salts. (7) [6R-[6α,7β(Z)]]-4-[[7-
[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-
5-thia-1-azabicyclo[4,2,0]octa-2
The derivative according to claim 1 or 5, which is an -en-3-yl]methyl]hexahydro-7a-cyano-1H-pyrrolidinium hydroxide inner salt, and its acid addition salt. (8) [6R-[6α,7β(Z)]]-4-[[7-
[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]2-carboxy-8-oxo-5
-thia-1-azabicyclo[4,2,0]octa-2-
The derivative according to claim 1 or 5, and its acid addition salt, which is an en-3-yl]methyl]hexahydro-7a-ethoxycarbonyl-1H-pyrrolidinium hydroxide inner salt. (9) [6R-[6α,7β(Z)]]-4-[[7-
[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-
5-thia-1-azabicyclo[4,2,0]octa-2
-en-3-yl]methyl]hexahydro-7a-methoxycarbonylmethyl-1H-pyrrolidinium hydroxide inner salt, and the derivative according to claim 1 or 5, and its acid addition salt. (10) [6R-[6α,7β(Z)]]-4-[[7
-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]octa-
The derivative according to claim 1 or 5, which is a 2-en-3-yl]methyl]hexahydro-7a-cyanomethyl-1H-pyrrolidinium hydroxide inner salt, and its acid addition salt . (11) [6R-[6α,7β(Z)]]-4-[[7
-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]octa-
The derivative according to claim 1 or 5, which is a 2-en-3-yl]methyl]hexahydro-7a-methylaminomethyl-1H-pyrrolidinium hydroxide inner salt, and its acid. Added salt. (12) Formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R' means an optionally protected organic residue well known for β-lactam antibiotics, and A is a carbonyl 7-acylamino-3-acetoxymethyl-cephalosporin (means a protecting group) is reacted with trialkylsilyl halide to obtain the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (Formula 7-acylamino-3-halomethylcephalosporin represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) (In the formula, R^1 is hydrogen, an alkyl group, or a group -(CH_2)
__nR^2, where R^2 is a cyano group, a carboxyl group that can be protected, an alkoxycarbonyl group, an amino group that can be protected or substituted, an aminocarbonyl group that can be substituted. (where n means an integer from 0 to 5) is reacted with the pyrrolitidine compound shown in There are formulas, mathematical formulas, chemical formulas, tables, etc., where , tables, etc. ▼ (means R^1 and dotted line have the meanings above)] A method for producing a novel cephalosporin derivative and its salt shown in . (13) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R means an organic residue well known for β-lactam antibiotics, and Q is a group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ , the dotted line indicates an optional double bond, and R^1 is hydrogen, an alkyl group, or a group -(CH_2)_n
R^2 means a cyano group, a carboxyl group,
an alkoxycarbonyl group, an optionally substituted amino group, an optionally substituted aminocarbonyl group, and n is an integer of 0-5); A therapeutic agent for infectious diseases, characterized in that it contains at least one salt thereof as an active ingredient. (14) The active ingredient is i) [6R-[6α,7β(Z)]]-4-[[7-[
[(2-amino-4-thiazolyl)(methoxyimino)
Acetyl]amino]-2-carboxy-8-oxo-5
-thia-1-azabicyclo[4,2,0]octa-2-
en-3-yl]methyl]hexahydro-1H-pyrrolidinium hydroxide inner salt, ii) [6R-[6α,7β(Z)]]-4-[[7-
[[2-amino-4-thiazolyl) (methoxyimino)
Acetyl]amino]-2-carboxy-8-oxo-5
-thia-1-azabicyclo[4,2,0]octa-2-
en-3-yl]methyl]hexahydro-7a-cyano-1H-pyrrolidinium hydroxide inner salt, iii) [6R-[6α,7β(Z)]]-4-[[7
-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]octa-
2-en-3-yl]methyl]hexahydro-7a-ethoxycarbonyl-1H-pyrrolidinium hydroxide inner salt, iv) [6R-[6α,7β(Z)]]-4-[[7-
[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-
5-thia-1-azabicyclo[4,2,0]octa-2
-en-3-yl]methyl]hexahydro-7a-methoxycarbonylmethyl-1H-pyrrolidinium hydroxide inner salt, v) [6R-[6α,7β(Z)]]-4-[[7-[
[(2-amino-4-thiazolyl)(methoxyimino)
Acetyl]amino]-2-carboxy-8-oxo-5
-thia-1-asabicyclo[4,2,0]octa-2-
en-3-yl]methyl]hexahydro-7a-cyanomethyl-1H-pyrrolidinium hydroxide inner salt, vi) [6R-[6α,7β(Z)]]-4-[[7-
[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-
5-thia-1-azabicyclo[4,2,0]octa-2
-en-3-yl]methyl]hexahydro-7a-methylaminomethyl-1H-pyrrolidinium hydroxide inner salt; and vii) at least one acid addition salt thereof. The infectious disease therapeutic agent according to item 13.