JPH0334986A - Cephalosporin compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [X and Y are halogen or one is halogen and the other is H; Z is H, halogen, (substituted) vinyl, lower alkoxy, lower alkylthio or CH2B (B is H or nucleophilic residue)]. EXAMPLE:7-[2-(2-Tritylaminothiazol-4-yl)-2(Z)-diphenylmethyloxycarbony l(3,4- diacetoxy-2,5-dichlorophenyl)methyloxyimino acetamido]-3-(1,2,3-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester of formula II. USE:An antibacterial agent. PREPARATION:The objective compound is produced by reacting a compound of formula III (R3 is H or carboxyl-protecting group) (or its reactive derivative) with a compound of formula IV (R1 is hydroxy-protecting group; R2 is H or amino-protecting group) (or its reactive derivative).

Description

Detailed Description of the Invention (a) Industrial Application Field The present invention relates to novel cephalosporin compounds having antibacterial activity, pharmaceutically acceptable salts or esters thereof, antibacterial agents containing them, and the production thereof. Regarding the law.

(b) Problems to be Solved by the Prior Art and the Invention Cephalosporin antibiotics exhibit a wide range of antibacterial activity against Durum-positive bacteria and Clam-negative bacteria, and various semi-synthetic cephalosporin compounds are already commercially available. It is used clinically as a therapeutic agent for various infectious diseases. However, among these compounds, there are only a few therapeutic agents that exhibit antibacterial activity against Pseudomonas aeruginosa and Proteus. In addition, many of these compounds are unstable against β-lactamase produced by resistant bacteria, and have drawbacks such as low antibacterial activity against Durham-positive bacteria and Pseudomonas aeruginosa, which are currently clinical problems ( W,
E. Wick, “Cephalosporins an
d Pen1cillinsChemistry an
d Biology”, E, H, Flynn gAca
demic Press, New York, N.Y., 1972.
Chapter 1I).

A compound having the formula is known as a substituent at the 7-position of a cephem compound (JP-A-62-2705
No. 89, see No. 63-99,077).

(c) Means for Solving the Problems The present inventors have already reported in Japanese Patent Application No. 1-106445 that the 2-(2-aminothiazol-4-yl)-2 of the amide side chain at the 7-position of the cephem ring -3.4hydroquino-2 at the oquinome substitution part of the substituted oxyiminoacetamide
, 5-dichlorobenzyl group has been found to have strong activity against a wide range of pathogenic bacteria. This time, the former 3,4-hydroquino-
As a result of focusing on the structure of the 25-dichlorobenzyl group and developing research, a new cephem compound shown by the formula (]) was discovered.
It has strong antibacterial activity against a wide range of Durham-positive and Durham-negative bacteria, and in particular shows extremely strong antibacterial activity against Pseudomonas aeruginosa, as well as strong antibacterial activity against various β-lactamase-producing bacteria. The present invention was completed by discovering that the compound exhibits the following properties, but has low toxicity and is well absorbed.

Therefore, the present invention provides a general formula (I) useful as an antibacterial agent, wherein X and Y are both halogen atoms, or one of them is a halogen atom and the other is a hydrogen atom.

Z is a hydrogen atom, a halogen atom, a vinyl group, a substituted vinyl group, a lower alkokino group, a lower alkylthio group, or a Cl-
In the 12BC formula, B does not represent a hydrogen atom or a nucleophilic residue. ]
The present invention provides a cephalosporin compound represented by the above formula, a pharmacologically acceptable salt or ester thereof, and an antibacterial agent containing the same as an active ingredient.

Since there is an asymmetric carbon atom in the side chain at position 7 of the cephem, racemic forms and optically active forms exist, but both are included in the present invention.

Pharmaceutically acceptable salts of the compound represented by formula (I) of the present invention include conventional non-toxic salts, such as sodium salts,
Alkali metal salts such as potassium salts, alkaline earth metal salts such as carunium salts and machinum salts, ammonium salts, salts with organic bases, such as triethylamine salts, pyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexynolamine Organic amine salts such as salts and lysine,
Examples include basic amino acid salts such as ornithine and arginine.

In the above general formula (I), examples of the halogen atoms in X, Y, and Z include a chlorine atom, a bromine atom, and a fluorine atom. Preferably it is a chlorine atom or a fluorine atom. More preferred is a chlorine atom. It is preferable that X and Y are both halogen atoms, one is a halogen atom and the other is a hydrogen atom, and both are chlorine atoms, or one is a chlorine atom and the other is a hydrogen atom.

Examples of the substituted vinyl group for the group Z include a medylhinyl group, a halogen medylhinyl group, a lower alkoxyvinyl group, and a lower alkoxymethylvinyl group.

Lower alkokyne groups in the group Z include methquine, ethquine, propoxy, isopropoquine, butoquino and isobutquine groups. Examples of the lower alkylthio group in the group Z include methylthio, ethylthio, propylthio, isopropylthio, methylthio and isomethylthio groups.

The nucleophilic residue in B of the group CH2B includes an acetoquine group, a carbamoyl oxine group, a halogen atom, an optionally substituted aromatic heterocyclic thio group, a lower alkylthio group, a lower alkokino group, a primary, Examples of secondary groups include tertiary amino groups, or heterocyclic groups containing at least one nitrogen atom and bonded to the methylene group via the nitrogen atom.

Examples of the halogen atom include those similar to the halokene atoms in X and Y. The aromatic heterocyclic group in the optionally substituted aromatic heterocyclic thio group includes a 5-membered ring or a 6-membered ring containing at least one heteroatom of a nitrogen atom, a sulfur atom, and an oxygen atom.

More specifically, thiazole, isothiazole, thianoazole, triazole, tetrazole, birinone, pyrimidine, pyridazino, oxazole, imidazole,
Includes pyrazoles, oxadiazoles, isoxazoles, pyridazines, triazinos, etc. Substituents for these aromatic heterocyclic groups include lower alkyl groups such as methyl, ethyl, and propyl, halogen atoms such as chlorine, bromine, and fluorine, amino groups, anano groups, and carboxyl methyl groups. It will be done. Lower alkylthio groups include methylthio, ethylthio, propylthio, and the like. Lower alkokino groups include metquino, ethoquino, propochino, and the like. Primary, secondary, and tertiary amino groups are
Examples of lower alkyl groups include aralkyl groups such as hennol, lflU, and 7-substituted amino groups, such as medylamino, edylamino, somedylamino, triethylamine, and methylhennolamino. Examples of the heterocyclic group containing at least one nitrogen atom and bonding to a methylene group via the nitrogen atom include those containing a nitrogen atom in the above-mentioned examples of aromatic heterocycles.

These heterocyclic groups may be substituted with a lower alkyl group such as methyl or ethyl, a halogen atom such as chlorine, bromine, or fluorine, an amino group, a soano group, or the like.

Compound (I) of the present invention can be produced by the method shown below.

That is, the following formula (II) (wherein, R3 is a hydrogen atom or a protective group for a carfoquinol group,
Z is the same as defined in formula (I)), te=8 The compound shown or a reactive derivative thereof at the amino group or a salt thereof is substituted with the following formula (ll'l) [wherein,
R3 is a hydroquino-protecting group; R2 is a hydrogen atom or an amino group-protecting group; Manufactured by

A suitable example of a reactive derivative at the amino group of compound (II) is a Nuch base-type imino or its tautomer formed by the reaction of compound (It) with a carbonyl compound such as an aldehyde, ketone, etc. Enamine type isomer 1 compound (II) and bis(trimethylsilyl)
Solyl derivative 1 compound (n) such as acetamide etc.
Examples include derivatives produced by the reaction of phosphorus trichloride or phosgene.

Suitable salts of compounds (II) and (II) include salts with organic acids such as acetic acid, maleinate, layerite,
Acid addition salts such as benzene sulfonate, toluene sulfonate, etc.) or salts with inorganic acids (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.) 1 Alkali metal salts or alkaline earth metal salts (e.g. sodium salts,
Examples include metal salts such as ammonium salts (such as potassium salts, calcium salts, and magnenoum salts), and organic amine salts (such as triethylamine salts and dinochlorohequinylamine salts).

Suitable examples of reactive derivatives at the carboxyl group of compound (III) include acid halides, acid azides, acid anhydrides, active amides, and active esters; more specifically, acid chlorides, acid anhydrides, and the like. Bromide, substituted phosphoric acid (e.g., noalkyl phosphoric acid, dihenenophosphoric acid, halokenated phosphoric acid, etc.), alkyl phosphorous acid, sulfite, thiosulfuric acid, sulfuric acid, alkyl carbonate (e.g., methyl carbonate, ethyl carbonate, etc.), IQ fatty layer carboxylic acid (e.g. pivalic acid, valeric acid, isovaleric acid, 2-ethyl acetic acid, trichloroacetic acid, etc.) or mixed acid anhydrides with acids such as aromatic carboxylic acids (e.g. benzoic acid), imidazole, dimethylpyrazole,
Active amides with triazoles or tetrazoles: or active esters (e.g. noanomethyl ester, methoxymethyl ester, nonthyliminomethyl [(CH3)2
N=CH-conistere, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, menorphenyl ester, phenylazophenyl ester, phenylthio ester, p- Nitrophenyl thioester, p-talesyl thioester, carboquinomethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8
-quinolyldioester, etc.), or N-hydroquine compounds (e.g., N,N-dimethylhydroquinamine, 1-hydroquino-2-(IH)-pyridone, N-hydroquinophthalimide, N-hydroquinophthalimide,
1-hydroquino-6-chloro IH-hensitriazole, etc.). These reactive derivatives are appropriately selected depending on the type of reactant compound (III) to be used.

The compound of formula (III) which is the raw material of the present invention, for example, as a representative example thereof, 1(2-tritylaminodeazol-4-yl)-2(Z)-diphenylmethyloquinocarbonyl ( 3
, 4-diacetoquine-2,5-dichlorophenyl)methyloquiniminoacetic acid can be synthesized by the following method.

Mass, 3,4-dihydroquine phenylacetic acid is reacted with sulfuryl chloride to produce 3,4-dihydroquine-2,5 dichlorophenylacetic acid (a), and then this (a) is reacted with acetic anhydride. 3. /I-Diacetquin 2.5-
Dichlorophenylacetic acid (b) is obtained. The obtained (b) is reacted with bromine in the presence of Pct to give (3,4 diacetoquine-2,5-dichlorophenyl)bromoacetic acid (C). Next, (c) is reacted with diphenylon azomethane to give nophenylmethyl 3,4-diacetoquino-25-dichlorophenyl)bromoacetate (d). Next, to this (d), in the presence of 2Co in DMF, allyl (21-ditylaminothiazol-4-yl)hydroquiniminoacetate was reacted with 2-(2-tritylaminothiazol-4-yl)- Allyl 2(Z)-phenylmethyloquinocarponyl(34-')acetoquino-2,5-dichlorophenyl)methyloquiniminoacetate (e) is obtained. Then, (e) is deallylated with Pd[(csHa)+p] to obtain the compound of formula (A) above.

The reaction between compound (n) and (III) is usually carried out using water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, N, N
-Nomethylformamide, birinone, or other organic solvents that do not adversely affect the reaction. These solvents may be used in combination with water.

In this reaction, when compound (III) is used in the form of free acid or salt, the condensing agent may be, for example, N,
N'-dinochlorohequinolcarbodiimide N-nochlorohequinru N'-morpholinoethylcarbonoimite, N-chlorohequinru N'' (4noethylaminone clohexol) carbonoimite: N,N'-noethylcarbonoimit N N'diisopropylcarbodiimide N-ethyl N'-(3-dimethylaminopropyl)carbodiimide; N,N-carbonylbis(2-sterimidazole), pentamethyleneketene-N-sochlorohekynylimine: diphenylketene-N-nocro Hequinolimine; Ethoquinoacetylene 1-alcoquino-■-chloroethylene, trialkyl phosphite, edyl polyphosphate, isopropyl polyphosphate, oxophosphorus chloride, phosphorus acid chloride, thionyl chloride oxalyl chloride: triphenylphosphine, 2-ethyl- 7-Hydroquinobenzitsuquizazolium salt, 2-
Ethyl-5-(m~sulfophenyl)isoxazolium hydroquinode inner salt, 1chlorobenzenesulfonyloquine)-6-chloro-IH-benzotriazole, dimethylformamide with thionyl chloride, phosgene, ochine phosphorus chloride, etc. Examples include the so-called Wilsmeier reagent obtained by reaction.

This reaction may also be carried out in the presence of an inorganic or organic base, examples of such bases being alkali metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal carbonates (e.g. sodium bicarbonate, potassium bicarbonate, etc.). Examples include calcium carbonate, etc.), tri(lower)alkylamines (eg, triethylamine, trimethylamine, etc.), birinone, N(lower)alkylmorpholine, and N,N-no(lower)-alkylbennoramine.

The reaction temperature is not particularly limited, and the reaction is usually carried out at It is carried out under heat.

Alternatively, a compound represented by the general formula (IV) [wherein; It is also possible to produce the compound of general formula (]) by removing. Further, when the Z group is an acetoxymethyl group, it may be converted into a heterocyclic thiomethyl derivative by later reacting with a heterocyclic mercaptan.

The products obtained by these methods are the target compound (I) of the present invention, or are protected forms of the amino group, carboxyl group, and phenolic hydroxyl group of the target compound (I), and therefore, if necessary, conventional methods can be used. Removal of each protecting group is carried out in . The method for removing the carboquine protecting group and the amine protecting group is appropriately selected depending on the type of the protecting group to be removed. The elimination reaction of the amino protecting group involves hydrolysis, reduction, and the reaction of an iminohalogenating agent and then an iminoetherifying agent on the compound that is the protective group Kaanol group, followed by hydrolysis if necessary. Any commonly used method can be applied. The method of hydrolysis using an acid is a general method, and is applied, for example, to the elimination of groups such as alkoxycarbonyl groups, formyl groups, and trityl groups. Further, as the acid used, formic acid, trifluoroacetic acid, hydrochloric acid, etc. are appropriately selected depending on the type of amino protecting group. The reaction can be carried out either in the absence of a solvent or in the presence of water, a hydrophilic organic solvent, or a mixed solvent thereof. Furthermore, when trifluoroacetic acid is used, the reaction may be carried out in the presence of anisole. Any commonly used method such as hydrolysis or reduction can be applied to the elimination reaction of the carboquine protecting group. Hydrolysis using an acid is one of the general methods and is applied, for example, to eliminate a noryl group, a p-methoxybenzyl group, a diphenylmethybenzyl group, and the like. Any commonly used methods such as hydrolysis and reduction can also be applied to the elimination reaction of the protecting group of the phenolic hydroxyl group. Hydrolysis using an acid or a base is one of the common methods. Base is applied.

The compound of general formula (I) obtained as described above is collected from the reaction waste by a conventional method.

For example, purification using an adsorption oven such as Amberlite IAI)-2 (manufactured by Rohm and Haas), Diaiont IP-20 or Sepapes 5P207 (manufactured by Mitsubishi Kasei Corporation), Hidenohiro, crystallization method, etc. Distant relatives can be obtained by combining them appropriately.

Antibacterial agents containing a compound represented by the general formula (D) or a salt thereof as a main component are mainly injectables such as static pressure and intramuscular injections, oral or rectal preparations such as capsules, tablets, and powders,
It is used in various dosage forms such as oil-based suppositories and water-soluble suppositories.

These @species preparations contain commonly used excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, and solubilizing agents. , a preservative, a flavoring agent, a neutralizing agent, etc., and can be manufactured by a conventional method. Specific examples of the formulation method will be explained in more detail in the Examples below.

The dosage is determined on a case-by-case basis, taking into account symptoms, age, gender, etc., but it is usually 250 to 250 mg per day for adults.
The dose is 3,000 snails, which is divided into 1 to 4 doses per day.

(D) Examples The present invention will be further explained in detail in the following Reference Examples and Examples, but these do not limit the present invention, and various modifications and modifications may be made without departing from the scope of the present invention. Needless to say, it is possible.

Note that the NMR data in the examples are 9 unless otherwise specified.
When using 0MHz, in the case of heavy water, the water peak is set to a δ value of 4.
82, and in the case of other heavy solvents, T
The δ value is shown based on MS.

9 Example-1 'l-[i (2-1-ditylaminothiazol-4yl)-2(Z)-nophenylsterooquinocarbonyl (
34-Diacetoquino-2,5-nochlorophenyl)steroquiniminoacetamito]-3(I,2,3-deadiazol-5-yl)thiomethyl 3-cephem-4-
Synthesis of carboxylic acid p-methoquinohensyl ester 1(2-)lytylaminothiazol-4-yl)2(Z
)-nophenylsteroquinocarbonyl (3,4-diacetoxy-2,5-dichlorophenyl)methyloxoiminoacetic acid 400 mg and 7-amino-3([,2,3-
Thianoazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid-p-methquinohene norester 29
Add 0% to 20mQ of methylene chloride, dissolve and cool to -20°C. Add pyrinone 2 to this solution.
Then, 84 mg of phosphorous ochinochloride was added and reacted at 15°C for 2 hours. After the reaction is complete, add 1 ethyl acetate
ooxf 15 Pour into a mixed solvent, and add 7% sodium bicarbonate water under cooling.
Adjust H to 7.0. The organic layer is separated and further washed with 15% brine. It was dried over anhydrous MgSO4 and the solvent was distilled off under reduced pressure. Column chromatography (Wako Gel C)
-300 100g developing solvent CHCI3-MeO11
・30:1) to produce the noastereomer of the title compound
1 Obtain 1 Shikaaimono.

r R (nujol) 3300.1780cmNM
R (CDCl2, δ) 2, 15-2.25 (I2H.sx4,0Acx4),
3.10-3.35 (4H, m2 position Ct12x2) 3
．． 80 (6h s, 0C1i3x2), 3.8-3.9
, 4.254 , 4 0 (ABq X 2 , 3
position Cl2X 2), 4.90.4.95 (2H.dX
2, J=5Hz. 1l-6x 2), 5.80(
2H. d, d x 2, J-5. 9tlzz+-
7 X 2)6, 05.6.15(21(,sX 2)
CHX 2), 6.80-7.40 (58H, mPh.
NHx 2, CPh, x 2, thiazole ring proton x 2) 8, 10 (2H.dX 2, J: 8Hz, C0N
HX 2), 8.40.8.45 (2H.sX2 deadiazole ring proton) Example-2? - [2- (2-aminothiazol-4-yl)2
(Z)-Carboquino(3,4-nohytoquino-2.5-chlorophenyl)methyloquiniminoacetamidoco-
Synthesis I of 3-(I.,2.3-thianazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 200M of the compound obtained in Example-1 was mixed with anisole 0,
5. Dissolve in cape and cool with water. Add 2 mQ of trifluoroacetic acid to this and stir for 1 hour while cooling with water. After the reaction is complete, 50 g of isopropyl ether is added, and the precipitated trifluoroacetate of the title compound is collected by filtration and dried. Suspend this in 1x water (7%) and adjust the pH to 7 with 7% sodium hydrogen carbonate solution while cooling with water.
．． 2 and use it as a solution. This solution was mixed with IP-2
Purification was performed by column chromatography (eluent: water, 5% methanol/water) at 0.0 and the eluate was condensed under reduced pressure to remove methanol. The resulting water-soluble group was freeze-dried to obtain 58 mg of the title compound as a disodium salt.

! R(nujol) 33001770cmNMr(
(D20.δ) 3, +5.3.58 (4) 1. ABQX 2.2nd place CH
2X2), 3.90-3.95 4.25-4.40 (4
H, ABQX 2.3rd CH2X2), 5.05 (2H
dX2 +16x 2), 5.42 (2H, sx 2.
Cl1x 2), 5.65(2H, dX 2.H-7x
2) 6.90-7.10 (4H, sx 4. Thiazole ring proton x 2 ring proton x 2), 8.75 (2H
,sX 2. Thiadiazole Ring Proton) Table 1 shows the results of measuring the minimum inhibitory concentration of the compound of Example 2 against Durum-positive bacteria and Durum-negative bacteria (agar dilution method).

(Left below) Table 1 Minimum inhibitory concentration (MIC) Test bacteria MIC 3t, aureus Smlth (I) 0
．． 20St, epidermidis
O, 39ATCC14990 B, 5ubtilis 1.58AT
CC6833 E, coli NIIIJ JC-20, 20P, m1
labilis GN310 0.05, p
pneumoniae GN118 0.05S
, typhimurium LT-20,10E, cl
oacae G-00050, 39S, marcesc
ens GN629 0.39P, aerug
inosa GN10857 0.78P, a
eruginosa M-01480, 39 (E) Effects of the Invention According to the present invention, an antibiotic having excellent antibacterial properties against Durham-positive and -negative bacteria can be obtained.

Claims (1)

[Claims] 1. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, both X and Y are halogen atoms, or one of them is a halogen atom and the other is a hydrogen atom represents. ;Z is a hydrogen atom, a halogen atom, a vinyl group, a substituted vinyl group, a lower alkoxy group, a lower alkylthio group, or a CH
_2B (in the formula, B is a hydrogen atom or a nucleophilic residue). ]
A cephalosporin compound and a pharmacologically acceptable salt or ester thereof. 2. An antibacterial agent containing the compound according to claim 1 as an active ingredient.