JPS615085A - 3-(pyrrolinium)methyl-3-cephem derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R1 is lower alkyl; R2 is lower alkyl which may be substituted with cyano, lower alkoxy groups) and its salts. EXAMPLE:7beta-[( Z )-2-(2-Aminothiazole-4-yl)-2-methoxyiminoacetamide]-3-(1-methyl- 3-pyrrolium)methyl-3-cephem-4-carboxylate. USE:Antibacterial against gram-positive and -negative bacteria. PREPARATION:The reaction of a compound of formula II (X is halogen) such as 7beta-[( Z )-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-iodomethyl-3-cephem- 4-carboxylic acid or its salt with another compound of formula III such as 1- methyl-3-pyrroline or its salt is conducted, preferably in the absence of solvents at 10-40 deg.C to give the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The present invention relates to novel compounds with antibacterial activity.

Many compounds have been known as 7-amituthiazolyl acetamido-3-cephem derivatives, but among them, compounds having a (pyrrolidinium) methyl group at the 3-position of the cephem skeleton have excellent antibacterial activity. (Japanese Unexamined Patent Publication No. 174387/1987).

The present inventors discovered that a compound having a (pyrrolidinium) methyl group, which is an unsaturated form of this (pyrrolidinium) methyl group, at the 3rd position has superior antibacterial activity, and completed the present invention. .

Accordingly, one object of the present invention is to provide a novel compound having excellent antibacterial activity, a method for producing the same, and a pharmaceutical use thereof as an antibacterial agent.

[Structure of the invention]

The target compounds of the present invention are shown below.

3-(pyrrolinium)methyl- represented by the general formula [wherein R1 is a lower alkyl group and R2 is a lower alkyl group substituted or unsubstituted with a cyano group or a lower alkoxy group]
3-cephem derivatives and their non-toxic salts Regarding R in the above general formula (k) and birds, lower alkyl groups include methyl, ethyl, n-propyl, 1-propyl, n-butyl, i-butyl. group, t-butyl group, etc. Further, the lower alkoxy group for R2 is a methoxy group or an ethoxy group.

Examples include n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, and t-butroxy group.

Non-toxic salts of the compound of general formula fIl include pharmaceutically acceptable salts such as hydrochloride, hydrobromide.

Inorganic acid salts such as sulfates, carbonates, hydroiodides and 9 bicarbonates; organic carboxylates such as acetates, maleates, lactates, tartrates; methanesulfonates.

Examples include organic sulfonates such as benzenesulfonate and toluenesulfonate; amino acid salts such as aspartate and glutamate.

Concerning the configuration of the following moiety of the compound of the present invention of general formula (Il).

C- ゝOR.

There is a syn isomer (Zl) and an anti isomer (El exists, but 2
The present invention also includes rain gear specimens.

The compound of the present invention can be produced by the method shown below.

A compound represented by the general formula [wherein R1 is the same as the above definition and X represents a halogen atom], a compound whose functional group is protected, or a salt thereof; The compound represented by the above general formula [11] or a non-toxic salt thereof can be obtained by reacting the compound represented by the above general formula [11] or a salt thereof, and removing the protecting group if necessary.

Examples of the halogen atom for X in the above general formula tnl include iodine atom, bromine atom, and chlorine atom, and iodine atom and bromine atom are particularly preferred.

The above reaction is carried out at a reaction temperature of 0°C to 60°C, preferably 10°C.
It can be carried out at ~40°C. Further, as the reaction solvent, an anhydrous organic solvent is preferable. Organic solvents that can be used include lower alkyl nitriles such as acetonitrile and propionitrile; halogenated lower alkyls such as chloromethane, dichloromethane, and chloroform; ethers such as tetrahydrofuran and dioxane;
Amides such as N-dimethylformamide; esters such as ethyl acetate; ketones such as acetone; and hydrocarbons such as benzene.

As the protective group for the functional group of the compound of general formula (II) and salts of saliva compounds, general formula groups, commonly used groups can be used as long as they do not interfere with the above reaction.

For example, a formyl group is a protecting group for an amino group.

Acetyl group, chloroacetyl group, dichloroacetyl group,
t-butoxycarbonyl group, benzyloxycarbonyl group, trityl group, p-methoxybenzyl group, diphenylmethyl group, etc.; protecting groups for carboxy groups include p-methoxybenzyl group, p-nitrobenzyl group, t-butyl group, Methyl group.

2.2.2-) 10-loethyl group, diphenylmethyl group,
Examples include pivaloyloxymethyl group. Also, bis(trimethylsilyl)acetamide, N-methyl-N
-(trimethylsilyl)acetamide, N-methyl-N
-) It is convenient to use a silylating agent such as trimethylsilylated trifluoroacetamide, since the amine group and the carboxy group can be protected at the same time.

Examples of salts of compounds of the general formula (2) include alkali metal salts such as sodium salts and potassium salts.

Alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; hydrochlorides and hydrobromides.

Inorganic acid salts such as sulfates, carbonates, hydroiodides, 9 bicarbonates; organic carboxylates such as acetates, maleates, lactates, tartrates; methanesulfonates.

Organic sulfonates such as benzenesulfonate, ) luenesulfonate; trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine amine salts such as jetanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt, phenethylbenzylamine salt; arginine salt, aspartate salt, lysine salt.

It can be appropriately selected from salts such as amino acid salts such as glutamate and serine salts.

Compounds of general formula (III), compounds with protected functional groups, and salts thereof, which are starting materials, are shown in [Tetrahedron Letters, Vol. 22, No. 40, pp. 3915-3918 (1981)]. It can be manufactured according to a known method.

For example, by reacting a compound represented by the general formula [wherein R1 is the same as defined above], a compound whose functional group is protected, or a salt thereof with a halogenating agent, a compound of the general formula (n), A compound whose functional group is protected or a salt thereof can be obtained. Regarding the reaction solvent, protecting group, and salt in this reaction, the same ones as in the reaction of the compound of general formula (ml) and the compound of general formula (2) can be used.As the halogenating agent, iodotrimethyl Silane etc. are used.

The compound of the general formula + IIl, the compound with its functional group protected, or the salt thereof obtained by the above method etc. is not purified (but is then reacted with the compound of the general formula (2) or the salt thereof to form a compound of the present invention). can be obtained.

The compounds of the present invention exhibit strong antibacterial activity against Durum-positive and Durum-negative bacteria. In addition, the acute toxicity value (LDso (mouse, oral)) was 2y/ky or higher for all of the following compounds.

7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide)-3-(1-
Methyl-3-pyrrolinium) Methyl-3-cephem-4
-Carboxylate 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide)-3-[1-
(2-methoxyethyl)-3-pyrroliniumcomethyl-
3-cephem-4-carboxylate The compounds of the present invention are therefore useful as antibacterial agents. When using the compound of the present invention as an antibacterial agent, the dosage is generally 2 to 300
w/ky/EJ, preferably 10-1001#g/#g
/ day. This antibacterial agent is available in powder, granule, and capsule form9.
Orally in the form of tablets, etc.

Alternatively, it can be administered parenterally in the form of injections, suppositories, etc. These formulations use pharmaceutically acceptable carriers,
It can be manufactured by conventional methods.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 7β-((Z)-2-(,2-aminothiazole-4-
yl)-2-methoxyiminoacetamide)-3-(1
-Methyl-3-pyrrolinium)methyl-3-cephem-
4-Carboxylate 7β-(I21-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide)-3-acetoxymethyl-3-cephem-4-carboxylic acid 480. was suspended in 8 ml of methylene chloride, 660 ml of N-methyl-N-)limethylsilyltrifluoroacetamide was added, and the mixture was stirred at room temperature for 30 minutes. After adding 400 μt of iodotrimethylsilane and stirring for 15 minutes, the solvent was distilled off under reduced pressure and 7β-(12+-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3
A silylated product of -iodomethyl-3-cephem-4-carboxylic acid was obtained.

This was dissolved in 6 rtcL of acetonitrile, and 120 μL of tetrahydrofuran was further added. 1 to the resulting solution
-Methyl-3-pyrroline 105+ag was added and stirred at room temperature for 2 hours. A mixed solution of 0.6 tnL of methanol and 4 mL of acetonitrile was added to the reaction solution, and the mixture was further stirred for 15 minutes. The resulting precipitate was collected and washed with acetonitrile. This was dissolved in 3096 ethanol and concentrated under reduced pressure, and then the residue was dissolved in acetone-water (7:1). This solution was subjected to silica gel column chromatography (3X25CI
11. Elution: acetone-water 7:1 and 5:1). The eluted fraction containing the target product was concentrated under reduced pressure, and the residue was lyophilized to obtain target product 57.

Example 2 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide)-3-[1-
(2-methoxyethyl)-3-pyrroliniumcomethyl-
3-cephem-4-carboxylate 7β-[(Z)-2-(2-aminothiazole-
4-yl)-2-methoxyiminoacetamide]-3-
Acetoxymethyl-3-cephem-4-carboxylic acid 48
0 H and 600 μt of iodotrimethylsilane, then 1-(2-methoxyethyl)-3-pyrroline 1
61 my wo react to the target object 28. I got it.

Example 3 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide)-3-[1-
(2-cyanoethyl)-3-pyrroliniumcomethyl-3
-cephem-4-carboxylate Same as Example 1'
Then, 7β-[(Z)-2-(2-aminothiazole-
4-yl)-2-methoxyiminoacetamide]-3-
Acetoxymethyl-3-cephem-4-carboxylic acid 48
0 ■ and 660 μt of iodotrimethylsilane,
Then 1-(2-cyanoethyl)-3-pyrroline 154
■ React to the target 10. I got it.

Example 4 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamide)-3-(1-
Methyl-3-pyrrolinium) Methyl-3-cephem-4
-Carboxylate 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamide)-3-acetoxymethyl-3-cephem-4-carboxylic acid (240 μl) in methylene chloride (5 ttrL) suspended, N-methyl-N-)
Limethylsilyltrifluoroacetamide 320μL
was added and stirred at room temperature for 1 hour. After adding 290 μt of iodotrimethylsilane and stirring for 15 minutes, the solvent was distilled off under reduced pressure to obtain 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamide]-
A silylated product of 3-iodomethyl-3-cephem-4-carboxylic acid was obtained.

Dissolve this in 1 nL of acetonitrile and add 1-methyl-3
A solution of 5 ml of -pyrroline 43 TILg in acetonitrile L was added, and the mixture was stirred at room temperature for 2 hours. Two drops of water were added to the reaction solution, and the mixture was further stirred for 15 minutes. The resulting precipitate was collected and washed with acetonitrile. Add this to acetone-water (7:1)
) and subjected to column chromatography on silica gel (3X25 cm, elution: acetone-water 7:1.5
:1 and 3:1). Concentrate the eluate fraction containing the target product under reduced pressure.

Freeze-dry the residue to obtain the desired product 42. I got it.

*β-lactamase producing bacteria

Claims (6)

[Claims] (1) General formula ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is a lower alkyl group, R_2 is a lower alkyl group substituted or unsubstituted with a cyano group or a lower alkoxy group] 3- (pyrrolinium)methyl-3-cephem derivatives and their non-toxic salts (2) The compound according to claim 1, wherein R_1 is a methyl group or an ethyl group (3) The compound according to claim 1, wherein R_2 is a methyl group, a methoxyethyl group, or a cyanoethyl group. (4) 7β-[(Z)-2-(2-aminothiazole-
4-yl)-2-methoxyiminoacetamide]-3-
The compound according to claim 1, which is (1-methyl-3-pyrrolinium)methyl-3-cephem-4-carboxylate. (5) 7β-[(Z)-2-(2-aminothiazole-
4-yl)-2-methoxyiminoacetamide]-3-
The compound according to claim 1, which is [1-(2-methoxyethyl)-3-pyrrolinium]methyl-3-cephem-4-carboxylate. (6) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is a lower alkyl group and It is characterized by reacting a compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 and R_2 are the same as defined above] Method for producing a compound or its non-toxic salt (7) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ An antibacterial agent consisting of a compound represented by the formula [wherein R_1 is a lower alkyl group and R_2 is a lower alkyl group substituted or unsubstituted with a cyano group or a lower alkoxy group] or a non-toxic salt thereof.