JPH0717980A - Carbapenem derivative or salt thereof - Google Patents

Abstract

PURPOSE:To provide a novel compound useful as a medicine, esp. an antibacterial agent for methicillin-resistant Staphylococcus aureus. CONSTITUTION:The compound of formula I (R is H, negative electric charge or ester residue; X is S, O or NH; Y is O, NH or H2), e.g. (1R,5S,6 S)-2-{[(Z)-3-(3,4-dihydro-2H-pyrido[4,3-b]-,4-thiazine-6-thio)-1-prope nyl]thio}-6-[(R)-1- hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate. The compound of the formula I can be obtained by reaction of a compound of formula II (R' is carboxyl- protecting group) with a phosphoric esterifying agent or sulfonic esterifying agent followed by substitution reaction with an amine reagent and then eliminating the protecting group. The compound of the present invention also provides excellent activity against both Gram-positive and Gram-negative bacteria, is stable to dehydropeptidase in the kidney, and can be used not as, an agent combined with a dehydropeptidase inhibitor such as cilastatin but as a single agent.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug, particularly a novel carbapenem derivative or a salt thereof which is useful as an antibacterial agent against methicillin-resistant Staphylococcus aureus (hereinafter abbreviated as MRSA).

[0002]

2. Description of the Related Art In recent years, due to the abuse of known antibiotics, MRSA showing a high degree of resistance to these antibiotics has appeared in the clinical field in great numbers. MRSA is considered to be one of the main causes of nosocomial infections and has become a serious social problem. Therefore, various compounds having an anti-MRSA action have been investigated. On the other hand, regarding the carbapenem compound, various studies have been conducted so far on its antibacterial action, but until now, no carbapenem compound having a remarkable effect on MRSA has been known. For example, imipenem [J.Med.Chem, 22 , 1435, (1979)], which is a carbapenem compound showing a wide range of antibacterial activity, was not sufficient in antibacterial activity against MRSA. Moreover, in general, carbapenem compounds are prone to decomposition inactivity by renal dehydropeptidase (hereinafter abbreviated as DHP-1) in vivo, and imipenem is also the same. Therefore, in order to prevent decomposition, DHP-1 is used.
Clinically used as a combination formulation of imipenem / cilastatin (IPM / CS) in combination with one of the inhibitors, cilastatin [Autimicrob Agents Chemother, 12
(Supp1D), 1, (1983)].

[0003]

At present, the creation of compounds having excellent antibacterial activity against MRSA is an important pharmaceutical problem. In order to solve the above problems, the present invention provides M
Has excellent antibacterial activity against RSA, and DH as a single agent
The object is to provide a carbapenem derivative stable to P-1.

[0004]

Against this background, the inventors of the present invention have conducted extensive studies and as a result, a novel carbapenem characterized by having a heterocycle at the 2-position of the penem ring via a substituted propenyl group. The inventors have found that the derivative has excellent antibacterial activity against MRSA and is stable to DHP-1 as a single agent, and completed the present invention. Further, the present inventors have found that the compound of the present invention has excellent antibacterial activity not only against MRSA but also against Gram-positive bacteria other than MRSA and Gram-negative bacteria such as Pseudomonas aeruginosa. That is, the present invention is a carbapenem derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical 2]

(The symbols in the formulas have the following meanings: R: hydrogen atom, negative charge or ester residue X: -S-, -O- or -NH-Y: O, NH or H ₂ )

The meaning of the symbols of the formula (I) will be further explained as follows.

In the formula (I), examples of the "ester residue" represented by R include an ester residue which is metabolized and hydrolyzed in vivo, or an ester residue which can be a protective group for a carboxyl group. Examples of the ester residue that is metabolized and hydrolyzed in vivo include a lower alkanoyloxy lower alkyl group, a lower alkenoyl lower alkyl group, a cycloalkylcarbonyloxy lower alkyl group,
Lower alkenoyloxy lower alkyl group, lower alkoxy lower alkanoyloxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower alkoxy lower alkoxycarbonyloxy lower alkyl group, benzoyl Commonly used oxy lower alkyl group, 2-oxotetrahydrofuran-5-yl group, 2-oxo-5-alkyl-1,3-dioxolen-4-ylmethyl group, tetrahydrofuranylcarbonyloxymethyl group, 3-phthalidyl group, etc. And the ester residue thereof. Examples of the ester residue that can be a protective group for a carboxyl group include a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a nitrobenzyl group, and a lower alkoxybenzhydryl group. In the above, the lower alkanoyl group has 2 to 6 carbon atoms, the lower alkyl group has 1 to 6 carbon atoms, the lower alkenoyl group has 2 to 6 carbon atoms, and the cycloalkyl group has 3 to 8 carbon atoms. , Especially those having 3 to 6 carbon atoms, having 1 carbon as an alkoxy group
Preferred examples include those having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, and the lower alkenyl group having 2 to 6 carbon atoms. Also, in the formula (I),

[0008]

[Chemical 3]

Preferred specific examples of the group represented by are:
Examples include the groups shown below.

[0010]

[Chemical 4]

The compound of the present invention comprises a cation having a hetero ring as a substituent at the 2-position and a carboxyl anion at the 3-position or a 3-position.
An intramolecular salt may be formed with the hydrogen atom substituted at the position [corresponding to the group R in the formula (I)]. For example, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, Mention may be made of acid addition salts with organic acids such as malic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid. When an ester residue is substituted at the 3-position [Formula (I)
Medium, corresponds to the group R], and may form an inner salt with anions. Examples thereof include halogen anions such as iodine anion and bromine anion, and sulfonate anions such as methyl sulfonate anion and aryl sulfonate anion. Since the compound of the present invention has an asymmetric carbon atom and a double bond, it has a plurality of isomers such as optical isomers, racemates, diastereomers, ketos, enols, cis and trans. The present invention includes separates or mixtures of these isomers. Furthermore, the compound of the present invention can take the state of its inner salt depending on the kind of the substituent. Preferred isomers in the carbapenem ring of the present invention are those having the configurations of 1R, 5S and 6S represented by the following formula. Furthermore, the compound of the present invention also includes a pharmaceutically acceptable hydrate, solvate or polymorphic substance thereof.

[0012]

[Chemical 5] (In the above formula, R, X and Y have the same meanings as described above.
The same applies below)

(Production Method) The production method of the compound of the present invention will be described below. First manufacturing method

[0014]

[Chemical 6] (In the formula, X and Y have the same meanings as described above, and R ¹ is
Diphenylphosphoryl group, lower alkylsulfonyl group,
R'the trihalogenomethyl Suho radicals are readily Z metal cation of the protecting group and M ⁺ a carboxyl group which may be removed, represents a halogen atom, lower alkylsulfonyloxy group or trihalogenomethyl sulfonyloxy group . The same applies hereinafter) Among the compounds of the present invention, the compound represented by the general formula (Ia) can be obtained by the process represented by the above reaction scheme. The first to fourth steps will be described below.

First Step The first step of this production method is a step of reacting the compound represented by the formula (II) with a phosphoric acid esterifying agent such as diphenylphosphoryl chloride or a sulfonic acid esterifying agent. The solvent used in this reaction may be ketones such as acetone and methyl ethyl ketone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, chloroform, acetonitrile or a mixed solvent thereof. In this reaction, a base can be added to accelerate the reaction. Examples of the salt in this case include organic bases such as triethylamine, diisopropylethylamine, DBU, N-methylmorpholine and quinuclidine, inorganic bases such as potassium hydroxide, sodium hydroxide and potassium carbonate, and metal alcoholates such as sodium methoxide. . The reaction temperature is set under cooling to room temperature, preferably under cooling.

Second Step Next, the obtained compound (III) is subjected to a substitution reaction with the compound represented by the general formula (IV). The compound (III) may be isolated once, or may be reacted with the compound (IV) without performing isolation after the reaction of the first step. As the solvent in this step, the solvent described in the first step is preferably used. Further, in this step, the reaction may be carried out in the presence of a base, and in this case, the base mentioned in the first step can be mentioned. Examples of the metal represented by M include lithium, potassium, sodium and silver. The compound (V) obtained in this step can be used as a raw material compound in the next step, but is a useful compound having antibacterial activity itself. Third step Further, in the third step, the compound (V) is reacted with i) a phosphoric acid esterifying agent or a sulfonic acid esterifying agent, and then in ii) i), a compound (V) is phosphoric esterifying agent. When is reacted, a halogen donor is reacted to give compound (VI). For the reaction with the phosphoric acid esterifying agent or the sulfonic acid esterifying agent, the method described in the first step is appropriately adopted. When it reacts with a phosphoric acid esterifying agent, it reacts with a halogenating agent such as potassium iodide or sodium iodide to give 2- (3-halogeno-
A compound having a 1-propenyl) thio group gives preferable results in the subsequent reactions.

Fourth Step The fourth step of this production method is a step of removing the protecting group by subjecting compound (VI) to a substitution reaction with various amine reagents. The substitution reaction with an amine reagent is carried out in a solvent inert to the reaction, such as tetrahydrofuran, acetonitrile, dioxane, dimethylsulfoxide, dimethylformamide, methylene chloride, dibrim, dimethoxyethane, etc., relative to the intermediate (VI) in a suitable amount or in a slight excess. It is carried out by reacting an amount of amine reagent.

Next, the removal of the protecting group is carried out in the case of having a p-nitrobenzyl group, a benzyl group, a benzhydryl group, etc.
Removal of these protecting groups can be carried out by subjecting compound (VI) to 1) reduction with zinc or iron, 2) liquid reduction or 3) catalytic reduction with palladium-carbon or palladium hydroxide-carbon. . The reduction method of 1) above is a compound
It can be carried out by adding (VI) to a buffer solution (an inert solvent is added if necessary), then adding a reaction-corresponding amount or an excess amount of zinc, and stirring under cooling or heating. Further, the reduction method of 3) can be carried out in the presence of a catalyst such as palladium-carbon or palladium hydroxide-carbon under cooling to room temperature. Second manufacturing method

[0019]

[Chemical 7]

This production method is a method in which the compound (VII) is reacted with the compound (VIII) and then the protecting group is removed. Compound
For the reaction with (VIII), the method used in the second step of the first production method is appropriately adopted, and the method used in the fourth step of the same method is also used for removing the protecting group. Third method

[0021]

[Chemical 8]

(In the formula, R ² means three phenyl groups, a lower alkyl group or a lower alkoxy group. The same applies hereinafter) Next, the compound (Ia) of the present invention or a salt thereof is a compound (IX) or a salt thereof. Is subjected to an intramolecular Wittig reaction, and then the protecting group is removed. Intramolecular Wi
The ttig reaction can be carried out in an inert solvent such as benzene or toluene under heating. In addition, the method described in the fourth step of the first production method is adopted for removing the protecting group. still,
The compound (IX) is converted to the compound (X).

[0023]

[Chemical 9] (In the formula, R ³ represents an active leaving group such as an ethoxycarbonyloxy group, an isobutyroxycarbonyloxy group, and a trimethylsilyloxy group. The same applies hereinafter.)

[0024]

[Chemical 10]

It can be obtained by reacting Isolation and purification of the target substance from the reaction solution obtained by the above first to third production methods are carried out by appropriately combining extraction with an organic solvent, chromatography, crystallization and the like.

[0026]

The compound of the present invention has excellent antibacterial activity against various Gram-positive bacteria and Gram-negative bacteria, especially against Gram-positive bacteria including MRSA. Further, the compound of the present invention is a dehydrogenase dehydropeptidase (DHP-1) in the kidney.
It is stable and has a good pharmacokinetic profile without being combined with a DHP-1 inhibitor such as cilastatin and can be a clinically useful antibacterial agent as a single agent. The antibacterial activity (MIC) of the compound of the present invention against MRSA was measured by the agar plate dilution method using the Mueller Hinton-Agar medium conventionally used for this purpose. Imipenem / cilastatin (IPM / CS) was also set as a control.
The measurement results are shown in Table 1 below.

[0027]

[Table 1]

A preparation containing one or more compounds represented by the general formula (I) as an active ingredient is prepared by using a carrier, an excipient and other additives usually used for preparation. It The carrier or excipient for the preparation may be either solid or liquid, for example lactose, magnesium stearate, starch, talc, gelatin, agar, pectin,
Examples include gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and other commonly used substances.

For administration, tablets, pills, capsules, granules,
It may be in any form of oral administration such as powder and liquid, or parenteral administration such as injection such as intravenous injection and intramuscular injection, suppository and transdermal preparation. The dose is appropriately determined according to each case in consideration of symptoms, age of the subject, sex and the like.

[0030]

EXAMPLES The compounds of the present invention and the method for producing the same have been described above. The compounds of the present invention will be described in more detail below with reference to Examples. The method for producing the starting material compound of the compound of the present invention will be described as a reference example. Reference example 1

[0031]

[Chemical 11]

1) (4R) -2-diazo-4-[(2
R, 3S) -3-((1R) -1-hydroxyethyl)
5.0 g of para-nitrobenzyl-4-oxoazetidin-2-yl] -3-oxopentanoate 55 ml of toluene
In addition, rhodium (II) acetate at 95 ° C under argon flow
After adding 2 mg of the dimer and stirring at the same temperature for 20 minutes, toluene was distilled off under reduced pressure. Obtained crude para-nitrobenzyl (1R, 3R, 5R, 6S) -6-[(1R) -1-
Hydroxyethyl] -1-methyl-2-oxocarbapenamu-3-carboxylate with acetonitrile 100 m
Then, 1.35 ml of diisopropylethylamine and 2.80 ml of diphenylphosphoric acid chloride were added at -5 ° C under an argon stream, and the mixture was stirred at -5 ° C for 2 hours.

2) (Z) -3- (triphenylmethylthio) allyl alcohol 7.70 g, tetrahydrofuran 100 ml, methanol 250 ml and pyridine 2.1.
silver nitrate dissolved in 10 ml of water.
2 g was gradually added and stirred at room temperature for 90 minutes. The deposited precipitate was collected by filtration and dried under reduced pressure, and then 220 m of acetonitrile
1 and 6.84 g of lithium iodide were added and stirred for 30 minutes. 3) The solution obtained in 2) was mixed with the solution obtained in 1) at 0 ° C, and then stirred at 10 ° C for 90 minutes. Ethyl acetate and cold phosphate buffer of pH 7.0 were added to the residue obtained by distilling off the solvent, and the ethyl acetate layer was washed with water and dried over magnesium sulfate.

The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel chromatography and eluted with chloroform-methanol (10: 1) to give para-nitrobenzyl (1
R, 5S, 6S) -6-[(1R) -1-Hydroxyethyl] -1-methyl-2-[(Z) -3-hydroxy-
1-propen-1-yl] thiocarbapene-2-em-
3.38 g of 3-carboxylate was obtained.

Physicochemical properties NMR (CDCl ₃ , δppm); 1.24 (3H,
d), 1.34 (3H, d), 3.32 (1H, d
d), 3.6 (1H, m), 4.2-4.4 (4H,
m), 5.40 (2H, ABq.), 5.92-6.4.
4 (2H, d), 7.64 (2H, d), 8.20 (2
H, d)

Reference Example 2

[0037]

[Chemical 12]

1) Paranitrobenzyl (1R, 5S,
6S) -6-[(1R) -1-hydroxyethyl] -1
-Methyl-2-[(Z) -3-hydroxy-1-propen-1-yl] thiocarbapene-2-em-3-carboxylate in 326 mg of dichloromethane in 6 ml of dichloromethane,
4-Dimethylaminopyridine 0.10 g and diphenylphosphoric acid chloride 0.165 at −40 ° C. under argon flow.
ml was added, and the mixture was stirred at -20 ° C for 1 hr.

After the reaction, 50 ml of dichloromethane was added, and the mixture was washed with cold water, cold sodium hydrogen carbonate aqueous solution, cold 0.5N hydrochloric acid water and cold water in this order, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and paranitrobenzyl (1R, 5S, 6S) -6-[(1R)-
1-hydroxyethyl] -1-methyl-2-[(Z)-
3-diphenylphosphoryloxy-1-propene-1-
Ill] thiocarbapene-2-em-3-carboxylate (458 mg) was obtained. Physicochemical properties IR (KBr): 1770 cm ^-1 Example 1 1)

[0040]

[Chemical 13]

Paranitrobenzyl (1R, 5S, 6S) -2-[(Z) -3-diphenylphosphoryloxy-1-propenyl] thio-6-obtained in Reference Example 2.
[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate (599 mg) was dissolved in acetonitrile (12 ml), and sodium iodide (16) was added.
After adding 2 mg and stirring at room temperature for 50 minutes, the precipitated insoluble matter was filtered. 3,4-dihydro-2 was added to the resulting solution.
H-pyrido [4,3-b] -1,4-thiazine 165m
g and stirred at room temperature for 5 hours. 80 ml of ether was added and the deposited precipitate was collected by filtration, dried under reduced pressure and dissolved in 200 ml of 25% acetonitrile aqueous solution.
Adsorb to P-20, elute with water, 20% acetonitrile water, then 40% acetonitrile water, collect the target fractions, concentrate under reduced pressure, and lyophilize to para-nitrobenzyl (1R, 5S, 6S)- 2-[[((Z) -3- (3,
4-dihydro-2H-pyrido [4,3-b] -1,4-
Thiazine-6-io) -1-propenyl] thio] -6-
[(R) -1-hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate iodide 20
5 mg was obtained. Physicochemical properties MS: 569 (M ⁺ ) 2)

[0042]

[Chemical 14]

200 mg of the compound obtained in 1) was added with 10 ml of tetrahydrofuran, 10 ml of 0.35 M phosphate buffer having a pH of 6.1 and 800 mg of zinc dust, and the mixture was allowed to stand at room temperature for 7 minutes.
Stir for 0 minutes. 100 ml of water to the Celite filtered solution
After washing with 50 ml of ethyl acetate, the aqueous layer is subjected to Amberlite IR120B resin column chromatography and eluted with 150 ml of water. The solution was concentrated to 100 ml under reduced pressure and adsorbed on Diaion HP-20.
Elute with water, 10% aqueous acetonitrile, then 15% aqueous acetonitrile, collect the target fractions, concentrate under reduced pressure, and lyophilize to give (1R, 5S, 6S) -2-[[(Z)-
3- (3,4-dihydro-2H-pyrido [4,3-b]
-1,4-thiazine-6-io) -1-propenyl] thio] -6-[(R) -1-hydroxyethyl) -1-methylcarbapene-2-em-3-carboxylate 48
mg was obtained. Physicochemical properties NMR (DMSO-d ₆ , δppm); 1.02 (3
H, d), 1.14 (3H, d), 3.12 (1H, d
d), 3.18 (1H, t), 3.32 (2H, m),
3.57 (2H, t), 3.91 (1H, t), 4.0
4 (1H, dd), 5.02 (2H, d), 5.87
(1H, q), 6.85 (1H, d), 7.59 (1
H, d), 7.86 (1H, d), 8.20 (1H,
s) MS: 434 (M ⁺⁺ 1) Example 2

[0044]

[Chemical 15]

In the same manner as in Example 1, (1R, 5S, 6
S) -2-[[(Z) -3- (3,4-dihydro-2H
-Pyrido [4,3-b] -1,4-oxazine-6-io) -1-propenyl] thio] -6- (R) -1-hydroxyethyl) -1-methylcarbapene-2-em- Three
-The carboxylate was obtained. Physicochemical properties NMR (DMSO-d ₆ , δppm); 1.00 (3
H, d), 1.14 (3H, d), 3.11 (1H,
d), 3.33 (1H, t), 3.40 (2H, t),
3.91 (1H, t), 4.03 (1H, dd), 4.
42 (2H, t), 5.03 (2H, d), 5.87
(1H, q), 6.85 (1H, d), 8.02 (1
H, d), 8.04 (1H, d), 8.29 (1H,
s) MS: 418 (M ⁺ +1) Example 3

[0046]

[Chemical 16] In the same way as in Example 1, (1R, 5S, 6S) -2-
[[Z] -3- (3,4-dihydro-2H-pyrido [4,3-b] -3-oxo-1,4-thiazine-6-
Io) -1-propenyl] thio] -6-[(R) -1-
Hydroxyethyl) -1-methylcarbapene-2-em-3-carboxylate was obtained. Physicochemical properties NMR (DMSO-d ₆ , δppm); 1.03 (3
H, dd), 1.15 (3H, d), 3.11 (1H,
m), 3.17 (1H, t), 3.74 (1H, d
d), 3.92 (2H, s), 4.06 (1H, m),
5.08 (1H, d), 5.17 (1H, d), 5.0
9 (1H, q), 6.89 (1H, d), 8.05 (1
H, d), 8.40 (1H, d), 8.68 (1H,
s) MS: 448 (M ⁺ +1)

The following are other compounds (1) to (6) of the present invention.
The chemical name of is posted. These compounds can be easily produced by using the same methods as those described in the above-mentioned Examples and production methods or their modified methods. (1) (1R, 5S, 6S) -2-[(Z)-[3-
(3,4-dihydro-3-oxo-2H-pyrido [4,
3-b] -1,4-Oxazine-6-io) -1-propenyl] thio] -6-((R) -1-hydroxyethyl) -1-methylcarbapene-2-em-3-carboxylate (2) (1R, 5S, 6S) -2-[(Z)-[3-
(3,4-dihydro-3-imino-2H-pyrido [4,
3-b] -1,4-thiazine-6-io) -1-propenyl] thio] -6-((R) -1-hydroxyethyl)
-1-Methylcarbapene-2-em-3-carboxylate (3) (1R, 5S, 6S) -2-[(Z)-[3-
(3,4-dihydro-3-imino-2H-pyrido [4,
3-b] -1,4-Oxazine-6-io) -1-propenyl] thio] -6-((R) -1-hydroxyethyl) -1-methylcarbapene-2-em-3-carboxylate (4) (1R, 5S, 6S) -6-((R) -1-hydroxyethyl) -1-methyl-2-[(Z)-[3-
(1,2,3,4-tetrahydro-pyrido [4,3-
b] -pyrazine-6-io) -1-propenyl] thio]
Carbapen-2-em-3-carboxylate (5) (1R, 5S, 6S) -6-((R) -1-hydroxyethyl) -2-[(Z)-[3- (3-imino-
1,2,3,4-tetrahydro-pyrido [4,3-b]
-Pyrazine-6-io) -1-propenyl] thio] -1
-Methylcarbapene-2-em-3-carboxylate (6) (1R, 5S, 6S) -6-((R) -1-hydroxyethyl) -1-methyl-2-[(Z)-[3 −
(3-oxo-1,2,3,4-tetrahydro-pyrido [4,3-b] pyrazine-6-io) -1-propenyl] thio] carbapene-2-em-3-carboxylate

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Masaki Yokota 2-5-9 Rumi Tsukuba, Ninomiya, Tsukuba, Ibaraki 315 (72) Inventor Tomio Shinki 2-5-9 Ninomiya, Tsukuba, Ibaraki 316, Rumi Tsukuba (72) Inventor Takeshi Murakami 3-13-1 Ninomiya, Tsukuba City, Ibaraki Prefecture Noumiya 422 (72) Inventor Chieko Nohara 3-24-6 Ninomiya, Tsukuba City, Ibaraki Prefecture No. 202 Heights Lilac 202

Claims (1)

[Claims] 1. A compound represented by the following general formula (I) or a salt thereof. [Chemical 1] (Symbols in the formula have the following meanings R: a hydrogen atom, negative charge or an ester residue X: -S -, - O- or -NH- Y:. O, NH or H ₂₎