JP2002020393A - Sulfonic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new bioactive peptide modifier suppressing the in-vivo metabolism of a bioactive peptide such as a neurotropic factor derived from the brain by an enzyme, and maintaining the activity for a long time. SOLUTION: This new sulfonic acid derivative capable of improving the activity of the bioactive peptide is represented by formula (1) [wherein, A1 is an alkylene, an alkenylene or the like; R1 is an alkyl, an alkenyl, -A2-SO3H (A2 is an alkylene, an alkenylene or the like); and R2, R3 and R4 are each a lower alkyl or H].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel sulfonic acid derivative. More specifically, the present invention relates to a novel sulfonic acid derivative that improves the physiological activity of peptides useful as pharmaceuticals.

[0002]

2. Description of the Related Art Peptides having a physiological activity are useful as pharmaceuticals and are used in actual medical practice. However, the physiologically active peptide is easily metabolized by enzymes and the like in the living body, and does not last long in the living body. In order to solve this problem, various modifiers and sustained-release preparations have been developed. As a modifying agent for a physiologically active peptide, a PEGylation reagent having a polyethylene glycol chain, a lecithin reagent having a lecithin and the like have been developed. However, since all the reagents form a direct covalent bond with the bioactive peptide, there is a possibility that a change in the physiological action by changing the three-dimensional structure of the peptide may occur. In addition, it is not easy to control the number of introduced peptide modifying agents, and it is necessary to perform purification in order to apply as a pharmaceutical, and it is difficult to obtain a target modified peptide in high yield.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a reagent which can be added to or mixed with a physiologically active peptide without using a covalent bond to improve its activity.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and found that a novel sulfonic acid derivative differs from various agents which have been tried in the past without using a covalent bond. Forms a complex with the bioactive peptide,
Alternatively, it has been found that the physiological activity of the peptide is remarkably improved in a simple mixed form, and the present invention has been completed.

That is, the present invention provides a novel sulfonic acid derivative represented by the following embodiments, a complex thereof with a physiologically active peptide, and a pharmaceutical composition comprising the complex or a mixture of both compounds.

(1) Equation (1)

Embedded image (Wherein A ¹ is an alkylene group having 1 to 20 carbon atoms, an alkenylene group having 2 to 20 carbon atoms, or a compound represented by the formula (2)

Embedded image (Wherein m represents an integer of 1 to 3, n represents an integer of 1 to 5), and R ¹ is an alkyl group having 1 to 20 carbon atoms, and an alkyl group having 2 to 20 carbon atoms. Alkenyl group or formula (3)

Embedded image (Wherein A ² represents an alkylene group having 1 to 20 carbon atoms, an alkenylene group having 2 to 20 carbon atoms, or a compound represented by the formula (4)

Embedded image (Wherein, m 'represents an integer of 1 to 3, n' is an integer of 1 to 5) represents a group represented by represents) a group represented by, R ²
Represents an alkyl group having 1 to 3 carbon atoms or a hydrogen atom, R ³ represents an alkyl group having 1 to 3 carbon atoms or a hydrogen atom, and R ⁴ represents an alkyl group having 1 to 3 carbon atoms or a hydrogen atom. A sulfonic acid derivative or a salt thereof;

(2) R ¹ is a sulfonic acid derivative or a salt thereof according to the above (1), wherein R ¹ is an alkyl group having 1 to 20 carbon atoms; (3) A ¹ is an alkylene group having 1 to 20 carbon atoms. (4) The above-mentioned (1) or (2), wherein R ² , R ³ and R ⁴ are methyl.
Or (3) the sulfonic acid derivative or a salt thereof according to (3); (5) a complex of the sulfonic acid derivative or salt thereof according to (1), (2), (3) or (4) above and a physiologically active peptide; ) The complex according to the above (5), wherein the bioactive peptide is a neutral peptide or a basic peptide; (7) the conjugate according to the above (5), wherein the bioactive peptide is a basic peptide
(8) a pharmaceutical composition comprising the sulfonic acid derivative or a salt thereof according to the above (1), (2), (3) or (4) and a physiologically active peptide; (9) the sulfonic acid derivative or The pharmaceutical composition according to the above (8), wherein the salt thereof and the physiologically active peptide form the complex according to the above (5), (6) or (7). (10) The pharmaceutical composition according to (8), wherein the sulfonic acid derivative or a salt thereof and the physiologically active peptide are contained in the form of a powder mixture; (11) a mixed aqueous solution of the sulfonic acid derivative or a salt thereof and the physiologically active peptide (12) The pharmaceutical composition according to (8), wherein the sulfonic acid derivative or a salt thereof and a physiologically active peptide are in the form of a freeze-dried product.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the novel sulfonic acid derivative of the present invention, a complex with a physiologically active peptide, a production method thereof, and effects thereof will be described in detail.

The alkylene groups having 1 to 20 carbon atoms in A ¹ and A ² are the same or different and are straight-chain or branched alkylene groups, specifically, methylene, ethylene, trimethylene, tetramethylene. Methylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene, tridecamethylene, tetradecamethylene, pentadecamethylene, hexadecamethylene, heptadecamethylene, octadecamethylene, nonadecamethylene, Eicosamethylene and the like. Preferred are octamethylene, nonamethylene, decamethylene, undecamethylene, dodecamethylene and the like.

The alkenylene groups having 2 to 20 carbon atoms in A ¹ and A ² are the same or different and are straight-chain or branched alkenylene groups, and the same alkylene groups as described above (however, Above) containing 1 to 5 double bonds, specifically, cis or trans vinylene, cis or trans-1-propenylene, cis or trans-1-butenylene, cis or trans-2-. Butenylene, cis or trans-1-
Pentenylene, cis or trans-2-pentenylene, cis or trans-1-hexenylene, cis or trans-2-hexenylene, cis or trans-
Examples include 3-hexenylene, cis or trans-1-heptenylene, cis or trans-2-heptenylene, cis or trans-3-heptenylene, cis-4-dodecenylene, cis, cis-6,9-heptenedienylene and the like.

Examples of the alkyl group having 1 to 20 carbon atoms for R ¹ include linear or branched ones. Specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-
Nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, n-pentadecanyl, n-hexadecanyl, n-heptadecanyl, n-octadecanyl, n-nonadecanyl, n-eicosanil and the like. Preferably, n-
Pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n
-Dodecanyl, n-tridecanyl, n-tetradecanyl, n-pentadecanyl and the like.

As the alkenyl group having 2 to 20 carbon atoms for R ¹ , a straight-chain or branched alkenyl group can be mentioned, and 1 to 5 double alkenyl groups in the above-mentioned alkyl groups (provided that the number of carbon atoms is 2 or more) are included. Examples include a bond, specifically, vinyl,
Allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2
-Pentenyl, 3-pentenyl, 4-pentenyl, 1-
Hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 4-dodecenyl, 6,9- Heptedieninyl and the like.

The alkyl groups having 1 to 3 carbon atoms for R ² , R ³ and R ⁴ are the same or different and include, for example, methyl, ethyl, n-propyl, isopropyl and the like.

The physiologically active peptide to which the sulfonic acid derivative of the present invention is applied includes, for example, a neutral peptide or a basic peptide, and specifically, a brain-derived neurotrophic factor.
(Brain derived nerve growth factor), Erythropoietin, Thrombopoietin
tin), interferon-β (Interferon-β), neurotrophic factor (Nerve growth factor), neurotrophin-
3 (Neurotrophin-3), Neurotrophin-4 / 5 (Neu
rotrophin-4 / 5), urokinase type plasminogen activator, plasminogen, interleukin-6 (In
terleukin-6), Interleukin-10 (Interleukin-1)
0), Insulin-like growth factor-1
actor-1), Insulin-like gr
owth factor-2), leukemia inhibitory factor (Leukemia inhibitory
factor), Platelet-derived grow factor
thfactor), Vascular endothelial g
rowth factor), Bone morphog protein-1
enic protein-1), fibroblast growth factor-1 (Fibroblast
growth factor-1), fibroblast growth factor-2 (Fibrobla
st growth factor-2), Keratinocyte
growth factor; Fibroblast growth factor-7
growth factor-7)), epidermal cell growth factor-2 (Keratinocy
te growth factor-2; Fibroblast growth factor-10 (Fibro
blast growth factor-10)), betacellulin (Betacellu
lin), galanin, calcitonin gene-related peptide, cholecystokinin, pituitary adenylate cyclase activating polypeptide (Pituitary adenylate cyclase)
activating polypeptide), vasoactive intestinal peptide (Va
soactive intestinal peptide), gastric inhibitory polypeptide (G
astric inhibitory polypeptide). Preferred are, for example, basic peptides. Specific examples include brain-derived neurotrophic factor, erythropoietin, thrombopoietin, interferon-β, neurotrophic factor, neurotrophin-3, neurotrophin-4 / 5. Urokinase-type plasminogen activator, plasminogen, leukemia inhibitory factor, platelet-derived growth factor, vascular endothelial growth factor, bone morphogenetic protein-1,
Fibroblast growth factor-2, epidermal growth factor (fibroblast growth factor-7), epidermal growth factor-2 (fibroblast growth factor-10), betacellulin, galanin, calcitonin gene-related peptide, cholecyst Kinin, pituitary adenylate cyclase activating polypeptide, vasoactive intestinal peptide, and the like.

Production Method The compound of the present invention can be produced, for example, by a method represented by the following reaction scheme.

Embedded image (Wherein, R ¹ , R ² , R ³ , R ⁴ and A ¹ have the same meaning as described above. X represents bromine or iodine, and X ′ represents chlorine or bromine.)

First, a solution of the compound represented by the formula (11) in an organic solvent (for example, an alcohol solution such as methanol, ethanol, propanol, or 2-propanol) is mixed with a solution (for example, a metal halide (for example, cadmium chloride)). For example,
(Aqueous solution) to give a compound of formula (11) to its metal salt. The reaction temperature is selected from the range of about −10 ° C. to the boiling point of the solvent. The metal salt of the compound of the formula (11) is reacted with a compound of the formula (14) in an inert solvent in the presence of a base to obtain a compound of the formula (12). Examples of the inert solvent include halogenated hydrocarbon solvents such as methylene chloride, chloroform, and dichloroethane.
Examples of the base include amines such as triethylamine, and pyridines such as pyridine and 4-dimethylaminopyridine. The reaction temperature is selected from the range of about −10 ° C. to the boiling point of the solvent.

Subsequently, the compound represented by the formula (1) is obtained by reacting the compound represented by the formula (12) with sodium sulfite in a solvent. As the solvent, for example,
Examples include water, alcohol solvents such as methanol, ethanol, propanol and 2-propanol, and mixed solvents thereof. The reaction temperature is selected from the range of about −10 ° C. to the boiling point of the solvent.

The compound (14) to be reacted with the starting compound (11) is obtained by converting a commercially available carboxylic acid compound of the formula (13) into a halogenated compound such as thionyl chloride, phosphorus pentachloride, thionyl bromide, boron tribromide and the like. Obtained by halogenation with an agent. Although a halogenating agent can be used as a solvent, it can be reacted in an inert solvent if necessary. Examples of the inert solvent include halogenated hydrocarbon solvents such as methylene chloride, chloroform, and dichloroethane.

Compound (1) of the present invention obtained by the above method
Alternatively, an intermediate for producing the same can be purified by a usual method. For example, column chromatography,
It can be purified by recrystallization or the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as toluene; and ketones such as acetone. Solvent, a hydrocarbon solvent such as hexane, etc., or a mixed solvent thereof.

When the above reaction is carried out, if necessary, a functional group such as a hydroxyl group or a carboxyl group contained in the compound may be protected with a usual protecting group, followed by deprotection after the reaction. These protection and deprotection technologies are described in Green et al. (TW Greene and P. GM Wuts, "Protect
ing Groups in Organic Synthesis ", 1991, JOHN WILEY
& SONS, INC.) And are performed according to those methods.

The sulfonic acid derivative of the present invention or a pharmaceutically acceptable salt thereof may form a solvate such as a hydrate, and the present invention also includes these.

The compounds of the present invention have an asymmetric carbon and exist in optical isomers and geometric isomers. The compounds of the present invention include mixtures of these isomers and isolated ones. As a method for obtaining such an optical isomer purely, for example, optical resolution can be mentioned.

In the optical resolution method, the compound of the present invention or an intermediate thereof is dissolved in an inert solvent (for example, an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as diethyl ether, or an ester solvent such as ethyl acetate). Solvents, aromatic hydrocarbon solvents such as toluene, acetonitrile and the like and mixed solvents thereof), optically active amines (e.g., α-phenethylamine, quinine, quinidine,
Salts with organic amines such as cinchonidine, cinchonine, strychnine, etc.).

The temperature at which the salt is formed may be in the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. Before the precipitated salt is collected by filtration, the salt can be cooled, if necessary, to improve the yield. The amount of the optically active amine to be used is in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, relative to the substrate. If necessary crystals in an inert solvent (e.g., methanol, ethanol, alcohol solvents such as 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, Recrystallization with acetonitrile or the like and a mixed solvent thereof) to obtain a high-purity optically active salt. If necessary, the obtained salt can be treated with an acid or a base by a usual method to obtain a free form.

The sulfonic acid derivative of the present invention can be converted to a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include base addition salts. Examples of base addition salts include inorganic base salts such as sodium salt and calcium salt, and organic base salts such as meglumine salt and trishydroxymethylaminomethane salt. The present invention also includes solvates such as hydrates of the sulfonic acid derivative or a pharmaceutically acceptable salt thereof.

The sulfonic acid derivative of the present invention has an effect of improving the physiological activity of a physiologically active peptide when applied to the peptide. To that end, the peptide is usually treated with the sulfonic acid derivative of the present invention to form a complex as described below. That is, a complex is formed by mixing the sulfonic acid derivative of the present invention with a physiologically active peptide in a buffer such as water or a phosphate buffer.
The number of moles of the sulfonic acid derivative with respect to the physiologically active peptide depends on the nature of the physiologically active peptide.
The molar ratio is, for example, a molar ratio of 00 times, specifically, a molar ratio of about 5 times to about 100 times.

As described above, the sulfonic acid derivative of the present invention can be formed into a complex with a physiologically active peptide. In another embodiment, the sulfonic acid derivative is used as a solid with the physiologically active peptide. And can be formulated in the form of a solution prepared by dissolving them in distilled water, physiological saline or the like. Furthermore, an aqueous solution of both compounds may be freeze-dried by a conventional method and used as a freeze-dried product.

The complex, mixture or solution of the sulfonic acid derivative and the physiologically active peptide of the present invention or a freeze-dried product thereof is converted into a pharmaceutical composition by a conventional method using a pharmaceutically acceptable non-toxic carrier. be able to. Examples of such a pharmaceutical composition include tablets, capsules, granules, fine granules, powders, preparations for oral administration such as pills, injections, creams, preparations for parenteral administration such as suppositories, and the like. Can be a preparation for nasal administration.

These pharmaceutical compositions are prepared according to a conventional method using pharmacologically acceptable pharmaceutical carriers, diluents and the like, and include, for example, Remington's Pharmaceutical Sciences (Mac Publishing Company, Easton, PA, 1970
) Can be prepared by any of the methods well known in the pharmaceutical arts, as described in

As a preferable preparation for oral administration, a sulfonic acid derivative of the present invention and a neurotrophic factor or a salt thereof, which is one of physiologically active peptides, are microencapsulated together with lecithin, cholesterol and free fatty acid, and gelatin is obtained. Formulations in which a neurotrophic factor or a salt thereof is encapsulated in an enteric capsule, and the like, such as a formulation encapsulated in a capsule and the like. The formulation may contain, for example, absorption enhancers, stabilizers, surfactants and the like.

When prepared for parenteral administration (subcutaneous injection, intramuscular injection or intravenous injection), a solution form or suspension form is particularly preferable, and for vaginal or rectal administration, cream or suppository is particularly preferable. Such a semi-solid dosage form is preferable, and for nasal administration, a powder, a nasal drop, or an aerosol dosage form is particularly preferable.

The injectable preparation may contain, as a pharmaceutical carrier, plasma-derived proteins such as albumin, amino acids such as glycine, and sugars such as mannitol. When used in the form of an injection, a buffer, a solubilizing agent, an isotonic agent and the like can be further added. When used as a water-soluble preparation or a lyophilized preparation, it is preferable to add a surfactant such as Tween 80 (registered trademark) or Tween 20 (registered trademark) to prevent aggregation. Parenteral administration forms other than those for injection may contain distilled water or physiological saline, polyalkylene glycol such as polyethylene glycol, oil of plant origin, hydrogenated naphthalene, and the like. Preparations for vaginal or rectal administration, for example suppositories, contain as common excipients, for example, polyalkylene glycols, petrolatum, cocoa oil and the like. Vaginal preparations may contain absorption enhancers such as bile salts, ethylenediamine salts and citrate. Formulations for inhalation may be solid, may contain, for example, lactose as an excipient, and nasal drops may be a water or oil solution.

[0033] The pharmaceutical composition of the present invention can also be administered in a single dose form. Dosage forms in which a single dose is intended to provide a subject with a compound of the present invention for an extended period of time, e.g., one week to one year, are particularly desirable. Various sustained release, depot or implant dosage forms may be used for that purpose. For example, the dosage form may contain a sulfonic acid derivative of the invention and a pharmaceutically acceptable salt of a neurotrophic factor as such or with low solubility in body fluids. Examples of such salts include (1): acid additions such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene mono- or disulfonic acid, polygalacturonic acid, etc. Salt, (2): a salt or complex with a polyvalent metal cation such as zinc, calcium, bismuth, barium, nickel or a combination of (1) and (2), for example, a zinc tannate salt and the like. The neurotrophic factor is preferably converted to a poorly water-soluble salt, which may be combined with a gel, for example, an aluminum monostearate gel, with sesame oil or the like to provide a suitable injection. Particularly preferred salts in this case are zinc salts, zinc tannate salts, pamoate salts and the like. Another dosage form of sustained-release preparation for injection contains neurotrophic factor,
Preferably, it is converted to a poorly water-soluble salt, which is encapsulated in a slowly disintegrating non-toxic, non-antigenic polymer such as a polylactic acid / polyglycolic acid polymer or a copolymer thereof. . Particularly preferred salts in this case are zinc salts, zinc tannate salts, pamoate salts and the like. In addition, it is possible to encapsulate a neurotrophic factor or a poorly water-soluble salt thereof in a cholesterol matrix or a collagen matrix to form a sustained-release preparation.

The number of moles of the sulfonic acid derivative relative to the physiologically active peptide in the pharmaceutical composition of the present invention varies depending on the kind of the physiologically active peptide, but is usually in the range of equimolar to about 500-fold molar, preferably about 500-fold. It is in the range of 5 moles to about 100 moles.

The complex, mixture or solution of the sulfonic acid derivative of the present invention and the physiologically active peptide or the lyophilized product thereof can be administered orally or parenterally, but is preferably administered parenterally. Another preferred method of administration is intranasal. Precise dosages and dosing regimens are determined by the required amount, treatment method, disease or degree of need for each bioactive peptide and individual subject to be treated, and are usually made according to the judgment of a physician. The dosage and number of administrations for parenteral administration vary depending on symptoms, age, body weight, dosage form and the like. For example, when administered subcutaneously or intravenously as an injection, the weight of an adult patient is 1 kg, about 1 day per day. The dose is selected from the range of from about to about 2500 μg (weight of the bioactive peptide, the same applies hereinafter), preferably from about 10 to about 500 μg, more preferably from about 20 to about 200 μg, for example, administered to the trachea as a spray. If so, the weight of an adult patient is 1 kg, in the range of about 1 μg to about 2500 μg per day, preferably about 10 to about 500 μg.
And more preferably in the range of about 20 to about 200 μg. Dosage regimens include daily administration or intermittent administration or a combination thereof. The dose and the number of times of oral administration vary depending on symptoms, age, body weight, administration form and the like. For example, for example, the body weight of an adult patient is 1 kg, the range of about 5 to about 2500 μg per day, preferably about 1 to about 2500 μg.
The dose is selected from the range of 0 to about 1000 μg.

[0036]

Examples The production examples of the sulfonic acid derivative of the present invention and the effect of improving the activity of the physiologically active peptide thereof will be shown more specifically with reference to examples and experimental examples, but the present invention is not limited thereto. Example 1 Synthesis of 1-palmitoyl-2- (11-sulfoundecanoyl) -glycero-3-phosphorylcholine sodium salt (1) 1-palmitoyl-2- (11-bromoundecanoyl) -glycero-3- Phosphorylcholine (1-Palmitoyl-
2- (11-bromoundecanoyl) -glycero-3-phosphorylcholin
Synthesis of e):

Embedded image

After dissolving 1.16 g of cadmium chloride 2.5 hydrate in 0.8 ml of water, 12.8 ml of ethanol was added, and the mixture was further stirred with 0.1 ml of La-lysolecithin palmitoyl.
15.2 ml of an 80 g ethanol solution were added. Stirring was continued for 1.5 hours under ice cooling, filtered, and washed sequentially with ethanol and diethyl ether. The filtrate was dried under reduced pressure to obtain "cadmium chloride adduct". 2.14 g of 11-bromoundecanoic acid was dissolved in 5.88 ml of thionyl chloride and stirred at room temperature for 1 hour. After thionyl chloride was distilled off under reduced pressure, "cadmium chloride adduct" was added to the solution obtained by adding 20 ml of chloroform, and 24 ml of a chloroform solution of 3.92 ml of pyridine was added dropwise over 20 minutes. After stirring for 2 hours as it was, the insolubles were filtered off and washed with chloroform. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column (80 g, chloroform-methanol-
Purified with water = 65: 25: 4) to give 1-palmitoyl-
0.3346 g (28%) of 2- (11-bromoundecanoyl) -glycero-3-phosphorylcholine was obtained. _{^{1 H-NMR (CDCl 3,}} 300MHz) δ0.88 (3H, t, J = 6.8Hz), 1.28-1.2
5 (40H, m), 1.42-1.37 (2H, m), 1.89-1.80 (2H, m), 2.32-
2.24 (4H, m), 3.34 (9H, s), 3.40 (2H, t, J = 7.0Hz), 3.77 (2
H, brs), 3.93-3.85 (2H, m), 4.15-4.08 (1H, m), 4.40-4.3
7 (1H, m), 5.19-5.18 (1H, m)

(2) 1-palmitoyl-2- (11-sulfoundecanoyl) -glycero-3-phosphorylcholine sodium salt (1-Palmitoyl-2- (11-sulfoundecanoyl)-
Synthesis of glycero-3-phosphorylcholine sodium salt):

Embedded image 1-palmitoyl-2- (11-bromoundecanoyl)
0.334 g of glycero-3-phosphorylcholine and 0.567 g of sodium sulfite in 6 ml of water and 2 m of ethanol
and heated under reflux for 5 hours. After concentrating the solvent, LC
/ MS using MS / MS, lyophilization, and 1-palmitoyl-2- (11-sulfoundecanoyl) -glycero-3.
0.142 g of phosphorylcholine sodium salt (30
%). ^{1 H-NMR (DMSO-d} 6, 300MHz) δ0.84 (3H, t, J = 7.0Hz), 1.22 (4
2H, brs), 2.42-2.23 (6H, m), 3.12 (9H, s), 3.61-3.57 (2
H, m), 3.97-3.96 (2H, m), 4.24-4.11 (4H, m), 5.13 (1H, br
s)

Example 2 1-Caproyl-2- (11-
Sulfoundecanoyl) -glycero-3-phosphorylcholine sodium salt (1-Caproyl-2- (11-sulfoundecanoy)
l) Synthesis of -glycero-3-phosphorylcholine sodium salt):

Embedded image La instead of La-lysolecithin palmitoyl
Synthesis was carried out in the same manner as in Example 1 using -lysolecithin caproyl to obtain 20.0 mg of 1-caproyl-2- (11-sulfoundecanoyl) -glycero-3-phosphorylcholine sodium salt. ^{1 H-NMR (DMSO-d} 6, 300MHz) δ0.84 (3H, t, J = 6.8Hz), 1.23 (2
2H, brs), 2.37-2.22 (6H, m), 3.11 (9H, s), 3.60-3.57 (2
H, m), 3.97-3.92 (2H, m), 4.28-4.01 (4H, m), 5.12 (1H, br
s)

Test Example 1 1-palmitoyl-2- (11-sulfoundecanoyl)
-Glycero-3-phosphorylcholine sodium salt (compound of Example 1) was used to prepare the bioactive peptide BDNF.
The effect activation effect on was tested. B for preparation of administration solution
DNF stock solution (23.2 mg / ml, dissolved in phosphate buffered saline) and compound stock solution of Example 1 (50 mg / ml,
(Dissolved in phosphate buffered saline). The BDNF dosing solution was prepared by using a BDNF stock solution at 1.25 mg / PBS using PBS.
It was used after being diluted to ml. The compound administration solution of Example 1 was
The compound stock solution of Example 1 was used after being diluted to 7.09 mg / ml with PBS. BDNF + the compound administration solution of Example 1 was prepared by diluting the BDNF stock solution to 2.5 mg / ml with PBS, and adding the compound stock solution of Example 1 with PBS.
A solution diluted to 4.18 mg / ml was prepared by mixing equal volumes.

9 week old C57BL / KsJ-db / db
Mice were dosed with BDNF and the compound of Example 1 via the tail vein. A phosphate buffered saline was administered to the vehicle administration group,
The brain-derived neurotrophic factor (hereinafter abbreviated as BDNF) solution administration group was administered with BDNF at 5 mg / kg (BDNF group).
BDNF was administered to the mixed solution administration group of BDNF and the compound of Example 1.
NF 5 mg / kg, compound of Example 1 28.4 mg
/ Kg of the mixed solution was administered (BDNF + Compound 1 group).
The compound of Example 1 was added to the group to which the compound solution of Example 1 was administered.
It was administered at 8.4 mg / kg (Compound 1 group). 0 administration
The test was performed once on the day and the seventh day. 0, 1, 3,
On days 7, 8, 10, and 14, a small amount of blood was collected from the tail vein, and the blood glucose level was measured by the mutarotase / glucose oxidase method. The area under the curve of the blood glucose level calculated from the blood glucose level on day 0 and the number of days for each individual was determined and used as an index of the blood glucose lowering effect. The results are shown in FIG. ** in the figure
Is the BDNF group and B in Student's t-test.
This indicates that a significant difference was observed between the DNF + compound 1 group (P <0.01). From the above results, Compound 1 was found to be BDN
F was shown to significantly enhance the hypoglycemic effect of F.

Test Example 2 1-Caproyl-2- (11-sulfoundecanoyl)-
Using glycero-3-phosphorylcholine sodium salt (the compound of Example 2), the effect of activating BDNF was tested. For the preparation of the administration solution, BDNF stock solution (23.2 mg /
ml, dissolved in phosphate buffered saline) and the stock solution of the compound of Example 2 (5 mg / ml, dissolved in phosphate buffered saline). For the BDNF administration solution, use BDNF stock solution as P
0.5mg / ml or 2.5mg / ml using BS
Used for dilution. The compound administration solution of Example 2 was used by diluting the compound stock solution of Example 2 to 0.58 mg / ml with PBS. BDNF + the compound administration solution of Example 2 was:
The BDNF stock solution was diluted to 1.0 mg / ml with PBS, and the compound stock solution of Example 1 was diluted to 1.16 with PBS.
A solution diluted to mg / ml was prepared by mixing equal volumes.

7 week old C57BL / KsJ-db / db
Mice were dosed with BDNF and the compound of Example 2 via the tail vein. Phosphate buffered saline was administered to the vehicle administration group.
(Solvent group) and the BDNF solution administration group were administered with BDNF at 2 and 10 mg / kg (BDNF 2 mg / kg group and BDNF 10 mg / kg group). In the group to which a mixed solution of BDNF and the compound of Example 2 was administered, BDNF was added at 2 mg / k.
g, the compound of Example 2 was administered at 2.3 mg / kg.
(BDNF 2 mg / kg + Compound 2 group). 2.3 mg / kg of the compound of Example 2 was administered to the compound solution administration group of Example 2.
(Compound 2 group). The administration was performed once on day 0 and on day 7. 0, 1, 3, 7, 8, 11, 14
On the day, a small amount of blood was collected from the tail vein, and the blood sugar level was measured by the mutarotase / glucose oxidase method. The area under the curve of the blood glucose level calculated from the blood glucose level on day 0 and the number of days for each individual was determined and used as an index of the blood glucose lowering effect. The results are shown in FIG. In the figure, ** indicates the BDNF 2 mg / kg group and BDNF in the Student's t-test.
It indicates that a significant difference was observed between 2 mg / kg + Compound 2 groups (P <0.01). BDNF10mg / kg
No significant difference was observed between the group and the BDNF 2 mg / kg + 2 group. From the above results, Compound 2 was found to be BDNF
Has been shown to significantly enhance the hypoglycemic effect of.

[0044]

EFFECT OF THE INVENTION The sulfonic acid derivative of the present invention does not bind to a physiologically active peptide such as a brain-derived neurotrophic factor or the like without a covalent bond such as a conventionally known modifying agent such as a PEGylating agent or a lecithinating agent. Simply forming or mixing a complex suppresses enzymatic metabolism of the peptide in vivo,
It has the effect of improving its bioactivity, and by using a complex or mixture with the bioactive peptide, it is possible to exhibit a sustainedly high bioactivity while keeping the dose of the bioactive peptide low, resulting in side effects. And an economically advantageous peptide-containing pharmaceutical composition is provided.

[Brief description of the drawings]

FIG. 1 shows the hypoglycemic effect of administration of the compound of Example 1 and BDNF.

FIG. 2 shows the hypoglycemic effect of administration of the compound of Example 2 and BDNF.

Claims (3)

[Claims] (1) Formula (1) (Wherein A ¹ represents an alkylene group having 1 to 20 carbon atoms, an alkenylene group having 2 to 20 carbon atoms, or a compound represented by the formula (2): (Wherein m represents an integer of 1 to 3, n represents an integer of 1 to 5), and R ¹ is an alkyl group having 1 to 20 carbon atoms, and an alkyl group having 2 to 20 carbon atoms. An alkenyl group or a compound of formula (3) (Wherein A ² represents an alkylene group having 1 to 20 carbon atoms, an alkenylene group having 2 to 20 carbon atoms, or a compound represented by the formula (4): (Wherein, m ′ represents an integer of 1 to 3, n ′ represents an integer of 1 to 5), and R ² represents a group having 1 to 3 carbon atoms. R ³ represents an alkyl group having 1 to 3 carbon atoms or a hydrogen atom, and R ⁴ represents an alkyl group having 1 to 3 carbon atoms or a hydrogen atom. Or its salt. 2. The sulfonic acid derivative or a salt thereof according to claim 1, wherein R ¹ is an alkyl group having 1 to 20 carbon atoms. 3. The sulfonic acid derivative or a salt thereof according to claim 1, wherein A ¹ is an alkylene group having 1 to 20 carbon atoms.