JPH03240762A - Sustained-release polymer compound - Google Patents

Abstract

NEW MATERIAL:The monomer containing 5-aminosalicylic acid group and expressed by formula I [R1 is H or alkyl; R2 is group of formula ll (X is halogen; n is 1-5) or formula III (R3 is H or lower alkyl)]. EXAMPLE:5-(Methacryloyl)amidosalicylic acid. USE:Useful as a remedy for inflammatory intestinal diseases. It can be used e.g. for the remedy of inflammatory intestinal diseases such as ulcerative colitis and Crohn's disease. It has sustained-release action and is free from side effect. It can be administered by oral administration. PREPARATION:The objective compound of formula I can be produced according to the reaction formula by reacting 1-3 pts. of the compound of formula IV or formula V with 1 pt. of 5-aminosalicylic acid or 5-aminosalicylic acid ester in an organic solvent at room temperature to 150 deg.C. The compound of formula I can be polymerized in the form of a homopolymer or a copolymer with other copolymerizable monomers.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a 5-aminosalicylic acid group-containing monomer and a polymeric compound having a sustained release action of 5-aminosalicylic acid obtained by using the monomer as at least one heptamer component. More specifically, polymerizable compounds having a 5-aminosalicylic acid residue, which is the pharmacologically active moiety of salazosulfapyridine, which is frequently used in the treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. The present invention relates to a polymer compound obtained by polymerizing at least one monomer component.

The 5-aminosalicylic acid group-containing monomer and its polymer compound of the present invention can be applied, for example, to a new drug that releases 5-aminosalicylic acid in a sustained manner.

Prior Art and Problems Salazosulfaviridine is frequently used to treat inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Salazosulfaviridine has side effects such as rash, nausea, vomiting, loss of appetite, and dizziness, so while suppressing these side effects,
In order to increase the therapeutic effect, we try to reduce the dose as much as possible.

However, in addition to side effects, Salazosulf 7-pyridine has problems with its sustained release effect, and even if the single dose is minimized, the duration of the effect is short. In some cases, the number of administrations may be increased, and in such cases, the above-mentioned side effects become more severe. Despite these problems, the reality is that no new pharmaceuticals have been developed since salazosulfapyridine.

Problems to be Solved by the Invention The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a novel drug that obtains the same pharmacological effect as salazosulfapyridine and achieves sustained release of the effect. With the goal.

Another objective of the present invention is to provide a new medicament that releases 5-aminosalicylic acid in a sustained manner.

The above object is achieved by introducing 5-aminosalicylic acid, the pharmacologically active moiety of salazosulfaviridine, into the polymer chain via a hydrolyzable bond.

The present invention is based on the following general formula [■]: H tl 2 [wherein, R is a hydrogen atom or an alkyl group; R3 is CO(CHt)nX (wherein, X is a halogen atom; n is an integer of 1 to 5) )
or COC=CH! The present invention relates to a 5-aminosalicylic acid group-containing monomer represented by R1 (wherein R1 represents a hydrogen atom or a lower alkyl group) and a polymer compound synthesized from it.

The polymer compound of the present invention can be used in drug delivery systems such as sustained release, controlled release, and targeting of drugs, and has pharmacological effects similar to those of salazosphapyridine, and has sustained release properties. It is something.

To explain in more detail the 5-aminosalicylic acid group-containing monomer represented by general formula [I], %R in general formula [1]
, represents a hydrogen atom or an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and stearyl.

R1 represents Co(CHt)nX or, in the above formula, X represents a halogen atom such as fluorine, chlorine, bromine, iodine, etc., and n represents an integer of 1 to 5. - means lower alkyl groups such as butyl and isobutyl. Hydrogen or methyl is preferred.

The polymer compound of the present invention, which is a 5-aminosalicylic acid group-containing monomer represented by the general formula [I], is obtained by first combining the 5-aminosalicylic acid group-containing monomer according to the chemical reaction formula below, and then combining the 5-aminosalicylic acid group-containing monomer. It can be produced by polymerizing the 7-mer alone or by copolymerizing it with other monomers that can be copolymerized with the 7-mer.

-COC-CH.

N R2 [wherein R1, R2, R1, X, and n are the same as above, and Y means a halogen atom. ] 5-aminosalicylic acid group content represented by general formula [I] - First, 5-aminosalicylic acid or 5-amine salicylic acid ester, etc. and 7-halogenoalkanoic acid represented by general formula [■] (e.g., heptanohalogeno fatty acids having 2 to 6 carbon atoms) (e.g., acid chloride) or reactive derivatives of acrylic acid or methacrylic acid (e.g., acid chloride) represented by the general formula [I[I]
1 to 3 times the molar amount of 5-aminosalicylic acid or 5-aminosalicylic acid ester, acetonitrile, tetrahydro7rane, methylene chloride, dichlorothane,
In organic solvents such as chloroform, carbon tetrachloride, dimethylformamide, and dimethyl sulfoxide (anhydrous organic solvents are preferable) at room temperature or under heating (1
The desired derivative can be obtained by reacting at a temperature of 50°C or lower).

It should be noted that the reaction proceeds more quickly when heated (40-150'O) during the reaction, and a reaction time of 0.5-3 hours is sufficient. Further, if the reaction is carried out under a nitrogen gas or argon gas stream, the yield can be improved, and it is desirable to carry out the reaction under an atmosphere of these gases as much as possible.

The thus obtained 5-aminosalicylic acid group-containing compound can be made into a highly pure compound by purification means such as recrystallization with an organic solvent or column chromatography.

When polymerizing the 5-aminosalicylic acid group content polymer represented by the general formula [I], a homopolymer of the obtained 5-aminosalicylic acid group content polymer may be used;
Other polymers that can be copolymerized with this, such as acrylamide, acrylamide derivatives, acrylic acid, acrylic acid derivatives (e.g. esters), acrylonitrile, methacrylic acid, methacrylic acid derivatives, methacrylic acid amide, methacrylonitrile, itaconic acid, itacone Copolymers with vinyl monomers such as acid amide, maleic anhydride, maleic anhydride derivatives, vinyl acetate, vinylpyrrolidone, vinylpyridine, styrene, and ethylene may also be used. By selecting the comonomer contained in the copolymer, it becomes possible to control the release of 5-aminosalicylic acid more accurately, and it is more likely that pharmacological activity will be sustained and side effects will be reduced.

In this way, by polymerizing 5-aminosalicylic acid group content, it is possible to obtain the same pharmacological activity as salicisluaaviridin, which is effective in the treatment of inflammatory diseases. It can be taken out.

Furthermore, since 5-aminosalicylic acid is introduced into the polymer side chain through an amide bond, 5-aminosalicylic acid is effectively released in the alkaline environment of the large intestine, which allows for targeting to specific organs. be done.

When the bulk 5-aminosalicylic acid compound of the present invention is used as an active ingredient and is used as a therapeutic agent for human inflammatory bowel disease, it is orally administered. The dosage varies depending on the amount, body weight, symptoms, therapeutic effect, etc.

Solid compositions for oral administration according to the present invention include tablets, powders, granules, and the like. In such solid compositions, one or more active substances are present in at least one inert diluent, such as lactose, mannitol, dextrose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metacalcine, etc. The acid is mixed with magnesium aluminate. The composition is prepared according to conventional methods with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as fibrillar calcium gluconate, σ-β- or γ-cyclodextrin, misopropylene. Stabilizers such as dole may also be included. Tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose hetartrate, or two or more layers, if necessary. Additionally, the capsule may be made of an absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, etc., and include commonly used inert diluents such as purified water, ethanol, etc. include. In addition to inert diluents, the compositions may also contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, perfuming agents, and preservatives.

Other compositions for oral administration include sprays containing one or more active substances and formulated in a manner known per se.

The present invention will be explained in more detail with reference to Examples below.
Of course, the present invention is not limited only to these examples.

Example 1 6.12 g of 5-amine salicylic acid was dissolved in 50 g of acetonitrile.
methacrylic acid chloride 4.0 at room temperature.
g was gradually withdrawn, and after completion, the mixture was stirred at room temperature for 12 hours.

Next, the solvent was distilled off under reduced pressure, and the residue was washed with n-hexane and then recrystallized from methanol/water (1/l) to form colorless needle-like crystals of 5-(methacryloyl)amidosalicylic acid 3. 1
3 g (yield 35%) was obtained.

The melting point and elemental analysis data of this substance are as follows.

Melting point 206-208°C Elemental analysis data Cr IHr, N O4CHN Calculated value 59.722 5.012 6.333 Actual value 59.492 5.115 6.216 Example 2 5-(methacryloyl)amidosalicylic acid (hereinafter referred to as MA
Pour 5v2 of a methanol solution containing 0.44 g (abbreviated as SA) and 13 mg of azobisisobutyronitrile into a cylindrical glass tube, remove dissolved oxygen under vacuum, and then melt-seal.
Polymerization was carried out at 0°C for 24 hours. After polymerization, 0.33 g of poly-5-(methacryloyl)amide salicylic acid (hereinafter abbreviated as pMASA) was precipitated in excess ether (yield 75%).
%) was obtained. After repeated washing with ether, under reduced pressure -
Dry overnight.

Next, pMAsA2.5m9 was adjusted to pH 7.0.
, 25 rn (l) of 1M phosphate buffer was added and shaken at 37°C. 5-aminosalicylic acid, which was extracted from the raw skin by hydrolysis, was quantified by high performance liquid chromatography.

The results are shown in FIG.

Example 3 MASA 0°44g was prepared in the same manner as in Example 2.
5 ml of methanol solution containing 0.14 g of acrylamide and 13 mg of azobisisobutyronitrile was placed in a cylindrical glass tube, dissolved oxygen was removed under vacuum, and the tube was melt-sealed and polymerized at 60°C for 24 hours to form a copolymer. 5-(methacryloyl)amidosalicylic acid-acrylamide (hereinafter referred to as poly(MASA-c)).

-AAm) 0.46 g (yield 79%) was obtained. Thereafter, the same procedure as in Example 2 was carried out to quantify the amount of 5-aminosalicylic acid in the raw hide by hydrolysis. The results are shown in FIG.

Effects The present invention provides novel 5-aminosalicylic acid derivatives and polymer compounds thereof that sustainably release 5-aminesalicylic acid, which is the therapeutically active moiety of salazosulfaviridine, which is frequently used in the treatment of inflammatory bowel diseases. .

The 5-aminosalicylic acid and its polymer compound of the present invention can serve as an active ingredient in a therapeutic agent for inflammatory bowel disease.

[Brief explanation of drawings]

FIG. 1 is a diagram showing sustained release of 5-aminosalicylic acid from a polymerized drug for sustained release of 5-aminosalicylic acid.

Claims (1)

[Claims] 1. The following general formula [I]; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 is a hydrogen atom or an alkyl group; R_2 is -CO(CH_2)nX (In the formula, (X is a halogen atom; n is an integer from 1 to 5)
or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R_3 represents a hydrogen atom or a lower alkyl group)] A 5-aminosalicylic acid group-containing monomer. 2. A polymer compound having the 5-aminosalicylic acid group-containing monomer according to claim 1 as at least one structural unit. 3. A therapeutic agent for inflammatory bowel disease comprising the polymer compound according to claim 2 as an active ingredient.