JPS63159316A - Antiinflammatory composition containing neutral copper bonded body - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to anti-inflammatory compositions containing novel neutral copper conjugates and methods of use thereof.

In recent years, many studies have been conducted and reported on the role of copper, especially the role of crude conjugates, in the treatment of inflammatory diseases. Most recent studies have reported the use of crude conjugates, particularly cupric salicylate salts, in the treatment of rheumatic diseases.

(5arenson &Hangarter;
Inflammation; 2 It has been described that various copper salicylic acid conjugates are produced by reacting inorganic copper (H) salts with salicylic acid in an aqueous solution.

The specific conjugates that form in aqueous solutions are determined by the pH of the aqueous solution.
It has been found that it depends on and anionic conjugates such as light blue crystalline bis(salicylate)copper(II) tetrahydrate, a compound represented by the general formula, and an olive green salicylate power plate (II) sodium salt, a compound represented by the general formula. Both are known.

The purpose of the present invention is to treat inflammatory diseases by using a composition containing as an active ingredient a novel crude conjugate produced by the reaction of a copper compound and substituted benzoic acid in a non-aqueous solvent. It is in providing drugs.

According to one aspect of the invention, the general formula Cu (CsH< (
X)COO)2ROH (However, RO)l represents an alkanol, preferably,
C-C6 aliphatic alkanol, X can be placed at any position, OH, 5H1SeH9NH2 or N
The present invention provides an anti-inflammatory composition comprising a novel neutral conjugate represented by HR' and R' representing HOOC CH3 and a pharmaceutically acceptable non-aqueous carrier.

According to the results of biochemical studies, the conjugates of the present invention appear to have the following duplex structure.

Note that the theory is not limited to this theory.

Preferred compounds for use as the dextral component of anti-inflammatory compositions according to the invention are copper salicylate conjugates, which are believed to have the general formula:

This compound, in the presence of alkanol, produces inorganic copper(II)
) compounds may be prepared, for example, by reacting copper salts or cupric hydroxide with the appropriate substituted benzoic acid.

For example, the reaction of cupric hydroxide with salicylic acid in anhydrous ethanol produces a compound with the general formula Cu(CeH(OH)).
A conjugate represented by COO)2C2850H (hereinafter referred to as general formula Cu(H9al)2-C2H50H) is produced.

The compound becomes dark green crystals when crystallized from absolute ethanol containing excess salicylic acid (approximately 5M).

This compound has been found to be particularly useful in the treatment of inflammatory diseases in humans and animals. However, the present invention
The present invention relates to a method and a drug thereof, characterized in that an effective amount of the above-mentioned compound is administered to humans or animals.

This compound has been found to be particularly effective when used topically in humans and animals in alleviating the symptoms of inflammatory diseases such as rheumatoid diseases, arthritis, and rheumatoid arthritis.

The anti-inflammatory agent of the present invention is preferably used in the form of a composition comprising the above-mentioned compound and a pharmaceutically acceptable carrier.

Therefore, the present invention provides an anti-inflammatory composition comprising the above-described compound and a pharmaceutically acceptable carrier, which composition can be applied topically to the human or animal being treated. It is suitable for

The compositions may be used in the form of gels, ointments, pastes, creams or lotions. The compositions of the present invention are particularly preferred as they are effective in penetrating the skin through the formulation of the above compounds in solution. .

Since the above compounds have low stability in the presence of water,
Preferably, the composition contains a non-aqueous carrier.
A particularly preferred composition is one in which the above compound is dissolved in a non-aqueous liquid auxiliary.

Preferred auxiliaries are, for example, short-chain (01-C1o) and long-fi (C12-C2o) alcohols, such as m-alcohols such as methanol, ethanol, propatool, butanol, cetyl alcohol, and alcohols such as ethylene glycol. alcohols, and monohydric, dihydric, and trihydric alkanols such as polyhydric alcohols such as glycerol.

A particularly preferred composition of the invention which has been found to have an unlimited lifespan is a solution of the above compound in a liquid adjuvant formulated with alkanols, glycerol and salicylic acid.

The amount of the above-mentioned compounds incorporated into the anti-inflammatory compositions of the present invention will vary depending on the inflammatory condition being treated, but will usually be 0.
．． 1 to 15% W/V, preferably 1 to 7% W/V
Copper binder is added.

The composition of the present invention is in the form of a pharmaceutical composition as described above,
This composition, which has been shown to be effective in reducing the symptoms of inflammatory diseases when applied topically to humans and animals, penetrates the skin immediately and is therefore effective in this type of treatment. It is believed that it will work. Furthermore, it is believed that the compositions of the present invention are non-toxic, making them particularly preferred for use in the treatment of inflammatory diseases in humans. this is,
This can be seen from the limited duration of the anti-inflammatory effect of the compounds of the invention, as evidenced by the immediate disappearance of the compounds from treated humans-animals.

The anti-inflammatory composition of the present invention may contain one or more L combination compounds and other active pharmaceutical ingredients such as anti-inflammatory agents and known pharmaceutical excipients.

The present invention will be further explained, but the present invention is not limited to the following examples.

1 steam 1" Production method of Cu (HSal)2-C2H50H).

20-97 g of freshly prepared Cu(OH) was added to a solution of 6.9 g of salicylic acid in 50 m of absolute ethanol. The suspension was rapid-waved on a water bath until all the copper hydroxide had reacted. The resulting dark green solution was filtered and green crystals were precipitated by cooling.

The precipitate was filtered and green crystals were precipitated by cooling.

The precipitate was filtered, washed with cold alcohol and air dried. The yield was 3.2 g, and the single element analysis results were as follows.

(c u c 18H1e O7) Cu CH Calculated value (n 16.8 5G, 1 4.2 Actual value (X) 18.8 50.2 4.2 Branch Jlヱ(:u (I(Sal)2eCH30H) and Cu (
HSal) 20G3) Production method of 170H.

In the method of Example 1, CuC
Cu (HSa l) analyzed as 1, Hl, 0□
) 2-CHOH and Cu C1? Cu(HSa1) No. 2 C3H7OH analyzed as Hla O7 was produced.

In this example, Cu (HSal), -C2H50)
1 shows a method for producing a composition containing 1.

Newly produced cupric hydroxide 1. Og was added to a solution of 7 g of salicylic acid in 80 ml of absolute ethanol. The suspension was heated until the cupric hydroxide reacted. The resulting dark green solution was filtered to separate the insoluble polymerized copper salicylate and added to a 20 ml glycerol filtrate.

Dark green 0.1M-Cu() obtained by this method!
The Sa+)2-C2H50)1 solution was stable for a long time.

This was used in the tests described in Examples 4 and 5.

This example shows the transdermal absorption of the compound Cu(HSal)2''02H50H.

Male Ista rats (average body weight 250 g) were anesthetized with diethyl ether and shaved over an area of 20 cm' to remove Cu()ISa prepared according to Example 3.
l)2-C,,H2O)1 composition was applied to each rat.

(20 m sentences per 3 rats) The rats were returned to the cage, and 2 days later, their urine was collected and compared with the urine of control non-treated rats using the method described below.

5 m of urine was acidified with 2 M -82So and stirred with 2 m of ethyl acetate. The ethyl acetate layer was centrifuged and analyzed by thin layer chromatography using silica gel. (Solvent: benzene, diethyl ether, glacial acetic acid, methanol l20:60:18:l volume ratio) Salicylic acid, salicyluric acid, gentisic acid, and ethyl salicylate were used as samples.

The results are shown in Figure 1. Figure 1 shows a chromatogram when the solvent was flowed in the direction of the arrow under the above conditions from the original line showing the points to which samples 1 to 9 were attached. It is a diagram.

Here, 1 and 9 indicate points where a chromatogram was performed using a sample of a mixture of salicyl uriquaside (a) and salicylic acid (b) for comparison.

2 and 8 are CuCHSal)2-C,,H50H
Points are shown using urine samples collected from rats treated with the composition.

3 and 7 indicate points using urine samples taken from control untreated rats.

4 and 6 are gentisic acid (C) and ethyl salicylate (
A chromatogram was performed using a sample of the mixture with b) for comparison.

5 is Cu(HSal)2 used for rat treatment.
The points using a sample of the composition of C2H50)1 are shown.

This chromatogram shows Cu()lsal)2-C
The presence of salicylic acid and gentisic acid in the urine of rats treated with 2H50H is clearly shown, indicating that the composition penetrated into the skin of the rats.

In this example, inflammation was artificially induced in rats, and in order to alleviate this symptom, u (H5a I)2 ・C2H
51) This shows the effect of topical application of the compound H.

Male Ista rats (average body weight 250 g) were anesthetized with diethyl ether, their buttocks were shaved over an area of 20 ctn'', and the rats were divided into 7 groups.

Group 1 is control rats, untreated.

The second group of rats was Cu()HSal)2-02H5
A 4=1 mixture of alcohol and glycerol was used as the auxiliary agent for the OH compound.

The third group of rats received 4:1 alcohol and glycerol.
was treated with a 7% W/V solution of salicylic acid in a mixture of

Rats in groups 4.5 and 6.7 received 154% of CuCHSal)2-C2H50)1 produced by the method of Example 3.
mg.

Treatment was performed using Cu(HSal)2-C2H50H compositions formulated at 231 mg, 462 mg, and 770 mg, respectively.

Approximately 6 hours after topical treatment of the rats, inflammation was induced in the paws of the rats in each group by injecting 0,1 mi of 1% saline solution of carrageenan sodium salt into the paw bed of each rat.

Inflammation in the paws of rats in each group was measured using a micrometer and screws.
Observations were made by measuring paw swelling using a gauge.

The results are shown in Figure 2, where each curve is a 0 curve showing the increase in rat paw thickness over time after injection of the inflammatory agent! 7 indicate the swelling of the paws of rats from groups 1 to 7, respectively.

Figure 2 clearly shows that Cu (HSal)2' C2
It has been shown that H50H compounds have anti-inflammatory effects when applied topically.

11j Process for producing Cu (CH(SH)COO)2-C2H50H.

2-thiobenzoic acid instead of salicylic acid7.
This compound was produced by the method of Example 1 except that 7 g was used.

Yield 2.9g (elemental analysis, actual value Cu t5.8B G
45.9; H3,6L CuCteHtaOsS2 (
7) Calculated values are Cu 15.4, C4B, 2; H3, 1
3) Support m Cu (CeH4(SeH)Coo)2 ” C2H5
OH manufacturing method.

2-Selenibenzoic acid 1 instead of salicylic acid
This compound was produced by the method of Example 1 except that 0.0 g was used.

Yield i8.1g (original, manufactured analysis, actual value Cu 12.3;
C3B,1; H3,5L CuCteHteOsSl
! 2(7) Calculated values are Cu12, fl, C37,7, H3
, 1$) Lll Cu (CH(NH)COO)2- C2H50H production method.

2-7 minobenzoic acid 6 instead of salicylic acid
．． The present compound was produced using the method of Example 1 except that 9 g was used.

Yield 5.6g (elemental analysis actual value Cu 1B, 4; C
50,8: )I 5.0%, CuC16N, 805
Calculated value of N2 Cu 1B, 8; C5o-3; H4,
7%) Mitateage'CuCC)l-Co-N)l-CN)I
-NH-C7H402) "Production method of C2) +50H.

The present compound was produced by the method of Example 1, except that 16.8 g of 2-[2-carboxyphenylcoamino-4-(2-carboxyphenylcoamino pyrimidine) was used instead of salicylic acid.

Yield 13.3g (Elemental analysis actual value Cu 24.5;
C4B,2; H3,2L Cu2C2oH1805N
The calculated value of , is Cu24.5; C4B, 0; )! 3
．． 5%)
-NH-C8)+4041 Method for producing -C2H50H.

2-[2-carboxyphenyl] instead of salicylic acid
This compound was prepared by the method of Example 1, except that 19.0 g of amino-4-(2,3-dicarboxyphenylcoamino-pyrimidine was used).

Yield i 14 , Og (elemental analysis, measured value Cu 22
．． 4; C44,7; H3,3L C2Cu21H,8
Calculated values for 07N4 are Cu22.6; C44,5; H
3,2%) Actual jL example-LyuCu,, (C6H4-CO2-NH-04N2H,,-
N) Method for producing I-(:8H404)-C2H50H.

2-[2-carboxyphenylcoamino-4-(2,4-dicarboxyphenylcoamino
This compound was produced by the method of Example 1 except that 19.0 g of pyrimidine was used.

Yield 15.3g (elemental analysis, actual value Cu 24.7;
C45,8: H3,? L Cu2C2, H180□N
4, the calculated value is Cu 24.5; C4B, θ,
H3,5 surprise) Actual jL example-LヱC:u (csHa WORK GO2@C4N,,H,,c
l: Manufacturing method of +2 and 02850H.

This compound was produced by the method of Example 1, except that 7 g of 4-(2-carboxyphenyl)amino-2-chloropyrimidine LL was used in place of salicylic acid.

Yield: 9.5g (elemental analysis, actual value Cu: 12.5;
C58,5; H3,9$, Cu C24H,80
Cu 12.7 as 5N4; C58,9,H3,6
%) Support χ■yu' Cu CCH-Go N)l-C3H9)2C:2H
50H manufacturing method.

The present compound was produced by the method of Example 1, except that 6.8 g of 2-(2,3-dimethylphenylcoaminobenzoic acid) was used in place of salicylic acid.

Yield 45.5 g (elemental analysis, measured value (u 11.2
;C84,! 3; H5,5L CttC3,,)1
Calculated value of 3405M2 Cu 10.9; C65,1;
H5,8$)

[Brief explanation of the drawing]

FIG. 1 shows thin layer chromatograms of urine of rats treated topically with a compound of the invention and of untreated rats and related samples. FIG. 2 is a graph showing paw swelling curves when carrageenan sodium salt is injected into the paws of rats treated topically with a compound of the present invention and untreated rats to induce inflammation. Agent: Patent attorney Yoshizo Yamaki (and 1 other person) Lu
lo lo
−～ −−

Claims (1)

[Claims] 1. General formula Cu[C_6H_4(X)COO]_2RO
H (However, ROH indicates alkanol, X may be in any position and indicates OH, SH, SeH, NH_2 or NHR', R' is ▲A mathematical formula, a chemical formula, a table, etc.▼ ▲A mathematical formula, There are chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ¥ or ¥ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ 1. An anti-inflammatory composition comprising a neutral copper binder represented by the following: and a pharmaceutically acceptable non-aqueous carrier. 2. The anti-inflammatory composition according to claim 1, which is used for topical application in the form of an anhydrous gel, ointment, paste, cream or lotion. 3. General formula Cu [C_6H_4(X)COO]_2RO
H (However, ROH indicates alkanol, X may be in any position and indicates OH, SH, SeH, NH_2 or NHR', R' is ▲A mathematical formula, a chemical formula, a table, etc.▼ ▲A mathematical formula, There are chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ¥ or ¥ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ 2. The anti-inflammatory composition according to claim 1, which is in the form of a solution and comprises a neutral copper conjugate represented by the formula (1), an excess molar amount of salicylic acid, and ethanol. 4. The anti-inflammatory composition according to claim 1, wherein the nonaqueous carrier is an alkanol, glycerol, or salicylic acid. 5. The neutral copper binder, which is an active ingredient, has a content of 0.1 to 15
%W/V blended claims 1 to 4
The anti-inflammatory composition according to any of paragraphs.