JPH03130255A - Aniline derivative and anti-inflammatory drug containing the same derivative as active ingredient - Google Patents

Abstract

NEW MATERIAL:An alkylsulfinylaniline derivative shown by formula I (R1 and R2 are independently H, 1-6C alkyl or 1-6C acyl; R3 and R4 are 1-6C alkyl) or an acid addition salt thereof. EXAMPLE:4-(n-Propylsulfinyl)-o-acetanisidine. USE:Useful as an anti-inflammatory drug, especially useful as antirheumatic agent having inhibitory action on Arthus type allergic reaction, suppressing action on delayed hypersensitivity, collagen arthritis, adjuvant arthritis and antibody production function and low side effects. PREPARATION:As shown by the reaction formula, an 2-alkoxy-4-alkylthio-aniline shown by formula II is acylated to give a compound shown by formula III. Then this compound is reacted with an alkyl halide in the presence of a base to give a compound shown by formula IV. Then the compound shown by formula IV is successively oxidized with an oxidizing agent such as sodium metaperiodate to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Background of the Invention] Technical Field The present invention relates to novel aniline derivatives and pharmaceutically acceptable acid addition salts of compounds capable of forming acid addition salts,
The present invention also relates to anti-inflammatory agents containing these as active ingredients.

Prior art> Until now, French Patent No. 1,489,916 and German Patent No. 2,706,104 have reported that certain aminophenylthioethers can be used as intermediates for dyes, and others have acaricidal activity. is listed. Furthermore, German Patent No. 2,114,578 and US Pat. No. 3,843,366 describe certain acetanilide derivatives as intermediates for color coupler synthesis. Furthermore, the applicant's patent application No. 1-667
No. 47 describes an anti-inflammatory agent containing 2-methoxy-4-(n~propylthio)aniline and its pharmaceutically acceptable acid addition salt as an active ingredient.

On the other hand, many non-steroidal anti-inflammatory drugs are used to treat inflammation, and most of them are acidic non-steroidal anti-inflammatory drugs, typified by indomethacin.

Although these are effective against acute inflammation, they do not show sufficient effects against chronic inflammation associated with immune abnormalities such as rheumatoid arthritis. Immunomodulators such as gold preparations and penicillamine have traditionally been used to improve immune abnormalities, but their effectiveness is insufficient, and immunosuppressants and steroids, which are highly effective drugs, have strong side effects. Difficult to use. Therefore, there is currently no anti-inflammatory drug with strong action and weak side effects for chronic inflammation such as rheumatoid arthritis, and there is a desire for the development of a new type of anti-inflammatory drug.

[Summary of the invention]

Abstract: Arthus-type allergic reactions, in which immune complexes activate complement and cause tissue damage, are deeply involved in the onset of rheumatoid arthritis.
I982)) Therefore, drugs that suppress this type of allergic reaction are useful as anti-inflammatory drugs.

The present invention aims to provide a novel compound suitable for a new type of anti-inflammatory drug and an anti-inflammatory drug containing this compound as an active ingredient. As a result of compound synthesis and drug efficacy testing, it was discovered that certain alkylsulfinylaniline derivatives, alkylthioaniline derivatives, and their acid addition salts have inhibitory and stimulant properties, and based on this knowledge, the present invention was completed. It's arrived.

That is, the compound according to the present invention has the following formula (I) [wherein R and R2 each independently represent a hydrogen atom, an alkyl having 1 to 6 carbon atoms, or an acyl having 1 to 6 carbon atoms, R3 and R4 each independently represents alkyl having 1 to 6 carbon atoms] and pharmaceutically acceptable acid addition salts of compounds capable of forming acid addition salts among them;
and the following formula (II) [in the formula, R and R2 each independently represent a hydrogen atom or an alkyl having 1 to 6 carbon atoms, except when they are also hydrogen atoms], R3 and R4 are each independently represents alkyl having 1 to 6 carbon atoms] and pharmaceutically acceptable acid addition salts of compounds capable of forming acid addition salts among them.

Furthermore, the anti-inflammatory agent according to the present invention is characterized in that it contains one or more of the above-mentioned compounds as an active ingredient.

Effects> The compound according to the present invention has the effect of suppressing Arthus-type allergic reactions, as well as delayed-type hypersensitivity, collagen arthritis,
The anti-inflammatory agent of the present invention, which has a suppressive effect on adjuvant arthritis and antibody production ability, and contains this compound as an active ingredient, can be expected as a new type of anti-inflammatory agent with less side effects, especially as an anti-rheumatic agent. .

C Detailed Description of the Invention Compounds The alkylsulfinylaniline derivatives and alkylthioaniline derivatives according to the present invention have the following formulas (I) and (I
It has been mentioned above that it is represented by I).

[The definitions of each substituent in both formulas are as described above].

Among the above-mentioned compounds, compounds capable of forming acid addition salts, that is, compounds having a free amino group or alkylamino group in formulas (I) and (II), or compounds of the present invention (such as compound 2.8) described below. Also within the scope of this invention are commercially acceptable acid addition salts. Examples of such acid addition salts include pharmaceutically usable acid addition salts, such as the corresponding mineral salts, such as hydrochlorides, hydrobromides or hydroiodides, sulfates, bisulfates or phosphates, or corresponding carboxylates, such as fumarates, maleates, malates, succinates, citrates, gluconates or salicylates, or corresponding sulfonates, such as methanesulfonic acid. salt, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,
etc. can be mentioned.

Representative examples of the compound represented by formula [T] or [■] according to the present invention include the following compounds.

■ 4-(n-propylsulfinyl)-0-acetanisidine (compound 1) ■ 4-(n-propylsulfinyl)-〇-anisidine (compound 2) ■ N-methyl-4-(n-propylthio)-〇-anidine (Compound 3) ■ N-methyl-4-(n-propylsulfinyl)-
o-anisidine (compound 4) ■ 4- (i-butylsulfinyl)-〇-acetoanidine (compound 5) ■ 4- (i-butylsulfinyl)-0-anisidine (compound 6) ■ 4- (n-butyl sulfinyl)-〇-acetanisidine (compound 7) ■ N, N-dimethyl-4-(n-propylthio)-
〇-anisidine (compound 8) ■ N,N-dimethyl-4-(n-propylsulfinyl)-〇-anisidine (compound 9) [phase] N-(n-
propyl)-4-(n-propylthio)-〇-anisidine (compound 10) QN-(n-butyl)-4-(n-propylthio)-o-anisidine (compound 11) @N-(n-hexyl)- 4-(n-propylthio)-
o-anisidine (compound 12) ■ N-acetyl-2-
(n-propoxy)-4-(n-propylsulfinyl)aniline (compound 13) [Phase] 2- (n-propoxy)-4-(n-propylsulfinyl)aniline (compound 14)■ N-acetyl-2- (n-hexyloxy)-4-(n-propylsulfinyl)aniline (compound 15) Also, among the compounds according to the present invention, in formula (I), R is acetyl, R2 is a hydrogen atom, R is methyl, R4 is n-propyl, i.e. the above compound 1, and in formula (n),
Particularly preferred are alkylthioaniline derivatives in which R1, R2 and R are all methyl and R4 is n-propyl, ie the above compound 8, and pharmaceutically acceptable acid addition salts thereof.

Production of compounds> The compounds of the present invention represented by formulas (I) and (II) are
It can be prepared by any suitable route, for example, by the following route A and route B.

[Route A]

In addition, Ra in the formulas of compounds (B) and (C) represents any alkyl group.

[Route B]

(D) (E) Route A) Acid nolide for acylation of 2-alkoxy-4-alkylthio-aniline (A) in an aprotic solvent (such as dichloromethane) in the presence of a base (such as triethylamine). Alternatively, it is led to compound (B) by reacting with an acid anhydride. Compound (C) obtained by further alkylating compound (B) with an alkyl halide having the desired alkyl group R2 in the presence of a base (such as sodium hydride)
Compound (II) can be produced by hydrolyzing in the presence of a base (such as potassium hydroxide). Compound (II) can also be produced by reducing compound (B) with lithium aluminum hydroxide or the like.

On the other hand, compound (I) can be produced by oxidizing the compound (B) or (C) obtained above with an oxidizing agent such as sodium metaperiosate, or by further hydrolyzing the oxidized product.

Route B) 2-Alkoxyaniline (D) is added to the target alkyl groups R1 and R2 in an aprotic solvent in the presence of a base.
A dialkyl body (
E) and further prepare this compound (E) by the method described in the literature (I, Monkovic et al.: J, Med, Che
31.1548 (I988)), followed by hydrolysis and further alkylation to introduce alkyl 2J, R4 to produce the compound (old). Compound (I) can be produced by oxidizing Compound (n) with an oxidizing agent such as sodium metaperiosate.

As mentioned above, pharmaceutically acceptable acid addition salts of compounds of formulas (I) and (II) that are capable of forming acid addition salts are also within the scope of the present invention. The compounds can be formed into acid addition salts using various acids.

Anti-inflammatory agent> The compound of the present invention is a new drug because it significantly suppresses Arthus-type allergic reactions, which are deeply involved in chronic inflammation such as rheumatoid arthritis, delayed-type hypersensitivity, collagen arthritis, adjuvant arthritis, and antibody production ability. It can be used as an active ingredient in some types of anti-inflammatory drugs.

The anti-inflammatory agent according to the present invention contains one or more of the above-mentioned compounds of the present invention as an active ingredient.

The compound of the present invention as an active ingredient of an anti-inflammatory agent can be applied in various forms, and can be applied alone or with an appropriate pharmaceutically acceptable carrier,
It can be used in the form of a mixture with excipients, diluents, and other drugs. The dosage form for the anti-inflammatory agent is appropriately selected from tablets, granules, powders, capsules, syrups, injections, active ingredients, etc., depending on the therapeutic purpose, and it can be administered orally or parenterally in these forms. can be administered.

The anti-inflammatory agent according to the invention can be prepared by applying any conventionally known manufacturing means.

When the compound of the present invention is used as an anti-inflammatory agent, the dosage is:
Although it may vary depending on the symptoms, compound, reaction to drugs, etc., it is usually about 5 to 1500 mg per day for adults.
Administered in one or more doses.

Experimental Examples The following are production examples, formulation examples, pharmacological test results, and acute toxicity test results of the compounds of the present invention, but the present invention is not equally limited by these experimental examples.

1) Production Example 4 - Dissolve 5.5 g of (n-propylthio)-0-anidine in 100 ml of dichloromethane, and then add 5.5 g of triethylamine and 3.3 g of acetic anhydride. The reaction was stirred at room temperature for 9 hours. Pour an appropriate amount of saturated aqueous sodium hydrogen carbonate solution into this and extract with chloroform. After drying the extract with Glauber's salt, the solvent was distilled off under reduced pressure to obtain 6.5 g of 4-(n-propylthio)-0-acetanisidine. 4
(n-propylthio)-0-acetanisidine 3.2g
was dissolved in 250 ml of methanol, and then 10 ml of an aqueous solution containing 5.6 g of sodium metaperiosate was added (
At this time, keep the internal temperature at 0-5°C). 8 at room temperature
After stirring for 5 hours, pour an appropriate amount of water and extract with chloroform. After drying the extract with Glauber's salt, it is concentrated under reduced pressure. The resulting crystalline solid is purified by silica gel column chromatography. Chloroform: methanol (99
: 2.5 g of 4-(n-propylsulfinyl)-0-acetanisidine was obtained from the elution portion of 1).

Melting point = 113-113.5°C (colorless crystals) MS (m/
z): 255 (M”) IH-NMR (δ, CD
Cl5): 8, 50 (IH, d, J praise 8.2
), 7.86 (IH, br HNH), 7.31
(LH, d, J-1, 8), 7.04 (IH, dd
, J-8,2゜1.8) ,3.97 (3H,s)
, 2.65-2.87 (2H, m) , 2.23 (
3H,s), 1.55-1.99 (2H,m), 1
．． 04(3H,t,J-7,2) (b) 4-(n-propylsulfinyl)-o-anisidine: Compound 2 N-methoxycarbonyl-4-(n-propylthio)-
1.5 g of 0-anisidine is dissolved in 100 ml of methanol, and then 6 ml of an aqueous solution containing 2.2 g of sodium metaperiosate is added (at this time, the internal temperature is maintained at O-5° C.). After stirring this at 0°C for 4 hours, an appropriate amount of water was added and extracted with ethyl acetate. The extract was washed with saturated brine and dried over Glauber's salt, and then the solvent was distilled off under reduced pressure to obtain a crude sulfoxide derivative [N-methoxycarbonyl-4-(lopropylsulfinyl)-0-anisidine].

This is dissolved in 100 ml of methanol, and then 50 ml of 35% aqueous potassium hydroxide solution is added. The reaction solution was stirred for 1.5 hours while refluxing. After cooling, add an equivalent amount of water and extract with chloroform. The extract was concentrated under reduced pressure and 4-
(n-propylsulfinyl)-〇-aningine 1.1
3g was obtained.

Melting point: 124-126°C (hydrochloride, purple crystals) MS (
m/z): 213 (M)lH-NMR (δ, C
DCl5) Near. 15 (IH, d, J-1, 8)
, 6.97 (IH, dd, J-8, 1, 1, 8) , 6
．． 73 (LH, d, J-1, 8), 4.10 (2H
.

b r ; N H2), ball 92 (3H, s), 2
, 71 (2H,t, J-7,1) ,1. 6
9 (2H, m), 1. 04 (3H, t, J-
7,1)(c) N-methyl-4-(n-propylthio)-〇-anisidine: Compound 3 4-(n-propylthio)-0-acetanisidine5.
Dimethylformamide (DMF) solution containing Og 120
ml of sodium hydride 1. Add 25 g in portions (keeping the internal temperature at 0-5° C.). 35 at 0℃
After stirring for a minute, 1.56 ml of methyl iodide is added dropwise. Stirring was continued for an additional 5.5 hours at 0°C. After adding an appropriate amount of water, extract with ethyl acetate. After washing the extract with saturated brine and drying over Glauber's salt, the solvent was distilled off under reduced pressure to obtain a crude product. This is purified by silica gel column chromatography. From the elution fraction of hexane:ethyl acetate (I: 1), N-methyl-4=(n-propylthio)-
4.21 g of 〇-acetanisidine was obtained.

3 in 150 ml of a methanol solution containing 2.1 g of N-methyl-4-(n-propylthio)-〇-acetanisidine.
Add 150 ml of 5% aqueous potassium hydroxide solution. Stirring is continued for 4 days while the reaction solution is refluxed. Add an appropriate amount of water and perform extraction with chloroform. The extract is concentrated under reduced pressure, and the resulting amorphous solid is purified by silica gel column chromatography. 1.3 N-methyl-4-(n-propylthio)-0-anisidine was obtained from the chloroform eluate.
8g was obtained.

Melting point: 9o, o~91.5℃ (hydrochloride, colorless crystals) MS (m/z): 211 (M'') IH-N
MR (δ, CDCl5): 6.99 (IH, dd
, J-7, 8, 1, 2), 6.85 (IH, d, J-
1,2), 6.49 (IH, d, J-7, 8), 4
．． 26 (IH.

b r ;NH), 3.84 (3H,s), 2.
85 (3H, s), 2.75 (2H, t, J=7.
2) 1.4-1.8 (2H, m), 0.98 (3
H.

t, Jw7,1) 2.0 g of N-methyl-4-(n-propylthio)-acetanisidine was dissolved in 150 ml of methanol, followed by 10 aqueous solution containing 3.0 g of sodium metaperiosate.
Add m1 (keeping the internal temperature at 0-5°C).

After stirring at room temperature for 6.5 hours, an appropriate amount of water is added and extraction is performed with ethyl acetate. After drying the extract with Glauber's salt, the solvent was distilled off under reduced pressure to obtain the crude sulfoxide [N-methyl-4-(
n-propylsulfinyl)-0-acetanisidine]
get.

The crude sulfoxide compound was dissolved in 150 ml of methanol,
Subsequently, 150 ml of 35% aqueous potassium hydroxide solution is added. After stirring for 27 hours under reflux, an appropriate amount of water was added and extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain N-
1.79 g of methyl-4-(n-propylsulfinyl)-〇-anisidine was obtained.

MS (m/z): 227 (M")'H-
NMR (δ, CDCl5) Near, 00-7.
17 (2H, m), 6. 56(2)1. d, J-
8,8), 4.58 (IH.

b r ;NH), 3.91 (3H,s), 2
．． 89 (3H, s), 2.57-2.96 (2H
, m), 1.47 (2H, m), 1.04 (
3H,t,J-7,5) (e) 4-(i-butylsulfinyl)-〇-acetanisidine: Compound 5 4-(i-butylthio)-〇-anidine hydrochloride 1
5.88 g was dissolved in 200 ml of dichloromethane, followed by 25.8 g of triethylamine. Add Og and 8.0 g of acetic anhydride. The reaction was stirred at room temperature for 4.5 hours. After adding an appropriate amount of chloroform, washing is performed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried with Glauber's salt and concentrated under reduced pressure to obtain a crude product. This is purified by silica gel column chromatography. From the hexane:ethyl acetate (4:1) eluate, 7.8 g of 4-(i-butylthio)-〇-acetanisidine was obtained as a crystalline solid.

4-(i-butylthio)-o-acetanisidine 6,
Og is dissolved in 300 ml of methanol, followed by the addition of 30 ml of an aqueous solution containing 8.0 g of sodium metaperiosate (while maintaining the internal temperature at 0-5°C). 3. At room temperature.
After stirring for 5 hours, an appropriate amount of water is added and extraction is performed with ethyl acetate. The extract was washed with saturated brine, dried over Glauber's salt, and concentrated under reduced pressure to obtain a crude product. This is purified by silica gel column chromatography. From the chloroform:methanol (99:1) eluate, 5.17 g of 4-(i-butylsulfinyl)-0-acetanisidine was obtained as a crystalline solid.

Melting point: 117-118°C (colorless crystals) MS (m/z): 269 (M) IH-NMR
(δ, CDCl5); 8.49 (IH, d, J■
8. 5), 7.87 (IH, b r ; NH),
7. 32 (IH, d, J-1, 7), 7.0
5 (IH, dd, J-8, 5゜1, 7), 3.
97 (3H, s), 2.82 (IH, dd, J-1
2,3,5,0), 2.45 (IH, dd, J-12
, 3, 8, 8), 2.23 (3H, s), 2.00
~2.30 (IH, m)1. 15 (3H, d,
J=6.4), 1.07 (3H,d, J-
6,4)(f')4-(i-butylsulfinyl)-o
- Aningin: Compound 6 2.50 g of 4- (i-butylsulfinyl)-〇-acetanisidine is dissolved in 150 ml of methanol, and then 130 ml of 35% aqueous potassium hydroxide solution is added.

The reaction solution was stirred under reflux for 15.5 hours. After cooling, add an equivalent amount of water and extract with chloroform. The extract was concentrated under reduced pressure to obtain 2.2 g of 4-(i-butylsulfinyl)-0-anisidine.

Melting point: 99-100°C (hydrochloride, dark purple crystals) MS (
m/z): 227 (M) IH-NMR (δ,
CDCl5) Near, 16 (IH, d, J-tai 1.
8), 6.98 (LH, dd, J-7,9,1,
8), 6.72 (IH, d, J 7.9), 4
．． 12 (2H.

b r ; NH2), 3.92 (3H,s), 2
．． 84 (IH, dd, J-12, 3, 5, 3), 2.
42 (IH, dd, J-12, 3, 8, 5), 1.
85-2.34 (IH, m), 1.12 (3H,
d, J■5.6), 1.06 (3H, d.

J-6,4) (g) 4-(n-butylsulfinyl)-o-acetanisidine: Compound 7 4-(n-butylthio)-0-anisidine hydrochloride 1
Dissolve 6.7 g in 200 ml of dichloromethane, then add 30.0 g of triethylamine and 10.0 g of acetic anhydride. The reaction was stirred at room temperature for 11 hours. After adding an appropriate amount of saturated aqueous sodium bicarbonate solution, extraction is performed with chloroform.

The extract was dried with Glauber's salt and then concentrated under reduced pressure to obtain a crude product.

This is purified by silica gel column chromatography. 4-(
11.2 g of n-butylthio)-〇-acetanisidine was obtained as a crystalline solid.

4-(n-butylthio)-〇-acetanisidine8.
Og is dissolved in 400 ml of methanol, followed by the addition of 50 ml of an aqueous solution containing 10.0 g of sodium metaperiosate (while maintaining the internal temperature at 0-5°C). 9 at room temperature
．． After stirring for 5 hours, an appropriate amount of water is added and extraction is performed with ethyl acetate. The extract was washed with saturated brine, dried over Glauber's salt, and concentrated under reduced pressure to obtain a crude product. This is purified by silica gel column chromatography. Chloroform:
From the methanol (99:1) eluate, 4.95 g of 4-(n-butylsulfinyl)-0-acetanisidine was obtained as a crystalline solid.

Melting point: 122-123°C (colorless crystals) MS (m/z): 269 (M”) IH-NMR
(δ, CDCl5): 8.50 (I)1. d
, J-8,5), 7.87 (IH,br;NH
), 7. 31 (IH, d, J-1, 8),
7.04 (IH, dd, J-8, 5°1.8)
, 3.97 (3H, s) , 2.78 (2H, t,
J-7, 6), 2. 23 (3H,s)1, 2
2-1.85 (4H, m), 0. 92 (3H, t
, J=6.8) (h) N,N-dimethyl-4-(n-propylthio)-
〇-anisidine: Compound 8 0-anisidine 10. 200ml of DMF solution containing Og
Sodium hydride 10. Add Og (keeping internal temperature at 0-5°C). After stirring at 0° C. for 40 minutes, 12.7 ml of methyl iodide was added dropwise. After stirring at room temperature for 3 hours, DMFlooml, 5.0 g of sodium hydride and 6.0 ml of methyl iodide were further added, and stirring was continued at room temperature for 14 hours. After adding an appropriate amount of water, extract with ethyl acetate. The extract is washed with saturated saline and then dried using Glauber's salt. After distilling off the solvent under reduced pressure, purification is performed by silica gel column chromatography. From the eluate of hexane:ethyl acetate (9:1), 4.9 g of N,N-dimethyl-〇-anisidine was obtained.

4.9 g of N,N-dimethyl-0-anisidine, 6.3 g of botium thiocyanate) and 6.5 g of triethylamine.
Dissolve in 200 ml of methanol.

100 ml of a methanol solution containing 1.3 ml of bromine is added dropwise at room temperature over 50 minutes. After stirring for 1.5 hours, 6.3 g of botasiram thiocyanate was further added, and then 40 ml of methanol solution containing 1.3 ml of bromine was added dropwise at room temperature over 5 minutes. After stirring for 1.5 hours and adding an appropriate amount of water, the mixture is made alkaline using a 35% aqueous potassium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated saline and further dried with Glauber's salt. The solvent was concentrated under reduced pressure to obtain N,N-dimethyl-4-cyanothio-〇-anisidine. This was dissolved in 200 ml of methanol, and 5.5 g of potassium hydroxide was added. After stirring for 50 minutes under reflux, 5.0 g of n-propylbromide are added. Continue stirring under reflux for an additional 1.5 hours. The solvent is distilled off under reduced pressure, an appropriate amount of water is added, and extraction is performed using ethyl acetate.

The extract is washed with saturated saline and dried with Glauber's salt.

The solid obtained by concentration is purified by silica gel column chromatography. Hexane:ethyl acetate (I9: 1
) to obtain 2.5 g of N,N-dimethyl-4-(rhopropylthio)-〇-anisidine. MS (m/z
): 225 (M)'H-NMR (δ, CDC
l5): 6, 76-7. 01 (3H, m)
, 3.88 (3H, s) , 2.84 (2H, t
, l-6,8)2, 77 (6H,s),
1.44-1.85 (2H, m), 1.01 (3
H, t, J-6,8) N, N dimethyl-4-(n
1.3 g of -propylthio)-〇-aningine is dissolved in 120 ml of methanol, followed by the addition of 10 ml of an aqueous solution containing 2.7 g of sodium metaperiosate (at this time the internal temperature is maintained at 0-5° C.). After stirring at room temperature for 22.5 hours, an appropriate amount of water is added and extraction is performed with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure to obtain a crude product. This is purified by silica gel column chromatography. Chloroform: methanol (9
9:1) 0.81 g of N,N-dimethyl-4-(n-propylsulfinyl)-〇-aningine was obtained from the eluate.

MS (m/z): 241 (M)'H-NMR (
δ, CDCl5): 6.90-7.23 (3H, m), 3.95 (3
H,s), 2.85 (6H,s), 2.65~2
．． 89 (2H, m), 1.53-1.87 (2H
,m) ,1.05 (3H,t,J-7,3)4-(
Tetrahydrofuran (TH) containing 4.1 g n-propylthio)-〇-anisidine and 8.96 g triethylamine.
F) 0.40 dimethylaminopyridine in 250 ml of solution
g and 3.06 g of propionyl chloride (while keeping the internal temperature at O-5°C). After stirring at room temperature for 3 hours, 1.02 g of propionyl chloride was added, and the mixture was further stirred at room temperature for 1 hour. An appropriate amount of 10% aqueous potassium hydroxide solution was added to the reaction solution, stirred for 30 minutes, and then extracted with chloroform. The extract is washed with saturated saline and then dried with Glauber's salt. The crude product obtained by distilling off the solvent under reduced pressure is purified by silica gel column chromatography. From the hexane:ethyl acetate (5:1) elution fraction, N-propionyl-4-(n-propylthio)-〇-anisidine 2.93
I got g.

0.9g of lithium aluminum hydride under nitrogen stream
Suspend in 50ml of F. To this, N-propionyl-4-
(n-propylthio)-0-anisidine2. 20 ml of THF solution containing Og are added in portions (keeping the internal temperature at 0-5° C.).

The reaction solution was stirred under heating under reflux for 2 hours. After returning to room temperature, add an appropriate amount of sodium sulfate hydrate and continue stirring. Dilute with water and perform extraction using chloroform. The extract is washed with saturated saline and then dried with Glauber's salt.

The solvent is distilled off under reduced pressure, and the resulting crude product is purified by silica gel column chromatography. Elute with hexane:ethyl acetate (I0:1) and N-(n-propyl)-4-(
0.53 g of n-propylthio)-〇-anisidine was obtained.

Melting point: 104-105°C (hydrochloride) MS (m/z): 267 (M)1H-NMR
(δ, CDCl5): 6, 7-6. 9 (2
H, m), 3. 90 (3H.

s), 3. 0 to 3.4 (3H, m), 2.
90 (2H, t, J-7, 1), 1.4-2.1 (
4H, m) , 0.8 to 1.2 (6H, m) 4- (
0.25 g of dimethylaminopyridine and 2.2 g of n-butyryl chloride are added to 150 ml of THE solution containing 2.5 g of n-propylthio)-0-anisidine and 5.5 g of triethylamine (at this time, the internal temperature is adjusted to 0-5°C). ).

After stirring at room temperature for 12 hours, an appropriate amount of 10% aqueous potassium hydroxide solution was added to the reaction mixture, and the mixture was further stirred for 30 minutes.

An extraction operation is performed using chloroform, and the extract is washed with saturated saline and then dried with Glauber's salt. The crude product obtained by distilling off the solvent under reduced pressure is purified by silica gel column chromatography. 2.72 g of N-(n-butyryl)-4-(n-propylthio)-〇-anisidine was obtained from the eluted fraction (hexane:ethyl acetate (C5:1)).

0.73g of lithium aluminum hydride under nitrogen stream
Suspend in 50 ml of HF. To this, N(n-butyryl)-
100 ml of a THF solution containing 1.7 g of 4-(n-propylthio)-0-anisidine are added in portions (keeping the internal temperature at 0-5° C.). The reaction was stirred at room temperature for 4 hours. Add appropriate amount of sodium sulfate hydrate and continue stirring. After diluting with water, extraction is performed using chloroform. The extract is washed with saturated saline and then dried with Glauber's salt. The solvent is distilled off under reduced pressure, and the resulting crude product is purified by silica gel column chromatography. Elute with hexane:ethyl acetate (I0:1) N-(n-butyl)-4-(n-propylthio)-o-anisidine 0
, 48g was obtained.

Melting point: 83.0-84.5°C (hydrochloride) MS (m/,
z): 253 (M) IH-NMR (δ, C
DCl5).

6.97 (IH, dd, J-8, 2, 2, 0), 6.
85 (IH, d, J-2, 0), 6.50 (IH
, d, J-8, 2) , 3.83 (3H, s) 3.
10 (2H, t, J-6,7), 2.74 (2H
, t, J-7, 2), 1.24-1.79 (6H, m
), 0.97 (6H,t,J-7,2)4-(n
Add 0.25 g of dimethylaminopyridine and 2.7 g of n-hexanoyl chloride to 150 ml of THE solution containing 2.5 g of -propylthio)-〇-anidine and 5.5 g of triethylamine (at this time, the internal temperature is brought to 0-5°C). keep).

After stirring at room temperature for 16 hours, an appropriate amount of 10% aqueous potassium hydroxide solution was added to the reaction mixture, and the mixture was further stirred for 30 minutes.

An extraction operation is performed using chloroform, and the extract is washed with saturated saline and then dried with Glauber's salt. The crude product obtained by distilling off the solvent under reduced pressure is purified by silica gel column chromatography. 3.09 g of N-(n-hexanoyl)-4-(n-propylthio)-0-anisidine was obtained from the hexane:ethyl acetate (5:1) elution fraction.

0.71g of lithium aluminum hydride under nitrogen stream
Suspend in 50 ml of HF. To this, N-(n-hexanoyl)-4-(n-propylthio)-〇-aningine 2.
50 ml of THF solution containing 0 g are added in portions (keeping the internal temperature at 0-5° C.). The reaction solution was heated at room temperature.
Stir for an hour. Add appropriate amount of sodium sulfate hydrate and continue stirring. After diluting with water, extraction is performed using chloroform. The extract is washed with saturated saline and then dried with Glauber's salt. The solvent is distilled off under reduced pressure, and the resulting crude product is purified by silica gel column chromatography. From the hexane:ethyl acetate (I0:1) elution fraction,
(n-hexyl)-4-(n-propylthio)-0-anisidine 0.72. I got it.

Melting point: 97.5-98.5°C (hydrochloride) MS (m/z
): 281 (M”) IH-NMR (δ, CDCl
5): 6, 97 (IH, dd, J-7, 9, 2, 1),
6.85 (IH, d, J-2, 1), 6.
50 (IH, d, J-8, 2), 4.20 (
IH.

br s ; NH), 3.85 (3H,s
), 3, 09 (2H,t, J-6,7)
, 2. 74 (2H, t, J-7, 2), 1
．． 28-1.77 (IOH, m), 0.97 (6
H, t, J, = 7, 3) 2) Formulation example (a) 50 parts of tablet active ingredient compound, 100 parts of corn starch, 25 parts of lactose, 2 parts of hydroxypropyl cellulose, 2 parts of talc, 1 part of magnesium stearate. The mixture is added, mixed well, and compressed using a key press to form tablets with a diameter of 10III11.

(b) Capsules 130 parts of corn starch, 40 parts of lactose, 20 parts of talc, and 10 parts of magnesium stearate are uniformly mixed with 100 parts of the active ingredient compound, and the mixture is made into powder or fine granules and placed in a capsule container to prepare capsules.

(e) Raw material 10 parts of the active ingredient compound are kneaded with 75,150 parts of Uitebusol E and 15,100 parts of Uitebusol E, and the mixture is filled into a raw material container to form a raw material.

3) Pharmacological test results (I) Inhibitory effect on Arthus reaction Method of Takahashi et al. (Japan Pharmacological Journal, 88.245-254 (I
The Arthus reaction was induced according to 986)), and the inhibitory effect of aniline derivatives on the reaction was investigated. ICR mice were intraperitoneally injected with 4 x 108 sheep red blood cells (SRBC), and 14 days later, the same number of 5RBCs were again intraperitoneally administered for sensitization. After 19 days, 2 x 108 5RBCs were injected into the paw of the hind paw to induce edema, and 4 hours later, the thickness of the paw was measured using a dial gauge. Test drug (300mg/
kg) was dissolved in distilled water or suspended in 0.596 carboxycellulose sodium solution and orally administered using a gastric tube 30 minutes before injection into the foot. Distilled water was administered to the control group, and (step thickness of control group) - (step thickness of drug group) (
The degree of suppression was expressed in mm).

The results are shown in Table 1.

(2) Suppressive effect on delayed-type hypersensitivity Takahashi et al. (Japanese Pharmacological Journal, 88.245, (I986)
). Balb/c male mice were sensitized by subcutaneously injecting 2 x 107 sheep red blood cells into the left hind paw. Four days later, 2 x 108 sheep red blood cells were subcutaneously administered to the right hind paw to induce a reaction. Paw thickness was measured 24 hours later. Dexamethacin, which is effective for rheumatoid arthritis, was used as a positive control, and the test drugs except Compound 3 were orally administered twice, on the day before sensitization and on the day of sensitization. Compound 3 was administered once on the day of sensitization. The results are shown in Table 3.

Administration of sheep red blood cells to sensitized animals increased paw thickness, whereas compounds 3 and 8 at 100 mg/k
This increase was significantly suppressed at 300 mg/kg or 300 mg/kg. In terms of inhibition rate, these compounds exceeded the control dexamethacin.

(3) Suppressive effect on collagen arthritis 0.1ag of bovine cartilage-derived type collagen was injected into the back skin of DBA/IJ female mice with complete Freund's adjuvant (08 days later), and 21 days later, 0.1g of collagen was injected with Freund's complete adjuvant. Injected intradermally at the base of the tail with incomplete adjuvant (day 21, 8). The tested drugs were 0.2.4, 8, 8.10.
100mg/9 times on the 12th and 21st and 23rd days
kg/day was administered orally. As a result, 7 out of 100 animals (70%) in the control group (non-administered group) developed arthritis, but only 2 out of 6 animals (33%) in the compound 8 administration group developed arthritis.

(4) Suppressive effect on adjuvant arthritis The suspension was suspended in liquid paraffin to serve as an adjuvant, and the suspension was injected intradermally into the right hind leg of SD male rats. The test drug was administered daily for 181 days from 5 days before the adjuvant injection until 17 days after the injection.
Eight days later, left hindlimb volume was measured. As shown in Table 4, Compound 8 showed a tendency to suppress the volume increase in the non-adjuvant-treated paw.

(5) Inhibitory effect on antibody production ability Cunningham method (Nature, 207.1106 (I
965)) was used. 4 x 108 sheep red blood cells are Ba
It was administered intraperitoneally to 1b/c female mice, and the lungs were removed 5 days later. Lung cells were prepared, filled in a Cunningham chamber with sheep red blood cells and complement, and left to stand at 37°C for 1 hour, after which hemolytic plaques were counted.

The test drug was orally administered at the time of red blood cell administration. The results are shown in Table 5.

The appearance of antibody-producing cells in mouse lungs against sheep erythrocytes was strongly suppressed by compound 8 and mildly suppressed by compound 3.

4) Acute toxicity test Weight 25. ICR male mice were used.

Aniline derivatives suspended in 0.5% sodium carboxymethyl cellulose solution or dissolved in distilled water were orally administered to mice, and observed for 7 days. Based on the mortality rate during the observation period, Lds was determined using the Litchfield-Wilcockkinson method.
The four results for which o was determined are shown in Table 2.

Table 1: 2 9 7 8 8 3 0 8 0 of aniline derivatives against Arthus reaction Table 2: Mouse 150 80 060 10 270 of aniline derivatives Table 3: Table 5: Antibody producing cells in mouse lung against sheep red blood cells Inhibitory effect of aniline derivatives on the appearance of the compound Dose (mg/kg/day) 3 300 8 25 0 00 Dexamethacin 0.05 (Dexar Aethasone) 0.10.2 0 00

Claims (1)

[Claims] 1. A pharmaceutically acceptable acid addition salt of an alkylsulfinylaniline derivative represented by the following formula (I) and a compound capable of forming an acid addition salt among them. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R_1 and R_2 each independently represent a hydrogen atom, an alkyl having 1 to 6 carbon atoms, or an acyl having 1 to 6 carbon atoms, and R_3 and R_4 each independently represent alkyl having 1 to 6 carbon atoms. 2. Pharmaceutically acceptable acid addition salts of alkylthioaniline derivatives represented by the following formula (II) and compounds capable of forming acid addition salts among them. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, R_1 and R_2 each independently represent a hydrogen atom or an alkyl having 1 to 6 carbon atoms (unless they are also hydrogen atoms), R_3 and R_4 each independently represent alkyl having 1 to 6 carbon atoms. 3. The alkylsulfinylaniline derivative according to claim 1, wherein in formula (I), R_1 is acetyl, R_2 is a hydrogen atom, R_3 is methyl, and R_4 is n-propyl. 4. The alkylthioaniline derivative and its pharmaceutically acceptable acid addition salt according to claim 2, wherein in formula (II), R_1, R_2 and R_3 are all methyl, and R_4 is n-propyl. 5. An anti-inflammatory agent containing any one or more of the compounds according to claims 1 to 4 as an active ingredient. 6. The anti-inflammatory agent according to claim 5, wherein the inflammation is due to rheumatoid arthritis.