JPS62132825A - Antirheumatic agent - Google Patents

Abstract

PURPOSE:To provide an antirheumatic agent containing a 2-acylthio-methyl-3- benzyolpropionic acid derivative as an active component, having weak side effect and toxicity and excellent immuno-regulation function and effective for the remedy of immuno-insufficiency diseases. CONSTITUTION:A benzoylpropionic acid derivative of formula I (R<1> is H, lower alkyl, etc.; R<2> is lower alkyl or phenyl; X is H, halogen, etc.; Y is H or lower alkyl) is used as an antirheumatic agent. The compound of formula I strongly suppresses adjuvant arthritis and has immuno-regulating activity and antiarthritis activity. The compound of formula I is useful also as a remedy for immuno- insufficiency diseases such as arthrorheumatism, autoimmune diseases, various carcinomas, bacteriosis, asthma, hepatopathy, etc., and has low side effect and toxicity. The compound can be produced by reacting the compound of formula II with the compound of formula R<2>COSH in an organic solvent in the presence of a basic catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION The invention relates to an anti-rheumatic agent, more specifically an anti-rheumatic agent having an immunoregulatory function and effective in treating diseases caused by immune dysfunction.
-An anti-rheumatic agent containing an acylthiomethyl-3-benzoylpropionic acid derivative as an active ingredient.

Conventionally, so-called immunosuppressants have been used to treat autoimmune diseases such as rheumatoid arthritis, but their suppressive effects are generally based on cytotoxicity, and their severe side effects require continuous use over long periods of time. It was difficult to say that it was suitable as a therapeutic agent for autoimmune diseases that require administration.

For this reason, in recent years, so-called immunomodulators have been developed that have the effect of normalizing immune function by activating immune function when it is weakened and suppressing it when it is abnormally active. It began to be used to treat diseases involving
This was also not necessarily satisfactory in terms of its effectiveness, side effects, toxicity, etc.

Between 1. In order to overcome these drawbacks, the present inventors have conducted extensive research and found that 2-acylthiomethyl-3-benzoylpropionic acid derivatives have excellent immunomodulatory functions and are free from side effects and toxicity. The present invention was completed by discovering that this is weak.

The object of the present invention has the general formula (wherein R1 represents a hydrogen atom, a lower alkyl group, or 1 represents a benzyl group, R1 represents a lower alkyl group or a phenyl group, and X represents a hydrogen atom, a halogen atom, The active ingredient is a benzoylpropionic acid derivative (hereinafter referred to as compound I) represented by a lower alkyl group, a lower alkoxy group, a phenoxy group, or a halogenophenoxy group, and Y represents a hydrogen atom or a lower alkyl group. It is an anti-rheumatic agent.

Here, the halogen atom represented by X is fluorine, chlorine, bromine, etc., and the lower alkyl group represented by R', R', It is an alkyl group with a shape.

Further, the lower alkoxy group represented by X is a lower alkoxy group having 3 or less carbon atoms, and the halogenophenoxy group includes a chlorophenoxy group, a bromphenoxy group, and the like.

Compound I can be produced, for example, by the following method.

That is, (1) a carboxylic acid compound represented by the general formula (wherein X and Y have the same meanings as above) (hereinafter referred to as compound 2) is dissolved in an organic solvent (for example, methanol, ethanol, acetone,
(dimethylformamide, hexamethylphosphoric acid triamide, dimethyl sulfoxide, etc.), and add an equivalent to 2 equivalents of a thiocarboxylic acid represented by the general formula % (wherein, R8 has the same meaning as above), and add 0.01 to 2 equivalents. 0.1
in the presence of an equivalent amount of a basic catalyst (e.g., sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, etc.) at -20 to 50°C.
By reacting for 4 hours, a carboxylic acid type compound I (a compound in which R' is a hydrogen atom in formula I) is produced.

(2) A base (e.g., sodium carbonate,
Potassium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide,
A common alkylating agent consisting of a lower alkyl group or benzyl group represented by R1 in formula (II) or benzyl is added to the carboxylic acid type compound I obtained in the previous section <1) in the presence of sodium hydride, sodium alkoxide, etc. An ester-type compound
' is a lower alkyl or benzyl group).

Compound (1), which is a starting material, is, for example, R, E, Lut
z) method (Journal of American
Chemical 5oci-ety, Volume 75,
page 5039 (1953)] or a method similar thereto, a benzene derivative represented by the general formula (wherein, It can be produced by subjecting it to a 7-Riedel-Kraf reaction.

Compound I can be prepared as powders, tablets, granules, etc. by dispersing the active ingredient in a commonly used carrier or diluent using a conventional method.
Can be used as solid preparations for oral administration such as capsules, microcapsules, and troches; liquid preparations for oral administration such as solutions, suspensions, and emulsions; or parenteral preparations such as injections, ointments, and creams. can be provided.

Carriers that can be used to prepare solid preparations for oral administration include:
Excipients such as lactose, glucose, crystalline cellulose, mannitol, corn starch, sugar, binders such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gelatin, gum acacia, wetting agents such as glycerin, ethylene glycol, There are disintegrants such as corn starch, potato starch, calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose, and lubricants such as calcium stearate, magnesium stearate, talc, polyethylene glyfur, and hydrogenated oil. Surfactants, colorants, flavoring agents, etc. can be used.

Diluents that can be used to prepare liquid preparations for oral administration include water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, tragacanth, and, if necessary, solubilizing agents, buffers, preservatives, fragrances,
Coloring agents, flavoring agents, etc. can be added.

In addition to the above, bases such as cocoa butter, polyethylene glyfur, witebsol, macrogol, white petrolatum, and the like can be used to prepare preparations for parenteral administration.

The dosage of compound ① varies depending on various factors such as the patient's weight, age, symptoms and their severity, and the route of administration, but is usually 10 to 1500 mg divided into 1 to 3 times a day. It is preferred to administer.

Compound l has an excellent immunoregulatory function and has few side effects and toxicity, so it is effective against diseases caused by immune dysfunction, such as rheumatoid arthritis, autoimmune diseases such as colic, bacterial infections, asthma, and liver disease. It is useful as a therapeutic agent for diseases, etc.

Hereinafter, the method for manufacturing Compound I and the method for preparing the preparation will be explained in Reference Examples and Examples, and the excellent effects of Compound I will be explained in detail in Test Examples.

Reference example 1 Toluene 35. Of and fi water Itaconic acid (22.4 f) was dissolved in methylene chloride (150 g), and anhydrous aluminum chloride (50 g) was added thereto while stirring while cooling with water. After gradually adding Of, the reaction mixture was stirred at room temperature for 5 hours.

After the reaction, the reaction solution was concentrated under reduced pressure and mixed with 40% of concentrated hydrochloric acid and 50% of ice.
The mixture was poured into a mixture of 0.02 and extracted with ethyl acetate. This extract was washed with water, dried over magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from hexane-ethyl acetate to give 3-(
4-Methylbenzoyl)-2-methylenepropionic acid (
In the above equation 1, X=C! H3, Y=H compound)2
1.6F (yield 53%) was obtained.

m, p, 157-138°C Reference Example 2 According to Reference Example 1, using the corresponding compound ■,
In the above formula (■), X = (aH3)2aH, Y =
H (m, p, 144-146°C, yield 51%);
= CH30゜Y =H(m, p, 13111-1
40°C, yield 44%): X = p -C7C6H40
, Y=H (m, p, 444~+45℃, yield 44%
); X=CH3, Y=2-CH3(m, p,
IO&5-1095°C, yield 12%); X=C
H3,Y=3-CH3(m,p,144-146℃,
Each compound was obtained in a yield of 55%.

Example 1 190 ml of 3-baesyl-2-methylenepropionic acid was dissolved in 30 ffl/dimethylformamide, thioacetic acid aoy was added thereto, and 30% potassium carbonate aqueous solution WL2.5- was added dropwise over 30 minutes while stirring at room temperature. Then, the reaction mixture was further stirred at room temperature for 30 minutes.

After the reaction was completed, ice water was added to the reaction solution, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. After washing the organic layer with water and drying with magnesium sulfate/rum, ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Fuco-gel C-
200, manufactured by Wako Pure Chemical Industries, Ltd.; developing solvent: hexane-chloroform), and then recrystallized from hexane-ethyl acetate to obtain crystals of 2-acetylthiomethyl-3-benzoylpropionic acid 24. s y (yield 92%) was obtained.

m, p, 100-101℃ Elemental analysis value Calculated value as C13H14o4S (%)
: 0 58.63. H5,30 actual measurement value (%):
C5&67, H5,3+Examples 2 to 11 The following Compounds I were synthesized according to Example 1 using the respective corresponding compound ports.

Example 12 The same procedure as in Example 1 was carried out using 10-thiopropionic acid instead of 110 m/s of thioacetic acid, resulting in crystals of 3-benzoyl-2-propionylthiomethylpropio/acid.
9.0! (yield: 68%).

m, p, 76-78℃ Elemental analysis value Calculated value as C14H1604S (%)
I C59,98, H5,75 actual value (%): C6
0,21,H5,69 Example 15 In Example 1, thiobenzoic acid i6.59 was used instead of thioacetic acid aO-, and the crystals of 3-benzoyl-2-benzoylthiomethylpropionic acid were obtained. +t2
f (yield 34%) was obtained.

m, p, iio~111℃ Elemental analysis value 0111 Calculated value as H16o4S (%
) I C65, B4. H4,9j actual value (%): C
6612, H5, 07 Example 14 In Example 1, 3-benzoyl-2-methylenepropionic acid 19. 3-(4-brombenzoyl)-2-methylenepropionic acid instead of Or 26.9! , thiopropionic acid 10- was used in place of thioacetic acid aO- to give 25.59 crystals of 3-(4-brombenzoyl)-2-propionylthiomethylpropionic acid (yield 71%). Ta.

m, p, 122.5-123℃ Elemental analysis value (calculated value as 44H15Br04 S (
%): C46,8+, H4,2+ actual measurement value (%)
: C46,77, H4,37 Example 15 In Example 14, thiobenzoic acid 1652 was used in place of thiopropionic acid 10-, and 3-(4
-Brombenzoyl)-2-benzoylthiomethylpropionic acid crystals +4.79 (yield 36%) were obtained.

m, p, 133-135 °C Elemental analysis value C (calculated value as 8H15Bro4S (%
): C53,08,H3,7+actual value (%):C
5i11. H3,87 Example 16 Dissolve 26.69 of 2-acetylthiomethyl-3-be/diylpropionic acid in 200 of dimethylformamide,
Diethyl sulfate 15.6 F and potassium carbonate i 4.
Of was added and stirred at room temperature for 3 hours to react.

After the reaction was completed, ice water was added to the reaction solution, and the mixture was extracted with ether. After washing the organic layer with water and drying with magnesium sulfate, the ether was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Cuco-gel C-200, manufactured by Wako Pure Chemical Industries, Ltd.; developing solvent: hexane-ether). The product was purified to obtain colorless oily 2-acetylthiomethyl-3-benzoylpropionic acid ethyl ester 22.1 F (yield 75%).

NMR (CDC1B), ppm 127 (3H, t, J = 7Hz), 2.36 (3H, s
).

3.12-5.60 (5H, m), 4.19 (2H
, q, J=7Hz).

7.52 (3H, m), 7.98 (2H, d, J=
8Hz) Elemental analysis value cts HI8 Calculated value as o4S (%): C61,20,H6,16 actual value (%
): C6110,H6,15 Example 17 In Example 16, 2-acetylthiomethyl-3-(4-brombenzoyl)propionic acid 54 was substituted for 2-acetylthiomethyl-3-benzoylpropionic acid 26.6 f. .5f, using dimethyl sulfate + 2.8f instead of diethyl sulfate 15,69, and treating in the same manner to obtain colorless oily 2-acetylthiomethyl-5-(4-frombenzoyl)furopionic acid methyl ester 34.89 (yield 97%).

NMR (CD(!t3), ppm 2.33 (3H, s), 107-156 (5H, m),
171 (3H, s), 7.62 (2H, d, J=8Hz
), 7.82 (2H.

6, :r=BHz) Elemental analysis value Calculated value as C14H15Br04S (%
): c 46.81. H4,21 actual measurement value (%)
:C! 46.55. H4,16 Example 18 In Example 17, diethyl sulfate 15.6 F was used instead of dimethyl sulfate 12.8 F, and 2-acetylthiomethyl-3-(4-brombenzoyl) was obtained as a colorless oil. 27.29 (yield 73%) of fropionic acid ethyl ester was obtained.

NMR (CDC13), ppm 1.26 (3H, t, J=7H2), 2.35 (
3H, 8), 3.06-3.54 (5H, m), 4.
18 (2H, q, J=7Hz).

7.62 (2H, d, J=8Hz), 7.83 (2H,
d, J+8Hz) Elemental analysis value C15H17Br04S
Calculated value (%): c 4a27. H4,5
9 Actual value (%): c 4a4s, H4,63 Example 19 In Example 17, 2-iodopropane 3402 was used in place of 12.8f of dimethyl sulfate and 2-iodopropane 3402 was used for the same treatment to produce colorless oily 2-acetylthio. Methyl-5-(4-brombenzoyl)propio/acid inglovir ester 50.2
f (yield 78%) was obtained.

NMR (cDCt3) + ppm 1.25 (5H, d, J=7Hz), 1.27 (
3H, d, J=7Hz).

2.34 (3H, s), xo4~154 (5H, m)
, 5.05 (IH.

5eptet, J=7Hz), 7.63 (2H, d
, J=8Hz).

184 (2H, d, J=8Hz) Elemental analysis value Calculated value as C16H1gC16H1 (%
): C49,62,H4,94 actual measurement value (%):
C49,65,H4,94 Example 20 In Example 17, 20.59% of benzyl bromide was used instead of 128% of dimethyl sulfate, and 2-
Acetylthiomethyl-3-(4-brombenzoyl)furopionic acid benzyl ester 37,09 (yield 85%)
) was obtained.

m, p, 79-80°C [recrystallized from hexane-ether] Elemental analysis value C! aH+ *Calculated value (%) as Br04S: C55,18, H4,40 theoretical value (%)
: C55,19, H4,58 Example 21 600 g of Compound I, 120 g of crystalline cellulose, and 126 g of corn starch were mixed to make a uniform mixed powder, and granules were prepared by wet granulation using 45 g of hydroxypropyl cellulose as a binder. . After mixing 9 g of magnesium stearate with this, it was compressed into tablets with a diameter of 9 mm.
, 3,000 tablets each weighing 300 mg were obtained.

Example 22 600 g of Compound I, 150 g of crystalline cellulose, 140 g of corn starch, and 10 g of magnesium stearate were uniformly mixed.

This mixed powder was filled into No. 1 hard capsules at a rate of 300 mg per capsule to obtain 3,000 capsules.

Example 23 200 g of Compound I, 300 g of mannitol, 450 g of corn octopus, and 10 g of magnesium stearate were mixed to form a uniform mixed powder, and granules were prepared by wet granulation using 50 g of hydroxypropyl cellulose as a binder. 1.000 g of the agent was obtained.

Example 24 200 g of Compound I and 800 g of lactose were uniformly mixed to prepare a powder, which was divided into 1.000 mg portions to form Powder 1.
．． 000 packets were obtained.

Test Example 1 [Adjuvant arthritis in Sprague-Dawley rats (
Effect on Chronic Rheumatoid Disease Model] 8-week-old Sprague-Dawley rats (weight 160-190 g) 10
Animals were subjected to the test as a group.

Rats in each group were sensitized by subcutaneous injection into the tail of a suspension of 0 or 6 mg of dead tuberculosis cells (bovine type) in liquid paraffin. Various compounds I were suspended in a 5% gum arabic solution, and varying amounts were orally administered to separate groups of rats once a day from the day of sensitization. The volume of edema in the hind limbs of the rats in the drug-administered group and the control group (no-drug-administered group) was measured over time to examine the swelling-inhibiting effect of the compound.

The results on the 21st day after sensitization are shown in Tables 1 and 2.

(Note) (1) Compound I produced in Examples was given the same number as the number of that Example to be used as a drug number.

(2) Umbrella: There is a significant difference at P<0.05 by T-test.

(3) Umbrella*: There is a significant difference at P<0.01 by T-test.

From the above results, it was confirmed that Compound I strongly suppressed adjuvant arthritis in Sprague-Dawley rats and had immunomodulatory and anti-arthritic effects.

Test Example 2 [Effect on adjuvant arthritis in Lewis rats (
9 slow-acting female Lewis rat (weight 180-190 g)
A group of 10 animals was used for the test.

Rats in each group were sensitized by subcutaneous injection into the tail of a suspension of 0 or 6 mg of dead tuberculosis cells (bovine type) in liquid paraffin. Various compounds I were suspended in a 5% gum arabic solution, and 100 mg/kg of compound I was orally administered to separate groups of rats once a day from the day of sensitization. D-penicillamine was used as a comparison drug, which was dissolved in water and administered orally to separate groups as in the case of Compound I.

The volume of edema in the hind limbs of the rats in the drug administration group and the control group (no drug administration group) was measured over time, and the compound ■
We investigated its anti-swelling effect.

Table 3 shows the results on the 211th day after sensitization.

(Note) (1) The same number as the number of the example was attached to the compound drug produced in the example to obtain the drug number.

(2) Umbrella: There is a significant difference at P<0.05 by T-test.

(3) Umbrella: There is a significant difference at P<0.01 by T-test.

From the above results, it was confirmed that compound (1), like D-penicillamine, promoted adjuvant arthritis in Lewis rats and had a cell immunostimulating effect.

Test Example 3 [Suppressive effect on delayed foot placement reaction (wipe immunomodulatory effect)] Bal b/c female mice, 8 to 12 weeks old (body weight 20
~24g) A group of 8 animals was used for the test. Mice in each group were sensitized by subcutaneously injecting IXIG' sheep red blood cells as an antigen directly into the right foot.

Various compounds I were suspended in 0.5% gum arabic-physiological saline, and varying amounts were administered intraperitoneally to separate groups of mice 2 hours after sensitization. On the 4th day after sensitization, 1×10” sheep red blood cells were injected subcutaneously into the right foot of each group of mice, using the method of Lagrange et al. (Journal of
Experimental Medicine, Vol. 139, p. 528 (1974)] to measure the increase in the thickness of the edematous foot, and to examine the inhibitory effect on the delayed foot placement response.

The results are shown in Table 4.

(Note) 1) The same number as the number of the example was attached to the compound (1) produced in the example to give the drug number.

(2) *; There is a significant difference at P<0.05 by T-test.

(3) II; There is a significant difference at P<0.01 by T-test.

From the above results, Compound I suppresses the delayed foot placement reaction,
It was found that it has a strong immunomodulatory effect.

Test Example 4 [Promoting effect on lymphocyte rejuvenation reaction (immunomodulatory activation effect)] A medium containing only compound ■ in RPMI-1640 (manufactured by GIBCO) and a rejuvenating agent (
Lipopolysaccharide 0.2 μg/-) and compound ■
B medium was prepared.

Female BDF, mouse, 8-12 weeks old (body weight 20-22 g)
) were cultured in separate media for 48 hours at 37°C in a 5% carbon dioxide incubator, and then 0.25 μCi of H-thymidine was added to each culture medium for an additional 22 After culturing, the lymphocytes were collected and their radioactivity was measured, and the degree of rejuvenation was determined from the amount of 1H-thymidine taken into the lymphocytes.The results were compared with the control medium (compound It is expressed as a percentage of the amount of H-thymidine taken into lymphocytes in a medium (without I added), and is shown in Table 5.

(Note) (1) The same number as the number of the example was attached to Compound I produced in the example to obtain the drug number.

(2> books; there is a significant difference at P<0.05 by T-test.

(3) * to +; There is a significant difference at P<0.01 by T-test.

From the above results, it was confirmed that Compound I promotes the rejuvenation of mouse lung lymphocytes by lipopolysaccharide and has an immunoregulatory function activation effect.

Test Example 5 [Acute toxicity test] 7 Appropriate age Wistar male rats (body weight 149-160
g) A group of 7 animals was used for the test.

A suspension of Compound I obtained in Example 1 in a 5% gum arabic solution was orally administered to the rats, and the progress for 7 days after administration was observed to determine the LDsa value.

This LD. The value was 1200 mg/kg or more.

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents a hydrogen atom, lower alkyl group, or benzyl group, R^2 represents a lower alkyl group or phenyl group, and X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a phenoxy group, or a halogenophenoxy group, and Y represents a hydrogen atom or a lower alkyl group. Rheumatism medicine.