JPS63277656A - Benzoic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula (n is 0-2; R1 and R2 are H, halogen, lower alkyl, lower alkoxy, etc.; R3 is H, lower alkyl, etc.) and its alkali metal salt. EXAMPLE:N,N'-diethyl-4-chloro-2,2'-thiodibenzoic acid diamide. USE:A prophylactic agent. It has strong activity to promote the migration and phagocytotic actions of macrophage and low toxicity and, accordingly, it is useful to the treatment of animal having lowered immunological competence caused by cancer, etc. PREPARATION:The compound of formula can be produced by adding thionyl chloride to a 2,2'-thiodibenzoic acid derivative, a 2,2'-sulfinyldibenzoic acid derivative or a 2,2'-sulfonyldibenzoic acid derivative, refluxing the mixture, removing the solvent under reduced pressure and reacting the resultant acid chloride with an aqueous solution of an alkylamine in THF solution.

Description

DETAILED DESCRIPTION OF THE INVENTION Part 1: The present invention relates to an agent for preventing infection. More specifically, the present invention is based on the general formula % (where n is an integer of 0 to 2, and R1-R2 are each the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a nitro group). , R3 represents a hydrogen atom or a lower alkyl group, provided that n is 0 to 2, all of R1-R2 are hydrogen atoms, and R3 is i
- when it is a propyl group, n is 0 or 2 and R1-
All of R2 are hydrogen atoms and R3 is a hydrogen atom or n
- except when it is a butyl group. ) or an alkali metal salt thereof.

Compounds represented by general formula (I), where n is 0 to 2
A compound in which all of R1-R2 are hydrogen atoms and R3 is an i-propyl group, and a compound in which n is O or 2 and R1-R2
Compounds in which all of are hydrogen atoms and R3 is a hydrogen atom or an n-butyl group are
American Chemical Society (Journal)
of the American Chemica
lSociety) 1978+upper d(3) 953-96
2 and (IL FARMACOEDIZIONE
5CIENTIFICA) 1959, X Sat ■ Ba 12
) 829-844'', the method for producing it is described.

However, the former literature does not mention its pharmacological effects. Moreover, the latter document only mentions antibacterial action.

Other compounds represented by general formula (I) are novel benzoic acid derivatives that have not been described in publications such as literature, and their pharmacological effects are, of course, unknown.

Mouth, (°　　　　.

Currently, infectious diseases are caused by microorganisms such as various viruses, chlamyzoia, rickettsiae, bacteria, fungi, protozoa, spirochetes, and parasites that invade the human body, overcome the host's resistance, and multiply within the body's organs and tissues. , 6 It is thought that the disease is caused by various types of microorganisms that cause various lesions. Various antibiotics and chemotherapeutic agents are used as treatment methods, but the spectrum of their anti-infection effects is not necessarily wide, and some types of microorganisms tend to develop resistance. There is no perfect treatment for infectious diseases.

Therefore, the present inventors have conducted extensive research to solve the above problems, and have found that the compound of the present invention particularly promotes the migration ability and phagocytosis ability of macrophages, and has an excellent effect on infection in animals with decreased immune function. We have completed the present invention by discovering that it has a protective effect and has very few side effects.

. The present invention provides an infection-preventing agent containing a novel benzoic acid derivative represented by the general formula (I) and its alkali metal salt as active ingredients.

Regarding general formula (I), the lower alkyl groups represented by R1-R2 and R3 include methyl, ethyl, n-propyl, i-propyl, and n-butyl.

Examples include i-butyl and t-butyl groups.

Lower alkoxy groups include methoxy, ethoxy, n-
Examples include propoxy, i-propoxy, n-butoxy, i-butoxy, and t-butoxy groups.

The compounds used in the infection prevention agent of the present invention are specifically disclosed below: N,N'-dimethyl-3-ethyl-2,2'-thiodibenzoic acid diamide, N,N'-dimethyl-5-n -Propyl-2,29-thiodibenzoic acid diamide, N, N'
-dimethyl 4,6-dimethyl-2゜2''-thiodibenzoic acid diamide, N,N'-dimethyl-5-ethyl-2,2
'-thiodibenzoic acid diamide, N,N'-dimethyl-4
-Chloro-2゜2'-thiodibenzoic acid diamide, N,N
'-Dimethyl-5-methyl-2,2'-thiodibenzoic acid diamide, N,N'-dimethyl-3-methyl-2゜2'
-thiodibenzoic acid diamide, N, N'-dimethyl-
5-n-butyl-2,2'-thiodibenzoic acid diamide,
N,N'-dimethyl-3,5-dimethyl-2,2''-thiodibenzoic acid diamideININ'-diethyl-4-chloro-2,2'-thousodibenzoic acid diamide, N,N''-diethyl-3 , 6-dimethyl-2,2'-thiodibenzoic acid diamide.

N,N'-di-mypropyl-4-chloro-2゜2'-
Thiodibenzoic acid diamide, N,N'-diethyl-4-chloro-2,2'-sulfinyldibenzoic acid diamide, N
, N''-dimethyl-5-n-butyl-2,2'-sulfinyldibenzoic acid diamide, N,N'-dimethyl-4-
Chloro-2,2'-sulfonyl dibenzoic acid diamide, N
, N'-dimethyl-5-nitro-2,2'-sulfonyl dibenzoic acid diamide, and the like.

The 2,2'-thiodibenzoic acid derivative serving as a raw material for the compound of the present invention has the general formula (wherein R1-R2 have the same meanings as above, and X is
Indicates a halogen atom. ) and thiosalicylic acid.

Examples of the halogenobenzoic acid derivative as a raw material include 2-bromo-3,4,5-)rimethoxybenzoic acid, 2-bromo-3,4,5-)rimethoxybenzoic acid,
Bromo-4,5-dimethoxybenzoic acid, 2,4-dichlorobenzoic acid, 2-iodo-3-methyl-4-chloro-benzoic acid, 2-iodo-4,5-dimethylbenzoic acid, 2-
iodo-4,6-dimethylbenzoic acid, 2-iodo-3,
4-dimethylbenzoic acid, 2-iodo-3,6-dimethylbenzoic acid, 2-iodo-3,5-dimethylbenzoic acid.

2-Iodo-5,6-dimethylbenzoic acid, 2-bromo-
4-t-butylbenzoic acid, 2-iodo-5-n-butylbenzoic acid, 2-iodo-5-n-propylbenzoic acid, 2
-iodo-5-ethylbenzoic acid, 2-iodo-5-methylbenzoic acid, 2-iodo-3-i-propylbenzoic acid,
2-Iodo-3-ethylbenzoic acid, 2-iodo-3-methylbenzoic acid, 2-chloro-4-nitrobenzoic acid, 2-
Chloro-5-nitrobenzoic acid, 2-chloro-3,5-dinitrobenzoic acid, etc. are used.

The reaction between the 2-halogenobenzoic acid derivative and thiosalicylic acid is carried out in the presence of a solvent using an alkali and a metal catalyst at a temperature of 90°C or higher, and is generally carried out at a temperature of 100 to 200°C for 2 to 200°C.
It is carried out for 10 hours, preferably at 110-130''C for 3-5 hours.

As a solvent, nitrobenzene, benzyl alcohol,
Dimethylformamide, xylene, toluene-dimethylformamide mixed solvent, etc. are used.

Thiosalicylic acid is a 2-halogenobenzoic acid derivative,
It is advisable to use an excess amount, preferably in an amount of 1.1 to 1.2 mol. As an alkali, anhydrous potassium carbonate,
Anhydrous sodium carbonate or the like is used, and as a metal catalyst, a metal compound such as copper powder, cuprous chloride, cupric chloride, cuprous bromide, cupric bromide, or cupric acetate is used.

The obtained 2,2''-thiodibenzoic acid derivative can be converted into an alkali metal salt such as a sodium salt or a potassium salt by a conventional method.

The 2,2''-sulfonyl dibenzoic acid derivative, which is a raw material for the compound of the present invention, can be obtained by oxidizing the 2,2''-thiodibenzoic acid derivative in formic acid or acetic acid with hydrogen peroxide at 25°C or higher. The obtained 2,2'-sulfonyldibenzoic acid derivative can be converted into an alkali metal salt such as a sodium salt or a potassium salt by a conventional method.

The 2,2''-sulfinyl dibenzoic acid derivative, which is a raw material for the compound of the present invention, is obtained by esterifying a 2,2'-thiodibenzoic acid derivative by a conventional method and oxidizing it with peracid to obtain 2,2'-sulfinyl dibenzoic acid diester. Obtained by obtaining a derivative and hydrolyzing the obtained compound. Obtained 2,
The 2'-sulfinyl dibenzoic acid derivative can be converted into an alkali metal salt such as a sodium salt or potassium salt by a conventional method.

The amide derivative represented by general formula (I) can be obtained by adding thionyl chloride to a 2゜2'-thiodibenzoic acid derivative, a 2,2'-sulfinyl dibenzoic acid derivative, or a 2,2'-sulfonyl dibenzoic acid derivative. The acid chloride is obtained by refluxing and removing the solvent under reduced pressure, and can be synthesized by reacting an aqueous solution of an alkylamine in a tetrahydrofuran solution.

1-The novel compound represented by the general formula (I) of the present invention exhibits an excellent infection-preventing effect on animals with low immune function.

As for its administration form, it is used orally or parenterally in the form of various pharmaceutical compositions. Examples of the dosage form of the pharmaceutical composition include turnips, granules, tablets, syrups, suspensions, injections, and the like. Further, these pharmaceutical compositions are formulated by conventional methods using conventional additives such as excipients, binders, disintegrants, lubricants, flavoring agents, preservatives, and stabilizers.

The dosage of the compound of the present invention as an infection-preventing agent varies depending on the patient's age, weight, symptoms, etc., but for a normal adult,
In the range of 0 mg to 2000-g/day, preferably 501
Administer in 1 to 3 divided doses per day within the range of g to 1000 g/day. Examples of unit dosages are 10-g and 50-g.
g, 100-g, 200+=g, etc., but of course it is not limited to these. Next, the present invention will be explained in more detail with reference to Production Examples, Examples, and Formulation Examples.

竫λ肚-1 7.64 g of 2,4-dichlorobenzoic acid and 7.16 g of thiosalicylic acid were suspended in 20 ml of benzyl alcohol, and 22.0 g of anhydrous potassium carbonate and 3
00-g of copper powder was added, and the mixture was heated under a nitrogen stream while stirring.
Heat at 10-120°C for 3 hours. After cooling, 10% aqueous potassium hydroxide solution (120 ml) was added and extracted with ether. The separated aqueous layer is filtered, acidified with 6N hydrochloric acid, and the precipitated crystals are filtered out. When this crystal was recrystallized from aqueous methanol, 4-chloro-2,2'-thiodibenzoic acid (compound N11) with a melting point of 241 to 242°C was obtained.
8.56 g (yield 70%) of 1) is obtained.

Elemental analysis value; Calculated value as C+4Hg C104S (
%) ;C,54,4G H,2,94CI, 11
．． 48 Actual value (%); C, 54,32H, 2,95CL 1
1.50 11 per 1 hour The compounds shown in Table 1 were obtained in the same manner as in Reference Example 1. (Compounds 2 to 22) Table 1 8.72 g of 4-chloro-2,2'-thiodibenzoic acid dimethyl ester was dissolved in methylene chloride, and 4 g of metachloroperbenzoic acid was added to this solution. Add acid and stir at room temperature for 6 hours. This reaction solution is poured into 10% caustic soda water, extracted with methylene chloride, and the methylene chloride layer is washed with saturated saline, dried over magnesium sulfate, and concentrated to obtain crystals. The crystals are heated with 20% caustic soda water at 60° C. for 3 hours, cooled, and then acidified with hydrochloric acid to obtain crystals. When these crystals are recrystallized from aqueous methanol, 4-chloro-2,2''-
Sulfinyl dibenzoic acid (compound N[123) is 4.5
g (yield 70%) is obtained.

Elemental analysis value; Calculated value (%) as C2ξH9C105S
;C,51,78H,2,79CI, 10.92 Actual value (%) ;C,51,85H,2,EiOCl,
11.13 -1'' - The compounds shown in Table 2 were obtained in the same manner as in Reference Example 23. (Compound positions 24 to 31) Table 2 RI C0OH pot 211-J" and 8.0 g of 4-chloro-2,2'-thiodibenzoic acid were
Suspended in 0 ml of acetic acid, added 21 ml of 35% hydrogen peroxide solution, reacted for 3 hours with stirring at room temperature, and then
Heat and stir at 0°C for 3 hours.

When this reaction solution is poured into ice water, crystals are precipitated. When these crystals are filtered and recrystallized from aqueous methanol, the melting point is 27.
6.2 g (yield: 70%) of 4-chloro-2,2.degree.-sulfonyl dibenzoic acid (compound No. 32) having a temperature of 6 to 277.degree. C. is obtained.

Elemental analysis value; Calculated value (%) as C14H9Cl08S; C,49,35H,2,l1ieCI, 1
0.40 Actual value (%); C, 49,52H, 2,89CI,
10J9 ~ The compounds shown in Table 3 were obtained in the same manner as in Reference Example 32. (Compounds N1133-54) Table 3 3.3 g of 3-ethyl-2,2'-thiodibenzoic acid was
Suspend in 0 ml of benzene, add 15 ml of thionyl chloride to this suspension, and reflux for 3 hours with stirring. Next, this reaction solution is concentrated to obtain crystals. 30 of these crystals
ml of tetrahydrofuran, and add 30 ml to this solution.
A 40% aqueous methylamine solution of No. 1 was added dropwise to the solution while cooling with water. After the completion of the dropwise addition, the reaction solution was stirred overnight at room temperature, concentrated, and then reduced to 10%
Add caustic soda water and filter the precipitated crystals.

By recrystallizing this crystal from a benzene-n-hexane mixture, 2 g (yield: 56%) of an amide compound (compound No. 55) having a melting point of 191 to 192° C. is obtained.

Elemental analysis value: C19Hz. 02 Calculated value as N2 S (%); C, 1li5.83 H, G, 14 Actual value (%); The compounds shown in Table 4 were obtained. (Compound positions 56 to 66) Table 4 CONHR 3% methylamine aqueous solution (50 ml) was added dropwise.

Fruit 19-13- 1,6 g of N,N''-diethyl-4-chloro-2,2'
−thiodibenzoic acid diamide with dry methylene chloride (
Dissolve m-chloroperbenzoic acid (80 ml) under water cooling.
0.8g). Stirring is performed at room temperature for 1.5 hours. The methylene chloride layer is washed with saturated sodium bicarbonate water and then with saturated saline, and then dried over magnesium sulfate. When the solvent is concentrated under reduced pressure, crystals are formed. When this crystal is recrystallized from a benzene-n-hexane mixture, N,N''-diethyl-4-chloro-2,2'-sulfinyldibenzoic acid diamide (compound N[187) with a melting point of 200-202°C is obtained. 1.5g is obtained.

Ura IJt-yu”.

5 g of 4-chloro-2,2'-sulfinyl dibenzoic acid are suspended in dry benzene (50 ml), 30 ml of thionyl chloride are added and refluxed for 3 hours. Subsequently, the solvent is removed under reduced pressure to obtain the acid chloride. This acid chloride was dissolved in tetrahydrofuran (50 ml), and 40 methylamine aqueous solution (50 ml) was added dropwise under water cooling. Concentrate under hot pressure and add 5% hydroxide) to form crystals. When these crystals are collected by filtration and recrystallized with a benzene-n-hexane mixture, the melting point is 203 ~
N,N'-dimethyl-4-chloro-2,2 at 205°C
'-Sulfinyl dibenzoic acid')amide (compound Na6
8) was obtained in an amount of 3.4 g.

Kencho-11 N, N with a melting point of 132 to 133°C in the same manner as in Example 14
'-Dimethyl-5-n-butyl-2,2'-sulfinyl dibenzoic acid diamide (compound Nf169) is obtained.

Example 1 1 - Above 4 g of 4-chloro-2,2'-sulfonyl dibenzoic acid was suspended in dry benzene (50 ml), thionyl chloride (20 ml) was added, and the mixture was refluxed for 3 hours. Subsequently, the solvent is removed under reduced pressure to obtain the acid chloride. This acid chloride was dissolved in tetrahydrofuran (50 ml),
(40% concentration under water cooling and 5% hydroxide) When an IJium aqueous solution is added, crystals are formed. The crystals were collected by filtration and recrystallized using a mixed solvent of benzene-〇-hexane to yield N,N'-dimethyl-4-chloro-2,2'-sulfonyldibenzoic acid diamide (melting point 221-222°C). Compound m70) is obtained.

The above compound [70] can also be obtained as follows.

3.3 g N,N"-dimethyl-4-chloro-2,2'
- Thiodibenzoic acid diamide is suspended in acetic acid (30 ml), 10 ml of 35% hydrogen peroxide solution is added, and the mixture is reacted for 3 hours with stirring at room temperature, and then heated and stirred at 50 to 60°C for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer (ethyl acetate) is washed with saturated hydrogen carbonate, saturated brine, and dried over magnesium sulfate.

Crystals are obtained by concentrating the solvent under reduced pressure. When this crystal is recrystallized from benzene-n-hexane, the melting point is 221
N,N'-dimethyl-4-chloro-2,2 at ~222°C
2.8 g of ``-sulfonyl dibenzoic acid diamide are obtained.

Disaster JL-LL N, N with a melting point of 221 to 223°C in the same manner as in Example 16
"-dimethyl-5-nitro-2,2'-sulfonyldibenzoic acid diamide (compound Nn71) is obtained.

Mouse leukemia cells EL4 subcutaneously on the back of C57BL mice
I x 10' cells were injected, and from the same day until the 4th day,
0 mg/ml of the compound of the present invention was orally administered at 0.2 ml/mouse/day, and peritoneal cells were collected on the 5th day and cultured in culture solution I for 2 ml.
Adjust to 10' cells/ml to obtain a peritoneal cell suspension. A Boyden chamber (Bio-rad Lab
Place 0.2 ml of the culture solution at the bottom of the filter, and add the above peritoneal cell suspension at the top.
．． Add 2ml each and place in a CO2 incubator for 3 minutes.
Incubate for 90 minutes at 7°C. The filter was removed, fixed with methanol, stained with Giemsa, and the number of cells passing through the filter per field of view was counted under a 400x microscope. The results are shown in Table 5.

Completion of culture: 10% beef fat serum [fetal calf
serum, (Fe2), Microbiologic
al Laboratories,
USA Co+ 50 units/ml Penicillin G
and RP containing 50 μg/ml streptomycin.
MI-1640 culture solution (manufactured by Hinaga Pharmaceutical Co., Ltd.) Culture solution ■: 10% zymosan activated human serum [zY
mosanactivatedhuman ser
RPMI-18 including um (ZAS)
40 culture solution.

Formulation example 1 (granules, fine granules) N,N'-diethyl-4-chloro-2,2'-thiodibenzoic acid diamide 5000 (g) Lactose
4000 (g) Hydroxypropyl cellulose 500 (g) Starch
500 (g) The above ingredients are mixed and made into granules using a conventional method.

Formulation example 2 (capsule) N,N'-dimethyl-4-chloro-2,2'-thiodibenzoic acid diamide 101000 (starch
950 (g) Magnesium stearate 50 (g) Mix the above ingredients and fill it in a standard gelatin capsule containing 100-g of the active ingredient.
o capsule.

Formulation example 3 (tablet) N,N'-diethyl-4-chloro-2,2'-thiodibenzoic acid diamide 2000 (g) Starch
1200 (g) Lactose 2500 (g) Ethyl cellulose 500 (g) Magnesium stearate 200 (g) Talc
10,100 (mix the above ingredients and compress into tablets in a conventional manner so that each tablet contains 100 ml of active ingredient).

Formulation Example 4 (Injection) A sterile injection is prepared by dissolving 10 ml of N,N'-dimethyl-4-chloro-2,2'-thiodibenzoic acid diamide in 1 ml of distilled water in a conventional manner.

hair cry proof 1

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. an alkoxy group or a nitro group, and R_3 represents a hydrogen atom or a lower alkyl group. However, when n is 0 to 2, all of R_1 to R_2 are hydrogen atoms, and R_3 is an i-propyl group,
Except when n is 0 or 2, all of R_1 to R_2 are hydrogen atoms, and R_3 is a hydrogen atom or an n-butyl group. ) or an alkali metal salt thereof.