JP2798078B2 - Immunomodulator - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an immunomodulator.

[0002]

2. Description of the Related Art Conventionally, imidazoline-substituted 2,4,5-triphenyl-substituted, 2,4,5-tri (4-chlorophenyl) -substituted and 2,4,5-tri (4-methylphenyl) -substituted Are all known [Merck Index 9]
Vol. 51, Klotika Chemika Acta 45, 51
9 (1973); and the Canadian Journal
Of Chemistry 50, 669 (1972)
)], But the efficacy of these compounds is not known at all.

[0003]

The present invention is different from the above known compounds having the same substituent at the 2, 4 and 5 positions.
It is intended to provide an excellent immunomodulator comprising an imidazoline derivative having different substituents at the 4-position and the 4- and 5-positions as active ingredients.

[0004]

That is, the present invention provides a compound represented by the general formula [I]:

[0005]

Embedded image

Wherein R represents a halogenophenyl group, a lower alkylphenyl group or a pyridyl group, and X ¹ and X ² represent a hydrogen atom or a lower alkoxy group, or a pharmacologically acceptable derivative thereof. The present invention relates to an immunomodulator comprising a salt as an active ingredient.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The imidazoline derivative [I], which is an active ingredient of the present invention, and a pharmaceutically acceptable salt thereof enhance immune activity when the immune response is reduced, and suppress it when the immune response is enhanced, In the macrophage migration test used for measuring cellular immunity, the compound has an excellent immunomodulatory effect, showing a remarkable macrophage migration promoting activity. Further, the imidazoline derivative [I] or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, has low toxicity and exhibits high safety as a medicament. For example, cis-2- (4-chlorophenyl) -4,5-diphenylimidazoline hydrochloride is orally administered to rats (Crj: SD system) (dose 500 mg / dose).
kg), observations were made for 14 days, and no deaths were observed.

A preferred therapeutic example of the imidazoline derivative [I] which is the active ingredient of the present invention is a compound wherein R is a halogenophenyl group or a pyridyl group, and X ¹ and X ² are hydrogen atoms.

The imidazoline derivative [I] is
General formula

[0010]

Embedded image

(Wherein R, X ¹ and X ² have the same meanings as described above), cis-trans stereoisomers based on two asymmetric carbon atoms, It is intended to include any of the mixtures.

The imidazoline derivative [I], which is the active ingredient of the present invention, can be used in the free form or in the form of a pharmaceutically acceptable salt thereof for the purpose of the present invention. Such pharmacologically acceptable salts include, for example, hydrochloride,
Inorganic acid addition salts such as hydrobromide, phosphate and sulfate, or oxalate, acetate, lactate, citrate, tartrate, fumarate, maleate, aspartate; Organic acid addition salts such as methanesulfonate and benzoate can be mentioned.

[0013] The immunomodulator of the present invention can be administered orally or parenterally.
It can be used as an appropriate pharmaceutical preparation such as granules, capsules, powders and injections.

The dose of the immunomodulator of the present invention varies depending on the method of administration, the age, weight and condition of the patient, and the type of disease to be treated, but the imidazoline derivative [I] as an active ingredient or its pharmacologically Acceptable doses of the salt are usually about 0.01 to 50 mg / kg per day, especially 0.1 mg / kg.
It is preferable to administer to be about 1 to 10 mg / kg.

As described above, the imidazoline derivative [I] and the pharmaceutically acceptable salt thereof, which are the active ingredients of the present invention, have excellent immunomodulatory effects. Therefore, the immunomodulator of the present invention can be used for treatment and / or prevention of multiple sclerosis, systemic lupus erythematosus, and the like.

The imidazoline derivative [I], which is an active ingredient of the present invention, has, for example, the general formula [II]

[0017]

Embedded image

(Wherein X ¹ and X ² have the same meanings as described above) or an acid addition salt thereof and a compound of the general formula [III]

[0019]

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(Wherein, R has the same meaning as described above;
Represents a lower alkyl group. ) Or an acid addition salt thereof with a base (eg, an alkali metal alkoxide, an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogencarbonate, or tri (lower alkyl)
(Amine and the like) in the presence or absence of the compound from room temperature to under heating.

[0021]

[Action]

Experimental Example 1 (Alveolar Macrophage Migration-Promoting Activity) Japanese white rabbits (female, weighing 3 to 4 kg) were exsanguinated and killed under anesthesia, and the lungs were washed with physiological saline to collect alveolar macrophages. The obtained alveolar macrophages were subjected to RPMI containing 5% rabbit serum containing 10 ^-7 M specimen according to a conventional method.
The cells were allowed to migrate for 24 hours at 37 ° C in -1640 medium. After the migrating part was magnified through and the outside of the migrating was traced, the migrating area was measured with a plumimeter.

The migration index was calculated by the following equation using the value obtained by migration in RPMI-1640 medium containing 5 mM rabbit serum containing 5 mM L-fucose as a control group.

[0023]

(Equation 1)

The judgment criteria are:
60 to 100 are shown as ++.

The results are as shown in Table 1 below.

[0026]

[Table 1]

Experimental Example 2 (Normalizing effect on the number of antibody-producing cells in an immune-enhancing animal) A BALB / c mouse (female, 10 weeks old, 8 animals per group) was intraperitoneally administered with colchicine (1 mg / kg) and immediately thereafter. And an antigen [bentonite particles adsorbed with 2,4,5-trinitrobenzene (TNP) -keyhole limpet hemocyanin (KLH)] per animal with a protein component of 0.1
The dose was administered intraperitoneally to give mg. Five days after the sensitization, the mice were bled to death, the spleen was excised, and the number of anti-TNP antibody-producing spleen cells was calculated by a sheep erythrocyte hemolytic spot count method.
This was 178% of that obtained when a normal mouse not treated with colchicine was sensitized with the antigen. On the other hand, the number of anti-TNP antibody-producing spleen cells in mice that were orally administered with 2 mg / kg of the sample the day before, on the day of, 1 day, 2 days, 3 days, and 4 days after sensitization was calculated. The results shown were obtained.

[0028]

[Table 2]

As is evident from Table 2, administration of the active ingredient compound of the present invention shows that the number of anti-TNP antibody-producing cells differs greatly from that of normal mice not treated with colchicine even when treated with colchicine. Is not seen.
This indicates that the active ingredient compound of the present invention has a significant immune response normalizing effect.

EXPERIMENTAL EXAMPLE 3 (Normalizing effect on the number of antibody-producing cells in immunocompromised animals) BALB / c mice (female, 10 weeks old, 8 animals per group) were treated with a sheep red blood cell (SRBC) suspension and 5 red blood cell counts. ×
Administered 10 within ^seven equivalent belly copy, it was antigen sensitization. Water immersion restraint was applied for 4 hours immediately after the sensitization and for 4 hours a day from the next day for 4 days. Five days after the sensitization, the mice were bled to death, the spleen was removed, and the number of anti-SRBC antibody-producing spleen cells was calculated by the method of counting sheep erythrocyte haemolysis. Normal mice without antigen sensitization were subjected to antigen sensitization. 53% of the cases. On the other hand, the number of anti-SRBC antibody-producing cells after 5 days of water immersion restraint in mice orally administered 2 mg / kg of the sample on the day before, on the day of, 1 day, 2 days, 3 days, and 4 days after sensitization was calculated. As a result, the results shown in Table 3 below were obtained.

[0031]

[Table 3]

As is apparent from Table 3 above, administration of the active ingredient compound of the present invention does not affect the number of anti-SRBC antibody-producing cells in normal mice that are not subjected to water immersion restraint even when water immersion restraint is applied. There is no significant difference. This indicates that the active ingredient compound of the present invention has a significant immune response normalizing effect.

[0033]

[Production example]

Production Example 1 16.1 g of erythro-1,2-diamino-1,2-diphenylethane diacetate, 13.7 g of 4-chlorobenziminoethyl ether hydrochloride, 260 ml of ethanol
Was added to the mixture, and the mixture was refluxed for 4 hours. After the reaction, the solvent was distilled off, and to the residue was added 1N-sodium hydroxide aqueous solution (77 ml), followed by extraction with chloroform. After the extract is washed with water and dried, the solvent is distilled off. The residue was recrystallized from methanol to obtain 12.0 g of cis-2- (4-chlorophenyl) -4,5-diphenylimidazoline.

Yield 75% p. 152-153 ° C IR ^Nujol ν _max (cm ^-1 ): 3200, 1619, 15
95 hydrochloride: M.P. p. > 280 ° C Maleate: M.P. p. 199-200 ° C (decomposition) Fumarate: M.P. p. 233-235 ° C (decomposition) DL-lactate: M.P. p. 143-144 ° C (decomposition) L-tartrate: M.P. p. 92-95 ° C (decomposition) Methanesulfonic acid salt: M.P. p. > 280 ° C Production Example 2 To a mixture of 2.9 g of erythro-1,2-diamino-1,2-diphenylethane dihydrochloride, 2.6 g of 4-tolyliminoethyl ether hydrochloride, and 60 ml of ethanol, 3 ml of triethylamine was added. Reflux for 4 hours. After the reaction, the solvent was distilled off.
Add ml and extract with chloroform. After the extract is washed with water and dried, the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; chloroform: ethanol = 9:
Purify in 1). The obtained product was dissolved in ethanol, and a 20% hydrochloric acid / ethanol solution was added to make the solution acidic. Then, the solvent was distilled off, and the residue was washed to obtain cis-2- (4-tolyl) -4,5-diphenylimidazoline. -Hydrochloride 2.2
g.

Yield 63% p. 284-285 ° C (decomposition) IR ^Nujol ν _max (cm ^-1 ): 2700, 1615, 15
95 Production Examples 3 to 8 The corresponding erythro-type starting compound [II] is treated in the same manner as in Production Example 2 to obtain cis-type imidazoline derivatives shown in Table 4 below.

IR ^* : represents IR ^Nujol ν _max (cm ⁻¹ ) (the same applies hereinafter).

[0037]

[Table 4]

Production Examples 9 to 11 The corresponding threo-type starting compound [II] is treated in the same manner as in Production Example 2 to obtain trans-type imidazoline derivatives shown in Table 5 below.

[0039]

[Table 5]

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Yoshiro Iwasawa 3-139-504 Kita Midorigaoka, Toyonaka-shi, Osaka (72) Inventor Tatsuro Yamamoto 2-5-13 Wakamatsu, Sagamihara-shi, Kanagawa-ken (58) Field surveyed (Int.Cl. ⁶ , DB name) A61K 31/415 A61K 31/44 C07D 233/20 C07D 233/22 C07D 401/04 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. A compound of the general formula [I] (Wherein, R represents a halogenophenyl group, a lower alkylphenyl group or a pyridyl group, and X ¹ and X ² represent a hydrogen atom or a lower alkoxy group) or a pharmacologically acceptable salt thereof. An immunomodulator as a component. 2. The immunomodulator according to claim 1, wherein R is a halogenophenyl group or a pyridyl group. 3. The immunomodulator according to claim 1, wherein R is a halogenophenyl group, and X ¹ and X ² are hydrogen atoms. 4. 4- (4-chlorophenyl) -4,5-
An immunomodulator comprising diphenylimidazoline or a pharmaceutically acceptable salt thereof as an active ingredient. 5. The immunomodulator according to claim 1, which is a therapeutic and / or prophylactic agent for multiple sclerosis and systemic lupus erythematosus.