JPH11217361A - Naphthoquinone compound and medicine composed of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel low molecular weight compound, having a function of controlling activation or growth of a lymphocyte, high in selectivity to the lymphocyte, reduced in side-effects, e.g. hematopoietic cell toxin, and useful as an active component for medicines, e.g. immunosuppressant agent. SOLUTION: This compound is a naphthoquinone compound shown by the formula [R1 is a (substituted) 1-20C hydrocarbon; R2 is H or a (substituted) 1-20C hydrocarbon; and R3 is hydroxy, a 1-4C alkoxy or (substituted) amino] or its salt, e.g. N-n-octyl-3-hydroxy-1,4-naphthoquinone-2-carboxamide. In order to obtain the objective compound, it is recommended to use, e.g. 1,4- dihyroxynaphthalene-2-phenyl carboxylate ester and n-octylamine as the stock compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel naphthoquinone compound useful as an active ingredient of a drug such as an immunosuppressant.

[0002]

2. Description of the Related Art Examples of immune diseases caused by abnormalities of the immune system include autoimmune diseases such as rheumatoid arthritis and multiple sclerosis; allergic diseases such as asthma and atopic dermatitis;
And organ transplant rejection are known (Cell, 85, 291,
1996; Am. Rev. Respir. Dis., 138, 685, 1988; Immu
nology, 69, 335, 1990). Since lymphocytes are often important effector cells in the development of these diseases, immunosuppressants that suppress the activation or proliferation of lymphocytes have been developed for the prevention and treatment of immune diseases.

[0003] As classical immunosuppressants, anticancer drugs such as cyclophosphamide and melphalan are known. However, they are highly toxic to hematopoietic cells due to their low selectivity for lymphocytes, and are currently rarely used in immunological diseases. Not been. Steroids are known as classical immunosuppressants with high lymphocyte selectivity, but their use is clinically limited due to their wide variety of side effects (JAMA, 158, 384, 1955).
Therefore, many immunosuppressants have been developed with the aim of improving the disadvantages of these immunosuppressants.

[0004] Among them, cyclosporin A plays an innovative role. Cyclosporin A is a 11-amino acid cyclic polypeptide that can exert a strong immunosuppressive effect by suppressing the production of IL-2 activated by T cells. It is widely used for treating anemia. FK-506 with almost the same mechanism of action (Fujisawa Pharmaceutical Co., Ltd., under clinical development)
It is also expected to be useful. These drugs are highly selective for lymphocytes and have significantly reduced hematopoietic cytotoxicity, but are highly toxic to the kidneys and liver. Therefore, there is a problem that the dose cannot be sufficiently increased for chronic inflammatory diseases such as autoimmune diseases that require long-term administration (Clin. Nephrol., 24, 107, 1985). In addition, azathioprine and 15-deoxyspagarin are known as immunosuppressants, but each has its own side effects. Therefore, it has been desired to develop an immunosuppressant having a low molecular weight compound, which has a strong activity on lymphocytes, and has reduced side effects.

On the other hand, as for the application of quinone compounds such as benzoquinone and naphthoquinone to medicines, for example, naphthoquinone compounds used in the treatment of infectious diseases in animals (US Pat. No. 5,559,156) and Alzheimer's disease are used. Anthraquinone compounds (EP 73761)
), A benzoquinone compound used as an anti-allergic agent (JP-A-8-217731), thromboxane A2
Benzoquinone compounds that are receptor inhibitors (JP-A-8-2313)
No. 89), a benzoquinone compound which is a brain function improving agent (JP-A-8-239340), and an aldose reductase inhibitor (Bioorganic & Medicinal Chem., 4, 49, 1).
996).

[0006]

An object of the present invention is to provide a novel compound useful as an active ingredient of a drug such as an immunosuppressant. More specifically, it is possible to provide a low-molecular compound having an effect of suppressing activation or proliferation of lymphocytes, which has high selectivity for lymphocytes and has reduced side effects such as hematopoietic cytotoxicity. It is an object of the present invention.

[0007]

The present inventors have made intensive efforts to solve the above-mentioned problems. As a result, a hydrophobic aminoacyl group was introduced at the 2-position, and an alkoxy group, a hydroxy group, or a substituted group was substituted at the 3-position. It has been found that a novel naphthoquinone compound having an amino group, which may have a group, has an immunosuppressive action and is useful as an active ingredient of a medicine. In addition, the present inventors have found that the above compounds have high selectivity for lymphocytes and have reduced side effects such as hematopoietic cytotoxicity. The present invention has been completed based on these findings.

That is, the present invention provides the following general formula (I):

Embedded image [Wherein, R ₁ represents an optionally substituted C _1-20 hydrocarbon group (including the number of carbon atoms of the substituent); R ₂ represents a hydrogen atom or an optionally substituted C _1-20. Represents a hydrocarbon group (including the number of carbon atoms of the substituent) (however, when R ₂ is a hydrocarbon group, R ₁ and R ₂ may be linked to each other to form a ring which may be substituted) R ₃ represents a hydroxy group, a C _1-4 alkoxy group, or an amino group which may be substituted) and a salt thereof.

According to a preferred embodiment of the present invention, the above compound wherein R ₂ is a hydrogen atom and a salt thereof; the above compound wherein R ₃ is a hydroxy group or an N, N-dialkyl-substituted amino group and a salt thereof; The compound and a salt thereof, wherein ₁ is an alkyl group substituted with an alkoxy group or an aryloxy group, are provided.

[0010] According to another aspect of the present invention, there is provided a medicament comprising a substance selected from the group consisting of the compound of the above general formula (I) and a physiologically acceptable salt thereof. According to a preferred embodiment of the present invention, the medicament in the form of a pharmaceutical composition comprising a substance selected from the group consisting of the compound and a physiologically acceptable salt thereof and a pharmaceutical additive; An immunosuppressant comprising a substance selected from the group consisting of chemically acceptable salts thereof as an active ingredient is provided.

According to still another aspect of the present invention, the compound of the formula (I) and a physiologically acceptable salt thereof are used as a medicine, preferably as an immunosuppressant, containing a substance selected from the group consisting of the salts thereof. Use of the above compound or a physiologically acceptable salt thereof for the manufacture of a medicament; and a method for treating and / or preventing a disease caused by an abnormality of an immune system, comprising the above compound and a physiologically acceptable salt thereof. And administering to a mammal, including a human, an effective amount of a substance selected from the group consisting of the salts thereof.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula (I), R ₁ represents an optionally substituted C _1-20 (C _1-20 ) hydrocarbon group. Unless otherwise specified herein, the term optionally substituted C _1-20 hydrocarbon group refers to the carbon atom (s) constituting the hydrocarbon group itself when the hydrocarbon group does not have a substituent. Is 20 or less, and when the hydrocarbon group has a substituent, it means that the total number of the carbon atoms of the substituent and the carbon atoms of the hydrocarbon group is 20 or less. I have. Examples of the hydrocarbon group include an alkyl group; an alkenyl group; an alkynyl group; a cycloalkyl group; and an aryl group, and a hydrocarbon group in which these groups are combined, such as a benzyl group, a phenethyl group, and a naphthylmethyl group. Aryl-substituted alkyl groups (aralkyl groups); cycloalkyl-substituted alkyl groups such as cyclohexylmethyl group and adamantylmethyl group.

[0013] Among these hydrocarbon groups, a linear or branched C _12-16 alkyl group is preferred. Preferred examples of the unsubstituted alkyl group include, for example, decanyl, dodecanyl, tetradecanyl, hexadecanyl, octadecanyl, 1-methylnonanyl, 1-propylheptanyl, 1-methylundecanyl, 7-dodecenyl, 9-tetradecenyl,
11-tetradecenyl, 11-hexadecenyl, 8,10-dodecadienyl, farnesyl, 1-adamantylmethyl, 3,
3'-diphenylpropyl and the like. Of these, dodecanyl and hexadecanyl are most preferred.

The substituent of R ₁ is not particularly limited, but preferred substituents include, for example, an alkoxy group and an aryloxy group. When R ₁ represents an alkoxy-substituted alkyl group, the alkoxy group substituted with the alkyl group may be linear or branched, and preferably has 8 to 12 carbon atoms. Preferred examples of the alkoxy-substituted alkyl group represented by R ₁ include, for example, 4-oxadodecanyl, 4-oxatetradecanyl, 4-oxahexadecanyl, 5-methyl-4-oxatridecanyl, 5-ethyl-4 -Oxadecanyl, 5-methyl-4-oxapentadecanyl, 3-oxapentadecanyl, 5-oxaheptadecanyl and the like. Of these, 4-oxahexadecanyl is most preferred.

When R ₁ represents an aryloxy-substituted alkyl group, the aryloxy group substituted on the alkyl group may be further substituted, and may have a straight-chain or branched chain C-ortho and / or para-position. Phenoxy groups having _1-5 alkyl groups are preferred. Preferred examples of the aryloxy-substituted alkyl group represented by R ₁ include, for example, 3-phenoxypropyl, 3- (2-naphthoxy) propyl, 3- (4-t
ert-pentylphenoxy) propyl, 3- (4-1,1 ', 3,3'-
Tetramethylbutyl) phenoxy) propyl, 3- (2,4-
Dimethylphenoxy) propyl, 3- (2,4-dimethylphenoxy) propyl, 3- (2,4-di-tert-pentylphenoxy) propyl, 4- (2,4-di-tert-pentylphenoxy)
Butyl, 2- (2,4-di-tert-pentylphenoxy) ethyl, 2,4-di-tert-pentylphenoxymethyl and the like. Of these, 3- (4- (1,1 ′, 3,3′-tetramethylbutyl) phenoxy) propyl and 3- (2,4-di-tert-pentylphenoxy) propyl are most preferred.

R ₂ represents a hydrogen atom or an optionally substituted C _1-20 hydrocarbon group, preferably a hydrogen atom. When R ₂ represents a C _1-20 hydrocarbon group which may be substituted, it is preferable to use those described as preferred examples of R ₁ above. When R ₂ is a hydrocarbon group, R ₁ and R ₂ may be linked to each other to form a ring. The ring formed by R ₁ and R ₂ is 5-7
Member rings are preferred, and particularly preferred examples include a pyrrolidino group, a piperidino group, a morpholino group, and the like.

R ₃ represents a hydroxy group, a C _1-4 alkoxy group or an amino group which may be substituted. Of these, a hydroxy group and a substituted amino group are preferred.
Preferred examples of the substituted amino group include methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, methoxyamino, hydroxyamino, anilino group and the like. Particularly preferred examples of R ₃ include a hydroxy group and a dimethylamino group.

The compounds of the present invention, for example, in the case where R ₃ represents a hydroxy group may form a base addition salt, to indicate also amino groups that R ₃ is substituted, the acid addition Salts may be formed, and all such salts are included in the scope of the present invention. Examples of the base addition salt include metal salts such as sodium salt and potassium salt, and organic amine salts such as methylamine, ethylamine, piperidine, pyrrolidine and morpholine. Examples of the acid addition salt include mineral salts such as hydrochloride, sulfate, and nitrate, and organic acid salts such as methanesulfonate, paratoluenesulfonate, and tartrate. As described below, the compound of the present invention can be used as an active ingredient of a medicament, and among these salts, physiologically acceptable salts are preferred salts.

The scope of the present invention includes the compounds of formula (I) in free form and the above salts, as well as any hydrates and solvates thereof. In addition, the above compound may have one or more asymmetric carbon atoms depending on the type of the substituent. Any optical isomer based on one or more asymmetric carbons, any mixture of optical isomers, racemate, any diastereomer based on two or more asymmetric carbons, any mixture of diastereomers, etc. All are included in the scope of the present invention.

Specific examples of the compounds included in the general formula (I) of the present invention are shown below, but the scope of the present invention is not limited to these compounds.

[0021]

Embedded image

[0022]

Embedded image

[0023]

Embedded image

[0024]

Embedded image

[0025]

Embedded image

[0026]

Embedded image

[0027]

Embedded image

The compound of the present invention has an excellent immunosuppressive action, and is useful as an active ingredient of a drug such as an immunosuppressant. Accordingly, the present invention provides a medicine comprising the compound represented by the above formula (I). The medicament of the present invention is particularly useful for the prevention and / or prevention of diseases caused by enhanced cellular immunity characterized by excessive proliferation of lymphocytes, and the solution characterized by excessive antibody production. It is also useful for preventing and / or treating diseases caused by enhanced sexual immunity. The subject of the medicament of the present invention includes, for example, transplant rejection, graft-versus-host disease, rheumatoid arthritis, insulin-dependent diabetes mellitus, multiple sclerosis, psoriasis, systemic lupus erythematosus (SLE), Sjogren's syndrome, myasthenia gravis Disease,
Autoimmune diseases such as ulcerative colitis or Crohn's disease; or allergic diseases such as asthma and atopic dermatitis. Among them, transplant rejection, graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, insulin-dependent diabetes mellitus and the like are preferable subjects to which the medicament of the present invention is applied.

The active ingredient of the medicament of the present invention is represented by the above formula
A substance selected from the group consisting of the free form compound represented by (I) and a salt thereof can be used. Hydrates or solvates of these substances may be used. The active ingredient of the medicament of the present invention is selected from these substances.
Seeds may be used, or two or more kinds may be used in combination. The medicament of the present invention is generally a pharmaceutically acceptable substance selected from the group consisting of the free form compound represented by the above formula (I) and a salt thereof, or a hydrate or solvate thereof. It is preferably used as a pharmaceutical composition containing a pharmaceutical additive.

The medicament of the present invention can be prepared, for example, by using appropriate pharmaceutical additives such as excipients, for example, tablets, granules, powders, soft capsules, hard capsules, liquids, syrups or suspensions. Pharmaceutical compositions in the form of oral preparations such as, or injections,
It is provided as a pharmaceutical composition in the form of parenteral preparations such as drops, eye drops, ear drops, suppositories, creams, ointments, transdermal absorbents, or transmucosal absorbents. Any of these pharmaceutical compositions can be manufactured according to a method generally used in the field of pharmaceuticals.

The pharmaceutical additives used include, for example, excipients (lactose, D-mannitol, corn starch, crystalline cellulose, etc.) and disintegrants (carboxymethylcellulose, carboxymethyl Methylcellulose calcium, etc.), binders (hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, etc.), coating agents (hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.), plasticizers ( Polyethylene glycol, etc.) and a base (polyethylene glycol, hard fat, etc.) can be used. In addition, for example, for the production of injections and eye drops, a solubilizer or a solubilizer (distilled water for injection, physiological saline, propylene glycol, etc.), a pH regulator (inorganic or organic acid or base), isotonic Pharmaceutical additives such as agents (salts, glucose, glycerin, etc.) and stabilizers can be used. Furthermore, in the manufacture of eye ointments and dermatological agents, use is made of pharmaceutical additives (white vaseline, macrogol, glycerin, liquid paraffin, cotton cloth, etc.) suitable as bases for ointments, creams and patches. be able to.

The dose of the medicament of the present invention should be appropriately selected according to the administration method, the purpose of prevention / treatment, the type of disease, or various conditions such as the age, symptoms, or weight of the patient. In general, the weight of an active ingredient for oral administration is about 1 to 1,000 mg, preferably 10 to 500 mg per day for an adult. For parenteral administration such as intravenous, subcutaneous, intramuscular, transdermal, rectal, ophthalmic, inhalation, etc., 0.1 to 200 mg, preferably 0.3 to 50 mg per day per adult
It is about mg.

[0033]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

PREPARATION EXAMPLES The structures of the novel substances and intermediate products in the Examples are as follows: NMR
And MS spectrum. Further, the compound numbers such as chemical formula I-2 in the examples correspond to the preferable compound numbers shown above. Example 1: Nn-octyl-3-hydroxy-1,4-naphthoquinone
2-Carboxamide (Chemical I-2) A) 12.5 g (45 mmol) of 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester in a 100 ml three-necked flask
Then, 6.8 g (54 mmol) of n-octylamine and 10 ml of dimethylacetamide were added, and the mixture was reacted at 90 ° C. for 8 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was extracted with 250 ml of ethyl acetate, and washed with 250 ml of 0.1N hydrochloric acid and 250 ml of saturated saline. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off to about half by an evaporator. Crystals were precipitated. The crystals were collected by filtration and washed with ethyl acetate. The filtrate was again concentrated by an evaporator, and crystals precipitated in the same manner were collected by filtration. These crystals were dried with a vacuum pump to obtain 15.1 g (81% yield) of orange crystals of Nn-octyl-1,4-dihydroxynaphthalene-2-carboxamide. Melting point: 161-163 ° C

B) In a 300 ml three-necked flask, add the above step A)
7.0 g (22 mmol) of the compound obtained in and acetonitrile 1
After adding 10 ml, 6.5 g of N-chlorosuccinimide (48
mmol) was added in small portions. After reacting at room temperature for 1 hour, the reaction was performed at 55 ° C. for 5.5 hours. After cooling to room temperature, the solvent was distilled off to about half by an evaporator, and crystals were precipitated. The crystals were collected by filtration and washed with acetonitrile. The crystals are dried and yellow crystals Nn-octyl-3-chloro-1,4-naphthoquinone-2-carboxamide
6.4 g (84% yield) were obtained. Melting point: 121-123 ° C

C) In a 100 ml three-necked flask, place the above step B)
After adding 3.5 g (10 mmol) of the compound obtained in the above and 20 ml of dimethyl sulfoxide, 2N aqueous potassium hydroxide solution 1
5 ml (30 mmol) were added in small portions. After reacting at room temperature for 1 hour, the mixture was neutralized with a 1N aqueous hydrochloric acid solution. Methylene chloride 200
The mixture was extracted with 200 ml and washed with 200 ml of water. After the methylene chloride layer was dried over sodium sulfate, the solvent was distilled off using an evaporator. The crude product was purified by column chromatography (hexane: ethyl acetate = 1: 1), and the target yellow crystalline Nn-octyl-3-hydroxy-1,4-naphthoquinone-2-carboxamide (compound I- 2) 0.6 g (Yield 18
%). Melting point: 102-104 ° C

Example 2: Nn-dodecanyl-3-hydroxy-1,4
-Naphthoquinone-2-carboxamide (Formula I-3) The title compound was obtained by the same synthetic method as in Example 1 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester and n-dodecanylamine. Melting point: 112-113 ° C

Example 3 Nn-dodecanyl-3-hydroxy-1,4
-Naphthoquinone-2-carboxamide morpholino salt
I-4) Step A) of Example 1 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, n-dodecanylamine
Nn-dodecanyl-3- obtained by the same synthetic method as in B)
Reaction of chloro-1,4-naphthoquinone-2-carboxamide with morpholine in dimethylformamide at room temperature gave the title compound as a product. Melting point: 91-92 ° C

Example 4: Nn-hexadecanyl-3-hydroxy
-1,4-Naphthoquinone-2-carboxamide (Formula I-5) The title compound was prepared in the same manner as in Example 1 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester and n-hexadecanylamine. Obtained. Melting point: 111-114 ° C

Example 5 N- (1-adamantylmethyl) -3-hydroxy-1,4-naphthoquinone-2-carboxamide (Formula I-7) 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, 1- The title compound was obtained by the same synthetic method as in Example 1 using adamantyl methylamine. Melting point: 167-171 ° C

Example 6: N- (3,3-diphenylpropyl) -3-hydroxy-1,4-naphthoquinone-2-carboxamide (compound I-
8) The title compound was obtained by the same synthetic method as in Example 1 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester and 3,3-diphenylpropylamine. Melting point: 151-153 ° C

Example 7: N- (4-oxahexadecanyl) -3-hydroxy-1,4-naphthoquinone-2-carboxamide (compound I-
11) The title compound was obtained by the same synthetic method as in Example 1 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester and 4-oxahexadecanylamine. Melting point: 67-71 ° C

Example 8: N- (3-phenoxypropyl) -3-hydroxy-1,4-naphthoquinone-2-carboxamide (formula I-1)
2) The title compound was obtained by the same synthetic method as in Example 1 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester and 3-phenoxypropylamine. Melting point: 119-124 ° C

Example 9: N- (3- (4- (1,1 ', 3,3'-tetramethylbutyl) phenoxy) propyl) -3-hydroxy-1,4-naphthoquinone-2-carboxamide -15) Synthesis similar to Example 1 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, 3- (4- (1,1 ′, 3,3′-tetramethylbutyl) phenoxy) propylamine The title compound was obtained by the method. Melting point: 89-91 ° C

Example 10: N- (3- (2,4-di-tert-pentylphenoxy) propyl) -3-hydroxy-1,4-naphthoquinone-2-
Carboxamide (Formula I-16) 1,4-Dihydroxynaphthalene-2-carboxylic acid phenyl ester, 3- (2,4-di-tert-pentylphenoxy) propylamine, and the title compound by the same synthetic method as in Example 1 I got Melting point: 140-141 ° C

Example 11: N- (3- (2,4-di-tert-pentylphenoxy) propyl) -3-hydroxy-1,4-naphthoquinone-2-
Carboxamide dimethylamine salt (Formula I-17) 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, 3- (2,4-di-tert-pentylphenoxy) propylamine using step A) of Example 1 And N- (3- (2,4-di-tert-pentylphenoxy) obtained by the same synthesis method as in B)
The title compound was obtained by reacting propyl) -3-chloro-1,4-naphthoquinone-2-carboxamide with a 50% aqueous solution of dimethylamine in methylene chloride at room temperature. Melting point: 137-138 ° C

Example 12: N- (4-Phenylpiperazyl) -3-hydroxy-1,4-naphthoquinone-2-carboxamide (formula I-1)
8) The title compound was obtained by the same synthetic method as in Example 1 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester and 4-phenylpiperazine. Melting point: 162-181 ° C

Example 13: N-Phenyl-3-hydroxy-1,4-naphthoquinone-2-carboxamide (Chemical Formula I-19) Example 1 was repeated using phenyl 1,4-dihydroxynaphthalene-2-carboxylate and aniline. The title compound was obtained by a similar synthetic method. Melting point: 205-212 ° C

Example 14 N-pentyl-3-methoxy-1,4-naphthoquinone-2-carboxamide (I-20) In a 200 ml three-necked flask, in the same manner as in steps A) and B) of Example 1 above. After adding 3.1 g (10 mmol) of the obtained N-pentyl-3-chloro-1,4-naphthoquinone-2-carboxamide and 10 ml of dimethylformamide, 2.4 g (11 mmol) of a 28% methanol solution of sodium methoxide was added. Added little by little. After reacting for 1 hour at room temperature, ethyl acetate 200 ml
And washed with 200 ml of 0.1N hydrochloric acid and 200 ml of a saturated aqueous solution of sodium hydrogen carbonate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off using an evaporator, and crystals were precipitated.These crystals were collected by filtration and yellow crystals of N-pentyl-3-methoxy-1,4-naphthoquinone-2 were obtained.
-2.4 g (79% yield) of carboxamide (I-20) was obtained. Melting point: 74-80 ° C

Example 15: N-cyclopropyl-3-methoxy-1,4
-Naphthoquinone-2-carboxamide (Formula I-21)) The title compound was obtained by the same synthetic method as in Example 14 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester and cyclopropylamine. Melting point: 122-124 ° C

Example 16: N-dodecanyl-3-methoxy-1,4-naphthoquinone-2-carboxamide (Formula I-22) Example using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, dodecanylamine The title compound was obtained by the same synthesis method as in 14. Melting point: 88-95 ° C

Example 17: N- (4-oxahexadecanyl) -3-methoxy-1,4-naphthoquinone-2-carboxamide (formula I-2)
4) Example 14 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, 4-oxahexadecanylamine
The title compound was obtained by the same synthetic method as in Example 1. Melting point: 72-73 ° C

Example 18: N- (2-phenylethyl) -3-methoxy
-1,4-Naphthoquinone-2-carboxamide (Formula I-25) The title compound was obtained by the same synthetic method as in Example 14 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester and 2-phenylethylamine. . Melting point: 145-146 ° C

Example 19: N- (3- (2,4-di-tert-pentylphenoxy) propyl) -3-methoxy-1,4-naphthoquinone-2-carboxamide (formula I-26) 1,4-dihydroxy The title compound was obtained by the same synthetic method as in Example 14 using naphthalene-2-carboxylic acid phenyl ester and 3- (2,4-di-tert-pentylphenoxy) propylamine. Melting point: 132-135 ° C

Example 20: N-anilino-3-methoxy-1,4-naphthoquinone-2-carboxamide (Formula I-27) 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, using aniline as in Example 14 The title compound was obtained by a similar synthetic method. Melting point: 179 ℃ (decomposition)

Example 21: N- (3- (2,4-di-tert-pentylphenoxy) propyl) -3-n-butoxy-1,4-naphthoquinone-2-
Steps A) and B) of Example 1 using carboxamide (Formula I-28) 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, 3- (2,4-di-tert-pentylphenoxy) propylamine N- (3- (2,4-di-tert-pentylphenoxy) obtained by a similar synthesis method
(Propyl) -3-chloro-1,4-naphthoquinone-2-carboxamide 2.6 g (5 mmol) was added to n-butanol 50 ml, and sodium hydride (60%) 0.22 g (5.5 mmol) was added little by little at room temperature. Then, the reaction was carried out at room temperature for 1 hour. The mixture was extracted with methylene chloride, and the crude product was purified by column chromatography (methylene chloride: methanol = 10: 1), and 2.3 g (yield)
(84%) of the title compound. Melting point: 102-107 ° C

Example 22: N- (3- (2,4-di-tert-pentylphenoxy) propyl) -3-amino-1,4-naphthoquinone-2-carboxamide (I-29) 200 ml three-necked flask To 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, 3- (2,4-di-tert-
Example 1 using pentylphenoxy) propylamine
N- (3-) obtained by the same synthesis method as in steps A) and B) of
(2,4-Di-tert-pentylphenoxy) propyl) -3-chloro-1,4-naphthoquinone-2-carboxamide 1.0 g (2 mmo
l) and 20 ml of tetrahydrofuran were added and reacted at room temperature for 1 hour while blowing excess ammonia gas. The reaction mixture was extracted with ethyl acetate (100 ml) and water (100 ml).
And washed. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off using an evaporator. The residue was purified by column chromatography (hexane: ethyl acetate = 4: 1), and the target yellow crystal N- (3- (2,4-di-t
ert-pentylphenoxy) propyl) -3-amino-1,4-naphthoquinone-2-carboxamide (formula I-29) 0.7 g (yield 76
%). Melting point: 107-107.5 ° C

Example 23: N- (3- (2,4-di-tert-pentylphenoxy) propyl) -3-methylamino-1,4-naphthoquinone-2-
Steps A) and B) of Example 1 using carboxamide (Formula I-30) 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, 3- (2,4-di-tert-pentylphenoxy) propylamine N- (3- (2,4-di-tert-pentylphenoxy) obtained by a similar synthesis method
Propyl) -3-chloro-1,4-naphthoquinone-2-carboxamide and a 2M solution of methylamine in methanol were reacted in methanol at room temperature for 1 hour, extracted with methylene chloride, and the crude product was subjected to column chromatography (methylene chloride). : Methanol = 10: 1) to give the title compound. Melting point: 95-97 ° C

Example 24: N- (3- (2,4-di-tert-pentylphenoxy) propyl) -3-n-butylamino-1,4-naphthoquinone
Step A) of Example 1 using -2-carboxamide (Formula I-31) 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, 3- (2,4-di-tert-pentylphenoxy) propylamine N- (3- (2,4-di-tert-pentylphenoxy) obtained by the same synthesis method as in B)
The title compound was obtained by reacting (propyl) -3-chloro-1,4-naphthoquinone-2-carboxamide with n-butylamine in n-butanol at room temperature. Melting point: 78-79 ° C

Example 25: N- (3- (2,4-di-tert-pentylphenoxy) propyl) -3- (3- (2,4-di-tert-pentylphenoxy) propyl) amino-1,4 -Naphthoquinone-2-carboxamide (I-32) 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester 5.6 g (20 mmol) and 3- (2,4-di-tert-pentylphenoxy) propylamine 6.4 g (22 mmol) was reacted for 1 hour at room temperature without solvent, extracted with methylene chloride, and the crude product was purified by column chromatography (methylene chloride: methanol = 10: 1) to obtain the title compound. Melting point: 115-118 ° C

Example 26: N- (3- (2,4-di-tert-pentylphenoxy) propyl) -anilino-1,4-naphthoquinone-2-carboxamide (formula I-33) 1,4-dihydroxynaphthalene- 2-Carboxylic acid phenyl ester, 3- (2,4-di-tert-pentylphenoxy) propylamine, and N- (3- (2 , 4-di-tert-pentylphenoxy)
The title compound was obtained by reacting propyl) -3-chloro-1,4-naphthoquinone-2-carboxamide with aniline in tetrahydrofuran. Melting point: 56.5-57.5 ° C

Example 27: N- (3- (2,4-di-tert-pentylphenoxy) propyl) -3-methoxyamino-1,4-naphthoquinone
Step A) of Example 1 using -2-carboxamide (Formula I-34) 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, 3- (2,4-di-tert-pentylphenoxy) propylamine N- (3- (2,4-di-tert-pentylphenoxy) obtained by the same synthesis method as in B)
The title compound was obtained by reacting propyl) -3-chloro-1,4-naphthoquinone-2-carboxamide with methoxyamine hydrochloride in tetrahydrofuran in the presence of triethylamine. Melting point: 97-105 ° C

Example 28: Nn-octyl-3-dimethylamino-
Example 1 using 1,4-naphthoquinone-2-carboxamide (Formula I-35) 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, 3- (2,4-di-tert-pentylphenoxy) propylamine N- (3- (2,4-di-tert-pentylphenoxy)) obtained by the same synthesis method as in steps A) and B) of
Propyl) -3-chloro-1,4-naphthoquinone-2-carboxamide (1.5 g, 4 mmol) and dimethylamine tetrahydrofuran 2N solution (4.3 ml, 9 mmol) were reacted in tetrahydrofuran (10 ml) at room temperature for 1 hour. . The reaction mixture was extracted with 100 ml of ethyl acetate, and washed with 100 ml of water and 100 ml of a saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was dried over sodium sulfate, and the solvent was distilled off using an evaporator. The residue was purified by column chromatography (hexane: ethyl acetate = 1: 1), and the target substance, N- (3- (2,4-di-tert-pentylphenoxy) propyl) -3-dimethylamino-1, 1.2 g (yield: 78%) of 4-naphthoquinone-2-carboxamide (I-35) was obtained. Melting point: 89-95 ° C

Example 29: N-dodecanyl-3-dimethylamino-
1,4-Naphthoquinone-2-carboxamide (Formula I-36) The title compound was obtained by the same synthetic method as in Example 28 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester and dodecanylamine. Melting point: 86-88 ° C

Example 30 N-hexadecanyl-3-dimethylamino-1,4-naphthoquinone-2-carboxamide (Formula I-37) 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester using hexadecanylamine The title compound was obtained by the same synthetic method as in Example 28. Melting point: 78-82 ° C

Example 31 N- (4-oxahexadecanyl) -3-dimethylamino-1,4-naphthoquinone-2-carboxamide (formula I-38) 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester The title compound was obtained by the same synthesis method as in Example 28, using 4-oxahexadecanylamine. Melting point: 48-49 ° C

Example 32: N- (1-adamantylmethyl) -3-dimethylamino-1,4-naphthoquinone-2-carboxamide
I-39) The title compound was obtained as an oil by a synthesis method similar to that of Example 28 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester and 1-adamantylmethylamine.

Example 33: N-Dodecanyl-N-methyl-3-dimethylamino-1,4-naphthoquinone-2-carboxamide (I
-40) 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester, 3- (2,4-di-tert-pentylphenoxy) propylamine was obtained by the same synthetic method as in Example 28 using propylamine. . Melting point: 112-120 ° C

Example 34: N-dodecanyl-N-methyl-3-dimethylamino-1,4-naphthoquinone-2-carboxamide (compound I-
41) The title compound was obtained as an oil by a synthesis method similar to that of Example 28 using 1,4-dihydroxynaphthalene-2-carboxylic acid phenyl ester and N-methyldodecanylamine.

Test Example A test of the immunosuppressive effect of the compound of the present invention was performed. The following compounds S-1 to S-4 similar in structure to the compound of the present invention were used as comparative compounds.

Embedded image Example 35: Inhibitory effect of human lymphocytes on the proliferation response to T cell mitogen Human peripheral blood mononuclear cells separated and washed by Ficoll gradient were adjusted to 5 × 10 ⁵ cells / ml, and 100 μl of 10% FBS
PHA (5 μl / ml) or superantigen SE in RPMI medium
The cells were cultured with B (100 μl / ml) in the presence or absence of the test compound for 4 days and 5 days, respectively. 0.5 in culture
% MTT solution (10 μl / ml) was added, and the cells were cultured for 5 hours. The formazan dye was dissolved in SDS-containing isopropyl alcohol solution (150 μl), colorimetrically measured at 570 nm, and the T cell proliferation was measured without compound addition. IC50 is ₅₀ % less than the concentration
It was determined as a value.

Example 36: Cytotoxicity test 1 x 105 human promyelocytic leukemia cell line HL60 at 10 ⁵ cells / ml
The cells were cultured in 0 μl of RPMI medium containing 10% FBS in the presence or absence of the test compound for 3 days, and quantified by the MTT method in the same manner as in Example 34. Table 1 shows the activity values of the representative compounds in a lymphocyte proliferation inhibition test by PHA stimulation, the cytotoxicity values for HL60, and the ratios thereof. From these results, the compounds of the present invention were compared with those of comparative compounds S-1 to S-4 having very similar structures.
Has higher selectivity for T lymphocytes than
It is clear that cytotoxicity is also reduced.

[0072]

[Table 1]

Example 37: Inhibition test on mouse lymphocyte mixed reaction 5 × 10 ⁵ / ml C57BL / 6 mouse spleen cells and 25 mM
Equal number of Balb washed 30 minutes after mitomycin treatment
/ c mouse spleen cells with 100 μl of 10% FBS in RPMI
Mixed culture was performed in the medium for 6 days. Then, 1 μCi of [ ³ H]
Thymidine was added and the cells were further cultured for 16 hours. Cells were harvested by cell harvester and the radioactivity incorporated into lymphocytes was measured. Table 2 shows IC ₅₀ values of typical compounds. These results indicate that the compounds of the present invention also have strong immunosuppressive activity against mouse cells.

[0074]

[Table 2]

Example 38: Inhibitory effect on mouse collagen arthritis 1: 1 of Freund's complete adjuvant of bovine type II collagen
An emulsion (final collagen concentration: 1 mg / ml) was prepared, and 100 μl of the solution was applied to the back of a 6-week-old DBA / 1 male mouse.
Immunization was performed by intracutaneous injection at each site. Three weeks later, a booster was performed under the same conditions. The test compound was intraperitoneally administered for two consecutive weeks from the day before the booster immunization. Judgment of swelling due to arthritis was basically made by the method of Wooley et al. (J. Exp. Med., 154, pp. 688-70).
0, 1981). FIG. 1 shows the compound I-26 of the present invention.
(■; 50 mg / kg) and in the absence of drug (control: ●; 100 μm)
l solvent). The results showed that the compounds of the present invention were effective in an arthritis animal model.

[0076]

The compound of the present invention is useful as an active ingredient of a drug such as an immunosuppressant.

[Brief description of the drawings]

FIG. 1 is a graph showing the inhibitory effect of the compound of the present invention on mouse collagen arthritis. In the figure, the vertical axis shows swelling score due to arthritis, the horizontal axis shows the number of days after administration,
■ indicates the results of the compound (I-26) of the present invention, and ● indicates the results in the absence of the drug.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Tomohiro Ogawa 210 Nakanakanuma, Minamiashigara-shi, Kanagawa Fuji Photo Film Inside Ashigara Research Laboratories (72) Inventor Masayoshi Yamamoto 3--11-46 Izumi, Asaka-shi, Saitama Shinji Fujisha Inside the Asaka Laboratory, Film Co., Ltd. (72) Inventor ▲ Taka ▼ Kazunobu 210 Nakanuma, Minamiashigara, Kanagawa Prefecture Fuji Photo Inside the Ashigara Research Laboratory, Film Co., Ltd. (72) Inventor Kaoru Ari Kansai, Changsha City, Hunan Province, China

Claims (6)

[Claims] 1. The following general formula (I): [Wherein, R ₁ represents an optionally substituted C _1-20 hydrocarbon group (including the number of carbon atoms of the substituent); R ₂ represents a hydrogen atom or an optionally substituted C _1-20. Represents a hydrocarbon group (including the number of carbon atoms of the substituent) (however, when R ₂ is a hydrocarbon group, R ₁ and R ₂ may be linked to each other to form a ring which may be substituted) And R ₃ represents a hydroxy group, a C _1-4 alkoxy group or an amino group which may be substituted) and a salt thereof. 2. The compound according to claim 1, wherein R ₂ is a hydrogen atom, and a salt thereof. _3. The compound according to claim 2, wherein R ₃ is a hydroxy group or an N, N-dialkyl-substituted amino group, and a salt thereof. 4. The compound according to claim 3, wherein R ₁ is an alkyl group substituted with an alkoxy group or an aryloxy group, and a salt thereof. 5. A pharmaceutical comprising the compound according to any one of claims 1 to 4 or a physiologically acceptable salt thereof. 6. An immunosuppressant comprising the compound according to any one of claims 1 to 4 or a physiologically acceptable salt thereof as an active ingredient.