MXPA99009124A

MXPA99009124A - 2-aminopropane-1,3-diol compounds, medicinal use thereof, and intermediates in synthesizing the same

Info

Publication number: MXPA99009124A
Application number: MXPA/A/1999/009124A
Authority: MX
Inventors: Adachi Kunitomo; Hanano Tokushi; Teshima Koji; Fujita Tetsuro; Aoki Yoshiyuki; Hoshino Yukio
Original assignee: Mitsubishi Pharma Corporation
Priority date: 1997-04-04
Filing date: 1999-10-04
Publication date: 2000-07-01

Abstract

Compounds represented by general formula (I), pharmaceutically acceptable acid addition salts thereof, or hydrates of the same;drugs containing these compounds;medicinal compositions containing these compounds together with pharmaceutically acceptable carriers;and 2-amino-2-(2-(4-(1-hydroxy-5-phenylpentyl)phenyl)ethyl)propane-1,3-diol or 2-amino-2-(2-(4-formylphenyl)ethyl)-propane-1,3-diol optionally protected at the amino and/or hydroxy group or salts thereof, each useful as an intermediate in synthesizing the above compounds. In said formula, R1, R2, R3 and R4 represent each hydrogen or acyl. Because of having little toxicity, high safety and excellent immunosuppressive effects, these compounds are useful as preventives or depressants for rejection reactions in organ or bone marrow transplantations and preventives or remedies for various autoimmune diseases, various allergic diseases, etc.

Description

COMPOSITE OF 2-AMINOPROPAN-1.3-DIOL. PHARMACEUTICAL USE OF THE SOMETHING AND SYNTHETIC INTERMEDIARIES FOR THE SAME TECHNICAL FIELD The present invention relates to a 2-aminopropane-1,3-diol compound useful for pharmaceutical compounds, in particular immunosuppressants, a pharmaceutical use thereof and a synthetic intermediate for the same.

BACKGROUND OF THE INVENTION WO94 / 08943 discloses 2-aminopropane-1,3-diol compounds which include 2-amino-2- (2- (4-octylphenyl) ethyl) propane-1,3-diol hydrochloride, useful as a suppressant of rejection in the transplantation of organs or bone marrow, or as a therapeutic agent of various autoimmune diseases such as psoriasis, Behcet's disease and the like, and rheumatic diseases. WO96 / 06068 discloses a benzene compound useful as a rejection suppressant in the transplantation of organs or bone marrow, or as a therapeutic agent of various autoimmune diseases such as psoriasis, Beh? Et disease and the like, and rheumatic diseases.

The reference J. Org. Chem., Vol. 25, p 2057-2059 (1960) describes 2-methylamino-2- (phenylmethyl or phenylmethyl substituted by 2-methyl, 3-methyl, 4-methyl, 4-methoxy or 4-hydroxy) propane-1,3-diol. In the patent of E.U.A. Do not.

No. 3,660,488, 2-amino-2- (p-chlorobenzyl) propane-1,3-diol is described as an anti-radiation drug. The aim of the present invention is to provide a more effective and highly secure compound as a rejection suppressant in the transplantation of organs or bone marrow, or as a therapeutic agent of autoimmune diseases such as atopic dermatitis, psoriasis, joint rheumatism and bone marrow disease. Behcet, a pharmaceutical compound comprising said compound, and a synthetic key compound of said compound. The present inventors have made intensive studies to achieve the aforementioned objective and found that, of the 2-aminopropane-1,3-dioI compounds represented by the general formula described in WO94 / 08943 CH2ORC RaRbN- C CH2ORd a compound wherein, in the R substituent of this compound, a p-phenylene group in the carbon chain and a phenyl group at the end of the carbon chain are substituted and, in the carbon chain between said p-phenylene group and the phenyl group, the carbon in the alpha position of the p-phenylene group is replaced by a carbonyl group (these compounds are not specifically described in said official gazette), they have less toxic, highly safe and superior immunosuppressing action, which gave as a result the completion of the present invention.

BRIEF DESCRIPTION OF THE INVENTION Namely, the present invention relates to the following: (1) a 2-aminopropane-1,3-diol compound of the general formula (hereinafter sometimes referred to as compound (I)) wherein R1, R2, R3 and R4 are the same or different, and each is a hydrogen or an acyl; a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof, (2) the 2-aminopropane-1,3-diol compound according to item (1) mentioned above, which is 2-amino-2- (2- (4- (1-oxo-5-phenylpentyl) phenyl) ethyl) propane-1,3-diol (hereinafter sometimes referred to as compound (Ia)), a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof, (3) a pharmaceutical compound comprising the 2-aminopropane-1,3-diol compound according to the above-mentioned items (1) or (2), a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof, (4) an immunosuppressant comprising, as an active ingredient, the 2-aminopropane-1,3-diol compound according to the above-mentioned clauses (1) or (2), a pharmaceutically acceptable acid addition salt acceptable thereof or a hydrate thereof, (5) a rejection suppressant comprising, as an active ingredient, the of 2-aminopropane-1,3-diol in accordance with subparagraphs (1) or (2) above, a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof, (6) an agent for the prevention or treatment of graft-versus-host diseases comprising, as an active ingredient, the 2-aminopropane-1, 3 compound -diol according to items (1) or (2) mentioned above, or a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof, (7) an agent for the prevention or treatment of autoimmune diseases or diseases allergic comprising, as an active ingredient, the 2-aminopropane-1,3-diol compound according to the above-mentioned clauses (1) or (2), a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof, (8) a pharmaceutical composition comprising the 2-aminopropane-1,3-diol compound according to items (1) or (2) mentioned above, a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof and a pharmaceutically acceptable carrier, (9) 2-amino-2- (2- (4- (1-hydroxy-5-phenylpentyl) phenyl) ethyl) propane-1,3-diol (in succession sometimes referred to as compound (II)), a compound thereof, wherein the amino group and / or the hydroxy group are protected, or a salt thereof, (10) 2-amino-2- (2- (4- formylphenyl) ethyl) propane-1,3-diol (hereinafter sometimes referred to as compound A), a compound thereof, wherein the amino group and / or the hydroxy group are protected, or a sai thereof. The compound of the present invention (I) is represented by the formula: (l) wherein each symbol is as defined above, and has as structural feature that, in the carbon chain at position 2 of the skeleton of 2-aminopropane-1,3-diol, a p-phenylene group on said chain of carbon and a phenyl group at the end of said carbon chain are substituted and, in the carbon chain between said p-phenylene group and the phenyl group, the carbon in the alpha position of the p-phenylene group is replaced by a group carbonyl. Due to this structural feature, the compound of the present invention possesses less toxicity and high safety and exhibits superior suppressive immunogenic action. The compound (II) of the present invention is represented by the formula: and compound A of the present invention is represented by the formula: The groups represented by the respective symbols in the present specification are explained as follows: The acyl in R1, R2, R3 and R4 is exemplified by a straight or branched chain alkanoyl having from 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and hexanoyl; a straight or branched chain alkanoyl having from 2 to 6 carbon atoms which is substituted by phenyl, such as phenylacetyl and phenylpropionyl; an aroyl such as benzoyl; an alkoxycarbonyl, wherein the alkoxy portion is a straight or branched chain alkoxy having from 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, ter- pentyloxycarbonyl and hexyloxycarbonyl; and an aralkyloxycarbonyl such as benzyloxycarbonyl. Examples of the pharmaceutically acceptable acid addition salts of the present compound (I) include salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, or salts with an organic acid such as acid acetic acid, maleic acid, fumaric acid, benzoic acid, citric acid, succinic acid, tartaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and 10-camphorsulfonic acid. The present compound can be converted to salts thereof with oxalic acid to obtain crystals. The salts of the compound (II) and the compound A also include the above-mentioned acid addition salts. Examples of the hydrate of the present compound (I) include monohydrate, hemihydrate, sesquihydrate, dihydrate and hemisesquihydrate. The present invention also encompasses solvates. The amino protecting group of compound (II) and compound A useful as a synthetic intermediate for the compound of the present invention is exemplified by an aliphatic acyl such as formyl, acetyl, propionyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methanesulfonyl and ethanesulfonyl, an aromatic acyl such as phthaloyl, benzoyl, p-nitrobenzoyl, p-tert-butylbenzoyl, p-tert-butylbenzenesulfonyl, benzenesulfonyl and toluenesulfonyl; a carbonate such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, 2-cyanoethoxycarbonyl, 2,2,2, -trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, diphenylmethoxycarbonyl, methoxymethyloxycarbonyl, acetyl-methyloxycarbonyl, phenyloxycarbonyl , methylsulfonylethyloxycarbonyl and 2-trimethylsilylethoxycarbonyl; an amino protecting group other than acyl, such as trityl, di- or trialkylsilyl, benzyl and p-nitrobenzyl. The hydroxyl protecting group of compound (II) and compound A useful as a synthetic intermediate for the compound of the present invention is exemplified by a lower alkyl which can be substituted, such as methyl, ethyl, propyl, butyl, ter- butyl, pentyl, hexyl, methoxymethyl and methoxyethoxy methyl; an allyl; an aralkyl, which can be substituted, such as benzyl, p-methoxybenzyl, triphenylmethyl and tris (p-methoxyphenyl) methyl; a trisubstituted silyl such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tri-tert-butylsilyl, methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl and tert-butyldiphenylsilyl; tetrahydropyranyl, tetrahydro-2-thiopyranyl, 2-thiolanyl; acyl such as an aliphatic acyl, an aromatic acyl and an aliphatic acyl substituted by an aromatic group, which are derived from carboxylic acids and sulfonic acids. The aliphatic acid is exemplified by a lower alkanoyl such as formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, carboxyacetyl, carboxypropionyl, trifluoroacetyl, chloroacetyl, methoxyacetyl and phenoxyacetyl; a carbonate such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl and p-nitrophenoxycarbonyl; and a sulfonyl such as methanesulfonyl and ethanesulfonyl. An aromatic acyl is exemplified by an aroyl such as benzoyl, toluoyl, naphthoyl, nitrobenzoyl and dinitrobenzoyl; a sulfonyl such as benzenesulfonyl, toluenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl and iodobenzenesulfonyl; and similar. The aliphatic acyl substituted by an aromatic group is exemplified by an arylalkanoyl such as phenylacetyl, phenylpropionyl and phenylbutyryl. In addition, the two hydroxyl groups can form in combination a cyclic acetal such as methylene acetal, ethylidene acetal, isopropylidene acetal, benzylidene acetal, anisilidene acetal and 2,4-dimethoxybenzylidene acetal. Oxazolidine and oxazine can be formed in conjunction with the hydroxyl group and the amino group.

In the present invention, an amino group and / or a hydroxy group of the compound (I) can be protected by these protecting groups, and the protected compound can be used as a synthetic intermediate for the compound (I) and, occasionally, can be used as a pharmaceutical compound by itself. The compound (I) of the present invention can be produced by the following methods.

Method A The compound (I-a), wherein R1, R2, R3 and R4 are hydrogen in the compound (I), are produced by the following method. Namely, the compound A wherein an amino group and / or a hydroxyl group are protected, are reacted with a compound of the formula (III) [hereinafter referred to as compound (III)] wherein M is a metal widely used in the field of organic synthesis chemistry, such as lithium, magnesium chloride, magnesium bromide, magnesium iodide, copper, lithium and nickel; and a protecting group is removed, if necessary, to give the compound (II) or a compound thereof, wherein an amino group and / or a hydroxyl group are protected; followed by oxidation of the hydroxyl group at the a position of the phenylene group with a suitable oxidizing agent, and a protecting group is removed, if necessary, to give the compound (l-a). Examples of the organic solvent to be used in the reaction with the compound (III) include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile. . The reaction temperature of the present reaction is generally from -100 to 80 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the present reaction is generally from 30 minutes to 2 days, and a reaction period greater or less than the indicated period can be selected during the demand. After the reaction is carried out under the conditions mentioned above, or after removal of the protecting groups during the demand, the compound (II) can be purified by a method known in the field of organic synthesis chemistry, such as extraction with solvent, recrystallization, chromatography or a method using an ion exchange resin. Examples of the oxidizing agent to be used in the oxidation reaction of compound (II) include chromic acid - sulfuric acid, chromium (VI) oxide - sulfuric acid - acetone (Jones reagent), chromium (VI) oxide - complex of pyridine (Collins reagent), dichromate (for example, sodium dichromate, potassium dichromate) - sulfuric acid, pyridinium chlorochromate (PPC), manganese dioxide, activated dimethyl sulfoxide electrophilic reagent, dicyclohexylcarbodiimide, acetic anhydride, pentaoxide (di) phosphoric, sulfur trioxide-pyridine complex, trifluoroacetic anhydride, oxalyl chloride, halogen, sodium hypochlorite, hypochlorite potassium, sodium bromide, N-bromosuccinimide, N-chlorosuccinimide, N-bromoacetamide, 2,3-dichloro-5,6-dicyan-p-benzoquinone, tetrachloro-p-benzoquinone, tetrachloro-o-benzoquinone, nitric acid, tetraoxide dinitrogenated, anhydrous benzene-alenic acid, ruthenium tetraoxide, ruthenium dioxide-sodium periodate, bischlorobis (triphenylphosphine) ruthenium-iodosylbenzene or sodium bismutate. Examples of the solvent to be used in the present reaction include water, acetic acid, diethyl ether, tretrahydrofuran, dioxane, acetone, tert-butyl alcohol, methylene chloride, chloroform, hexane, benzene, toluene, or a mixture thereof. The reaction temperature of the present reaction is generally from 0 to 100 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand.

The reaction time of the present reaction is generally from 30 minutes to 2 days, and a reaction period greater or less than the indicated period can be selected during the demand. After the reaction is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the compound (Ia) can be purified by a known method in the field of organic synthesis chemistry, such as extraction with solvent, recrystallization, chromatography or a method using an ion exchange resin.

Method B The compound (I), wherein R1, R2, R3 and R4 are acyl, is produced by the following method. Namely, the compound (Ia) is protected during the demand and reacted with an acyl halide in the presence of a base, followed by the removal of the protecting groups during the demand to give the compound, wherein the amino group and or the corresponding hydroxyl group are acylated. In the present method, the compound (II) instead of the compound (Ia) is reacted and treated in the same manner to allow the production of the compound (II), wherein an amino group and / or a hydroxyl group are acylated . The compound (I), wherein R1, R2, R3 and R4 are acyl, is treated with an acid or a base to produce the compound (I-a).

The compound A useful as a synthesis intermediate for the compound (I) of the present invention, can be produced by the following method.

Method C A compound of the general formula (IV) [in the sequential referred as compound (IV)] wherein Lv is a leaving group widely used in the field of organic synthesis chemistry, such as halogen (fluorine, chlorine, bromine, iodine), methanesulfonyloxy, p-toluenesulfonyloxy and trifluoromethanesulfonyloxy, and a compound of the general formula (V) [ in the consecutive referred to as compound (V)] COOR5 R6NH -CH (V) COOR5 wherein R5 is a lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl, or aralkyl such as benzyl, nitrobenzyl, methoxybenzyl and methylbenzyl, R6 is an amino protecting group widely used in the field of chemistry of organic synthesis, such as acetyl, benzoyl, tert-butoxycarbonyl and benzyloxycarbonyl, and the two R5s in the molecule can form in combination a ring such as dioxane, and R5 and R6 in the molecule can form in combination a ring such as oxazolidine and oxazine, are condensed in the presence of a base to give a compound of the general formula (VI) [in the sequential referred as compound (VI) wherein R5 and R6 are as defined above; the ester groups are reduced with a suitable reducing agent and protective groups are introduced or removed during the demand to give a compound of the general formula (VII) [in the consecutive referred to as compound (VII)] wherein R7 is a hydroxyl protecting group widely used in the field of organic synthesis chemistry such as acetyl, benzoyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, methoxyethoxymethyl and tetrahydropyranyl, and R6 is as defined above; the obtained compound is reacted with dichloromethyl methyl ether in the presence of a Lewis acid, and protecting groups can be introduced or removed as necessary to give compound A or a protected N- and / or O- compound thereof. Examples of the base to be used in the condensation include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, butyl lithium, lithium hexamethyldisilazane, triethylamine, diisopropylethylamine and 1, 8- diazabicyclo [5.4.0] undec-7-ene. Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile. The reaction temperature of the condensation is generally from -20 to 150 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the condensation is generally 30 minutes to 2 days, and a period of reaction greater or less than the indicated period can be selected during the demand. After the condensation is carried out under the conditions mentioned above, or after removal of the protecting groups during the demand, the compound (VI) can be purified by a method known in the field of organic synthesis chemistry., such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin. Examples of the reducing agent that will be used in the reduction of the ester include, for example, a metal-reducing reagent such as sodium borohydride, lithium borohydride or lithium-aluminum hydride, or diborane. Examples of the solvent to be used in the reduction of the ester include, for example, water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, dimethyl ether of ethylene glycol, or a mixture thereof. The reaction temperature of the ester reduction is generally from -20 to 80 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the ester reduction is generally from 30 minutes to 10 hours, and a reaction period greater or less than the indicated period can be selected during the demand. After the reduction is carried out under the conditions mentioned above, or after removal of the protecting groups during the demand, the objective compound can be purified by a method known in the field of organic synthesis chemistry, such as solvent extraction , recrystallization, chromatography or a method using an ion exchange resin.

Examples of the Lewis acid to be used in the reaction with dichloromethyl methyl ether include aluminum chloride, titanium tetrachloride, tin tetrachloride, antimony chloride (V), iron chloride (III), boron trifluoride, bismuth chloride ( Ill), zinc chloride and mercury chloride (II). Examples of the organic solvent to be used in the reaction with dichloromethyl methyl ether include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, acetonitrile, nitromethane and carbon disulfide. The reaction can be carried out without solvent, as necessary. The temperature of the reaction with dichloromethyl methyl ether is generally from -20 ° C to 0 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time with dichloromethyl methyl ether is generally from 30 minutes to 24 hours, and a reaction time greater or less than the indicated period can be selected during the demand. After the reaction with dichloromethyl methyl ether is carried out under the conditions mentioned above, or after removal of the protecting group during the demand, the objective compound can be purified by a known method in the field of organic synthesis chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.

Other methods for synthesizing compound A from compound (VII) include (1) a method comprising Vilsmeier reaction using N, N-dimethylformamide, N-methylformanilide, N-formylmorpholine or N, N-diisopropylformamide, and a reagent halogenation such as phosphoryl chloride, phosgene, oxalyl chloride, thionyl chloride, triphenylphosphine bromide or hexachlorotriphosphazatriene, and hydrolysis, (2) a method comprising reaction with hexamethylenetetramine in the presence of an acid catalyst (eg, acetic acid, triphenylacetic acid) and hydrolysis (Duff method), (3) a method comprising reaction of a combination of carbon monoxide and hydrogen chloride, or a combination of formic acid and chlorosulfuric acid, thionon chloride or phosphorus oxychloride in the presence of of aluminum chloride using copper (I) chloride as co-catalyst, as needed (Gattermann-Koch method), (4) a method comprising reaction n of dry hydrogen cyanide and hydrochloric acid (Gattermann method), and the like.

Method D Using in the method C a compound of the general formula (VIII) [referred to in the following as compound (VIII)] wherein Hal is halogen such as chlorine, bromine or iodine, Lv is as defined above, instead of compound (IV), a compound of the general formula (IX) is obtained [hereinafter referred to as compound (IX)] wherein R6, R7 and Hal are as defined above; the obtained compound is reacted with a formylating agent in the presence of magnesium and subjected to hydrolysis; and the protecting groups are removed, if necessary, to give the compound A or a protected N- and / or O- compound thereof. Examples of the formylating agent to be used in the present reaction include formate such as methyl orthoformate, ethyl orthoformate, ethyl formate or lithium formate, or formamide such as N-methylformanilide, NN-dimethylformamide, N-methyl-N- (2-pyridyl) formamide, 1-formylpiperidine, 4-formylmorpholine or ethoxymethyleneaniline produced from ethyl and aniline orthoformate, fluoroformaldehyde (FCHO), formic anhydride ((HCO) 2 O) and formic acetic anhydride (HCOOCOCH 3). Examples of the organic solvent to be used in the present reaction include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile. The reaction temperature of the present reaction is generally from -100 to 80 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction period of the present reaction is generally from 30 minutes to 2 days, and a period of reaction greater or less than the indicated period can be selected during the demand. After the reaction is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the compound A can be purified by a method known in the field of organic synthesis chemistry, such as solvent extraction , recrystallization, chromatography or a method using an ion exchange resin.

Method E A compound of the general formula (X) [in the sequential referred as compound (X)] wherein Y is a formyl group or a protected formyl equivalent such as dimethoxymethyl, diethoxymethyl, ethylenedioxymethyl, propylenedioxymethyl, ethylenedithiomethyl or propylenedithiomethyl, Lv is as defined above; it is subjected to condensation, in the presence of a base, with a compound of the general formula (XI) [in the consecutive referred to as compound (XI)] wherein R5, Rd and R7 are as defined above; to give a compound of the general formula (XII) [in the consecutive referred to as compound (XII)] wherein R5, R6, R7 and Y are as defined above; the ester group is subjected to reduction with a suitable reducing agent, and protecting groups are introduced or removed, as necessary, to give the compound A or an N- and / or O-protected compound thereof. Examples of the base to be used in the condensation include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, butyllithium, lithium hexamethyldisilazane, triethylamine, diisopropylethylamine and 1, 8 -diazabicyclo [5.4.0] undec-7-ene.

Examples of the organic solvent that will be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile. The reaction temperature of the condensation is generally from -20 to 150 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction period of the condensation is generally from 30 minutes to 2 days, and a period of reaction greater or less than the indicated period can be selected during the demand. After the condensation is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the compound (XII) can be purified by a method known in the field of organic synthesis chemistry, such as extraction with solvent, recrystallization, chromatography or a method using an ion exchange resin. Examples of the reducing agent that will be used in the reduction of the ester include metal-reducing reagent, such as sodium borohydride, lithium borohydride or lithium-aluminum hydride, or diborane. Examples of the solvent to be used in the reduction of the ester include water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, or a mixture thereof. The reaction temperature of the ester reduction is generally from -20 to 80 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction period of the ester reduction is generally from 30 minutes to 10 hours, and a period of reaction greater or less than the indicated period can be selected during the demand. After the reduction is carried out under the conditions mentioned above, or after removal of the protecting groups during the demand, the objective compound can be purified by a method known in the field of organic synthesis chemistry, such as solvent extraction , recrystallization, chromatography or a method using an ion exchange resin.

Method F A compound of the general formula (XIII) [in the sequential referred as compound (XIII)] wherein R5 is as defined above; it is subjected to condensation, in the presence of a base, with the compound (X) to give a compound of the general formula (XIV) [in the consecutive referred to as compound (XIV)] wherein R5 and Y are as defined above; the ester groups and the azide group are subjected to reduction with a suitable reducing agent, and protective groups are introduced or removed, as necessary, to give the compound A or an N- and / or O-protected compound thereof. Examples of the base to be used in the condensation include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, butyl lithium, lithium hexamethyldisilazane, triethylamine, diisopropylethylamine and 1, 8- diazabicyclo [5.4.0] undec-7-ene. Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.

The reaction temperature of the condensation is generally from -20 to 150 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the condensation is generally 30 minutes to 2 days, and a period of reaction greater or less than the indicated period can be selected during the demand. After the condensation is carried out under the conditions mentioned above, or after removal of the protecting groups during the demand, the compound (XIV) can be purified by a method known in the field of organic synthesis chemistry, such as extraction with solvent, recrystallization, chromatography or a method using an ion exchange resin. Examples of the reducing agent that will be used in the reduction of the ester include, for example, a metal-reducing reagent such as sodium borohydride, lithium borohydride or lithium-aluminum hydride, or diborane. Examples of the solvent to be used in the reduction of the ester include, for example, water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, or a mixture thereof. The reaction temperature of the ester reduction is generally from -20 to 80 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand.

The reaction time of the ester reduction is generally from 30 minutes to 10 hours, and a reaction period greater or less than the indicated period can be selected during the demand. Examples of the reducing agent that will be used in the reduction of the azide include a metal-reducing reagent such as sodium borohydride, lithium borohydride or lithium-aluminum hydride, and triphenylphosphine. Catalytic reduction using transition metal such as palladium-carbon, platinum oxide, Raney nickel, rhodium or ruthenium is also effective. Examples of the solvent that will be used in the reduction of azide include water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, acetone, ethyl acetate, acetic acid, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, or a mixture thereof. The reaction temperature of the azide reduction is generally from -20 to 80 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. After the reduction is carried out under the conditions mentioned above, or after removal of the protecting groups during the demand, the objective compound can be purified by a method known in the field of organic synthesis chemistry, such as solvent extraction , recrystallization, chromatography or a method using an ion exchange resin.

Method G A compound of the general formula (XV) [in the sequential referred as compound (XV)] CH2OR7 02N - -CH (X V) CH2OR7 wherein R7 is a hydroxyl group protecting group widely used in the field of organic synthesis chemistry, such as acetyl, benzoyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, methoxyethoxymethyl or tetrahydropyranyl, and the two R7s can form in combination a ring such as dioxane; it is subjected to condensation, in the presence of a base, with the compound (X) to give a compound of the general formula (XVI) [in the consecutive referred to as compound (XVI)] wherein R7 and Y are as defined above; and the nitro group is subjected to reduction with a suitable reducing agent, and protecting groups are introduced or removed, as necessary, to give the compound A or a protected N- and / or O- compound thereof. Examples of the base to be used in the condensation include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide., butyllithium, lithium hexamethyldisilazane, triethylamine, diisopropylethylamine and 1,8-diazabicyclo [5.4.0] undec-7-ene. Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane or acetonitrile. The reaction temperature of the condensation is generally from -20 to 150 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the condensation is generally 30 minutes to 2 days, and a period of reaction greater or less than the indicated period can be selected during the demand. After the condensation is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the compound (XVI) can be purified by a method known in the field of organic synthesis chemistry, such as extraction with solvent, recrystallization, chromatography or a method using an ion exchange resin.

Examples of the reducing agent that will be used in the reduction of the nitro include a metal reducing reagent such as sodium borohydride, lithium borohydride or lithium-aluminum hydride, transition metal such as palladium-carbon, platinum oxide, Raney nickel , rhodium or ruthenium for catalytic reduction, a metal such as iron, zinc or tin. Examples of the solvent to be used in nitro reduction include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, acetone, ethyl acetate, acetic acid, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide. , or a mixture thereof. The reaction temperature of the nitro reduction is generally from -20 to 80 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. After the reduction is carried out under the conditions mentioned above, or after removing the protecting groups during demand, the objective compound can be purified by a method known in the field of organic synthesis chemistry, such as solvent extraction , recrystallization, chromatography or a method using an ion exchange resin.

Method H A compound of the general formula (XVII) [in the sequential referred as compound (XVII)] where M and Y are as defined above; is subjected to nucleophilic addition with a compound of the general formula (XVIII) [in the sequential referred as compound (XVIII)] wherein R8 is an imino protecting group widely used in the field of organic synthesis chemistry, such as acetyl, benzoyl or tert-butoxycarbonyl, benzyloxycarbonyl, and R5 is as defined above; to give a compound of the general formula (Vl-a) [in the sequential referred as compound (Vl-a)] wherein R5, R8 and Y are as defined above; the ester groups are subjected to reduction with a suitable reducing agent, and protecting groups are introduced or removed, as necessary, to give the compound A or a protected N- and / or O- compound thereof. Examples of the organic solvent to be used in the addition include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane or acetonitrile. The reaction temperature of the addition is generally from -100 to 80 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the addition is generally from 30 minutes to 2 days, and a period of reaction greater or less than the indicated period can be selected during the demand. After the addition is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the compound (Vl-a) can be purified by a method known in the field of organic synthesis chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin. Examples of the reducing agent that will be used in the reduction of the ester include a metal-reducing reagent such as sodium borohydride, lithium borohydride or lithium-aluminum hydride, or diborane. Examples of the solvent to be used in the reduction of the ester include water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, dimethyl ether of ethylene glycol, or a mixture thereof. The reaction temperature of the ester reduction is generally from -20 to 80 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the ester reduction is generally from 30 minutes to 10 hours, and a reaction period greater or less than the indicated period can be selected during the demand. After the reduction is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the objective compound can be purified by a method known in the field of organic synthesis chemistry, such as solvent extraction , recrystallization, chromatography or a method using an ion exchange resin.

Method I The compound (XVI) can also be produced by the following method. The compound (X) and a compound of the general formula (XIX) [in the consecutive referred to as compound (XIX)] COOR5 C ^ N CH2 (X I X) wherein R5 is as defined above; they are subjected to condensation in the presence of a base to give a compound of the general formula (XX) [in the consecutive referred to as compound (XX)] wherein R5 and Y are as defined above; the compound obtained is subjected to condensation, in the presence of a base, with formalin and protection of the hydroxyl group, if necessary, to give a compound of the general formula (XXI) [hereinafter referred to as compound (XXI)] wherein R5, R7 and Y are as defined above; the ester group is subjected to reduction with a suitable reducing agent, and protection of the hydroxyl groups if necessary, to give the compound (XVI). Examples of the solvent to be used in the condensation include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform. or acetonitriio. Examples of the base to be used in the condensation include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, triethylamine, diisopropylethylamine and 1,8-diazabicyclo [5.4.0] undec-7-ene. . The reaction temperature of the condensation is generally from -20 to 150 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the condensation is generally 30 minutes to 2 days, and a period of reaction greater or less than the indicated period can be selected during the demand. After the condensation is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the compound (XX) can be purified by a known method in the field of organic synthesis chemistry, such as extraction with solvent, recrystallization, chromatography or a method using an ion exchange resin. Examples of the solvent to be used in formalin condensation include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride , chloroform or acetonitrile.

Examples of the base to be used in the condensation include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, triethylamine, diisopropylethylamine and 1,8-diazabicyclo [5.4.0] undec-7-ene. . The reaction temperature of the condensation is generally from -20 to 150 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the condensation is generally 30 minutes to 2 days, and a period of reaction greater or less than the indicated period can be selected during the demand. After the condensation is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the compound (XXI) can be purified by a known method in the field of organic synthesis chemistry, such as extraction with solvent, recrystallization, chromatography or a method using an ion exchange resin. Examples of the reducing agent that will be used in the reduction of the ester include a metal-reducing reagent such as sodium borohydride, lithium borohydride or lithium-aluminum hydride, or diborane. Examples of the solvent to be used in the reduction of the ester include water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, or a mixture thereof.

The reaction temperature of the ester reduction is generally -20 to 80 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the ester reduction is generally from 30 minutes to 10 hours, and a reaction period greater or less than the indicated period can be selected during the demand. After the reduction is carried out under the conditions mentioned above, or after removal of the protecting groups during the demand, the compound (XVI) can be purified by a method known in the field of organic synthesis chemistry, such as extraction with solvent, recrystallization, chromatography or a method using an ion exchange resin.

Method J The compound (Vl-a) can also be produced by the following method. A compound of the general formula (XXII) [in the sequential referred as compound (XXII)] wherein R5 is as defined above and compound (X) is subjected to condensation in the presence of a base to give a compound of the general formula (XXIII) [hereinafter referred to as Compound (XXIII)] wherein R5 and Y are as defined above; the obtained compound is reacted, in the presence of a base, with an aminating agent of the general formula (XXIV) H2N-Le (XXIV) wherein Le is a leaving group such as 2,4-dinitrofenoxi; and protecting groups are introduced or removed, as necessary, to give the compound (Vl-a). Examples of the base to be used in the condensation include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, butyl lithium, lithium hexamethyldisilazane, triethylamine, diisopropylethylamine and 1, 8- diazabicyclo [5.4.0] undec-7-ene. Examples of the solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane or acetonitrile. The reaction temperature of the condensation is generally from -20 to 150 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the condensation is generally 30 minutes to 2 days, and a period of reaction greater or less than the indicated period can be selected during the demand. After the condensation is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the compound (XXIII) can be purified by a method known in the field of organic synthesis chemistry, such as extraction with solvent, recrystallization, chromatography or a method using an ion exchange resin. Examples of the base to be used in the amination reaction include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, butyl lithium, lithium hexamethyldisilazane, triethylamine, diisopropylethylamine and 1, 8-diazabicyclo [5.4.0] undec-7-ene. Examples of the solvent to be used in the amination reaction include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride. , chloroform, dichloroethane or acetonitrile. The reaction temperature of the amination reaction is generally from -20 to 150 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the amine reaction is generally 30 minutes to 2 days, and a reaction period greater or less than the indicated period can be selected during the demand. After the aminating reaction is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the compound (Vl-a) can be purified by a method known in the field of organic synthesis chemistry , such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.

Method K In method E to method J, compound (IV) or compound (VIII) is used in place of compound (X) to give compound (VII) or compound (IX), respectively.

Method L In method C, compound (X) is used in place of compound (IV) to give compound (Vl-a). The compound (I-a) of the present invention can also be produced by the following method.

Method M A compound of the general formula (XXV) [in a row referred to as Compound (XXV)] where Lv is as defined above; it is reacted with dichloromethyl methyl ether in the presence of a Lewis acid to give a compound of the general formula (XXVI) [hereinafter referred to as compound (XXVI)] Lv (CH2) 2- W // -CHO (XXV I ) where Lv is as defined above; the compound obtained is reacted with the compound (III) to give a compound of the general formula (XXVII) [in the sequential referred as compound (XXVII)] where Lv is as defined above; the compound obtained is subjected to oxidation with a suitable oxidizing agent to give a compound of the general formula (XXVIII) [hereinafter referred to as Compound (XXVIII)] where Lv is as defined above; the compound obtained is subjected to condensation with the compound (V) in the presence of a base to give a compound of the general formula (XXIX) [hereinafter referred to as Compound (XXIX)] wherein R5 and R6 are as defined above; the carbonyl group of the compound (XXIX) is subjected to protection and reduction with a reducing agent to give a compound of the general formula (1-b) [hereinafter referred to as Compound (1-b)] wherein P1 and P2 are a carbonyl protecting group widely used in the field of organic synthesis chemistry, such as lower alkoxy such as methoxy, ethoxy, propoxy, isopropoxy or butoxy, or P1 and P2 together form an alkylenedioxy such as ethylenedioxy, or a compound thereof, wherein the amino group and / or the hydroxyl group are protected; and the obtained compound is subjected to deprotection to give the compound (I-a). Examples of the Lewis acid to be used in the reaction with dichloromethyl methyl ether include aluminum chloride, titanium tetrachloride, tin tetrachloride, antimony chloride (V), iron chloride (III), boron trifluoride, bismuth chloride ( III), zinc chloride or mercury chloride (II). Examples of the organic solvent that will be used in the reaction with dichloromethyl methyl ether include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, acetonitrile, nitromethane or carbon disulfide. The reaction can be carried out without solvent during the demand. The temperature of the reaction with dichloromethyl methyl ether is generally from -20 ° C to 0 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time with dichloromethyl methyl ether is generally from 30 minutes to 24 hours, and a reaction time greater or less than the indicated period can be selected during the demand. After the reaction with dichloromethyl methyl ether is carried out under the conditions mentioned above, or after removal of the protecting group during the demand, the objective compound can be purified by a known method in the field of organic synthesis chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin. Examples of the organic solvent to be used in the reaction with the compound (III) include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane or acetonitrile. .

The reaction temperature of the present reaction is generally from -100 to 80 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the present reaction is generally from 30 minutes to 2 days, and a reaction period greater or less than the indicated period can be selected during the demand. After the reaction is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the compound (XXVII) can be purified by a method known in the field of organic synthesis chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin. Examples of the oxidizing agent to be used in the oxidation of the compound (XXVII) include chromic acid - sulfuric acid, chromium (VI) oxide - sulfuric acid - acetone (Jones reagent), chromium (VI) oxide - pyridine complex ( Collins reagent), dichromate (sodium dichromate, potassium dichromate) - sulfuric acid, pyridinium chlorochromate (PPC), manganese dioxide, dimethyl sulfoxide activated electrophilic reagent, dicyclohexylcarbodiimide, acetic anhydride, phosphorus pentaoxide, trioxide complex sulfur- pyridine, trifluoroacetic anhydride, oxalyl chloride, halogen, sodium hypochlorite, potassium hypochlorite, sodium bromide, N-bromosuccinimide, N-chlorosuccinimide, N-bromoacetamide, 2,3-dichloro-5,6-dicyano- p-benzoquinone, tetrachloro-p-benzoquinone, tetrachloro-o-benzoquinone, nitric acid, dinitrogenated tetraoxide, benzene anhydrous acid, ruthenium tetraoxide, ruthenium dioxide sodium periodate, bischlorobis (tri phenylphosphine) ruthenium-iodosylbenzene or sodium bismutate. Examples of the solvent to be used in the present reaction include water, acetic acid, diethyl ether, tretrahydrofuran, dioxane, acetone, tert-butyl alcohol, methylene chloride, chloroform, hexane, benzene, toluene, or a mixture thereof. The reaction temperature of the present reaction is generally from 0 to 100 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the present reaction is generally from 30 minutes to 2 days, and a reaction period greater or less than the indicated period can be selected during the demand. After the reaction is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the compound (XXVIII) can be purified by a method known in the field of organic synthesis chemistry, such as extraction. with solvent, recrystallization, chromatography or a method using an ion exchange resin. Examples of the base to be used in the condensation include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, butyl lithium, lithium hexamethyldisilazane, triethylamine, diisopropylethylamine and 1, 8- diazabicyclo [5.4.0] undec-7-ene.

Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane or acetonitrile. The reaction temperature of the condensation is generally from -20 to 150 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction period of the condensation is generally 30 minutes to 2 days, and a period of reaction greater or less than the indicated period can be selected during the demand. After the condensation is carried out under the conditions mentioned above, or after removing the protecting groups during the demand, the compound (XXIX) can be purified by a method known in the field of organic synthesis chemistry, such as extraction with solvent, recrystallization, chromatography or a method using an ion exchange resin. The compound (XXVIII), wherein Lv is halogen, in particular chlorine or bromine, is also subjected to iodination using sodium iodide followed by reaction with the compound (V). The protection of the carbonyl group of the compound (XXIX) can be carried out by a method known in the field of organic synthesis chemistry. For example, the compound (XXIX) is treated with ethylene glycol in the presence of an acid catalyst such as paratoluenesulfonic acid, or with a lower alcohol in the presence of an acid such as hydrochloric acid or sulfuric acid to give the corresponding protected carbonyl compound. Examples of the reducing agent to be used in the reduction include a metal-reducing reagent such as sodium borohydride, lithium borohydride or lithium-aluminum hydride, or diborane. Examples of the solvent to be used in the reduction include water, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, or a mixture thereof. The reaction temperature of the reduction is generally from -20 to 80 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the reduction is generally from 30 minutes to 10 hours, and a period of reaction greater or less than the indicated period can be selected during the demand. After the reduction is carried out under the conditions mentioned above, or after removal of the protecting groups during the demand, the objective compound can be purified by a method known in the field of organic synthesis chemistry, such as solvent extraction , recrystallization, chromatography or a method using an ion exchange resin.

Examples of the reagent to be used in the deprotection include an acid such as hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid, a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide. Examples of the solvent to be used in the deprotection include water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide or dimethyl sulfoxide. The reaction temperature of the deprotection is generally from -20 to 100 ° C, and a temperature lower or higher than said temperature scale can be selected during the demand. The reaction time of the deprotection is generally from 30 minutes to 5 hours, and a period of reaction greater or less than the indicated period can be selected during the demand. After the deprotection is carried out under the conditions mentioned above, or after removal of the protecting groups during the demand, the objective compound can be purified by a method known in the field of organic synthesis chemistry, such as solvent extraction , recrystallization, chromatography or a method using an ion exchange resin.

Method N Compound (XXVI) can also be produced by reacting the compound (VIII) with a formylating agent in the presence of magnesium, followed by hydrolysis.

Method O The compound (Ia) of the present invention can also be produced by reacting and treating in the same manner as in the method E after condensation, the compound (XXVIII) with the compound (XI), in the same manner as in the method F after the condensation of the compound (XXVIII) with the compound (XIII), in the same manner as in the method G after the condensation of the compound (XXVIII) with the compound (XV), in the same manner as in Method I after the condensation of the compound (XXVIII) with the compound (XIX), in the same manner as in the method J after the condensation of the compound (XXVIII) with the compound (XXII), respectively. The compound (I) of the present invention is treated, in a suitable solvent such as water, methanol, ethanol, diethyl ether, tetrahydrofuran or dioxane if necessary, with an acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid Nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, benzoic acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or -alphafor sulfur, to give an acid addition salt thereof. When the crystals of a compound of the present invention obtained are anhydrides, the crystals are treated with water, aqueous solvent or other solvent to give a hydrate such as monohydrate, hemihydrate, sesqui hydrate, dihydrate and hemisesquihydrate, or solvates. The compound (I) of the present invention, a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof, can be used for the prevention and suppression of rejection caused by the transplantation of organs (liver, heart, kidney, etc.). ) or bone marrow between mammals of the same type or of different types including human, dog, cat, cattle, horse, pig, monkey, rat, etc., and for the prevention and treatment of various autoimmune diseases or various allergic diseases. Namely, the compounds of the present invention have pharmacological activities such as immunosuppressive activity or antimicrobial activity and, therefore, are useful for the prevention or treatment of transplant resistance or rejection of organ or tissue transplantation (such as heart, kidney, liver, lung, bone marrow, cornea, pancreas, small intestine, extremities, muscle, nerve, fatty marrow, duodenum, skin or pancreatic islet cells, etc., including xenotransplantation), graft diseases against host by bone marrow transplantation, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome lupus, Hashimoto's thyroiditis, multiple sclerosis; myasthenia gravis, type I diabetes mellitus, incipient type II diabetes mellitus, uveitis, nephrotic syndrome, steroid-resistant and steroid-resistant nephrosis, palmoplantar pustulosis, allergic encephalomyelitis, glomerulonephritis, etc., and infectious diseases caused by pathogenic microorganisms. The compounds of the present invention are useful for the treatment of inflammatory, proliferative and hyperproliferative diseases of the skin, and cutaneous manifestations of immunologically mediated diseases, such as psoriasis, psoriatic arthritis, atopic eczema (atopic dermatitis), contact dermatitis and other dermatitis. eczematoses, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid syndrome, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, acne, alopecia areata, eosinophilic fasciitis and atherosclerosis. More particularly, the compounds of the present invention are useful in the revitalization of hair, as in the treatment of male or female alopecia or senile alopecia, providing prevention of epilation, as well as hair growth and / or promotion of the generation and growth of hair. The compounds of the present invention are further useful in the treatment of respiratory diseases, eg, sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia and reversible obstructive airway disease, including conditions such as asthma, including bronchial asthma, childhood asthma, allergic asthma , intrinsic asthma, extrinsic asthma and asthma by dust, particularly chronic asthma or by invertebrates (for example, delayed asthma and airway hypersensitivity), bronchitis, and the like. The compounds of the present invention may also be useful for the treatment of liver disease associated with ischemia. The compounds of the present invention are also indicated in certain eye diseases such as conjunctivitis, keratoconjunctivitis, keratitis, vernal conjunctivitis, uveitis associated with Behget's disease, herpetic keratitis, conical cornea, epithelialis corneae dystrophy, keratoleukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, severe intraocular inflammation, and the like. The compounds of the present invention are also useful for preventing or treating inflammation of mucous membranes or blood vessels (such as leukotriene B4 mediated diseases, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflammatory bowel disease (for example, Crohn's disease, ulcerative colitis and necrotizing enterocolitis), or intestinal lesions associated with thermal burns In addition, the compounds of the present invention are also useful for treating or preventing kidney diseases including interstitial nephritis, Goodpasture syndrome, uremic hemolytic and diabetic nephropathy, selected nervous diseases of multiple myositis, Guillain-Barré syndrome, Meniere's disease and radiculopathy; endocrine diseases that include hyperthyroidism and Basedow's disease; blood diseases including pure erythrocyte aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, and aneuritroplasia; bone diseases that include osteoporosis; respiratory diseases that include sarcoidosis, interstitial pneumonia, diopta and fibroid; skin diseases including dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photo-allergic sensitivity and cutaneous T-cell lymphoma; circulatory diseases that include arteriosclerosis, aortitis, polyarteritis nodosa and myocardosis; collagen disease that includes scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis, periodontal disease, nephrotic syndrome; hemolytic uremic syndrome; and muscular dystrophy. In addition, the compounds of the present invention are indicated in the treatment of diseases including intestinal inflammations or allergies such as celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease or ulcerative colitis; and food-related allergic diseases, which have symptomatic manifestation remotely from the gastrointestinal tract, for example, migraine, rhinitis and eczema. The compounds of the present invention also have liver regenerative activity and / or activity to promote hypertrophy and hyperplasia of hepatocytes. Therefore, they are useful for the treatment and prevention of liver diseases such as immunogenic diseases (e.g., chronic autoimmune liver diseases including autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial hepatic resection, acute hepatic necrosis (e.g. , necrosis caused by toxins, viral hepatitis, shock or anoxia), viral hepatitis type B, non-type A / non-type B hepatitis, and cirrhosis. The compounds of the present invention are also indicated for use as antimicrobial agents, and can thus be used in the treatment of diseases caused by pathogenic microorganisms and the like. In addition, the compounds of the present invention can be used in the prevention or treatment of malignant rheumatoid arthritis, amyloidosis, fulminating hepatitis, Shy-Drager syndrome, pustular psoriasis, Behcet's disease, systemic lupus erythematosus, endocrine ophthalmopathy, progressive systemic sclerosis. , mixed connective tissue disease, aortitis syndrome, Wegener's granulomatosis, chronic active hepatitis, Evans syndrome, pollinosis, idiopathic hypoparathyroidism, Addison's disease (autoimmune adrenalitis), autoimmune orchitis, autoimmune oophoritis, common cold hemagglutinin, paroxysmal hemoglobinuria common cold, pernicious anemia, adult T cell leukemia, autoimmune atrophic gastritis, lupoid hepatitis, tubulointestinal nephritis, membranous nephritis, amyotrophic lateral sclerosis, rheumatic fever, post-myocardial infarction syndrome and sympathetic ophthalmitis. The compounds of the present invention have an antifungal effect and are useful as an antifungal agent.

In addition, the compounds of the present invention, pharmaceutically acceptable acid addition salts thereof, or hydrates thereof, may be used in combination with other immunosuppressants, steroids (prednisolone, methylprednisolone, dexamethasone, hydrocortisone, and the like) or antiviral agent. inflammatory non-steroidal acid. The other preferred immunosuppressant is selected in particular from azathioprine, brequinar sodium, deoxyspergualin, mizoribine, 2-morpholinoethyl mycophenolate, cyclosporin, rapamycin, tacrolimus monohydrate, leflunomide and OKT-3. When the compound (I) of the present invention thus obtained, a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof, is used as a medicament, the compound (I) is mixed with a pharmaceutically acceptable carrier (e.g. excipients, binders, disintegrators, corrective agents, emulsifiers, diluents, solubilizers and the like) to give a pharmaceutical composition or a pharmaceutical agent (tablets, pills, capsules, granules, powders, syrups, emulsions, elixirs, suspensions, solutions, injections, transfusions or preparations for external use), which can be administered orally or parenterally. The pharmaceutical composition can be formulated into a pharmaceutical preparation by a conventional method. In the present specification, "parenterally" includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, transfusion and topical administration (administration through the skin, eye, lung, bronchus, nose, rectum).

The preparation for injection, such as a sterile aqueous or oily suspension for injection, can be prepared using a suitable dispersing agent or a wetting agent and a suspending agent, in accordance with a method known in the pertinent field. The sterile preparation for injection may be a sterile injectable solution or suspension in a non-toxic diluent or solvent that allows parenteral administration, such as an aqueous solution. Examples of the vehicle and the solvent that may be used include water, Ringer's solution, isotonic saline, and the like. In addition, a sterile non-volatile oil may generally be used as a solvent or a solvent for suspension. For this purpose, any fatty acid or non-volatile oil, including fatty acid or natural, synthetic or semi-synthetic fatty oil, and natural, synthetic or semi-synthetic mono, di or triglycerides can be used. The solid dosage form for oral administration includes those mentioned above, such as powders, granules, tablets, pills, capsules and the like. In these dosage forms, the active ingredient is mixed with at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, cytokines, chitosans, pectins, gums of tragacanth, gum arabica, gelatin, collagen, casein, albumin, polymers and synthetic or semi-synthetic glycerides. In these dosage forms, routine additives may be added, which may be inert diluents, lubricants such as magnesium stearate, preservatives such as parabens and sorbic acid, antioxidants such as ascorbic acid, -tocopherol and cysteine, disintegrators, binders, tackifiers, pH regulators, sweeteners, flavors, perfumes, and the like. An enteric coating can be applied to tablets and pills. Liquid agents for oral administration may be pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which may contain inert diluents (e.g., water), which are generally used in the pertinent field. The external agent applicable to the compound (I) of the present invention; a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof, includes an ointment, a paste, a liniment, a lotion, a poultice, a poultice, an eye drop, an eye ointment, a suppository, a fomentation, an inhalant, a spray, a spray, a paint, a nasal drop, a cream, a tape, a patch, and Similar. The external agent of the present invention contains the compound of the present invention in the form of a mixture with an organic or inorganic carrier or excipient and, for example, can be used in the form of a solid, semi-solid or liquid pharmaceutical preparation. The compound of the present invention can be mixed, for example, with a non-toxic and pharmaceutically acceptable carrier which is often used to obtain an external preparation for topical administration. A vehicle that can be used includes water, glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other vehicles which are suitable for preparing a solid, semi-solid or solution composition. In addition, an adjuvant, a stabilizer, a thickener, a coloring matter or a flavoring agent may be added. The compound of the present invention as an active ingredient of the pharmaceutical composition may be contained in an amount sufficient to exhibit the desired activity, depending on the symptom or the severity of the diseases. In the case of the treatment of the symptom and the diseases induced by an immune disorder, the compound of the present invention can be administered by topical administration, an aerosol or a rectal administration in the form of a unit dosage composition containing vehicle, adjuvant and non-toxic and pharmaceutically acceptable excipient. In the treatment of reversible obstructive airway disease, the compound of the present invention is preferably administered to the lung by an aerosol, particularly in the form of a powder or a solution. The amount of the compound of the present invention that can be mixed with a vehicle can vary, depending on the host to be treated and a specified dosage form. The specified dose of the specified patient should be determined depending on various factors such as age, body weight, general health condition, sex, diet, time of administration, route of administration, excretion regimen, drug combination and the severity of the diseases specified under treatment.

When the compound of the present invention is used in the form of an ointment, it is contained in an amount of 0.01 to 10% w / w in the ointment. The ointment base that can be used includes oil base (a natural wax such as white beeswax or carnauba wax, a petroleum wax such as hard paraffin or microcrystalline wax, a hydrocarbon wax such as liquid paraffin, white petrolatum or yellow petrolatum, plastibase, zelen 50W, silicone, a vegetable oil, lard, beef tallow, a simple ointment or lead oleate poultice), an emulsion-based ointment base (an oil-in-water type base (type O / W) such as a hydrophilic ointment or a base cream or a water-in-oil type base (W / O type) such as a hydrophilic petrolatum, a purified lanolin, aquahole, eucelin, neoseline, an absorbent ointment, a lanolin hydrated, skin cream, a hydrophilic plastibase), a hydrosoluble base (a macrogol ointment or sun-based ointment), or a suspension-type ointment base (a lyogel base, for example, a hydrogel base such as a non-oily ointment, a base d The gel or lotion, or a base of FAPG (a suspension of a microparticle of an aliphatic alcohol such as stearyl alcohol or cetyl alcohol in propylene glycol), and these ointment bases can be used alone or in combination of not less than two bases. In addition, when used as an ointment, the compound of the present invention is dissolved in an absorption and solubilizing agent of absorption, and is added to the ointment base mentioned above. The solubilizing agent and absorption accelerator to be used means the agent in which the compound of the present invention is soluble at a concentration of at least not less than 0.01% w / w, and which can accelerate the absorption of the compound of the present invention of the skin when formulated as an ointment, and includes a lower alkanediol (e.g., ethylene glycol, propylene glycol or butylene glycol), an alkylene carbonate (e.g., propylene carbonate or ethylene carbonate), an alkanedicarboxylic acid (eg, dimethyl adipate, diethyl adipate, diisopropyl adipate, diethyl pimelate, diethyl sebacate or dipropyl sebacate), a glycerin ester of higher alkanoic acid (eg, monolaurate, dilaurate or trilaurate), a glycerin ester of higher alkeneic acid (e.g., monooleate, dioleate or trioleate), an alkanoic ester of higher alkanoic acid (e.g., isoprop myristate) ilo or ethyl myristate), a higher unsaturated alcohol (for example, geraniol or oleyl alcohol) or an azacycloalkane (for example, 1 -dodecylazacycloheptan-2-one). These solubilizing and absorption accelerating agents may be used alone or in a mixture of not less than two agents, and may be added to an amount sufficient to dissolve the compound of the present invention. The amount generally ranges from 2 parts by weight to 200 parts by weight per one part by weight of the compound of the present invention. The superior amount is limited not to deteriorate the physicochemical properties of the ointment. The ointment containing the compound of the present invention may contain, in addition to the aforementioned ointment base, other additives such as an emulsifier (eg, hydrogenated polyoxyethylene castor oil, glycerol monostearate, sorbitan sesquioleate or lauromacrogol); a suspending agent (for example, polyethylene glycol, polyvinyl pyrrolidone or sodium carboxymethyl cellulose); an antioxidant (for example, a phenol or a quinone); a preservative (for example, para-oxybenzoic acid ester); a humectant (e.g., glycerin, D-sorbitol or propylene glycol); a flavoring agent, a coloring matter; an antiseptic; a higher alkeneic acid (eg, oleic acid), and in addition other drugs that are useful for the treatment of skin diseases. When the compound of the present invention is used as an ointment, the ointment can be prepared by mixing a solution containing the compound of the present invention with an ointment base in accordance with a conventional method. In the formulation process, not less than one of the adjuvants or additives mentioned above can be added simultaneously to the ointment base. In addition, the ointment can be manufactured by dissolving the compound of the present invention in the solubilizing and absorption accelerating agent, mixing the obtained solution with the ointment base, stirring the obtained mixture under heating, and then cooling the resulting mixture. The ointment containing the compound of the present invention can be used by application to the affected part of the skin one to several times (e.g., one to four times) per day.

The paste or liniment containing the compound of the present invention can be prepared using the same base and in accordance with the same method used for the ointment, as mentioned above. The lotion containing the compound of the present invention means a preparation wherein the compound of the active ingredient is dispersed homogeneously or, in some cases, partially dissolved in a liquid medium, and an emulsifier may be added thereto, as necessary. In the case where the compound of the present invention is used as a lotion, the content can be adjusted from 0.01 to 10% w / w of the lotion. The liquid medium that will be used in the lotion containing the compound of the present invention includes water, a lower alcohol, a glycol, glycerin, or a mixture thereof. Among them, all the lower alcohols which do not decompose the compound of the active ingredient and which do not irritate the skin can be used, and include methanol, ethanol, isopropyl alcohol, propanol or butanol. The glycol includes ethylene glycol, propylene glycol, butylene glycol or lower monoethers thereof. Among these liquid media, water, the lower alcohol or a mixture thereof, is more preferable because these means improve the absorption of the compound of the active ingredient to the skin. The amount of these liquid media preferably ranges from 5 parts by weight to 1000 parts by weight per one part by weight of the compound of the present invention.

To the lotion containing the compound of the present invention, an absorption and solubilizing agent may be added in which the compound of the active ingredient is soluble at a concentration of at least not less than 0.01% w / w, and which can accelerate the absorption of the compound of the active ingredient of the skin when formulated in a lotion, and includes an alkanedicarboxylic acid ester (for example, dimethyl adipate, diethyl adipate, diisopropyl adipate, diethyl pimelate, sebacate of diethyl or dipropyl sebacate) or an alkanoic acid ester of higher alkanoic acid (eg, isopropyl myristate or ethyl myristate). These solubilizing and absorption accelerating agents can be used alone or in a mixture of not less than two agents, and the amount generally varies from 5 parts by weight to 5000 parts by weight per one part by weight of the compound of the present invention. The content of the solubilizing agent and absorption accelerator preferably ranges from 1 to 30% w / w. The emulsifier for the lotion containing the compound of the present invention is used for the purpose of dispersing an insoluble drug continuously and homogeneously in an aqueous solution, and must be non-toxic to humans, and includes natural emulsifiers and pharmaceutically acceptable synthetic emulsifiers. Various emulsifiers derived from animals and vegetables can be used as the natural emulsifier, and include egg yolk lecithin, soy lecithin or a hydrogenated product thereof, phosphatidyl choline, sphingomyelin, gum arabic or gelatin. Cationic, anionic or nonionic surfactants may be used as the synthetic emulsifier, and preferably include a castor oil surfactant, especially an HCO (hydrogenated polyoxyethylene castor oil) such as HCO-60, HCO-50 and HCO- 40 In addition, an aliphatic ester of polyoxyethylene sorbitan such as polysorbate 80, an aliphatic ester of glycerin such as glycerin monocaprylate, an ester of aliphatic polyethylene acid such as polyoxyethylene monostearate 40, a mono (or di) may be used. medium chain aliphatic acid glyceride (eg, mono (or di) glycerides of C6-C12 aliphatic acid such as caprylic acid diglyceride, caprylic acid monoglyceride or caproic acid diglyceride), or a polyoxyethylated glyceride such as glyceride polyoxyethylated oleic acid. The emulsifiers mentioned above can be used as the primary emulsifier and, if necessary, in combination with an auxiliary emulsifier. The auxiliary emulsifier is conventional and non-toxic to humans, and includes cholesterol, agar, magnesium hydroxide, methylcellulose or pectin. The primary emulsifier and the auxiliary emulsifier can be used respectively alone or in combination of two or more of them. The emulsifier is contained in the lotion containing the compound of the present invention in an amount sufficient to emulsify the compound of the present invention and other additives to be contained, and preferably ranges from 0.1 part by weight to 10 parts by weight per one. part by weight of the compound of the present invention.

To increase the viscosity, a viscosity enhancing agent containing the compound of the present invention can be added to the lotion. The viscosity enhancing agent is any conventional agent that is usually added to give viscosity to the liquid and is non-toxic to humans, and includes carboxypolymethylene. The viscosity enhancing agent is used when a lotion with a high viscosity is desired. When the viscosity enhancing agent is used, the content of said agent may vary depending on the desired viscosity of the lotion to be used, and preferably ranges from 0.01 to 5% w / w. The lotion containing the compound of the present invention may further contain a solubilizer which is used for the stabilization of the compound of the active ingredient in an aqueous solution. If necessary, it may also contain other additives which are useful for the lotion, such as a flavoring agent, a coloring matter, an antiseptic or a higher alkeneic acid such as oleic acid, or other drugs that are useful for the treatment of diseases of the skin. The lotion containing the compound of the present invention can be prepared by a conventional method in this field. The solution containing the compound of the present invention can be used by application to the affected part of the skin one to several times (e.g. 1 to 4 times) per day. When the lotion has a reduced viscosity, it can be applied by filling a spray container with the composition of the lotion, and spraying the lotion directly to the skin. In cases where the compound of the present invention is used in the form of an eye drop or a nasal drop, the solvent to be used includes sterile distilled water or, in particular, distilled injectable water. The concentration of the active compound usually varies from 0.01 to 2.0% in w / v, and may be increased or decreased, depending on the purpose of use. The eye drop or nasal drop containing the compound of the present invention may further contain various additives such as a pH regulator, a sotonic agent, a solubilizing agent, a preservative, a viscosity enhancing agent, a chelating agent, a pH adjuster or an aromatic compound. The pH regulator includes, for example, a phosphate pH regulator (eg, sodium diacid phosphate-disodium hydrogen phosphate or potassium dihydrogen phosphate-potassium hydroxide), a borate pH regulator (eg, boric acid) borax), a pH regulator of citrate (eg, sodium citrate-sodium hydroxide), a pH regulator of tartrate (eg, tartaric acid-sodium tartrate), an acetate pH regulator (e.g. , acetic acid-sodium acetate), a carbonate pH regulator (e.g., sodium carbonate-citrate or sodium carbonate-boric acid) or an amino acid (e.g., sodium glutamate or e-aminocaproic acid).

The isotonic agent includes a saccharide such as sorbitol, glucose or mannitol, a polyhydric alcohol such as glycerin or propylene glycol, a salt such as sodium chloride or borax or boric acid and the like. The solubilizing agent includes a nonionic surfactant such as polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene monostearate, polyethylene glycol or hydrogenated polyoxyethylene castor oil and the like. The preservative includes, for example, a quaternary ammonium salt such as benzalkonium chloride, benzethonium chloride or cetylpyridinium chloride, an ester of parahydroxybenzoic acid such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate or butyl parahydroxybenzoate, benzyl alcohol , phenethyl alcohol, sorbic acid or a salt thereof, thimerosal, chlorobutanol or sodium dehydroacetate. The viscosity enhancing agent includes, for example, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose or a salt thereof. The chelating agent includes sodium edetate or citric acid and the like. The pH adjuster includes hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate and the like. Aromatic compounds include 1-menthol, borneol, a camphor (eg, dl-camphor) or eucalyptus oil and the like.

When the compound of the present invention is used as ophthalmic drops, it is thus usually adjusted to a pH of about 4.0 to 8.5, and when used as nasal drops, it can usually be adjusted to a pH between 4.0 and 8.5. In the manufacture of the nasal drops and the eye drops containing the compound of the present invention, a known method can be applied in each of the preparations themselves, depending on the type of each preparation. When the compound of the present invention is used as an ophthalmic drop, it may contain an active ingredient in an amount sufficient to allow effective prevention of ocular inflammation, which may vary depending on the symptoms or type of inflammation, and usually it varies from 5.0 to 1, 000μg for an administration. This can be administered once only several times (for example one to four times) per day. The aerosol containing the compound of the present invention means a pharmaceutical preparation which can be applied at the time of treatment by sprinkling a solution or suspension of the compound of the active ingredient using a pressure of a liquefied gas or a compressed gas filled in the same container or in another container. The aerosol can be prepared by dissolving the compound of the present invention in purified water and, if necessary, by dissolving or suspending the same solubilizing and absorption accelerating agent as mentioned above in the solution, and if necessary, adding such an additive. as a pH adjuster or an antiseptic as mentioned above, and then closing in a sealed manner with a valve and compressing the propellant. The propellant to be used includes dimethyl ether, liquefied natural gas, carbon dioxide, nitrogen gas, a substituted flon gas and other conventional propellants. The aerosol containing the compound of the present invention may further contain a coolant such as 1-methole, a camphor, methyl salicylate and the like. The inhalant or spray containing the compound of the present invention can be prepared according to the same methods as those mentioned for aerosols, a nebulizer or an inhaler can be used for the inhalant and a sprinkler container can be used for the spray. When the compound of the present invention is used as a suppository, the suppository can be prepared in a conventional manner using a conventional suppository base, and the compound of the active ingredient is contained in the suppository in an amount sufficient to show pharmaceutical effect, the which may vary depending on the age or symptom of the patient, and preferably varies from 0.1 to 60 mg. The suppository base of the present invention is the conventional base, and includes oils and fats of animal and vegetable origin such as olive oil, corn oil, castor oil, cottonseed oil, wheat germ oil, oil of cocoa, beef tallow, butter, wool fat, turtle tallow, squalene or a hydrogenated oil, oils and fats of mineral origin such as petrolatum, white petrolatum, hard paraffin, liquid paraffin, anhydrous lanolin or silicone oil, a wax such as jojoba oil, carnauba wax, yellow beeswax or lanolin, an aliphatic acid ester and partially synthetic or fully synthetic glycerin such as mono-, di- and triglycerides of a higher or intermediate aliphatic acid such as saturated aliphatic acids straight chain (for example lauric acid, myristic acid, palmitic acid or stearic acid), or a straight chain unsaturated aliphatic acid (for example oleic acid, inoléic or linolenic acid). Commercially available products are exemplified by Witepsol [manufactured by Dynamitnobel Co .; a mixture of mono-, di- and triglycerides of C12-C18 saturated aliphatic acid, in greater detail, include the Witepsol H series (e.g., Witepsol H5, H12, H19, H32, H35, H37, H39, H42, H175 or H185), the Witepsol W series (for example Witepsol W25, W31, W35 O W45), the Witepsol E series (for example Witepsol E75, E76, E79 or E85) or the Witepsol S series (for example Witepsol S52, S55) , or S58)]; Pharmasol (manufactured by Nippon Oils and Fats Co.); Isocacao (manufactured by Kao Co.); SB (manufactured by Kanegafuchi Chemical Co. and Taiyo Yusi Co), a mixture of mono-, di- and triglycerides of saturated C12-C18 aliphatic acid, in greater detail, include SB-H, SB-E or SB-AM ); Nopata (manufactured by Henkel AG); Sapoyer (manufactured by Gattfords Co), a mixture of mono-, di- and triglycerides of saturated C10-C18 aliphatic acid, in greater detail, include Sapoyer NA, Sapoyer OS, Sapoyer AS, Sapoyer BS, Sapoyer BM or Sapoyer DM ); Masaesthalinum (manufactured by Dynamitnobel Co., A mixture of mono-, di- and triglycerides of saturated C10-C18 aliphatic acid, in greater detail, include Masaesthalinum A, AB, B, BB, BC, BCF, C, D, EO BD and Masaesthalinum 299); or Migriol 810 or Migriol 812 (manufactured by Dynamitnobel Co .: a mixture of triglycerides of C8-C12 saturated aliphatic acid, in greater detail, one or more of these can be optionally incorporated when the aliphatic acid esters are incorporated and partially synthetic or fully synthetic glycerin as mentioned above). In addition, other synthetic products such as polyethylene glycol or polyoxyethylene alcohol can be exemplified. The bases are used in an amount of 25 to 99.9% by weight based on the total weight of the suppository. If necessary, a preservative, a stabilizer, a surfactant, an aromatic compound, a pH adjuster or purified water can be added to the suppository containing the compound of the present invention. The suppository containing the compound of the present invention can be in various forms such as rectal suppositories which are solid at normal temperature and melt at body temperature; an ointment or a liquid enema that can be prepared by dissolving or dispersing the compound of the present invention in a liquid base; a soft capsule for rectal administration; or an injection for rectal administration. The manufacture of the suppository containing the compound of the present invention is carried out using a method known in the art. The dose for a given patient is determined according to age, body weight, general health conditions, sex, diet, time of administration, route of administration, elimination rate, combination of drugs, degree of disease status by which the patient is undergoing treatment, and other factors. The compound of the present invention, a pharmaceutically acceptable acid addition salt thereof and a salt thereof exhibit low toxicity and can be used safely. While the daily dose varies depending on the condition and body weight of the patient, the type of compound and route of administration and the like, for example, this is between 0.01-50mg / person / day, preferably 0.01-20mg / person / day , for parenteral administration subcutaneously, intravenously or intramuscularly, or through the skin, eye, lungs, bronchi, nose or rectum, and approximately 0.01-150mg / person / day, preferably 0.1-100mg / person / day, for oral administration. The compound A useful as a synthetic intermediate for the compound (I) of the present invention is also useful as a synthetic intermediate for a compound of the general formula (ll-a) [hereinafter referred to as the compound (I Ia)] , which encompasses the compound (I) of the present invention, wherein m is 0 to 9, preferably 4, and R1a, R2a, R3a and R4a are the same or different and each is a hydrogen, an acyl (a straight or branched alkanoyl having from 1 to 20 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, eicosanoyl, and the like; a chain alkanoyl straight or branched having 2 to 20 carbon atoms which may be substituted by phenyl, such as phenylacetyl, phenylpropionyl and the like, an aroyl such as benzoyl and the like, a straight or branched chain alkoxycarbonyl wherein the alkoxy portion has 1 to 20 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl , ter-pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, tridecyloxycarbonyl, tetradecyloxycarbonyl, pentadecyloxycarbonyl, hexadecyloxycarbonyl, heptadecyloxycarbonyl, octadecyloxycarbonyl, nonadecyloxycarbonyl, eicosiloxycarbonyl and the like; aralkyloxycarbonyl such as benzyloxycarbonyl and the like), or an alkyl (a straight or branched chain alkyl having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl , heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and the like) or R3a and R4a can be combined by an alkylene chain which can be substituted by an alkyl having 1 to 4 carbon atoms such as those mentioned above, an aryl such as phenyl and the like or an aralkyl such as benzyl and the like, and Y1 and Y2 are the same or different and each is a hydrogen, an alkyl having from 1 to 4 carbon atoms such as those mentioned above, an alkoxy having from 1 to 4 carbon atoms (methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like), halogen (fluorine, chlorine, bromine) , iodine) or hydroxyl group ilo, and as a synthetic intermediate of a compound of general formula (l-c) [hereinafter referred to as the compound (l-c)] wherein m, R1a, R2a, R3a, R4a, Y1 and Y2 are as defined above, which is produced by oxidizing the compound (I I-a) with an appropriate oxidizing agent. The compound wherein, in the carbon chain at position 2 of the skeleton 2-amino-1,3-propanediol, the p-phenylene group in the carbon chain and the phenyl group at the end of the carbon chain are substituted and, in the carbon chain between said p-phenylene group and said phenyl group, the carbon atom at the position of the p-phenylene group is substituted by a carbonyl group, which is represented by the compound (lc), shows less toxicity and increased safety, and is useful as a superior immunosuppressant agent, such as the compound of the present invention. The compuet (I I-a) is useful as a synthetic intermediate of the compound (l-c), also shows less toxicity and greater security, and is useful as a superior immunosuppressive agent, such as the compound (l-c). The compound (I I-a) and the compound (I-c) can be produced by reacting and treating a compound of the general formula (XXX) [hereinafter referred to as a compound (XXX)]. wherein M, m, Y1 and Y2 are as defined above, in place of the compound (III) in method A, with compound A protected in the amino- and / or hydroxy- group of confomity with method A and In addition, by reacting and treating in the same manner using an alkyl halide instead of an acyl halide in method B, the corresponding amino- and / or hydroxy-alkylated compound can be produced. furtherby reacting and treating in the same way using the compound (XXX) instead of the compound (III) in the method M, the compound (I-c) can be produced. The compound (I I-a) and the compound (I-c) obtained can be converted into an acid addition salt thereof, a hydrate thereof and the like in the same manner mentioned above. In the compound (I I-a), a compound of the general formula (ll-b) [hereinafter referred to as a compound (ll-b)] is preferred] (ll-b) wherein R1, R2, R3, and R4, are as defined above, and a 2-amino-2- (2- (4- (1-hydroxy-5-phenylpentyl) phenyl) ethyl) propane -1,3-diol is particularly preferable. In the compound (l-c), the compound (I) is preferred wherein R1, R2, R3, and R4, are as defined above, and 2-amino-2- (2- (4- (1-oxo-5-phenylpentyl) phenyl) ethyl) propane-1, 3- Diol is particularly preferred. In addition, instead of the compound (XXX), a compound of the formula (XXXI) [hereinafter referred to as compound (XXXI)] (XXXI) is reacted where n is an integer from 0 to 12, preferably 6, and M is as defined above, and is treated with the amino- and / or hydroxy-protected compound A according to method A and method B [comprising the method of reacting and treating in the same manner using a alkyl halide in place of an acyl halide in the method B] or reacted and treated using the compound (XXXI) in place of the compound (III) in the method M to produce a compound of the general formula (XXXII) or (XXXIII) [hereinafter referred to as compound (XXXII) and compound (XXXIII)] (XXXII) (XXXIII) wherein R1a, R2a, R3a, R4a, and n are as defined above. The compound (XXXII) and the compound (XXXIII) obtained respectively show less toxicity and greater safety, and are useful as a superior immunosuppressive agent, such as the compound (I) of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the results of the experimental example 12, where it shows the result of the comparative compound 1, shows the result of the comparative compound 2 and - shows the result of the compound (I-a) of the present invention. Figure 2 is a graph showing the results of the experimental example 13, where -O- shows the result of the control, - • - shows the result of the comparative compound 1 (10 mg / kg), -A- shows the result of the Comparative compound 2 (10 mg / kg) and -M- shows the result of the compound (Ia) of the present invention (10 mg / kg).

BEST MODE TO MODALIZE THE INVENTION » The present invention is explained in detail, hereinafter, by illustrative examples, to which it is intended that the present invention is not limited. Of the symbols used in the formula, Ac is acetyl, Et is ethyl, TBDEM is tert-butyldimethylsilyl.

WORK EXAMPLE 1 Synthesis of 2-amino-2- (2- (4- (1-oxo-5-phenylpentyl) phenyl) ethyl) propane-1,3-diol (1) Synthesis of diethyl 2-acetamido-2- (2-phenylethyl) malonate To a suspension of sodium hydride (50.6 g) in dimethylformamide (1500 ml) was added dropwise a solution of diethyl acetamido malonate (250 g) in dimethylformamide (200 ml) under ice-cooling, and the mixture was stirred at room temperature. room temperature for 30 minutes. 2-phenylethyl bromide (156 ml) was added dropwise thereto and the resulting mixture was stirred for 7 hours at room temperature. The reaction mixture was poured into ice with water (1500 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried with anhydrous magnesium sulfate and the solvent was distilled. The obtained residue was crystallized with toluene to give the title compound (102 g) as white crystals, melting point 15-117 ° C. 1 H-NMR (CDCl 3) d: 1.25 (6 H, t, J = 7.3 Hz), 1.97 (3 H, s), 2.48 (1 H, d, J = 1 1.2 Hz), 2.50 (1 H, d, J = 9.2Hz), 2.69 (1 H, d, J = 9.2Hz), 2.71 (1 H, d, J = 1 1.2Hz), 4.19 (4H, q, J = 7.3Hz), 6.77 (1 H, s) , 7.13-7.20 (3H, m), 7.20-7.30 (2H, m).

IR (KBr): 3236, 1745, 1635 crn "1 MS (EI): 321 (M +) Elemental analysis: C? 7H23NO5 Calculated: C; 63.54, H; 7.21, N; 4.36 Found: C; 63.44, H; 7.29 , N; 4.44. (2) Synthesis of 2-acetamido-1,3-diacetoxy-2- (2-phenylethyl) propane To a solution of lithium aluminum hydride (1 1.8 g) in anhydrous tetrahydrofuran (1500 ml) was added dropwise a solution of diethyl 2-acetamido-2- (2-phenylethyl) malonate (50 g) in Anhydrous tetrahydrofuran (300 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium sulfate (150 ml) was added dropwise thereto to decompose the lithium aluminum hydride. The precipitate was filtered with celite and the solvent was distilled under reduced pressure to give a pale brown oily substance. It was dissolved in pyridine (90 ml), acetic anhydride (70 ml) was added thereto and the mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of ammonium chloride, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was crystallized with toluene to give the title compound (29.3 g) as white crystals, melting point 16-117 ° C. 1 H-NMR (CDCl 3) d: 1.96 (3H, s), 2.09 (6H, s), 2.20 (2H, m), 2.64 (2H, m), 4.35 (4H, s), 5.69 (1H, s), 7.10-7.20 (3H, m), 7.20-7.30 (2H, m). IR (KBr): 3315, 1732, 1652 cm "1 Elemental analysis: C17H23NO5 Calculated: C; 63.54, H; 7.21, N; 4.36 Found: C; 63.37, H; 7.30, N; 4.35. (3) Synthesis of 2-acetamido-1,3-diacetoxy-2- (2- (4-formylphenyl) ethyl) propane To a solution of 2-acetamido-1,3-diacetoxy-2- (2-phenylethyl) propane (10 g) in anhydrous dichloromethane (150 ml) was added titanium tetrachloride (15.4 ml) and dichloromethylmethyl ether (5.63 ml) under a nitrogen atmosphere at -15 ° C. The mixture was stirred at room temperature for 2 hours, poured into ice water and extracted with chloroform. The chloroform layer was washed with water, a saturated aqueous solution of sodium bicarbonate and saturated brine, dried with anhydrous magnesium sulfate and the solvent was distilled under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: dubopropyl ether: ethyl acetate = 1: 1) to give the title compound (5.1 g) as a white solid, melting point 98-100. ° C. 1 H-NMR (CDCl 3) d: 1.99 (3H, s), 2.10 (6H, s), 2.25 (2H, m), 2.70 (2H, m), 4.34 (4H, s), 5.82 (1 H, s) , 7.35 (2H, d, J = 7.9Hz), 7.80 (2H, d, J = 7.9Hz), 9.97 (1H, s). IR (KBr): 3313, 3205, 3082, 1735, 1706, 1652 cm'1 MS (EI): 349 (M +) Elemental analysis: C? 8H23NO6 «1/5 H2O Calculated: C; 61.25, H; 6.68, N; 3.97 Found: C; 61.40, H; 6.70, N; 3.96. (4) Synthesis of 2-acetamido-2- (2- (4-formylphenyl) ethyl) propane-1,3-diol To a solution of 2-acetamido-1,3-diacetoxy-2- (2- (4-formylphenyl) ethyl) propane (3.4 g) in ethanol (100 ml) was added sodium ethoxide (1.46 g) and the mixture it was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography with silica gel (eluent; chloroform: methanol = 9: 1) to give the title compound (1.7 g) as a pale yellow oily substance. 1 H-NMR (CDCl 3) d: 2.00 (2H, m), 2.01 (3H, s), 2.70 (2H, m), 3.70-3.90 (4H, m), 4.45 (2H, brs), 6.36 (1H, s), 7.35 (2H, d, J = 7.9Hz), 7.77 (2H, d, J = 7.9Hz), 9.94 (1H, s). MS (EI): 265 (M +). (5) Synthesis of 2-acetamido-1,3-bis (tert-butylmethylsilyloxy) -2- (2- (4-formylphenyl) ethyl) propane To a solution of 2-acetamido-2- (2- (4-formylphenyl) ethyl) propane-1,3-diol (9.7 g) in dimethyl formamide (150 ml) was added midazole (5.36 g) and tert-butyldimethylchlorosilane. (1.1 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 1) to give the title compound (13.5 g) as a pale yellow oily substance. 1 H-NMR (CDCl 3) d: 0.07 (12H, s), 0.90 (18 H, s), 1.95 (3H, s), 2.14 (2H, m), 2.68 (2H, m), 3.66 (2H, d, J = 9.9Hz), 3.78 (2H, d, J = 9.9Hz), 5.60 (1H, s), 7.36 (2H, d, J = 7.9Hz), 7.78 (2H, d, J = 7.9Hz), 9.96 (1 H, s). IR (pure): 3365, 3087, 2954, 1702 crn'1 MS (EI): 493 (M +). Elemental analysis: C26H4 NO4Si2 • 1/5 H2O Calculated: C; 62.78, H; 9.60, N; 2.82 Found: C; 62.59, H; 9.64, N; 2.66 (6) Synthesis of 2-acetamido-1,3-bis (tert-butyldimethylsilyloxy) -2- (2- (4- (1-hydroxy-5-phenylpentyl) phenyl) eti-propane To a solution of magnesium (0.27 g) in anhydrous tetrahydrofuran (5 ml) was added dropwise a solution of 1-bromo-4-phenylbutane (2.35) in anhydrous tetrahydrofuran (5 ml) under nitrogen atmosphere, and the mixture was stirred for 1.5 hours. To this solution was added dropwise a solution of 2-acetamido-1,3-bis (tert-butyldimethylsilyloxy) -2- (2- (4-formylphenyl) ethyl) propane (1.2 g) in anhydrous tetrahydrofuran (15 g. mi) and the mixture was stirred for one hour. 3% hydrochloric acid was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography with silica gel (eluent; hexane: ethyl acetate = 2: 1) to give the title compound (1.27 g) as a colorless transparent oily substance. 1 H-NMR (CDCl 3) d: 0.06 (12H, s), 0.90 (18H, s), 1.20-1.80 (7H, m), 1.87 (3H, s), 2.05 (2H, m), 2.50-2.60 (4H , m), 3.61 (2H, d, J = 9.9 Hz), 3.72 (2H, d, J = 9.9Hz), 4.55 (1H, t, J = 5.9Hz), 5.50 (1H, s), 7.00 -7.20 (9H, m). IR (pure): 3296, 3086, 3062, 1657 cm'1 MS (EI): 570 ((M-AcNH) +). (7) Synthesis of 2-acetamido-1,3-bis (tert-butyldimethylsilyloxy) -2- (2- (4- (1-oxo-5-phenylpentyl) phenyl) ethyl) propane To a solution of dimethyl sulfoxide (0.73 ml) in dichloromethane (8 ml) was added oxalyl chloride (0.23 ml) under a nitrogen atmosphere at -78 ° C, and then 2-acetamido-1,3-bis (tetrahydrofuran). butyldimethylsilyloxy) -2- (2- (4- (1-hydroxy-5-phenylpentyl) pheny1) ethyl) propane (1.1 g) in dichloromethane (7 ml), and the mixture was stirred at said temperature for 1 hour. Then triethylamine (1.2 ml) was added thereto and the temperature of the mixture was raised to room temperature. The reaction mixture was poured into water and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried with anhydrous magnesium sulfate and the solvent was distilled under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: hexane: ethyl acetate = 4: 1) to give the title compound (0.91 g) as a colorless transparent oily substance. 1 H-NMR (CDCl 3) d: 0.06 (12H, s), 0.90 (18H, s), 1.65-1.85 (4H, m), 1.95 (3H, s), 2.14 (2H, m), 2.60-2.70 (4H, m), 2.95 (2H, t, J = 7.3Hz), 3.66 (2H, d, J = 9.3Hz), 3.78 (2H, d, J = 9.3Hz), 5.58 (1H, s), 7.10-7.20 (3H, m), 7.20-7.30 (4H, m), 7.84 (2H, d, J = 8.6Hz). IR (pure): 3313, 1741, 1684 cm "1 MS (EI): 568 ((M-AcNH) +) Elemental analysis: C36H59NO Si2 • 1/5 H2O Calculated: C; 68.09, H; 9.52, N; 2.21 Found: C; 68.05, H; 9.54, N; 2.19. (8) Synthesis of 2-amino-2- (2- (4- (1-oxo-5-phenylpentyl) phenyDethyl) propane-1,3-diol To a solution of 2-acetamido-1-3-bis (tert-butyldimethylsiloxy) -2- (2- (4- (1-oxo-5-phenylpentyl) phenyl) ethyl) propane (0.9 g) in tetrahydrofuran (10 g) mi) was added a solution of tetra-n-butylammonium fluoride (1.2 g) in tetrahydrofuran (5 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried with anhydrous magnesium sulfate and the solvent was distilled under reduced pressure to give 2-acetamido-2- (2- (4- (1-oxo-5-phenylpentyl) phenyl) ethyl) propane-1,3-diol as a residue. The obtained residue was dissolved in water (5 ml) -methanol (5 ml) -tetrahydrofuran (3 ml), and lithium hydroxide monohydrate (0.3 g) was added thereto. The mixture was refluxed with heating for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried with anhydrous magnesium sulfate and the solvent was distilled under reduced pressure to give a white solid. The white solid obtained was recrystallized with ethanol-ethyl acetate-hexane to give the title compound (220 mg) as white crystals, melting point 126-127 ° C. 1 H-NMR (CDCl 3) d: 1.60-1.80 (6H, m), 2.00 (4H, brs), 2.60-2.75 (4H, m), 2.95 (2H, t, J = 7.2Hz), 350-3.65 (4H, m), 7.10-7.15 (3H, m), 7.20-7.25 (4H, m), 7.86 (2H, d) , J = 7.9Hz). IR (KBr): 3349, 3290, 3025, 1678 crt? 1 MS (EI): 355 (M +) Elemental analysis: C22H29N? 3. Calculated: C; 74.33, H; 8.22, N; 3.94. Found: C; 74.17, H; 8.29, N; 3.87.

WORK EXAMPLE 2 Synthesis of 2-amino-2- (2- (4- (1-oxo-5-phenylpentyl) phenyl) ethyl) propane-1,3-diol (another method) (1) synthesis of 4- (2-bromoetiQbenzaldehyde To a solution of dichloromethyl methyl ether (62 ml) in methylene chloride (400 ml) was added titanium tetrachloride (75 ml) over a period of 10 minutes under a nitrogen atmosphere at 4-5 ° C. Then, a solution of phenethyl bromide (85 ml) in methylene chloride (50 ml) was added thereto over a period of 50 minutes at 5-7 ° C and the mixture was stirred for 5 hours while rising gradually the temperature of the mixture up to room temperature. Water (200 ml) was added to the reaction mixture over the course of 1 hour and the mixture was extracted with chloroform (200 ml). The chloroform layer was washed with water, with a saturated aqueous sodium bicarbonate solution and with saturated brine, dried with anhydrous sodium sulfate and the solvent was distilled under reduced pressure to give a brown oily substance (167 g) . The brown oily substance obtained was purified by column chromatography with silica gel (eluent; hexane: ethyl acetate = 20: 1) to give 4- (2-bromoethyl) benzaldehyde (32.3 g) as a yellow solid. , melting point 50-52 ° C. 1 H-NMR (270 MHz / CDCl 3) d: 3.25 (2H, t, J = 7.3 Hz), 3.61 (2H, t, J = 7.3 Hz), 7.39 (2H, d, J = 7.9 Hz), 7.84 (2H , d, J = 7.9 Hz), 9.99 (1 H, s). MS (EI): m / z 213 (M +). (2) Synthesis of 1-r4- (2-bromoethyl) phen-p-5-phenylpentan-1-ol To a solution of magnesium (4.4 g) in tetrahydrofuran (20 mL) was added dibromoethane (1.6 mL) under a nitrogen atmosphere, and the mixture was stirred for 10 minutes. A solution of 1-bromo-4-phenylbutane (38.8 g) in tetrahydrofuran (30 ml) was added to the reaction mixture over a period of 30 minutes, and the mixture was stirred for 40 minutes. The obtained Grignard reagent was added dropwise to a solution of 4- (2-bromoethyl) benzaldehyde (32.3 g) in tetrahydrofuran (250 ml) with cooling on ice over a period of 30 minutes and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture. (200 ml) with ice cooling and the mixture was extracted with ethyl acetate (200 mi). The ethyl acetate layer was washed with saturated brine, dried with anhydrous magnesium sulfate and the solvent was distilled under reduced pressure to give a brown oily substance (70.5 g). The obtained brown oily substance was purified by column chromatography with silica gel (eluent: hexane: ethyl acetate = 10: 1) to give 1- [4- (2-bromoethyl) phenyl] -5-phenylpentan-1. -ol (32 g) as an oily yellow substance. 1 H-NMR (270 MHz / CDCl) d: 1.30-1.90 (7H, m), 2.59 (2H, t, J = 7.3 Hz), 3.15 (2H, t, J = 7.3 Hz), 3.55 (2H, t, J = 7.3 Hz), 4.65 (1 H, dt, J = 2.0, 5.3 Hz), 7.10-7.20 (5H, m), 7.20-7.35 (4H, m). MS (EI): m / z 330 ((M-17) +). (3) Synthesis of 1-r4- (2-bromoethyl) phenyl] -5-phenylpentan-1-one OH Br- (CH2) 2- ~ CH- (CH2) 4? To a solution of dimethyl sulfoxide (12.7 ml) in methylene chloride (320 ml) was added a solution of oxalyl chloride (7.7 ml) in methylene chloride (320 ml) in the course of 10 minutes under a nitrogen atmosphere. between -68 and -65 ° C, and the mixture was stirred at said temperature for 10 minutes. Then, a solution of 1- [4- (2-bromoethyl) phenyl] -5-phenylpentan-1-ol (20.7 g) in methylene chloride (80 ml) was added thereto between -68 and -65 ° C. in a period of 20 minutes and the mixture was stirred at said temperature for 1 hour. Triethylamine (41.6 ml) was also added thereto over a course of 10 minutes at said temperature and the mixture was stirred for 2.5 hours while the temperature of the mixture was raised gradually to 0 ° C. The reaction mixture was washed with water (100 ml) and saturated brine (100 ml), dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give a brown oily substance. The obtained brown oily substance was purified by column chromatography with silica gel (eluent: hexane: ethyl acetate = 20: 1) to give 1- [4- (2-bromoethyl) phenyl] -5-phenylpentan-1 -one (18.2 g) as an oily yellow substance. 1 H-NMR (270 MHz CDCIs) d: 1.65-1.90 (4H, m), 2.67 (2H, t, J = 7.3 Hz), 2.97 (2H, t, J = 7.3 Hz), 3.22 (2H, t, J = 7.3 Hz), 3.59 (2H, t, J = 7.3 Hz), 7.15-7.20 (3H, m), 7.20-7.35 (4H, m), 7.90 (2H, d, J = 7.9 Hz). MS (EI): m / z 345 (M +). (4) Synthesis of 1-r4- (2-vodoethyl) phenyl1-5-phenylpentan-1-one A solution of 1- [4- (2-bromoethyl) phenyl] -5-phenylpentan-1-one (18.2 g) and sodium iodide (9.5 g) in 2-butanone (180 ml) was stirred at 60 ° C. 3.5 hours The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and the solvent was distilled under reduced pressure to give a brown oily substance (19.2 g). The brown oily substance obtained was purified by column chromatography with silica gel (eluent: hexane: ethyl acetate = 20: 1) to give 1- [4- (2-iodoethyl) phenyl] -5-phenylpentan-1. -one (17.2 g) as an oily yellow substance. 1 H-NMR (270 MHz / CDCl 3) d: 1.65-1.85 (4H, m), 2.67 (2H, t, J = 7.3Hz), 2.97 (2H, t, J = 7.9Hz), 3.23 (2H, m), 3.36 (2H, m), 7.10-7.20 (3H, m), 7.20-7.35 (4H, m), 7.90 (2H, d, J = 8.6Hz). MS (El) m / z 392 (M +). IR (pure) cm-1: 3025, 2935, 2858, 1684, 1571. (5) Synthesis of 2-acetamido-2-. { 2-r4- (1-oxo-5-phenylpentyl) for.! Ll-etJI} diethyl malonate A solution of diethyl 2-acetamidomalonate (30.6 g), sodium ethoxide (7.6 g) and 3A molecular sieves (5.5 g) in ethanol (80 ml) was stirred at room temperature for 20 hours. A solution of 1- [4- (2-iodoethyl) phenyl] -5-phenylpentan-1-one (18.4 g) in tetrahydrofuran (60 ml) was added thereto over a period of 10 minutes and the mixture was refluxed with heating for 15 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate and the solvent was paraffined under reduced pressure to give a brown oily substance (40 g). The brown oily substance obtained was purified by column chromatography on silica gel (eluent: hexane: ethyl acetate = 2: 1) to give 2-acetamido-2-. { 2- [4- (1-oxo-5-phenylpentyl) phenyl] ethyl} diethyl malonate (13.8 g) as a pale yellow oily substance. 1 H-NMR (270 MHz / CDCl 3) d: 1.25 (6H, t, J = 7.3Hz), 1.665-1.85 (4H, m), 1.98 (3H, s), 2.50-2.60 (2H, m), 2.65-2.80 (4H, m), 2.90-3.00 (2H, m), 4.15-4.30 (4H, m), 6.78 (1H , s), 7.15-7.30 (7H, m), 7.84 (2H, d, J = 8.6 Hz). MS (EI) m / z 482 (M + 1) + IR (neat) cm'1: 3381, 2981, 2937, 1739, 1681, 1606. (6) Synthesis of 2-acetamido-2-. { 2-R4- (1, 1-ethylenedioxy-5-phenylpentyl) pheninethyl) -diethylmalonate COOEt OR AcNH- C- (CH2) 2 - < > - C- (CH2) 4- COOEt A solution of 2-acetamido-2 was refluxed. { 2- [4-1 -oxo-5-phenylpentyl) phenyl] ethyl} diethyl malonate (13.5 g), ethylene glycol (3.1 ml) and p-toluenesulfonic acid (0.53 g) in benzene (135 ml) with heating for 20 hours, while dehydrating with a Dean-Stark trap. The reaction mixture was treated with triethylamine (2.4 ml) and ethyl acetate (200 ml) was added thereto. The mixture was washed with water and saturated brine, dried with anhydrous sodium sulfate and the solvent was distilled under reduced pressure to give a pale yellow oily substance (15.9 g). The pale yellow oily substance obtained was purified by column chromatography on silica gel (eluent; hexane: ethyl acetate = 1: 1) to give 2-acetamido-2-. { 2- [41- (1,1-ethylenedioxy-5-phenylpentyl) phenyl] ethyl} dimethyl malonate (14.1 g) as a colorless transparent oily substance. 1 H-NMR (270 MHz / CDCl 3) d: 1.25 (6H, t, J = 7.3Hz), 1.30-1.45 (2H, m), 1.50-1.60 (2H, m), 1.85-1.95 (2H, m), 1.98 (3H, s), 2.45-2.60 (4H, m), 2.65-2.65 (2H, m), 3.70-3.75 (2H, m), 3.95-4.00 (2H, m), 4.15-4.30 (4H , m), 6.77 (1 H, s), 7.05-7.25 (7H, m), 7.33 (2H, d, J = 8.6 Hz). MS (El) m / z 525 (M +). IR (pure) cm'1: 3410, 2942, 1739, 1683, 1496. (7) Synthesis of 2-acetamido-2-. { 2-f4- (1,1-ethylenedioxy-5-phenylpentyl) feriyl] ethyl} -propane-1, 3-diol To a solution of lithium aluminum hydride (2.0 g) in tetrahydrofuran (100 ml) was added dropwise a solution of 2-acetamido-2-. { 2- [4- (1, 1-ethylenedioxy-5-phenylpentyl) phenyl] ethyl} diethyl malonate (14.0 g) in tetrahydrofuran (50 ml) at 3-13 ° C over the course of 30 minutes, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium sulfate (27 ml) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitate was filtered through celite and the filtrate was concentrated under reduced pressure to give a colorless transparent oily substance (1.7 g). The obtained colorless transparent oily substance was purified by column chromatography on silica gel (eluent: chloroform: methanol = 20: 1) to give 2-acetamido-2-. { 2- [4- (1, 1-ethylenedioxy-5-phenylpentyl) phenyl] ethyl} propane-1,3-diol (5.8 g) as a colorless transparent oily substance. 1 H-NMR (270 MHz / CDCl 3) d: 1.30-1.45 (2H. M), 1.53-1.65 (2H, m), 1.80-2.00 (4H, m), 1.96 (3H, s). , 2.54 (2H, m), 2.64 (2H, m), 3.55-3.65 (2H, m), 3.70-3.80 (2H, m), 3.80-3.90 (2H, m), 3.95-4.05 (2H, m) , 5.98 (1 H, s), 7.05-7.25 (4H, m), 7.10-7.15 (3H, m), 7.20-7.25 (7H, m), 7.35 (2H, d, J = 8.6 Hz). MS (El) m / z 441 (M +). IR (pure) cm'1: 3323, 2945, 1652. (8) Synthesis of 2-amino-2-. { 2-r4- (1-oxo-5-phenylpentyl) phenytriethyl) propane-1,3-diol A solution of 2-acetamido-2-. { 2- [4- (1,1-ethylenedioxy-5-phenyl-pentyl) phenyl] ethyl} propane-1,3-diol (5.5 g), concentrated hydrochloric acid (7 ml) and water (20 ml) in tetrahydrofuran (200 ml) were refluxed with heating for 7 hours. The mixture was adjusted to pH 12 with 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and the solvent was distilled under reduced pressure to give a yellow solid (4.7 g). The yellow solid obtained was purified by column chromatography on silica gel (eluent: chloroform: methanol = 9: 1) to give a white solid (3.76 g). The white solid obtained was crystallized from ethyl acetate and the obtained crystals were recrystallized from ethyl acetate-ethanol to give 2-amino-2- (2- (4- (1-oxo-5-phenylpentyl) phenyl) ethyl. ) propane-1,3-diol (2.34 g) as white crystals, melting point 126-127 ° C. 1 H-NMR (270 MHz / CDCl 3) d: 1.60-1.80 (6H, m), 2.00 (4H, brs), 2.60-2.75 (4H, m), 2.95 (2H, t, J = 7.2 Hz), 3.50- 3.65 (4H, m), 7.10-7.15 (3H, m), 7.20-7.25 (4H, m), 7.86 (2H, d, J = 7.9 Hz). MS (El) m / z 355 (M +). IR (pure) cm'1: 3349, 3290, 3025, 1678. Elemental analysis: Calculated: C, 74.33; H, 8.22; N, 3.94. Found: C, 74.35; H, 8.38; N, 3.86.

WORK EXAMPLE 3 Synthesis of 2-acetamido-1,3-diacetoxy-2- (2- (4- (1-oxo-5-phenylpentyl) phenyl) ethyl) propane 2-Acetamido-2- (2- (4- (1-oxo-5-phenylpentyl) phenyl) ethyl) -propane-1,3-diol was dissolved in pyridine, acetic anhydride was added thereto with ice-cooling and the mixture was allowed to stand at room temperature. The reaction mixture was poured into an aqueous solution of hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of potassium bicarbonate and saturated brine, dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by column chromatography with silica gel to give 2-acetamido-1,3-diacetoxy-2- (2- (4- (1-oxo-5-phenylpentyl) phenyl) ethyl) propane.

EXAMPLE OF PREPARATION 1 Synthesis of 2-amino-2- (2- (4- (1-oxo-6-phenylhexyl) phenyl) ethyl) propane-1,3-diol (1) Synthesis of 2-acetamido-1,3-bis (tert-butyldimethylsiloxy) -2- (2- (4- (1-hydroxy-6-phenylhexyl) phenyl) ethyl) propane 2-Acetamido-1,3-bis (tert-butyldimethylsilyoxy) -2- (2- (4-formylphenyl) ethyl) propane (3.0 g) and 1-bromo-5-phenylpentane (4.1 g) were reacted and treated in the same manner as in working example 1 (6) to give the title compound (2.7 g) as a pale yellow oily substance. 1 H-NMR (CDCl 3) d: 0.6 (12H, s), 0.84 (18H, s), 1.20-1.80 (9H, m), 1.87 (3H, s), 2.04 (2H, m), 2.49-2.56 (4H , m), 3.61 (2H, d, J = 9.2Hz), 3.72 (2H, d, J = 9.2Hz), 4.54 (1H, t, J = 6.6Hz), 5.50 (1H, s), 7.07 -7.1 1 (5H, m), 7.15-7.23 (4H, m). MS (EI): 584 ((M-AcNH) +). (2) Synthesis of 2-acetamido-1,3-bis (tert-butyldimethylsilyloxy) -2- (2- (4- (1-oxo-6-phenylhexyl) phenyl) ethyl) propane 2-Acetamido-1,3-bis (tert-butyldimethylsilyloxy) -2- (2- (4- (1-hydroxy-6-phenylhexyl) phenyl) ethyl) propane (2.2 g) was reacted and treated therein. so as in working example 1 (7) to give the title compound (2.1 g) as a pale yellow oily substance. 1 H-NMR (CDCi 3) d: 0.06 (12H, s), 0.83 (18H, s), 1.35 (2H, m), 1.54-1.75 (4H, m), 1.89 (3H, s), 2.06 (2H, m), 2.53-2.62 (4H, m), 2.86 (2H, t, J = 7.3Hz), 3.60 (2H, d, J = 9.2Hz), 3.71 (2H, d, J = 9.2Hz) , 5.52 (1 H, s), 7.07-7.11 (3H, m), 7.12-7.23 (4H, m), 7.78 (2H, d, J = 8.6Hz). IR (pure): 331 1, 2952, 2929, 1683, 1657 cm'1 MS (El): 582 ((M-AcNH) +). Elemental analysis: C37H61NO4 Si2 «1/5 H2O Calculated: C; 68.96, H; 9.60, N; 2.17 Found: C; 68.99, H; 9.72, N; 2.20. (3) Synthesis of 2-amino-2- (2- (4- (1-oxo-6-phenylhexyl) phenyl) ethyl) propane-1,3-diol 2-Acetamido-1,3-bis (tert-butyldimethylsilyloxy) -2- (2- (4- (1-oxo-6-phenylhexyl) phenyl) ethyl) propane (2.0 g) was reacted and treated therein. in the working example 1 (8) to give the title compound (310 mg) as a white crystalline substance, melting point 118-120 ° C. 1 H-NMR (CDCl 3) d: 1.42 (2H, m), 1.61-1.81 (6H, m), 2.00-2.30 (4H, brs), 2.62 (2H, t, J = 7.3Hz), 2.70 (2H, m ), 2.92 (2H, t, J = 7.3Hz), 3.52 (2H, d, J = 10.6Hz), 3.61 (2H, d, J = 10.6Hz), 7.14-7.18 (3H, m), 7.19-7.29 (4H, m), 7.86 (2H, d, J = 8.6Hz). IR (KBr): 3352, 2933, 1676 cm'1 MS (El): 369 (M +). Elemental analysis: C23H3iO3 • Calculated H2O: C; 71.29, H; 8.58, N; 3.61 Found: C; 71.50, H; 8.32, N; 3.58 EXAMPLE OF PREPARATION 2 Synthesis of 2-amino-2- (4- (1-oxo-7-phenylheptyl) phenyl) ethyl) propane-1,3-diol (1) Synthesis of 2-acetamido-1,3-bis (tert-butyldimethylsilyloxy) -2- (2- (4- (1-hydroxy-7-phenylheptyl) phenyl) ethyl) propane 2-Acetamido-1,3-bis (tert-butyldimethylsilyloxy) -2- (2- (4-formiiphenyl) ethyl) propane (3.0 g) and 1-bromo-6-phenylhexane (3.1 g) were reacted and treated in the same manner as in working example 1 (6) to provide the title compound (2.6 g) as a pale yellow oily substance. 1 H-NMR (CDCl 3) d: 0.06 (12H), s), 0.84 (18H, s), 1.20-2.10 (16H, m), 2.45-2.55 (4H, m), 3.64 (2H, d), J = 9.2Hz), 3.72 (2h, d, J = 9.2Hz), 4.55 (2H, t, J = 6.6Hz), 5.50 (1H, s), 7.05-7.20 (9H, m). IR (neat): 3304, 3086, 3026, 2929, 1741 cm'1 MS (EI): 656 (M +). (2) Synthesis of 2 acetamido-1,3-bis (tert-butyldimethylsilyloxy) -2- (2- (4- (1-oxo-7-phenylheptyl) phenylethyl) propane Reacted was 2-acetamido-1,3-bis (tert-butyldimethyl) -2-yl) -2- (2- (4- (1-hydroxy-7-phenylheptyl) phenyl) ethyl) propane (2.2 g) and treated in the same manner as in working example 1 (7) to give the title compound (1.8 g) as a colorless transparent oily substance. 1 H-NMR (CDCl 3) d: 0.06 (12H, s), 0.84 (18H, s), 1.25-1.35 (4H, m), 1.50-1.75 (4H, m), 1.89 (3H, s), 2.07 (2H , m), 2.50-2.65 (4H, m), 2.85 (2H, t, J = 7.3Hz), 3.60 (2H, d, J = 9.2Hz), 3.71 (2H, d, J = 9.2Hz), 5.52 (1 H, s), 7.05-7.15 (3H, m), 7.18-7.24 (4H, m), 7.79 (2H, d, J = 7.9Hz). IR (pure): 3313, 2929, 2856, 1684, 1606 cm "1 MS (EI): 596 ((M-cNH) +) Elemental analysis: C38H63NO4 Si2" 1/5 H2O Calculated: C; 69.40, H; 9.72, N; 2.13, Found: C; 69.12, H; 9.65, N; 2.02. (3) Synthesis of 2-amino-2- (2- (4- (1-oxo-7-phenylheptiPfeniPet¡Ppropane-1,3-diol 2-Acetamido-1,3-bis (tert-butyldimethylsilyloxy) -2- (2- (4- (1-oxo-7-phenylheptyl) phenyl) ethyl) propane (1.8 g) was reacted and treated in a the same way as in working example 1 (8) to give the title compound (390 mg) as a white crystalline substance, melting point 121-122 ° C. 1 H-NMR (CDCl 3) d: 1.30-1.45 (4H, m), 1.55-1.75 (6H, m), 2.00- 2.20 (4H, brs), 2.60 (2H, t, J = 7.9Hz) , 2.71 (2H, m), 3.52 (2H, d, J = 10.6Hz), 3.61 (2H, d, J = 10.6Hz), 7.13-7.20 (3H, m), 7.20-7.30 (4H, m), 7.86 (2H, d, J = 8.6Hz) IR (KBr): 3288, 2929, 2854, 1676 cm "1 MS (EI): 383 (M +). Elemental analysis: C24H33N? 3 • 1/5 H2O. C, 74.46, H, 8.70, N, 3.62, Found: C, 74.54, H, 8.77, N, 3.58.

EXAMPLE OF FORMULATION (1) Tablets A tablet containing a compound of the present invention and having the following formulation was produced. Compound (1) 1 mg Lactose 90 mg Crystalline cellulose 25 mg Magnesium stearate 4 mg (2) Soft capsules (per capsule) Compound (I) 30 mg Polyethylene glycol-300 300 mg Polysorbate 80 20 mg Production method Polyethylene glycol-300 and polysorbate 80 were added to a compound of the present invention and the mixture was packed into a soft capsule. (3) Inventions (for every 10 ml in an ampule) Compound (I) 0.3% Polyethylene glycol-300 20% Ethanol 60% Injectable distilled water Amount to make a total of 10 ml Production method Ethanol and polyethylene glycol-300 were added to a compound of the present invention and injectable distilled water was added to achieve total volume. In this way, injections containing 30 mg of the compound of the present invention were obtained in an ampule (10 ml). (4) 5% Ointment Compound of the present invention i g Hydrophilic petrolatum 19 g Production method A compound of the present invention (1 g) was dissolved in 19 g of hydrophilic petrolatum with heating at 60 ° C, and the mixture was cooled with stirring to prepare an ointment containing 5% of the compound of the present invention. (5) 5% Ointment Compound of the present invention 1 9 Plastibase 19 g Production method A compound of the present invention (1 g) was mixed well with 19 g of plastibase (hydrocarbon gel) in a mortar for 30 minutes to prepare an ointment containing 5% of the compound of the present invention. (6) Suppositories Compound of the present invention 30 mg Witepsol H15 72.47 g Production method Witepsol H15 (72.47 g) was melted at 40 ° C and a compound of the present invention (30 mg) was added. The mixture was stirred to disperse the compound. The homogeneous mixture was filled into a container at a weight of 725 mg each to prepare a suppository containing 0.3 mg of the compound of the present invention in 725 mg of the suppository. (7) Ophthalmic drops Compound of the present invention 0.2 g Polyvinyl alcohol 0.2 g Hydrogenated polyoxyethylene castor oil 60 0.1 g Disodium phosphate 0.5 g Monosodium phosphate 0.1 g Sodium chloride 0.8 g Benzethonium chloride 0.007 g Sterile purified water Quantity to make 100 my total Production method 0.2 g of polyvinyl alcohol was added to 70 ml of sterile purified water and the mixture was dissolved by heating to 70 ° C with stirring. 0.1 g of hydrogenated castor oil-polyoxyethylene 60 was dispersed homogeneously in the solution, and then the mixture was cooled to room temperature. In this solution 0.2 g of a compound of the present invention, 0.5 g of disodium phosphate, 0.1 g of sodium phosphate, 0.8 g of sodium chloride and 0.007 g of benzethonium chloride were dissolved. Sterile purified water was added to the solution to make the total volume of 100 ml to prepare ophthalmic drops containing the compound of the present invention. (8) Nasal drops Compound of the present invention 0.4 g Sodium citrate 0.2 g Polysorbate 80 0.1 g Glycerin 2.6 g Benzethonium chloride 0.007 g Sterile purified water Amount to make the total of 100 ml Production method 0.4 g of a compound was dissolved of the present invention, 0.2 g of sodium citrate, 0.1 g of polysorbate 80, 2.6 g of glycerin and 0.007 g of benzethonium chloride in 70 ml of sterile purified water. Sterile purified water was added to the obtained solution to make the total volume of 100 ml to prepare a solution of nasal drops containing the compound of the present. (9) 2% Lotion Compound of the present invention 100 mg Soapyl myristate 1 ml Ethanol 4 ml Production method To 100 mg of a compound of the present invention were added 1 ml of isopropyl myristate and 4 ml of ethanol to dissolve the compound at room temperature to prepare a lotion containing 2% of the compound of the present invention. The action and effect of the present invention are explained in detail by illustrative experimental examples in the following. To determine the immunosuppressive activity, various immune reactions can be measured using mouse, rat or human lymphocytes. The immunosuppressive activity can be determined with a high sensitivity, for example, by an aiogenic reaction of mixed lymphocyte (allogeneic MLR) of mouse, rat or human. The allogeneic MLR reaction is a lymphocyte blastogenesis induced by a mixed culture of lymphocytes such as spleen cells, lymph node cells and peripheral blood lymphocytes, obtained from two individuals, which are allogeneic and have different major histocompatibility antigens. The allogeneic MLR reaction is a phenomenon induced by and reflects the difference in the major histocompatibility antigens of the lymphocyte donors, and a blastogenesis phenomenon of lymphocytes is not developed in a mixed culture of lymphocytes from monozygotic twins. Accordingly, the allogeneic MLR reaction is widely used in the selection of donor-recipient in organ transplants. When the allogeneic MLR reaction is desired, MLR can be performed in one sense, where the lymphocytes of one of them are used as the stimulator cells after being irradiated with X-rays or treated with mitomycin C to inhibit proliferation and when determined the blastogenesis of the other's lymphocytes (response cells). In addition, the immunosuppressive activity can be determined as an activity to inhibit the induction of cytotoxic T cells having the major histocompatibility antigen restrictive property during the allogeneic MLR reaction.

In addition, the immunosurper activity can be determined, apart from the allogeneic MLR reaction, as a lymphocyte blastogenesis inhibitory activity induced by the stimulation of various mitogens such as concanavalin A, phytohemagglutinin and carmine herb mitogen or it can be determined as a inhibitory activity of lymphocyte proliferation induced by a cytokine (eg, interleukin 1, 2, 3, 4, 5 or 6) having an activity to enhance proliferation or to promote the differentiation of lymphocytes such as T cells or B cells, or the manifestation of said function. Furthermore, it is possible to evaluate the immunosuppressive activity in accordance with the inhibition of the production of these cytokines from T cells or macrophages. Alternatively, the activity can be evaluated as an inhibitory activity of the induction of allogeneic cell-specific cytotoxic T-cells induced in mouse spleen cells previously immunized for example, with allogenic cells by administering to the mice a compound intraperitoneally, orally , intravenous, intradermal, subcutaneous or intramuscular; as an activity to inhibit the production of an allogeneic cell-specific antibody produced in the blood serum of mice immunized with aiogenic cells or the like. The activity can also be evaluated as an activity to inhibit the rejection of organ transplants between skin, heart, liver, allogeneic kidney, etc. or the graft-versus-host reaction (GvHR) and the host-versus-graft reaction (HvGR) administering a compound to a rat, dog or the like.

In addition, the activity can be evaluated as an activity to inhibit the delayed hypersensitivity reaction, arthritis by adjuvant, experimental allergic encephalomyelitis, experimental autoimmune uveitis or the like by administering a compound to mouse, rat or the like. In addition, immunosuppressive activity can be evaluated as an activity to inhibit for example, the production of anti-DNA antibodies, the production of rheumatoid factors, nephritis, abnormal proliferation of lymphocytes or urinary protein; or a macrobiotic effect by administering a compound to MRL / 1 pr mice, NZB / WF-i mice, BXSB mice, NOD mice and the like which are spontaneous model animals with autoimmune diseases.

EXPERIMENTAL EXAMPLE 1 Inhibition of the allochene reaction of mixed lymphocytes in rat The allogenic reaction of mixed lymphocytes in rat (hereinafter referred to as an MLR allogenic reaction in rat) is reacted by a mixed culture of non-adhesive spleen cells to nylon and wool from F344 rats as response cells and spleen cells from rat WKAH treated with mitomycin C as stimulator cells that are used in the same relationship. The response cells are prepared as follows.

A spleen from a F344 rat of four to ten weeks of age is removed and a single cell suspension of spleen cells is obtained using RPMI1640 medium (containing 60 μg / ml kanamycin sulfate, 100 units / ml penicillin G potassium, 10 mM L-hydroxyethylpiperazine-N'-2-ethanesulfonate, 0.1% sodium bicarbonate and 2 mM L-glutamine) supplemented with heat-activated 5% fetal bovine serum (hereinafter referred to as FCS ). After the hemolysis treatment, the spleen cells are passed through a nylon-wool column and the non-adhesive cells are collected. The non-adhesive cells to the nylon are adjusted to a concentration of 107 cells / ml using RPMI1640 medium containing 10"4 M of 2-mercaptoethanol and 10% FCS and used as a suspension of response cells. as follows: A spleen of a WKAH rat of 4 to 10 weeks of age is removed and a suspension of individual cells of spleen cells is obtained using RPMI1640 medium After the hemolysis treatment, the suspension is treated with 40 μg / ml mitomycin C at 37 ° C for 60 minutes. After washing three times, the suspension is adjusted to a concentration of 107 cells / ml using RPMI 1640 medium containing 104 M of 2-mercaptoethanol and 10% FCS and used as a suspension of stimulator cells. The cell suspension response (50 μl) prepared by the method described above, the suspension of stimulator cells (50 μl) prepared by the method described above and a test sample (100 μl) prepared using medium containing FCS ai 10% it is placed in a 96-well flat-bottom microtiter plate and grown at 37 ° C under a mixture of 5% CO2-95% air for 4 days. The reaction of blastogenesis of lymphosites in the rat MLR reaction is determined by a method that uses 3 H-thymidine as an indicator. Namely, after cultivation, 18.5 KBq / 3H-thymidine cavity is added and the cells are cultured for 4 hours. The cells are collected by a cell harvester and the radioactivity incorporated into the cells is determined by a liquid flash counter and used as an indicator of lymphocyte blastogenesis in the rat allogenic MLR test. The inhibition of the allogeneic MLR reaction in rat is calculated by the following formula and is evaluated in accordance therewith.

Inhibition = X100 (%) The compounds of the present invention show a value CI or (a concentration to inhibit 50%) of about 1 nM to about 50 nM in an aiogenic reaction of mixed lymphocytes in rat.

EXPERIMENTAL EXAMPLE 2 Inhibition of IL-2-induced interleukin-2 (IL-2) -dependent mouse T cell proliferation of the CTLL-2 line A CTLL-2 line of IL-2-dependent mouse T cells is prepared at a concentration of 2 x 10 5 cells / ml in RPMI1640 medium containing 10% FCS. A cell suspension thereof (50 μl), 40 U / ml (50 μl) of human recombinant IL-2 (rh-IL-2) and a test sample (100 μl) prepared using RPMI1640 medium containing FCS at 10% are placed in a 96-well flat bottom microplate and grown at 37 ° C under an atmosphere of 5% CO2-95% air for 68 hours. After cultivation, 100 μl of the supernatant from each well is removed and 5 mg / ml of a solution of MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenylethrazole bromide is added to each well per 20 μl and the cells are incubated at 37 aC for 4 hours. Then add (100 μl) of 0.01 N hydrochloric acid solution containing 10% sodium dodecylsulfate and the cells are incubated at 37 ° C overnight. The purple-formed formazan crystals produced are dissolved and the absorbance at 570 nm is measured using a microplate absorbance photometer and used as an indicator of the proliferation of IL-2-dependent CTLL-2 cells. The inhibition (%) of IL-2 dependent proliferation is calculated with the following formula.

Absorbance when absorbance is added when the sample is not added rh-IL-2 test and rh-IL-2 X100 absorbance when absorbed when not adding rh-IL-2 only rh-IL-2 is added The compounds of the present invention show an IC50 value (a concentration to inhibit 50%) of about 1 nM to about 50 nM in the IL-2 dependent proliferation of the mouse T-cell CTLL-2 line.

EXPERIMENTAL EXAMPLE 3 Inhibitory effect in delayed-type hypersensitivity reaction in mice BALB / c mice of 5 weeks of age were sensitized by subcutaneous injection in the back with 0.1 ml of 0.25% methylated human serum albumin solution (MeHSA). Four days after sensitization, the volume of the right hind paw was measured using an apparatus for measuring the volume of the legs (TK-102, Neuroscience Co., Ltd) and After that 25 μl of 0.25% MeHSA was injected into the bearing of the right hind leg to properly induce a delayed hypersensitivity reaction (DTH reaction). After 24 hours of injection, ie after 5 days of sensitization, the volume of the right hind paw was measured again. Test compounds are examined for differences in paw volumes between 5 days and 4 days, i.e. swelling in the bearing volume of the right hind paw as an indicator of the DTH reaction. At this time, the body weight, the wet weight of the thymus and spleen and the number of peripheral lymphocytes are also measured. The test compounds are administered orally for 5 days after the day of sensitization. The compounds of the present invention show statistically significant inhibitory effect on the DTH reaction by administration at 0.1 to 10 mg / kg.

EXPERIMENTAL EXAMPLE 4 Inhibitory effect of host versus graft reaction in rats The spleen of a male WKAH rat from 4 to 5 weeks of age was excised and used to obtain a suspension of individual cells of spleen cells using RPMI1640 medium (containing 60 μg / ml kanamycin sulfate, 100 units / ml of G potassium penicillin, 10 nM N-2-hydroxyethylperazine-N'-2-ethansulfate, 0.1% sodium bicarbonate and 2 mM L-glutamine). After the hemolysis treatment, the cells are washed 3 times with RPMI1640 medium and adjusted to 5 x 10 7 cells / ml with physiological saline for injection. By injecting 100 μl of the spleen cell suspension into the right rear leg bearing of male LEW rats 4-5 weeks old, the host versus graft reaction is induced (HvG reaction). After 4 days of the injection of the cells both the left and right popliteal lymph nodes are removed and the weight thereof is measured. The test compounds are examined for the difference between the weight of the right popliteal lymph node and the weight of the left popliteal lymph node as an indicator of the HvG reaction. Furthermore, after 4 days from the injection of the cells, blood was obtained from the tail vein of the rats and the number of peripheral leukocytes was measured using an automatic hemocytometer for animal (MEK-5158, Nihonkouden Co., Ltd) . The test compounds were administered intravenously or orally daily for 4 days after injection of the cells.

EXPERIMENTAL EXAMPLE 5 Inhibitory effect in the graft versus host reaction in rats There are two types of graft versus host reactions (GvH reaction) which are systemic and local GvH reactions. The systemic GvH reaction is induced by the intravenous administration of cyclophosphamide at 150 ml / kg to rats (LEWxBN) F? females 5 weeks of age and injecting these, intravenously, with 5 x 107 spleen cells from female LEW rats from 5 weeks of age to the next day. The test compounds are examined by determining the survival time after the induction of the systemic GvH reaction. The local GvH reaction is induced by subcutaneous injection of 2 x 10 7 spleen cells from 5-week-old male LEW rats in the rat hind paw bearing (LEWxBN) F! females 5 weeks of age and after 7 days, the popliteal lymph nodes are removed and their weights are measured. The test compounds are administered orally daily for 30 days and for 7 days from the day of cell injection in the case of the systemic reaction and the local GvH reaction, respectively.

EXPERIMENTAL EXAMPLE 6 Inhibitory effect on the production of antibodies against sheep erythrocytes in rats Male F344 rats from 4 to 6 weeks of age were immunized by intravenous injection of 1 x 108 sheep erythrocytes. After 4 days from immunization, the spleen was excised and the number of sheep anti-erythrocyte antibody-producing cells counted by direct evidence of hemolytic plaque formation using sheep erythrocytes and guinea pig complement. In this case, the body weights, the wet weights of the thymus and spleen and the number of spleen cells were also measured. The test compounds are administered orally for 4 days after the day of immunization.

EXPERIMENTAL EXAMPLE 7 Inhibitory effect in arthritis by adjuvant in rat Dead tuberculosis bacteria (strain R35H5v-1 0.5 mg) were suspended as an adjuvant in 0.1 ml of liquid paraffin and inoculated into the tail root of an 8-week-old male LEW rat. After inoculation of the adjuvant and until day 21, the presence or absence of the onset of arthritis was observed and the day of onset of arthritis and the relationship of the cases of onset was determined. The swelling of the bearing of the hind leg of the rat is measured periodically using an apparatus for measuring the volume of the leg (TK-102, Neuroscience Co., Ltd.). On day 21, the radiograph of the rats' hind leg was taken, based on the degree of destruction of the joint evaluated. The test compounds are administered orally or intravenously from the day of adjuvant inoculation every day for 21 days. When the test compound was not administered, arthritis was found in the 7 rats inoculated with adjuvant on day 9.6 + 0.5, together with swelling of the hind limbs and destruction of the joint. The compounds of the present invention delayed the attack of and decreased the ratio of attack cases of arthritis by adjuvant to a statistically significant degree and administration of 0.1-10 mg / kg. it significantly suppressed the swelling of the hind limbs and the destruction of the joint.

EXPERIMENTAL EXAMPLE 8 Inhibitory effect in collagen-induced arthritis in rats Male Spregue-Dawley rats from seven to eight weeks of age were injected intracutaneously by division of 5 portions with 1 ml of emulsion which are prepared by mixing 0.1 N acetic acid solution containing bovine type II collagen at a concentration of 2 mg / kg. ml with incomplete Freund's adjuvant with a volume ratio of 1: 1. After 7 days, immunization was performed by intracutaneous injection of collagen emulsion prepared with the same method at the root of the tail. The swelling of the bearing of the right hind leg of the rat was periodically measured using an apparatus for measuring the volume of the leg (TK-102; Neuroscience Co., Ltd.). Additionally, after 10 and 21 days from the primary immunization with collagen, blood was collected and the type II anticolagen antibody titer of the serum was measured with the Elisa method. The test compounds were administered orally or intravenously every day for 21 days from the day of primary immunization.

EXPERIMENTAL EXAMPLE 9 Inhibitory effect in experimental allergic encephalomyelitis in rats Female eight-week-old LEW rats were immunized by intracutaneous injection into the right hind foot bearing with 0.1 ml of Freund's complete adjuvant emulsion containing 100 μg of purified myelin basic protein (MBP) from the spinal cord. of guinea pigs and 100 μg of Mycobacterium tuberculosis H37 RA killed. After this the somatic symptoms were judged after the immunization in accordance with the 6-level standards. Score 0: no symptoms Score 1: weakness of the tail Score 2: weakness of the hind limbs Score 3: paralysis of only one hind limb Score 4: paralysis of both hind limbs Score 5: urinary incontinence or death Additionally, after 20 days after immunization with MBP, the spinal cord of the rats was excised to make tissue sections and their histology was investigated after staining with the hematoxylin-eosin method. The test compounds were administered orally every day for 20 days after the day of immunization.

EXPERIMENTAL EXAMPLE10 Inhibitory effect in experimental autoimmune uveitis Female eight-week-old LEW rats were immunized by intracutaneous injection into the right hind leg bearing with 0.1 ml of Freund's complete adjuvant emulsion containing 30 μg of soluble antigen (antigen-s) purified from the retina of bovine and 100 μg of Mycobacterium tuberculosis H37 RA died. Periodically the attack and seriousness of uveitis was inspected after immunization. The severity of uveitis was judged in accordance with the following standards. Score 0: no inflammation Score 1: weak or light (hyperemia of the iris and emergence of exudate in the anterior chamber) Score 2: medium (small hypopyon) Score 3: strong (remarkable hypopion and exophthalmos) Additionally, after 15 days of immunization with s antigens, the ocular blood cells of the rats were excised to make sections of tissue and the histology thereof was investigated after staining them with the hematoxylin-eosin method. Score 0: no infiltration of cells associated with inflammation Score 1: light infiltration Score 2: weak or light infiltration Score 3: average infiltration and partial destruction of the visual cell layer Score 4: remarkable infiltration and destruction of the visual cell layer Test compounds were administered orally every day for 15 days after the day of immunization.

EXPERIMENTAL EXAMPLE11 Effect on the survival of MRL / lpr mice as a model of spontaneous systemic lupus erythematosus The test compounds were orally administered to male MRL / pr mice. For the evaluation of the prophylactic effect, daily administration was continued until 8-45 weeks of age and for the evaluation of the therapeutic effect, up to 16-20 weeks of age. Mortality was recorded during the period of administration and the blood and urine obtained periodically from the animals was measured for the titers of antinuclear antibodies and rheumatoid factor in the serum, and protein in the urine.

EXPERIMENTAL EXAMPLE 12 Prolonged effect of skin graft on allogeneic skin graft in rats A full-thickness skin graft (1 5 x 1.5 cm) of a 4-week-old male WKAH rat or an LEW rat was grafted into a graft bed on the back of a 4-week-old male F344 rat. by suture. The graft was covered with sterile gauze and secured. The bandage was removed 5 days after grafting and the skin graft was observed daily until it is rejected. It is considered that the skin graft is rejected when 90% or more of the epithelium of the skin graft shows necrosis and acquires a brown color. The number of days from the graft to its rejection is taken as the days of graft survival. The test compounds were administered intraperitoneally, intravenously or orally repeated once a day for 14 days. In the control group to which only vehicle was administered, the mean survival time for skin grafting from a WKAH rat to a F344 rat was 7.0 + 0.0 days. The results obtained by oral administration of the compound (I-a) of the present invention at a dose of 1 mg / kg or 10 mg / kg are shown in Figure 1. Comparative compound 1 was 2-amino-2- (2- (4- (4-phenylbutyloxy) phenyl) -ethyl) propane-1,3-dol described in WO94 / 08943, comparative compound 2 was 2 -amino-2-methyl-2- (2- (4- (4-phenylbutyloxy) phenyl) butanol described in WO96 / 06068.

As shown in Figure 1, the mean survival time of the group to which the compound of the present invention was administered after grafting the skin of a WKAH rat in a F344 rat was 16.6 + 1.2 days, and the average survival time of comparative compound 1 and comparative compound 2 was 1 1 .9 + 0.7 days and 15.6 + 1.4 days, respectively. The compound of the present invention prolonged the days of graft survival in a statistically significant manner compared to the control group and the group of comparative compound 1. This showed an equivalent prolongation effect with the comparative compound 2. The average survival time after of grafting the skin of a LEW rat in a F344 rat was 8.2 + 0.4 days, whereas after administration of the compound of the present invention was 20 days or more, thus showing a statistically significant prolongation effect in comparison with the control group to which only vehicle was administered.

EXPERIMENTAL EXAMPLE 13 Change of body weight in allogenic skin graft in rats The changes in body weight of the rats of the experimental example 12 when testing allogenic skin grafts in rats, after 13 days of consecutive oral administration of 10 mg / kg of the test compound are shown in figure 2. As shown in Figure 2, the group to which the compound of the present invention was administered showed a natural gain in body weight as did the control group, while the group to which the comparative compound 1 was administered and the group to which the comparative compound 2 was administered showed a suppressive effect in the gain of body weight, which can be attributed to gastrointestinal organ disorders and the decrease in food absorption associated therewith. As a result, there is a risk of serious side effects such as nutrition disorders due to increased dose and long-term consecutive administration, and in addition, fatal consequences. In contrast, the group to which the compound of the present invention was administered showed an increase in body weight similar to that of the control group, which indicates that the compound of the present invention is a highly safe immunosuppressant with less toxicity, which is Free of the above-mentioned side effects.

EXPERIMENTAL EXAMPLE 14 Prolonged survival effect of heart graft graft in allogeneic heart graft in rats The hearts of male WKAH rats from 10 to 14 weeks of age were transplanted heterotopically in subcutaneous locations in the cervices of male ACI / N rats from 10 to 14 weeks of age using vascular anastomosis. It was judged that the transplanted hearts were rejected in the case of cessation of the heartbeat, then the survival time was calculated. The test compounds were orally administered repeatedly for 15 days from the day of transplantation.

EXPERIMENTAL EXAMPLE 15 Prolonged effect on graft survival of kidney graft in allogeneic renal graft in dogs Mestizo dogs and small hound dogs were used as donors and recipients, respectively, and the prolonged effect on the survival of the transplanted kidney was then examined by performing kidney transplant surgery. After the transplant, the blood of the transplanted animals was periodically collected to measure the levels of serum creatinine and blood urea nitrogen (BUN).

EXPERIMENTAL EXAMPLE 16 Inhibition of the blastogenesis reaction of rat spleen cells induced by stimulation with concanavalin A The effects of the inhibition of the blastogenesis reaction of rat spleen cells induced by stimulation with concanavalin A were tested in the following manner. The spleen of a male F344 rat from 4 to 10 weeks of age was excised. The excised spleen was opened with scissors and filtered through RPMI1640 medium supplemented with 10% FCS using a stainless steel sieve to give a suspension of individual cells of spleen cells. After hemolysis treatment, the spleen cells are passed through a nylon-wool column and the non-adhesive cells are collected. The nylon non-adhesive cells collected (5X106 cells / ml) are cultured in RPM 11640 medium containing 5 μg / ml concanavalin A, 5x10"5 M 2-mercaptoethanol and 10% FCS at 37 ° C under 5% CO2 -95% air for 72 hours, 18.5 KBq / 3H-thymidine cavity is added and the cells are cultured for 4 hours.The cells are collected by a cell harvester and the radioactivity incorporated in the cells is determined by a flash counter liquid and is used as an indicator of the blastogenesis of rat spleen cells The compounds of the present invention show a Cl50 value (a concentration to inhibit 50%) from about 1 nM to about 50 nM in the blastogenesis reaction of rat spleen cells induced by stimulation with concanavalin A.

INDUSTRIAL APPLICABILITY It is evident, from various pharmacological tests including the experimental examples mentioned above and the toxicity tests, that the compound (I) of the present invention, a pharmaceutically acceptable acid addition salt thereof and a hydrate thereof show superior immunosuppressive action without inhibitory action on the increase in body weight which is related to serious side effects, and are useful as higher immunosuppressants with less toxicity and greater safety. In addition, the compound (II) and the compound A of the present invention are useful as synthetic intermediates for the compound (I) which is useful as an immunosuppressant. The present application is based on Patent Application no. 86255/1997 filed in Japan, the contents of which are incorporated herein by reference.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A 2-aminopropane-1,3-diol compound of the general formula wherein R1, R2, R3 and R4 are the same or different and each is hydrogen or an acyl; a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof.

2. The 2-aminopropane-1,3-diol compound according to claim 1, which is 2-amino-2- (2- (4- (1-oxo-5-phenylpentyl) phenyl) ethyl) - propane-1,3-diol, a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof.

3. A pharmaceutical composition comprising the compound 2-aminopropane-1,3-diol according to claim 1 or 2, a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof.

4. An immunosuppressant comprising, as an active ingredient, the 2-aminopropane-1,3-diol compound according to claim 1 or 2, a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof.

5. A rejection suppressant comprising, as an active ingredient, the 2-aminopropane-1,3-diol compound according to claim 1 or 2, a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof .

6. An agent for the prevention or treatment of graft-versus-host diseases comprising, as an active ingredient, the 2-aminopropane-1,3-diol compound according to claim 1 or 2, a salt pharmaceutically acceptable addition acid thereof or a hydrate thereof.

7. An agent for the prevention or treatment of autoimmune diseases or allergic diseases comprising, as an active ingredient, the compound 2-aminopropane-1,3-diol according to claim 1 or 2, a pharmaceutically acceptable acid addition salt acceptable from it or a hydrate thereof.

8. A pharmaceutical composition comprising the compound 2-aminopropane-1,3-diol according to claim 1 or 2, a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof, and a pharmaceutically acceptable carrier.

9.- 2-Amino-2- (2- (4- (1-hydroxy-5-phenylpentyl) phenyl) ethyl) propane-1,3-diol, a compound thereof characterized in that the amino group and / or the group hydroxy are (are) protected or a salt thereof.

10. - 2-Amino-2- (2- (4-formylphenyl) ethyl) propane-1,3-diol, a compound thereof characterized in that the amino group and / or the hydroxy group are (are) protected or a salt thereof .