WO2005014603A1

WO2005014603A1 - Phosphinane compounds with immunomodulating activity

Info

Publication number: WO2005014603A1
Application number: PCT/JP2004/011867
Authority: WO
Inventors: Masao Chino; Kunitomo Adachi; Yoshihito Tanaka; Kunio Sugahara; Hirofumi Matsuyuki; Ayumi Tomatsu; Masatoshi Kiuchi
Original assignee: Mitsubishi Pharma Corporation
Priority date: 2003-08-12
Filing date: 2004-08-12
Publication date: 2005-02-17
Also published as: TW200510437A

Abstract

The invention is directed to a phosphinane compound having a unique immunomodulating activity, a process for a preparation thereof, a pharmaceutical composition containing the same, and a method of preventing or treating disorders or diseases mediated by T lymphocytes by administering the compound to a subject in need of treatment.

Description

DESCRIPTION

PHOSPHINANE COMPOUNDS WITH IMMUNOMODULATING ACTIVITY

TECHNICAL FIELD The invention is directed to a novel phosphinane compound having a unique immunomodulating activity, a process for a preparation thereof, a pharmaceutical composition containing the same, and a method of preventing or treating disorders or diseases mediated by T lymphocytes by administering the compound.

BACKGROUND ART 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-l,3-diol hydrochloride (hereinafter referred as to FTY720) is disclosed in International Patent Application Publication WO 94/08943. FTY720 is a unique immunomodulating agent, which is currently being studied as an immunosuppressive agent to the acute rejection reaction in organ transplantation. FTY720 exhibits its immunosuppressive activity by acting on mature lymphocytes, enhancing the responsiveness of the lymphocytes to homing chemokines, and inducing the sequestration of circulating mature lymphocytes into secondary lymphoid organs. FTY720 has been shown to convert into FTY720 phosphate [i.e., (±)2-amino-2- phosphoryloxymethyl-4-(4-octylphenyl)butanol, hereinafter referred as to FTY720-P] in vivo as disclosed in Mandala et al., Science, 296, 346-349 (2002). FTY720-P has also been shown to act on the sphingosine 1-phosphate (hereinafter referred as to SIP) receptor(s) and enhance homing chemokine-induced lymphocyte migration. WO 94/08943, WO 96/06068, WO 98/45249, WO 02/076995, WO 03/099192, WO

03/059880, WO 02/06268, Japanese Patent AppHcation Pubhcation No. 2002/0316985, WO 03/061567, WO 03/062248, WO 03/062252, WO 03/073986, WO 03/074008, Japanese Patent Application Publication Nos. 2002/053575, 2003/267936, 2003/267950 and 2003/267974, WO03/029184, WO03/029205, WO02/18395, WO03/105771, WO04/024763 and WO04/026817 disclose compounds having an activity on SIP receptor(s) for the treatment and/or prevention of diseases or disorders mediated by lymphocytes interactions. There remains a need for more effective and more tolerable compounds for use as immunomodulating agents. The invention provides such a compound, as well as a process of preparation thereof, pharmaceutical compositions comprising the compound, and a method of preventing or treating disorders or diseases mediated by T lymphocytes by administering the compound. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.

BRIEF SUMMARY OF THE INVENTION The invention provides the compound 5-amino-5-[2-(4-octylphenyl)ethyl]-2-oxo- 2λ⁵-l,3,2-dioxaphosphinan-2-ol, solvates thereof, and pharmaceutically acceptable salts thereof, as well as a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, and a method of preventing or treating disorders or diseases mediated by T lymphocytes by administering the compound or a pharmaceutically acceptable salt thereof. The invention also provides a novel phosphinane compound, solvates thereof, and pharmaceutically acceptable salts thereof, as well as a pharmaceutical composition comprising the compound, and a method of preventing or treating disorders or diseases mediated by T lymphocytes by administering the compound, a solvate thereof, or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a Western blot analysis demonstrating the effect of the compound of the invention (i.e., test compound) on ERK1/2 activity in SlP-transfected CHO cells.

DETAILED DESCRIPTION OF THE INVENTION The invention is directed to the compound 5-amino-5-[2-(4-octylphenyl)ethyl]-2- oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol (hereinafter referred as to cFTY720-P), solvates thereof, and pharmaceutically acceptable salts thereof. The chemical structure of cFTY720-P is as follows:

Solvates of cFTY720-P include, but are not limited to, hydrates such as monohydrates, hemihydrates (1/2 hydrates), and 1/4 hydrates, as well as other solvates with a non-toxic organic solvent. Pharmaceutically acceptable salts of cFTY720-P include, but are not limited to, alkaline metal salts (e.g. sodium salt or potassium salt) and alkahne earth metal salts, (e.g. calcium salt or magnesium salt). cFTY720-P, solvates thereof, and pharmaceutically acceptable salts thereof are herein referred to as the compound of the invention. According to the invention, cFTY720-P can be prepared by any suitable means. Preferably, cFTY720-P is prepared by reacting FTY720 (which is protected by a conventional protecting group on the amino group, such as tert-butyloxycarbonyl, benzyloxycarbonyl, or 2-cyanoethyloxycarbonyl) with a phosphinane-forming reagent, treating with an oxidizing agent, and then removing the protecting group. Any suitable phosphinane-forming reagent may be utilized in the preparation method. Preferably, the phosphinane-forming reagent is tert-butyl tetraisopropylphosphorodiamidite or di-tert-butyl diisopropylphosphoroamidite in the presence of lH-tetrazole as a catalyst. The reaction is carried out in an inert solvent such as a chlorinated alkane (e.g., dichloromethane or chloroform), an ether (e.g., diethyl ether, methyl ethyl ketone, dioxane, or tetrahydrofuran), dimethylformamide, dimethyl sulfoxide, or acetonitrile at a temperature of from about -78°C to the boiling point of the solvent employed, for about 30 minutes to about 48 hours (e.g., about 1 hour, about 2 hours, about 5 hours, about 10 hours, about 15 hours, about 20 hours, about 25 hours, about 30 hours, about 40 hours, about 45 hours, and ranges thereof). Any suitable oxidizing agent can be utilized in the preparation method. Preferably, the oxidizing agent is 3-chloroperoxybenzoic acid, peracetic acid, tert-butylhydroperoxide, hydrogen peroxide, or iodine. The oxidizing reaction is carried out under the same conditions described above. Any suitable agent can be used to remove the protecting group of the amino group.

Preferably, the agent for removing the protecting group of the amino group is trifluoroacetic acid or hydrogen chloride (e.g., HCl solution in diethyl ether, 1,4-dioxane, or an alcohol) when the protecting group is tert-butyl group. The reaction to remove the protecting group of the amino group is usually carried out in an inert solvent such as an alcohol (e.g. methanol or ethanol), a chlorinated alkane (e.g., dichloromethane or chloroform), an ether (e.g., diethyl ether, methyl ethyl ketone, dioxane or tetrahydrofuran), dimethylformamide, dimethyl sulfoxide, or acetonitrile at a temperature from about -78°C to the boiling point of the solvent employed for about 30 minutes to about 48 hours (e.g., about 1 hour, about 2 hours, about 5 hours, about 10 hours, about 15 hours, about 20 hours, about 25 hours, about 30 hours, about 40 hours, about 45 hours, and ranges thereof). The preferable reaction scheme of the invention is as follows:

Phosphorus oxychloride is also available to provide the desired protected phosphate ester. In this case, the reaction scheme is as follows:

Another reaction scheme of the invention is as follows:

Another example of a phosphinane-forming reaction is the sequential additions of phosphorus trichloride, any alcohol (e.g., tert-butyl alcohol), and any oxidizing reagent (e.g. hydrogen peroxide) to provide the desired protected phosphate ester. This particular reaction scheme is as follows:

^o. ° ° mCPBA MJOΓ

The reaction is carried out in an inert solvent such as a chlorinated alkane (e.g., dichloromethane or chloroform), an ether (e.g., diethyl ether, methyl ethyl ketone, dioxane or tetrahydrofuran), dimethylformamide, dimethyl sulfoxide, acetonitrile, or pyridine at a temperature of about room temperature (e.g., about 15-30°C) to the boiling point of the solvent employed for about 30 minutes to about 48 hours (e.g., about 1 hour, about 2 hours, about 5 hours, about 10 hours, about 15 hours, about 20 hours, about 25 hours, about 30 hours, about 40 hours, about 45 hours, and ranges thereof). In the above schemes, R is octyl group [-CH2(CH₂)6CH₃], -Pr is isopropyl group, and mCPB A is 3-chloroperoxybenzoic acid. The compound of the invention can be purified by any suitable method known in the field of the organic synthetic chemistry such as solvent extraction, recrystallization, chromatography or methods using an ion exchange resin. cFTY720-P can be converted into the solvates thereof or the pharmaceutically acceptable salts thereof by conventional manners known in organic synthetic chemistry. The starting compound (i.e., FTY720 protected by a conventional amino-protecting group (e.g. tert-butyloxycarbonyl group, benzyloxycarbonyl group or 2- cyanoethyloxycarbonyl group)) can be prepared by any method known in the field of organic chemistry, for example, as described in International Patent Application Pubhcation WO 94/08943. The protecting group can be removed by any known process in organic synthetic chemistry. For example, the benzyloxycarbonyl group can be removed by subjecting a catalytic hydrogenation or treating under an acid condition. Alternatively, the 2-cyanoethyloxycarbonyl group can be removed by treating under a basic condition by employing methylamine. The invention is directed to a novel phosphinane compound of the formula:

n is an integer of 1 to 20, preferably 1 to 8, R is a thiol group or -OR_3> wherein R₃ is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may be substituted by one to three halogen atoms or an aryl group, or an aryl group which may be substituted by one to three halogen atoms or an aryl group, preferably a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may be substituted by an aryl group or an aryl group, more preferably a hydrogen atom, alkyl group having 1 to 12 carbon atoms which may be substituted by an aryl group or a phenyl group; Ri and R₂ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may be substituted by one to three halogen atoms or an acyl group having 1 to 20 carbon atoms, preferably a hydrogen atom; and X is an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms or an arylene group and each may be substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, an acyl group having 1 to 20 carbon atoms, an alkyl group having 1 to 20 carbon atoms substituted by an aryl group, an alkyl group having 1 to 20 carbon atoms substituted by halogen- substituted aryl group, an alkyl group having 1 to 20 carbon atoms substituted by d-₂₀ alkoxy -substituted aryl group, an alkyl group having 1 to 20 carbon atoms substituted by d-₂₀ alkyl -substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by an aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by halogen-substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by d-₂₀ alkoxy -substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by d-₂₀ alkyl -substituted aryl group, an acyl group having 1 to 20,carbon atoms substituted by an aryl group, an acyl group having 1 to 20 carbon atoms substituted by halogen-substituted aryl group, an acyl group having 1 to 20 carbon atoms substituted by d- ₂0 alkoxy -substituted aryl group and an acyl group having 1 to 20 carbon atoms substituted by d-₂₀ alkyl -substituted aryl group, preferably an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms or an arylene group and each may be substituted by 1 to 3 substituents selected from the above group, more preferably an alkyl group having 1 to 12 carbon atom, an alkoxy group having 1 to 12 carbon atoms or an arylene group and the arylene group which may be substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, an acyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms substituted by an aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by halogen- substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by d-₂₀ alkoxy -substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by d-20 alkyl -substituted aryl group, an acyl group having 1 to 20 carbon atoms substituted by an aryl group, The "alkyl group having 1 to 20 carbon atoms" is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, and icosyl. Preferred is an alkyl group having 1 to 12 carbon atoms, and more preferred is an alkyl group having 1 to 8 carbon atoms. The "halogen atom" is exemplified by fluorine, chlorine, bromine, and iodine. The "aryl group" means a monocyclic or fused bicyclic aromatic ring moiety, e.g. containing 6 to 10 ring carbon atoms. For example, aryl may be a phenyl group or naphthyl group. Preferred is a phenyl group. The "acyl group having 1 to 20 carbon atoms" is exemplified by acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, and icosanoyl. Preferred is an acyl group having 1 to 12 carbon atoms, and more preferred is an acyl group having 1 to 8 carbon atoms. The "alkoxy group having 1 to 20 carbon atoms" is exemplified by methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, and icosyloxy. Preferred is a straight-chain alkoxy having 1 to 12 carbon atoms. More preferred is an alkoxy having 1 to 8 carbon atoms. The "arylene group" means a divalent radical derived from an aryl group. For example, arylene as used in this invention may be a phenylene group or naphthylene group. Preferred is a phenylene group. The invention is also directed to pharmaceutically acceptable salts of the compound of formula (I), solvates thereof, and optically active isomers thereof. Examples of the salts of the compound of formula (I) include salts with alkali metals, alkahne earth metals, inorganic acids, such as sodium salt, potassium salt, calcium salt, magnesium salt, hydrochloride, hydrobromide, sulfate and phosphate, salts with organic acid, such as acetate, fumarate, maleate, benzoate, citrate, succinate, malate, methanesulfonate, benzenesulfonate, and tartrate. When the salts of the compound of formula (I) are used as pharmaceuticals, preferred are these pharmaceutically acceptable salts. The invention also encompasses hydrates and solvates. When the compound of formula (I) has one or more asymmetric centers in the molecules, various optical isomers are obtained. The invention also encompasses optical isomers, racemates, diastereomers, and the mixture thereof. Moreover, when the compound of formula (I) include geometric isomers, the invention encompasses cis-compounds, trans- compounds, and the mixture thereof. The compound of formula (I), pharmaceutically acceptable salts of the compound of formula (I), solvates thereof, and optically active isomers thereof are herein collectively referred to as the compound of the invention. The compound of the invention can be administered to a mammal in any conventional manner. While it is possible for the compound to be administered as the raw chemical, it is preferably administered as a pharmaceutical composition. The pharmaceutical composition comprises the compound of the invention with one or more additives, such as pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents and/or components. For example, the compound of the invention can be used together with known pharmaceutically acceptable diluents, extenders, disintegrators, stabilizers, preservatives, buffers, emulsifiers, aromatics, colorants, sweeteners, viscosity increasing agents, flavor improving agents, solubilizers, and other additives. These additives must be acceptable in the sense of being compatible with the other ingredients and not deleterious to the recipient thereof. When the compound of the invention is used as a medicament, the compound is admixed with a pharmaceutically acceptable carrier (e.g., excipients, binders, disintegrators, correctives, corrigents, emulsifiers, diluents, solubilizers, and the like) to yield a pharmaceutical composition or a pharmaceutical preparation (tablets, pills, capsules, granules, powders, syrups, emulsions, elixirs, suspensions, solutions, injections, transfusions, or external preparations), which can be administered orally or parenterally. The pharmaceutical composition can be formulated into a pharmaceutical preparation by any suitable (e.g., conventional) method. The term "parenterally" includes subcutanous injection, intravenous injection, intramuscular injection, intraperitoneal injection, transfusion, and topical administration (administration through the skin, eye, lung, bronchus, nose, or 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, according to any suitable method as known in the pertinent field. The sterile preparation for injection may be a sterile mjectable solution or suspension in a non- toxic diluent or solvent permitting parenteral administration, such as an aqueous solution. Examples of the vehicle and solvent that can be used include water, Ringer solution, isotonic saline, and the like. In addition, sterile nonvolatile oil can be generally used as a solvent or a solvent for suspension. For this end, any nonvolatile oil or fatty acid can be used, inclusive of natural, synthetic, or semi- synthetic fatty oil or fatty acid, and natural, synthetic, or semi- synthetic mono-, di-, or tri-glycerides. The pharmaceutical composition preferably is formulated as a solid dosage form for oral administration. The solid dosage form includes the above-mentioned preparations, such as powders, granules, tablets, pills, capsules, and the like. In these dosage forms, the compound of the invention is admixed with at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, arginates, chitins, chitosans, pectins, tragacanth gums, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi- synthetic polymers, and glycerides. In these dosage forms, routine additives can be added, which may be inert diluents, lubricants such as magnesium stearate, preservatives such as parabens and sorbic acid, antioxidants such as ascorbic acid, alpha-tocopherol, and cysteine, disintegrators, binders, tackifiers, buffers, sweeteners, flavors, perfumes, and the like. An enteric coating may be applied to tablets and pills. The 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), such as are generally used in the pertinent field. The external agent applicable to the compound of the invention can be, for example, an ointment, a paste, a liniment, a lotion, a plaster, a cataplasm, an eye drop, an eye ointment, a suppository, a fomentation, an inhalant, a spray, an aerosol, a paint, a nasal drop, a cream, a tape, a patch, and the like. The external agent contains the compound of the invention in the form of a mixture with an organic or inorganic carrier or excipient. The external agent can be used, for example, in the form of a solid, semi-solid, or liquid pharmaceutical preparation. The compound of the invention can be mixed with, for example, a non-toxic and pharmaceutically acceptable carrier, which is usually employed for obtaining an external preparation for topical administration. A carrier which can be used includes water, glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloid silica, potato starch, urea and other carriers which are suitable for preparing a solid, semi-solid, or solution composition. Further, an adjuvant, a stabilizer, a thickener, a coloring matter, or a flavoring agent can be added. The compound of the invention (as an active ingredient of the pharmaceutical composition) can be contained in an amount to exhibit the desired activity depending on the symptom or severity of the diseases. In the case of the treatment of the symptom and diseases induced by immune disorder, the compound of the invention can be administered by way of a topical administration, an aerosol, or a rectal administration in a form of a dosage unit composition, which contains a pharmaceutically acceptable and non-toxic carrier, adjuvant, and/or excipient. In the treatment of reversible obstructive airways disease, the compound of the invention preferably is administered to lung by an aerosol in a form of a powder or a solution. The amount of the compound of the invention that can be mixed with a carrier 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 the various factors such as age, body weight, the whole condition of health, sex, meal, time for administration, administration route, rate of excretion, combination of drugs, and the severity of the specified diseases under treatment. When the compound of the invention is used in the form of an ointment, it is contained in an amount of about 0.01% to about 10% (w/w) in the ointment. Suitable ointment bases, include, for example, oleaginous bases (e.g., 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 plaster), emulsion type ointment bases (e.g., an oil in water type (O/W type) base such as a hydrophihc ointment or a vanishing cream, or a water in oil type (W/O type) base such as a hydrophilic petrolatum, a purified lanolin, aquaphor, eucelin, neoselin, an absorptive ointment, a hydrous lanolin, cold cream, or a hydrophihc plastibase), water-soluble bases (e.g., a macrogol ointment or solbase), suspension type ointment bases (e.g., a lyogel base or a hydrogel base such as a non-fat ointment, a gelbase, or lotion), and FAPG bases (e.g., a suspension of microparticles of an aliphatic alcohol such as stearyl alcohol or cetyl alcohol in propylene glycol). These ointment bases can be used alone or in a combination of two or more bases. Further, when used as an ointment, the compound of the invention is dissolved in a solubilizing and absorptive accelerating agent and added to the above-mentioned ointment base. The solubilizing and absorptive accelerating agent to be used is an agent in which the compound of the invention is soluble at a concentration of at least about 0.01% (w/w) and which desirably can accelerate the absorption of the compound from skin when formulated as an ointment. Suitable solubilizing and absorptive agents include, for example, lower alkanediols (e.g., ethylene glycol, propylene glycol or butylene glycol), alkylene carbonates (e.g., propylene carbonate or ethylene carbonate), alkanedicarboxyhc acid esters (e.g., dimethyl adipate, diethyl adipate, diisopropyl adipate, diethyl pimelate, diethyl sebacate or dipropyl sebacate), higher alkanoic acid glycerin esters (e.g., monolaurate, dilaurate or trilaurate), higher alkenoic acid glycerin esters (e.g., monooleate, dioleate, or trioleate), higher alkanoic acid alkyl esters (e.g., isopropyl myristate or ethyl myristate), higher unsaturated alcohols (e.g., geraniol or oleyl alcohol), and azacycloalkanes (e.g., 1- dodecylazacycloheptan-2-one). These solubilizing and absorptive accelerating agents can be used alone or in a mixture of not less than two agents, and can be added at a sufficient amount to dissolve the compound of the invention. The amount generally ranges from about 2 parts by weight to about 200 parts by weight per one part by weight of the compound of the invention. The upper amount is limited so as to not deteriorate the physicochemical properties of the ointment. The ointment which contains the compound of the invention can contain, in addition to the above-mentioned ointment base, other additives such as an emulsifier (e.g., polyoxyethylene hydrogenated castor oil, glycerol monostearate, sorbitan sesquioleate, or lauromacrogol); a suspending agent (e.g., polyethylene glycol, polyvinylpyrrolidone, or sodium carboxymethylcellulose); an antioxidant (e.g., a phenol or a quinone); a preservative (e.g., paraoxybenzoic acid ester); a humectant (e.g., glycerin, D-sorbitol or propylene glycol); a favoring agent, a coloring matter; an antiseptic; a higher alkenoic acid (e.g., oleic acid), and other drugs or compounds which are useful for the treatment of a skin diseases. When the compound of the invention is used in an ointment, the ointment can be prepared by mixing a solution containing the compound of the invention with an ointment base in accordance with a conventional method. In the process of formulation, not less than, one of the adjuvant or additive mentioned above can be simultaneously added to the ointment base. Furthermore, the ointment can be manufactured by dissolving the compound of the invention in the solubilizing and absorptive accelerating agent, admixing the obtained solution with the ointment base, stirring the obtained mixture while heating, and then cooling the resultant mixture. The ointment containing the compound of the invention can be used by applying the ointment to the affected part of the skin once to several times (e. g., once to four times) a day. The paste or liniment containing the compound of the invention can be prepared by using the same base and according to the same method as the ointment as mentioned above. The lotion containing the compound of the invention is a preparation wherein the active ingredient (i.e., a compound of the invention such as cFTY720-P) is homogeneously dispersed or, in some cases, partially dissolved in a liquid medium, and an emulsifier is added thereto as necessary. In a case where the compound of the invention is formulated as a lotion, the content may be adjusted to about 0.01% to about 10% (w/w) of the lotion. The liquid medium to be used in the lotion containing the compound of the invention includes water, a lower alcohol, a glycol, glycerin, or a mixture thereof. Lower alcohols that do not decompose the active ingredient compound and are not an irritant to skin are suitable, including methanol, ethanol, isopropyl alcohol, propanol, and butanol. The glycol includes ethylene glycol, propylene glycol, butylene glycol, or mono lower ethers thereof. Among these liquid media, water, the lower alcohols, and mixtures thereof are most preferable because these media improve the absorption of the active ingredient compound to the skin. The amount of these liquid media preferably ranges from about 5 parts by weight to about 1000 parts by weight per one part by weight of the compound of the invention. A solubilizing and absorptive accelerating agent can be added to the lotion containing the compound of the invention in which the active ingredient is soluble at a concentration of at least about 0.01% (w/w) and which can accelerate the absorption of the active ingredient compound from the skin when formulated into a lotion. The solubilizing and absorptive accelerating agent preferably is an alkanedicarboxylic acid ester (e.g., dimethyl adipate, diethyl adipate, diisopropyl adipate, diethyl pimelate, diethyl sebacate or dipropyl sebacate) or a higher alkanoic acid alkyl ester (e.g., isopropyl myristate or ethyl myristate). These solubilizing and absorptive accelerating agents can be used alone or in a mixture of two or more agents, and the amount generally ranges from about 5 parts by weight to about 5000 parts by weight per one part by weight of the compound of the invention. The content of the solubilizing and absorptive accelerating agent desirably ranges from about 1% to about 30% (w/w). The emulsifier for the lotion containing the compound of the invention is employed for the purpose of dispersing an insoluble medicine minutely and homogeneously in an aqueous solution, and should be non-toxic to human beings. The emulsifier can be a pharmaceutically acceptable natural or synthetic emulsifier. Various emulsifiers, which are derived from animals and vegetables, can be used as the natural emulsifier. Such emulsifiers include egg yolk lecithin, soybean lecithin or a hydrogenated product thereof, phosphatidyl choline, sphingomyelin, gum arabic, and gelatin. Cationic, anionic, or non-ionic surfactants can be used as the synthetic emulsifier, which preferably is a castor oil surfactant, especially an HCO (polyoxyethylene hydrogenated castor oil) such as HCO-60, HCO-50, HCO-40. Further, the emulsifier can be a polyoxyethylenesorbitan aliphatic acid ester such as polysorbate 80, a glycerin aliphatic acid ester such as glycerin monocaprylate, a polyethylene aliphatic acid ester such as polyoxyethylene 40 monostearate, a middle chain aliphatic acid mono (or di) glyceride (e.g., C₆-Ci₂ aliphatic acid mono (or di) glycerides such as caprylic acid diglyceride, caprylic acid monoglyceride, or caproic acid diglyceride), or a polyoxyethylated glyceride such as polyoxyethylated oleic acid glyceride. The above- mentioned emulsifiers can be used as the primary emulsifier, and, if necessary, in combination with an auxihary emulsifier. The auxiliary emulsifier is a conventional emulsifier and non-toxic to humans, and such emulsifiers include cholesterol, agar, magnesium hydroxide, methylcellulose, and pectin. These primary emulsifiers and auxihary emulsifiers can be used alone or in combinations of two or more emulsifiers. The emulsifier is present in the lotion containing the compound of the invention in an amount sufficient to emulsify the compound and other additives. The emulsifier preferably ranges from about 0.1 part by weight to about 10 parts by weight per one part by weight of the compound of the invention. In order to increase the viscosity, a viscosity-increasing agent can be added to the lotion that contains the compound of the invention. The viscosity-increasing agent can be any conventional agent which usually is added to increase viscosity of the liquid and is non- toxic to human beings, such as carboxypolymethylene. The viscosity-increasing agent is used when the lotion with a high viscosity is desired. When the viscosity-increasing agent is used, the content of the viscosity-increasing agent varies depending on the desired viscosity of the lotion to be used. Preferably, the viscocity-increasing agent is present in an amount ranging from about 0.01% to about 5% (w/w). The lotion that contains the compound of the invention also can contain a solubilizer which is used for the stabihzation of the active ingredient in an aqueous solution. If necessary, the lotion can further contain other additives which commonly are used in lotions, such as a flavoring agent, a coloring matter, an antiseptic, a higher alkenoic acid such as oleic acid, and/or other drugs which are useful for the treatment of the skin diseases. The lotion that contains the compound of the invention can be prepared by any conventional method known in the art. The lotion that contains the compound of the invention can be used by applying the lotion to the affected part of the skin once to several times (e.g., once, twice, three times, or four times) a day. When the lotion has a low viscosity, it can be applied by filling a spray vessel with the composition of the lotion and spraying the lotion directly to the skin. In the case where the compound of the invention is used in the form of an eye drop or a nasal drop, the solvent to be employed includes sterile distilled water or, in particular, distilled water for injection. The concentration of the active compound usually ranges from about 0.01% to about 2% (w/v), and may be increased or decreased depending on the aim of use. The eye drop or nasal drop that contains the compound of the invention also can contain various additives such as a buffer, an isotonic agent, a solubihzing agent, a preservative, a viscosity-increasing agent, a chelating agent, a pH adjustor, and/or an aromatic. Suitable buffers include, for example, phosphate buffers (e.g., sodium dihydrogen phosphate-disodium hydrogen phosphate or potassium dihydrogen phosphate-potassium hydroxide), borate buffers (e.g., boric acid-borax), citrate buffers (e.g., sodium citrate- sodium hydroxide), tartrate buffers (e.g., tartaric acid-sodium tartrate), acetate buffers (e.g., acetic acid-sodium acetate), carbonate buffers (e.g., sodium carbonate-citrate or sodium carbonate-boric acid), and amino acids (e.g., sodium glutamate or epsilon-aminocaproic acid). Suitable isotonic agents include, for example, saccharides such as sorbitol, glucose, or mannitol, polyhydric alcohols such as glycerin or propylene glycol, salts such as sodium chloride or borax, boric acid, and the hke. Suitable solubihzing agents include, for example, non-ionic surfactants such as polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene monostearate, polyethylene glycol, or polyoxyethylene hydrogenated castor oil, and the hke. Suitable preservatives include, for example, quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, or cetylpyridinium chloride, parahydroxybenzoic acid esters such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, or butyl parahydroxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid or a salt thereof, thimerosal, chlorobutanol, and sodium dehydroacetate. Suitable viscosity-increasing agents include, for example, polyvinylpyrrohdone, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and salts thereof. Suitable chelating agents include, for example, sodium edetate, citric acid, and the like. Suitable pH adjustors include, for example, hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and the hke. Suitable aromatics include, for example, 1-menthol, borneol, camphors (e.g., dl-camphor), eucalyptus oil, and the hke. When the compound of the invention is formulated as an eye drop, the pH of the formulation can be from about 4 to about 8.5 (e.g., about 5, about 6, about 7, about 7.5, about 8, and ranges thereof). When formulated as a nasal drop, the formulation comprising the compound of the invention can have a pH from about 4 to about 8.5. The eye drop and the nasal drop formulations that contain the compound of the invention can be prepared by any suitable (e.g., conventional) method. Additionally, when the compound of the invention is formulated as an eye drop, the eye drop formulation contains the compound in a sufficient amount to be able to effectively prevent eye inflammation, which varies depending on the symptom or the type of inflammation, and usually ranges from about 5 to about 1000 μg for one administration. The eye drop formulation can be administered once to several times (e.g., once to four times) a day. The aerosol-containing the compound of the invention is a pharmaceutical preparation that can be applied at the time of treatment by spraying a solution or a suspension of the active ingredient compound using a pressure of a liquefied gas or compressed gas filled in the same vessel or another vessel. The aerosol can be prepared by dissolving the compound of the invention in a purified water, and, if necessary, dissolving or suspending a solubilizing and absorptive accelerating agent (as described above) in the solution, and, if necessary, adding an additive such as pH adjustor or antiseptic (as described above), and then sealing closely with a valve and compressing the propellant. Suitable propellants include dimethyl ether, liquefied natural gas, carbon dioxide, nitrogen gas, a substituted flon gas, and other conventional propellants. The aerosol that contains the compound of the invention also can contain a refrigerant, such as 1-menthol, a camphor, methyl salicylate, and the like. The inhalant or spray that contains the compound of the invention can be prepared according to the same methods as those described for an aerosol, wherein a nebulizer or an inhaler can be used for an inhalant, and a spraying vessel can be used for a spray. When the compound of the invention is used as a suppository, the suppository can be prepared in a conventional manner using a conventional base for suppository. The active ingredient (i.e., the compound of the invention) is contained in the suppository in an amount sufficient to exhibit the pharmaceutical effect, which can vary depending on the age or symptom of the patient. Preferably, the active ingredient (i.e., the compound of the invention) is present in a range of from about 0.1 to about 60 mg (e.g., about 1 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, and ranges thereof). The base for the suppository of the invention desirable is a conventional base. Suitable bases include, for example, oil and fat from animal and vegetable (such as ohve oil, corn oil, castor oil, cotton seed oil, wheat germ oil, cacao oil, beef tallow, lard, wool fat, turtle tallow, squalane, or a hydrogenated oil), oil and fat from mineral (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, partially synthetic or totally synthetic glycerin aliphatic acid esters such as mono-, di-, and tri-glycerides of a middle or higher ahphatic acid such as a straight-chain saturated aliphatic acid (e.g., lauric acid, myristic acid, palmitic acid, or stearic acid), and straight-chain unsaturated aliphatic acids (e.g., oleic acid, linoleic acid, or linolenic acid). The commercially available products are exemplified by Witepsol products (manufactured by Dynamitnobel Co.), which are mixtures of mono-, di-, and tri-glycerides of C_2-C₁₈ saturated aliphatic acids, such as, more specifically, Witepsol H series (e.g., Witepsol H5, H12, H19, H32, H35, H37, H39, H42, H175, or H185), Witepsol W series (e.g., Witepsol W25, W31, W35, or W45), Witepsol E series (e.g., Witepsol E75, E76, E79, or E85), or Witepsol S series (e.g., Witepsol S52, S55, or S58); Pharmasol products (manufactured by Nippon Oils and Fats Co.); Isocacao products (manufactured by Kao Co.); SB products (manufactured by Kanegafuchi Chemical Co. and Taiyo Yusi Co.), which are mixtures of mono-, di-, and tri-glycerides of C_₂-C₁₈ saturated ahphatic acids, such as, more specifically, SB-H, SB-E, or SB-AM; Nopata products (manufactured by Henkel AG); Sapoyer products (manufactured by Gattfords Co.), which are mixtures of mono-, di-, and tri-glycerides of do-C₁₈ saturated ahphatic acids, such as, more specifically, Sapoyer NA, Sapoyer OS, Sapoyer AS, Sapoyer BS, Sapoyer BM, or Sapoyer DM); Masaesthahnum products (manufactured by Dynamitnobel Co.), which are mixtures of mono-, di-, and tri-glycerides of do-C₁₈ saturated ahphatic acids, such as, more specifically, Masaesthahnum A, AB, B, BB, BC, BCF, C, D, E, or BD and Masaesthahnum 299); and Migriol 810 or Migriol 812 (manufactured by Dynamitnobel Co.), which are mixtures of triglycerides of C₈-Ci₂ saturated ahphatic acids, wherein one or more of them may optionally be incorporated when a partially synthetic or totally synthetic glycerin ahphatic acid ester as mentioned above is incorporated). Further, other synthetic products such a polyethylene glycol or polyoxyethylene alcohol can be utilized. The bases are used in an amount of about 25% to about 99.9% by weight based on the total weight of the suppository. If necessary, a preservative, a stabilizer, a surfactant, an aromatic, a pH adjustor, or purified water can be added to the suppository. The suppository containing the compound of the invention can be in various forms, such as a rectal suppository which is solid at the normal temperature and melts at a body temperature; an ointment or liquid enema which can be prepared by dissolving or dispersing the compound of the invention in a hquid base; a soft capsule for rectal administration; or an injection for rectal administration. The suppository can be manufactured by any suitable (e.g., conventional) method. The dose for a certain patient is determined according to age, body weight, general health conditions, sex, diet, administration time, administration route, clearance rate, combination of drugs, degree of the state of the disease for which the patient is then undergoing treatments, and other factors. The compound of the invention shows low toxicity and can be used safely. While the daily dose varies depending on the condition and body weight of the patient, the kind of compound, the administration route, and the like, the daily dose is, for example, about 0.01-50 mg/person/day (e.g., about 0.5 mg/person/day, about 1 mg/person/day, about 5 mg/person/day, about 10 mg/person/day, about 15 mg/person/day, about 20 mg/person/day, about 25 mg/person/day, about 30 mg/person/day, about 35 mg/person/day, about 40 mg/person/day, about 45 mg/person/day, and ranges thereof) for parenteral administration by a subcutaneous, intravenous, or intramuscular route, or through the skin, eye, lung, bronchus, nose, or rectum. Preferably, the daily dose is about 0.01-20 mg/person/day, for parenteral administration by a subcutaneous, intravenous, or intramuscular route, or through the skin, eye, lung, bronchus, nose, or rectum. For oral administration, the daily dose is about 0.01-150 mg/person/day (e.g., about 0.5 . mg/person/day, about 1 mg/person/day, about 5 mg/person/day, about 10 mg/person/day, about 15 mg/person/day, about 20 mg/person/day, about 25 mg/person/day, about 30 mg/person/day, about 35 mg/person/day, about 40 mg/person/day, about 45 mg/person/day, about 50 mg/person/day, about 60 mg/person/day, 70 mg/person/day, about 80 mg/person/day, about 90 mg/person/day, 100 mg/person/day, about 110 mg/person/day, about 120 mg/person/day, about 130 mg/person/day, about 140 mg/person/day, and ranges thereof), and preferably 0.1-100 mg/person/day. The compound of the invention can be used to treat or prevent disorders and diseases mediated by T lymphocytes. As such, the invention is directed to a method for treating or preventing disorders and diseases mediated by T lymphocytes, in a subject in need of such treatment, which method comprises administering to the subject an effective amount of the compound of the invention or a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier. The compound of the invention can be used for the prevention and suppression of rejection caused by transplanting an organ (e.g., hver, heart, kidney, and the hke) or bone marrow among the same kind or different kinds of mammals. Mammals include, but are not hmited to, humans, dogs, cats, pigs, monkeys, rats, mice, and the hke. Additionally, the compound of the invention can be used for the prevention and treatment of various autoimmune diseases or various allergic diseases. Preferably, the compound of the invention has pharmacological activity such as immunosuppressive activity and, therefore, is useful for the prevention or treatment of resistance to transplantation, or transplantation rejection, of organs or tissues (such as heart, kidney, hver, lung, bone manow, cornea, pancreas, intestinum tenue, limb, muscle, nervus, fatty marrow, duodenum, skin, pancreatic islet cell, etc., including xeno-transplantation, either acute or chronic), graft-versus-host diseases by bone manow transplantation, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome lupus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes melhtus, type II adult onset diabetes mellitus, uveitis, nephrotic syndrome, steroid-dependent and steroid-resistant nephrosis, palmoplantar pustulosis, encephalomyehtis, glomerulonephritis, and infectious diseases caused by pathogenic microorganisms. The compound of the invention can be used to treat inflammatory, prohferative, and hyperprohferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses such as psoriasis, psoriatic arthritis, atopic eczema (atopic dermatitis), contact dermatitis and further eczematous dermatitises, sebonheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophiha, acne, alopecia areata, eosinophihc fasciitis, and atherosclerosis. The compound of the invention can be used in hair revitalizing, such as in the treatment of female or male pattern alopecia, or senile alopecia, by providing epilation prevention, hair germination, and/or a promotion of hair generation and hair growth. The compound of the invention can be used in the treatment of respiratory diseases, for example, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, COPD (chronic obstructive pulmonary disease), and reversible obstructive airways disease, including conditions such as asthma, including bronchial asthma, infantile asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma, particularly chronic or inveterate asthma (for example late asthma and airway hypenesponsiveness), bronchitis, and the like. The compound of the invention can be used to treat hepatopathy associated with ischemia. The compound of the invention can be used for the treatment or prevention of certain eye diseases such as conjunctivitis, keratoconjunctivitis, keratitis, vernal conjunctivitis, uveitis associated with Behcet's disease, herpetic keratitis, conical cornea, dystorphia epitheliahs corneae, keratoleukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, severe intraocular inflammation, and the hke. The compound of the invention can be used for the treatment or prevention of inflammation of mucosa or blood vessels (such as leukotriene B4-mediated diseases, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, irritable bowel disease (e.g., Crohn's disease and ulcerative colitis), and necrotizing enterocolitis), or intestinal lesions associated with thermal burns. The compound of the invention is useful for treating or preventing renal diseases including interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, and diabetic nephropathy; nervous diseases including multiple myositis, GuiUain-Bane syndrome, Meniere's disease, and radiculopathy; endocrine diseases including hyperthyroidism and Basedow's disease; hematic diseases including pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, and anerythroplasia; bone diseases including osteoporosis; respiratory diseases including sarcoidosis, fibroid lung, and idiopathic interstitial pneumonia; skin diseases including dermatomyositis, vitihgo vulgaris, ichthyosis vulgaris, photoallergic sensitivity, and cutaneous T cell lymphoma; circulatory diseases including arteriosclerosis, aortitis, polyarteritis nodosa, and myocardosis; collagen disease including scleroderma, Wegener's granuloma, and Sjogren's syndrome; adiposis; eosinophihc fasciitis; periodontal disease; nephrotic syndrome; hemolytic uremic syndrome; and muscular dystrophy. The compound of the invention can be used in the treatment of intestinal inflammations or allergies such as Coeliac disease, proctitis, eusinophilic gastroenteritis, mastocytosis, Crohn's disease, or ulcerative colitis. The compound of the invention can be used in the treatment of food related allergic diseases, which exhibit symptomatic manifestations remote from the gastrointestinal tract, for example, migraine, rhinitis, and eczema. The compound of the invention has hver regenerating activity and/or activity in promoting hypertrophy and hyperplasia of hepatocytes. Therefore, the compound of the invention is useful for the treatment and prevention of hepatic diseases such as immunogenic diseases (e.g. chronic autoimmune liver diseases including autoimmune hepatitis, primary biliary cirrhosis, and sclerosing cholangitis), partial hver resection, acute hver necrosis (e.g. necrosis caused by toxins, viral hepatitis, shock, or anoxia), viral hepatitis type B, viral hepatitis type C, and c rhosis. The compound of the invention can be used in the prevention or treatment of malignant rheumatoid arthritis, amyloidosis, fulminant hepatitis, Shy-Drager syndrome, pustular psoriasis, Behcet's disease, systemic lupus erythematosus, endocrine opthalmopathy, progressive systemic sclerosis, mixed connective tissue disease, aortitis syndrome, Wegener' s gramulomatosis, active chronic hepatitis, Evans syndrome, polhnosis, idiopathic hypoparathyroidism, Addison disease (autoimmune adrenalitis), autoimmune orchitis, autoimmune oophoritis, cold hemagglutinin, paroxysmal cold hemoglobinuria, pernicious anemia, adult T cell leukemia, autoimmune atrophic gastritis, lupoid hepatitis, tubulointerstitial nephritis, membranous nephritis, amyotrophic lateral sclerosis, rheumatic fever, postmyocardial infarction syndrome, and sympathetic ophthalmitis. The compound of the invention can be used in combination with other immunosuppressant(s), steroid(s) (e.g., prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), anti-rheumatoid agent(s) (e.g., methotrexate, leflunomide, a gold agent, penicillamine, bucillamine, lobenzarit, actarit, or salazosulfapyridine), and/or nonsteroidal acid anti-inflammatory agent(s). Preferably, the other immunosuppressant is selected from azathioprine, brequinar sodium, cyclophosphamide, cyclosporin, deoxyspergualin, everolims, mizoribine, 2-morphohnoethyl mycophenolate, pimecrolimus, rapamycin, tacrohmus monohydrate, OKT-3, anti-TNF-a antibody, soluble TNF-a receptor, anti-IL-6 receptor antibody, anti-CD20 antibody, hCTLA4-Ig, anti-IL-2 receptor antibody, FTY720, FTY720- P, and analogues of FTY720 and FTY720-P. Preferably, the nonsteroidal acid anti- inflammatory agent is selected from aspirin, indomethacin, indomethacin farnesil, diclofenac sodium, alclofenac, alclofenac sodium, ibuprofen, ketoprofen, loxoprofen sodium, naproxen, pranoprofen, zaltoprofen, mefenamic acid, fufenamic acid, tolfenamic acid, phenylbutazone, satophenylbutazone, piroxicum, tenoxicum, ampiroxicum, celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib. This invention provides a method for preventing or treatment disorders or diseases mediated by T lymphocytes, in a subject in need of such treatment, which method comprises administering to the subject an effective amount of the compound of the formula:

n is an integer of 1 to 20; R is a thiol group or -OR_3> wherein R₃ is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may be substituted by one to three halogen atoms or an aryl group, or an aryl group which may be substituted by one to three halogen atoms or an aryl group; R_ and R₂ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may be substituted by one to three halogen atoms or an acyl group having 1 to 20 carbon atoms; and X is an appropriate substituent which is disclosed by WO 94/08943, WO 96/06068,

WO 98/45249, WO 02/076995, WO 03/099192, WO 03/059880, WO 02/06268, Japanese Patent AppHcation Publication No. 2002/0316985, WO 03/061567, WO 03/062248, WO 03/062252, WO 03/073986, WO 03/074008, Japanese Patent Application Publication Nos. 2002/053575, 2003/267936, 2003/267950 and 2003/267974, WO03/029184, WO03/029205, WO02/18395, WO03/105771, WO04/024673 and WO04/026817. The following examples further iUustrate the invention but, of course, should not be construed as in any way limiting its scope.

EXAMPLE 1 This example describes the preparation of 5-amino-5-[2-(4-octylphenyl)ethyl]-2- oxo-2λ⁵- 1 ,3 ,2-dioxa-phosphinan-2-ol.

(1) Preparation of 2-tert-butyloxycarbonylamino-2-[2-(4-octylphenyl)ethyl]propane-l,3- diol Triethylamine (4.18 ml) and di-tert-butyldicarbonate (3.27 g) were added to a solution of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-l,3-diol hydrochloride (3.44 g) in methanol (30 ml), and the whole mixture was sthred at room temperature for 9 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The resulting extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtering, the solvent was distilled off under reduced pressure. Purification of the residue by silica gel chromatography (50 g, hexane : ethyl acetate = 1 : 1) gave 3.08 g of the titled compound as a white soHd.

1H-NMR (CDC1₃) δ (ppm) : 0.91 (3H, t, / = 6.8 Hz), 1.25-1.38 (10H, m), 1.48 (9H, s), 1.59- 1.62 (2H, m), 89-1.94 (2H, m), 2.56-2.62 (4H, m), 3.65 (2H, dd, / = 5.6, 11.2 Hz), 3.89 (2H, dd, /= 5.6, 11.2 Hz), 4.03 (2H, br s), 5.21 (IH, s), 7.09-7.14 (4H, m).

(2) Preparation of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[2-(4-octylphenyl)- ethyl] -2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinane (Method 1) tert-Butyl-tetraisopropyl-phosphorodiamidite (100 mg) and 1H- tetrazole (63 mg) were added in order under ice-cooling to a solution of the product (122 mg) as obtained by the procedure in the above Example 1(1) in dichloromethane (3 ml). The whole mixture was stined at room temperature for 80 minutes. After further cooling, tert-butyl-tetraisopropylphosphorodiamidite (100 mg) and lH-tetrazole (63 mg) were added to the reaction solution in order, and the whole mixture was stined at room temperature for 30 minutes. 3-chloroperoxybenzoic acid (202 mg) was added to the reaction solution under ice-cooling, and the resultant mixture was stined at room temperature for an hour. Then, a saturated sodium bicarbonate solution was added to the reaction solution, and the solution was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered off, and the solvent was distilled off under reduced pressure. The purification of the residue by siΗca gel chromatography (10 g, hexane : ethyl acetate = 2 : 1) gave 121 mg of the titled compound as a colorless oily substance.

1H-NMR (CDC1₃) δ (ppm) : 0.87 (3Η, t, /= 6.8 Hz), 1.23-1.30 (10H, m), 1.48 (9H, s), 1.53 (9H, s), 1.53-1.60 (2H, m), 1.95-1.98 (2H, m), 2.50-2.58 (4H, m), 4.04 (2H, d, / = 10.2 Hz), 4.43 (4H, dd, / = 11.2, 23.2 Hz), 5.13 (IH, s), 7.05-7.10 (4H, m). (Method 2) A solution of the product (68.4 mg) as obtained by the procedure in the above Example 1(1) and di-tert-butyldiisopropylphosphoroamidite (46.1 mg) in dichloromethane (3 ml) at 0°C was treated with lH-tetrazole (26 mg). The resulting mixture was stined at room temperature for 80 minutes, and then cooled to 0°C. 5 M tert-butyl hydroperoxide in decane solution (50 μl) was added, the coohng bath was removed, and the reaction mixture was stined at ambient temperature for an hour. The reaction was quenched with 5 ml of saturated sodium bicarbonate solution, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. Concentration in vacuo followed by silica gel chromatography (hexane : ethyl acetate = 2 : 1) gave the titled compound (52.3 mg) as a colorless oily substance.

(3) Preparation of

5-amino-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l ,3,2-dioxa-phosphinan-2-ol 1/4 hydrate. Trifluoroacetic acid (0.5 ml) was added to a solution of the product (121 mg) as obtained by the procedure in the above Example 1(2) in dichloromethane (0.5 ml) under ice- coohng, and the whole mixture was sti ed at room temperature for 3 hours. The reaction solution was distiUed off under reduced pressure, and ethanol was added to the residue. The filtration of the precipitate obtained gave 54 mg of the titled compound as a white solid, having a melting point of 262-264°C. MS (ESI) m/z : 370 [M+Η] .

1H-NMR (CD₃OD) δ (ppm) : 0.89 (3Η, t, / = 6.8 Hz), 1.23-1.35 (10H, m), 1.55-1.59 (2H, m), 1.92-1.96 (2H, m), 2.54-2.58 (2H, m), 2.65-2.69 (2H, m), 4.39 (2H, dd, / = 12.4, 22.0 Hz), 4.61 (2H, d, / = 12.4 Hz), 7.11 (2H, d, / = 8.0Hz), 7.16 (2H, ά, J= 8.0 Hz). ³¹P-NMR (proton decoupled, CD₃OD) δ (ppm) : -6.9. Elemental Analysis (C ι₉H₃₂NO₄P • 1 /4 hydrate) : Calculated - C , 61.03 ; H, 8.76 ; N, 3.75. Found - C, 61.17; H, 8.61; N, 3.86.

Example 2 5-Amino-5-[2-(4-dodecylphenyl)ethyl]-2-oxo-2λ^s-l ,3,2-dioxaphosphinan-2-ol 1/4 hydrate

(2-l) 2-tert-Butyloxycarbonylamino-2-[2-(4-dodecylphenyl)ethyl]propane-l,3-diol Triethylamine (0.188 ml) and di-tert-butyldicarbonate (147 mg) were added to a solution of 2-amino-2-[2-(4-dodecylphenyl)ethyl]propane-l ,3-diol hydrochloride (180 mg) in methanol (2.3 ml), and the whole mixture was stined at room temperature for 4 hours.

Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.

The resulting extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtering, the solvent was distilled off under reduced pressure. Purification of the residue by silica gel chromatography (25 g, hexane:ethyl acetate = 3:1) gave 151 mg of the titled compound as a white solid.

1H-NMR (CDC ) δ (ppm): 0.88 (3H, t, / = 6.7 Hz), 1.25-1.30 (20H, m), 1.45 (9H, s), 1.85-

1.90 (2H, m), 2.53-2.62 (4H, m), 3.32 (2H, br s), 3.64 (2H, dd, /= 6.9, 11.5 Hz), 3.89 (2H, dd, /= 6.9, 11.5 Hz), 4.99 (IH, s), 7.09 (4H, s).

(2-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-[2-(4-dodecylphenyl)ethyl]-2-oxo-

2λ⁵- 1 ,3 ,2-dioxaphosphinane tert-Butyl tetraisopropylphosphorodiamidite (119 mg) and lH-tetrazole (68 mg) were added at 0°C to a solution of the product (151 mg) as obtained by the procedure in the above Example (2-1) in dichloromethane (3.3 ml). The whole mixture was stined at room temperature for 3 hours. 3-Chloroperoxybenzoic acid (219 mg) was added to the reaction solution under ice-coohng, and the resultant mixture was stined at room temperature for an hour. Then, a saturated sodium bicarbonate solution was added to the reaction solution, and the solution was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The purification of the residue by silica gel chromatography (20 g, hexane:ethyl acetate = 4:1) gave 110 mg of the titled compound as a colorless oily substance. Η-NMR (CDCI3) δ (ppm): 0.88 (3H, t, / = 6.6 Hz), 1.22-1.29 (20H, m), 1.47 (9H, s), 1.56 (9H, s), 1.92-1.98 (2H, m), 2.50-2.58 (4H, m), 4.04 (2H, d, / = 10.2 Hz), 4.43 (2H, dd, / = 11.1, 23.0 Hz), 5.11 (IH, s), 7.04-7.10 (4H, m).

(2-3) 5-Amino-5-[2-(4-dodecylphenyl)ethyl]-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol 1/4 hydrate. Trifluoroacetic acid (0.5 ml) was added to a solution of the product (110 mg) as obtained by the procedure in the above Example (2-2) in dichloromethane (1.0 ml) under ice-cooling, and the whole mixture was stined at room temperature for 3 hours. The reaction solution was distiUed off under reduced pressure, and ethanol was added to the residue. The yielded precipitate was collected to give 68 mg of the titled compound as a white solid, having a melting point of 261 -263 °C .

MS (ESI) m/z: 426 [M+H].

1H-NMR (CD₃OD) δ (ppm): 0.89 (3H, t, / = 6.9 Hz), 1.28 (18H, m), 1.58 (2H, m), 1.79-

1.85 (2H, m), 2.54-2.66 (4H, m), 4.06 (2H, dd, /= 12.6, 21.0 Hz), 4.44 (2H, d, / = 12.0 Hz), 7.12 (4H, s).

Elemental Analysis (C₂₃H₄₀NO₄P • 1/4 hydrate): Calculated - C, 64.24; H, 9.49; N, 3.26.

Found - C, 64.46; H, 9.46; N, 3.22.

Example 3 5-Amino-5-(2-(4-undecyloxyphenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol 1/10 hydrate

(3-1) 2-tert-Butyloxycarbonylamino-2-(2-(4-undecyloxyphenyl)ethyl)propane-l,3-diol The amino group of 2-amino-2-(2-(4-undecyloxyphenyl)ethyl)propane-l ,3-diol hydrochloride was protected in a similar manner to that described in Example (2-1) to give the title compound as white crystals, m.p. 15-lTC. (3-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-[2-(4-undecyloxyphenyl)ethyl]-2- oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[2-(4- undecyloxyphenyl)ethyl] propane- 1 ,3-diol obtained in Example (3-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as white crystals.

1H-NMR (CDC1₃) δ (ppm): 0.88 (3H, t, / = 6.7 Hz), 1.22-1.41 (18H, m), 1.48 (9H, s), 1.53 (9H, s), 1.78 (2H, m), 1.92 (2H, m), 2.51 (2H, m), 3.91 (2H, t, /= 6.1 Hz), 4.01 (2H, d, / = 11.2 Hz), 4.41 (2H, dd, / = 11.2, 23.6 Hz), 5.13 (IH, s), 6.80 (2H, d, / = 8.4 Hz), 7.05 (2H, d, 7 = 8.4 Hz)..

(3-3) 5-Amino-5-[2-(4-undecyloxyphenyl)ethyl]-2-oxo-2λ^s-l ,3,2-dioxaphosphinan-2-ol 1/10 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[2-(4- undecyloxyphenyl)ethyl]-2-oxo-2λ⁵- 1,3 ,2-dioxaphosphinane obtained in Example (3-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as white crystals. m.p. 274-276°C. Elemental Analysis (C₂₂H₃₈NO₅P • 1/10 hydrate): Calculated - C, 61.55; H, 8.97; N, 3.26.

Found - C, 61.24; H, 8.81; N, 3.32.

Example 4 5-Amino-5-(2-(4-(6-phenylhexyloxy)phenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol

(4- 1 ) 2-tert-Butyloxycarbonylamino-2- { 2- [4-(6-phenylhexyloxy)phenyl] ethyl } propane- 1 ,3- diol The amino group of 2-amino-2-(2-(4-(6-phenylhexyloxy)phenyl)ethyl)-l,3- propanediol hydrochloride was protected in a similar manner to that described in Example (2-1) to give the title compound as white crystals. 1H-NMR (CDC1₃) δ (ppm): 1.36-1.88 (10H, m), 1.45 (9H, s), 2.61 (4H, m), 3.35 (2H, br s), 3.63 (2H, dd, /= 7.2, 11.7 Hz), 3.89 (4H, m), 4.99 (IH, s), 6.80 (2H, d, / = 6.3 Hz), 7.09 (2H, d, / = 6.3 Hz), 7.17 (2H, m), 7.27 (3H, m).

(4-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-(2-(4-(6- phenylhexyloxy)phenyl)ethyl)-2-oxo-2λ⁵-l ,3 ,2-dioxaphosphinane A reaction of 2-amino-2-(2-(4-(6-pheny exyloxy)phenyl)ethyl)propane-l,3_Tdiol obtained in Example (4-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oil. 1H-NMR (CDC1₃) δ (ppm): 1.38-1.93 (10H, m), 1.47 (9H, s), 2.51 (2H, m), 2.61 (2H, m),

3.91 (2H, t, / = 6.5 Hz), 4.03 (2H, d, /= 11.3 Hz), 4.41 (2H, dd, /= 11.2, 22.3 Hz), 5.12 (IH, s), 6.79 (2H, d, /= 8.6 Hz), 7.04 (2H, d, /= 8.6 Hz), 7.17 (2H, m), 7.27 (3H, m).

(4-3) 5-Amino-5-(2-(4-(6-phenylhexyloxy)ρhenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan- 2-ol A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-(2-(4-(6- phenylhexyloxy)phenyl)ethyl)-2-oxo-2λ⁵-l, 3 ,2-dioxaphosphinane obtained in Example (4-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as white crystals. m.p. 268-270°C

Elemental Analysis (C23H₃_NO₅P): Calculated - C, 63.73; H, 7.44; N, 3.23. Found - C,

63.37; H, 7.48; N, 3.30.

Example 5 5-Amino-5-[2-(2-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol

(5-1) 2-tert-Butyloxycarbonylamino-2-[2-(2-octylphenyl)ethyl]propane-l,3-diol The amino group of 2-amino-2-[2-(2-octylphenyl)ethyl]propane-l ,3-diol hydrochloride was protected in a similar manner to that described in Example (2-1) to give the title compound as a colorless oily substance.

1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, t, / = 6.9 Hz), 1.21-1.39 (10H, m), 1.46 (9H, s), 1.52- 1.62 (2H, m), 1.78-1.84 (2H, m), 2.55-2.66 (4H, m), 3.68 (2H, d, / = 11.1 Hz), 3.92 (2H, d, = 11.1 Hz), 5.04 (IH, s), 7.12-7.14 (4H, m).

(5-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-[2-(2-octylphenyl)ethyl]-2-oxo-2λ⁵-

1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[2-(2-octylphenyl)ethyl]propane-l ,3- diol obtained in Example (5-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance.

1H-NMR (CDCI3) δ (ppm): 0.88 (3H, t, / = 6.9 Hz), 1.21-1.38 (10H, m), 1.48 (9H, s), 1.54

(9H, s), 1.54-1.60 (2H, m), 1.85-1.91 (2H, m), 2.53-2.60 (4H, m), 4.05 (2H, d, / = 11.1 Hz), 4.48 (2H, dd, / = 11.1, 23.1 Hz), 5.14 (IH, s), 7.07-7.12 (4H, m).

(5-3) 5-Amino-5-[2-(2-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[2-(2- octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinane obtained in Example (5-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid, having a melting point of 250-252°C. MS (ESI) m/z: 370 [M+H]. 1H-NMR (CD₃OD) δ (ppm): 0.90 (3H, t, / = 6.6 Hz), 1.24-1.46 (10H, m), 1.50-1.63 (2H, m), 1.75-1.81 (2H, m), 2.58-2.70 (4H, m), 4.11 (2H, dd, /= 12.0, 21.6 Hz), 4.51 (2H, dd, / = 2.4 12.0 Hz), 7.08-7.16 (4H, m). Example 6

5-Amino-5-[4-(4-butylphenyl)butyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol

(6-1) 2-tert-Butyloxycarbonylamino-2-[4-(4-butylphenyl)butyl]propane-l,3-diol The amino group of 2-amino-2-[4-(4-butylphenyl)butyl]propane-l ,3-diol hydrochloride was protected in a similar manner to that described in Example (2-1) to give the title compound as a colorless oily substance.

1H-NMR (CDC1₃) δ (ppm): 0.92 (3H, t, / = 7.1 Hz), 1.23-1.38 (4H, m), 1.43 (9H, s), 1.51- 1.64 (6H, m), 2.50-2.61 (4H, m), 3.57 (2H, d, /= 11.7 Hz), 3.83 (2H, d, / = 11.7 Hz), 4.87

(IH, s), 7.05-7.09 (4H, m).

(6-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-[4-(4-butylphenyl)butyl]-2-oxo-2λ⁵-

1 ,3 ,2-dioxaphosphinane Areaction of 2-tert-butyloxycarbonylamino-2-[4-(4-butylphenyl)butyl]propane-l,3- diol obtained in Example (6-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance.

1H-NMR (CDC1₃) δ (ppm): 0.92 (3H, t, / = 6.9 Hz), 1.20-1.39 (4H, m), 1.42 (9H, s), 1.52 (9H, s), 1.52-1.66 (2H, m), 2.53-2.59 (4H, m), 4.00 (2H, d, /= 11.1 Hz), 4.38 (2H, dd, / =

11.1, 23.1 Hz), 5.01 (IH, s), 7.01-7.10 (4H, m).

(6-3) 5-Amino-5-[4-(4-butylphenyl)butyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[4-(4- butylphenyl)butyl]-2-oxo-2λ⁵-l,3,2- dioxaphosphinane obtained in Example (6-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid, having a melting point of 273-276°C. MS (ESI) m/z: 342 [M+H].

1H-NMR (CD₃OD) δ (ppm): 0.93 (3H, t, / = 7.2 Hz), 1.23-1.40 (4H, m), 1.51-1.69 (6H, m), 2.53-2.63 (4H, m), 3.98 (2H, dd, / = 12.6, 21.0 Hz), 4.36 (2H, dd, /= 2.7, 12.6 Hz), 7.08 (4H, s). Example 7

5-Amino-5-(2-(4-octanoylphenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol hydrate

(7-1) 2-tert-Butyloxycarbonylamino-2-(2-(4-octanoylphenyl)ethyl)propane-l ,3-diol The amino group of 2-amino-2-(2-(4-octanoylphenyl)ethyl)propane-l,3-diol hydrochloride was protected in a similar manner to that described in Example (2-1) to give the title compound as white crystals. m.p. 74-75 °C

(7-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-(2-(4-octanoylphenyl)ethyl)-2-oxo-

2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-(2-(4-octanoylphenyl)ethyl)propane-

1,3-diol obtained in Example (7-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a faintly yeHow oil.

1H-NMR (CDC1₃) δ (ppm) : 0.88 (3H, t, / = 6.7 Hz), 1.25-1.45 (10H, m), 1.48 (9H, s), 1.54

(9H, s), 1.70 (2H, m), 2.01 (2H, m), 2.61 (2H, m), 2.92 (2H, t, / = 7.5 Hz), 4.06 (2H, d, / = 10.2 Hz), 4.43 (2H, dd, / = 11.1, 22.8 Hz), 5.16 (IH, s), 7.23 (2H, d, / = 8.4 Hz), 8.08 (2H, d, / = 8.4Hz).

(7-3) 5-Amino-5-(2-(4-octanoylphenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-^;2-ol hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-(2-(4- octanoylphenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinane obtained in Example (7-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as white crystals, m.p. 257-259°C MS (ESI) m/z: 384 [M+H] .

Elemental Analysis (C₁₉H₃₀NO₅P* monohydrate): Calculated - C, 56.85; H, 8.03; N.,3.49. Found - C, 56.70; H, 8.25; N, 3.49.

Example 8 5-Amino-5-[2-(4-nonyloxyphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol

(8-1) 2-tert-Butyloxycarbonylamino-2-[2-(4-nonyloxyphenyl)ethyl]propane-l,3-diol The amino group of 2-amino-2-[2-(4-nonyloxyphenyl)ethyl]propane-l ,3-diol hydrochloride was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid. -NMR (CDC ) δ (ppm): 0.88 (3H, t, = 6.6 Hz), 1.27 (10H, m), 1.41-1.45 (2H, m), 1.45

(9H, s), 1.73-1.88 (4H, m), 2.53-2.59 (2H, m), 3.35 (2H, br s), 3.63 (2H, dd, / = 6.6, 11.4 Hz), 3.85-3.94 (4H, m), 4.99 (IH, s), 6.81 (2H, d, / = 8.4 Hz), 7.09 (2H, d, / = 8.4 Hz)

(8-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-[2-(4-nonyloxyphenyl)ethyl]-2-oxo- 2λ⁵-l ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[2-(4- nonyloxyphenyl)ethyl] propane- 1,3 -diol obtained in Example (8-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a white solid. 1H-NMR (CDC ) δ (ppm): 0.88 (3H, t, / = 6.8 Hz), 1.27 (10H, m), 1.40-1.50 (2H, m), 1.47 (9H, s), 1.54 (9H, s), 1.70-1.80 (2H, m), 1.88-1.96 (2H, m), 2.48-2.53 (2H, m), 3.91 (2H, t, / = 6.6 Hz), 4.04 (2H, d, /= 11.1 Hz), 4.41 (2H, dd, = 11.1, 23.1 Hz), 5.12 (IH, s), 6.80 (2H, d, / = 8.4 Hz), 7.05 (2H, d, / = 8.4 Hz).

(8-3) 5-Amino-5-[2-(4-nonyloxyphenyl)ethyl]-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[2-(4- , nonyloxyphenyl)-ethyl]-2-oxo-2λ⁵-l,3,2dioxaphosphinan obtained in Example (8-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white soHd. m.p. 254-256°C.

MS (ESI) m/z: 400 [M+H].

1H-NMR (CD₃OD) δ (ppm): 0.88-1.90 (3H, m), 1.30-1.46 (12H, m), 1.72-1.84 (4H, m),

2.57-2.63 (2H, m), 3.93 (2H, t, / = 6.5 Hz), 4.06 (2H, dd, / = 12.0, 21.3 Hz), 4.44 (2H, d, /

= 12.0 Hz), 6.83 (2H, d, / = 8.7 Hz), 7.11 (2H, d, / = 8.7 Hz).

Example 9 5-Amino-2-oxo-5-[3-(4-undecylphenyl)propyl]-2λ⁵-l ,3,2-dioxaphosphinan-2-ol 1/4 hydrate

(9-1) 2-te? -Butyloxycarbonylamino-2-[3-(4-undecylphenyl)propyl]propane-l,3-diol The amino group of 2-amino-2-[3-(4-undecylphenyl)propyl]propaneJ ,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid.

1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, t, /= 6.6 Hz), 1.26-1.29 (16H, m), 1.43 (9H, s), 1.58-

1.59 (6H, m), 2.53-2.58 (4H, m), 3.39 (2H, br s), 3.57 (2H, dd, /= 7.3, 11.5 Hz), 3.82 (2H, dd, / = 7.3, 11.5 Hz), 4.86 (IH, s), 7.08-7.11 (4H, m).

(9-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-2-oxo-5-[3-(4-undecylphenyl)propyl]-

2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[3-(4- undecylphenyl)propyl] propane- 1,3 -diol obtained in Example (9-1) and tert-butyl tetraisopropylphosphorodiamidite was carried out in a similar manner to that described in

Example (2-2) to give the title compound as a white solid.

1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, t, / = 6.9 Hz), 1.24-1.28 (16H, m), 1.43 (9H, s), 1.55-

1.72 (15H, m), 2.53-2.59 (4H, m), 4.01 (2H, d, /= 10.2 Hz), 4.40 (2H, dd, /= 11.1, 23.1

Hz), 5.02 (IH, s), 7.02-7.H (4H, m).

(9-3) 5-Amino-2-oxo-5-[3-(4-undecylphenyl)propyl]-2λ⁵-l ,3,2-dioxaphosphinan-2-ol 1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-2-oxo-5-[3-(4- undecylphenyl)propyl]- 2λ⁵- 1,3 ,2-dioxaphosphinane obtained in Example (9-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid. m.p. 263-265°C.

MS (ESI) m/z: 426 [M+H].

1H-NMR (CD₃OD) δ (ppm): 0.90 (3H, t, /= 6.9 Hz), 1.28 (16H, m), 1.57-1.66 (6H, m), 2.53-2.61 (4H, m), 3.98 (2H, dd, / = 11.9, 20.6 Hz), 4.36 (2H, d, / = 8.5 Hz), 7.09 (4H, s).

Found - C, 64.35; H, 9.46; N, 3.20.

Example 10 5-Amino-5-[4-(4-octylphenyl)butyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol

(10-1) 2-tert-Butyloxycarbonylamino-2-[4-(4-octylphenyl)butyl]propane-l,3-diol The amino group of 2-amino-2-[4-(4-octylphenyl)butyl]propane-l ,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid.

1H-NMR (CDCU) δ (ppm): 0.87 (3H, t, / = 6.6 Hz), 1.26-1.37 (12H, m), 1.43 (9H, s), 1.54- 1.66 (6H, m), 2.53-2.61 (4H, m), 3.40 (2H, br s), 3.58 (2H, d, /= 11.4 Hz), 3.83 (2H d, / = 11.4 Hz), 4.87 (IH, s), 7.04-7.10 (4H, m).

(10-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-[4-(4-octylphenyl)butyl]-2-oxo-2λ⁵-

1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2- [4-(4-octylphenyl)butyl] propane- 1 ,3 - diol obtained in Example (10-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance.

1H-NMR (CDCI₃) δ (ppm): 0.82-0.90 (3H, m), 1.22-1.30 (12H, m), 1.42 (9H, s), 1.53 (9H, s), 1.58-1.72 (6H, m), 2.04-2.58 (4H, m), 4.02 (2H, d, /= 10.2 Hz), 4.40 (2H, dd, /= 11.4, 22.5 Hz), 5.01 (IH, s), 7.03-7.10 (4H, ).

(10-3) 5-Amino-5-[4-(4-octylρhenyl)butyl] -2-oxo-2λ⁵- 1 ,3 ,2-dioxaρhosρhinan-2-ol A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[4-(4- octylphenyl)butyl]-2-oxo-2λ⁵-l,3,2- dioxaphosphinane obtained in Example (10-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid, m.p. 263-265°C. MS (ESI) m/z: 398 [M+H]. 1H-NMR (CD₃OD) δ (ppm): 0.89 (3H, t, /= 7.2 Hz), 1.29 (12H, m), 1.54-1.64 (6H, m), 2.53-2.63 (4H, m), 3.97 (2H, dd, / = 13.2, 20.1 Hz), 4.36 (2H, d, J= 12.3 Hz), 7.07 (4H, s).

Example 11 5-Amino-5-[3-(4-hexyloxyphenyl)propyl]-2-oxo-2λ^s-l ,3,2-dioxaphosphinan-2-ol 1/2 hydrate

(11-1) 2-tert-Butyloxycarbonylamino-2-[3-(4-hexyloxyphenyl)propyl]propane-l,3-diol The amino group of 2-amino-2-[3-(4-hexyloxyphenyl)propyl]propane-l,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid.

1H-NMR (CDC1₃) δ (ppm): 0.90 (3H, t, / = 6.9 Hz), 1.33-1.35 (4H, m), 1.43 (9H, s), 1.55-

1.58 (6H, m), 1.72-1.79 (2H, m), 2.54 (2H, br s), 3.34 (2H, br s), 3.57 (2H, dd, / = 5.6, 11.6 Hz), 3.82 (2H, dd, /= 5.6, 11.6 Hz), 3.93 (2H, t, / = 6.6 Hz), 4.84 (IH, s), 6.81 (2H, d, / =

8.4 Hz), 7.06 (2H, d, /= 8.4 Hz).

(ll-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-[3-(4-hexyloxyphenyl)propyl]-2- oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[3-(4- hexyloxyphenyl)propyl]proρane-l,3-diol obtained in Example (11-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in

Example (2-2) to give the title compound as a colorless oily substance.

1H-NMR (CDC1₃) δ (ppm): 0.86-0.94 (3H, m), 1.33-1.36 (4H, m), 1.43 (9H, s), 1.52 (9H, s), 1.65-1.78 (8H, m), 2.51-2.56 (2H, m), 3.92 (2H, t, / = 6.8 Hz), 4.00 (2H, d, = 12.0 Hz),

4.39 (2H, m), 5.02 (IH, s), 6.81 (2H, d, /= 8.4 Hz), 7.03 (2H, d, /= 8.4 Hz).

(ll-3) 5-Amino-5-[3-(4-hexyloxyphenyl)propyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol 1/2 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[3-(4- hexyloxyphenyl)propyl]-2-oxo-2λ⁵- 1,3 ,2-dioxaphosphinane obtained in Example (11-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid, m.p. 258-260°C. MS (ESI) m/z: 372 [M+H]. H-NMR (CD₃OD) δ (ppm): 0.92 (3H, t, /= 6.6 Hz), 1.32-1.37 (4H, m), 1.47-1.60 (6H, m), 1.72-1.77 (2H, m), 2.56-2.60 (2H, m), 3.90-4.03 (4H, m), 4.36 (2H, d, / = 11.7 Hz), 6.82 (2H, d, / = 8.4 Hz), 7.08 (2H, d, / = 8.4 Hz).

Elemental Analysis (Cι₈H₃₀NO_sP • 1/2 hydrate): Calculated - C, 56.83; H, 8.21; N, 3.68. Found - C, 56.77; H, 8.00; N, 3.63.

Example 12 5-Amino-5-[4-(4-heptyloxyphenyl)butyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol

(12-1) 2-tert-Butyloxycarbonylamino-2-[4-(4-heptyloxyphenyl)butyl]propane-l,3-diol The amino group of 2-amino-2-[4-(4-heptyloxyphenyl)butyl]propaneJ ,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid.

1H-NMR (CDC1₃) δ (ppm): 0.89 (3H, t, / = 6.9 Hz), 1.31 (8H, m), 1.40-1.43 (11H, m), 1.53- 1.61 (4H, m), 1.74-1.79 (2H, m), 2.53-2.58 (2H, m), 3.35 (2H, br s), 3.58 (2H, dd, /= 7.2, 11.4 Hz), 3.82 (2H, dd, / = 7.2, 11.4 Hz), 3.92 (2H, t, /= 6.4 Hz), 4.87 (IH, s), 6.81 (2H, d, / = 8.4 Hz), 7.05 (2H, d, / = 8.4 Hz).

(12-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-[4-(4-heptyloxyphenyl)butyl]-2- oxo-2λ⁵-l ,3,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[4-(4- heptyloxyphenyl)butyl]propane-l,3-diol obtained in Example (12-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance. 1H-NMR (CDC1₃) δ (ppm): 0.87-0.91 (3H, m), 1.30 (8H, m), 1.42 (11H, s), 1.54 (9H, s), 1.55-1.70 (4H, m), 1.74-1.79 (2H, m), 2.53 (2H, t, / = 7.4 Hz), 3.92 (2H, t, /= 6.6 Hz), 4.02 (2H, d, 7 = 10.8 Hz), 4.40 (2H, dd, 7 = 10.8, 23.1 Hz), 5.03 (IH, s), 6.80 (2H, d, 7 = 8.4 Hz), 7.04 (2H, d, 7= 8.4 Hz).

(12-3) 5-Amino-5-[4-(4-heptyloxyphenyl)butyl]-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[4-(4- , heptyloxyphenyl)butyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinane obtained in Example (12-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid. m.p. 252-254°C.

MS (ESI) m/z: 400 [M+H].

*H-NMR (CD₃OD) δ (ppm): 0.91 (3H, t, 7 = 6.9 Hz), 1.33-1.47 (10H, m), 1.53-1.64 (4H, m),

1.72-1.77 (2H, m), 2.55-2.60 (2H, m), 3.90-4.03 (4H, m), 4.36 (2H, d, 7= 11.7 Hz), 6.81

(2H, d, 7 = 8.4 Hz), 7.07 (2H, d, 7 = 8.4 Hz). Elemental Analysis (C₂₀H₃₄NO₅P): Calculated - C, 60.13; H, 8.58; N, 3.51. Found - C,

59.86; H, 8.66; N, 3.44.

Example 13 5-Amino-5-(2-(4-(5-phenylpentanoyl)phenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol

(13-1) 2-te/t-Butyloxycarbonylamino-2-(2-(4-(5-phenylpentanoyl)phenyl)ethyl)propane- 1,3-diol The amino group of 2-amino-2-(2-(4-(5-phenylpentanoyl)phenyl)ethyl)propane- 1,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as white crystals. 1H-NMR (CDC1₃) δ (ppm): _.1.45 (9H, s), 1.70-1.76 (4H, m), 1.91 (2H, m), 2.66 (4H, m), 2.95 (2H, t, 7 = 7.5 Hz), 3.30 (2H, br s), 3.66 (2H, dd, 7 = 11.4, 5.4 Hz), 3.87 (2H, dd, 7 = 11.4, 5.4 Hz), 5.06 (IH, s), 7.14-7.32 (8H, m), 7.86 (2H, d, 7 = 10.2 Hz).

(13-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-(2-(4-(5- phenylpentanoyl)phenyl)ethyl)-2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-(2-(4-(5- phenylpentanoyl)phenyl)ethyl)propane-l,3-diol obtained in Example (13-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in

Example (2-2) to give the title compound as a colorless oil. 1H-NMR (CDCI₃) δ (ppm): 1.48 (9H, s), 1.54 (9H, s), 1.69-1.76 (4H, m), 1.99 (2H, m), 2.64

(4H, m), 2.95 (2H, t, 7 = 7.1 Hz), 4.05 (2H, d, 7= 10.2 Hz), 4.43 (2H, dd, 7 = 23.1, 11.1 Hz),

5.16 (IH, s), 7.15-7.30 (8H, m), 7.85 (2H, d, 7 = 8.1 Hz).

(13-3) 5-Amino-5-(2-(4-(5-ρhenylpentanoyl)phenyl)ethyl)-2-oxo-2λ⁵-l,3,2- dioxaphosphinan-2-ol A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-(2-(4-(5- phenylpentanoyl)phenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinane obtained in Example (13-

2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as white crystals. m.p. 261-263°C.

MS (ESI) m/z: 418 [M+H].

Example 14 5-Amino-5-[3-(4-heptyloxyphenyl)proρyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol 1/4 hydrate

( 14- 1 ) 2-te rt-Butyloxycarbonylamino-2- [3 -(4-heptyloxyphenyl)propyl] propane- 1 ,3-diol The amino group of 2-amino-2-[3-(4-heptyloxyphenyl)propyl]propane-l,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white sohd.

1H-NMR (CDCI3) δ (ppm): 0.89 (3H, t, 7 = 6.9 Hz), 1.31-1.37 (6H, m), 1.39-1.43 (11H, m), 1.56-1.59 (4H, m), 1.74-1.79 (2H, m), 2.53-2.55 (2H, m), 3.40 (2H, br s), 3.57 (2H, dd, 7 = 7.5, 11 A Hz), 3.81 (2H, dd, 7 = 7.5, 11.4 Hz), 3.92 (2H, t, 7 = 6.6 Hz), 4.85 (IH, s), 6.81 (2H, d, 7 = 8.4 Hz), 7.06 (2H, d, 7 = 8.4 Hz).

(14-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-[3-(4-heptyloxyphenyl)propyl]-2- oxo-2λ^s- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[3-(4- heptyloxyphenyl)propyl] propane- 1,3-diol obtained in Example (14-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance. 1H-NMR (CDC1₃) δ (ppm): 0.89 (3H, t, 7 = 6.9 Hz), 1.31 (6H, m), 1.43 (11H, m), 1.52 (9H, s), 1.55-1.76 (6H, m), 2.54 (2H, m), 3.92 (2H, t, 7 = 6.5 Hz), 3.98 (2H, d, 7= 11.7 Hz), 4.40 (2H, dd, 7 = 11.1, 22.8 Hz), 5.03 (IH, s), 6.81 (2H, d, 7 = 8.7 Hz), 7.03 (2H, d, 7 = 8.7 Hz).

(14-3) 5-Amino-5-[3-(4-heptyloxyphenyl)propyl_-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol 1/4 hydrate. A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[3-(4- heptyloxyphenyl)propyl]-2-oxo-2λ⁵-l ,3,2-dioxaphosphinane obtained in Example (14-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid, m.p. 258-260°C. MS (ESI) m/z: 386 [M+H].

1H-NMR (CD₃OD) δ (ppm) : 0.91 (3H, t, 7 = 6.9 Hz), 1.33-1.77 (14H, m), 2.56-2.60 (2H, m), 3.90-4.02 (4H, m), 4.35 (2H, d, 7 = 11.4 Hz), 6.82 (2H, d, 7= 8.4 Hz), 7.09 (2H, d, 7 = 8.4 Hz). Elemental Analysis (C₁₉H₃₂NO₅P * 1/4 hydrate): Calculated - C, 58.52; H, 8.40; N, 3.59. Found - C, 58.78; H, 8.25; N, 3.50.

Example 15 5-Amino-5-[3-(4-octyloxyphenyl)propyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol

( 15 - 1 ) 2-te rt-Butyloxycarbonylamino-2- [3 -(4-octyloxyphenyl)propyl] propane- 1 ,3 -diol The amino group of 2-amino-2-[3-(4-octyloxyphenyl)propyl]propane-l ,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid.

1H-NMR (CDC1₃) δ (ppm): 0.88 (3H, t, 7 = 6.9 Hz), 1.29-1.36 (8H, m), 1.39-1.46 (11H, m), 1.56-1.58 (4H, m), 1.72-1.79 (2H, m), 2.54-2.55 (2H, m), 3.39 (2H, br s), 3.57 (2H, dd, 7 = 6.9, 11.7 Hz), 3.81 (2H, dd, 7 = 6.9, 11.7 Hz), 3.92 (2H, t, 7 = 6.6 Hz), 4.85 (IH, s), 6.81 (2H, d, 7 = 8.4 Hz), 7.06 (2H, d, 7 = 8.4 Hz).

(15-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-[3-(4-octyloxyphenyl)propyl] -2- oxo-2λ⁵-l ,3,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[3-(4- octyloxyphenyl)propyl]propane- 1,3-diol obtained in Example (15-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance. 1H-NMR (CDC1₃) δ (ppm): 0.86-0.91 (3H, m), 1.29-1.31 (8H, m), 1.39-1.47 (4H, m), 1.44

(9H, s), 1.53 (9H, s), 1.60-1.80 (4H, m), 2.54 (2H, t, 7 = 7.2 Hz), 3.92 (2H, t, 7= 6.8 Hz),

4.00 (2H, d, 7 = 10.5 Hz), 4.40 (2H, dd, 7 = 10.5 Hz, 23.1 Hz), 5.04 (IH, s), 6.81 (2H, d, 7 =

8.7 Hz), 7.03 (2H, d, 7= 8.7 Hz).

(15-3) 5-Amino-5-[3-(4-octyloxyphenyl)propyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[3-(4- octyloxyphenyl)propyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinane obtained in Example (15-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white sohd. m.p. 256-258°C.

MS (ESI) m/z: 400 [M+H].

1H-NMR (CD₃OD) δ (ppm): 0.90 (3H, t, 7 = 6.6 Hz), 1.31-1.76 (16H, m), 2.56-2.60 (2H, m),

3.90-4.03 (4H, m), 4.36 (2H, d, 7 = 12.0 Hz), 6.82 (2H, d, 7 = 8.4 Hz), 7.09 (2H, d, 7 = 8.4 Hz).

Elemental Analysis (C2oH₃ NO_sP): Calculated - C, 60.13; H, 8.58; N, 3.51. Found - C,

59.83; H, 8.46; N, 3.46.

Example 16 5-Amino-2-oxo-5-[3-(3-undecyloxyphenyl)propyl]- 2λ⁵-l,3,2-dioxaphosphinan-2-ol 1/4 hydrate

(16-1) 2-tert-Butyloxycarbonylamino-2-[3-(3-undecyloxyphenyl)propyl]propane-l ,3-diol The amino group 2-amino-2-[3-(3-undecyloxyphenyl)propyl]propane-l,3-diol of was protected in a similar manner to that described in Example (2-1) to give the title compound as a colorless oily substance. 1H-NMR (CDC1₃) δ (ppm): 0.88 (3H, t, 7 = 6.9 Hz), 1.27 (14H, m), 1.43 (11H, s), 1.59-1.60

(4H, m), 1.72-1.79 (2H, m), 2.58 (2H, br s), 3.34 (2H, br s), 3.57 (2H, dd, 7 = 7.4, 11.6 Hz),

3.82 (2H, dd, 7= 7.4, 11.6 Hz), 3.93 (2H, t, 7 = 6.6 Hz), 4.86 (IH, s), 6.71-6.75 (3H, m),

7.15-7.21 (2H, m).

(16-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-2-oxo-5-[3-(3- undecyloxypheny_)propyl] - 2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[3-(3- undecyloxyphenyl)propyl]propane-l,3-diol obtained in Example (16-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in

Example (2-2) to give the title compound as a colorless oily substance.

1H-NMR (CDC ) δ (ppm): 0.88 (3H, t, 7 = 7.2 Hz), 1.27 (16H, m), 1.44 (9H, s), 1.53 (9H, s), 1.56-1.80 (6H, m), 2.57 (2H, t, 7= 1.4 Hz), 3.93 (2H, t, 7 = 6.8 Hz), 4.01 (2H, d, 7 = 11.1

Hz), 4.40 (2H, dd, 7 = 23.1 Hz), 5.05 (IH, s), 6.68-6.75 (3H, m), 7.15-7.21 (IH, m).

(16-3) 5-Amino-2-oxo-5-[3-(3-undecyloxyphenyl)propyl]- 2λ⁵-l ,3,2-dioxaphosphinan-2-ol

1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-2-oxo-5-[3-(3- undecyloxyphenyl)propyl]- 2λ⁵- 1,3 ,2-dioxaphosphinane obtained in Example (16-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid. m.p. 247-249°C.

MS (ESI) m/z: 442 [M+H].

1H-NMR (CD₃OD) δ (ppm) : 0.90 (3H, t, 7 = 6.7 Hz), 1.30-1.77 (22H, m), 2.59-2.63 (2H, m), 3.92-4.03 (4H, m), 4.36 (2H, d, 7 = 12.0 Hz), 6.71-6.76 (3H, m), 7.14-7.19 (IH, m).

Elemental Analysis (dsH^NOsP ^• 1/4 hydrate) : Calculated - C, 61.93; H, 9.15; N, 3.14.

Found - C, 62.14; H, 9.03; N, 3.12.

Example 17 5-Amino-2-oxo-5-(2-[4-(3-phenylpropoxy)phenyl]ethyl)-2λ⁵-l,3,2-dioxaphosρhinan-2-ol 1/4 hydrate

(17-1) 2-tert-Butyloxycarbonylamino-2-(2-[4-(3-phenylpropoxy)phenyl]ethyl)propane-l,3- diol The amino group of 2-amino-2-{2-[4-(3-phenylpropoxy)phenyl]ethyl}propane-l,3- diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid.

1H-NMR (CDC1₃) δ (ppm): 1.45 (9H, s), 1.83-1.88 (2H, m), 2.01-2.11 (2H, m), 2.54-2.59 (2H, m), 2.77-2.82 (2H, m), 3.30 (2H, br s), 3.64 (2H, dd, 7 = 6.8, 11.6 Hz), 3.85-3.95 (4H, m), 4.99 (IH, s), 6.79-6.82 (2H, m), 7.07-7.10 (2H, m), 7.19-7.22 (2H, m), 7.28-7.31 (3H, m).

(17-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-2-oxo-5-(2-[4-(3- phenylpropoxy)phenyl] ethyl)-2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-(2-[4-(3- phenylpropoxy)phenyl]ethyl)propane-l,3-diol obtained in Example (17-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in

Example (2-2) to give the title compound as a white solid. 1H-NMR (CDC1₃) δ (ppm): 1.47 (9H, s), 1.53 (9H, s), 1.90-1.96 (2H, m), 2.04-2.11 (2H, m),

2.48-2.52 (2H, m), 2.77-2.83 (2H, m), 3.93 (2H, t, 7 = 6.3 Hz), 4.03 (2H, d, 7 = 9.9 Hz),

4.36-4.47 (2H, m), 5.12 (IH, s), 6.80 (2H, d, 7= 8.7 Hz), 7.05 (2H, d, 7 = 8.7 Hz), 7.19-7.21

(3H, m), 7.26-7.31 (2H, m).

(17-3) 5-Amino-2-oxo-5-{2-[4-(3-phenylpropoxy)phenyl]ethyl}-2λ⁵-l ,3,2- dioxaphosphinan-2-ol 1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-2-oxo-5-{2-[4-(3- phenylpropoxy)phenyl]ethyl}-2λ⁵-l,3,2-dioxaphosphinane obtained in Example (17-2) was carried out in a similar manner to that described in Example (2-3) to give the title compound as a white solid, m.p. 253-255°C. MS (ESI) m/z: 392 [M+H] .

1H-NMR (CD₃OD) δ (ppm) : 1.79-1.83 (2H, m), 2.03-2.07 (2H, m), 2.58-2.63 (2H, m), 2.78 (2H, t, 7 = 7.6 Hz), 3.92 (2H, t, 7 = 6.2 Hz), 4.06 (2H, dd, 7 = 12.0, 21.2 Hz), 4.44 (2H, d, 7 = 11.6 Hz), 6.84 (2H, d, 7 = 8.4 Hz), 7.11-7.27 (7H, m).

Elemental Analysis (C₂₀H₂₆ O5P * 1/4 hydrate): Calculated - C, 60.68; H, 6.75; N, 3.54. Found - C, 60.60; H, 6.55; N, 3.51.

Example 18 5-Amino-2-oxo-5-{2-[4-(3- ?-tolylpropoxy)phenyl]ethyl}-2λ⁵-l,3,2-dioxaphosphinan-2-ol 1/4 hydrate

(18-1) 2-tert-Butyloxycarbonylamino-2- { 2-[4-(3 - ?-tolylpropoxy)phenyl] ethyl} propane- 1 ,3- diol The amino group of 2-amino-2-{2-[4-(3-^-tolylpropoxy)phenyl]ethyl}propane-l,3- diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid.

1H-NMR (CDC1₃) δ (ppm): 1.45 (9H, s), 1.83-1.88 (2H, m), 2.04-2.09 (2H, m), 2.32 (3H, s), 2.54-2.59 (2H, m), 2.73-2.78 (2H, m), 3.30 (2H, br s), 3.64 (2H, dd, 7 = 6.8, 11.6 Hz), 3.85- 3.95 (4H, m), 4.98 (IH, s), 6.81 (2H, d, 7 = 8.7 Hz), 7.07-7.93 (6H, m).

(18-2) 2-te7-t-Butyloxy-5-tert-butyloxycarbonylamino-2-oxo-5-{2-[4-(3-_jp- tolylpropoxy)phenyl]ethyl}-2λ⁵J ,3,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-{2-[4-(3-_;p- tolylpropoxy)phenyl]ethyl}propane-l,3-diol obtained in Example (18-1) and tert- Butyltetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a white solid

1H-NMR (CDC1₃) δ (ppm): 1.47 (9H, s), 1.53 (9H, s), 1.90-1.96 (2H, m), 2.04-2.09 (2H, m), 2.32 (3H, s), 2.48-2.54 (2H, m), 2.73-2.78 (2H, m), 3.92 (2H, t, 7 = 6.3 Hz), 4.03 (2H, d, 7 = 10.5 Hz), 4.41 (2H, dd, 7 = 10.9, 23.0 Hz), 5.12 (IH, s), 6.80 (2H, d, 7 = 8.4 Hz), 7.05 (2H, d, 7 = 8.4 Hz), 7.09 (4H, s).

(18-3) 5-Amino-2-oxo-5-{2-[4-(3-p-tolylpropoxy)phenyl]ethyl}-2λ⁵-l,3,2-dioxaphosphinan-

2-ol 1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-2-oxo-5-{2-[4-(3-?-tolylpropoxy)-phenyl]ethyl}-2λ⁵-l,3,2-dioxaphosphinane obtained in Example (18-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white sohd. m.p. 258-260°C.

MS (ESI) m/z: 406 [M+H].

1H-NMR (CD₃OD) δ (ppm) : 1.79-1.83 (2H, m), 2.00-2.04 (2H, m), 2.28 (3H, s), 2.58-2.62 (2H, m), 2.73 (2H, t, 7 = 7.4 Hz), 3.91 (2H, t, 7 = 6.2 Hz), 4.06 (2H, dd, 7 = 12.2, 21.0 Hz),

4.44 (2H, d, 7 = 11.2 Hz), 6.83 (2H, d, 7 = 8.8 Hz), 7.07 (4H, s), 7.12 (2H, d, 7 = 8.8 Hz).

Elemental Analysis (diH_∑sNOsP * 1/4 hydrate) : Calculated - C, 61.53; H, 7.01; N, 3.42.

Found - C, 61.67; H, 6.87; N, 3.39. Example 19

5-Amino-5-(2-{4-[4-(4-bromophenyl)butoxy]phenyl}ethyl)-2-oxo-2λ⁵-l,3,2- dioxaphosphinan-2-ol 1/4 hydrate

(19-1) 2-tert-Butyloxycarbonylamino-2-(2-{4-[4-(4-bromophenyl)butoxy]phenyl}- ethyl)propane- 1 ,3-diol The amino group of 2-amino-2-(2-{4-[4-(4-bromophenyl)butoxy]phenyl}ethyl)- propane- 1,3 -diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a colorless oily substance.

1H-NMR (CDCI₃) δ (ppm): 1.45 (9H, s), 1.76-1.88 (6H, m), 2.54-2.63 (4H, m), 3.30 (2H, br s), 3.64 (2H, dd, 7 = 6.9, 11.4 Hz), 3.85-3.93 (4H, m), 4.99 (IH, s), 6.79 (2H, d, 7= 8.4 Hz), 7.05-7.10 (4H, m), 7.39 (2H, d, 7 = 8.4 Hz).

(19-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-(2-{4-[4-(4- bromophenyl)butoxy]phenyl}ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-(2-{4-[4-(4- bromophenyl)butoxy] phenyl }ethyl)propane-l ,3-diol obtained in Example (19-1) and tert- butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance. 1H-NMR (CDCI3) δ (ppm): 1.47 (9H, s), 1.53 (9H, s), 1.77-1.79 (4H, m), 1.90-1.95 (2H, m), 2.48-2.54 (2H, m), 2.61-2.66 (2H, m), 3.91-3.95 (2H, m), 4.03 (2H, d, 7= 10.2 Hz), 4.41 (2H, dd, 7= 11.1, 23.1 Hz), 5.12 (IH, s), 6.79 (2H, d, 7 = 8.7 Hz), 7.03-7.08 (4H, m), 7.39 (2H, d, 7= 8.7 Hz).

(19-3) 5-amino-5-(2-{4-[4-(4-bromoρhenyl)butoxy]phenyl}ethyl)-2-oxo-2λ⁵-l,3,2- dioxaphosphinan-2-ol 1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-(2-{4-[4-(4- bromophenyl)butoxy]phenyl}ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinane obtained in Example (19-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid. m.p. 251-253°C. MS (ESI) m/z : 484 [M+H].

1H-NMR (CD₃OD) δ (ppm) : 1.75-1.83 (6H, m), 2.58-2.67 (4H, m), 3.93-3.96 (2H, m), 4.06 (2H, dd, 7= 12.0, 21.6 Hz), 4.42-4.45 (2H, m), 6.83 (2H, d, 7= 8.8 Hz), 7.10-7.14 (4H, m), 7.39 (2H, d, 7= 8.8 Hz).

Elemental Analysis (C₂₁H₂₇BrNO₅P ^• 1/4 hydrate): Calculated - C, 51.60; H, 5.67; N, 2.87. Found - C, 51.72; H, 5.54; N, 2.86.

Example 20 5-Amino-5-(2-{4-[4-(4-methoxyphenyl)butoxy]phenyl}ethyl)-2-oxo-2λ⁵-l,3,2-dioxa- phosphinan-2-ol 1/4 hydrate

(20-1 ) 2-tert-Butyloxycarbonylamino-2-(2- { 4- [4-(4-methoxyphenyl)butoxy] phenyl } - ethyl)propane-l ,3-diol The amino group of 2-amino-2-(2-{4-[4-(4- methoxyphenyl)butoxy]phenyl}ethyl)propaneJ ,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white sohd.

1H-NMR (CDCI₃) δ (ppm): 1.45 (9H, s), 1.75-1.88 (6H, m), 2.53-2.65 (4H, m), 3.30 (2H, br s), 3.64 (2H, dd, 7 = 6.9, 11.4 Hz), 3.79 (3H, s), 3.85-3.95 (4H, m), 4.99 (IH, s), 6.79-6.84 (4H, m), 7.07-7.12 (4H, m).

(20-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-(2- { 4-[4-(4- methoxyphenyl)butoxy] phenyl } ethyl)-2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-(2-{4-[4-(4- methoxyphenyl)butoxy]phenyl}ethyl)propane-l,3-diol obtained in Example (20-1) and ten- butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a white soUd.

1H-NMR (CDCI₃) δ (ppm): 1.47 (9H, s), 1.53 (9H, s), 1.73-1.81 (4H, m), 1.91-1.95 (2H, m), 2.48-2.52 (2H, m), 2.60-2.64 (2H, m), 3.79 (3H, s), 3.93 (2H, t, 7 = 6.0 Hz), 4.03 (2H, d, 7 = 10.4 Hz), 4.41 (2H, dd, 7 = 11.2, 23.2 Hz), 5.13 (IH, s), 6.78-6.84 (4H, m), 7.04 (2H, d, 7 = 8.8 Hz), 7.11 (2H, d, 7 = 8.8 Hz).

(20-3) 5-Amino-5-(2-{4-[4-(4-methoxyphenyl)butoxy]phenyl}ethyl)-2-oxo-2λ⁵-l,3,2- dioxaphosphinan-2-ol 1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-(2- {4-[4-(4- methoxyphenyl)butoxy]phenyl}ethyl)-2-oxo-2λ^s-l,3,2-dioxaphosphinane obtained in

Example (20-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white sohd. m.p. 255-257°C. MS (ESI) m/z: 436 [M+H] .

1H-NMR (CD₃OD) δ (ppm) : 1.74-1.83 (6H, m), 2.58-2.62 (4H, m), 3.75 (3H, s), 3.94-3.95

(2H, m), 4.06 (2H, dd, 7 = 12.4, 21.2 Hz), 4.44 (2H, d, 7= 12.4 Hz), 6.80-6.84 (4H, m),

7.08-7.12 (4H, m).

Elemental Analysis (C22H30NO6P * 1/4 hydrate): Calculated - C, 60.06; H, 6.99; N, 3.18. Found - C, 60.03; H, 7.09; N, 3.15.

Example 21 5-Amino-5-(8-benzyloxyoctyl)-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol 1/4 hydrate

(21-1) 2-tert-Butyloxycarbonylamino-2-(8-benzyloxyoctyl)propane-l,3-diol The amino group of 2~amino-2-(8-benzyloxyoctyl)propane- 1,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a colorless oily substance.

1H-NMR (CDC1₃) δ (ppm): 1.24-1.28 (10H, m), 1.44 (9H, s), 1.51-1.63 (4H, m), 3.46 (2H, t, 7 = 6.6 Hz), 3.58 (2H, dd, 7 = 7.2, 11.4 Hz), 3.83 (2H, dd, 7= 7.2, 11.4 Hz), 4.50 (2H, s), 4.87 (IH, s), 7.27-7.35 (5H, m.

(21-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-(8-benzyloxyoctyl)-2-oxo-2λ⁵-

1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-(8-benzyloxyoctyl)propane-l ,3-diol obtained in Example (21-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance.

1H-NMR (CDCI3) δ (ppm): 1.22-1.27 (10H, m), 1.44 (9H, s), 1.54 (9H, s), 1.58-1.65 (4H, m), 3.44-3.47 (2H, m), 4.03 (2H, d, 7= 10.4 Hz), 4.41 (2H, dd, 7 = 11.2, 22.8 Hz), 4.50 (2H, s), 5.03 (IH, s), 7.28-7.37 (5H, m).

(21-3) 5-Amino-5-(8-benzyloxyoctyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol 1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-(8- benzyloxyoctyl)-2-oxo-2λ⁵-l ,3,2-dioxaphosphinane obtained in Example (21-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid. m.p. 246-248°C.

MS (ESI) m/z: 372 [M+H].

1H-NMR (CD₃OD) δ (ppm) : 1.34 (10H, m), 1.51-1.61 (4H, m), 3.48 (2H, t, 7 = 6.4 Hz), 4.00 (2H, dd, 7 = 12.4, 21.6 Hz), 4.37 (2H, d, 7= 13.6 Hz), 4.48 (2H, s), 7.27-7.33 (5H, m).

Elemental Analysis (C₁₈H₃oNO₅P ^• 1/4 hydrate) : Calculated - C, 57.51; H, 8.18; N, 3.73.

Found - C, 57.52; H, 8.30; N, 3.71.

Example 22 5-Amino-5-[8-(4-methoxyphenyl)octyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol 1/4 hydrate

(22-1) 2-tert-Butyloxycarbonylamino-2-[8-(4-methoxyphenyl)octyl]propane-l,3-diol The amino group of 2-amino-2-[8-(4-methoxyphenyl)octyl]propane-l ,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a colorless oily substance.

1H-NMR (CDC1₃) δ (ppm): 1.28 (10H, m), 1.44 (9H, s), 1.51-1.57 (4H, m), 2.51-2.55 (2H, m), 3.43 (2H, br s), 3.58 (2H, dd, 7= 7.6, 11.6 Hz), 3.79 (3H, s), 3.84 (2H, dd, 7 = 7.6, 11.6 Hz), 4.87 (IH, s), 6.81-6.84 (2H, m), 7.07-7.10 (2H, m).

(22-2) 2-tert-Butyloxy-5 -te rt-butyloxycarbonylamino-5 - [ 8-(4-methoxyphenyl) octyl] -2-oxo-

2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[8-(4-methoxyphenyl)octyl]propane- 1 ,3-diol obtained in Example (22-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance.

1H-NMR (CDCI₃) δ (ppm): 1.22-1.28 (10H, m), 1.44 (9H, s), 1.54 (9H, s), 1.54-1.65 (4H, m), 2.53 (2H, t, 7 = 7.6 Hz), 3.79 (3H, s), 4.03 (2H, d, 7 = 10.8 Hz), 4.41 (2H, dd, 7 = 10.8, 22.8 Hz), 5.03 (IH, s), 6.82 (2H, d, 7 = 8.4 Hz), 7.08 (2H, d, 7 = 8.4 Hz).

(22-3) 5-Amino-5-[8-(4-methoxyphenyl)octyl]-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol 1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[8-(4- methoxyphenyl)octyl]-2-oxo-2λ⁵J ,3,2-dioxaphosphinane obtained in Example (22-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid. m.p. 251-253°C. MS (ESI) m/z: 372 [M+H].

1H-NMR (CD₃OD) δ (ppm): 1.33-1.34 (10H, m), 1.51-1.59 (4H, m), 2.53 (2H, t, 7 = 8.0 Hz), 3.75 (3H, s), 4.00 (2H, dd, 7= 12.4, 21.2 Hz), 4.35-4.39 (2H, m), 6.81 (2H, d, 7= 8.4 Hz), 7.06 (2H, d, 7 = 8.4 Hz). Elemental Analysis (C₁₈H₃oNO₅P ^• 1/4 hydrate): Calculated - C, 57.51; H, 8.18; N, 3.73. Found - C, 57.26; H, 8.31; N, 3.66.

Example 23 5-Amino-5-octadecyl-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol 1/4 hydrate

(23-1) 2-tert-Butyloxycarbonylamino-2-octadecylpropane-l ,3-diol The amino group of 2-amino-2-octadecylpropane-l ,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white sohd.

1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, t, 7 = 6.6 Hz), 1.25 (32H, m), 1.44 (9H, s), 1.51-1.55 (2H, m), 3.44 (2H, br s), 3.59 (2H, dd, 7 = 7.5, 11.4 Hz), 3.85 (2H, dd, 7 = 7.5, 11.4 Hz),

4.87 (IH, s).

(23-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-octadecyl-2-oxo-2λ⁵-l,3,2- dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-octadecyl-propane- 1 ,3-diol obtained in Example (23-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a white sohd. 1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, t, 7 = 6.6 Hz), 1.25 (32H, m), 1.44 (9H, s), 1.54 (9H, s), 1.59-1.65 (2H, m), 4.04 (2H, d, 7 = 10.4 Hz), 4.42 (2H, dd, 7= 10.8, 22.8 Hz), 5.02 (IH, s).

(23-3) 5-Amino-5-octadecyl-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol 1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-octadecyl-2- oxo- 2λ⁵- 1,3 ,2-dioxaphosphinane obtained in Example (23-2) was carried out in a similar manner to that described in Example (2-3) to give the title compound as a white sohd. m.p. 257-259°C. MS (ESI) m/z: 406 [M+H]. Elemental Analysis (C₂₁H₄₄NO₄P ^• 1/4 hydrate): Calculated - C, 61.51 ; H, 10.94; N, 3.42. Found - C, 61.33; H, 11.11; N, 3.40.

Example 24 5-Amino-5-(6-octyloxyhexyl)-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol 1/4 hydrate

(24-1) 2-tert-Butyloxycarbonylamino-2-(6-octyloxyhexyl)propane-l,3-diol The amino group of 2-amino-2-(6-octyloxyhexyl)propane-l,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a colorless oily substance.

1H-NMR (CDC1₃) δ (ppm): 0.88 (3H, t, 7 = 6.6 Hz), 1.24-1.30 (16H, m), 1.44 (9H, s), 1.51- 1.58 (6H, m), 3.37-3.40 (4H, m), 3.48 (2H, br s), 3.58 (2H, dd, 7= 7.2, 11.2 Hz), 3.84 (2H, dd, 7= 7.2, 11.2 Hz), 4.89 (IH, s).

(24-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-(6-octyloxyhexyl)-2-oxo-2λ⁵-l, 3 ,2- dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-(6-octyloxyhexyl)propane-l ,3-diol obtained in Example (24-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance.

1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, t, 7 = 6.8 Hz), 1.25-1.32 (16H, m), 1.44 (9H, s), 1.54 (9H, s), 1.57-1.62 (6H, ), 3.36-3.39 (4H, m), 4.03 (2H, d, 7= 10.4 Hz), 4.41 (2H, dd, 7 = 11.2, 23.2 Hz), 5.03 (IH, s).

(24-3) 5-Amino-5-(6-octyloxyhexyl)-2-oxo-2λ^s-l,3,2-dioxaphosphinan-2-ol 1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-(6- - octyloxyhexyl)-2-oxo-2λ⁵- 1,3 ,2-dioxaphosphinane obtained in Example (24-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white sohd. m.p. 248-250°C. MS (ESI) m/z: 366 [M+H]. 1H-NMR (CD₃OD) δ (ppm): 0.90 (3H, t, 7 = 6.8 Hz), 1.30-1.37 (16H, m), 1.53-1.58 (6H, m), 3.40-3.43 (4H, m), 4.01 (2H, dd, 7 = 12.4, 22.0 Hz), 4.36-4.39 (2H, m). Elemental Analysis (C1₇H_3.NO5P * 1/4 hydrate): Calculated - C, 55.19; H, 9.94; N, 3.79. Found - C, 55.13; H, 10.03; N, 3.73. Example 25

5-Amino-5-(2-(4-(4-hexylphenyl)phenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol

(25-1) 2-tert-Butyloxycarbonylamino-2-(2-(4-(4-hexylphenyl)phenyl)ethyl)propane-l ,3-diol The amino group of 2-amino-2-(2-(4-(4-hexylphenyl)phenyl)ethyl)propane- 1,3-diol hydrochloride was protected in a similar manner to that described in Example (2-1) to give the title compound as white crystals. m.p. 113-H5°C. 1H-NMR (CDCI3) δ (ppm): 0.89 (3H, t, 7 = 6.7Hz), 1.26-1.66 (8H, m), 1.46 (9H, s), 1.92

(2H, m), 2.65 (4H, m), 3.37 (IH, br s), 3.66 (2H, dd, 7 = 5.8, 11.4 Hz), 3.90 (2H, dd, 7 = 4.6,

11.4 Hz), 5.04 (IH, s), 7.22-7.26 (4H, m), 7.47-7.51 (4H, m). (25-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-(2-(4-(4-hexylphenyl)phenyl)ethyl)- 2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-(2-(4-(4- hexylphenyl)phenyl)ethyl)propane-l ,3-diol obtained in Example (25-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oil.

1H-NMR (CDC ) δ (ppm): 0.89 (3H, t, 7 = 6.9Hz), 1.28-1.70 (8H, m), 2.00 (2H, m), 2.62 (4H, m), 4.07 (2H, d, 7= 10.2 Hz), 4.35 (2H, dd, 7 = 11.1, 23.1 Hz), 5.16 (IH, s), 7.20-7.26 (4H, m), 7.46-7.51 (4H, m).

(25-3) 5-Amino-5-(2-(4-(4-hexylρhenyl)phenyl)ethyl)-2-oxo-2λ⁵- 1 ,3 ,2-dioxaρhosρhinan-2- ol A deprotection of 2-tert-butyloxy-5-tert butyloxycarbonylamino-5-(2-(4-(4- hexylphenyl)phenyl)ethyl)-2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinane obtained in Example (25-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as white crystals. m.p. 282-284°C.

MS (ESI) m/z: 418 [M+H]. Elemental Analysis (C₂₃H₃₂NO₄P): Calculated - C, 66.17; H, 7.73; N, 3.36. Found - C,

65.79; H, 7.50; N, 3.31.

Example 26 5-Amino-5-[4-(4-chlorophenyl)butyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol

(26- 1 ) 2-tert-Butyloxycarbonylamino-2- [4-(4-chlorophenyl)butyl] ropane- 1 ,3-diol The amino group of 2-amino-2-[4-(4-chlorophenyl)butyl]propaneJ ,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a colorless oily substance.

1H-NMR (CDCI₃) δ (ppm): 1.26-1.36 (2H, m), 1.43 (9H, s), 1.54-1.65 (4H, m), 2.59 (2H, t, 7 = 7.7 Hz), 3.32 (2H, br s), 3.58 (2H, dd, 7 = 7.2, 11.7 Hz), 3.81 (2H, dd, 7 = 5.4, 11.4 Hz), 4.88 (IH, s), 7.07-7.10 (2H, m), 7.22-7.25 (2H, m).

(26-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-[4-(4-chlorophenyl)butyl]-2-oxo-

2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[4-(4-chlorophenyl)butyl]propane-

1,3-diol obtained in Example (26-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance.

1H-NMR (CDC ) δ (ppm): 1.24-1.28 (2H, m), 1.42 (9H, s), 1.54 (9H, s), 1.57-1.63 (4H, m), 2.57 (2H, t, 7 = 7.4 Hz), 4.02 (2H, d, 7 = 10.4 Hz), 4.40 (2H, dd, 7 = 10.8, 23.2 Hz), 5.04

(IH, s), 7.07 (2H, d, 7 = 8.0 Hz), 7.23 (2H, t, 7 = 8.0 Hz).

(26-3) 5-Amino-5-[4-(4-chlorophenyl)butyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[4-(4- chlorophenyl)butyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinane obtained in Example (26-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white sohd. m.p. 248-250°C.

MS (ESI) m/z: 320 [M+H]. 1H-NMR (CD₃OD) δ (ppm): 1.36-1.38 (2H, m), 1.55-1.65 (4H, m), 2.64 (2H, t, 7 = 7.6 Hz),

3.98 (2H, dd, 7= 12.0, 21.2 Hz), 4.36 (2H, d, 7 = 12.0 Hz), 7.17 (2H, d, 7 = 8.4 Hz), 7.26

(2H, t, 7 = 8.4 Hz).

Elemental Analysis (d^ONO^): Calculated - C, 48.84; H, 5.99; N, 4.38. Found - C,

48.57; H, 5.97; N, 4.33. Example 27 5-Amino-5-[2-(4-heptyloxyphenyl)ethyl]-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol 1/4 hydrate

(27-1) 2-tert-Butyloxycarbonylamino-2-[2-(4-heptyloxyphenyl)ethyl]propane-l,3-diol The amino group of 2-amino-2-[2-(4-heptyloxyphenyl)ethyl]propane-l,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid. ^XH-NMR (CDC ) δ (ppm): 0.91 (3H, t, 7 = 6.6 Hz), 1.26-1.36 (6H, m), 1.40-1.45 (2H, m), 1.45 (9H, s), 1.73-1.80 (2H, m), 1.83-1.87 (2H, m), 2.54-2.58 (2H, m), 3.36 (2H, br s), 3.63 (2H, dd, 7= 7.2, 11.6 Hz), 3.86-3.93 (4H, m), 4.99 (IH, s), 6.81 (2H, d, J = 8.4 Hz), 7.09 (2H, d, 7= 8.4 Hz).

(27-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-[2-(4-heptyloxyphenyl)ethyl]-2- oxo-2λ⁵-l ,3,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[2-(4- heptyloxyphenyl)ethyl]propane-l,3-diol obtained in Example (27-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance.

1H-NMR (CDCI₃) δ (ppm): 0.89 (3H, t, 7 = 6.8 Hz), 1.28-1.37 (6H, m), 1.47 (9H, s), 1.54 (9H, s), 1.72-1.80 (4H, m), 1.89-1.95 (2H, m), 2.49-2.53 (2H, m), 3.92 (2H, t, 7 = 6.6 Hz), 4.03 (2H, d, 7 = 10.8 Hz), 4.41 (2H, dd, 7 = 10.8, 22.8 Hz), 5.13 (IH, s), 6.81 (2H, d, 7 = 8.4 Hz), 7.05 (2H, t, 7 = 8.4 Hz).

(27-3) 5-Amino-5-[2-(4-heptyloxyphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol 1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-[2-(4- heptyloxyphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinane obtained in Example (27-2) was carried out in a similar manner to that described in Example (2-3) to give the title compound as a white sohd. m.p. 257-259°C. MS (ESI) m/z: 372 [M+H].

1H-NMR (CD₃OD) δ (ppm): 0.91 (3H, t, 7 = 6.8 Hz), 1.33-1.38 (6H, m), 1.42-1.46 (2H, m), 1.71-1.83 (4H, m), 2.58-2.62 (2H, m), 3.93 (2H, t, 7 = 6.4 Hz), 4.06 (2H, dd, 7 = 12.4, 21.2 Hz), 4.44 (2H, d, 7 = 12.4 Hz), 6.83 (2H, d, 7 = 8.8 Hz), 7.12 (2H, t, 7 = 8.8 Hz). Elemental Analysis (C__H₃₀NO₅P ^• 1/4 hydrate) : Calculated - C, 57.51; H, 8.18; N, 3.73. Found - C, 57.25; H, 7.90; N, 3.68.

Example 28 5-Amino-5-(8-hexyloxyoctyl)-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol 1/4 hydrate

(28-1) 2-tert-Butyloxycarbonylamino-2-(8-hexyloxyoctyl)propane-l ,3-diol The amino group of 2-amino-2-(8~hexyloxyoctyl)propane-l ,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a colorless oily substance.

1H-NMR (CDC1₃) δ (ppm): 0.89 (3H, t, 7 = 6.6 Hz), 1.29-1.37 (16H, m), 1.44 (9H, s), 1.50- 1.58 (6H, m), 3.37-3.41 (4H, m), 3.47 (2H, br s), 3.59 (2H, dd, 7 = 7.2, 11.6 Hz), 3.84 (2H, dd, 7= 5.2, 11.6 Hz), 4.88 (IH, s).

(28-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-(8-hexyloxyoctyl)-2-oxo-2λ⁵-l ,3,2- dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-(8-hexyloxyoctyl)propane- 1,3-diol obtained in Example (28-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance.

1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, t, 7 = 6.8 Hz), 1.23-1.30 (16H, m), 1.44 (9H, s), 1.54 (9H, s), 1.58-1.64 (6H, m), 3.36-3.40 (4H, m), 4.04 (2H, d, 7 = 10.4 Hz), 4.42 (2H, dd, 7 = 10.8, 23.2 Hz), 5.03 (IH, s).

(28-3) 5-Amino-5-(8-hexyloxyoctyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol 1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-(8- hexyloxyoctyl)-2-oxo-2λ⁵- 1,3 ,2-dioxaphosphinane obtained in Example (28-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white sohd. m.p. 250-252°C.

MS (ESI) m/z: 366 [M+H].

1H-NMR (CD₃OD) δ (ppm) : 0.91 (3H, t, 7 = 6.6 Hz), 1.29-1.34 (16H, m), 1.53-1.55 (6H, m), 3.39-3.43 (4H, m), 4.00 (2H, dd, 7 = 12.4, 21.6 Hz), 4.37 (2H, d, 7 = 12.4 Hz).

Elemental Analysis (C₁₇H₃₆NO₅P ^• 1/4 hydrate): Calculated - C, 55.19; H, 9.94; N, 3.79.

Found - C, 55.17; H, 9.61; N, 3.76.

Example 29 5-Amino-2-oxo-5-{2-[4-(7-phenylheptanoyl)phenyl]ethyl}-2λ⁵-l,3,2-dioxa-phosphinan-2-ol

(29-1) 2-tert-Butyloxycarbonylamino-2-{2-[4-(7-phenylheptanoyl)phenyl]ethyl}propane- 1,3-diol The amino group of 2-amino-2-{2-[4-(7-phenylheptanoyl)phenyl]ethyl}propane- 1,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid.

1H-NMR (CDCI₃) δ (ppm): 1.38-1.40 (4H, m), 1.46 (9H, s), 1.59-1.65 (2H, m), 1.71-1.74 (2H, m), 1.89-1.93 (2H, m), 2.58-2.62 (2H, m), 2.66-2.70 (2H, m), 2.90-2.94 (2H, m), 3.26 (2H, br s), 3.66 (2H, dd, 7 = 6.4, 11.6 Hz), 3.89 (2H, dd, 7 = 6.4, 11.6 Hz), 5.05 (IH, s), 7.16-7.18 (3H, m), 7.25-7.29 (4H, m), 7.86-7.88 (2H, m).

(29-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-2-oxo-5- { 2-[4-(7- phenylheptanoyl)phenyl] ethyl } -2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-{2-[4-(7- phenylheptanoyl)phenyl]ethyl}propane-l,3-diol obtained in Example (29-1) and tert-butyl- tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a colorless oily substance. MS (ESI) m/z: 624 [M+Na].

(29-3) 5-amino-2-oxo-5-{2-[4-(7-phenylheρtanoyl)phenyl]ethyl}-2λ⁵-l ,3,2-dioxa- phosphinan-2-ol A deprotection reaction of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-2-oxo-5-

{2-[4-(7-phenylheptanoyl)phenyl]ethyl}-2λ⁵-l,3,2-dioxaphosphinane obtained in Example

(29-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid. m.p. 248-250°C.

MS (ESI) m/z: 446 [M+H].

*H-NMR (CD₃OD) δ (ppm) : 1.37-1.40 (4H, m), 1.60-1.70 (4H, m), 1.85-1.89 (2H, m),

2.58-2.61 (2H, m), 2.73-2.77 (2H, m), 2.96-3.00 (2H, m), 4.08 (2H, dd, 7 = 12.0, 20.8 Hz), 4.45 (2H, d, 7 = 12.0 Hz), 7.10-7.16 (3H, m), 7.21-7.25 (2H, m), 7.37 (2H, d, 7 = 8.0 Hz),

7.93 (2H, d, 7 = 8.0 Hz).

Example 30 5-Amino-5-tetradecyl-2-oxo-2λ^s-l ,3,2-dioxaphosphinan-2-ol 1/4 hydrate

(30-1) 2-tert-Butyloxycarbonylamino-2-tetradecyl-propane- 1,3-diol The amino group of 2-amino-2-tetradecylpropane-l,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white sohd. 1H-NMR (CDC1₃) δ (ppm): 0.88 (3H, t, 7 = 6.8 Hz), 1.25-1.90 (24H, m), 1.44 (9H, s), 1.52- 1.54 (2H, m), 3.44 (2H, br s), 3.59 (2H, dd, 7 = 7.6, 11.6 Hz), 3.85 (2H, dd, 7 = 5.2, 11.2 Hz), 4.87 (IH, s).

(30-2) 2-te/t-Butyloxy-5-tert-butyloxycarbonylamino-5-tetradecyl-2-oxo-2λ⁵-l ,3,2- dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-tetradecyl-propane- 1,3 -diol obtained in Example (30-1) and tert-butyl tetraisopropylphosphorόdiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a white sohd. 1H-NMR (CDC1₃) δ (ppm): 0.88 (3H, t, 7 = 6.8 Hz), 1.25 (24H, m), 1.44 (9H, s), 1.54 (9H, s), 1.61-1.70 (2H, m), 4.04 (2H, d, 7 = 11.2 Hz), 4.42 (2H, dd, 7 = 11.2, 22.8 Hz), 5.02 (IH, s).

(30-3) 5-Amino-5-tetradecyl-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol 1/4 hydrate A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-tetradecyl-2- oxo-2λ⁵- 1,3 ,2-dioxaphosphinane obtained in Example (30-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid. m.p. 249-251°C.

MS (ESI) m/z: 350 [M+H]. Elemental Analysis (CπHsgNO^ ^• 1/4 hydrate): Calculated - C, 57.69; H, 10.39; N, 3.96.

Found - C, 57.72; H, 10.37; N, 3.91.

Example 31 5-Amino-2-oxo-5-[2-(4-pentyloxyphenyl)ethyl]-2λ⁵-l,3,2-dioxaphosphinan-2-ol trifluoroacetate

(31-1) 2-tert-Butyloxycarbonylamino-2-[2-(4-pentyloxyphenyl)ethyl]propane-l ,3-diol The amino group of 2-amino-2-[2-(4-pentyloxyphenyl)ethyl]propaneJ ,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid. 1H-NMR (CDC1₃) δ (ppm): 0.93 (3H, t, 7 = 6.9 Hz), 1.39-1.45 (4H, m), 1.45 (9H, s), 1.74- 1.88 (4H, m), 2.53-2.59 (2H, m), 3.35 (2H, br s), 3.64 (2H, dd, 7= 6.9, 11.5 Hz), 3.85-3.94 (4H, m), 4.99 (IH, s), 6.81 (2H, d, 7 = 8.5 Hz), 7.08 (2H, d, 7 = 8.5 Hz).

(31-2) 5-tert-Butyloxycarbonylamino-2-oxo-5-[2-(4-pentyloxyphenyl)ethyl]-2λ⁵-l,3,2- dioxaphosphinan-2-ol A reaction of 2-tert-butyloxycarbonylamino-2-[2-(4- pentyloxyphenyl)ethyl]propane-l,3-diol obtained in Example (31-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in

Example (2-2) to give the title compound as a white amorphous. MS (ESI) m/z: 344 [M-Boc+H].

(31-3) 5-Amino-2-oxo-5-[2-(4-pentyloxyphenyl)ethyl]-2λ⁵-l,3,2-dioxaphosphinan-2-ol trifluoroacetate Trifluoroacetic acid (0.5 ml) was added to a solution of the product (99 mg) as obtained by the procedure in the above Example (31-2) in dichloromethane (1.0 ml) under ice-coohng. The mixture was stined at room temperature for 3 hours. The reaction solution was distilled off under reduced pressure to give 86 mg of the titled compound as a white solid, having a melting point of 242-244°C. MS (ESI) m/z: 344 [M+H].

1H-NMR (CD₃OD) δ (ppm): 0.94 (3H, t, 7 = 7.1 Hz), 1.38-1.45 (4H, m), 1.73-1.84 (4H, m), 2.57-2.63 (2H, m), 3.93 (2H, t, 7 = 6.5 Hz), 4.07 (2H, dd, 7 = 12.6, 21.3 Hz), 4.43-4.47 (2H, m), 6.83 (2H, d, 7 = 8.4 Hz), 7.12 (2H, d, 7 = 8.4 Hz).

Example 32 5-Amino-5-[2-(4-hexyloxyphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol trifluoroacetate

(32-1) 2-tert-Butyloxycarbonylamino-2-[2-(4-hexyloxyphenyl)ethyl]propane-l,3-diol The amino group of 2-amino-2-[2-(4-hexyloxyphenyl)ethyl]propaneJ ,3-diol was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid.

1H-NMR (CDC1₃) δ (ppm): 0.90 (3H, t, 7 = 6.6 Hz), 1.31-1.35 (4H, m), 1.45 (11H, m), 1.74- 1.88 (4H, m), 2.54-2.59 (2H, m), 3.35 (2H, br s), 3.64 (2H, dd, 7= 6.9, 11.4 Hz), 3.86-3.94 (4H, m), 4.99 (IH, s), 6.81 (2H, d, 7= 8.4 Hz), 7.08 (2H, d, 7 = 8.4 Hz).

(32-2) 5-tert-Butyloxycarbonylamino-5-[2-(4-hexyloxyρhenyl)ethyl]-2-oxo-2λ^s-l ,3,2- dioxaphosphinan-2-ol A reaction of 2-tert-butyloxycarbonylamino-2-[2-(4- hexyloxyphenyl)ethyl]propane-l ,3-diol obtained in Example (32-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a white amorphous.

MS (ESI) m/z: 358 [M-BOC+H].

(32-3) 5-Amino-5-[2-(4-hexyloxyphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol trifluoroacetate Trifluoroacetic acid (0.5 ml) was added to a solution of the product (123 mg) as obtained in Example (32-2) in dichloromethane (1.0 ml) under ice-cooling. The mixture was stined at room temperature for 3 hours. The reaction solution was distilled off under reduced pressure, and diisopropyl ether was added to the residue. The precipitate was collected to afford 81 mg of the titled compound as a white sohd, having a melting point of 214-216°C.

MS (ESI) m/z: 358 [M+H].

1H-NMR (CD₃OD) δ (ppm) : 0.90-0.94 (3H, m), 1.30-1.46 (6H, m), 1.72-1.84 (4H, m), 2.57-2.63 (2H, m), 3.91-4.12 (4H, m), 4.44 (2H, d, 7= 12.3 Hz), 6.82-6.85 (2H, m), 7.11- 7.14 (2H, m).

Example 33 5-Amino-5-(4-nonylphenyl)methyl-2-oxo-2λ⁵-l,3,2-dioxa-phosphinan-2-ol

(33-1) 2-tert-Butyloxycarbonylamino-2- [(4-nonylphenyl)methyl] propane- 1 ,3-diol The amino group of 2-amino-2-[(4-nonylphenyl)methyl]propane-l,3-diol hydrochloride was protected in a similar manner to that described in Example (2-1) to give the title compound as a white solid.

1H-NMR (CDC1₃) δ (ppm): 0.88 (3H, t, 7 = 6.9 Hz), 1.18-1.36 (12H, m), 1.45 (9H, s), 1.51- 1.68 (2H, m), 2.54-2.58 (2H, m), 2.86 (2H, s), 3.57 (2H, d, 7= 11.5 Hz), 3.77 (2H, d, 7 = 11.5 Hz), 4.92 (IH, s), 7.11-7.13 (4H, m).

(33-2) 2-tert-Butyloxy-5-tert-butyloxycarbonylamino-5-(4-nonylphenyl)methyl-2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinane A reaction of 2-tert-butyloxycarbonylamino-2-[(4-nonylphenyl)methyl]propane- 1,3-diol obtained in Example (33-1) and tert-butyl tetraisopropylphosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as colorless oily substance.

1H-NMR (CDC ) δ (ppm): 0.88 (3H, t, 7 = 6.9 Hz), 1.20-1.38 (12H, m), 1.49 (9H, s), 1.52 (9H, s), 1.52-1.62 (2H, m), 2.57 (2H, t, 7 = 7.8 Hz), 2.98 (2H, s), 4.14 (2H, d, 7 = 11.1 Hz), 4.39 (2H, dd, 7 = 11.1, 22.8 Hz), 4.84 (IH, s), 6.99 (2H, d, 7 = 7.8 Hz), 7.10 (2H, d, 7 = 7.8 Hz).

(33-3) 5-Amino-5-(4-nonylphenyl)methyl-2-oxo-2λ⁵-l,3,2-dioxa-phosphinan-2-ol A deprotection of 2-tert-butyloxy-5-tert-butyloxycarbonylamino-5-(4- nonylphenyl)methyl-2-oxo-2λ⁵-l,3,2-dioxaphosphinane obtained in Example (33-2) was canied out in a similar manner to that described in Example (2-3) to give the title compound as a white solid, having a melting point of 253°C.

MS (ESI) m/z: 370 [M+H]. 1H-NMR (CD₃OD) δ (ppm): 0.89 (3H, t, 7 = 7.1 Hz), 1.21-1.41 (12H, m), 1.57-1.63 (2H, m),

2.61 (2H, t, 7= 7.4 Hz), 2.87 (2H, s), 4.02 (2H, dd, 7= 12.1, 21.0 Hz), 4.46 (2H, dd, 7 = 2.7,

12.0 Hz), 7.12 (2H, d, 7 = 8.0Hz), 7.21 (2H, d, 7 = 8.0 Hz).

Example 34 5-Amino-5-(3-{2-chloro-4-[3-(3,5-dichlorobenzyloxy)phenoxyj-phenyl}propyl)-2-oxo-2λ^s- 1 ,3,2-dioxaphosphinan-2-ol

(34-1) 5-Amino-5-(3-{2-chloro-4-[3-(3,5-dichlorobenzyloxy)phenoxy]-phenyl}propyl)-2- oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinan-2-ol The title compound was obtained from 2-amino-2-(3-{2-chloro-4-[3-(3,5- dichlorobenzyloxy)phenoxy] phenyl }propyl)propane- 1,3 -diol according to the procedure described in Example 2. m.p. 254.5 °C.

MS (ESI) m/z: 572 [M+H].

1H-NMR (CD₃OD) δ (ppm) : 1.61-1.66 (4H, m), 2.74-2.78 (2H, m), 4.00 (2H, dd, 7 = 12.4,

21.2 Hz), 4.38 (2H, d, 7= 12.4 Hz), 5.07 (2H, s), 6.58-6.63 (2H, m), 6.81 (IH, dd, 7 = 2.4,

8.4 Hz), 6.87 (IH, dd, 7 = 2.4, 8.4 Hz), 6.98 (IH, d, 7 = 2.4 Hz), 7.26-7.31 (2H, m), 7.39 (3H, s).

Elemental Analysis (C25H25CI3NO.P): Calculated - C, 52.42; H, 4.40; N, 2.45. Found - C,

52.18; H, 4.59; N, 2.44.

Example 35 5-Amino-2-ethoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxa-phosphinane

(35-l) 5-Amino-2-chloro-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinane

To a solution of the 2-benzyloxycarbonylamino-2-[2-(4-octylphenyl)ethyl]propane- 1,3-diol (221 mg) and triethylamine (0.146 ml) in 1 ml of dichloromethane was added a solution of phosphorus oxychloride (80 mg) in 1.5 ml of dichloromethane at 0°C. The mixture was refluxed for 3 hours, and then allowed to cool to room temperature. The mixture was poured into water, and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 245 mg of the title compound as a white solid. MS (ESI) m/z: 504 [M-C1+NH₄] .

(35-2) 5-Benzyloxycarbonylamino-2-ethoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2- dioxaphosphinane

To a solution of 5-amino-2-chloro-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2- dioxaphosphinane (245 mg) as obtained by the procedure in the above Example (35-1) and ethanol (137 μl) in 5 ml of dichloromethane was added triethylamine (0.327 ml), and the mixture was stined at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by sihca gel chromatography (20 g, hexane:ethyl acetate = 1 :1) to give 142 mg of the title compound (mixture of isomers) as a oily substance. Further purification by CAPCELL PAK C18 (20 mm x 250 mm, 85% 0.05%TFA/H₂O-CH₃CN) gave isomer 1 (56.6 mg) as a colorless oil and isomer 2 (79.5 mg) as a colorless oil.

(isomer 1)

MS (ESI) m/z: 532 [M+H].

1H-NMR (CDC1₃) δ (ppm) : 0.88 (3H, t, 7 = 6.8 Hz), 1.26-1.30 (10H, m), 1.36 (3H, t, 7 = 7.2 Hz), 1.51-1.59 (2H, m), 2.04-2.13 (2H, m), 2.53-2.60 (4H, m), 4.16-4.30 (4H, m), 4.55-4.62

(2H, m), 4.91 (IH, s), 5.10 (2H, s), 7.03 (2H, d, 7 = 8.0 Hz), 7.08 (2H, d, 7= 8.0 Hz), 7.32-

7.39 (5H, m).

(isomer 2)

MS (ESI) m/z: 532 [M+H]. 1H-NMR (CDCI₃) δ (ppm) : 0.88 (3H, t, 7= 6.8 Hz), 1.26-1.30 (10H, m), 1.38 (3H, t, 7 = 7.2

Hz), 1.51-1.59 (2H, m), 1.97-2.01 (2H, m), 2.50-2.57 (4H, m), 4.11 (2H, d, 7 = 11.2 Hz),

4.16-4.23 (2H, m), 4.47 (2H, dd, 7 = 11.2, 22.8 Hz), 5.12 (2H, s), 5.31 (IH, s), 7.00 (2H, d, 7

= 8.0 Hz), 7.07 (2H, d, 7 = 8.0 Hz), 7.31-7.38 (5H, m).

(35-3) 5-Amino-2-ethoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l ,3,2-dioxaphosphinane

To a solution of the isomer 1 (56.6 mg) as obtained by the procedure in the above Example (35-2) in 5ml of methanol was added 10% wet Pd-C (10 mg). The flask was evacuated and replaced with H₂, and the mixture was stined at room temperature. After 3.5 hours, the flask was evacuated and replaced with N₂. Then the mixture was filtered through Celite, and concentrated. The residue was purified by sihca gel chromatography (20g, chloroform:methanol = 50:1) to give 34.6 mg of the title compound as a white amorphous. MS (ESI) m/z: 398 [M+H].

1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, t, 7 = 6.8 Hz), 1.27-1.30 (10H, m), 1.40 (3H, t, 7 = 7.2 Hz), 1.57 (2H, m), 2.54-2.58 (2H, m), 2.67-2.71 (2H, m), 3.99 (2H, dd, 7= 8.0, 10.8 Hz), 4.14-4.26 (4H, m), 7.11 (4H, m).

Example 36 5-Amino-2-ethoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinane

To a solution of the isomer 2 (79.5 mg) as obtained by the procedure in the above Example (35-2) in 5ml of methanol was added 10% wet Pd-C (10 mg). The flask was evacuated and replaced with hydrogen, and the mixture was stined at room temperature. After 3.5 h, the flask was evacuated and replaced with N₂. Then the mixture was filtered through Cehte, and concentrated. The residue was purified by sihca gel chromatography (20g, chloroform :methanol = 50:1) to give 38.5 mg of the title compound as a white solid, having a melting point of 59.6 °C. MS (ESI) m/z: 398 [M+H].

1H-NMR (CDCI₃) δ (ppm): 0.87 (3H, t, 7 = 6.8 Hz), 1.26-1.29 (10H, m), 1.39 (3H, t, 7 = 7.2 Hz), 1.59-1.63 (4H, m), 2.54-2.58 (2H, m), 2.63-2.68 (2H, m), 4.00 (2H, dd, 7= 10.8, 22.0 Hz), 4.19 (2H, q, 7 = 7.2 Hz), 4.25 (2H, d, 7 = 10.8 Hz), 7.06-7.12 (4H, m). Example 37 5-Amino-5-[2-(4-octylphenyl)ethyl]-2-oxo-2-phenylethyloxy-2λ⁵-l,3,2-dioxaphosphinane

(37-1) 5-Benzyloxycarbonylamino-5-[2-(4-octylphenyl)ethyl]-2-oxo-2-phenylethyloxy-2λ⁵- 1 ,3 ,2-dioxaphosphinane

To a solution of 5-amino-2-chloro-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2- dioxaphosphinane (350 mg) as obtained by the procedure in the above Example (35-1) and phenylethylalcohol (164 mg) in 6.7 ml of dichloromethane was added triethylamine (467 μl).

The mixture was stined at room temperature for 28 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (30 g, hexane:ethyl acetate = 3:1 to 2:1) to give isomer 1 (108 mg) as a white sohd and isomer 2 (20.6 mg) as a colorless oil.

(isomer 1)

MS (ESI) m/z: 608 [M+H].

1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, t, 7 = 6.8 Hz), 1.27-1.30 (10H, m), 1.57-1.59 (2H, m),

1.71-1.75 (2H, m), 2.35-2.39 (2H, m), 2.55-2.58 (2H, m), 3.01 (2H, t, 7= 6.0 Hz), 3.57 (2H, d, 7 = 11.2 Hz), 4.21-4.33 (4H, m), 5.08 (2H, s), 5.20 (IH, s), 6.96 (2H, d, 7 = 8.0 Hz), 7.08

(2H, d, 7 = 8.0 Hz), 7.22-7.26 (4H, m), 7.31-7.36 (6H, m).

(isomer 2)

MS (ESI) m/z: 608 [M+H].

1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, t, 7 = 6.8 Hz), 1.26-1.30 (10H, m), 1.57-1.59 (2H, m), 2.09-2.13 (2H, m), 2.53-2.58 (4H, m), 3.02 (2H, t, 7 = 7.2 Hz), 4.22 (2H, t, 7 = 11.6 Hz),

4.28-4.33 (2H, m), 4.38-4.44 (2H, m), 4.76 (IH, s), 5.09 (2H, s), 7.02 (2H, d, 7 = 8.0 Hz),

7.08 (2H, d, 7= 8.0 Hz), 7.20-7.26 (2H, m), 7.27-7.30 (4H, m), 7.32-7.39 (4H, m).

(37-2) 5-Amino-5-[2-(4-octylphenyl)ethyl]-2-oxo-2-phenylethyloxy-2λ⁵-l,3,2- dioxaphosphinane

A deprotection of the isomer 1 obtained in Example (37-1) was canied out in a similar manner to that described in Example (35-3) to give the title compound as a white solid. The stereochemistry was confirmed by X-ray analysis, m.p. 92.6°C .

MS (ESI) m/z: 474 [M+H]. 1H-NMR (CDC1₃) δ (ppm): 0.88 (3H, t, 7 = 6.8 Hz), 1.27-1.30 (10H, m), 1.37-1.41 (2H, m), 1.57-1.63 (2H, m), 2.49-2.53 (2H, m), 2.55-2.59 (2H, m), 3.02 (2H, t, 7= 6.4 Hz), 3.74 (2H, d, 7 = 10.8 Hz), 3.81-3.86 (2H, m), 4.31 (2H, q, 7 = 6.4 Hz), 7.04 (2H, d, 7 = 8.0 Hz), 7.12 (2H, d, 7= 8.0 Hz), 7.22-7.35 (5H, m). Example 38

5-Amino-5-[2-(4-octylphenyl)ethyl] -2-oxo-2-phenylethyloxy-2λ⁵- 1 ,3 ,2-dioxaphosphinane

A deprotection of the isomer 2 obtained in Example (37-1) was canied out in a similar manner to that described in Example (35-3) to give the title compound as a white amorphous.

MS (ESI) m/z: 474 [M+H]. -NMR (CDCI₃) δ (ppm): 0.87 (3H, m), 1.26-1.29 (12H, m), 1.91-1.95 (2H, m), 2.53-2.57 (2H, m), 2.61-2.65 (2H, m), 3.04 (2H, t, 7 = 6.4 Hz), 3.54 (2H, dd, 7= 5.6, 11.2 Hz), 3.94

(2H, dd, 7 = 11.2, 19.2 Hz), 4.32 (2H, q, 7 = 6.4 Hz), 7.09 (4H, s), 7.25-7.36 (5H, m). Example 39 5-Amino-2-tβ^butyloxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinane

(39-1) 5-Benzyloxycarbonylamino-2-tert-butyloxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinane

A reaction of 2-benzyloxycarbonylamino-2-[2-(4-octylphenyl)ethyl]propane-l ,3- diol and tert-butyl tetraisopropyl-phosphorodiamidite was canied out in a similar manner to that described in Example (2-2) to give the title compound as a white sohd. 1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, t, 7 = 6.8 Hz), 1.25-1.30 (10H, m), 1.55-1.59 (2H, m), 1.73-2.00 (2H, m), 2.49-2.57 (4H, m), 4.07 (2H, d, 7 = 10.8 Hz), 4.44 (2H, dd, 7 = 10.8, 22.8 Hz), 5.H (2H, s), 5.35 (IH, s), 7.01 (2H, d, 7 = 8.0 Hz), 7.07 (2H, d, 7 = 8.0 Hz), 7.32-7.40 (5H, m).

(39-2) 5-Amino-2-tert-butyloxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2- dioxaphosphinane

A deprotection of 5-benzyloxycarbonylamino-2-tert-butyloxy-5-[2-(4- octylphenyl)ethyl]-2-oxo-2λ⁵- 1,3 ,2-dioxaphosphinane obtained in Example (39-1) was canied out in a similar manner to that described in Example (35-3) to give the title compound as a white solid, m.p. 74.3°C. MS (ESI) m/z: 370 [M-tert-Bu+H] .

1H-NMR (CDC1₃) δ (ppm): 0.86-0.89 (3H, m), 1.26-1.29 (10H, m), 1.54 (9H, s), 1.57-1.62 (4H, m), 2.54-2.58 (2H, m), 2.63-2.67 (2H, m), 3.96 (2H, dd, 7 = 10.8, 22.0 Hz), 4.20 (2H, dd, 7 = 1.2, 10.8 Hz), 7.06-7.11 (4H, m).

Example 40 5-Amino-2-methoxy-5- [2-(4-octylphenyl)ethyl] -2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinane

(40-l) 5-Benzyloxycarbonylamino-2-methoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2- dioxaphosphinane

To a solution of 2-benzyloxycarbonylamino-2-[2-(4-octylphenyl)ethyl]propane-l,3- diol (400 mg) in dichloromethane (9 ml) were added methyl tetraisopropylphosphorodiamidite (285 mg) and lH-tetrazole (190 mg) under ice-coohng. The mixture was stined at room temperature for 3 hours. 3-Chloroperoxybenzoic acid (609 mg) was added to the reaction solution under ice-cooling, and the resultant mixture was stined at room temperature for 30 minutes. A saturated sodium bicarbonate solution was added to the reaction solution, and the solution was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (30 g, hexane:ethyl acetate = 1:1) to give 367 mg of the title compound (mixture of isomers) as an oily substance. Further purification by CAPCELL PAK C18 (20 mm x 250 mm, 85% 0.05%TFA/Η O-CΗ₃CN) gave isomer 1 (124 mg) as a colorless oil and isomer 2 (218 mg) as a white solid, (isomer 1)

MS (ESI) m/z: 518 [M+Η]. 1H-NMR (CDCI₃) δ (ppm): 0.88 (3Η, t, 7 = 6.8 Hz), 1.26-1.30 (10H, m), 1.52-1.59 (2H, m), 2.10-2.14 (2H, m), 2.53-2.61 (4H, m), 3.83 (3H, d, 7 = 11.2 Hz), 4.23-4.29 (2H, m), 4.58-

4.65 (2H, m), 4.88 (IH, s), 5.09 (2H, s), 7.03 (2H, d, 7= 8.0 Hz), 7.08 (2H, d, 7= 8.0 Hz),

7.32-7.39 (5H, m).

(isomer 2)

MS (ESI) m/z: 518 [M+H].

1H-NMR (CDC1₃) δ (ppm) : 0.88 (3H, t, 7 = 6.8 Hz), 1.26-1.30 (10H, m), 1.51-1.59 (2H, m),

1.96-2.00 (2H, m), 2.50-2.57 (4H, m), 3.83 (2H, d, 7 = 11.2 Hz), 4.10 (2H, d, 7 = 10.4 Hz),

4.48 (2H, dd, 7 = 11.2, 22.8 Hz), 5.12 (2H, s), 5.30 (IH, s), 7.00 (2H, d, 7 = 8.0 Hz), 7.07

(2H, d, 7 = 8.0 Hz), 7.31-7.38 (5H, ).

(40-2) 5-Amino-2-methoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinane

A deprotection of the isomer 1 obtained in Example (40-1) was canied out in a similar manner to that described in Example (35-3) to give the title compound as a white amorphous.

MS (ESI) m/z: 384 [M+H].

1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, m), 1.27-1.30 (12H, m), 1.95-1.99 (2H, m), 2.55-2.58 (2H, m), 2.67-2.72 (2H, m), 3.85 (3H, d, 7 = 11.2 Hz), 3.98 (2H, dd, 7 = 7.2, 11.2 Hz), 4.16

(2H, dd, 7= 11.2, 17.2 Hz), 7.11 (4H, s).

Example 41 5-Amino-2-methoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinane

A deprotection of the isomer 2 obtained in Example (40-1) was canied out in a similar manner to that described in Example (35-3) to give the title compound as a white amorphous.

MS (ESI) m/z: 384 [M+H]. 1H-NMR (CDCI₃) δ (ppm): 0.88 (3H, t, 7 = 6.8 Hz), 1.26-1.29 (10H, m), 1.56-1.63 (4H, m), 2.54-2.58 (2H, ), 2.63-2.67 (2H, m), 3.83 (3H, d, 7= 11.2 Hz), 4.01 (2H, dd, 7 = 10.8, 22.0 Hz), 4.16 (2H, dd, 7 = 1.6, 10.8 Hz), 7.06 (2H, d, 7 = 8.0 Hz), 7.10 (2H, d, 7 = 8.0 Hz).

Example 42 5-Amino-2-phenoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinane

(42-1) 5-tert-Butyloxycarbonylamino-2-phenoxy-5-[2-(4-octylphenyl)-ethyl]-2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinane

Phenylphosphoryldichloride (0.163 ml) were added under ice-coohng to a solution of the product (408 mg) as obtained by the procedure in the above Example (2-1) and triethylamine (0.307 ml) in dichloromethane (10 ml). The mixture was stined at room temperature for 2.5 hours and heated under reflux for 2.5 hours. Then, brine was added to the reaction solution, and the solution was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The purification of the residue by sihca gel chromatography (25 g, hexane:ethyl acetate = 2:1) gave 363 mg of the isomers mixture of the titled compound as a colorless oily substance. This was further purified by HPLC to give isomer 1 (37 mg) as a white sohd and isomer 2 (45 mg) as a colorless oil. (isomer 1) ^XH-NMR (CDCI₃) δ (ppm) : 0.88 (3H, t, 7 = 6.8 Hz), 1.20-1.37 (10H, m), 1.43 (9H, s), 1.53- 1.63 (2H, m), 2.11-2.20 (2H, m), 2.50-2.63 (4H, m), 4.28 (2H, dd, 7 = 11.3, 14.5 Hz), 4.46 (IH, s), 4.78 (2H, d, 7 = 10.8 Hz), 7.05-7.10 (4H, m), 7.16-7.40 (5H, m). (isomer 2)

1H-NMR (CDC1₃) δ (ppm) : 0.88 (3H, t, 7= 6.8 Hz), 1.19-1.37 (10H, m), 1.49 (9H, s), 1.50- 1.63 (2H, m), 1.92-2.05 (2H, m), 2.45-2.59 (4H, m), 4.26 (2H, d, 7 = 10.2 Hz), 4.58 (2H, dd, 7 = 11.4, 23.4 Hz), 5.16 (IH, s), 6.95-7.10 (4H, m), 7.15-7.40 (5H, m).

(42-2) 5-Amino-2-phenoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan

Trifluoroacetic acid (0.6 ml) was added to a solution of isomer 1 (37 mg) as obtained by the procedure in the above Example (42-1) in dichloromethane (0.6 ml) under ice-coohng, and the mixture was stined at room temperature for 9 hours. Then, a saturated sodium bicarbonate solution was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled off under reduced pressure to give 30 mg of the titled compound as a white solid. MS (ESI) m/z: 446 [M+H]. 1H-NMR (CDCI₃) δ (ppm) : 0.88 (3H, t, 7 = 6.8 Hz), 1.20-1.39 (12H, m), 1.45-1.69 (2H, brs), 2.01-2.08 (2H, m), 2.54-2.59 (2H, m), 2.70-2.74 (2H, m), 4.10-4.27 (4H, m), 7.11 (4H, s), 7.16-7.39 (5H, m).

Example 43 5-Amino-2-phenoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l, 3 ,2-dioxaphosphinane

Isomer 2 (45 mg) as obtained by the procedure in the above Example (42-1) was subjected to deprotection in a similar manner to that described in Example (42-2) to give 43 mg of the titled compound as a pale yellow sohd. MS (ESI) m/z: 446 [M+H].

1H-NMR (CDC1₃) δ (ppm): 0.87 (3H, t, 7 = 6.8 Hz), 1.20-1.38 (12H, m), 1.50-1.70 (4H, m), 2.53-2.59 (2H, m), 2.64-2.70 (2H, m), 4.10 (2H, dd, 7= 11.1, 22.7 Hz), 4.61 (2H, dd, 7= 1.7 11.1 Hz), 7.06 (2H, d, 7= 8.2 Hz), 7.11 (2H, d, 7= 8.2 Hz), 7.16-7.39 (5H, m).

Example 44 5-Amino-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-[l,3,2]dioxaphosphinane-2-thiol

(44-1) Phosphoric acid {2-tert-butoxy-5-[2-(4-octylphenyl)ethyl]-2-thioxo-2λ⁵- [l,3,2]dioxaphosphinan-5-yl}carbamic acid tert-butyl ester

tert-Butyl tetraisopropylphosphorodiamidite (560 mg, 1.84 mmol) and lH-tetrazole

(258 mg, 3.69 mmol) were added in order under ice-cooling to a solution of [1,1- Bishydroxymethyl-3-(4-octylphenyl)propyl]carbamic acid tert-butyl ester (500 mg, 1.2 mmol) in dichloromethane (12 ml). The mixture was stined at room temperature for 3 hours. A solution of sulfur (236 mg, 1.4 mmol) in pyridine (10 mL) and carbon disulfide (2 mL) was added to the reaction mixture under ice-cooling, and the resultant mixture was stined at room temperature for an hour. After confirming the completion of reaction by TLC, a saturated sodium bicarbonate solution was added to the reaction solution, and the solution was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated. The purification of the residue by HPLC gave 404 mg (61%) of the titled compound.

1H-NMR (CDCI3) δ (ppm): 0.90 (3H, t, 7 = 7.2 Hz), 1.22-1.35 (10H, m), 1.50 (9H, s), 1.61

(9H, s), 1.95-2.00 (2H, m), 2.56 (2H, t, 7 = 8.4 Hz), 2.58 (2H, t, 7 = 8.0 Hz), 4.11 (2H, m),

4.12 (IH, d, 7 = 10.8 Hz), 4.13 (IH, d, 7 = 10.8 Hz), 5.20 (IH, s), 7.08 (2H, d, 7 = 8.0 Hz),

7.09 (2H, d, 7 = 8.0 Hz).

¹³C-NMR (CDCI3) δ (ppm): 14.05, 22.62, 28.34, 28.72, 29.22, 29.29, 29.44, 29.59, 29.63,

31.49, 31.85, 35.50, 53.13 (d, 7 = 5.4 Hz), 72.35 (d, 7 = 8.9 Hz), 85.12 (d, 7= 7.5 Hz),

128.10, 128.59, 138.02, 140.92, 154.70.

31 P-NMR (CDCI3, decoupled) δ (ppm): 50.996.

(44-2) 5-Amino-5- [2-(4-octylρhenyl)ethyl] -2-oxo-2λ⁵- [ 1 ,3 ,2] dioxaphosphinane-2-thiol

Trifluoroacetic acid (7.5 ml) was added to a solution of the product (404 mg) obtained in Example (44-1) in dichloromethane (7.5 ml) under ice-cooling. The mixture was stined at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The purification of the residue by HPLC gave 78.4 mg (27 %) of the titled compound as white crystals, m.p. 224-226 °C. MS (El) m/z: 386 [M+H].

1H-NMR (CDCI₃) δ (ppm): 0.89 (3H, t, 7 = 7.2 Hz), 1.22-1.35 (10H, ), 1.53-1.62 (2H, m), 1.84-1.89 (2H, m), 2.56 (2H, t, 7 = 7.6 Hz), 2.60-2.66 (2H, m), 4.00 (IH, d, 7 = 12.0 Hz), 4.05 (IH, d, 7 = 11.6 Hz), 4.46 (IH, d, 7 = 11.6 Hz), 4.47 (IH, d, 7 = 12.0 Hz), 7.11 (4H, brs). ³¹P-NMR (CDCI₃, decoupled) δ (ppm): 55.178.

Anal. Calcd. for C₁₉H₃₂NO₃PSJ/3HCl: C, 57.39; H, 8.20; N, 3.52. Found: C, 57.22; H,

8.06; N, 3.61. EXPERIMENTAL EXAMPLE 1 This example demonstrates the affinity of the compound of the invention for S1P„, S1P₂, S1P₃, S1P₄, and S1P₅ receptors. [³²P]S1P was synthesized enzymatically using [γ³²P] adenosine triphosphate (ATP) (Perkin Elmer), sphingosine (Sigma) and recombinant sphingosine kinase. CHO cells stably expressing S1P_, S1P₂, SIP3, S1P₄, or SIP5 receptors were washed twice with ice-cold binding buffer (20 mmol/1 Tris(hydroxymethyl)aminomethane-HCl, pH 7.5, 100 mmol/1 NaCl, 15 mmol/1 NaF, and 0.4% (w/v) fatty acid free bovine serum albumin), and incubated with cFTY720-P (OJ-10000 nmol/1) and the 50 nmol/1 [³²P]S1P in binding buffer. After incubation for 30 minutes at 4°C, the CHO cells were lysed with extraction buffer (0.1% SDS, 0.4% NaOH and 2% Na₂CO₃), and the amount of bound [³²P]S1P was determined by scintillation counting. Binding of [³²P]S1P was inhibited by cFTY720-P, which demonstrates that the compound of the invention binds SIP receptors on the order of nmol/1. EXPERIMENTAL EXAMPLE 2 This example demonstrates the effects of the compound of the invention on extracellular- signal related kinase (ERK) 1/2 activity in SIP receptor-transfected cells CHO cells stably expressing SlPi, SIP₂, S1P₃, S1P₄, or SIP5 were grown on culture plates in Ham's F12 medium (Sigma) containing 10% fetal bovine serum (FBS, Sigma) to about 70-80% confluency. Cells were serum-starved in Ham' s F12 medium containing 0J % (m/v) fatty-acid free bovine serum albumin (Sigma) for another 24 hours until used for the experiments. Serum-starved cells on 12-well plates were stimulated with SIP (Avanti) and cFTY720-P at 37°C. After incubation for 3 min, the cells were washed with ice cold phosphate buffered saline, pH 1.4, and were extracted with lysis buffer (50 mmol/1 Tris(hydroxymethyl)aminomethane-HCl, pH 7.5, 500 mmol 1 NaCl, 0.1% sodium dodecyl sulfate (SDS), 0.5% sodium deoxycholate, 1% Triton X-100, 10 mmol/1 MgCl₂, and protease inhibitors cocktail (Roche)). Cell lysates were solubihzed in SDS-polyacrylamide gel electrophoresis (PAGE) sample buffer. These samples were then analysed by Western blot using an anti-phosphorylated ERK antibody (Santa Cruz), and quantified by densitometry with the Chemi-Imager (Alpha innotech.). Figure 1 shows the effect of cFTY720-P (i.e., test compound) on ERKl/2 activity in SlPi-transfected CHO cells by Western blot analysis. SIP and cFTY720-P induced ERKl/2 activation in SlPi-transfectants. From these results, it is demonstrated that a compound of the invention, hke SIP, acts as a S1P„ agonist.

EXPERIMENTAL EXAMPLE 3 This example demonstrates the enhancing effect of the compound of the invention on CCL19, CCL21, CXCL12, or CXCL13-induced chemotaxis. RPMI 1640 (Sigma) supplemented with 10 mmol/14-(2-hydroxyethyl)piperazine-l -ethanesulfonic acid (HEPES), 100 U/ml penicillin, 60 μg/ml kanamycin sulfonate, 50 μmol/12-mercaptoethanol, and 0.5% fatty-acid free bovine serum albumin (Sigma) was used for the assay. cFTY720-P was diluted with 80% ethanol. Lymphocytes from mesenteric lymph nodes of B ALB/c mice (Japan Charles River) were prepared by mincing and passage through a cell strainer (100 μm, BD Biosciences). To examine the effect on chemotaxis, cell suspensions (5 x 10⁵cells/100 μl) were pretreated for 3 hours with cFTY720-P (0.3-300 nM) at 37°C in 5% CO₂. After incubation, cells were added to the Transwell culture inserts (6.5 mm diameter and 5.0 μm pore size, Corning Costar) in a final volume of 100 μl. Chemokines (CCL21, CCL19, CXCL12, and CXCL13) were purchased from Genzyme Techne. Each chemokine (300 ng/ml) was diluted with assay medium and added to 24-well tissue culture plates (Corning Costar) in a final volume of 600 μl. Following incubation for 90 min at 37°C in 5% CO2, the cells were stained with fluorescein isothiocyanate (FITC)-conjugated anti-mouse CD4 monoclonal antibody (mAb: L3T4) and CyChrome™-conjugated anti-mouse CD8a mAb (Ly-2), or FITC-conjugated anti-mouse CD3e mAb (145-2C11) and R-phycoerythrin-conjugated anti-mouse CD45R B220 mAb (RA3-6B2), and then analyzed with a FACScan (Becton Dickinson). Monoclonal antibodies used in these experiments were purchased from BD Biosciences. The number of cells in the starting population and the migrated population was calculated using Flow-Count Fluorospheres (Coulter), and the percent of migration was determined from these values. The effect of cFTY720-P on chemotaxis was calculated by the following formula:

% of migration = 100 x ( the cell number of each subset in lower chamber ) / (the cell number of each subset in input cells)

Table 1 shows the effect of cFTY720-P on CD3⁺ T cell migration for CCL21. cFTY720-P enhanced CCL21 -induced chemotaxis of CD3⁺ T cells in a dose dependent manner. Thus, the compound of the invention acts as a SIP agonist and enhances migration of lymphocytes in the presence of homing chemokines.

Table 1

Concentration of % of migration CFTY720-P (nM) (Mean±SEM) 0 34.9±4.8 0.3 36.3±0.8 3 41.0±4.7 30 42.1±2.8 300 45.3±1.5

EXPERIMENTAL EXAMPLE 4 This example demonstrates the effect of the compound of the invention on the number of lymphocytes, T cells, and B cells in peripheral blood in mice. cFTY720-P dissolved in 20% 2-hydroxypropyl-β-cyclodextrine (Nihon Shokuhin Kako Co., Ltd.) was orally, intraperitoneally, or intravenously administered to 8 -week old male BALB/c mice (Japan Charles River) at a dose of 0.01 to 10 mg/kg. At 24 hours after drug administration, approximately 0.3 ml of peripheral blood was collected from the posterior vena cava using a heparinized syringe. 0.1 ml of blood was hemolyzed and fixed by using TQ-prep (Coulter Corp.) and counted for lymphocytes, T cells, and B cells by using a flow cytometer (EPICS XL-MCL, Coulter Corp.). The number of lymphocytes were calculated using Flow-count Fluorospheres (Coulter) as the internal standard particle by lymphocytes gating method which employed forward and side scatters as the measures. T cells and B cells were counted by two-color flow cytometry after staining with FITC- conjugated anti-mouse CD3e monoclonal antibody (BD Biosciences) and PE-conjugated anti-mouse CD45R (B220) monoclonal antibody (BD Biosciences). Table 2 shows the effect of the compound of the invention on the number of lymphocytes in peripheral blood. The compound of the invention significantly decreased the number of lymphocytes in peripheral blood in mice in a dose dependent manner. Table 2

Concentration of Number of Lymphocytes, CFTY720-P Percent of Control (mg/kg, i.p.) (Mean±SEM, n = 3) 0 (control) 100 1 44.2±3.8 ** 3 22.9±7.2 ** 10 8.4±1.3 **

* : p<0.05, ** : p<0.01 vs vehicle-treated control group (Dunnett's method)

Table 3 shows the ED₅₀ value of the title compound of Examples (41), (42) and (44) on the decreasing effect of lymphocyte number. The title compound of Examples (41), (42) and (44) decreased the number of peripheral blood lymphocytes, at ED50 value of 4.03, 0.45 and 3.7 mg/kg, respectively.

Table 3 Decreasing effect of Example lymphocyte number,

41 4.03 42 0.45 44 3.7

EXPERIMENTAL EXAMPLE 5 This example demonstrates the inhibitory effect of the compound of the invention on host versus graft reaction in mice. cFTY720-P was diluted in 20% 2-hydroxypropyl-β-cyclodextrin (Nihon Shokuhin Kako Co., Ltd). Splenocytes from BALB/c mice (H-2^d, Japan Charles River) were prepared by mincing and passage through a stainless-steel gauze. The red blood cells were lysed with hypotonic lysis buffer. Host versus Graft Reaction (HvGR) was induced by immunization of BALB/c splenocytes (5 x 10⁶ cells/mice) into the left footpad of C57BL/6 mice (H-2 , Japan Charles River). cFTY720-P (1-10 mg kg) was orahy, intraperitoneally, or intravenously administered for 4 days after injection of BALB/c splenocytes. HvGR was determined by popliteal lymph node (PLN) gain assay based on the enlargement of left PLN versus right PLN on day 4. Table 4 shows the effect of the compound of the invention on HvGR (n=6).

Table 4

Concentration of Difference Between Left PLN CFTY720-P and Right PLN (mg) (mg/kg) (Mean±SEM) vehicle 2.5±0.3 1 1.3±0.3* 3 1.0±0.2** 10 0.9±0.3** : p<0.05, ** : p<0.01 vs vehicle-treated control group (Dunnett's method) Intravenous administration of the compound of the invention at 1 to 10 mg/kg significantly inhibited HvGR in a dose dependent manner. EXPERIMENTAL EXAMPLE 6 This example demonstrates a procedure for evaluating the inhibitory effect of the compound of the invention on host versus graft reaction in rats. A spleen is removed from a male WKAH rat (RTl^k) at 4 to 5 weeks of age and used to obtain a single cell suspension of spleen cells using RPMI1640 medium (containing kanamycin sulfate at 60 μg/ml penicillin G potassium at 100 units/ml, N-2- hydroxyethylpiperazine-N'-2-ethanesulfate at 10 mmol/1, 0.1% sodium bicarbonate, and L- glutamine at 2 mmol/1). After hemolysis treatment, the cells are washed three times with RPMI1640 medium and are adjusted at 5 x 10⁷ cells/ml with physiological saline for immunization. By immunization of 100 μl of the spleen cell suspension into the right hind footpad of male LEW rats (RT1¹) at 4-5 weeks of age, HvGR is induced. On day 4 after immunization of the allogeneic cells, both of the right and left popliteal lymph nodes are removed, and the weight of the nodes is measured. The difference between the right pophteal lymph node weight and the left popliteal lymph node weight is used as an indicator of HvGR. Additionally, on day 4 after immunization of the allogeneic cells, blood is obtained from the tail vein of the rats, and the number of peripheral white blood cells is measured using an automatic hemocytometer for animals (MEK-5158, Nihon Kouden Co., Ltd.). cFTY720-P is orally, intraperitoneally, or intravenously administered daily for 4 days after the immunization of the allogeneic cells to evaluate the inhibitory effect of the compound of the invention on host versus graft reaction.

EXPERIMENTAL EXAMPLE 7 This example demonstrates the prolonging effect of the compound of the invention on graft survival of allogeneic cardiac graft in rats. The hearts from male WKAH rats (RTl^k) at 10 to 14 weeks of age were heterotopically transplanted in subcutaneous locations at cervixes of male ACI/N rats (RTl^avl) at 10 to 14 weeks of age using vascular anastomosis. The transplanted hearts were judged to be rejected in the case of the cessation of heart beat, and survival time was calculated. cFTY720-P was orally, intraperitoneally, or intravenously administered repeatedly for 14 days from the day of transplantation. cFTY720-P significantly prolonged the graft survival of WKAH heart transplanted to ACI/N rats in a dose dependent manner. FORMULATION EXAMPLES cFTY720-P, the compound of the invention utilized in these formulation examples (and recited in the various formulation recitations below), may exist in the form of the 1/4 hydrate described herein.

(1) Tablets A tablet containing the compound of the invention and having the following formulation was produced:

CFTY720-P 1 mg Lactose 90 mg

Crystalhne cellulose 25 mg

Magnesium stearate 4 mg

(2) Soft capsules (per capsule) To produce the soft capsule, polyethylene glycol-300 and polysorbate 80 were added to the compound of the invention, and the mixture was packed in a soft capsule. The following formulation is exemplary:

CFTY720-P 30 mg Polyethylene glycol-300 300 mg Polysorbate 80 20 mg

(3) Injections (per 10 ml in an ampoule) Ethanol and polyethylene glycol-300 were added to the compound of the invention, and injectable distiUed water was added to reach the total volume. An injection containing 30 mg of the compound of the invention in an ampoule (10 ml) of the following formulation was thus obtained:

CFTY720-P 0.3 % Polyethylene glycol-300 20 %

Ethanol 60 %

Injectable distiUed water amount to make the total 10 ml

(4) 5% Ointment (a) cFTY720-P (1 g) was dissolved in 19 g of hydrophihc petrolatum under heating at 60°C, and the mixture was cooled with stining to prepare an ointment containing 5% of the compound of the invention, with the foUowing formulation:

CFTY720-P 1 g Hydrophihc petrolatum 19 g

(5) 5% Ointment (b) cFTY720-P (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 invention, with the following formulation:

Plastibase 19 g

(6) Suppository Witepsol H15 (72.47 g) was melted at 40°C, and cFTY720-P (30 mg) was added. The mixture was stined to disperse the compound. The homogeneous mixture was fiUed in a container at a weight of 725 mg to prepare a suppository containing 0.3 mg of the compound of the invention in 725 mg of the suppository, having the following formulation:

CFTY720-P 30 mg

Witepsol HI 5 72.47 g

(7) Eye drop 0.2 g of polyvinyl alcohol was added to 70 ml of sterile purified water, and the mixture was dissolved by heating at 70°C with stining. 0.1 g of polyoxyethylene hydrogenated castor oil 60 was dispersed homogeneously in the solution, and the mixture was cooled to room temperature. 0.2 g of cFTY720-P, 0.5 g of disodium hydrogen phosphate, 0.1 g of sodium dihydrogen phosphate, 0.8 g of sodium chloride, and 0.007 g of benzethonium chloride were dissolved in the solution. Sterile purified water was added to the solution to make the total volume 100 ml, having the following formulation:

CFTY720-P 0.2 g

Polyvinyl alcohol 0.2 g Polyoxyethylene hydrogenated castor oil 60 0.1 g

Disodium hydrogen phosphate 0.5 g

Sodium dihydrogen phosphate 0.1 g

Sodium chloride 0.8 g

Benzethonium chloride 0.007 g Sterile purified water amount to make the total 100 ml

(8) Nasal drop 0.4 g of cFTY720-P, 0.2 g of sodium citrate, 0.1 g of polysorbate 80, 2.6 g of glycerin, and 0.007 g of benzethonium chloride were dissolved in 70 ml of sterile purified water. Sterile purified water was added to the solution to make the total volume 100 ml, with the following formulation:

CFTY720-P 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 100 ml

(9) 2% Lotion 1 ml of isopropyl myristate and 4 ml of ethanol were added to 100 mg cFTY720- P to dissolve the compound at room temperature to prepare a lotion containing 2% of the compound of the invention, having the following formulation:

CFTY720-P lOO mg

Isopropyl myristate 1 ml

Ethanol 4 ml AU references, including pubhcations, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especiaUy in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not hmited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of refening individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individuaUy recited herein. AU methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and aU examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better iUuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non- claimed element as essential to the practice of the invention. Prefened embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those prefened embodiments may become apparent to those of ordinary skiU in the art upon reading the foregoing description. The inventors expect skiUed artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specificaUy described herein. Accordingly, this invention includes aU modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in aU possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. This apphcation is based on and claims the benefit of U. S . Provisional Patent

Application No. 60/494,543 filed on August 12, 2003, and the contents of which are hereby incorporated by reference.

Claims

1. A phosphinane compound of the formula:

n is an integer of 1 to 20; R is a thiol group or -OR₃, wherein R₃ is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may be substituted by one to three halogen atoms or an aryl group, or an aryl group which may be substituted by one to three halogen atoms or an aryl group; R_ and R₂ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may be substituted by one to three halogen atoms or an acyl group having 1 to 20 carbon atoms; and X is an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms or an arylene group and each may be substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, an acyl group having 1 to 20 carbon atoms, an alkyl group having 1 to 20 carbon atoms substituted by an aryl group, an alkyl group having 1 to 20 carbon atoms substituted by halogen-substituted aryl group, an alkyl group having 1 to 20 carbon atoms substituted by d-20 alkoxy -substituted aryl group, an alkyl group having 1 to 20 carbon atoms substituted by d-20 alkyl -substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by an aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by halogen-substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by d-20 alkoxy -substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by d-₂₀ alkyl -substituted aryl group, an acyl group having 1 to 20 carbon atoms substituted by an aryl group, an acyl group having 1 to 20 carbon atoms substituted by halogen-substituted aryl group, an acyl group having 1 to 20 carbon atoms substituted by d-₂₀ alkoxy -substituted aryl group and an acyl group having 1 to 20 carbon atoms substituted by d-₂₀ alkyl -substituted aryl group; or a pharmaceuticaUy acceptable salt thereof, or a pharmaceuticaUy acceptable solvate thereof.

2. A compound according to claim 1, wherein n is an integer of 1 to 8.

3. A compound according to claim 1 or 2, wherein R₃ is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may be substituted by an aryl group or an aryl group.

4. A compound according to claim 1 or 2, wherein R₃ is a hydrogen atom , alkyl group having 1 to 12 carbon atoms which may be substituted by an aryl group or a phenyl group.

5. A compound according to claims 1 to 4, wherein Ri and R₂ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may be substituted by one to three halogen atoms or an acyl group having 1 to 20 carbon atoms.

6. A compound according to claims 1 to 4, wherein Ri and R₂ are a hydrogen atom

7. A compound according to claims 1 to 6, wherein X is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms or an arylene group and each may be substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, an acyl group having 1 to 20 carbon atoms, an alkyl group having 1 to 20 carbon atoms substituted by an aryl group, an alkyl group having 1 to 20 carbon atoms substituted by halogen-substituted aryl group, an alkyl group having 1 to 20 carbon atoms substituted by d-20 alkoxy -substituted aryl group, an alkyl group having 1 to 20 carbon atoms substituted by d-₂o alkyl -substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by an aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by halogen- substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by d-20 alkoxy -substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by d-20 alkyl -substituted aryl group, an acyl group having 1 to 20 carbon atoms substituted by an aryl group, an acyl group having 1 to 20 carbon atoms substituted by halogen- substituted aryl group, an acyl group having 1 to 20 carbon atoms substituted by d-20 alkoxy -substituted aryl group and an acyl group having 1 to 20 carbon atoms substituted by d-₂₀ alkyl -substituted aryl group.

8. A compound according to claims 1 to 6, wherein X is an alkyl group having 1 to 12 carbon atom, an alkoky group having 1 to 12 carbon atoms or an arylene group and the arylene group which may be substituted by 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, an acyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms substituted by an aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by halogen-substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by d-₂₀ alkoxy -substituted aryl group, an alkoxy group having 1 to 20 carbon atoms substituted by C₁-₂₀ alkyl -substituted aryl group, an acyl group having 1 to 20 carbon atoms substituted by an aryl group.

9. 5-Amino-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol or a pharmaceutically acceptable salt thereof or a pharmaceuticaUy acceptable solvate thereof.

10. 5-Amino-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol or a solvate thereof.

11. 5-Amino-5-[2-(4-octylphenyl)-ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol l/4 hydrate.

12. A compound selected from the group consisting of:

(1). 5-amino-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(2). 5-Amino-5-[2-(4-dodecylphenyl)ethyl]-2-oxo-2λ^s-l,3,2-dioxaphosphinan-2-ol,

(3). 5-Amino-5-(2-(4-undecyloxyphenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(4). 5-Amino-5-(2-(4-(6-phenylhexyloxy)phenyl)ethyl)-2-oxo-2λ⁵-l,3,2- dioxaphosphinan-2-ol,

(5). 5-Amino-5-[2-(2-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(6) . 5-Amino-5- [4-(4-butylphenyl)butyl] -2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinan-2-ol,

(7). 5-Amino-5-(2-(4-octanoylphenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(8). 5-Amino-5-[2-(4-nonyloxyphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(9). 5-Amino-2-oxo-5-[3-(4-undecylphenyl)propyl]-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(10). 5-Amino-5-[4-(4-octylphenyl)butyl]-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol,

(11). 5-Amino-5-[3-(4-hexyloxyphenyl)propyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(12). 5-Amino-5-[4-(4-heptyloxyphenyl)butyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(13). 5-Amino-5-(2-(4-(5-phenylpentanoyl)phenyl)ethyl)-2-oxo-2λ⁵-l,3,2- dioxaphosphinan-2-ol,

(14). 5-Amino-5-[3-(4-heptyloxyphenyl)propyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(15). 5-Amino-5-[3-(4-octyloxyphenyl)propyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(16). 5-Amino-2-oxo-5-[3-(3-undecyloxyphenyl)propyl]- 2λ⁵-l,3,2-dioxaphosphinan-2- ol,

(17). 5-Amino-2-oxo-5-(2-[4-(3-phenylρropoxy)ρhenyl]ethyl)-2λ⁵-l,3,2- dioxaphosphinan-2-ol,

( 18) . 5-Amino-2-oxo-5- { 2-[4-(3 -/?-tolylpropoxy)phenyl] ethyl } -2λ⁵- 1 ,3 ,2- dioxaphosphinan-2-ol,

(19). 5-Amino-5-(2- { 4-[4-(4-bromophenyl)butoxy] phenyl} ethyl)-2-oxo-2λ⁵- 1 ,3 ,2- dioxaphosphinan-2-ol,

(20). 5-Amino-5-(2- { 4-[4-(4-methoxyphenyl)butoxy]phenyl} ethyl)-2-oxo-2λ⁵- 1 ,3 ,2- dioxa-phosphinan-2-ol,

(21). 5-Amino-5-(8-benzyloxyoctyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(22). 5-Amino-5-[8-(4-methoxyphenyl)octyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(23). 5-Amino-5-octadecyl-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol,

(24). 5-Amino-5-(6-octyloxyhexyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(25). 5-Amino-5-(2-(4-(4-hexylphenyl)phenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-

2-ol,

(26). 5-Amino-5-[4-(4-chlorophenyl)butyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(27). 5-Amino-5-[2-(4-heptyloxyphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(28) 5-Amino-5-(8-hexyloxyoctyl)-2-oxo-2λ^s-l,3,2-dioxaphosphinan-2-ol,

(29). 5-Amino-2-oxo-5-{2-[4-(7-ρhenylheptanoyl)phenyl]ethyl}-2λ⁵-l,3,2-dioxa- phosphinan-2-ol,

(30). 5-Amino-5-tetradecyl-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol,

(31). 5-Ammo-2-oxo-5-[2-(4-pentyloxyphenyl)ethyl]-2λ⁵-l ,3,2-dioxaphosphinan-2-ol,

(32). 5-Amino-5-[2-(4-hexyloxyphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(33). 5-Amino-5-(4-nonylphenyl)methyl-2-oxo-2λ⁵-l,3,2-dioxa-phosphinan-2-ol,

(34). 5-Amino-5-(3-{2-chloro-4-[3-(3,5-dichlorobenzyloxy)phenoxy]-phenyl}propyl)-

2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(35). 5-Amino-2-ethoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxa-phosphinane,

(36). 5-Amino-2-ethoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l, 3 ,2-dioxaphosphinane,

(37). 5-Amino-5-[2-(4-octylphenyl)ethyl]-2-oxo-2-phenylethyloxy-2λ⁵-l,3,2- dioxaphosphinane,

(38) . 5-Amino-5-[2-(4-octylphenyl)ethyl] -2-oxo-2-phenylethyloxy-2λ⁵- 1,3,2- dioxaphosphiriane,

(39). 5-Amino-2-tert-butyloxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2- dioxaphosphinane,

(40). 5-Amino-2-methoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2- dioxaphosphinane,

(41).5-Amino-2-methoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinane,

(42).5-Amino-2-phenoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ^s-l,3,2-dioxaphosphinane, (43) .5-Amino-2-phenoxy-5- [2-(4-octylphenyl)ethyl] -2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinane and

(44). 5-Amino-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-[l,3,2]dioxaphosρhinane-2-thiol or a pharmaceutically acceptable salt thereof or a pharmaceuticaUy acceptable solvate thereof.

13. A compound selected from the group consisting of:

( 1 ) . 5-amino-5 -[2-(4-octylphenyl)ethyl] -2-oxo-2λ⁵- 1 ,3 ,2-dioxa-phosphinan-2-ol,

(2). 5-Amino-5-[2-(4-dodecylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(3) . 5-Amino-5-(2-(4-undecyloxyphenyl)ethyl)-2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinan-2-ol,

(6). 5-Amino-5-[4-(4-butylphenyl)butyl]-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol,

(7). 5-Amino-5-(2-(4-octanoylphenyl)ethyl)-2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinan-2-ol,

(8) . 5-Amino-5 - [2-(4-nonyloxyphenyl)ethyl] -2-oxo-2λ⁵-.l ,3 ,2-dioxaphosphinan-2-ol,

(10). 5-Amino-5-[4-(4-octylphenyl)butyl] -2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinan-2-ol,

(12). 5-Amino-5 -[4-(4-heptyloxyphenyl)butyl] -2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinan-2-ol,

(17). 5-Amino-2-oxo-5-(2-[4-(3-phenylpropoxy)ρhenyl]ethyl)-2λ⁵-l,3,2- dioxaphosphinan-2-ol,

(18). 5-Amino-2-oxo-5-{2-[4-(3- ?-tolylproρoxy)ρhenyl]ethyl}-2λ⁵-l ,3,2- dioxaphosphinan-2-ol,

(19). 5- Amino-5-(2- { 4-[4-(4-bromophenyl)butoxy] phenyl } ethyl)-2-oxo-2λ⁵- 1 ,3 ,2- dioxaphosphinan-2-ol,

(20) . 5- Amino-5-(2- { 4-[4-(4-methoxyphenyl)butoxy] phenyl } ethyl)-2-oxo-2λ⁵- 1 ,3 ,2- dioxa-phosphinan-2-ol, (24). 5-Amino-5-(6-octyloxyhexyl)-2-oxo-2λ⁵-l,3,2-dioxaphosphinan-2-ol, (25). 5-Amino-5-(2-(4-(4-hexylphenyl)phenyl)ethyl)-2-oxo-2λ⁵-l,3,2-dioxaphosρhinan- 2-ol,

(27) . 5- Amino-5 -[2-(4-heptyloxyphenyl)ethyl] -2-oxo-2λ⁵- 1 ,3 ,2-dioxaphosphinan-2-ol, (29) . 5-Amino-2-oxo-5 - { 2-[4-(7-phenylheptanoyl)phenyl] ethyl} -2λ⁵- 1 ,3 ,2- dioxaphosphinan-2-ol,

(30). 5-Amino-5-tetradecyl-2-oxo-2λ⁵-l ,3,2-dioxaphosphinan-2-ol, (40). 5-Amino-2-methoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2- dioxaphosphinane,

(41). 5-Amino-2-methoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2- dioxaphosphinane,

(42) . 5-Amino-2-phenoxy-5- [2-(4-octylρhenyl)ethyl] -2-oxo-2λ⁵- 1 ,3 ,2- dioxaphosphinane, and

(43). 5-Amino-2-ρhenoxy-5-[2-(4-octylphenyl)ethyl]-2-oxo-2λ⁵-l,3,2- dioxaphosphinane or a pharmaceuticaUy acceptable salt thereof or a pharmaceutically acceptable solvate thereof.

14. A pharmaceutical composition comprising (a) the compound of claims 1 to 12 and (b) a pharmaceuticaUy acceptable diluent or canier therefor.

15. A method for preventing or treating disorders or diseases mediated by T lymphocytes, in a subject in need of such treatment, which method comprises administering to the subject an effective amount of the compound of claims 1 to 12.

16. A method for preventing or treatment disorders or diseases mediated by T lymphocytes, in a subject in need of such treatment, which method comprises administering to the subject an effective amount of the compound of the formula:

n is an integer of 1 to 20; R is a thiol group or -OR3, wherein R3 is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may be substituted by one to three halogen atoms or an aryl group, or an aryl group which may be substituted by one to three halogen atoms or an aryl group; Ri and R₂ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may be substituted by one to three halogen atoms or an acyl group having 1 to 20 carbon atoms; and X is an appropriate substituent which is disclosed by WO 94/08943, WO 96/06068, WO 98/45249, WO 02/076995, WO 03/099192, WO 03/059880, WO 02/06268, Japanese Patent Application Publication No. 2002/0316985, WO 03/061567, WO 03/062248, WO 03/062252, WO 03/073986 and WO 03/074008, Japanese Patent Application Pubhcation Nos. 2002/53575, 2003/267936, 2003/267950 and 2003/267974, WO03/029205, WO02/18395, WO03/105771, WO04/024673 and WO04/026817.