TW200402299A - Drugs improved in tissue selectivity - Google Patents

Abstract

Drugs containing, as the active ingredient, compounds represented by the general formula (III) or salts thereof, or hydrates or solvates of both are described for improved tissue selectivity following undergoing metabolism: (III) wherein Q is a parent core having a medical effect; X is a substituent effective in enhancing the targeting effect of a drug; and R2 and R3 are each independently an ethyl substituted with one or more halogen atoms.

Description

200402299 (1) 发明. Description of the invention [The technical field to which the invention belongs] The combination of rounds, but the influence can be exemplified only by. Caused by a virus. 2-Phosphine Enhancement No. is from 8 3 9-.V. 37, and the present invention relates to a medicine for improving the aggregation or avoidance of the identification tissue. [Prior art] In the past, for the identification of cancer, viruses, etc., although drugs have been developed for the purpose of blocking nucleic acids, or blocking and activating various enzymes, these drugs are generally too potent, and they have an increase in normal cell lines.値 Obstacles and other issues. As a specific example of an infectious hepatitis virus, such as the hepatitis virus, which is considered to be a medically important problem, there are few effective drugs for treatment at present. As an effective drug, interferon or lamivudine is produced, but 10 to 30% of patients who have been treated with interferon are effective. Lamivudine has the problem of showing resistance to the drug when taken. This is also discussed today. A phosphonate nucleotide compound 9-(fluorenylmethoxy) b, which is an antiviral agent, has been reported as an antiviral agent for the purpose of treating such diseases, and has anti-activity and does not increase the activity of normal cell lines. Adenovir dipivoxi (PMEA), which is orally absorbable after prodrug conversion of adenosine (PMEA) (EP Publication No. 205 826 (Patent Document 1)). After being absorbed, this compound will quickly form a precursor (KC Cundy et. Al., Pharm. Res., 11, 843 (1 994) (Non-Patent Document 1)), so the membrane permeability is relatively low (F Srinvas et. al.? Antimicrob. Agents Chemother "2247_225 0 (1 993) (Non-Patent Document 2)), the reduction of the rate of confirmation of the effective components in the cells to identify the liver fineness of the tissue (2) (2) 200402299. However, Specific ester derivatives of phosphonate nucleotides that are known to have antiviral activity and are excellent in oral absorption and safety (Japanese Patent Application Laid-Open No. 9-255695 (Patent Document 2) and WO01 / 64693 (Patents Document 3)), these publications do not describe the improvement of the tissue aggregation of the drug. [Patent Document 1] EP Publication No. 205 826 [Patent Document 2] JP 9-25 5 695 [Patent Document 3] ] WO 01/64693 [Non-patent document 1] KC Cundy et. Al., Pharm. Res., 11, 83 9-843 (1 994) [Non-patent document 2] RV Srinivas et. Al., Antimicrob. Agents Chemother "37, 2247-2250 (1 993) [Summary of the Invention] The object of the present invention is to provide Agents for improving the organization of a gathering place, or show agents to avoid the kidney. The present inventor intends to solve the above-mentioned problems and conducts a detailed investigation and review, and finds that a specific compound exhibits a high degree of identification of organs, and at the same time shows that he avoids identifying organs, thereby completing the present invention. That is, the gist of the present invention is as follows. (1) An antiviral agent characterized by the following formula (1) (3) 200402299

ί / H (where R1 represents a hydrogen atom, an alkoxy group of Cl to C6, an alkoxy group of C1 to C4 which may be substituted by one or more halogen atoms, a halogen atom, an amine group, a nitro group, or a hydroxyl group; R2 And R3 each independently represent an ethyl group substituted by one or more halogen atoms; R4 represents a hydrogen atom, an alkyl group of C1 to C4, a hydroxyalkyl group of C1 to C4, or C1 to C4 substituted by one or more halogen atoms Alkyl group; M represents CH or nitrogen atom) The phosphonate nucleotide compound or its salt, or these hydrates or solvents as active ingredients, the metabolites are compared in the plasma, and more in the liver High aggregators. (2) In the formula (I), R1 represents a hydrogen atom, a C1 to C6 alkoxy group, or a compound of a hydroxyl group as an active ingredient. (3) As in the aforementioned formula (I), Ri represents a hydrogen atom, and C1 to C4 are alkoxy groups or hydroxyl groups; R2 and R3 represent 2,2,2-trifluoroethyl groups; R4 represents a hydrogen atom or a methyl compound As an active ingredient. (4) The aforementioned antiviral agent is selected from the following compounds: -7- (4) (4) 200402299 2-amino-6-phenylthio-9- [2- (phosphonocarboxymethoxy) ethyl ] Purine bis (2,2,2 · trifluoroethyl) ester; 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl ] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl ] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (2-methoxyphenylthio) -9- [2 · (phosphonocarboxymethoxy) ethyl ] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-ethoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl ] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6-phenylthio-9- [2- (phosphonocarboxymethoxy) propyl] purine bis (2,2 , 2-trifluoroethyl) ester; 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) propyl] purinebis (2,2 2,2-trifluoroethyl) ester; 2-amino-6- (4-butoxyphenylsulfide) -9- [2- (subscale residue methoxy) ethyl] purine bis (2, 2,2-trifluoroethyl) Esters; 2-amino-6- (4-propoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] hehabis (2,2,2-diethyl) ) Vinegar; 2-amino-6- (4-isopropoxyphenylsulfur) -9- [2- (phenylenemethoxy) ethyl] purinebis (2,2,2-trifluoro Ethyl) esters; 2-Amino-6- (4-isobutoxyphenylthio) -9- [2- (Residenemethoxy) ethyl] purinebis (2,2,2- Trifluoroethyl) ester; 2-amino-6 · (4-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2,2 · trifluoro Ethyl) esters; -8- (5) (5) 200402299 2-amino-6- (3-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis ( 2,2,2-trifluoroethyl) ester; 2-amino-6- (2-mercaptophenylsulfanyl) -9- [2- (phenylidenemethoxy) ethyl] purinebis ( 2,2,2 · trifluoroethyl) ester; 2-amino · 6 · (4-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) propyl] purinebis (2, 2,2-trifluoroethyl) ester; 2-amino-6- (3-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) propyl] purinebis (2,2, 2-trifluoroethyl) ester; and 2-amine -6- (2-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) propyl] purine bis (2,2,2-trifluoroethyl) esters are effective as a group of compounds Ingredients. (5) As in the aforementioned formula (I), R1 represents a hydrogen atom, an alkoxy group or a hydroxyl group of C1 to C4; R2 and R3 represent a 2,2,2-trifluoroethyl group; and R4 represents a hydrogen atom compound as an effective cost By. (6) The aforementioned antiviral agent is a compound selected from the group consisting of 2-amino-6-phenylthio-9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2,2- Trifluoroethyl) ester; 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2,2- Trifluoroethyl) ester; 2-amino-6- (3-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2,2- Trifluoroethyl) ester; 2-amino-6- (2-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] urethane bis (2,2, 2 -diacetic acid) vinegar; 2 · amino-6- (4 · ethoxyphenylsulfur) -9- [2- (isophosphine-9-(6) (6) 200402299 oxygen ) Ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-butoxyphenylthio) -9- [2- (phosphonocarboxymethoxy ) Ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-propoxyphenylthio) -9- [2- (phosphonocarboxymethoxy ) Ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-isopropoxybenzylsulfanyl) -9- [2- (ortho-octylmethoxy) Yl) ethyl] purine bis ( 2,2,2-trifluoroethyl) ester; 2-amino-6- (4-isobutylene basic sulfur) -9- [2- (o-octenylmethoxy) ethyl] purinebis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] hehabis ( 2,2,2-difluoro (ethyl) vinegar; 2-amino-6- (3-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2 , 2,2-trifluoroethyl) ester; and 2-amino-6- (2-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2 (2-trifluoroethyl) esters as a group of compounds as an active ingredient. (7) The aforementioned antiviral agent is selected from the following compounds: 2-amino-6-phenylthio-9- [2- ( Phenylene methoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-methoxyphenylthio) -9- [2- (Phenylene methoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-methoxyphenylthio) -9- [2_ (Residyl methoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (2-methoxyphenylsulfur) -9- [ 2- (phosphonocarboxymethyl-10-200402299 σ) oxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; and 2-amino-6- (4-hydroxyphenylsulfide ) -9- [2- (phosphonocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) group of compounds as an active ingredient. (8) The aforementioned antiviral agent is 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2, 2-trifluoroethyl) ester as an active ingredient. (9) The aforementioned antiviral agent, wherein 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purine (2,2, 2-trifluoroethyl) ester, or 2-amino-6- (4-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purine (2,2,2- Trifluoroethyl) ester as an active ingredient. (10) an antiviral agent, which is administered into a living body by the following formula (II)

Or these hydrates are metabolized by a compound represented by -11 ^ (8) (8) 200402299 or a solvent. The compound is compared in plasma and shows higher aggregation in the liver. (11) In the aforementioned formula (Π), R1 represents a metabolizer of a compound of a hydroxyl group or an alkoxy group of C1 to C4. (12) In the aforementioned formula (II), R1 represents a hydroxyl group or an alkoxy group of C1 to C4; R2 represents a metabolizer of a compound of an ethyl group substituted with one or more halogen atoms. (13) In the aforementioned formula (II), R1 represents a hydroxyl group or an alkoxy group of C1 to C4; R2 represents a 2,2,2-trifluoroethyl group; and R4 represents a metabolizer of a hydrogen atom or a methyl compound. (1 4) The aforementioned antiviral agent is selected from the following compounds: 2-amino-6- (4-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purine ( 2,2,2-trifluoroethyl) ester; 2-amino-6- (3-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purine (2,2 , 2-trifluoroethyl) ester; 2-amino-6- (2-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] 2,2-diethyl ethyl) vinegar; 2-amino-6- (4-hydroxyphenylthio) -9- [2 · (phosphoruscarboxymethoxy) propyl] purine (2,2,2 · Trifluoroethyl) ester; 2-amino · 6- (3-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) propyl] purine (2,2,2-trifluoroethyl Esters; 2-amino-6- (2-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) propyl] purine (2,2,2-trifluoroethyl) ester ; 2-Amino-6- (4-methoxyphenylthio) -9- [2- (Avicenylmethyl-12-200402299 0) oxy) ethyl] purine (2,2,2 · Trifluoroethyl) ester; 2-amino-6- (3-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purine (2,2,2-tri Fluoroethyl) ester; 2-amino-6- (2-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purine (2,2J-trifluoroethyl ) Ester; 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethyl) propyl] purine (2,2,2-trifluoroethyl) Esters; 2-amino-6- (3-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) propyl] purine (2,2,2-trifluoroethyl) ester ; And compounds formed by 2-amino-6- (2-methoxyphenylthio) -9- [2- (phosphonocarboxypropyl] purine (2,2,2-trifluoroethyl) esters (15) The antiviral agent is 2-amino-6- (4-methoxyphenylthio) -9 r ^ [2, (phosphonocarboxymethoxy) ethyl] purine (2 , 2,2-TriM ^ > Vinegar metabolizer. (16) The aforementioned antiviral agent is 2-amino-6- (4-hydroxyphenylthio) r_L2, (phosphonocarboxymethoxy) Ethyl] purine (2,2,2-trifluoroethyl _) jealous place @_ metabolizer. Base sulfur) (2, 2 above) The aforementioned antiviral agent is administered 2-amino-6- (4-methyl 9- [2- (phosphonocarboxymethoxy) ethyl] purine ditrifluoroethyl) ester. 18) Agents virus is hepatitis B virus. 19) ~ medicines, which are characterized by the following formula (III) -13- (10) (10) 200 402 299 II 2 X-Q-P-〇Rz (111) OR3 (wherein Q represents a drug The core 'x represents a substituent which can effectively improve the recognition effect of the drug, and R2 and R3 represent the same meaning as above) If the compound represented by the salt, or these hydrates or solvents, is metabolized, it can be Compounds that enhance tissue selectivity as effective ingredients. (20) In the foregoing formula (III), the pharmacological effects of the mother nucleus with pharmacological effects are anti-cancer effect, anti-leukemia effect, metabolic abnormality improvement effect, anti-inflammatory effect, anti-viral effect, anti-cancer cell metastasis effect, and immunosuppression The effect or antigenic insect effect 'is effective in identifying the substituents of the musical object recognition effect as being selected from the group consisting of cancer cells, liver®, kidney M, spleen, pancreas, lymphatic vessels, polyphagocytes, lungs, and vascular inflammation sites Or the identification of the central nervous system, and the purpose of avoiding the liver. (21) In formula (III), the pharmacological effect of a mother nucleus having a pharmacological effect is an anticancer effect or an antiviral effect. (22) In the aforementioned formula (III), X represents a substituent which can increase the fat solubility of the compound and effectively improve the recognition effect on cancer cells and liver. (23) In the aforementioned formula (III), Q represents an inositol analog, nucleotide -14- (11) 200402299 analog, sugar analog, lipid, steroid, peptide, or formula (IV)

CH2CHOCH2— R4 (wherein R4 and M represent the same meanings as above), or in formula (III) of the 19th scope of the patent application, QP20 (〇-) 2 is a bisphosphonate analog Presenter. (24) In the formula (III), X represents morpholine, choline phospholipid, alkyl group, amine group, carboxyl group, peptide, mannose, or the following formula (V)

(Wherein R1 has the same meaning as above). (25) In the foregoing formula (III), XQ represents a Fludarabine residue, a pencyclobil residue, or a Ribavirin residue; for example, in formula (III) of the 19th scope of the patent application, XQP 20-15 (12) 200402299 (0 -) 2 represents a cidofovir residue or an adefovir residue; or as formula (III) in item 19 of the patent application scope is glucose-6-phosphonate; selected from hydroxyethylene diphosphate, Ibandronic acid, Zoledronic Acid, Alendronate and Clodronate Tetra (2,2,2-trifluoroethyl) bisphosphonate; and selected from the following formula (I)

M- / V R1 (wherein R1, R2, R3, R4, and M represent the same as described above) or a phosphonate nucleotide compound or a salt thereof, or these hydrates or solvents. (26) In the formula (I), R2 and R3 represent a 2,2,2-trihaloethyl group, R4 represents a hydrogen atom, R1 represents a hydrogen atom, an alkoxy group of C1 to C4, or a hydroxyl group, and M indicates CH or nitrogen atom. (27) The compound represented by the formula (I) is a compound selected from the group consisting of 2-amino-6-phenylthio-9- [2- (phosphonocarboxymethoxy) ethyl] purine bis (2 , 2,2-trifluoroethyl) ester; -16- (13) (13) 200402299 2 -amino-6- (4-methoxyphenylthio) -9_ [2_ (phosphonocarboxymethoxy ) Ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-methoxyphenylthio) _9- [2- (phosphonocarboxymethoxy) Ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (2-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl Group] purine bis (2,2,2-trifluoroethyl) ester; and 2-amino-6- (4-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] Compounds of purine bis (2,2,2-trifluoroethyl) esters as active ingredients. (28) The aforementioned medicine is 2-amino-6- (4-methoxyphenylthio) -9_ [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2,2-trifluoro (Ethyl) ester. (29) The aforementioned medicine is characterized in that after the compound is metabolized, it becomes a compound formed by any of R2 or R3 in the formula (III) as a trihaloalkyl group. (30) The aforementioned medicine is characterized in that the compound is a compound that can be metabolized to increase the selectivity to the liver. (31) The aforementioned medicine is characterized by an antiviral agent. (32) The aforementioned medicine, characterized in that the virus is hepatitis B virus. (33) A medicine characterized by the following formula (I,) (14) (14) 200402299

(Wherein R2 'and R3' represent 2,2,2-trihaloethyl, and R1, R4, and M have the same meanings as above) The phosphonate nucleotide compound or a salt thereof, or these hydrates Or a solvent, and a compound that can improve cell permeability as an active ingredient. (34) The medicine described above is characterized in that the permeability of cells is through cells that are tightly bound to the gastrointestinal tube. (35) A medicine characterized by the following formula (Γ)

• 18- (15) 200402299 (wherein Ri, R2 ', R3', R4, and M and the phosphonate nucleotide compound or its salt or solvent as described above, and compounds that can avoid the kidney are described Meaning the same), or those active ingredients of hydrates. (Γ) (36) — a medicine characterized by the following formula

(In the formula, R1, R2 ', R3', R4, and M are the phosphonate nucleotide compounds or their salts or solvents described above, and those which can improve the skin and / or sciatica as an active ingredient (37) The aforementioned medicine, wherein the aforementioned formula (I,) group, R4 represents a hydrogen atom, and M represents a compound of CH. (38) The aforementioned medicine is characterized by an antiviral agent (39) The aforementioned medicine is characterized by a virus (B) The aforementioned medicine is characterized by the virus being toxic. The meaning is the same), or in the aggregation of these hydrated nerves, 'R1 represents methoxide as an active ingredient of the hepatitis O virus. Varicella zoster -19- (16) 200402299 [Embodiment] [Best Mode for Carrying Out the Invention] The present invention will be described in detail below. First, for the first gist of the present invention, a phosphonate nucleotide compound or a salt thereof represented by the aforementioned formula (:) or these hydrates or compounds is used as an active ingredient. An antiviral agent exhibiting higher aggregation will be described. The active ingredient of the present invention is a salt nucleotide compound or a salt thereof represented by the aforementioned formula (I), or these hydrates or solvents. Regarding the above formula (I For phosphonate nucleotide compounds, C1 to C6 alkoxy represented by R1 include methoxy, ethoxypropoxy, isopropoxy, n-butoxy, and isobutyl , Second butoxydibutoxy, n-pentyloxy, n-hexyloxy, etc. In addition, as the alkoxy group of C1 to C4 which may be substituted by one or more halogen atoms in R1, a monofluoromethoxy group, Dioxymethoxy, trifluoromethoxy, monofluoroethoxydifluoroethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxyfluoropropoxy, difluoropropoxy, Trifluoropropoxy, tetrafluoropropoxy, propoxy, hexafluoropropoxy, heptafluoropropoxy, monofluoroisopropoxy, isopropoxy, trifluoropropoxy Isopropoxy, tetrafluoroisopropoxy, pentafluoroisopropyl, hexafluoroisopropoxy, heptafluoroisopropoxy, etc. R2 and R3 represent a halogen atom in which one or more halogen atoms are substituted. The type may be a fluorine atom, a chlorine atom, a bromine atom, or any of the atoms. As an ethyl group substituted with a halogen atom, it may be.) The phosphonic acid in the solvent is represented by the following formulae: Monopentafluorodifluoropropoxyethyl iodide is listed as -20- (17) (17) 200402299 1-fluoroethyl, 2-fluoroethyl, 1-chloroethyl, 2-chloroethyl, 2-bromo Ethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2-dibromoethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl Radical, 2,2,2-tribromoethyl. Particularly, the first position of the ethyl group is preferably substituted. As the halogen atom, a fluorine atom is preferred. Examples of the C1-C4 alkyl group represented by R4 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, and third butyl. Examples of C1 to C4 hydroxyalkyl represented by R4 include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, and the like. Examples of the C1 to C4 alkyl group substituted by one or more halogen atoms represented by R4 include halogen atoms such as fluorine atom and chlorine atom, and methyl, ethyl, n-propyl, isopropyl, n-butyl, and iso Bonded groups such as butyl, second butyl, and third butyl. Specific examples are fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, chloroethyl, fluoropropyl, chloropropyl, fluorobutyl, and chlorobutyl. In the present invention, R1 represents a hydrogen atom, C1 to C4 alkoxy group or hydroxyl group. R2 and R3 represent a 2,2,2-trifluoroethyl group, and R4 represents a hydrogen atom or a methyl group as the first condition of a preferred compound. . In addition, Ri represents an alkoxy group or a vial group of Ci to C4, R2 and R3 represent a 2,2,2-trifluoroethyl group, and R4 represents a hydrogen atom. The second condition is a preferred compound. For example, a specific preferred compound that satisfies the first condition is the following compound: 2-amino-6-phenylthio-9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2,2 -Trifluoroethyl) ester; -21 · (18) (18) 200402299 2-amino-6- (4-methoxyphenylsulfur) -9- [2- (phosphonocarboxymethoxy) ethyl ] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl ] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (2 · methoxybenzylthio) -9 · [2- (phenylene residue methoxy) ethyl ] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-ethoxyphenylthio) -9- [2- (phenylene methoxy) ethyl Group] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6-phenylthio-9- [2- (phosphonocarboxymethoxy) propyl] purine bis (2, 2,2-trifluoroethyl) ester; 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) propyl] purinebis (2, 2,2-trifluoroethyl) ester; 2-amino-6- (4-butoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purine Bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-propoxyphenylsulfan) -9- [2- (Avicenylmethoxy) ethyl ] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-isopropoxyphenylsulfide) -9_ [2- (phenylene methoxy) ethyl Group] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-isobutoxyphenylsulfide) -9- [2- (phosphonocarboxymethoxy) Ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl ] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-triphenylphenylsulfan) -9- [2- (isophosphinomethoxy) ethyl ] Purine bis (2,2,2-trifluoroethyl) ester; -22- (19) (19) 200402299 2-amino-6- (2-hydroxyphenylsulfide) -9- [2- (sub Phosphonocarboxymethoxy) ethyl] helium bis (2,2,2-difluoroethyl) ester; 2-amino-6- (4-hydroxyphenylthio) -9- [2- (sub Phosphocarboxymethoxy) propyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-basic sulfur) -9- [2- ( Methoxy) propyl] purinebis 2,2,2-trifluoroethyl) ester; and 2-amino-6- (2-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) propyl] purinebis (2 , 2,2-trifluoroethyl) ester. In addition, the compounds satisfying the second condition are the following compounds: 2-amino-6-phenylthio-9- [2- (phenylidenemethoxy) ethyl] purinebis (2,2,2- Trifluoroethyl) ester; 2-amino-6- (4-methoxyphenylthio) -9- [2- (isophosphinomethoxy) ethyl] purinebis (2,2,2 -Trifluoroethyl) ester; 2-amino-6- (3-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2,2 · Trifluoroethyl) ester; 2-amino-6- (2-methoxyphenylthio) -9- [2- (phenylenemethoxy) ethyl] purinebis (2,2, 2-trifluoroethyl) ester; 2-amino-6- (4-ethoxyphenylthio) -9 · [2- (phenylidenemethoxy) ethyl] purinebis (2,2 , 2-trifluoroethyl) ester; 2-amino-6- (4-butoxyphenylsulfide) -9- [2- (phenylidenemethoxy) ethyl] purinebis (2, 2,2-trifluoroethyl) ester; 2-amino-6- (4-propoxyphenylsulfide) -9- [2- (subdichloromethoxy) ethyl] purinebis (2, 2,2-trifluoroethyl) ester; 2-amino-6- (4-isopropoxyphenylsulfide) -9- [2- (phenylene residue-23- (20) (20) 200402299(Oxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-isobutoxyphenylthio) -9- [2- (phosphonocarboxyl (Methoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy (Yl) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-acylphenylsulfanyl) -9- [2- (isopropylidenemethoxy) (Yl) ethyl] purine bis (2,2,2-trifluoroethyl) ester; and 2-amino-6- (2-acylphenylsulfanyl) -9- [2- (o-ocenylenemethyl) (Oxy) ethyl] purine bis (2,2,2 · trifluoroethyl) ester. Preferred compounds include 2-amino-6-phenylthio-9- [2- (phosphonocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester ; 2-Amino-6- (4-methoxyphenylsulfur) -9- [2- (Iridylmethoxy) ethyl] purinebis (2,2,2-trifluoroethyl) Ester; 2-amino-6- (3-methoxyphenylthio) -9- [2- (phenylenemethoxy) ethyl] purinebis (2,2,2-trifluoroethyl ) Ester; 2-amino-6- (2-methoxyphenylsulfur) -9 · [2- (phenylenemethoxy) ethyl] purinebis (2,2,2-trifluoroethyl Ester); and 2-amino-6- (4-acylphenylsulfanyl) -9- [2- (phenylidene methoxy) ethyl] purine bis (2,2,2-trifluoro Ethyl) esters; the best compound is 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2 , 2-trifluoroethyl) ester. Examples of the compound of the formula (I) and a pharmaceutically acceptable salt thereof include acid addition salts of inorganic salts and organic salts. -24- (21) (21) 200402299 The compound of formula (I) and hydrate or a pharmaceutically acceptable salt or hydrate or solvent thereof may exist in the form of each of these hydrates and solvents. Substances are also included in the present invention. When the compound of the formula (I) has an asymmetric atom, at least two types of optical isomers exist. These optical isomers and their palm isomers are also included in the present invention. Furthermore, these phosphonate nucleotide compounds are known compounds, and can be easily synthesized by the methods described in, for example, Japanese Patent Application Laid-Open No. 9-25 5 695 and WO 0 1/64693, and they are compounds that can be easily obtained by experts. . However, although the phosphonate nucleotide compounds described in Japanese Patent Application Laid-Open No. 9-2 5 5 695 and WO 0 1/64693 as effective ingredients of the present invention can be effectively used as antivirals, the examples are described below. As shown, the concentration of its metabolites in the plasma is compared, and the technique of higher aggregation in the liver is not described in the above publication. An example of the metabolite of the antiviral agent of the present invention shown above is a compound represented by the aforementioned formula (11). The compound represented by the formula (11) is a publicly known compound disclosed in JP 9-2 5 5 695 and WO 0 1/64693, and specific compounds can be identified by referring to these publications. As shown in the examples described below, these compounds show higher aggregation in plasma than in liver, and are not described at all in the aforementioned publication. The compound of the formula (I) can be used as an active ingredient of medicine, and specifically, it is useful as an active ingredient of an antiviral agent as shown in the test examples described later. The virus to which the present invention is applicable is not particularly limited. Specific examples include human immunodeficiency virus, influenza virus, and hepatitis C. -25- (22) (22) 200402299

DNA viruses such as RN A virus or herpes simplex virus i, herpes simplex virus 11, cytomegalovirus, chickenpox zoster, and hepatitis B virus. Varicella zoster virus or hepatitis B virus is preferred, and hepatitis B virus is more preferred. When the phosphonate nucleotide compound of the present invention, the optical isomer or a pharmaceutically acceptable salt thereof is used as a medicine, it can be administered alone, but a pharmaceutical acceptable additive is used. It is better to manufacture and administer a pharmaceutical composition containing the above compound as an active ingredient. The formulation may be administered orally or parenterally. It can be formulated according to the general method of pharmaceutical composition. In the description of the present invention, the so-called parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, or drip method. Dispensing for injection can be prepared by methods known in the art. Rectal administration suppositories are prepared by mixing the drug with an appropriate supplement and the like. Examples of the solid dosage form for oral administration include powders, granules, lozenges, coating agents, capsules, and the like. Examples of liquid preparations for oral administration include emulsifiers, syrups, flavoring agents, suspending agents, and solutions which are acceptable as medicines. The compound of the present invention is particularly an ester derivative represented by the aforementioned formula (I) because it has an oral absorbency with a high pass rate as disclosed in Japanese Patent Application Laid-Open No. 9-255 695 and WO 0 1/64693. Therefore, oral administration is the best way to administer the medicine of the present invention. In addition, the preparation of each of the above-mentioned preparations can be performed according to a general method. The clinical administration amount of the medicine of the present invention is the weight of the compound of the present invention when it is administered orally, and it is generally 0.1 to 500 mg / kg, preferably 1 to 50 mg / kg per day for an adult. In addition, the above-mentioned dosage can be appropriately increased or decreased according to the age of -26- (23) (23) 200402299, age, symptoms, symptoms, and the presence or absence of simultaneous administration. The amount of the aforementioned one-day administration may be divided into one-day administration or divided into two to several administrations at appropriate intervals, or the administration may be conducted one or more days apart. When an injection is used, the weight of the mouthpiece of the present invention is 0.001 to 50 jng / kg per day for an adult, and preferably 0.1 to 5 mg / kg. Next, the second gist of the present invention will be described with reference to the compound represented by the above formula (II) or a salt thereof, or a hydrate or a solvent thereof, and a compound capable of improving local tissue selectivity through metabolism as an active ingredient. The active ingredient that achieves the object of the second gist of the present invention is a compound represented by the aforementioned formula (III) or a salt thereof, or a hydrate or a solvent compound thereof. In the aforementioned formula (III), Q represents a mother nucleus having a medicinal effect. Specific examples of the medicinal effect include anti-cancer effect, anti-leukemia effect, metabolic abnormality improvement effect, anti-inflammatory effect, anti-viral effect, anti-cancer cell metastasis effect, immunosuppressive effect or anti-protozoal effect. An anti-cancer effect or an anti-viral effect is more preferable, and an anti-viral effect is mentioned. Specific examples of Q include inositol analogs, nucleotide analogs, sugar analogs, lipids, steroids, peptides, or the like represented by the aforementioned formula (IV), and preferably Q represents the above formula (IV) Happening. In addition, when Q-P = 0 (0-) 2 of the aforementioned formula (III) is represented by a bisphosphonate analog, it is taken as a preferable specific example. In the aforementioned formula (III), X represents a functional group that can effectively improve the recognition effect of a drug. Among them, the so-called identification means that the compound accumulates in specific cells or organs -27- (24) (24) 200402299, or avoids specific cells or organs. Examples of X include functional groups for identifying cancer cells, livers, kidneys, spleens, pancreas, lymphatic vessels, macrophages, lungs, vascular inflammation sites, or central nerves, and for the purpose of avoiding livers. A functional group capable of recognizing cancer cells or liver is preferable, and a functional group capable of recognizing liver is most preferable. Specific examples of X are morpholine, choline phospholipid, alkyl group, amine group, carboxyl group, peptides, mannose, or those represented by the following formula (v). Preferably, it is represented by said Formula (V). Examples of the alkyl group include those described in the first gist. As a specific example of the formula (III), XQ represents a Fludarabine residue, a pencyclobil residue, or a Ribavirin residue; or in the formula (III), XQP = 〇 (〇- ) 2 represents a cidofovir residue or an adefovir residue; or the aforementioned formula (in) represents glucose-6-phosphonate; a tetrakis () of a bisphosphonate selected from hydroxyethylene diphosphate, Ibandronic acid, Zoledronic Acid, Alendronate, and Clodronate 2,2,2-trifluoroethyl) ester; and a phosphonate nucleotide compound or a salt thereof selected from the aforementioned formula (I), or these hydrates or solvents. The phosphonate nucleotide compound or a salt thereof represented by the above formula (I) or a hydrate or a solvent thereof is preferred. Among them, the substituents as the formula (I) may be those shown in the first gist. In the second gist of the present invention, the so-called metabolism is that when a compound is ingested in vivo or in a cell, one or two trihaloethanol esters are cleaved. -28- (25) (25) 200402299 Those with hydroxyl. The so-called increased tissue selectivity means that, compared with plasma, it shows high aggregation for a specific tissue. Examples of tissues include cancer cells, liver, kidneys, spleen, pancreas, lymphatic vessels, macrophages, lungs, inflammatory sites of blood vessels, and central nerves. Cancer cells or livers are preferred. Even better is the liver. The compound of the formula (I) can be easily synthesized by the method shown in the first gist, and can be easily obtained by a practitioner. Fludarabine was synthesized based on JA Montgomery, K. Hewson, J. Med. Chem., 12, 492 (1969); cidofovir was based on P. Alexander, A. Holy, Collection Czechoslovak C he m. Commu "58, 1151. -1163 (1993) Synthesized; adefovir is synthesized based on A. Holy, I. Rosenberg, Collection Czechoslovak Chem. Commu.? 52, 2 80 1 -2 809 (1 9 87). Pencyclobil is Glaxosmithkline. Listed trade names; Hydroxyethylene diphosphate is a trade name listed by Sumitomo Pharmaceuticals; Ibandronic acid is a trade name listed by Roche; Zoledronic Acid is a trade name listed by Novartis; Alendronate is listed by Universal Pharmaceuticals Clodronate is a trade name listed by Kissei. Ribavirin is a test drug available from Sigma. See also Halina T. Serafino wska et al., Synthesis and in Vivo Evalution of pro drugs of 9-[2 -(Phosphonomethoxy) ethoxy] adenine, J Med Chem 3 8, 1 3 72- 1 379 (1 995), can introduce phosphate groups into compounds, according to John E. S tarrett et al., Synt hesis, oral bioavilability determination, and in vitro evalution of -29- (26) (26) 200402299 prodrugs of the antivirul agent 9- [2 (Phosphonomethoxy) ethoxy] adenine (PMEA), J. Med. Chem, 3 7, 1 8 5 7- 1 8 64 (1 994) The phosphate group can be introduced into the ester. The second gist of the present invention is that the compound represented by the aforementioned formula (III) can be effectively used as an active ingredient of medicine, and specifically, it can be used. As an active ingredient in antiviral agents. Examples of the virus to which the present invention is applicable include the ones described in the first gist. The phosphonate nucleotide compound of the formula (I) of the present invention, the optical isomer thereof or a pharmaceutically acceptable salt thereof, as a method for preparing and administering the drug when it is used in medicine, include the aforementioned first 1 points are shown. In addition, it is preferable that the amount of the pharmaceutical product to be marketed is based on each usage. Next, a phosphonate nucleotide compound or a salt thereof, or a hydrate or a solvent thereof represented by the formula (Γ) of the third aspect of the present invention, is a compound which can improve cell permeability as an active ingredient. Medicine to illustrate. The active ingredient of the present invention is a compound represented by the aforementioned formula (Γ) or a salt thereof, or these hydrates or solvents. Regarding the phosphonate nucleotide compound represented by the aforementioned formula (Γ), R2 ′ and R3 ′ represent 2,2,2-trihaloethyl, and R1, R4, and M may include the first gist of the foregoing. Show. In the third gist of the present invention, the cells include cells that form organs such as blood vessels, skin, nerves, kidneys, and livers, or cells with tight junctions (called closed junctions or closed bands). The so-called permeability is that the compound passes through the cell to reach the separated organs through the cell -30- (27) (27) 200402299 organ, blood or body fluid, or enters the cell through the cell membrane. Among them, the passage of cells includes those whose compounds are taken in by tissues through close bonding. The passage of the cell membrane includes a compound that reaches the cells of the organs through blood or body fluids, and preferably passes from the plasma through the cell membrane and into the cells to be liver. The so-called tight bonding is that the adjacent cell membranes in the tissue are tightly attached to each other, which prevents the substances that pass through the cells from diffusing and moving. It is preferably present in a close bond in the gastrointestinal tube. Next, a medicine for a phosphonate nucleotide compound or a salt thereof, or a hydrate or a solvent thereof which is represented by the aforementioned formula (I,) of the fourth gist of the present invention, and can avoid kidney compounds as an active ingredient Explain. Examples of the active ingredient of the present invention include those shown in the third gist of the present invention. In the fourth gist of the present invention, the so-called kidney avoidance means reducing the accumulation of the kidneys. Specifically, it reduces the amount of compounds accumulated on the kidneys. Next, a compound which can improve the aggregation of the skin and / or the sciatic nerve to a phosphonate nucleotide compound or a salt thereof, or a hydrate or a solvent thereof, represented by the formula (I,) of the fifth gist of the present invention. Description of medicine as an active ingredient. Examples of the active ingredient of the present invention include those shown in the third gist of the present invention. In the fifth gist of the present invention, the so-called increase in the aggregation of the skin and / or the sciatic nerve is to increase the number of compounds having one or more trifluoroethanol esters in the skin compared with compounds having no phosphonate nucleotides. Or the concentration of the compound in the sciatica. -31 · (28) 200402299 In the third, fourth, and fifth gist of the present invention, the compound represented by the formula () can be effectively used as an active ingredient of medicine. Specifically, it can be used as an active ingredient of an antiviral agent. The virus can be as shown in the first gist. The preparation method and administration method when used as medicine are the same as those described in the first gist. The formula (Γ) can be easily obtained by the method shown in the first gist. Synthesizers can easily obtain it. Examples The present invention will be described in more detail by way of examples below, but the present invention is beyond the gist and is not limited by these examples. Reference Example 1 2-Amine-6- (4- Production of methoxyphenylthio) -9- [2- (phosphonocarboxyoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester 87 g of 2-chloroethylchloroform Ether (67 0 mmol) and (610 mmol) of tris (2,2,2-trifluoroethyl) phosphate at 16 0 ° C should give 7-hour quantitative 2- [bis (2,2,2-tris) Fluoroethyl) phosphorous methoxy] ethyl chloride. 2 06 g of 2 · (phosphonocarboxymethoxy) ethyl chloride (2,2,2-trifluoroethyl) was dissolved in 2000 ml of 270 g of methyl ethyl ketone was refluxed for 8 hours. After the reaction, it was cooled to room temperature and concentrated to dryness. The residue was dissolved in chloroform / hexane and dissolved in chloroform / hexane with a silica gel column to obtain a quantitative 2-( Phosphorous carboxymethoxy Γ) is an example of a chemical formula, which is a transcarboxylic bis (2,2,3,4,4,4-, 3-dimethyl) group at a temperature of 200 g, and ethyl, 32- (29) (29) 200402299 iodide bis ( 2,2,2-trifluoroethyl). 15.0 g (8.8 mmole) of 2-amino-6-chloropurine was suspended in 360 ml of dimethylformamide, and 13.9 ml (93 mmol) of 1,8-diazabicyclo [5. 4.0] Undec-7-ene was reacted at 8 ° C for 1 hour. Next, 23.8 ml of 2- (phosphorous carboxymethoxyethyl iodide bis (2,2,2-trifluoroethyl)) was added to the above. The reaction solution was reacted at 100 ° C for 5 hours. After the reaction, it was cooled to room temperature and concentrated to dryness. The residue was dissolved in chloroform and adsorbed on a silica gel column, and then 5% -methanol-chloroform was used to obtain 23.3 g (yield 56). %) Of 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2,2-trifluoroethyl ) 7.1 g of 2 · amino-6-chloro-9- [2- (phosphonocarboxymethoxy) ethyl] purine [2- [bis (2,2,2-trifluoroethyl)]] To 68 ml of dimethylformamide solution, 2.1 ml of triethylamine and 3.1 ml of 4-methoxythiophenol were added, and the mixture was stirred at 100 ° C for 2 hours. The reaction mixture was cooled to room temperature, Dried with concentrated acid. The residue was dissolved in chloroform, adsorbed on a silica gel column, and dissolved with 5% -methanol-chloroform to obtain 2-amino-6- (4-methoxy Phenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester. Mp ·: 93-95 ° C (diisopropyl Ether) j-NMR (CDC13,5): 3.85 (s, 3H), 3. 9 2-4 · 0 0 (m '4H), 4.24-4.45 (m, 6H), 4.75 (s, 2H) , 6.95 (d 'J = 9.0 Hz, 2H), 7.53 (d, J = 9.0 Hz, 2H), 7.71 (s' 1H) -33- (30) 200402299 Example 1 100 mg / kg of 2-amino- 6- (4-methoxyphenylthio) (phosphonocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroester) dissolved in 10 ml of tragacanth aqueous solution, androgen C57B The concentration of metabolites in plasma and liver during a single oral administration was measured at / 6J. Plasma was collected from the blood of 2 mice at each time and was adjusted to the level of 2 mice at each time. The liver was prepared by adding 2 physiological saline and emulsified. The measurement was performed using HP LC. (HPLC measurement conditions) Column: Capcell Pack C18D column (Shiseido)

Detection wavelength: 3 1 1 nm Flow rate: 0.8 mL / min Temperature: 30 ° C Mobile phase: Aqueous solution containing 35% acetonitrile and 1.25 mM PicA (Waters) When using HPLC to characterize metabolites, it was found that The main generation is 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxyl) ethyl] purine (2,2,2-trifluoroethyl) ester. The 2-amino-6- (4-methoxyphenylsulfide) -9- [2- (phosphonocarboxyl group) was determined based on the descriptions in JP 9-2 5 5 695 and WO 0 1/64693. ) Ethyl] purine (2,2,2-trifluoroethyl) ester during type B liver activity, it was found that HBV-DNA 50% synthesis of the metabolite blocks -9-[2-ethyl). . Conditions for liver multiples

PicA: The grave is based on the methoxymethoxamine, and the concentration of methinovirus is -34- (31) (31) 200402299 0.07 μM, which has antiviral activity. Fig. 1 shows the results of metabolite concentrations in plasma and liver measured by HPLC. In the first figure, # represents a metabolite in the liver (2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purine (2 , 2,2-trifluoroethyl) ester), which means the concentration of the same metabolite in plasma. It can be seen from the figure that the metabolite shows a higher aggregation concentration in the liver than in the plasma. Example 2 2-Amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2,2-trifluoroethyl) The compound labeled 14c at the 8th position of the ester) was measured for the concentration change of this tissue when a single oral administration of 2 mg / kg was performed on male mice under fasting conditions. Liver tissue was collected from the large vein after a predetermined time (15 minutes, 1, 4, 8, 24, 48, 9 and 18 hours). The radioactivity was measured by a liquid flash counter (manufactured by Bajin Aima Co., Ltd.) which was quench-corrected by the tSIE method. The results were calculated using drug dynamics test support software (Drug Dynamics System, Fuji Faccom Systems). The results are shown in Table 1. ° -35- (32) (32) 200402299 Table 1 Time concentration in liver (comparison of plasma concentration) Plasma concentration-Xtteq / mL) (ugeq / mL) 1 5 minutes 6.7 times 0.133 1 Hours ^^ 0 ^ 291 6.9 times 0.042 4 hours 1 6 8.4 times 0.019 8 hours __〇 ^ 071 8 times 0.009 2 4 hours __ ^. 03 2 11 times 0.003 4 8 hours __〇 ^ .05 6 28 times 0.002 9 6 hours 0.0 17-below the detection limit 1 6 8 hours 0.0 11-below the detection limit As shown in Table 1, we can know from 2-amino-6- (4-methoxyphenylsulfur) -9- [ The radioactive energy of 2 · (phosphonocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester can be quickly absorbed by tissues (the highest concentration time in the liver Tmax = 15 minutes) and Compared to plasma, it shows higher aggregation in the liver. In addition, it is p-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2,2-trifluoroethyl To review the metabolic mechanism of the ester), 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2, The compound labeled with 14C at the 8th position of 2-trifluoroethyl) ester was administered to male-36- (33) 200402299 mice and female mice in a single oral administration of 2 mg / kg under fasting conditions. Plasma Radioactive high-speed liquid chromatography (HPLC) was used to obtain 2-amino-6- (4-methoxyphenylsulfur) -9 · [2- (oxy) ethyl] xanthyl.bis ( The estimated metabolites of 2,2,2-diperethyl) vinegar are shown below. In addition, the following I.S. represents compounds used. In the second figure described later, M-2p is a lower monophosphate, and M-2PP is a -diphosphate of M-2 described below. The monophosphate of the following M-4, and M-4pp is the dimer of the following M-4. The structural formula of phosphocarboxyl and r reference material is M-2, and M-4p is an acid ester. -37- (34) 200402299 Putative metabolites

M-3 ’〇 OCH2CF3 och2cf3

(HPLC measurement conditions) Column: Deveiosil ODS-UG-54.6x250 (Nomura Chemical Co., Ltd.) Column temperature: 40 ° C Mobile phase: A liquid; 25% acetonitrile + Pic A reagent (Waters) B liquid; 50% Acetonitrile + Pic A reagent (Waters) Flow rate: 1.0ml / min -38-(35) 200402299 Detection: UV (3 1 5 nm) detector; SPD -10 0 Shimadzu Corporation Radiation Energy (14C) detector: Flo-ONE (made by Ba Jin Aima Co.) Smelting counter: UltimaflowM (made by Ba Jin Aima Co.), the flow rate of the flash counter: 3ml / min. The results are shown in Figure 2, Figure 3, and Figure 4. Figure 2-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) purine bis (2,2,2-trifluoroethyl) ester and the above Figure 9 shows the dissolution time of a given metabolite. Figure 3 shows the results obtained after administration of the compound to male monkeys for 0.5 hours, and the results were measured by HPLC and RI test. Figure 4 shows the results of administration to male mice. Plasma samples after the compound hours were injected into the HPLC and measured by the RI detector. The ratios of the absorption peaks in Figure 2, Figure 3, and Figure 4 can be affirmed by the mechanism that determines the major components of the compound's plasma. The metabolite is a monoester of the compound. Example 3 2-Amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxyoxy) ethyl] purinebis (2 2,2-trifluoroethyl) ester (Sample E 2-Amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxyl) ethyl] purine (Sample D The 8th place marked with 14C 'is quickly injected into the veins of 8-week-old male mice at the amount of 10 mL / kg' after taking the kidneys and livers. Weigh out a portion of the kidney and liver tissues in a small amount to Liquid scintillation flask weighing. Plasma and tissue The calculations are based on confirmation of the firing and flashing). A second set of 0.25 is used to replace the chemical base, and the methylation tail is cut and added -39- (36) (36) 200 402 299 0.5 ml tissue dissolving agent. (SOLUENE-3 50: Bajin Aima · Laffes Co., Ltd.), dissolve by heating at 60 ° C, and add 10ml of liquid flash solution (HIONIC_FLUOR: Bajin Aima-Laffas Co., Ltd. ). The radioactivity in each sample was measured using a flash counter (LSC-2900 type: Barking Alpha-Laffes Co., Ltd.) for 5 minutes. The computational efficiency is corrected using the standard method of external light sources. Kp (radiation energy concentration in the tissue / radiation energy concentration in the plasma) was calculated by displaying the mobility of the liver tissue. The evaluation of renal avoidance was calculated by calculating the amount of aggregated tissues using the following formula. Kidneys transition value = Kidneys concentration per lg The results are shown in Table 2. Based on the results, it was found that when administered to the blood circulation, the sample D, which is a monoester, was more metabolized than the sample B of the diester, which showed high aggregation to the liver and avoidance of the kidney. The so-called blood circulation is blood that circulates through the body after passing through the liver. Table 2 Amount of liver Kp 値 kidney accumulation (nmol / g) Sample B 5.65 1011.9 Sample D 18.24 809 Example 4 Using 9-(2 -phosphinofluorenyl-methoxyethyl) -guanine (sample A) and examples 2 The sample used was 0, each of the 8th chemistry compounds labeled with 14C-40-(37) (37) 200402299 was rapidly administered to the total portal vein of an 8-week-old male rat at an amount of 1 mL / kg. The kidney and liver were collected, and the liver tissue mobility and kidney avoidance were evaluated according to the measurement method shown in Example 3. In addition, the evaluation of renal avoidance was calculated by the following formula to calculate the amount of tissue aggregation. Kidneys transition value = concentration in the kidney X kidney tissue weight The results are shown in Table 3. From this result, it is understood that the modification group existing at the 6th position in the above formula (I) is that when the compound is administered in portal blood, there is a possibility of giving aggregation to the liver and avoidance of the kidney. The so-called portal blood is the blood in the portal vein of the mesenteric vein that enters the liver when the compound is absorbed by the intestine. Table 3 Kidney Kp 値 Liver Kp 値 Kidney Aggregation (nmol) Sample A 6.016 0.186 463.68 Sample D 1.173 0.552 3 08.5 Example 5 2 -Amino-6- (4-methoxyphenylsulfur) -9- [2 -(Sub-residue residue methoxy) ethyl] purine (2,2,2-trifluoroethyl) ester (sample C) and the eighth position of sample B and sample D used in Example 3 are identified by 14C The compounds are used as test substances. As an internal standard, a solution of 100 μM Lucifer Yellow CH (manufactured by Sigma) -41 · (38) (38) 200402299 diluted 100-fold with the culture medium for the mucosal side permeation test was used. As the culture medium for the mucosal side permeation test, Hank's balanced salt solution (manufactured by HBSS Gibuco) was added. Mess (Gibuco) was added to a final concentration of 20 mmole / L, and the pH was adjusted to pH 6.5 with sodium hydroxide or hydrochloric acid. By. The test substance was prepared to a concentration of 20 μM using a 100 // M Lucifer Yellow solution (final concentration containing 1% DMSO). The monolayer membrane (ATCC NO.HTB37) of Caco-2 cells cultured for 4 days was observed under a microscope to check for damage and recorded on the test paper. Those who observed significant abnormalities in the microscope were not used experimentally. Put 2.0 mL of mucosal-side permeation test medium on the mucosal side (top), put 2.0 mL of serous-membrane-side permeation test medium on the serosal side (bottom), and perform pre-culture at 37 ° C for 10 minutes at 35 min-1. The serosal-side permeation test medium was prepared by adding mes s (Gib UC 0) to a final concentration of 20 mmole / L and adjusting the pH to 7.4 with sodium hydroxide or hydrochloric acid. The film resistance tester milicell-ESR (Minipore) was used to measure the film resistance at three positions in each groove, and recorded on the test paper. The measurement 値 is calculated in the following equation, and the film resistance is calculated with the film surface area corrected. The corrected film resistance (Ω · cm2) is two (measured at three positions 値 average 値 -103) X4.71 At this time, the ditch of 値 that does not reach 3 00 Ω is not used for experiments. Put the serosal side correctly. 2. OmL of serosal side permeation test medium is placed on the mucosal side. • 42- (39) (39) 200402299 2. OmL of the test substance solution is passed through the serous membrane side through the test medium. The flash flask was taken out 100 μL each, and the removal period was 15, 30, 60 ′ 120 minutes. 10 ml of a liquid scintillation liquid was added to the sample taken out, the radioactivity of the sample was measured, and the concentration after transmission was measured. The results are shown in Figure 5. In Fig. 5, ♦ represents sample B, represents sample C and ▲ represents the cell passing concentration of sample D. After 2 hours, the passing concentrations were 1168.3ng / mL, 103.3ng / mL, and 7.4ng / mL. The Caco-2 permeability improving effect of the trifluoroethanol ester residue was about 10 times. From this result, it is understood that the trifluoroethanol ester 'bonded to a phosphate group can improve the passage of cells having a tightly bound tissue. Example 6 The compound labeled 8 at the 8th position of each of the sample B, sample C, or sample D used in Example 3 or Example 5 was rapidly administered to an open-labeled 8-week-old male rat at an amount of imL / kg. After the total portal vein, kidney and liver samples were taken, and kidney avoidance was evaluated according to the measurement method shown in Example 3. The evaluation of 'renal avoidance' was performed according to the evaluation method of Example 4. The results are shown in Table 4. From this result, it was found that when g-form B having two dichloroethanol esters was administered to a portal vein, the kidneys could be avoided. -43- (40) 200402299 Table 4 Kidney accumulation amount (nm0l) Specimen B 168.6 Specimen c 291.1 Specimen D 642.9 Example 7 Suspend the eighth-identified compounds of specimen b and specimen D used in Example 3 0.5% tragacanth gum was suspended at 2 mg / ml to prepare a dosing solution. The administration solution was kept for 9 weeks. The rat was heat-resistant. A disposable plastic tube was connected to the heat-resistant syringe for forced oral administration. 15 minutes after the abdominal aorta, a heparin-treated syringe was cut open to stop bleeding. The sampled blood was quickly ice-bathed, and the plasma was separated by the method of separation (3000 rpm, 10 minutes), and 50 into a liquid flash flask. Sampling the abdominal skin (approximately 2cm X 4 cm) legs and weighing the tissue. The radiant energy in each sample was measured according to the implementation method. Table 5 shows the aggregation of tissues. The amount of tissue aggregation was measured using the amount of tissue aggregation as in Example 3. The results are shown in Table 5. The results are shown in Table 5. The table shows Kp 値 and the concentration in tissues of the sciatic nerve 15 minutes after administration. At the same dosage (medium 'compared with sample D without trifluoroethanol ester, sample B with alcohol ester has more aggregation on the skin and sciatic nerve. It can be known that the introduction of fluoroethanol can effectively improve the tissue Polymers were given in 14C liquid to 2.5mL each. Blood was collected, and the blood was quickly divided into centrifugal fractions. The measurement of left and right Example 3: Kp. Estimation. The skin and mg / kg were diethyl ether. Results -44-(41) (41) 200402299 Table 5 Skin sciatic nerve sample B sample D sample B sample D concentration (ng / g) 245.0 37.7 57.5 7.9 Kp 0.21 0.15 0.05 1 0.025 [Industrial availability] The present invention is To provide an agent that enhances the aggregation of identification tissues or the avoidance of identification tissues. Moreover, this case is the applicant claiming the priority of Patent Application No. 2002- 1 5 1 506 and Patent Application No. 2002_ 1 2 1 207. [Brief description of the figure] Figure 1 is a graph showing the concentration of metabolites in plasma and liver measured by HP LC. Figure 2 is a graph showing the dissolution time of each compound determined by HPLC. Fig. 3 is a graph showing the concentration of each compound in the plasma after 0.5 hours when the labeled compounds are administered to monkeys. Fig. 4 is a graph showing the concentration of each compound in plasma after 0.25 hours when the labeled compounds are administered to mice. Fig. 5 is a graph showing the compound concentration after passage of the cell monolayer membrane of the labeled compound. -45-

Claims (1)

(1) 200402299 Patent application scope 1 · An antiviral agent characterized by the following formula (I) (Where 'R1 represents a hydrogen atom, C1 to C6 alkoxy or more halogen atoms substituted with C 1 to C4 alkoxy, haloamino, nitro, or hydroxyl; R2 and R3 each independently represent a A halogen atom-substituted ethyl group; R4 represents a hydrogen atom, a C1 ~ group, a hydroxyalkyl group of Cl ~ C4, or a C1 ~ C4 alkyl group consisting of one or more halogens; M represents a CH or nitrogen atom) As an active ingredient, an acid salt nucleotide compound or a salt thereof, or a solvent thereof, and its metabolite show higher aggregates in plasma than in the viscera. 2. An antiviral agent according to claim 1 in the scope of patent application, wherein in the formula (I) of claim 1, Ri represents a hydrogen atom, a C1 oxygen group or a hydroxyl group as an active ingredient. 3 · If you apply for the antiviral agent in item 1 of the patent scope, in which some hydrates can be replaced by 1 prime atom and more than 1 C4 alkane atom. (2) (2) In the formula (I) of the first range of 200,402,299, R1 represents a hydrogen atom, Cl to C4 to obtain an alkoxy group or a hydroxyl group; R2 and R3 represent 2,2,2-trifluoroethyl groups; R4 A compound representing a hydrogen atom or a methyl group as an active ingredient. 4. The antiviral agent according to claim 1 in the scope of patent application, which is selected from the following compounds: 2-amino-6-phenylthio-9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-methoxyphenylsulfur) -9- [2- (phenylidenemethoxy) ethyl] purine Bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-methoxyphenylthio) -9- [2- (isophosphinomethoxy) ethyl] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (2-methoxyphenylsulfanyl) -9- [2- (idenylmethoxy) ethyl ] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-ethoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl ] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6-phenylthio-9- [2- (phenylene methoxy) propyl] purine bis (2, 2,2-trifluoroethyl) ester; 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) propyl] purinebis (2, 2,2-trifluoroethyl) ester; 2-amino-6- (4-butoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purinebis (2, 2 , 2-trifluoroethyl) ester; 2-amino-6- (4-propoxyphenylthio) -9- [2- (o-octylmethoxy) ethyl] purinebis (2, 2,2-trifluoroethyl) ester; 2-amino-6- (4-isopropoxyphenylsulfide) -9- [2- (phosphonocarboxyl-47- (3) (3) 200402299 (Oxy) ethyl] purine bis (2,2,2 · trifluoroethyl) ester; 2-amino-6- (4-isobutoxyphenylthio) -9- [2- (phosphonocarboxyl (Methoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-hydroxyphenylthio) -9- [2- (phosphonocarboxymethyloxy ) Ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-basic sulfur) -9- [2- (phenylene methoxy ) Ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (2-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl Yl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-triphenylphenylsulfanyl) -9- [2- (sulylene residue methoxy) propyl ] Purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) propyl] purine double (2,2,2-trifluoroethyl) ester; and 2-amino-6- (2-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) propyl] purinebis ( 2,2,2-trifluoroethyl) group of compounds as an active ingredient. 5. The antiviral agent according to item 1 of the scope of patent application, wherein in the formula (I) of item 1 of the scope of patent application, R1 represents a hydrogen atom, an alkoxy group of C1 to C4 or a hydroxyl group; R2 and R3 represent 2, 2,2-trifluoroethyl; compounds in which R4 represents a hydrogen atom are effective costers. 6. The antiviral agent according to claim 1 in the scope of patent application, which is selected from the following compounds: 2-amino-6-phenylsulfan-9- [2- (phenylidenemethoxy) ethyl] purine Bis (2,2,2-trifluoroethyl) ester; -48- (4) (4) 200402299 2-amino-6- (4-methoxyphenylthio) -9- [2 · (sub Phosphocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-methoxybenzylsulfur) -9- [2- (phosphonium Residue methoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (2-methoxyphenylthio) -9 · [2- (sub Phosphocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-ethoxyphenylthio) -9_ [2- (phenylene Residue methoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-butoxyphenylthio) -9- [2- (sub Phosphocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4 · propoxyphenylthio) -9- [2- (sub Phosphocarboxymethoxy) ethyl] purine bis (2,2,2 · trifluoroethyl) ester; 2-amino-6- (4-isopropoxyphenylsulfide) -9- [2 -(Phenylene methoxy) ethyl] purine bis (2,2,2 · trifluoroethyl) ester; 2-amino-6- (4-isobutoxyphenylthio) -9- [2- (Phenylenemethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-hydroxyphenylthio) -9- [ 2- (phosphonocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-triphenylphenylthio) -9- [2 -(O-ocenylenemethoxy) ethyl] purine bis (2,2,2 · trifluoroethyl) ester; and 2-amino-6- (2-triphenylphenylthio) -9- [ Compounds in the group consisting of 2- (idenylmethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) esters as active ingredients. 7. The antiviral agent according to item 1 of the scope of patent application, which is selected from the following compounds: -49- (5) (5) 200402299: 2-amino-6 · phenylthio-9- [2- (phosphonocarboxyl (Methoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-methoxyphenylthio) [2- (phosphonocarboxymethoxy) Ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) Ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (2-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) Ethyl] purine bis (2,2,2-trifluoroethyl) ester; and 2-amino-6- (4-hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl Group] compounds containing a group of bis (2,2,2 · trifluoroethyl) esters as active ingredients. 8. The antiviral agent according to item 1 of the scope of patent application, wherein 2-amino-6- (4-methoxyphenylsulfide) _9_ [2- (phosphonocarboxymethoxy) ethyl] purha Bis (2,2,2-trifluoroethyl) ester as an active ingredient. 9 · The antiviral agent according to item 1 of the scope of patent application, wherein 2-_amino-6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purine (2,2,2-trifluoroethyl) ester, or 2-amino-6 · (hydroxyphenylthio) -9- [2- (phosphonocarboxymethoxy) ethyl] purine (2,2 , 2, trifluoroethyl) ester as an active ingredient. 1. A type of antiviral agent, which is characterized in that when administered into a living body, the following formula (II) -50- (6) (6) 200402299 (Wherein R1, R2, R4 and M have the same meanings as above.) The phosphonate nucleotide compounds or salts thereof shown in the table, or compounds represented by these hydrates or solvents are metabolized. Comparing in plasma, showing higher aggregates in the liver. 11. The antiviral agent according to claim 10, wherein Ri is a metabolizer of a compound of formula (η) of claim 1 in which Ri represents a hydroxyl group or a C1 to C4 alkoxy group. 12 · The antiviral agent according to item 10 of the scope of patent application, wherein in the formula (] []) of the item 10 of the scope of patent application, R1 represents a hydroxy group or a hydroxy group of c to C 4; R2 represents A metabolizer of an ethyl compound substituted with one or more halogen atoms. 13 · An antiviral agent according to item 10 of the scope of patent application, wherein in formula (II) as described in item 10 of the scope of patent application, R1 represents a hydroxyl group or a k-oxyl group of C1 to C4; R2 represents 2, 2, 2 • Trifluoroethyl; R4 represents a metabolizer of a hydrogen atom or a methyl compound. -51-(7) (7) 200402299 1 4. The antiviral agent according to item 10 of the patent application scope, which is selected from the following compounds: 2-amino-6- (4-acylphenylsulfide) -9- [2- (Avicenylmethoxy) ethyl] purine (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-hydroxyphenylthio) -9 -[2- (phosphonocarboxymethoxy) ethyl] purine (2,2,2-trifluoroethyl) ester; 2-amino-6- (2-basic sulfur) -9 · [2 -(Phenylidene methoxy) ethyl] purine (252,2-trifluoroethyl) ester; 2-amino-6- (4-triphenylphenylsulfan) -9- [2- (sub Phenylmethoxy) propyl] purine (2,2,2 · trifluoroethyl) ester; 2-amino-6- (3-triphenylphenylsulfide) -9- [2- (phenylene Benzylmethoxy) propyl] HeiLing (2,2,2-difluoro ^ ethyl) vinegar; 2-amino-6- (2-transylphenylthio) -9- [2- ( O-Cenylenemethoxy) propyl] purine (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-methoxyphenylthio) -9- [2- ( Phosphorous carboxymethoxy) ethyl] purine (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-methoxyphenylthio) -9- [2- (o-octylenemethoxy) ethyl] purine (2,2,2 · trifluoroethyl) ester; 2-amino-6_ (2-methoxyphenylsulfur) -9- [ 2- (phenylidene methoxy) ethyl] purine (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-methoxyphenylthio) -9- [ 2- (Squamethylene residue methoxy) propyl] purine (2,2,2 · trifluoroethyl) ester; 2-amino-6- (3-methoxyphenylsulfur) -9- [ 2- (ortho-residue methoxy) propyl] purine (2,2,2-trifluoroethyl) ester; -52- (8) (8) (Sichuan) 200402299 and 2-amino-6- (2-methoxyphenylthio) -9- [2- (methoxy) propyl] purine (2,2,2-trifluoroethyl) ester metabolizer. 1 5. According to the antiviral agent in the scope of the patent application No. 10, j- 6- (4-methoxyphenylthio) -9- [2- (phosphonocarboxymethyl] purine (2,2, 2-Trifluoroethyl) ester metabolizers. 1 6 · As an antiviral agent under the scope of application for patent No. 10, j group-6- (4-hydroxyphenylthio) -9- [2- (phosphonocarboxyl group A: phenyl] purine (2,2,2-trifluoroethyl) ester metabolizer. 1 7 · If the anti-patent scope of item 15 or item 16 is applied, it is the administration of 2-amino-6- (4-methoxyphenylthio) -9- [2-ylmethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester Any of the poisons of item 17, wherein the virus is hepatitis B virus. 19. A medicine characterized by the following formula (III): 0 X-Q-P-OR2 OR3 (where Q represents a drug with a medicinal effect The parent nucleus X represents a substituent capable of recognizing a drug, and R2 and r3 represent the same meanings as above) If the compound represented by the salt, or these hydrates or phosphorous carboxyl groups are grouped by 2-amine oxygen Base) Ethyl 2-aminooxy) B virus agent, (Phosphorus carboxylate. The anti-disease effect of the phase is improved Italian mediators, -53-(9) (9) 200402299 and compounds that can be used to increase tissue selectivity as effective ingredients by being metabolized. 2 0 · For the application for the medicine in item 19 of the patent scope, of which In formula (III) of the 19th scope of the patent, the pharmacological effects of the mother nucleus with medicinal effects are anti-cancer effect, anti-leukemia effect, metabolic abnormality improvement effect, anti-inflammatory effect, anti-viral effect, anti-cancer cell metastasis effect, The immunosuppressive effect or the antiprotozoal effect, the identification of the substituents that can effectively improve the drug identification effect is selected from the group consisting of cancer cells, liver, kidneys, spleen, pancreas, lymphatics, macrophages, lungs, vascular inflammation sites or centers Identification of nerves and identification for the purpose of avoiding the liver. 21. If the medicine of the 19th or 20th scope of the patent application, the formula (III) of the 19th scope of the patent application has medicinal effects. The efficacy of the mother nucleus is an anti-cancer effect or an anti-viral effect. 2 2. If the medicine of any one of the scope of patent application No. 19 to 21, the formula (III) of the scope of patent application No. 19 Medium, X means This compound is fat-soluble and a substituent that effectively improves the recognition effect on cancer cells and livers. 23. For example, the medicine of any one of the 19th to the 22nd patent applications, including the 19th of the patent application scope. In the formula (III) of the item, Q represents an inositol analog, a nucleotide analog, a sugar analog, a lipid, a steroid, a peptide, or the following formula (IV) -54- (iv) (10) 200402299 (In the formula, R4 and M represent the same meaning as described above.) In the formula (III) of the 19th scope of the patent application, Q-P = 〇 (〇-) 2 is represented by a bisphosphonate analog. 2 4. The medicine according to any one of claims 19 to 23 in the scope of the patent application, wherein in formula (III) in the scope of the patent application, X represents morpholine, choline phospholipid, alkyl group, amino group , Carboxyl, peptides, mannose or the following formula (V) S R1 (V) (wherein R1 has the same meaning as above). 25. The medicine according to any one of claims 19 to 24 in the scope of patent application, wherein, in formula (III) in the scope of application for the patent, item XQ table-55- (11) 200402299 shows Fludarabine residue, pencyclobil Residues or Ribavirin residues in formula (III) in item 19 of the scope of patent application, XQP 20 (〇 ·) 2 represents cidofovir residues or adefovir residues; or in formula (III) of item 19 of scope of patent application, Glucose-6-phosphonate; a tetra (2,2,2-trifluoroethyl) bisphosphonate selected from the group consisting of bisphosphonates via oxalic acid, Ibandronic acid, Zoledronic Acid, Alendronate, and Clodronate; and Formula (I) π ·, π2 0 II ch2choch2-p-or2 R4 OR3 (wherein R1, R2, R3, R4, and M represent the same as described above) or a phosphonate nucleotide compound or a salt thereof, or these hydrates or Solvent. 26. If the medicine is applied for item 25 in the scope of patent application, wherein in formula (I) in the scope of application for item 25, R2 and R3 represent 2,2,2-trihaloethyl, R4 represents a hydrogen atom, R1 represents a hydrogen atom, a C1-C4 oxo group, or -56- (12) (12) 200402299 hydroxyl group, and M represents a CH or nitrogen atom. 27. The antiviral agent according to claim 25 or 26, wherein the compound represented by formula (I) in claim 25 is selected from the following compounds, 2-amino-6-benzene Thio-9- [2- (phosphonocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (4-methoxyphenyl Sulfur) -9- [2_ (phosphonocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (3-methoxyphenylsulfide ) -9- [2- (phosphonocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; 2-amino-6- (2-methoxyphenylsulfide ) -9- [2- (phosphonocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester; and 2-amino-6- (4-hydroxyphenylthio) A group of -9- [2- (phosphonocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) esters as an active ingredient. 2 8 · If the medicine in any one of the 25th to 27th scope of the patent application 'It is 2-amino-6- (4-methoxyphenylthio) -9- [2- ( Phosphocarboxymethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester. 29. If the medicine of any one of claims 19 to 28 of the scope of patent application 'wherein the compound is metabolized to formula (III) of the scope of patent application item 19, either R2 or R3 is a trihaloalkyl group The resulting compound. 30. The medical practitioner of any one of the 19th to the 29th in the scope of patent application _ 'wherein the compound is metabolized to improve the selectivity to the liver. -57- (13) 200402299 3 1 · If the medicine of any one of items 19 to 30 in the scope of patent application, it is an antiviral agent. 3 2. If the medicine in the scope of patent application No. 31, the virus is hepatitis B virus. 33. A medicine characterized by the following formula (Γ) η ^^ ι Π2 〇II 2, Toch2-p-or2 OR3 · (wherein R2 'and R3' represent 2,2,2-trihaloethyl, R1, R4 and M have the same meaning as above) A phosphonate nucleotide compound or a salt thereof, or a hydrate or a solvent thereof, and a compound that can improve cell permeability as an active ingredient. 34. The medicine of claim 33, wherein the permeability of the cells is through the cells tightly bound on the gastrointestinal tube. 35. A medicine characterized by the following formula (Γ)-58- (14) (14) 200402299 (Wherein R, R, R, and "same meaning as above") are represented by phosphonate nucleotide compounds or their salts, or these hydrates or solvents, and those compounds that can avoid kidneys are used as active ingredients 36 · —A kind of medicine characterized by the following formula (1,) (Wherein R1, R2 ', R3', R4, and M have the same meanings as described above) The phosphonate nucleotide compound or a salt thereof, or these hydrates or solvents, can improve the skin and / Or the aggregation of the sciatic nerve -59- (15) (15) 200402299 as an active ingredient. 37. The medicine according to any one of the items 33 to 36 in the scope of patent application, wherein in the formula (Γ) of the items 33, 35, and 36 in the scope of patent application, R1 Compounds which represent a methoxy group, R4 represents a hydrogen atom, and M represents CH as active ingredients. 38. The medicine of any one of items 33 to 37 in the scope of application for a patent is an antiviral agent. 39. The medicine according to item 38 of the patent application scope, wherein the virus is hepatitis B virus. 40. The medicine according to item 38 of the patent application scope, wherein the virus is spasm zoster virus. 200402299 柒 Designated representative map: (1). The designated representative map of this case is: None. (2). The component representative symbols of this representative map are simply explained: None. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention. ··