WO2003099294A1

WO2003099294A1 - Drugs improved in tissue selectivity

Info

Publication number: WO2003099294A1
Application number: PCT/JP2003/006463
Authority: WO
Inventors: Ken Ubasawa; Kouichi Sekiya; Yoshiyuki Fujimura; Yasuhiro Kuwahara; Yukiko Nishimura
Original assignee: Mitsubishi Pharma Corporation
Priority date: 2002-05-24
Filing date: 2003-05-23
Publication date: 2003-12-04
Also published as: TW200402299A; AU2003242428A1

Abstract

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

Description

Specification

Pharmaceutical technology with improved tissue selectivity

The present invention relates to a drug having improved accumulation in a target tissue or avoidance of the target tissue. Background art

Recently, development of drugs targeting cancer and viruses as targets for inhibiting nucleic acid biosynthesis and inhibiting and activating various enzymes has been promoted, but these drugs are generally used. In addition, there are problems such as a strong medicinal effect and an effect such as growth inhibition on normal cell lines. Taking the infectious hepatitis virus as a specific example, the hepatitis virus is recognized as a medically important problem, but at present, only a few drugs are effective in treating it. Interferon oral peramibudine is a drug that has been established for its efficacy, but only 10 to 30% of patients are treated with interferon. Lamivudine also has a problem in that it shows drug resistance during taking. Therefore, the development of drugs that have antiviral activity and, at the same time, do not have growth inhibitory activity against normal cell lines, with the aim of treating such diseases, is being studied. I have.

Also, it is possible to convert prophosphonate of a phosphonate-nucleotide compound 91- (2-phosphoninolemethoxy) ethyl adenylin (PMEA), which has been reported as an anti-inflammatory agent. Thus, studies have been made to improve oral absorption (Adefohi, Nori-Pi-Pho-Sinore, adef 0 V irdipivoxi 1) EP Publication No. 258 826 (Patent Reference 1)). The compound Since the substance is rapidly integrated after absorption (KC Cundy et. Al. Pharm. Res., 11, 839-843 (1994) (Non-Patent Document 1)), the membrane permeability is reduced (R , V. Srinivas et. Al., Antimicrob. Agents Chemother., 37, 2247-2250 (1993) (Non-Patent Document 2)) The probability of accumulation of active ingredients in hepatocytes, which is the target tissue, decreases. This is a problem.

In this regard, a specific ester derivative of a phosphonate nucleotide having an antiviral activity and excellent in oral absorption and safety is known (Japanese Patent Application Laid-Open No. Hei 9-256569). No. 5 (Patent Literature 2) and WO 01/64693 (Patent Literature 3)), these publications have no mention of improvement in tissue accumulation of drugs.

[Patent Document 1] EP Publication No. 0 5 8 26

[Patent Document 2] Japanese Patent Application Laid-Open No. Hei 9-125556995

[Patent Document 3] W O 0 l Z 6 4 6 9 3

[Non-Patent Document 1] Cundy et. Al., Pharm. Res., 11, 839-843 (1994)

[Non-Patent Document 2] R. V. Srinivas et. Al., Antimicrob. Agents Chemother., 37, 2247-2250 (1993)

Disclosure of the invention

An object of the present invention is to provide a drug that has improved accumulation in tissues or a drug that shows kidney evasion.

The present inventors have conducted intensive studies to solve the above problems, and as a result, they have found that a specific compound shows high accumulation in a target organ and also shows avoidance of a target organ. The present invention has been completed.

That is, the gist of the present invention is as follows.

(1) The following formula (I)

(I)

CHzCHOCHz-P-OR "

R 4 OR,

(Wherein, R ¹ is a hydrogen atom, a C 1 -C 6 anorecoxyl group, a C 1 -C 4 alkoxynole group substituted with one or more nitrogen atoms, a nitrogen atom, an amino group, R ² and R ³ each independently represent an ethyl group substituted with one or more halogen atoms; represents a hydrogen atom, a C 1 -C 4 alkyl group, or Cl Represents a C1 to C4 hydroxyalkyl group or a C1 to C4 alkyl group substituted with one or more halogen atoms; M represents CH or a nitrogen atom.)

The active ingredient is a phosphatonucleotide compound or a salt or hydrate or solvate thereof represented by, and its metabolites are more highly accumulated in the liver than in plasma Antiviral agent

(2) The antiviral agent according to the above formula (I), wherein R ¹ is a hydrogen atom, a C 1 -C 6 alkoxyl group or a hydroxyl group as an active ingredient.

(3) In the formula (I), R ¹ is a hydrogen atom, a C 1 -C 4 alkoxyl group or a hydroxyl group; and R and 2, 2, 2 — Trifluoro 13 ethyl group and R 4

Wherein said compound is a hydrogen atom or a methyl group as an active ingredient.

(4) A group consisting of the following compounds:

2 — Amino 6 — Phenylthio 9-1 1 [21 (phosphonomethoxy) ethyl] purinbis (2,2,2 — Trifnoroleethyl) Estenolle

2 — Amino 6 _ (4-methoxyphenylthio)-9-[21- (phosphonomethoxy) ethyl] purinbis (2,2,2,1-triphenylenothiophene) Esthenore;

2 — Rho-mino 6 1 (3 — methoxyphenylthio) — 9-1 [2 (phosphonomethoxy) ethyl] purinbis (2,2,2,1 triphenylphenol) Esthenore;

2 — Amino 6 — (2 — methoxyphenylthio)-9-[21 (phosphonomethoxy) ethyl] purinbis (2,2,2-trifluoro) Echinore) Estel;

2 — Rho-mino 6- (4-ethoxyphenylthio) -9- [21- (phosphonomethoxy) ethyl] purinbis (2,2,2-trifluoroethylene) ) Estenolle;

2-amino-6-phenylthiol 9-1 [2-(phosphonomethoxy) propyl] primbis (2,2, 2-triphenylenoethyl) ester;

2 — Amino 6 — (4-Methoxy phenylthio) 1 9 1 [2 1 (phosphonomethoxy) pip pill] Prinbis (2,2,2 — Trifnoleo mouth) Esthenore

2 — Amino 6-1- (4-butoxyphenylthio) -9-1 [21- (phosphonomethoxy) ethyl] purinbis (2,2,2-trifluorophenol) Estel; 2 — Amino-6- (4-propoxyphenyl) 1 9 1 [2 (phosphonomethoxy) ethyl] purinbis (2,2,2—tri- Husuleo Lo チ chinore) S Tenoré;

2—Amino 6— (4—Isopropoxyphenyl) 1 9 1 [2-(phosphonomethoxy) ethyl] purinbis (2,2,2 — Tri-Fnoreo Loetinole) Estel;

2—Amino 6— (4—Isobutoxyphenyltio) -9- [2— (phosphonomethoxy) ethyl] purinbis (2,2,2— Tri-Funoleroethyl) ester;

2—Amino—6— (4—Hydroxyphenethyl) 191 [2- (phosphonomethoxy) ethyl] purinbis (2,2,2— Rifnoreo Loetinole) Esthenore;

2—Amino 6— (3—Hydroxy phenylthio) —9-1-1 (phosphomethoxy) ethyl] primbis (2,2,2- Rifluro etil) Estel;

2 — Amino 1 6 — (2 — Hydroxyphenyl) 1 9 1 [2 ― (Hoshonometokishi) ethyl] Prinbis (2, 2, 2-) Trif Noreo Loetinole) Estel;

2—Amino 6— (4-Hydroxy fuinoreichi) 1 9- [2- (Hoshonometokishi) Propyl] Prinbis (2,2,2 (1 Trif Nole O Lochinore) Esthenore;

2 — Amino — 6 — (3 — Hydroxy fenthio) 1 9 1 [2 1 (Hoshonomoxy) Propyl] Prinbis (2,2, 2 Tri-Fnoreo Loetinole) Esthenore;

And 2—Amino 6— (2—Hydroxyfificylthio) 1 9— [2— (Hoshonomoxy) Propyl] Prinbis (2,2 , 2 _ Tri Fenole Loch)

Wherein the compound selected from the above is used as an active ingredient. Anti-inflammatory agent.

(5) In the above formula (I), R ¹ is a hydrogen atom, a C ¹ to C 4 alkoxy group or a hydroxyl group; R ² and R ³ ^s 2,2,2-trif noreolo The antiviral agent according to the above, wherein a compound in which R ⁴ is a hydrogen atom is an active ingredient. (6) A group consisting of the following compounds:

2 _ Amino 1 6-Phenylthio 1-9 [2-(Hoshonomethoxy) ethyl] Prinbis (2,2,2-Trifluorene) Tenore;

2 — AMINO — 6 — (4-METHOD FUSION)-9- [2-(HOS HONOMETHOXY) ETYL] PRIMBIS (2, 2, 2 1 TRI) Funenole mouth) es tenore;

2 — amino — 6 — (3-methoxyethoxy) 1 9 1 [2 1 (phosphonomethoxy) ethyl] primbis (2,2,2—trifunoleo) Mouth ethyl) ester;

2 — Amino 6 — (2-Methoxy thiol thiol) 1 9 1 [2 1 (phosphonomethoxy) ethyl] purinbis (2,2,2-tri) Funoleo mouth) ester;

2—Amino 6- (4—Ethoxy thiol) 19_ [21- (phosphomethoxy) ethyl] purinbis (2,2,21-tris) Funenole mouth) es tenore;

2 — amino — 6 — (4-butoxy) 2-9 — [21-phosphomethoxy] ethyl] primbis (2,2,2—triff Nole Lo ェ chinore) S Tenoré;

2—Amino 6— (4——Propoxyphenethyl) 1 9 1 [2-(phosphonomethyoxy) ethyl] purinbis (2,2,2- Tri-funoleo) ethyl ester; 6463

7

2 — Amino 6 — (41-isopropoxy phenylthio) -19- [21- (phosphonomethoxy) ethyl] purinbis (2,2,2— Tri-Fnoleo Loetinole) Estel;

2—Amino 6— (4—Isobutoxyphenylthio) -1 9— [2— (Hoshonometokishi) ethyl] Prinbis (2,2,2— Trif Norele Lochinore) Esthenore;

2—Amino 6— (4—Hydroxy phenyl) 1 9 1 [2 1 (phosphomethoxy) ethyl] PRIMBIS (2, 2, 2 1) Trinity (Letchinore) Esthenore;

2 — Amino 1 6 — (3—Hydroxy F 2 N 2 Recho) 1 9 1 [2— (Hoshonometokishi) Echil] Prinbis (2,2,2— Tri-Fonore)

And 2 — Amino 6 — (2 — Hydroxif e Ninorechio)-9-1 [2-(Phosphonomethoxy) ethyl] Prinbis (2, 2, 2 — Tri-no-e-ro-e-no-e)

The anti-inflammatory agent according to the above, characterized in that a compound selected from the above is used as an active ingredient.

(7) A group consisting of the following compounds:

2—Amino 6—Feninolechi 9 1 [2— (Hoshonometokishi) ethyl] Prinbis (2,2,2_trifloro ロ etinole) Esthenore ;

2 — Amino 6 — (4-Methoxy thiolthio) — 9 — [21- (phosphomethoxy) ethyl] primbis (2,2,2— Rifnoré Loch チル l) Esthenore;

2 — Amino 6 — (3 — Methoxy thiolthio) 1 9 1 [2 1 (phosphomethoxy) ethyl] primbis (2, 2, 2 — (Rifnoleo-rochiru) Estel;

2—Amino 6— (2—Methoxy thiolthio) —9—1 [2 (Phosphonometoxy) ethyl] Prinbis (2,2,2,1 Trifnoreo lochinore) Esthenore;

And 2—Amino 6— (4—Hydroxyx Enorechio) 1 9- [21 (Phosphonomethoxy) ethyl] Prinbis (2,2,2—T Li Funoleo Rocheil) S Tenoré

(8) 2—Amino 6— (4-Methoxysilane) 1 9 1 [2— (Hoshonomexoxy) ethyl] Prinbis (2, 2, 2 — Trifrenole lotinol) The antiviral agent as described above, which comprises ester as an active ingredient.

(9) Metabolite power S2—Amino 6— (4—Methoxy phenyl) 1 9 1 [2— (Phosphonomethoxy) ethyl] purine (2 2 , 2 — Trinoleroethyl) Estel or 2 — Amino 1 6 — (4-Hydroxysif e 2norrecho) — 9 1 [2-(Hoshonometoki) The above-mentioned anti-winolescent agent, which is a purine (2,2,2-tritrifluoroethyl) ester.

(10) When administered in vivo, the following formula (II)

(Wherein, R ¹ R ² , R ⁴ and M have the same meanings as described above), or a phosphonate nucleotide compound represented by the formula: or a salt thereof, or a hydrate or a hydrate thereof. An antiviral agent that is metabolized by a compound represented by a solvate and shows higher accumulation in the liver than in plasma.

(11) The antiviral agent as described above, wherein in the formula (II), R ¹ is metabolized to a compound in which R ¹ is a hydroxyl group or a C 1 to C 4 alkoxy group.

(12) In the compound of the above formula (II), R ¹ is a hydroxyl group or a C 1 to C 4 alkoxy group; and R is an ethyl group substituted with one or more halogen atoms. The antiviral agent as described above, which is metabolized.

(13) In the above formula (II), R ¹ is a hydroxyl group or a C 1 to C 4 alkoxy group; R force S 2, 2,2—trifnorolenoethyl group The antiviral agent according to the above, wherein R ⁴ is a hydrogen atom or a methyl group;

(14) A group consisting of the following compounds: 2 —Amino 6 — (4—Hydroxyphenethylthio) — 9-1 [21- (phosphonomethoxy) ethyl] purine (2,2,2—Trifluorene) Estenolle ;

2 — Amino 1 6 — (3—Hydroxyfie '2 Norethio) 1 9 1 [2 1 (Phosphonomethoxy) ethyl] purin (2,2,2—Trifluro ) Estenolle;

2 —Amino 6 — (2—Hydroxyfixinolechio) _9_ [21- (phosphonomethoxy) ethyl] purin (2,2,2—Trifluro ethinole) Estenolle ;

2-Amino 6 — (4—Hydroxyf-Enorecho) 1 9-1 [21 (Phosphonomethoxy) Propyl] Prin (2,2,2—Trifnorole Chinore) Estenolle;

2 — Amino 6 — (3 — Hydroxyphenyl) 1 9 — [2- (Phosphonomethoxy) propyl] purin (2, 2, 2 — Trifnorole Chinore) ester;

2—Amino 6— (2—Hydroxyfifenylthio) 1 9 1 [2 1 (Phosphonomethoxy) propyl] purin (2,2,2—Triphenylene) ) Estenore;

2-amino 6-1 (4-methoxyphenol thiol)-9-[21-(phosphonomethoxy) ethyl] pyridine (2, 2, 2-trifluoroethylenol) ester;

2—Amino 6- (3—Methoxy thiolthio) -9- [21- (Phosphonomethoxy) ethyl] purine (2,2,2—Trifluo p-ethinole) Esthenore;

2-amino-6- (2-methoxyethoxy) thiol 9-1 [2- (phosphonomethoxy) ethyl] purine (2,2,2-trifluorethynole) estenole;

2 — Amino 6 1 (4 — Methoxyxenilthio) 1 9 — [2 I (Hoshonometoxy) Propyl] Purin (2,2,2-Trifnorolecinole) Esthenole;

2—Amino 6— (3—Methoxy ethoxylthio) 1 9 1 [2 1 (phosphonoxy) propyl] purin (2,2,2-tri) Phenolic ester) ester;

And 2-amino 6-(2-methoxyphenoxy) 1 9-[2-(phosphonomethoxy) propyl] pyridine (2, 2, 2- Li Funoleo Loetinole) Estel

The above anti-Winnoles agent, which is metabolized to a compound selected from the group consisting of:

(1 5) 2 — Amino 6 — (4-Methoxy thiolthio)-

9 — [2-(Hoshonometokishi) etil] print (2, 2,,

2 (Trifluoroethyl) The above antiviral agent, which is metabolized to ester.

(1 6) 2 — Amino 6 — (4 — Hydroxif etherio)

-9-[21 (Hoshonometokishi)] Print] (2,

2, 2 — Trifrenole lochinole) The antiviral agent as described above, which is characterized by being metabolized to estenole.

(1 7) 2 — Amino 6 — (4-Methoxy ethoxy) 1 9 — [2 — (Hoshonomeoxy) ethyl]

(2, 2_ trifluoroethyl) The antiviral agent as described above, which is characterized by administering an ester.

(18) The anti-viral agent according to the above, wherein the immunoresin is hepatitis B virus.

(19) The following formula (III) o

X-Q-P-OR OR _t 2

OR ³

(In the formula, Q represents a mother nucleus having a medicinal effect, X represents a substituent effective for improving the targeting effect of the drug, and R ² and R ¹³ have the same meanings as described above.)

A compound or a salt thereof, or a hydrate or solvate thereof, which is improved in tissue selectivity by undergoing metabolism. Pharmaceuticals as active ingredients.

(20) In the above formula (III), the drug effect of the mother nucleus having a drug effect is an anti-cancer effect, an anti-leukemia effect, a metabolic disorder improving effect, an anti-inflammatory effect, an anti-viral effect, an anti-cancer metastatic effect, an immunological effect. The targeting of substituents that are inhibitory or antiprotozoal and that are effective in improving the drug's targeting effect include cancer cells, liver, kidney, spleen, spleen, lymph, maca, etc. The aforementioned medicament, which is selected from targeting for loft, lung, vascular inflammation site or center, and targeting for liver avoidance.

(21) In the above formula (III), the medical effect of the mother nucleus having a medical effect is an anti-cancer effect or an anti-viral effect.

(22) In the above formula (III), X is represented by a substituent effective for enhancing the fat solubility of the compound and improving a targeting effect on cancer cells and liver. The above-mentioned medicine.

(23) In the above formula (III), Q is an inositol analog, a nucleotide analog, a sugar analog, a lipid, a steroid, a peptide or a compound represented by the following formula ( IV)

(In the formula, R ⁴ and M are as defined above.)

Or the formula (III), wherein Q—P = O (0—) ₂ is represented by a bisphosphonate analog.

(24) In the above formula (III), X is morpholine, phosphatidylzolin, anoalkyl group, amino group, carboxyl group, peptide, mannose or the following formula ( V)

(In the formula, R ¹ has the same meaning as described above.)

The medicament described above, which is represented by the following formula:

(25) In the above formula (III), whether X_Q is represented by a fludarabine residue, a pencyclovir residue or a lipapirin residue; , X—Q—P = O (O—) ₂ is the force represented by a sidefovir or adefovir residue;

Or, the above formula (m) is a compound of the formula: 6-phosphonate; etidronate, indondronic acid, zoledronic acid, and allende Tetrakis (2,2,2—Trifnorole Loch) Estenolle of bisphosphonets selected from Lonet and Crodronetka;

And the following formula (I)

(Wherein, R ¹ , R ² , R °, R ⁴ and Μ have the same meanings as described above.) Or a salt thereof, or a salt or hydrate thereof. The medicament described above, which is represented by a compound selected from solvates.

(26) In the above formula (I), R ² and R ³ represent a 2,2,2-trihaethyl group, R ⁴ represents a hydrogen atom, R ¹ represents a hydrogen atom, C 1 The above-mentioned medicine, which represents an alkoxyl group or a hydroxyl group of C 4 to C 4, and wherein M is represented by CH or a nitrogen atom.

(27) A group wherein the compound represented by the formula (I) comprises the following compounds:

2 — Amino 6 — Feninorecho 1 9-1 [21 (phosphonomethoxy) ethyl] purinbis (2,2,2 — Trifnorolechoethyl) Estenolle;

2 — Amino 6 — (4-Methoxyxenylthio)-9-[2 I (Phosphonomethoxy) ethyl] Prinbis (2,2,2,1 Trifnoreo Loetinole) Esthenore;

2—Amino 6— (3—Methoxy thiol) _9—1—21 (phosphonomethyoxy) ethyl) Prinbis (2,2,2—1 Trif Nole Lo ェ chinore) S Tenoré;

2 — Amino 1 6 _ (2 — methoxy thiol thiol) 1 9 — [21 (phosphonomethyoxy) ethyl] primbis (2, 2, 2 1 tri)テレオ Tenoré;

And 2-amino 6-(4-hydroxyphenothio) 1 9-1 [2-(phosphonoxy) ethyl] primbis (2, 2, 2) — Tri Fenole Roetil) es Tenoré

The above-mentioned medicine characterized by being selected from the group consisting of:

(28) The compound represented by the formula (I) is 2-amino-6- (4-methoxyethoxy) —9— [21- (phosphonomethoxine) [Ethyl] primis (2,2,2-triffinoleoethyl) ester.

(29) By the fact that the compound undergoes metabolism, it is determined that one of R ^{2 and} R ^{3 in} the above formula (m) is a trino or an alkyl group. The above-mentioned medicine characterized by the above-mentioned.

(30) The aforementioned medicament, characterized in that the compound is a compound capable of improving selectivity to the liver by undergoing metabolism.

(31) The above drug, which is an antiviral agent. (32) The drug as described above, wherein the virus is hepatitis B virus.

(33) The following formula (Γ)

(In the formula, R and R ³ ′ represent a 2,2,2_trinopropyl group, and R ¹ R ⁴ and M have the same meaning as described above.)

Or a salt thereof, or a hydrate or solvate thereof, and a compound comprising, as an active ingredient, a compound capable of improving cell permeability.

(34) The drug as described above, wherein the permeability of the cells is the passage of tight junction cells present in the gastrointestinal tract.

(35) The following formula (Γ)

(In the formula, R ¹ R ² ′, R ³ ′, R ⁴ and M have the same meanings as described above.)

Or a salt thereof, or a hydrate or solvate thereof, and a medicament comprising a compound that avoids the kidneys as an active ingredient.

(36) The following formula (1 ')

(In the formula, R ¹ R 2 R 3 R ⁴ and M have the same meaning as described above.)

Or a salt thereof, or a hydrate or solvate thereof, and has an improved accumulation in the skin and / or sciatic nerve A drug containing a compound as an active ingredient.

(37) The drug as described above, wherein in the formula (I ′), R ^{1 is a} methoxy group, R 4 is a hydrogen atom, and M is CH.

(38) The drug as described above, which is an antiviral agent.

(39) The drug as described above, wherein the innorace is a hepatitis B virus. (40) The drug as described above, wherein the virus is varicella-zoster virus. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram showing the concentrations of metabolites in plasma and liver measured by HPLC.

FIG. 2 is a diagram showing the elution time of each compound measured by HPLC.

FIG. 3 shows the concentration of each compound in plasma 0.5 hour after administration of the labeled compound to monkeys.

FIG. 4 is a graph showing the concentration of each compound in plasma 25 hours after administration of a labeled compound to a rat.

FIG. 5 is a graph showing the concentration of a compound after passing through the cell monolayer membrane for the permeability of the labeled compound. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

First, a phosphonate-nucleotide compound represented by the formula (I) or a salt thereof, or a hydrate or solvate thereof, which is the first gist of the present invention, is provided. Antiviral agents that show higher concentrations of metabolites in the liver than in plasma as active ingredients will be described.

The active ingredient of the present invention is a phosphonate nucleotide compound represented by the formula (I) or a salt thereof, or a hydrate or solvate thereof.

In the phosphonate nucleotide compound of the above formula (I),

Examples of the C 1 -C 6 alkoxyl group represented by R ¹ include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, Examples include n_butoxy, isobutoxy, sec—butoxy, tert—butoxy, n—pentynoleoxy, and n—hexynoleoxy. Examples of the C 1 -C 4 alkoxyl group substituted with one or more halogen atoms represented by R ¹ include a monophenolic methoxy group, a difluoro methoxy group, and a Rifnoreolo ethoxy group, Mono phenoleo ethoxy group, Diphnoleo ethoxy group, Trifluoro ethoxy group, Tetra phenol ethoxy group, Pentafluoro ethoxy group, Mono Fluoropropoxy group, difluoropropoxy group, trifluorene mouth Propropoxy group, tetrafluoropropoxy group, pentafluoropropoxy group, hexafluoropropoxy group, heptafluorene mouth Propoxy group, monophenolic isopropoxy group, difluoroisopropoxy group, trifluorophenolic isopropoxy group, tetrafluoro Examples include an iso-opened oxy group, a pentafluoroisopropoxy group, a hexafluoroisopropoxy group, and a heptafluoroisopropoxy group.

In the ethyl group substituted with one or more halogen atoms represented by R ² and R ^種類 , the type of the hydrogen atom or the halogen atom is the fluorine atom, the chlorine atom, the bromine atom, or the iodine atom. Either is acceptable. Examples of the ethyl group substituted with one or more halogen atoms include: 1 -fluoroethylene group, 2 -chloroethylene group, 1 -chloroethylene group, and 2 -chloroethylene group. Group, 2 — Promotinole group, 2, 2 — Difluoroethyl group, 2, 2 — Dichloroethynole group, 2, 2 — Jib mouth Moethyl group, 2, 2, 2, 2 _ Trifnorre O-ethyl group, 2,2,2—trichloroethynole group, 2,2,2—tribromoethyl group and the like. In particular, it is preferable that the 2-position of the ethyl group is substituted, and as the halogen atom, a fluorine atom is preferable. Examples of the C 1 to C 4 alkyl group represented by R ⁴ include a methyl group, an ethyl group, n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and a sec-butyl group. And a tert-butynole group. Examples of the C 1 -C 4 hydroxyalkyl group represented by R ⁴ include a hydroxymethyl group, 1 —hydroxyethyl group, 2 —hydroxyxethyl group, and 1 —hydroxy group. Xypropynole group, 2—hydroxypropyl group, 3—hydroxypropyl group, 1-hydroxybutyl group, 2—hydroxybutyl group, 3—hydroxybutyl group, 4—hydroxy A xybutyl group and the like can be mentioned. As the C 1 -C 4 alkyl group substituted with one or more halogen atoms represented by R ⁴ , a halogen atom such as a fluorine atom and a chlorine atom is a methyl group, an ethyl group, n-propyl group, isopropynole group, n-butynole group, isobutynole group, sec-butynole group, tert-butyl group, and the like. Specific examples include a fluoromethyl group, a diphenylolemethyl group, a trifluoromethyl group, a phenolic methyl group, a chloroethynole group, a phenolic propyl group, and a chloromethyl propyl group. , A fluorobutyl group, a butyl mouth group and the like. In the present invention, R ¹ is a hydrogen atom, Ri alkoxyl group or a hydroxyl group der of C 1 ~ C 4, 11 ² and 1 ^ ³ months'; 2, 2, 2 - Ri Application Benefits Furuoro Echiru group der, Examples of the first condition of the compound in which R ⁴ preferably is a hydrogen atom or a methyl group are preferred. R ¹ is a C 1 -C 4 alkoxy group or a hydroxyl group;

R ² and R ³ are 2,2,2_trifluoroethyl groups, and the second condition of the compound in which R ⁴ is preferably a hydrogen atom is mentioned. For example, specific preferred compounds satisfying the first condition include the following compounds:

2-Amino 6-phenylthio-9- [2 (phosphonomethoxy) ethyl] primbis (2,2,2 trifluorene) ester;

2 — Amino 6 _ (4-methoxyphenyl)-9-[21 (phosphonomexyl) primine (2,2,21 tri) Funenore Lo ロ chinore Estel;

2 — Amino 6 — (3 methoxy phosphine) 1 9 — [21 phosphonomethycinethyl] Prinbis (2,2,2 1 trifluorophenol) Loetinole Est Tenoré;

2 — Amino 6 — (2 methoxy phenyl thiol)-9-[21 (phosphono methicillethyl) primis (2, 2, 2 1 trifluorophenol)才ロエチテテテ;

2 — Amino 6 — (4-ethoxyphenyl) -9- [2- (phosphonomethoxy) ethyl] primbis (2,2,21-triethyl) Fuenore sue tenore;

2 — Amino 6 — Phenylthio 1 9 1 [2 1 (Phoshonomexioxy) Pout Pill] Plimbis (2,2,2 — Trifnoreo Mouth Etinole) d Stainless steel;

2 — Amino 6 — (4-Methoxy cinnamon)-9-1 [2-1 (Hoshonomoxy) Propyl] Prinbis (2, 2, 2) -Tri-Funole Loetinole) ES Tenore;

2—Amino 6— (4-butoxyphenylthio) 19— [21- (phosphonomethoxy) ethyl] purinbis (2,2,21-trif)レロ Tenoré;

2—Amino 6— (4.-Propoxy thienylthio) -9_ [21- (phosphonomethoxy) ethyl] purinbis (2,2,2 (1) trifluorene) ester;

2 — amino _ 6 _ (4 — isopropoxyphenethylthio)-9-[2 — (phosphonomethoxy) ethyl] primbis (2, 2, 2 — trifluorene) ) Ester;

2 — amino — 6 — (4 — isobutoxy ethoxylthio)-9-[2-(phosphonomethoxy) ethyl] purinbis (2,2,2 — trifluorethyl) Ester;

2 —Amino 1 6 — (4—Hydroxyphenethyl) 1 9 — [2- (Phosphonomethoxy) ethyl] purinbis (2,2,2 1 Trif Noreo Loetinore) Esthenore;

2—Amino 1 6— (3—Hydroxyphenethyl) 1 9— [2- (Phosphonomethoxy) ethyl] Primbis (2,2,2—Trif ) Estenolle;

2 — Amino 6 — (2 — Hydroxyphenyl) 1 9 — [21 (Phosphonomethoxy) ethyl] Primbis (2,2,2-Trifluorophenol) Esthenore;

2—Amino 6— (4—Hydroxifeninorecho) 1 9— [21 (Phosphonomethoxy) propyl] Primbis (2,2,2—Trifnoreo Lo チ chinore) Estenolle;

2—Amino—6— (3—Hydroxyifenthio) 19— [21- (phosphonomethoxy) propyl] purinbis (2,2,2-trif)レテチレステテテテ;

And 2 _ amino 6-(2-hydroxyphenethyl) 1 9-[2- (phosphonomethoxy) propyl] primbis (2, 2, 2-tri) Fluoroethyl) Ester

Are mentioned.

In addition, as the compound satisfying the second condition, the following compound: 2 —amino 6 — phenylthio-19-1 [2- (phosphonomet W 03

23 kishi) ethyl] primbis (2,2,2-trifluorethyl) estenole;

2—Amino 1 6— (4—Methoxy thiol) 1 9 1 [2 1 (phosphomethoxy) ethyl] PRIMBIS (2,2,2 1 tri) (Funolero-Echil) S;

2—Amino 1 6— (3—Methoxy thiolthio) 1 9 1 [2 1 (phosphomethonoxy) ethyl] purinbis (2,2,2— Rif Noreo L チ chinore) S Tenoré;

2—Amino 1 6— (2—Methoxy thiol) 1 9 1 [2— (Hoshonomexoxy) ethyl] Prinbis (2,2,2—T Rifnoreo Loetinole) S Tenoré;

2 — Amino 6 _ (4 — Ethoxyfurnthio) 1 9 1 [2 1 (phosphomethoxy) ethyl] PRIMBIS (2, 2, 2 1 Rifnoreo Roeti / Les) Tenoré;

2—Amino 6— (4—butoxy thiolthio) 1 9-1 [21 phoshon methoxy] ethyl] Prinbis (2,2,2—Tri Funeno Leo Chinole) S Tenoré;

2—Amino 6— (4—Propoxyphenethyl) 1 9 1 [2 1 (Phosphonomethoxy) ethyl] Prinbis (2,2,2 1) Lif Noleo Lechil) S Tenorée;

2 — Amino 6 _ (4 — Isopropoxy fenthio) 1 9 1 [2 — (Hoshonomexoxy) ethyl] Prinbis (2, 2, 2) — Tri Fleur Lochinole) Estel;

2—Amino 1 6— (4—Isotokoxy) 1 9— [2— (Hoshonomexoxy) ethyl] Prinbis (2, 2,

2 — Tri Fnoreo Loetinole) Estel;

2 — Amino 6 — (4-hydroxy phenyl) 1 9 1 [2 1 (phosphonoxy) ethyl] primbis (2, 2, 2- Tri-Fnoreo Loetinole) S Tenoré;

2 — Amino 1 6 — (3 — Hydroxyl ether) 1 9 1 [2-(phosphomethoxy) ethyl] purinbis (2,2,2 -to) Rif Noreo L チ chinore) S Tenoré;

And 2 — Amino 6 — (2 — Hydroxyphenyl) 1 9-[21 (Hoshonomexoxy) ethyl] Prinbis (2, 2, 2 — Tri Fleur Loechil Estel

Is mentioned.

As more preferred compounds,

2 — Amino 1 6 — Huininolechi 9 — [2 — (Hoshonometokishi) ethyl] Prinbis (2,2,2 — Trihnolle Lo chinore) Esthenore;

2—Amino 6— (4—Methoxy thiolthio) -9- [2- (phosphonomethyoxy) ethyl] purinbis (2,2,2 Rifnoreo Loetinole) Estel;

2 — Amino 6 — (3 — Methoxy thiolthio) 1 9 — [21 (phosphonomethyoxy) ethyl] PRIMBIS (2, 2, 2 —フレロロチテテテテテ;

2 — Amino 1 6 — (2 — methoxy thiol thiol)-9-[21 (phosphonomethyoxy) ethyl] PRIMBIS (2, 2, 2) (Funole Lochinore) es tenore;

And 2—Amino 6— (4—Hydroxysfino) 1 9— [2— (Hoshonometoxy) ethyl] Prinbis (2,2,2) — Trif Noreo Loechnore)

And the most preferred compound is 2-amino-6- (4-methoxyphenyl) -9- [21- (phosphonomethoxy) ethyl] pre] Nbis (2,2,2—trifnorolecho) ester. Examples of the compound of the formula (I) and a pharmaceutically acceptable salt thereof include an acid addition salt with an inorganic acid or an organic acid.

Since the compound of the formula (I) and the hydrate or a pharmaceutically acceptable salt thereof may exist in the form of a hydrate or a solvate, these hydrates and solvates may be used. Objects 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 racemates are included in the present invention.

These phosphonucleotide compounds are known compounds and are described, for example, in JP-A-9-255695 and WO01 / 64693. It is a compound that can be easily synthesized by the method of (1) and can be easily obtained by those skilled in the art.

Incidentally, the above-mentioned Japanese Patent Application Laid-Open Nos. Hei 9-256569 and WO01 / 64693 disclose a phosphonate nucleotide compound as an active ingredient in the present invention. Although it is described that it is useful as an antiviral agent, as shown in the Examples below, it is related to the fact that its metabolite shows higher accumulation in the liver than in plasma. Are not described in the above publication.

An example of a metabolite of the antiviral agent of the present invention shown above is a compound represented by the formula (11). The compound represented by the formula (11) is a compound known from JP-A-9-25695 and WO01 / 64693. The compound can be specified with reference to the gazette. Further, as shown in the examples described below, there is no mention in the above-mentioned publications that these compounds show higher accumulation in the liver than in plasma.

The compound of the formula (I) is useful as an active ingredient of a medicament, Specifically, it is useful as an effective component of an antiviral agent as shown in the test examples described below.

The virus to which the medicament of the present invention can be applied is not particularly limited, and specifically, RNA virus such as human immunodeficiency virus, influenza virus, hepatitis C virus, and simple virus. DNA viruses such as Inores I, simple heterozygous inoresin 11, site megalovirus, varicella-zoster virus, and hepatitis B virus. Preferable is varicella-zoster virus or hepatitis B virus, and more preferable is hepatitis B-inores.

When the phosphonate nucleotide compound of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof is used as a medicament, it may be administered alone, but it may be pharmaceutically acceptable. It is preferable to produce and administer a pharmaceutical composition containing the above compound as an active ingredient using the obtained pharmaceutical additive. It can also be administered orally or parenterally in the form of a formulation. The pharmaceutical composition can be formulated according to a usual method. In this specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, and infusion. Injection preparations can be prepared by methods known in the art. Suppositories for rectal administration can be prepared by mixing the drug with an appropriate excipient and the like. Examples of solid dosage forms for oral administration include powders, granules, tablets, pills, capsules, and the like. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions.

The compound of the present invention, in particular, the ester derivative represented by the above formula (I) is disclosed in Japanese Patent Application Laid-Open No. Hei 9-256565 / 95 and WO 01/664. Oral administration is a preferred route of administration of the medicament of the present invention because of its high oral absorption as shown in JP 693. The preparation of each of the above-mentioned preparations can be carried out according to a conventional method. The clinical dose of the medicament of the present invention, when used orally, is generally 0.1 to 500 mg / kg, preferably 0.1 to 500 mg / kg per adult day, based on the weight of the compound of the present invention. Is between 1 and 5 O mg / kg. Particularly, the above dosage may be appropriately increased or decreased depending on age, medical condition, symptom, presence / absence of simultaneous administration, and the like. The daily dose may be administered once a day, or divided into two to several times a day at appropriate intervals, or may be administered intermittently every few days. When used as an injection, the compound of the present invention is used in an amount of 0.01 to 50 mg / kg, preferably 0.1 to 5 mg / kg, per day for an adult. is there. Next, the second aspect of the present invention is a compound represented by the formula (III) or a salt thereof, or a hydrate or solvate thereof, and which is subject to metabolism. Accordingly, a drug containing a compound that improves tissue selectivity as an active ingredient will be described.

The active ingredient which fulfills the purpose of the second aspect of the present invention is represented by the formula

The compound represented by (m) or a salt thereof, or a hydrate or solvate thereof.

In the formula (m), Q represents a mother nucleus having a medicinal effect.

Specific examples of the medicinal effect include substances having an anticancer effect, an antileukemia effect, a metabolic abnormality improving effect, an antiinflammatory effect, an antiviral effect, an anticancer metastatic effect, an immunosuppressive effect, or an antiprotozoal effect. Preferable is an anticancer effect or antiviral effect, and more preferable is an antiviral effect. Specific examples of Q include inositol analogues, nucleoside analogues, bran analogues, lipids, steroids and peptides, or the formula (IV) And preferably Q is the above formula (IV).

Further, when Q—P = 〇 (0—) ₂ in the above formula (ΠΙ), a case where the compound is a bisphosphonate analog is also a preferred specific example.

In the above formula (ΠΙ), X represents a functional group effective for improving the targeting effect of the drug.

Here, targeting refers to the accumulation of a compound on a specific cell or organ or the avoidance of a specific cell or organ.

X is for the purpose of targeting cancer cells, liver, kidney, spleen, kidney, lymph, macrophage, lung, vascular inflammation site or center and avoiding liver. Functional groups that can be targeted. Preferably, a functional group capable of targeting to cancer cells or the liver is mentioned, and most preferably, a functional group capable of targeting to the liver is mentioned. Specific examples of X Examples thereof include monorefolin, phosphatidylcholine, anoalkyl group, carboxyl group, amino group, peptide, mannose, and a case represented by the formula (V). It is possible. Preferred is a case represented by the above formula (V). As the alkyl group, those described in the first aspect can be used. Further, as a specific example of the above formula (m), in the above formula (m), X—Q is represented by a fludarabine residue, a pensic bil building residue or a lipavirin residue. , Or X — Q — p = O (O −) ₂ is a group represented by a sideophyl or adefovir residue; or the above formula (ΠΙ) is a glucose 16-phosphonate; A bisphosphonate selected from the group consisting of lonetronic acid, indronic acid, zoledronic acid, allendronate, and crossdronate. Tetrax (2,2,2—trifluoroethyl) ester; and a phosphonate-nucleotide compound represented by the formula (I) or a salt thereof, or Hydrates or solvates thereof can be mentioned. Preferably, a phosphonate nucleotide compound represented by the above formula (I) or a salt thereof, or a hydrate or solvate thereof is mentioned. Here, examples of the substituent of the formula (I) include those described in the first aspect.

In the second aspect of the present invention, the term “metabolism” means that when a compound is taken up into a living body or a cell, one or two of trinoperethanol esters are cleaved to form a hydroxyl group. And.

Improved tissue selectivity refers to higher accumulation in specific tissues than in plasma. Tissues include cancer cells, liver, kidney, spleen, lymph, macrophage, lung, vascular inflammation site or center, preferably cancer cells or liver. More preferably, it includes the liver. The compound of the formula (I) can be easily synthesized by the method described in the first aspect, and can be easily obtained by those skilled in the art. Can be done. Fludarabine is in accordance with J. A. Montgomery, K. Heson, J. Med. Chem., 12 and 492 (19669), and sidfovir is P According to A lexander, A. Holy, Collection C zechoslovak Chem. Comm., 58, 11 15 1-1 16 3 (1993), Adefoville is A. Ho 1 According to y, I. Rosenberg, Collection Czechoslovak Chem. Commu., 52, 2801-11-2809 (19987), each can be synthesized. In addition, the Pensikguchi building is from GlaxoSmithKline, the etidronet is from Sumitomo Pharmaceuticals, the Ivandronsan is from Kashishsha, and Zoredro. Acid is marketed as a pharmaceutical by Nonorenotes, Allendronate is marketed by Banyu Pharmaceuticals, and Croduronate is marketed by Kitsushi Pharmaceutical. Rivapirin can be purchased as a reagent from Sigma. Also, referring to Hal ina T. Serafinowska eta 1, Synthesis and m'Vivo Evalution of prodrugs of 9- [2- (Phosphonomethoxy) ethoxy] adenine, J Med Chem 38, 1372-1379 (1995), It is possible to introduce a phosphate group, and John E. Starrett et al, Synthesis, or al bioavilability determination, and in vitro evalution of prodrugs of the antivirul agent 9-[2 (Phosphonomethoxy) ethoxy] adenine (PMEA ), J. Med. Chem, 37, 1857-1864 (1994), it is possible to introduce an ester into a phosphate group.

In the second gist of the present invention, the compound represented by the formula (III) is effective as an active ingredient of a drug, and specifically, as an active ingredient of an antiviral agent. Useful.

Viruses to which the medicament of the present invention is applied include those described in the first aspect. The method of formulation and administration when the phosphonate nucleotide compound of the formula (I) of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof is used as a medicament, are described in The ones mentioned in the summary of 1 are mentioned. In addition, it is preferable to follow the dosage for each drug on the market. Next, a compound represented by the above formula (I ′), which is the third aspect of the present invention, is: -phosphonate nucleotide compound or a salt thereof, or a hydrate or a hydrate thereof. A medicament containing a compound that is a solvate and improves cell permeability as an active ingredient will be described.

The active ingredient of the present invention is a compound represented by the formula (I ′) or a salt thereof, or a hydrate or solvate thereof. In the phosphonate nucleotide compound of the above formula (1), R

² and R ³ force S 2, 2, 2 — represents a trihaloethyl group, R ¹

R ⁴ and M include those described in the first aspect. In the third aspect of the present invention, a cell refers to a cell that forms an organ such as a blood vessel, skin, nerve, kidney or liver, or a tight junction (also referred to as a closed junction or a closed zone). Cells that form.

Permeability refers to the passage of a compound through a cell to reach organs, blood or body fluids separated by the cell, or to be taken up by the cell membrane through the cell membrane. Let's check what is done. Here, the passage of cells includes the entry of a compound into a tissue through tight junctions. The passage through the cell membrane includes the arrival of the compound from the blood or body fluid into the cells of the organ, preferably from plasma through the cell membrane and into the cells of the liver. Is mentioned. Tight junctions refer to tissues in which adjacent cell membranes are in close contact with each other and are prevented from moving by diffusion through cell gaps. Preferably, the tight junctions present in the gastrointestinal tract are fisted.

Next, a fourth aspect of the present invention is a phosphonate nucleotide compound represented by the formula (II) or a salt thereof, or a hydrate or solvate thereof. A medicine comprising a compound that avoids the kidney as an active ingredient will be described.

The active ingredients of the present invention include those described in the third aspect of the present invention.

In the fourth aspect of the present invention, avoidance of the kidney refers to a decrease in accumulation in the kidney. Specifically, it refers to a decrease in the accumulation of the compound in the kidney.

Next, a fifth aspect of the present invention is a phosphonate nucleotide compound represented by the formula (II) or a salt thereof, or a hydrate or solvate thereof, In addition, a medicament containing as an active ingredient a compound capable of improving accumulation on the skin and / or sciatic nerve will be described.

In the fifth aspect of the present invention, the enhancement of accumulation on the skin and / or sciatic nerve means that one or more trifluoroethanol esters are compared with a compound having no trifluoroethanol ester. Refers to an increase in the concentration of a compound having the compound in the skin and / or sciatic nerve.

In the third, fourth, and fifth aspects of the present invention, the compound represented by the formula (I ′) is effective as an active ingredient of a medicament, and specifically, an active ingredient of an antiviral agent. Useful as Will Three

Examples of the materials include those described in the first gist. In addition, the method of preparation and the method of administration when used as a medicament are the same as those described in the first aspect.

The formula (I ′) can be easily synthesized by the method described in the first aspect, and can be easily obtained by those skilled in the art. Example

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to the following examples as long as the gist is not exceeded. Reference example 1

2 — Amino et al. (4-Methoxy ethoxy) 1 9 — [21 (phosphonoxy) ethyl] primbis (2,2,2,1 trifluoro) (Echinore) Manufacturing of ester

2 — Chloro ノメレクメメ 8 7 8 7 g (670 mmo 1) and tris (2,2,2 — trifluoroethyl) phosphite 20 g (6 With 10 mm 0 1) at 16 ° C for 7 hours to give 2— [bis (2,2,2 trifluoroethyl) phosphonomethoxy] ethyl chloride Was quantitatively obtained.

Dissolve 206 g of 2-(phosphonomethoxy) ethyl chloride chloride (2,2,2-triphenylenole) in 200 ml of methylethyl ketone. The mixture was refluxed with sodium iodide (270 g) for 8 hours. After the reaction, the mixture was cooled to room temperature and concentrated to dryness. The residue is dissolved in black-mouthed form / hexane, adsorbed on gel gel, eluted with chloroform / hexane, and 2- (phosphonomethoxy) ethylenol Zidbis (2,2,2—trifluoroethyl) was obtained quantitatively. 2 — Amino _ 6 — Black-mouthed purine 15.0 g (88 mm 0 1) was suspended in dimethylformamide 36 Oml, and 1,8-diazabicyclo [5 [4.0] The reaction was carried out with 13.9 ml (93 mmo 1) at 80 ° C. for 1 hour. Next, add 23.8 ml of 2 — (phosphomethosyl chloride, bis (2,2,2 — trifnoroleethyl)) to the above reaction solution, and add 100 ° C After the reaction, the mixture was cooled to room temperature, concentrated to dryness, and the residue was dissolved in porcelain form, adsorbed on a gel gel column, and 5% methanol-free. Elution with honolem, 2 _ amino 6-black 9-[2-(phosphonomethoxy) ethyl]-primbis (2,2,2-trifnoroleroethyl) 2 3.3 g (yield 56%) was obtained.

2 — Amino 6 — Black mouth 1 9 1 [2 — (phosphonomethoxy) ethyl] 1 purine [2 — [bis (2,2,2 — trifnoreoloetinole) 7. To a 6 ml solution of lg's dimethylfonoleamide, add 2.1 ml of triethylamine and 3.1 ml of 4-methoxythiol enol, and stir at 100 ° C for 2 hours. did. The reaction mixture was cooled to room temperature and concentrated to dryness.

The residue is dissolved in porphyrin sorbent, adsorbed on gel gel, and eluted with 5%>-methanol chlorophoronelem. Eninoretchi) 1 9 1 [2— (Phosphonometroxethyl) ethyl] Primbis (2,2,2-trifnorreroethyl) ester was obtained.

m.p .: 93-95 ° C (diisopropyl ether) χ-NMR (CDC13, δ): 3.85 (s, 3H),

3.92-4.00 (m, 4H), 4.24-4.45 (m, 6H), 4.75 (s, 2H), 6.95 (d, J-29.OHz, 2H), 7.53 (d, J = 9.0Hz, 2H), 7.7 (s, 1H) Example 1

2-Amino 1 6 — (4-Methoxy thiolthio) 1 9 1 [2 1 (phosphonoxymethyl) ethyl] PRIMBIS (2,2,2 1 100 mg / kg of ester was dissolved in 1 mm 1 of aqueous tragacanth solution in plasma and liver after a single oral administration to male C57B6J mice. The concentration of the metabolite in was determined. Plasma was prepared by collecting blood from two mice each time. The liver was prepared by extracting the liver from each of two mice at each time and emulsifying by adding twice the volume of physiological saline. In addition, HPLC was measured under the following conditions.

(HPLC measurement conditions)

Power ram: mosquitoes Tsu capsule Nono ⁰ click _{(C apcell P ack) C 18} D mosquitoes ram (Shiseido Co., Ltd.)

Detection wavelength: 3 1 1 nm

Flow velocity: 0.8 mL / min

: 30 ° C

Mobile phase: 35% acetonitrile and 1.25 mM pick A (P

1 c A: Aqueous solution containing Waters

When metabolites were identified using HPLC, the major metabolites were 2—amino-6— (4—methoxydiphenol).

[2-(Hoshonometokishi) ethyl] Prin (2,2,21 Trifnorolech) It was Este Nore. Further, according to the method described in JP-A-9-125659-5 and WOO 1/64693, 2-amino-6- (4-methoxyethoxy) is used. 9 One [2— (Hoshonometokishi)] printer] (2

2, 2 — Trifluoroethyl) Hepatitis B virus of Estenolle When the activity was measured, the HBV-DNA 50% synthesis inhibitory concentration of the metabolite was 0.07 μΜ, indicating that it had antiviral activity.

FIG. 1 shows the results of the metabolite concentrations in plasma and liver measured by HPLC. In Fig. 1, Hata is a metabolite in the liver (21-amino-6- (4-methodoxy-n-recho) -19- [21- (phospho-methoxy) -ethyl ] Shows the concentration of purine (2,2,2—trifnorolecholine) ester, and the country shows the concentration of the metabolite in plasma.

FIG. 1 clearly shows that the metabolite shows higher accumulation in the liver than in plasma. Example 2

2—Amino 1 6— (4—methoxy thiol) 1 9— [21 (phosphonomethyoxy) ethyl] primbis (2,2,2 1 tri) off Ruoro Echiru) was measured tissue concentration transition of Chi was administered a single oral position 8 labeled of compound at ¹⁴ C of S. ether at a dose of 2 mg Z kg to male rats fasting conditions. Liver tissue was collected from the posterior vena cava at predetermined times (15 minutes, 1, 4, 8, 24, 48, 96, 168 hours) and then removed. The radioactivity was measured by a liquid scintillation counter (Perkin Elmer) which performs quenching correction by the tSIE method. The results were calculated using a pharmacokinetic study support software (pharmacokinetic system, Fuji Facom System). The results are shown in Table 1. Concentration in liver Concentration in plasma Time

V jU geq./mL) (jligeq./m

15 minutes 0.894 6.7 times.0.133

1 hour 0.291 6.9 times 0.042

4 hours 0.16 8.4 times 0.019

8 hours 0.071 8 times 0.009

24 hours 0.032 11 times 0.003

48 hours 0.056 28 times 0.002

96 hours 0.017 Detection limit or less

168 hours 0.011 detection limit or less As shown in Table 1, 2-Amino 1 6-(4-methoxyphenyl) 1-9 1 [2-(Hoshonomexoxy) ethyl] The radioactivity derived from bis (2,2,2—trifnoreoloetinole) ester is rapidly incorporated into the tissue (maximum concentration time in the liver T max = 15 minutes) and into the plasma. Compared to the higher accumulation in the liver, 2—amino 6— (4—methoxy feninolechio) 1 9 1 [2— (phosphonomethox) ethyl] purine To study the metabolic profile of bis (2,2,2—trifnorolecholine) ester metabolites, 2—amino 1 6— (4—metoki) [Shifeniruchio] 1 9 1 [2-(Phosphonometxo) echinole] Purbis (2,2,2-Trifnoreoloye) Chinore) d scan the S-position of te Honoré single oral administration at a dose of 2 mg / kg labeled for compounds to male monkey and male rats Bok fasting conditions at ¹ C, resulting plasma Nitsu physician The high performance liquid chromatograph (HPLC) method was used for the measurement.

2—Amino 6— (4—Metxif-Norrecho) 1 9— [2— (Hoshonometokichi) ethyl] Prinbis (2,2,2 for replacement) Paper (Rule 2 The structural formula of (trifluoroethyl) ester and its estimated metabolites are shown below. In addition, IS below shows the compound used as a standard substance. In FIG. 2 to be described later, M_2p is the monophasic of the following M-2, and M-2pp is the diphosphath of the following M-2. . M-4p is a monophosphate of the following M-4, and M-4pp is a diphosphate of the following M-4.

Putative metabolite

2—Amino—6— (4

(HPLC measurement conditions)

Column: Dev eio s i ls O D S — UG—54. 6 X 250 mm (Nomura Chemical Co., Ltd.)

Column temperature: 40 degrees

Mobile phase: Solution A: 25% acetonitrile + PicA reagent (W aters)

Solution B: 50% acetonitrile + Pic A reagent (Waters)

Flow velocity: 1.0 m1 / min

Detection: UV (315 nm) Detector: SPD—10 A Shimadzu Corporation, Radioactivity ( ¹⁴ C) Detector: F 10—ONE (PerkinElmer), Scintillator: Unorechima full b over M (Nono ⁰ - key Nenorema one company), shea inch, single-te flow rate: 3 ml / min

The results are shown in FIGS. 2, 3 and 4. Fig. 2 shows 2-amino 6- (4-methoxyphenyl) -9-1 [2- (phosphonomethyoxy) ethyl] primbis (2, The elution times of 2, 2-trifluoroethyl) ester and the nine putative metabolites shown above were confirmed. Figure 3 shows 0.5 hours after administration of the compound to male monkeys. The results were obtained by injecting the blood plasma sample into HPLC and measuring with an RI detector. Fig. 4 shows the results obtained by injecting a plasma sample 0.25 hours after administration of the compound to a male rat into HPLC and measuring with a RI detector.

The metabolic profile can be estimated from the ratios of the peaks in FIGS. 2, 3 and 4, and the major metabolite in plasma of the compound is the monoesthesis of the compound. It became clear that it was a ter body. Example 3

2 — Amino 6 — (4-Met.

-(Phosphonomethoxy) ethyl] Primbis (2,2,21-trifnoroleoethyl) ester (sample B) and 21-amino-1-61 (4-methodoxy) (Shifuurchio) 1 9 1 [2 1 After a rapid administration of a 10-mL LZ kg dose of a compound labeled with ¹⁴ C at position 8 of methine) .ethyl] purine (sample D) to an 8-week-old male mouse, And liver were collected. After weighing the total amount of the kidney and liver tissues, the tissue was cut into small pieces, and a portion was collected in a liquid scintillation pipet and weighed. Thereafter, 0.5 mL of lj (S0LUENE-350: Norkin Nole Life Science) was added to the plasma and tissues, and the mixture was dissolved by heating at 60 ° C and the liquid scintillation. (HI0NIC-FLU0R, Kineruma Life Science Co., Ltd.) 1 OmL was added. The radioactivity in each sample was measured for 5 minutes with a liquid scintillation counter (LSC-2900: Parkin Elmer Life Science). Correction of counting efficiency was performed by the external source standard method.

Kp (radioactive concentration in tissue / radioactive concentration in plasma) was calculated as a value indicating the transferability to liver tissue.

The evaluation of renal avoidance was evaluated by calculating the amount of accumulation in tissues using the following formula.

Kidneys transition value = Kidney concentration per 1 g

Table 2 shows the results. These results indicate that when administered to the circulating blood, sample D, which is a metabolized monoester, has higher accumulation in the liver and kidneys than sample B, which is a ester form. It was clear that it showed organ avoidance. Here, circulating blood refers to blood circulating throughout the body after passing through the liver.

Table 2 Liver Kp value Kidney accumulation (nmol / g)

Sample B. 5.65

sample. 18.24 Example 4

9 1- (2-Phosphonyl-methoxetil) -guanine (sample A) and sample D used in Example 3 were used to label each compound at the 8th position with ¹⁴ C, and the male was aged 8 weeks after laparotomy. After rapid administration at a dose of 1 mL / kg to the total portal vein of the rat, the kidney and liver were collected and evaluated for their transfer to liver tissue and kidney avoidance according to the measurement method described in Example 3. Was.

Kidneys transition value = Kidney concentration X Kidney tissue weight

Table 3 shows the results. These results indicate that the modifying group at the 6-position in the formula (I) may contribute to accumulation in the liver and kidney avoidance when the compound is administered to portal venous blood. Something became clear. Here, portal vein blood refers to blood in the portal vein, which is a blood vessel from the mesenteric vein to the liver, which is taken in when the compound is absorbed from the intestinal tract.

Table 3

Kidney Kp value Liver Κρ value Kidney accumulation (nmol)

Sample A 6.016 0.186 463.68

Sample D 1.173 0.552 308.5

Example 5

2—Amino 6— (4-Methoxy ethoxylthio) 191 [2- (phosphonomethoxy) ethyl] purine (2,2,2—Trifluoroethyl) ester (Sample C) ), And the compounds in which the 8-position of sample B and sample D used in Example 3 were labeled with ¹⁴ C were used as test substances, respectively. As an internal standard, a solution of Μμ ノレフ ((Lucifer Yellow CH: Sigma, Inc.) diluted 100-fold with a culture medium for permeation test on the mucosal side was used.

As a culture medium for the mucosal side permeation test, a medium prepared by Hank's balanced salt solution (HBSS Gibco) was used so that the final concentration was 20 mmo1 / L. Gibco) and added to sodium hydroxide or hydrochloric acid to pH 6.5.

The test substances were prepared in 20 μl each (containing 1% final concentration of dimethyl sulfoxide (DMS0)) using 1 μl of Lucifer Yellow solution.

The monolayer membrane of Caco-2 cells (ATCC No. HTΒ37) cultured for 4 days was observed under a microscope, checked for damage and recorded on a peak sheet. If any abnormalities were apparent from the microscopic examination, they were not used for experiments.

On the mucosal side (upper), put 2. OmL of medium for permeation test on mucosal side, and on the serosal side (lower), put 2. OmL of medium for permeation test on serosal side, and play at 37 ° C, 35 min " ¹ for 10 minutes. Incubated.

The medium for the serosa-side permeation test was prepared by adding Mess® (Gibco) to HBSS to a final concentration of 20 mm 01 ZL, and adjusting the pH to 7.4 with sodium hydroxide or hydrochloric acid. The one prepared was used.

In addition, the film resistance was measured at three locations on each panel using a film resistance measuring device, Miricell®_ESR (Millipore), and recorded on the worksheet. The measured value was applied to the following equation, and the film resistance value corrected by the film surface area was calculated.

Corrected membrane resistance (Ω · cm ² ) = (average of three measured values-103) X 4.71

At this time, a well showing a value less than 300 Ω should not be used for experiments. And Serosa-side permeation test medium 2.OmL is accurately placed in the serosal side, mucosal side is filled with test substance solution 2.OmL, and serosal-side permeation test medium is placed in liquid scintillation vial over time. Collected in 100 L increments. The sampling time was 15, 30, 60 and 120 minutes.

10 mL of liquid scintillator was added to the collected sample, and the radioactivity of the sample was measured to determine the concentration after permeation.

Figure 5 shows the results. In Fig. 5, ♦ indicates sample B, country indicates sample C, and ▲ indicates sample D concentration. After 2 hours, the passage concentrations were 68.3 ng / mL, 103.3 ng / mL and 7.4 ng / mL, respectively, indicating the permeability of Caco-2 per trifluoroethanol ester residue. The improvement effect was about 10 times. These results clearly indicate that the trifluoroethanol ester bound to the phosphate group contributes to the improvement of cell passage in tissues having tight junctions. Example 6

The compound labeled with ¹⁴ C at position 8 of sample B, sample C or sample D used in Example 3 or Example 5 was applied to the total portal vein of an 8-week-old male rat who had undergone laparotomy for 1 mlLZ kg. After rapid administration at a dose of, the kidney and liver were collected and evaluated for renal avoidance according to the measurement method described in Example 3.

The evaluation of kidney evasion was performed according to the evaluation method of Example 4. Table 4 shows the results. The results revealed that sample B, which has two trifluorethanol ester groups, could bypass the kidney when administered to portal vein blood.

Table 4 Kidney accumulation (nmol)

Sample B 168.6

sample. 291.1

Sample D 642.9

Example 7

The compounds labeled with ^14C at position 8 of sample B and sample D used in Example 3 were suspended in a 0.5% tragacanth rubber suspension in an agate mortar to a concentration of 2 mg / mL. A dosing solution was prepared. A disposable plastic plastic sonde was connected to a 9-week-old rat via a 2.5 mL thermosyringe, and the solution was administered by oral gavage. Fifteen minutes after the administration, blood was collected from the abdominal aorta using a syringe treated with parylene, and the heart was immediately opened to stop the blood flow. The collected blood was immediately cooled on ice, centrifuged (3000 rpm for 10 minutes) to obtain plasma, and 50 μL was collected in a liquid scintillation vial. The abdominal skin (about 2 cm x 4 cm) and the sciatic nerves of the left and right thighs were collected, and the tissues were weighed. According to the measurement method of Example 3, the radioactivity in each sample was measured.

Kp shown in Example 3 was used as the value indicating the accumulation in the tissue. The amount of tissue accumulation was evaluated based on the tissue concentration (ng / g).

Table 5 shows the results. The table shows Kp values and tissue concentrations of skin and sciatic nerve 15 minutes after administration. At the same dose (mg / kg), sample B having trifluorene ethanol ester compared to sample D having no ethanol ester of trifnoreo mouth had higher skin And more accumulated in the sciatic nerve. As a result, it became clear that the introduction of trifluorene ethanol was effective in improving organizational accumulation.

Table 5 Skin sciatic nerve

Sample Β Sample D Sample B Sample D Concentration (ng / g) 245; 0 37. 7 57. 5 7. 9

Kp 0.21 0.15 0.051 0.025

Industrial applicability,

According to the present invention, it is possible to provide a drug with improved accumulation in a target tissue or avoidance of the target tissue. The present application was filed by claiming the priority of Japanese Patent Application No. 2002-15152016 and Japanese Patent Application No. 2002-151507.

Claims

The scope of the claims

1. The following formula (I)

(In the formula, R is a hydrogen atom, a C 1 -C 6 alkoxylinole group, a C 1 -C 4 anorecoxyl group substituted with one or more halogen atoms, a halogen atom, an amino group, 'Represents a group or a hydroxyl group;

R ² and R ³ each independently represent an ethyl group substituted with one or more halogen atoms; R ⁴ is a hydrogen atom, a C 1 -C 4 alkyl group, and a C 1 -C 4 hydrogen group; Represents a xyalkyl group or a C 1 -C 4 alkynole group substituted with one or more halogen atoms; M represents CH or a nitrogen atom. )

A phosphonate compound or a salt or a hydrate or solvate thereof represented by the formula (1) as an active ingredient, and its metabolites are more likely to be transmitted to the liver than in plasma. Antivirals showing high accumulation

2. In the formula of claim 1 (I), R ¹ is a hydrogen atom, an antiviral agent according to claim 1, wherein the this to compound an active ingredient an alkoxyl group or a hydroxyl group of C 1 ~ C 6 .

3. In the formula (I) of claim 1, R ¹ is a hydrogen atom, a C 1 -C 4 alkoxy group or a hydroxyl group; R ² and R ³ are 2, 2,,

2. The antiviral agent according to claim 1, wherein a compound having R ⁴ is a hydrogen atom or a methyl group as an active ingredient.

4. A group consisting of the following compounds:

2-Amino 6-Phenylthio 9-[2-(Hoshonometoxy) ethyl] Prinvis (2, 2, 2-Trifnorölöchinolle) S Tenore;

2 — Amino 6 — (4-Methoxy ethoxy)-9-[21 (phosphonoxy) ethyl] PRIMBIS (2, 2, 2 1 Tay Roetchinore) es tenoret;

2—Amino 6— (3—Methoxy thiol) 1 9 1 [2 1 (Phosphonomethyx) Etinole] Prinbis (2,2,2—Tri Es tenore;

2 _amino 6-(2-methoxysilane)-9-[21 (phosphomethoxy) ethyl] purinbis (2, 2, 2 1) Riff Norellol) Estel;

2—Amino 6— (4—Ethoxyfurnthio) 1 9-1 [21 (phosphonomethoxy) ethyl] purinbis (2,2,2,1 trif nore) Lo ェ chinore) Esthenore;

2 — Amino 6 — Phenylthio 1 9 1 [2 — (Hoshonome I, Kishi) Propyl] Prinbis (2,2,2 — Trifnoreo Mouth Echinole) Es Tenoré

2 — Amino 6-(4-methodoxy) 1 9 — [21- (phosphonometh) propinole] primbis (2, 2, 2 — Tri-Fnoleo mouth) 2'—Amino 6-1 (4-butoxymethyl) 1 9— [21 (phosphonomethyoxy) ethyl] primbis (2,2,2toフステエエステステステ

2-Amino 6-1 (4-Propoxy thienylthio) 1-9 [21-1 (phosphonomethoxy) ethyl] prinbis (2, 2, 2-tri) Fluorenechor) Esthenore;

2-Amino 6-1 (.4-1-propoxy)-9-1-[2-(Hoshonometoxy) ethyl] Purinbis (2,

2, 21 Trifnoreo Loetinole) Esthenore;

2-AMINO 6-1 (41 isobutoxy)-9-[21-phosphine methyl) ethyl] Prinvis (2, 2, 2-) Tri-Florécinole;) Estenore;

2—Amino 6 1 (4—Hydroxy phenyl) 1 9 1 [2 1 (phosphomethoxy) ethyl] Prinbis (2, 2, 2 1) Tri-Fenole (Echinore)

2 — Amino _ 6 1 (3 — Hydroxy fetinorecho) 1 9 1 [2 ― (Hoshonometokishi) ethyl] Prinbis (2, 2, 2-) Trif Norre Lochénore) Esthenore;

2—Amino 6 1 (2—Hydroxy fuino) 1 9— [2 1 (Phosphonomethoxy) ethyl] Prinbis (2,2,2—T) Rifluo Loetinole) Estel;

2—Amino 6— (4—Hydroxy phenyl) 1 9 1 [2 1 (Phosphonometrox) propinole] Primbis (2, 2, 2. フフテテエステテテテ

2—Amino 6— (3—Hydroxy fuñinorecho) 1 9 1 [2 1 (Hoshonometokishi) Propyl] Prinbis (2,2, 2 2 フテテテテテ

And, 2-Amino 6-(2-Hydroxy 9-[2 — (Hoshonomokutoshi) Propyl] Prinbis (2,2,2 — Trifluoroethyl) Estel

The antiviral agent according to claim 1, wherein a compound selected from the above is used as an active ingredient.

5. In the formula (I) of claim 1 ′, R ¹ is a hydrogen atom, a C 1 -C 4 alkoxyl group or a hydroxyl group; R ² and R ^{3 are} S 2, 2,

2. The antiviral agent according to claim 1, wherein the active ingredient is a compound in which R ⁴ is a hydrogen atom.

6. Consists of the following compounds

2—Amino diphenyl 9-11 [2— (phosphonomethoxy) ethyl] purinbis (2,2,2—trifnoroleethyl) ester;

2 — Amino 6 — (41 methoxy thiolthio) 1 9 1 [2

― (/ J スノメ)

— Tri Fnoreo Loetinole Esthenore;

2 — Amino 6 — (3 methoxyphenylthio)-9-[2-(Phosphonomethoxyethylenol)] Prinbis (2,2,2,1 Trifnoreo mouth Tenore;

2 — Amino 6- (2 methoxy fluthio) 1 9 1 [2-(phosphono methoxyethyl) purinbis (2,2,2 1 trifluorophenol) Tenore;

2 — Amino 6 — (4 Ethoxyphenylthio)-9-[21 (phosphonomethoxyethyl) purinbis (2,2,2,1 trifnoroleol) Tenore;

2 — Amino 6- (4-butoxyphenylthio) _91- [21-phosphonomethyoxy] ethyl] purinbis (2,2,21- Tri-Fonore)

2 — Amino 1 6 _ (4 _Propoxy) 2 9 1 [2 1 (2) (2, 2, 2) Rifnoreo Loetinole) S Tenoré;

2 — Amino 6 — (4-Isopropoxyphenylthio)-9-1 [2-(Hoshonomethoxy) ethyl] Prinbis (2, 2, 2 — Trif Noreo Loetinole) Estel;

2—Amino 6— (4—Isobutoxy fenthio) 1 9 1 [2— (Hoshonometokishi) ethyl] Prinbis (2,2,2) — Tri Fenolle Loechil) S Tenoré;

2—Amino 6— (4—Hydroxy fuino) 1 9— [2 1 (Hoshonometo) ethyl] Prinbis (2,2,2 1) Trif Noreo Loetinole) Esthenore;

2 _Amino 6 — (3 — Hydroxenophene) 1 9 1 [2 1 (Phosphonomethoxy) ethyl] Print (2, 2, 2 1) Tri-Fnoreo Loetinole) S Tenoré;

And 2-amino 6-(2-hydroxyphenethyl) 1-9-[2-(phosphomethoxy) ethyl] prinbis (2, 2,, 2 — Tri Fleur Loetinole et Stenole

7. A group consisting of the following compounds:

2—Amino 6—Feninolethiol 91 [2- (Phosphonomethoxy) ethyl] Primebis (2,2,2_trifnoroleroethyl) Esthenore ;

2—Amino 6— (4—Methoxy thiolthio) 1 9 1 [2 1 (phosphonomethoxy) ethyl] purinbis (2,2,2 1 tri) Funoleo Loetinole) Esthenore; 2—Amino 6— (3—Methoxy ethoxylthio) —9— [2- (Phosphonomethoxy) ethyl] purinbis (2,2,2—Trif noreolo Echinore) Esthenore;

2 — Amino 6 — (2 — methoxydithiol) 191 [21 (phosphonomethoxy) ethyl] purinbis (2,2,2

— Tri-Floré _: Chinore) Estel;

And 2—amino-6- (4-hydroxyphenoxy) -19- [2— (phosphonomethoxy) ethyl] purinbis (2,2,2-tri) (Funorero etchinore) es Tenoré

8.2—Amino 6— (4—Methoxy thiolthio) -9- [2— (Phosphonomethoxy) ethynole] Prinbis (2,2,2-Trifluo) 2. The antiviral agent according to claim 1, wherein an ester is used as an active ingredient.

9. The metabolite is 2-amino-6- (4-methoxyethoxythio) —9— [2— (phosphonomethoxy) ethyl] purine (2,

2, 2 — Trif-noreo lochinole) Ester or 2 _ amino-6- (4-hydroxif-e-no-retio) 1 9 — [2-(Phosphonomethoxy) echinole] 2. The anti-inoline agent according to claim 1, which is a purine (2,2,2-tritrifluoroethyl) ester.

10. When administered in vivo, the following formula (II)

(Wherein R 丄, R 2 R ⁴ and M have the same meanings as described above), a phosphonate nucleotide compound represented by the formula: or a salt thereof, or a hydrate or a hydrate thereof. An antiviral agent that is metabolized by a compound represented by a solvate and shows higher accumulation in the liver than in plasma.

11. In the formula (II) of claim 10, R ¹ is a hydroxyl group or CC

10. The antiviral agent according to claim 10, wherein the antiviral agent is metabolized to a compound having an alkoxyl group of 4.

12. In the formula (II) of claim 10, R ¹ is a hydroxyl group or C 1 to C 1.

4 Anoreko key Shinore groups der Ri; anti c I Luz agent according to claim 1 0, wherein that you are metabolized to compounds that are Echiru group substituted with R ^A force more Nono b Gen atoms.

13. In the formula (II) of claim 10, R ¹ is a hydroxyl group or C 1 to C 1.

R 2 is a S 2, 2,2 triphenyl alcohol group; and R ⁴ is a hydrogen atom or a methyl group. 10. The antiviral agent according to claim 10, wherein:

1 4. A group consisting of the following compounds:

2 _Amino 6 — (4-Hydroxyshift.ruthio) 1 9 — [2- (Phosphonomethoxy) ethyl] purin (2,2,2-Trifrenorelo) Echil) Esthenore;

2 — Amino 6 — (3-Hydroxysif. Norecho) _ 9 _ [2- (phosphonomethoxy) ethyl] purin (2, 2, 2 — Trifnoreo Lochininole);

2—Amino 6— (2-Hydroxy fu-Ninorechi) 1 9 1 [2- (Hoshonomethoxy) ethyl] purin (2,2,2-tri) Fenole Lochél) Esthenore;

2—Amino 6— (4—Hydroxy shift) 1 9— [2-(Hoshonomethoxy) propyl] Print (2,2,2- Rifnoreo Roetil) S Tenoré;

2—Amino 6— (3—Hydroxy shift) 1 9— [2— (Hoshonomethoxy) propy] Prin (2,2,2—To Ref noreo) es tenore;

2—Amino 6— (2—Hydroxysulfinylthio) —9— [21- (phosphonomethoxy) propyl] purine (2,2,2—Tris Funenole mouth et.

2—Amino 6— (4—Methoxy thiolthio) 1 9-1 [2 (phosphonomethoxy) ethyl] purin (2,2,2—Trifレオェテテテ;

2 — amino — 6 _ (3-methoxyphenoxy) 1 9 — [21- (phosphonomethoxy) ethyl] purin (2,2,2—trifnoreo L'Echillel;

2 — Amino 6 — (2 — Methoxy hex)-9-[2-(Hoshonomethoxy) ethyl] Print (2, 2, 2 — Trifテテテレ; 2 — Amino 6 _ (4 — Methoxy Feninolechio)-9-[21 (Hoshonometokishi) Propyl] Purin (2, 2, 2 — Trifluroethyl) ester;

2 — Amino 6 — (3 — Methoxy thiolthio)-9-[2-(Hoshonometokishi) propyl] Print (2, 2, 2- Trifluroethyl) ester;

And 2-amino 6 _ (2-methoxyphenothio)-9-[2-(phosphonomethoxy) propyl] pulin (2, 2,, 2-Tri Funoleo Loetinole)

10. The antiviral agent according to claim 10, which is metabolized to a compound selected from the group consisting of:

15.2—Amino 6— (4—Methoxy thiolthio) 1 9-1 [2— (Hosono methoxy) ethyl] purine (2,2,

10. The antiviral agent according to claim 10, wherein the antiviral agent is metabolized into 2-trifluoroethyl) ester.

16.2—Amino _6— (4-Hydroxy phenyl)-9- [2- (phosphomethoxy) ethyl] purine (2, 2, 10. The antiviral agent according to claim 10, wherein the antiviral agent is metabolized to 2-trifluoroethyl) ester.

17.2—Amino 6— (4—methoxy thiolthio) 1 9 1 [2 1 (phosphomethoxy) ethyl] purinbis (2,2, 2—Trifluoroethyl) The antiviral agent according to claim 15 or claim 16, characterized in that an ester is administered.

18. The antiviral agent according to claim 1, wherein the virus is hepatitis B virus.

1 9. The following formula (III)

Blue

(Wherein Q represents a nucleus having a medicinal effect, X represents a substituent effective for improving the targeting effect of the drug, and R ² and R ³ have the same meanings as described above. .)

Or a salt thereof, or a hydrate or solvate thereof, and a compound capable of improving tissue selectivity by undergoing metabolism Pharmaceutical ingredients.

20 In formula (III) of claim 19, the medicinal effect of the mother nucleus having a medicinal effect is an anti-cancer effect, an anti-leukemia effect, a metabolic abnormality improving effect, an anti-inflammatory effect, an anti-viral effect, an anti-cancer metastatic effect, an immunosuppressive effect. Alternatively, the targeting of a substituent that is an antiprotozoal effect and is effective in improving the drug's targeting effect is achieved by cancer cell, liver, kidney, spleen, kidney, lymph, macrophage 10. The medicament according to claim 19, wherein the medicament is selected from targeting for lung, vascular inflammation site or center, and targeting for liver avoidance.

21. The method according to claim 19 or 20, wherein, in the formula (III) of claim 19, the drug effect of the mother nucleus having a drug effect is an anticancer effect or an antiviral effect. Medicine.

22. In the formula (III) of claim 19, X is represented by a substituent effective to increase the fat-solubility of the compound and to enhance a targeting effect on cancer cells and liver. Claim 1 characterized by the following:

The medicament according to any one of 9 to 21.

23. In formula (III) of claim 19, Q is an inositol analog, a nucleoside analog, a bran analog, a lipid, a steroid, a peptide. The following equation (IV)

(In the formula, R ⁴ and M are as defined above.)

Or Q—P = 0 in formula (III) of claim 19

The medicament according to any one of claims 19 to 22, wherein (0-) ₂ is represented by a bisphosphonate analog.

24. In the formula (III) of claim 19, X is morpholine, phosphatidinolecholine, alkynole group, amino group, canolepoxinole group, peptide, mannolone. Or the following formula (V)

(In the formula, R ¹ has the same meaning as described above.)

The medicament according to any one of claims 19 to 23, characterized by being represented by:

25. In the formula (I11) of claim 19, whether X—Q is represented by a fludarabine residue, a pen mouth mouth residue, or a linopirin residue? ,;

In the formula (ΠΙ) in claim 19, X—Q—P = 0 (O—). Force S side Or a force represented by a fovir residue or an adefovir residue; or the formula (m) according to claim 19, wherein the formula (m) is glucose-16-phosphonate;

Tetrakis of a bisphosphonate selected from etidronate, innodronic acid, zoledronic acid, alendronate and clodronateka 2, 2, 2 — Trifluoroethyl) Esthenore;

And the following formula (I)

(Wherein, R ¹ , R ² , R ³ , R ⁴ and M have the same meanings as described above.) Or a salt thereof, a hydrate or a solvent thereof. The medicament according to any one of claims 19 to 24, characterized by being represented by a compound selected from the group consisting of:

26. In the formula (I) of claim 25, R ² and R ³ represent a 2,2,2-trinopropyl group, R ⁴ represents a hydrogen atom, and R ¹ represents water. 26. The medicament according to claim 25, wherein the medicament represents a hydrogen atom, a C1 to C4 alkoxy group or a hydroxyl group, and M is a CH or a nitrogen atom.

27. A compound represented by the formula (I) of claim 25, which is a group consisting of the following compounds:

2 — Amino 6 — Phenylthio 9 — [2 — (Hoshonomethoxy) ethyl] purinbis (2,2,2 — Trifnorole Lochinole) Estel ;

2 — Amino 6 — (4 — Methoxy thiolthio) — 9-1 [2-(Hoshonomexoxy) ethyl] Prinbis (2,2,2 — Rifnoreo Loetinole) es tenore;

2 — Amino 6 — (3 — Methoxy thiolthio)-9-[21 (phosphonomethyoxy) ethyl] PRIMBIS (2, 2, 2, 2-ton) Rifluo Loetinole) es tenore;

2 — Amino 6 — (2 — methoxy thiol thiol)-9-[21 (phospho meth oxy) ethyl] PRIMBIS (2, 2, 2-) Rifnoreo Loetinole) Estel;

And 2—amino 6— (4—hydroxy thiol thiol) -9— [2- (phosphonomethoxy) ethyl] purinbis (2,2,2) — Tri Fenole Lo chinore es Tenoré

27. The antiviral agent according to claim 25, wherein the antiviral agent is selected from the group consisting of:

28.2—Amino 6— (4—Methoxy ethoxylate) 1 9 1 [2— (Hosono methoxy) ethyl] Prinbis (2,2,2) — The pharmaceutical according to any one of claims 25 to 27, characterized in that the drug is trifluorene.

29. The compound of claim 19, wherein the compound undergoes metabolism.

([Pi) in, either one force Application Benefits c b Anorekiru of R ² or R ⁰ The medicament according to any one of claims 19 to 28, which is a compound serving as a base.

30. The medicament according to any one of claims 19 to 29, characterized in that the compound is a compound that is improved in liver selectivity by undergoing metabolism.

31. The medicament according to any one of claims 19 to 30, characterized in that it is an antiviral agent.

32. The medicament according to claim 31, wherein the innores is hepatitis B virus.

3 3. The following formula (I ')

(Wherein, and R ³ represent a 2,2,2-trinopropyl group, and R ¹ R ⁴ and M have the same meanings as described above.)

The active ingredient is a phosphonate nucleotide compound or a salt or a hydrate or solvate thereof represented by the formula (1), which compound improves cell permeability. Do medicine.

34. The medicament according to claim 33, wherein the permeability of cells is the passage of tight junction cells present in the gastrointestinal tract.

3 5. The following formula (（)

(Wherein, R ¹ R ² ′, R ³ ′, R ⁴ and M have the same meanings as described above.) Or a salt thereof, or a salt thereof, or a salt thereof. A medicament which is a hydrate or a solvate of the above, and which comprises a compound that avoids the kidneys as an active ingredient.

3 6. The following formula (Γ)

(In the formula, R ¹ , R ² R ³ , R ⁴ and M are as defined above.)

Phosphonatonucleotide compound or salt thereof represented by Alternatively, a medicament comprising, as an active ingredient, a compound which is a hydrate or a solvate thereof, and which enhances accumulation in skin and / or sciatic nerve.

3 7. 'In, R 3. 3, 3 5 and 3 6 Formula (1)' Ri ¹ turtles preparative alkoxy group der, Ri Oh R ⁴ is a hydrogen atom, a compound M is CH The method according to any one of claims 33 to 36, which is an active ingredient.

38. The medicament according to any one of claims 33 to 37, which is an antiviral agent.

39. The medicament according to claim 38, wherein the immune response is hepatitis B infection.

40. The medicament according to claim 38, wherein the virus is varicella-zoster virus. .