JP2000072773A - Purine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine which does not have serious side effects, exhibits a remarkable effect even in oral administration, and is useful against hepatitis C and so on by incorporating a specific purine derivative as an active ingredient. SOLUTION: This medicine contains, as an active ingredient, a purine derivative shown by formula I [R1 and R2 are each H, (CH2)nR6 (R6 is H, a 1-6C alkyl, or the like; (n) is 1-6), or the like; R3 is H, a halogen or the like; R4 is H or a 1-6C alkyl; R5 is a 1-6C alkyl, an alkoxy or the like; L1 and L2 are each a single bond, a 1-6C alkylene or the like] or a pharmacologically acceptable salt thereof [e.g. 6-(methylamino)-9-(2-quinolylmethyl)-2-(trifluoromethyl) purine]. The former derivative, for example, is obtained by reacting a compound shown by formula II with a compound shown by formula III in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide. When administered by injection, the former compound is administered at a does of about 0.5-100 mg/day.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a purine derivative useful as a therapeutic agent for liver disease.

[0002]

2. Description of the Related Art At present, commercially available remedies for liver diseases include interferon (IFN), ursodeoxycholic acid, glycyrrhetinic acid, DL-methionine, glycyrrhizin and the like. Of these, interferon is known to be effective for hepatitis C,
It is a problem that serious side effects such as the occurrence of interstitial pneumonia and the occurrence of severe depression may occur.
In addition, other compounds such as glycyrrhizin have a weak effect when administered orally. Therefore, they are usually used as injectable drugs which are inconvenient to take. Therefore, there is a strong demand for a therapeutic agent for liver disease which has no serious side effects and shows a remarkable effect even by oral administration.

[0003] The following compounds having a purine ring as a mother skeleton are known, although they have no use as therapeutic agents for liver diseases. It has been reported that 6- (methylamino) -9- (2-fluorobenzyl) purine (BWA78U) has an anticonvulsant activity [JP-A-60-226880].
And J. Gazette. Med. Chem. , 29, p113
3-1134 (1986)]. 6- (methylamino)-
9- (2-Fluorobenzyl) -2- (trifluoromethyl) purine (NCS-613) has been reported to have a selective phosphodiesterase (IV) inhibitory action [J. Med. Chem. , 40, p1768-
1770 (1997)]. Also, 6- (dimethylamino) -9- (3-dimethylaminobenzyl) -2- (trifluoromethyl) purine, 6- (dimethylamino)-
9- (3-aminobenzyl) -2- (trifluoromethyl) purine, 6- (dimethylamino) -9-benzyl-
2- (trifluoromethyl) purine, and 6- (dimethylamino) -9- (2-fluorobenzyl) -2-
(Trifluoromethyl) purine has been reported to have anti-rinovirus activity [J. Med. Che
m. , 32, pp. 1757-1763 (1989)]. Furthermore, 6- (dimethylamino) -9-benzylpurine (JP-A-60-226880), 6- (methylamino) -9-benzylpurine [J. Med. Che
m. , 31, p606-612 (1988)] and 9
-(2-Fluorobenzyl) purine [J. Med. Ch
em. , 29, p1133-1134 (1986)].
Have been reported to have antiepileptic activity, respectively.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel therapeutic agent for liver diseases such as hepatitis C, alcoholic hepatitis, and cirrhosis, and a novel purine derivative useful for treating liver diseases. .

[0005]

DISCLOSURE OF THE INVENTION As a result of research, the present inventors have found that a purine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof has an excellent liver injury-suppressing action. And completed the present invention. That is, the present invention resides in a therapeutic agent for liver disease, comprising a purine derivative represented by the following general formula (1) or a pharmacologically acceptable salt thereof as an active ingredient.

[0006]

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In the general formula (1), the meaning of each symbol is as follows.

R ¹ and R ² may be the same or different from each other and represent a hydrogen atom or — (CH ₂ ) _n
Represents a group represented by —R ⁶ , wherein R ⁶ is a hydrogen atom,
An alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms as a substituent, an alkoxy group having 1 to 6 carbon atoms, and the number of ring-constituting carbon atoms. An aryl group having 6 to 12 ring carbon atoms which may have 1 to 5 groups selected from the group consisting of 6 to 10 aryl groups, or an alkyl having 1 to 6 carbon atoms as a substituent A group, an alkoxy group having 1 to 6 carbon atoms, and 1 to 5 groups selected from the group consisting of an aryl group having 6 to 10 ring carbon atoms. Represents a heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of O and S;
Represents an integer of 6.

R ³ represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a nitro group.

R ⁴ is a hydrogen atom or a group having 1 to 1 carbon atoms.
6 represents an alkyl group.

R ⁵ is a substituent having an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a carboxyl group, a hydroxyl group, an amino group, and having 1 to 6 carbon atoms. And an aryl having 6 to 12 ring-forming carbon atoms which may have 1 to 5 groups or atoms selected from the group consisting of an alkylamino group and an aryl group having 6 to 10 ring-forming carbon atoms An alkyl group having 1 to 6 carbon atoms as a group or a substituent,
6, an alkoxy group, a halogen atom, a nitro group, a carboxyl group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms, and an aryl group having 6 to 10 ring carbon atoms. Or 1-5 atoms
N, O and S as ring-constituting atoms which may have
A heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of

L ¹ and L ² may be the same or different and represent a single bond or an alkylene group having 1 to 6 carbon atoms.

However, when R ¹ is a hydrogen atom, R ² is a methyl group, L ¹ and L ² are both a single bond, and R ³ is a trifluoromethyl group, the number of ring-constituting carbon atoms in R ⁵ The phenyl group of the aryl group having 6 to 12 is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a chlorine atom, a carboxyl group, a hydroxyl group, an amino group, and a 1 to 6 carbon atoms. It has, as a substituent, a group or atom selected from the group consisting of an alkylamino group and an aryl group having 6 to 10 ring carbon atoms.

Preferred embodiments of the therapeutic agent for liver disease of the present invention are as follows.

1) R ^{6 in the} general formula (1) is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms as a substituent A phenyl group, a naphthyl group, a quinolyl group, which may have 1 to 5 groups selected from the group consisting of an alkoxy group having 1 to 6 carbon atoms and an aryl group having 6 to 10 ring carbon atoms. A purine derivative or a drug thereof, which represents a 1,2,3,4-tetrahydroquinolyl group, a benzimidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyridyl group or a pyrimidyl group, and n represents an integer of 1 to 3, or a drug thereof. A therapeutic agent for liver disease, comprising a physiologically acceptable salt as an active ingredient.

[0016] 2) R ³ in the general formula (1) is a hydrogen atom, a fluorine atom or a trifluoromethyl group, R ⁴ is,
A therapeutic agent for liver disease, comprising a purine derivative representing a hydrogen atom or a methyl group or a pharmaceutically acceptable salt thereof as an active ingredient.

3) In the general formula (1), R ⁵ is a substituent having an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a carboxyl group, a hydroxyl group, an amino group. A quinolyl group optionally having 1 to 5 groups or atoms selected from the group consisting of an alkylamino group having 1 to 6 carbon atoms and an aryl group having 6 to 10 ring carbon atoms, 1 , A liver containing a purine derivative representing a 2,3,4-tetrahydroquinolyl group, a benzimidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyridyl group or a pyrimidyl group, or a pharmaceutically acceptable salt thereof as an active ingredient Disease treatment agent.

4) R ^{3 in the} general formula (1) is a halogen atom, and R ⁵ is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, A nitro group, a carboxyl group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms, and an aryl group having 6 to 10 ring carbon atoms, which has 1 to 5 groups or atoms. A therapeutic agent for liver disease, which comprises a purine derivative representing a phenyl group or a naphthyl group or a pharmacologically acceptable salt thereof as an active ingredient.

5) A therapeutic agent for liver disease containing, as an active ingredient, a purine derivative or a pharmacologically acceptable salt thereof, in which both L ¹ and L ² of the general formula (1) represent a single bond.

6) A purine derivative or a pharmaceutically acceptable salt thereof, wherein R ^{1 in the} formula (1) represents a hydrogen atom and R ² represents a methyl group, isobutyl group, benzyl group or methoxyethyl group. A therapeutic agent for liver disease contained as an ingredient.

The present invention also provides a novel purine derivative or a pharmacologically acceptable salt thereof represented by the following general formula (2) and exhibiting an excellent therapeutic effect on liver disease.

[0022]

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In the general formula (2), the meaning of each symbol is as follows.

R ²⁰ represents a group represented by — (CH ₂ ) _m —R ⁶⁰ , wherein R ⁶⁰ is a hydrogen atom or a group having 1 to 6 carbon atoms.
An alkyl group, an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms as a substituent, and 1 carbon atom
6 to 6 alkoxy groups and 6 to 1 ring-constituting carbon atoms
An aryl group having 6 to 12 ring carbon atoms which may have 1 to 5 groups selected from the group consisting of 0 aryl groups, or an alkyl group having 1 to 6 carbon atoms as a substituent, It may have 1 to 5 groups selected from the group consisting of an alkoxy group having 1 to 6 carbon atoms and an aryl group having 6 to 10 ring-constituting carbon atoms, and N, O and One heteroatom selected from the group consisting of S
Represents a heterocyclic group containing from 1 to 4, and m represents an integer from 1 to 6.

R ³⁰ represents a fluorine atom or a trifluoromethyl group.

R ⁴⁰ is a hydrogen atom or a group having 1 to 6 carbon atoms.
Represents an alkyl group.

R ⁵⁰ represents a substituent as an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a carboxyl group, a hydroxyl group, an amino group, a 1 to 6 carbon atoms. And an aryl having 6 to 12 ring-forming carbon atoms which may have 1 to 5 groups or atoms selected from the group consisting of an alkylamino group and an aryl group having 6 to 10 ring-forming carbon atoms An alkyl group having 1 to 6 carbon atoms as a group or a substituent,
6, an alkoxy group, a halogen atom, a nitro group, a carboxyl group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms, and an aryl group having 6 to 10 ring carbon atoms. Or 1-5 atoms
N, O and S as ring-constituting atoms which may have
A heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of

L ¹⁰ and L ²⁰ may be the same or different from each other, and represent a single bond or a group having 1 to 6 carbon atoms.
Represents an alkylene group.

However, when R ²⁰ is a methyl group and R ³⁰ is a trifluoromethyl group, the aryl group having 6 to 12 ring carbon atoms in R ⁵⁰ is an alkyl group having 1 to 6 carbon atoms. An alkoxy group having 1 to 6 carbon atoms, a chlorine atom, a carboxyl group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms and a ring having 6 to 10 carbon atoms.
As a substituent, a group or an atom selected from the group consisting of the above aryl groups.

Preferred embodiments of the purine derivative of the general formula (2) or a pharmaceutically acceptable salt thereof are as follows.

1) R ⁶⁰ is a hydrogen atom or a carbon atom having 1
And m represents 1, R ³⁰ represents a fluorine atom or a trifluoromethyl group, R ⁴⁰ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
⁵⁰ represents an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a carboxyl group, a hydroxyl group, an amino group, and a carbon atom having 1 to 6 carbon atoms.
To 6 alkylamino groups and 6 ring-constituting carbon atoms
A phenyl group, a thienyl group, a pyridyl group, a furyl group, a quinolyl group, a 1,2,2 group which may have 1 to 5 groups or atoms selected from the group consisting of 10 to 10 aryl groups
Represents a 3,4-tetrahydroquinolyl group or a benzimidazolyl group, and L ¹⁰ and L ²⁰ both represent a single bond. Provided that when R ⁶⁰ is a hydrogen atom and R ³⁰ is a trifluoromethyl group, the phenyl group for R ⁵⁰ is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a chlorine atom, Characterized by having a substituent or a group selected from the group consisting of a group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms and an aryl group having 6 to 10 ring carbon atoms as a substituent. A purine derivative of the general formula (2) or a pharmacologically acceptable salt thereof.

2) R ²⁰ represents a methyl group, R ³⁰ represents a fluorine atom, R ⁴⁰ represents a hydrogen atom or a methyl group, and R ⁵⁰ represents a nitro group, a chlorine atom, an amino group or dimethylamino as a substituent. A purine derivative of the general formula (2) representing a phenyl group which may have one group, or a pharmaceutically acceptable salt thereof.

3) A purine derivative of the general formula (2) wherein R ²⁰ represents a methyl group, R ³⁰ represents a trifluoromethyl group, R ⁴⁰ represents a hydrogen atom, and R ⁵⁰ represents a thienyl group or a furyl group. Or a pharmacologically acceptable salt thereof.

[0034]

BEST MODE FOR CARRYING OUT THE INVENTION The therapeutic agent for liver disease containing as an active ingredient a purine derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof of the present invention will be described in detail.

In the purine derivative of the general formula (1), R ¹ and R ² may be the same or different from each other and are represented by a hydrogen atom or — (CH ₂ ) _n —R ⁶ Represents a group. Here, R ⁶ is a hydrogen atom, a methyl group,
An alkyl group having 1 to 6 carbon atoms such as an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group; a carbon atom having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group and a propoxy group
An alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group as a substituent, a methoxy group, an ethoxy group, and a propoxy group; The number of ring-constituting carbon atoms, such as 6 to 6 alkoxy groups and phenyl groups, is 6 to 1
It may have 1 to 5 groups selected from 0 aryl groups, may have 6 to 12 ring-forming carbon atoms such as a phenyl group, or may have a similar substituent. It is a heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S as ring-constituting atoms such as a pyridyl group, a furyl group and a thienyl group. n is an integer of 1 to 6. Preferably, it is 1 or 2. Preferred R ¹ ,
The combination of R ² is such that R ¹ is a hydrogen atom and R ² is
It is the case of a methyl group, an ethyl group, a propyl group, an isobutyl group, a benzyl group, a methoxyethyl group, a furfuryl group or a thienylmethyl group.

R ³ is preferably a hydrogen atom, a fluorine atom, a chlorine atom or a trifluoromethyl group,
More preferably, they are a hydrogen atom, a fluorine atom or a trifluoromethyl group.

R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and an isobutyl group, and is preferably a hydrogen atom.

R ⁵ represents a C1-C6 alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a methoxy group, an ethoxy group, An alkoxy group having 1 to 6 carbon atoms such as a propoxy group, a halogen atom such as a fluorine atom and a chlorine atom, a nitro group, a carboxyl group, a hydroxyl group, an amino group, a methylamino group, an ethylamino group, a propylamino group, and an isopropylamino group Groups selected from aryl groups having 6 to 10 ring carbon atoms, such as alkylamino groups having 1 to 6 carbon atoms such as butylamino group, isobutylamino group, dimethylamino group, diethylamino group and phenyl group Or an aryl group having 6 to 12 ring carbon atoms which may have 1 to 5 atoms or a similar substituent. N as also a good ring-constituting atoms optionally a hetero atom selected from the group consisting of O and S is a 1-4 containing heterocyclic group. Preferred as the above substituents are a chlorine atom, a fluorine atom, a tert-butyl group, a hydroxyl group, a nitro group, a phenyl group, a carboxyl group,
It is a dimethylamino group or an amino group. Preferred as an aryl group having 6 to 12 ring carbon atoms is
It is a phenyl group or a naphthyl group. Preferred as the heterocyclic group are a quinolyl group, a 1,2,3,4-tetrahydroquinolyl group, a benzimidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyridyl group or a pyrimidyl group. Even more preferred are quinolyl groups, 1,
2,3,4-tetrahydroquinolyl group, benzimidazolyl group, furyl group or thienyl group. Particularly preferred are thienyl or furyl groups.

L ¹ and L ² may be the same or different from each other and represent a single bond or a methylene group, an ethylene group,
An alkylene group having 1 to 6 carbon atoms such as a propylene group, an isopropylene group, a butylene group, and an isobutylene group, and both are preferably single bonds.

Among the purine derivatives represented by the general formula (1), examples of known compounds or compounds obtained by a method according to a known method are shown in Table 2 later.

Next, the novel purine derivative represented by the general formula (2) or a pharmacologically acceptable salt thereof will be described in detail.

In the purine derivative of the general formula (2), R ²⁰ , R ⁴⁰ , R ⁵⁰ , L ¹⁰ , L ²⁰ and m are preferably R ² , R ⁴ , R ^{5 of the} general formula (1), respectively. , L
^The same groups, atoms and numbers as in ¹ , L ² and n are used.

Next, examples of some methods for producing the novel purine derivatives represented by the general formula (2) will be described.

Synthesis Route of Purine Derivative of General Formula (2) (I)

[0045]

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In the above formula (I), X is a halogen atom such as a chlorine atom or a bromine atom, Z is a chlorine atom,
Represents a leaving group such as a bromine atom, an iodine atom, a tosyloxy group or a mesyloxy group. ^{R 20, R 30, R 40} , R 50, L
¹⁰ and L ²⁰ each have the meaning described above. Purine compound (c) is obtained by reacting purine compound (a) with compound (b). This reaction is carried out in the presence of a base such as potassium carbonate, sodium carbonate, triethylamine and sodium hydride in the presence of dimethylformamide (D
MF), dimethylsulfoxide (DMSO), benzene, toluene, acetone, dichloromethane and the like. Purine compound (a), which is a raw material,
For example, Ginner-Solar
a) etc. [J. Am. Chem. Soc. , 80,
pp. 5744 to 5752 (1958)]. Next, the obtained purine compound (c) is reacted with the amine compound (d) to obtain a purine derivative represented by the general formula (2) of the present invention. This reaction can be carried out in a solvent such as ethanol, methanol, benzene, dichloromethane, tetrahydrofuran (THF) in the presence of a base such as potassium carbonate or triethylamine.

Synthesis Route of Purine Derivative of General Formula (2) (II)

[0048]

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The formula of the above synthetic route (II) is a synthetic route when R ³⁰ is a fluorine atom in the purine derivative of the general formula (2). ^{X, R 20, R 40,} R 50, L
¹⁰ and L ²⁰ are as defined above. Purine compound (f) is obtained by reacting purine compound (e) with compound (b). This reaction is based on synthetic route (I)
A method similar to the reaction described in (1) is used. The obtained purine compound (f) is subjected to diazotization by the action of sodium nitrite in a solvent such as water, DMF or THF, and then a 70% hydrofluoric acid-pyridine solution, tetrafluoroboronic acid, tetrafluorophosphoric acid The purine compound (g) can be obtained by reacting an acid or a fluorinating agent such as hexafluorogermanic acid, and then further reacting an alkali such as sodium hydroxide. The purine compound (g) can also be obtained by obtaining the purine compound (h) by first performing diazotization and fluorination, and then reacting the compound with the compound (b). By reacting the purine compound (g) with the amine compound (d), the purine derivative (2 ′) of the present invention in which R ³⁰ is a fluorine atom among the purine derivatives represented by the general formula (2) is obtained. be able to.

Synthesis route of the purine derivative of the general formula (2) (III)

[0051]

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In the above synthetic route (III), A represents an aryl group or a heterocyclic group having 6 to 12 ring carbon atoms, and R ²⁰ , R ³⁰ , R ⁴⁰ , L ¹⁰ and L ²⁰ are It has the same meaning as above. In the general formula (2), when the substituent of the aryl group or the heterocyclic group having 6 to 12 ring-constituting carbon atoms in R ⁵⁰ is an amino group, the nitro compound (i) is
The purine derivative (2 ″) of the present invention can be obtained by catalytic reduction using platinum oxide, palladium carbon, or the like in a solvent such as ethanol, ethyl acetate, methanol, or THF. With tin chloride (I) in acetic acid, iron or zinc, or in ethanol
The above purine derivative (2 ″) can also be obtained by reduction according to I) or the like.

Synthesis Route of Purine Derivative of General Formula (2) (IV)

[0054]

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In the above formula (IV), Y represents a halogen atom, and R represents an alkyl group having 1 to 6 carbon atoms.
X, R ³⁰ , R ⁴⁰ , R ⁵⁰ , L ¹⁰ and L ²⁰ have the same meaning as described above. Pyrimidine compound (l) obtained by reacting pyrimidine compound (j) with amine compound (k)
Then, an orthoformate (m) is reacted and the ring is closed to obtain a purine compound (n). Next, this is reacted with the amine compound (d) to obtain a purine derivative represented by the general formula (2) of the present invention.

Next, Table 1 (Table 1-1, Table 1-2 and Table 1-3) show typical examples of the purine derivatives represented by the general formula (2). However, Table 1-1 and Table 1
In -2 Table, L ¹⁰ and L ²⁰ are both single bonds.

[0057]

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[0058]

[Table 1]

[0059]

[Table 2]

[0060]

[Table 3]

Next, Table 2 shows typical examples of the purine derivatives represented by the general formula (1). The general formula (1)
Purine derivatives included in both of the formulas (1) and (2) are exemplified only in Table 1.

[0062]

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[0063]

[Table 4]

Any of the purine derivatives represented by the general formula (1) or (2) of the present invention can be converted into a pharmacologically acceptable salt according to a conventional method. Such salts include, for example, acid addition salts with inorganic salts such as hydrochloride, carbonate, sulfate, phosphate, hydrobromide, hydroiodide, or acetate, oxalate, malonate Acid, succinate, maleate, fumarate, lactate,
Acid addition salts with organic acids such as malate, citrate, tartrate, methanesulfonate and the like can be mentioned.

The therapeutic agent for liver disease of the present invention can be used as a general oral preparation or parenteral preparation (injection) for humans. For the preparation of the purine derivative represented by the general formula (1), which is a medicinal component of the therapeutic agent for liver disease of the present invention, a method generally used in the technical field of preparation can be used. Dosage forms include tablets, granules, powders, capsules,
General dosage forms such as suspensions, injections, and suppositories can be used.

In producing the above therapeutic agent for liver disease, ordinary excipients, disintegrants, binders, lubricants, coloring agents, diluents and the like can be used. Examples of excipients include lactose, D-mannitol, crystalline cellulose, glucose and the like. Examples of disintegrants include starch and calcium carboxymethylcellulose (CMC-Ca). Examples of the binder include hydroxypropylcellulose (HPC) and polyvinylpyrrolidone (PVP). Examples of the lubricant include magnesium stearate and talc.

The dose to humans is determined based on the amount of the purine derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof, which is the active ingredient of the therapeutic agent for liver disease of the present invention. Is usually selected in the range of about 0.5 mg to 100 mg per day, and in the case of oral administration, usually about 5 m / day.
An amount ranging from g to 1000 mg is selected.

The purine derivative represented by the above general formula (1) of the present invention may be used as a therapeutic agent for liver disease in combination with a pharmaceutically active ingredient of a known therapeutic agent for liver disease such as interferon or glycyrrhizin, if necessary. Can also.

[0069]

EXAMPLES [Pharmacological test 1] Concanavalin A (Con.
A) Evaluation of the inhibitory effect on liver injury in a mouse liver injury model induced by A) [Con. A: GPT inhibition% (30
mg / kg, p. o. )]

(Test Method) 2.5 mg / mL of Con.
A physiological saline solution of A was administered to a BALB / C mouse (17-22 g female, manufactured by Charles River Japan Co., Ltd .: obtained from Japan Biomaterials Center) at a rate of 12.5 mg / kg from the tail vein, After 24 hours, blood was collected from the abdominal vena cava, and the collected blood was centrifuged to obtain plasma. The amount of GPT (transaminase) in plasma was measured by an enzyme analyzer using Autocera ALT (manufactured by Daiichi Pure Chemicals Co., Ltd.) using an automatic analyzer (Model 7060, manufactured by Hitachi, Ltd.). Test compound (30 mg / k
g) was suspended in a 1% aqueous solution of methylcellulose (MC). Oral administration was performed 1 hour before A administration. As a control, a 1% aqueous solution of methylcellulose was used.

[Pharmacological test 2] Evaluation of inhibitory action on lipopolysaccharide-galactosamine-induced liver injury in a mouse liver injury model [LPS-GalN:% inhibition of GPT
(30 mg / kg, po)]

(Test method) A 5-week-old male BALB / C mouse (manufactured by Charles River Japan Co., Ltd.) was used in groups of 6
And D-galactosamine (700 m
g / kg) was administered intraperitoneally, then a lipopolysaccharide (3 μg / kg) saline solution was administered via the tail vein, and after 8 hours, blood was collected from the abdominal vena cava under ether anesthesia and blood was collected. Blood was centrifuged to obtain plasma. The amount of transaminase (GPT) in plasma was measured by an automatic analyzer (Model 7060, manufactured by Hitachi, Ltd.) by an enzyme method using Autocera ALT (manufactured by Daiichi Pure Chemicals). Test substance (30mg / kg)
Is suspended in a 1% aqueous solution of methylcellulose (MC),
-One of galactosamine and lipopolysaccharide administration
Oral administration was given hour before. As a control, a 1% aqueous solution of methylcellulose was used.

(Test results) Table 3 below shows the test results for some of the compounds of the following Preparation Examples. The suppression rate is a value calculated by the following equation.

Inhibition rate (%) = [(GP of control group)
(Average T value) − (Average GPT value of test compound administration group)] / [Average GPT value of control group] × 10
0

[0075]

TABLE 3 Test compound GPT inhibition rate% (30 mg / kg, po) Con. A LPS-GalN──────────────────────────────── Compound 2 80.2 --- Compound 6 53.3- Compound 7 74.4 86.8 Compound 10 47.7 --- Compound 18 58.8 --- Compound 19 49.0 --- Compound 20 74.6 --- Compound 21 57.9 --- Compound 22 60.0 --- Compound 23 91.4 92.7 Compound 46 58.0 ────────────────────────────────

From Table 3, it can be seen that the purine derivative represented by the general formula (1) strongly deviates from GPT against liver injury induced by concanavalin A and liver injury induced by lipopolysaccharide-galactosamine. It was confirmed that suppression was performed.

[Toxicity test] BALB / C female mice (1
A test compound was orally administered by gavage to 7 to 24 g, manufactured by Charles River Japan Co., Ltd., and the state of death until 7 days after the administration was observed. The test compound was 1% methylcellulose (MC)
It was suspended in an aqueous solution and administered in a volume of 10 mL / kg.

Table 4 shows the results of the toxicity test.

[0079]

[Table 6] Table IV Test Compound Dose-Death (number of dead animals / (Number of animals administered) ────────────────────────────── Compound 2 1000 mg / kg- (0/3) Compound 7 500 mg / kg -(0/3) Compound 18 500 mg / kg- (0/1) Compound 19 500 mg / kg- (0/3) ────────────────────── ────────

Accordingly, it was revealed that the purine derivatives of Table 4 included in the general formula (1) of the present invention have high safety.

The test compounds in Tables 3 and 4 mean the following purine derivatives. Production examples or physical property data of these compounds will be described later. Compound 2: 6- (methylamino) -9- (3-thienylmethyl) -2- (trifluoromethyl) purine Compound 6: 6- (methylamino) -9- (furfuryl)
2- (trifluoromethyl) purine Compound 7: 6- (methylamino) -9- (2-thienylmethyl) -2- (trifluoromethyl) purine Compound 10: 6- (methylamino) -9-[( 3,5-
Di-tert-butyl-4-hydroxy) benzyl]-
2- (trifluoromethyl) purine Compound 18: 6- (methylamino) -9- (3-aminobenzyl) -2- (trifluoromethyl) purine Compound 19: 6- (methylamino) -9- (3- Dimethylaminobenzyl) -2- (trifluoromethyl) purine Compound 20: 9-benzyl-6- (methylamino) -2
-Fluoropurine Compound 21: 9- (3-chlorobenzyl) -6- (methylamino) -2-fluoropurine Compound 22: 2-Fluoro-6- (methylamino) -9
-(Α-methylbenzyl) purine Compound 23: 2-fluoro-6- (methylamino) -9
-(3-nitrobenzyl) purine Compound 46: 6- (methylamino) -9- (4-phenylbenzyl) -2- (trifluoromethyl) purine

[Production Example 1] 6- (methylamino) -9-
(2-quinolylmethyl) -2- (trifluoromethyl)
Purine (Compound 1) 1) 6-Chloro-9- (2-quinolylmethyl) -2-
Production of (trifluoromethyl) purine The method of Ginner-Solara et al. [J. Am. Chem. Soc. 80, p5744 ~
6652 (1958)].
-(Trifluoromethyl) purine (500 mg, 2.2
5 mmol) in DMF (10 mL), then potassium carbonate (465 mg, 3.37 mmol) and 2
-(Chloromethyl) quinoline (598 mg, 3.37 mmol) was added, and the mixture was stirred at room temperature for 20 hours. After confirming the completion of the reaction, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. After separating the ethyl acetate layer, it was washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1; volume ratio) to obtain 390 mg of the title compound as a slightly yellowish white powder. (Yield 49%)

[0083] _{^{1 H-NMR (CDCl 3)}} δ; 5.81 (2H, s) 7.49 (1H, d, J = 8Hz) 7.57 (1H, t, J = 8Hz) 7.74 (1H , T, J = 8 Hz) 7.83 (1 H, d, J = 8 Hz) 8.00 (1 H, d, J = 9 Hz) 8.20 (1 H, d, J = 9 Hz) 8.64 (1 H, s) )

2) Preparation of 6- (methylamino) -9- (2-quinolylmethyl) -2- (trifluoromethyl) purine 6-chloro-9- (2-quinolylmethyl) -2- obtained in 1) above. (Trifluoromethyl) purine (380m
g, 1.08 mmol) was dissolved in 4 mL of ethanol, and then a 40% aqueous solution of monomethylamine (0.5%) was added at room temperature.
ml) was added. After stirring at room temperature for 20 hours, water (1
0 mL) was added. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure for 3 hours to obtain 310 mg of the title compound as a white powder. (80% yield)

Mp: 206-208 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.25 (3H, bs) 5.69 (2 H, s) 5.85 (1 H, bs) 7.42 (1 H, d) , J = 8 Hz) 7.56 (1 H, t, J = 8 Hz) 7.74 (1 H, t, J = 8 Hz) 7.80 (1 H, d, J = 8 Hz) 8.04 (1 H, d, J) = 9 Hz) 8.10 (1H, s) 8.14 (1H, d, J = 9 Hz) IR (KBr) cm ^-1 : 3250, 1640, 160
0, 1550, 1490, 1440, 1420, 138
0,1280,1220,1200,1130,98
0,940,820,760,740,640.

[Production Example 2] 6- (methylamino) -9-
(3-thienylmethyl) -2- (trifluoromethyl)
Purine (Compound 2) 6-chloro-2- (trifluoromethyl) purine (30
After dissolving 0 mg, 1.35 mmol) in 10 mL of DMF, potassium carbonate (280 mg, 2.03 mmol), 3- (bromomethyl) thiophene (713 mg,
4.05 mmol) and stirred at room temperature for 20 hours.
After confirming the disappearance of the raw materials, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, and dried over anhydrous sodium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1; volume ratio) to give 6-chloro-9- (3-thienylmethyl) as a yellow oil. ) -2- (trifluoromethyl) purine (180 m
g) was obtained as a crude product. After dissolving this crude product (180 mg) in ethanol (4 mL), a 40% aqueous solution of monomethylamine (0.3 mL) was added. After stirring at room temperature for 20 hours, water (10 mL) was added, and the precipitated crystals were collected by filtration and washed with water. Subsequently, after dissolving the crude crystals in ethanol (1 mL), water (2 mL) was slowly added. The precipitated crystals were collected by filtration and dried under reduced pressure for 5 hours to obtain 80 mg of the title compound as a white powder. (2
(Process yield: 19%)

Mp: 162 to 166 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.24 (3H, bs) 5.39 (2 H, s) 5.85 (1 H, bs) 7.06 (1 H, dd) , J = 1, 5 Hz) 7.29 (1 H, dd, J = 1, 3 Hz) 7.33 (1 H, dd, J = 3.5 Hz) 7.79 (1 H, s) IR (KBr) cm ^-1 : 3300, 1640, 150
0, 1440, 1350, 1340, 1290, 125
0, 1220, 1190, 1120, 990, 940,
930, 800, 760, 740, 700, 640.

[Production Example 3] 9-benzyl-2-fluoro-6- (methylamino) -purine (compound 20) 1) 9-benzyl-6-chloro-2-fluoropurine 2-amino-6-chloropurine (2.00 g, 11.8
Was dissolved in DMF (30 mL), potassium carbonate (2.44 g, 17.7 mmol) and benzyl bromide (2.10 mL, 17.7 mmol) were added, and the mixture was stirred at room temperature for 40 hours. Water (100m
After L) was added and the mixture was further stirred for one hour, the precipitated crystals were collected by filtration, washed with water, and air-dried overnight. The crude crystals (2.30
g) in a 48% aqueous solution of tetrafluoroboric acid (30 mL)
And the temperature was adjusted to −20 ° C., and a 0.3 M aqueous sodium nitrite solution (50 mL) was added dropwise over 40 minutes. After stirring for another 20 minutes under the same conditions, the mixture was once returned to room temperature and stirred for 30 minutes. Return to -20 ° C again and 10N
After neutralization by slowly adding an aqueous sodium hydroxide solution, water and ethyl acetate were added to the reaction solution, followed by extraction with ethyl acetate. The ethyl acetate layer was separated, washed with water, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 2).
/ L; volume ratio) to give 680 mg of the title compound as a colorless oil. (Two-step yield 27%)

[0089] _{^{1 H-NMR (CDCl 3)}} δ; 5.39 (2H, s) 7.30~7.40 (5H, m) 8.06 (1H, s)

2) 6- (Methylamino) -9-benzyl-2-fluoropurine 9-benzyl-6-chloro-2-fluoropurine (640 mg, 2.43 mmol) obtained in the above 1) was added to 3 mL of ethanol. After dissolution, a 40% aqueous monomethylamine solution (0.64 mL) was added. After stirring at room temperature for 1 hour, water and ethyl acetate were added, and the organic layer was separated. After washing the organic layer with a 2N aqueous hydrochloric acid solution until the aqueous layer is neutralized,
The organic layer was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1; volume ratio) to give 210 mg of the title compound as a white powder.
I got (30% yield)

Mp: 140 to 141 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.18 (3H, bs) 5.28 (2 H, s) 5.92 (1 H, bs) 7.20 to 7.40 (5H, m) 7.64 (1H, s) IR (KBr) cm ^-1 : 3250,1660,158
0, 1540, 1500, 1450, 1390, 136
0, 1340, 1240, 1160, 1000, 78
0,720,690,640,600.

[Production Example 4] 6- (methylamino) -9-
(3-aminobenzyl) -2- (trifluoromethyl)
Purine (compound 18) 1) 6-chloro-9- (3-nitrobenzyl) -2-
(Trifluoromethyl) purine The above compound was obtained in the same manner as in Production Example 3-1). _{^{1 H-NMR (CDCl 3)}} δ; 5.62 (2H, s) 7.61 (1H, t, J = 8Hz) 7.71 (1H, d, J = 8Hz) 8.24~8.27 ( 2H, m) 8.31 (1H, s)

2) 6- (Methylamino) -9- (3-nitrobenzyl) -2- (trifluoromethyl) purine The above compound was obtained in the same manner as in Production Example 3-2). mp: 163-169 ° C ¹ H-NMR (CDCl ₃ ) δ; 3.24 (3H, bs) 5.50 (2H, s) 5.93 (1H, bs) 7.55 (1H, t, J = 8 Hz) 7.68 (1 H, d, J = 8 Hz) 7.85 (1 H, s) 8.20 to 8.21 (2 H, m)

3) 6- (methylamino) -9- (3-aminobenzyl) -2- (trifluoromethyl) purine 6- (methylamino) -9- (3-nitrobenzyl)-
2- (trifluoromethyl) purine (2.70 g, 7.
66 mmol) in dioxane (54 mL) and 1
0% Pd / C (440 mg) was added, and the mixture was stirred at room temperature for 14 hours under a hydrogen stream. The catalyst was removed by filtration through celite, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate).
Recrystallization from hexane gave the title compound as white crystals (1.6
0 g). (Yield 65%)

Mp: 180.5-182.5 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.24 (3H, bs) 3.70 (2H, bs) 5.28 (2H, s) 5.91 (1H, bs) 6.59 (1H, bs) 6.63 (1H, dd, J = 2.8 Hz) 6.69 (1H, bd, J = 8 Hz) 7.13 (1H, t, J = 8 Hz) ) 7.78 (1H, s) IR (KBr) cm ^-1 : 3457, 1655, 162
6,1577,1551,1491,1466,143
7,1400,1379,1350,1286,124
4,1225,1198,1124,987,935,
800, 785, 766, 713, 692, 646.

[Production Example 5] 6- (methylamino) -9-
(1-methyl-2-benzimidazolylmethyl) -2-
(Trifluoromethyl) purine (compound 4) The title compound was obtained in the same manner as in Production Example 1. 1) 6-chloro-9- (1-methyl-2-benzimidazolylmethyl) -2- (trifluoromethyl) purine ¹ H-NMR (CDCl ₃ ) δ; 3.98 (3H, s) 5.80 (2H) , S) 7.30 to 7.40 (3H, m) 7.75 (1H, dd, J = 2.9 Hz) 8.63 (1H, s)

2) 6- (methylamino) -9- (1-methyl-2-benzimidazolylmethyl) -2- (trifluoromethyl) purine mp: 210-220 ° C. ¹ H-NMR (CDCl ₃ ) δ; .22 (3H, br) 3.94 (3H, s) 5.68 (2H, s) 5.93 (1H, br) 7.30-7.40 (3H, m) 7.75 (1H, dd) , J = 2.9 Hz) 8.12 (1H, s) IR (KBr) cm ^-1 : 3250, 1690, 154
0, 1480, 1440, 1400, 1370, 134
0, 1290, 1230, 1180, 1120, 93
0,740,630.

[Production Example 6] 6- (methylamino) -9-
[(1,2,3,4-Tetrahydroquinolin-2-yl) methyl] -2- (trifluoromethyl) purine (Compound 5) The title compound was obtained in the same manner as in Production Example 1. _{^{1 H-NMR (CDCl 3)}} δ; 1.60~1.80 (1H, m) 1.90~2.10 (1H, m) 3.80~3.90 (1H, m) 3.24 ( 3H, bs) 4.24 (1H, dd, J = 7, 14 Hz) 4.40 (1H, dd, J = 4, 14 Hz) 4.44 (1H, br) 5.92 (1H, br) 47 (1H, d, J = 8 Hz) 6.63 (1H, t, J = 8 Hz) 6.70 to 7.10 (2H, m) 7.84 (1H, s)

[Production Example 7] 9- (furfuryl) -6
(Methylamino) -2- (trifluoromethyl) purine (Compound 6) The title compound was obtained in the same manner as in Production Example 1. 1) 6-chloro-9- (furfuryl) -2- (trifluoromethyl) purine ¹ H-NMR (CDCl ₃ ) δ; 5.50 (2H, s) 6.40 (1H, t, J = 2 Hz) 6.55 (1H, d, J = 2 Hz) 7.43 (1H, d, J = 2 Hz) 8.31 (1H, s)

2) 9- (furfuryl) -6- (methylamino) -2- (trifluoromethyl) purine mp: 158-162 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.23 (3H, brs) 5.37 (2H, s) 5.85 (1H, br) 6.37 (1H, t, J = 2 Hz) 6.46 (1H, d, J = 2 Hz) 7.41 (1H, d, J = 2 Hz) 7.86 (1H, s)

[Production Example 8] 6- (methylamino) -9-
(2-thienylmethyl) -2- (trifluoromethyl)
Purine (Compound 7) The title compound was obtained in the same manner as in Production Example 1. 1) 6-chloro-9- (2-thienylmethyl) -2-
(Trifluoromethyl) purine ¹ H-NMR (CDCl ₃ ) δ; 5.69 (2H, s) 7.03 (1H, dd, J = 4.5 Hz) 7.22 (1H, bd) 7.35 ( 1H, dd, J = 1, 5 Hz) 8.28 (1H, s)

2) 6- (methylamino) -9- (2-thienylmethyl) -2- (trifluoromethyl) purine mp: 154 ° -156 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.23 (3H , Bs) 5.55 (2H, s) 5.87 (1H, bs) 6.99 (1H, dd, J = 4.5 Hz) 7.15 (1H, dd, J = 1, 4 Hz) 7.30 (1H, dd, J = 1, 5 Hz) 7.83 (1H, s) IR (KBr) cm ^-1 : 3294, 1649, 158
1,1549,1491,1443,1400,137
1,1354,1325,1286,1221,119
8,1130,1039,984,928,854,8
00,708.

[Production Example 9] 6- (methylamino) -9-
(8-quinolylmethyl) -2- (trifluoromethyl)
Purine (Compound 8) The title compound was obtained in the same manner as in Production Example 1. 1) 6-chloro-9- (8-quinolylmethyl) -2-
(Trifluoromethyl) purine ¹ H-NMR (CDCl ₃ ) δ; 6.13 (2H, s) 7.48 (1H, dd, J = 4, 8 Hz) 7.55 (1H, t, J = 8 Hz) 7.84 (1H, dd, J = 1,8 Hz) 7.98 (1H, d, J = 7 Hz) 8.19 (1H, dd, J = 1, 8 Hz) 8.80 (1H, s) 99 (1H, dd, J = 1, 4 Hz)

2) 6- (methylamino) -9- (8-quinolylmethyl) -2- (trifluoromethyl) purine mp: 194 ° -197 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.21 (3H, bs) 5.82 (1H, bs) 6.06 (2H, s) 7.46 (1H, dd, J = 4, 8 Hz) 7.51 (1H, dd, J = 7, 8 Hz) 7.80 ( 1H, dd, J = 1,8 Hz) 7.85 (1H, d, J = 7 Hz) 8.17 (1H, dd, J = 2.8 Hz) 8.24 (1H, s) 8.99 (1H, dd, J = 1, 4 Hz) IR (KBr) cm ^-1 : 3282, 1630, 150
0, 1441, 1402, 1373, 1335, 128
8,1221,1203,1165,1144,109
9,1076,985,931,876,823,78
9,768,710,648,575,532.

[Production Example 10] 6- (methylamino) -9
-(3-Chlorobenzyl) -2-fluoropurine (Compound 21) The title compound was obtained in the same manner as in Production Example 3. 1) 6-Chloro-9- (3-chlorobenzyl) -2-fluoropurine ¹ H-NMR (CDCl ₃ ) δ; 5.36 (2H, s) 7.20 (1H, dd, J = 1,8 Hz) ) 7.30 to 7.40 (3H, m) 8.07 (1H, s)

2) 6- (methylamino) -9- (3-chlorobenzyl) -2-fluoropurine mp: 156 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.18 (3H, bs) 5.30 (2H, s) 5.94 (1H, bs) 7.16 (1H, d, J = 6 Hz) 7.20 to 7.40 (3H, m) 7.65 (1H, s) IR (KBr) cm ^-1 : 3350, 1650, 160
0, 1580, 1550, 1500, 1470, 138
0, 1360, 1340, 1280, 1240, 116
0, 1100, 1000, 980, 960, 870, 8
30,780,760,450,730,690,64
0.

[Production Example 11] 6- (methylamino) -9
-(Α-Methylbenzyl) -2-fluoropurine (Compound 22) The title compound was obtained in the same manner as in Production Example 3. 1) 6-chloro-9- (α-methylbenzyl) -2-aminopurine ¹ H-NMR (CDCl ₃ ) δ; 1.95 (3H, d, J = 7 Hz) 5.10 (2H, bs) 5 0.77 (1H, q, J = 7 Hz) 7.29 to 7.39 (5H, m) 7.76 (1H, s)

2) 6-chloro-9- (α-methylbenzyl) -2-fluoropurine ¹ H-NMR (CDCl ₃ ) δ; 2.02 (3H, d, J = 7 Hz) 5.89 (1H, q, J = 7 Hz) 7.34 to 7.43 (5H, m) 8.06 (1H, s)

3) 6- (methylamino) -9- (α-methylbenzyl) -2-fluoropurine mp: 112-116 ° C. ¹ H-NMR (CDCl ₃ ) δ; 1.95 (3H, d, J) = 7 Hz) 3.16 (3H, bs) 5.81 (1H, q, J = 7 Hz) 6.00 (1H, bs) 7.30 to 7.39 (5H, m) 7.65 (1H, s) )

[Production Example 12] 2-Fluoro-6- (methylamino) -9- (3-nitrobenzyl) purine (compound 23) The title compound was obtained in the same manner as in Production Example 3. 1) 6-chloro-9- (3-nitrobenzyl) -2-fluoropurine ¹ H-NMR (CDCl ₃ ) δ; 5.51 (2H, s) 7.61 (1 H, t, J = 8 Hz) 7 .66 (1H, dd, J = 1, 8 Hz) 8.14 (1H, s) 8.20 to 8.30 (2H, m)

2) 2-fluoro-6- (methylamino)
-9- (3-Nitrobenzyl) purine mp: 216-218 ° C ¹ H-NMR (CDCl 3) δ; 3.19 (3H, bs) 5.40 (2H, s) 6.01 (1 H, bs) 7 .56 (1H, t, J = 8 Hz) 7.64 (1H, dd, J = 1, 8 Hz) 7.71 (1H, s) 8.14 (1H, d, J = 2 Hz) 8.19 (1H) , Dd, J = 2.8 Hz) IR (KBr) cm ^-1 : 3350, 1650, 160
0, 1580, 1550, 1500, 1470, 138
0, 1360, 1340, 1280, 1240, 116
0, 1100, 1000, 980, 960, 870, 8
30,780,760,450,730,690,64
0.

[Production Example 13] 9- (2-Fluorobenzyl) -6- (benzylamino) -2- (trifluoromethyl) purine (Compound 42) The title compound was obtained in the same manner as in Production Example 1. mp: 157-160 ° C ¹ H-NMR (CDCl ₃ ) δ; 4.86 (2H, bs) 5.43 (2H, s) 6.20 (1 H, bs) 7.00 to 7.20 (2H, m) 7.30 to 7.50 (7H, m) 7.86 (1H, s) IR (KBr) cm ^-1 : 3270, 1610, 158
0, 1480, 1450, 1370, 1350, 128
0, 1220, 1200, 1150, 1100, 107
0,940,760,740.

[Production Example 14] 6- (methylamino) -9
-(1-Naphthylmethyl) -2- (trifluoromethyl) purine (Compound 75) The title compound was obtained in the same manner as in Production Example 1. 1) 6-chloro-9- (1-naphthylmethyl) -2-
(Trifluoromethyl) purine ¹ H-NMR (CDCl ₃ ) δ; 5.94 (2H, s) 7.49-7.60 (4H, m) 7.92-7.98 (3H, m) 05 (1H, s)

2) 6- (methylamino) -9- (1-naphthylmethyl) -2- (trifluoromethyl) purine mp: 187-190 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.23 (3H , Bs) 5.83 (2H, s) 5.88 (1H, bs) 7.44-7.60 (4H, m) 7.61 (1H, s) 7.89-8.02 (3H, m) ) IR (KBr) cm ^-1 : 3298,1655,154
7,1491,1443,1396,1375,134
6,1288,1227,1200,1119,98
0,945,924,798,779,739,70
8,648,633,496.

[Production Example 15] 9-benzyl-6- (2-
Methoxyethylamino) -2- (trifluoromethyl)
Purine (Compound 43) The title compound was obtained in the same manner as in Production Example 1. mp: 147 to 148 ° C ¹ H-NMR (CDCl ₃ ) δ; 3.39 (3H, s) 3.63 (2H, t, J = 5 Hz) 3.89 (2H, bs) 5.38 (2H, s) 6.24 (1H, br) 7.30 to 7.40 (5H, m) 7.79 (1H, s) IR (KBr) cm ^-1 : 3500, 1620, 158
0, 1540, 1480, 1450, 1440, 141
0, 1380, 1350, 1280, 1240, 122
0, 1180, 1150, 1120, 1100, 100
0,960,940,800,740,720,70
0,640,540.

[Production Example 16] 6- (furfurylamino)
-9-Benzyl-2- (trifluoromethyl) purine (Compound 44) The title compound was obtained in the same manner as in Production Example 1. mp: 122-123 ° C ¹ H-NMR (CDCl ₃ ) δ; 4.87 (2H, bs) 5.39 (2H, s) 6.21 (1 H, bs) 6.30 to 6.40 (2H, m) 7.30 to 7.40 (6H, m) 7.79 (1H, s) IR (KBr) cm ^-1 : 3250, 1620, 157
0, 1480, 1440, 1410, 1390, 138
0, 1340, 1280, 1240, 1220, 119
0, 1150, 1080, 1000, 930, 820,
800,760,730,700,640,600,5
40.

[Production Example 17] 6- (methylamino) -9
-(2-Naphthylmethyl) -2- (trifluoromethyl) purine (Compound 76) The title compound was obtained in the same manner as in Production Example 1. 1) 6-chloro-9- (2-naphthylmethyl) -2-
(Trifluoromethyl) purine ¹ H-NMR (CDCl ₃ ) δ; 5.55 (2H, s) 7.41 (1H, dd, J = 2.8 Hz) 7.52 to 7.56 (2H, m) 7.82 to 7.89 (4H, m) 8.25 (1H, s)

2) 6- (Methylamino) -9- (2-naphthylmethyl) -2- (trifluoromethyl) purine mp: 173-175 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.25 (3H , Bs) 5.55 (2H, s) 5.88 (1H, bs) 7.40 (1H, dd, J = 2.8 Hz) 7.48 to 7.53 (2H, m) 7.78 to 7 .85 (5H, m) IR (KBr) cm ^-1 : 3290,1655,154
7,1491,1443,1377,1340,128
8,1236,1223,1196,1122,98
2,931,800,777,762,742,63
4.

[Production Example 18] 6- (benzylamino)-
9-Benzyl-2- (trifluoromethyl) purine (Compound 45) The title compound was obtained in the same manner as in Production Example 1. _{^{1 H-NMR (CDCl 3)}} δ; 4.87 (2H, bs) 5.39 (2H, s) 6.21 (1H, bs) 7.20~7.40 (10H, m) 7.76 ( 1H, s) IR (KBr) cm ^-1 : 3270, 1610, 158
0, 1480, 1450, 1370, 1350, 128
0, 1220, 1200, 1150, 1100, 107
0,940,760,740.

[Production Example 19] 6- (isobutylamino)
-9-Benzyl-2- (trifluoromethyl) purine (Compound 9) The title compound was obtained in the same manner as in Production Example 1. _{^{1 H-NMR (CDCl 3)}} δ; 1.01 (3H, d, J = 6Hz) 1.90~2.10 (1H, m) 4.87 (2H, bs) 5.38 (2H, s) 5.93 (1H, bs) 7.30 to 7.40 (5H, m) 7.70 (1H, s) IR (KBr) cm ^-1 : 3270, 1610, 158
0, 1480, 1450, 1370, 1350, 128
0, 1220, 1200, 1150, 1100, 107
0,940,760,740.

[Production Example 20] 6- (methylamino) -9
-(4-Phenylbenzyl) -2- (trifluoromethyl) purine (Compound 46) The title compound was obtained in the same manner as in Production Example 1. 1) 6-chloro-9- (4-phenylbenzyl) -2-
(Trifluoromethyl) purine ¹ H-NMR (CDCl ₃ ) δ: 5.54 (2H, s) 7.35 to 7.63 (9H, m) 8.26 (1H, s)

2) 6- (Methylamino) -9- (4-phenylbenzyl) -2- (trifluoromethyl) purine mp: 187-189 ° C. ¹ H-NMR (CDCl ₃ ) δ; 3.24 (3H) , Bs) 5.43 (2H, s) 5.87 (1H, bs) 7.34 to 7.59 (9H, m) 7.82 (1 H, s) IR (KBr) cm ^-1 : 3304,1635 , 148
9,1439,1377,1340,1282,122
5,1194,1122,985,928,800,7
52,725,696,644.

[Production Example 21] 6- (methylamino) -9
-[(3-Dimethylamino) benzyl] -2- (trifluoromethyl) purine (Compound 19) The title compound was obtained in the same manner as in Production Example 1. 1) 6-chloro-9-[(3-dimethylamino) benzyl] -2- (trifluoromethyl) purine ¹ H-NMR (CDCl ₃ ) δ; 2.94 (6H, s) 5.41 (2H, s) 6.64 (1H, bd, J = 8 Hz) 6.70 (1H, dd, J = 2.8 Hz) 6.75 (1H, t, J = 2 Hz) 7.23 (1H, t, J = 8Hz) 8.22 (1H, s)

2) 6- (Methylamino) -9-[(3-
Dimethylamino) benzyl] -2- (trifluoromethyl) purine mp: 161-165 ° C ¹ H-NMR (CDCl ₃ ) δ; 2.92 (6H, s) 3.24 (3H, bs) 5.31 ( 2H, s) 5.84 (1H, bs) 6.63 (1H, bd, J = 8 Hz) 6.67 (1H, dd, J = 2.8 Hz) 6.77 (1H, bs) 7.20 (1H, bs) 1H, t, J = 8Hz) 7.79 (1H, s) IR (KBr) cm ^-1 : 3292,1647,160
8,1500,1439,1356,1282,122
3,1194,1126,1003,930,860,
800, 754, 735, 712, 650.

[Production Example 22] 6- (methylamino) -9
-[(3,5-Di-tert-butyl-4-hydroxy) benzyl] -2- (trifluoromethyl) purine (Compound 10) The title compound was obtained in the same manner as in Production Example 1. 1) 6-chloro-9-[(3,5-di-tert-butyl-4-hydroxy) benzyl] -2- (trifluoromethyl) purine ¹ H-NMR (CDCl ₃ ) δ; 1.41 (18H , S) 5.38 (2H, s) 7.27 (2H, s) 8.25 (1H, s)

2) 6- (Methylamino) -9-[(3,
5-Di-tert-butyl-4-hydroxy) benzyl] -2- (trifluoromethyl) purine ¹ H-NMR (CDCl ₃ ) δ; 1.41 (18H, s) 3.23 (3H, bs) 5 .26 (2H, s) 5.29 (1H, s) 6.00 (1H, bs) 7.26 (2H, s) 7.80 (1H, s)

[0127]

EFFECT OF THE INVENTION The purine derivative represented by the general formula (1) of the present invention has an excellent inhibitory effect on transaminase activity increase in a mouse liver injury model induced by concanavalin A, which is a useful liver disease model. In addition, it also showed a significant inhibitory effect in the D-galactosamine-induced liver injury model. Therefore, the purine derivative of the present invention or a pharmacologically acceptable salt thereof is, for example, C
It is particularly useful as a therapeutic agent for liver diseases such as hepatitis hepatitis, alcoholic hepatitis, and cirrhosis.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Tsuyoshi Endo 1-22 Hikogawado Misato-shi, Saitama Japan Nippon Chemiphar Misato Kensei Dormitory Co., Ltd.

Claims (11)

[Claims] 1. A therapeutic agent for liver disease containing a purine derivative represented by the following general formula (1) or a pharmacologically acceptable salt thereof as an active ingredient: [Wherein, R ¹ and R ² may be the same or different from each other and represent a hydrogen atom or a group represented by — (CH ₂ ) _n —R ⁶ , wherein R ⁶ is Hydrogen atom, carbon atom number 1
Alkyl groups of 6 to 6, alkoxy groups having 1 to 6 carbon atoms,
As a substituent, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and 6 carbon atoms constituting a ring.
A group selected from the group consisting of
The number of ring-constituting carbon atoms which may be 6 to 12 or an aryl group having 6 to 12 carbon atoms, or an alkyl group having 1 to 6 carbon atoms as a substituent, an alkoxy group having 1 to 6 carbon atoms, and It may have 1 to 5 groups selected from the group consisting of 6 to 10 aryl groups, and contains 1 to 4 heteroatoms selected from the group consisting of N, O and S as ring-constituting atoms Represents a heterocyclic group, n represents an integer of 1 to 6; R ³ represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a nitro group; R ⁴ represents a hydrogen atom or a carbon atom having 1 to 6 carbon atoms; R ⁵ represents an alkyl group having 1 to 6 carbon atoms as a substituent,
6, an alkoxy group, a halogen atom, a nitro group, a carboxyl group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms, and an aryl group having 6 to 10 ring carbon atoms. Or 1-5 atoms
An aryl group having 6 to 12 ring carbon atoms which may be present, or an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, or a nitro group as a substituent Having 1 to 5 groups or atoms selected from the group consisting of a carboxyl group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms and an aryl group having 6 to 10 ring carbon atoms. A heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S as ring-constituting atoms; and L ¹ and L ² may be the same or different from each other Represents a single bond or an alkylene group having 1 to 6 carbon atoms; provided that R ¹ is a hydrogen atom, R ² is a methyl group, L ¹ and L ² are both a single bond, and R ³ is a trifluoromethyl group of the R ^5, ring-constituting carbon The number of atoms is 6 to 12
The phenyl group of the aryl group is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a chlorine atom,
Carboxyl group, hydroxyl group, amino group, 1 to 6 carbon atoms
An alkylamino group having 6 to 1 ring carbon atoms
A substituent or a group selected from the group consisting of 0 aryl groups]. 2. In the formula (1), R ⁶ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms as a substituent. ,
A phenyl group, a naphthyl group, or a quinolyl group which may have 1 to 5 groups selected from the group consisting of an alkoxy group having 1 to 6 carbon atoms and an aryl group having 6 to 10 ring carbon atoms. , 1,2,3,4-tetrahydroquinolyl group, benzimidazolyl group, furyl group, thienyl group,
The therapeutic agent for liver disease according to claim 1, comprising a purine derivative or a pharmaceutically acceptable salt thereof, which represents a thiazolyl group, a pyridyl group or a pyrimidyl group, and n represents an integer of 1 to 3, as an active ingredient. 3. A purine derivative represented by the formula (1), wherein R ³ represents a hydrogen atom, a fluorine atom or a trifluoromethyl group, and R ⁴ represents a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. The therapeutic agent for liver disease according to claim 1, which comprises a salt as an active ingredient. 4. A compound represented by the formula (1) wherein R ⁵ is a substituent having an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a carboxyl group,
A hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms and 1 to 5 groups or atoms selected from the group consisting of an aryl group having 6 to 10 ring carbon atoms, A purine derivative representing a quinolyl group, a 1,2,3,4-tetrahydroquinolyl group, a benzimidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyridyl group or a pyrimidyl group, or a pharmacologically acceptable salt thereof; The therapeutic agent for liver disease according to claim 1, which is contained as a drug. R ³ is a halogen atom wherein the general formula (1), R ⁵ is an alkyl group having 1 to 6 carbon atoms as a substituent, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, A nitro group, a carboxyl group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms, and an aryl group having 6 to 10 ring carbon atoms, which has 1 to 5 groups or atoms. The therapeutic agent for liver disease according to claim 1, further comprising a purine derivative representing a phenyl group or a naphthyl group, or a pharmacologically acceptable salt thereof, as an active ingredient. 6. The treatment for liver disease according to claim 1, wherein L ¹ and L ^{2 in} the general formula (1) each contain, as an active ingredient, a purine derivative or a pharmaceutically acceptable salt thereof which represents a single bond. Agent. 7. R ^{1 in the} general formula (1) represents a hydrogen atom,
R ² is a methyl group, an isobutyl group, liver disease therapeutic agent according to claim 1 which comprises, as an active ingredient, a purine derivative or a pharmacologically acceptable salt thereof a benzyl group or a methoxyethyl group. 8. A purine derivative represented by the following general formula (2) or a pharmacologically acceptable salt thereof: [Wherein, R ²⁰ represents a group represented by — (CH ₂ ) _m —R ⁶⁰ , wherein R ⁶⁰ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and a 1 to 6 carbon atoms. An alkoxy group, an alkyl group having 1 to 6 carbon atoms as a substituent, 1 to 6 carbon atoms
An aryl group having 6 to 12 ring carbon atoms, which may have 1 to 5 groups selected from the group consisting of an alkoxy group and an aryl group having 6 to 10 ring carbon atoms, or It has 1 to 5 groups selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and an aryl group having 6 to 10 ring carbon atoms as a substituent. A heteroatom selected from the group consisting of N, O and S as a ring-constituting atom
Represents an integer of 1 to 6; m represents an integer of 1 to 6; R ³⁰ represents a fluorine atom or a trifluoromethyl group; R ⁴⁰ represents a hydrogen atom or an alkyl having 1 to 6 carbon atoms. R ⁵⁰ represents 1 to 6 carbon atoms as a substituent
An alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a carboxyl group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms and a ring having 6 to 10 carbon atoms. An aryl group having 6 to 12 ring-forming carbon atoms which may have 1 to 5 groups or atoms selected from the group consisting of aryl groups, or an alkyl group having 1 to 6 carbon atoms as a substituent, 1 carbon atom
6, an alkoxy group, a halogen atom, a nitro group, a carboxyl group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms, and an aryl group having 6 to 10 ring carbon atoms. Or 1-5 atoms
N, O and S as ring-constituting atoms which may have
L ¹⁰ and L ²⁰ may be the same or different from each other, and may be a single bond or an alkylene group having 1 to 6 carbon atoms selected from the group consisting of Wherein, when R ²⁰ is a methyl group and R ³⁰ is a trifluoromethyl group, the number of ring-constituting carbon atoms of R ⁵⁰ is from 6 to 12;
Is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a chlorine atom, a carboxyl group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms, and a ring constituting carbon. As a substituent, a group or an atom selected from the group consisting of aryl groups having 6 to 10 atoms]. 9. R ^{60 in the} general formula (2) represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and m represents 1.
R ³⁰ represents a fluorine atom or a trifluoromethyl group; R ⁴⁰ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R ⁵⁰ represents an alkyl group having 1 to 6 carbon atoms as a substituent; It is composed of an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a carboxyl group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms, and an aryl group having 6 to 10 ring carbon atoms. A phenyl group, a thienyl group, a pyridyl group, a furyl group, a quinolyl group, a 1,2,3,4-tetrahydroquinolyl group or a benzimidazolyl group which may have 1 to 5 groups or atoms selected from the group; And L ¹⁰ and L ²⁰ both represent a single bond; provided that when R ⁶⁰ is a hydrogen atom and R ³⁰ is a trifluoromethyl group,
^{The 50} phenyl groups are an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a chlorine atom, a carboxyl group, a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms and a ring constitution. The purine derivative or a pharmaceutically acceptable salt thereof according to claim 8, wherein the purine derivative or a pharmaceutically acceptable salt thereof has a group or an atom selected from the group consisting of an aryl group having 6 to 10 carbon atoms as a substituent. 10. R ^{20 in the} general formula (2) represents a methyl group, R ³⁰ represents a fluorine atom, R ⁴⁰ represents a hydrogen atom or a methyl group, and R ⁵⁰ represents a nitro group or a chlorine atom as a substituent. The purine derivative according to claim 8, which represents a phenyl group optionally having one amino group or one dimethylamino group, or a pharmaceutically acceptable salt thereof. 11. The compound according to claim 2, wherein R ^{20 in the} general formula (2) represents a methyl group, R ³⁰ represents a trifluoromethyl group, R ⁴⁰ represents a hydrogen atom, and R ⁵⁰ represents a thienyl group or a furyl group. 9. The purine derivative or a pharmacologically acceptable salt thereof according to item 8.