JP2001114678A - Tyrosine phosphatase inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a drug having a novel mechanism of action, which is involved in activation of T cells and mast cells involved in immunity and allergic reactions and inhibits tyrosine phosphatase possessed by CD45 antigen. SOLUTION: The formula: (Wherein R ¹ is a phenyl group; a phenyl group substituted by 1 to 3 groups selected from a halogen atom, a C _1-5 alkyl group and a C _1-5 alkoxy group; a naphthyl group; a C _1-10 alkyl group;
C _3-8 cycloalkyl group; phenyl C _1-5 alkyl group; or a benzene ring substituted with 1 to 3 halogen atoms, trifluoromethyl group, C _1-5 alkyl group and C _1-5 alkoxy group. A phenyl C _1-5 alkyl group, wherein R ² is a phenyl group; 1 selected from a halogen atom, a C _1-5 alkyl group, a C _1-5 alkoxy group and a phenyl group
Represents a phenyl group substituted by up to 3; or a naphthyl group, and R ³ represents a hydrogen atom or a benzyl group. A tyrosine phosphatase inhibitor comprising the compound represented by the formula (1) as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a tyrosine phosphatase inhibitor, and more particularly, to a tyrosine phosphatase inhibitor possessed by the CD45 antigen, which is expected to be used as a medicament useful for treating allergies. is there.

[0002]

2. Description of the Related Art Reversible phosphorylation of tyrosine residues in proteins plays an important role in signaling systems involved in the expression of cell functions. Molecules involved in signal transduction induce enzymatic activity depending on the phosphorylation state of the tyrosine residue and change the molecular structure. This phosphorylation state is controlled by a phosphorylase (kinase) and a phosphatase (phosphatase). CD45, a common human leukocyte antigen
Is a molecule that regulates signaling required for activation of T cells and mast cells involved in immune and allergic reactions.
Therefore, by inhibiting the tyrosine phosphatase activity of the CD45 antigen, immune responses such as T cell-derived type IV allergy, IgE-derived type I allergy, and dermatitis involving both can be suppressed at an early stage. it is conceivable that.

Sodium vanadate and phenyl arsenic oxide have been reported as tyrosine phosphatase inhibitors, and are known to inhibit IgE-induced degranulation of mast cells. However, these compounds have a problem of toxicity due to heavy metals. Therefore, inhibitors of low molecular organic compounds are desired.

[0004]

The present invention relates to a drug having a novel mechanism of action, which is involved in the activation of T cells and mast cells involved in immunity and allergic reactions and inhibits the tyrosine phosphatase possessed by the CD45 antigen. The purpose is to provide.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies for the above purpose, and as a result, have found that a certain imidazolidinone derivative can achieve the above object, and have completed the present invention. That is, the present invention provides a compound of the formula (I)

[0006]

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Wherein R ¹ is a phenyl group; a phenyl group substituted by 1 to 3 groups selected from a halogen atom, a C _1-5 alkyl group and a C _1-5 alkoxy group; a naphthyl group;
_1-10 alkyl group; C _3-8 cycloalkyl group; phenyl C
_1-5 alkyl group; or phenyl C _1-5 in which a benzene ring is substituted with 1 to 3 selected from a halogen atom, a trifluoromethyl group, a C _1-5 alkyl group and a C _1-5 alkoxy group.
R ² represents a phenyl group; a halogen atom,
A phenyl group substituted by 1 to 3 groups selected from a C _1-5 alkyl group, a C _1-5 alkoxy group and a phenyl group; or a naphthyl group, and R ³ represents a hydrogen atom or a benzyl group. ) Is a tyrosine phosphatase inhibitor possessed by the CD45 antigen, which comprises a compound represented by the formula (1) as an active ingredient.

[0008]

BEST MODE _FOR CARRYING OUT THE INVENTION In the present invention, a C _1-5 alkyl group means a linear or branched alkyl group having 1 to 5 carbon atoms, for example, a methyl group, an ethyl group, a propyl group,
Examples include isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and the like. The C _1-10 alkyl group means a linear or branched alkyl group having 1 to 10 carbon atoms. For example, in addition to the above, a hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, decyl group And the like.
Further, the C _3-8 cycloalkyl group means a cycloalkyl group having 3 to 8 carbon atoms, which is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The C _1-5 alkoxy group means a linear or branched alkoxy group having 1 to 5 carbon atoms,
For example, a methoxy group, an ethoxy group and the like can be mentioned. The phenyl C _1-5 alkyl group means a linear or branched C _1-5 alkyl group substituted with a phenyl group, such as a benzyl group, a phenethyl group, a phenylpropyl group, and a phenylbutyl group. Can be mentioned.

The compound represented by the above formula (I) is described in J. Chem.
oc., p. 2969 (1959) or a method analogous thereto. The compounds according to the invention can be administered orally or parenterally. The dosage form is a tablet, capsule, granule, powder, powder, troche, ointment, cream, emulsion, suspension, suppository, injection, etc. (The method prescribed in the 12th revised Japanese Pharmacopoeia). These dosage forms can be appropriately selected depending on the condition, age and purpose of treatment of the patient. In the preparation of various dosage forms, conventional excipients (eg, crystalline cellulose, starch, lactose, mannitol, etc.), binders (eg, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), lubricants (eg, stearin Magnesium oxide, talc, etc.), disintegrants (eg, carboxymethylcellulose calcium, etc.) and the like can be used.

[0010] The dose of the compound of the present invention is 50 to 2000 mg per day when treating an adult.
Administer once or several times a day. This dosage can be appropriately increased or decreased depending on the age, weight and condition of the patient.

[0011]

The compounds according to the present invention exhibit the activity of inhibiting the activity of tyrosine phosphatase possessed by the CD45 antigen, and are associated with tyrosine phosphatase-related diseases in humans and animals (including farm animals), such as immunity and various allergic diseases. It is useful as a therapeutic agent for.

[0012]

The present invention will be described in more detail with reference to production examples and test examples.

Production Example 1 (1) Triethylamine (6.6) was added to a solution of aniline (3.72 g) in methylene chloride (50 ml) cooled at 0 ° C. (ice bath).
9 ml) and further added chloroacetyl chloride (3.82).
ml) of methylene chloride (10 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was mixed with chloroform (200
ml), and then diluted with a 7% citric acid aqueous solution (100 m
l) and water (100 ml × 2 times). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained crude crystals were recrystallized from ethyl acetate / hexane to give phenylcarbamoylmethyl chloride (5.61) as a light brown powder.
g) was obtained. 135-136 ° C

[0014]

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(2) Ethanol (90 ml) was added to phenylcarbamoylmethyl chloride (5.44 g) and dissolved by heating under reflux. Add sodium thiosulfate (10.14
g) in water (18 ml) was added, and the mixture was heated under reflux for 3 hours. After allowing the reaction mixture to cool, it was concentrated under reduced pressure, and azeotroped three times with ethanol to obtain crude crystals of sodium phenylcarbamoylmethylthiosulfate.

[0016]

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(3) 1-Naphthylamine (4.59 g) was added to a solution of sodium phenylcarbamoylmethylthiosulfate in pyridine (50 ml), and the mixture was heated under reflux for 3 hours. After evaporating the solvent, dilute with ethyl acetate (450 ml),
The mixture was washed sequentially with 1N hydrochloric acid (150 ml), saturated aqueous sodium hydrogen carbonate (150 ml), and saturated saline (150 ml). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. Silica gel flash column chromatography (50-100%
After removing sulfur as a by-product with a toluene / hexane gradient), the residue was recrystallized from ethyl acetate to give compound 1 as yellow crystals.
(Compound 1 in Table 1) (3.82 g) was obtained. Melting point 169-17.5 ° C

[0018]

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The same operation as in Production Example 1 was carried out using the corresponding starting materials to obtain the compounds shown in Table 1. Table 1 shows a list of compounds produced, including Compound 1.

[0020]

[Table 1]

[0021]

[Table 2]

[0022]

[Table 3]

Test Example [Protein phosphatase CD4
5 Inhibitory Action] Protein tyrosine phosphatase CD45 is a cultured cell
It was prepared from the cell membrane of Ball-1. Human leukemia cells Ball-1 expressing CD45 in large amounts were cultured in an incubator at 37 ° C. in RPMI 1640 medium containing 10% calf serum, saturated with 5% carbon dioxide and water vapor. The cells were prepared at 5 × 10 ⁷ cells / ml, 25 mM Tris-HCl (pH 7.5), 25 mM sucrose, 0.1 mM ethylenediaminetetraacetic acid disodium salt (EDTA), 5 mM magnesium chloride, 1 mM phenylmethylsulfonylfluoride. After suspension in a composition buffer of Ride (PMSF), the cells were sonicated and centrifuged for 5 minutes to give the supernatant as an enzyme solution.

In the test, a series of dilution factors to be measured were added to an enzyme solution containing CD45, and Attophos was used as a substrate.
Use TM Substrate (Amersham) at 37 ° C for 30
After reacting for 1 minute, Attophos ™ Calibrator (manufactured by Amersham) was added to stop the reaction. The fluorescence intensity of the reaction solution was measured with a fluorescence plate reader (model: 1420 ARVOTM: manufactured by Wallac), and this was used as an index of phosphatase activity.

Results The protein phosphatase activity when no drug was added was 100
Table 2 shows the 50% inhibitory activity when the compound was added or the inhibitory rate when the compound was added at 10 μM when the compound was added.

[0026]

[Table 4]

[0027]

[Table 5]

[0028]

[Table 6]

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Takuya Hamaguchi 3-24-1, Takada, Toshima-ku, Tokyo Taisho Seiyaku Co., Ltd. F-term (reference) 4C206 AA01 AA02 JA25 MA01 MA04 NA14 ZB13 ZC20

Claims (1)

[Claims] (1) Formula (1) (Wherein R ¹ is a phenyl group; a phenyl group substituted by 1 to 3 groups selected from a halogen atom, a C _1-5 alkyl group and a C _1-5 alkoxy group; a naphthyl group; a C _1-10 alkyl group;
C _3-8 cycloalkyl group; phenyl C _1-5 alkyl group; or a benzene ring substituted with 1 to 3 halogen atoms, trifluoromethyl group, C _1-5 alkyl group and C _1-5 alkoxy group. A phenyl C _1-5 alkyl group, wherein R ² is a phenyl group; 1 selected from a halogen atom, a C _1-5 alkyl group, a C _1-5 alkoxy group and a phenyl group
Represents a phenyl group substituted by up to 3; or a naphthyl group, and R ³ represents a hydrogen atom or a benzyl group. A tyrosine phosphatase inhibitor comprising the compound represented by the formula (1) as an active ingredient.