JP2001114753A - N-arylthiooxamide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine participating in activation of T cell and mastocyte participating in immunization and allergic reaction, inhibiting tyrosine phosphatase which CD45 antigen has, having a new mechanism of action. SOLUTION: This N-arylthiooxamide derivative is represented by formula I [R1 is a 6-1C alkyl group, a 2-5C alkoxycarbonyl 1-5C alkyl group, a phenyl group substituted with a phenyl group or benzyloxy group, a thienyl 1-5C alkyl group, an adamanthyl methyl group, a 1-2-5C alkoxycarbonyl-4-piperidyl group, a phenyl imidazolyl group or a group of formula II (R is a hydrogen atom or a 2-5C alkoxycarbonyl group; R' is a 1-5C alkyl group); R2 is a phenyl group, a phenyl group which is substituted with 1-3 groups selected from a halogen atom, a 1-5C alkyl group, a 1-5C alkoxy group and a phenyl group or a naphthyl group].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound having an inhibitory effect on tyrosine phosphatase, and more specifically to CD45.
The present invention relates to a novel N-arylthiooxamide derivative which has a tyrosine phosphatase inhibitory activity of an antigen and is expected to be used as a medicament useful for treating allergy.

[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 As a result of diligent studies, the present inventors have found that a certain thiooxamide 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 C _6-10 alkyl group, a C _2-5 alkoxycarbonyl C _1-5 alkyl group, a styryl group,
_1-5 alkoxy-substituted styryl, phenyl or benzyloxy-substituted phenyl; C _1-5 alkoxy C _1-5 alkyl; di (C _1-5 alkoxy) C _1-5 alkyl; thienyl C _1-5 alkyl groups; 1 C _1-5 alkoxy group; adamantylmethyl; 1-C _2-5 alkoxycarbonyl-4-piperidyl group; a phenyl imidazolylmethyl group; C _1-5 phenyl imidazolylmethyl group substituted by an alkyl group A pyrimidyl group substituted with up to 3 benzothiazolyl groups; or a formula

[0008]

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Wherein R represents a hydrogen atom or a C _2-5 alkoxycarbonyl group, and R ′ represents a C _1-5 alkyl group; R ² represents a phenyl group; A phenyl group substituted with 1 to 3 atoms selected from an atom, a C _1-5 alkyl group, a C _1-5 alkoxy group and a phenyl group;
Or a naphthyl group. And a N-arylthiooxamide derivative represented by the formula:

In the present invention, a C _1-5 alkyl group means a linear or branched alkyl group having 1 to 5 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group. , An isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group and the like.
The C _6-10 alkyl group means a linear or branched alkyl group having 6 to 10 carbon atoms, for example, hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, decyl group and the like. Can be. The C _1-5 alkoxy group means a linear or branched alkoxy group having 1 to 5 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, and a propoxy group.

A halogen atom is a fluorine, chlorine, bromine or iodine atom. The _C2-5 alkoxycarbonyl group means a linear or branched alkoxycarbonyl group having 2 to 5 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxy. Examples include a carbonyl group. The C _2-5 alkoxycarbonyl C _1-5 alkyl group means a C _1-5 alkyl group wherein the alkoxycarbonyl group is substituted at any position, for example, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, ethoxycarbonylethyl group , Propoxycarbonylmethyl group, tert-butoxycarbonylmethyl group and the like.

A C _1-5 alkoxy-substituted styryl group is a C _1-5
A styryl group in which an alkoxy group is substituted at an arbitrary position of a benzene ring, such as a 4-methoxystyryl group,
An ethoxystyryl group, a 4-tert-butoxystyryl group and the like can be mentioned.

A C _1-5 alkoxy C _1-5 alkyl group is
_1-5 alkoxy group is a C _1-5 alkyl group substituted at an arbitrary position, for example, methoxymethyl group, methoxypropyl group, ethoxymethyl group, ethoxyethyl group, propoxymethyl group, 2-ethoxypropyl group, tert -Butoxymethyl group, isopropoxypropyl group and the like. What is a di (C _1-5 alkoxy) C _1-5 alkyl group?
One of C _1-5 alkoxy group means a C _1-5 alkyl group substituted on the same carbon, for example 2,2-dimethoxyethyl group,
Examples thereof include a 2,2-diethoxyethyl group and a 2,2-dimethoxypropyl group. The thienyl C _1-5 alkyl group means a C _1-5 alkyl group substituted by a thienyl group, and examples thereof include a thienylmethyl group, a thienylethyl group, and a thienylpropyl group.

The compound of the present invention is described in J. Chem. Soc., P. 2969 (1959).
) Can be synthesized by the method shown in the following reaction formula (wherein R ¹ and R ²
Is as defined above).

[0015]

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Compound (a) is reacted with chloroacetyl chloride in a solvent in the presence of a base to obtain compound (b).
This is reacted with sodium thiosulfate in a solvent to give the compound
(c) is obtained. This can be reacted with a primary amine without a solvent or in a solvent to lead to the compound of the present invention. When a base is used in the above reaction, for example, an alkali such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, dimesyl sodium, sodium hydride, sodium amide, tert-butyl potassium, etc. Metals, triethylamine, diisopropylethyl, amines such as aminepyridine, sodium acetate, potassium acetate and the like can be used.As the reaction solvent, water, methanol, ethanol, isopropyl alcohol, alcohols such as tert-butyl alcohol, Ethers such as dioxane and tetrahydrofuran,
Inert solvents such as dimethylformamide, dimethylsulfoxide, pyridine, methylene chloride, chloroform, acetone and acetic acid can be used.

[0017]

Industrial Applicability The compounds of the present invention exhibit the activity of inhibiting the activity of tyrosine phosphatase possessed by the CD45 antigen, and are useful for the prevention of tyrosine phosphatase-related diseases in humans and animals (including farm animals), such as immunity and various allergic diseases. Useful as a therapeutic.

[0018]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1 Synthesis of Compound 1 (1) 2-Aminobiphenyl cooled at 0 ° C. (ice bath)
To a solution of (4.23 g) in methylene chloride (40 ml) was added triethylamine (4.18 ml), and a solution of chloroacetyl chloride (2.39 ml) in methylene chloride (10 ml) was added dropwise, followed by stirring at room temperature for 30 minutes. After diluting the reaction mixture with chloroform (160 ml), a 7% aqueous citric acid solution was used.
(70 ml) and water (70 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 colorless crystals of 2-biphenylcarbamoylmethyl chloride.
(4.70 g) was obtained. 97.5-98.5 ° C

[0020]

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(2) Ethanol (80 ml) was added to 2-biphenylcarbamoylmethyl chloride (4.62 g) and dissolved by heating under reflux. Add sodium thiosulfate (5.
A solution of 95 g) in water (12 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,
Further azeotrope twice with ethanol to obtain crude crystalline sodium 2-
Biphenylcarbamoylmethylthiosulfate was obtained.

[0022]

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(3) 1-Naphthylamine (2.80 g) was added to a solution of sodium 2-biphenylcarbamoylmethylthiosulfate in pyridine (40 ml), and the mixture was heated under reflux for 3 hours. After evaporating the solvent, the mixture was diluted with ethyl acetate (400 ml), 1N hydrochloric acid (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml).
l) and washed with saturated saline (100 ml) in that order. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. Silica gel flash column chromatography (33 ~
After removing sulfur as a by-product with a 50% toluene / hexane gradient), the residue was recrystallized from ethyl acetate to give the title compound (compound 1 in Table 1) as yellow crystals (4.75 g). Melting point 161.5-162.5 ° C

[0024]

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

[0026]

[Table 1]

[0027]

[Table 2]

[0028]

[Table 3]

[0029]

[Table 4]

[0030]

[Table 5]

[0031]

[Table 6]

[0032]

[Table 7]

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 this 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%.
%, The 50% inhibitory activity (IC ₅₀ ) when the compound was added is shown in Table 2.

[0036]

[Table 8]

[0037]

[Table 9]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/426 A61K 31/426 4H006 31/428 31/428 31/4409 31/4409 31/505 31/505 A61P 37/00 A61P 37/00 37/08 37/08 43/00 111 43/00 111 C07D 211/56 C07D 211/56 231/38 231/38 Z A 239/52 239/52 277/56 277/56 277/82 277/82 333/20 333/20 (72) Inventor Takuya Hamaguchi 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. F term (reference) 4C023 CA02 4C033 AD03 AD15 AD17 AE14 AE17 4C054 AA02 CC09 DD01 EE01 FF30 4C086 AA03 BB02 BC21 BC36 BC42 BC82 BC84 MA01 NA14 ZB07 ZB13 ZC20 4C206 AA03 JA76 MA01 NA14 ZB07 ZB13 ZC20 4H006 AA01 AB20 TN10 TN30 TN60

Claims (1)

[Claims] (1) Formula (1) [Wherein, R ¹ is phenyl substituted with a C _6-10 alkyl group, a C _2-5 alkoxycarbonyl C _1-5 alkyl group, a styryl group, a C _1-5 alkoxy-substituted styryl group, a phenyl group or a benzyloxy group. Group; C _1-5 alkoxy C _1-5 alkyl group; di (C _1-5 alkoxy) C _1-5 alkyl group; thienyl C _1-5 alkyl group; adamantylmethyl group; 1-C _2-5 alkoxycarbonyl- 4-piperidyl group; phenylimidazolyl group; phenylimidazolyl group substituted with C _1-5 alkyl group; pyrimidyl group substituted with 1 to 3 C _1-5 alkoxy groups; benzothiazolyl group; (Wherein, R represents a hydrogen atom or a C _2-5 alkoxycarbonyl group; R ′ represents a C _1-5 alkyl group); R ² represents a phenyl group; a halogen atom; A phenyl group substituted by 1 to 3 groups selected from a _1-5 alkyl group, a C _1-5 alkoxy group and a phenyl group; or a naphthyl group. ] The N-arylthio oxamide derivative represented by these.