JP5617970B2 - Novel compounds and binding inhibitors, antiallergic agents, antiasthmatic agents, and antiinflammatory agents - Google Patents

Description

  The present invention relates to a novel compound, an inhibitor of binding between IgE and IgE receptor containing the novel compound, an antiallergic agent, an antiasthma agent, and an antiinflammatory agent containing the binding inhibitor.

Type I allergic reaction, represented by hay fever and bronchial asthma, is the production of human IgE antibodies when antigens (allergens) contained in pollen, ticks, etc. enter the human body. It binds to the high affinity IgE receptor (FcεRI) present on the surface of basophils and mast cells, which are present in large amounts in the sensitized state.
When the antigen (allergen) re-enters the human body and binds to the human IgE antibody bound to the sensitized IgE receptor (FcεRI), the binding is triggered, and mast cells and the like produce inflammatory cytokines and , Chemical mediators such as histamine and leukotriene are released, causing allergic symptoms.

For such allergic symptoms, antihistamines, antiallergic agents and the like have been conventionally used as drugs having antiallergic action.
The antihistamine is effective against histamine that induces allergic symptoms, and is effective for itching such as eczema, hives and allergic rhinitis. However, as side effects, there are problems in that it has an anticholinergic action accompanied by symptoms such as wrinkles and clogging of the nose, and that it acts on the central nerve to induce sleepiness.
The antiallergic agent can also suppress chemical mediators other than histamine and can be applied to asthma because of its relatively weak anticholinergic action. However, it is generally delayed, and depending on the symptom, it takes time until a sufficient effect appears after administration.

  Further, an anti-IgE antibody preparation Zolea (generic name: omalizumab (Novartis Pharma)) is known as a drug having a mechanism of action different from that of conventional drugs. Since the anti-IgE antibody preparation Zolea binds to IgE and inhibits the binding between IgE and IgE receptor (FcεRI), which are the basis of type I allergy, it has a stronger antiallergic effect than conventional drugs. However, since it is a protein preparation and requires injection once or twice a month, a high drug price has been a problem. Furthermore, the administration by injection is problematic because it is not convenient.

Further, it has been reported that zeta-peptide (zeta-peptide) inhibits the binding between IgE and IgE receptor (FcεRI) by binding to IgE receptor (FcεRI) (see Non-Patent Document 1). However, since peptides generally have antigenicity, safety is a problem, and clinical development has not been achieved.
In contrast, non-protein low molecular weight compounds generally have no antigenicity as they are (see Non-Patent Document 2), and thus are known to have high safety because they do not cause an immune response. However, there is no known drug having an antiallergic action using a non-protein low molecular weight compound.

  As described above, a novel non-proteinaceous low molecular weight compound having a chemical structure different from those of these conventional drugs, being inexpensive and easy to administer, and capable of inhibiting the binding between IgE and IgE receptor (FcεRI) In addition, the development of excellent antiallergic agents, antiasthma agents, and antiinflammatory agents is desired at present.

Nakamura GR et al. , PNAS, vol. 99, no. 3, 2002, p. 1303-1308 Ueda H, YAKUGAKU ZASSHI, 127, 2007, p. 71-80

  An object of the present invention is to solve the conventional problems and achieve the following objects. That is, the present invention provides a novel compound having an excellent binding inhibitory activity for binding between IgE and IgE receptor (FcεRI), an inhibitor of binding between IgE and IgE receptor (FcεRI), allergic action, asthma action, An object of the present invention is to provide an excellent antiallergic agent, antiasthma agent, and antiinflammatory agent that have high safety against inflammatory action and are inexpensive and easy to administer.

Means for solving the problems are as follows.
That is, one of the present invention is a compound represented by the following general formula (1).
In the general formula (1), Z represents an atom of carbon, nitrogen, oxygen, or sulfur. Two Z's are bonded in a straight chain and may be the same or different. The Z may have a side chain (Z ¹ ) _k . Z ¹ represents any of carbon, nitrogen, oxygen, sulfur, and hydrogen, and k represents an integer of 0 to 2. When k represents an integer other than 0, Z and Z ¹ may be the same as or different from each other.
E represents an aromatic ring in which two 6-membered rings represented by the following general formula (2A) are condensed. F represents an aromatic 6-membered ring represented by the following general formula (3).
In the general formula (2A), a represents an integer of 0 to 4, and b represents an integer of 0 to 3. When a and b represent an integer other than 0, R ¹ and R ² represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. R ¹ and R ² may be the same as or different from each other.
The compound represented by the general formula (2A) has one bond represented by “*”, and the bond represents a bond with Z.
In the general formula (3), d represents an integer of 0 to 5. When the d represents an integer other than 0, R ³ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom.
The compound represented by the general formula (3) has one bond represented by “*”, and the bond represents a bond with Z.

One of the present invention is a compound represented by the following general formula (5).
In the general formula (5), V, W, and X each represent an atom of carbon, nitrogen, oxygen, or sulfur. The Vs are bonded in a straight chain and may be the same or different. The V may have a side chain (V ¹ ) _g , the W may have a side chain (W ¹ ) _h , and the X may have a side chain (X ¹ ) _i . V ¹ , W ¹ , and X ¹ each represent carbon, nitrogen, oxygen, sulfur, or hydrogen, and g, h, and i each independently represent an integer of 0 to 2. When g, h, and i represent an integer other than 0, the V and the V ¹ , the W and the W ¹ , and the X and the X ¹ may be the same as each other; May be different.
A is a 5-membered ring represented by the following general formula (6A), an aromatic ring condensed with at least one of the 6-membered ring and the 6-membered ring, and an aromatic 6-membered represented by the following general formula (6B) Represents one of the rings. B represents a saturated 6-membered ring represented by the following general formula (7). C represents either a 5-membered ring represented by the following general formula (8A) and an aromatic ring condensed with a 6-membered ring, or an aromatic 5-membered ring represented by the following general formula (8B). D represents an aromatic 6-membered ring represented by the following general formula (9A).
In the general formula (6A), G ¹ represents at least ^one of a 6-membered ring and a 5-membered ring. e represents an integer of 0 to 4, and f represents an integer of 0 to 3. When e and f represent an integer other than 0, R ⁴ and R ⁵ represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. R ⁴ and R ⁵ may be the same as or different from each other.
The compound represented by the general formula (6A) has one bond represented by “*”, and the bond represents a bond with V.
In the general formula (6B), m represents an integer of 0 to 5. When m represents an integer other than 0, R ⁶ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom.
The compound represented by the general formula (6B) has one bond represented by “*”, and the bond represents a bond with V.
In the general formula (7), n represents an integer of 0 to 4. When n represents an integer other than 0, R ⁷ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom.
The compound represented by the general formula (7) has two bonds represented by “*”, one of the bonds represents a bond with V, and the other represents a bond with W. Represents.
In the general formula (8A), o represents an integer of 0 to 1, and p represents an integer of 0 to 4. When o and p represent an integer other than 0, R ⁸ and R ⁹ represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. R ⁸ and R ⁹ may be the same as or different from each other.
The compound represented by the general formula (8A) has two bonds represented by “*”, one of the bonds represents a bond with W, and the other represents a bond with X. Represents.
In the general formula (8B), q represents an integer of 0 to 3. When q represents an integer other than 0, R ¹⁰ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom.
The compound represented by the general formula (8B) has two bonds represented by “*”, one of the bonds represents a bond with W, and the other represents a bond with X. Represents.
In the general formula (9A), r represents an integer of 0 to 5. When r represents an integer other than 0, R ¹¹ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, a methylene carboxyl group, an amino group, and a halogen atom.
The compound represented by the general formula (9A) has one bond represented by “*”, and the bond represents a bond with X.

One aspect of the present invention is a compound represented by the following general formula (11).

In the general formula (11), V, W, X, Y, and Z each represent an atom of carbon, nitrogen, oxygen, or sulfur. The V and Y may be bonded in a straight chain and may be the same or different from each other. Two Z's are bonded in a straight chain and may be the same or different. The V represents a side chain (V ¹ ) _g , the W represents a side chain (W ¹ ) _h , the X represents a side chain (X ¹ ) _i , the Y represents a side chain (Y ¹ ) _j , the Z May have a side chain (Z ¹ ) _k . V ¹ , W ¹ , X ¹ , Y ¹ , and Z ¹ each represent carbon, nitrogen, oxygen, sulfur, or hydrogen, and g, h, i, j, and k are Each represents an integer of 0 to 2 independently. When the g, the h, the i, the j, and the k represent non-zero integers, the V and the V ¹ , the W and the W ¹ , the X and the X ¹ , the Y and the Y ¹ , and Z and Z ¹ may be the same as or different from each other.
A is a 5-membered ring represented by the following general formula (6A), an aromatic ring condensed with at least one of the 6-membered ring and the 6-membered ring, and an aromatic 6-membered represented by the following general formula (6B) Represents a ring. B represents a saturated 6-membered ring represented by the following general formula (7). C represents either a 5-membered ring represented by the following general formula (8A) and an aromatic ring condensed with a 6-membered ring, or an aromatic 5-membered ring represented by the following general formula (8B). D represents an aromatic 6-membered ring represented by the following general formula (9B). E represents an aromatic ring in which two 6-membered rings represented by the following general formula (2B) are condensed. F represents an aromatic 6-membered ring represented by the following general formula (3).

In the general formula (6A), G ¹ represents at least ^one of a 6-membered ring and a 5-membered ring. e represents an integer of 0 to 4, and f represents an integer of 0 to 3. When e and f represent an integer other than 0, R ⁴ and R ⁵ represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. R ⁴ and R ⁵ may be the same as or different from each other.
The compound represented by the general formula (6A) has one bond represented by “*”, and the bond represents a bond with V.
In the general formula (6B), m represents an integer of 0 to 5. When m represents an integer other than 0, R ⁶ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom.
The compound represented by the general formula (6B) has one bond represented by “*”, and the bond represents a bond with V.

In the general formula (7), n represents an integer of 0 to 4. When n represents an integer other than 0, R ⁷ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom.
The compound represented by the general formula (7) has two bonds represented by “*”, one of the bonds represents a bond with V, and the other represents a bond with W. Represents.
In the general formula (8A), o represents an integer of 0 to 1, and p represents an integer of 0 to 4. When o and p represent an integer other than 0, R ⁸ and R ⁹ represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. R ⁸ and R ⁹ may be the same as or different from each other.
The compound represented by the general formula (8A) has two bonds represented by “*”, one of the bonds represents a bond with W, and the other represents a bond with X. Represents.

In the general formula (8B), q represents an integer of 0 to 3. When q represents an integer other than 0, R ¹⁰ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom.
The compound represented by the general formula (8B) has two bonds represented by “*”, one of the bonds represents a bond with W, and the other represents a bond with X. Represents.
In the general formula (9B), r represents an integer of 0 to 4. When r represents an integer other than 0, R ¹¹ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom.
The compound represented by the general formula (9B) has two bonds represented by “*”, one of the bonds represents a bond with X, and the other represents a bond with Y. Represents.

In the general formula (2B), a and b each independently represent an integer of 0 to 3. When a and b represent an integer other than 0, R ¹ and R ² represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. R ¹ and R ² may be the same as or different from each other.
The compound represented by the general formula (2B) has two bonds represented by “*”, one of the bonds represents a bond with Y, and the other represents a bond with Z. Represents.
In the general formula (3), d represents an integer of 0 to 5. When the d represents an integer other than 0, R ³ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom.
The compound represented by the general formula (3) has one bond represented by “*”, and the bond represents a bond with Z.

  One of the present invention contains at least one of a compound represented by the general formula (1), a compound represented by the general formula (5), and a compound represented by the general formula (11). It is a binding inhibitor that inhibits the binding between IgE and IgE receptor.

  One of the present invention is an antiallergic agent, antiasthma agent and antiinflammatory agent containing the binding inhibitor.

  According to the present invention, various problems in the prior art can be solved and the above-mentioned object can be achieved, and a novel compound having excellent binding inhibitory activity for binding between IgE and IgE receptor (FcεRI), and IgE An anti-allergic agent, anti-asthma agent, and anti-inflammatory agent that are highly safe, inexpensive and easy to administer to inhibitors of binding to IgE receptor (FcεRI), allergic action, asthma action, and inflammatory action Can be provided.

FIG. 1 is an NMR spectrum of the compound represented by Structural Formula (1), which is a preferred example of the compound represented by General Formula (1). FIG. 2A shows LC (liquid chromatography) (upper stage) and MS (mass spectrometry) in LC-MS analysis of the compound represented by Structural Formula (1), which is a preferred example of the compound represented by General Formula (1). ) (Bottom) chromatogram image. FIG. 2B shows the results of mass spectrometry of the peak component having a retention time of 1.296 in LC-MS analysis of the compound represented by Structural Formula (1), which is a preferred example of the compound represented by General Formula (1). It is a figure. FIG. 3 is an NMR spectrum of the compound represented by Structural Formula (2), which is a preferred example of the compound represented by General Formula (5). FIG. 4A shows LC (liquid chromatography) (upper) and MS (mass spectrometry) in LC-MS analysis of the compound represented by Structural Formula (2), which is a preferred example of the compound represented by General Formula (5). ) (Bottom) chromatogram image. FIG. 4B shows the results of mass spectrometry of the peak component having a retention time of 1.613 in LC-MS analysis of the compound represented by Structural Formula (2), which is a preferred example of the compound represented by General Formula (5). It is a figure. FIG. 5 is an NMR spectrum of the compound represented by Structural Formula (3), which is a preferred example of the compound represented by General Formula (11). FIG. 6A shows LC (liquid chromatography) (upper) and MS (mass spectrometry) in LC-MS analysis of the compound represented by Structural Formula (3), which is a preferred example of the compound represented by General Formula (11). ) (Bottom) chromatogram image. FIG. 6B shows the results of mass spectrometry of the peak component having a retention time of 1.796 in LC-MS analysis of the compound represented by Structural Formula (3), which is a preferred example of the compound represented by General Formula (11). It is a figure. FIG. 7 is a diagram showing a sensorgram in which IgE receptor (FcεRI) is immobilized on a sensor chip in Test Example 2. The vertical axis represents mass change (RU) on the sensor chip surface, and the horizontal axis represents time (seconds).

(New compound)
<Compound represented by the general formula (1)>
The first novel compound of the present invention is represented by the following general formula (1).
In the general formula (1), Z represents an atom of carbon, nitrogen, oxygen, or sulfur. Two Z's are bonded in a straight chain and may be the same or different. The Z may have a side chain (Z ¹ ) _k . Z ¹ represents any of carbon, nitrogen, oxygen, sulfur, and hydrogen, and k represents an integer of 0 to 2. When k represents an integer other than 0, Z and Z ¹ may be the same as or different from each other.
E represents an aromatic ring in which two 6-membered rings represented by the following general formula (2A) are condensed. F represents an aromatic 6-membered ring represented by the following general formula (3).
In the general formula (2A), a represents an integer of 0 to 4, and b represents an integer of 0 to 3. When a and b represent an integer other than 0, R ¹ and R ² represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine. R ¹ and R ² may be the same as or different from each other.
The compound represented by the general formula (2A) has one bond represented by “*”, and the bond represents a bond with Z.
In the general formula (3), d represents an integer of 0 to 5. When the d represents an integer other than 0, R ³ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine.
The compound represented by the general formula (3) has one bond represented by “*”, and the bond represents a bond with Z.

There is no restriction | limiting in particular as a compound represented by the said General formula (1), Although it can select suitably according to the objective, The compound represented by the following general formula (4) is preferable, and following Structural formula (1) ) Is more preferable.
In the general formula (4), R ¹ and R ³ represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine. R ¹ and R ³ may be the same as or different from each other.

-Physicochemical properties-
Among the compounds represented by the general formula (1), the physicochemical properties of the compound represented by the structural formula (1) are:
(1) The molecular formula is represented by C ₁₈ H ₁₅ NO ₃ .
(2) The proton nuclear magnetic resonance spectrum was measured at 25 ° C. in 6 deuterated dimethyl sulfoxide (DMSO-d6) at 400 MHz. The proton NMR spectrum is as shown in FIG.
(3) The experimental value by mass spectrum (LC-MS: positive ion mode) is m / z 293.9 (M + H) ⁺ , and the calculated value of M is m / z 293.1 (C ₁₈ H ₁₅ NO ₃ ). The upper part of FIG. 2A shows a chromatographic image of LC (liquid chromatography), and the lower part shows a chromatographic image of MS (mass spectrometry). FIG. 2B shows the mass analysis result of the peak component with a retention time of 1.296.

  Whether or not the novel compound has the structure represented by the general formula (1) can be confirmed by various analysis methods selected as appropriate. For example, the proton nuclear magnetic resonance spectrum, the mass spectrum, This can be confirmed by analyzing carbon-13 nuclear magnetic resonance spectrum, infrared absorption spectrum, high performance liquid chromatography and the like.

  In the present invention, the compound represented by the general formula (1) includes a tautomer.

-Manufacturing method-
There is no restriction | limiting in particular as a manufacturing method of the compound represented by the said General formula (1), According to the objective, it can select suitably, For example, the method by chemical synthesis etc. can be used.
Hereinafter, taking the compound represented by the structural formula (1) as an example, an example of a method for producing the compound represented by the general formula (1) will be described.

A method for obtaining the compound represented by the structural formula (1) by chemical synthesis is not particularly limited and may be appropriately selected depending on the intended purpose. For example, as a starting material, the following 6-bromo-naphthalene-2- Using all, the compound represented by the structural formula (1) can be produced through an intermediate.
The method for producing the compound represented by the structural formula (1) using the starting material 6-bromo-naphthalen-2-ol is not particularly limited and may be appropriately selected depending on the purpose. For example, a method of passing through four intermediates can be mentioned.
Examples of the intermediate include, firstly, the following compound 11 (hereinafter sometimes referred to as “intermediate 1”), and secondly, the following 6-benzyloxy-naphthalen-2-ylamine (hereinafter referred to as “intermediate 1”). 3) the following 6-amino-naphthalen-2-ol (hereinafter sometimes referred to as “intermediate 3”), and fourth, the following segment C (Hereinafter sometimes referred to as “intermediate 4”).
There is no restriction | limiting in particular as a method of obtaining the said intermediates 1-4, According to the objective, it can select suitably, For example, the method by chemical synthesis etc. are mentioned. Moreover, a commercial item can also be used irrespective of chemical synthesis.

The reaction temperature, reaction time, synthesis method, and amount of the compound used in the chemical synthesis are not particularly limited and may be appropriately selected depending on the target intermediate.
The state of the compound used for the chemical synthesis is not particularly limited and can be appropriately selected depending on the purpose. For example, the liquid state, the solid state, the dried state, the oily state, the recrystallized state The state etc. are mentioned.
The method for confirming the intermediate is not particularly limited and may be appropriately selected depending on the intended purpose. For example, proton nuclear magnetic resonance spectrum, mass spectrum, carbon-13 nuclear magnetic resonance spectrum, infrared absorption spectrum, high-speed A method such as liquid chromatography can be used.

The product obtained by the chemical synthesis can be purified as necessary.
The purification method is not particularly limited and may be appropriately selected depending on the intended purpose. Can be used.

<Compound represented by formula (5)>
The second novel compound of the present invention is represented by the following general formula (5).
In the general formula (5), V, W, and X each represent an atom of carbon, nitrogen, oxygen, or sulfur. The Vs are bonded in a straight chain and may be the same or different. The V may have a side chain (V ¹ ) _g , the W may have a side chain (W ¹ ) _h , and the X may have a side chain (X ¹ ) _i . V ¹ , W ¹ , and X ¹ each represent carbon, nitrogen, oxygen, sulfur, or hydrogen, and g, h, and i each independently represent an integer of 0 to 2. When g, h, and i represent an integer other than 0, the V and the V ¹ , the W and the W ¹ , and the X and the X ¹ may be the same as each other; May be different.
A is a 5-membered ring represented by the following general formula (6A), an aromatic ring condensed with at least one of the 6-membered ring and the 6-membered ring, and an aromatic 6-membered represented by the following general formula (6B) Represents one of the rings. B represents a saturated 6-membered ring represented by the following general formula (7). C represents either a 5-membered ring represented by the following general formula (8A) and an aromatic ring condensed with a 6-membered ring, or an aromatic 5-membered ring represented by the following general formula (8B). D represents an aromatic 6-membered ring represented by the following general formula (9A).
In the general formula (6A), G ¹ represents at least ^one of a 6-membered ring and a 5-membered ring. e represents an integer of 0 to 4, and f represents an integer of 0 to 3. When e and f represent an integer other than 0, R ⁴ and R ⁵ represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine. R ⁴ and R ⁵ may be the same as or different from each other.
The compound represented by the general formula (6A) has one bond represented by “*”, and the bond represents a bond with V.
In the general formula (6B), m represents an integer of 0 to 5. When m represents an integer other than 0, R ⁶ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine.
The compound represented by the general formula (6B) has one bond represented by “*”, and the bond represents a bond with V.
In the general formula (7), n represents an integer of 0 to 4. When n represents an integer other than 0, R ⁷ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine.
The compound represented by the general formula (7) has two bonds represented by “*”, one of the bonds represents a bond with V, and the other represents a bond with W. Represents.
In the general formula (8A), o represents an integer of 0 to 1, and p represents an integer of 0 to 4. When o and p represent an integer other than 0, R ⁸ and R ⁹ represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine. R ⁸ and R ⁹ may be the same as or different from each other.
The compound represented by the general formula (8A) has two bonds represented by “*”, one of the bonds represents a bond with W, and the other represents a bond with X. Represents.
In the general formula (8B), q represents an integer of 0 to 3. When q represents an integer other than 0, R ¹⁰ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine.
The compound represented by the general formula (8B) has two bonds represented by “*”, one of the bonds represents a bond with W, and the other represents a bond with X. Represents.
In the general formula (9A), r represents an integer of 0 to 5. When r represents an integer other than 0, R ¹¹ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, a methylene carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine.
The compound represented by the general formula (9A) has one bond represented by “*”, and the bond represents a bond with X.

There is no restriction | limiting in particular as a compound represented by the said General formula (5), Although it can select suitably according to the objective, The compound represented by the following general formula (10) is preferable, and following Structural formula (2) ) Is more preferable.

In the general formula (10), V ¹ and W ¹ represent any of carbon, nitrogen, oxygen and sulfur, and the V ¹ and W ¹ may be the same as or different from each other. May be. R ¹¹ represents any one of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, a methylene carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine.

-Physicochemical properties-
Of the compounds represented by the general formula (5), the physicochemical properties of the compounds represented by the structural formula (2) are:
(1) The molecular formula is represented by C ₃₄ H ₃₂ N ₄ O ₄ .
(2) The proton nuclear magnetic resonance spectrum was measured at 25 ° C. in 6 deuterated dimethyl sulfoxide (DMSO-d6) at 400 MHz. The proton NMR spectrum is as shown in FIG.
(3) The experimental value by mass spectrum (LC-MS: positive ion mode) is m / z 561.1 (M + H) ⁺ , and the calculated value of M is m / z 560.24 (C ₃₄ H ₃₂ N ₄ O ₄ ). The upper part of FIG. 4A shows a chromatographic image of LC (liquid chromatography), and the lower part shows a chromatographic image of MS (mass spectrometry). FIG. 4B shows the result of mass spectrometry of the peak component with a retention time of 1.613.

  Whether or not the novel compound has the structure represented by the general formula (5) can be confirmed by various analysis methods selected as appropriate. For example, the proton nuclear magnetic resonance spectrum, the mass spectrum, This can be confirmed by analyzing carbon-13 nuclear magnetic resonance spectrum, infrared absorption spectrum, high performance liquid chromatography and the like.

  In the present invention, the compound represented by the general formula (5) includes a tautomer.

-Manufacturing method-
There is no restriction | limiting in particular as a manufacturing method of the compound represented by the said General formula (5), According to the objective, it can select suitably, For example, the method by chemical synthesis etc. can be used.
Hereinafter, an example of a method for producing the compound represented by the general formula (5) will be described by taking the compound represented by the structural formula (2) as an example.

The method for obtaining the compound represented by the structural formula (2) by chemical synthesis is not particularly limited and may be appropriately selected depending on the intended purpose. For example, using the following compound 3 as a starting material, Then, the compound represented by the structural formula (2) can be produced.
There is no restriction | limiting in particular as a method of manufacturing the compound represented by the said Structural formula (2) using the said starting material compound 3, According to the objective, it can select suitably, For example, as shown below And a method using 5 intermediates.
Examples of the intermediate include, firstly, the following compound 4 (hereinafter sometimes referred to as “intermediate 5”), and secondly, the following compound 5 (hereinafter referred to as “intermediate 6”). Third, the following segment A (hereinafter sometimes referred to as “intermediate 7”), and fourthly, the following compound 14 (hereinafter sometimes referred to as “intermediate 8”), And fifthly, the following compound 15 (hereinafter sometimes referred to as “intermediate 9”) may be mentioned.
There is no restriction | limiting in particular as a method of obtaining the said intermediates 5-9, According to the objective, it can select suitably, For example, the method by chemical synthesis etc. are mentioned. Moreover, a commercial item can also be used irrespective of chemical synthesis.

The reaction temperature, reaction time, synthesis method, and amount of the compound used in the chemical synthesis are not particularly limited and may be appropriately selected depending on the target intermediate.
The state of the compound used for the chemical synthesis is not particularly limited and can be appropriately selected depending on the purpose. For example, the liquid state, the solid state, the dried state, the oily state, the recrystallized state The state etc. are mentioned.
The method for confirming the intermediate is not particularly limited and may be appropriately selected depending on the intended purpose. For example, proton nuclear magnetic resonance spectrum, mass spectrum, carbon-13 nuclear magnetic resonance spectrum, infrared absorption spectrum, high-speed A method such as liquid chromatography can be used.

The product obtained by the chemical synthesis can be purified as necessary.
The purification method is not particularly limited and may be appropriately selected depending on the intended purpose. Can be used.

<Compound represented by formula (11)>
The third novel compound of the present invention is represented by the following general formula (11).
In the general formula (11), V, W, X, Y, and Z each represent an atom of carbon, nitrogen, oxygen, or sulfur. The V and Y may be bonded in a straight chain and may be the same or different from each other. Two Z's are bonded in a straight chain and may be the same or different. The V represents a side chain (V ¹ ) _g , the W represents a side chain (W ¹ ) _h , the X represents a side chain (X ¹ ) _i , the Y represents a side chain (Y ¹ ) _j , the Z May have a side chain (Z ¹ ) _k . V ¹ , W ¹ , X ¹ , Y ¹ , and Z ¹ each represent carbon, nitrogen, oxygen, sulfur, or hydrogen, and g, h, i, j, and k are Each represents an integer of 0 to 2 independently. When the g, the h, the i, the j, and the k represent non-zero integers, the V and the V ¹ , the W and the W ¹ , the X and the X ¹ , the Y and the Y ¹ , and Z and Z ¹ may be the same as or different from each other.
A is a 5-membered ring represented by the following general formula (6A), an aromatic ring condensed with at least one of the 6-membered ring and the 6-membered ring, and an aromatic 6-membered represented by the following general formula (6B) Represents a ring. B represents a saturated 6-membered ring represented by the following general formula (7). C represents either a 5-membered ring represented by the following general formula (8A) and an aromatic ring condensed with a 6-membered ring, or an aromatic 5-membered ring represented by the following general formula (8B). D represents an aromatic 6-membered ring represented by the following general formula (9B). E represents an aromatic ring in which two 6-membered rings represented by the following general formula (2B) are condensed. F represents an aromatic 6-membered ring represented by the following general formula (3).
In the general formula (6A), G ¹ represents at least ^one of a 6-membered ring and a 5-membered ring. e represents an integer of 0 to 4, and f represents an integer of 0 to 3. When e and f represent an integer other than 0, R ⁴ and R ⁵ represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine. R ⁴ and R ⁵ may be the same as or different from each other.
The compound represented by the general formula (6A) has one bond represented by “*”, and the bond represents a bond with V.
In the general formula (6B), m represents an integer of 0 to 5. When m represents an integer other than 0, R ⁶ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine.
The compound represented by the general formula (6B) has one bond represented by “*”, and the bond represents a bond with V.
In the general formula (7), n represents an integer of 0 to 4. When n represents an integer other than 0, R ⁷ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine.
The compound represented by the general formula (7) has two bonds represented by “*”, one of the bonds represents a bond with V, and the other represents a bond with W. Represents.

In the general formula (8A), o represents an integer of 0 to 1, and p represents an integer of 0 to 4. When o and p represent an integer other than 0, R ⁸ and R ⁹ represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine. R ⁸ and R ⁹ may be the same as or different from each other.
The compound represented by the general formula (8A) has two bonds represented by “*”, one of the bonds represents a bond with W, and the other represents a bond with X. Represents.
In the general formula (8B), q represents an integer of 0 to 3. When q represents an integer other than 0, R ¹⁰ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine.
The compound represented by the general formula (8B) has two bonds represented by “*”, one of the bonds represents a bond with W, and the other represents a bond with X. Represents.
In the general formula (9B), r represents an integer of 0 to 4. When r represents an integer other than 0, R ¹¹ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine.
The compound represented by the general formula (9B) has two bonds represented by “*”, one of the bonds represents a bond with X, and the other represents a bond with Y. Represents.
In the general formula (2B), a and b each independently represent an integer of 0 to 3. When a and b represent an integer other than 0, R ¹ and R ² represent any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine. R ¹ and R ² may be the same as or different from each other.
The compound represented by the general formula (2B) has two bonds represented by “*”, one of the bonds represents a bond with Y, and the other represents a bond with Z. Represents.
In the general formula (3), d represents an integer of 0 to 5. When the d represents an integer other than 0, R ³ represents any of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine.
The compound represented by the general formula (3) has one bond represented by “*”, and the bond represents a bond with Z.

There is no restriction | limiting in particular as a compound represented by the said General formula (11), Although it can select suitably according to the objective, The compound represented by the following general formula (12) is preferable, and following Structural formula (3) ) Is more preferable.

In the general formula (12), V ¹ , W ¹ , and Y ¹ represent any one of carbon, nitrogen, oxygen, and sulfur, and the V ¹ , W ¹ , and Y ¹ are the same as each other. It may be different or different. R ³ represents any one of a methyl group, an ethyl group, a hydroxy group, a carboxyl group, an amino group, and a halogen atom. The halogen atom is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluorine, chlorine, bromine and iodine.

-Physicochemical properties-
Among the compounds represented by the general formula (11), the physicochemical properties of the compound represented by the structural formula (3) are:
(1) The molecular formula is represented by C ₅₂ H ₄₅ N ₅ O ₆ .
(2) The proton nuclear magnetic resonance spectrum was measured at 25 ° C. in 6 deuterated dimethyl sulfoxide (DMSO-d6) at 400 MHz. The proton NMR spectrum is as shown in FIG.
(3) The experimental value by mass spectrum (LC-MS: positive ion mode) is m / z 836.34 (M + H) ⁺ , and the calculated value of M is m / z 835.34 (C ₅₂ H ₄₅ N ₅ O ₆ ). The upper part of FIG. 6A shows an LC (liquid chromatography) chromatographic image, and the lower part shows an MS (mass spectrometry) chromatographic image. FIG. 6B shows the mass analysis result of the peak component with a retention time of 1.796.

  Whether or not the novel compound has the structure represented by the general formula (11) can be confirmed by various analysis methods selected as appropriate. For example, the proton nuclear magnetic resonance spectrum, the mass spectrum, This can be confirmed by analyzing carbon-13 nuclear magnetic resonance spectrum, infrared absorption spectrum, high performance liquid chromatography and the like.

  In the present invention, the compound represented by the general formula (11) includes a tautomer.

-Manufacturing method-
There is no restriction | limiting in particular as a manufacturing method of the compound represented by the said General formula (11), According to the objective, it can select suitably, For example, the method by chemical synthesis etc. can be used.
Hereinafter, an example of a method for producing the compound represented by the general formula (11) will be described by taking the compound represented by the structural formula (3) as an example.

The method for obtaining the compound represented by the structural formula (3) by chemical synthesis is not particularly limited and may be appropriately selected depending on the intended purpose. For example, using the following compound 3 as a starting material, Then, the compound represented by the structural formula (3) can be produced.
There is no restriction | limiting in particular as a method of manufacturing the compound represented by said Structural formula (3) using the said starting material compound 3, According to the objective, it can select suitably, For example, as shown below And a method of passing through 7 intermediates.
Examples of the intermediate include, firstly, the following compound 4 (hereinafter sometimes referred to as “intermediate 5”), and secondly, the following compound 5 (hereinafter referred to as “intermediate 6”). Third, the following segment A (hereinafter sometimes referred to as “intermediate 7”), and fourthly, the following compound 14 (hereinafter sometimes referred to as “intermediate 8”), Fifth, the following compound 15 (hereinafter sometimes referred to as “intermediate 9”), sixth, the following compound 16 (hereinafter sometimes referred to as “intermediate 10”), and seventh. The following compound 17 (hereinafter sometimes referred to as “intermediate 11”) can be obtained.
There is no restriction | limiting in particular as a method of obtaining the said intermediates 5-11, According to the objective, it can select suitably, For example, the method by chemical synthesis etc. are mentioned. Moreover, a commercial item can also be used irrespective of chemical synthesis.

The reaction temperature, reaction time, synthesis method, and amount of the compound used in the chemical synthesis are not particularly limited and may be appropriately selected depending on the target intermediate.
The state of the compound used for the chemical synthesis is not particularly limited and can be appropriately selected depending on the purpose. For example, the liquid state, the solid state, the dried state, the oily state, the recrystallized state The state etc. are mentioned.
The method for confirming the intermediate is not particularly limited and may be appropriately selected depending on the intended purpose. For example, proton nuclear magnetic resonance spectrum, mass spectrum, carbon-13 nuclear magnetic resonance spectrum, infrared absorption spectrum, high-speed A method such as liquid chromatography can be used.

The product obtained by the chemical synthesis can be purified as necessary.
The purification method is not particularly limited and may be appropriately selected depending on the intended purpose. Can be used.

<Binding inhibitory activity between IgE and IgE receptor (FcεRI)>
The novel compounds represented by the general formula (1), the general formula (5), and the general formula (11) are compounds having binding inhibitory activity between IgE and IgE receptor (FcεRI) (tests described later) Described in Example 1).
There is no restriction | limiting in particular as a method to confirm the said binding inhibitory activity, According to the objective, it can select suitably, For example, the method etc. which confirm by an immunological measuring method etc. are mentioned.
There is no restriction | limiting in particular as said immunological measuring method, According to the objective, it can select suitably, For example, measuring methods, such as an immuno-staining method, an immunoprecipitation method, a Western blot method, ELISA method, are mentioned.

<Application>
The novel compounds represented by the general formula (1), the general formula (5), and the general formula (11) include, for example, a binding inhibitor between IgE and IgE receptor (FcεRI) of the present invention described later, It can be suitably used as an antiallergic agent, antiasthma agent, and anti-inflammatory agent.

(Binding inhibitors, antiallergic agents, antiasthmatic agents, and antiinflammatory agents)
<Binding inhibitor>
The binding inhibitor between IgE and IgE receptor (FcεRI) of the present invention (hereinafter sometimes referred to as “binding inhibitor”) is the general formula (1) or general formula (5) of the present invention described above. And at least one of the novel compounds represented by the general formula (11), and further contains other components appropriately selected as necessary.

The novel compound contained in the binding inhibitor may be in a salt state. There is no restriction | limiting in particular as said salt, According to the objective, it can select suitably, For example, carboxylate, an inorganic acid salt, an amino acid salt, a sulfonate, etc. are mentioned.
Examples of the carboxylate include trifluoroacetate, acetate, trichloroacetate, hydroxyacetate, lactate, citrate, tartrate, oxalate, benzoate, butyrate, maleate, Examples include propionate, formate and malate.
Examples of the inorganic acid salt include hydrohalide, sulfate, nitrate, phosphate, carbonate, and the like.
Examples of the amino acid salt include arginate, aspartate, glutamate and the like.
Examples of the sulfonate include methanesulfonate and p-toluenesulfonate.

  There is no restriction | limiting in particular as content of the said novel compound thru | or its salt contained in the said binding inhibitor, According to the objective, it can select suitably. The binding inhibitor may be the novel compound or a salt thereof.

There is no restriction | limiting in particular as said other component, According to the objective, it can select suitably from the carriers accept | permitted pharmacologically, For example, ethanol, water, starch, etc. are mentioned.
There is no restriction | limiting in particular as content of the other component in the said binding inhibitor, According to the objective, it can select suitably.

<Anti-allergic agent, anti-asthma agent, and anti-inflammatory agent>
The anti-allergic agent, anti-asthma agent, and anti-inflammatory agent of the present invention contain the above-described binding inhibitor and optionally contain other components as necessary.

  There is no restriction | limiting in particular as content of the said binding inhibitor in the said antiallergic agent, the said antiasthma agent, and the said anti-inflammatory agent, According to the objective, it can select suitably. Further, the anti-allergic agent, the anti-asthma agent, and the anti-inflammatory agent may be the binding inhibitor itself.

There is no restriction | limiting in particular as said other component, According to the objective, it can select suitably from the carriers accept | permitted pharmacologically, For example, ethanol, water, starch, etc. are mentioned.
There is no restriction | limiting in particular as content of the other component in the said anti-allergic agent, the said anti-asthma agent, and the said anti-inflammatory agent, According to the objective, it can select suitably.

<Use>
The binding inhibitor, the anti-allergic agent, the anti-asthma agent, and the anti-inflammatory agent may be used singly or may be used in combination with a medicine containing another component as an active ingredient. . Moreover, the said binding inhibitor, the said antiallergic agent, the said antiasthmatic agent, and the said anti-inflammatory agent may be used in the state mix | blended in the pharmaceutical which uses another component as an active ingredient.

<Dosage form>
The dosage form of the binding inhibitor, the anti-allergic agent, the anti-asthma agent, and the anti-inflammatory agent is not particularly limited and may be appropriately selected depending on the intended purpose. For example, oral solid preparations, oral liquid preparations Injections, inhalation powders, and the like.

-Oral solid agent-
There is no restriction | limiting in particular as said oral solid agent, According to the objective, it can select suitably, For example, a tablet, a coated tablet, a granule, a powder, a capsule etc. are mentioned.
There is no restriction | limiting in particular as a manufacturing method of the said oral solid preparation, A conventional method can be used, for example, it manufactures by adding an excipient | filler and various additives as needed to the said novel compound. be able to. Here, the excipient is not particularly limited and may be appropriately selected depending on the intended purpose. For example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, etc. Is mentioned. Moreover, there is no restriction | limiting in particular also as said additive, According to the objective, it can select suitably, For example, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring / flavoring agent etc. are mentioned.
The binder is not particularly limited and may be appropriately selected depending on the intended purpose. For example, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxy Examples include propyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, and polyvinyl pyrrolidone.
The disintegrant is not particularly limited and may be appropriately selected depending on the intended purpose. Is mentioned.
The lubricant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include purified talc, stearate, borax, and polyethylene glycol.
The colorant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include titanium oxide and iron oxide.
The flavoring / flavoring agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include sucrose, orange peel, citric acid, and tartaric acid.

-Oral solution-
There is no restriction | limiting in particular as said oral liquid agent, According to the objective, it can select suitably, For example, an internal use liquid agent, a syrup agent, an elixir etc. are mentioned.
There is no restriction | limiting in particular as a manufacturing method of the said oral liquid preparation, A normal method can be used, For example, it can manufacture by adding an additive to the said novel compound. Here, there is no restriction | limiting in particular as said additive, According to the objective, it can select suitably, For example, a flavoring / flavoring agent, a buffering agent, a stabilizer, etc. are mentioned.
The flavoring / flavoring agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include sucrose, orange peel, citric acid, and tartaric acid.
There is no restriction | limiting in particular as said buffering agent, According to the objective, it can select suitably, For example, sodium citrate etc. are mentioned.
There is no restriction | limiting in particular as said stabilizer, According to the objective, it can select suitably, For example, tragacanth, gum arabic, gelatin, etc. are mentioned.

-Injection-
There is no restriction | limiting in particular as said injection, According to the objective, it can select suitably, For example, a solution, a suspension, the solid agent for use, etc. are mentioned.
The method for producing the injection is not particularly limited, and a conventional method can be used. For example, the novel compound includes a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. It can manufacture by adding. Here, there is no restriction | limiting in particular as said pH regulator and said buffer, According to the objective, it can select suitably, For example, sodium citrate, sodium acetate, sodium phosphate etc. are mentioned. Moreover, there is no restriction | limiting in particular as said stabilizer, According to the objective, it can select suitably, For example, sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid etc. are mentioned. The tonicity agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include sodium chloride and glucose. The local anesthetic agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include procaine hydrochloride and lidocaine hydrochloride.

<Administration>
There are no particular restrictions on the administration method, dose, administration time, and administration target of the binding inhibitor, the anti-allergic agent, the anti-asthma agent, and the anti-inflammatory agent, and may be appropriately selected according to the purpose. it can.
There is no restriction | limiting in particular as said administration method, According to the objective, it can select suitably, For example, the method of oral administration, the method by injection, the method by inhalation, etc. are mentioned. Among these, the oral administration method is preferable. Since the novel compound of the present invention contained in the binding inhibitor, the anti-allergic agent, the anti-asthma agent, and the anti-inflammatory agent is a non-protein low molecular weight compound, the oral administration method can be used. This is advantageous in that it has no antigenicity.
The dosage is not particularly limited and may be appropriately selected in consideration of various factors such as the age, weight, constitution, symptom, and presence / absence of administration of a drug containing other ingredients as active ingredients. it can.
The animal species to be administered is not particularly limited and can be appropriately selected according to the purpose. For example, human, monkey, pig, cow, sheep, goat, dog, cat, mouse, rat, bird, etc. Among them, it is preferably used for humans.

  The binding inhibitor, the antiallergic agent, the antiasthma agent, and the anti-inflammatory agent can be suitably used not only for pharmaceutical ingredients but also for cosmetics, foods, bathing agents, etc. It is advantageous in that it can be added with antiallergic action, antiasthmatic action, and antiinflammatory action.

  Examples of the present invention will be described below, but the present invention is not limited to these examples. In the following Production Examples 1 to 3, the yield “%” of the compound represents “mol%” unless otherwise specified.

(Production Example 1: Production of compound represented by structural formula (1))
<Synthesis method>
-Synthesis of Compound 11-
As shown in the following reaction formula, 6-bromo-naphthalen-2-ol (manufactured by Aldrich) (20 g) was dissolved in dry N, N-dimethylformamide (dry DMF) (150 mL), and then at 0 ° C. To this solution, sodium hydride (NaH) (4.0 g) was added in small portions and stirred for 1 hour. Then benzyl bromide (PhCH ₂ Br) (16.0 g) was added and the reaction mixture was stirred overnight at ambient temperature. Water (100 mL) was added to the obtained reaction mixture solution, and the mixture was stirred at room temperature for 1 hour. The solution was then filtered and the resulting filter cake was washed with methanol. The filter cake was collected and dried to obtain 28 g of the following compound 11. The yield of the compound 11 was 100%.

-Synthesis of Compound 12-
Hexamethyldisilazane ((CH ₃ ) ₆ Si ₂ NH) (11.17 g) was dissolved in dry tetrahydrofuran (dry THF) (180 mL) at −78 ° C. in a nitrogen atmosphere, and then 2.5 M n-butyllithium. (27.7 mL) was added dropwise, and the mixture was stirred at -78 ° C for 1 hour to obtain lithium hexamethyldisilazane (LiHMDS). The solution was returned to room temperature, then, as shown in the following reaction formula, the compound 11 (18 g), tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ ) (0.28 g), And biphenyl-2-yldicyclohexylphosphine (0.32 g) was added. The mixture was stirred at 65 ° C. overnight and returned to room temperature, and the resulting reaction mixture was stirred with 1N aqueous hydrochloric acid (100 mL) for several minutes and washed with ethyl acetate. The aqueous layer was neutralized with sodium hydroxide to adjust the pH to 9, and then extracted with dichloromethane (DCM). Next, the organic layer was washed with brine, dried and concentrated to obtain 10.1 g of the following compound 12. The yield of Compound 12 was 68%.

-Synthesis of Compound 13-
As shown in the following reaction formula, the compound 12 (6-benzyloxy-naphthalen-2-ylamine) (9.8 g) was dissolved in ethanol (100 mL), and then palladium / carbon (Pd / C) (3 g) was dissolved. Added. The mixture was then stirred overnight at room temperature under a hydrogen (H ₂ ) atmosphere. The obtained mixture was filtered and concentrated to obtain 5.0 g of the following compound 13. The yield of the compound 13 was 80%.

-Synthesis of segment C-
As shown in the following reaction formula, the compound 13 (6-amino-naphthalen-2-ol) (500 mg) was dissolved in DMF (15 mL), and then sodium hydride (125 mg) was added at room temperature. The solution was stirred at room temperature for 45 minutes. A solution of 3-bromomethyl-benzoic acid methyl ester (720 mg) in DMF (10 mL) was then added dropwise to the solution. Subsequently, the mixed solution was stirred at room temperature for 3 hours, water was added to the obtained solution, and the mixture was extracted with ethyl acetate. The extract was washed several times with brine and the organic layer was dried and concentrated. The residue was purified twice by silica gel chromatography (manufactured by Merck) (eluent: petroleum ether: ethyl acetate = 10: 1 to 5: 1 (V / V)) to obtain 150 mg of the following segment C. The yield of segment C was 16%.

-Synthesis of the compound represented by the structural formula (1)-
As shown in the following reaction formula, methyl esterified segment C (157 mg, 0.51 mmol) was mixed with THF and 2M lithium hydroxide (LiOH) (1: 1 (V / V)) mixed solution ( 20 mL) and stirred at 25 ° C. overnight. Then added 10% potassium hydrogen sulfate (KHSO ₄₎ aqueous solution (30 mL), and adjusted to acidic. The mixture was extracted with ethyl acetate (50 mL), washed with brine, dried and concentrated to obtain 100 mg of a compound represented by the following structural formula (1). The yield of the compound represented by the structural formula (1) was 67%.

<Physical and chemical properties>
About the compound represented by Structural formula (1) obtained by the said chemical reaction, the molecular weight and the structure were confirmed using the mass spectrum and the proton nuclear magnetic resonance spectrum. These results are shown below.
(1) The molecular formula is represented by C ₁₈ H ₁₅ NO ₃ .
(2) The proton nuclear magnetic resonance spectrum was measured at 25 ° C. in 6 deuterated dimethyl sulfoxide (DMSO-d6) at 400 MHz and was as follows.
FIG. 1 shows a proton NMR spectrum chart.
δ8.00 (1H, s), 7.84 (1H, d, 7.6 Hz), 7.69 (1H, dd, 2.8, 8.8 Hz), 7.49-7.40 (2H, m ), 7.33 (1 H, t, 7.2 Hz), 7.16 (1 H, bs), 7.01 (1 H, d, 9.2 Hz), 6.86 (1 H, 8.8 Hz), 6. 76 (1H, bs), 5.11 (2H, s), 5.10 (2H, bs).
(3) The experimental value by mass spectrum (LC-MS: Shim-pack ODS inner diameter 3.0 × 30 mm (manufactured by Shimadzu Corporation), positive ion mode) is m / z 293.9 (M + H) ⁺ , M The calculated value of was m / z 293.1 (C ₁₈ H ₁₅ NO ₃ ).
The upper part of FIG. 2A shows a chromatographic image of LC (liquid chromatography), and the lower part shows a chromatographic image of MS (mass spectrometry).
FIG. 2B shows the mass analysis result of the peak component with a retention time of 1.296.

(Production Example 2: Production of compound represented by structural formula (2))
<Synthesis method>
-Synthesis of Compound 1 and Compound 2-
2-Methylphenylacetic acid (Princeton) (9.3 g, 62 mmol) and potassium carbonate (21.4 g, 155 mmol) were added to DMF (75 mL) as shown in the following reaction formula, and then the mixture was iodinated. Methyl (MeI) (17.6 g, 124 mmol) was added dropwise. The resulting mixture was then stirred overnight at room temperature. It was then diluted with dichloromethane (DCM) (150 mL), washed with water (70 mL, 3 times), and brine (70 mL), dried over sodium sulfate, and concentrated to give the following compound 1 as a brown liquid. 10.1 g of a crude product was obtained. The yield of Compound 1 was 98%. Compound 1 was used in the next step without purification.
As shown in the following reaction formula, the compound 1 (10.9 g, 66.5 mmol), azobisisobutyronitrile (AIBN) (2.3 g, 13 mmol), and N-bromosuccinimide (NBS) (11. 8 g, 67 mmol) was dissolved in carbon tetrachloride (CCl ₄ ) (100 mL) and the mixture was refluxed for 3 hours. The obtained reaction mixture was filtered, and the filtrate was washed with water and brine, dried using sodium sulfate, and concentrated to obtain 14.2 g of a crude product of the following compound 2 as a brown liquid. The yield of Compound 2 was 88%. The compound 2 was used in the next step without purification.

-Synthesis of Compound 4-
Compound 3 (manufactured by Aldrich) (100 mg, 0.62 mmol) was dissolved in toluene (1 mL), and trifluoroacetic anhydride ((CF ₃ CO) ₂ O) (157 mg, 0.73 mmol) was added dropwise under a nitrogen atmosphere. did. The resulting mixture was stirred at room temperature for 3 hours until the reaction turned red. As shown in the following reaction formula, benzyl alcohol (BnOH) (80 mg, 0.7 mmol) was added and the reaction mixture was stirred for another 2 hours. The mixture was diluted with ethyl acetate (2 mL), washed with 2M aqueous sodium hydroxide (1 mL, 2 ×), and brine (1 mL), dried over sodium sulfate, concentrated, and prep-TLC (Merck To obtain 64 mg of the following compound 4 as a white solid. The yield of Compound 4 was 43%.

-Synthesis of Compound 5-
As shown in the following reaction formula, the compound 4 (8.27 g, 33 mmol) was dissolved in DMF (80 mL) in a water-cooled bath, and sodium hydride (1.98 g, 50 mmol) was added little by little. After the addition, the resulting mixture was stirred for 3 hours, and then the compound 2 (12 g, 50 mmol) was added. The mixture was then stirred overnight at room temperature. The reaction mixture is diluted with ethyl acetate (200 mL), washed with water (70 mL, 3 times), and brine (70 mL), dried over sodium sulfate, concentrated, and silica gel column (Merck) (eluent). : Petroleum ether: ethyl acetate = 20: 1 to 15: 1 (V / V)) to obtain 4.3 g of the following compound 5 as a red oily substance. The yield of Compound 5 was 33%.

-Synthesis of segment A-
As shown in the following reaction formula, the compound 5 (2.5 g, 6 mmol) and palladium / carbon (Pd / C) (250 mg) were added to ethyl acetate (20 mL), and a hydrogen (H ₂ ) atmosphere at room temperature was added. Stir overnight. Pd / C was removed by filtration, and the filtrate was concentrated. The residue was recrystallized using ethyl acetate / petroleum ether (2: 1 (V / V)) to obtain 1.5 g of the following segment A as a gray solid. The yield of segment A was 77%.

-Synthesis of Compound 8-
As shown in the following reaction formula, compound 7 (manufactured by Aldrich) (21.4 g, 89 mmol) and triethylamine (TEA) (22 mL, 159 mmol) were dissolved in toluene (200 mL), and compound 6 ( Aldrich) (15.0 g, 63.4 mmol) was added dropwise. The mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was filtered and washed with ether. The filtrate was washed with aqueous sodium bicarbonate and brine, dried and concentrated. The obtained crude product was purified with a silica gel column (Merck) to obtain 15.0 g of the following compound 8. The yield of Compound 8 was 82%.

-Synthesis of Compound 9-
As shown in the following reaction formula, lithium aluminum hydride (LiAlH ₄ ) (2.7 g, 71 mmol) was suspended in THF (150 mL). To this solution, a solution of the compound 8 (7.0 g, 24 mmol) dissolved in THF (50 mL) was added dropwise at 0 ° C. The resulting mixture was stirred at 25 ° C. overnight. After 10% by mass aqueous sodium hydroxide (2.7 mL) was added dropwise, water (2.7 mL) was added. The mixture was filtered, and the filtrate was concentrated to obtain 6.0 g of the following compound 9 as a colorless oil. The yield of Compound 9 was 85%. Compound 9 was used in the next step without purification.

-Synthesis of Compound 10-
Compound 9 (3.0 g, 10 mmol), 2-naphthalenecarboxylic acid (2.1 g, 12.2 mmol), 1-hydroxybenzotriazole (HOBt) (2.1 g, 15.5 mmol), and N-methylmorpholine ( NMM) (3.1 g, 31 mmol) was dissolved in a mixed solvent (80 mL) of DMF / THF (1: 1 (V / V)), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCl ) (3.5 g, 18.3 mmol) was added and the resulting mixture was stirred at 25 ° C. overnight. Then water (100 mL) was added and extracted with ethyl acetate (50 mL, 3 times). The combined organic phases were washed with saturated aqueous sodium bicarbonate and brine, dried and concentrated. The obtained crude product was precipitated from ethyl acetate to obtain 3.5 g of the following compound 10 as a white solid. The yield of Compound 10 was 66%.

-Synthesis of segment B-
As shown in the following reaction formula, the compound 10 (1.0 g, 2.2 mmol) was dissolved in methanol (25 mL), concentrated hydrochloric acid (1 mL) was added, and then 10% by mass wet Pd / C (100 mg). Was added and the resulting mixture was hydrogenated at 50 ° C. under a pressure of 50 psi overnight. The mixture was filtered and concentrated to obtain about 800 mg of the following segment B as a white solid. The segment B was used in the next step without purification.
In addition, the crude product of the segment B contained a by-product which was overreduced (according to LC-MS, about 10% by mass of the benzyl group was reduced to a cyclohexanyl group). The by-product was purified by prep-HPLC (manufactured by Merck).

-Synthesis of Compound 14-
To a suspension of segment A (200 mg, 0.62 mmol) in anhydrous toluene (5 mL) was added thionyl chloride (SOCl ₂ ) (0.8 mL), and the resulting mixture was stirred at 25 ° C. for 4 hours. After that, it was concentrated and the residue was dissolved in anhydrous THF (15 mL).
This solution was slowly added dropwise to a solution of segment B (390 mg, 1.14 mmol) in triethylamine (TEA) (0.5 g, 4.9 mmol) at 0 ° C., and the resulting mixture was mixed at 25 ° C. Stir overnight. Then saturated aqueous sodium bicarbonate (30 mL) was added, extracted with ethyl acetate (100 mL), dried and concentrated.
The residue was dissolved in a mixed solution of dichloromethane (DCM) (15 mL) and di-t-butyl dicarbonate ((Boc) ₂ O) (500 mg, 2.29 mmol), and then triethylamine (TEA) (0.5 g , 2.29 mmol) was added and the resulting mixture was stirred at 25 ° C. overnight.
The mixture was diluted with dichloromethane (DCM) (50 mL), washed with brine, dried and concentrated. The obtained crude product was fractionated by prep-HPLC (manufactured by Merck) in a solvent to which trifluoroacetic acid (TFA) was added, and a fraction containing the following compound 14 was basified with saturated sodium bicarbonate, and acetic acid was added. Extracted with ethyl. 340 mg of the following compound 14 was obtained by drying and concentrating the extract. The yield of Compound 14 was 82% based on Segment A.

-Synthesis of Compound 15-
As shown in the following reaction formula, the compound 14 (340 mg, 0.51 mmol) was suspended in a mixed solution (20 mL) prepared by adding 2 M lithium hydroxide (LiOH) aqueous solution (10 mL) to THF (10 mL). The mixture was stirred at 25 ° C. overnight. After adding 10% by mass aqueous potassium hydrogen sulfate (30 mL), the mixture was extracted with ethyl acetate (50 mL), washed with brine, dried and concentrated to obtain 230 mg of the following compound 15 as an off-white solid. Obtained. The yield of the compound was 69%. Compound 15 was used in the next step without purification.

-Synthesis of the compound represented by the structural formula (2)-
The compound 15 (66 mg, 0.1 mmol) was suspended in dichloromethane (DCM) (5 mL), hydrochloric acid / ether (Et ₂ O) (about 5 M, 2 mL) was added to the mixture, and the mixture was stirred at 25 ° C. overnight. After that, the mixture was concentrated. The residue was suspended in acetonitrile (2 mL), and the crude product was purified by prep-HPLC (manufactured by Merck) to obtain 30 mg of a pure substance of the compound represented by the following structural formula (2). The yield of the compound represented by the structural formula (2) was 54%.

<Physical and chemical properties>
About the compound represented by Structural formula (2) obtained by the said chemical reaction, the molecular weight and the structure were confirmed using the mass spectrum and the proton nuclear magnetic resonance spectrum. These results are shown below.
(1) The molecular formula is represented by C ₃₄ H ₃₂ N ₄ O ₄ .
(2) The proton nuclear magnetic resonance spectrum was measured at 25 ° C. in 6 deuterated dimethyl sulfoxide (DMSO-d6) at 400 MHz and was as follows. FIG. 3 shows a proton NMR spectrum chart.
δ12.53 (1H, bs), 9.37 (1H, bs), 9.15 (1H, bs), 8.96 (1H, bs), 8.46 (1H, s), 8.01-7 .90 (4H, m), 7.76 (1H, d, 7.2 Hz), 7.65-7.58 (2H, m), 7.30-7.26 (2H, m), 7.20 −7.04 (4H, m), 6.44 (1H, d, 7.2 Hz), 5.47 (2H, s), 4.50 (1H, d, 13.6 Hz), 4.32 (1H) , D, 10 Hz), 3.78 (2H, s), 3.69-3.56 (3H, m), 3.45 (2H, m), 3.23-3.14 (2H, m).
(3) The experimental value by mass spectrum (LC-MS: Shim-pack XR-ODS inner diameter 3.0 × 30 mm (manufactured by Shimadzu Corporation), positive ion mode) is m / z 561.1 (M + H) ⁺ , M was m / z 560.24 (C ₃₄ H ₃₂ N ₄ O ₄ ).
The upper part of FIG. 4A shows a chromatographic image of LC (liquid chromatography), and the lower part shows a chromatographic image of MS (mass spectrometry).
FIG. 4B shows the mass analysis result of the peak component with the retention time of 1.613.

(Production Example 3: Production of the compound represented by the structural formula (3))
<Synthesis method>
-Synthesis of Compound 16-
The compound 15 (193 mg, 0.29 mmol), N, N-diisopropylethylamine (DIPEA) (188 mg, 1.5 mmol), and the segment C (90 mg, 0.29 mmol) were mixed with dichloromethane as shown in the following reaction formula. (DCM) (5 mL) was dissolved in this solution and O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) (133 mg, 0.35 mmol) was added to this solution. The resulting mixture was stirred at 25 ° C. overnight. The mixture was diluted with dichloromethane (DCM) (25 mL), washed with brine, dried and concentrated to obtain 300 mg of the following compound 16 as a gray solid crude product. Compound 16 was used in the next step without purification.

-Synthesis of Compound 17-
As shown in the following reaction formula, the compound 16 (300 mg, 0.315 mmol) was suspended in a THF / 2M lithium hydroxide aqueous solution (LiOH) (1: 1 (V / V)) mixed solution (20 mL), After stirring overnight at 25 ° C., the mixture was stirred at 40 ° C. for 2 hours. 10 mass% potassium hydrogen sulfate aqueous solution was added until pH became 3-4, and this mixture was extracted with ethyl acetate (50 mL), washed with brine, dried and concentrated. The residue was purified by prep-HPLC (manufactured by Merck) (neutral) to obtain 100 mg of the following compound 17 as a pink solid. The yield of Compound 17 was 36.6% based on Compound 15.

-Synthesis of the compound represented by the structural formula (3)-
As shown in the following reaction formula, the compound 17 (45 mg, 0.048 mmol) was dissolved in dichloroethane (DCE) (5 mL), and hydrochloric acid / ether (HCl / Et ₂ O) (about 5 M, 2 mL) was added. The mixture was stirred at 25 ° C. overnight and then concentrated. Acetonitrile (2 mL) was added, the residue was dissolved, and concentrated under vacuum to obtain 35 mg of a compound represented by the following structural formula (3). The yield of the compound represented by the structural formula (3) was 87%.

<Physical and chemical properties>
About the compound represented by Structural formula (3) obtained by the said chemical reaction, the molecular weight and the structure were confirmed using the mass spectrum and the proton nuclear magnetic resonance spectrum. These results are shown below.
(1) The molecular formula is represented by C ₅₂ H ₄₅ N ₅ O ₆ .
(2) The proton nuclear magnetic resonance spectrum was as follows when measured at 25 ° C. in 6 deuterated dimethyl sulfoxide (DMSO-d6) at 400 MHz. FIG. 5 shows a proton NMR spectrum chart.
δ 9.70 (1H, bs), 8.50 (1H, s), 8.24 (1H, s), 8.06 (1H, s), 7.9-7.93 (5H, m), 7 .90 (1 H, d, 7.6 Hz), 7.73-7.74 (4 H, m), 7.64 (1 H, d, 8.4 Hz), 7.61-7.51 (3 H, m) 7.42 (1 H, d, 7 Hz), 7.38-7.34 (2 H, m), 7.22-7.00 (6 H, m), 6.47 (1 H, d, 8 Hz), 5 .64 (2H, s), 5.26 (2H, s), 4.48 (1H, bd, 12.8 Hz), 4.30 (1 H, bd, 16.8 Hz), 3.94 (2H, s) ), 3.72-3.50 (5H, m), 3.15-3.12 (2H, m).
(3) The experimental value by mass spectrum (LC-MS: Shim-pack XR-ODS inner diameter 3.0 × 30 mm (manufactured by Shimadzu Corporation), positive ion mode) is m / z 836.34 (M + H) ⁺ , the calculated value of M is _{m / z835.34 (C 52 H 45} N 5 O 6).
The upper part of FIG. 6A shows an LC (liquid chromatography) chromatographic image, and the lower part shows an MS (mass spectrometry) chromatographic image.
FIG. 6B shows the mass analysis result of the peak component with the retention time of 1.796.

(Test Example 1: Measurement of binding inhibitory activity between IgE and IgE receptor (FcεRI))
The compound represented by Structural Formula (1) synthesized in Production Example 1, the compound represented by Structural Formula (2) synthesized in Production Example 2, and the structural formula (3) synthesized in Production Example 3 The binding inhibition activity of IgE and IgE receptor (FcεRI) of the represented compounds was confirmed using the following method.

<Preparation of recombinant human IgE receptor (FcεRI)>
-Cloning of human IgE receptor (FcεRI) DNA-
In the human IgE receptor (FcεRI) DNA (NCBI Nucleotide: ACCESSION L14075, total length 7,659 bp), a 77 bp to 603 bp gene region was amplified by PCR, and the restriction enzyme NotI of the pAB-Bee vector (manufactured by AB Vector LLC). -Cloned into the EcoRI site.

-Transfection and virus amplification-
Sf9 cells (Invitrogen) were maintained in Sf-900 II (Invitrogen) serum-free medium. The Sf9 cells were prepared using BacPAK Baculovirus Expression System reagent (Clontech), and 0.45 μg of the pAB-Bee vector was used for each well as described in the instruction manual. In order to perform virus production and amplification, the Sf9 cells were incubated with the pAB-Bee vector for 96 hours, and the virus-containing supernatant (P0) was collected. Subsequently, Sf-900 II (manufactured by Invitrogen) medium containing 5 mass% FCS (Calf Serum) was used, and reinfection of the P0 with Sf9 cells was repeated to amplify the virus (P1, P2). , P3, P4).

-Production of recombinant human IgE receptor (FcεRI) protein-
High Five cells (Invitrogen) were maintained in Express Five SFM medium. The HighFive cells were seeded in a flask and infected by adding a supernatant containing the virus (P4). HighFive cells infected with the virus were cultured for 4 days to produce recombinant human IgE receptor (FcεRI) protein.

-Purification of recombinant human IgE receptor (FcεRI) protein-
The supernatant of the HighFive cells after the culture for 4 days was collected, and the same amount of Phosphate Buffered Saline (PBS) Dulbecco's Formula (w / o calcium, magnesium) (manufactured by DS Pharma Biomedical Co., Ltd.) was used. Diluted. The diluted supernatant was purified using Ni-NAT agarose (manufactured by QIAGEN) to obtain a recombinant human IgE receptor (FcεRI) protein (26AA-201AA).

<Measurement by ELISA method>
1.3 ng of the purified recombinant human IgE receptor (FcεRI) was suspended in a coating buffer (0.1 M sodium carbonate) and added to a 96-well plate. The recombinant human IgE receptor was affixed to the plate by incubation at 4 ° C.
The sample added to the plate to which the recombinant human IgE receptor was fixed was prepared as shown in Table 1 below.

No. in Table 1 Reference numeral 1 denotes only a human IgE antibody and a solution to which neither of the samples is added (20 mM HEPES (pH 7.4), 140 mM sodium chloride). No. in Table 1 2-6, human IgE antibody (manufactured by SCIPAC) was prepared to 0.3 nM by suspending in 20 mM HEPES (pH 7.4), 140 mM sodium chloride. No. in Table 1 3 to 5 are compounds represented by Structural Formula (1) synthesized in Production Example 1, compounds represented by Structural Formula (2) synthesized in Production Example 2, and solutions containing the above human IgE antibodies; The compound represented by Structural Formula (3) synthesized in Production Example 3 was added so that the final concentration was 0.1 μM to 200 μM, respectively. No. in Table 1 In No. 6, zeta-peptide (e131) was added to the human IgE antibody solution so that the final concentration was 0.078 μM to 200 μM.
In addition, zeta-peptide (e131) is a known peptide known to inhibit the binding between IgE and IgE receptor (FcεRI), and Nakamura GR et al. , PNAS, vol. 99, no. 3, 2002, p. Solid phase synthesis and purification were performed based on 1303-1308.

No. in Table 1 above. 1-6 were added to each well of the plate to which the human IgE receptor (FcεRI) was fixed, respectively, and incubated at 25 ° C. for 2 hours. The solution containing 1-6 was removed. Subsequently, each sample in Table 1 and the human IgE antibody were removed by washing with a washing buffer (PBS / 0.05% by mass Tween 20).
Next, anti-human IgE antibody (manufactured by Southern Biotech) conjugated with horseradish peroxidase (HRP) is suspended in 10% Blocking one (manufactured by Nacalai Tesque) and the concentration is adjusted to 0.4 μg / mL. After adding to each well and incubating at 25 ° C. for 2 hours, the solution containing the anti-human IgE antibody bound to the HRP was removed. Subsequently, the anti-human IgE antibody bound to the free HRP was removed by washing with the washing buffer.
Next, TMB (manufactured by SIGMA) as a substrate for HRP was added to each well and reacted with the HRP, and then hydrochloric acid was added as a reaction stop solution to stop the reaction.

The absorbance at 450 nm of each well after the reaction was measured using a plate reader (Wallac 1420 ARVO sx multilabel counter: manufactured by Perkin Elmer), and based on the obtained absorbance value, the human IgE antibody and the above-mentioned The binding inhibitory activity with the recombinant human IgE receptor (FcεRI) was calculated. The results are shown in Table 2.
As the method for calculating the binding inhibitory activity, the absorbance in the case where the human IgE antibody was not added (Table 1, No. 1) was added with a coloring rate of 0%, and only the human IgE antibody was added. The color development rate was calculated from the absorbance at each concentration of each of the samples (Table 1, No. 3 to 6), and the color development rate was calculated. The value obtained by subtracting from 100% was defined as the binding inhibitory activity (%) of the recombinant human IgE receptor (FcεRI). Based on the data on the binding inhibitory activity (%), IC ₅₀ (μM) of each compound was calculated.
Here, the IC ₅₀ (μM) is defined as the activity when 50% of the binding between the human IgE antibody and the recombinant human IgE receptor (FcεRI) is inhibited. A lower IC ₅₀ (μM) value indicates higher binding inhibitory activity.

(Test Example 2: Analysis of dissociation constant with IgE receptor (FcεRI))
The compound represented by Structural Formula (1) synthesized in Production Example 1, the compound represented by Structural Formula (2) synthesized in Production Example 2, and the structural formula (3) synthesized in Production Example 3 And the dissociation constant of zeta-peptide (e131) with IgE receptor (FcεRI) using a surface plasmon resonance measuring apparatus (product name: Biacore T100, manufactured by GE Healthcare Biosciences) Analyzed with

<Immobilization of IgE receptor (FcεRI) to sensor chip>
A His-tagged IgE receptor (FcεRI) (WuXi App Tec, Co., Ltd.) is used as a sensor chip (product name: Series S Sensor Chip CM5, product number: BR-1006-68, GE Healthcare Biosciences, Inc.). The product was immobilized by the amine coupling method described later. As a running buffer, 20 mM 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 140 mM sodium chloride, 0.005 mass% polyoxyethylene sorbitan nonionic surfactant (product name: Surfactant P20 , Product number: BR-1000-54, 0.05% by mass of GE Healthcare Bioscience Co., Ltd. (10% by mass aqueous solution of polyoxyethylene sorbitan nonionic surfactant) was used.), PH 7.4 Used, the flow cell 2 was immobilized at 25 ° C. with a flow rate of 10 μL / min.

  For amine coupling, an amine coupling kit (product number: BR-1000-50, manufactured by GE Healthcare Bioscience Co., Ltd.) was used. In the amine coupling method, equal amounts of 400 mM 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 100 mM N-hydroxysuccinimide (NHS) contained in the amine coupling kit are mixed. After adding the mixed solution to the flow cell 2 for 7 minutes (from a to b in FIG. 7), a 10 mM sodium acetate buffer (pH 4.5, product number: BR-1003-50, manufactured by GE Healthcare Bioscience Co., Ltd.) The His tag fusion IgE receptor (FcεRI) diluted to 10 μg / mL was added for 10 minutes (c to d in FIG. 7). The remaining active ester was inactivated by adding 1M ethanolamine / hydrochloric acid solution (pH 8.5) for 7 minutes (from e to f in FIG. 7).

The above operation was performed twice to confirm reproducibility. FIG. 7 shows the first sensorgram. In FIG. 7, the vertical axis represents the mass change on the sensor chip surface. “RU”, which is a unit of the vertical axis, is a resonance unit and corresponds to 1RU = 1 pg / mm ² . Here, 1,000 RU or more was set as the target amount of the immobilization amount.
In FIG. 7, the amount of immobilization is calculated by the following equation from the value of RU after immobilization represented by h and the value of RU before immobilization represented by g.
Immobilization amount (RU) = h−g
As a result, the His tag-fused IgE receptor (FcεRI) was immobilized at 3,407.8 RU for the first time, second time for 2,773.0 RU.

<Analysis of dissociation constant between IgE receptor (FcεRI) and zeta-peptide (e131)>
Using the surface (flow cell 2) on which the His tag-fused IgE receptor (FcεRI) is immobilized on the sensor chip by the above method and the surface (flow cell 1) on which nothing is immobilized on the sensor chip as a reference, IgE Specific binding between the receptor (FcεRI) and zeta-peptide (e131) was measured by a multicycle method.
20 mM HEPES, 140 mM sodium chloride, 1% by weight dimethyl sulfoxide (DMSO), 0.005% by weight as a running buffer Polyoxyethylene sorbitan nonionic surfactant (product name: Surfactant P20, product number: BR-1000-54) , GE Healthcare Bioscience Co., Ltd. was used at 0.05% by mass.
The concentration of zeta-peptide (e131) was diluted with the running buffer so as to be a 5-step concentration (100 nM, 50 nM, 25 nM, 12.5 nM, and 6.25 nM) in a 2-fold dilution series.
Samples of each concentration were added for 2 minutes and dissociation was observed for 5 minutes. Since all bound zeta-peptide (e131) spontaneously dissociated after 5 minutes of dissociation, no regeneration was performed.
From the obtained sensorgram, the dissociation constant (KD) was calculated by equilibrium value analysis using dedicated analysis software Biacore T100 Evaluation Software version 2.0 (manufactured by GE Healthcare Biosciences).

A sensorgram depending on the concentration of zeta-peptide (e131) was obtained. There was no non-specific binding to the reference cell, and all zeta-peptide (e131) bound by dissociation for 5 minutes was dissociated.
From the equilibrium value analysis of the obtained sensorgram, the dissociation constant (KD) between IgE receptor (FcεRI) and zeta-peptide (e131) was as shown in Table 3 below.

<Analysis of dissociation constant between IgE receptor (FcεRI) and compounds represented by structural formulas (1) to (3)>
Using the surface (flow cell 2) on which the His tag-fused IgE receptor (FcεRI) is immobilized on the sensor chip by the above method and the surface (flow cell 1) on which nothing is immobilized on the sensor chip as a reference, IgE Specific binding between the receptor (FcεRI) and the compounds represented by structural formulas (1) to (3) was measured by a multicycle method.
20 mM HEPES, 140 mM sodium chloride, 1% by weight DMSO, 0.005% by weight as a running buffer Polyoxyethylene sorbitan nonionic surfactant (product name: Surfactant P20, product number: BR-1000-54, GE Healthcare Biomass, Inc., 0.05% by mass was used.), PH 7.4 was used, and measurement was performed at a flow rate of 30 μL / min and 25 ° C.
The concentration of the compound represented by the structural formulas (1) to (3) is adjusted so that the running buffer has a five-level concentration (100 nM, 50 nM, 25 nM, 12.5 nM, and 6.25 nM) in a 2-fold dilution series. Diluted with liquid.
Precipitation of the compound represented by Structural Formula (1) and the compound represented by Structural Formula (2) was confirmed in a 20 mM 100% by mass DMSO stock solution. Suspension was performed so that the solution was uniform.
Samples of each concentration were added for 2 minutes and dissociation was observed for 5 minutes. From the obtained sensorgram, the dissociation constant (KD) was calculated by equilibrium value analysis using dedicated analysis software Biacore T100 Evaluation Software version 2.0 (manufactured by GE Healthcare Biosciences).

Sensorgrams depending on the concentrations of the compounds represented by structural formulas (1) to (3) were obtained. There was no non-specific binding to the reference cell, and all the compounds represented by structural formulas (1) to (3) bound by dissociation for 5 minutes were dissociated.
From the equilibrium value analysis of the obtained sensorgram, the dissociation constant (KD) between the IgE receptor (FcεRI) and the structural formulas (1) to (2) was as shown in Table 3 below.

From Table 2 of Test Example 1, the compound represented by Structural Formula (1) obtained in Production Examples 1 to 3 (No. 3 to 5), the compound represented by Structural Formula (2), and the structural formula ( It was confirmed that the compound represented by 3) has an inhibitory activity on binding between IgE and IgE receptor (FcεRI).
From Table 3 of Test Example 2, it was confirmed that the compounds represented by the structural formulas (1) to (3) bind to the IgE receptor (FcεRI).
zeta-peptide (e131) has a low IC ₅₀ (μM) value, and thus has a high inhibitory activity, but is a peptide and thus has antigenicity. On the other hand, the compound represented by Structural Formula (1), the compound represented by Structural Formula (2), and the compound represented by Structural Formula (3) (No. 3 to 5) do not have antigenicity. Since it is a non-protein low molecular weight compound, it can be suitably used as an antiallergic agent, antiasthma agent, and antiinflammatory agent.

  Since the novel compound of the present invention has an excellent binding inhibitory activity for binding between IgE and IgE receptor (FcεRI), it is preferably used as a binding inhibitor that inhibits binding between IgE and IgE receptor (FcεRI). it can. The binding inhibitor is useful as an antiallergic agent, antiasthma agent, and antiinflammatory agent.

Claims (3)

A compound represented by the following structural formula (3):
A binding inhibitor comprising the compound according to claim 1 and inhibiting binding between IgE and an IgE receptor. An antiallergic agent, an antiasthma agent, and an antiinflammatory agent, comprising the binding inhibitor according to claim 2.