JP3265134B2 - Nitrogen-containing bicyclic heterocyclic derivative and pharmaceutical preparation containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a nitrogen-containing bicyclic heterocyclic derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition, an agent for allergic diseases and an agent for immunological diseases containing the same as an active ingredient.

[0002]

2. Description of the Related Art It is known that the release of various chemical mediators from mast cells plays a major role in allergic diseases such as bronchial asthma, atopic dermatitis and allergic conjunctivitis. I have. And the reaction is immunoglobulin E (Ig
It is known that it is caused by the binding of the Fc part of a molecule called E) to a receptor on the cell membrane. In fact, it is known that the concentration of IgE in the serum or tissue of allergic disease patients is higher than that in healthy subjects, and that it is known to play an important role in IgE production in allergic patients. Some sustained production of interleukin 4 has also been observed. Therefore, Ig
It is thought that if the production of E antibody can be suppressed, it will be effective in treating and preventing allergic diseases,
In the current therapeutic drugs for allergy, drugs which correct allergic diseases by suppressing the production of IgE antibodies have not been used for the treatment. Therefore, if a novel IgE antibody production inhibitor can be obtained, it will be useful as an allergic disease therapeutic agent of a new concept.

In addition, in the case of transplant rejection, graft-versus-host disease, asthma, nephritis, hepatitis, autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, etc., excessive production of antibodies and immune complexes containing them. It is known that enhanced cellular immune responses are involved in the onset and continuation of the disease state. Steroids and existing immunosuppressants have been commonly used for these diseases, but their strong side effects limit their treatment, and antibody production inhibitors or immunosuppressants that have novel mechanisms of action Was desired.

On the other hand, compounds having an inhibitory action on IgE antibody production have hitherto been disclosed, for example, in JP-A-1-106818.
And International Patent Publication WO 90/12001 report an anthranilic acid-based compound having an inhibitory action on IgE antibody production. However, the substances described in these patents are limited to the naphthalene skeleton, and their mother nuclei are completely different from the nitrogen-containing heterocycle of the present invention.

Japanese Patent Application Laid-Open No. 55-079372 reports that a compound having both a carbostyril skeleton and an anthranilic acid skeleton has been synthesized. However, unlike the nitrogen-containing aromatic ring skeleton of the present invention, a carbostyril skeleton is provided. No description or suggestion is made regarding the antibody production-suppressing action or the immune-correcting function.

In view of such prior art, the present inventors have conducted studies to provide agents for allergic diseases and immunological diseases based on a new mechanism of action different from those for conventional allergic diseases. The invention has been reached.

[0007]

That is, the present invention provides a compound of the formula [I]:

[0008]

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(Where A is CH ₂ —CH ₂ , CH = C
H, C * C (* indicates a triple bond; the same applies hereinafter), S-CH ₂ , CH ₂ —S, O—CH ₂ , or CH ₂ —O; X, X ′ and X ′ 'Represents a carbon atom or a nitrogen atom (although not all of them are carbon atoms at the same time); Y represents NHR, OH, or CO ₂ R
(R is a hydrogen atom or a C ₁ - represents a ₄ lower alkyl group) represents; n is an integer of 0-8. A) a nitrogen-containing bicyclic heterocyclic derivative or a pharmaceutically acceptable salt thereof, and an allergic or immunological agent containing the same as an active ingredient, and a pharmaceutically acceptable carrier thereof. A pharmaceutical composition comprising:

In the above formula [I], A is CH ₂ -C
H ₂ , CH = CH, C * C (* indicates a triple bond; the same applies hereinafter), S-CH ₂ , CH ₂ -S, O-CH
_2, or represents an O-CH _2, A is CH = CH Among these, S-CH _2, CH ₂ -S, represents a O-CH ₂ or O-CH _2, are preferred.

In the formula [I], X, X 'and X "represent a carbon atom or a nitrogen atom (but not all of them are carbon atoms at the same time), but in particular, any one of X, X' and X" One represents a nitrogen atom and the other two represent carbon atoms, ie a quinoline skeleton is preferred.

In the formula [I], X represents a nitrogen atom and X '
And X ″ represents a carbon atom, especially A is CH =
_{CH, S-CH 2, O} -CH 2, CH 2 -O, CH 2 -
S is desirable. Above all _{CH = CH, S-CH 2} , CH 2
-S is desirable.

In the formula [I], when X ′ represents a nitrogen atom and X and X ″ represent carbon atoms, A is preferably CH ₂
-CH _2, CH = CH is preferred. Among them, CH = CH is desirable.

In the formula [I], when X ″ represents a nitrogen atom and X and X ′ each represent a carbon atom, particularly A is OC—C.
H _2, S-CH ₂ is preferable. Among these O-CH ₂ is preferable.

In the formula [I], Y is NHR, OH,
Is CO_TwoR (R is a hydrogen atom or C ₁−_FourLow-grade archi
Represents, among others, NHR or CO_Two
R is desirable.

When Y in the formula [I] is represented by NHR, R is preferably a hydrogen atom, a methyl group, an ethyl group,
A (n-, i-) propyl group and a (n-, i-, t-) butyl group are mentioned, and among them, a hydrogen atom is preferable.

When Y in the formula [I] is represented by CO ₂ R, R is preferably a hydrogen atom, a methyl group, an ethyl group,
An (n-, i-) propyl group and an (n-, i-, t-) butyl group are mentioned, and among them, a hydrogen atom or a methyl group is preferable.

N represents an integer of 1 to 8;
Is preferably an integer.

In the formula [I], preferred combinations of X, X, 'and X "and A with Y and n include X, X and X'.
X, 'and X "and A are each preferred examples as described above,
When defined as a combination example, the case where Y is NH ₂ or CO ₂ R (R represents a hydrogen atom or a methyl group) and n is an integer of 2 to 6 can be mentioned.

Preferred specific examples of the novel bicyclic heterocyclic derivative of the present invention include the following compounds. Incidentally, the 2-quinolinyl group is called a quinolyl group according to customary usage.

Compound number Compound name ─────────────────────────
１０１ 101 2- (3-quinolyloxypropionamide) benzoic acid 102 methyl 2- (3-quinolyloxypropionamide) benzoate 103 2- (3-quinolyl) Oxypropionamide) ethyl benzoate 104 2- (4-quinolyloxybutanamide) benzoic acid 105 Methyl 2- (4-quinolyloxybutanamide) benzoate 106 2- (4-quinolylthiobutanamide) benzoic acid Acid 107 methyl 2- (4-quinolylthiobutanamide) benzoate 108 2- (5-quinolylthiopentanamide) benzoic acid 109 2- (5-quinolylthiopentanamide) methyl benzoate 110 2- (6-quinolylthiohexanamide) benzoic acid 111 2- (6-quinolylthiohexanamide) methyl benzoate 112 2- (4-quinolylmethylthio) Tanamido) benzoic acid 113 2-(4-quinolyl methyl thio flatweed bromide) benzoate 114 2 chromatography (5 over quinolyl methylthiophenyl penta cyanamide)
Benzoic acid 115 2- (5-quinolylmethylthiopentanamide)
Methyl benzoate 116 2- (6-quinolylmethylthiohexanamide)
Benzoic acid 117 2- (6-quinolylmethylthiohexanamide)
Methyl benzoate 118 (E) -2- (5-quinolyl-4-pentenamide) benzoic acid 119 (E) -2- (5-quinolyl-4-pentenamide) methyl benzoate 120 (E) -2- (6-quinolyl-5) -Hexenamide) benzoic acid 121 (E) -2- (6-quinolyl-5-hexenamide) methyl benzoate 122 (E) -2- (7-quinolyl-6-heptenamide) benzoic acid 123 (E) -2- (7-quinolyl) -6-heptenamide) methyl benzoate 124 (E) -2- (5- (3-quinolinyl) -4-
Pentenamide) benzoic acid 125 (E) -2- (5- (3-quinolinyl) -4-
Pentenamide) methyl benzoate 126 (E) -2- (6- (3-quinolinyl) -5-
Hexenamide) benzoic acid 127 (E) -2- (6- (3-quinolinyl) -5-
Hexenamide) methyl benzoate 128 (E) -2- (7- (3-quinolinyl) -6-
Heptenamide) benzoic acid 129 (E) -2- (7- (3-quinolinyl) -6-
Heptenamide) methyl benzoate 130 2- (3- (6-quinolinyloxy) propionamide) benzoic acid 131 2- (3- (6-quinolinyloxy) propionamide) methyl benzoate 132 2- (4- (6 -Quinolinyloxy) butanamide) benzoic acid 133 2- (4- (6-quinolinyloxy) butanamide) methyl benzoate 134 2- (5- (6-quinolinyloxy) pentanamide) benzoic acid 135 2- (5- (6-quinolinyloxy) pentanamide) methyl benzoate 136 2- (6- (6-quinolinyloxy) hexanamide) benzoic acid 137 2- (6- (6-quinolinyloxy) hexanamide) Methyl benzoate 138 2- (5- (6-quinolinylthio) pentanamide) benzoic acid 139 2- (6-quinolylmethyloxyhexana B) Benzoic acid 140 N- (2-aminophenyl) -3- (6-quinolinyloxy) propionamide 141 N- (2-aminophenyl) -3-quinolylthiopropionamide 142 N- (2-aminophenyl) -4- ( 6-quinolinyloxy) butanamide 143 N- (2-aminophenyl) -4-quinolylthiobutanamide 144 N- (2-aminophenyl) -5- (6-quinolinyloxy) pentanamide 145 N- (2-aminophenyl)- 5-quinolylthiopentanamide 146 N- (2-methylaminophenyl) -3-quinolylthiopropionamide ──
─────────── The present invention also relates to an agent for allergic disease or immunological disease comprising the nitrogen-containing bicyclic heterocyclic derivative or a pharmaceutically acceptable salt thereof as an active ingredient, Among such agents for allergic diseases or agents for immunological diseases, preferred are agents for allergic diseases characterized by an inhibitory action on IgE antibody production or immunosuppressants characterized by an excessive inhibitory action on antibody production.

The agent for allergic diseases characterized by inhibiting the production of IgE antibodies of the present invention includes preventive and therapeutic agents for allergic diseases. Examples of such allergic diseases include bronchial asthma, allergic rhinitis, Examples include atopic dermatitis, allergic conjunctivitis, hives, anaphylactic shock, contact hypersensitivity and the like. Among these, preferred examples include bronchial asthma, allergic rhinitis, allergic conjunctivitis, and atopic dermatitis.

The immunosuppressive agent of the present invention characterized by excessive suppression of antibody production refers to suppression of IgE and IgG antibody production, suppression of IgG antibody production, proliferation of DTH reaction-inducing T cells and cytotoxic T cells, and the like. It is an agent that blocks activation. Diseases for which such effects can be expected include, for example, rheumatoid arthritis, systemic lupus erythematosus (SLE),
Scleroderma, dermatomyositis, polymyositis, polyarteritis nodosa,
Autoimmune diseases such as rheumatic fever, autoimmune hemolytic anemia, Hashimoto's thyroiditis, ulcerative colitis, pernicious anemia, uveitis, pemphigus, Sjogren's syndrome, idiopathic leukopenia, transplant rejection, graft-versus-host Diseases, hepatitis, nephritis, diabetes, sarcoidosis, leprosy, orchitis, ovitis and the like.

The nitrogen-containing bicyclic heterocyclic derivative represented by the above formula [I] or a pharmaceutically acceptable salt thereof according to the present invention can be produced, for example, according to the following known scheme. That is, by condensing a carboxylic acid having a heterocyclic skeleton with an aniline derivative, the desired compound of [I] can be obtained.

[0025]

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In the above formulas, A, X, X ', X ", and n have the same meanings as defined above.
Can be obtained by a conventionally known method.

The condensation method is roughly classified into a method via an acid halide and an activation method without an acid halide, and both methods are basically known.

In the case of passing through an acid halide, [II] is converted to DMF
Oxalyl chloride in the presence or absence of additives such as
[I] can be obtained by reacting a halogenating agent such as thionyl chloride or the like with [III] in the presence or absence of a base to produce an acid halide of [II].

On the other hand, in the activation method not via an acid halide, [II] can be prepared by using various activators such as mixed acid anhydrides, carbodiimides, imidazole agents, halophosphate esters, and cyanophosphate esters. Activation and reaction of this with [III] give [I].

In the thus obtained [I], when Y represents CO ₂ R and R represents a lower alkyl group, hydrolysis is carried out, if necessary, under acidic or basic conditions, so that R represents a hydrogen atom. Can be converted to the compound represented.

The compound represented by the above formula [I] thus obtained can be converted to a pharmaceutically acceptable salt, if necessary. When the compound has a carboxylic acid residue, it can be converted to a salt with a non-toxic cation. Such cations include alkali metal cations such as Na and K; alkaline earth metal cations such as Mg and Ca; metal cations such as Al and Zn; or ammonia, triethylamine, ethylenediamine, pyridine, lysine, Choline, arginine, guanidine, triethanolamine, N, N-dimethylethanolamine,
Organic bases such as 4-hydroxyethylmorpholine, 4-hydroxypiperidine, N-methylglucamine, glucosamine and the like can be mentioned. Among them, preferred are alkali metal cations such as Na and K, lysine, choline, N, N-dimethylethanolamine, N-methylglucamine and glucosamine.

The compounds represented by the above formula [I] have a nitrogen atom in the skeletal molecule thereof, and these compounds usually show basicity. Thus, these compounds can also be converted into the corresponding acid addition salts. Such acids include mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid, or acetic acid,
Benzoic acid, fumaric acid, maleic acid, methanesulfonic acid,
Pharmaceutically acceptable organic acids such as toluenesulfonic acid. Among them, hydrochloric acid, sulfuric acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, and toluenesulfonic acid are preferred.

The nitrogen-containing bicyclic heterocyclic derivative or a pharmaceutically acceptable salt thereof of the present invention can be orally prepared by preparing a pharmaceutical composition comprising a pharmaceutically acceptable carrier as described below. It can be administered parenterally, such as intravenously, subcutaneously, intramuscularly, transdermally, rectally, ophthalmically, or by inhalation. Examples of the dosage form for oral administration include tablets, pills, granules, powders, solutions, suspensions, syrups, capsules and the like.

For tableting, excipients such as lactose, starch and crystalline cellulose; binders such as carboxymethylcellulose, methylcellulose and polyvinylpyrrolidone; disintegrants such as sodium alginate, sodium hydrogencarbonate and sodium lauryl sulfate And the like, and can be molded by an ordinary method.

Similarly, pills, granules and powders can be molded by the usual methods using the above-mentioned excipients and the like.

Examples of the liquid, suspension and syrup are glycerin esters such as tricaprylin and triacetin;
An alcohol such as ethanol; water; a corn oil, a cottonseed oil, a coconut oil, an almond oil, a peanut oil, a vegetable oil such as an olive oil, or the like can be molded by an ordinary method.

Capsules are formed by filling granules, powders, liquids or the like into capsules made of gelatin or the like.

As a dosage form for intravenous, subcutaneous or intramuscular administration, there is an injection in the form of a sterile aqueous or non-aqueous solution. As the aqueous solution, for example, physiological saline is used. Examples of the non-aqueous solution include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. If necessary, these preparations are added with a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, and the like, and a filtration through a bacteria-retaining filter, blending of a bactericide, heating, irradiation, etc. Sterility can be achieved by appropriate treatment. Alternatively, a sterile solid preparation can be produced and dissolved in sterile water or a sterile solvent for injection immediately before use.

Examples of dosage forms for transdermal administration include ointments,
Creams and the like are mentioned, and ointments are molded by a usual method using oils and fats such as castor oil and olive oil; vaseline and the like, and creams are emulsified by using emulsifiers such as fatty oil; diethylene glycol; sorbitan monofatty acid ester and the like. You.

For rectal administration, usual suppositories such as gelatin soft capsules are used.

Examples of the dosage form of eye drops include aqueous and non-aqueous eye drops. Aqueous eye drops use sterilized purified water, physiological saline, or an appropriate aqueous solvent as a solvent. Aqueous eye drops using only sterilized purified water as a solvent; carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, etc. Viscous ophthalmic solution with a mucilage; aqueous suspension ophthalmic solution with a suspending agent such as a surfactant and a polymeric thickener; solubilized ophthalmic solution with a solubilizing agent such as a nonionic surfactant There are liquids. Non-aqueous ophthalmic solution uses non-aqueous solvent for injection as a solvent. Non-aqueous ophthalmic solution using vegetable oil, liquid paraffin, mineral oil, propylene glycol, etc .; suspended using thixotropic colloid such as aluminum monostearate And non-aqueous suspension eye drops. These preparations may contain tonicity agents, preservatives, buffers,
Emulsifiers, stabilizers and the like can be added. In addition, sterilization can be performed by appropriately performing treatment such as filtration through a bacteria retaining filter, blending of a bactericide, heating, and irradiation. Alternatively, a sterile solid preparation can be produced and dissolved or suspended in an appropriate sterile solution immediately before use.

As ophthalmic preparations other than eye drops, ophthalmic ointments molded using petrolatum or the like; coating solutions using diluted iodine tincture, zinc sulfate solution, methylrosaniline chloride solution, etc .; fine powder of the active ingredient Spray for direct administration of;
There is an insert agent or the like in which the active ingredient is blended or impregnated with a suitable base or material, and this is inserted into the eyelid or the like.

For inhalation, solutions or suspensions of the active ingredients with conventional pharmaceutical excipients are used, for example as aerosol sprays for inhalation. The active ingredient in dry powder form can also be administered by an inhaler or other device that allows direct contact with the lungs.

The dose of the active ingredient varies depending on the administration method, but is usually about 1 to 500 mg / day / person, preferably 10 to 300 mg / day / person for oral administration, and is intravenous, subcutaneous or intramuscular. For parenteral administration such as percutaneous, transdermal, rectal, ophthalmic, and inhalation, the dose is about 0.1 to 100 mg / day / person, preferably 0.3 to 30 mg / day / person, which satisfies such conditions. It is preferable to formulate it in

[0045]

EXAMPLES Examples will be described below, but the present invention is not limited to only these examples. Further, a hydrogen atom of the carboxylic acid may not be observed in NMR.

Example 1 2- (4- (6-quinolinyloxy) butanamide) benzoate
Methyl perfume (Compound No. 133)

[0047]

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Under a nitrogen atmosphere, 278 mg (1.2 mmol) of 4- (6-quinolinyloxy) butyric acid was dissolved in 5 ml of thionyl chloride and stirred at 35 ° C. for 2 hours. The reaction solution was concentrated by an evaporator, and the residue was dissolved in dry methylene chloride (15 mL).
In a nitrogen atmosphere, add this solution to methyl anthranilate 180 m
g (1.3 mmol) and triethylamine (300 mg, 3.0 mmol) in dry methylene chloride solution (5 mL) were added dropwise at −78 ° C., and the mixture was further stirred at room temperature for 4 hours and overnight. Water was added to the reaction solution, which was extracted twice with methylene chloride. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to give the title compound (130 mg, 0.36 mmol).

Yield 30% ¹ H-NMR (DMSO-d6) d: 2.32 (2 H, quint, J = 7 Hz), 2.72 (2 H, t, J = 7)
Hz), 3.87 (3 H, s), 4.21 (2 H, t, J = 7 Hz), 7.05
-7.11 (2 H, m), 7.31 -7.38 (2 H, m), 7.55 (1 H, t
d, J = 7 and 1 Hz), 7.96-8.03 (3 H, m), 8.71-8.77
(2 H, m) 11.17 (1 H, sbr)

Example 2 2- (4- (6-quinolinyloxy) butanamide) benzoate
Perfumed acid (Chemical number 132)

[0051]

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The title compound is obtained in a quantitative yield by hydrolyzing the compound obtained in Example 1 with sodium hydroxide or lithium hydroxide.

¹ H-NMR (DMSO-d6) δ: 2.16 (2 H, quint, J = 7 Hz), 2.62 (2 H, t, J = 7
Hz), 4.19 (2 H, t, J = 6 Hz), 7.12 (1 H, t-like, J
= 8 Hz), 7.36 to 7.41 (2 H, m), 7.45 (1 H, dd, J =
8 and 4 Hz), 7.55 (1 H, t-like, J = 8 Hz), 7.89
(1 H, d, J = 10 Hz), 7.97 (1 H, dd, J = 8 and 2 H
z), 8.22 (1 H, d, J = 8 Hz), 8.50 (1 H, d, J = 8 H
z), 8.72 (1 H, dd, J = 4 and 2 Hz), 11.5 (1 H, s,
br) The following compounds were synthesized in the same manner as in Examples 1 and 2.

[Embodiment 3]2- (4-quinolylthiobutanamide) methyl benzoate
(Compound No. 107)

[0055]

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Yield 61% ¹ H-NMR (CDCI ₃ ) δ: 2.27 (2 H, quint, J = 7 Hz), 2.67 (2 H, t, J = 7)
Hz), 3.48 (2 H, t, J = 6 Hz), 3.85 (3 H, s), 7.06
(1 H, td, J = 7 and 1 Hz) 7.21 (1 H, d, J = 8 Hz),
7.39 (1 H, t-like, J = 8 Hz), 7.51-7.59 (2 H, m),
7.68 (1 H, d-like, J = 8 Hz), 7.83-7.88 (2 H.
m). 7.98 (1 H, dd, J = 8 and 2 Hz), 8.74 (1 H, d,
J = 8 Hz), 11.06 (1 H, s br)

Example 4 2- (4-quinolylthiobutanamide) benzoic acid (compound
Number 106)

[0058]

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[0059] 55% yield ^{1 H-NMR (DMSO-d6} ) δ: 2.08 (2 H, quint, J = 7 Hz), 2.55 (2 H, t, J = 7
Hz), 3.37 (2 H, t, J = 7 Hz), 7.02 (1 H, t, J = 7
Hz), 7.38 (1 H, d, J = 9 Hz), 7.40-7.45 (1 H, m),
7.49 (1 H, d, J = 8 Hz), 7.65 (1 H, td, J = 7 and
1 Hz), 7.81 (1 H, d, J = 8 Hz), 7.88 (1 H, d, J
= 7 Hz), 7.98 (1 H, dd, J = 8 and 2 Hz), 8.15 (1
H, d, J = 9 Hz), 8.50 (1 H, d, J = 8 Hz), 12.9
(1 H, s br)

Example 5 N- (2-aminophenyl) -4- (6-quinolinyl)
Xy) butanamide (Compound No. 142)

[0061]

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Yield 31% ¹ H-NMR (DMSO-d6) δ: 2.13 (2 H, quint, J = 7 Hz), 2.57 (2 H, t, J = 7)
Hz), 4.18 (2 H, t, J = 7 Hz), 6.54 (1 H, td, J = 8
and 1 Hz), 6.71 (1 H, dd, J = 1 and 8 Hz), 6.89
(1 H, t-like, J = 8 Hz), 7.17 (1 H, dd, J = 8 and 1
Hz), 7.39-7.50 (3 H, m), 7.92 (1 H, d, J = 9 H
z), 8.24 (1 H, d, J = 8 Hz), 8.73 (1 H, dd, J = 4
and 2 Hz), 9.17 (1 H, s br)

Example 6 N- (2-aminophenyl) -4-quinolylthiobutana
Mid (Compound No. 143)

[0064]

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Yield 43% ¹ H-NMR (DMSO-d6) δ: 2.05 (2 H, quint, J = 7 Hz), 2.53 (2 H, t, J = 7)
Hz), 3.37 (2 H, t, J = 7 Hz), 4.85 (2 H, br s), 6.5
3 (1 H, td, J = 7 and 1 Hz), 6.71 (1 H, dd, J =
8 and 1 Hz), 6.89 (1 H, t-like, J = 8 Hz), 7.16
(1 H, dd, J = 8 and 1 Hz), 7.38 (1 H, d, J = 9 Hz),
7.49 (1 H, t-like, J = 8 Hz), 7.70 (1 H, td, J =
8 and 1 Hz), 7.88 (2 H, t, J = 8 Hz), 8.16 (1 H,
d, J = 9 Hz), 9.15 (1 H, s br)

Example 7 Methyl 2- (6-quinolylthiohexanamide) benzoate
(Compound No. 111)

[0067]

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Yield 60% ¹ H-NMR (CDCI ₃ ) δ: 1.53-1.66 (2 H, m), 1.80-1.91 (4 H, m), 2.48
(2 H, t, J = 7 Hz), 3.36 (2 H, t, J = 7 Hz), 3.90
(3 H, s), 7.07 (1 H, t, J = 8 Hz), 7.19 (1 H, d, J
= 8 Hz), 7.40 (1 H, t, J = 8 Hz), 7.54 (1 H, t-li
ke, J = 8 Hz), 7.61 (1 H, t-like, J = 8 Hz), 7.70
(1 H, d, J = 8 Hz), 7.86 (1 H, d, J = 9 Hz), 7.91
(1 H, d, J = 9 Hz), 8.02 (1 H, dd, J = 8 and 2 H
z), 8.74 (1 H, d, J = 8 Hz), 11.07 (1 H, br s)

Example 8 2- (6-quinolylthiohexanamide) benzoic acid (compound
Article number 110)

[0070]

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[0071] 55% yield _{^{1 H-NMR (CDCI 3)}} δ: 1.61 (2 H, quint, J = 7 Hz), 1.80-1.91 (4 H, m),
2.49 (2 H, t, J = 7 Hz), 3.35 (2 H, t, J = 7 Hz),
7.10 (1 H, t, J = 8 Hz), 7.21 (1 H, d, J = 9 Hz),
7.41 (1 H, t-like, J = 8 Hz), 7.57 (1 H, d, J =
9 Hz), 7.63 (1 H, d, J = 9 Hz), 7.70 (1 H, d, J =
8 Hz), 7.87 (1 H, d, J = 9 Hz), 7.94 (1 H, d, J =
9 Hz), 8.09 (1 H, d, J = 8 Hz), 8.72 (1 H, d, J =
9 Hz), 10.94 (1 H, s)

Example 9 (E) -2- (7- (3-quinolinyl) -6-heptena
Mido) Methyl benzoate (Compound No. 129)

[0073]

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Yield 72% ¹ H-NMR (CDCI ₃ ) δ: 1.65 (2 H, quint, J = 7 Hz), 1.87 (2 H, quint, J
= 7 Hz), 2.36 (2 H, q, J = 7 Hz), 2.51 (2 H, t, J
= 7 Hz), 3.90 (3 H, s), 6.41-6.59 (2 H, m), 7.07
(1 H, t-like, J = 7 Hz), 7.48-7.67 (3 H, m), 7.76
(1 H, d, J = 7 Hz), 7.98-8.07 (3 H, m), 8.75 (1
H, d, J = 9 Hz), 8.96 (1 H, d, J = 2 Hz), 11.1
(1 H, s, br)

Example 10 (E) -2- (7- (3-quinolinyl) -6-heptena
Mido) Benzoic acid (Compound No. 128)

[0076]

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Yield 53% ¹ H-NMR (DMSO-d6) δ: 1.58 (2 H, quint, J = 7 Hz), 1.72 (2 H, quint, J
= 7 Hz), 2.28-2.32 (2 H, m br), 2.45 (2 H, t, J =
7 Hz), 6.62 (2 H, m), 7.12 (1 H, t, J = 7 Hz), 7.
52-7.59 (2 H, m), 7.68 (1 H, dt, J = 2 and 7 Hz),
7.91 (1 H, d, J = 7 Hz), 7.95-8.00 (2 H, m), 8.2
5 (1 H, d, J = 8 Hz), 8.52 (1 H, d, J = 8 Hz), 9.0
1 (1 H, d, J = 2 Hz), 11.36 (1 H, s br)

Example 11 (E) -2- (7-quinolyl-6-heptenamide) benzoate
Methyl perfume (Compound No. 123)

[0079]

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Yield 69% ¹ H-NMR (CDCI ₃ ) δ: 1.67 (2 H, quint, J = 7 Hz), 1.87 (2 H, quint, J
= 7 Hz), 2.40 (2 H, q, J = 7 Hz), 2.50 (2 H, t, J
= 7 Hz), 3.90 (3 H, s), 6.70-6.89 (2 H, m) .7.06
(1 H, t-like, J = 7 Hz), 7.43-7.69 (4 H, m), 7.75
(1 H, d, J = 8 Hz), 8.00-8.07 (3 H, m), 8.74 (1 H,
d, J = 9 Hz), 11.1 (1 H, s br)

Example 12 2- (6-quinolylmethylthiohexanamide) benzoic acid
Methyl (Compound No. 117)

[0082]

Embedded image

Yield: 72% ¹ H-NMR (CDCI ₃ ) δ: 1.40-1.48 (2 H, m), 1.57-1.76 (4 H, m), 2.39
(2 H, t, J = 8 Hz), 2.50 (2 H, t, J = 7 Hz), 3.92
(3 H, s), 4.00 (2 H, s), 7.06 (1 H, t-like, J = 8
Hz), 7.46-7.57 (4 H, m), 7.68 (1 H, m), 7.78 (1
H, d, J = 9 Hz), 8.00-8.05 (2 H, m), 8.12 (1 H,
d, J = 8 Hz), 11.2 (1 H, s br)

Example 13 2- (6-quinolylmethylthiohexanamide) benzoic acid
(Compound No. 116)

[0085]

Embedded image

Yield 61% ¹ H-NMR (CDCI ₃ ) δ: 1.40-1.52 (2 H, m), 1.62-1.79 (4 H, m), 2.43
(2 H, t, J = 7 Hz), 2.57 (2 H, t, J = 7 Hz), 4.26
(2 H, s), 7.5-7.9 (6 H, m) .8.18 (1 H, dd, J = 8 a
nd 2 Hz), 8.29 (1 H, d, J = 9 Hz), 8.30 (1 H, d,
J = 9 Hz), 8.57 (1 H, d, J = 9 Hz), 11.1 (1 H, s
br)

Example 14 From human peripheral blood of a healthy subject,
Lymphocytes are separated by density gradient centrifugation and the stimulant IL
-4 (2000 μg / ml), anti-CD40 antibody (2 mg / ml), and IL-10
(100 μg / ml) in the presence of
The amounts of gE and IgG were measured by a sandwich ELISA method. The results are shown in Table 1. Selective suppression of IgE production was observed in the presence of Compound No. 110.

[0088]

[Table 1]

Example 15 An experiment was conducted in the same manner as in Example 14, and the results are shown in Table 2. The compound of Compound No. 142 exhibited an IgE-selective antibody production inhibitory effect, and the compound of Compound No. 106 exhibited an antibody production inhibitory effect.

[0090]

[Table 2]

Example 16 A tablet was prepared in which one tablet had the following composition.

[0092] Compound No. 106, lactose and potato starch were mixed, and this was mixed with 20% of polyvinylpyrrolidone.
Wet evenly with the ethanol solution, passed through a 20 nm mesh sieve, dried at 45 degrees and again passed through a 15 nm mesh. The granules thus obtained were mixed with magnesium stearate and compressed into tablets.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 37/08 A61P 37/08 C07D 215/20 C07D 215/20 215/36 215/36 (72) Inventor Toshiaki Harada Hino, Tokyo 4-3-2 Asahigaoka, Tokyo Teijin Limited Tokyo Research Center (72) Inventor Hitoshi Omori 3-1-1 Tsushimanaka, Okayama City, Okayama Pref. Okayama University Faculty of Engineering (56) References 106818 (JP, A) International Publication 90/12001 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 215/12 C07D 215/20 C07D 215/36 A61K 31/47 CA ( STN) CAOLD (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. A compound of the formula [I] (Where A is CH ₂ —CH ₂ , CH ＝ CH, C * C (* indicates a triple bond; the same applies hereinafter), S-CH
_{2, CH 2 -S, O-} CH 2, or an CH ₂ -O; X, X 'and X "represents a carbon atom or a nitrogen atom (provided that all of these are not simultaneously a carbon atom); Y is A nitrogen-containing bicyclic heterocyclic derivative represented by NHR, OH or CO ₂ R (R represents a hydrogen atom or a C _1-4 lower alkyl group; n represents an integer of 1-8); Or a pharmaceutically acceptable salt thereof. 2. A is CH = CH, S-CH ₂ , CH _2-
S, O-CH ₂ or a nitrogen-containing bicyclic heterocyclic derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein represents a CH ₂ -O,. 3. The nitrogen-containing bicyclic heterocyclic derivative according to claim 1, wherein one of X, X ′ and X ″ represents a nitrogen atom and the remaining two represent carbon atoms, or a pharmaceutically acceptable salt thereof. Salt. 4. X is a nitrogen atom, X ′ and X ″ are carbon atoms,
A represents S-CH _2, CH ₂ -S or CH = CH;
Or X ′ is a nitrogen atom, X and X ″ are carbon atoms, A is CH
The nitrogen-containing bicyclic heterocyclic derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein を represents CH; or X ″ represents a nitrogen atom, X and X ′ represent a carbon atom, and A represents O—CH ₂ . 5. n is an integer of 2 to 6, and Y is NH ₂ ,
Or CO ₂ R (R represents a hydrogen atom or a methyl group)
The nitrogen-containing bicyclic heterocyclic derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof. 6. The nitrogen-containing bicyclic heterocyclic derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient .
Allergic disease treatment based on IgE antibody production inhibitory action
Care agent or immune disease therapeutic agents. 7. The therapeutic agent for an allergic disease according to claim 6, wherein the allergic disease is bronchial asthma, allergic rhinitis, allergic conjunctivitis, and atopic dermatitis.