JPH1135559A - Phthalimide derivative and medicine containing the derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having activities for selectively suppressing the production of IgE and IL-5, capable of manifesting activities in the immediate and chronic allergy, and becoming an active ingredient of antiallergic agent. SOLUTION: The subject compound is a phthalimide derivative of the formula [R<1> to R<4> are each H, hydroxy group, a lower alkyl, carbamoyl, amino, nitro, etc.; A is N atom, etc.; B is H, a lower alkyl, a cycloalkyl, an aryl, etc.; X is 1-4C alkylene, etc.; Y is O atom, S atom, etc.; Z is a 1-4C alkylene, a 2-4C alkenylene, etc.; (l), (m) and (n) are each independently 0 or 1; Cy is an aryl, a heterocyclic group, etc.] or a pharmaceutically acceptable salt thereof. For example, 2-[(S) -2-benzyloxy -1-phenylethyl] -2,3-dihydro -1,3-dioxo -1H -isoindole -5-carboxylic acid is cited. An antiallergic agent having both effectiveness and safety is provide by using the compound of the formula as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel phthalimide derivatives and antiallergic agents containing these compounds. More specifically, a novel phthalimide derivative which has an action of selectively suppressing the production of IgE and IL-5, is effective for immediate allergy and chronic allergy, is useful for allergy prevention and treatment, and a compound thereof as an active ingredient Anti-allergic agents.

[0002]

2. Description of the Related Art An allergy is a phenomenon in which an immune reaction occurs in an excessively or inappropriate manner and causes tissue damage, such as bronchial asthma, hay fever, atopic dermatitis, and urticaria. This is a representative case. Coombs and Gel defined this allergy as a condition in which the response to the antigen changed from normal and classified it from type I to type IV. In the case of type I allergy, first, the production of antigen-specific immunoglobulin E (IgE) is induced, and mast cells and basophils activated via the induced IgE produce various chemical mediators (histamine). , Leukotriene, thromboxane, eosinophil chemotactic factor, neutrophil chemotactic factor, platelet activating factor, etc.) are produced and released. It is a reaction that causes inflammation by this chemical mediator. Type II allergy is a reaction in which antibodies (IgG, IgM) act on cells of the living body, and as a result, phagocytic cells and complement damage their own cells. Type III allergy is defined as immune complex ｛antigen and antibody (Ig
G, IgM) is deposited on the tissue, and the tissue is damaged by activated complement, leukocytes, platelets and the like. Type IV allergy is a reaction in which a chemical mediator is released by a reaction between an antigen and T cells regardless of antibodies, and as a result, tissues are damaged by leukocytes, platelets, and the like. Type I allergy is also called immediate allergy or anaphylactic allergy.
Only type allergies are often referred to as allergies.

[0003] Among allergic reactions, as a biological mechanism that is particularly deeply involved in the present invention, firstly, B cells that begin to differentiate into T cells
There is IgE production from the cells. That is, naive helper T cells that have not been subjected to antigen stimulation can at least have Th1 and T
h2, which induces class switching and induces IgE through cytokines such as IL-4 produced from Th2 cells and CD40 molecules on B cells.
Promotes the production of IgE produced in this way as a result of differentiation into Th2 cells binds via FCεRI, a high-affinity IgE receptor on mast cells. Release of chemical mediators called granules occurs. This includes histamine, leukotriene and PAF (platelet activating factor)
In addition, mast cells also produce IL-4, thereby causing the proliferation of T cells, B cells and mast cells themselves, and increasing the production of IgE, thereby causing a vicious cycle. The second mechanism is the production of IL-5 from Th2 cells. IL-
5 is a specific differentiation, proliferation and activator of eosinophils, which is considered to be involved in the allergic severities. The presence of high concentrations in alveolar lavage fluid was observed, resulting in infiltration and activation of eosinophils in the respiratory tract, sustained inflammation by various mediators released,
It is considered to be severe.

[0004]

As described above, the production of IgE, which is central to allergic reactions, and the phenomena caused by it, and the activation of eosinophils by IL-5, are associated with asthma and dermatitis. It is extremely important as a factor leading to onset, chronicity, and seriousness, and development of an antiallergic drug that selectively and strongly suppresses IgE and IL-5 is strongly desired. The expected indications of the IgE production inhibitor and IL-5 production inhibitor include bronchitis, dermatitis, conjunctivitis, rhinitis, eczema, eosinophilic inflammation, pemphigus, psoriasis, chronic obstructive pulmonary disease. Diseases, hepatitis, pulmonary aspergillosis, eosinophilic pneumonia, eosinophilic granulomatosis, polyarteritis nodosa, endothelitis reffel, disseminated eosinophilic collagen disease, eosinophilic gastroenteritis Ulcerative colitis, eosinophilia, and is particularly expected to be applied to atopic dermatitis and atopic bronchial asthma.
Until now, antiallergic agents having various basic skeletons have been developed. Among them, JP-A-56-1157
No. 73 (PAF antagonistic action), JP-A-6-220044 (anti-complementary action), JP-A-6-312978 (phospholipase A2 inhibitory action), WO94 / 06431 (Ig
The compound described in E) has a phthalimide skeleton, but as in the present invention, IgE and IL-
There is no description of selectively suppressing the production of 5. On the other hand, those having a phthalimide skeleton other than antiallergic agents include those described in JP-A-8-143546 (antithrombotic agents) and WO96.
No./20705, WO96 / 20926 and US57
No. 03098 (TNFα inhibitor) is disclosed, but there is no description of selectively suppressing the production of IgE and IL-5 as in the present invention. Similarly, there have been many disclosures of phthalimide derivatives other than pharmaceutical applications (for example, see JP-A-6-2).
No. 39017), which are widely used in chemical synthesis as protecting groups for synthetic intermediates, but there is no description having the action as in the present invention.

[0005]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, the novel phthalimide derivative selectively inhibits the production of IgE and IL-5, thereby providing an excellent phthalimide derivative. The present inventors have found that the present invention has an antiallergic effect and completed the present invention. The present invention relates to an IgE and IL-5 production inhibitor containing a compound represented by the following general formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also relates to a novel phthalimide compound having an inhibitory action on IgE and IL-5 production, or a pharmaceutically acceptable salt thereof. More specifically, (1) to (1)
This is as shown in 4).

(1) General formula [I]

Embedded image [Wherein, R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxyl group, a lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted alkoxycarbonyl group, a carbamoyl group, A represents an alkylaminocarbonyl group, a carboxy group, an amino group, a nitro group or a halogen atom; A represents —CB ¹ — (wherein B ¹ represents a hydrogen atom, an optionally substituted lower alkyl group, a cycloalkyl group, Represents an aryl group, an aralkyl group, a heterocyclic group, a carboxy group or an aralkyloxyalkyl group which may be substituted) or a nitrogen atom; B represents a hydrogen atom, an optionally substituted lower alkyl group, a cycloalkyl group, It is aryl group, an aralkyl group, a heterocyclic group, a carboxy group or an aralkyloxy group, B, consequent B ¹ and a together Is alkyl or substituted may form a well heterocyclic; X is alkylene or 1 to 4 carbon atoms _{- (CONH) p - (CHR} 5) q - ( wherein, R ⁵ is a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group, p is an integer of 0 or 1, q represents an 0 or an integer of 1 to 2);. Y is oxygen atom, -NR ⁶ - (wherein, R ⁶
Is a hydrogen atom or a lower alkyl group. ) Or a sulfur atom;. Z is alkylene of 1 to 4 carbon atoms, alkenylene of 2 to 4 carbon atoms, -CHR ⁷ - (wherein, R ⁷ is a phenyl group), - CONH -, - CO- Or -SO ₂
Represents-; l, m and n each independently represent 0 or 1, and Cy represents an optionally substituted aryl group, an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group. ] The phthalimide derivative represented by these, or its pharmaceutically acceptable salt is contained as an active ingredient an IgE production inhibitor.

(2) An IL-5 production inhibitor containing, as an active ingredient, a phthalimide derivative represented by the general formula [I] or a pharmaceutically acceptable salt of the compound.

(3) General formula [II]

Embedded image (Wherein R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom, a hydroxyl group, a lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted alkoxycarbonyl group, a carbamoyl group, an alkylaminocarbonyl group , A carboxy group, an amino group, a nitro group or a halogen atom, provided that R ¹ ,
At least one of R ² , R ³ and R ⁴ is a substituent other than a hydrogen atom; A represents a carbon atom or a nitrogen atom; B ² is a cycloalkyl group, an optionally substituted aryl group, an aralkyl group or Y ¹ represents an oxygen atom, -NH
- or a sulfur atom; Z ¹ is an alkylene or -CHR ⁷ of 1 to 4 carbon atoms - indicates (wherein, R ⁷ is a phenyl group.); T is an integer of 0 or 1 to 4; m and n each independently represent 0 or 1; Cy represents an optionally substituted aryl group, an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group. Or a pharmaceutically acceptable salt thereof.

(4) R ¹ , R ³ and R ⁴ are hydrogen atoms; R ² is an optionally substituted alkoxycarbonyl group;
A carbamoyl group, an alkyl amino group or a carboxy group; A is a carbon atom; B ² is a cycloalkyl group, and which may be substituted aryl group or a heterocyclic group (3) of the phthalimide derivative or a pharmaceutically Acceptable salt.

(5) R ² is a carboxy group; B ² is a cycloalkyl group or an optionally substituted aryl group; Z ¹ is an alkylene having 1 to 4 carbon atoms; The phthalimide derivative or a pharmaceutically acceptable salt thereof according to (4), which is a good aryl group or a cycloalkyl group which may be substituted.

(6) The phthalimide derivative according to (4) or (5), wherein Cy is a cycloalkyl group which may be substituted, or a pharmaceutically acceptable salt thereof.

(7) The phthalimide derivative according to (4) or (5), wherein Y ¹ is —NH— or a sulfur atom, m is 1, and Cy is an optionally substituted aryl group, or a pharmaceutically acceptable salt thereof. Acceptable salt. (8) Z ¹ is alkylene having 2 to 4 carbon atoms, m
Is the phthalimide derivative according to (4) or (5), or a pharmaceutically acceptable salt thereof. (9) The phthalimide derivative according to (6), wherein m is 0, or a pharmaceutically acceptable salt thereof.

(10) 2-[(S) -2-benzyloxy-1-phenylethyl] -2,3-dihydro-1,
3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(R) -2-cyclohexylmethyloxy-
1-phenylethyl] isoindole-1,3-dione, 2-[(S) -2-benzyloxy-1-phenylethyl] -4-hydroxyisoindole-1,3-dione, 2-[(R) -2-benzyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1
H-isoindole-5-carboxylic acid, 2-[(S)-
2-benzyloxy-1-phenylethyl] -2,3-
Dihydro-1,3-dioxo-1H-isoindole-
5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2-[(R) -2-benzyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-
1H-isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2-[(S) -1-benzyl-2-benzyloxyethyl] -2,3-dihydro-1,3-dioxo-1H- Isoindole-5-carboxylic acid, 2-[(S) -2-benzyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-4-carboxylic acid, 2-
[(S) -2-benzyloxy-1-phenylethyl]
-5-hydroxyisoindole-1,3-dione,
2,3-dihydro-1,3-dioxo-1H-2-
[(R) -1-phenyl-2- (2-pyridyloxy)
Ethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2-[(S) -1-
Phenyl-2-picolyloxyethyl] isoindole-5-carboxylic acid, 2-[(S) -1-phenyl-2-
Picolyloxyethyl] isoindole-1,3-dione hydrochloride, 2-[(S) -2-benzyloxy-1-
Phenylethyl] -4,5,6,7-tetrafluoroisoindole-1,3-dione, 2-[(S) -2-benzyloxy-1-phenylethyl] -4-methoxyisoindole-1,3 -Dione, 2-[(S) -2-
(4-methoxybenzyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(S) -2-cyclohexylmethyloxy-1 -Phenylethyl]-
2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(S) -1-phenyl-2- (3-phenylpropyloxy) ethyl] -2,
3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2-[(S) -2- (4-methylsulfonylbenzyloxy) ) -1-Phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2-[(S) -2- (4-methylbenzyloxy) -1-phenylethyl ] Indole-5
-Carboxylic acids,

2,3-dihydro-1,3-dioxo-1
H-2-[(S) -2- (3-methylbenzyloxy)
-1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2-
[(S) -2- (2-methylbenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2-
[(S) -2- (3,5-dimethylbenzyloxy)-
1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-
[(S) -2- (2-cyclohexylethyloxy)-
1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-
(2-benzyloxy-1-cyclohexylethyl)-
2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(S) -2-cyclopentyloxy-1-phenylethyl] -2,3-dihydro-1,3- Dioxo-1H-isoindole-5-carboxylic acid, 2-[(S) -2-cyclohexylmethyloxy-1-phenylethyl] -2,3-dihydro-1,
3-dioxo-1H-isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2-
[(S) -diphenylmethoxy-1-phenylethyl]
-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3
-Dioxo-1H-2-[(S) -1-naphthylmethoxy-1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2
-[(S) -2-naphthylmethoxy-1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2-[(S) -2- (2
-Methoxybenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2-[(S) -2-
(2-chlorobenzyloxy) -1-phenylethyl]
-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3
-Dioxo-1H-2-[(S) -2- (2,6-dimethylbenzyloxy) -1-phenylethyl] -isoindole-5-carboxylic acid, 2,3-dihydro-1,3
-Dioxo-2-[(S) -2-diphenylmethoxy-
1-phenylethyl] -1H-isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2,3-dihydro-1,3-dioxo-2-
[(S) -2-diphenylmethoxy-1-phenylethyl] -1H-isoindole-5-carboxylic acid N-methyl-D-gluconate, 2,3-dihydro-1,3-
Dioxo-1H-2-[(S) -2- (3-hydroxybenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2-[( R) -2-Diphenylmethoxy-1-phenylethyl) -1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2-
[(S) -2- (9-fluorenyl) -1-phenylethyl] -1H-isoindole-5-carboxylic acid,

2,3-dihydro-1,3-dioxo-2
-[(S) -2-diphenylmethoxy-1-benzylethyl] -1H-isoindole-5-carboxylic acid, 2-
[(S) -2- (2-chlorobenzyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt , 2,3-dihydro-
1,3-dioxo-1H-2-[(S) -2- (2-fluorobenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3
-Dioxo-1H-2-[(S) -2- (2-phenylbenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2-[(S) -2- (3-chlorobenzyloxy) ) -1-Phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5
-Carboxylic acid, 2-[(S) -2- (4-chlorobenzyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, -[(S) -2- (2,6-dichlorobenzyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[( S) -2- (2-Bromobenzyloxy) -1-phenylethyl] -2,3-dihydro-1,
3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2-
[(S) -2- (2-nitrobenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2-
[(S) -2- (2-cyanobenzyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1 , 3-Dioxo-1H-2-[(S) -2-
(2-trifluoromethylbenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2-
[(R) -2-cyclohexylmethyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-
1H-isoindole-5-carboxylic acid, 2- [2-benzyloxy-1- (4-chlorophenyl) ethyl]-
2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2- [2-benzyloxy-
1- (2-thienyl) ethyl] -2,3-dihydro-
1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2-
[(S) -2-diphenylmethyloxy-1-phenylethyl] -1H-isoindole-5-carboxylic acid sodium salt, 2-[(S) -2-cyclohexylmethyloxy-1-phenylethyl] -2, 3-dihydro-
1,3-dioxo-1H-isoindole-5-carboxylic acid sodium salt, 2-[(S) -2-benzyloxy-1-phenylethyl] -2,3-dihydro-1,3
-Dioxo-1H-isoindole-5-carboxylic acid
Sodium salt, 2-[(S) -2-cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3
-Dioxo-1H-isoindole-5-carboxylic acid,
2-[(S) -1-benzyl-2-cyclohexyloxyethyl] isoindole-1,3-dione, 2-
[(S) -2-cyclohexyl-1-phenyloxyethyl] -5-hydroxyisoindole-1,3-dione,

2-[(S) -1-benzyl-2-cyclohexyloxyethyl] -2,3-dihydro-1,3-
Dioxo-1H-isoindole-5-carboxylic acid, 2
-[(S) -2-cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H
-Isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2-[(R) -2-cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-iso Indole-5
Carboxylic acid, 2-[(S) -2-cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3-
Dioxo-1H-isoindole-5-carboxylic acid sodium salt, 2-[(S) -2-cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3-
Dioxo-1H-isoindole-5-carboxylic acid 1
/ 2 calcium salt, 2-[(S) -2-cyclohexyloxy-1-phenylethyl] -2,3-dihydro-
1,3-Dioxo-1H-isoindole-5-carboxylic acid potassium salt, 2-[(R) -2-cyclohexyloxy-1-phenylethyl] -2,3-dihydro-
1,3-dioxo-1H-isoindole-5-carboxylic acid sodium salt, 2- (1-phenyl-2-phenyloxyethyl) -2,3-dihydro-1,3-dioxo-1H-isoindole-5 -Carboxylic acid, 2-dibenzylmethyl-2,3-dihydro-1,3-dioxo-
1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2- [2- (4-methoxyphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2- [2- (4-benzyloxyphenyloxy) -1-phenylethyl] -2,3
-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2- [2- (4-hydroxyphenyloxy) -1-phenylethyl ] Isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-
2- [2- (2-methylphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-
Dihydro-1,3-dioxo-1H-2- [2- (3-
Methylphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3
-Dioxo-1H-2- [2- (4-methylphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2- [2- (4-chlorophenyloxy)-
1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-
[2- (3,5-dimethylphenyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-
1H-isoindole-5-carboxylic acid, 2-[(S)
-2- (3-tert-butylphenyloxy) -1-
Phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-
Dihydro-1,3-dioxo-2- [2- (3,5-di-tert-butylphenyloxy) -1-phenylethyl] -1H-isoindole-5-carboxylic acid, 2,
3-dihydro-1,3-dioxo-1H-2- [2-
(3-methoxyphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid,

2- [2- (4-tert-butylphenyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3- Dihydro-1,3-dioxo-1H-
2- [2- (3-isopropylphenyloxy) -1-
Phenylethyl] isoindole-5-carboxylic acid,
2,3-dihydro-1,3-dioxo-1H-2- [2
-(4-Isopropylphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2- [2- (3,4
-Methylenedioxyphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2- [2-
(3,5-dimethoxyphenyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H
-Isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2- [2- (3,4,5-
[Trimethoxyoxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-
Dioxo-1H-2- [2- (3,4-dimethoxyoxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2-
[2- (4-ethylphenyloxy) -1-phenylethyl] -1H-isoindole-5-carboxylic acid, 2,
3-dihydro-1,3-dioxo-1H-2- [2-
(1-Naphthyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3
-Dioxo-1H-2- [2- (2-naphthyloxy)
-1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2- [2-
(3-ethylphenyloxy) -1-phenylethyl]
-1H-isoindole-5-carboxylic acid, 2- [2-
(3,4-Dimethylphenyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-
Isoindole-5-carboxylic acid, 2,3-dihydro-
1,3-dioxo-1H-2- [2- (3,4,5-trimethylphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,
3-dioxo-2- (1,4-diphenylbutyl) -1
H-isoindole-5-carboxylic acid, 2- (2-cyclohexyl-1-phenylethyl) -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2- [N- (3-Phenylpropyl) anilino] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2- [N- (2-cyclohexylethyl) anilino] -2,3-dihydro −
1,3-dioxo-1H-isoindole-5-carboxylic acid, 2- (2-benzylsulfanyl-1-phenylethyl) -2,3-dihydro-1,3-dioxo-1H
-Isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2 [(S) -2-diphenylmethylamino-1-phenylethyl] -1H-isoindole-5-carboxylic acid, 2 -[(R) -1-benzyl-2
-Morpholinoethyl] isoindole-1,3-dione, 2-[(R) -1-benzyl-2-morpholinoethyl] -4-hydroxyisoindole-1,3-dione,

2-[(S) -2-anilino-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1
H-isoindole-5-carboxylic acid, 2-[(S)-
(Benzylcarbamoyl) phenylmethyl] -2,3-
Dihydro-1,3-dioxo-1H-isoindole-
5-carboxylic acid, 2-[(S) -phenyl (phenylcarbamoyl) methyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,
3-dihydro-1,3-dioxo-2-[(S)-
(1,4-diphenylbutyl)]-1H-isoindole-5-carboxylic acid, 2-[(R) -3-cyclohexyl-1-phenylpropyl] isoindole-1,3-
Dione, 2-[(R) -4-cyclohexyl-1-phenylbutyl] isoindole-1,3-dione, 2-
[(S) -3-cyclohexyl-1-phenylpropyl] isoindole-1,3-dione, 2-[(R)-
1,4-diphenylbutyl] isoindole-1,3-
Dione, 2-[(S) -1,4-diphenylbutyl] isoindole-1,3-dione, 2-[(R) -1,4
-Diphenylbutyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-
[(R) -1,4-diphenylbutyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-
Carboxylic acid sodium salt, 2-[(R) -3-cyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(R) -4-cyclohexyl-1-phenylbutyl] -2,3-dihydro-1,3-dioxo-
1H-isoindole-5-carboxylic acid, 2-[(S)
-2-cyclohexyl-1-phenylpropyl] -2,
3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2-[(R) -1,3-diphenylpropyl]-
1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2-[(S) -1,3-diphenylpropyl] -1H-isoindole-5-carboxylic acid, 2- [ (R) -3-cyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3-dioxo-
1H-isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2-[(R) -3-cyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3-dioxo-1H-iso Indole-5
Carboxylic acid choline salt, 2-[(S) -2- (3,5-
Dimethylphenyloxy) -1-phenylethyl]-
2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(R) -2- (3,5
-Dimethylphenyloxy) -1-phenylethyl]-
2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid,

2-[(S) -2- (3,5-dimethylphenyloxy) -1-phenylethyl] isoindole-1,3-dione, 2-[(R) -2- (3,5- Dimethylphenyloxy) -1-phenylethyl] isoindole-1,3-dione, 2-[(S) -2-benzyloxy-1-phenylethyl] -2,3-dihydro-
1,3-dioxo-1H-isoindole-N-methyl-5-carboxamide, methyl 2-[(S) -2-benzyl-1-phenyloxyethyl] -2,3-dihydro-1,3-dioxo- 1H-isoindole-5-carboxylate, 2-[(S) -2-benzyloxy-
1-phenylethyl] -5-carbamoylisoindole-1,3-dione, ethoxyethyl 2-[(S)-
Cyclohexyloxy-1-phenylethyl] -2,3
-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylate, ethyl 2-[(S) -cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H- Isoindole-5
-Carboxylate, 2- (N, N-dimethylamino)
Ethyl 2-[(S) -cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylate hydrochloride, pivaloyloxymethyl 2-[( S) -Cyclohexyloxy-1-phenylethyl) -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylate, [2-{(S) -2-benzyloxy-1-phenyl) Ethyl {-2,3-dihydro-1,3-
Dioxo-1H-isoindol-4-yloxy] acetic acid tert-butyl ester, [2-{(S) -2-
Benzyloxy-1-phenylethyl {-2,3-dihydro-1,3-dioxo-1H-isoindole-5
Yloxy] acetic acid tert-butyl ester, 4-
[2- (tert-butyloxycarbonylamino) ethyloxy] -2-[(S) -2-benzyloxy-1
-Phenylethyl] isoindole-1,3-dione,
5- [2- (tert-butyloxycarbonylamino) ethyloxy] -2-[(S) -2-benzyloxy-1-phenylethyl] isoindole-1,3-dione, 5-cyanomethoxy-2- [ (S) -2-cyclohexyloxy-1-phenylethyl] isoindole-1,3-dione, 2-[(S) -2-benzyloxy-1-phenylethyl] -5-methoxyisoindole-1,3 -Dione, 2-[(S) -2-benzyloxy-1-phenylethyl] -4-pentyloxyisoindole-1,3-dione, 2-[(S) -2-benzyloxy-1-phenylethyl ] -5-Pentyloxyisoindole-1,3-dione, 4- (2-aminoethyloxy) -2-[(S) -2-benzyloxy-1-
Phenylethyl] isoindole-1,3-dione hydrochloride, 5- (2-aminoethyloxy) -2-[(S)
-2-benzyloxy-1-phenylethyl] isoindole-1,3-dione hydrochloride, [2-{(S) -2]
-Benzyloxy-1-phenylethyl} -2,3-dihydro-1,3-dioxo-1H-isoindole-4
-Yloxy] acetic acid,

[2-{(S) -2-benzyloxy-1]
-Phenylethyl {-2,3-dihydro-1,3-dioxo-1H-isoindol-5-yloxy] acetic acid,
2-[(S) -2-cyclohexyloxy-1-phenylethyl] -5- (1H-tetrazol-5-ylmethoxy) isoindole-1,3-dione, 2- (N, N
-Diphenylamino) isoindole-1,3-dione, 2- (N, N-diphenylamino) -4-hydroxy-isoindole-1,3-dione, 2-diphenylmethylisoindole-1,3-dione, 2,3-dihydro-1,3-dioxo-2-diphenylmethyl-1H
-Isoindole-5-carboxylic acid, 2-[(R) -3
-(Trans-4-hydroxycyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-
[(R) -3- (cis-4-hydroxycyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3
-Dioxo-1H-isoindole-5-carboxylic acid and (+)-2-[(R) -3-cyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3-dioxo-1H-isoindole -5-carboxylic acid A compound selected from the group consisting of tris (hydroxymethyl) aminomethane salt monohydrate, or a pharmaceutically acceptable salt thereof.

(11) A pharmaceutical composition comprising the compound according to any one of claims 3 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient.

(12) An IgE production inhibitor comprising the phthalimide derivative according to any one of claims 3 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient.

(13) An IL-5 production inhibitor comprising the phthalimide derivative according to any one of claims 3 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient.

(14) An antiallergic agent comprising the compound according to any one of claims 1 or 3 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient.

The definitions of the substituents and phrases used in the present specification are as follows. "Halogen atom"
It is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The term "lower alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert. -Butyl group, pentyl group, isopentyl group, tert-pentyl group, hexyl group and the like. R ¹ , R ² , R ³ and R ⁴ are preferably a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, particularly preferably a methyl group and a tert-butyl group. R ⁶ is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, and particularly preferably a methyl group.

The "alkylene having 1 to 4 carbon atoms" is methylene, ethylene, trimethylene or tetramethylene, preferably methylene, ethylene or trimethylene. The “alkylene having 2 to 4 carbon atoms” is ethylene, trimethylene or tetramethylene, preferably ethylene or trimethylene. "Alkenylene having 2 to 4 carbon atoms" is vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene or 3-butenylene, and preferably 1-propenylene or 2-propenylene.

The term "lower alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, sec-butoxy group, pentyloxy group, tert-pentyloxy group, hexyloxy group and the like. Preferably, they are a methoxy group and an ethoxy group.

The "cycloalkyl group" is a cyclic saturated alkyl group having 3 to 10 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group. Preferred are a cyclopentyl group and a cyclohexyl group, and particularly preferred is a cyclohexyl group.

The "alkoxycarbonyl group" is a straight-chain or branched-chain alkoxycarbonyl group having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy. Examples include a carbonyl group, a tert-butoxycarbonyl group, a sec-butoxycarbonyl group, a pentyloxycarbonyl group, a tert-pentyloxycarbonyl group, and the like. Preferably, they are a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group.

The term "alkylaminocarbonyl group" means a mono- or di-substituted amino group with a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methylaminocarbonyl group and an ethylaminocarbonyl group. Propylaminocarbonyl group, isopropylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group and the like. Preferably, a straight-chain alkyl group having 1 to 6 carbon atoms is mono-substituted with an amino group, and particularly preferably a methylaminocarbonyl group.

The "aryl group" includes a phenyl group, a naphthyl group, an anthracene group, an indene group, an azulene group,
Examples thereof include aromatic hydrocarbon groups such as a fluorene group, a phenanthrene group, and a pyrene group, preferably a phenyl group, a naphthyl group, and a fluorene group, and particularly preferably a phenyl group.

The "aralkyl group" is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms which is substituted with an aryl group.
Examples include a phenylpropyl group and a naphthylmethyl group. Preferably, a benzyl group and a phenethyl group,
Particularly preferred is a benzyl group.

The "aralkyloxyalkyl group" is a lower alkyl group as defined above, which is substituted by an oxygen atom which is substituted with an aralkyl group as defined above. And preferably a benzyl group in the aralkyl moiety.

The "cycloalkene-3-yl group" is a group in which a cyclic alkenyl having 4 to 10 carbon atoms is substituted at the 3-position, such as cyclopentyl-3-yl group, cyclohexyl-3-yl group, cycloheptyl. -3-yl group and the like. Preferred are a cyclopentyl-3-yl group and a cyclohexyl-3-yl group.

"Heterocyclic group" refers to furyl, pyranyl, benzofuranyl, chromenyl, indanyl,
1,3-dioxaindanyl group, chromanyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, imidazole group, indolyl group, indolinyl group, quinolyl group, thienyl group, thiazolyl group, etc. And B, B ¹ and B ² are preferably a thienyl group.

The term "cycloalkyl formed by B, B ¹ and A together" means cyclopentyl, cyclohexyl or cycloheptyl which is a saturated cycloalkyl having 5 to 7 carbon atoms, preferably cyclohexyl.
The “optionally substituted heterocyclic ring formed by B, B ¹ and A together” means that a carbon atom on a saturated cycloalkyl having 5 to 7 carbon atoms is an oxygen atom, a nitrogen atom, a sulfur atom or the like. Those in which one or more hetero atoms have been replaced (excluding the A site) may be substituted with an aralkyl group other than the atom A. Examples of the heterocyclic ring include piperidine, piperazine, morpholine, pyrrolidine, oxacyclohexane, thiacyclohexane, and the like, preferably piperidine, and the substituent is preferably an unsubstituted or benzyl group.

The term "optionally substituted lower alkyl group" means that the lower alkyl group as defined above may be substituted by 1 to 3 hydroxyl groups or a halogen atom as defined above. In the lower alkyl moiety, a linear or branched alkyl group having 1 to 4 carbon atoms is preferable, and a methyl group, an ethyl group, an isopropyl group, and an isobutyl group are particularly preferable.

The "optionally substituted aryl group" refers to a phenyl group, a naphthyl group, an anthracene group, an indene group,
Azulene group, fluorene group, phenanthrene group, aromatic hydrocarbon group such as pyrene group, hydroxyl group, nitro group, cyano group, phenyl group, morpholino group, benzyl group, benzyloxy group, benzylamino group, methylsulfonyl group, the above It may be independently substituted with 1 to 5 halogen atoms, lower alkyl groups or lower alkoxy groups as defined above. The aryl moiety is preferably a phenyl group, a naphthyl group or a fluorene group, and particularly preferably a phenyl group. As the substituent, unsubstituted or the above-defined halogen atom in B, B ¹ and B ² is preferable, and unsubstituted in Cy is preferable.

The "optionally substituted heterocyclic group" includes a furyl group, a pyranyl group, a benzofuranyl group, a chromenyl group,
Indanyl group, 1,3-dioxaindanyl group, chromanyl group, pyrrolyl group, imidazolyl group, pyrazolyl group,
Pyridyl group, pyrazinyl group, pyrimidinyl group, imidazole group, indolyl group, indolinyl group, quinolyl group,
A saturated or unsaturated heterocyclic group such as a thienyl group or a thiazolyl group is a hydroxyl group, a nitro group, a cyano group, a phenyl group, a morpholino group, a benzyl group, a benzyloxy group, a benzylamino group, a methylsulfonyl group, or a halogen atom as defined above; And a lower alkyl group as defined above or a lower alkoxy group as defined above, each of which may be independently substituted one to three times. The heterocyclic ring is preferably a pyridyl group or a piperidyl group, and the substituent is preferably an unsubstituted or morpholino group.

The "optionally substituted cycloalkyl group" is a cycloalkyl group as defined above which may be substituted by a hydroxy group. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, Examples include a heptyl group, a cyclooctyl group, a 4-hydroxycyclohexyl group, a 1-hydroxycyclohexyl group, and a 2,4-dihydroxycyclohexyl group. Preferred are a cyclopentyl group and a cyclohexyl group, and particularly preferred is a cyclohexyl group.

The "optionally substituted lower alkoxy group" means that the lower alkoxy group as defined above is an amino group, a cyano group, a carboxy group, a heterocyclic group as defined above, a lower alkoxy group as defined above, an alkoxy group as defined above. It may be substituted by a carbonyl group or an amino group substituted by an alkoxycarbonyl group as defined above, and is preferably an alkoxy group having a linear alkyl group having 1 to 6 carbon atoms in the base alkoxy moiety. And particularly preferably a methoxy group, an ethoxy group or a pentyloxy group.

The "optionally substituted alkoxycarbonyl group" means that the above-defined alkoxycarbonyl group is a phenyl group, a tert-butyloxycarbonyl group, a tert-butyloxycarbonyl group,
-A butylcarbonyloxy group, a lower alkoxy group as defined above, an amino group or a heterocyclic group which may be substituted with a lower alkyl as defined above.
The alkoxycarbonyl moiety is preferably an ethoxycarbonyl group or a methoxycarbonyl group.

The "amino protecting group" is a commonly used protecting group, and is not particularly limited as long as it protects the amino group from various reactions. For example, acyl groups such as acetyl group, benzoyl group and phthaloyl group; alkoxycarbonyl groups such as tert-butoxycarbonyl group; alkenyloxycarbonyl groups such as vinyloxycarbonyl group; aralkyloxycarbonyl groups such as benzyloxycarbonyl group; trimethylsilyl group A lower alkylsilyl group such as
An alkylthiocarbonyl group such as an alkylenebis (dialkylsilyl) group; a tert-butylthiocarbonyl group;
An aralkylthiocarbonyl group such as a benzylthiocarbonyl group; a phosphoryl group such as a diphenylphosphoryl group; and a phosphinyl group such as a diphenylphosphinyl group.

The "pharmaceutically acceptable salt" may be any salt which forms a nontoxic salt with the phthalimide derivative represented by the above general formula [I], for example, hydrochloric acid, sulfuric acid, phosphoric acid , Inorganic acids such as hydrobromic acid, or oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid,
Organic acids such as succinic acid, tartaric acid, acetic acid, gluconic acid, ascorbic acid, or sodium hydroxide, potassium hydroxide,
Inorganic bases such as calcium hydroxide, magnesium hydroxide and ammonium hydroxide, or organic bases such as methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, guanidine, choline, cinchonine, or lysine , Arginine, alanine and the like. In some cases, it may be a hydrate, a hydrate or a solvate. They may also be prodrugs. A “prodrug” is a derivative of a compound of the present invention that has a group that can be chemically or metabolically degraded and that, after being administered to a living organism, reverts to the original compound and exhibits its original efficacy. Conjugates and salts.

In the phthalimide derivative represented by the above general formula [I], various isomers may exist.
For example, E-form and Z-form may exist as geometric isomers.
When an asymmetric carbon atom is present, enantiomers and diastereomers as stereoisomers based on these may exist. In some cases, tautomers may exist.
Accordingly, the scope of the present invention includes all these isomers and their mixtures.

When the compound of the present invention is used as an antiallergic agent, it is usually administered systemically or locally, orally or parenterally. The dosage varies depending on the age, body weight, symptoms, therapeutic effect, administration method and the like, but it is usually in the range of 10 mg to 1 g at a time, and once to several times a day per adult. The compound of the present invention comprises a solid composition and a liquid composition for oral administration, or a diluent, dispersant, adsorbent, and dissolving agent suitable for preparing a formulation such as an injection and a coating for parenteral administration. Etc. can be mixed. In addition, the compound of the present invention is not limited to humans,
In particular, it can be used for the treatment and prevention of mammals.

[0047]

Next, an example of a method for producing a compound for carrying out the present invention will be described. However, the production method of the compound of the present invention is not limited to these. Further, in each step, the reaction treatment may be performed by a commonly used method, and a commonly used method such as isolation and purification, crystallization, recrystallization, silica gel chromatography, and preparative HPLC is appropriately selected and combined. Just do it.

General Production Method Production Method a-1 This production method is a method in which an alcohol having an amino group and a halide are ether-bonded to obtain an ether having an amino group.

Embedded image (In the formula, A ′ is —CB ^{1 ′} — (wherein B ^{1 ′} represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a heterocyclic group or an aralkyloxycarbonyl group.) B ^′ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a heterocyclic group or an aralkyloxycarbonyl group, and B ^′ and B ^{1 ′}
And A together may form a cycloalkyl or an optionally substituted heterocyclic ring, Hal is a halogen atom, and X, Z, l, n and Cy are as defined in claim 1. The compound [3] can be obtained by reacting the compound [1] with the compound [2] in a solvent at room temperature or reflux temperature in the presence of a base. Examples of the base include lithium hydride, sodium hydride, potassium hydride,
As the solvent, a polar solvent such as dimethylformamide and dimethylsulfoxide and an ether-based solvent such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane and tetrahydrofuran are preferable.

Production Method a-2 When Cy is an optionally substituted cycloalkyl group in the compound [3] and n is 0, the following production method may be used to increase the yield.

Embedded image (Wherein A ′, B ′, X, 1 and Hal are as described in Production method a-1, Cy ′ is a cycloalkene-3-yl group, and Cy ″ is an optionally substituted cycloalkyl 1st step Compound [1] is compound [2 '] in a solvent in the presence of a base.
Is reacted at room temperature or reflux temperature to give compound [3 ']. Examples of the base include lithium hydride, sodium hydride, and potassium hydride. Examples of the solvent include polar solvents such as dimethylformamide and dimethyl sulfoxide, and 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran. And the like. Step 2 Compound [3 ″] can be obtained by reducing compound [3 ′] obtained in step 1 of production method a-2 using a catalyst in a solvent at room temperature under a hydrogen atmosphere. As the solvent, alcohol solvents such as methanol, ethanol, propanol and butanol, and ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane and tetrahydrofuran are preferable. As a catalyst,
Palladium catalysts such as palladium-carbon, palladium hydroxide and palladium black are exemplified.

Production Method b-1 This production method is a method for obtaining an ether having an amino group through an ether bond formation reaction and an amination reaction of a carbonyl compound having a halogen atom.

Embedded image (Wherein B ′, X, Z, 1, n, Cy and Hal are as described in Production method a-1). ] At room temperature or reflux temperature to give compound [6]. As the base, potassium carbonate, sodium carbonate, lithium hydride, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, and as the solvent, dimethylformamide,
Dimethyl sulfoxide, acetonitrile, polar solvents such as acetone and 1,4-dioxane, diethyl ether,
Ether solvents such as 1,2-dimethoxyethane and tetrahydrofuran are preferred. Second Step The compound [6] obtained in the first step of the production method b-1 is reduced at room temperature in the presence of an ammonia source such as ammonium chloride, ammonium acetate or the like with a reducing agent such as sodium cyanoborohydride or sodium cyanoborohydride. The compound [7] can be obtained by reducing the imine site generated in the reaction system using If necessary, a desiccant such as molecular sieve may be added to the reaction solution. As the solvent, alcohol solvents such as methanol, ethanol, propanol and butanol are preferable.

Production Method b-2 In this production method, an aldehyde is alkylated by a Grignard reaction, and then amination of a carbonyl compound produced by a Mitsunobu reaction (fourth step) or oxidation of alcohol (second,
3) to obtain an amine.

Embedded image (Wherein B ″ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group or an aralkyl group, and Cy ′ ″
Is an optionally substituted aryl group or an optionally substituted cycloalkyl group, and X, Z, l, n and Hal are as described in Production method a-1. 1) Step 1 Compound [10] is obtained by reacting compound [8] with compound [9] in a solvent at room temperature or reflux temperature. As the solvent, ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran are preferable. Step 2 Compound [11] can be obtained by oxidizing compound [10] using an oxidizing agent such as chromic acid. As the solvent, an organic solvent such as chloroform, carbon tetrachloride, methylene chloride, nitrobenzene, and acetic acid is preferable. Third Step Compound [13] can be obtained by reducing compound [11] obtained in the second step of production method b-2 in the same manner as in the second step of the production method b-1. Fourth step The compound [10] obtained in the first step of the production method b-2 is mixed with phthalimide in a solvent in the presence of a condensing agent under ice-cooling, and reacted at room temperature or reflux temperature. Compound [12] can be obtained. As a condensing agent, triphenylphosphine, trimethylphosphine, triethylphosphine, triphenyl phosphite, trimethyl phosphite, triethyl phosphite and the like were combined with diisopropyl azodicarboxylate, diethyl azodicarboxylate, dicyclohexyl azodicarboxylate and the like. Are preferred.
As a solvent, 1,4-dioxane, diethyl ether,
Preferred are ether solvents such as 1,2-dimethoxyethane and tetrahydrofuran, and hydrocarbon solvents such as benzene, toluene, hexane and xylene, or mixed solvents thereof. Fifth Step The compound [1] is subjected to dephthaloylation of the compound [12] obtained in the fourth step of the production method b-2 in a solvent in the presence of hydrazine or a hydrate thereof at room temperature or at a reflux temperature to give the compound [1].
3] can be obtained. Examples of the solvent include alcohol solvents such as methanol, ethanol, propanol, and butanol, 1,4-dioxane, diethyl ether, and 1,2-
Ether solvents such as dimethoxyethane and tetrahydrofuran are preferred.

Production Method b-3 In this production method, the secondary amine was converted into an N-nitroso compound,
This is a method for obtaining hydrazine by reduction, and synthesis was performed with reference to the method described in the prior art (Japanese Patent Laid-Open No. 1-222433).

Embedded image [Wherein, B ′, X, Z, 1, n, and Cy are the same as in the production method a-1.
As described, Y ′ is an oxygen atom, —NR ^{6 ′} — (where R ^{6 ′} is a lower alkyl group) or a sulfur atom,
m is as defined in claim 1. Step 1 The compound [14] obtained by a known method is added in a solvent with an inorganic acid such as acetic acid and a nitrite such as nitrous acid or sodium nitrite sequentially, and reacted at room temperature or reflux temperature to obtain a compound [14]. 15] can be obtained. As the solvent, alcohol solvents such as methanol, ethanol, propanol and butanol are preferable. Second Step A compound [16] can be obtained by sequentially adding a base and thiourea dioxide in a solvent to the compound [15] obtained in the first step of the production method b-3 and performing a reduction reaction. Examples of the base include potassium carbonate, sodium carbonate, lithium hydride, sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride.The solvent is preferably an alcohol solvent such as methanol, ethanol, propanol, and butanol. .

Production Method b-4 This production method is a method in which a carboxylic acid compound and an aromatic compound are acylated by a Friedel-Crafts reaction and then oxime-ized to obtain an amine.

Embedded image (Wherein B ″ ″ is an aryl group, and X, Y, Z, l,
m, n and Cy are as described above. 1) Step 1 After reacting compound [42] with thionyl chloride, thionyl chloride-dimethylformamide or phosphorus oxychloride in a solvent at reflux temperature, the mixture is added dropwise to a mixed solution of Lewis acid and compound [43] under ice-cooling. By reacting at room temperature, compound [44] can be obtained. As the solvent, a solvent that does not react with the acyl halide, such as dichloromethane, tetrahydrofuran, and ethyl acetate, is used. Examples of the Lewis acid include aluminum chloride and zinc chloride. A catalyst such as polyphosphoric acid or hydrogen fluoride may be used instead of the Lewis acid. Second step In a solvent in which the compound [44] obtained in the first step of the production method b-4 is made weakly basic with sodium acetate or the like, hydrochloride or sulfate of hydroxyamine or sodium hydroxyamine sulfonate or the like is used. Compound [45] can be obtained by reacting with an oximation agent. As the solvent,
Alcohol solvents such as methanol, ethanol, propanol and butanol and water or a mixed solvent thereof are preferred. Third step The compound [45] obtained in the second step of the production method b-4 is subjected to catalytic reduction in a solvent under a medium pressure using a palladium catalyst such as palladium-carbon, a nickel catalyst, a catalyst such as a platinum catalyst, Alternatively, the compound [4] is reduced by using a reducing agent such as aluminum hydride or sodium-alcohol.
6] can be obtained. As the solvent, methanol,
Alcohol solvents such as ethanol, propanol and butanol are preferred.

Production Method c This production method is a method for obtaining a sulfide having an amino group through sulfidation of a carbonyl compound having a halogen atom.

Embedded image (Wherein B ′, X, Z, 1, n, Cy and Hal are as described in Production method a-1). −
By reacting butylammonium bromide and compound [18] at room temperature or reflux temperature, compound [1]
9] can be obtained. Examples of the base include potassium carbonate, sodium carbonate, lithium hydride, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, and the like.As the solvent, benzene, toluene,
Hydrocarbon solvents such as hexane and xylene are preferred. 2nd step By aminating the carbonyl site of compound [19] in the same manner as in the 2nd step of production method b-1, compound [2]
0] can be obtained.

Production method d-1 This production method is a method for obtaining an ester having an amino group or a sulfonate having an amino group by condensing an alcohol having an amino group using an amino protecting group and then deprotecting the alcohol.

Embedded image (Wherein B ″, X, 1, n, Hal and Cy ″ are as described above, Z ′ is —CONH—, —CO— or —SO ₂ —, and Pro is amino-protected. 1st step (When the protecting group is a tert-butoxycarbonyl group) Compound [21] was reacted with di-tert-butyl carbonate in a solvent at room temperature or reflux temperature to protect the amino group. Compound [22] can be obtained. Organic solvents such as chloroform, carbon tetrachloride, methylene chloride, nitrobenzene, and acetic acid are preferred. (When the protecting group is a benzyloxycarbonyl group) Compound [21] can be reacted with benzyloxycarbonyl chloride in a solvent in the presence of a base at room temperature or reflux temperature to obtain compound [22] having an amino group protected. it can.
Examples of the base include sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, triethylamine, and the like, and examples of the solvent include organic solvents such as chloroform, carbon tetrachloride, methylene chloride, nitrobenzene, and acetic acid. Step 2 Compound [22] obtained in Step 1 of Production Method d-1 is added with compound [23] in a solvent in the presence of a base under ice-cooling, followed by ester condensation at room temperature or reflux temperature. To give compound [24]. Examples of the base include pyridine, triethylamine, N-methylmorpholine, and the like. As the solvent, a solvent that does not react with an acyl halide such as dichloromethane, tetrahydrofuran, ethyl acetate, and pyridine is used. Third Step (When the protecting group is a tert-butoxycarbonyl group) The compound [24] obtained in the second step of the production method d-1 is subjected to hydrochloric acid, hydrobromic acid, hydrochloric acid-acetic acid, trifluoroacetic acid- The deprotected compound [25] can be obtained by reacting at room temperature or reflux temperature in the presence of an acid catalyst such as dichloromethane. Examples of the solvent include ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran; organic solvents such as chloroform, carbon tetrachloride, methylene chloride, nitrobenzene, and acetic acid; methanol, ethanol, propanol, Alcohol solvents such as butanol, hydrocarbon solvents such as benzene, toluene, hexane, and xylene, water, a mixed solvent thereof, or no solvent are preferred. (When the protecting group is a benzyloxycarbonyl group)
-1 in a solvent in the presence of a metal catalyst such as palladium carbon or Raney nickel in a solvent,
The deprotected compound [25] can be obtained by catalytic reduction with hydrogen gas at room temperature or reflux temperature. Examples of the solvent include alcohol solvents such as methanol, ethanol, propanol and butanol; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane and tetrahydrofuran; dimethylformamide;
Polar solvents such as dimethyl sulfoxide, acetonitrile and acetone: chloroform, carbon tetrachloride, methylene chloride,
Organic solvents such as nitrobenzene and acetic acid; water; or a mixed solvent thereof.

Production method d-2 This production method is a method in which an alcohol having an amino group protected is esterified with an isocyanate, and then an ester having an amino group is obtained by deprotection.

Embedded image (In the formula, B ″, X, 1, Cy ″ and Pro are as described above.) First Step In the same manner as in the fourth step of production method b-2 or the first step of production method d-1. The compound [2] is reacted with the compound [27] at room temperature or reflux temperature in a solvent in the presence of an acid catalyst such as hydrogen chloride at room temperature or reflux temperature, in a solvent.
8] can be obtained. As the solvent, ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran are preferable. Second step The compound [28] obtained in the first step of the production method d-2 is deprotected in the same manner as in the fourth step of the production method b-2 or the fifth step of the production method d-1, whereby the compound is obtained. [29] can be obtained.

Production method d-3 This production method is a method in which an amino-protected carboxylic acid is condensed with a secondary or tertiary amine, and then the amine is obtained by deprotection.

Embedded image Wherein X, l and Pro are as described above,
B '' ′ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, an aralkyl group or a heterocyclic group;
The Nrr ′ site includes a nitrogen atom in the optionally substituted heterocyclic group represented by —Cy (general formula [I], and substitutes the carbonyl group in the reaction formula with a nitrogen atom. ) Or -NR ^{6 '} -Cy (Cy and R ^6' are as described above). Step 1 In a solvent, a compound [30] amino-protected in the same manner as in Step 4 of Production Method b-2 or Step 1 of Production Method d-1, is treated with a base and 1-ethyl-3- (3-dimethylaminopropyl). ) Carbodiimide Compound [32] can be obtained by adding compound [31] under ice-cooling in the presence of a condensing agent such as carbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyldiimidazole, and reacting at room temperature or reflux temperature to obtain compound [32]. Hydroxysuccinimide, 1
Activators such as -hydroxybenzotriazole may be added. Examples of the base include potassium carbonate, sodium carbonate, lithium hydride, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, dimethylaminopyridine, and the like.Examples of the solvent include chloroform, carbon tetrachloride, and methylene chloride. Organic solvents such as benzene, nitrobenzene, acetic acid, etc .; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane and tetrahydrofuran; and polar solvents such as dimethylformamide and dimethylsulfoxide. Second step The compound [32] obtained in the first step of the production method d-3 is deprotected in the same manner as in the fifth step of the production method b-2 or the third step of the production method d-1, whereby the compound is obtained. [33] can be obtained. Third Step A reducing agent such as lithium aluminum hydride or diborane is added to the compound [33] obtained in the second step of the production method d-3 in a solvent, and the compound [34] is reduced at room temperature or reflux temperature to give the compound [34]. Obtainable. As the solvent, organic solvents such as chloroform, carbon tetrachloride, methylene chloride, nitrobenzene, and acetic acid, and ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran are preferable.

Production Method e This production method is a method for obtaining an optically active amine by optical resolution of a racemic amine.

Embedded image (In the formula, B ″, X, l, and Cy are as described above, and * indicates that the carbon atom is an asymmetric atom.) Production method e-1 Obtained by a production method similar to the above production method. The obtained compound [35] is subjected to optical resolution using an optically active carboxylic acid such as optically active tartaric acid, malic acid, aspartic acid and N-acetyl-L-leucine in a solvent to obtain an optically active amine. it can. As the solvent, an alcohol solvent such as methanol, ethanol, propanol and butanol, water or a mixed solvent thereof, or a mixed solvent of an alcohol solvent and ethyl acetate, chloroform, and toluene is preferable. Is preferably a mixed solvent of these alcohols.

Process e-2 This process is a process for obtaining an optically active amine by Mitsunobu reaction after asymmetric reduction of a carbonyl compound.

Embedded image (In the formula, X, Z, 1, n, Cy, B ″ ′ and * are as described above.) Step 1 Compound [3] obtained in the same manner as in Step 2 of Production Method b-2
Compound [38] can be obtained by subjecting 7] to asymmetric reduction using a chiral reducing agent such as (-)-B-chlorodiisopinocamphenylborane in a solvent under cooling. As the solvent, 1,4-dioxane, diethyl ether,
Ether solvents such as 1,2-dimethoxyethane and tetrahydrofuran are preferred. Step 2 The compound [38] obtained in the first step of the production method e-2 is subjected to phthaloylation in the same manner as in the fourth step of the production method b-2, whereby a compound [39] having a reversed configuration is obtained. Can be. Third Step The compound [39] obtained in the second step of the production method e-2 is dephthaloylated in the same manner as in the fifth step of the production method b-2 to give a compound [40].

Production Method f This production method is a method for obtaining a phthalimide derivative by condensation of phthalic anhydride and a primary amine.

Embedded image (Wherein, R ¹ , R ² , R ³ , R ⁴ , A, B, X, Y, Z, C
y, l, m and n are as defined in claim 1. ) A compound which is a commercially available phthalic anhydride derivative or a phthalic anhydride derivative produced therefrom by a conventional method [40]
The compound [I] can be obtained by reacting the compound [41], which is a primary amine obtained by the above-mentioned production method or a commercially available primary amine, with or without a solvent at room temperature or reflux temperature. Examples of the solvent include hydrocarbon solvents such as benzene, toluene, hexane, and xylene; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone; chloroform,
Organic solvents such as carbon tetrachloride, methylene chloride, nitrobenzene, acetic acid, pyridine and the like are preferred.

Production Method g-1 to g-6 This production method is a method of introducing a new substituent using the phthalimide derivative obtained by the above production method.

Embedded image (Wherein A, B, X, Y, Z, Cy, l, m and n are as defined in claim 1, and R ′ is a hydroxyl group, a carboxy group, a cyanomethyloxy group, a nitro group, —O— (C
H ₂₎ u-Pro and -O- (CH ₂₎ u-NHPro
Wherein u is an integer having 1 to 4 carbon atoms and Pro represents an amino-protecting group, and R ″ is an optionally substituted alkoxycarbonyl group, carbamoyl group or alkylaminocarbonyl group; 'Is an optionally substituted alkoxycarbonyl group, and R "" is an optionally substituted lower alkoxy group. Production Method g-1 When R 'is a carboxy group in compound [I'] (however, a compound having a hydroxyl group, an amino group or a carboxy group as a ring substituent in Cy is excluded). The ester can be reacted with a primary alcohol at room temperature or reflux temperature in the presence of a condensing agent, and the compound [I ″] can be obtained by condensing it with a primary amine. If necessary, an activator such as hydroxysuccinimide and 1-hydroxybenzotriazole may be added. Examples of the base include potassium carbonate, sodium carbonate, lithium hydride, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, pyridine, triethylamine, N-methylmorpholine, and the like.Examples of the solvent include dimethylformamide, dimethyl Preferred are polar solvents such as sulfoxide, acetonitrile and acetone, and organic solvents such as chloroform, carbon tetrachloride, methylene chloride, nitrobenzene and acetic acid. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyldiimidazole or the like, or triphenylphosphine, trimethylphosphine, triethylphosphine, triphenyl phosphite, trimethyl phosphite. , Triethyl phosphite and the like and diisopropyl azodicarboxylate, diethyl azodicarboxylate, dicyclohexyl azodicarboxylate and the like are preferable. Production Method g-2 When R 'is a carboxy group in compound [I'] (however, a compound having a hydroxyl group, an amino group, or a carboxy group as a ring substituent in Cy is excluded). Compound [I ″ ′] can be obtained by reacting with a halogen compound at room temperature or reflux temperature in the presence of a base. Examples of the base include potassium carbonate, sodium carbonate, lithium hydride, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, pyridine, triethylamine, N-methylmorpholine, and the like.Examples of the solvent include dimethylformamide, dimethyl Polar solvents such as sulfoxide, acetonitrile, acetone, methyl ethyl ketone, chloroform,
Organic solvents such as carbon tetrachloride, methylene chloride, nitrobenzene and acetic acid are preferred. Production Method g-3 When R ′ is a hydroxyl group in compound [I ′] (provided that Cy is
In the above, compounds having a hydroxyl group, an amino group, or a carboxy group as a ring substituent are excluded. ) The compound [I "" can be obtained by reacting the compound [I '] with a halogen compound in the same manner as in Production Method g-2. Production Method g-4 In the case where R 'is a cyanomethyloxy group in compound [I'], compound [I '] is reacted with sodium azide and ammonium chloride in a solvent at room temperature or reflux temperature to obtain R'''. Is 1H-tetrazol-5-ylmethoxy [I ″ ″]. As the solvent, a polar solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone is preferable. Process g-5 compound 'in R [I]' is -O- (CH ₂₎ u-Pr
o or _{-O- (CH 2) u-NHPro} ( wherein, u
Represents an integer of 1 to 4, and Pro represents an amino protecting group. In the case of), the compound [I ′ ″] can be obtained by deprotecting the compound [I ′] in the same manner as in the third step of the production method d-1. Production Method g-6 When R 'is a nitro group in compound [I'] Compound [I "" is reduced by reducing compound [I '] with a reducing agent such as tin chloride in a solvent at room temperature or reflux temperature. '] Can be obtained. As the solvent, alcohol solvents such as methanol, ethanol, propanol and butanol are preferable.

[0062]

EXAMPLES Next, the compounds represented by the general formula [I] according to the present invention and the production methods thereof will be described specifically with reference to Examples. However, needless to say, the present invention is not limited by these examples.

Example 1 2-[(S) -2-benzyloxy-1-phenylethyl] -2,3-dihydro-1,
3-Dioxo-1H-isoindole-5-carboxylic acid a) (S) -2-benzyloxy-1-phenylethylamine 60% in a solution of (S) -phenylglycinol (5.0 g) in tetrahydrofuran (THF, 100 ml) Oily sodium hydride (1.60 g) was added, and the mixture was heated under reflux for 1 hour. After allowing to cool, benzyl bromide (6.23 g) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The reaction solution was added to saturated saline and extracted with diethyl ether, and the organic layer was extracted with 10% hydrochloric acid.
After the aqueous layer was made alkaline with a sodium hydroxide solution, the organic layer was washed with saturated saline and extracted with diethyl ether. After drying over potassium carbonate and concentration under reduced pressure, the title compound (6.69 g) was obtained. b) 2-[(S) -2-benzyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H
-Isoindole-5-carboxylic acid (S) -2-benzyloxy-1-phenylethylamine (258 mg) obtained in Example 1a) and trimellitic anhydride (258 mg) were dissolved in acetic acid (5 ml). And refluxed for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: acetic acid = 30:
Purification was performed in 1) to give the title compound (383 mg). Table 1 shows the physical property values. Examples 2 to 74 The compounds of Examples 2 to 74 were obtained in the same manner as in Example 1. Physical property values are shown in Tables 1 to 19.

Example 75 2-[(S) -2-Cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid a) (1S) -2- (3-cyclohexenyloxy)-
1-Phenylethylamine (S) -Phenylglycinol (5.0 g) in THF (100 m
l) To the solution was added 60% oily sodium hydride (1.60 g), and the mixture was heated under reflux for 1 hour. After cooling, 3-bromocyclohexene (5.87 g) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The reaction solution was added to saturated saline and extracted with diethyl ether. The organic layer was dried over potassium carbonate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (triethylamine: ethyl acetate: hexane = 1: 1).
4:12) to give the title compound (3.06 g). b) (S) -2-cyclohexyloxy-1-phenylethylamine (1S) -2- (3-cyclohexenyloxy) -1-phenylethylamine obtained in a) of Example 75 (3.
06g) in ethanol (60 ml) was added to 10% palladium-
The mixture was vigorously stirred for 2 hours under a hydrogen stream in the presence of carbon (0.3 g). The reaction solution was filtered under Celite and concentrated under reduced pressure. The residue was purified by silica gel chromatography (triethylamine: ethyl acetate: hexane = 1: 4: 12) to obtain the title compound (2.89 g). c) 2-[(S) -2-Cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid Obtained in Example 75 b). The title compound (888 mg) was obtained from (S) -2-cyclohexyloxy-1-phenylethylamine (658 mg) in the same manner as in Example 1 b). Table 19 shows the physical property values. Examples 76 to 88 The compounds of Examples 76 to 88 were obtained in the same manner as in Example 75. The physical property values are shown in Tables 19 to 22.

Example 89 2- (1-phenyl-2-phenyloxyethyl) -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid a) 2-phenoxy-1-phenyl Ethanone Phenol (0.94g) in dimethylformamide (DM
F, 30 ml) solution, potassium carbonate (2.76 g) and phenacyl bromide (1.99 g) were sequentially added, and the mixture was stirred at 80 ° C. for 20 minutes. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (2.29 g). b) 2-Phenoxy-1-phenylethylamine To a solution of 2-phenoxy-1-phenylethanone (2.29 g) obtained in a) of Example 89 in methanol (50 ml),
Molecular sieve 3A (5g), ammonium acetate (7.71
g) and sodium cyanoborohydride (628 mg) were sequentially added at room temperature, and the mixture was stirred for 12 hours. The reaction solution was filtered under Celite and concentrated under reduced pressure. Diethyl ether was added to the residue and 1
The mixture was washed sequentially with an aqueous solution of N sodium hydroxide and water. After the organic layer was extracted with 1N hydrochloric acid, the aqueous layer was made alkaline with an aqueous sodium hydroxide solution and extracted with diethyl ether.
The organic layer was washed with saturated saline, dried over potassium carbonate,
The title compound was obtained by concentration under reduced pressure (1.03
g). c) 2- (1-phenyl-2-phenyloxyethyl)
-2,3-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid From 2-phenoxy-1-phenylethylamine (469 mg) obtained in b) of Example 89, b) of Example 1 In the same manner as in the above, the title compound (740 mg) was obtained. Table 23 shows the physical property values. Embodiments 90 to 115 Embodiment 9 is similar to Embodiment 89.
Compounds 0 to 115 were obtained. The physical property values are shown in Tables 23 to 29.

Example 116 2,3-Dihydro-1,3
-Dioxo-2- (1,4-diphenylbutyl) -1H
-Isoindole-5-carboxylic acid a) 1,4-diphenylbutan-1-ol To a solution of benzaldehyde (2.09 g) in THF (10 ml),
Under ice cooling, phenylpropylmagnesium bromide (1M
/ THF, 30 ml). After stirring at room temperature for 1 hour, the reaction solution was added to a saturated aqueous solution of ammonium chloride, and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to give the title compound (4.21 g). b) 2- (1,4-diphenylbutyl) isoindole-1,3-dione 1,4-diphenylbutan-1-ol (1.0 g) obtained in a) of Example 116, phthalimide (715 mg) and Triphenylphosphine (1.28 g) was added to THF (10 ml), a solution of diethyl azodicarboxylate (848 mg) in THF (4 ml) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane: chromium = 1: 25: 4) to give the title compound (1.04
g) was obtained. c) 1,4-Diphenylbutylamine 2- (1,4-diphenylbutyl) isoindole-1,3-dione obtained in b) of Example 116 (972 mg)
Hydrazine monohydrate (1.3ml) in ethanol (30ml)
Was added and heated under reflux for 1 hour. After filtering off the precipitated white solid, the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue,
The extract was washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (578 mg). d) 2,3-dihydro-1,3-dioxo-2- (1,
4-diphenylbutyl) -1H-isoindole-5-
Carboxylic acid The title compound (920 mg) was obtained from 1,4-diphenylbutylamine (562 mg) obtained in Example 116 c) in the same manner as in Example 1 b). Table 29 shows the physical property values. Examples 117 to 126 The compounds of Examples 117 to 126 were obtained in the same manner as in Example 116. Table 30-3
It is shown in FIG.

Example 127 2,3-Dihydro-1,3
-Dioxo-1H-2- [N- (3-phenylpropyl) anilino] isoindole-5-carboxylic acid a) 3-phenylpropionanilide According to a conventional method of amide condensation, aniline (2.05 g) and 3-
To a solution of phenylpropionic acid (3.00 g) in DMF (100 ml) was added 1-hydroxybenzotriazole monohydrate (HOBT.H 2 O, 2.97 g) and 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl, 4.22 g) was added in sequence, and 12
Stirred for hours. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (4.01 g). b) 1-phenyl-1- (3-phenylpropyl) amine According to the customary method for reduction of the carbonyl group, a) of Example 127)
3-phenylpropionanilide obtained in step (3.38 g)
To a THF (70 ml) solution was added lithium aluminum hydride (1.71 g) in portions under ice-cooling, and the mixture was refluxed for 2 hours. Water (1.7 ml), 15% sodium hydroxide (1.7 ml) and water (5.1 ml) were sequentially added to the reaction solution under ice cooling. Potassium carbonate was added to the reaction solution, which was dried, filtered through celite, and concentrated under reduced pressure to obtain the title compound (2.94 g). c) 1-phenyl-1- (3-phenylpropyl) hydrazine 1-phenyl-1- (3) obtained in b) of Example 127
-Phenylphenyl) amine (2.0 g) in methanol (20
acetic acid (1.35 ml) and sodium nitrite (1.31 ml)
aqueous solution (5 ml) was sequentially added, and the mixture was stirred at room temperature for 2 hours. A 10% aqueous sodium hydroxide solution (20 ml) and thiourea dioxide (2.43 g) were sequentially added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 16 hours and at 50 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ether. The organic layer was washed with brine, dried over potassium carbonate, and concentrated under reduced pressure to give the title compound (1.55 g). d) 2,3-dihydro-1,3-dioxo-1H-2-
[N- (3-phenylpropyl) anilino] isoindole-5-carboxylic acid 1-phenyl-1- (3) obtained in Example 127 c)
The title compound (1.06 g) was obtained in the same manner as in Example 1 b) from -phenylpropyl) hydrazine (679 mg). Table 33 shows the physical property values. Example 128 Example 128 was performed in the same manner as in Example 127.
Was obtained. Table 32 shows the physical property values.

Example 129 2- (2-benzylsulfanyl-1-phenylethyl) -2,3-dihydro-
1,3-dioxo-1H-isoindole-5-carboxylic acid a) 2-benzylsulfanyl-1-phenylethanone phenacyl bromide (3.98 g), benzylisothiourea
To a suspension of hydrochloride (4.05 g) and tetra-n-butylammonium bromide (64 mg) in benzene (35 ml) was added a 30% aqueous sodium hydroxide solution (35 ml), and the mixture was stirred at room temperature for 16 hours. After separating the reaction solution, the aqueous layer was extracted with benzene. The combined organic layers were washed sequentially with water and saturated saline,
After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain the title compound (3.90 g). b) 2-Benzylsulfanyl-1-phenylethylamine 2-benzylsulfanyl-1-phenylethanone (3.80 g) obtained in a) of Example 129 in methanol (80 m
l) To the solution, at room temperature, molecular sieve 3A (8 g),
Ammonium acetate (12.1 g) and sodium cyanoborohydride (1.18 g) were sequentially added, and the mixture was stirred for 16 hours. The reaction solution was filtered under Celite and concentrated under reduced pressure. 1N Sodium hydroxide was added to the residue, and extracted with diethyl ether. The organic layer was extracted with 10% hydrochloric acid, the aqueous layer was made alkaline with an aqueous sodium hydroxide solution, and then extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (0.1%).
57 g). c) 2- (2-benzylsulfanyl-1-phenylethyl) -2,3-dihydro-1,3-dioxo-1H-
Isoindole-5-carboxylic acid Example 1 from 2-benzylsulfanyl-1-phenylethylamine (243 mg) obtained in b) of Example 129.
The title compound (244 mg) was obtained in the same manner as in b). Table 33 shows the physical property values.

Example 130 2-((S) -2-cyclohexanecarbonyloxy-1-phenylethyl)-
2,3-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid a) N-tert-butoxycarbonyl- (S) -phenylglycinol Phenylglycinol (1.37 g) in methylene chloride (50 m
l) Add di-tert-butyl dicarbonate (2.4
0g) was added and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, which was washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate: hexane to give the title compound (1.93 g). b) N-butoxycarbonyl- (S) -2-cyclohexanecarbonyloxy-1-phenylethylamine of N-tert-butoxycarbonyl- (S) -phenylglycinol (1.0 g) obtained in a) of Example 130. Cyclohexanecarbonyl chloride (679 mg) was added to a pyridine (20 ml) solution under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with a 5% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (820 m
g) was obtained. c) (S) -2-cyclohexanecarbonyloxy-1
-Phenylethylamine N-butoxycarbonyl- (S) -2-cyclohexanecarbonyloxy-1- obtained in Example 130 b)
4N Hydrogen chloride-dioxane solution (20 ml) was added to phenylethylamine (1.49 g), and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 6: 4) to give the title compound (820 m
g) was obtained. d) 2-[(S) -2-cyclohexanecarbonyloxy-1-phenylethyl] -2,3-dihydro-1,3
-Dioxo-1H-isoindole-5-carboxylic acid (S) -2-cyclohexanecarbonyloxy-1-phenylethylamine (49) obtained in Example 130 c)
5 mg) and the title compound (620) in the same manner as in Example 1 b).
mg). Table 33 shows the physical property values. Example 131 Example 131 was performed in the same manner as in Example 130.
Was obtained. Table 33 shows the physical property values.

Example 132 2-[(S)-(2-Cyclohexanecarbamoyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid a) N-phthaloyl- (S) -phenylglycinol According to a conventional method of phthaloylation, phthalic anhydride (4.44 g),
(S) -Phenylglycinol (4.12 g) in toluene (1
The suspension was heated at reflux for 2 hours. The reaction solution was washed sequentially with 1N hydrochloric acid, water, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (7.69).
g) was obtained. b) 2-[(S) -2- (cyclohexylcarbamoyloxy) -1-phenylethyl] -isoindole-
1,3-dione N-phthaloyl- (S) obtained in a) of Example 132
To a solution of phenylglycinol (500 mg) in THF (15 ml) was added cyclohexyl isocyanate (516 mg), 4N
Hydrogen chloride-1,4-dioxane solution (0.2 ml) was sequentially added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (712 mg). c) (S) -2- (cyclohexylcarbamoyloxy) -1-phenylethylamine 2-[(S) -2- (cyclohexylcarbamoyloxy) -1-phenylethyl) -iso obtained in b) of Example 132 The title compound (454 mg) was obtained from indole-1,3-dione (700 mg) in the same manner as in Example 116 c).
I got d) 2-[(S) -2- (cyclohexylcarbamoyloxy) -1-phenylethyl] -2,3-dihydro-
1,3-Dioxo-1H-isoindole-5-carboxylic acid From Example 132b, (S) -2- (cyclohexylcarbamoyloxy) -1-phenylethylamine (158 mg) obtained in Example 132 c). ) To give the title compound (178 mg). Table 33 shows the physical property values. Example 133 Example 133 was performed in the same manner as Example 132.
Was obtained. Table 34 shows the physical property values.

Example 134 2,3-Dihydro-1,3
-Dioxo-2 [(S) -2-diphenylmethylamino-1-phenylethyl] -1H-isoindole-5-
Carboxylic acid a) N- (tert-butoxycarbonyl) -L-phenylglycine benzhydrylamide N- (tert-butoxycarbonyl) -L-phenylglycine (3.02 g), benzhydrylamine (2.20 g) in DMF (60 ml) ) Solution was added to HOBT.H ₂ O (1.7
8g) and WSC · HCl (2.53 g) were sequentially added, and the mixture was stirred at room temperature for 12 hours. Dilute the reaction with ethyl acetate and add 1
The extract was washed sequentially with 0% citric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified by column silica gel chromatography (ethyl acetate: hexane = 3: 7) to give the title compound (5.24).
g) was obtained. b) L-phenylglycine benzhydrylamide hydrochloride From N- (tert-butoxycarbonyl) -L-phenylglycinebenzhydrylamide (5.2 g) obtained in a) of Example 134, c) of Example 130) In the same manner as in the above, the title compound (4.54 g) was obtained. c) (S) -2-Diphenylmethylamino-1-phenylethylamine THF (45 ml) of L-phenylglycine benzhydrylamide hydrochloride (3.41 g) obtained in b) of Example 134.
Lithium aluminum hydride (1.03 g) was added to the suspension under ice cooling, and the mixture was heated under reflux for 4 hours. Water (1m
l), 15% sodium hydroxide (1 ml) and water (3 ml) were sequentially added under ice cooling. The reaction solution was added with potassium carbonate, dried, filtered through celite, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (chloroform: methanol = 9).
6: 4) to give the title compound (2.39 g). d) 2,3-dihydro-1,3-dioxo-2 [(S)
-2-diphenylmethylamino-1-phenylethyl]
-1H-isoindole-5-carboxylic acid From the (S) -2-diphenylmethyl-1-phenylethylamine (605 mg) obtained in c) of Example 134, the title compound (605 mg) was obtained in the same manner as in Example 1 b). 436 mg).
Table 34 shows the physical property values. Examples 135 to 142 The compounds of Examples 135 to 142 were obtained in the same manner as in Example 134. Table 34-3
6 is shown.

Example 143 2-[(S)-(1,4-
Diphenylbutyl)]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid a) (S) -1,4-diphenylbutylamine 1,4-diphenylbutylamine (2.25 g, racemic )
And a mixture of L-malic acid (1.34 g) with ethanol:
It was recrystallized three times with 2-propanol (1: 1). A 1N aqueous sodium hydroxide solution was added to the obtained crystals (1.03 g), and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (618 mg, optical purity 99%).
Above). b) 2-[(S) -1,4-diphenylbutyl] -2,
3-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid From (S) -1,4-diphenylbutylamine (501 mg) obtained in a) of Example 143, b) of Example 1 and The title compound (822 mg) was obtained in the same manner. Table 36 shows the physical property values.

Example 151 2-[(R) -3-Cyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid a) 3-cyclohexyl- 1-phenylpropane-1-
Thionyl chloride (219 ml) and DMF (3 ml) were sequentially added to a solution of on 3-cyclohexanepropionic acid (312 g) in ethyl acetate (2 L), and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure,
Distilled off azeotropically with benzene. The residue was added dropwise to a suspension of aluminum chloride (307 g) in benzene (2 L) under ice cooling, and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and extracted with toluene. The organic layer was sequentially washed with water, 5% potassium carbonate and water, and concentrated under reduced pressure. The residue was recrystallized from ethanol-water (5: 1) to give the title compound (393 g). b) 3-cyclohexyl-1-phenylpropane-1-
On oxime 3-cyclohexyl-1 obtained in example 151 a)
-Phenylpropan-1-one (392 g) in ethanol (1.44 L) was added to hydroxylamine hydrochloride (139 g).
g), sodium acetate (164 g) and water (360 ml) were sequentially added, and the mixture was heated under reflux for 1.5 hours. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with toluene. The organic layer was washed with water and concentrated under reduced pressure to obtain the title compound (446g). c) 3-cyclohexyl-1-phenylpropylamine 7.5% palladium on carbon (wet, 50% water) (40.7 g) in methanol suspension obtained in Example 151 b)
Cyclohexyl-1-phenylpropan-1-one oxime (407 g) was added, and medium pressure hydrogenation (3.
0 kgf / cm ² ). The reaction solution was filtered through celite and concentrated under reduced pressure. Toluene was added to the residue, and the mixture was washed sequentially with 1N aqueous sodium hydroxide solution and water, and concentrated under reduced pressure to give the title compound (372 g).
I got d) (R) -3-Cyclohexyl-1-phenylpropylamine A solution of cyclohexyl-1-phenylpropylamine (371 g, racemate) obtained in Example 151c) in methanol-water (2: 1, 8.5 L) was added. At room temperature, N-acetyl-L-
Leucine (296 g) was added, and the mixture was heated under reflux for 1 hour. After cooling, the precipitated crystals were collected by filtration, and the obtained crystals (254 g) were recrystallized from methanol-water (2: 1, 3.8 L). A 1N aqueous sodium hydroxide solution (510 ml) was added to the obtained crystals (191 g).
And extracted with toluene. The organic layer was washed with water and concentrated under reduced pressure to give the title compound (103 g, optical purity 99% or more). e) 2-[(R) -3-cyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3-dioxo-1
H-isoindole-5-carboxylic acid (R) -3-cyclohexyl-1-phenylpropylamine (95.0 g) obtained in Example 151 d) acetic acid (45.0 g)
50 ml) solution was added with trimellitic anhydride (84.0 g).
The mixture was heated under reflux for 2 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and a 10% aqueous sodium hydrogen carbonate solution was added.
Washed sequentially with 1N hydrochloric acid, water, and saturated saline. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the title compound (171 g) was obtained. Table 38 shows the physical property values. Examples 144 to 157 Example 143 or Example 151
In the same manner as in the above, the compounds of Examples 144 to 157 were obtained. Physical properties are shown in Tables 36 to 40.

Example 158 2,3-Dihydro-2-
[(S) -2- (3,5-dimethylphenyloxy)-
1-phenylethyl] -1,3-dioxo-1H-isoindole-5-carboxylic acid a) 2- (3,5-dimethylphenoxy) -1-phenylethanone 3) The title compound (9.55 g) was obtained from a solution of 5,5-dimethylphenol (6.72 g) in DMF (150 ml), potassium carbonate (15.2 g), and phenacyl bromide (9.95 g). b) (R) -2- (3,5-dimethylphenoxy) -1
-Phenylethanol (-)-B-chlorodiisopinocanphenylborane (2.
To a solution of 94 g) in THF (30 ml) was added a solution of 2- (3,5-dimethylphenoxy) -1-phenylethanone (2.0 g) obtained in Example 158a) in THF (10 ml) for -25.
C., and the mixture was stirred at the same temperature for 19 hours. The reaction solution was concentrated under reduced pressure, ether (30 ml) and diethanolamine (1.93 g) were added to the residue, and the mixture was stirred at room temperature for 3 hours. After filtering off the white solid, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purification was performed in 9) to give the title compound (1.76 g). c) 2-[(S) -2- (3,5-dimethylphenoxy) -1-phenylethyl] -isoindole-1,3
-Dione (R) -2- (3,5-) obtained in Example 158b)
Dimethylphenoxy) -1-phenylethanol (727m
g), phthalimide (486 mg), and triphenylphosphine (866 mg) in THF (15 ml) were added with diethyl azodicarboxylate (575 mg) under ice-cooling, followed by stirring at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
1: 9) to give the title compound (925 mg). d) (S) -2- (3,5-dimethylphenoxy) -1
-Phenylethylamine 2-[(S) -2- obtained in Example 158 c).
The title compound (624 mg) from (3,5-dimethylphenoxy) -1-phenylethyl] -isoindole-1,3-dione (918 mg) in the same manner as in Example 116 c).
I got e) 2,3-dihydro-2-[(S) -2- (3,5-
Dimethylphenyloxy) -1-phenylethyl]-
1,3-dioxo-1H-isoindole-5-carboxylic acid (S) -2- (3,5-) obtained in Example 158d).
Dimethylphenoxy) -1-phenylethylamine (48
3 mg) and the title compound (731) in the same manner as in Example 1 b).
mg). Table 40 shows the physical property values. Examples 159 to 161 The compounds of Examples 159 to 161 were obtained in the same manner as in Example 158. Table 40-4
It is shown in FIG.

Example 162 2-[(S) -2-benzyloxy-1-phenylethyl] -2,3-dihydro-
1,3-Dioxo-1H-isoindole-N-methyl-5-carboxamide 2-[(S) -2-benzyloxy-1-phenylethyl] -2,3- obtained in the same manner as in Example 1. HO was added to a solution of dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid (300 mg) in DMF (5 ml) under ice-cooling.
BT.H ₂ O (111 mg), WSC.HCl (158 mg), triethylamine (83 mg), methylamine hydrochloride (56 mg)
Were added successively, and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate, and 10% citric acid, water, saturated aqueous sodium bicarbonate,
The extract was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 2) to give the title compound (266 mg). Table 41 shows the physical property values. Examples 163 to 168 The compounds of Examples 163 to 168 were obtained in the same manner as in Example 162. Table 41-4
It is shown in FIG.

Example 169 Pivaloyloxymethyl
2-[(S) -cyclohexyloxy-1-phenylethyl) -2,3-dihydro-1,3-dioxo-1H-
Isoindole-5-carboxylate 2-[(S) -2-cyclohexyloxy-1-phenylethyl] -2,3- obtained in the same manner as in Example 75.
Dihydro-1,3-dioxo-1H-isoindole-
Triethylamine (93 mg) and chloromethyl pivalate (138 mg) were sequentially added to a solution of 5-carboxylic acid (300 mg) in DMF (2 ml) under ice cooling, followed by stirring at room temperature for 12 hours.
The reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purification was performed in 9) to give the title compound (309 mg). Table 43 shows the physical property values.

Example 170 Tert-butyl [2-{(S) -2-benzyloxy-1-phenylethyl} -2,3-dihydro-1,3-dioxo-1H-isoindol-4-yloxy] acetate Ester 2-[(S) -2-benzyloxy-1-phenylethyl] -4-hydroxy- obtained in the same manner as in Example 1.
Isoindole-1,3-dione (373 mg) and bromoacetic acid tert-butyl ester (390 mg) in DMF (5 mg)
ml) solution in ice-cooled 60% oily sodium hydride (48 ml).
mg) and stirred at room temperature for 14 hours. Reaction solution is 10
% Citric acid aqueous solution, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (481 mg). Table 43 shows the physical property values.
Shown in Examples 171 to 177 The compounds of Examples 171 to 177 were obtained in the same manner as in Example 170. Table 43-4
It is shown in FIG.

Example 178 4- (2-Aminoethoxy) -2-[(S) -2-benzyloxy-1-phenylethyl] isoindole-1,3-dione hydrochloride a) [2- {2- ((S) -2-benzyloxy-1-
Phenylethyl) -2,3-dihydro-1,3-dioxo-1H-isoindol-4-yloxydiethyl]
Carbamic acid tert-butyl ester (2-hydroxyethyl) in the same manner as in Example 162
Carbamic acid tert-butyl ester (177 mg),
Triphenylphosphine (289 mg) and 2-[(S) -2-benzyloxy-1 obtained in the same manner as in Example 1.
-Phenylethyl] -4-hydroxy-isoindole-1,3-dione (373 mg) in THF (3 ml) under ice-cooling was added diethyl azodicarboxylate (192 mg) in THF (3 mg).
ml) solution and stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane: chloroform = 1: 3:
Purification was performed in 2) to give the title compound (460 mg). b) 4- (2-aminoethoxy) -2-[(S) -2-
Benzyloxy-1-phenylethyl] isoindole-1,3-dione hydrochloride [2- {2-} obtained according to Example 178a).
((S) -2-benzyloxy-1-phenylethyl)
-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yloxydiethyl] carbamic acid t
A 4N hydrogen chloride-dioxane solution (6 ml) was added to ert-butyl ester (451 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and hexane was added to the residue for crystallization to obtain the title compound (354 mg). Table 45 shows the physical property values. Examples 179 to 181 The compounds of Examples 179 to 181 were obtained in the same manner as in Example 178. Tables 45-4
6 is shown.

Example 182 2-[(S) -2-cyclohexyloxy-1-phenylethyl] -5- (1H-
Tetrazol-5-ylmethoxy) isoindole-
1,3-dione a) [2-{(S) -2-cyclohexyloxy-1-
Phenylethyl {-2,3-dihydro-1,3-dioxo-1H-isoindol-5-yloxy) acetonitrile 2-[(S) -2-cyclohexyloxy-1- obtained in the same manner as in Example 75. Phenylethyl] -5-hydroxyisoindole-1,3-dione (1.0 g) was dissolved in methyl ethyl ketone (30 ml) in the same manner as in Example 169, and bromoacetonitrile (0.99 g) and potassium carbonate (0.38 g) were added. The mixture was heated under reflux for 2 hours. The reaction solution was added to 10% aqueous citric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (1.11 g). b) 2-[(S) -2-cyclohexyloxy-1-phenylethyl) -5- (1H-tetrazol-5-ylmethoxy) isoindole-1,3-dione Obtained in a) of Example 182 [ 2-{(S) -2-cyclohexyloxy-1-phenylethyl} -2,3-
Dihydro-1,3-dioxo-1H-isoindole-
5-yloxy) acetonitrile (101 mg) in DMF (5
ml) solution, ammonium chloride (40 mg) and sodium azide (49 mg) were added, and the mixture was stirred at 80 ° C for 22 hours. The reaction solution was added to 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (chloroform: methanol: acetic acid = 15).
0: 10: 1) to give the title compound (112 mg). Table 46 shows the physical property values.

Example 183 4-Amino-2-[(S)
-2-benzyloxy-1-phenylethyl] isoindole-1,3-dione 2-[(S) -2-benzyloxy-1-phenylethyl] -4-nitro obtained in the same manner as in Example 1. Isoindole-1,3-dione (402 mg) in ethanol (2 m
l) To the solution, add tin (II) chloride dihydrate (1.13g)
The mixture was heated under reflux for 3 hours. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (372 mg). Table 46 shows the physical property values. Example 184 Example 184 was performed in the same manner as in Example 183.
Was obtained. Table 46 shows the physical property values.

Examples 185 to 219 Examples 185 to 219 were obtained in the same manner as in Example 1 b) from commercially available reagents or amines obtained by a combination of the above-mentioned production methods, and from commercially available reagents or phthalimides obtained by a combination of the above-mentioned production methods. . The physical properties are shown in Tables 47 to 55. Examples 220 to 221 Examples 220 to 221 were obtained in the same manner as in Example 151. The physical properties are shown in Tables 55 to 56.

Example 222 (+)-2-[(R) -3
-Cyclohexyl-1-phenylpropyl] -2,3-
Dihydro-1,3-dioxo-1H-isoindole-
5-carboxylic acid tris (hydroxymethyl) aminomethane salt monohydrate 2-[(R) -3- obtained in the same manner as in Example 151
Cyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5
Tris (hydroxymethyl) aminomethane (50.1 g) was added to a solution of carboxylic acid (170 g) in ethyl acetate-ethanol-water (20: 2: 1), and the mixture was heated under reflux for 1 hour. After cooling, the obtained crystals were collected by filtration to give the title compound (194 g). Table 56 shows the physical property values.

Next, the compounds of the present invention were tested for their inhibitory effects on IgE production and IL-5 production. Test Example [I] In Vitro IgE Production Inhibition Test Balb / c mice (female, 7 weeks old) were sacrificed by decapitation, spleen cells were overlaid on Ficoll separation solution, and specific gravity separation was performed (rt 700 g, 30 min). The obtained mononuclear cells were treated with 2 mM
Wash with EDTA-PBS (-) solution, 10% FCS,
The cell concentration was adjusted to 1 × 10 ⁷ cells / ml with RPMI1640 containing 50 μM 2-ME. Anti-Thy1.2-magnetic
Beads were added and reacted in a refrigerator for 15 minutes. Magnetic
The cells were applied to a cell separetor (MACS), and non-adsorbed cells were collected. Prepare these cells at 1 × 10 ⁷ cells / ml,
Seed at × 10 ⁶ cells / 100 μl / well, LPS (Salmon
SIGMA from ella typhosa; final concentration 20 μg / ml) was added. 24 hours later, the test substance and IL-4 (Recombinan
t mouse IL-4, GIBCO BRL; final concentration 200 U / ml), and cultured for 7 days. All these operations were performed aseptically. After 7 days, the culture supernatant was subjected to IgE or IgM measurement ELI.
It was added to an SA plate, and the production amount was determined. Table 57 shows the results.
To 59.

Test Example [II] In Vivo IgE
Production inhibition test In Balb / c mice (female, 7 weeks old), 2,4-dinitrophen
alate (3 mg / m2) using ilate-Ascaris (10 μg) as antigen
Sensitization was performed in the abdomen together with l). Ten days after sensitization, blood was collected to separate serum. The test substance was 30 sensitized.
The administration was started 1 minute before and oral administration was performed once a day until 9 days later. The antibody titer in the obtained serum was measured by ELISA. The results are shown in Table 60 together with suplatast tosylate (Taiho Pharmaceutical) as a control compound.

Test Example [III] In vitro I
L-5 Production Inhibition Test Balb / c mice (female, 7 weeks old) were sacrificed by decapitation and their spleens were aseptically removed. 1 × 10 ⁷
cells / ml, seed at 1 × 10 ⁶ cells / 100 μl / well, add ConA (final concentration 2 μg / ml) and add 3-4 cells
Incubate for a day. The same cells were treated with ConA (final concentration 2 μg / m
l) and PMA (Phenylmercuric acetate, final concentration 5n)
g / ml). The test substance is added at the time of restimulation,
After 24 hours, the culture supernatant was collected, and IL-
The amount of 5 and the amount of IL-4 were measured. The results are shown in Table 61.

The following are formulation examples, but the formulation examples of the compound of the present invention are not limited thereto. Formulation Example (a) 10 g of the compound of Example 1 (b) lactose 50 g (c) corn starch 15 g (d) sodium carboxymethylcellulose 44 g (e) magnesium stearate 1 g (a), (b), (c) total amount and 30 g of (d) is kneaded with water, dried in vacuum, and then granulated. 14 at the end of this granulation
g (d) and 1 g (e) are mixed and made into tablets with a tableting machine to produce 1000 tablets each containing 10 mg of (a).

[0087]

As is clear from the above test results, the novel compounds of the present invention selectively inhibit IgE production and
L-5 production was selectively suppressed. These compounds are effective against immediate allergies and chronic allergies, and are useful antiallergic agents for preventing and treating allergies.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[Table 16]

[Table 17]

[Table 18]

[Table 19]

[Table 20]

[Table 21]

[Table 22]

[Table 23]

[Table 24]

[Table 25]

[Table 26]

[Table 27]

[Table 28]

[Table 29]

[Table 30]

[Table 31]

[Table 32]

[Table 33]

[Table 34]

[Table 35]

[Table 36]

[Table 37]

[Table 38]

[Table 39]

[Table 40]

[Table 41]

[Table 42]

[Table 43]

[Table 44]

[Table 45]

[Table 46]

[Table 47]

[Table 48]

[Table 49]

[Table 50]

[Table 51]

[Table 52]

[Table 53]

[Table 54]

[Table 55]

[Table 56]

[Table 57]

[Table 58]

[Table 59]

[Table 60]

[Table 61]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 401/04 209 C07D 401/04 209 401/06 209 401/06 209 401/12 209 401/12 209 405/12 209 405 / 12 209 409/06 209 409/06 209

Claims (14)

[Claims] 1. A compound of the general formula [I] [Wherein, R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxyl group, a lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted alkoxycarbonyl group, a carbamoyl group, A represents an alkylaminocarbonyl group, a carboxy group, an amino group, a nitro group or a halogen atom; A represents —CB ¹ — (wherein B ¹ represents a hydrogen atom, an optionally substituted lower alkyl group, a cycloalkyl group, Represents an aryl group, an aralkyl group, a heterocyclic group, a carboxy group or an aralkyloxyalkyl group which may be substituted) or a nitrogen atom; B represents a hydrogen atom, an optionally substituted lower alkyl group, a cycloalkyl group, It is aryl group, an aralkyl group, a heterocyclic group, a carboxy group or an aralkyloxy group, B, consequent B ¹ and a together Is alkyl or substituted may form a well heterocyclic; X is alkylene or 1 to 4 carbon atoms _{- (CONH) p - (CHR} 5) q - ( wherein, R ⁵ is a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group, p is an integer of 0 or 1, q represents an 0 or an integer of 1 to 2);. Y is oxygen atom, -NR ⁶ - (wherein, R ⁶
Is a hydrogen atom or a lower alkyl group. ) Or a sulfur atom;. Z is alkylene of 1 to 4 carbon atoms, alkenylene of 2 to 4 carbon atoms, -CHR ⁷ - (wherein, R ⁷ is a phenyl group), - CONH -, - CO- Or -SO ₂
Represents-; l, m and n each independently represent 0 or 1, and Cy represents an optionally substituted aryl group, an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group. ] The phthalimide derivative represented by these, or its pharmaceutically acceptable salt is contained as an active ingredient an IgE production inhibitor. 2. An IL-5 production inhibitor comprising, as an active ingredient, a phthalimide derivative represented by the general formula [I] or a pharmaceutically acceptable salt of the compound. 3. A compound of the general formula [II] (Wherein R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom, a hydroxyl group, a lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted alkoxycarbonyl group, a carbamoyl group, an alkylaminocarbonyl group , A carboxy group, an amino group, a nitro group or a halogen atom, provided that R ¹ ,
At least one of R ² , R ³ and R ⁴ is a substituent other than a hydrogen atom; A represents a carbon atom or a nitrogen atom; B ² is a cycloalkyl group, an optionally substituted aryl group, an aralkyl group or Y ¹ represents an oxygen atom, -NH
- or a sulfur atom; Z ¹ is an alkylene or -CHR ⁷ of 1 to 4 carbon atoms - indicates (wherein, R ⁷ is a phenyl group.); T is an integer of 0 or 1 to 4; m and n each independently represent 0 or 1; Cy represents an optionally substituted aryl group, an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group. Or a pharmaceutically acceptable salt thereof. Wherein R ^1, R ³ and R ⁴ are hydrogen atoms; R ²
Is an optionally substituted alkoxycarbonyl group, carbamoyl group, alkylaminocarbonyl group or carboxy group; A is a carbon atom; B ² is a cycloalkyl group, an optionally substituted aryl group or a heterocyclic group The phthalimide derivative according to claim 3, or a pharmaceutically acceptable salt thereof. 5. R ² is a carboxy group; B ² is a cycloalkyl group or an optionally substituted aryl group;
The phthalimide derivative or a pharmaceutically acceptable salt thereof according to claim 4, wherein ¹ is alkylene having 1 to 4 carbon atoms; Cy is an optionally substituted aryl group or an optionally substituted cycloalkyl group. 6. The phthalimide derivative or the pharmaceutically acceptable salt thereof according to claim 4, wherein Cy is an optionally substituted cycloalkyl group. 7. Y ¹ is —NH— or a sulfur atom;
Is 1 and Cy is an optionally substituted aryl group, or the phthalimide derivative or a pharmaceutically acceptable salt thereof according to claim 4 or 5. 8. The phthalimide derivative or the pharmaceutically acceptable salt thereof according to claim 4, wherein Z ¹ is alkylene having 2 to 4 carbon atoms, and m is 1. 9. The phthalimide derivative according to claim 6, wherein m is 0, or a pharmaceutically acceptable salt thereof. 10. [2-[(S) -2-benzyloxy-]
1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-
[(R) -2-cyclohexylmethyloxy-1-phenylethyl] isoindole-1,3-dione, 2-
[(S) -2-benzyloxy-1-phenylethyl]
-4-hydroxyisoindole-1,3-dione, 2
-[(R) -2-benzyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(S) -2-benzyloxy -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2-[(R) -2-benzyloxy-1 -Phenylethyl] -2,3-dihydro-1,3-dioxo-1H
-Isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2-[(S) -1-benzyl-2-benzyloxyethyl] -2,3-dihydro-
1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(S) -2-benzyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1
H-isoindole-4-carboxylic acid, 2-[(S)-
2-benzyloxy-1-phenylethyl] -5-hydroxyisoindole-1,3-dione, 2,3-dihydro-1,3-dioxo-1H-2-[(R) -1-phenyl-2- (2-pyridyloxy) ethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-
Dioxo-1H-2-[(S) -1-phenyl-2-picolyloxyethyl] isoindole-5-carboxylic acid, 2-[(S) -1-phenyl-2-picolyloxyethyl] isoindole -1,3-dione hydrochloride, 2
-[(S) -2-benzyloxy-1-phenylethyl] -4,5,6,7-tetrafluoroisoindole-1,3-dione, 2-[(S) -2-benzyloxy-1- Phenylethyl] -4-methoxyisoindole-1,3-dione, 2-[(S) -2- (4-methoxybenzyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo -1H-isoindole-5
-Carboxylic acid, 2-[(S) -2-cyclohexylmethyloxy-1-phenylethyl] -2,3-dihydro-
1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(S) -1-phenyl-2- (3-phenylpropyloxy) ethyl] -2,3-dihydro-1,
3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2-
[(S) -2- (4-methylsulfonylbenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-
2-[(S) -2- (4-methylbenzyloxy) -1
-Phenylethyl] isoindole-5-carboxylic acid,
2,3-dihydro-1,3-dioxo-1H-2-
[(S) -2- (3-methylbenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,
3-dihydro-1,3-dioxo-1H-2-[(S)
-2- (2-methylbenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2-[(S)
-2- (3,5-dimethylbenzyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-
1H-isoindole-5-carboxylic acid, 2-[(S)
-2- (2-cyclohexylethyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-
1H-isoindole-5-carboxylic acid, 2- (2-benzyloxy-1-cyclohexylethyl) -2,3-
Dihydro-1,3-dioxo-1H-isoindole-
5-carboxylic acid, 2-[(S) -2-cyclopentyloxy-1-phenylethyl] -2,3-dihydro-1,
3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(S) -2-cyclohexylmethyloxy-
1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2-[(S)
-Diphenylmethoxy-1-phenylethyl] -2,3
-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2-[(S) -1-naphthylmethoxy-1-
Phenylethyl] isoindole-5-carboxylic acid,
2,3-dihydro-1,3-dioxo-1H-2-
[(S) -2-naphthylmethoxy-1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2-[(S) -2- (2
-Methoxybenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2-[(S) -2-
(2-chlorobenzyloxy) -1-phenylethyl]
-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3
-Dioxo-1H-2-[(S) -2- (2,6-dimethylbenzyloxy) -1-phenylethyl] -isoindole-5-carboxylic acid, 2,3-dihydro-1,3
-Dioxo-2-[(S) -2-diphenylmethoxy-
1-phenylethyl] -1H-isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2,3-dihydro-1,3-dioxo-2-
[(S) -2-diphenylmethoxy-1-phenylethyl] -1H-isoindole-5-carboxylic acid N-methyl-D-gluconate, 2,3-dihydro-1,3-
Dioxo-1H-2-[(S) -2- (3-hydroxybenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2-[( R) -2-Diphenylmethoxy-1-phenylethyl) -1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2-
[(S) -2- (9-fluorenyl) -1-phenylethyl] -1H-isoindole-5-carboxylic acid, 2,
3-dihydro-1,3-dioxo-2-[(S) -2-
Diphenylmethoxy-1-benzylethyl] -1H-isoindole-5-carboxylic acid, 2-[(S) -2-
(2-chlorobenzyloxy) -1-phenylethyl]
2,3-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2,3-dihydro-1,3-dioxo-1H-2-[(S ) -2- (2-Fluorobenzyloxy) -1-phenylethyl] isoindole-5
-Carboxylic acid, 2,3-dihydro-1,3-dioxo-
1H-2-[(S) -2- (2-phenylbenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2-[(S) -2- (3-chlorobenzyloxy) -1 -Phenylethyl] -2,3-dihydro-1,
3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(S) -2- (4-chlorobenzyloxy)
-1-phenylethyl] -2,3-dihydro-1,3-
Dioxo-1H-isoindole-5-carboxylic acid, 2
-[(S) -2- (2,6-dichlorobenzyloxy)
-1-phenylethyl] -2,3-dihydro-1,3-
Dioxo-1H-isoindole-5-carboxylic acid, 2
-[(S) -2- (2-bromobenzyloxy) -1-
Phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-
Dihydro-1,3-dioxo-1H-2-[(S) -2
-(2-nitrobenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2-[(S)-
2- (2-cyanobenzyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-
1,3-dioxo-1H-2-[(S) -2- (2-trifluoromethylbenzyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2-[(R)-
2-cyclohexylmethyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2- [2-benzyloxy-1- (4-chlorophenyl) ethyl ] -2,3-
Dihydro-1,3-dioxo-1H-isoindole-
5-carboxylic acid, 2- [2-benzyloxy-1- (2
-Thienyl) ethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,
3-dihydro-1,3-dioxo-2-[(S) -2-
Diphenylmethyloxy-1-phenylethyl] -1H
-Isoindole-5-carboxylic acid sodium salt, 2
-[(S) -2-cyclohexylmethyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid sodium salt, 2-[(S) -2 -Benzyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H
-Isoindole-5-carboxylic acid sodium salt, 2
-[(S) -2-cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H
-Isoindole-5-carboxylic acid, 2-[(S) -1
-Benzyl-2-cyclohexyloxyethyl] isoindole-1,3-dione, 2-[(S) -2-cyclohexyl-1-phenyloxyethyl] -5-hydroxyisoindole-1,3-dione, 2- [(S) -1
-Benzyl-2-cyclohexyloxyethyl] -2,
3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(S) -2-cyclohexyloxy-1-phenylethyl] -2,3-dihydro-
1,3-dioxo-1H-isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2
-[(R) -2-cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H
-Isoindole-5-carboxylic acid, 2-[(S) -2
-Cyclohexyloxy-1-phenylethyl] -2,
3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid sodium salt, 2-[(S) -2
-Cyclohexyloxy-1-phenylethyl] -2,
3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid 1/2 calcium salt, 2-
[(S) -2-cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-
Isoindole-5-carboxylic acid potassium salt, 2-
[(R) -2-cyclohexyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-
Isoindole-5-carboxylic acid sodium salt, 2-
(1-phenyl-2-phenyloxyethyl) -2,3
-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-dibenzylmethyl-2,3-dihydro-1,3-dioxo-1H-isoindole-5
-Carboxylic acid, 2,3-dihydro-1,3-dioxo-
1H-2- [2- (4-methoxyphenyloxy) -1
-Phenylethyl] isoindole-5-carboxylic acid,
2- [2- (4-benzyloxyphenyloxy) -1
-Phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3
-Dihydro-1,3-dioxo-1H-2- [2- (4
-Hydroxyphenyloxy) -1-phenylethyl]
Isoindole-5-carboxylic acid, 2,3-dihydro-
1,3-dioxo-1H-2- [2- (2-methylphenyloxy) -1-phenylethyl] isoindole-
5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2- [2- (3-methylphenyloxy) -1
-Phenylethyl] isoindole-5-carboxylic acid,
2,3-dihydro-1,3-dioxo-1H-2- [2
-(4-methylphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2- [2- (4
-Chlorophenyloxy) -1-phenylethyl]-
2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2- [2- (3,5-dimethylphenyloxy) -1-phenylethyl] -2,3-
Dihydro-1,3-dioxo-1H-isoindole-
5-carboxylic acid, 2-[(S) -2- (3-tert-
Butylphenyloxy) -1-phenylethyl] -2,
3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2- [2- (3,5-di-tert-butylphenyloxy) -1-phenylethyl] -1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-
Dioxo-1H-2- [2- (3-methoxyphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2- [2- (4-tert-butylphenyloxy) -1-phenylethyl] -2,3-dihydro-
1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2
-[2- (3-isopropylphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,
3-dihydro-1,3-dioxo-1H-2- [2-
(4-Isopropylphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2- [2- (3,4-
Methylenedioxyphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2- [2-
(3,5-dimethoxyphenyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H
-Isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-1H-2- [2- (3,4,5-
[Trimethoxyoxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-
Dioxo-1H-2- [2- (3,4-dimethoxyoxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2-
[2- (4-ethylphenyloxy) -1-phenylethyl] -1H-isoindole-5-carboxylic acid, 2,
3-dihydro-1,3-dioxo-1H-2- [2-
(1-Naphthyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3
-Dioxo-1H-2- [2- (2-naphthyloxy)
-1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2- [2-
(3-ethylphenyloxy) -1-phenylethyl]
-1H-isoindole-5-carboxylic acid, 2- [2-
(3,4-Dimethylphenyloxy) -1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H-
Isoindole-5-carboxylic acid, 2,3-dihydro-
1,3-dioxo-1H-2- [2- (3,4,5-trimethylphenyloxy) -1-phenylethyl] isoindole-5-carboxylic acid, 2,3-dihydro-1,
3-dioxo-2- (1,4-diphenylbutyl) -1
H-isoindole-5-carboxylic acid, 2- (2-cyclohexyl-1-phenylethyl) -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro -1,3-dioxo-1H-
2- [N- (3-phenylpropyl) anilino] -isoindole-5-carboxylic acid, 2- [N- (2-cyclohexylethyl) anilino] -2,3-dihydro-1,
3-dioxo-1H-isoindole-5-carboxylic acid, 2- (2-benzylsulfanyl-1-phenylethyl) -2,3-dihydro-1,3-dioxo-1H-
Isoindole-5-carboxylic acid, 2,3-dihydro-
1,3-dioxo-2 [(S) -2-diphenylmethylamino-1-phenylethyl] -1H-isoindole-5-carboxylic acid, 2-[(R) -1-benzyl-2-
Morpholinoethyl] isoindole-1,3-dione,
2-[(R) -1-benzyl-2-morpholinoethyl]
-4-hydroxyisoindole-1,3-dione, 2
-[(S) -2-anilino-1-phenylethyl]-
2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(S)-(benzylcarbamoyl) phenylmethyl] -2,3-dihydro-
1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(S) -phenyl (phenylcarbamoyl) methyl] -2,3-dihydro-1,3-dioxo-
1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2-[(S)-(1,4-diphenylbutyl)]-1H-isoindole-5-carboxylic acid, -[(R) -3-cyclohexyl-1-phenylpropyl] isoindole-1,3-dione, 2
-[(R) -4-cyclohexyl-1-phenylbutyl] isoindole-1,3-dione, 2-[(S)-
3-cyclohexyl-1-phenylpropyl] isoindole-1,3-dione, 2-[(R) -1,4-diphenylbutyl] isoindole-1,3-dione, 2-
[(S) -1,4-diphenylbutyl] isoindole-1,3-dione, 2-[(R) -1,4-diphenylbutyl] -2,3-dihydro-1,3-dioxo-1H
-Isoindole-5-carboxylic acid, 2-[(R)-
1,4-diphenylbutyl] -2,3-dihydro-1,
3-dioxo-1H-isoindole-5-carboxylic acid sodium salt, 2-[(R) -3-cyclohexyl-1
-Phenylpropyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-
[(R) -4-cyclohexyl-1-phenylbutyl]
-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, 2-[(S) -2-cyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3- Dioxo-1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,3-dioxo-2-
[(R) -1,3-diphenylpropyl] -1H-isoindole-5-carboxylic acid, 2,3-dihydro-1,
3-dioxo-2-[(S) -1,3-diphenylpropyl] -1H-isoindole-5-carboxylic acid, 2-
[(R) -3-cyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid tris (hydroxymethyl) methylamine salt, 2-[(R ) -3-Cyclohexyl-1-phenylpropyl] -2,3-dihydro-
1,3-dioxo-1H-isoindole-5-carboxylic acid choline salt, 2-[(S) -2- (3,5-dimethylphenyloxy) -1-phenylethyl] -2,3-
Dihydro-1,3-dioxo-1H-isoindole-
5-carboxylic acid, 2-[(R) -2- (3,5-dimethylphenyloxy) -1-phenylethyl] -2,3-
Dihydro-1,3-dioxo-1H-isoindole-
5-carboxylic acid, 2-[(S) -2- (3,5-dimethylphenyloxy) -1-phenylethyl] isoindole-1,3-dione, 2-[(R) -2- (3, 5-
Dimethylphenyloxy) -1-phenylethyl] isoindole-1,3-dione, 2-[(S) -2-benzyloxy-1-phenylethyl] -2,3-dihydro-1,3-dioxo-1H -Isoindole-N-methyl-5-carboxamide, methyl 2-[(S) -2-
Benzyl-1-phenyloxyethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-
Carboxylate, 2-[(S) -2-benzyloxy-1-phenylethyl] -5-carbamoylisoindole-1,3-dione, ethoxyethyl 2-[(S)
-Cyclohexyloxy-1-phenylethyl] -2,
3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylate, ethyl 2-[(S) -cyclohexyloxy-1-phenylethyl] -2,3-
Dihydro-1,3-dioxo-1H-isoindole-
5-carboxylate, 2- (N, N-dimethylamino) ethyl 2-[(S) -cyclohexyloxy-1
-Phenylethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylate
Hydrochloride, pivaloyloxymethyl 2-[(S) -cyclohexyloxy-1-phenylethyl) -2,3-dihydro-1,3-dioxo-1H-isoindole-5
-Carboxylate, [2-{(S) -2-benzyloxy-1-phenylethyl} -2,3-dihydro-1,
3-dioxo-1H-isoindol-4-yloxy] acetic acid tert-butyl ester, [2-{(S)
-2-benzyloxy-1-phenylethyl} -2,3
-Dihydro-1,3-dioxo-1H-isoindol-5-yloxy] acetic acid tert-butyl ester;
4- [2- (tert-butyloxycarbonylamino) ethyloxy] -2-[(S) -2-benzyloxy-1-phenylethyl] isoindole-1,3-dione, 5- [2- (tert- [Butyloxycarbonylamino) ethyloxy] -2-[(S) -2-benzyloxy-1-phenylethyl] isoindole-1,3
-Dione, 5-cyanomethoxy-2-[(S) -2-cyclohexyloxy-1-phenylethyl] isoindole-1,3-dione, 2-[(S) -2-benzyloxy-1-phenylethyl ] -5-methoxyisoindole-1,3-dione, 2-[(S) -2-benzyloxy-1-phenylethyl] -4-pentyloxyisoindole-1,3-dione, 2-[(S ) -2-Benzyloxy-1-phenylethyl] -5-pentyloxyisoindole-1,3-dione, 4- (2-aminoethyloxy) -2-[(S) -2-benzyloxy-
1-phenylethyl] isoindole-1,3-dione hydrochloride, 5- (2-aminoethyloxy) -2-
[(S) -2-benzyloxy-1-phenylethyl]
Isoindole-1,3-dione hydrochloride, [2-
{(S) -2-benzyloxy-1-phenylethyl}
-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yloxy] acetic acid, [2-{(S) -2]
-Benzyloxy-1-phenylethyl} -2,3-dihydro-1,3-dioxo-1H-isoindole-5
-Yloxy] acetic acid, 2-[(S) -2-cyclohexyloxy-1-phenylethyl] -5- (1H-tetrazol-5-ylmethoxy) isoindole-1,3-
Dione, 2- (N, N-diphenylamino) isoindole-1,3-dione, 2- (N, N-diphenylamino) -4-hydroxy-isoindole-1,3-dione, 2-diphenylmethyliso Indole-1,3-dione, 2,3-dihydro-1,3-dioxo-2-diphenylmethyl-1H-isoindole-5-carboxylic acid, 2-[(R) -3- (trans-4-hydroxy Cyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5
Carboxylic acid, 2-[(R) -3- (cis-4-hydroxycyclohexyl-1-phenylpropyl] -2,3-
Dihydro-1,3-dioxo-1H-isoindole-
5-carboxylic acid and (+)-2-[(R) -3-cyclohexyl-1-phenylpropyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid tris (hydroxy Methyl) aminomethane salt
A compound selected from the group consisting of monohydrates or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition comprising the compound according to claim 3 or a pharmaceutically acceptable salt thereof as an active ingredient. 12. An IgE production inhibitor comprising the phthalimide derivative according to any one of claims 3 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient. 13. An IL-5 production inhibitor comprising the phthalimide derivative according to any one of claims 3 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient. 14. An antiallergic agent comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. [0001]