JP2002338537A - Amide compounds and their pharmaceutical uses - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a drug which selectively suppresses the production of IL-4, which is particularly involved in the pathogenesis and progression of allergic diseases, among cytokines produced from Th2 cells. Aim. SOLUTION: General formula (I) (Wherein, R ¹ represents halogen, alkyl, alkoxy or the like, ring Q represents benzene or a heteroaromatic ring which may have a substituent, R ² represents hydrogen, alkyl, or the like, Z represents CH or N, R ³ is halogen, cyano, nitro, amino, R ⁵ is alkyl, group: N (R ⁶ ) (R ⁷ ) (wherein R ⁶ and R ⁷ are the same or different and each represents hydrogen,
It represents an alkyl or the like, or a group in which R ⁶ and R ⁷ together with an adjacent nitrogen atom form a cyclic amine. And the like). Or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to interleukin-4 (hereinafter referred to as Th2 cytokine) produced by T cells sensitized with a foreign antigen or a self-antigen, in particular, type 2 helper T cells (hereinafter abbreviated as Th2 cells). A novel amide derivative having an action of selectively suppressing the production of IL-4), which is useful for the prevention and treatment of allergic diseases, and a pharmaceutically acceptable salt thereof.

2. Description of the Related Art International Publication WO00 / 47558 discloses an inhibitory effect on lymphocyte proliferation, in particular, IL-2, IL-4 and I.
Disclosed are compounds such as pyrazole-4-carboxamide derivatives which have L-7, IL-9, IL-13 or IL-15-dependent lymphocyte proliferation inhibitory activity and are useful as preventive and therapeutic agents for various immune diseases. I have.

[0005] Antigen-specific helper T cells sensitized by a foreign antigen or a self-antigen are capable of producing various cytokines having physiological activities that promote the division and proliferation and differentiation of effector T cells and B cells. Produces and elicits a specific immune response to the antigen. Unsensitized helper T cells are usually sensitized with antigen,
After differentiation into type 0 helper T cells (Th0 cells) capable of producing interleukin (IL) 2 (hereinafter, IL-2), two types of helper T cells that produce different cytokines, namely, 1 Type helper T cells (T
h1 cells) or type 2 helper T cells (Th2 cells)
It is known to differentiate into Th1 cells are IL-
Interferon-gamma (hereinafter referred to as IFN)
-Γ), produce cytokines such as tumor necrosis factor (hereinafter, TNF-α), and mainly promote cell-mediated immunity. On the other hand, Th2 cells are IL-4, IL-5, IL-6, IL-6
-10, producing cytokines such as IL-13 and promoting mainly humoral immunity, that is, antibody production. The immune response is regulated on a balance between Th1 and Th2 cells,
IFN-γ produced by Th1 cells promotes differentiation into Th1 cells and inhibits differentiation into Th2 cells. Also, T
IL-4 produced by h2 cells promotes differentiation into Th2 cells and inhibits differentiation into Th1 cells. In recent years, Th1
It has been revealed that various immune diseases are caused by the disruption of the balance of Th2 cells. Th2 cells are used in allergic diseases and systemic autoimmune diseases, and Th1 cells are used in organ-specific autoimmune diseases. Is reported to be in a superior state. Among the cytokines produced by Th2 cells, IL-4 has an action such as class switching to immunoglobulin E (IgE) and induction of differentiation into Th2 cells, and is particularly deeply involved in allergic pathogenesis. Has been suggested. actually,
High levels of IL-4 in the alveolar lavage fluid of asthmatic patients and mRN of IL-4 in the eruption of atopic dermatitis patients
It has been reported that the expression of A is enhanced.
Hyperactivity of h2 cells is thought to play an important role in the development and progression of these diseases (Am. J. R.
espir. Cell Mol. Biol. , Vol.
12, pp. 477-487, 1995; Imm
unol. , Vol. 158, pp. 3539-354
4 and J.I. Exp. Med. , Vol. 173, p
p. 775-778, 1991). In addition, since various allergic reactions are unlikely to occur in mice deficient in the IL-4 gene, I
It has been suggested that Th2 cells producing L-4 are deeply involved in the induction of allergic reactions (Nat).
ure, Vol. 362, pp. 245-247, 19
93 and J.M. Exp. Med. , Vol. 183, p
p. 195-201, 1996). From the above findings, it is considered that a drug which selectively suppresses IL-4 production from Th2 cells and suppresses an immune response involving Th2 cells in a patient with an allergic disease can be a useful antiallergic drug. Can be At present, steroids are widely used as remedies for allergic diseases and have shown high efficacy. Steroids have a strong anti-inflammatory effect, but also have an inhibitory effect on lymphocyte proliferation, an inhibitory effect on the production of cytokines, an inhibitory effect on the production of mediators such as leukotriene, and the like. However, steroids are known to exhibit serious side effects such as femoral head necrosis due to long-term continuous use or large doses due to their wide-ranging effects. It has become a challenge. The recently developed suplatast tosilate (IPD-1151T) is Th
It has an effect of selectively suppressing the production of IL-4 and IL-5 from two cells and is reported to be effective against asthma and atopic dermatitis (Clinical Medicine, Vol. 8, No. 7, 1992). However, IP
Since D-1151T is not potent in suppressing the production of IL-4 and IL-5 and exhibits an effect only at a high concentration, development of a drug having a stronger effect is expected. On the other hand, tacrolimus, which exerts an immunosuppressive action by inhibiting the calcineurin pathway, not only suppresses the production of IL-2 and IFN-γ from Th1 cells but also strongly suppresses the production of IL-4 from Th2 cells. However, it has been shown that, in addition to suppressing acute rejection, it is also effective against allergic diseases such as atopic dermatitis. However, tacrolimus not only has side effects such as neurotoxicity and nephrotoxicity, but also has
It is not selective for L-4 production and has a problem of susceptibility to infectivity because it suppresses the production of cytokines such as IL-2 widely. Therefore, it has a strong antiallergic effect equivalent to steroids or tacrolimus, etc.
In addition, at present, the emergence of therapeutic drugs for allergic diseases with few side effects is expected. IL from Th2 cells
A compound that strongly suppresses the production of Th2 cytokines such as -4 and has a weak inhibitory effect on the production of IL-2 and IFN-γ from Th1 cells, that is, a compound that selectively inhibits the production of Th2 cytokines, Allergic reactions such as atopic dermatitis, bronchial asthma, and allergic rhinitis, which can suppress the enhancement of cell-related immune responses and improve the bias of Th1 / Th2 balance and have fewer side effects compared to existing drugs It is expected that it can be a useful drug for prevention and treatment of diseases. An object of the present invention is to provide, among cytokines produced from Th2 cells,
In particular, it is an object of the present invention to provide a drug which selectively inhibits the production of IL-4 which is deeply involved in the pathogenesis and progress of allergic diseases.

[0002]

The present inventors have conducted intensive studies in view of the above situation, and as a result, have found that an amide compound represented by the following general formula or a pharmaceutically acceptable salt thereof is represented by the following formula:
The present inventors have found that the production of L-4 is selectively suppressed, and have completed the present invention. That is, the present invention is as follows. 1. General formula (I)

Embedded image (Wherein, R ¹ is halogen, alkyl, alkoxy, nitro, optionally substituted amino, hydroxy, optionally substituted aryl, optionally substituted arylalkyl A heteroaryl which may have a substituent, a heteroarylalkyl which may have a substituent, a cycloalkyl which may have a substituent or a cycloalkenyl which may have a substituent Ring Q is benzene which may have a substituent, cyclohexane which may have a substituent or a heteroaromatic ring which may have a substituent, wherein R ² is hydrogen, alkyl, hydroxyalkyl, acyloxyalkyl, aminoalkyl, .R ³ .Z is showing a CH or N indicating the hydroxycarbonylalkyl or alkoxycarbonylalkyl Ha Gen, cyano, nitro, amino, alkyl, alkoxy, carboxy, alkoxycarbonyl, carbamoyl, alkenyl, and .R ⁵ .R ⁴ showing the alkynyl or haloalkyl showing hydrogen, halogen, cyano or nitro, alkyl, hydroxyalkyl, hydroxy Carbonylalkyl, optionally substituted aminoalkyl, hydroxyl group, alkoxy, haloalkoxy, aryloxy, cycloalkyloxy, hydroxyalkoxy, hydroxycarbonylalkoxy, optionally substituted aminoalkoxy, mercapto, Alkylthio, hydroxyalkylthio, hydroxycarbonylalkylthio, aminoalkylthio optionally having substituent (s), group: O-Het (wherein Het is an oxygen atom which may have substituent (s)) Or to a saturated heterocyclic ring containing a hetero atom selected from a nitrogen atom) ^group:. N (in ^R 6) ^(R 7) ^(wherein, R 6, ^{R 7} are the same or different, are each hydrogen, alkyl, hydroxy Represents an alkyl or aminoalkyl, or R ⁶ and R ⁷ together with an adjacent nitrogen atom form one oxygen atom, sulfur atom, or nitrogen atom in the ring.
And a group forming a cyclic amine which may contain two or more. ) Or the expression

Embedded image (Wherein, R ⁸ represents hydrogen, halogen, alkyl, alkoxy, nitro, amino, or hydroxy; X represents ethylene ketal or propylene ketalized methylene; n represents 0, 1, or 2). Shows the group represented. Or a pharmaceutically acceptable salt thereof. 2. Ring Q is the following formula

Embedded image (Wherein R ¹¹ represents hydrogen, halogen, alkyl, alkoxy, nitro, amino, hydroxy, carboxyl or alkoxycarbonyl. R ¹² represents hydrogen, alkyl,
Represents alkoxycarbonylalkyl, hydroxycarbonylalkyl, acyloxyalkyl or hydroxyalkyl. ) The amide compound according to the above 1, which is benzene or a heteroaromatic ring represented by the formula: or a pharmaceutically acceptable salt thereof. Other symbols are as described in the above item 1. 3. The amide compound according to the above-mentioned 1, wherein Z represents CH, R ⁴ represents hydrogen, and R ³ is halogen, cyano, nitro or haloalkyl substituted at the 3-position of the phenyl group based on the anilide group, or a pharmaceutically acceptable salt thereof. Salt. Other symbols are as described in the above item 1. 4. Ring Q is the following formula

Embedded image (R ¹¹ represents hydrogen, halogen, alkyl, alkoxy, nitro, amino, hydroxy, carboxyl or alkoxycarbonyl). Z represents CH, R ² represents hydrogen or alkyl. And R ³ represents a halogen, cyano, nitro or haloalkyl substituted at the 3-position of the phenyl group based on the anilide group, and R ⁴ is hydrogen, or a pharmaceutically acceptable salt thereof. . Other symbols are the same as those in the above 1, except that R ⁵ is substituted at the 4-position of the phenyl group based on the anilide group. 5. Ring Q is the following formula

Embedded image (Wherein R ¹¹ represents hydrogen, halogen, alkyl, alkoxy, nitro, amino, hydroxy, carboxyl or alkoxycarbonyl), Z represents CH, R ² represents hydrogen or alkyl, and R ³ represents A halogen substituted on the 3-position of the phenyl group based on the anilide group,
2. The amide compound according to the above 1, wherein the amide compound represents cyano, nitro or haloalkyl, and R ⁴ is hydrogen, or a pharmaceutically acceptable salt thereof. Other symbols are the same as those in the above 1, except that R ⁵ is substituted at the 4-position of the phenyl group based on the anilide group. 6. R ⁵ group: In N (R ⁶ ) (R ⁷ ), R ⁶ ,
A group in which R ⁷ together with an adjacent nitrogen atom forms a cyclic amine which may contain one or two oxygen atoms, sulfur atoms and nitrogen atoms in the ring is represented by the formula:

Embedded image (Wherein, R ^8a represents hydrogen, halogen, alkyl, alkoxy, nitro, amino or hydroxy. Y is CH
_2, ^{CH-R 9} or an N-R ^10,. m represents 0, 1 or 2. Where R ⁹ is hydroxy, alkyl,
Represents hydroxyalkyl, 4-piperidinyl or morpholino; R ¹⁰ represents hydrogen, alkyl, hydroxyalkyl, 4-piperidinyl or 3,4,5,6-tetrahydro-2H-pyran-4-yl; ) The amide compound according to the above 1, which is a group represented by the formula: or a pharmaceutically acceptable salt thereof. 7. (1) N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] -4-iodobenzamide, (2) 4- (4-chlorophenyl) -N- [3-cyano-4 -(4-hydroxypiperidin-1-yl) phenyl] benzamide, (3) N- [3-cyano-4-
(4-hydroxypiperidin-1-yl) phenyl]-
3-iodobenzamide, (4) 3- (4-chlorophenyl) -N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] benzamide, (5) 5-
(4-chlorophenyl) -N- [3-cyano-4- (4
-Hydroxypiperidin-1-yl) phenyl] furan-2-carboxamide, (6) 5- (4-chlorophenyl) -N- [3-cyano-4- (2,2-dimethyl-3)
-Hydroxypropoxy) phenyl] furan-2-carboxamide, (7) 5- (4-chlorophenyl) -N-
[2- (4-hydroxypiperidin-1-yl) pyridin-5-yl] furan-2-carboxamide, (8) 5
-(4-chlorophenyl) -N- [3-cyano-4-
(4-morpholinopiperidin-1-yl) phenyl] furan-2-carboxamide, (9) 5- (4-chlorophenyl) -N- [3-cyano-4- [4- (3,4,
5,6-tetrahydro-2H-pyran-4-yl) piperazin-1-yl] phenyl] furan-2-carboxamide, (10) 5- (4-chlorophenyl) -N- (3
-Cyano-4-piperidinophenyl) furan-2-carboxamide, (11) 5- (4-chlorophenyl) -N
-[3-Cyano-4- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) phenyl] furan-2
-Carboxamide, (12) 5- (4-chloro-2-nitrophenyl) -N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] furan-2-carboxamide, (13) 5 -(4-chlorophenyl)-
N- [3-cyano-4- (4-hydroxypiperidine-
1-yl) phenyl] thiophen-2-carboxamide, (14) N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] -5- (1-cyclohexenyl) thiophen-2-carboxamide , (1
5) 4- (4-chlorophenyl) -N- [3-cyano-
4- (4-hydroxypiperidin-1-yl) phenyl] thiazole-2-carboxamide, (16) 5-
(4-chlorophenyl) -N- [3-cyano-4- (4
-Hydroxypiperidin-1-yl) phenyl] oxazole-2-carboxamide, (17) 3- (4-chlorophenyl) -N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] -5 -Ethoxycarbonylbenzamide, (18) 3- (4-chlorophenyl) -5-{[3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] aminocarbonyl} benzoic acid, (19) 5- (4-chlorophenyl) -N- [3
-Cyano-4- (4-hydroxypiperidin-1-yl) phenyl] nicotinamide, (20) 6- (4-chlorophenyl) -N- [3-cyano-4- (4-hydroxypiperidin-1-yl) Phenyl] pyridine-2-
Carboxamide, (21) N- [3-cyano-4- (4
-Hydroxypiperidin-1-yl) phenyl] -4-
The amide compound according to the above 1, which is selected from cyclohexylbenzamide, (22) N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] -4- (1-pyrrolo) benzamide, or a medicament thereof Above acceptable salts. 8. A pharmaceutical composition comprising the amide compound or the pharmaceutically acceptable salt thereof according to the above 1, and a pharmaceutically acceptable carrier. 9. A medicament comprising the amide compound of the above-mentioned 1 or a pharmaceutically acceptable salt thereof. 10. 2. An inhibitor of cytokine production from activated lymphocytes, comprising the amide compound or the pharmaceutically acceptable salt thereof according to the above 1. 11. 2. A selective inhibitor for the production of interleukin-4 from T helper type 2 cells, comprising the amide compound or the pharmaceutically acceptable salt thereof according to the above 1. 12. A preventive or therapeutic agent for an allergic disease, comprising the amide compound or the pharmaceutically acceptable salt thereof according to the above 1. 13. A prophylactic or therapeutic agent for atopic dermatitis, asthma, or allergic rhinitis, comprising the amide compound or the pharmaceutically acceptable salt thereof according to the above 1. 14． A combination composition comprising the amide compound or a pharmaceutically acceptable salt thereof according to the above 1, and one or more drugs selected from immunosuppressants, steroids and antiallergic drugs. 15. 15. The combination composition according to the above 14, wherein the immunosuppressant is selected from tacrolimus hydrate, ascomycin and FTY720. 16. Steroids are prednisolone, methylprednisolone, dexamethasone, hydrocortisone, clobetasone, flumethasone, triamcinolone acetonide,
Alclomethasone, fluorosinolone acetonide, beclomethasone, betamethasone, deprodone, halcinonide, amcinonide, fluocinonide, diflucortron, budesonide, difluperednate, diflorazone,
15. The combination composition according to the above 14, wherein the composition is selected from clobetasol and fatty acid esters thereof. 17． Anti-allergic agent is sodium cromoglycate,
Tranilast, Amlexanox, Repirinast, Ibudilast, Tazanolast, Pemirolast, Ozagrel,
Splatast, pranlukast, ketotifen, azelastine, oxatomide, mequitazine, terfenadine,
15. The combination composition according to the above 14, wherein the composition is selected from emedastine, epinastine, astemizole, and various antihistamines. 18. An action enhancer comprising the amide compound or the pharmaceutically acceptable salt thereof according to the above 1, and one or more drugs selected from immunosuppressants, steroids and antiallergic agents. 19. 19. The effect enhancer according to the above 18, wherein the immunosuppressant is selected from tacrolimus hydrate, ascomycin and FTY720. 20. Steroids are prednisolone, methylprednisolone, dexamethasone, hydrocortisone, clobetasone, flumethasone, triamcinolone acetonide,
Alclomethasone, fluorosinolone acetonide, beclomethasone, betamethasone, deprodone, halcinonide, amcinonide, fluocinonide, diflucortron, budesonide, difluperednate, diflorazone,
19. The action enhancer according to the above 18, which is selected from clobetasol and fatty acid esters thereof. 21. Anti-allergic agent is sodium cromoglycate,
Tranilast, Amlexanox, Repirinast, Ibudilast, Tazanolast, Pemirolast, Ozagrel,
Splatast, pranlukast, ketotifen, azelastine, oxatomide, mequitazine, terfenadine,
19. The action enhancer according to the above 18, which is selected from emedastine, epinastine, astemizor and various antihistamine drugs.

[0003]

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to antigen-sensitized Th
Focusing on IL-4, which is produced from two cells and also promotes the induction of differentiation into Th2 cells, to provide a synthetic low-molecular compound having an action of selectively suppressing IL-4 production from Th2 cells And Here, the background of the selective inhibitory action on IL-4 production is based on the transcription factors NFAT, c-Maf, NIP45, and GAT that regulate transcription of IL-4.
The presence of A-3 and JunB also includes suppression of pathways involving these transcription factors. Furthermore, it suppresses the proliferation and differentiation induction of Th2 cells through suppression of IL-4 production, and improves the bias of the Th2 cells toward the immune response involved.
-4 In addition to suppressing production, I2 produced from Th2 cells
The present invention also includes providing a compound that also suppresses the production of Th2 cytokines such as L-5, IL-6, and IL-13.

[0004] The substituents represented by each symbol in the present specification are described below. The halogen in R ¹ is
Indicates fluorine, chlorine, bromine and iodine. The alkyl in R ¹ is a linear or branched alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl. Methyl. The alkoxy in R ¹ is a linear or branched alkoxy having 1 to 4 carbon atoms, and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy and the like. The optionally substituted amino in R ¹ includes alkyl having 1 to 4 carbons (as defined above), acyl having 1 to 4 carbons (formyl, acetyl, propionyl, etc.) and It may be mono- or di-substituted by a substituent selected from benzoyl, and specific examples include amino, methylamino, dimethylamino, ethylamino, diethylamino, formylamino, acetylamino, propionylamino and benzoylamino. The aryl optionally having a substituent in R ¹ represents phenyl, naphthyl, or the like, and halogen (fluorine, chlorine, bromine, iodine), alkyl having 1 to 4 carbons (methyl, ethyl, Propyl, isopropyl, butyl, etc.), alkoxy having 1 to 4 carbon atoms (methoxy, ethoxy, propoxy, isopropoxy,
Butoxy), cyano, nitro, carboxy, alkylene dioxy having 1 to 4 carbon atoms (such as methylenedioxy, ethylenedioxy, propylenedioxy, 1,1-dimethylmethylenedioxy) and 1 to 4 carbon atoms May have 1 to 3 groups selected from haloalkyl (such as fluoromethyl, chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl), and preferred substituents are halogen, alkyl, and alkoxy. , Haloalkyl, alkylenedioxy and nitro. Specific examples of the substituted aryl include 4-chlorophenyl, 3-
Chlorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 4-cyanophenyl, 4-carboxyphenyl, 4-trifluoromethylphenyl, 3-triphenyl Fluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 4-nitrophenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl and the like can be mentioned. The arylalkyl which may have a substituent in R ¹ is an aryl (phenyl, naphthyl, or the like) substituted with an alkyl having 1 to 4 carbon atoms, for example, phenylmethyl, 2-phenylethyl, 1-phenylethyl, 3-
Phenylpropyl, 4-phenylbutyl and the like. Examples of the substituent include the same substituents as the above-mentioned aryl. The optionally substituted heteroaryl for R ¹ is a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, Alkyl having 1 to 4 carbon atoms, halogen (such as fluorine, chlorine, and bromine) may be substituted as a group, for example, pyrimidyl, 4,6-dimethylpyrimidyl, pyridazinyl, 6-
Chloropyridazinyl, thienyl, 5-methylthienyl,
5-chlorothienyl, pyridyl and the like. R ¹
The optionally substituted heteroarylalkyl in the above is a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (as defined above). Substituted with alkyl having 1 to 4 carbon atoms, such as 2-thienylmethyl, 2- (2-thienyl) ethyl, 3- (2-thienyl) propyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl and the like. Examples of the substituent on the heteroaryl include the same substituents as those described above for the heteroaryl. The optionally substituted cycloalkyl in R ¹ is cycloalkyl having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the substituent include the same substituents as the above-mentioned aryl. The optionally substituted cycloalkenyl in R ¹ is cycloalkenyl having 3 to 6 carbon atoms, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. Examples of the substituent include the same substituents as the above-mentioned aryl.

The optionally substituted heteroaromatic ring in ring Q is a 5- or 6-membered aromatic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen. And for example, pyridine, pyrazine,
Pyridazine, furan, thiophene, oxazole, thiazole, imidazole and the like, and alkyl having 1 to 4 carbons as a substituent, halogen (fluorine, chlorine,
And the like may be substituted. Benzene and cyclohexane in the ring Q can have the same substituents as the above-mentioned heteroaromatic ring.

The alkyl in R ² is a linear or branched alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like, preferably methyl, ethyl It is. R
The hydroxyalkyl in ² is an alkyl having 1 to 4 carbon atoms (as defined above) substituted with a hydroxyl group, and examples thereof include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and 4-hydroxybutyl. Is raised. The acyloxyalkyl in R ² and R ¹² is the alkyl having 1 to 4 carbons (as defined above) substituted with an acyloxy having 1 to 4 carbons (formyloxy, acetyloxy, propionyloxy, butyryloxy, etc.). And specific examples include formyloxymethyl, 2-formyloxyethyl, acetyloxymethyl, 2-acetyloxyethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, propionyloxymethyl, and the like. 2-acetyloxyethyl. The aminoalkyl in R ² is alkyl having 1 to 4 carbon atoms (as defined above) substituted with an amino group, and examples thereof include aminomethyl, aminoethyl, dimethylaminomethyl, and diethylaminomethyl. The Hydroxycarbonylalkyl in R ^2, R ^12, it is those hydroxycarbonyl is substituted 1 -C 4 alkyl (as defined above), for example, hydroxycarbonyl, 2- hydroxycarbonylethyl, 3 Examples include hydroxycarbonylpropyl, 4-hydroxycarbonylbutyl and the like, and preferred are hydroxycarbonylmethyl and 3-hydroxycarbonylpropyl. R ² ,
The alkoxycarbonylalkyl for R ¹² is an alkyl having 1 to 4 carbons (as defined above) substituted with an alkoxycarbonyl having 1 to 4 carbons (as defined above). Methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl and the like are preferable, and ethoxycarbonylmethyl is preferable.

The halogen in R ³ represents fluorine, chlorine, bromine and iodine, preferably chlorine and bromine. The alkyl in R ³ represents a linear or branched alkyl having 1 to 6 carbon atoms, for example, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, etc. are preferred, and alkyl having 1 to 3 carbon atoms is preferred, and methyl is particularly preferred. The alkoxy in R ³ represents a straight-chain or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
Tertiary butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like can be mentioned, among which alkoxy having 1 to 3 carbon atoms is preferable.
The alkenyl in R ³ is a linear or branched alkenyl having 2 to 4 carbon atoms, for example, ethenyl,
Examples thereof include 1-propenyl and 1-butenyl, and ethenyl is particularly preferable. The haloalkyl for R ³ is a straight-chain or branched haloalkyl having 1 to 4 carbon atoms, for example, fluoromethyl, chloromethyl, bromomethyl, trifluoromethyl, 2-fluoroethyl, 2-fluoroethyl,
Chloromethyl, 2,2,2-trifluoroethyl and the like can be mentioned, and trifluoromethyl is particularly preferable. The alkoxycarbonyl in R ³ represents an alkoxycarbonyl having 1 to 4 carbon atoms (as defined above), such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl and the like. Is raised. The alkynyl for R ³ is a linear or branched alkynyl having 1 to 4 carbon atoms, for example, ethynyl, 1-propynyl, 1-butynyl and the like.
Particularly, ethynyl is preferable.

[0008] The halogen in R ⁴ represents fluorine, chlorine, bromine or iodine, preferably chlorine. R ⁵
The alkyl in the above is a linear or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl,
Hexyl, isohexyl, neohexyl and the like can be mentioned, and among them, alkyl having 4 to 6 carbon atoms is preferable. R
The hydroxyalkyl in ⁵ is a straight-chain or branched-chain alkyl having 1 to 4 carbon atoms (as defined above) substituted with a hydroxyl group. Examples thereof include hydroxymethyl, 2-hydroxyethyl, and 3-hydroxyalkyl. Hydroxypropyl,
4-hydroxybutyl and the like. The hydroxycarbonylalkyl for R ⁵ is an alkyl having 1 to 4 carbon atoms (as defined above) substituted with hydroxycarbonyl, for example, hydroxycarbonylmethyl, 2-hydroxycarbonylethyl, 3-hydroxycarbonylpropyl , 4-hydroxycarbonylbutyl and the like. The optionally substituted aminoalkyl for R ⁵ is an alkyl having 1 to 4 carbons (as defined above) substituted with an amino group,
The amino group may be mono- or di-substituted as a substituent by an alkyl having 1 to 4 carbons (as defined above), an acyl having 1 to 4 carbons (as defined above), or benzoyl. Include aminomethyl, 2-aminoethyl, dimethylaminomethyl, 2-diethylaminomethyl, formylaminomethyl, acetylaminomethyl,
-Formylaminoethyl, 2-acetylaminoethyl,
Benzoylaminomethyl and the like. The amino group may form a cyclic amine which may contain one or two oxygen atoms, sulfur atoms and nitrogen atoms in the ring, such as pyrrolidine and piperidine which may have a substituent. , Homopiperidine, piperazine optionally having a substituent, homopiperazine optionally having a substituent,
And morpholine and thiomorpholine. Specifically, piperidinomethyl, 2-piperidinoethyl,
Morpholinomethyl, 2-morpholinoethyl, thiomorpholinomethyl, piperazinomethyl, (4-morpholinopiperidin-1-yl) methyl and the like.

The alkoxy in R ⁵ is a linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy,
Butoxy, isobutoxy, tertiary butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy, neohexyloxy and the like, among which alkoxy having 4 to 6 carbon atoms is preferable. The haloalkoxy for R ⁵ is an alkoxy having 1 to 4 carbon atoms (as defined above) substituted with a halogen (as defined above), and examples thereof include fluoromethoxy, chloromethoxy, 2-fluoroethoxy,
Examples thereof include 2,2-trifluoroethoxy, and preferably 2,2,2-trifluoroethoxy. The aryloxy for R ⁵ includes phenyloxy, naphthyloxy and the like, with phenyloxy being preferred.

The cycloalkyloxy for R ⁵ is
Cycloalkyloxy having 3 to 6 carbon atoms, for example, cyclopentyloxy, cyclohexyloxy and the like, with cyclohexyloxy being preferred. The hydroxyalkoxy in R ^5, be one hydroxy-substituted C 3 -C 6 straight-chain or branched alkoxy, for example, 3-hydroxypropoxy, 1
-Methyl-1-hydroxyethoxy, 4-hydroxybutoxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy. The hydroxycarbonyl alkoxycarbonyl in R ^5, be one hydroxycarbonyl is substituted 1 -C 4 straight-chain or branched alkoxy, for example, hydroxycarbonyl methoxy, 2-hydroxycarbonyl-ethoxy, 3-hydroxy Carbonylpropoxy and 4-hydroxycarbonylbutoxy.

The optionally substituted aminoalkoxy in R ⁵ is a straight-chain or branched-chain alkoxy having 1 to 6 carbon atoms (as defined above) substituted with amino, The amino group may have as substituents alkyl having 1 to 4 carbons (as defined above), acyl having 1 to 4 carbons (as defined above), and benzoyl. The amino group may form a cyclic amine which may contain one or two oxygen atoms, sulfur atoms and nitrogen atoms in the ring, for example, pyrrolidine and piperidine which may have a substituent. , Homopiperidine, optionally substituted piperazine, optionally substituted homopiperazine, morpholine and thiomorpholine. Specifically, aminomethoxy, aminoethoxy,
Aminopropoxy, methylaminomethoxy, dimethylaminomethoxy, 2-dimethylaminoethoxy, formylaminomethoxy, acetylaminomethoxy, propionylaminomethoxy, benzoylaminomethoxy, morpholinomethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2,2- Dimethyl-3-morpholinopropoxy, 4-morpholinobutoxy, 5-morpholinopentyloxy, 6-morpholinohexyloxy, thiomorpholinomethoxy, 2-thiomorpholinoethoxy, 3-thiomorpholinopropoxy, 2,2-dimethyl-3-thiomorpholino Propoxy, 4-thiomorpholinobutoxy,
5-thiomorpholinopentyloxy, 6-thiomorpholinohexyloxy, piperidinomethoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2,2-dimethyl-3-piperidinopropoxy, 4-piperidi Nobutoxy, 5-piperidinopentyloxy, 6-piperidinohexyloxy, piperazinomethoxy, 2-piperazinoethoxy, 3-piperazinopropoxy, 2,2-dimethyl-3-piperazinopropoxy , 4-piperazinobutoxy, 5-piperazinopentyloxy, 6-piperazinohexyloxy, 2-pyrrolidinoethoxy, 3-pyrrolidinopropoxy and the like. Of these, 2-dimethylaminoethoxy, 4-morpholinobutoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, morpholinomethoxy, and 2,2-dimethyl-3-morpholinopropoxy are preferred.

The alkylthio represented by R ⁵ has an alkyl moiety having 1 to 6 carbon atoms and includes, for example, methylthio, ethylthio, propylthio, n-butylthio, pentylthio, neopentylthio, hexylthio and the like. The hydroxyalkylthio represented by R ⁵ has an alkyl moiety of 1 to 6 carbon atoms and includes, for example, hydroxymethylthio, 2-hydroxyethylthio, 3-hydroxypropylthio, 4-hydroxybutylthio, 5-hydroxypentylthio, -Hydroxyhexylthio. The hydroxycarbonylalkylthio in R ⁵ has 1 to 4 carbon atoms in the alkyl moiety and includes, for example, hydroxycarbonylmethylthio, 2-hydroxycarbonylethylthio, 3-hydroxycarbonylpropylthio, and 4-hydroxycarbonylbutylthio. .

The optionally substituted aminoalkylthio in R ⁵ is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms (as defined above). And alkyl having 1 to 4 carbons (as defined above), acyl having 1 to 4 carbons (as defined above) and benzoyl may be substituted as substituents. The amino group may form a cyclic amine which may contain one or two oxygen atoms, sulfur atoms and nitrogen atoms in the ring, for example, pyrrolidine and piperidine which may have a substituent. , Homopiperidine, optionally substituted piperazine, optionally substituted homopiperazine, morpholine and thiomorpholine. Specifically, aminomethylthio, 2-aminoethylthio, 3-aminopropylthio, 4-aminobutylthio,
Dimethylaminomethylthio, diethylaminomethylthio, 2-dimethylaminoethylthio, 3-dimethylaminopropylthio, 4-dimethylaminobutylthio, etc.
Formylaminomethylthio, 2-formylaminoethylthio, acetylaminomethylthio, 2-acetylaminoethylthio, benzoylaminomethylthio, 2-benzoylaminoethylthio, morpholinomethylthio, 2-morpholinoethylthio, 3-morpholinopropylthio,
-Morpholinobutylthio, 5-morpholinopentylthio, 6-morpholinohexylthio, thiomorpholinomethylthio, 2-thiomorpholinoethylthio, 3-thiomorpholinopropylthio, 4-thiomorpholinobutylthio,
5-thiomorpholinopentylthio, 6-thiomorpholinohexylthio, piperidinomethylthio, 2-piperidinoethylthio, 3-piperidinopropylthio, 4-piperidinobutylthio, 5-piperidinopentylthio , 6-piperidinohexylthio, piperazinomethylthio, 2-piperazinoethylthio, 3-piperazinopropylthio,
-Piperazinobutylthio, 5-piperazinopentylthio, 6-piperazinohexylthio, 2-pyrrolidinoethylthio, 3-pyrrolidinopropylthio. R
The alkyl in R ⁶ and R ⁷ is alkyl having 1 to 4 carbon atoms (as defined above), and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl. Is ethyl.

The hydroxyalkyl represented by R ⁶ and R ⁷ is a C 1 to C 4 alkyl (as defined above) substituted by a hydroxyl group. Examples thereof include hydroxymethyl, 2-hydroxyethyl, and 3-hydroxyethyl. Propyl,
4-hydroxybutyl and the like, preferably 2-
Hydroxyethyl. Aminoalkyl in R ⁶ and R ⁷ is alkyl having 1 to 4 carbons (as defined above).
Wherein the amino group is substituted by alkyl having 1 to 4 carbons (as defined above), acyl having 1 to 4 carbons (as defined above), and benzoyl. More specifically, specific examples include aminomethyl, aminoethyl, dimethylaminomethyl, diethylaminomethyl, formylaminomethyl, 2-formylaminoethyl, acetylaminomethyl, 2-acetylaminoethyl, benzoylaminomethyl and the like. R ⁶ ,
The group which forms a cyclic amine optionally containing one or two oxygen atoms, sulfur atoms and nitrogen atoms in the ring together with an adjacent nitrogen atom in R ⁷ includes pyrrolidine and a substituent. A cyclic amine selected from piperidine which may be substituted, homopiperidine, piperazine which may have a substituent, homopiperazine which may have a substituent, morpholine and thiomorpholine.

The substituents of the above-mentioned optionally substituted piperidine include hydroxy; carboxy; alkoxycarbonyl having 1 to 4 carbon atoms as defined above; and alkoxycarbonyl having 1 to 4 carbon atoms; Hydroxyalkyl (as defined above); alkoxyalkoxy having 1 to 4 carbon atoms (methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 4-methoxybutoxy, etc.); Carboxyalkylcarbonyloxy having 1 to 4 carbon atoms (carboxymethylcarbonyloxy, 2-carboxyethylcarbonyloxy, etc.); acyloxy having 1 to 4 carbon atoms (as defined above); benzoyloxy; phenyl; 1 to 4 alkylene dioxo (Methylenedioxy, ethylenedioxy, etc.); oxo; an alkyl having 1 to 4 carbons (as defined above), an alkoxy moiety and an alkoxyalkyl having an alkyl moiety having 1 to 4 carbons, respectively (methoxymethyl, ethoxymethyl, Amino which may be mono- or di-substituted by 2-methoxyethyl, 2-ethoxyethyl or the like or hydroxyalkyl having 1 to 4 carbons (as defined above); substituents (hydroxy, 1 to 4 carbons) Piperidine, morpholine, thiomorpholine, and a substituent (having 1 to 1 carbon atoms) which may have an alkoxy, oxo, etc.
A cyclic amine selected from piperazine and the like which may have 4 alkyls, 1 to 4 carbon acyls and the like (the cyclic amine may be an N-oxide);
And morpholinomethyl. Specifically, piperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-carboxypiperidin-1-yl, 4-methoxycarbonylpiperidin-1-yl, 4-ethoxycarbonylpiperidin-1-yl, ((2-carboxyethyl) carbonyloxy) piperidin-1-yl, 4
-Benzoyloxypiperidin-1-yl, 4-piperidinopiperidin-1-yl, 4-morpholinopiperidin-1-yl, 4-thiomorpholinopiperidin-1-yl, 4- (N-oxidemorpholino) piperidin-1 −
Yl, 4,4-ethylenedioxypiperidin-1-yl, 4-oxopiperidin-1-yl, 4-aminopiperidin-1-yl, 4-dimethylaminopiperidin-1
-Yl, 4- (N- (2-hydroxyethyl) amino)
Piperidin-1-yl, 4- (N, N-bis (2-hydroxyethyl) amino) piperidin-1-yl, 4-
(N- (2-hydroxyethyl) -N-methylamino)
Piperidin-1-yl, 4- (4-methylpiperazine-
1-yl) piperidin-1-yl, 4- (N- (2-hydroxyethyl) amino) piperidin-1-yl, 4-
(Piperazin-1-yl) piperidin-1-yl, 4-
(4- (4-acetylpiperazin-1-yl) piperidin) -1-yl, 4-phenylpiperidin-1-yl,
4- (N- (2-methoxyethyl) amino) piperidin-1-yl, 4- (N- (2-methoxyethyl) -N-
Methylamino) piperidin-1-yl, 4- (N, N-
Bis (2-methoxyethyl) amino) piperidine-1-
Yl, 4-methoxymethoxypiperidin-1-yl, 4
-(2-methoxyethyl) oxypiperidin-1-yl, 4- (2-hydroxyethyl) piperidin-1-yl, 4- (4-hydroxypiperidin-1-yl) piperidin-1-yl, 4- (4 -Morpholinomethyl) piperidin-1-yl, 4- (4-methoxypiperidine-1
-Yl) piperidin-1-yl, 4- (4-oxopiperidin-1-yl) piperidin-1-yl and the like.

The substituent in the above-mentioned piperazine which may have a substituent is alkyl having 1 to 4 carbons (as defined above); carboxyalkyl having an alkyl moiety having 1 to 4 carbons (carboxylmethyl). , Carboxyethyl, etc.); hydroxyalkyl having 1 to 4 carbon atoms (as defined above);
4 alkoxyalkyls (as defined above); an alkoxy moiety and an alkyl moiety each having 1 to 4 carbon atoms; hydroxyalkoxyalkyl (such as hydroxymethoxymethyl, hydroxyethoxyethyl); carboxy; an alkoxy moiety having 1 to 4 carbon atoms An alkoxycarbonyl (as defined above); an alkoxy moiety and an alkyl moiety each having 1 to 4 carbon atoms (as defined above); an acyl having 1 to 4 carbons (as defined above); an acyl moiety and an alkyl An acyloxyalkyl having 1 to 4 carbon atoms (as defined above); an aminoalkyl having 1 to 4 carbon atoms which may have a substituent (as defined above); an alkyl moiety having 1 to 4 carbon atoms Carboxyalkylcarbonyloxy (carboxymethylcarbonyloxy, (2-car Kishiechiru) carbonyloxy, etc.); heteroaralkyl (pyridyl 1 -C 4 alkyl, those thienyl, heteroaryl such as furyl and substituted), a halogen (as defined above), 1 to carbon atoms
Phenyl substituted with a substituent selected from 4 alkyl (as defined above) and alkoxy having 1 to 4 carbon atoms (as defined above); 3,4,5,6-tetrahydro-2H-
Pyran-4-yl; 3,4,5,6-tetrahydro-2
H-thiopyran-4-yl; 5-methylisoxazol-4-ylcarbonyl; 2-cyano-3-hydroxycrotonoyl and the like. Specifically, piperazine-
1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-hydroxymethylpiperazin-1-yl, 4- (2-hydroxyethyl) piperazin-1-yl, 4- (3 -Hydroxypropyl) piperazin-1-yl, 4- (tert-butoxycarbonyl)
Piperazin-1-yl, 4- (ethoxycarbonylmethyl) piperazin-1-yl, 4- (2-ethoxycarbonylethyl) piperazin-1-yl, 4- (3-ethoxycarbonylpropyl) piperazin-1-yl, −
(Carboxymethyl) piperazin-1-yl, 4- (2
-Carboxyethyl) piperazin-1-yl, 4- (3
-Carboxypropyl) piperazin-1-yl, 4-
((2-carboxyethyl) carbonyloxy) piperazin-1-yl, 4- (5-methylisoxazole-4
-Ylcarbonyl) piperazin-1-yl, 4- (2-
Cyano-3-hydroxycrotonoyl) piperazine-1
-Yl, 4- (dimethylaminomethyl) piperazine-1
-Yl, 4- (2-dimethylaminoethyl) piperazin-1-yl, 3,5-dimethyl-4-ethoxycarbonylmethylpiperazin-1-yl, 3,5-dimethyl-4
-Carboxymethylpiperazin-1-yl, 4- (3-
(3-pyridyl) propyl) piperazin-1-yl, 4
-(2- (2-hydroxyethoxy) ethyl) piperazin-1-yl, 4- (2-acetyloxyethyl) piperazin-1-yl, 4- (3,4,5,6-tetrahydro-2H-pyran- 4-yl) piperazin-1-yl,
4- (3,4,5,6-tetrahydro-2H-thiopyran-4-yl) piperazin-1-yl, 4- (4-chlorophenyl) piperazin-1-yl, 4- (4-fluorophenyl) piperazine- 1-yl, 4- (4-methylphenyl) piperazin-1-yl, 4- (4-methoxyphenyl) piperazin-1-yl, 4-methoxymethylpiperazin-1-yl, 4- (2-methoxyethyl) Piperazin-1-yl, 4- (3-methoxypropyl) piperazin-1-yl and the like.

The above-mentioned homopiperazine which may have a substituent is an alkyl having 1 to 4 carbons (as defined above) or a hydroxyalkyl having 1 to 4 carbons (as defined above) as a substituent. May be substituted, specifically, homopiperazine, 4- (hydroxymethyl) homopiperazin-1-yl, 4- (2-hydroxyethyl) homopiperazin-1-yl, 4-methylhomopiperazin-1 -Il and the like. The saturated heterocyclic ring containing a hetero atom selected from an oxygen atom or a nitrogen atom which may have a substituent in Het is a 5- or 6-membered ring, and the substituent is an alkyl having 1 to 4 carbon atoms. (As defined above),
Arylalkyl (as defined above) and the like. Specifically, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-
Benzylpiperidin-4-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, 1-ethylpyrrolidin-3-yl, 1-benzylpyrrolidin-3-yl, 3,4,5,6-tetrahydro- 2H-pyran-4
-Yl, 2,3,4,5-tetrahydrofuran-3-yl and the like.

The alkyl in R ⁸ , R ^8a , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² is a straight-chain or branched alkyl having 1 to 4 carbon atoms, such as methyl, ethyl and propyl. Isopropyl, butyl, isobutyl, tertiary butyl and the like, and preferably methyl. R ⁸ ,
Halogen in R ^8a and R ¹¹ represents fluorine, chlorine, bromine or iodine. The alkoxy in R ⁸ , R ^8a and R ¹¹ is a linear or branched alkoxy having 1 to 4 carbon atoms, and includes methoxy, ethoxy, propoxy,
Isopropoxy, butoxy, tertiary butoxy and the like. The hydroxyalkyl in R ⁹ and R ¹² is a C 1 to C 4 alkyl (as defined above) substituted with a hydroxyl group, and includes, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
4-hydroxybutyl and the like, preferably hydroxymethyl. The alkoxycarbonyl in R ¹¹ represents an alkoxycarbonyl having 1 to 4 carbon atoms (as defined above), such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl and the like. Is raised.

The pharmaceutically acceptable salts of the compounds of the present invention include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate, or acetate, propionate,
Succinate, maleate, fumarate, benzoate,
Salts with organic acids such as citrate, malate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or, when containing a carboxyl group, sodium, potassium, calcium, aluminum Examples thereof include salts, metal salts such as magnesium salts, salts with amines such as triethylamine, and salts with dibasic amino acids such as lysine. The compound of the present invention is a hydrate (1
Hydrate, hemihydrate, 3/4 hydrate, 1/4 hydrate, etc.), solvates and the like. Further, the compound of the present invention also includes an N-oxide compound. When a geometric isomer is present in the compound of the present invention, the present invention includes a cis form, a trans form, and a mixture thereof.
Further, when one or more asymmetric centers are present in the molecule in the present invention, various optical isomers exist from them. The present invention also includes optical isomers, racemates, and diastereoisomers, and mixtures thereof.

General Synthetic Method Method 1: The compound (I) of the present invention can be produced by the following method.

Embedded image (In the formula, each symbol is as defined above.) Compound (VI)
The condensation reaction of the compound (VII) with the following method (1)
(2) and (3) can be performed. (1) Compound (VI) is converted into an acid halide by a conventional method using a halogenating agent such as thionyl chloride, and then, in a suitable solvent (dichloromethane, dichloroethane, chloroform, etc.), a base (triethylamine, pyridine, sodium methoxide) , Sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium acetate, etc.)
Compound (VII) and 30 at the reflux temperature of the solvent from -20 ° C.
Compound (I) is obtained by condensing for 12 to 12 hours. In this reaction, the base used can also be used as a solvent. (2) Compound (VI) in a suitable solvent (dimethylformamide, dimethylsulfoxide, methanol, ethanol, isopropyl alcohol, butanol, etc.) if necessary, with a condensing agent (1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, carbonyldiimidazole, etc.)
Or condensed with compound (VII) in the presence of a compound (VII) or in a suitable solvent (dimethylformamide, dimethylsulfoxide, etc.) in the presence of a phosphoric acid ester such as diethyl cyanophosphate and a base (triethylamine, pyridine etc.). ) To produce compound (I). The reaction temperature is usually from 0 ° C to 100 ° C, and the reaction time is usually from 30 minutes to 24 hours. The reaction using the condensing agent can be performed in the presence of 1-hydroxybenztriazole or the like, if necessary. (3) Compound (VI) is converted to a lower alcohol (methanol,
After conversion to a mixed acid anhydride with, for example, ethanol or a carbonate (such as methyl chlorocarbonate or ethyl chlorocarbonate), a suitable solvent (methanol, ethanol, isopropyl alcohol, butanol, ethylene glycol, tetrahydrofuran, toluene, nitrobenzene or These solvents are used at room temperature to the reflux temperature of the solvent in the presence of a base (triethylamine, pyridine, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, etc.) in a solvent or in the absence of a solvent.
From Compound (VII) for 24 hours to obtain Compound (I). In this reaction, when R ² of compound (VII) is hydrogen, a protecting group usually used in the field of organic synthetic chemistry, for example, tertiary butoxycarbonyl group, 9-fluorenylmethoxycarbonyl group, benzyloxy group The reaction can be carried out using a carbonyl group or the like.

Method 2: Compound (I) wherein R ² is alkyl or hydroxycarbonylalkyl can be produced by the following method.

Embedded image (In the formula, Wa represents a group other than hydrogen in the substituent of R ² , Hal represents a halogen such as chlorine, bromine or iodine, and other symbols have the same meanings as described above.) Compound (VIII) is suitable. Base (sodium hydride, sodium hydroxide, potassium hydroxide) in a solvent (dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol, etc.) , Potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, triethylamine, etc.) to react with compound (VIII) at -20 ° C to 100 ° C for 30 minutes to 24 hours to obtain compound (I-1). Can be.

Method 3: When the compound of the present invention has a hydroxyl group, the corresponding ester compound is produced by subjecting the compound to a condensation reaction commonly used in the field of synthetic organic chemistry with a carboxylic acid compound, acid halide compound or acid anhydride compound. can do. When the compound of the present invention has a carboxylic acid group, the corresponding ester compound can be produced by subjecting the compound to a condensation reaction usually used in the field of organic synthetic chemistry with an alcohol compound or a phenol compound. Further, when the compound of the present invention has an ester group, the corresponding carboxylic acid compound can be produced by hydrolysis with an acid (such as hydrochloric acid or sulfuric acid) or a base (such as sodium hydroxide or potassium hydroxide) in a conventional manner. it can. When the compound of the present invention has an amino group, a base (triethylamine, pyridine, etc.)
N-alkylation or N-acylation can be carried out by an ordinary method using an alkyl halide or an acyl halide in the presence.

Method 4: In the compound (VII), R ²
Can be produced by the following method.

Embedded image (Wherein the symbols have the same meanings as described above.) The compound (X) is reduced by a method generally used in the field of synthetic organic chemistry, for example, a suitable solvent (water, methanol, ethanol, propanol, butanol, ethylene glycol or a mixture thereof). A mixed solvent of), a treatment using iron powder as a catalyst with dilute hydrochloric acid or a catalytic amount of ammonium chloride, or a catalytic reduction method in which hydrogenation is performed in the presence of a catalyst such as nickel, palladium, or platinum. The compound (VII-1) can be obtained by a method used, a Birch reduction method using an alkali metal such as sodium or lithium in liquid ammonia, or the like. The reaction temperature is usually from room temperature to the reflux temperature of the solvent, and the reaction time is usually from 1 to 24 hours.

Method 5: Compound (XI) can also be produced by the following method.

Embedded image (Wherein each symbol has the same meaning as described above.) Compound (XII) is subjected to a suitable solvent (water, methanol, ethanol, propanol, butanol, tertiary butyl alcohol, ethylene) by utilizing a Schmidt reaction. Glycol, benzene, toluene, xylene, preferably benzene) and sodium azide and a strong acid (sulfuric acid, trifluoroacetic acid, etc.) at room temperature to the reflux temperature of the solvent for 1 to 24 hours, or a suitable solvent (methanol, Triethylamine and diphenylphosphonyl azide in ethanol, isopropyl alcohol, butanol, tertiary butanol, preferably tertiary butanol) and from room temperature to the reflux temperature of the solvent from 1 to 24.
After reacting for an hour, treatment with an acid (hydrochloric acid, sulfuric acid, etc.) gives compound (XI).

Method 6: In the compound (X), R ⁵ is alkoxy, haloalkoxy, aryloxy, cycloalkyloxy, hydroxyalkoxy, hydroxycarbonylalkoxy, optionally substituted aminoalkoxy, alkylthio, hydroxyalkylthio , Hydroxycarbonylalkylthio, aminoalkylthio optionally having substituent (s) or group N (R ⁶ ) (R ⁷ )
In the case of, it can be produced by the following method.

Embedded image (Wherein Ya is alkoxy, haloalkoxy, aryloxy, cycloalkyloxy, hydroxyalkoxy, hydroxycarbonylalkoxy, optionally substituted aminoalkoxy, alkylthio, hydroxyalkylthio, hydroxycarbonylalkylthio,
It represents an aminoalkylthio which may have a substituent or a group N (R ⁶ ) (R ⁷ ), and other symbols are as defined above. Compound (XIII) is converted to a suitable solvent (chloroform, acetonitrile, water, methanol, ethanol, tetrahydrofuran, diethyl ether, dimethylformamide,
Compound (XIV) in dimethyl sulfoxide or a mixed solvent thereof or in the absence of a solvent in the presence of a base (sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, butyllithium, etc.)
With -20 ° C to 100 ° C for 1 to 24 hours to give compound (XV).

Method 7: Compound (XIII)
^The compound in which ³ is cyano can be produced by the following method.

Embedded image (In the formula, G represents nitro or carboxy, and other symbols are as defined above.) Compound (XVI) is dissolved in a suitable solvent (water, methanol, ethanol, propanol, ethylene glycol, dimethyl sulfoxide, dimethylformamide or the like). Cyanating agent (sodium cyanide, potassium cyanide, cuprous cyanide, etc.) in a mixed solvent) and room temperature to 100 ° C
(XVI) for 1 to 24 hours.
I) can be obtained.

Method 8: Compound (XIX) can be produced by the following method.

Embedded image (In the formula, each symbol is as defined above.) Compound (XVIII) in the presence of sodium acetate without solvent or in a suitable solvent (tetrahydrofuran, diethyl ether, dimethylformamide, dimethylsulfoxide, etc.), compound (IX) And from room temperature to 60 ° C. for 1 to 24 hours to give compound (XIX). After protecting the compound (XVIII) with a tertiary butoxycarbonyl group usually used as an amino-protecting group by a conventional method, the compound (IX) is reacted with the compound (IX) in the presence of sodium metal, sodium hydride or sodium amide. The compound (XIX) can also be obtained by reacting and deprotecting by a conventional method.

Method 9: Compound (I) can be produced by the following method.

Embedded image (Wherein each symbol has the same meaning as described above.) Compound (VII) is condensed with halogen-substituted benzene or carboxylic acid (XX) having a heteroaromatic ring by the method of Method 1 to obtain an amide (XXI). Can be. The obtained amide form (XXI) was prepared in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium.
Using aryl borane or heteroaryl borane,
In a suitable solvent (water, methanol, ethanol, propanol, butanol, tertiary butyl alcohol, ethylene glycol, benzene, toluene, xylene, dimethylformamide, etc.), use a base such as an aqueous solution of sodium carbonate or potassium carbonate to form a solvent at room temperature. Compound (I) can be obtained by treating with the Suzuki coupling method in which the treatment is performed at the reflux temperature of 1 to 24 hours. Alternatively, the obtained amide compound (XXI) can be prepared by using an alkyltin such as aryltrimethyltin or heteroaryltrimethyltin in the presence of a palladium catalyst such as tetrakistriphenylphosphinepalladium and a suitable solvent (water, methanol, ethanol, propanol, butanol). , Tertiary butyl alcohol, ethylene glycol, benzene, toluene, xylene, dimethylformamide, etc.) at room temperature to the reflux temperature of the solvent for 1 to 24 hours to obtain compound (I). can get.

The compound of the present invention may be used, if necessary, in an appropriate solvent (water, methanol, ethanol, propanol, isopropyl alcohol, diethyl ether, tetrahydrofuran, dioxane, etc.) in an acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphorus Acid, an inorganic acid such as nitric acid, or an organic acid such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, benzoic acid, citric acid, malic acid, methanesulfonic acid, benzenesulfonic acid). It can be an addition salt. When the obtained compound contains a carboxyl group, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, magnesium hydroxide, it can be a corresponding metal salt by treating with sodium alcoholate, Further, if necessary, a corresponding salt can be obtained by treating with an amine such as triethylamine or a dibasic amino acid such as lysine in an appropriate solvent. When the crystals of the compound of the present invention are anhydrous, hydrates (monohydrate, hemihydrate, 3 /
Tetrahydrate) and solvates. Furthermore, the compound of the present invention can be converted to an N-oxide compound by treating the compound with an oxidizing agent such as hydrogen peroxide or metachloroperbenzoic acid in a conventional manner.

The compound of the present invention thus obtained can be isolated and purified by a known method in the field of synthetic organic chemistry such as a recrystallization method and a column chromatography method. When the obtained product is a racemic form, for example, by fractional crystallization using a salt with an optically active acid or base, or by passing through a column packed with an optically active carrier,
It can be divided into desired optically active substances. These can also be produced by using an optically active raw material compound or the like.

The compound of the present invention or a pharmaceutically acceptable salt thereof can be prepared from Th2 cells activated with an antigen or the like.
4 has the effect of selectively suppressing production,
It is effective as a selective inhibitor of an immune response involving two cells as a preventive or therapeutic agent for various allergic diseases. More specifically, the compound of the present invention or a pharmaceutically acceptable salt thereof is a disease caused by abnormal proliferation or hyperactivity of Th2 cells, for example, lupus erythematosus, nephrotic syndrome lupus, Hashimoto goiter, multiple sclerosis. It can be used for the treatment and prevention of symptoms, myasthenia gravis, nephrotic syndrome, steroid-dependent and steroid-resistant nephrosis, allergic encephalomyelitis, glomerulonephritis and the like. Also, the onset of inflammatory, proliferative and hyperproliferative skin diseases, and immune-mediated diseases in the skin, such as psoriasis, psoriatic arthritis, atopic eczema (atopic dermatitis), contact dermatitis, and even eczema dermatitis , Seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,
It can also be used to treat angioedema, vasculitis, erythema, cutaneous eosinophilia, acne, alopecia areata, eosinophilic fasciitis and atherosclerosis.

The compounds of the invention may be used for respiratory diseases such as sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia and reversible obstructive airway diseases such as bronchial asthma, pediatric asthma, allergic asthma, endogenous asthma, exogenous asthma It is also applicable to the treatment of asthma and dusty asthma, in particular asthma, including chronic or refractory asthma (eg late onset and airway hyperresponsiveness), bronchitis and the like. The compounds of the present invention can also be used to treat liver damage associated with ischemia. In addition, certain eye diseases, such as allergic conjunctivitis, keratoconjunctivitis,
Keratitis, spring catarrh, uveitis associated with Behcet's disease, herpetic keratitis, keratoconus, corneal epithelial degeneration,
It is also effective against corneal vitiligo, pemphigus ulcer, Mohren's ulcer, scleritis, Graves' eye disease, severe intraocular inflammation and the like. The composition of the present invention is a renal disease such as interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome and diabetic nephropathy; a neurological disease selected from polymyositis, Guillain-Barre syndrome, Meniere's disease and radiculopathy; Endocrine disorders such as hyperthyroidism and Graves'disease; sarcoidosis,
Respiratory diseases such as pulmonary fibrosis and idiopathic interstitial pneumonia;
Skin diseases such as dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T-cell lymphoma; cardiovascular diseases such as arteriosclerosis, aortitis, polyarteritis nodosa and cardiomyopathy; It can also be used in the treatment or prevention of dermatoses, collagen diseases such as Pegner's granulomas and Sjogren's syndrome; steatosis; eosinophilic fasciitis; periodontal disease; nephrotic syndrome; hemolytic uremic syndrome; and muscular dystrophy. The compounds of the present invention may be used for intestinal inflammation / allergy, such as C
oeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis, and food-related allergic diseases that show symptoms not directly related to the gastrointestinal tract, such as Also suitable for the prevention or treatment of migraine, rhinitis and eczema. Furthermore, the compound of the present invention has immunogenic diseases (eg, autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis) because it has liver regeneration activity and / or activity to promote hepatocyte hypertrophy and hyperplasia. Chronic autoimmune liver disease including), hepatitis B viral hepatitis, non-A / non-B hepatitis and liver diseases such as cirrhosis.

The compound of the present invention may also be used for the following: Tumor,
Active chronic hepatitis, Evans syndrome, hay fever, idiopathic hypoparathyroidism, Addison's disease (autoimmune adrenalitis), autoimmune orchitis, autoimmune ovitis, cold hemagglutininosis, paroxysmal cold Hemoglobinuria, pernicious anemia, adult T-cell leukemia, autoimmune atrophic gastritis, lupus hepatitis, tubular interstitial nephritis, membranous nephritis, amyotrophic lateral sclerosis, rheumatic fever, post-myocardial infarction syndrome, It can be used for the prevention or treatment of sympathetic ophthalmitis. The compound of the present invention or a pharmaceutically acceptable salt thereof may optionally contain other immunosuppressive agents (tacrolimus hydrate, ascomycin, FTY720, etc.), steroidal agents (prednisolone, methylprednisolone, dexamethasone, hydrocortisone, clobetasone, flumethasone). , Triamcinolone acetonide, alclomethasone, fluorosinolone acetonide, beclomethasone, betamethasone, deprodone, halcinonide,
Amcinonide, fluocinonide, diflucortron, budesonide, difluperedonate, diflorazone, clobetasol or their fatty acid esters, etc., antiallergic agents (sodium cromoglycate, tranilast, amlexanox, repirinast, ibudilast,
Tazanolast, pemirolast, ozagrel, supratast, pranlukast, ketotifen, azelastine, oxatomide, mequitazine, terfenadine, emedastine, epinastine, astemiso, or various antihistamines).

As described above, the compound of the present invention or a pharmaceutically acceptable salt thereof has a novel mechanism of action for selectively suppressing the production of IL-4 from Th2 cells, and has various allergic diseases or autoimmune diseases. It has a different mechanism of action from existing immunosuppressants, steroids, antiallergic agents, etc. used in the treatment of, and can be expected to exhibit a synergistic effect when used in combination with the existing drugs. When the compound of the present invention or a pharmaceutically acceptable salt thereof is used as a medicament, the compound of the present invention can be converted into a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, Pharmaceutical compositions or preparations (tablets, pills, capsules, granules, dispersion, syrups, emulsions, elixirs, suspensions, solutions, injections, infusions) obtained by mixing with a solubilizing agent or the like. Preparations, eye drops, eye ointments, suppositories, ointments or lotions) can be administered orally or parenterally.

The pharmaceutical composition can be formulated according to a usual method. In the present specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, instillation, eye drop, and the like. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as an aqueous solution. Examples of acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic saline and the like. In addition, sterile, fixed oils can be conventionally employed as a solvent or suspending solvent. For this purpose, any non-volatile oil and fatty acid can be used, including natural, synthetic or semi-synthetic fatty oils or fatty acids, and natural, synthetic or semi-synthetic mono-, di- or triglycerides. When preparing an injection, an appropriate suspending agent, a nonionic surfactant, a solubilizing agent, and the like may be used in combination as necessary. Suppositories for rectal administration are solid at room temperature, such as the drug and a suitable nonirritating excipient, for example, cocoa butter or polyethylene glycols, but liquid at intestinal temperatures and melt in the rectum. , Can be manufactured by mixing with a substance that releases a drug. Examples of solid dosage forms for oral administration include those described above such as powders, granules, tablets, and pill capsules. In such dosage forms, the active ingredient compound comprises at least one additive,
For example, sucrose, lactose, cellulose sugar, mannitol,
Maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers, or glycerides And can be mixed.
Such dosage forms may contain, as usual, further additives, such as inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbins, ascorbic acid, Examples include antioxidants such as α-tocopherol and cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavorants, and perfumes. Tablets and pills can also be prepared with an enteric coating. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which include inert diluents commonly used in the art, such as water. May be. In the case of eye drops, aqueous solutions or aqueous solutions are used, and particularly, a sterile aqueous solution for injection is used. Various additives such as a buffer, an isotonicity agent, a solubilizer, a preservative, a thickener, a chelating agent, a pH adjuster, and a fragrance may be appropriately added to the ophthalmic solution. In the case of an ointment, an oil base, an emulsion base, a water-soluble base, a suspendable base and the like are used, and a dissolution / absorption promoter can be appropriately compounded. When using a lotion, disperse or partially dissolve in a liquid medium,
An emulsifier, a dissolution / absorption accelerator, a thickening agent, and a stabilizer can be appropriately compounded.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has excellent therapeutic effects when used in combination with an immunosuppressant, a steroid or an antiallergic agent. You can expect.
Here, the “combination” refers to a combination composition of the compound of the present invention or a pharmaceutically acceptable salt thereof and an immunosuppressant, a steroid or an antiallergic agent, and the compound of the present invention or a pharmaceutically acceptable salt thereof. Means the use of immunosuppressants, steroids or anti-allergic agents as a potentiator, including both simultaneous use without mixing and use with a time lag, including combined use and combined use It is a thing. The medicament of the present invention, which is characterized by using a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof and an immunosuppressant, a steroid or an antiallergic agent in combination with the general formula (I) The form of use is not particularly limited as long as the compound represented by I) or a pharmaceutically acceptable salt thereof is used in combination with an immunosuppressant, a steroid or an antiallergic agent. For example, (A) a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, and (B) an immunosuppressant, a steroid or an antiallergic agent, are each administered as a preparation which is usually administered. Or a composition obtained by combining them in advance. As the concomitant drug of the present invention, for example, a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof and an immunosuppressant, a steroid or an antiallergic agent can be prepared by a known pharmaceutical production method. In accordance with the following, if desired, using a pharmaceutically acceptable diluent, excipient, etc., and mixing to form one agent, or separately, optionally, a pharmaceutically acceptable diluent, excipient, etc. Each preparation may be used, or a combination preparation (set, kit, pack) may be prepared by separately preparing each preparation into a single container.
For example, the concomitant drug of the present invention comprises (1) a preparation containing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, and an immunosuppressant, a steroid or an antiallergic agent, which are the same or different. Or a composition comprising (2) a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, and an immunosuppressant, a steroid or an antiallergic agent. Can be used.

The administration route of the concomitant drug of the present invention may be either oral administration or parenteral administration, similarly to the above-mentioned administration route of the compound of the present invention. It is determined in consideration of the site of the disease to be caused.
When the compound of the present invention or a pharmaceutically acceptable salt thereof and an immunosuppressant, a steroid or an antiallergic agent are separately formulated, they may be separately, simultaneously, or with a time lag applied to the same subject by the same route. Or they may be administered by different routes. Upon administration of the concomitant drug of the present invention, the compound of the present invention or a pharmaceutically acceptable salt thereof, or an immunosuppressant, a steroid or an antiallergic drug is prepared by an agent prepared by the same conventional method as described above. It can be administered in the form. When the compound of the present invention or a pharmaceutically acceptable salt thereof is used as a drug or a concomitant drug, the dose is determined by the age, body weight, general health condition, sex, diet, administration time, administration method, excretion rate, drug , The degree of the condition of the patient being treated at that time, or considering other factors.
The compound of the present invention or a pharmaceutically acceptable salt thereof has low toxicity and can be used safely. The daily dose varies depending on the condition and weight of the patient, the type of the compound, the administration route, and the like. Parenterally, subcutaneously, intravenously, intramuscularly or rectally, about 0.01 to 100 mg / person /
Daily, preferably 0.01 to 50 mg / person / day, and orally about 0.01 to 1000 mg / person / day, preferably 0.01 to 500 mg / person / day. .

EXAMPLES Hereinafter, the present invention will be described in detail with reference to raw material synthesis examples, examples, and experimental examples, but the present invention is not limited thereto.

Raw material synthesis example 1: 5-amino-2- (4-hydroxypiperidin-1-yl) pyridine

Embedded image Diisopropylethylamine (22 mL) was added to a solution of 2-chloro-5-nitropyridine (10 g) and dimethylformamide (50 mL) of 4-hydroxypiperidine (7.7 g), and the mixture was stirred at 110 ° C for 2 hours. After cooling with ice, water was added, and the precipitated solid was collected by filtration. The resulting solid,
A suspension of methanol (200 mL), hydrazine monohydrate (7.2 g), anhydrous ferrous chloride (0.2 g) and activated carbon (2 g) was stirred at 60 ° C. for 2 hours. After the reaction, the mixture was filtered through celite and concentrated. The residue was chloroform /
Extracted with methanol (4/1) and washed with saturated saline.
After drying over magnesium sulfate, the residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain a reddish brown liquid (2.9 g). ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.3-1.4 (2H, m), 1.7
-1.8 (2H, m), 2.75 -2.85 (2H, m), 3.55-3.65 (1
H, m), 3.7-3.8 (2H, m), 4.50 (2H, s), 4.61 (1H,
d, J = 4.4 Hz), 6.61 (1H, d, J = 8.8 Hz), 6.89 (1
H, dd, J = 8.8, 3.0 Hz), 7.57 (1H, d, J = 3.0 Hz).

Raw material synthesis example 2: 5- (1-cyclohexenyl) thiophene-2-carboxylic acid

Embedded image a) 1- (1-cyclohexenyl) thiophene

Embedded image A 1.6 N N-butyllithium / hexane solution (182 mL) was added dropwise to an ice-cooled solution of thiophene (20 g) in tetrahydrofuran (200 mL). The reaction solution was stirred at 0 ° C. for 0.5 hour and cooled to −30 ° C., and then cyclohexanone (28 g) was added dropwise, followed by stirring at −30 ° C. to −15 ° C. for 1 hour. The reaction solution was added to a 4N aqueous hydrochloric acid solution, and the organic layer was extracted with ether (0.5 L).
Washed with saturated saline. After drying over magnesium sulfate and concentration, a light brown liquid (48 g) was obtained. A 30% aqueous sulfuric acid solution (150 mL) was added to this liquid (26 g), and the solution was added at room temperature for 0.5 hour.
After stirring for an hour, the solution was neutralized with potassium carbonate and extracted with ether. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and concentrated to give a pale brown liquid (22 g). ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.5-1.6 (2H, m), 1.65
-1.7 (2H, m), 2.1 -2.2 (2H, m), 2.3-2.4 (2H, m
m), 6.05-6.15 (1H, m), 6.95-7.05 (2H, m), 7.15
-7.35 (1H, m). B) 5- (1-cyclohexenyl) thiophene-2-carboxylic acid

Embedded image Ice-cooled 1- (1-cyclohexenyl) thiophene (1
5 g) in a solution of tetrahydrofuran (200 mL) in 1.6 N N-butyllithium / hexane (73 m
L) was added dropwise, and the mixture was stirred at 0 ° C for 15 minutes and cooled to -60 ° C. Then, dry ice (about 15 g) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was ice-cooled, the pH of the solution was adjusted to 10 with a 10% aqueous potassium carbonate solution, and the aqueous layer was separated. After the aqueous layer was washed with ethyl acetate and cooled again, the pH of the aqueous layer was adjusted to 2 with 4N hydrochloric acid, and the precipitated solid was collected by filtration. Recrystallization from acetone / water gave pale yellow crystals. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.5-1.6 (2H, m), 1.65
-1.75 (2H, m), 2.1 -2.2 (2H, m), 2.3-2.4 (2H, m
m), 6.3-6.4 (1H, m), 7.09 (1H, d, J = 3.9Hz), 7.
59 (1H, d, J = 3.9 Hz), 12.95 (1H, brs).

Raw material synthesis example 3: 4- (4-chlorophenyl) thiazole-2-carboxylic acid sodium salt

Embedded image a) 4- (4-chlorophenyl) thiazole-2-carboxylic acid ethyl ester

Embedded image A solution of 4-chlorophenacyl bromide (2.4 g) and ethylthiooxamate (1.35 g) in ethanol was refluxed for 2 hours. After evaporating the solvent and extracting the residue with ethyl acetate,
The organic layer was washed with water and saturated saline and dried over magnesium sulfate. After concentration, it was precipitated from ethyl acetate / diisopropyl ether / hexane to give a pale yellow solid (1.25).
g) ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.36 (3H, t, J = 6.9 H
z), 4.42 (2H, q, J = 6.9 Hz), 7.56 (2H, d, J = 8.8
Hz), 8.04 (2H, d, J = 8.8 Hz), 8.66 (1H, s). B) 4- (4-Chlorophenyl) thiazole-2-carboxylic acid sodium salt

Embedded image 4- (4-chlorophenyl) thiazole-2-carboxylic acid ethyl ester (1.25 g), 10 N aqueous sodium hydroxide solution (1 mL) and ethanol (20 m
The solution of (L) was heated under reflux for 2 hours, diisopropyl ether was added, and the precipitated solid was collected by filtration (1.27).
g). ¹ H-NMR (400 MHz, DMSO-d ₆ ): 7.48 (2H, d, J = 8.3 H
z), 8.00 (2H, d, J = 8.3 Hz), 8.06 (1H, s).

Raw material synthesis example 4: 5- (4-chlorophenyl) oxazole-2-carboxylic acid ethyl ester

Embedded image a) 2-Amino-4'-chloroacetophenone hydrochloride

Embedded image 2-bromo-4'-chloroacetophenone (12.7
g) and a solution of potassium phthalimide (10.1 g) in dimethylformamide (50 mL) was stirred at room temperature for 3 hours. Water was added and the precipitated solid was collected by filtration and washed with water. Acetic acid (100 mL) and hydrochloric acid (100 mL) were added to the obtained solid, and the mixture was heated under reflux for 15 hours. After cooling, the solvent was concentrated, and the precipitated solid was collected by filtration and washed with chloroform to obtain a pale yellow solid (5.0 g). ¹ H-NMR (400 MHz, DMSO-d ₆ ): 4.59 (2H, s), 7.68 (2H,
d, J = 8.3 Hz), 8.05 (2H, d, J = 8.3 Hz), 8.52 (2
H, s). B) N- (4'-chlorophenacyl) oxamic acid ethyl ester

Embedded image 2-amino-4'-chloroacetophenone hydrochloride (5.
0 g) and a suspension of ethyl chlorooxoacetate (3.3 g) in benzene (50 mL) were heated under reflux for 15 hours, then the solvent was distilled off, and the residue was precipitated from water / acetone to obtain a pale yellow solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.30 (3H, t, J = 6.8 H
z), 4.28 (2H, q, J = 6.8 Hz), 4.70 (2H, d, J = 5.8
Hz), 7.62 (2H, d, J = 8.8 Hz), 8.03 (2H, d, J = 8.
8 Hz), 9.14 (1H, t, J = 5.8 Hz). C) 5- (4-chlorophenyl) oxazole-2-carboxylic acid ethyl ester

Embedded image Phosphorus oxychloride (6.2 mL) was added to a solution of N- (4'-chlorophenacyl) oxamic acid ethyl ester (3.6 g) in benzene (20 mL), and the mixture was heated under reflux for 5 hours, and then the solvent was distilled off. did. The residue was extracted with ether, and the organic layer was washed with water and saturated saline and dried over magnesium sulfate. After concentration of the solvent, recrystallization from ether / hexane gave pale red crystals. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.35 (3H, t, J = 7.3 H
z), 4.40 (2H, q, J = 7.3 Hz), 7.61 (2H, d, J = 8.7
Hz), 7.85 (2H, d, J = 8.7 Hz), 8.04 (1H, s).

Raw material synthesis example 5: 5- (4-chlorophenyl) -3-ethoxycarbonylbenzoic acid

Embedded image a) Dimethyl 5- (4-chlorophenyl) isophthalate

Embedded image Ice-cooled dimethyl 5-hydroxyisophthalate (1
Trifluoromethanesulfonic anhydride (8.8 mL) was added dropwise to a solution of 0 g) in pyridine (100 mL), and the mixture was stirred for 1 hour. Then, the solvent was distilled off, and the mixture was extracted with ethyl acetate. The organic layer is washed with water and saturated saline and dried over magnesium sulfate,
Concentration gave a light brown oil (15 g). Obtained oil (5 g), 4-chlorophenylboronic acid (3.0 g)
, An ethanol solution (10 mL), a 2M aqueous sodium carbonate solution (18 mL) and toluene (30 mL) were replaced with nitrogen. Tetrakistriphenylphosphine palladium (1.7 g) was added to the obtained reaction solution, and the mixture was heated under reflux for 3 hours, and then extracted by adding water and ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. After concentration, the residue was subjected to silica gel column chromatography (chloroform / hexane) to obtain a pale yellow solid (3.7 g). ¹ H-NMR (400 MHz, DMSO-d ₆ ): 3.93 (6H, s), 7.57 (2H,
d, J = 8.3 Hz), 7.79 (2H, d, J = 8.3 Hz), 8.39 (2
H, d, J = 1.4 Hz), 8.46 (1H, t, J = 1.4 Hz). B) 5- (4-chlorophenyl) -3-ethoxycarbonylbenzoic acid

Embedded image Sodium hydroxide (0.1 mL) was added to a solution of dimethyl 5- (4-chlorophenyl) isophthalate (3.1 g) in ethanol (30 mL) and tetrahydrofuran (15 mL).
41 g) of an aqueous solution (1 mL) was added. After stirring this solution at room temperature for 15 hours, ether was added and the precipitated solid was collected by filtration, 1N hydrochloric acid was added to the collected solid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration, the residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain a white solid (2.4 g). ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.37 (3H, t, J = 7.3 H
z), 4.39 (2H, q, J = 7.3 Hz), 7.57 (2H, d, J = 8.7
Hz), 7.79 (2H, d, J = 8.7 Hz), 8.37 (1H, d, J = 1.
4 Hz), 8.39 (1H, d, J = 1.4 Hz), 8.47 (1H, s), 13.
50 (1H, brs).

Example 1 N- [3-cyano-4- (4-
Hydroxypiperidin-1-yl) phenyl] -4-iodobenzamide

Embedded image 5-Amino-2- described in WO 00/47558
(4-hydroxypiperidin-1-yl) benzonitrile (5 g) and 4-iodobenzoic acid (6.3 g), 1
-Hydroxybenzotriazole monohydrate (HOBT:
3.7 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI: 5.3 g)
And dimethylformamide (100 mL) were added, and the mixture was stirred at room temperature for 2 days. Water (200 mL) was added to the reaction solution, and the precipitated solid was collected by filtration, and the obtained solid was recrystallized from acetone / water to obtain light brown crystals (9.3 g). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.4-1.6 (2H, m), 1.
8-1.9 (2H, m), 2.85-2.95 (2H, m), 3.3-3.4 (2
H, m), 3.6-3.7 (1H, m), 4.76 (1H, d, J = 3.9 H
z), 7.19 (1H, d, J = 8.8 Hz), 7.74 (2H, d, J = 8.3
Hz), 7.85-7.9 (1H, m), 7.93 (2H, d, J = 8.3 H
z), 8.08 (1H, d, J = 2.0 Hz), 10.41 (1H, s). Melting point: 176-180 ° C.

Example 2: 4- (4-chlorophenyl)-
N- [3-cyano-4- (4-hydroxypiperidine-
1-yl) phenyl] benzamide

Embedded image N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] -4-iodobenzamide obtained in Example 1 (0.5 g), 4-chlorophenylboronic acid (0.27 g) , 2M sodium carbonate aqueous solution (1.5m
L) and dimethylformamide (10 mL) were replaced with nitrogen. Tetrakistriphenylphosphine palladium (0.66 g) was added to the obtained reaction solution, followed by stirring at 80 ° C. for 15 hours. After the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with water and brine, and dried over magnesium sulfate. After concentration, the residue was subjected to silica gel column chromatography (chloroform / methanol), and further recrystallized from acetone / water to obtain pale yellow crystals (0.18 g). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.5-1.6 (2H, m), 1.
8-1.9 (2H, m), 2.85-2.95 (2H, m), 3.3-3.4 (2
H, m), 3.6-3.7 (1H, m), 4.73 (1H, d, J = 4.4 H
z), 7.21 (1H, d, J = 9.2 Hz), 7.57 (2H, d, J = 8.8
Hz), 7.81 (2H, d, J = 8.8 Hz), 7.86 (2H, d, J = 8.
3 Hz), 7.93 (1H, dd, J = 2.5, 9.2 Hz), 8.06 (2H, d,
J = 8.3 Hz), 8.13 (1H, d, J = 2.5 Hz), 10.42 (1H,
brs). Melting point: 230-235 ° C.

Example 3 N- [3-cyano-4- (4-
Hydroxypiperidin-1-yl) phenyl] -3-iodobenzamide

Embedded image 5-Amino-2- (4-hydroxypiperidin-1-yl) benzonitrile By performing the same operation as in Example 1, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.5-1.6 (2H, m), 1.
85-1.95 (2H, m), 2.85-2.95 (2H, m), 3.3-3.4
(2H, m), 3.6-3.7 (1H, m), 4.70-4.75 (1H, m), 7.2
0 (1H, d, J = 8.7 Hz), 7.35 (1H, dd, J = 7.8, 7.8
Hz), 7.8-8.0 (3H, m), 8.05-8.1 (1H, m), 8.29
(1H, s), 10.42 (1H, s). Melting point: 178-182 ° C.

Example 4: 3- (4-chlorophenyl)-
N- [3-cyano-4- (4-hydroxypiperidine-
1-yl) phenyl] benzamide

Embedded image By performing the same operation as in Example 2 using the compound obtained in Example 3 and 4-chlorophenylboronic acid, white crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.55-1.65 (2H, m),
1.85-1.95 (2H, m), 2.85-2.95 (2H, m), 3.3-3.
4 (2H, m), 3.6-3.7 (1H, m), 4.74 (1H, d, J = 4.4
Hz), 7.22 (1H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.
3 Hz), 7.64 (1H, dd, J = 7.8, 7.8 Hz), 7.81 (2H,
d, J = 8.3 Hz), 7.9-8.0 (3H, m), 8.11 (1H, d, J
= 2.5 Hz), 8.22 (1H, s), 10.45 (1H, s). Melting point: 125-127 ° C.

Example 5: N- [3-cyano-4- (2,
2-dimethyl-3-hydroxypropoxy) phenyl]
-4-Iodobenzamide

Embedded image A white crystal was obtained by performing the same operation as in Example 1 using 5-amino-2- (2,2-dimethyl-3-hydroxypropoxy) benzonitrile and 4-iodobenzoic acid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.96 (6H, s), 3.31 (2
H, d, J = 5.4 Hz), 3.85 (2H, s), 4.69 (1H, t, J =
5.4 Hz), 7.26 (1H, d, J = 9.2 Hz), 7.74 (2H, d, J =
8.3 Hz), 7.9-8.0 (3H, m), 8.08 (1H, d, J = 3.0
Hz), 10.41 (1H, s). Melting point: 128-130 ° C.

Example 6: 4- (4-chlorophenyl)-
N- [3-cyano-4- (2,2-dimethyl-3-hydroxypropoxy) phenyl] benzamide

Embedded image By performing the same operation as in Example 2 using the compound obtained in Example 5 and 4-chlorophenylboronic acid, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.97 (6H, s), 3.3-
3.35 (2H, m), 3.86 (2H, s), 4.65-4.75 (1H, m), 7.
28 (1H, d, J = 9.3 Hz), 7.57 (2H, d, J = 8.3 Hz),
7.81 (2H, d, J = 8.8 Hz), 7.87 (2H, d, J = 8.3 H
z), 7.9-8.0 (1H, m), 8.07 (2H, d, J = 8.8 Hz), 8.
1-8.15 (1H, m), 10.43 (1H, s). Melting point: 185-187 ° C.

Example 7: N- [3-cyano-4- (2,
2-dimethyl-3-hydroxypropoxy) phenyl]
-3-Iodobenzamide

Embedded image By performing the same operation as in Example 1 using 5-amino-2- (2,2-dimethyl-3-hydroxypropoxy) benzonitrile and 3-iodobenzoic acid, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.96 (6H, s), 3.3-
3.4 (2H, m), 3.85 (2H, s), 4.65-4.75 (1H, m), 7.2
-7.4 (2H, m), 7.9-8.0 (3H, m), 8.08 (1H, d, J =
2.5 Hz), 8.30 (1H, s), 10.43 (1H, s). Melting point: 145-147 ° C.

Example 8: 3- (4-chlorophenyl)-
N- [3-cyano-4- (2,2-dimethyl-3-hydroxypropoxy) phenyl] benzamide

Embedded image By performing the same operation as in Example 2 using the compound obtained in Example 7 and 4-chlorophenylboronic acid, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.97 (6H, s), 3.3-
3.4 (2H, m), 3.86 (2H, s), 4.65-4.75 (1H, m), 7.2
8 (1H, d, J = 8.8 Hz), 7.5-7.7 (3H, m), 7.82 (2
H, d, J = 7.4 Hz), 7.9-8.0 (3H, m), 8.11 (1H,
s), 8.23 (1H, s), 10.46 (1H, s). Melting point: 140-142 ° C.

Example 9: 5- (4-chlorophenyl)-
N- [3-cyano-4- (4-hydroxypiperidine-
1-yl) phenyl] furan-2-carboxamide

Embedded image By performing the same operation as in Example 1 using 5-amino-2- (2,2-dimethyl-3-hydroxypropoxy) benzonitrile and 5- (4-chlorophenyl) furan-2-carboxylic acid, Yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.55-1.65 (2H, m), 1.
85-1.95 (2H, m), 2.85-2.95 (2H, m), 3.3-3.4
(2H, m), 3.6-3.7 (1H, m), 4.74 (1H, d, J = 3.9 H
z), 7.2-7.3 (2H, m), 7.40 (1H, d, J = 3.4 Hz),
7.58 (2H, d, J = 8.3 Hz), 7.85-7.95 (1H, m), 8.01
(2H, d, J = 8.3 Hz), 8.06 (1H, s), 10.31 (1H, s). Melting point: 139-140 ° C.

Example 10: 5- (4-chlorophenyl)
-N- [3-cyano-4- (2,2-dimethyl-3-hydroxypropoxy) phenyl] furan-2-carboxamide

Embedded image By performing the same operation as in Example 1 using 5-amino-2- (2,2-dimethyl-3-hydroxypropoxy) benzonitrile and 5- (4-chlorophenyl) furan-2-carboxylic acid, Yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 0.97 (6H, s), 3.32 (2H,
d, J = 5.4 Hz), 3.86 (2H, s), 4.70 (1H, t, J = 5.4
Hz), 7.25 (1H, d, J = 3.9 Hz), 7.29 (1H, d, J =
9.3 Hz), 7.40 (1H, d, J = 3.9 Hz), 7.58 (2H, d, J
= 8.8 Hz), 7.96 (1H, dd, J = 9.3, 2.9 Hz), 8.01 (2
H, d, J = 8.8 Hz), 8.07 (1H, d, J = 2.9 Hz), 10.32
(1H, s). Melting point: 155-157 ° C.

Example 11: 5- (4-chlorophenyl)
-N- [2- (4-hydroxypiperidin-1-yl)
Pyridin-5-yl] furan-2-carboxamide

Embedded image Example 1 Using 5-amino-2- (4-hydroxypiperidin-1-yl) pyridine obtained in Raw Material Synthesis Example 1 and 5- (4-chlorophenyl) furan-2-carboxylic acid.
By performing the same operation as in above, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.3-1.4 (2H, m), 1.65
-1.75 (2H, m), 3.0 -3.1 (2H, m), 3.65-3.75 (1
H, m), 3.95-4.05 (2H, m), 4.69 (1H, s), 6.88 (1
H, d, J = 9.3 Hz), 7.22 (1H, d, J = 3.4 Hz), 7.34
(1H, d, J = 3.4 Hz), 7.57 (2H, d, J = 8.7 Hz), 7.8
3 (1H, dd, J = 9.3, 2.4 Hz), 8.01 (2H, d, J = 8.7 H
z), 8.40 (1H, d, J = 2.4 Hz), 10.12 (1H, s). Melting point: 187-190 ° C.

Example 12: 5- (4-chlorophenyl)
-N- [3-cyano-4- (4-morpholinopiperidin-1-yl) phenyl] furan-2-carboxamide

Embedded image By performing the same operation as in Example 1 using 5-amino-2- (4-morpholinopiperidin-1-yl) benzonitrile and 5- (4-chlorophenyl) furan-2-carboxylic acid, a pale yellow crystal was obtained. I got ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.5-1.6 (2H, m), 1.85
-1.95 (2H, m), 2.25- 2.35 (1H, m), 2.45-2.55
(4H, m), 2.75-2.85 (2H, m), 3.45-3.55 (2H, m),
3.5-3.6 (4H, m), 7.21 (1H, d, J = 8.8 Hz), 7.25
(1H, d, J = 3.9Hz), 7.40 (1H, d, J = 3.9Hz), 7.58
(2H, d, J = 8.8 Hz), 7.85-7.95 (1H, m), 8.00 (2
H, d, J = 8.8 Hz), 8.06 (1H, d, J = 2.5 Hz), 10.3
1 (1H, s). Melting point: 214-216 ° C.

Example 13: 5- (4-chlorophenyl)
-N- [3-cyano-4- [4- (3,4,5,6-tetrahydro-2H-pyran-4-yl) piperazine-1
-Yl] phenyl] furan-2-carboxamide

Embedded image 5-Amino-2- [4- (3,4,5,6-tetrahydro-2H-pyran-4-yl) piperazin-1-yl]
Benzonitrile and 5- (4-chlorophenyl) furan-
By performing the same operation as in Example 1 using 2-carboxylic acid, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.35-1.45 (2H, m), 1.
7-1.8 (2H, m), 2.4 -2.5 (1H, m), 2.6-2.7 (4H,
m), 3.05-3.15 (4H, m), 3.25-3.35 (2H, m), 3.85
-3.95 (2H, m), 7.20 (1H, d, J = 8.8 Hz), 7.24 (1
H, d, J = 3.4 Hz), 7.41 (1H, d, J = 3.4 Hz), 7.57
(2H, d, J = 8.8 Hz), 7.93 (1H, dd, J = 8.8, 2.5 H
z), 8.00 (2H, d, J = 8.8 Hz), 8.08 (1H, d, J = 2.5
Hz), 10.32 (1H, s). Melting point: 226-227 ° C.

Example 14: 5- (4-chlorophenyl)
-N- (3-cyano-4-piperidinophenyl) furan-2-carboxamide

Embedded image 5-amino-2-piperidinobenzonitrile and 5- (4
By performing the same operation as in Example 1 using -chlorophenyl) furan-2-carboxylic acid, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.5-1.6 (2H, m), 1.65
-1.75 (4H, m), 3.05- 3.10 (4H, m), 7.20 (1H, d,
J = 8.8 Hz), 7.25 (1H, d, J = 3.4 Hz), 7.40 (1H, d,
J = 3.4 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.91 (1H,
dd, J = 2.5, 8.8 Hz), 8.01 (2H, d, J = 8.3 Hz), 8.
06 (1H, d, J = 2.5 Hz), 10.31 (1H, s). Melting point: 145-147 ° C.

Example 15: 5- (4-chlorophenyl)
-N- [3-cyano-4- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) phenyl] furan-2-carboxamide

Embedded image 5-Amino-2- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) benzonotrile and 5- (4
By performing the same operation as in Example 1 using -chlorophenyl) furan-2-carboxylic acid, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.75-1.85 (4H, m), 3.
15-3.25 (4H, m), 3.93 (4H, s), 7.2-7.3 (2H,
m), 7.41 (1H, d, J = 3.5 Hz), 7.58 (2H, d, J = 8.3
Hz), 7.9-7.95 (1H, m), 8.00 (2H, d, J = 8.3 Hz),
8.08 (1H, d, J = 2.4 Hz), 10.32 (1H, s). Melting point: 187-189 ° C.

Example 16: 5- (4-Chloro-2-nitrophenyl) -N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] furan-2-carboxamide

Embedded image Performing the same operation as in Example 1 using 5-amino-2- (4-hydroxypiperidin-1-yl) benzonitrile and 5- (4-chloro-2-nitrophenyl) furan-2-carboxylic acid As a result, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.5-1.6 (2H, m), 1.8
-1.9 (2H, m), 2.85 -2.95 (2H, m), 3.3-3.4 (2H, m
m), 3.6-3.7 (1H, m), 4.72 (1H, d, J = 4.4Hz), 6.
99 (1H, d, J = 4.4 Hz), 7.19 (1H, d, J = 8.7 Hz),
7.45 (1H, d, J = 3.9 Hz), 7.8-8.05 (4H, m), 8.22
(1H, d, J = 1.9 Hz), 10.32 (1H, s). Melting point: 224-226 ° C.

Example 17 5-Bromo-N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] thiophen-2-carboxamide

Embedded image By performing the same operation as in Example 1 using 5-amino-2- (4-hydroxypiperidin-1-yl) benzonitrile and 5-bromothiophene-2-carboxylic acid, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.5-1.6 (2H, m), 1.8
-1.9 (2H, m), 2.85 -2.95 (2H, m), 3.3-3.4 (2H, m
m), 3.6-3.7 (1H, m), 4.73 (1H, brs), 7.19 (1H, d,
J = 8.8 Hz), 7.37 (1H, d, J = 3.4 Hz), 7.75-7.8
5 (2H, m), 8.00 (1H, d, J = 2.5 Hz), 10.39 (1H, br
s).

Example 18: 5- (4-chlorophenyl)
-N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] thiophen-2-carboxamide

Embedded image 5-Bromo-N- [3-cyano-4- obtained in Example 17
By performing the same operation as in Example 2 using (4-hydroxypiperidin-1-yl) phenyl] thiophen-2-carboxamide and 4-chlorophenylboronic acid, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.5-1.6 (2H, m), 1.85
-1.95 (2H, m), 2.85- 2.95 (2H, m), 3.3-3.4 (2
H, m), 3.6-3.7 (1H, m), 4.74 (1H, d, J = 4.4 H
z), 7.21 (1H, d, J = 9.3 Hz), 7.53 (2H, d, J = 8.1
Hz), 7.67 (1H, d, J = 3.9 Hz), 7.78 (2H, d, J = 8.
1 Hz), 7.8-7.9 (1H, m), 7.99 (1H, d, J = 3.9 Hz),
8.0-8.1 (1H, m), 10.38 (1H, s). Melting point: 246-249 ° C.

Example 19: N- [3-cyano-4- (4
-Hydroxypiperidin-1-yl) phenyl] -5-
(1-cyclohexenyl) thiophene-2-carboxamide

Embedded image 5-Amino-2- (4-hydroxypiperidin-1-yl) benzonitrile and 5- (1
By performing the same operation as in Example 1 using (-cyclohexenyl) thiophene-2-carboxylic acid, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.5-1.6 (4H, m), 1.65
-1.7 (2H, m), 1.8 -1.9 (2H, m), 2.1-2.2 (2H,
m), 2.3-2.4 (2H, m), 2.8-2.9 (2H, m), 3.25-
3.35 (2H, m), 3.6-3.7 (1H, m), 4.72 (1H, d, J =
4.4 Hz), 6.25-6.35 (1H, m), 7.12 (1H, d, J = 3.9
Hz), 7.17 (1H, d, J = 9.2 Hz), 7.8-7.9 (2H, m),
8.01 (1H, d, J = 2.5 Hz), 10.24 (1H, s). Melting point: 180-182 ° C.

Example 20: 4- (4-chlorophenyl)
-N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] thiazole-2-carboxamide

Embedded image 5-Amino-2- (4-hydroxypiperidin-1-yl) benzonitrile and 4- (4
By performing the same operation as in Example 1 using sodium salt of (-chlorophenyl) thiazole-2-carboxylic acid, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.55-1.65 (2H, m), 1.
85-1.95 (2H, m), 2.85-2.95 (2H, m), 3.3-3.4
(2H, m), 3.6-3.7 (1H, m), 4.75 (1H, d, J = 3.9 H
z), 7.23 (1H, d, J = 9.3 Hz), 7.59 (2H, d, J = 8.3
Hz), 8.03 (1H, dd, J = 9.3, 2.9 Hz), 8.1-8.2 (3
H, m), 8.57 (1H, s), 10.77 (1H, s). Melting point: 104-107 ° C.

Example 21: 5- (4-chlorophenyl)
-N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] oxazole-2-carboxamide

Embedded image 5- (4-chlorophenyl) oxazole-2-carboxylic acid ethyl ester obtained in Starting Material Synthesis Example 4 (2.0
g), sodium hydroxide (0.48 g) and a 50% aqueous ethanol solution were heated under reflux for 1 hour. After evaporating the solvent,
The residue was treated with 1N hydrochloric acid to obtain an ocher solid (1.5 g). This solid was air-dried at 60 ° C. and used as it was in the next reaction. 5- (4-chlorophenyl) oxazole-2-carboxylic acid obtained by the above method and 5-amino-2- (4-
A yellow crystal was obtained by performing the same operation as in Example 1 using (hydroxypiperidin-1-yl) benzonitrile. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.55-1.6 (2H, m), 1.8
5-1.90 (2H, m), 2.85- 2.95 (2H, m), 3.3-3.4 (2
H, m), 3.6-3.7 (1H, m), 4.73 (1H, d, J = 4.4 Hz),
7.21 (1H, d, J = 8.8 Hz), 7.62 (2H, d, J = 8.2 H
z), 7.89 (2H, d, J = 8.2 Hz), 7.98 (1H, dd, J = 8.
8, 2.4 Hz), 8.07 (1H, s), 8.11 (1H, d, J = 2.4 H
z), 11.01 (1H, s). Melting point: 193-195 ° C.

Example 22: 3- (4-chlorophenyl)
-N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] -5-ethoxycarbonylbenzamide

Embedded image 5-Amino-2- (4-hydroxypiperidin-1-yl) benzonitrile and 5- (4
By performing the same operation as in Example 1 using -chlorophenyl) -3-ethoxycarbonylbenzoic acid, pale yellow crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.38 (3H, d, J = 7.3 H
z), 1.55-1.65 (2H, m), 1.85-1.95 (2H, m), 2.85
-2.95 (2H, m), 3.3-3.4 (2H, m), 3.6-3.7 (1H,
m), 4.35-4.45 (2H, m), 4.74 (1H, d, J = 3.9 Hz),
7.21 (1H, d, J = 8.8 Hz), 7.60 (2H, d, J = 8.3 H
z), 7.84 (2H, d, J = 8.3 Hz), 7.85-7.95 (1H, m),
8.10 (1H, d, J = 2.4 Hz), 8.34 (1H, s), 8.46 (1H,
s), 8.49 (1H, s), 10.60 (1H, s).

Example 23: 3- (4-chlorophenyl)
-5-[[3-Cyano-4- (4-hydroxypiperidin-1-yl) phenyl] aminocarbonyl] benzoic acid

Embedded image 3- (4-chlorophenyl) -N obtained in Example 22
-[3-cyano-4- (4-hydroxypiperidine-1
A solution of 2N sodium hydroxide (5 mL) was added to an ethanol solution of (-yl) phenyl] -5-ethoxycarbonylbenzamide (1 g), and the mixture was stirred at room temperature for 3 hours. Then, the solvent was distilled off, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. Recrystallization from N-methylpyrrolidone / water gave brown crystals (0.32 g). ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.55-1.65 (2H, m), 1.
85-1.95 (2H, m), 2.85-2.95 (2H, m), 3.3-3.4
(2H, m), 3.6-3.7 (1H, m), 4.74 (1H, brs), 7.22 (1
H, d, J = 8.8 Hz), 7.60 (2H, d, J = 8.8 Hz), 7.84
(2H, d, J = 8.8Hz), 7.9-7.95 (1H, m), 8.11 (1H,
d, J = 2.5 Hz), 8.36 (1H, s), 8.44 (1H, s), 8.52
(1H, s), 10.62 (1H, s). Melting point: 120-125 ° C

Example 24: 5-Bromo-N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] nicotinamide

Embedded image By performing the same operation as in Example 1 using 5-amino-2- (4-hydroxypiperidin-1-yl) benzonitrile and 5-bromonicotinic acid, a pale yellow solid was quantitatively obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.5-1.6 (2H, m), 1.8
-1.9 (2H, m), 2.8-2.9 (2H, m), 3.3-3.4 (2H, m
m), 3.6-3.7 (1H, m), 4.75 (1H, brs), 7.19 (1H, d,
J = 8.7 Hz), 7.84 (1H, d, J = 8.8 Hz), 8.05 (1H,
s), 8.51 (1H, s), 8.89 (1H, s), 9.04 (1H, s).

Example 25: 5- (4-chlorophenyl)
-N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] nicotinamide hydrochloride

Embedded image The same procedure as in Example 2 was carried out using the compound obtained in Example 24 and 4-chlorophenylboronic acid. The obtained crude product was made into hydrochloride by adding 4N hydrochloric acid / dioxane, and crystallized from N-methyl-2-pyrrolidone / ether / water to obtain pale yellow crystals. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.5-1.6 (2H, m), 1.8
-1.9 (2H, m), 2.85 -2.95 (2H, m), 3.25-3.35 (2
H, m), 3.6-3.7 (1H, m), 4.34 (1H, s), 7.22 (1H,
d, J = 8.8 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.9-8.
0 (3H, m), 8.13 (1H, d, J = 2.4 Hz), 8.73 (1H, s),
9.13 (1H, d, J = 1.9 Hz), 9.15 (1H, d, J = 1.9 H)
z), 10.83 (1H, s). Melting point: 195-200 ° C.

Example 26 6-bromo-N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] pyridine-2-carboxamide

Embedded image By performing the same operation as in Example 1 using 5-amino-2- (4-hydroxypiperidin-1-yl) benzonitrile and 6-bromopyridine-2-carboxylic acid,
A pale yellow amorphous was obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.55-1.6 (2H, m), 1.8
-1.9 (2H, m), 2.85 -2.95 (2H, m), 3.3-3.4 (2H, m
m), 3.6-3.7 (1H, m), 4.73 (1H, d, J = 4.4 Hz),
7.20 (1H, d, J = 8.8 Hz), 7.9-8.35 (5H, m), 10.5
9 (1H, s).

Example 27: 6- (4-chlorophenyl)
-N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] pyridine-2-carboxamide

Embedded image By performing the same operation as in Example 2 using the compound obtained in Example 26 and 4-chlorophenylboronic acid,
A pale yellow amorphous was obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.55-1.65 (2H, m), 1.
85-1.95 (2H, m), 2.85-2.95 (2H, m), 3.3-3.4
(2H, m), 3.6-3.7 (1H, m), 4.75 (1H, d, J = 4.4 H
z), 7.23 (1H, d, J = 8.8 Hz), 7.61 (2H, d, J = 8.3
Hz), 8.05-8.35 (5H, m), 8.43 (2H, d, J = 8.3 H
z), 10.62 (1H, s). Melting point: 98-100 ° C.

Example 28: N- [3-cyano-4- (4
-Hydroxypiperidin-1-yl) phenyl] -4-
Cyclohexyl benzamide

Embedded image By performing the same operation as in Example 1 using 5-amino-2- (4-hydroxypiperidin-1-yl) benzonitrile and 4-cyclohexylbenzoic acid, white crystals were obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.2-1.85 (14H, m),
2.5-2.6 (1H, m), 2.8- 2.9 (2H, m), 3.25-3.35
(2H, m), 3.6-3.7 (1H, m), 4.72 (1H, d, J = 4.4 H
z), 7.17 (1H, d, J = 9.3 Hz), 7.36 (2H, d, J = 7.8
Hz), 7.8-7.9 (3H, m), 8.09 (1H, d, J = 2.4 Hz),
10.26 (1H, s). Melting point: 218-220 ° C

Example 29: N- [3-cyano-4- (4
-Hydroxypiperidin-1-yl) phenyl] -4-
(1-pyrrolo) benzamide

Embedded image White crystals were obtained by performing the same operation as in Example 1 using 5-amino-2- (4-hydroxypiperidin-1-yl) benzonitrile and 4- (1-pyrrolo) benzoic acid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.5-1.6 (2H, m), 1.
8-1.9 (2H, m), 2.85-2.9 (2H, m), 3.3-3.4 (2H, m
m), 3.6-3.7 (1H, m), 4.72 (1H, d, J = 3.9 Hz),
6.31 (2H, dd, J = 2.0, 1.9 Hz), 7.19 (1H, d, J =
9.3 Hz), 7.52 (2H, dd, J = 2.0, 1.9 Hz), 7.76 (2
H, d, J = 8.7 Hz), 7.90 (1H, dd, J = 9.3, 2.9 Hz),
8.04 (2H, d, J = 8.8 Hz), 8.11 (1H, d, J = 2.5 H
z), 10.35 (1H, s). Melting point: 236-238 ° C.

Formulation example 1 (mg) Compound of the present invention 10.0 Lactose 109.6 Microcrystalline cellulose 27.4 Light anhydrous silicic acid 1.5 Magnesium stearate 1.5 150.0 (1 tablet) Compound of the present invention 30 g, lactose 328.8 g and microcrystalline cellulose 82.2 g are mixed. The mixture is compression molded using a roller compactor to obtain a flake-like compact. Using a hammer mill, crush the compressed flakes,
The pulverized product is sieved using a 20 mesh sieve. To the sieved product, 4.5 g of light anhydrous silicic acid and 4.5 g of magnesium stearate were added and mixed. The mixture is tableted using a 7.5 mm diameter mortar and punch, and a tablet 300 weighing 150 mg per tablet is prepared.
Obtain 0 tablets.

Hereinafter, the effects of the present invention will be described in detail with reference to experimental examples. Experimental Example 1: Inhibitory effect on IL-4 and IFN-γ production from mouse T cells stimulated with mitogen or antigen Mouse spleen T cells were cultured in the presence of the compound of the present invention,
Concanavalin A as a mitogen
When (Con A) was added and activated, IL-4 and IFN-γ produced in the culture supernatant were quantified by an enzyme antibody method using a specific antibody, whereby the compound of the present invention was quantified. The effect on IL-4 and IFN-γ production was evaluated. The experimental method is described below. 6-12
Spleens were aseptically excised from week-old male BALB / c mice and loosened using forceps in RPMI 1640 medium (Sigma) supplemented with 10% heat-inactivated fetal calf serum (FCS). After removing the erythrocytes by the toning treatment, a single cell suspension of splenocytes was prepared by washing three times with RPMI 1640 medium. Note that F
CS used was heat-inactivated at 56 ° C. for 30 minutes beforehand, and RPMI 1640 medium contained 10%.
mmol / L of 2- [4- (2-hydroxyethyl)-
1-piperazinyl] ethanesulfonic acid (HEPES),
60 μg / mL kanamycin sulfate and 100,000 units /
mL penicillin G potassium was added and used. Splenocytes were added to a 48-well plate at 2.5 × 10 ⁵ c / well, and the compound of the present invention was added at 0.0001 to 10 μmol / well.
L at each concentration, and 10 μg / mL Con A
(Type IV, manufactured by Sigma) in a CO ₂ incubator at 37 ° C. and 5% CO ₂ -95% air for 24 hours. The final volume of each well was 1.0 mL. After completion of the culture, the culture supernatant was collected and used for the quantification of IL-4 and IFN-γ. The culture supernatant was stored at -20 ° C until used for quantification. Quantification of IL-4 and IFN-γ in the culture supernatant was performed by the following method. 1 μg / mL rat anti-mouse IL-4 monoclonal antibody (Pharmingen) or rat anti-mouse IFN-γ monoclonal antibody (Pharmingen) is added to a 96-well microtest plate at 50 μL / well. And left at 4 ° C. overnight. After washing three times with the washing solution, Block Ace (Dainippon Pharmaceutical Co., Ltd.) was added at 200 μL / well,
Blocking was performed by allowing to stand at room temperature for 2 hours. After washing three times with the washing solution, the culture supernatant sample was
It was added at μL / well and left at 4 ° C. overnight. After washing four times with a washing solution, 1 μg / mL of biotin-labeled rat anti-mouse IL-4 monoclonal antibody (Pharmingen) or biotin-labeled rat anti-mouse IFN-
50 gamma monoclonal antibodies (Pharmingen)
μL / well was added and left at room temperature for 1 hour. After washing 6 times with the washing solution, 50% avidin-peroxidase was added.
μL / well, leave at room temperature for 40 minutes,
After washing 6 times, O-phenylenediamine as a substrate and hydrogen peroxide were added to develop color. The absorbance at 490 nm of each well was measured using a 1420 multilabel counter (Pharmacia Biotech). Recombinant mouse IL- as a standard sample
4 (manufactured by Pharmingen) or recombinant mouse IFN-γ (manufactured by Pharmingen)
From the standard curve, IL-4 or IFN-
The concentration of γ was quantified. Regarding the inhibitory effect of the compound of the present invention on IL-4 or IFN-γ production, a 50% inhibitory concentration (IC ₅₀ ) was determined by non-linear regression based on a dose-response curve. As a result, the compound of the present invention showed a decrease in IL-4 production of 0.0001 to 0.01 μm.
A strong inhibitory effect was exhibited in the concentration range of mol / L mol / L. On the other hand, the inhibitory effect on IFN-γ production is IL-
It was found that the compound of the present invention exhibited a selective inhibitory effect on IL-4 production, which was 1/10 to 1/1000 weaker than the inhibitory effect on 4 production. Further, IL-4 production induced when spleen T cells derived from BALB / c mice were activated using ovalbumin as an antigen, and a mouse Th2 cell line, D10. G4.1 cells were also evaluated for IL-4 production induced by stimulation with conalbumin, a specific antigen of the present cells, in the same manner as described above. It was suggested to show an effect.

Experimental Example 2: Effect on ovalbumin-induced biphasic ear edema in mice 0.5 ml of physiological saline containing 10 μg of ovalbumin (manufactured by Sigma) and 1 mg of aluminum hydroxide gel
Was intraperitoneally immunized twice at 6-week old male BALB / c mice (Charles River Japan Co., Ltd.) at 2-week intervals. One week later, mice were challenged with 10 μg of ovalbumin injected subcutaneously into the pinna of the mice to induce biphasic ear edema with bimodal edema 1 and 24 hours after challenge. The compound of the present invention or a pharmaceutically acceptable salt thereof is suspended or dissolved in 0.5% hydroxypropylmethylcellulose,
Oral administration was performed at a dose of 0.01 to 100 mg / kg body weight using an oral sonde for 3 weeks from the first immunization day. In this model, the thickness of the pinna of the mouse was measured using a dial gauge and used as an index of ear edema. The thickness of the pinna was expressed as an average value and a standard error for each group (n = 5 to 10), and statistically analyzed by the Dunnett method using the group administered with the vehicle alone as a control. The following cases were determined to be significant. A compound of the present invention or a pharmaceutically acceptable salt thereof,
Repeated oral doses of 0.1-100 mg / kg body weight induced edema in both the immediate phase at 1 hour after challenge and the late phase at 24 hours after challenge as compared to the vehicle-only control group. In addition, it was suggested that the inhibitory activity was suppressed in a dose-dependent manner, and that an allergic reaction involving Th2 cells was inhibited. Experimental Example 3: Toxicity test 100 mg / kg of the compound of the present invention was repeatedly orally administered to male SD rats and male BALB / c mice for 14 days, and no deaths were found.

[0075]

As is clear from the above-mentioned experimental examples, the compound of the present invention was obtained from IL-2 from Th2 cells sensitized with an antigen.
4. It has an effect of selectively inhibiting production, and thus is useful as an agent for preventing or treating allergic diseases. It is also useful as an agent for preventing or treating various autoimmune diseases.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61K 31/4525 A61K 31/4525 4C086 31/4535 31/4535 4C206 31/454 31/454 4H006 31/4545 31/4545 45 / 06 45/06 A61P 11/02 A61P 11/02 17/00 17/00 37/08 37/08 43/00 111 43/00 111 C07D 211/46 C07D 211/46 307/68 307/68 401/12 401/12 405/12 405/12 405/14 405/14 407/12 407/12 409/12 409/12 413/12 413/12 417/12 417/12 491/113 491/113 (72) Masahiko Kagoshima 3-7-1, Koyata, Iruma City, Saitama Prefecture Inside the Drug Discovery Laboratory, Welphide Co., Ltd. (72) Inventor Koichi Onoshi 3-5-25 Koyada, Iruma City, Saitama Prefecture, Japan 72) Inventor Hirotoshi Kataoka 3-25-25 Koyata, Iruma City, Saitama Prefecture Inside the Drug Discovery Research Laboratories Co., Ltd. (72) Inventor Kenji Chiharu 7-25, Koyata Iruma City, Saitama Prefecture 4C037 MA03 4C050 AA04 BB07 CC17 EE01 FF01 GG01 HH02 4C054 AA02 CC06 DD01 EE01 FF24 4C063 AA01 AA03 BB09 CC10 CC12 CC52 CC62 CC75 CC78 CC92 DD04 DD10 DD12 DD4 EA19 MA4 ZB13 4C086 AA01 AA02 AA03 BA03 BC21 CB22 GA02 GA04 GA07 GA08 GA09 GA10 GA12 MA01 MA02 MA52 NA05 NA14 ZA34 ZA89 ZB13 4C206 AA01 AA02 AA03 GA08 HA14 KA01 MA01 MA02 MA13 MA14 MA55 MA72 NA05 NA14 ZA34 AA ZA89

Claims (21)

[Claims] 1. A compound of the general formula (I) (Wherein, R ¹ is halogen, alkyl, alkoxy, nitro, optionally substituted amino, hydroxy, optionally substituted aryl, optionally substituted arylalkyl A heteroaryl which may have a substituent, a heteroarylalkyl which may have a substituent, a cycloalkyl which may have a substituent or a cycloalkenyl which may have a substituent Ring Q is benzene which may have a substituent, cyclohexane which may have a substituent or a heteroaromatic ring which may have a substituent, wherein R ² is hydrogen, alkyl, hydroxyalkyl, acyloxyalkyl, aminoalkyl, .R ³ .Z is showing a CH or N indicating the hydroxycarbonylalkyl or alkoxycarbonylalkyl Ha Gen, cyano, nitro, amino, alkyl, alkoxy, carboxy, alkoxycarbonyl, carbamoyl, alkenyl, and .R ⁵ .R ⁴ showing the alkynyl or haloalkyl showing hydrogen, halogen, cyano or nitro, alkyl, hydroxyalkyl, hydroxy Carbonylalkyl, aminoalkyl which may have a substituent, hydroxyl group, alkoxy, haloalkoxy, aryloxy, cycloalkyloxy, hydroxyalkoxy, hydroxycarbonylalkoxy, aminoalkoxy which may have a substituent, mercapto, Alkylthio, hydroxyalkylthio, hydroxycarbonylalkylthio, aminoalkylthio optionally having substituent (s), group: O-Het (wherein Het may have substituent (s) A saturated heterocyclic ring containing a heteroatom selected from a good oxygen atom or nitrogen atom is shown.) Group: N (R ⁶ ) (R ⁷ ) (wherein R ⁶ and R ⁷ are the same or different and each represents hydrogen, Represents an alkyl, hydroxyalkyl or aminoalkyl, or R ⁶ and R ⁷ together with an adjacent nitrogen atom form one oxygen, sulfur or nitrogen atom in the ring.
And a group forming a cyclic amine which may contain two or more. ) Or the formula (Wherein, R ⁸ represents hydrogen, halogen, alkyl, alkoxy, nitro, amino, or hydroxy; X represents ethylene ketal or propylene ketalized methylene; n represents 0, 1, or 2). Shows the group represented. Or a pharmaceutically acceptable salt thereof. 2. The ring Q has the following formula: (Wherein R ¹¹ represents hydrogen, halogen, alkyl, alkoxy, nitro, amino, hydroxy, carboxyl or alkoxycarbonyl. R ¹² represents hydrogen, alkyl,
Represents alkoxycarbonylalkyl, hydroxycarbonylalkyl, acyloxyalkyl or hydroxyalkyl. 2. The amide compound according to claim 1, which is benzene or a heteroaromatic ring represented by the formula: or a pharmaceutically acceptable salt thereof. Other symbols are as defined in claim 1. 3. Z represents CH, R ⁴ represents hydrogen, R
^2. The amide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ³ is halogen, cyano, nitro or haloalkyl substituted at the 3-position of the phenyl group based on the anilide group. Other symbols are as defined in claim 1. A ring Q is represented by the following formula: (R ¹¹ represents hydrogen, halogen, alkyl, alkoxy, nitro, amino, hydroxy, carboxyl or alkoxycarbonyl). Z represents CH, R ² represents hydrogen or alkyl. And R ³ represents a halogen, cyano, nitro or haloalkyl substituted at the 3-position of the phenyl group based on the anilide group, and R ⁴ is hydrogen, or a pharmaceutically acceptable salt thereof. . While other symbols are as in Claim 1, R ⁵ is substituted at the 4-position of the phenyl group relative to the anilide group. A ring Q is represented by the following formula: (Wherein R ¹¹ represents hydrogen, halogen, alkyl, alkoxy, nitro, amino, hydroxy, carboxyl or alkoxycarbonyl), Z represents CH, R ² represents hydrogen or alkyl, and R ³ represents A halogen substituted on the 3-position of the phenyl group based on the anilide group,
The amide compound according to claim 1, which represents cyano, nitro or haloalkyl, and R ⁴ is hydrogen, or a pharmaceutically acceptable salt thereof. Other symbols are as defined in claim 1, but R ⁵
Is substituted at the 4-position of the phenyl group based on the anilide group. 6. A group of R ⁵ : N (R ⁶ ) (R ⁷ ), wherein R ⁶ and R ⁷ are combined with an adjacent nitrogen atom to form an oxygen atom, a sulfur atom and a nitrogen atom in the ring by 1 to 5. The group forming a cyclic amine which may contain two is represented by the formula: (Wherein, R ^8a represents hydrogen, halogen, alkyl, alkoxy, nitro, amino or hydroxy. Y is CH
_2, ^{CH-R 9} or an N-R ^10,. m represents 0, 1 or 2. Where R ⁹ is hydroxy, alkyl,
Represents hydroxyalkyl, 4-piperidinyl or morpholino; R ¹⁰ represents hydrogen, alkyl, hydroxyalkyl, 4-piperidinyl or 3,4,5,6-tetrahydro-2H-pyran-4-yl; The amide compound according to claim 1, which is a group represented by the formula: or a pharmaceutically acceptable salt thereof. (1) N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] -4-iodobenzamide, (2) 4- (4-chlorophenyl) -N-
[3-Cyano-4- (4-hydroxypiperidine-1-
Yl) phenyl] benzamide, (3) N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] -3-iodobenzamide, (4) 3- (4-chlorophenyl) -N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] benzamide, (5)
5- (4-chlorophenyl) -N- [3-cyano-4-
(4-Hydroxypiperidin-1-yl) phenyl] furan-2-carboxamide, (6) 5- (4-chlorophenyl) -N- [3-cyano-4- (2,2-dimethyl-3-hydroxypropoxy) Phenyl] furan-2-
Carboxamide, (7) 5- (4-chlorophenyl)-
N- [2- (4-hydroxypiperidin-1-yl) pyridin-5-yl] furan-2-carboxamide;
(8) 5- (4-chlorophenyl) -N- [3-cyano-4- (4-morpholinopiperidin-1-yl) phenyl] furan-2-carboxamide, (9) 5- (4-chlorophenyl) -N -[3-cyano-4- [4- (3,
4,5,6-tetrahydro-2H-pyran-4-yl)
Piperazin-1-yl] phenyl] furan-2-carboxamide, (10) 5- (4-chlorophenyl) -N-
(3-cyano-4-piperidinophenyl) furan-2-
Carboxamide, (11) 5- (4-chlorophenyl)
-N- [3-cyano-4- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) phenyl] furan-2-carboxamide, (12) 5- (4-chloro-2
-Nitrophenyl) -N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] furan-2
-Carboxamide, (13) 5- (4-chlorophenyl) -N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] thiophen-2-carboxamide, (14) N- [3-cyano -4- (4-hydroxypiperidin-1-yl) phenyl] -5- (1-cyclohexenyl) thiophene-2-carboxamide,
(15) 4- (4-chlorophenyl) -N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] thiazole-2-carboxamide, (16) 5-
(4-chlorophenyl) -N- [3-cyano-4- (4
-Hydroxypiperidin-1-yl) phenyl] oxazole-2-carboxamide, (17) 3- (4-chlorophenyl) -N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] -5 -Ethoxycarbonylbenzamide, (18) 3- (4-chlorophenyl) -5-{[3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] aminocarbonyl} benzoic acid, (19) 5- (4-chlorophenyl) -N- [3
-Cyano-4- (4-hydroxypiperidin-1-yl) phenyl] nicotinamide, (20) 6- (4-chlorophenyl) -N- [3-cyano-4- (4-hydroxypiperidin-1-yl) Phenyl] pyridine-2-
Carboxamide, (21) N- [3-cyano-4- (4
-Hydroxypiperidin-1-yl) phenyl] -4-
The amide compound according to claim 1, which is selected from cyclohexylbenzamide, (22) N- [3-cyano-4- (4-hydroxypiperidin-1-yl) phenyl] -4- (1-pyrrolo) benzamide, or the amide compound thereof. Pharmaceutically acceptable salts. 8. A pharmaceutical composition comprising the amide compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 9. A pharmaceutical comprising the amide compound according to claim 1 or a pharmaceutically acceptable salt thereof. 10. An inhibitor of cytokine production from activated lymphocytes, comprising the amide compound according to claim 1 or a pharmaceutically acceptable salt thereof. 11. A type 2 helper T containing the amide compound according to claim 1 or a pharmaceutically acceptable salt thereof.
A selective inhibitor of interleukin 4 production from cells. 12. A preventive or therapeutic drug for an allergic disease, comprising the amide compound according to claim 1 or a pharmaceutically acceptable salt thereof. 13. An atopic dermatitis containing the amide compound according to claim 1 or a pharmaceutically acceptable salt thereof,
Preventive or therapeutic drug for asthma or allergic rhinitis. 14. A combination composition comprising the amide compound according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more drugs selected from immunosuppressants, steroids and antiallergic drugs. 15. The combination composition according to claim 14, wherein the immunosuppressant is selected from tacrolimus hydrate, ascomycin and FTY720. 16. The steroid agent may be prednisolone, methylprednisolone, dexamethasone, hydrocortisone, clobetasone, flumethasone, triamcinolone acetonide, alclomethasone, fluorocinolone acetonide, beclomethasone, betamethasone, deprodone, halcinonide, amshinonide, fluocinonide difluocinonide. 15. The combination composition according to claim 14, wherein the composition is selected from: difluperednate, diflorazone, clobetasol and fatty acid esters thereof. 17. The antiallergic agent may be sodium cromoglycate, tranilast, amlexanox, repirinast, ibudilast, tazanolast, pemirolast, ozagrel, supratast, pranlukast, ketotifen, azelastine, oxatomide, mequitazine, terfenadine, emedastamine, various kinds of azelastine, 15. A drug selected from antihistamines.
3. The combination composition according to item 1. 18. An amide compound according to claim 1 or a pharmaceutically acceptable salt thereof, and 1-2 selected from an immunosuppressant, a steroid and an antiallergic.
An action enhancer comprising the above drug. 19. The agent according to claim 18, wherein the immunosuppressant is selected from tacrolimus hydrate, ascomycin and FTY720. 20. The steroid agent, wherein the steroid is prednisolone, methylprednisolone, dexamethasone, hydrocortisone, clobetasone, flumethasone, triamcinolone acetonide, alclomethasone, fluorocinolone acetonide, beclomethasone, betamethasone, deprodone, halcinonide, amcinonide, fluocinonide, fluocinonidone. 19. The action enhancer according to claim 18, wherein the action enhancer is selected from, difluperednate, diflorazone, clobetasol and fatty acid esters thereof. 21. The anti-allergic agent, wherein sodium cromoglycate, tranilast, amlexanox, repirinast, ibudilast, tazanolast, pemirolast, ozagrel, supratast, pranlukast, ketotifen, azelastine, oxatomide, mequitazine, terfenadine, various kinds of medastatin epi- 19. A drug selected from an antihistamine drug.
The action enhancer according to the above.