JPWO2001007401A1 - Tricyclic compounds and pharmaceutical compositions containing the same - Google Patents

Abstract

(57) [Abstract] A compound of formula (I): [wherein ring A, ring B and ring C are aromatic carbocycles or heterocycles or the like; when ring A or the like is a 5-membered heterocycle which may have a substituent, ^W1 or the like represents a bond; X and X' are -O- or -NH- or the like; Y is lower alkyl, lower alkenyl or the like; ^V1 and ^V2 are single bonds or the like; ^Ra and ^Rb are hydrogen, lower alkyl, lower ^alkenyl or the like, or are joined together to form ^RcRdC = or -( ^CReRf )r-; ^Rc and ^Rd are hydrogen, lower alkyl, lower alkoxy or the like; ^Re and ^Rf are hydrogen, lower alkyl or the like; n is 0 ^to 2; and r is 2 to 6]; a prodrug thereof; a salt thereof; or a solvate thereof; and a pharmaceutical composition containing them are provided.

Description

Description: TECHNICAL FIELD The present invention relates to a novel tricyclic compound, and to an immunosuppressant, an antiallergic agent and an IgE antibody production inhibitor containing the same.

BACKGROUND ART A major problem in the recent surgeries for transplanting tissues and organs is the rejection reaction that attempts to reject the transplanted part after surgery. Avoiding this reaction is extremely important for the success of transplant surgery.

Various immunosuppressants such as azathioprine, corticoids, cyclosporine A, and tacrolimus have been developed and put to practical use and are used to prevent and treat rejection reactions after organ or tissue transplants and graft-versus-host reactions that occur after bone marrow transplants.
These methods are not necessarily satisfactory in terms of efficacy and side effects.

On the other hand, allergic diseases such as atopic dermatitis, allergic rhinitis, bronchial asthma, and allergic conjunctivitis have been increasing worldwide in recent years, posing a major problem. Conventional antiallergic drugs include inhibitors of the release of chemical mediators from mast cells, receptor inhibitors of the released chemical mediators, and inhibitors of allergic inflammatory reactions, but these are all symptomatic treatments and do not serve as therapeutic agents for the underlying allergic diseases.

In view of these points, there has been a demand for the development of more effective and safer medicines.

Compounds having a similar skeleton to the compound of the present invention and having immunosuppressive or antiallergic effects are disclosed in WO94/27980, WO95/13067, WO96/15123
, WO95/15318, WO96/40659, WO96/40143, WO
96/38412, WO96/10012, WO97/24356, WO97/
27181, WO97/24324, WO97/39999, WO97/443
33, WO97/46524, WO98/04508, WO98/24766,
WO98/24782, WO98/56785, FR2301250, US55
93991, JP-B 47-7368, JP-A 51-91259, JP-A 8-31
63, JP-A-9-124571, JP-A-9-71564, JP-A-9-12457
1, Japanese Patent Application Publication No. 11-79993, Bioorganic & Medicinal
Chemistry Letters, Vol. 5, No. 18, p 214
3-2146 (1995), J. Med. Chem. , 1974, Vol. 17
, No. 11, 1177-1181, etc. Liquid crystal compounds having a skeleton similar to that of the compound of the present invention are described in JP-A-58-121225 and JP-A-9-8725.
3, JP-A-63-253065, JP-A-1-106864, JP-A-1-1068
71, JP-A-2-83346, JP-A-9-48760 and JP-A-9-3106
3, WO88/07992, etc. disclose compounds having insecticidal and acaricidal activity.
EP06193067 discloses compounds having therapeutic effects on cardiovascular diseases and psychiatric disorders.
00717A1, a compound having a therapeutic effect on central nervous system diseases is disclosed in WO95/159
54, compounds having platelet aggregation inhibitory activity are disclosed in WO93/08181 and WO93
/10091, WO93/14077.

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a compound having excellent immunosuppressive and/or antiallergic activity and a pharmaceutical composition containing the same.

The present invention relates to a compound of formula (I): [In the formula, ring A, ring B and ring C each independently represent an aromatic carbon ring which may have a substituent or a 5- or 6-membered heterocycle which may have a substituent and which may be fused with a benzene ring, and when ring A, ring B and/or ring C is an optionally substituted 5-membered heterocycle, W ¹ , W ² and/or W ³ represent a bond.]

X is -O-, _-CH2- , ^-NR1- (wherein ^R1 is hydrogen, optionally substituted lower alkyl, lower alkenyl or lower alkylcarbonyl), or -
S(O)p- (wherein p is an integer of 0 to 2), X' is -O- or -NH-, Y is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted lower alkoxycarbonyl, optionally substituted sulfamoyl, optionally substituted amino, optionally substituted aryl or an optionally substituted 5- or 6-membered heterocyclic group, when X is _-CH2 or ^-NR1- , Y may be halogen, and when X is -O- or ^-NR1- , Y may be optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl.

One of ^V1 and ^V2 is a single bond, and the other is a single bond, —O—, —NH—, —O
_CH2- , _-CH2O- , -CH=CH-, -C≡C-, -CH( ^OR2 )-(
^R2 is hydrogen or lower alkyl), -CO-, ^-NHCHR3- or -CHR
³ NH— (R ³ is hydrogen or hydroxy).

R ^a and R ^b each independently represent hydrogen, optionally substituted lower alkyl,
optionally substituted lower alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted lower alkoxycarbonyl or optionally substituted lower alkylsulfonyl, or together represent R ^c R ^d C= or -
(CR ^e R ^f )r-, wherein R ^c and R ^d each independently represent hydrogen or optionally substituted lower alkyl;
[2] a compound represented by the formula (I): optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, optionally substituted lower alkenyloxy, optionally substituted lower alkynyloxy, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted 5- or 6-membered heterocyclic group, or taken together with the carbon atom to which it is attached form an optionally substituted cycloalkylidene, each R ^e is independently hydrogen, lower alkyl, lower alkoxy, or amino, each R ^f is independently hydrogen, lower alkyl, lower alkoxy, or amino, n is an integer of 0 to ² , and r is an integer of 2 to ⁶ ; [3] a compound represented by the formula (I):
[4] the compound according to [1] or [2], wherein ring B is an optionally substituted benzene ring, an optionally substituted pyridine ring, an optionally substituted pyrimidine ring, an optionally substituted pyridazine ring, or an optionally substituted pyrazine ring; [5] the compound according to [1] or [2], wherein two of ring A, ring B, and ring C are optionally substituted benzene rings, and one is an optionally substituted 6-membered heterocycle; [6] the optionally substituted 6-membered heterocycle is an optionally substituted pyridine ring, an optionally substituted pyrimidine ring, an optionally substituted pyridazine ring, or an optionally substituted pyrazine ring;
Or the compound according to [5], [7] a compound of formula (I'): (wherein Ring C is an optionally substituted benzene ring or an optionally substituted 6-membered heterocycle containing 1 or 2 heteroatoms; Y is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted amino; R ⁴ , R ⁵ , R 6 , R ⁷ , R ⁸ , R ⁹ , R ^{10 and R 11 each} independently is hydrogen, halogen, optionally protected hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted cycloalkoxy, optionally substituted lower alkylthio, optionally substituted lower alkylsulfonyloxy, carboxy or optionally substituted lower alkoxycarbonyl; and X, X′, R ^a , R ^b and n are as defined in [1]), [8] the compound according to [7], wherein R ⁴ and R ⁵ each independently are hydrogen, halogen, hydroxy or lower alkoxy, [9] The compound according to [7], wherein R ⁶ and R ⁷ are both hydrogen; [10] The compound according to [7], wherein R ⁸ is hydrogen or optionally substituted lower alkyl.
[11] The compound according to [7], wherein R ⁹ is optionally protected hydroxy, optionally substituted lower alkyl, or optionally substituted lower alkoxy, [12] The compound according to [7], wherein R ¹⁰ is optionally protected hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, or optionally substituted lower alkoxycarbonyl, [13] The compound according to [7], wherein R ¹¹ is hydrogen, optionally protected hydroxy, or optionally substituted lower alkyl, [14] The compound according to [1], wherein Ring C is an optionally substituted benzene ring, an optionally substituted pyridine ring, an optionally substituted pyrimidine ring, an optionally substituted pyridazine ring, or an optionally substituted pyrazine ring,
[15] The compound according to any one of [1], [2] or [7], wherein X is -O-, _-CH2- or -NH-, [16] The compound according to any one of [1], [2] or [7], wherein X is -NH-, [17] The compound according to any one of [1], [2] or [7], wherein Y is hydrogen, lower alkyl, arylalkyl, lower alkenyl or cycloalkyl, [18] ^Ra and ^Rb are each independently hydrogen, lower alkyl having 1 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms or alkoxycarbonyl having 1 to 6 carbon atoms,
Together they form ^RcRdC = or -( ^{CReRf )} r-, ^{and Rc} and R
each ^d is independently hydrogen, alkyl having 1 to 6 carbon atoms, or alkenyl having 2 to 6 carbon atoms;
each R ^{e is independently hydrogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, or amino; each R f is} independently hydrogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, or amino;
or 5; [19] the compound according to any one of [1], [2], or [7], wherein n is 0 or 1, X′ is —O—, R ^a and R ^b together form R ^c R ^d C=, and R ^c and R ^d are each independently hydrogen, a C-C ...
[20] a compound according to any one of [1], [2] or [7], wherein n is 0, X' is -NH-, Ra and ^{Rb are taken together to form RcRdC =} , and ^Rc and ^Rd are each independently hydrogen, alkyl having 1 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms or ^phenyl , or are taken together to form a cycloalkylidene having 5 or 6 carbon atoms with the carbon atom to which they are attached; [ ²¹ ] a compound according to any one of [1], [2] or [7], wherein n is 0, X' is -NH-, ^Ra and ^Rb are each independently hydrogen, lower alkyl, lower alkenyl or lower alkoxycarbonyl, or are taken together to form - ^{( CReRf} )r-, and R Each ^e is independently hydrogen, lower alkyl, lower alkoxy, or amino; each ^Rf is independently hydrogen, lower alkyl, lower alkoxy, or amino; and r is 4 or 5. [1]
, the compound according to either [2] or [7], [22] Ring C is a benzene ring optionally substituted with halogen, lower alkyl or lower alkoxy, or a pyridine ring optionally substituted with halogen, lower alkyl or lower alkoxy, X and X' are each independently -O- or -NH-, Y is hydrogen, lower alkyl, arylalkyl, lower alkenyl or cycloalkyl, ^R4 and ^R5 are each independently hydrogen or halogen, ^R6 and ^R7 are both hydrogen, ^R8 is hydrogen or lower alkyl, ^R9 is hydroxy, lower alkyl or lower alkoxy, ^R10 is hydroxy, lower alkyl, lower alkoxy or lower alkoxycarbonyl, ^R11 is hydrogen, hydroxy or lower alkyl, ^Ra and ^Rb are each independently hydrogen, lower alkyl, lower alkenyl or lower ^{alkoxycarbonyl} , or are taken together to form ^RcRdC = or -( ^CReR
Rc and ^Rd are each independently hydrogen, lower alkyl, lower alkenyl, lower alkoxy, or phenyl, or are taken together with the carbon atom to which they are attached to form a cycloalkylidene having 5 or 6 carbon atoms; ^Re are each independently hydrogen, lower alkyl, lower alkoxy, or amino; ^Rf are each independently hydrogen, lower alkyl, lower alkoxy, or amino; n is 0 or 1; and r is ⁴ or 5.

In another aspect, the present invention provides a pharmaceutical composition containing the compound according to any one of [1] to [22], a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, more specifically an immunosuppressant, an antiallergic agent, or an IgE antibody production inhibitor. The present invention also provides the use of the compound according to any one of [1] to [22], a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a medicament for suppressing immune responses and treating and/or preventing allergic diseases.
A method for suppressing an immune response, comprising administering the compound according to any one of [22], a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
Methods for treating and/or preventing allergic diseases are provided.

BEST MODE FOR CARRYING OUT THE INVENTION In this specification, the term "halogen" includes fluorine, chlorine, bromine and iodine. Fluorine and chlorine are particularly preferred.

As the protecting group for the "optionally protected hydroxy", any commonly used group can be suitably used, including, for example, t-butyl, benzyl, t-butyldimethylsilyl, methoxymethyl, and acetyl.

The term "lower alkyl" includes straight-chain or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl.

Substituents of "optionally substituted lower alkyl" include halogen; optionally protected hydroxy; lower alkoxy optionally substituted with lower alkoxy; acyl; acyloxy; carboxy; lower alkoxycarbonyl; mercapto; lower alkylthio; amino optionally substituted with hydroxy, lower alkyl or acyl optionally having a substituent; hydroxy, lower alkoxy, carboxy lower alkoxy, aryl lower alkoxy or 5- or 6-membered alkyl.
imino optionally substituted with a 3-membered heterocyclic group; hydrazono optionally substituted with carbamoyl or lower alkoxycarbonyl; carbamoyl optionally substituted with lower alkyl or amino; thiocarbamoyl optionally substituted with lower alkyl; cycloalkyl optionally substituted with lower alkyl or lower alkoxy; cycloalkenyl optionally substituted with lower alkyl;
Examples include cyano; phenyl which may be substituted with one or more of hydroxy, lower alkyl, carboxy, lower alkoxycarbonyl, or lower alkoxy; 5- or 6-membered heterocyclic groups which may be substituted with lower alkyl and which may be fused with a benzene ring, and the like, and one or more arbitrary positions may be substituted with these substituents. Preferred are halogen; hydroxy; acyl; acyloxy; carboxy;
Lower alkoxycarbonyl; phenyl; lower alkylphenyl; lower alkoxyphenyl; or lower alkyl optionally substituted by pyridyl or the like, more preferably lower alkyl optionally substituted by phenyl, and most preferably unsubstituted lower alkyl.

The lower alkyl moiety of "lower alkoxy", "lower alkoxycarbonyl", "lower alkylsulfonyl", "lower alkylsulfonyloxy", "lower alkylthio", "lower alkylamino", "aromatic heterocyclic lower alkyl" and "lower alkylenedioxy" is the same as the above "lower alkyl".

Substituents of "optionally substituted lower alkoxy", "optionally substituted lower alkoxycarbonyl", "optionally substituted lower alkylsulfonyl" and "optionally substituted lower alkylthio" include halogen; optionally protected hydroxy; lower alkoxy optionally substituted with acyloxy; acyl; acyloxy optionally substituted with hydroxy or carboxy; carboxy; lower alkoxycarbonyl; lower alkylthio; amino optionally substituted with lower alkyl; phenyl optionally substituted with lower alkyl or lower alkoxy; heterocyclic group; heterocyclic carbonyloxy and the like, which may be substituted with one or more of these substituents. Preferably, it is unsubstituted lower alkoxy.

The term "lower alkenyl" refers to a group having 2 to 10 carbon atoms and one or more double bonds at any position.
10, preferably straight-chain or branched alkenyl having 2 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. Specific examples include vinyl, propenyl (e.g., 2-propenyl, isopropenyl, etc.), butenyl, isobutenyl, prenyl, butadienyl,
pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl,
It includes hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.

The substituents of the "optionally substituted lower alkenyl" are the same as those of the above-mentioned "optionally substituted lower alkoxy", and any one or more positions may be substituted with these substituents. Particularly preferred are those substituted with halogen or unsubstituted.

The lower alkenyl moiety of "lower alkenyloxy", "lower alkenyloxycarbonyl" and "lower alkenylamino" is the same as the above "lower alkenyl".

The substituents of "optionally substituted lower alkenyloxy", "optionally substituted lower alkenyloxycarbonyl" and "optionally substituted lower alkenylthio" are the same as the substituents of the above-mentioned "optionally substituted lower alkoxy". One or more arbitrary positions may be substituted with these substituents.

The term "lower alkynyl" includes straight-chain or branched alkynyl having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, and specifically includes ethynyl, propynyl (e.g., 2-propynyl), butynyl (e.g., 2-butynyl), etc.
pentynyl, hexynyl, heptynyl, octynyl, nonyl, decynyl, etc. These have a triple bond at one or more arbitrary positions, and may further have a double bond.

The substituents of the "optionally substituted lower alkynyl" are the same as the substituents of the above-mentioned "optionally substituted lower alkoxy". One or more arbitrary positions may be substituted with these substituents.

The lower alkynyl moiety of "lower alkynyloxy" and the substituents of "optionally substituted lower alkynyloxy" are the same as those of the above "lower alkynyl" and "optionally substituted lower alkynyloxy".

"Acyl" refers to a straight-chain or branched alkylcarbonyl having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 4 carbon atoms, or a straight-chain or branched alkylcarbonyl having 3 to 10 carbon atoms.
, more preferably straight-chain or branched alkenylcarbonyl having 3 to 6 carbon atoms, most preferably 3 to 4 carbon atoms, cycloalkylcarbonyl and arylcarbonyl having 4 to 9 carbon atoms, preferably 4 to 7 carbon atoms. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl,
Examples include hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl, and benzoyl.

The term "aroyl" refers to arylcarbonyl and aromatic heterocyclecarbonyl. Here, examples of aromatic heterocycle include pyrrole ring, imidazole ring, pyrazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazole ring, triazine ring, isoxazole ring, oxazole ring, oxadiazole ring,
Examples include an isothiazole ring, a thiazole ring, a thiadiazole ring, a furan ring, and a thiophene ring.

The substituents of the "optionally substituted acyl" are the same as the substituents of the above-mentioned "optionally substituted lower alkoxy", and the arylcarbonyl may further have a lower alkyl as a substituent.

The acyl moiety of "acyloxy" is the same as the above-mentioned "acyl". The substituents of "optionally substituted acyloxy" are the same as those of the above-mentioned "optionally substituted acyl", and any one or more positions may be substituted with these substituents.

The term "lower alkylcarbonyl" includes aliphatic acyl having 2 to 4 carbon atoms, such as acetyl, propionyl, butyryl, and isobutyryl. Acetyl is particularly preferred.

"Cycloalkyl" refers to a carbocyclic group of 3 to 6 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Substituents of "optionally substituted cycloalkyl" include lower alkyl, halogen, optionally protected hydroxy, carboxy, lower alkoxycarbonyl, lower alkoxy, lower alkylenedioxy, imino optionally substituted with lower alkoxy, aryl, or 5- or 6-membered heterocyclic group, and may be substituted at any one or more positions. Unsubstituted cycloalkyl is preferred.

The term "cycloalkenyl" includes the above-mentioned cycloalkyls having one or more double bonds at any position in the ring, and specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclohexadienyl.

The substituents of the "optionally substituted cycloalkenyl" are the same as those of the above-mentioned "cycloalkyl". Any one or more positions may be substituted with these substituents.

"Cycloalkylidene" includes divalent carbon ring groups having 3 to 6 carbon atoms, and specifically includes cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene. The substituents of "optionally substituted cycloalkylidene" are the same as those of the above-mentioned "cycloalkyl," and any one or more positions may be substituted with these substituents. Unsubstituted cycloalkylidene is preferred.

Substituents of the "optionally substituted amino" include optionally substituted lower alkyl [wherein the substituent is lower alkoxy, cycloalkyl, optionally substituted amino (wherein the substituent is aroyl optionally substituted with acyloxy-lower alkoxy), optionally substituted aryl (wherein the substituent is lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl) or heterocyclic group]; lower alkenyl; lower alkynyl; cycloalkyl; aryl optionally substituted with lower alkyl, carboxy, acyl, lower alkoxycarbonyl; sulfamoyl optionally substituted with lower alkyl; optionally substituted lower alkoxycarbonyl [wherein the substituent is halogen, acyloxy, hydroxy-substituted acyloxy, carboxy-substituted acyloxy, heterocyclic carbonyloxy, etc.]; lower alkylsulfonyl, etc. Preferred examples of substituted amino include lower alkylamino, lower alkenylamino, cycloalkylamino, phenylamino, and lower alkoxycarbonylamino. One or more arbitrary positions may be substituted with these substituents.

The term "carbamoyl which may be substituted" includes carbamoyl which may be substituted with one or more groups selected from lower alkyl, lower alkenyl, lower alkynyl, and the like.

The term "optionally substituted sulfamoyl" includes sulfamoyl and the like which may be substituted with one or more groups selected from lower alkyl, lower alkenyl, lower alkynyl and the like.

The term "aromatic carbocycle" refers to a monocyclic or polycyclic aromatic carbocycle, such as a benzene ring,
It includes a naphthalene ring, an anthracene ring, a phenanthrene ring, etc. A benzene ring is particularly preferred. The "aromatic carbocyclic ring" may be condensed with another carbocyclic ring, and also includes an indane ring, an indene ring, and a dihydronaphthalene ring.

"Aryl" refers to a group in which one hydrogen atom has been removed from a monocyclic or polycyclic aromatic carbon ring, and includes phenyl, naphthyl, anthryl, phenanthryl, and the like. Phenyl is particularly preferred. Furthermore, "aryl" may be fused with another carbon ring, and the fused carbon ring may have a bond. Examples include indanyl, indenyl, dihydronaphthyl, and the like.

Substituents of the "optionally substituted aromatic carbocycle", the "optionally substituted aryl" and the "optionally substituted benzene ring" include halogen; optionally protected hydroxy; lower alkyl optionally substituted with halogen or carboxy; lower alkoxy optionally substituted with halogen, aryl, aromatic heterocyclic group or lower alkoxy; lower alkenyl;
Lower alkynyl; cycloalkyl; lower alkenyloxy; lower alkynyloxy; cycloalkoxy; acyl; acyloxy; carboxy; lower alkoxycarbonyl; lower alkenyloxycarbonyl; lower alkylthio; lower alkynylthio; lower alkyl, cycloalkyl lower alkyl, aryl lower alkyl,
Examples include heteroaryl lower alkyl, lower alkenyl, cycloalkyl, acyl which may be substituted with halogen, amino which may be substituted with lower alkoxycarbonyl or lower alkylsulfonyl; guanidino; nitro; lower alkylsulfonyl; dihydroxyboryl; lower alkylsulfonyloxy which may be substituted with halogen; arylsulfonyl; arylsulfonyloxy; aryl; or a 5- or 6-membered heterocyclic group, and any one or more positions may be substituted with these substituents. Preferred substituents are halogen; optionally protected hydroxy; lower alkyl optionally substituted with halogen; lower alkoxy optionally substituted with aryl or lower alkoxy; lower alkenyl; lower alkenyloxy; acyl; acyloxy; lower alkoxycarbonyl; lower alkylthio; amino optionally substituted with lower alkyl, lower alkenyl, acyl optionally substituted with halogen or lower alkylsulfonyl; nitro; lower alkylsulfonyl; lower alkylsulfonyloxy optionally substituted with halogen; or arylsulfonyloxy, more preferably halogen, hydroxy, lower alkyl, lower alkoxy, carboxy or lower alkoxycarbonyl.

The aryl moiety of "arylalkyl", "arylsulfonyl", "arylsulfonyloxy" and "arylcarbonyl" is the same as the above "aryl", and phenyl is particularly preferred.

The substituents of the "optionally substituted arylsulfonyl" are the same as those of the above-mentioned "optionally substituted aryl", and any one or more positions may be substituted with these substituents. Unsubstituted ones are particularly preferred.

The term "5- or 6-membered heterocycle" includes 5- or 6-membered heterocycles having one or more heteroatoms selected from O, S, and N in the ring, and specifically includes pyrrole rings, imidazole rings, pyrazole rings, pyridine rings (4-pyridyl, etc.),
aromatic heterocycles such as a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazole ring, a triazine ring, an isoxazole ring, an oxazole ring, an oxadiazole ring, an isothiazole ring, a thiazole ring, a thiadiazole ring, a furan ring, and a thiophene ring, a tetrahydropyran ring, a dihydropyridine ring, a dihydropyridazine ring, a dihydropyrazine ring, a dioxane ring, an oxathiolane ring, a thiane ring, a pyrrolidine ring,
Examples of the heterocyclic ring include a non-aromatic heterocyclic ring such as a pyrroline ring, an imidazolidine ring, an imidazoline ring, a pyrazolidine ring, a pyrazoline ring, a piperidine ring, a piperazine ring, and a morpholine ring.

The "5- or 6-membered heterocycle containing one or two heteroatoms" includes aromatic heterocycles such as pyrrole ring, imidazole ring, pyrazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, furan ring, and thiophene ring, and non-aromatic heterocycles such as dioxane ring, oxathiolane ring, thiane ring, dihydropyridine ring, pyrrolidine ring, pyrroline ring, imidazolidine ring, imidazoline ring, pyrazolidine ring, pyrazoline ring, piperidine ring, piperazine ring, and morpholine ring. Aromatic heterocycles are particularly preferred.

The "5- or 6-membered heterocyclic ring" in ring A, ring B or ring C is preferably a pyridine ring or a pyrimidine ring having bonds at the 2- and 5-positions, respectively.

The "5- or 6-membered heterocyclic group" for Y is preferably 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1,2-dihydropyridin-5-yl, 2,3-dihydropyridazin-6-yl, 1,2-dihydropyrazin-5-yl, or the like.

Examples of the "5- or 6-membered heterocyclic ring optionally condensed with a benzene ring" include an indole ring, an isoindole ring, a benzimidazole ring, an indazole ring,
a cinnoline ring, a phthalazine ring, a quinazoline ring, a benzisoxazole ring, a benzoxazole ring, a benzoxadiazole ring, a benzothiazole ring, a benzisothiazole ring, a benzofuran ring, a benzothiophene ring, a benzotriazole ring,
Examples include an isobenzofuran ring, an indoline ring, an isoindoline ring, and a chromene ring, which may have a bond to the fused hetero ring.

Substituents of the "optionally substituted 5- or 6-membered heterocycle", the "optionally substituted 5- or 6-membered heterocycle which may be fused with a benzene ring" and the "optionally substituted 5- or 6-membered heterocycle containing 1 or 2 heteroatoms" include halogen; optionally protected hydroxy; lower alkyl which may be substituted with hydroxy or acyloxy; halogen,
lower alkoxy optionally substituted with aryl or a 5- or 6-membered heterocycle; lower alkenyl; lower alkenyloxy; lower alkynyl; lower alkynyloxy; acyloxy; carboxy; lower alkoxycarbonyl; mercapto; lower alkylthio; lower alkenylthio; amino optionally mono- or di-substituted with halogen, optionally substituted lower alkyl (the substituent is cycloalkyl or a 5- or 6-membered heterocycle), acyl optionally substituted with halogen, lower alkenyl, cycloalkyl or lower alkylsulfonyl;
Examples include imino optionally substituted with lower alkylsulfonyl, nitro, lower alkylsulfonyl, aryl, 5- or 6-membered heterocycle, oxo, or oxide, which may be substituted at any one or more positions. Preferred are halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, amino optionally substituted with lower alkyl or lower alkenyl, and particularly preferred is lower alkyl.

The substituents of the "optionally substituted 5- or 6-membered heterocycle containing 1 or 2 heteroatoms" are the same as those described above, but are preferably unsubstituted or substituted with lower alkyl.

The phrase "when ring A, ring B and/or ring C is a 5-membered heterocyclic ring which may have a substituent, W ¹ , W ² and/or W ³ represent a bond" means that when ring A is a 5-membered heterocyclic ring, W ¹ represents a bond, and the bonding positions of V ¹ and X to ring A are Similarly, when ring B or ring C is a 5-membered heterocycle, ^W2 or ^W3 represents a bond, and the bonding positions of ^V1 and ^V2 are X, ^V1 or ^V2 may be directly bonded to a heteroatom which is a constituent atom of ring A, ring B or ring C, respectively.

"R ^a and R ^b together form -(CR ^e R ^f )r-" means that R
^{R a} and R ^b together with the N atom to which they are bonded form a nitrogen-containing saturated heterocycle which may have a substituent, and examples thereof include aziridine which may have a substituent, azetidine which may have a substituent, pyrrolidine which may have a substituent, piperidine which may have a substituent, and perhydroazepine which may have a substituent (wherein the substituent is lower alkyl, lower alkoxy, or amino). A plurality of R ^e and a plurality of R ^f may each independently represent hydrogen, lower alkyl, lower alkoxy, or amino, and specifically, -(CH ₂ )
_2- , -( _CH2 ) _3- , -CH(Me)( _CH2 ) _3- , _-CH2CH (OM
e) ( _CH2 ) _3- , -( _CH2 ) _3CH ( _NH2 )( _CH2 ) _2- and the like.

The present invention includes pharmaceutically acceptable salts of Compound (I) of the present invention. For example, salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, etc.; salts of formic acid, acetic acid,
Salts of organic acids such as tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, and succinic acid;
Examples include salts of organic bases such as ammonium, trimethylammonium, and triethylammonium; salts of alkali metals such as sodium and potassium, and salts of alkaline earth metals such as calcium and magnesium.

The present invention includes solvates (preferably hydrates) of Compound (I) of the present invention. Examples of solvates include solvates with organic solvents and/or water. When forming a hydrate, the compound may be coordinated with any number of water molecules.

The present invention includes all stereoisomers (for example, atropisomers) of compound (I).

All of the compounds (I) have immunosuppressive, antiallergic and/or IgE antibody production inhibitory effects, but the following compounds are particularly preferred.

In formula (I), 1) ring A is an aromatic carbocyclic ring which may have a substituent, or
A compound having a 5- or 6-membered heterocyclic ring (hereinafter, the A ring is assumed to be A-1).
wherein ring A is an optionally substituted benzene ring or an optionally substituted 6
a compound in which ring A is a benzene ring optionally having a substituent (hereinafter, a compound in which ring A is A-3)
a compound in which ring A is substituted with a substituent (halogen, optionally protected hydroxy, lower alkyl,
lower alkoxy, carboxy or lower alkoxycarbonyl).
A compound in which ring A is a benzene ring (hereinafter referred to as A-4), wherein ring A may have a substituent (halogen, hydroxy, or lower alkoxy).
Compounds in which the A ring is an optionally halogen-substituted benzene ring (hereinafter, the A ring is referred to as A-6)
2) a compound in which ring B is an aromatic carbocyclic ring optionally having a substituent, or
A compound having a 5- or 6-membered heterocyclic ring (hereinafter, the B ring is assumed to be B-1).
wherein ring B is an optionally substituted benzene ring or an optionally substituted 6
a compound in which ring B is a benzene ring optionally having a substituent (hereinafter, a compound in which ring B is B-3);
) compounds in which ring B has a substituent (halogen, optionally protected hydroxy,
optionally substituted lower alkyl, optionally substituted lower alkoxy, or substituted
Benzene optionally having a lower alkoxycarbonyl group)
A compound in which ring B is a ring (hereinafter, ring B is referred to as B-4), where ring B is a substituent (hydroxy, lower alkyl, lower alkoxy, or lower alkoxy)
The B ring is B-5.
(Let's say the compound has ring B.)(hereinafter, the B ring is referred to as B-6), 3) a compound in which the C ring is an aromatic carbocycle which may have a substituent or a
A compound having a 5- or 6-membered heterocyclic ring (hereinafter, the C ring is assumed to be C-1)
The C ring is an optionally substituted benzene ring or an optionally substituted benzene ring,
It is a 6-membered heterocycle containing 1 or 2 heteroatoms (hereinafter, the C ring is C-2
a compound in which the C ring is a benzene ring optionally having a substituent,
pyridine ring, optionally substituted pyrimidine ring, optionally substituted pyrimidine ring,
a pyridazine ring or a pyrazine ring which may have a substituent (hereinafter referred to as C ring)
is C-3), wherein the C ring is a benzene ring, pyridine ring, pyrimidine ring, pyridazine ring, or pyrazine ring
(These may be substituted with halogen, lower alkyl or lower alkoxy.
(Hereinafter, the C ring is assumed to be C-4) Compounds in which the C ring is a benzene ring or a pyridine ring (these are not halogenated, lower alkyl, or lower alkyl).
(hereinafter, the C ring is assumed to be C-5.)
4) Compounds in which X is —O—, —CH₂-or-NR¹- (where R¹is hydrogen or a substituent
(hereinafter, X is assumed to be X1)
substance, X is -O-, -CH₂- or -NH- (hereinafter, X is assumed to be X2).
Compounds in which X is -O- or -NH- (hereinafter referred to as X3), Compounds in which X is -NH- (hereinafter referred to as X4), 5) Compounds in which Y is hydrogen, optionally substituted lower alkyl, or optionally substituted lower alkyl
and optionally substituted lower alkenyl or optionally substituted cycloalkyl (the following
(Hereinafter, Y is assumed to be Y1) Compounds in which Y is hydrogen, lower alkyl, arylalkyl, lower alkenyl, or cycloalkyl
Compounds in which Y is lower alkyl, benzyl, or lower alkenyl (hereinafter, Y is Y2), compounds in which Y is lower alkyl, benzyl, or lower alkenyl (hereinafter, Y is Y3),
(hereinafter, Y is assumed to be Y4) 6) Compounds where Y is prenyl (hereinafter, Y is assumed to be Y4) 7) Compounds where V¹and V²and R are both single bonds, 7) R^aand R^bare each independently hydrogen, lower alkyl, lower alkenyl, or
lower alkoxycarbonyl, or together with R^cR^dC= or −(CR
^eR^f)r-, and R^cand R^dare each independently hydrogen, lower alkyl, lower
lower alkenyl, lower alkoxy, aryl or heterocyclic group, or together
together with the carbon atom to which they are attached form a cycloalkylidene, and R^eEach is unique
R is hydrogen, lower alkyl, lower alkoxy, or amino;^fEach is unique
each independently represents hydrogen, lower alkyl, lower alkoxy, or amino; and r is 2 to 6.
is an integer (hereinafter referred to as R^aand R^b(where R is Rab-1)^aand R^beach independently represents hydrogen, alkyl having 1 to 6 carbon atoms,
alkenyl or alkoxycarbonyl having 1 to 6 carbon atoms, or together
R^cR^dC= or −(CR^eR^f)r-, and R^cand R^dare independent
and hydrogen, alkyl having 1 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms,
alkoxy, phenyl or a 5- or 6-membered aromatic heterocyclic group of the formula
, and the carbon atoms to which they are bonded together form a cycloalkyl group having 5 or 6 carbon atoms.
Form a den and R^eare each independently hydrogen, alkyl having 1 to 6 carbon atoms,
6 alkoxy or amino, and R^fare each independently hydrogen, a C1 to C6
alkyl, alkoxy having 1 to 6 carbon atoms, or amino; and r is 4 or 5.
(hereinafter referred to as R^aand R^b(where R is Rab-2)^aand R^beach independently represents hydrogen, alkyl having 1 to 3 carbon atoms, or alkyl having 1 to 3 carbon atoms
4 alkoxycarbonyl, or together with R^cR^dC= or −(CR
^eR^f)r-, and R^cand R^dare each independently hydrogen, a C 1-3 alkyl group
alkyl, alkenyl having 2 to 4 carbon atoms, or alkoxy having 1 to 3 carbon atoms; R
^eare each independently hydrogen or alkyl having 1 to 3 carbon atoms; R^fare independent of each other
is hydrogen or alkyl having 1 to 3 carbon atoms, and r is 4 or 5 (hereinafter referred to as R
^aand R^b(where R is Rab-3)^aand R^beach independently represents hydrogen, alkyl having 1 to 3 carbon atoms, or alkyl having 1 to 3 carbon atoms
4 alkoxycarbonyl, or together with R^cR^dC=, and R^c
and R^done of which is alkyl having 1 to 3 carbon atoms, and the other is hydrogen,
or lower alkoxy having 1 to 3 carbon atoms (hereinafter referred to as R^aand R^b
(assuming that R is Rab-4)^aand R^bTogether, R^cR^dC=, and R^cand R^dOne of the
alkyl having 1 to 3 carbon atoms, and the other is alkyl having 1 to 3 carbon atoms or
and lower alkoxy having a molecular weight of 1 to 3 (hereinafter referred to as R^aand R^bLet be Rab-5
) Compounds, 8) Compounds where n is 0 or 1 (hereinafter referred to as n1), Compounds where n is 1 (hereinafter referred to as n2), 9) Ring A, Ring B, Ring C, X, Y, R^a, R^band n is one of the following combinations:
Reka and V¹and V²A compound in which both are single bonds.

In formula (I'), 1) the C ring is an aromatic carbocyclic ring optionally having a substituent or a substituted or unsubstituted aromatic carbocyclic ring.
Compounds in which the C ring is C-1', compounds in which the C ring is C-2, compounds in which the C ring is C-3, compounds in which the C ring is C-4
a compound in which the C ring is C-5, 2) a compound in which X is X1, a compound in which X is X2, a compound in which X is X3,
is X4, 3) a compound where Y is Y1, a compound where Y is Y2, a compound where Y is Y3,
is Y4, 4) R⁴, R⁵, R⁶and R⁷are each independently hydrogen, halogen, or protected
Optionally, hydroxy, lower alkyl, lower alkoxy, carboxy or lower alkyl
alkoxycarbonyl (hereinafter referred to as R⁴~R⁷is R47-1) Compound
thing, R⁴, R⁵, R⁶and R⁷are each independently hydrogen or halogen (hereinafter,
R⁴~R⁷(where R is R47-2) Compound, R⁴and R⁵one of which is hydrogen and the other is halogen, and R⁶and R⁷but
Both are hydrogen (hereinafter referred to as R⁴~R⁷is R47-3) Compound, 5) R⁸, R⁹, R¹⁰and R¹¹are each independently hydrogen, halogen, or protected
optionally substituted hydroxy, optionally substituted lower alkyl,
optionally substituted lower alkoxy, carboxy or optionally substituted lower
alkoxycarbonyl (hereinafter referred to as R⁸~R¹¹is R811-1
(R) compound,⁸, R⁹, R¹⁰and R¹¹each independently represents hydrogen, optionally protected hydroxyl
hydroxy, lower alkyl, lower alkoxy or lower alkoxycarbonyl
(hereinafter referred to as R⁸~R¹¹(assuming that R811-2) Compound, R⁸and R¹¹are each independently hydrogen, hydroxy, lower alkyl or lower alkyl
alkoxycarbonyl, and R⁹and R¹⁰are each independently hydroxy, lower alkyl
alkyl, lower alkoxy, or lower alkoxycarbonyl (hereinafter referred to as R⁸
~R¹¹(assuming that R811-3) Compound, R⁸is hydrogen or lower alkyl, and R⁹is hydroxy, lower alkyl or
lower alkoxy, and R¹⁰is hydroxy, lower alkyl, lower alkoxy or
or lower alkoxycarbonyl, R¹¹is hydrogen, hydroxy or lower alkyl
alkyl or lower alkoxycarbonyl (hereinafter referred to as R⁸~R¹¹is R811
-4) compound, R⁸, R⁹, R¹⁰and R¹¹Each combination is the same as B-6 above.
(hereinafter referred to as R⁸~R¹¹is R811-5) Compound, 6) R^aand R^ba compound in which R is Rab-1;^aand R^bis Rab-2
A compound, R^aand R^ba compound in which R is Rab-3;^aand R^bRa
b-4, the compound R^aand R^bis Rab-5, 7) Compounds where n is n1, compounds where n is n2, 8) Compounds where C ring, X, Y, R^a, R^band n is any of the following combinations:
R⁴~R⁷is R47-3, and R⁸~R¹¹A compound in which R811-4 is

More specifically, preferred examples of the present invention include compounds (I) in which ring A, ring B
The combinations of the ring, ring C, X, Y, ^Ra and ^Rb (represented by (ABC,RaRb)) are as shown below, and ^V1 and ^V2 are single bonds.

(Tables 1 to 3 are A1, A2, ..., B1, B2, ... C used in Tables 4 to 12.
Tables 4 to 12 show the partial structures represented by the symbols ABC1, A, C2, ...
The combinations of rings A, B and C represented by the symbols BC2, ... are shown in Table 1.
3 shows the combinations of ^Ra and ^Rb represented by each symbol RaRb1, RaRb2, ... In the table, cHex represents cyclohexyl, and cPr represents cyclopropyl.
) The combinations of ring A, ring B, ring C, X, Y, R ^a and R ^b are preferably as follows.

Among the above compounds, more preferred are compounds in which X' is -O- and n is 0, compounds in which X' is -O- and n is 1, and compounds in which X' is -NH- and n is 0.

The method for producing compound (I) is explained below.

[Method A] For example, a compound represented by the following formula (I') (hereinafter referred to as compound (I')) can be produced from a compound represented by formula (II) (hereinafter referred to as compound (II)) and a compound represented by formula (III) (hereinafter referred to as compound (III)).

(wherein the substituent L is halogen, lower alkylsulfonyl, arylsulfonyl,
The other symbols are as defined above. Compounds (II) and (III) are dissolved in a suitable solvent (e.g., benzene, toluene,
The target compound (
I') is obtained.

When compound (I'') in which R ^a and R ^b combine to form R ^c R ^d C= can be obtained, it can be prepared from R ^c R ^d C=N-X'H and compound (II) in the same manner as above, or a compound (I'') in which R ^a and R ^b are hydrogen, obtained from compound (II) can be prepared.
I') and a compound represented by formula (IV) (hereinafter referred to as compound (IV)).

(wherein each symbol has the same meaning as defined above) First, compound (II) is dissolved in a suitable solvent (e.g., toluene, tetrahydrofuran,
N,N-dimethylformamide, dimethyl sulfoxide, pyridine, methanol, ethanol, or the like) or without a solvent to give compound (I'
, X' = NH) or Journal of Chemical Society, 192
Compound (I', X' = O) is obtained by a method using N-hydroxyphthalimide as described in Journal of Chemical Society, 6, 2348, or a method using benzohydroxamic acid as described in Journal of Chemical Society, 1927, 874. The obtained compound is subjected to dehydration condensation with a carbonyl compound (IV) such as a ketone or aldehyde, if necessary, in the presence of an acid catalyst (hydrochloric acid, acetic acid, trifluoroacetic acid, lower alkanesulfonic acid, arylsulfonic acid, etc.), to obtain the target compound (I'').

Furthermore, when either R ^c or R ^d of the obtained compound (I″) is lower alkoxy, the compound (I″) can be reacted with an acid (hydrochloric acid, acetic acid, perchloric acid, etc.) in a suitable solvent (e.g., toluene, tetrahydrofuran, dioxane, dichloromethane, etc.)
In the presence of a carbonyl compound (R ^c C(═O)R ^d ), the compound can be converted to a target compound having different R ^c and R ^d .

The compound (I') in which R ^a and R ^b are hydrogen can also be synthesized from a compound represented by formula (II') (hereinafter referred to as compound (II')).

(wherein Q is _NH2 or a group that does not adversely affect the Suzuki reaction and can be converted to the substituent L by a general method, and other symbols have the same meanings as above.) For example, compound (II', Q = OH) is converted into an alkoxide or phenoxide using a suitable base (e.g., sodium hydride, potassium t-butoxide, potassium carbonate, sodium hydroxide, potassium hydroxide, etc.), and the alkoxide or phenoxide is reacted with chloramine or O-arylsulfonylhydroxylamine (described in Journal of Organic Chemistry, 1973 (38) 1239-1241, etc.), or compound (II', Q = _NH2 ) is converted into an alkoxide or phenoxide with chloramine or O-arylsulfonylhydroxylamine (described in Journal of Organic Chemistry, 1949 (14) 888-890, etc.).
13).

[Method B] Compound (I') can also be produced by reacting a compound represented by formula (V) (hereinafter referred to as compound (V)) with a compound represented by formula (VI) (hereinafter referred to as compound (VI)).

(wherein one of M and D is dihydroxyboryl, di-lower alkylboryl, or
di-lower alkoxyboryl, the other being halogen or —OSO₂(C_qF2_q
+1) (q is an integer from 0 to 4, and the other symbols are as defined above). Compound (V) and compound (VI) are dissolved in a suitable solvent (e.g., benzene, toluene).
, N,N-dimethylformamide, dimethoxyethane, tetrahydrofuran, di
Paraffin is a mixture of water and ethanol or anhydrous water.
Pd(PPh₃) 4, PdCl₂(PPh₃)₂, PdCl
₂, Pd(OAc)₂or PdCl₂(CH₃CN)₂etc., preferably Pd(
PPh₃)₄) in the presence of basic conditions (for example, K₃P.O.₄, NaH
CO₃, NaOEt, Na₂CO₃, Et₃N, Ba(OH)₂, Cs₂CO₃
, CsF, NaOH or Ag₂CO₃etc.) at room temperature or under heating for several tens of minutes to several tens of hours
The reaction gives compound (I').

Compound (VI) may be a known compound, and the compounds (I') and (I
Compounds obtained by the same method as in the compound (II) may also be used.

One of the substituents M and D is a group selected from the group consisting of ...
nication 1979, 866, Journal of the Society of Synthetic Organic Chemistry, 1993, No. 5
Any boryl group applicable to the present invention (Vol. 1, No. 11, pp. 91-100) may be used.
The other is applicable to the Suzuki reaction.
Any available leaving group may be used, for example, halogen or -OSO₂(C_q
F_2q+1) (where q is an integer of 0 to 4), etc. can be used.
or trifluoromethanesulfonyloxy (hereinafter referred to as OTf), etc. are preferred.
Most preferred is bromine, iodine or OTf.

Other substituents on rings A, B and C of compounds (V) and (VI) and
-X-Y is a group that does not adversely affect the Suzuki reaction, such as halogen and -OSO₂
(C_qF_2q+1) (where q is an integer of 0 to 4)
Even if any of the substituents on rings A, B and C is halogen, the substituent M
If the reactivity of with the substituent D is higher than that of the substituent D, this reaction can proceed without any problems.
It is Noh.

Among the compounds (V), in particular those of the following formula: (wherein one of ^R4 and ^R5 is hydrogen and the other is halogen; ^R9 and ^R10 each independently represent lower alkyl or lower alkoxy; and M represents dihydroxyboryl, di-lower alkylboryl, or di-lower alkoxyboryl). Most preferred is compound (V-1) represented by the formula:

The compounds (II) and (II') in the above reaction scheme may be known compounds, and can be synthesized by known methods or the following method.

(wherein the formula, the substituent Q is _NH2 or a group that does not adversely affect the Suzuki reaction and can be converted to the substituent L by a conventional method, and the other symbols have the same meanings as above.) Compound (V) obtained by a known compound or the method described in WO98/04508 and compound (VI') obtained by a known compound or a conventional method from a known compound are used to obtain compound (II) by Suzuki reaction in the same manner as in the above step. When the substituent L adversely affects the Suzuki reaction, compound (II') can be first obtained using compound (VI''), and then the substituent Q can be converted to the substituent L.

For example, when the substituent Q is hydroxy, it can be converted to halogen under ordinary conditions, and the target compound can also be obtained using an appropriate sulfonylating agent (e.g., methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc.).
In the case of a hydroxy protected with a suitable protecting group such as butyldimethylsilyl or methoxymethyl, the target compound can be obtained by the above-mentioned method after deprotection to the hydroxy by a conventional method.

When the substituent Q is a lower alkylthio or an optionally substituted arylthio, it may be converted into the corresponding sulfone using an appropriate oxidizing agent (e.g., hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, oxone-persulfuric acid compound, etc.).

Among the compounds (VI″), in particular those of the following formula: wherein ring C is a pyridine ring optionally substituted with a lower alkyl or a pyrimidine ring optionally substituted with a lower alkyl; Q is a protected hydroxyl group;
Preferred are compounds represented by the formula: Q is lower alkylthio or arylthio, D is dihydroxyboryl, di-lower alkylboryl, or di-lower alkoxyboryl, and n is an integer of 0 to 2, and more preferred are compounds in which Q is lower alkylthio or phenylthio, n is 0, and D is dihydroxyboryl. Unsubstituted pyridineboronic acids are extremely difficult to synthesize due to their high water solubility, but the introduction of the substituent Q facilitates synthesis and enables production in high yields.

The compound (V) used in the above reaction may be a known compound, and when V ¹ is a single bond, it may be prepared from a known compound by Suzuki reaction in the same manner as above.

V ¹ is -O-, -NH-, _-OCH2- , _-CH2O- , -CH=CH-, -
C≡C—, —CH(OR ² )— (R ² is hydrogen or lower alkyl), —CO—,
When the compound is —NHCHR ³ — or —CHR ³ NH— (R ³ is hydrogen or hydroxy), it can be synthesized by the following method.

(wherein M' is a group which can be converted to M by a conventional method and does not adversely affect the condensation reaction of E and G; one of E and G is hydroxy or amino, and the other is halogen, lower alkylsulfonyloxy, arylsulfonyloxy, lower alkylsulfonyl, arylsulfonyl, or methyl having any of these as a substituent; one of E and G is lithium or Mg(Hal) (wherein Hal is halogen) and the other is carboxy, lower alkoxycarbonyl, carbamoyl, or formyl; or one of E and G is formyl;
and the other is a halogenated methyl, or either one is ethynyl and the other is halogen. Other symbols are as defined above.) The compound (V') of interest, wherein V ¹ is -O-, -NH-, -OCH ₂ -, -C
When the substituents E and G are _H2O- , _-NHCH2- , or _-CH2NH- , one of the substituents E and G is hydroxy or amino, and the other is a leaving group such as halogen, lower alkylsulfonyloxy, arylsulfonyloxy, lower alkylsulfonyl, or arylsulfonyl, or methyl having such a leaving group as a substituent. Compounds (VII) and (VIII) are reacted in a suitable solvent (e.g., benzene, toluene, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, methanol, or ethanol) in the presence of a base (e.g., sodium hydride, pyridine, triethylamine, potassium carbonate, sodium hydroxide, or potassium hydroxide), and if necessary, with a copper catalyst (e.g., copper powder, CuCl, or CuO), at 0°C or under heat for several minutes to several tens of hours to obtain compound (V').

In the reaction of compound (VII) and compound (VIII), V of the target compound
When ¹ is -CO- or -CH(OH)-, one of the substituents E and G is an organic metal such as lithium or Mg(Hal) (wherein Hal is a halogen), and the other is carboxy, lower alkoxycarbonyl, carbamoyl, or formyl. These two compounds are reacted in an appropriate solvent (e.g., diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, etc.) at -78°C or under heating for several minutes to several hours to obtain compound (V').

When V ¹ of the target compound is —CH(OR ² )— (R ² is lower alkyl), a compound in which V ² is —CH(OH)— is first obtained, and then this compound is alkylated.

In addition, in the compound (V'), V ¹ is -CO-, V ¹ is -CH(OH)
- can also be obtained by reacting compound (V') where V 1 of compound (V') is - with an oxidizing agent such as chromic anhydride or Jones reagent in a solvent such as t-butyl alcohol or acetone under heating at ⁰ °C for several hours depending on the oxidizing agent.
A compound in which V1 is —H)— can also be produced by reducing a compound in which ^V1 is —CO— with sodium borohydride, lithium aluminum hydride, or the like in a suitable solvent (e.g., diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, methanol, ethanol, etc.).

When ^V1 of compound (V') is -CH=CH-, one of the substituents E and G is formyl, and the other is a methyl halide (e.g., chlorine, bromine, or iodine as the halogen). In this case, Wittig
ig) Reaction (Organic Reaction)
), 1965, vol. 14, p. 270) to obtain the compound (V').

When V ¹ of compound (V′) is —CH≡CH—, one of the substituents E and G is ethynyl, and the other is halogen (preferably bromine or iodine), a coupling reaction (for example, Synthesis (1980) 627, Tetrahedron (Te
trahedron), 1982, 38, 631).

Subsequently, compound (V') is converted to compound (V) by a conventional method.

For example, when M' is hydroxy, a base (
For example, sodium hydride, pyridine, triethylamine, or potassium carbonate.
In the presence of the compound (III), the target compound in which M is OTf is obtained by reacting the compound with a trifluoromethanesulfonylating agent (e.g., trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, or N-phenyltrifluoromethanesulfonimide) at −20° C. or under heating for several minutes to several tens of hours.

When M' is hydrogen, the reaction is carried out in a suitable solvent (e.g., acetic acid, dichloromethane,
The target compound in which M is a halogen atom is obtained by reacting the compound with a halogenating agent (e.g., chlorine, bromine, iodine, or N-bromosuccinimide) in a solvent (e.g., chloroform, carbon tetrachloride, N,N-dimethylformamide, or water) at −20° C. or under heating for several minutes to several tens of hours.

When M' is formyl, it can be converted to a Baeyer-Villiger methyl ester by a conventional method.
Then, the compound in which M is OTf can be obtained by the same method as above.

When M' is nitro, it is reduced to amino, and the Sandmeyer (
A compound in which M is halogen can be obtained by a Sandmeyer reaction.

The method for synthesizing compound (I) is preferably the Suzuki reaction described above, which is the most efficient, simplest, and most preferable. However, as described in WO98/04508, it is also possible to carry out the reaction using silicon, zinc, tin, etc. in place of the boryl group in the above scheme.

For compounds having a substituent that would interfere with the above reaction, the group may be protected in advance with an appropriate protecting group and then removed by a conventional method at an appropriate stage. For example, when a hydroxyl group interferes with the reaction, the group may be protected with methoxymethyl, methanesulfonyl, benzyl, trifluoromethanesulfonyl, t-butyldimethylsilyl, etc. and then removed at an appropriate stage.

For example, when protecting a hydroxyl group with methanesulfonyl, methanesulfonyl chloride may be reacted in the presence of a base such as triethylamine or pyridine in a solvent such as dichloromethane, chloroform, or carbon tetrachloride under ice-cooling to room temperature for several hours. When deprotecting the compound, 1 to 4 N sodium hydroxide, potassium hydroxide, an aqueous solution thereof, sodium methoxide, or ethyl magnesium bromide may be added in a solvent such as dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, dioxane, or dimethoxyethane, and the reaction may be carried out at room temperature or under heating for several tens of minutes to several hours.

When methoxymethyl is used as a protecting group for hydroxy, tetrahydrofuran,
A protected hydroxyl group can be obtained by reacting with chloromethyl methyl ether in the presence of sodium hydride, diisopropylethylamine, etc. in a solvent such as dioxane or dimethoxyethane. For deprotection, a conventional deprotection reaction can be carried out using hydrochloric acid, sulfuric acid, etc. in a solvent such as methanol, tetrahydrofuran, or acetic acid.

When t-butyldimethylsilyl is used as the protecting group, the protecting group can be reacted with t-butyldimethylsilyl chloride, t-butyldimethylsilyl triflate, etc. in a solvent such as N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, etc., in the presence of imidazole, triethylamine, 2,6-lutidine, etc. In the deprotection reaction, the protecting group can be removed by reacting with tetrabutylammonium fluoride, etc., in a solvent such as tetrahydrofuran.

The compound of the present invention obtained as described above can be further converted into a prodrug.

"Prodrugs" are a group of compounds that can be easily converted in vivo into the active compounds of the present invention, and prodrug formation can be carried out by any commonly used method. Methods for selecting and producing appropriate prodrug derivatives are described, for example, in Design of Prodrugs, El
Sevier, Amsterdam, 1985. According to this, a group generally used for prodrug formation may be introduced into carboxy, hydroxy, amino, or the like, bonded to any position of the compound of the present invention.

For example, when hydroxy is present as a substituent on the A ring or C ring, —COCH₂
CH₂COOH, -COCH=CHCOOH, -COCH₂SO₃H, -PO_{3
H 2}, -COCH₂NMe₂, -CO-Py (Py represents pyridyl), etc.
It is possible.

When the A ring or C ring has an amino group as a substituent, for example, —COO
CR^gR^hOCOCH₂Rⁱ[R^gand R^hare each independently hydrogen or a lower alkyl group.
It is Rukill and Rⁱis H, —OH, —CONHR^j-OCONHR^j, -(NH
COCR^kR^l) tNHCOCH₃, -(NHCOCR^kR^l) tNHCOC₂
H₅, -CSNH₂, −(OCH₂CH₂)_SOH, -OCH₃, −(OCH₂
CH₂)_SOCH₃, -COCH₃, -COC₂H₅, -OCOCH₃, -OC
O.C.₂H₅, -NHOH, -NHCONH₂, -NHCSNH₂, -NHSO₂
CH₃, -N(SO₂CH₃)₂, -SO₂NH₂, -SOCH₃, -SO₂C
H₃, -OCH₂CONH₂, -OCH₂CON (CH₃)₂, -SO₂N (C
H₃)₂, -PO(OCH₃)₂, -NHCSNHC₂H₅, —CH═NNHC
ONH₂, -CH=NNHCSNH₂, -CH=NNHSO₂CH₃, triazo
aryl and tetrazolyl, and R^j, R^kand R¹is hydrogen or lower alkane
where s is 1 or 2, and t is an integer from 0 to 2;
(CH₃)OCOC(CH₃)₃, -COOCH₂OCO (CH₂)₁₄CH₃
, -COOCH₂OCO-Pyr, -CH₂NHCO-C₆H₄-o-OCH₂
OAc or the like may be introduced.

When the above-mentioned substituted acyloxycarbonyl (-COOCR ^g R ^h OCOCH ₂ R ⁱ ) is introduced into an amino group present at any position of the compound of the present invention to form a prodrug, for example, an amino group present at any position of the compound of the present invention is α-haloalkoxycarbonylated, and then an appropriate carboxylic acid is reacted under appropriate conditions to obtain a prodrug compound.

The synthesis of such acyloxyalkyl carbamates is described in WO96/1860.
5 and the like.

Specifically, first, the compound of the present invention having an amino group and an α-haloalkyl chloroformate are dissolved in an inert solvent (diethyl ether, tetrahydrofuran, 1,4-
The resulting compound is reacted in a solvent (N,N-dioxane, ethyl acetate, toluene, etc.) at 0° C. to room temperature in the presence of a base (pyridine, triethylamine, N-methylmorpholine, etc.) to obtain a haloalkoxycarbamate compound.
A prodrug compound is obtained by reacting a substituted carboxylic acid compound with a salt (e.g., alkali metal salt, alkaline earth metal salt, silver salt, mercury salt, etc.) in an aqueous solvent (e.g., dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, etc.) at room temperature or under heat for several hours to several days.

When there is a substituent that interferes with the formation of a prodrug, the group may be protected in advance with an appropriate protecting group, and then removed by a conventional method at an appropriate stage.

IgE is produced by B cells and sensitizes mast cells to degranulation, inducing allergy. Therefore, the compounds of the present invention suppress IgE antibody production and can be used as immunosuppressants or antiallergic agents.

The immunosuppressant or antiallergic agent of the present invention is effective in treating rejection reactions after organ or tissue transplantation, graft-versus-host reactions caused by bone marrow transplantation, atopic allergic diseases (
For example, bronchial asthma, allergic rhinitis, allergic dermatitis, etc.), hypereosinophilic syndrome, allergic conjunctivitis, systemic lupus erythematosus, polymyositis, dermatomyositis, scleroderma, MCTD, rheumatoid arthritis, inflammatory bowel disease, ischemia-reperfusion injury,
It is useful for the prevention or treatment of allergic diseases such as hay fever, allergic rhinitis, urticaria, and psoriasis.

When the compound of the present invention is administered as an immunosuppressant, antiallergic agent and/or IgE antibody production inhibitor, it can be administered either orally or parenterally. For oral administration, it may be prepared in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccal preparations or sublingual preparations according to a conventional method and administered. For parenteral administration, it may be administered in the form of injections such as intramuscular and intravenous injections, suppositories,
It can be suitably administered in any commonly used dosage form such as transdermal absorption agents, inhalants, etc. Oral administration is particularly preferred.

An effective amount of the compound of the present invention is mixed with an excipient, binder, wetting agent, disintegrant, etc., suitable for the dosage form.
Pharmaceutical preparations can be prepared by mixing with various pharmaceutical additives such as lubricants and diluents as necessary. In the case of injections, the preparations can be prepared by sterilizing the mixture together with a suitable carrier.

Specifically, examples of excipients include lactose, sucrose, glucose, starch, calcium carbonate, crystalline cellulose, etc.; binders include methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, etc.; disintegrants include carboxymethylcellulose, sodium carboxymethylcellulose, starch, sodium alginate, agar powder, sodium lauryl sulfate, etc.; and lubricants include talc, magnesium stearate, macrogol, etc. As a suppository base, cocoa butter, macrogol, methylcellulose, etc. can be used. Furthermore, when preparing a liquid, emulsion, or suspension injection, commonly used solubilizers,
Suspending agents, emulsifying agents, stabilizers, preservatives, isotonic agents, etc. may be added as appropriate, and in the case of oral administration, flavoring agents, aromatics, etc. may also be added.

The dosage of the compound of the present invention as an immunosuppressant, antiallergic agent and/or IgE antibody production inhibitor is preferably determined taking into consideration the age and weight of the patient, the type and severity of the disease, the route of administration, etc., but when orally administered to adults, it is usually 0.05
In the case of parenteral administration, the dose varies greatly depending on the administration route, but is usually 0.00 to 100 mg/kg/day.
The dose is 5 to 10 mg/kg/day, preferably 0.01 to 1 mg/kg/day, and may be administered once or several times a day.

The present invention will be described in more detail below with reference to examples, but these examples are not intended to limit the scope of the present invention.

Examples Example 1 Synthesis of Compound (I-1) (Step 1) To a solution of compound (1) (23.7 g, 0.1 mol, described in Journal of Organic Chemistry, 1961 (26) 3351-3356) in dimethoxyethane (300 ml)-ethanol (150 ml) was added boronic acid (2) (22.
An aqueous solution (150 ml) of tetrakis(triphenylphosphine)palladium (3.47 g, 3 mmol) and sodium carbonate (31.8 g, 0.3 mol) was added, and the reaction mixture was degassed. Tetrakis(triphenylphosphine)palladium (3.47 g, 3 mmol) was added, and the mixture was heated under reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried, and concentrated, and the resulting residue was crystallized from hexane to give compound (3) (24.92 g; yield 84%).

(Step 2) In the same manner as in Step 1, compound (4) (1.56 g;
A yield of 92% was obtained.

(Step 3) Compound (4) (1.56 g, 4.62 mmol) in dichloromethane (5 ml)
To the solution, pyridine (0.56 ml, 6.92 mmol) was added under ice-cooling, followed by trifluoroacetic anhydride (0.78 ml, 5.54 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed successively with water, a 5% aqueous solution of sodium bicarbonate, and saturated saline, and then dried and concentrated. To a solution of the residue in dichloromethane (16 ml), metachloroperbenzoic acid (2.0 g, 11.6 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Aqueous sodium thiosulfate was added to the reaction mixture, which was extracted with chloroform and washed twice with a 5% aqueous solution of sodium bicarbonate, then dried and concentrated. The residue was dissolved in dimethylformamide (8 ml) and diluted with potassium carbonate (720 mg, 5.21 mmol).
mol), followed by prenyl bromide (0.52 ml, 4.34 mmol), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate 2:1) to obtain compound (5) (1.71 g; yield 69%).

(Step 4) Acetoxime (137 mg, 1.87 mmol) in dimethylformamide (3
ml) solution with sodium hydride (60% mineral oil, 137 mg, 1.87
After stirring at room temperature for 1 hour, compound (5) (250 mg, 0
468 mmol) was added. After stirring at room temperature for 14 hours, the reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous citric acid solution and saturated brine, dried, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate 7:3) to obtain compound (I-1) (126 mg; yield 62%).

Reference Example 1 Synthesis of Compound (2) 1,4-Dibromo-2,5-dimethylbenzene (154 g, 583 mmol)
A suspension of the above in tetrahydrofuran (1.31) was cooled to -78°C, and a 1.53M butyllithium-hexane solution (400 ml, 612 mmol) was added dropwise over 30 minutes. The reaction mixture was stirred at the same temperature for another hour, and then triisopropyl borate (1
A solution of 70 ml of HCl (734 mmol) was added in one go, and the refrigerant was removed. The mixture was stirred for 1 hour while the temperature was gradually raised. Water (300 ml) and 1N hydrochloric acid (650 ml) were added, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, dried, and concentrated. The crystalline residue was washed with hexane and filtered to obtain compound (2) (115 g; yield 86%).
Reference Example 2 Synthesis of Compound (VI''-2) A solution of 1.53 M butyllithium in hexane (500 ml, 765 mmol) in tetrahydrofuran (1.28 l) was cooled to -78°C, and 5-bromo-2-
Methylthiopyridine (142 g, 695 mmol) in tetrahydrofuran (40
A solution of water (320 ml) was added dropwise over 40 minutes. The reaction mixture was stirred at the same temperature for another 30 minutes, and then triisopropyl borate (195 ml, 834 mmol) was added dropwise over 30 minutes. The refrigerant was removed, and the mixture was stirred for 30 minutes while gradually increasing the temperature.
After adding 3N hydrochloric acid (ml), the mixture was concentrated under reduced pressure, and the residue was further diluted with water (710 ml) and isopropyl ether (210 ml).
The precipitated crystals were filtered, washed with water and isopropyl ether, and dried to obtain compound (VI''-2) (111 g; yield 95%).

Melting point: 151-154°C _. Elemental analysis calculated ( _C6H8BNO2S ): C, _42.64 ; H, 4.77; N
, 8.29; S, 18.97 Measured values: C, 42.56; H, 4.88; N, 8.14; S, 18.
79. ¹ H-NMR (DMSO-d ₆ ) δ 2.51 (s, 3H), 7.25 (dd,
J = 0.9, 8.1, 1H), 7.93 (dd, J = 2.1, 8.1, 1H),
8.73 (dd, J = 0.9, 2.1, 1H) Example 2 Synthesis of Compound (I-3) (Step 1) Synthesis of Compound (6) Compound (5) (380 mg, 0.921 m) was synthesized in the same manner as in Step 4 of Example 1.
Compound (6) (240 mg; yield 56%) was obtained from the above-mentioned 2-amino-3-methyl-2-propanol (2-methyl-2-propanol).

(Step 2) Synthesis of Compound (I-3) A solution of compound (6) (200 mg, 0.433 mmol) in dioxane (1 ml) and ethanol (1 ml) was added with 3-pentanone (0.23 ml, 2.17 mmol).
To the reaction mixture, 2N hydrochloric acid (0.476 ml, 0.953 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated brine, dried, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate 87:13) and then crystallized from hexane to obtain compound (I-3) (149 mg; yield 75%).

Example 3 Synthesis of Compound (I-61) Compound (7) (261 mg, 0
A solution of 251 mg of O-mesitylenesulfonylhydroxylamine (described in Journal of Organic Chemistry, 1973 (38) 1239-1241) in methanol (4 ml) was cooled to 0°C, and potassium t-butoxide (75 mg, 0.65 mmol) was added and stirred for 15 minutes. The solvent was evaporated under reduced pressure, and the residue was dried and then dissolved in N,N-dimethylformamide (2.5 ml).
After adding 1.16 mmol) and stirring for 1 hour, the reaction mixture was poured into water and extracted with ethyl ether:ethyl acetate (1:1). The extract was washed with water and saturated brine, dried, and concentrated. The residue was dissolved in methanol (3 ml) and added with acetone (0.48 ml, 6.5
The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (hexane-ethyl acetate 10:1) to obtain compound (I-
61) (118 mg; yield 40%) was obtained.

Example 4 Synthesis of Compounds (V-2) and (I-169) (Step 1) Synthesis of Compound (9) Compound (8) (4.41 g, 15.0 mmol) was dissolved in dichloromethane (45 ml
) solution, 3-methyl-2-butenal (1.74 ml, 18.0 mmol),
Acetic acid (1.8 g, 30.0 mmol) and sodium triacetoxyborohydride (6.36 g, 30.0 mmol) were added sequentially, and the reaction mixture was stirred for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate and saturated brine, dried, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate 9:1) to obtain compound (9) (4.09 g; yield 75%).
obtained.

(Second Step) Synthesis of Compound (V-2) Compound (9) (2.4 g, 6.62 mmol) was dissolved in tetrahydrofuran (24 m
l) The solution was cooled to -78°C and 1.53M butyllithium (10.4 ml, 1
To the reaction mixture was added dropwise 5.9 mmol) over 30 minutes. After stirring for another 2 hours, triisopropyl borate (5.5 ml, 23.8 mmol) was added, and the refrigerant was removed and the mixture was stirred for 30 minutes while gradually warming to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with an aqueous ammonium chloride solution and saturated brine, dried, and concentrated. The crystalline residue was washed with hexane and filtered to obtain compound (V-2) (1.82 g;
The yield was 87%). ¹ H-NMR (DMSO-d ₆ ) δ 1.70 (s, 3H), 1.72 (s, 3H).
H), 2.12 (s, 3H), 2.63 (s, 3H), 3.63 (br t, 2
H), 5.28 (br t, 1H), 6.01 (br t, 1H), 6.37 (
dd, J=2.1, 13.2, 1H), 6.46(dd, J=2.1, 8.4,
1H), 6.92 (s, 1H), 6.97 (t, J=8.4, 1H), 7.77
(s, 1H) (Step 3) Synthesis of Compound (I-169) Compound (10) (175 mg, 0.75 m) was synthesized in the same manner as in Step 1 of Example 1.
Compound (I-169) (268 mg; yield 83%) was obtained from (I-168) (1.5 mol) and boronic acid (V-2) (245 mg, 0.75 mmol).

Reference Example 3 Synthesis of Compound (10) 5-bromo-2-hydrazinopyridine (described in Journal of Heterocyclic Chemistry, 1986 (23) 1071) (376 mg, 2.0 mmol)
The compound (10) was heated under reflux in acetone (1 ml) and ethanol (4 ml) for 15 minutes, and the reaction mixture was concentrated to give compound (10) (456 mg, quantitative yield) as a crystalline residue.

Example 5 Synthesis of Compound (I-92) (Step 1) Synthesis of Compound (13) Compound (11) (500 mg, 1.42 mmol) was dissolved in dimethoxyethane (6 m
l)-To a solution of boronic acid (12) (624 mg, 1.5 ml) in ethanol (1.5 ml),
57 mmol) and 2M aqueous sodium carbonate solution (3 ml) were added, and the reaction mixture was degassed.
The mixture was heated under reflux for 18 hours under a nitrogen atmosphere, cooled, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried, and concentrated. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate 4:1) to give compound (13) (604 mg; yield 95%).

(Step 2) Synthesis of Compound (14) Compound (13) (604 mg, 1.36 mmol) was dissolved in tetrahydrofuran (6
ml) solution was added triethylamine (0.28 ml, 2.03 mmol) under ice cooling.
Then, trifluoroacetic anhydride (0.23 ml, 1.63 mmol) was added, and 1
The reaction mixture was stirred for 5 minutes, diluted with ethyl acetate, washed with water and saturated brine, and then
It was dried and concentrated.

To a solution of the crude product in N,N-dimethylformamide (4 ml), potassium carbonate (
375 mg, 2.71 mmol), followed by prenyl bromide (0.31 ml, 2.7
The reaction mixture was poured into water and mixed with ethyl acetate-
The extract was extracted with ethyl ether (1:1), and the extract was washed with water and saturated brine, dried, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate 1:1).
After purification with tetrahydrofuran (9:1), the product was dissolved in tetrahydrofuran (8 ml).
Tetrabutylammonium fluoride in tetrahydrofuran (1.04 ml, 1
The reaction mixture was poured into water, extracted with ethyl acetate, and the extract was washed with saturated brine, dried, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate 3:1) to give compound (14) (543 mmol).
g (yield 81%).

(Step 3) Synthesis of Compound (I-92) Compound (14) (236 mg, 0.48 mmol) in dichloromethane (4 ml
) solution was added triphenylphosphine (162 mg, 0.62 mmol) under ice cooling.
Subsequently, carbon tetrabromide (205 mg, 0.62 mmol) was added and stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate 9:1) and then dissolved in N,N-dimethylformamide (3 ml).

To a solution of acetoxime (139 mg, 1.9 mmol) in N,N-dimethylformamide (2 ml), potassium t-butoxide (187 mg, 1.67 mmol) was added
After stirring at room temperature for 30 minutes, the mixture was cooled to 0° C. The reaction mixture was cooled to 0° C.
A 1,2-dimethylformamide solution was added and stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl ether:ethyl acetate (1:1). The extract was washed with saturated brine, dried, and concentrated. The residue was purified by silica gel chromatography (hexane:ethyl acetate 10:1) and then crystallized from ethyl ether-hexane to give compound (I-92) (117 mg; yield 54%).

Compound (I) was synthesized in the same manner as above. The structural formula is shown below.

A1, A2, ..., B1, B2, ..., C1, C2, ... used in Table 14 and later
The symbols have the same meanings as above.

Test Example 1 Inhibitory effect on IgE antibody production against anti-ovalbumin (OVA) 1) Animals BALB/c mice (female, 8-10 weeks old) and Wistar rats (female, 8-10 weeks old) purchased from Japan SLC (Shizuoka) were used.

BALB/c mice were immunized by intraperitoneal injection of 0.2 ml of a solution prepared by suspending 2 μg of ovalbumin (OVA) and 2 mg of aluminum hydroxide gel in physiological saline. Ten days later, blood was collected from the heart, and serum was separated and stored at −40° C. until measurement of IgE antibody titer.

The compound of the present invention was dissolved or suspended in N,N-dimethylacetamide, and then diluted 20-fold with Miglyol 812 neutral oil. 0.1 ml of the solution was orally administered to each mouse (dose: 40 mg/kg). The administration was continued for 10 consecutive days from the day of immunization to the day before blood collection.

4) Measurement of anti-OVA IgE antibody titer (PCA titer) The obtained mouse serum was serially diluted 2-fold with physiological saline, and 50 μl of each was injected intradermally into the dorsal skin of a pre-shaved Wistar rat. After 24 hours, the rats were injected with 0.5 ml of physiological saline solution containing 1 mg of OVA and 5 mg of Evans blue dye.
A passive cutaneous anaphylaxis (PCA) reaction was induced by intravenous injection of 1 ml of OVA. Thirty minutes later, the maximum dilution of serum that showed a positive PCA reaction with a pigmented spot of 5 mm or more in diameter was determined, and the PCA titer was calculated as _Log2 of that dilution. For example, if a serum showed a positive PCA reaction up to a ^27- fold dilution, the anti-OVA IgE antibody titer of that mouse was determined to be 7. The results are shown in Table 32.

The PCA titer of the compound-unadministered group was about 9 to 12. These results demonstrate that the compound of the present invention has an inhibitory effect on IgE antibody production.

Formulation Example 1 Tablet Compound of the present invention (I-1) 15 mg Starch 15 mg Lactose 15 mg Crystalline cellulose 19 mg Polyvinyl alcohol 3 mg Distilled water 30 ml Calcium stearate 3 mg The ingredients other than calcium stearate were uniformly mixed, crushed, granulated, and dried to prepare granules of suitable size. Next, calcium stearate was added and compressed to form tablets.

INDUSTRIAL APPLICABILITY As is clear from the above test examples, the compounds of the present invention have strong immunosuppressive and/or anti-inflammatory effects.
Therefore, the compounds of the present invention are very useful as immunosuppressants, antiallergic agents and/or agents for suppressing IgE antibody production.

─────────────────────────────────────────────────────────Continued from the front page (51) Int.Cl. ⁷ Identification Symbol FI A61K 31/50 A61K 31/50 31/505 31/505 A61P 37/06 A61P 37/06 37/08 37/08 C07C 251/58 C07C 251/58 251/84 251/84 251/86 251/86 C07D 213/64 C07D 213/64 213/77 213/77 237/10 237/10 239/34 239/34 241/14 241/14 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), UA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, C A, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (Note) This publication is based on the gazette published internationally by the International Bureau (WIPO). The effect of the international publication of the Japanese patent application (Japanese utility model registration application) related to this publication arises pursuant to Article 184-10, Paragraph 1 of the Patent Act (Article 48-13, Paragraph 2 of the Utility Model Act), and is unrelated to this publication.

Claims (29)

[Claims] [Claim 1] Formula (I): [wherein ring A, ring B and ring C each independently represent an aromatic carbocycle which may have a substituent or a 5- or 6-membered heterocycle which may have a substituent and which may be fused with a benzene ring, and when ring A, ring B and/or ring C is a 5-membered heterocycle which may have a substituent, W ¹ , W ² and/or W ³ represent a bond. X represents -O-, -CH ₂ -, -NR ¹ - (wherein R ¹ is hydrogen, optionally substituted lower alkyl, lower alkenyl or lower alkylcarbonyl), or -
S(O)p- (wherein p is an integer of 0 to 2), X' is -O- or -NH-, Y is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted lower alkoxycarbonyl, optionally substituted sulfamoyl, optionally substituted amino, optionally substituted aryl, or an optionally substituted 5- or 6-membered heterocyclic group, when X is _-CH2 or ^-NR1- , Y may be halogen, and when X is -O- or ^-NR1- , Y may be optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl. One of ^V1 and ^V2 is a single bond, and the other is a single bond, -O-, -NH-, -O
_CH2- , _-CH2O- , -CH=CH-, -C≡C-, -CH( ^OR2 )-(
^R2 is hydrogen or lower alkyl), -CO-, ^-NHCHR3- or -CHR
³ NH— (R ³ is hydrogen or hydroxy); R ^a and R ^b each independently represent hydrogen, optionally substituted lower alkyl,
optionally substituted lower alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted lower alkoxycarbonyl or optionally substituted lower alkylsulfonyl, or together represent R ^c R ^d C= or -
(CR ^e R ^f )r-, wherein R ^c and R ^d each independently represent hydrogen or optionally substituted lower alkyl;
optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, optionally substituted lower alkenyloxy, optionally substituted lower alkynyloxy, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted 5- or 6-membered heterocyclic group, or together with the carbon atoms to which they are bonded form an optionally substituted cycloalkylidene, each R ^e independently represents hydrogen, lower alkyl, lower alkoxy or amino,
Each ^Rf is independently hydrogen, lower alkyl, lower alkoxy, or amino;
n is an integer of 0 to 2, and r is an integer of 2 to 6.], a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. [Claim 2] Ring A, ring B and ring C are each independently a benzene ring which may have a substituent or a 6-membered heterocycle which may have a substituent, ^{V1 and V2 are each independently a benzene ring which may have a substituent or a 6-} membered heterocycle which may have a substituent,
² is a single bond, and n is 0, or a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1. 3. The compound according to claim 1 or 2, wherein ring A is a benzene ring which may have a substituent, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. [Claim 4] The compound according to claim 1 or 2, wherein ring B is a benzene ring which may have a substituent, a pyridine ring which may have a substituent, a pyrimidine ring which may have a substituent, a pyridazine ring which may have a substituent, or a pyrazine ring which may have a substituent, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. [Claim 5] The compound according to claim 1 or 2, wherein two of ring A, ring B and ring C are benzene rings which may have a substituent, and one is a 6-membered heterocycle which may have a substituent, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. 6. The method of claim 1, wherein the 6-membered heterocycle optionally having a substituent is a pyridine ring optionally having a substituent, a pyrimidine ring optionally having a substituent, a pyridazine ring optionally having a substituent, or a pyrazine ring optionally having a substituent.
10. The compound according to claim 2 or 5, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. [Claim 7] Formula (I'): (wherein Ring C is an optionally substituted benzene ring or an optionally substituted 6-membered heterocycle containing 1 or 2 heteroatoms; Y is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted amino; ^R4 , ^R5 , ^R6 , R7, ^R8 , ^R9 , ^R10 and ^R11 each independently is hydrogen, ^halogen , optionally protected hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted cycloalkoxy, optionally substituted lower alkylthio, optionally substituted lower alkylsulfonyloxy, carboxy or optionally substituted lower alkoxycarbonyl; and X, X', ^Ra , ^Rb and n are as defined in claim 1), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. 8. The compound according to claim 7, wherein R ⁴ and R ⁵ each independently represent hydrogen, halogen, hydroxy or lower alkoxy, or a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. 9. The compound according to claim 7, wherein R ⁶ and R ⁷ are both hydrogen, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. 10. The compound according to claim 7, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R ⁸ is hydrogen or optionally substituted lower alkyl. 11. The compound according to claim 7, wherein R ⁹ is optionally protected hydroxy, optionally substituted lower alkyl, or optionally substituted lower alkoxy, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 12. The compound according to claim 7, wherein R ¹⁰ is optionally protected hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, or optionally substituted lower alkoxycarbonyl, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 13. The compound according to claim 7, wherein R ¹¹ is hydrogen, optionally protected hydroxy, or optionally substituted lower alkyl, or a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 14. The compound according to any one of claims 1, 2 and 7, wherein Ring C is a benzene ring which may have a substituent, a pyridine ring which may have a substituent, a pyrimidine ring which may have a substituent, a pyridazine ring which may have a substituent or a pyrazine ring which may have a substituent, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. 15. The compound according to any one of claims 1, 2 and 7, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein X is -O-, -CH ₂ - or -NH-. 16. The compound according to any one of claims 1, 2 and 7, wherein X is -NH-, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. 17. The compound of any one of claims 1, 2, or 7, wherein Y is hydrogen, lower alkyl, arylalkyl, lower alkenyl, or cycloalkyl.
A prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 18. R ^a and R ^b are each independently hydrogen, alkyl having 1 to 6 carbon atoms,
each ^Rc and ^Rd are independently hydrogen, ^alkyl having 1 ^to 6 carbon atoms, ^alkenyl having 2 to 6 carbon atoms, ^{alkoxycarbonyl} having 1 to 6 carbon atoms, phenyl, or a 5- or 6-membered aromatic heterocyclic group, or together with the carbon atom to which they are attached form a cycloalkylidene having 5 or 6 carbon atoms, each Re is independently hydrogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, or amino, each ^Rf is independently hydrogen ^,
8. The compound according to claim 1, 2 or 7, wherein r is alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms or amino, and r is 4 or 5, or a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. 19. The compound according to any one of claims 1, 2 and 7, its prodrug, its pharmaceutically acceptable salt or a solvate thereof, wherein n is 0 or 1, X' is -O-, R ^a and R ^b together form R ^c R ^d C=, and R ^c and R ^d each independently represent hydrogen, alkyl having 1 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms or phenyl, or together form a cycloalkylidene having 5 or 6 carbon atoms together with the carbon atom to which they are attached. 20. The compound according to claim 20, wherein n is 0, X' is -NH-, R ^a and R ^b together form R ^c R ^d C=, and R ^c and R ^d each independently represent hydrogen, a group having 1 to 10 carbon atoms,
6 alkyl, C2 to C6 alkenyl, C1 to C6 alkoxy, or phenyl, or together with the carbon atom to which it is attached form a cycloalkylidene having 5 or 6 carbon atoms, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of claims 1, 2, and 7. 21. The compound according to claim 21, wherein n is 0, X' is -NH-, R ^a and R ^b are each independently hydrogen, lower alkyl, lower alkenyl, or lower alkoxycarbonyl, or are joined together to form -(CR ^e R ^f )r-, wherein R ^e is each independently hydrogen, lower alkyl, lower alkoxy, or amino, R ^f is each independently hydrogen, lower alkyl, lower alkoxy, or amino, and r is 4 or 5.
10. The compound according to claim 1, 2 or 7, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. [Claim 22] Ring C is a benzene ring optionally substituted with halogen, lower alkyl or lower alkoxy, or a pyridine ring optionally substituted with halogen, lower alkyl or lower alkoxy, X and X' are each independently -O- or -NH-, Y is hydrogen, lower alkyl, arylalkyl, lower alkenyl or cycloalkyl, ^R4 and ^R5 are each independently hydrogen or halogen, ^R6 and ^R7 are both hydrogen, ^R8 is hydrogen or lower alkyl, R9 is hydroxy, lower alkyl or lower alkoxy, ^R10 is hydroxy, lower alkyl, lower alkoxy or lower alkoxycarbonyl, ^R11 is hydrogen, hydroxy or lower alkyl, ^Ra and ^Rb are each independently hydrogen, lower alkyl, lower alkenyl or lower alkoxycarbonyl, or are taken together to ^{form RcRdC} = ^or -( ^CReR
Rc and ^{Rd are} each independently hydrogen, lower alkyl, lower alkenyl, lower alkoxy, or phenyl, or are joined together with the carbon atom to form a cycloalkylidene having 5 or 6 carbon atoms; ^Re are each independently hydrogen, lower alkyl, lower alkoxy, or amino; ^Rf are each independently hydrogen, lower alkyl, lower alkoxy, or amino; n is 0 or 1; and r is 4 or 5. The compound according to claim 7, its prodrug, its pharmaceutically acceptable salt, or a solvate thereof. 23. A compound according to any one of claims 1 to 23, or a prodrug thereof.
A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof or a solvate thereof. 24. An immunosuppressant comprising the compound according to any one of claims 1 to 22, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 25. An antiallergic agent comprising the compound according to any one of claims 1 to 22, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 26. An IgE antibody production inhibitor comprising the compound according to any one of claims 1 to 22, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 27. A compound according to any one of claims 1 to 22 for producing a medicament for suppressing immune responses and treating and/or preventing allergic diseases.
Use of a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. 28. A method for suppressing an immune response, comprising administering the compound according to any one of claims 1 to 22, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 29. A method for treating and/or preventing an allergic disease, which comprises administering a compound according to any one of claims 1 to 22, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.