WO2002034719A1 - Nitrogenous saturated heterocycle compounds - Google Patents

Abstract

Nitrogenous saturated heterocycle compounds of general formula (I), pharmacologically acceptable salts of the same, or esters or other derivatives thereof, having an excellent TH1-selective immunosuppressive effect: (I) wherein R?1 and R2¿ are each aryl or the like; X is oxygen or the like; Y is alkylene or the like; and L is C(R3)(R4)- (wherein R3 is aryl, heteroaryl, or the like; and R4 is CO-R5, or alternatively R?3 and R4¿ together with the carbon atom to which they are bonded may form a five- to eight-membered saturated heterocycle, a three- to ten-membered saturated carbon ring, or the like).

Description

Technical field of nitrogen-containing saturated heterocyclic compounds

 The present invention relates to a nitrogen-containing saturated heterocyclic compound having a selective immunosuppressive activity, a pharmacologically acceptable salt thereof, an ester thereof, or an excellent TH1 (refers to TH1 cells which are one of a subset of helper T cells). Other derivatives, pharmaceutical compositions containing them as an active ingredient, their use for producing pharmaceutical compositions, or methods for preventing autoimmune diseases by administering a pharmacologically effective amount of these to warm-blooded animals Or about the treatment method. Technology background

 Conventionally, in the treatment of immune-related diseases such as rheumatism and other autoimmune diseases, anti-inflammatory drugs such as steroids have been used for inflammatory reactions caused by abnormal immune responses. However, these are symptomatic treatments, not radical treatments.

Also, diabetes mellitus, also involving abnormalities of the immune system in the development of nephritis is reported les, Ru force ^{s [Kidney Internat ional, 51,} 94 (1997) Journal oi E thigh unoiogy, 1 57, 4691 (1996 ) ], No drug has been developed to improve the abnormality.

 Helper T cells that play a central role in the immune response are classified into two different subsets: type 1 helper T cells (hereinafter abbreviated as Th1 cells) and the above Th2 cells. You.

Th1 cells produce cytokines such as interleukin 2 (hereinafter, IL-2), interferon-a (hereinafter, IFN), and TNF--, and are mainly involved in cell-mediated immunity. On the other hand, Th2 cells produce cytokines such as IL-4 and IL-10 and are mainly involved in humoral immunity (J. Immunol., Vol. 136, 2348-2357, 1986). Images produced by Th1 cells γ inhibits the function of Th2 cells. Conversely, IL-4 and IL-10 produced by Th2 cells inhibit the function of Th1 cells. It is considered that the balance between Th1 cells and Th2 cells via these cytokines is important for normal immune function in vivo. In recent years, it has become clear that imbalance of Th1 / Th2 cells is involved in the development of various immune-related diseases. The balance bias toward Th1 cells is used for organ-specific autoimmune diseases such as rheumatoid arthritis, diabetes, multiple sclerosis, inflammatory bowel disease, and glomerulonephritis. It has been reported to be involved in allergic diseases and systemic autoimmune diseases (hmmmol. Today, Vol. 16, 34-38, 1995; Science Vol. 260, 547-549, 1993; Immunity, Vol. 3, 171-174, 1995; J. Exp. Med., Vol. 190, 995-1003, 1999; Kidney Int., Vol. 52, 52-59, 1997; J. Exp. Med., Vol. 185, 65-70, 1997). Regarding immune-related diseases, the involvement of various cytokines produced by helper T cells has been proven for each disease state, and inducing or suppressing the production of these cytokines is effective for the treatment of immune-related diseases. It is considered that .

 In studies to date, compounds known to have an effect of increasing IL-4 in the body include, for example, 1,25-dihydroxyvitamin D3. The effect is considered to be indirect. [Journal of Immunology, 160, 5314 (1998)]. Gold and D-^^ nisilamine are also known to have similar effects, but these effects are weak and have not been proven to be direct IL-14 production-inducing effects [Clinical Experimental Immunology, 438, 108 (1997 ^). "

 On the other hand, as a compound having an action of increasing IL-10 in the body, for example, 2,4-dinitroclo-mouth benzene is known. Is this action also a direct action of inducing IL-10 production? It has not been proven [Immunology, 89, 502 (1996)]. '

Under such circumstances, attempts have been made to find a compound having an action of selectively inducing the production of IL-4 and IL-10. Prior art relating to compounds similar to the compounds of the present invention includes the following. .

 (1) JP-A-50-89363 (US Pat. No. 3,962,259) and

 JP-A-50-100052 (US Pat. No. 3,959,475) JP-A-50-89363 discloses the following general formula (A)

In [the compound (A), is a Jifuenirume Toki Shiarukiru group represented by the formula (C¾) nOCHPh _2, Y is CH ₂ or O0. ] Is disclosed,

 JP-A-50-100052 discloses the following general formula (B)

In [the compound (B), is a Jifuenirumetoki Shiarukiru group represented by the formula (C) nOCHPh _2. ] Has been disclosed.

In the compound (I) of the present invention, a compound having a structure similar to that of the powerful prior art includes a 5- to 8-membered saturated heterocyclic ring including R ³ and R ⁴ together and the carbon atom to which they are bonded. The compound (I) of the present invention is different from the above compounds (A) and (B) because tetrahydrofuran is excluded from the saturated heterocycle. Further, the present publication discloses a compound having a structure similar to that of the compound (I) of the invention. Nothing is specifically disclosed, and even if a compound closest to the structure of the compound (I) of the present invention is selected, at most only the following compounds are disclosed.

 Further, the compounds (A) and (B) are disclosed as antidepressants, tranquilizers, and analgesics, and their use as TH1-selective immunosuppressive effects is not described or suggested.

(2) JP-A-50-142574 (EP 751 937A)

 In this gazette, the following general formula (C)

 [In the above compound (C), A is the following general formula (A-1)

(A-1)

を有する基を示す。] を有する化合物が開示されている。 Or (A-2)

A group having the formula: ] Has been disclosed.

In the compound (I) of the present invention, a compound of the prior art having the general formula (A_l) described above. As a compound having a structure similar to that of (C), R ³ and R ⁴ are bonded together to form a bond. The compound (I) of the present invention is the same as the compound (C) in that imidazolidin is excluded from the saturated heterocyclic ring, except that imidazolidin is removed from the saturated heterocyclic ring. Is different from

In the compound (I) of the present invention, a compound having a structure similar to that of the prior art compound (C) having the general formula (A_2) includes an aryl and a formula COR ⁵ at the 4-position of piperidine. It has a group, but is different from the compound (C) in the substituent at the 4-position of piperidin.

 Further, this publication does not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and describes a compound closest to the structure of the compound (I) of the present invention. Even if selected, at best, only the following compounds are disclosed

また、 上記化合物 （c) は中枢神経抑制作用、 自律神経作用を有する化合物とし て開示されており、 ΤΗ 1選択的免疫抑制作用としての用途は記載も示唆もされて いない。 ( 3 ) 特開昭 56— 1 28782号公報 （EP 073845A) 本公報には、 向精神作用を有する化合物として下記一般式 （D)

Further, the above compound (c) is disclosed as a compound having a central nervous system inhibitory action and an autonomic nervous action, and its use as a selective immunosuppressive action is not described or suggested. (3) JP-A-56-122872 (EP 073845A) In this publication, compounds having a psychotropic effect represented by the following general formula (D)

[In the above compound (D), R represents the following general formula (R-1)

A group having the formula: ]

Are disclosed.

In the compound (I) of the present invention, those having a structure close to that of the powerful prior art include a 5 'to 8 membered saturated heterocyclic ring including a carbon atom to which R ³ and R ⁴ are bonded together. However, the compound (I) of the present invention is different from the above-mentioned compound (D) in that imidazolidin is excluded from the saturated heterocyclic ring.

 Further, this publication does not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and describes a compound closest to the structure of the compound (I) of the present invention. Even if selected, at best only the following compounds are disclosed:

また、 上記化合物 （D) は向精神作用を有する化合物として開示されており、 T H 1選択的免疫抑制作用としての用途は記載も示唆もされていない。

The compound (D) is disclosed as a compound having a psychotropic effect, and its use as a TH1-selective immunosuppressive effect is not described or suggested.

(4) JP-A-59-53489 (EP 102034A)

In this gazette, the following general formula (E)

[In the above compound (E), 1 ^ is represented by the following general formula:

—— (CH ₂ ) ₂ — O-CH

R ₅

(In the above formula, R ₅ represents an optionally substituted phenyl group.) ] Has been disclosed.

In the compound (I) of the present invention, a compound whose structure is close to that of the powerful prior art is that R ³ and R ⁴ together form a 5- to 8-membered saturated heterocycle including a carbon atom to which they are bonded. The compound (I) of the present invention differs from the compound (E) in that dioxepane is excluded from the saturated heterocycle.

Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and the compound closest to the structure of the compound (I) of the present invention is not disclosed. Even if is selected, at most, only the following compounds are disclosed.

また、 上記化合物 （E) は高血圧治療剤、 鎮痛治療剤として開示されており、 T H 1選択的免疫抑制作用としての用途は記載も示唆もされていない。

Further, the above compound (E) is disclosed as a therapeutic agent for hypertension and a therapeutic agent for analgesia, and its use as a TH1-selective immunosuppressive effect is neither described nor suggested.

(5) FR271 7803 publication (WO 95/26336)

 In this gazette, the following general formula (F)

[In the above compound (F), R ³ and R ⁴ , R ⁵ and R ⁶ , or R ³ form a 5- to 7-membered heterocyclic ring. ] 'Are disclosed.

In the compound (I) of the present invention, those having a structure close to that of the prior art include 5 to 5 carbon atoms including R ³ and R ⁴ together at the 4-position of piperidine, including the carbon atom to which they are bonded. Although the compound (F) forms an 8-membered saturated heterocycle, the compound (F) has a 5- to 7-membered heterocycle including a carbon atom other than the 4-position of piperidine, and thus the present invention Has a structure different from that of compound (I).

また、 上記化合物 （F ) は 「うつ病、 衝動的脅迫観念、 パニック発作、 記憶障害 、 精神分裂症、 パーキンソン病、 依存症等」 の治療に有用な化合物として開示され ており、 T H 1選択的免疫抑制作用としての用途は記載も示唆もされていない。 Further, this publication does not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the above compound is selected, at most, only the following compound is disclosed.

The above compound (F) is disclosed as a compound useful for the treatment of "depression, impulsive threat, panic attack, memory disorder, schizophrenia, Parkinson's disease, dependence, etc." The use as an immunosuppressive effect is neither described nor suggested.

(6) WO 97/27 17 75

In this gazette, the following general formula (G)

[In the above compound (G), Y may have a substituent, and may be a saturated or unsaturated aliphatic or aromatic heterocyclic amine radical (the substituent may be a C ₆ alkyl, And at least one group selected from the group consisting of a group consisting of norebone, ketone, estenole, cyclohexynole, cyclohexeneol and aryl.) ]

Are disclosed.

 In this publication, the saturated or unsaturated aliphatic or aromatic heterocyclic amine radical in Y is azetidine, pyrrolidine, pyrroline, pyrrole, piperidine, pyridine, imidazole and unsubstituted or substituted. There is only description that the compound is selected from pyrimidine radicals, and no compound having a spiro bond has been disclosed.

Therefore, the compound (I) of the present invention has a structure similar to that of the prior art. For example, a group having aryl and a formula CO—R ⁵ at the 4-position of piperidine can be mentioned. In the above compound (G), as a substituent for a heterocyclic amine radical, Cf Csanolekyl or canolepo2 There is only a statement that the compound has at least one group selected from the group consisting of phenol, ketone, estenole, cyclohexynole, cyclohexeninole and aryl, and no specific description or examples of each substituent are given. Not disclosed. Further, this publication does not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if a compound is selected, at most only the following compounds are disclosed.

また、 上記化合物 （G) は、 ドパミン摂取阻害作用を有する化合物として開示さ れており、 T H 1選択的免疫抑制作用としての用途は記載も示唆もされていない。

Further, the above compound (G) is disclosed as a compound having a dopamine uptake inhibitory effect, and its use as a TH1-selective immunosuppressive effect is not described or suggested.

(7) Japanese Patent Publication No. 40-6465

 In this gazette, the following general formula (H)

[In the above compound (H), represents a hydrogen atom or a rubamoyl group, and R ₂ and R ₃ are the same or different and represent an alkyl group or a group which forms a pyrrolidino or piperidino group together with nitrogen. ] Are disclosed.

In the compounds of the present invention (I), a force, a hunt as prior art that the structure is close to the group that have a heteroaryl group及Pi formula over CO- R ⁵ to an aromatic heterocycle in the 4-position of the pin Perijin Although the compound (H) has a pyrrolidino or piperidino group which is a saturated heterocyclic ring at the 4-position of piperidine, and a compound of the present invention (I) Is different from

 Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention. Even if similar compounds are selected, at most, only the following compounds are disclosed.

 Further, the above compound (H) is disclosed as an antihistamine and an antispasmodic, and its use as a TH1 selective immunosuppressive effect is neither described nor suggested.

(8) Japanese Patent Publication No. 40-12290.

 In this gazette, the following general formula (J)

[In the above compound (J), Z is a cyano group, an alkoxycarbonyl group, an acyl group, Indicates an aminomethyl group. ]

Are disclosed.

In the compound (I) of the present invention, a compound having a structure close to the powerful prior art includes a group having an aryl and a CO—R ⁵ at the 4-position of piperidine (wherein R ⁵ is And a substituent at the 4-position of piperidine is different between compound (I) and compound (J) of the present invention.

 Furthermore, this publication does not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and the compound closest to the structure of the compound (I) of the present invention is not disclosed. Even if you choose, at most, only the following compounds are disclosed

 Further, the above compound (J) is disclosed as an antihistamine and an antispasmodic, and its use as a TH1 selective immunosuppressive effect is not described or suggested.

(9) US P 323821 6 Gazette '' This gazette contains the general formula (K)

[In the above compound (K), R ₄ represents a group having (aryl) ₂ CH-0-. ] Has been disclosed. In the compound (I) of the present invention, a compound whose structure is close to that of the powerful prior art is that R ³ and R ⁴ together form a 5- to 8-membered saturated heterocycle including a carbon atom to which they are bonded. The compound (I) of the present invention is different from the compound (K) in that imidazolidin is removed from the saturated heterocyclic ring.

また、上記化合物 （K) は中枢神経抑制作用を有する化合物として開示されてお り、 TH 1選択的免疫抑制作用としての用途は記載も示唆もされていない。 Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if a compound is selected, at most only the following compound is disclosed.

In addition, the above compound (K) is disclosed as a compound having a central nervous system inhibitory effect, and its use as a TH1-selective immunosuppressive effect is not described or suggested.

(10) Chem. Pharm. Bull., 1 (5), 882-888 (1993)

In this document, the following general formulas (L) and (Μ) ■

[In the above compounds (L) and (M), R ₃ is a phenyl group. ]

Are disclosed.

In the compounds of the present invention (I), as those close structural force mow the prior art, radical (R ⁵ having Ariru and Shikiichi CO- R ⁵ in the 4-position of the pin Perijin is an Amin residue like Show. ), But the substituent at the 4-position of piperidine is different between the compound (I) of the present invention and the above compounds (L) and (M).

 Further, the above compounds (L) and (M) are only disclosed as intermediates of compounds having an antihistamine action, and their use as TH1 selective immunosuppressive action is neither described nor suggested. Disclosure of the invention

 The present inventors have conducted intensive studies on derivatives having a TH1-selective immunosuppressive effect, and have found that nitrogen-containing saturated heterocyclic compounds, pharmacologically acceptable salts thereof, esters or other derivatives thereof, The present inventors have found that they have an excellent TH1-selective immunosuppressive action, and have completed the present invention.

 Another object of the present invention is to provide a pharmaceutical composition containing the above-mentioned nitrogen-containing saturated heterocyclic compound, a pharmaceutically acceptable salt thereof, an ester or other derivative thereof as an active ingredient.

 Another object of the present invention is to use the above-mentioned nitrogen-containing saturated heterocyclic compound, a pharmaceutically acceptable salt thereof, an ester or other derivative thereof for producing a pharmaceutical composition, and Provided is a method for preventing or treating an autoimmune disease, which comprises administering to a warm-blooded animal a pharmacologically effective amount of the nitrogen-containing saturated heterocyclic compound, a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof. That is.

(1) The nitrogen-containing saturated heterocyclic compound of the present invention, its pharmaceutically acceptable salt, its ester or other derivative has the following general formula (I).

 [Where,

R ¹ and R ² are the same or different and each represents an aryl group, a heteroaryl group, a substituent group an aryl group substituted by 1 to 3 groups with a group selected from a, or a heteroaryl group substituted by 1 to 3 groups with a group selected from a substituent group a,

 Represents an oxygen atom, a sulfur atom, or a group having the formula —NR—, wherein R is a hydrogen atom or a group selected from substituent group b.

Y represents a C i-Cs alkylene or C ₂ _ C ₈ 7 Rukeeren group.

L is a group having the formula C (R ³ ) (R ⁴ )

 [Where,

R ³ is an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from the substituent group a, or a heteroaryl substituted 1 to 3 groups with a group selected from the substituent group a. Represents a group,

R ⁴ is a group having the formula: CO—R ⁵ (wherein R ⁵ is an aryl group substituted by 1 to 3 groups selected from an amide residue, an aryl group, a heteroaryl group, and a substituent group _a ) Or a heteroaryl group substituted by 1 to 3 groups selected from a substituent group a).

R ³ and R ⁴ are taken together to form a group including the carbon atom to which they are bonded, and are substituted with 1 to 3 5- to 8-membered saturated heterocycles or a group selected from substituent group c. Or a 5- to 8-membered saturated heterocyclic ring (provided that the saturated heterocyclic ring excludes tetrahydrofuran, imidazolidine or dioxepane), or

R ³ and R ⁴ are taken together to form a 3- to 10-membered saturated carbocyclic ring formed by including the carbon atom to which they are bonded, or 1 to 3 substituted with a group selected from the group of substituents a and c. 3 to 10-membered saturated carbocycle. ]. ]

<Substituent group a> '

Halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxy group, hydroxyl group, lower aliphatic acyl group, lower aliphatic acylamino group, amino group, and cyano group

<Substituent group b> Lower alkyl group, aryl group, aralkyl group, lower alkyl group substituted with 1 to 3 groups selected from substituent group a, aryl group substituted with 1 to 3 groups selected from substituent group a Groups, an aralkyl group substituted by 1 to 3 groups selected from the substituent group a, a lower aliphatic acyl group, and a lower alkylsulfonyl group

<Substituent group c>

An oxo group, and a group selected from substituent group b as a substituent on the nitrogen atom when there is a nitrogen atom.

 Of these, preferred compounds include

(2) R ¹ and R ^{2 are the} same or different, and are an aryl group, a heteroaryl group or an aryl group substituted by 1 to 3 groups selected from a substituent group a,

(3) R ¹ and R ^{2 are the} same or different and are an aryl group or an aryl group substituted by 1 to 3 groups selected from a substituent group a,

(4) R ¹ and R ² , the same or different, an aryl group or an aryl group substituted by 1 to 3 (the substituent is a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group) A group selected from the group :)

(5) R ¹ and R ^{2 are the} same or different and are an aryl group or an aryl group substituted by one halogen atom,

(6) R ¹ and R ² i are the same aryl group substituted by one halogen atom.

 (7) a compound wherein X is an oxygen atom, a sulfur atom or a group having the formula -NH-,

(8) The compound wherein X is an oxygen atom.

(9) Y is a 〇 "〇 ₈ alkylene group compound,

 (10) a compound wherein Y is a Ci—Cs alkylene group,

(1 1) a compound wherein Y is a C ₂ -C ₃ alkylene group,

 (1 2) compounds wherein Y is an ethylene group,

(1 3) a group having the formula _C (R ³ ) (R ⁴ ) (Where

R ³ is an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from substituent group a, or a heteroaryl group substituted with 1 to 3 groups selected from substituent group a. A teloaryl group,

R ⁴ is a group having the formula CO—R ⁵ . A compound which is

(14) the compound, wherein R ³ is an aryl group or a heteroaryl group,

(15) a compound wherein R ³ is a phenyl group or a pyridyl group,

(16) the compound, wherein R ³ is a pyridyl group,

(17) a compound wherein R ⁵ is an amine residue.

(18) a compound wherein R ⁴ is a carbamoyl group,

(1 9) is a group having the formula C (R ³ ) (R ⁴ ) 1, wherein R ³ and R ⁴ are taken together to form a carbon atom to which they are bonded, A compound which is a 5- to 8-membered saturated heterocycle substituted with 1 to 3 member (s) selected from a substituent selected from substituent group c or a group selected from substituent group c,

 (20) a compound wherein L is a 5- to 6-membered saturated heterocyclic ring or a 5- to 6-membered saturated heterocyclic ring substituted by 1 to 3 groups with a group selected from substituent group c,

 (21) a compound that is a 5- to 6-membered saturated heterocyclic ring substituted by 1 to 3 groups with a group selected from L group substituent group c,

 (22) a compound wherein L is a 5- or 6-membered saturated heterocyclic ring which may be substituted by one oxo group and further substituted by 1 or 2 groups selected from substituent group c,

(23) L is the following formula (L-1) (レ 1)-

(Wherein, G and J are the same or different and each represent an oxygen atom, a sulfur atom or a group having the formula NR—. However, G and J each represent a group having the same formula NR—. No.) A compound that is a group having

 (24) a compound wherein G is an oxygen atom or a sulfur atom, and J is a group having —NH—,

(25) L is a group having the formula _C (R ³ ) (R ⁴ ) —, wherein R ³ and R ⁴ are taken together to form the carbon atom to which they are attached; A compound which is a 3- to 10-membered saturated carbocyclic ring substituted with 1 to 3 10-membered saturated carbocycles or groups selected from substituent groups a and c,

 (26) a compound wherein L is a 5- to 6-membered saturated carbocyclic ring or a 5- to 6-membered saturated carbocyclic ring substituted by 1 to 3 groups with a group selected from substituent groups a and c,

 (27) a compound wherein L is a 5- or 6-membered saturated carbocyclic ring condensed with a benzene ring (the 5- or 6-membered saturated carbocyclic ring has an oxo group or a hydroxyl group as a substituent);

 (28) The compound wherein L is 2-hydroxyindane or 2-oxoindane group

(29) any one compound selected from the following,

 1_ [2-bis (4-fluorophenyl) methoxethyl] -4-phenyl / leviperidine-4-force rubonic acid amide,

 1_ [2-bis (4-fluorophenyl) methoxethyl] -4- 4-phenylbiperidine-4-force rubonic acid morpholine amide,

 1- [2-bis (4-furofilophenyl) methoxhetyl] -4- (2-pyridyl) piperidine-4-carboxylic acid amide,

 8_ [2_Bis (4-fluorophenyl) methoxethyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one,

 8-[3-Bis (4-fluorofurnyl) methoxypropyl]-1-oxa-3,8-diazaspira [4,5] decane-2-one,

8- [2-bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-oxa-3,8-dazaspiro [4.5] decane-2-one, 8- [2-bis (4-fluorophenyl) methoxethyl] -3-benzyl-1-oxa-3,8-dazaspiro [4.5] decane-2-one,

 8_ [2-bis (4-fluorophenyl) methoxy'ethylthio-3,8-diazaspiro [4.5] degan_2_one,

 8- [2-bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-thio-3,8-diaspiro [4.5] decane-2-one,

 1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [2,3-dihydrobenzozothiophene-3,4'-piperidine]-1-oxide,

 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4-piperidine],

 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4'-piperidine] -2_oxide,

 1_ [2-bis (4-fluorophenyl) methoxetyl] spiro [(1,4-dihydro-2H-isoquinolin-3-one) -1,4'-piperidine],

 1- [2-Bis (4-fluorophenyl) methoxhetyl] spiro [(indane) -1,4-dipyridine],

 1_ [2-bis (4-fluorophenyl) methoxethyl] spiro [(indan-1-one) -3,4'-piperidine],

 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(2-hydroxy) indane-1,4'-piperidine],

 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4'-piperidine] -2,2-dioxide, and

 8- [2-Bis (4-co-mouth phenyl) methoxhetyl]-1-oxa-3,8-dazaspiro [4.5] decane-2-one

Can be mentioned.

(30) The TH1-selective immunosuppressant of the present invention further comprises a compound having the general formula (II): Products, pharmacologically acceptable salts, esters or other derivatives thereof as active ingredients. '

 [Where,

R ¹ and R ² are the same or different and are selected from an aryl group, a heteroaryl group, an aryl group substituted by 1 to 3 groups selected from a substituent group a, or a substituent group a Represents a heteroaryl group substituted by 1 to 3 groups,

 X represents an oxygen atom, a sulfur atom, or a group having the formula —NR—, wherein R is a hydrogen atom or a group selected from substituent group b.

Y represents an C ₈ Arukiren group or C ₂ _〇 ₈ Aruke two alkylene groups,

L ¹ is a group having the formula C (R ^3a ) (R ^4a )

 [Where,

R ^3a is a hydrogen atom, an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from substituent group a, or 1 to 3 groups selected from substituent group a Indicates a substituted heteroaryl group,

R ^4a is a group having the formula —D—E—R ⁶ [wherein

D represents a single bond or a group having the formula —C (R ⁷ ) H— (wherein R ⁷ is a hydrogen atom or a group selected from substituent group a);

E represents a single bond or a C ₈ alkylene group,

R ⁶ is a hydrogen atom, a hydroxyl group, an amino group, a lower aliphatic acylamino group, an aromatic acylamino group, or a group having the formula CO—R ^5a (wherein

R ^5a is a lower alkyl group, a lower alkoxy group, an amine residue, a hydroxyl group, an aryl group, a heteroaryl group, an aryl group substituted by 1 to 3 groups selected from _a substituent group _a , or a substituent group a heteroaryl group substituted by 1 to 3 groups selected from a. ). ] R ^3a and R ^4a are taken together and include 1 to 3 substituted 5- to 8-membered saturated heterocycles or a group selected from substituent group c, including the carbon atom to which they are attached. Forms an 8-membered saturated heterocycle, or

R ^3a and R ^4a are taken together and are substituted by 1 to 3 3-membered saturated carbocycles or a group selected from substituent groups a and c, including the carbon atom to which they are attached. To form a 3- to 10-membered saturated carbocycle. ]

A group having the formula N ( ^R4b ) 1

[Wherein, R ^4b represents a group having the formula D_E—R ⁶ (wherein D, E and R ⁶ have the same meanings as described above)]. ], Or

Group of the formula C (R ^4c )

Wherein, R ^4C has the formula ^{= C (R 7) - E} - indicates a group having a R ⁶ (wherein, E, R ⁶及Pi R ⁷ represents the same meanings as defined before mentioned.) The. ]

<Substituent group a>

Halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxy group, hydroxyl group, lower aliphatic acyl group, lower aliphatic acylamino group, amino group, and cyano group

<Substituent group b>

Lower alkyl group substituted with 1 to 3 groups selected from lower alkyl group, aryl group, aralkyl group, and substituent group a; aryl group substituted with 1 to 3 groups selected from substituent group a Group, an aralkyl group, a lower aliphatic acyl group, and a lower alkylsulfonyl group substituted with 1 to 3 groups selected from the group of substituents a '

Substituent group c>

An oxo group, and a group selected from substituent group b as a substituent on a nitrogen atom when there is a nitrogen atom. -Of these, preferred compounds include

(31) R ¹ and R ² force are the same or different, aryl group, heteroaryl group or Is a compound which is an aryl group substituted by 1 to 3 groups selected from a substituent group a,

(32) a compound wherein R ¹ and R ^{2 are} the same or different and are aryl groups or aryl groups substituted by 1 to 3 aryl groups or groups selected from substituent group a;

(3 3) R ¹及Pi R ² 1 the same or different, Ariru group, or 1 to 3 substitution has been Ariru group (the substituent is a halogen atom, a lower alkyl group, a halogeno-lower Arukiru group and a lower A group selected from an alkoxy group.)

(34) R ¹ and R ² , the same or different, are an aryl group or a compound which is an aryl group substituted by one halogen atom,

(3 5) R ¹ and R ² force S, a compound which is the same aryl group substituted by one halogen atom,

 (36) A compound wherein X is an oxygen atom, a sulfur atom or a group having the formula -NH-,

(3 7) compounds wherein X is an oxygen atom,

(38) a compound wherein Y is C `` C ₈ alkylene group,

(39) a compound wherein Y is one C _s alkylene group;

(40) a compound wherein Y is a C ₂ -C ₃ alkylene group,

 (41) a compound wherein Y is an ethylene group,

(4 2) L ¹ , a group having the formula: C (R ^3a ) (R ^4a ) —

 (Where

R ^3a is an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from a substituent group a, or a heteroaryl group substituted with 1 to 3 groups with a group selected from a substituent group a. A teloaryl group,

R ^4a is a group having the formula —D—E—R ⁶ . A compound which is

(4 3) a compound wherein R ^3a is an aryl group or a heteroaryl group,

(44) a compound wherein R ^3a is a phenyl group or a pyridyl group,

(45) a compound wherein R ^3a is a pyridyl group,

(4 6) a compound wherein D and E are a single bond, (4.7) a compound having the formula R ⁶ —CO—R ^5a ,

(48) the compound, wherein R ^5a is an amine residue,

(49) the compound, wherein R ^5a is an amino group,

(50) Group having L ¹ force formula _C (R ^3a ) (R ^4a )

 (Where

R ^3a is a hydrogen atom,

R ^4a is a group having the formula D—E—R ⁶ . ).

(51) the compound, wherein D is a group having the formula: C (R ⁷ ) H—,

(52) a compound which is R ⁷ S, a cyano group or a lower alkyl group,

 (53) the compound, wherein E is a single bond,

(54) R ⁶ is a compound having the formula _CO_R ^5a ,

(55) the compound, wherein R ^5a is a lower alkoxy group,

(56) L ¹ is a group having the formula _C (R ^3a ) (R ^4a ) —, wherein R ^3a and R ^4a are linked together to form the carbon atom to which they are bonded, A compound, which is a 5- to 8-membered saturated heterocyclic ring substituted with 1 to 3 member (s) or a group selected from substituent group c,

(57) L ^{1 is a} 5- to 6-membered saturated heterocyclic ring or a compound which is a 5- to 6-membered saturated heterocyclic ring substituted by 1 to 3 substituents with a group selected from substituent group c,

(58) L ¹ force S, a compound which is a 5- or 6-membered saturated heterocyclic ring substituted by 1 to 3 groups selected from a substituent group c,

(59) L is substituted with ^one oxo group and further selected from a substituent group c.

A compound which is a 5- or 6-membered saturated heterocyclic ring which may be substituted by 1 or 2 members,

(60) L ¹ , the following formula (L-1)

 0

G person J (Le 1) '' (Wherein G and J are the same or different and are an oxygen atom, a sulfur atom or a group having the formula NR_).

 (61) the compound, wherein G is an oxygen atom or a sulfur atom, and J is a group having — NH_,

. (62) L ¹ is a group having the formula C (R ^3a ) (R ^4a ) —, wherein R ^3a and R ^4a together form the carbon atom to which they are attached, A 3 to 10-membered saturated carbon ring or a compound which is a 3 to 10-membered saturated carbon ring substituted by 1 to 3 groups with a group selected from substituent groups a and c,

(63) L ¹ , a compound having 5 to 6 membered saturated carbocycle or a 5 to 6 membered saturated carbocyclic ring substituted by 1 to 3 members with a group selected from substituent groups a and c,

(64) L ¹ force A compound which is a 5- or 6-membered saturated carbocyclic ring condensed with a benzene ring (the 5- or 6-membered saturated carbocyclic ring has an oxo group or a hydroxyl group as a substituent),

(65) a compound which is L ¹ , 2-hydroxyindane or 2-oxoindane group,

(66) a compound which is a group having the formula L N ¹ (R ^4b ) —

(67) The compound, wherein R ^4b is a group having the formula D—E—R ⁶ (where D is a single bond).

 (68) The compound wherein E is a single bond,

(69) R ⁶ force S, a compound having the formula: CO_R ^5a ,

(70) R ⁶ , a compound which is a lower alkoxycarbonyl group,

(71) a compound wherein L ¹ is a group having the formula _C (R ^4c ) —, wherein R ^4c is a group having the formula: CC (R ⁷ ) ER ⁶ ,

(72) a compound which is a R ⁷ force cyano group or a lower alkyl group,

 (73) the compound, wherein E is a single bond,

(74) compounds is a group having R ⁶ force equation one CO- R ^5a,

(75) the compound, wherein R ^5a is a lower alkoxy group, (76) any one compound selected from the following,

 1- [2-bis (4-fluorophenyl) methoxethyl] _4_phenylpiperidine-4-force rubonic acid amide,

 1- [2-Bis (4-fluorophenyl) methoxethyl] -4-phenylpiperidine-4-forceRubonic acid morpholine amide,

 1- [2-bis (4-funolelofur) methoxhetyl] -4-methyl-4-ester (4-chlorobenzyl) piperidine-4-carboxylate,

 1- [2-bis (4-fluorophenyl) methoxethyl]-4- [1- (4-fluorobenzinole) -1H-benzimidazol-2-yl] -4-hydroxypiperidine,

 1- [2_Bis (4-year-old rofjell) methoxhetyl] -4- (2-pyridyl) piperidine-4_carboxylic acid amide,

 8_ [2-Bis (4-fluorophenyl) methoxhetyl]-1-oxa-3,8-diazaspiro [4.5] decane-2-one, '

 8- [3-bis (4-fluorophenyl) methoxypropyl]-1-oxa-3,8-diazaspirate [4.5] decane-2-one,

 8- [2-bis (4-fluorophenyl) methoxethyl] -3- 3-phenyl-1-oxa_3,8-diazaspiro [4.5] decane-2-one,

 8- [2-bis (4-fluorophenyl) methoxyl] -3--3-benzyl-1-oxa-3,8-dazaspiro [4.5] decane-2-one,

 8-[2-Bis (4-fluorophenyl) methoxethylthio-3,8-dazaspiro [4.5] decane-2-one,

 8-[2-Bis (4-fluorophenyl) methoxhetyl]-3-phenyl-tothio-3,8-diazaspiro [4.5] decane-2-one,

 8- [2-bis (4-fluorophenyl) methoxshetyl phenyl-1,3,8-triaza spiro [4.5] decane-4-one,

1- [2-bis (4-fluorophenyl) methoxethyl] spiro [2, .3-dihydrobenzothi Offen-3,4'-piperidine] -1-oxoxide,

 1- [2-Bis (4-funoreo fu-norre) methoxetinole] spiro [benzo [c] thiophene-1 (3Η), 4, -piperidine],

 1_ [2-bis (4-fluorophenyl) methoxil] spiro [benzo [c] thinphen-1-(3Η), 4-piperidine] -2-oxide,

 1_ [2_bis (4-fluorophenyl) methoxetyl] spiro [, 4-dihydro-2Η-disoquinolin-3-one) -1,4 and piperidine],

 1- [2-bis (4-fluorene methoxy) methoxil) spi ρ [(indane) -1,4-dipyridine],

 1- [2-bis (4-fluorophenyl) methoxshetyl] spiro [(indane-1-one) -3,4'-piperidine],

 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(2-hydroxy) indane-1,4'-piperidine],

 2- [1_ [2-bis (4-fluorophenyl) methoxyl] -piperidin-4-yl] propionate

 1- [2-Bis (4-fluorophenyl) methoxethyl] -piperidine-4-ylidene] -methionoleestenole

 1- [2-bis (4-fluoromethyl) methoxil) piperidine-4-benzolamide

 1_ [2-bis (4-furofilophenyl) methoxhetyl] piperidine-4-methylidene 4-ylideneacetate

 1-[2-Bis (4-fluorophenyl) methoxil]-4-ethoxycanoleponinolevipera

1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3Η), 4-piperidine] -2′2-dioxide,

1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [isobenzofuran- 1 (3Η), 4'-piperidine], and

 8- [2-Bis (4-tert-phenyl) methoxyethyl]-1-oxa-3,8-dazaspiro [4,5] decane-2-one

 (77) The compound according to any one of (30) to (76), which promotes production of IL-4.

 (78) The compound according to (30) to (76), which promotes production of IL-10.

Can be mentioned. In the above formula, RR ² , R ³ , R ^3a , R ⁵ , R ^5a and “aryl group” and “1 to 3 groups selected from substituent group a” in the definition of substituent group b. The aryl moiety of the “substituted aryl group” includes, for example, aromatic hydrocarbon groups having 6 to 10 carbon atoms such as fuel, indul, and naphthyl, and is preferably a phenyl group. In the above formula, `` heteroaryl group '' in the definition of RR <sup>2</sup> , R <sup>3</sup> , R <sup>3a</sup> , R <sup>5</sup> and R <sup>5a</sup> and `` heteroaryl group substituted by 1 to 3 groups selected from substituent group a '' The teloaryl moiety may be, for example, furyl, phenyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiaziazolyl, pirael, An aromatic heterocyclic group such as pyridyl, pyridazinyl, pyrimidiel, and pyrazinyl; and the above-mentioned heteroaryl group may be condensed with another cyclic group such as a benzene ring, for example, benzothienyl, benzothiazolyl, Groups such as benzoxazolyl and isobenzofurael can be mentioned. . In such a heteroaryl group, a 5- to 6-membered aromatic heterocyclic group is preferred, a pyridyl or pyrazur group is more preferred, and a 2-pyridyl group is most preferred. In the above formula, "one C _B alkylene group" in the definitions of Y and E, for example, methylcarbamoyl Ren, Mechinoremechiren, ethylene, propylene, trimethylene, 1-Mechinoreechire , Tetramethylene, 1-methylinoletrimethylene, 2-methinoletrimethylene, 3_methinoletrimethylene, 1-methinolepropylene, 1,1-dimethyleneethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methinoletetramethylene, 1,1-dimethinoletrimethylene, 2,2-dimethinoletrimethylene, 3,3-dimethinoletrimethylene, hexamethylene, 1- Methylpentamethylene, 2-methinolepentamethylene, 3-methinolepentamethylene, 4-methinolepentamethylene, 5-methylpentamethylene, 1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene, 3,3-dimethyl Tetramethylene, 4,4-dimethyltetramethylene, heptamethylene, 1-methylhexame Len, 2-methynolehexamethylene, 5-methynolehexamethylene, 3-ethynolepentamethylene, octamethylene, 2-methynoleheptamethylene, 5-methylheptamethylene, 2-ethylhexamethylene, 2-ethynoley 3-methynole Pentamethylene, 3-ethyl

A linear or branched alkylene group having 1 to 8 carbon atoms, such as 2-methyl pentamethylene group, in Y, preferably a C i-C ₅ alkylene group, more preferably C ₂ — A C ₃ alkylene group, most preferably an ethylene group, and in E, preferably a C ″ C ₄ alkylene group, more preferably — an alkylene group, most preferably a methylene group. is there.

In the above formula, "C ₂ -〇 ₈ Arukeeren group" in the definition of Y are, for example, Eteyure down, 2-propenylene, 1-Mechinore 2 propenylene, 2-methyl 'single 2- propenyl two Len , 2-Echinolene 2-Probelene, 2-Phtenylene, 1-Methynole 2-butenylene, 2-Methizole-1-butenylene, 1-Echinolene 21-butenylene, 3-butenylene, 1-Methynole 3 _ Butenylene, 2-Methynole 3- 3-ptenelen, 1-et / re

3-pentenylene, 2-pentenylene, 1-methinolene 2-pentenylene, 2-methinole 1-2-pentenylene, 3_pentenylene, 1-methinole-1 3-pentenylene, 2-methinole_3 —Pentenylene, 4-pentenylene, 1-methinolene 4-pentenylene, 2-methinolene 4 _pentenylene, 2-hexenylene, 3-hexenylene. 4-hexenylene In Ren group - Two Len, the 5-xenon - Ren, 9 from 2 to 8 carbon atoms, such as one to Kisadeseniren group or a linear or branched Aruke two alkylene groups, preferably a ^ one C ₅ Aruke There, more suitably C ₂ -. a C ₃ 7 "Luque two alkylene groups," Amin residue "in the most preferably a Eteyuren group in the above formula, R ⁵ and R ^5a definition are, for example, amino An amino group substituted by one or two “lower alkyl groups” such as methylamino, ethylamino, isopropylamino, butylamino, dimethylamino, acetylamino, diisopropylamino, dibutylamino; cyclopentylamino, cyclohexylamino, diamino Amino groups substituted by 1 or 2 "cycloalkyl groups having 5 to 7 carbon atoms" such as cyclopentylamino and dicyclohexylamino; pyrrolidino, pipe Saturated cyclic amine residues having a nitrogen atom in the ring, such as dino, piperazino, N-methylbiperazino, morpholino, thiomorpholino; nitrogen, such as a-lino, benzylamino, N-methylanilino, N-methylbenzylamino An aryl or aralkylamino group in which an atom may be substituted with a "lower alkyl group"; a nitrogen atom such as pyridylamino, N-methylpyridylamino, N-ethylpyridylamino is substituted with a "lower alkyl group" And an amino group bonded by a nitrogen atom such as a heteroarylamino group which may be substituted, preferably an amino group; an amino group substituted with one or two "lower alkyl groups"; Nitrogen atoms such as pyrrolidino, piperidino, piperazino, N-methylbiperazino, morpholino, and thiomorpholino A saturated cyclic amine residue and an aryl or aralkylamino group in which the nitrogen atom may be substituted by a "lower alkyl group", such as azirino, benzylamino, N-methylanilino, N-methylbenzylamino And most preferably an amino group.

In the above formula, “5 to 8 membered saturated heterocyclic ring” formed by R ^3a and R ^4a together including the carbon atom to which they are bonded, and “a group selected from the substituent group c. The 5- to 8-membered saturated heterocyclic moiety of the `` 5 to 8-membered saturated heterocyclic substituted with 3 to 3 carbon atoms '' is a 5- to 8-membered saturated heterocyclic ring containing 1 to 3 sulfur atoms, oxygen atoms, and 1 to 3 Z or nitrogen atoms. . Such 5- to 8-membered saturated heterocycles include, for example, tetrahydrobiranyl, morpholine Groups such as nil, thiomorpholinyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, piperidinyl, piperadiel, oxazolidiel, isoxazolidinyl, thiazolidinyl, and pyrazolidinyl; and further, the 5- to 8-membered saturated heterocyclic group is It may be condensed with another cyclic group such as a benzene ring. In such a 5- to 8-membered saturated heterocyclic ring, a 5- to 6-membered saturated heterocyclic group is preferable.

In the above formula, a group selected from the group consisting of “5- to 8-membered saturated heterocycle” and “substituent group c”, wherein R ³ and R ⁴ are taken together to include the carbon atom to which they are bonded, The 5- to 8-membered saturated heterocyclic group substituted by 3 to 3 membered 5- to 8-membered saturated heterocyclic ring, excluding tetrahydrofuran, imidazolidine or dioxepane, is the same as the above R ^3a and R ^4a together. 5 of the “5- to 8-membered saturated heterocycle” formed including the carbon atoms bonded thereto and “5- to 8-membered saturated heterocycle substituted by 1 to 3 groups selected from the substituent group c” It has the same meaning as a to 8-membered saturated heterocyclic moiety.

In the above formula, “3 to 10-membered saturated carbocycle” and “substituent group” formed by including R ³ and R ⁴ , or carbon atoms to which R ^3a and R ^4a are bonded together The 3- to 10-membered saturated carbocyclic moiety of the 3- to 10-membered saturated carbocyclic ring substituted by 1 to 3 groups selected from a and c is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Examples thereof include groups such as Xinole, Cycopenia, Puchinore, Nonolepornyl, Adamantyl, and Indanore, and may be condensed with another cyclic group such as a benzene ring. Such a 3- to 10-membered saturated carbocycle is preferably a 5- to 6-membered saturated cyclic hydrocarbon group which may be condensed with a benzene ring, and most preferably an indanyl group. In the above formula, the “halogen atom” in the definition of the substituent group “a” is fluorine, chlorine, bromine or iodine atom, preferably fluorine atom or chlorine atom, and most preferably fluorine atom.

In the above formula, R ^5a represents a lower alkyl group of “lower alkyl group” in the definition of the substituent groups a and b and “lower alkyl group substituted by 1 to 3 groups selected from the substituent group a”. The parts are, for example, methyl, ethyl, propyl, isopropyl, butyl, isopti , S-butyl, t_butylinole, pentinole, isopentyl / le, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentinole, 3-methylpentyl, 2-methylpentyl, 1-Methynolepentinole, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethynolebutyl, 1,2-dimethynolebutyl, 1,3-dimethylbutyl, 2,3-dimethynolebutyl , 2 Echirupuchiru a linear or branched alkyl group having 1 to 6 carbon atoms such as groups, preferably a ^ one C ₄ alkyl group, more preferably a C -Cs alkyl group, Most preferably, it is a methyl group.

In the above formula, the “halogeno lower alkyl group” in the definition of the substituent group a represents a group in which the above “lower alkyl group” has been substituted with a halogen atom, for example, trifluoromethyl, trichloromethyl, difluoromethino. , Dichloromethinole, dibromomethinole, fenoleolomethinole, 2,2,2-triphneolenochinole, 2,2,2-trichloroethinole, 2-promo chinole, 2-chloroethinole, 2-phenylenolenolle A lower alkyl group having 1 to 6 carbon atoms, such as 2-ethyl ethynole, 3-chloropropyl, 4-fluorobutyl, 6-hexylhexyl, and 2,2-dibutyl moethyl. Is a halogeno _4- alkyl group, more preferably a halogeno-C ₂ alkyl group, and most preferably a trifluoromethyl group.

In the above formula, “lower alkoxy group” in the definition of R ^5a and the substituent group a represents a group in which the above “lower alkyl group” is bonded to an oxygen atom, and is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy. , Inobutoxy, s_butoxy, t-butoxy, pentoxy, isopentoxy, 2-methinolebutoxy, neopentoxy, hexinoleoxy, 4-methinolepentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylpropyl A straight chain with 1 to 6 carbon atoms such as toxic, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy Or a branched chain alkoxy group, preferably a 1 C ₄ alkoxy group, more preferably a 1 C ₂ alkoxy group, Most preferably, it is a methoxy group.

 In the above formula, the “lower alkoxycarbonyl group” in the definition of the substituent group “a” is as defined above.

A "lower alkoxy group" represents a group bonded to a carboxyl group, for example, methoxy canolebonyl, ethoxycarbur, propoxypropyl, isopropoxycarbonyl, butoxycarbol, isobutoxycarbel, sbutoxy Carbonyl, t-butoxycarbonyl, pentoxycarbol, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonel, hexyloxycarbel, 4-methylpentoxycarbonyl, 3-methylpen Toxicylcarbonyl, 2-Methyl grepentoxy force / report, 3,3-Dimethynolebutoxy force / Repotinole, 2,2-Dimethylbutoxycarbonyl, 1,1-Dimethylbutoxycarbol, 1,2-Dimethylbutane Toxicylcarbonyl, 1,3-dimethylbutoxycarbur, 2,3-dimethyl Help butoxy carbonyl having 2 to 7 amino lower alkoxycarbonyl group carbons such as groups, are, preferably a C ₂ -C ₅ alkoxycarbonyl group, more preferably C ₂ one C ₃ alkoxycarbonyl - And most preferably a methoxycarbonyl group.

In the above formula, the “lower aliphatic acyl group” in the definition of the substituent groups a and b represents a hydrogen atom or a group in which a saturated or unsaturated chain hydrocarbon group is bonded to a carboel group, for example, formyl Acetyl, propionyl, butyryl, isoptyryl, norrelyl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, and octyl tonnyl. Or a propioel group, most preferably an acetyl group.

In the above formula, “lower aliphatic acylamino group” in the definition of R ⁶ and the substituent group a represents a group in which the above “lower aliphatic acyl group” is bonded to an amino group, such as formylamino, acetylamino, propio- Lumino, butyrylamino, isopyrylamino, norrelylamino, isovalerylamino, vivaloylamino, hexanoylamino, acryloylamino, methacryloylamino, crotonylamino group It is preferably an acetylamino or propionylamino group, and most preferably an acetylamino group. ''

 In the above formula, the aralkyl part in the “aralkyl group” and the “aralkyl group substituted by 1 to 3 groups selected from the substituent group a” in the definition of the substituent group b is benzyl.

, Α-naphthinolemethinole, β-naphthinolemethyle / β, indeninolemethinele, diphenenolemethyl, triphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl

, 2 naphthylechinole, 1-huerup mouth pill, 2-phenylpropyl, '3-fenolepropinele, 1-naphthinolepropinele, 2 naphtinolepropinele, 3-naphtinolepropinele, 1 fueninolebutinole, 2 1-Feninolebutinole, 3-Fuereptyl, 4-1Finoleptinole, 1-Naphtinolebutinole, 2-Naphtinoleptinole, 3-Naphthylptinole, 4-Naphtinolebutinole, 1-Feninolepentinole, 2 —Feninole Pentinole, 3—Feninole Pentinole, 4-Feninole Pentinole, 5—Fenenole Pentinole, 1—Naphtinole Pentinole

, 2-naphthinopentenole, 3-naphthylpentinole, 4-naphthinolepentinole, 5-naphthylpentyl, 1-pheninolehexenole, 2-phenenolehexenole, 3-phenohexenole, 4-fuenorexine, 4-fuenomi Norehexinole, 5- Hue-norexinole, 6-Fenolehexinole,

C ₇ such as 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthynolehexyl, 5-naphthylhexyl or 6-naphthylhexyl group

A C ₁₆ aralkyl group, preferably a benzyl group.

ニル基であり、 更に好適には 一 C₂アルキルスル ホニル基であり'、 最も好適にはメチルスルホニル基である。 上記式中、 R⁶の定義における 「芳香族ァシルァミノ基」 は、 前記ァリール基が カルボニルァミノ基に結合した基を示し、 例えば、 ベンゾィルァミノ、 1—インダ ンカルボニルァミノ、 2—インダンカルボ-ルァミノ、 1—若しくは 2—ナフトイ ルァミノ基であり、 好適には、 ベンゾィルァミノ基である。 In the above formula, the “lower alkylsulfoyl group” in the definition of the substituent group b represents a group in which the above “lower alkyl group” is bonded to a sulfonyl group, for example, methylsulfonyl, ethynolesnorhonol, Pinores Nolehoninole, Isopropinoles Nolehoninole, Petit / Lesnole Honinore, Isobutylsulfoninole, s-Ptinoles, / Lehoninole, t-Ptylsnolehoninole, Pentylsulfonyl, Isopentylsulfur, 2-Methyl Butinolesulhoninole, Neopentylsnolejoel, 1-ethylpropinolesulhonle, hexinolesulhol, i-hexhexylsnolehoninole, 4-methinolespentinolesnorenole, 3-methylpenty Noresnolehonyl, 2-Methylpentinolesnorehonyl, 1-Methylpentylsnolehoninole, 3, 3 -Dimethylbutynoles / levonyl, 2,2-dimethylbutylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 2 —A straight-chain or branched-chain alkylsulfoer group having 1 to 6 carbon atoms, such as ethyl butyl / resulforyl group, preferably

And more preferably a 1 C ₂ alkylsulfonyl group, and most preferably a methylsulfonyl group. In the above formula, the “aromatic acylamino group” in the definition of R ⁶ represents a group in which the aryl group is bonded to a carbonylamino group, and examples thereof include benzoylamino, 1-indancarbonylamino, and 2-indanecarbonylamino. , 1- or 2-naphthoylamino group, preferably a benzoylamino group.

In the above formula, specific examples of the `` aryl group substituted by 1 to 3 groups selected from the substituent group a '' in the definition of RRRR ^3a , R ⁵ , R ^5a and the substituent group b include, for example, 2 —, 3— or 4—fluorophenyl, 2 _, 3— or 4 _ chlorophenol, 2 —, 3 — or 4 bromophenyl, 2-, 3 _ or 4 phenyl, 2 —, 3 — Or 4-methylphenyl, 2-, 3- or 4-methylphenyl, 2_, 3- or 4-trifluoromethylphenyl, 2_, '3

— Or 4-methoxyethoxy, 2-, 3- or 4-ethoxyethoxy, 21-, 3- or 4-methoxycarbylphenyl, 2_, 3- or 4-ethoxycarbole, 2- , 3- or 4-hydroxycarbyl, 2_, 3- or 4-hydroxyphenol, 2-, 3- or 4-formylphenol,

2-, 3- or 4-acetylphenyl, 2-, 3- or 4-propioylphenyl, 2_, 3- or 4-formylaminophenyl, 2-, 3- or

4-acetylaminophenol, 2-, 3_ or 4-propio-laminophenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-cyanophenol, 3, 4- Diphnolerophe / le, 3,4-dicloth fenole, 3,4-dibutene morphene, 2,3-dimethoxyphene, 3,4-dimethoxyphene, 3,5 Dimethoxyphenyl, 3,4,5-Trimethoxyphenyl, 3-Fluoro, 4-Methoxyphenyl, 4-Methyl-12-Methoxyphenyl, 6-Fluoro-4-Methyl1-2-Methoxyphenyl, 5-Funoleo Mouth indene 3-inole, 5-funoleo mouth indene 3-yl, 5-methinolein-dene 3-isle, 5-methoxyindene 1-3-yl, 5-husleo indene 1-2-inole, 5-chloroindene 1-yl, 5-methylindene-1-yl, 5-methoxyindene-2-yl, 5-fluoronaphthalene-1-yl, 5-fusoleronaphthalene_2-isle, 5-methylinole Naphthalene-1-yl, 5-methoxynaphthalene-2-yl, 5-funolelonaphthalene-1-inole, 5-fluoronaphthalene-1-yl, 5-methinolenaphthalene-11 Le, 5 Methoxynaphthalene-11-yl, 5-hydroxyindene-3-yl, 5-hydroxynaphthalene-12-yl, 5-hydroxynaphthalene-11-yl group, preferably halogen Atom, a lower alkyl group, an aryl group substituted by 1 to 3 groups selected from a halogeno lower alkyl group and a lower alkoxy group, more preferably an aryl group substituted by 1 halogen atom, More preferably, it is a phenyl group substituted by a fluorine atom or a chlorine atom, and most preferably, a 4-fluorophenyl group. In the above formula, `` 5 to 8 substituted by 1 to 3 groups selected from the substituent group c, which R <sup>3</sup> and R <sup>4</sup> together form including the carbon atom to which they are bonded, The `` membered saturated heterocyclic ring '' is preferably a 5- to 6-membered saturated heterocyclic ring substituted by 1 to 3 groups with a group selected from substituent group c, and more preferably 1-membered with an oxo group And a 5- or 6-membered saturated heterocyclic ring which may be further substituted by 1 or 2 groups selected from the substituent group c, and more preferably represented by the following formula (L-11)

(In the above formula, G and J are the same or different, and are an oxygen atom, a sulfur atom or a formula NR. Is a group having However, G and J do not represent a group having the same formula NR—.

Most preferably, in the above formula, G is an oxygen atom or a sulfur atom.

, J is a group having —N H—.

In the above formula, R ^3a and R ^4a are taken together to form a `` 5- to 8-membered saturated group substituted by 1 to 3 groups selected from a substituent group c, including the carbon atom to which they are bonded. The `` complex ring '' is preferably substituted with 1 to 3 substituent groups c or a selected group.

A 5- or 6-membered saturated heterocyclic ring, more preferably a 5- or 6-membered saturated heterocyclic ring which may be substituted by one oxo group and further substituted by 1 or 2 groups selected from substituent group c And more preferably, the following formula (L-1)

 (In the above formula, G and J are the same or different and each represents an oxygen atom, a sulfur atom or a group having the formula NR—). And J is a group having —NH—.

In the above formula, R ³ and R ⁴ , or R ^3a and R ^4a together form a carbon atom to which they are bonded to form a `` substituent group a and c selected from 1 to The `` 3-substituted 3- to 10-membered saturated carbocycle '' is preferably a 5- to 6-membered saturated carbocyclic ring substituted by 1 to 3 groups with a group selected from substituent groups a and c. More preferably, it is a 5- or 6-membered saturated carbocyclic ring condensed with a benzene ring (the 5- or 6-membered saturated carbocyclic ring has an oxo group or a hydroxyl group as a substituent), and most preferably. , 2-hydroxyindane or 2-oxoindane group.

"Pharmacologically acceptable salt thereof" means that the compound (I) or (II) of the present invention is reacted with an acid when it has a basic group such as an amino group, When the compound has an acidic group such as a carboxy group, it can be converted to a salt by reacting with a base. The salt based on a basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid Inorganic acid salts such as salts and phosphates; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, benzenesulfonates and ρ-toluenesulfonates. Organic acid salts such as lillsulfonate, acetate, malate, fumarate, succinate, quanate, ascorbate, tartrate, oxalate and maleate; and glycine Examples include salts, amino acids such as lysine, arginine, oleetine, glutamate and aspartate, and most preferably organic acid salts.

 On the other hand, the salt based on the acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt, a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, an aluminum salt, Metal salts such as iron salts; inorganic salts such as ammonium salts, octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methyldalcamine salts, guanidine salts, getylamine salts , Triethylamine, dihexylhexylamine, N, N'-dibenzylethylenediamine, chloroproline, proline, diethanolamine, N-benzylphenethylamine, Lazine salt, tetramethylammonium salt, tris (hydroxymethyl) a Amin salts such good Una organic salts Nometan salts; and Darishin salts, lysine salts, arginine salts, Orunichi down, glutamate, Ru can be mentioned Amino acid salts such as Asuparagin acid salt. '

The compound having the general formula (I) or (II) of the present invention has various isomers since an asymmetric carbon atom is present in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, by the general formula (I) or (II). Accordingly, the present invention includes all these isomers, as well as mixtures of these isomers in any proportion. The compound represented by the general formula (I) or (II) of the present invention absorbs water, becomes adsorbed water, or becomes a hydrate when left in the air or recrystallized. Such hydrates may be included in the salts of the present invention.

 The “ester” in the above refers to the ester of the compound (I) or (II) of the present invention because it can be converted into an ester, and such esters include “ester of hydroxyl group” and “carboxy group”. And an ester in which each ester residue is a “general protecting group” or a “protecting group that can be cleaved in vivo by a biological method such as hydrolysis”.

 “General protecting group” refers to a protecting group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis.

 As the “general protecting group” for the “ester of hydroxyl group”, preferably, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl

, Valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethynoleoctanoyl, 3,7-dimethinole otatanyl, pentadecyl, dodecanol, tridecanol, tridecanol, tridecanol 1-methinolepentadecanoyl, 14-methylpentadecanoyl, 13, 13-dimethyltetradecanoyl, heptadecanol, 15-methylhexadecanoyl, octadecanol, 1-methylheptadecanol, Alkanoyl groups such as nonadecanoyl, eicosanoyl, henicosanoyl, halogenated alkylcarboyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, and methoxyase Lower aliphatic acetyls such as alkoxyalkyl carboxy groups such as alkyl, acryloyl, propioloyl, methacryloyl, crotonyl, isocrotonyl, and unsaturated alkylcarbonyl groups such as (E) _2-methyl-12-butenoyl; Group (preferably a lower aliphatic acetyl group having 1 to 6 carbon atoms); benzoyl, -naphthoyl, aryl-carbonyl group such as β-naphthoinole, 2-bromobenzoyl, 4-bromobenzoyl Black mouth Benzo Arylcarbonyl groups such as 2,4-, 6-trimethylbenzoyl and 4-toluoyl, and lower alkoxylated arylcarbonyl groups such as 4-anisole. Nitrobenzene, a nitrated arylcarbonyl group such as 2-nitrobenzoyl, a lower alkoxycarbylated arylcarbonyl group such as 2- (methoxycarbonyl) benzoyl, "Aromatic acyl groups" such as arylated carbyl groups such as fuel benzoyl; methoxy canoleponinole, ethoxy canolebinore, propoxy canolebonore, butoxycyanoleboninole, sutoki Lower alkoxycarboyl groups such as shikanoreboninore, .t-butoxycanoleponinole, isopoxycarbonyl, 2,2 "Alkoxycarbonyl groups" such as nodogens such as 1,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl or lower alkoxycarbol groups substituted with tri-lower alkylsilyl groups; Such as 3-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropropylan _4_yl, tetrahydroxytetrahydropyran-1-2-yl, 4-methoxytetrahydrothiopyran-1-4-yl "Tetrahydrodrobilanyl or tetrahydrothiopiroel group";"tetrahydrofuranyl or tetrahydrothiofuranyl group" such as tetrahydrofuran-12-yl or tetrahydrofurothiofuran-2-yl; trimethinoresilinole, triethylsilyl, isopropyldimethyl Silyl, 1: 1-butyldimethylsilyl Tri-lower alkylsilyl groups such as methyldiisoprovirsilyl, methyldi-tert-butylsilyl, triisopropylsilyl, diphen-olemethinoresilisle, diphenoleptis resilisle, dibenzo-noreisoprovirsilyl, phe “Silyl groups” such as tri-lower alkylsilyl groups substituted by one or two aryl groups such as eldiisopropylsilyl; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl A lower alkoxymethyl group such as propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl; a lower alkoxylated lower alkoxymethyl group such as 2-methoxyhexoxymethyl; 2,2,2-trichlethoxymethyl, bis (2-black ethoxy) Mechinore "Alkoxymethyl groups" such as halogeno-lower alkoxymethyl such as; ethoxy groups such as 1-ethoxyshethyl and 1_ (isopropoxy) ethyl; and halogenated groups such as 2,2,2-trichloroethyl. "Substituted ethyl group" such as tyl group; one to three aryl groups such as benzyl, α-naphthylmethyl,] 3-naphthylmethyl, diphenylmethyl, triphenylmethyl, _α -naphthyldiphenylmethinole, 9-anthrinolemethyl A lower alkyl group substituted with 4, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxybenzyldiphenylmethyl, 2 —Dutrobenzyl, 4-12 Toro Benzinole, 4 _Black Benzinole, 4—Bromobenzinole, 4 _Cyanobenzinole An "aralkyl group" such as a lower alkyl group substituted with one to three aryl groups in which the aryl ring has been replaced by a lower alkyl, lower alkoxy, ethoxy, halogen, or cyano group; , Such as aryloxycarboel, "alkenyloxyforce / reponinole group"; pendinoleoxycanoleponinole, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxypentyloxycarbonyl An "aralkyloxycarbyl group" in which the aryl group may be substituted with one or two lower alkoxy or ditro groups, such as 2-, 2-nitrobenzyloxycarbonyl, and 4-nitrobenzenecarbonyl. Can be mentioned.

As the “general protecting group” for the “ester of a carboxy group”, preferably, the above “lower alkyl group”; ether, 1-propyl, 2-propyl, 1-methyl-12 —Properinole, 1-methinole, 1-propernole, 2-methyl_1-prole, 2-methyl-1-propernyl, 2-ethyl-2-prole, 1-butyr, 2 — Butenyl, 1-methyl-2-butul, 1-methyl-1-butur, 3-methyl-1-buteninole, 1-ethynorre _ 2-butur, 3-buteninole, 1-methinolle 3-butur, 2-methinolé 31 Buteninole, 1-Ethylou 3 1 Buteninole, 1—Pentinole, 2—Pentinole, 1-Methinole 2—Penten / le, 2-Methinole 2—Pentennole, 3—Pentennole, 1—Mentinole 3-Pente Ninore, 2—Mechinore 3 one pair Te two Norre, 4- Pentinole, 1-methyl-1-pentenyl, 2-methinole 4-penteninole 1-hexeninole, 2-hexennole, 3-hexeninole, 4-hexennole, 5-hexennole, etc. Lower alkenyl groups; ethel, 2-propiel, 1-methyl-2-probuyl, 2-methyl-2-propiel, 2-ethyl-12-probuyl, 2-petiel, 1-methyl1-2-butul, 2-methinole-2 -Buchininore, 1-Echinore 1 2-Petinore, 3-Petinole, 1-Mechinore 1-Petite-Nore, 2-Mechinore 3-Puchenole, 1-Echinole_3—Petinole, 2-Pentinole, 1—Methinole 2—Pentinole, 2—Methinole — 2—Pennice / Re, 3 _Pentinole, 1—Methinole 3—Pentinole, 2-Methinole 3 _Pentinole, 4—Pentinole Nore, 1—Metino Lower alkynyl groups such as 4-pentynole, 2-methinole, 4-pentynole, 2-hexynyl, 3-hexyl, 4-hexyl, 5-hexynyl; the above-mentioned "halogeno lower alkyl""Hydroxy" lower alkyl group "such as 2-hydroxytinol, 2,3-dihydroxypropionyl, 3-hydroxypropynole, 3,4-dihydroxymethyl butyl, 4-hydroxybutyl; acetylmethyl Such as "lower aliphatic acyl", "lower alkyl group", "aralkyl group", and "silyl group".

 "A protective group that can be cleaved in vivo by a biological method such as hydrolysis" means a protective group that is cleaved in a human body by a biological method such as hydrolysis to produce a free acid or a salt thereof. A derivative is administered to a laboratory animal such as a rat or a mouse by intravenous injection, and then the body fluid of the animal is examined to determine whether the derivative is the original compound or a pharmacologically acceptable salt thereof. Can be determined by being able to detect

As the “protecting group capable of being cleaved in vivo by a biological method such as hydrolysis” as the “ester of a hydroxyl group”, preferably, formyloxymethyl, acetoxmethyl, dimethylaminoacetoxymethyl , Propionyloxymethyl, petyryloxymethyl, bivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethinole, hexanoinoleoxymethinole, 1-formyloxyxethyl, 1-acetoxyethyl, 1-propionylo Kisekil. 1—Butyrilokixil, 1-Pivalo 1-hexanolyloxetil, 1-formyloxypropyl, 1-acetoxyp Propionyloxypropynole, 1-butyryloxypropynole, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl , 1_propioninoleoxybutyl, 1-butylinoleoxypuccinole, 1-Vivainoleoxypuccine 1-acetoxoxypentyl, 1-propioninoleoxypentyl, 1-butylinoleoxypentyl, 1-pivaloy 11-(“lower aliphatic acryl” oxy), such as loxypentyl, 1-piva- mouthyloxyhexyl “lower alkyl group, cyclopentyl Carbonyloxymethyl, hexyl carbyloxymethyl, 1-pent pentyl phenol, 1-cyclohexyl carbonyl oxetyl, 1-cyclopentyl canoleboninoleoxypropyl, 1-cycl pentyl 1-("cycloalkyl" carbonyloxy) "lower alkyl", such as hexylcarbonyloxypropinole, 1-cyclohexyl pentynole / repoenoleoxybutynole, 1-cyclohexyl / recanololevoxybutyl 1-("aromatic acyl" oxy) such as benzoyloxymethyl, "lower alkyl", etc. 1- (acyloxy) "lower alkyl group"; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl , Propoxy canolebonoxy methoxy / isopropoxy canolepo eroki Methinole, Butoxycarboninoleoxymethinole, Isobutoxycarbonyloxymethyl, Pentyloxycarbonyloxymethyl, Hexyloxycarbonyloxymethyl, Cycoxyhexylcarbonyloxymethyl, Cyclohexyloxy Carbonyloxy (cyclohexanol) methyl, 1- (methoxy carbonyl-reoxy) ethynole, 1— (ethoxycarbo-noroxy) ethyl, 1- (propoxycarboxy-roxy) ethyl, 1 _ (isopropoxyl-ponyloxy) ) Ethyl, 1- (butoxycarboxy-loxy) ethyl, 1- (isoptoxycanolevoni, / reoxy) ethyl, 1- (t-butoxycanolepo2 / reoxy) ethyl, 1- (pentyloxycarbonyloxy) ethyl, 11 (Hexyloxy Power Report) 1- (cyclopentyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) propyl, 1- (cyclohexyl / reoxycanolebonyloxy) propyl, 1- (cyclopentyloxycarbonyl) 1- (cyclohexyloxycarbo- / reoxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 1- (methoxycarbonyl) Xy) propyl, 1- (ethoxycarbonylcarbonyl) propy ^ \ 11- (propoxycarboninoleoxy) propynole, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1-yl

(Isobutoxycarboxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- (hexyloxycarboxy) propyl, 11- (methoxycarbo-noroxy) Ethoxy canoleponoleoxy) butyl, 11

(Propoxycarbonyloxy) butyl, 1- (isopropoxycarbonyloxy) butyl, 1- (butoxycarboxy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) pentyl 1- (ethoxycanoleponinoleoxy) pentyl, 1- (methoxycarbonyloxy) hexyl, 1

-(Lower alkoxy group / leoxy) alkyl group such as (ethoxycarbonyloxy) hexyl; (5-phenyl-12-oxo_1,3-dioxolen-1-yl) methyl, [5- ( 4-methyl-1) 2-oxo-1, 3-dioxolen-14-yl) Methyl, [5- (4-methoxyphenyl) 1-2-oxo-1 1, '3-dioxolen-1 4-yl Methyl, [5- (4-fluoropheninole) -2-oxo-1,3-dioxolene 4-inole] Methyl, [5- (4-chlorophene) 12-year-old 1,3-dioxolene (4-yl) Methyl, (2-oxo-1,3-dioxolen-1-4-inole) Methyl, (5-methyl-2-oxo-1,3-dioxolen-1-41) methinole, (5-ethinole-1) 2-oxo-1,3-dioxolen-4-yl) methyl, (5 Propyl one 2- Okiso one 1, 3-Jiokisoren one 4 one I le) methylation, (5-isopropyl one 2- Okiso one 1, 3-Jiokisoren one 4 one ^ le) methylcarbamoyl Carbodioxy lower alkyl group such as oxo, dioxolenylmethyl group such as methyl, (5-ptinole_2-oxo-1,1,3-dioxolen-14-yl): phthalidyl, dimethylphthalidyl "Phthalidyl group" such as dimethoxyphthalidyl: the above-mentioned "lower aliphatic acyl group": the above-mentioned "aromatic acyl group": "the residue of a succinic acid salt": "the residue of a phosphate salt": " Ester-forming residues of amino acids, etc .: carbamoyl group: carbamoyl group substituted by one or two lower alkyl groups: and “a-yloxy” such as pinoloyloxymethyloxycarboel An alkyloxycarbyl group "can be mentioned, and preferably, a" carbonyloxyalkyl group ".

On the other hand, as the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of a carboxy group”, preferably, methoxyxyl, 1-ethoxyxyl, 1-methyl-1 1-Methoxyxetil, 1- (isopropoxy) ethyl, ₂ -Methoxyxyl, 2-Ethoxytyl, 1,1-dimethyl-1-methoxethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, t-butoxy A lower alkoxy lower alkyl group such as methyl, a lower alkoxylated lower alkoxy lower alkyl group such as 2-methoxyxetoxymethyl, an “aryl” oxy “lower alkyl group” such as phenoxymethyl, 2, 2, 2 —Haguchigens such as trichloroethoxymethyl, bis (2-chloroethoxy) methyl An "alkoxyalkyl group" such as a lower alkoxy lower alkyl group; a "lower alkoxy" carbonyl "lower alkyl group" such as methoxycarbonylmethyl; a "cyano" lower alkyl group "such as cyanometyl or 2-cyanoethyl; "Lower alkyl" thiomethyl groups, such as methylthiomethyl and ethylthiomethyl; "aryl" thiomethyl groups, such as phenylthiomethyl and naphthylthiomethyl; 2-methanesulfonylethyl, 2-trifluoromethanes / lefonyletyl Such as "lower alkyl" which may be substituted with halogen, "lower alkyl group", sulfoel "lower alkyl group";"" arinole " Nil “lower alkyl group”; the above “(a-loxy)“ lower alkyl group ””; the “phthalidyl group”; the “aryl group”; the “lower alkyl group”; “carboxyalkyl” such as carboxymethyl Group ";and" amino acid amide-forming residues "such as phenylalaene.

 The “other derivative” refers to the compound (I) or (II) of the present invention.

If the compound has a carboxy group, it can be a derivative other than the above “pharmacologically acceptable salt” and the above “ester”. An example of such a derivative is an amide derivative.

 Specific examples of the compound having the general formula (I) or (II) of the present invention include, for example, the compounds shown in Table 1 below, but the present invention is not limited to these compounds. The compounds in Table 1 have the structural formula (II-11).

In Table 1, the substituents of M represent the following groups.

 ο

00 00 00

The abbreviations in the table are as follows.

 Ac acetyl group

 B z benzyl group

 E tethyl group

 Me methyl group

 P h phenyl group.

[table 1]

Compd. R ¹ R ^2. XYM

 No. Substituent No.

1 Ph Ph -0--(C¾) _2- (1)

3 Ph Ph-0--(c¾) _2- (2)

4 Ph Ph -0--(c¾) _2- (3)

5 Ph Ph -0--(CH ₂ ) _2- (15)

6 Ph Ph-0--(C¾) _3- (15)

7 Ph Ph -0- - (c¾) 4 - (15)

8 Ph Ph -0--(c¾) _2- (16)

9 Ph Ph -0--(c¾) _2- (17)

10 Ph Ph -0--(c¾) _2- (18)

11 Ph Ph -0--(c¾) _3- (18)

12 Ph Ph-0--(CH ₂ ) _2- (19) ''

13 Ph Ph-0--(C¾) _2- (20) Ph Ph-0--(c¾) _2- (21)

Ph Ph -0--(c¾) _3- , (21)

Ph Ph -0--(CH ₂ ) _2- (22)

Ph Ph-0--(CH ₂ ) _2- (23)

Ph Ph-0--(CH ₂ ) _2- (30)

Ph Ph-0--(CH ₂ ) _3- (30)

Ph Ph - 0 - - (CH 2) 4 - (30)

Ph Ph-0--(c) _2- (31)

Ph Ph-0--(C¾) _2- (32)

Ph Ph-0--(C) _3- (32)

Ph Ph -0--(c¾) _2- (33)

Ph Ph -0--(C¾) _3- (33)

Ph Ph-0--(C¾) _2- (34)

Ph Ph-0--(c¾) _2- (35)

Ph Ph -0--(CH ₂ ) _2- (36)

Ph Ph -0--(CH ₂ ) _3- (36)

Ph Ph-0--(C¾) _2- (37)

Ph Ph-0--(C¾) _2- (38)

Ph Ph -0--(CH ₂ ) _2- (59)

Ph Ph -0--(c¾) _2- (73)

Ph Ph-0--(c¾) _2- (74)

Ph Ph -0--(C¾) _3- (74)

Ph Ph-0--(c¾) _2- (75)

2-F-Ph 2-F-Ph-0--(C¾) _2- (1)

2-F-Ph 2-F-Ph-0--(c¾) _3- (1)

2-F-Ph 2-F -Ph - 0 - - (CH 2) 4 - (1)

 I I I I I I I I I I I I I I S I I I I I I I I I I> I

I I I I I I I I f I I I ' 1 I

IIIIIIII f III '1

O 00 oo CO OO oo OO 00 CO OO oo-] ^ 3

o CO cr> C71 CO t 1 ¹ o OO cn OO DO o O OO CD

to to DO CO to t t IN CO t CO t CO t IN (ND to CO CO t CO

 I 1 1 I 1 1 1 1 1 1 1 1 1 I 1 I 1 1 1 1 [1 I 1 1 1

 • ^ d

1 1 1 1 1 1 1 1 II 1 1 1 i 1 I 1 1 I 11 1 i T ⁵

 nr tr r! = r! = r i =! = r! = r! = r

CO c t t t CO t DO CO CO t CO CO CO t CO t t

 1 1 1 1 1 1 i I 1 1 1 1 1 1! 1 1 1 1 1 I 1 1 1 1 1

 ¾d ^

i 1 1 1 1. I 1 1 1 1 I 1 1 1 1 1 1 Γ i [1 I 1 I I

 • ■ d • "0

 r i = r! = r 13-

I I I 1 i 1 I 1 [1 1 1 1 1 1 1! 1 1 1 c

I 1 1 1 1 1

o O o o o o o o O o O o o o o o cn o O o o O o o o

 1 1 1 1 1 1] 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

 1

1 1 1 I 1 l i 1 1 [1 1 1 1 1 I 1 I 1 1 1 1 1 1 I 1 o s o o o o o o o s o o

 ! -r ^

! 1 1 1 1 1 I 1 1 1 I I 1 1 1 1 1 1 1 I 1 1 1 I 1

GO O C CO CO O O OO O OO OO O OO CO CO OO CO CO CO O t CO t t CO

n ^ OOO to CO 1 "~ ¹ oo CO CO t

33FphFhp -—— l

 3Fph 3Fphl ---- o o o o o o o o D OO-3 a ^ n ^ D en CO

 3F 3phFphI-—l

 3Fph 3FPhI —--

3F 3phFph——I—

F 3 3phFph-—I—

 (^? P <p

t »--l

i I I I-IIIIIII i IIIIIIIII i II.

i II

F 2phFph—— ——

σχFphFph 21- —l ph 2FPhF-- -—

σχ

I! I I I I

o o o o o o o o o o o o o o o o o o o o o o o o o o

 1 I I I

I I I I I I I i I I I 1 I I I I I I I I I I i I I I I

 3 3FPhFph --——

 3 3FPhFph -—-- n

 t ^ o o oo oo oo-] ^] a ^ cr5 n,

3 3FPhFph --- l

3 3FphFph ----

3F 3Fphph——Il

3 3pFhFhp ——- l

3 3FFPhph --- I

3 3FPhFPh ----

3 3FphFph——1l hFpFph —— -l

FPhhFP-- O ^ Oi nn ri oi n cn n ^ ^ ^

 οο cn

o o o o o

I 1

o S Q β o o 1 1 1 1 ί 1 1 1! 1 1 1 1 1 1 .1 1 1 1 1 1 1 1 1

OO OO Cn n O O tN t to »f- * o O o o CO

3hFphFP-—-

3hFpFhP—-- 170 3-F-Ph 3-F-Ph -0--(CH ₂ ) _2- (40)

171 3-F-Ph 3-F-Ph -0--(CH ₂ ) _2- (42)

172 3-F-Ph 3-F-Ph-Q--(c¾) _2- (55)

173 3-F-Ph 3-F-Ph-0--(C¾) _2- (56)

174 3-F-Ph 3-F-Ph-0--(CH ₂ ) _2- (57)

175 3-F-Ph 3-F-Ph -0--(CH ₂ ) _2- (58)

176 3-F-Ph 3-F-Ph -0--(c¾) _2- (59)

177 3-F-Ph 3-F-Ph -0--(C¾) _3- (59)

178 3-F-Ph 3-F-Ph -0--(C¾) _2- (60)

179 3-F-Ph 3-F-Ph -0--(c¾) _2- (73)

180 3-F-Ph '3-F-Ph -0--(C¾) _3- (73)

181 3-F-Ph 3-F-Ph -0- _ (c¾) _2- (74)

182 3-F-Ph 3-F-Ph-0--(c¾) _3- (74)

183 3-F-Ph 3- F-Ph - 0- - (CH 2) 4 - (74)

184 3-F-Ph 3-F-Ph -0--(c¾) _2- (75)

185 3-F-Ph 3-F-Ph -0--(C¾) _3- (75)

186 3-F-Ph 3-F-Ph-0,-(C¾) _2- (78)

187 4-F-Ph 4-F-Ph -0- -c¾-(1)

188 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (1)

189 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (1)

190 4-F-Ph 4- F-Ph - 0- - (CH 2) 4 - (1)

191 4-F-Ph 4-F-Ph-0--(c¾) _5- (1)

192 4-F-Ph 4-F-Ph-S--(C¾) _2- (1)

193 '4-F-Ph 4-F-Ph -S- _ (CH ₂ ) _3- (1)

194 '-F-Ph 4-F-Ph -NH--(c¾) _2- (1)

195 4-F-Ph 4-F-Ph -NH--(C¾) _3- (1) t

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248 4-F-Ph 4-F-Ph -S--(C¾) _2- (16)

249 4-F-Ph 4-F-Ph Good-(c¾) _2- (16)

250 4-F-Ph 4-F-Ph '-0--(CH ₂ ) _2- (17)

251 4-F-Ph 4-F-Ph -0- _ (c¾) _3- (17)

252 4-F-Ph 4- F-Ph - 0 - - (c¾) 4 - (17)

253 4-F-Ph 4-F-Ph-S--(CH ₂ ) _2- (17)

254 4-F-Ph 4-F-Ph -NH--(c¾) _2- (17)

255 4-F-Ph 4-F-Ph-0--CH _2- (18)

256 4-F-Ph 4-F-Ph -0--(CH ₂ ) _2- (18)

257 4-F-Ph 4-F-Ph-0-_ (C¾) _3- (18)

258 4-F-Ph 4- F-Ph -0- - (CH 2) 4 - (18)

259 4-F-Ph 4-F-Ph -0--(C¾) _5- (18)

260 4-F-Ph 4-F-Ph-S--(C¾) _2- (18)

261 4-F-Ph 4-F-Ph -S--(C¾) _3- (18)

262 4-F-Ph 4-F-Ph -NH--(C¾) _2- (18)

263 4-F-Ph 4-F-Ph -NH--(C¾) _3- (18)

264 4-F-Ph 4-F-Ph -0-_ (C¾) _2- (19)

265 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (19)

266 4-F-Ph 4- F-Ph - 0- - (CH 2) 4 - (19)

267 4-F-Ph 4-F-Ph -S--(CH ₂ ) _2- (19)

268 4-F-Ph 4-F-Ph -NH--(C¾) _2- (19)

269 4-F-Ph 4-F-Ph -0--(C¾) _2- (20)

270 4-F-Ph 4-F-Ph -0- _ (C¾) _3- (20)

271 4-F-Ph 4- F-Ph - 0 - - (C¾) 4 - (20)

272 4-F-Ph 4-F-Ph -S--(CH ₂ ) _2- (20)

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404 4-F-Ph 4-F-Ph -0--(C¾) _3- (51)

405 • 4-F-Ph 4-F-Ph -0--(CH ₂ ) _2- (52)

406 4-F-Ph 4-F-Ph -0--(CH ₂ ) _3- (52)

407 4-F-Ph 4-F-Ph -0--(C¾) _2- (53)

408 4-F-Ph 4-F-Ph-0--(C¾) _3- (53)

409 4-F-Ph 4-F-Ph-0--(c¾) ₂ _ (54)

410 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (54)

411 4-F-Ph 4-F-Ph -0--(CH ₂ ) _2- (55)

412 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (55)

413 4-F-Ph 4- F-Ph -0- - (CH 2) 4 - (55)

414 4-F-Ph 4-F-Ph-0--(C¾) _2- (56)

415 4-F-Ph 4-F-Ph-0_-(CH ₂ ) _3- (56)

416 4-F-Ph 4- F-Ph -0- - (c¾) 4 - (56)

417 4-F-Ph 4-F-Ph -0--(c¾) ₂ _ (57)

418 4-F-Ph 4-F-Ph -0--(CH ₂ ) _3- (57)

419 4-F-Ph 4- F-Ph -0- - (CH 2) 4 - (57)

420 4-F-Ph 4-F-Ph -0--(C¾) _2- (58)

421 4-F-Ph 4-F-Ph-0--(C¾) _3- (58)

422 4-F-Ph 4- F-Ph -0 - - (CH 2) 4 - (58)

423 4-F-Ph 4-F-Ph -0--(CH ₂ ) _2- (59)

424 4-F-Ph 4-F-Ph -0--(CH ₂ ) _3- (59)

425 4-F-Ph 4- F-Ph -0- - (CH 2) 4 - (59)

426 4-F-Ph 4-F-Ph -S--(CH ₂ ) _2- (59)

427 4-F-Ph 4-F-Ph -NH--(c¾) ₂ — (59)

428 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (60)

429 4-F-Ph 4-F-Ph -0--(C¾) _3- (60) ^ ^ • ^ ^ ^

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508 2-CI-Ph 2-Cl-Ph-0--(c¾) _2- (3)

509 2-Cl-Ph 2-Cl-Ph -0--(CH ₂ ) _2- (15)

510 2-Cl-Ph 2- CI-Ph -0--(c) _3- (15)

511 2-Cl-Ph 2- Cl-Ph -0 - - (CH 2) 4 - (15)

512 2-Cl-Ph 2-CI-Ph-0--(c) _2- (16)

513 2- CI-Ph 2-Cl-Ph -0--(CH ₂ ) _2- (17)

514 2-Cl-Ph 2-CI-Ph-0--(CH ₂ ) _2- (18)

515 2-Cl-Ph 2-Cl-Ph -0--(C¾) _3- (18)

516 2-Cl-Ph 2-CI-Ph -0--(CH ₂ ) _2- (19)

517 2-Cl-Ph 2-Cl-Ph-0--(c¾) _2- (20)

518 2-Cl-Ph 2- CI- Ph-0--(CH ₂ ) _2- (21)

519 2-Cl-Ph 2-Cl-Ph -0--(CH ₂ ) _3- (21)

520 2-Cl-Ph 2-CI-Ph-0--(CH ₂ ) _2- (22)

521 2- CI- Ph 2-CI-Ph-0--(CH ₂ ) _2- (23)

522 2-Cl-Ph 2-Cl-Ph-0--(CH ₂ ) _2- (30)

523 2- CI- Ph 2-Cl-Ph-0--(C¾) _3- (30)

524 2-Cl-Ph 2- Cl-Ph - 0- - (CH 2) 4 - (30)

525 2-Cl-Ph 2-CI-Ph -0--(c¾) _2- (31)

526 2-Cl-Ph 2-Cl-Ph-0- _ (c¾) _2- (32)

527 2-CI-Ph 2-Cl-Ph -0-'_ (C¾) _3- (32)

528 2-CI-Ph 2-CI-Ph -0--(c) _2- (33)

529 2-CI-Ph 2-CI-Ph -0--(C¾) _3- (33)

530 2-Cl-Ph 2-Cl-Ph-0--(C¾) _2- (34)

531 2-Cl-Ph 2-Cl-Ph-0--(CH ₂ ) _2- (35)

532 2-CI-Ph 2-Cl-Ph-0--(c¾) _2- (36)

533 2-Cl-Ph 2-Cl-Ph-0--(c¾) _3- (36) 534 2-Cl-Ph 2-Cl-Ph _0--(c¾) _2- (37)

535 2-Cl-Ph 2-Cl-Ph -0--(CH ₂ ) _2- (38)

536 2-Cl-Ph 2-Cl-Ph -0--(c¾) _2- (59)

537 2-Cl-Ph 2-Cl-Ph-0--(CH ₂ ) _2- (73)

538 2-Cl-Ph 2- Cl-Ph-0--(C¾) _2- (74)

539 2-Cl-Ph 2-Cl-Ph _0--(C¾) _3- (74)

540 2-Cl-Ph 2-Cl-Ph -0--(c¾) _2- (75)

541 3-Cl-Ph 3-Cl-Ph -0--(CH ₂ ) _2- (1)

542 3-CI-Ph 3-Cl-Ph -0--(CH ₂ ) _3- (1)

543 3-Cl-Ph 3-Cl-Ph -0--(CH ₂ ) _2- (2)

544 3-Cl-Ph 3- Cl-Ph -0--(CH ₂ ) _2- (3)

545 3-Cl-Ph 3-Cl-Ph -0--(c¾) _2- (15)

546 3-Cl-Ph 3- Cl-Ph _0--(C¾) _3- (15)

547 3 - Cl-Ph 3- Cl-Ph -0 - - (C¾) 4 - (15)

548 3-Cl-Ph 3-Cl-Ph _0--(CH ₂ ) _2- (16)

549 3-Cl-Ph 3-Cl-Ph-0--(c) _2- (17)

550 3-Cl-Ph 3-Cl-Ph-0--(c¾) _2- (18)

551 3-CI-Ph 3-Cl-Ph -0--(C¾) _3- (18)

552 3-Cl-Ph 3-Cl-Ph -0--(c¾) _2- (19)

553 3-CI-Ph 3- Cl-Ph-0--(CH ₂ ) _2- (20)

554 3-Cl-Ph 3-Cl-Ph -0--(c¾) _2- (21)

555 3-CI- Ph 3- Cl-Ph -0--(c¾) _3- (21)

556 3-Cl-Ph 3-Cl-Ph -0--(c¾) ₂ — (22)

557 3-Cl-Ph 3-CI- Ph -0--(c) _2- (23)

558 3-Cl-Ph 3- Cl-Ph-0--(c¾) _2- (30)

559 3-Cl-Ph 3-CI-Ph-0--(c¾) _3- (30) 560 3 - Cl-Ph 3- CI- Ph _0 - - (CH 2) 4 - (30)

561 3-Cl-Ph 3-Cl-Ph -0--(c¾) _2- (31)

562 3-Cl-Ph 3- CI- Ph -0--(c¾) _2- (32)

563 + 3-Cl-Ph 3-CI- Ph _0--(CH ₂ ) _3- (32)

564 3-Cl-Ph 3-Cl-Ph-0--(c¾) _2- (33)

565 3-Cl-Ph 3-Cl-Ph -0--(CH ₂ ) _3- (33)

566 3-Cl-Ph 3-Cl-Ph -0--(CH ₂ ) _2- (34)

567 3-Cl-Ph 3-Cl-Ph -0-'-(c¾) _2- (35)

568 3-Cl-Ph 3-Cl-Ph-0--(C) _2- (36)

569 3-Cl-Ph 3-Cl-Ph-0--(c¾) _3- (36)

570 3- Cl-Ph 3-Cl-Ph -0--(CH ₂ ) _2- (37)

571 3-Cl-Ph 3-Cl-Ph-0--(CH ₂ ) _2- (38)

572 3-CI-Ph 3-Cl-Ph -0--(c¾) _2- (59)

573 3-CI- Ph 3-Cl-Ph-0--(C¾) _2- (73)

574 3-CI-Ph 3-Cl-Ph -0--(c¾) _2- (74)

575 3-Cl-Ph 3- CI-Ph -0--(CH ₂ ) _3- (74)

576 3-Cl-Ph '3-Cl-Ph -0--(C¾) _2- (75)

577 4-Cl-Ph 4-CI- Ph-0--(CH ₂ ) _2- (1)

578 4-Cl-Ph 4-CI-Ph -0--(c¾) _3- (1)

579 4 - Cl-Ph 4- Cl-Ph -0- - (CH 2) 4 - (1)

580 4- Cl-Ph 4-Cl-Ph -S--(CH ₂ ) _2- (1)

581 4-Cl-Ph 4-Cl-Ph -NH--(c¾) ₂ -'(1)

582 4- CI-Ph 4-CI-Ph-0--(C¾) _2- (2)

583 4-CI- Ph 4-Cl-Ph-0--(CH ₂ ) _3- (2)

584 4- CI - Ph 4 - CI- Ph -0- _ (CH 2) 4 - (2)

585 4-Cl-Ph 4-Cl-Ph-0--(c¾) _2- (3) Ri ichi (Ίichi L ϋ y

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Sl7C.0 / 00df / X3d 61 ^ OAV 612 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _3- (16)

613 4-Cl-Ph 4- Cl-Ph - 0 - - (CH 2) 4 - (16)

614 4-Cl-Ph 4-Cl-Ph -0--(c¾) _2- (17)

615 4-Cl-Ph 4-Cl-Ph-0--(c¾) _3- (17)

616 '4-Cl-Ph 4 -Cl-Ph -0- - (C¾) 4 - (17)

617 4-Cl-Ph 4-Cl-Ph _0--(CH ₂ ) _2- (18)

618 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _3- (18)

619 4-Cl-Ph 4- Cl-Ph -0- - (CH 2) 4 - (18)

620 4-Cl-Ph 4-Cl-Ph-s--(c¾) _2- (18)

621 4-Cl-Ph 4-Cl-Ph -NH--(C¾) _2- (18)

622 4-Cl-Ph 4-Cl-Ph-0- _ (c) _2- (19)

623 4-Cl-Ph 4-Cl-Ph-0--(C¾) _3- (19)

624 4-Cl-Ph 4- Cl-Ph - 0- - (C¾) 4 - (19)

625 4-Cl-Ph 4-Cl-Ph-0--(C¾) _2- (20)

626 4-Cl-Ph 4-Cl-Ph _0--(CH ₂ ) _3- (20)

627 4-Cl-Ph 4- Cl-Ph -0- - (c¾) 4 - (20)

628 4-Cl-Ph 4-Cl-Ph -0- _ (CH ₂ ) _2- (21)

629 4-Cl-Ph 4-Cl-Ph-0_-(C¾) _3- (21)

630 4-Cl-Ph 4- Cl-Ph - 0- - (CH 2) 4 - (21)

631 4-Cl-Ph 4-Cl-Ph-S--(C¾) _2- (21)

632 4-Cl-Ph 4-Cl-Ph -NH--(CH ₂ ) _2- (21)

633 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (22)

634 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _3- (22)

635 4-Cl-Ph 4- Cl-Ph - 0- - (CH 2) 4 - (22)

636 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _2- (23)

637 4-Cl-Ph 4-Cl-Ph-0--(C) _3- (23) 638 4-Cl-Ph 4- Cl-Ph -0- - (C¾) 4 - (23)

639 4-Cl-Ph 4-Cl-Ph -0- _ (c¾) _2- (24)

640 4-Cl-Ph 4-Cl-Ph -0--(C¾) _3- (24)

641 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (25)

642 4-Cl-Ph 4-Cl-Ph-0--(C¾) _2- (26)

643 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (27)

644 4-Cl-Ph 4-Cl-Ph -0--(C¾) _3- (27)

645 4-Cl-Ph 4-Cl-Ph-0- _ (c¾) _2- (28)

646 4-Cl-Ph 4-Cl-Ph-0--(c¾) _2- (29)

647 4-Cl-Ph 4-Cl-Ph -0--C¾-(30)

648 4-Cl-Ph 4-Cl-Ph-0--(C¾) _2- (30)

649 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _3- (30)

650 4-Cl-Ph 4- Cl-Ph - 0- - (CH 2) 4 - (30)

651 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _5- (30)

652 4-Cl-Ph. 4-Cl-Ph -S--(C¾) _2- (30)

653 4-Cl-Ph 4-Cl-Ph-S--(C¾) _3- (30)

654 4-Cl-Ph 4-Cl-Ph -NH--(CH ₂ ) _2- (30)

655 4-Cl-Ph 4-Cl-Ph -NH--(c¾) _3- (30)

656 4-Cl-Ph 4-Cl-Ph-0--(C¾) ₂ --(31)

657 4-Cl-Ph 4-Cl-Ph-0--(C¾) _3- (31)

658 4-Cl-Ph 4- Cl-Ph - 0 - - (c¾) 4 - (31)

659 4-Cl-Ph 4- Cl-Ph-S--(CH ₂ ) _2- (31)

660 4-Cl-Ph 4-Cl-Ph -NH--(C¾) _2- (31)

661 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (32)

662 4-Cl-Ph 4-Cl-Ph-0--(C¾) _3- (32)

663 4-Cl-Ph 4- Cl-Ph -0--(c¾) ₄ _ (32) σ

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690 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _3- (40)

691 4-Cl-Ph 4-Cl-Ph -0--(c¾) _2- (41)

692 4-Cl-Ph 4-Cl-Ph -0--(c¾) _2- (42)

693 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _3- (42)

694 4-Cl-Ph 4-Cl-Ph -0--(c) _2- (43)

695 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _2- (44)

696 4-Cl-Ph 4-Cl-Ph-0--(c¾) _2- (45)

697 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _2- (46)

698 4-Cl-Ph 4-Cl-Ph -0--(C¾) _2- (47)

699 4-Cl-Ph 4-Cl-Ph-0--(C¾) _2- (48)

700 4-Cl-Ph 4-Cl-Ph -0- _ (c¾) _2- (49)

701 4-Cl-Ph 4-Cl-Ph -0--(c¾) _2- (50)

702 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _2- (51)

703 4-Cl-Ph 4-Cl-Ph-0--(C¾) _2- (52)

704 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (53)

705 4-Cl-Ph 4-Cl-Ph-0--(c¾) _2- (54)

706 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _2- (55)

707 4-Cl-Ph 4-Cl-Ph-0--(C¾) _3- (55)

708 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _2- (56)

709 4-Cl-Ph 4-Cl-Ph-0--(C¾) _3- (56)

710 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _2- (57)

711 4-Cl-Ph 4-Cl-Ph -0--(C¾) _3- (57)

712 4-Cl-Ph 4-Cl-Ph -0--(c¾) _2- . (58)

713 4-Cl-Ph 4-Cl-Ph-0--(C¾) _3- (58)

714 4-Cl-Ph 4- Cl-Ph-0--(c¾) _2- (59)

715 4-Cl-Ph 4-Cl-Ph-0--(c¾) _3- (59) 716 4-Cl-Ph 4- Cl-Ph -0- - (CH 2) 4 - (59)

717 4-Cl-Ph 4-Cl-Ph -0--(C¾) _2- (60)

718 4-Cl-Ph 4-Cl-Ph -0- _ (c¾) _3- (60)

719 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _2- (61)

720 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _2- (62)

721 4-Cl-Ph 4-Cl-Ph -0--(C¾) _2- (63)

722 4-CI- Ph 4-Cl-Ph- ⁰ --(C¾) _2- (64)

723 4- CI-Ph 4-Cl-Ph -0--(CH ₂ ) _2- (65)

724 4-CI-Ph 4-Cl-Ph-0--(C¾) _2- (66)

725 4-CI- Ph 4-Cl-Ph -0--(CH ₂ ) _2- (67)

726 4-Cl-Ph 4-Cl-Ph-0--(c¾) ₂ _ (68)

727 4-Cl-Ph 4-Cl-Ph-0--(C¾) _2- (69)

728 4-Cl-Ph 4-Cl-Ph -0--(C¾) _2- (70)

729. 4-Cl-Ph 4-Cl-Ph -0- _ (c¾) _2- (71)

730 4- CI-Ph 4-CI-Ph-0--(C¾) _2- (72)

731 4- CI-Ph 4-CI-Ph -0--(C¾) _2- (73)

732 4-Cl-Ph 4-Cl-Ph -0--(C¾) _3- (73)

733 4- CI - Ph 4-Cl -Ph -0 - - (CH 2) 4 - (73)

734 4-Cl-Ph 4-CI- Ph -0--(CH ₂ ) _2- (74)

735 4-Cl-Ph 4-CI-Ph -0--(C¾) _3- (74)

736 4 - CI - Ph 4- Cl-Ph - 0- - (c¾) 4 - (74)

737 4-Cl-Ph 4-Cl-Ph -S--(c¾) _2- (74)

738 4-Cl-Ph 4-Cl-Ph Good _ (c¾) _2- (74)

739 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _2- (75)

740 4-Cl-Ph 4-Cl-Ph-0--(c¾) _3- (75)

741 4 - CI - Ph 4- Cl-Ph -0- - (C¾) 4 - (75) -] -a-^ 3 ^ 3 * 1--1

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?

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^{(ιι) - ε () -} - 0- ¾I- · ¾ 88

(ιι)-HO)-_0- L2L

(9ΐ) ^-S (¾))--0-9 L

^{(9Τ) - Ζ (Η3)} - - 0 - - Interview 3 - n S8Z

^{- 2 (Ή3) - -ΗΝ- n} WL

^{(ST) - ζ (¾)} ) - -S- ¾I - Interview 3- £

(ST)-(¾))--0-- ^j an Z2L

^{(5ΐ) - ε (Ή3)} - - 0 - - · ¾- T8Z

^{(ST) - 2 (Ή3)} - - 0 - - - 08

(9)-(¾))--0-n QLL

^{(S) - Ζ (Ή0)} - - 0- L

^{() - Ζ (Ή0) -} -0 - - ILL

^{(ε) - ε (Ή3)} - - 0 - n - Interview 3- 9LL

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^{(2) - ε (Ή3)} - _0 - n LL) - Η3) - - 0- ¾ι - Interview a - £ LL

(τ)-^ (¾3)--0-■ ¾-ILL

^{(ΐ) - ε (Ή3)} - - 0- ¾ι - j a ILL

(I)-0-n OIL

^{(U) - ζ (¾3)} - -0 - mother ε n 69Z

^{(9ε) - ζ (¾3)} - -0- ϋ 29L

08 st'C / .o / oodf / xad 6i / Z0 OAV 794 4-Br-Ph 4-Br-Ph -0--(CH ₂ ) _2- (20)

795 .4-Br-Ph 4-Br-Ph _0--(c) _3- (20)

796 4-Br-Ph 4-Br-Ph -0--(CH ₂ ) ₂ -'(21)

797 4-Br-Ph 4-Br-Ph -0--(c¾) _3- (21)

798 4-Br-Ph 4- Br-Ph - 0- - (CH 2) 4 - (21)

799 4-Br-Ph 4-Br-Ph -0--(CH ₂ ) _2- (22)

800 4-Br-Ph 4-Br-Ph-0--(CH ₂ ) _3- (22)

801 4-Br-Ph 4-Br-Ph-0--(C¾) _2- (23)

802 4-Br-Ph 4-Br-Ph-0--(CH ₂ ) _3- (23)

803 4-Br-Ph. 4-Br-Ph -0- _ (CH ₂ ) _2- (24)

804 4-Br-Ph 4-Br-Ph-0--(CH ₂ ) _2- (30)

805 4-Br-Ph 4-Br-Ph-0--(c¾) _3- (30)

806 4-Br-Ph 4- Br-Ph -0 - - (CH 2) 4 - (30)

807 4-Br-Ph 4-Br-Ph -S--(CH ₂ ) _2- (30)

808 4-Br-Ph 4-Br-Ph -NH--(CH ₂ ) _2- (30)

809 4-Br-Ph 4-Br-Ph-0--(CH ₂ ) _2- (31)

810 4-Br-Ph 4-Br-Ph-0-_ (CH ₂ ) _3- (31)

811 4-Br-Ph 4-Br-Ph -0--(CH ₂ ) _2- (32)

812 4-Br-Ph 4-Br-Ph -0--(CH ₂ ) _3- (32)

813 4-Br-Ph 4- Br-Ph - 0- - (c) 4 - (32)

814 4-Br-Ph 4-Br-Ph -0--(CH ₂ ) _2- (33)

815 4-Br-Ph 4-Br-Ph-0--(C¾) _3- (33)

816 4-Br-Ph 4- Br-Ph -0- - (CH 2) 4 - (33)

817 4-Br-Ph 4-Br-Ph-0--(c¾) _2- (34)

818 4-Br-Ph 4-Br-Ph -0--(CH ₂ ) _3- (34)

819 4-Br-Ph 4-Br-Ph -0--(C¾) _2- (35) ^{(τ) - ζ (¾3)} - - 0 - - S ^ 8ヽ

 )-(.) _-0-

^{(SZ) - ε (¾3)} - - 0 - ¾1 - · ¾ H ε 8

^{(SA) - ζ (¾ο)} - - 0 - ϋ z

 -(H3)--0-m

-(Ή3)--0-0 ^ 8, ヽ

^{(t) - ζ (¾3)} - - 0 - ¾ -! Interview 3 688

(21)-(HO) _-0-888

 One (Η3)--0--

^{(09) - ζ (¾3)} - - 0 - - 9 £ S

/ C ヽ ε "ヽ

 (63) '(Η.)--0-SS8

^{(69) -. Ζ (¾} )) _ _0_ n £ 2

(/ 8ha3 ヽ)-HO)--0-£ 88

^{(S) - s (¾3)} - - 0 - Z £ 2

(99)-(ro)--0-H l £ 2

/ Ha ha,

 (S3)-H)--0-New 3-088

^{(Z) - z (¾3)} - - 0 - Ή- · ¾ n 628

(ο ^)-(Ή3)--0-2Z

^{(8 £) - ε (¾3} ) - - 0 - n LZ

^{(8ε) - z (¾3)} - -0- ¾H 9Z2 \

^{(Ε) - ε (¾3)} - - 0 - - · ¾_

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 (AS) (Η3)--0- Ή-n tzs θε) (HO)--0- Ή- n £ ZS

^{(9ε) - ε (¾3)} - - 0- ¾ ¾ ZZ

^{(9ε) - 2 (¾ο)} - -! 0- ¾ ΪΖ2

^{- ε (¾3) - -0- -} 028

St £ L0 / 00d £ / ∑Jd 6UWZ0 OAV 846 2-Me-Ph 2-Me-Ph -0--(c¾) _2- (15)

847 2-Me-Ph 2-Me-Ph -0--(CH ₂ ) _3- (15)

848 2-Me-Ph 2-Me-Ph _0--(c¾) _2- (18)

849 2-Me-Ph 2-Me-Ph -0--(CH ₂ ) _2- (21)

850 2-Me-Ph 2-Me-Ph-0-.- (c¾) _2- (30)

851 2-Me-Ph 2-Me ^ Ph -0- (c¾) _3- (30)

852 2-Me-Ph 2-Me-Ph-0--(c¾) _2- (32)

853 2-Me-Ph 2-Me-Ph-0--(CH ₂ ) _2- (33)

854 2-Me-Ph 2-Me-Ph -0--(c¾) _2- (36)

855 2-Me-Ph 2-Me-Ph-0--(c¾) _2- (74)

856 3-Me-Ph 3-Me-Ph-0--(c¾) _2- (1)

857 3-Me-Ph 3-Me-Ph-0--(c¾) _2- (15)

858 3-Me-Ph 3-Me-Ph -0--(C¾) _3- (15)

859 3-Me-Ph 3-Me-Ph -0--(c¾) ₂ -'(18)

860 3-Me-Ph 3-Me-Ph -0--(c¾) _2- (21)

861 3-Me-Ph 3-Me-Ph-0--((¾) ₂ -'(30)

862 3-Me-Ph 3-Me-Ph -0--(C¾) _3- (30)

,

863 3-Me-Ph 3-Me-Ph-0--(c¾) _2- (32)

864 3-Me-Ph 3-Me-Ph-0--(c¾) _2- (33)

865 3-Me-Ph 3-Me-Ph-0--(CH ₂ ) _2- (36)

866 '3-Me-Ph 3-Me-Ph -0--(CH ₂ ) _2- (74)

867 4-Me-Ph 4-Me-Ph-0--(c¾) _2- (1)

868 4-Me-Ph 4-Me-Ph -0--(c¾) _3- (1)

869 4-Me-Ph 4-Me-Ph-0--(c¾) _2- (2)

870 4-Me-Ph 4-Me-Ph-0--(CH ₂ ) _2- (3)

871 4-Me-Ph 4-Me-Ph -0--(C¾) _2- (15) eeMphMph —-— I

 eeMPPhMh —---

CO CO o

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Meph Mephl—

Meph Meph—— 898 4-Me-Ph 4-Me-Ph -0--(CH ₂ ) _2- (59)

899 4-Me-Ph 4-Me-Ph -0--(c¾) _2- (73)

900 4-Me-Ph 4-Me-Ph-0--(CH ₂ ) _2- (74)

901 4-Me-Ph 4-Me-Ph -0--(C¾) _3- (74)

902 4-Me-Ph 4-Me-Ph-0--(c¾) _2- (75)

903 2-CF ₃ -Ph 2-CF ₃ -Ph-0--(CH ₂ ) _2- (1)

_{904 2 - CF 3 - Ph 2} -CF 3 -Ph - 0- - (CH 2) 2 -. (15)

905 2-CF ₃ -Ph 2-CF ₃ -Ph -0--(c¾) _3- (15)

906 2-CF ₃ -Ph 2-CF ₃ -Ph -0--(CH ₂ ) _2- (18)

907 2-CF ₃ -Ph 2-CF3-PI1-0--(CH ₂ ) _2- (21)

908 2-CF ₃ -Ph 2-CF ₃ -Ph -0--(c¾) _2- (30)

909 2-CF ₃ -Ph 2-CF ₃ -Ph -0--(C¾) _3- (30)

910 2-CF3-PI1 2-CF ₃ -Ph -0--(CH ₂ ) _2- (32)

911 2-CF ₃ -Ph 2-CF3-PI -0--(CH ₂ ) _2- (33)

_{912 2 - CF 3 - Ph 2} -CF 3 -Ph -0- - (C¾) 2 - (36)

_{913 2 - CF 3 - Ph 2} -CF 3 -Ph -0 - - (CH 2) 2 - (74)

914 3-CF ₃ -Ph 3-CF ₃ -Ph-0--(C¾) _2- (1)

915 3-CF ₃ -Ph 3-CF ₃ -Ph-0--(CH ₂ ) _2- (15)

916 3-CF ₃ -Ph 3-CF ₃ -Ph-0--(CH ₂ ) _3- (15)

917 3-CF ₃ -Ph 3-CF ₃ -Ph-0--(CH ₂ ) _2- (18)

918 3-CF ₃ -Ph 3-CFs-Ph _0--(c) _2- (21)

919 3-CF ₃ -Ph 3-CFg-Ph-0--(CH ₂ ) _2- (30)

920 3-CF ₃ -Ph 3-CF3-PI1 -0--(C¾) _3- (30)

921 3-CF3-PI1 3-CF ₃ -Ph -0--(C¾) _2- (32)

922 3-CF ₃ -Ph 3-CF ₃ -Ph-0--(C¾) _2- (33)

923 3-CF ₃ -Ph 3-CF ₃ -Ph -0--(CH ₂ ) _2- (36) 924 3-CF ₃ -Ph 3-CF ₃ -Ph -0- _ (CH ₂ ) _2- (74)

925 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(CH ₂ ) _2- (1)

926 4-CF ₃ -Ph 4-CF ₃ -Ph-0--(c¾) _3- (1)

_{927 4-CF 3 -Ph 4 -} CF 3 - Ph - 0 - - (CH 2) 2 - (2)

928 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(C¾) _2- (3)

_{929 4-CF 3 -Ph 4 -} CF 3 - Ph - 0- - (CH 2) 2 - (15)

930 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(CH ₂ ) _3- (15)

_{931 4-CF 3 -Ph 4-} CF 3 -Ph -0 - - (CH 2) 4 - (15)

932 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(C¾) _2- (16)

933 4-CF ₃ -Ph 4-CF ₃ -Ph.-0--(CH ₂ ) _2- (17)

_{934 4-CF 3 -Ph 4 -} CF 3 - Ph - 0 - - (C¾) 2 - (18)

935 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(C¾) _3- (18)

_{936 4 - CF 3 - Ph 4} -CF 3 -Ph -0 - - (CH 2) 2 - (19)

937 4-CF ₃ -Ph 4-CF ₃ -Ph-0--(C¾) _2- (20)

938 4-CF ₃ -Ph 4-CF ₃ -Ph-0--(C¾) _2- (21)

939 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(C¾) _3- (21)

940 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(c¾) _2- (22)

941 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(C¾) _2- (23)

942 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(c¾) _2- (30)

943 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(c¾) _3- (30)

_{944 4-CF 3 -Ph 4-} CF 3 -Ph -0- - (C¾) 4 - (30)

945 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(c¾) _2- (31)

946 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(C¾) _2- (32)

947 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(C¾) _3- (32)

948 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(CH ₂ ) _2- (33)

949 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(C¾) _3- (33) 950 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(CH ₂ ) _2- (34)

951 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(c¾) _2- (35)

952 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(CH ₂ ) _2- (36)

953 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(C¾) _3- (36)

954 4-CF ₃ -Ph 4-CF ₃ -Ph-0--(CH ₂ ) _2- (37)

955 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(C¾) _2- (38)

956 4-CF ₃ -Ph, 4-CF ₃ -Ph-0--(CH ₂ ) _2- (59)

957 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(CH ₂ ) _2- (73)

958 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(c¾) _2- (74)

959 4-CF ₃ -Ph 4-CF3-PI1-0--(C¾) _3- (74)

960 4-CF ₃ -Ph 4-CF ₃ -Ph-0--(CH ₂ ) _2- (75) In the above table, preferred compounds are

Compound number: 188-214, 231-357, 377-398, 481, 482, 577-593, 602-676, 688-699, and 746,

 Further preferred compounds include

Compound number: 188-191, 196-198, 201-203, 206-214, 231-236, 245-247, 250-252, 255-259, 264-266, 269-271, 274-278, 283-285 , 288-290, 293-312, 321-325, 330-334, 339-343, 348-350, 353-355, 377-398, 481, 482, and 648.

 More preferred compounds include

Compound number: 188, 196, 201, 206, 209, 212, 215, 217, 219, 221, 223, 225, 227, 229, 232, 245, 250, 256, 264, 269, 275, 283, 288, 293 , 296, 298, 300, 303, 305, 308, 322, 331, 340, 348, 353, 359, 367, 372, 377, 379, 382, 384, 387, 389, 391, 393, 395, 397, 399 , 401, 403, 405, 407, 409, 411, 414, 417, 420, 423, 428, 431, 433, 435, 437.439, 441, 443, 445, 447, 449, 451, 453, 455, 461, 469, 474, 476, 478, 481, 483, 485, 488, 491, 495, 498 and 502;

 The most preferred compounds include

Compound No. 188: 1- [2-bis (4-fluorophenyl) methoxethyl] -4-phenylpiperidine-4-carboxylic acid amide,

Compound No. 212: 1- [2-bis (4-fluorophenyl) methoxethyl] -4-phenylpiperidine-4-carboxylic acid morpholine amide,

Compound No. 232: 1- [2-Bis (4-fluorophenyl) methoxethyl] -4- (2-pyridyl) piperidine-4-hexanoic acid amide,,

Compound No. 308: 8- [2-bis (4-fluorophenyl) methoxhetyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one,

Compound No. 309: 8- [3-Bis (4-fluorophenyl) methoxypropyl] -1-oxa-3,8-diazaspirate [4.5] decane-2-one,

Compound No. 322: 8- [2-bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-oxa-1,3-diazaspiro [4.5] decane-2-one,

Compound No. 331: 8- [2-bis (4-fluorophenyl) methoxethyl] -3-benzyl-1-oxa-3,8-diazaspiro [4.5] de-2-one,

Compound No. 340: 8- [2-bis (4-fluorophenyl) methoxhetyl]-1-thio-3,8-diazaspis [4.5] decane-2-one,

Compound No. 348: 8- [2-bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-thio-3,8-diazaspiro [4.5] decane-2-one,

Compound No. 379: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [2,3-dihydrobenzothiophene-3,4, -piperidine oxide,

Compound No. 382: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4, -piperidine],

Compound number 384: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4, -piperidine] -2-oxide,

Compound number 389: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(1,4-dihydro-2H-isoquinolin-3-one) -1,4, -piperidine],

Compound number 393: 1- [2-bis (4-fluorophenyl) methoxhetyl] spiro [(indane) -1,4, -piperidine],

Compound No. 395: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(indane-1-one) -3,4, -piperidine],

Compound No. 397: 1- [2-bis (4-fluorophenyl) methoxhetyl] spiro [(2-hydroxy) indane-1,4, -piperidine],

Compound number 481: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo

[c] thiophen-1 (3H), 4, -piperidine]-2,2-dioxide, and

Compound No. 648: 8- [2-bis (4-chlorophenyl) methoxexetil] -1 -oxa-3,8-diazaspi [4.5] decane-2-one

Can be mentioned.

 In the above table, compounds suitable as TH1-selective immunosuppressants include Compound Nos. 188-504 and 577-747,

 Further preferred compounds include

Compound number: 188-191, 196-198, 201-203, 206-236, 245-247, 250-252, 255-259, 264-266, 269-271, 274-278, 283-285, 288-290 , 293-312, 321-325, 330-334, 339-343, 348-350, 353-355, 358-362, 367-369, 372-374, 377-425, 428-457, 460-464, 469 -471 and 474-504,

 More preferred compounds include

Compound No .: 188, 196, .201, 206, 209, 212, 215, 217, 219, 221, 223, 225, 227, 229, 232, 245, 250, 256, 264, 269, 275, 283, 288, 293, 296, 298, 300, 303, 305, 308, 322, 331, 340, 348, 353, 359, 367, 372, 377, 379, 382, 384, 387, 389, 391, 393, 395, 397, 399, 401, 403, 405, 407, 409, 411, 414, 417, 420, 423, 428, 431, 433, 435, 437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 461, 469, 474, 476, 478, 481, 483, 485, 488, 491, 495, 498 and 502;

 The most preferred compounds include

Compound No. 188: 1- [2-bis (4-fluorophenyl) methoxethyl] 4-phenylpyridine-4-carboxylic acid amide,

Compound No. 212: 1- [2-bis (4-fluorophenyl) methoxethyl] -4-phenylpiperidine-4-carboxylic acid morpholine amide,

Compound No. 219: 1- [2-bis (4-fluorophenyl) methoxethyl] -4- (4-cyclobenzyl) piperidine-4-carboxylic acid methyl ester,

Compound No. 229: 1- [2-bis (4-fluorophenyl) methoxhetyl] -4- [1- (4-fluorobenzyl) -1H_benzimidazol-2-yl] -4-hydroxypiperidine, compound No. 232: 1- [2-Bis (4-fluorophenyl) methoxhetyl] -4- (2-pyridyl) piperidine-4-carboxylic acid amide, '

Compound number 308: 8- [2-bis (4-fluorophenyl) methoxethyl] -1-oxoxa-3,8-dazaspiro [4.5] decane-2-one,

Compound No. 309: 8- [3-bis (4-fluorophenyl) methoxypropyl] -1-oxoxa-3,8-dazaspiro [4.5] decane-2-one,

Compound No. 322: 8- [2-bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-oxa-3,8-dazaspiro [4.5] decane-2-one,

Compound number 331: 8- [2-bis (4-fluorophenyl) methoxethyl] -3-benzyl-1-oxa-3,8-dazaspiro [4.5] decane-2-one,

Compound number 340: 8- [2_bis (4-fluorophenyl) methoxyethyl] -1-thio-3,8-diazaspiro [4.5] decane-2-one,

Compound No. 348: 8- [2-bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-thio-3,8-diazaspi [4.5] decane-2-one, ' Compound No. 367: 8- [2-bis (4-fluorophenyl) methoxethyl] -1-phenyl-1,3,8-tria, zaspiro [4.5] decane-4-one,

Compound number 379: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [2,3-dihydrobenzothiophene-3,4, -piperidine] -1-oxide,

Compound number 382: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4, -piperidine],

Compound No. 384: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4-piperidine] -2-oxoxide,

Compound No. 389: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(1,4-dihydror2H-isoquinolin-3-one) -1,4 and piperidine],

Compound number 393: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(indane) -1,4, -piperidine],

Compound No. 395: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(indane-leon) -3,4-piperidine],

Compound No. 397: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(2-hydroxy) indane-1,4-dipyridine],

Compound No. 417: 2- [1- [2-bis (4-fluorophenyl) methoxethyl] -piberidin_4-yl] propionate ethyl ester,

Compound No. 423: 2- [1- [2-bis (4-fluorophenyl) methoxethyl] -piberidin-4-yl] -1-2-cyanoacetic acid methyl ester,

Compound number 441: 1- [2-bis (4-fluorophenyl) methoxethyl] piperidine-4-carboxylic acid benzylamide,

Compound No. 61: 1- [2-bis (4-fluorophenyl) methoxethyl] -piperidine-4-ylidene] -propionic acid methyl ester,

Compound number 478: 1- [2-Bis (4-fluorophenyl) methoxethyl] -4-ethoxycarbonyldibiperazine, Compound number 481: 1- [2-bis (^ fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4-piperidine] -2,2-dioxide,

Compound number 483: 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [isobenzofuran-1 (3H), '-piperidine], and

Compound No. 648: 8- [2-bis (4-chlorophenyl) methoxhetyl]-1-oxa-3,8-diazaspi [4.5] decane-2-

Can be mentioned.

The compound having the general formula (II) of the present invention can be produced according to the method described below. In addition, the compound having the general formula (I) of the present invention can also be produced by a method similar to the method for producing the compound having the general formula (II).

Method A is a method for producing compound (II).

 Method A

 (IV)

In the above formula, R ¹ , R ² , X, Y and have the same meanings as described above, and R ^la , R ^2a and L _la are R ¹ , R ² and ぴThe amino group, hydroxyl group and / or carboxy group contained in the amino group, hydroxyl group and / or carbonyl group which may be protected are the same as those defined for R ¹ , R ² and ぴ. And Q represents a group which is usually a nucleophilic residue and is not particularly limited, provided that it is preferably a halogen atom such as chlorine, bromine or iodine; Lower halogen alkenyl sulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno lower alkyl sulfonyloxy groups such as trifluoromethane sulfonyloxy and pentafluoro mouth ethane sulfonyloxy; Benze Examples include arylsulfonyloxy groups such as sulfonyloxy, p-toluenesulfonyloxy, and p-nitrobenzenesulfonyloxy. Particularly preferred are a halogen atom and a lower alkyl sulfonyloxy group. It is.

In the above, the “protecting group” of the “optionally protected amino group” in the definition of R ^la , R ^2a and L _la is not particularly limited as long as it is a protecting group for an amino group used in the field of synthetic organic chemistry. Although not mentioned, for example, the above-mentioned halogeno C ₂ -C ₇ alkylcarbonyl group such as a C ₇ aliphatic acyl group, chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl, and a C ^ -Ce alkoxy group such as methoxyacetyl Put in Conversion has been c ₂ - c ₇ "aliphatic Ashiru such" such as an alkyl force Ruponiru group; C ₇ Karuponiru group to the c ₆ _ c ₁₀ § Li Ichiru is bound - C _u aromatic Ashiru group, 2- Buromobenzoiru , 4 halogeno C ₇ -C _u aromatic Ashiru groups such as single black port Benzoiru, 2, 4, 6-Application Benefits methylbenzoyl I le, C substituted with C i-C ₆ alkyl, such as 4 one toluoyl ₇ one C _u aromatic Ashiru group, C ₇ substituted by d-C ₆ alkoxy such as 4 Anisoiru - C u aromatic Ashiru group, 4-nitro downy Nzoiru, nitro, such as 2-two Torobenzoiru has been C ₇ - C _u aromatic Ashiru group, 2- (main butoxycarbonyl) such as benzo I le C ₂ - C ₇ alkoxycarbonyl C ₇ is substituted with two Le - C _u aromatic Ashiru group, 4 one C ₆ — like Huenil Penzil. “Aromatic acyls” such as C ₇ —Cu aromatic acyl groups substituted with aryl; the aforementioned C ₂ —C ₇ alkoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilyl “Alkoxycarbonyls” such as C ₂ -C ₇ alkoxycarbonyl substituted by halogen or tri-C ₆ alkylsilyl such as ethoxycarbonyl; “alkenyloxy” such as vinyloxycarbonyl and aryloxycarbonyl Carbonyls ”; benzyloxycarbonyl, phenyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzoyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 1 or two d-C ₆ alkoxy or an optionally § Li one Le ¾ force ^s nitro Ararukiruokishi Carbonyl compounds "; trimethylsilyl, Toryechirushiriru, I isopropyl dimethylsilyl, t one butyldimethylsilyl, methylation Jie isopropyl silyl, Mechiruji t Buchirushiriru, tri d-C ₆ alkylsilyl group such as triisopropyl silyl, Jifuenirumechiru silyl, Jifue sulfonyl butylsilyl, Jifue two Le triisopropylsilyl, phenylene Le Jie Seo professional buildings, such as three-substituted silyl groups from § Li Ichiru及Pi C i one C ₆ alkyl in selected groups such as silyl "Silyls"; such as benzyl, phenethyl, 3-phenylpropyl, a-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, a-naphthyldiphenylmethyl, 9-anthrylmethyl, etc. to 3 one C ₆ alkyl group substituted with Ariru group, 4 one methylate Benzyl, 2, 4, 6-trimethyl Benzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4 (Ci-C ₆ alkyl, C ^ —Ce alkoxy, nitro, halogen, cyano, etc. 1-3 substituted aryl rings with 1-cyanobenzyldiphenylmethyl, bis (2-ditrophenyl) methyl, piperonyl "Araruki Le such" such as C replaced by the Ariru group "C ₆ alkyl group; or N, N-dimethylaminomethylene, benzylidene, 4 Metokishiben Jiriden, 4 twelve Torobe Njiriden, Sarishiriden, 5- Kurorosarishiri Such as den, diphenylmethylene, (5_chloro-1--2-hydroxyphenyl) phenylmethylene A substituted methylene group which forms a Schiff base "; preferably an aliphatic acyl, an alkoxycarbonyl or an alkenyloxycarbonyl, particularly preferably an alkoxycarbonyl.

In the above, the `` protecting group '' of the `` optionally protected hydroxyl group '' in the definition of R ^la , R ^2a and L _la is not particularly limited as long as it is a protecting group for a hydroxyl group used in the field of synthetic organic chemistry. For example, the above C 1 -C ₇ aliphatic acyl group, succinoyl, glutaroyl, carboxy-substituted C ₂ -C ₇ alkylcarbonyl group such as aziboyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc. a halogeno C ₂ - C ₇ alkyl group, C ₂ substituted with one C ₆ alkoxy, such as main Tokishiasechiru - "aliphatic Ashiru such" such as C ₇ alkylcarbonyl alkylsulfonyl group; a C ₇ - aromatic Ashiru group, 2-Puromobenzoiru, halogeno C ₇ -C _u aromatic Ashiru groups such as base 4 black port Nzoi Le, 2, 4, 6-trimethylbenzoyl I le, A C r C u aromatic group substituted with one C ₆ alkyl, such as 4-toluoyl; a C ₇ _C _U aromatic group, substituted with d—C ₆ alkoxy, such as 4-anisole; such as C _u aromatic Ashiru group, 4-Nitorobenzoi Le, base 2 nits port Nzoiru - that carboxybenzotriazole I le, 3 _ carboxybenzotriazole I le, 4-carboxyphenyl C ₇ substituted by Karupoki such as benzo I le C ₂ —C ₇ alkoxycarbonyl, such as _2- substituted C ₇ —C _u aromatic aromatic group, 2- (methoxycarbonyl) benzoyl Substituted C ₇ - C _u aromatic Ashiru group, C _6, such as 4-phenylene Rupenzoiru - C ₁₀ C ₇ substituted by Ariru - "aromatic Ashiru such" such as C _u aromatic Ashiru group; Tetorahi Such as droppyran 1-2-yl, 3-bromotetrahydrodropyrane 2-yl, 4-methoxytetrahydrodropyrane 1-4-yl, tetrahydrothiopyran 1-2-yl, 4-methoxytetrahydro-dropiopyran 1-4-yl and the like "Tetrahydrofuranyl or tetrahydrothiopyranyls";"tetrahydrofuranyl or tetrahydrothiofuranyls" such as tetrahydrofuran-2-yl and tetrahydrothiofuran-12-yl; trimethylsilyl, triethylsilyl, isopropylpropylsilyl, t-butyldimethylsilyl, methyldisoprovirsilyl, methyldi-t-butylsilyl Le, tri C i-C ₆ alkylsilyl group such as triisopropylsilyl, Jifueeru methylsilyl, diphenyl butylsilyl, diphenyl isopropylsilyl, § Li Ichiru及Pi one C ₆ alkyl, such as phenylene Le Jie isopropyl silyl "Silyls" such as a silyl group substituted with three groups selected from the group consisting of: methoxymethyl, 1,1-dimethyl-1-methyloxy, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t— butoxymethyl, such as (C'i- C ₆ alkoxy) methylcarbamoyl group, 2-main Toki Chez butoxy substituted with one C ₆ alkoxy, such as methyl (C i-C e alkoxy) methyl group, 2, 2 , 2 _ trichloro port ethoxymethyl, bis (2 one black hole ethoxy) halogeno such as methyl (C i-C ₆ alkoxy) methyl such as "“Rucoxymethyls”; “substitution” such as (C f Cs alkoxy) such as 1-ethoxyxethyl, 1- (isopropoxy) ethyl, ethyl group, and halogenated ethyl group such as 2,2,2-trichloromethylethyl 1-C ₆ substituted with one to three aryl groups such as benzyl, naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, a-naphthyldiphenylmethyl, and 9-anthrylmethyl Alkyl group, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl , 4 black port benzyl, 4 _ bromobenzyl, 4 one Shianobenjiru, methyl, one C ₆ Al such as piperidines Roniru Kill one C ₆ alkoxy, halogen, § Li Ichiru ring 1 to 3 substituted amino § Li in Shiano - "Ararukiru such" such as one C ₆ alkyl group substituted with Le group; the C ₂ - A C ₇ -alkoxycarbonyl group, a C ₂ -C ₇ alkoxycarbonyl group substituted by a halogen such as 2,2,2-trichloromouth ethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or a tri d -C ₆ -alkylsilyl group; "Alkoxycarbonyls";"alkenyloxycarbonyls" such as vinyloxycarbonyl and aryloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, and 3,4-dimethoxybenzyl One or two C ₆ , such as oxycarbonyl, 2-nitrobenzoyloxycarbonyl, 4-nitrobenzyloxycarbonyl "Aralkyloxycarbonyls" which may be substituted on the aryl ring with alkoxy or nitro, preferably aliphatic acyls, aromatic acyls or silyls, most preferably silyls It is.

In the above, the "protecting group" of the "optionally protected carboxy group" in the definition of R ^la , R ^2a and L _la is not particularly limited as long as it is a carboxy group protecting group used in the field of synthetic organic chemistry. But not necessarily, for example, a C ₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, diphenylmethyl, bird whistle Nirumechiru, 4 one-methylbenzyl, 4-main Tokishibenjiru, 4 twelve Torobenjiru, 4 one Furuorobenjiru one C ₆ alkyl, such as 4-Shianobenjiru, C "C ₆ alkoxy, nitro, optionally substituted by halogen or Shiano good from 1-3 C ₆ -. a C "C ₆ alkyl group substituted by Ariru, preferably one C ₆ alkyl Le group Ri, most preferably a methyl or Echiru group.

Step A1 is a step of producing the compound (II), in which the compound having the general formula (III) is reacted with a compound having the general formula (IV) in an inert solvent in the presence of a base. After reacting with an acid addition salt (eg, a steel salt such as a hydrochloride, a nitrate, a sulfate), if necessary, a protecting group for an amino group, a hydroxyl group and a Z or carboxy group in R ^la , R ^2a and L _la . Is carried out. The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, and examples thereof include hexane, heptane, rigoin, and Ishigami ether. Aliphatic hydrocarbons; Aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, and dichlorobenzene Esters such as antroethyl, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; acetoneton, methyle Tilketone, 4-me Ketones such as 2-pentanone, isophorone and cyclohexanone; ditoxinated compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N -Amides such as dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide and sulfolane; Sulfolane; preferably, ketones, 7-mids, ethers or nitriles (particularly preferably ketones).

The base used in the above reaction is not particularly limited as long as it is used as a base in a usual reaction. For example, alkalis such as lithium iodide, sodium iodide, and potassium iodide Alkali metal carbonates such as lithium carbonate, sodium carbonate, and lithium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and lithium hydrogen carbonate; lithium hydride, hydrogen Alkali metal hydrides such as sodium fluoride and lithium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; or lithium fluoride Combination with inorganic bases such as alkali metal fluorides such as sodium fluoride, sodium fluoride and potassium fluoride, or N-methylmorpholine, trie Tilamine, propylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylbiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4 1- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) 1-4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-getylaniline, 1,5-diazabicyclo [4. 3.0] Nona-1-ene (DBN), 1,4-Diazabicyclo [2.2.2] Octane (DABCO), 1,8-Diazabicyclo [5.4.0] — 7-Dendene (DBU )), Preferably a combination of a metal iodide and an inorganic base, and more preferably a combination of a metal iodide and an alkali metal carbonate.

 The reaction temperature varies depending on the starting compound, the reagent used, the solvent and the like, but is usually from −20 ° C. to 150 ° C. (preferably from 0 ° C. to 100 ° C.).

 The reaction time varies depending on the starting compound, the reagent used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 50 hours (preferably 1 hour to 12 hours).

 The elimination of protecting groups for amino group, hydroxyl group and hydroxyl group is different depending on the kind, but generally, methods well known in the art of organic synthetic chemistry, for example, TWGreen, (Protective Groups in Organic Synthesis), Jolin Wiley & Sons: JFWk: 0mis, (Protective Groups in Organic Chemistry). The method described in Plenum Press can be performed as follows.

 When the protecting group of the amino group is a silyl, it usually produces a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, monopyridine hydrofluoride, or potassium fluoride. By treatment with a compound of interest.

 The solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether. It is suitable.

 The reaction temperature and reaction time are not particularly limited, but the reaction is usually carried out at 0 ° C to 50 ° C for 10 hours to 18 hours.

When the protecting group for the amino group is an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group or a substituted methylene group which forms a Schiff base, the presence of an aqueous solvent is prohibited. In the presence, it can be removed by treatment with an acid or a base.

 The acid used in the above reaction is not particularly limited as long as it is a commonly used acid and does not inhibit the reaction. Examples thereof include hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, An inorganic acid such as nitric acid, preferably hydrochloric acid.

 The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound, but is preferably an alkali metal carbonate such as lithium carbonate, sodium carbonate, or lithium carbonate. Salts; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, and potassium l-butoxide Ommonia water, ammonia such as concentrated ammonia-methanol;

The solvent used in the above reaction is not particularly limited as Re der those used in the conventional hydrolysis reaction force ^s, for example, methanol, ethanol, n- propanol, I isopropanol, n- butanol, isobutanol Alcohols such as ethyl, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methylacetosolve; dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether Such as ethers; water; a mixed solvent of water and the above organic solvent; and preferably ethers (particularly preferably dioxane).

 The reaction temperature and the reaction time vary depending on the starting compound, the solvent, and the acid or base used, and are not particularly limited. Incubate for 1 hour to 10 hours.

When the protecting group for the amino group is an aralkyl or aralkyloxycarbonyl, the protecting group is usually brought into contact with a reducing agent in an inert solvent (preferably, at room temperature in the presence of a catalyst at room temperature). Reduction) A method of removing or using an oxidizing agent is preferred. The solvent used in removal by catalytic reduction, as long as the present reaction inert particularly but not exclusively the force ^s, for example, hexane, heptane, rig port-in petroleum ether Aliphatic hydrocarbons; aromatic hydrocarbons such as toluene, benzene, and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, and tetrahydrofuran. Ethers such as dioxane, dimethoxetane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, and isoprono. Alcohols such as ethanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methylcellulose; organic acids such as acetic acid; water; And a mixed solvent of water and water; preferably, alcohols, ethers, organic acids, or water (particularly preferably, alcohols or organic acids).

 The catalyst used for the removal by the catalytic reduction is not particularly limited as long as it is usually used for the catalytic reduction reaction. Preferably, it is preferably palladium monocarbon, Raney nickel, acid chloride or the like. Platinum, platinum black, rhodium aluminum monoxide, triphenylphosphine monochloride rhodium, and palladium barium monosulfate are used.

 The pressure is not particularly limited, but it is usually 1 to 10 atm.

 The reaction temperature and the reaction time vary depending on the starting compound, the catalyst, the solvent and the like, but are usually carried out at 0 ° C. to 100 ° C. for 5 minutes to 24 hours.

 The solvent used in the removal by acidification is not particularly limited as long as it does not participate in the present reaction, but is preferably a water-containing organic solvent.

Such organic solvents include, for example, chloroform, dichloromethane, 1,2-dichloroethane, halogenated hydrocarbons such as carbon tetrachloride; nitriles such as acetonitrile, getyl ether, diisopropyl ether, Ethers such as droflan, dioxane, dimethoxetane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide And sulfoxides such as dimethyl sulfoxide; sulfolane; preferably, halogenated hydrocarbons, ethers or sulfoxides (particularly preferably halo Genated hydrocarbons or sulfoxides).

 The acid-forming agent used is not particularly limited as long as it is a compound used for acid-forming, but preferably potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3-dichloro-5,6-dicyanol p-benzoquinone (DDQ) is used.

 The reaction temperature and the reaction time vary depending on the starting compound, the catalyst, the solvent and the like, but are usually from 0 ° C. to 150, for 10 minutes to 24 hours.

 When the protecting group for an amino group is an aralkyl, the protecting group can be removed using an acid.

 The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction.For example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid Brönsted acids such as organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfonic acid, trifluorosulfonic acid, trifluoromethanesulfonic acid; zinc chloride, tin tetrachloride Lewis acids such as pollon trichloride, pollon trifluoride and pollon tripromide; acidic ion exchange resins; preferably inorganic acids or organic acids (particularly preferably hydrochloric acid, acetic acid or trifluoroacetic acid). ).

The inert solvent used in the first-stage reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether Aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated carbons such as chloroform, dichloromethane, 1,2-dichloroethane, and tetrahydrocarbon; methyl acetate, ethyl acetate; Esters such as propyl acetate, butyl acetate, and getyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n —Butanol, isobutanol, t-butano , Isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol Alcohols such as toluene, methylacetate sorb; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; water; or a mixed solvent of water or the above solvent; And preferably ethers, alcohols or water (particularly preferred are dioxane, tetrahydrofuran, ethanol or water).

 The reaction temperature varies depending on the starting compound, the acid used, the solvent and the like, but is usually from 120 ° C to the boiling point (preferably from 0 ° C to 100 ° C).

 The reaction time varies depending on the starting compound, the acid used, the solvent, the reaction temperature and the like, but is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours).

 When the protecting group for an amino group is an alkenyloxycarbonyl, the protecting group for the amino group is usually substituted to form the above-mentioned aliphatic acyls, aromatic acyls, alkoxycarbonyls or Schiff bases. The reaction is performed by treating with a base in the same manner as the conditions for the removal reaction in the case of a methylene group.

 In the case of a 7-lyloxycarbonyl group, particularly, The removal method using radium, triphenylphosphine, or nickel tetracarbonyl is simple and can be performed with few side reactions.

 When a silyl is used as a protecting group for a hydroxyl group, it is usually a compound that produces fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, monopyridine pyridine, and potassium fluoride. Treatment or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, It can be removed by treatment with an organic acid such as trifluoromethanesulfonic acid.

 In addition, when removing with a fluorine anion, the reaction may be accelerated by adding an organic acid such as formic acid, acetic acid or propionic acid.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction, but is preferably dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, Diethylene glycol dimethyl Ethers such as ethers; nitriles such as acetonitrile and isoptyronitrile; organic acids such as acetic acid; water;

 The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from o ° C to 100 ° C (preferably from 10 ° C to 50 ° C), and Implemented for 4 hours. When the protecting group for the hydroxyl group is an aralkyl or aralkyloxycarbonyl, it is usually contacted with a reducing agent in an inert solvent (preferably, catalytic reduction at room temperature under a catalyst). The removal method or the removal method using an oxidizing agent is preferable. The solvent used for the removal by catalytic reduction is not particularly limited as long as it does not participate in this reaction. Aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; Aromatic hydrocarbons such as benzene and xylene; esters such as ethyl acetate and propyl acetate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether; Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorb. Amides such as amide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethyl phosphate triamide; fatty acids such as formic acid and acetic acid; water; mixed solvents of the above solvents And preferably alcohols (particularly preferably methanol).

The catalyst used for the removal by catalytic reduction is not particularly limited as long as it is usually used for the catalytic reduction reaction.For example, palladium-carbon, palladium-black, Raney-nickel, platinum oxide, platinum black, rhodium Ichisani匕aluminum, triphenyl phosphine monochloride port Jiumu a palladium one barium sulfate, preferably Parajiu the arm ~ J ~ C ¹ Mel o

 The pressure is not particularly limited, but it is usually 1 to 10 atm.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent, etc. To 100 ° C. (preferably, 20 ° C. to 70 ° C.) for 5 minutes to 48 hours (preferably, 1 hour to 24 hours).

 The solvent used in the removal with acid is not particularly limited as long as it does not participate in the reaction, but is preferably a water-containing organic solvent. '

 Preferred as such organic solvents are ketones such as acetone; halogenated carbons such as methylene chloride, chloroform, and carbon tetrachloride; nitriles such as acetonitrile; And ethers such as tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphate triamide; and sulfoxides such as dimethylsulfoxide.

The acid-forming agent used is not particularly limited as long as it is a compound used for acid-forming, but is preferably potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2, 3-dichloro-5, used 6 Jishiano p- benzoquinone (DDQ) force ^s.

 The reaction temperature and the reaction time vary depending on the starting compound, the catalyst, the solvent and the like, but the reaction is usually carried out at 0 ° C. to 150 ° C. for 10 minutes to 24 hours.

Also in liquid ammonia or like methanol, ethanol, n-propanol, isopropanol, _n- butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methylcellosesolve It can also be removed by reacting alkali metals such as lithium metal and sodium metal at −78 ° C. to 0 ° C. in alcohols.

 Furthermore, it can be removed by using an alkylsilyl halide such as aluminum chloride sodium monoiodide or trimethylsilyl iodide in a solvent.

The solvent to be used, so long as it does not participate in the present reaction is not particularly limited force ^s,. Preferably, Mechirenkurori de, black hole Holm, halogen Kasumyi匕hydrogen, such as Yonshioi匕炭element ; nitrile compounds such as Asetonitoriru; a mixed solvent of the above solvents; force ^s mentioned are _c The reaction temperature and reaction time vary depending on the starting compound, solvent, etc.

Performed at 50 ° C for 5 minutes to 72 hours.

 When the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used.

 'When the hydroxyl-protecting group is an aliphatic acyl, an aromatic acyl or an alkoxycarbonyl group, it is removed by treating with a base in a solvent.

 The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound. For example, alkali metal carbonates such as lithium carbonate, sodium carbonate, and lithium carbonate; Alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide; Metal alkoxides such as sodium methoxide, sodium ethoxide, potassium l-t-butoxide; and ammonias such as aqueous ammonia and concentrated ammonia-methanol; preferably, an alkali metal hydroxide. Substances, metal alkoxides or ammonia (particularly preferably, metal hydroxides or metals) Mel in Rukokishido acids).

 The solvent to be used is not particularly limited as long as it is one used in a usual hydrolysis reaction, and examples thereof include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether. Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycinol, octanol, cyclohexanol, methyl cellosolve; Water; a mixed solvent of the above solvents is preferred.

 The reaction temperature and the reaction time vary depending on the starting compound, the base used, the solvent, and the like, and are not particularly limited. It takes between 10 and 10 hours.

Hydroxyl protecting groups are alkoxymethyls, tetrahydrovinyls, tetrahydrides In the case of thiopyranyls, tetrahydrofuranyls, tetrahydrothiofuranyls or substituted ethyls, they are usually removed by treatment with an acid in a solvent.

The acid used is not particularly limited as long as it is usually used as Brenstead acid or Lewis acid, and is preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid, or nitric acid; or acetic acid or trifluoromethane. Brenstead acids such as organic acids such as acetic acid, methanesulfonic acid, and p-toluenesulfonic acid: Lewis acids such as boron trifluoride, but strongly acidic cation exchange resins such as Dowex 50 W Can be used. The solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples of the solvent include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; benzene, Aromatic hydrocarbons such as toluene and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorine benzene, dichloromethane ethyl; ethyl formate, ethyl acetate, propyl acetate Esters such as butyl ether, butyl acetate, and getyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and dimethyl glycol dimethyl ether; methanol, ethanol, n-propanol, and isopropanol , _n - butanol, isobutanol Alcohols such as knol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorb; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, and cyclohexanone; Water; a mixed solvent of the above solvents; and preferably ethers (particularly preferably tetrahydrofuran) or alcohols (particularly preferably methanol).

 The reaction temperature and the reaction time are different depending on the starting compound, the acid used, the solvent, and the like. 48 hours (preferably 30 minutes to 10 hours).

When the protecting group of the hydroxyl group is an alkenyloxycarbonyl, the hydroxyl group is usually Can be achieved by treating with a base in the same manner as in the removal reaction when the protecting group is an aliphatic acyl, an aromatic acyl or an alkoxycarbonyl. In the case of an aryloxycarbonyl group, use is preferably made of palladium, triphenylphosphine, or bis (methyldiphenylphosphine) (1,5-cyclooctagen) iridium (I) .hexafluorophosphate. The method of removal is simple and can be carried out with few side reactions.

Protecting group of a carboxyl group, C "C ₆ alkyl group or a C" C ₆ alkyl, Cf Cs alkoxy, nitro, halogen or three 1 to may be substituted with Shiano C ₆ -. C substituted with Ariru when "C ₆ alkyl groups are usually aliphatic Ashiru such coercive Mamorumoto of the hydroxyl groups, as in the conditions of the removal reaction when an aromatic Ashiru acids or alkoxy force Lupo two Le acids, bases Is achieved by processing.

 In addition, the removal of the protecting group for the amino group, the hydroxyl group and / or the carboxy group can be carried out in any order by sequentially performing a desired removal reaction.

After completion of the reaction, the target compound (II) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture was appropriately neutralized, and, after more removed filtration if present insolubles force ^s, the immiscible organic solvent, such as water and acetic acid Echiru added, separating the organic layer containing the desired compound After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound may be appropriately combined with a conventional method such as recrystallization, reprecipitation or the like, which is usually used for the separation and purification of organic compounds, and by applying chromatographic techniques, Separation and purification can be achieved by elution with an eluent.

Method B is a method for producing compound (II) separately from method A. B method

 (IV)

In the above formula, R ¹ , R ^la , R ² , R ^2a , X, Y, and L _la have the same meanings as described above, and Y, represents “a C ₈ alkylene group or C 1 _An alkylene group or alkenylene group having one less carbon atom than “ ₂ —C ₈ alkenylene group”. Step B1 is a step of producing compound (II). Compound (IV) or an acid addition salt thereof (e.g., hydrochloride, nitric acid, etc.) is reacted with compound (IV) in an inert solvent. Salt, steel salt such as sulfate) by reductive amination, followed by removal of amino, hydroxyl and / or carboxy group protecting groups in R ^la , R and L _la if desired. Will be

 The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, ethanol such as methanol, ethanol, and propanol; Ethers such as tyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane and diethylene glycol dimethyl ether, preferably alcohols (particularly preferably methanol or ethanol).

The reducing agent used in the above reaction is not particularly limited as long as it is generally used as a reducing agent, and examples thereof include sodium borohydride, lithium borohydride, and sodium cyanoborohydride. Aluminum hydride compounds such as diisobutylaluminum hydride, lithium aluminum hydride and lithium triethoxide aluminum; tellurium hydride; di (isobutyl) aluminum hydride; bis (Methoxyethoxy) Hydride such as hydrogenated organic aluminum-based reducing agents such as aluminum sodium hydride And preferably borohydride hydride metals.

 The reaction temperature varies depending on the starting compound, the reagent used, the solvent and the like, but is usually from −20 ° C. to 100 ° C. (preferably from room temperature to 80 ° C.).

 The reaction time varies depending on the starting compound, the reagent used, the solvent, the reaction temperature and the like, but is usually from 10 minutes to 50 hours (preferably from 1 hour to 6 hours).

R ^la performed optionally, the amino group in R ^2a and L _la, a method of removing a protecting group for a hydroxyl group and / or Cal Bokishi group, the method A the amino group of the A 1 step, hydroxyl group and / or force Rupokishi group In the same manner as the method for removing the protecting group of

 After completion of the reaction, the target compound (II) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the target compound obtained may be appropriately eluted by a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. It can be separated and purified by elution with an agent.

C method, in the compounds (II), 1 ^ has the formula ^-? CH (R ^4a) is a group having an R ^½ Ca formula one CH (R ⁷⁾ -ER ⁶ is a group having a compound (II a) Is a group having the formula C (R ^4c ) — and R ^4c is a group having the formula = C (R ⁷ ) -ER ⁶ (IIb), and 1 ^ is a compound having the formula —CH (CH ) A method for producing a compound (lie) which is a group having one. c method

 (IVa)

(IX)

 (Ha) Step C5

(IX)

(nb)

 (VI) (nc)

In the above formula, R ¹ , R ^la , R ² , R ^2a , R ⁶ , R ⁷ , X, Y, E and Q are as defined above, and R ^6a and R ^7a are Amino group, hydroxyl group and Z or carboxy group in the definition of groups ⁶ and R ⁷ are optionally protected amino group, hydroxyl group and / or carboxy group, and the same as the groups in the definition of groups R ⁶ and R ⁷ R ⁸ represents a lower alkyl group (having the same meaning as described above). Step C1 is a step of producing a compound having the general formula (VI), and converting the compound having the general formula (III) to a compound having the general formula (IVa) in an inert solvent in the presence of a base. This step is carried out in the same manner as in the above-mentioned Method A, Step A1 by reacting with a compound or an acid addition salt thereof (eg, a steel salt such as hydrochloride, nitrate, sulfate). Step C2 is a step for producing a compound having the general formula (VII), and is carried out by bringing the compound (VI) into contact with an oxidizing agent in an inert solvent.

 The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, and examples thereof include hexane, heptane, lignin, and petroleum ether. Aliphatic hydrocarbons; Aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, and dichlorobenzene Ethers such as getyl ether, disopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and methylenglycol dimethyl ether; methanol, ethanol, n-prono. Alcohols such as ethanol, isopropyl alcohol, n-butanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, ethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; formamide, N Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphoric acid triamide; acetic acid, propionic acid Such acids; sulfoxides such as dimethyl sulfoxide and sulfolane; sulfolane; or a mixed solvent of the above solvents; preferably, halogenated hydrocarbons (particularly preferably, dichloromethane).

The oxidizing agent used in the above reaction is not particularly limited as long as it is usually used in the oxidizing reaction. Examples thereof include manganese oxides such as potassium permanganate and manganese dioxide; and ruthenium tetroxide. Such as ruthenium oxides; a selenium compound such as selenium dioxide; an iron compound such as iron chloride; an osmium compound such as osmium tetroxide, potassium osmate-dihydrate (K ₂ 0s0 ₄ '2¾0); an acid A silver compound such as a dangin; Mercury compounds such as mercury acetate; lead oxide compounds such as lead oxide and lead tetraacetate; chromic acid compounds such as potassium chromate, chromate monosulfate complex, and oxalate-pyridine complex, ammonium Inorganic metal oxidizing agents such as cerium compounds such as cerium nitrate (CAN); halogen molecules such as chlorine, bromine and iodine molecules; periodic acids such as sodium periodate; ozone; Hydrogen water; nitrite compounds such as nitrous acid; chlorite compounds such as potassium chlorite and sodium chlorite; potassium sulfide compounds such as potassium persulfate and sodium persulfate Inorganic oxidizing agents such as DMSO reagents used in the oxidation (dimethylsulfoxide and dicyclohexylcarpoimide, oxalyl chloride, complex with acetic anhydride or phosphorus pentoxide, or pyridine monohydrate) A combination of a peroxide such as t-butyl hydroperoxide and a vanadium or molybdenum complex; a stable cation such as a triphenylmethyl cation; a succinic acid such as N-bromosuccinic acid imide. Combinations of acid imides and alkalis; oxysilanes such as dimethyldioxysilane; hypochlorite compounds such as t-butyl hypochlorite; azodicarboxylic acid compounds such as azodicarboxylate; m-chloroperbenzoic acid Acids, peracids such as perphthalic acid; disulfides such as dimethyl disulfide, diphenyl disulfide and dipyridyl disulfide and triphenyl phosphine; nitrites such as methyl nitrite; Tetrahalogenated carbon, such as methane chloride, 2,3-dichloro-5,6-dicyano p-benzo Organic oxidizing agents such as quinone compounds such as quinone (DDQ); and preferred are reagents (particularly preferred are dimethylsulfoxide and oxalyl chloride) used for DMSO. The reaction temperature varies depending on the starting compound, the oxidizing agent used, the solvent and the like, but is usually from 100 to 50 ° C (preferably from 180 to 40 ° C).

 The reaction time varies depending on the starting compound, the oxidizing agent used, the solvent, the reaction temperature and the like, but is usually 5 minutes to 50 hours (preferably 10 minutes to 25 hours).

After completion of the reaction, the target compound (VII) of the reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added to the mixture to obtain the desired compound. The organic layer containing the substance is separated, washed with water or the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, or the like, and the solvent is distilled off. If necessary, the obtained target compound may be appropriately combined with a conventional method, for example, recrystallization, reprecipitation, or the like, by appropriately combining the methods that have been falsely used in the separation and purification of organic compounds, by applying chromatography. Separation and purification can be achieved by elution with an eluent.

 Step C3 is a step of producing a compound having the general formula (IX) by the HORNER-EMMONS reaction, and treating the compound having the general formula (VI II) with a base in an inert solvent in a nitrogen stream. And then reacting with the compound (VI I).

 The inert solvent used when reacting the compound having the general formula (VI II) with a base is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; Aromatic hydrocarbons such as benzene, toluene, and xylene; Ethers such as dimethyl ether; preferably ethers (particularly preferably tetrahydrofuran).

 The base used when reacting the compound having the general formula (VI II) with a base is not particularly limited as long as it is used as a base in a usual reaction. A The same ones as used in Step 1 can be mentioned, and preferred are alkali metal hydrides (particularly preferred is sodium hydride).

 The reaction temperature for reacting the compound having the general formula (VI II) with a base varies depending on the starting conjugate, the oxidizing agent, the solvent, and the like, and is generally -70 ° C to 80 ° C (preferably Is between 20 ° C and 50 ° C).

 The reaction time for reacting the compound having the general formula (VI II) with a base varies depending on the starting compound, the oxidizing agent used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 50 hours (preferably Is from 1 hour to 25 hours).

Inert solvent used when reacting compound (VI I) with compound (VI II) Is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.For example, the same as the inert solvent used when reacting compound (VI II) with a base Can be mentioned.

 The reaction temperature at which the compound (VI I) is reacted with the compound (VI II) varies depending on the starting compound, the oxidizing agent used, the solvent and the like. Generally, the reaction temperature ranges from 100 ° C to 50 ° C (preferably , O ° c to around room temperature).

Compound (VI I) The compound (VI II) and the reaction time for reacting the starting compound, the oxidizing agent used, the solvent, different forces ^s the reaction temperature and the like, usually, 30 minutes to 5 0 hours (preferably 1 hour to 25 hours).

 After completion of the reaction, the target compound (IX) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the desired compound obtained can be combined with conventional methods, such as recrystallization and reprecipitation, etc., as appropriate, using methods commonly used for the separation and purification of organic compounds. Can be separated and purified.

Step C4 is a step of producing a compound having the general formula (IIa). After performing a catalytic reduction reaction on compound (IX) in an inert solvent, R ^la , R ^2a , R ^6a and amino group in R ^7a, performed by the child removing the protecting group of the hydroxyl and / or carboxy groups.

The inert solvent used in the catalytic reduction reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.Examples include hexane, heptane, rig-in, petroleum Aliphatic hydrocarbons such as ethers; aromatic hydrocarbons such as toluene, benzene, and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, disopropyl Ether, tetrahydrofuran, dioxane, dimethoxetane, diethyleneglycol Ethers such as coal dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorb Organic solvents such as acetic acid; water; a mixed solvent of the above solvent and water; preferably alcohols (particularly preferably ethanol).

The catalyst used in the catalytic reduction reaction is not particularly limited as long as it is usually used in the catalytic reduction reaction, but is preferably palladium monocarbon, Raney Nickel, Sanilide platinum, platinum black, rhodium Ichisani匕aluminum, triphenyl phosphine one Shioi匕rhodium, used palladium monosulfate barium force ^s.

 The pressure is not particularly limited, but it is usually 1 to 10 atm.

 The reaction temperature and reaction time vary depending on the starting compound, the catalyst, the solvent and the like, but are usually from 0 ° C to 100 ° C for 5 minutes to 24 hours.

The method of removing the protecting group for the amino group, hydroxyl group and / or carboxy group in R ^la , R ^2a , R ^6a and R ^7a , which is carried out as desired, is as follows. It is carried out in the same manner as the method of removing the protecting group of Z or carboxy group.

 After completion of the reaction, the target compound (IIa) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc., the solvent is distilled off. Separation and purification can be achieved by appropriately combining commonly used methods for separation and purification of organic compounds, such as recrystallization and reprecipitation, by applying chromatography and eluting with an appropriate eluent. .

Step C5 is a step of producing a compound having the general formula (IIb), and in an inert solvent, the amino group, hydroxyl group and / or R ^la , R ^2a , R ^6a and R ^7a of compound (IX) Alternatively, this step is performed by removing the protecting group of the carboxy group. It is carried out in the same manner as in the method of removing the protecting group for the amino group, hydroxyl group and / or carbonyl group in one step.

'Step C6 is a step for producing a compound having the general formula (IIc), in which an amino group, a hydroxyl group and / or a carboxy group at R ^la and R of compound (VI) is protected in an inert solvent. This step is carried out by removing the group, and this step is carried out in the same manner as the method for removing the protecting group for the amino group, hydroxyl group and Z or carboxy group in Step A1 of Method A. The starting compounds (111), (IV), (I Va), (V) and (VI II) are commercially available or easily produced according to known methods or methods similar thereto. For example, compound (III) can be produced according to the method described in J. Med. Chem. 23, 149 (1980) and the like, and (IV), (IVa) and (V) can be produced according to EP 47068 9A, It can be produced according to the method described in EP776893A, USP5578593 and the like. The invention's effect

 The compound of the present invention having the general formula (I) or (II), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof has an excellent TH1-selective immunosuppressive action, It is useful as a pharmaceutical composition containing a compound having the general formula (I) or (II), a pharmacologically acceptable salt thereof, or an ester or other derivative thereof as an active ingredient, particularly a prophylactic or therapeutic agent for an autoimmune disease. is there. Industrial applicability

 When the compound of the present invention having the above general formula (I) or (II), or a pharmaceutically acceptable salt or ester thereof, is used as the above-mentioned therapeutic or prophylactic agent, the compound itself or appropriate pharmacology may be used. Mixed with excipients, diluents and the like, for example, administered orally with tablets, capsules, granules, powders or syrups, or parenterally with injections or suppositories be able to.

These preparations contain excipients (eg, lactose, sucrose, dextrose, mannitol, sorbitol). Sugar derivatives such as tall; corn starch, starch, _α- starch, starch derivatives such as xistrin; cellulose derivatives such as crystalline cellulose; arabian gum; dextran; organic excipients such as pullulan; Silicic acid derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium aluminate metaphosphate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate; Inorganic excipients. ), Lubricants (eg, stearic acid metal salts such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal sily; waxes such as veegum, gay; boric acid; adipic acid; Folic acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate, magnesium lauryl sulfate; silicic acids such as silicic anhydride, silicic acid hydrate; And the above-mentioned starch derivatives.), A binder (for example, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same as the above-mentioned excipients) Compounds; disintegrants (eg, low substituted Cellulose derivatives such as roxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; chemically modified starches such as carboxymethylstarch, sodium carboxymethylstarch, crosslinked polyvinylpyrrolidone Cell mouths), stabilizers (esters of para-hydroxybenzoic acid such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride) Phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.), Flavoring agents (eg, commonly used) , A sweetener, an acidulant, a flavor, etc.), and a known method using additives such as a diluent.

The amount used depends on the symptoms, age, etc., and in the case of oral administration, the lower limit is 1 mg per day (preferably 1 mg), the upper limit is 200 mg (preferably 4 mg / day). 0 0 mg) In the case of intravenous administration, a lower limit of 0.1 mg (preferably lmg) per day and an upper limit of 50 Omg (preferably 30 Omg) per day is 1 to 6 times daily for adults. It is desirable to administer according to the symptoms.

BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.

Example 1

 8- [2-bis (4-fluorophenyl) methoxethyl] -3-benzyl-1-oxa-3,8-diazaspiro [4.5] decane-2-one and its oxalate (Exemplified Compound No. 331 )

 (1a) 8- [2-Bis (4-fluorophenyl) methoxethyl] -3-benzyl-1-oxa-3,8-diazaspiro [4.5] decane-2-one

3-Benzyl-1-oxa-3,8-dazaspiro [4.5] decane-2-one hydrochloride 283 mg (1.00 tol) and bis (4-7-fluorophenyl) methyl 2-cloethyl ether 283 mg (1.00 Was dissolved in 10 ml of 4-methyl-2-pentanone, then 318 mg (3.00 s) of sodium carbonate and 15 mg (0.10 mmol) of sodium iodide were added, and the mixture was added at 130 ° C for 16 hours. Heated. After cooling to room temperature, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was silica force gel column chromatography (developing solvent; methylene chloride: methanol = 10: 1) to give the title compound 294 mg of _(60%) ό

 (l b) 8- [2-bis (4-fluorophenyl) methoxethyl] -3-benzyl-1-oxa-

3,8-diazaspirate [4.5] decane-2-one oxalate

 The compound obtained in Example (la) was dissolved in 5 ml of ethyl ethyl acetate, and 54 mg (0.60 t) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (306 mg, 88).

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 6} ) δ ppm: ' 7.14-7.42 (13H, m), 5.55 (lH, s), 4.37 (2H, s), 3.61 (2H, m), 3.25 (2H, s), 2.9-3.2 (6H, m), 1.9-2.1 ( 4H, m).

Infrared absorption spectrum cm- ¹ (KBr): 1752, 1729, 1604, 1509, 1224.

Mass spectrum (FAB) m / z 493 ((M + H) +, free form)

Elemental analysis value (as C ₃₁ H ₃₂ N ₂ 0 ₇ F ₂ (%))

 Calculated value: C: 63.91; H: 5.54; N: 4.81; F: 6.52%

 Found: C: 63.79; H: 5.68; N: 4.69; F: 6.21%. Example 2

 8- [2_bis (4-fluorophenyl) methoxhetyl] -3-phenyl-1-oxa-3,8-diazaspiro [4.5] de-2-enone and its oxalate (example) (Compound No. 322)

 (2a) 8- [2-Bis (4-fluorophenyl) methoxethyl] -3-phenyl-reoxa-3,8-diazaspiro [4.5] decane-2-one

 In the same manner as in Example (la), 3-phenyl-1-oxa-3,8-dazaspiro [4.5] decane-2-one hydrochloride (269 mg, 1.00 ol) and bis (4-fluorophenyl) methyl 2-chloro 318 mg (66%) of the title compound was obtained using 283 mg (1.00 t ol) of ethyl ether.

 (2 b) 8- [2-bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-oxa-

3,8-Diazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Example (2a) was dissolved in 5 ml of ethyl acetate, 60 mg (0.67 ol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (318 mg, 84%).

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0 - d 6} ) 8 ppm:

7.12- 7.58 (13H, m), 5.58 (lH, s), 3.93 (2H, s), 3.64 (2H, m), 2.9-3.3 (6H, m), 2.0-2.2 (4H, m). External absorption spectrum y _MX cm- ¹ (KBr): 1756, 1602, 1507, 1409, 1224. Mass spectrum (FAB) m / z 479 ((M + H) ⁺ , free form)

Elemental analysis value (as C ₃₀ H ₃₀ N ₂ 0 ₇ F ₂ (%))

 Calculated: C: 63.37; H: 5.32; N: 4.93; F: 6.68%

 Found: C: 63.48; H: '5.42; N: 4.84; F: 6.40%. Example 3

 1- [2-Bis (4-fluorophenyl) methoxethyl] -4 -phenylbiperidine-4-carbonamide and its oxalate (Exemplified Compound No. 188)

 (3a) 1- [2-bis (4-fluorophenyl) methoxethyl] -4-phenylpiperidine-4-carboxylic acid amide

 As in Example (la), 4-phenylbiperidine-4-carboxylic acid amide hydrochloride 24 1 mg (1.00 mmol) and bis (4-fluorophenyl) methyl 2-chloroethyl ether 283 mg (1.00 mmol) to give 414 mg (92%) of the title compound.

 (3 b) 1- [2-Bis (4-fluorophenyl) methoxethyl] -4-phenylbiperidine-4-ammonium oxalate

 The compound obtained in Example (3a) was dissolved in 5 ml of ethyl acetate, and 83 mg of oxalic acid was dissolved.

(0.92 mmol) and left at room temperature overnight. The precipitated crystals were collected by filtration to give 407 mg (82%) of the title compound as white crystals.

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 6} ) δ ppm:

 7.16-7.42 (13H, m), 5.56 (lH, s), 3.64 (2H, m), 3.2-3.5 (4H, m), 2.9-3.l (2H, m), 2.5-2.8 (2H , m), 1.9-2.2 (2H, m).

Infrared absorption spectrum _max cm- ¹ (KBr): 1668, 1604, 1508, 1405, 1221.

Mass spectrum (FAB) m / z 451 ((M + H) ⁺ , free form)

Elemental analysis (as _{C 29 H 30 N 2 0 6} F 2 (¾))

 Calculated value: C: 64.44; H: 5.59; N: 5.18; F: 7.03%

Found: C: 63.79; H: 5.73; N: 5.08; F: 6.78%. Example 4

 1- [2-Bis (4-fluorophenyl) methoxethyl] -4-phenylbiperidine-4-carboxylic acid 'morpholine amide and its oxalate (Exemplified Compound No. 212)

 (4a) 1- [2-bis (4-fluorophenyl) methoxethyl] -4-phenyl repiperidine-4-carboxylic acid morpholine amide

 As in Example (la), 4-phenylpiperidine-4-carboxylic acid morpholine amide hydrochloride 311 mg (1.00 t) and bis (4-fluorophenyl) methyl 2-chloroethyl ether 283 mg (1.00 mg) 390 mg (75%) of the title compound.

(4b) 1- [2-bis (4-fluorophenyl) methoxethyl] -4-phenylpiperidine-4-carboxylic acid morpholine amide oxalate

 Compound obtained in Example M (4a) This compound was dissolved in ethyl acetate '5 ml, oxalic acid 68 mg (0.76 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give 361 mg (79%) of the title compound as white crystals.

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 6} ) δ ppm:

7.16- 7.44 (13H, m), 5.58 (1H, s), 3.65 (2H, m), 2.8-3.5 (14H, m), 2.1-2.4 (4H, m) Infrared absorption spectrum cm- ¹ KBr): 1631, 1604, 1508, 1422, 1226.

Mass spectrum (FAB) m / z 521 ((M + H) ⁺ , free form)

Elemental analysis (as _{C 33 H 36 N 2 0 7} F 2 (%))

 Calculated value: C: 64.91; H: 5.94; N: 4.59; F: 6.22%

 Obtained: C: 64.84; H: 5.91; N: 4.53; F: 6.00%. Example 5

 1- [2-bis (4-fluorophenyl) methoxethyl] -4- (2-pyridyl) piperidine-4-carboxylic acid amide and its oxalate (Exemplified Compound No. 232)

(5a) 1- [2-Bis (4-fluorophenyl) methoxhetyl] -4- (2-pyridyl) piperi Gin-4-carboxylic acid amide

 In the same manner as in Example (1a), 4- (2-pyridyl) piperidine-4-potassium amide dihydrochloride 139 mg (0.50 mol) and bis (4_fluorophenyl) methyl 2- Using 141 mg (0.50 t) of cloethyl ether, 204 mg (90%) of the title compound was obtained.

 (5 b) 1- [2-bis (4-fluorophenyl) methoxethyl] -4_ (2-pyridyl) piperidine-4-carboxylic acid amide oxalate

 The compound obtained in Example (5a) was dissolved in 5 ml of ethyl acetate, 41 mg (0.46 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (203 mg, 83%).

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 6} ) δ ppm:

 8.57 (lH, m), 7.82 (lH, m), 7.12- 7.47 (10H, m), 5.55 (1H, s), 3.64 (2H, m), 3.0-3.5 (6H, m), 2.2-2.8 ( 4H, m).

Infrared absorption spectrum cm- ¹ (KBr): 1669, 1605, 1508, 1220.

Mass spectrum (FAB) m / z 452 ((M + H) +, free form)

Elemental analysis _{(C 28 H 29 N 3 0} 6 F 2 0)

 Calculated value: C: 62.10; H: 5.40; N: 7.76; F: 7.02%

 Found: C: 61.62; H: 5.50; N: 7.63; F: 6.73%. Example 6

 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(2-hydroxy) indane-1,4'-piperidine] and its oxalate salt (Exemplified Compound No. 397)

 (6a) 1- [2_bis (4-fluorophenyl) methoxhetyl] spiro [(2-hydroxy) indane-1,4, -piperidine]

In the same manner as in Example (1a), spiro [(2-hydroxy) indane-1,4, -piperidine] hydrochloride 187 mg (0.78 ol) and bis (4-fluorophenyl) methyl 2-chloro Using 200 mg (0.71 mmol) of ethyl ether, 256 mg (81%) of the title compound was obtained. (6b) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(2-hydroxy) indane-1,4, -piperidine] oxalate

 The compound obtained in Example (6a) was dissolved in 5 ml of ethyl acetate, 51 mg (0.57 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (246 mg, 64%).

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 6} ) δ ppm:

7.42-7.45 (4H, m), 7.17-7.22 (8H, m), 5.60 (1H, s), 4.3-4.4 (lH, m), 3.71 (2H, tJ = 4.9Hz), 3.1-3.4 (7H, m), 2.7-2.8 (lH, m), 1.8-2.2 (3H, m), 1.6-1.7 (lH, m) · Infrared absorption spectrum _max cm— ¹ (KBr): 3364, 2938, 2676, 1721, 1604, 1509, 122 4.

Mass spectrum (FAB) m / z 450 ((M + H) ⁺ , free form)

Elemental analysis value (as C ₃₀ H ₃₁ N0 ₆ F ₂ (%))

 Calculated values: C: 66.78; H: 5.79; N: 2.60; F: 7.04%

 Found: C, 66.38; H, 5.93; N, 2.48; F, 6.81%. Example 7

 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [2,3-dihydrobenzothiophene-3,4-dipyridine] -1-oxide and its oxalate salt (Exemplary Compound No. 379)

(7a) 1- [2_Bis (4-fluorophenyl) methoxethyl] spiro [2,3-dihydrobenzothiophene-3,4, -piperidine] -1-oxide

 As in Example (la), spiro [2,3-dihydrobenzothiophene-3,4, -piberidine] -1-oxide 172 mg (0.78 mol) and bis (4-fluorophenyl) methyl 2-chloride Using lorethyl ether 200 mg (0.71 mol), 243 mg (73%) of the title compound was obtained.

(7 b) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [2,3-dihydrobenzothiophene-3,4'-piperidine] -1-oxoxide oxalate The compound obtained in Example (7a) was dissolved in 5 ml of ethyl acetate, 47 mg (0.52 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature for one hour. The precipitated crystals were collected by filtration to give the title compound as white crystals (261 mg, 66%).

Nuclear magnetic resonance spectrum _{(400 MHz, DMSO- d 6)} δ 'ppm:

 7.92 (1H, dJ = 7.6Hz), 7.68-7.71 (lH, m), 7.54-7.57 (2H, m), 7.42-7.45 (4H, m), 7.

17-7.21 (4H, m), 5.60 (lH, s), 3.69 (2H, t, J = 5.OHz), 3.50 (1H, d, J = 14.2Hz), 3.34 (lH, d, J = 14.2 Hz), 2.9-3.5 (6H, m), 2.0-2.5 (3H, m), 1.6-1.7 (lH, m).

Infrared absorption spectrum cm- ¹ (KBr): 3436, 2927, 2572, 1721, 1604, 1508, 122

3.

Mass spectrum (EI) m / z 467 ((M) ⁺ , free form)

Elemental analysis value (as C ₂₉ H ₂₉ N0 ₆ SF ₂ (%))

 Calculated: C: 62.47; H: 5.24; N: 2.51; S: 5.75; F: 6.81%

 Found: C: 62.30; H: 5.36; N: 2.43; S: 5.65; F: 6.70%. Example 8

 1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4, -piperidine] -2-oxide and its oxalate salt (Exemplary Compound No. 384)

 (8 a) l- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4-piperidine] -2-oxide,

 Spiro [benzo [c] thiophene-1 (3H), 4, -piperidine] -2-oxide hydrochloride 182 mg (0.71 thighol) and bis (4-fluorophenyl) methyl as in Example (la) 132 mg (45%) of the title compound was obtained using 200 mg (0.71 mol) of 2-chloroethyl ether.

 (8 b) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4, -piperidine] -2-oxide oxalate

The compound obtained in Example (8a) was dissolved in ethyl acetate 3 ml, and oxalic acid 20 mg (0.22 tmol) was added and left overnight at room temperature. The precipitated crystals were collected by filtration to give the title compound as white crystals (75 mg, 63%).

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 6} ) δ ppm:

 7.36- 7.45 (8H, m), 7.19 (4H, t, J = 8.9Hz), 5.58 (lH, s), 4.63 (1H, d, J = 7. OHz), 4.04

(2H, d, J = 7.0Hz), 3.66 (2H, t, J = 5.2Hz), 3.29-3.40 (2H, m), 3.20 (2H, brs), 2.86-2

.97 (2H, m), 2,57 (lH, m), 2,20 (lH, m), 2.06 (lH, m), 1.90 (lH, m).

Infrared absorption spectrum (KBr): 3438, 2903, 2540, 1720, 1604, 1508, 122

3.

Mass spectrum (FAB) m / z 468 ((M + H) ⁺ , free form)

Elemental analysis (C ₂₉ H ₂₉ N0 ₆ F ₂ S · 1 / 4¾0 (%))

 Calculated: C: 61.96; H: 5.29; N: 2.49; F: 6.76; S 5.70%

 Found: C: 61.92; H: 5.40; N: 2.42; F: 6.69; S 5.71%. Example 9

 1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4, -piperidine] and its oxalate (Exemplified Compound No. 382)

 (9a) l- [2-Bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4, -piperidine]

 Spiro [benzo [c] thiophene-1 (3H), 4, -piperidine] hydrochloride 171 mg (0.71 tmol) and bis (4-fluorophenyl) methyl as in Example (la) By using 200 mg (0.71 mol) of 2-chloroethyl ether, 222 mg (80 ° /.) Of the title compound was obtained.

 (9 b) 1- {2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4, -piperidine] oxalate

 The compound obtained in Example (9a) was dissolved in ethyl acetate 3 ml, and oxalic acid 41 mg

(0.44 tmol) was added and left overnight at room temperature. The precipitated crystals were collected by filtration to give the title compound as white crystals (205 mg, 87%). Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 6} ) δ ppm:

 7.42- 7.45 (4H m), 7.28-7.33 (4H, m), 7.16-7.21 (4H, m), 5.59 (lH s), 4.21 (2H, s) 3.68 (2H t J = 5.0Hz), 3.45 ( 2H m), 3.23 (2H brs) 2.95 (2H, m), 2.48 (2H, m), 1.92 (2H m).

Infrared absorption spectrum cm- ¹ (KBr): 3436 3012 2562, 1719 1655, 1604, 15 07 1224.

Mass vector (FAB) m / z 452 ((M + H) ⁺ , free form). Example 10

 1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [(indane) -14, -piperidine] and its oxalate salt (Exemplary Compound No. 393)

 (10a) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(indane) -1,4, -piperidine] 'Spiro [(indane) -1 as in Example (1a) , 4, -Piperidine] hydrochloride 79 mg (0.35 t ol) and bis (4-fluorophenyl) methyl 2-chloromethyl ether 100 mg (0.35 t ol) were used to give 43 mg (28 %).

 (10b) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(indane) -14-piperidine] oxalate

 The compound obtained in the example (10a) was dissolved in 5 ml of ethyl acetate, 8.9 mg (0.099 t) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (28 mg, 55%).

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 6} ) δ ppm:

 7.13- 7.46 (12H, m 5.60 (lH, s), 3.66- 3.74 (2H, m), 3.31-3.48 (4H, m), 3.00-3.18 (2H, m), 2.88-2.94 (2H, m), 1.98-2.16 (4H, m), 1.58-1.67 (2H, m).

Infrared absorption spectrum cm- ¹ (KBr): 3427, 2941 2648, 2568 1721, 1702, 163 4 1604, 1508, 1405, 1223, 1155, 835, 721. Mass vector (FAB) m / z 434 ((M + H) ⁺ , free form)

Elemental analysis value (as C ₃₀ H ₃₁ N 0 ₅ F ₂ + H ₂₀ (%))

 Calculated value: C: 66.53; H: 6.14; N: 2.59; F: 7.02%

 Found: C: 65.91; H: 5.86; N: 2.46; F: 6.78%. Example 1 1

 1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [(indan-1-one) -3,4, -piperidine] and its oxalate salt (Exemplary Compound No. 395)

 (11a) l- [2-Bis (4-fluorophenyl) methoxhetyl] spiro [(indan-1-one) -3,4'-piperidine]

 Spiro [(indan-1-one) -3,4, -piperidine] hydrochloride 84 mg (0.35 bandol) and bis (4-fluorophenyl) methyl 2-chloro mouth as in Example (1a) Ethyl ether (100 mg, 0.35 t) was used to obtain 50 mg (32%) of the title compound.

 (1 1 b) l- [2-Bis (4-fluorophenyl) methoxethyl] spiro [(indane-1-one) -3,4, -piperidine] oxalate

 The compound obtained in Example (11a) was dissolved in 5 ml of ethyl acetate, 10.4 mg (0.11 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (51.5 mg, 95%).

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0 - d 6} ) δ ppm:

 7.15-7.77 (12H, m), 5.61 (lH, s), 3.67-3.73 (2H, m), 3.22-3.48 (4H, m), 2.87-3.11 (2H, m), 2.71 (2H, s), 2.18-2.33 (2H, m), 1.63-1.74 (2H, m).

Infrared absorption spectrum cm- ¹ (KBr): 3412, 2927, 2568, 1715, 1635, 1603, 1508, 1404, 1223, 1156, 1097, 837.

Mass spectrum (FAB) m / z 448 ((M + H) +, free form)

Elemental analysis (as _{C 30 H 29 N0 6 F 2} + l / 2¾0) ·

Calculated values: C: 65.93; H: 5.53; N: 2.56; F: 6.95% Found: C: 65.73; H: 5.12; N: 2.55; F: 6.40%. Example 1 2

 1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [(1,4-dihydro-2H-isoquinolin-3-one) -1,4, -piperidine] and its oxalate ( (Exemplary compound number 389)

(1 2 a) l- [2-Bis (4-fluorophenyl) methoxethyl] spiro [(1,4-dihydro-2H-isoquinolin-3-one) -1,4, piperidine]

 Spiro [(1,4-dihydro-2H-isoquinolin-3-one) -1,4, -piperidine] 63 mg (0.29 mmol) and bis (4-fluorophenyl) were prepared in the same manner as in Example (la). ) 69 mg (42 ° /.) Of the title compound was obtained using 100 mg (0.35 mol) of methyl 2-chloroethyl ether.

(12b) 1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [(1,4-dihydro-2H-isoquinolin-3-one) -1,4dipiperidine] oxalate

 The compound obtained in Example (12a) was dissolved in 5 ml of ethyl acetate, 13.4 mg (0.15 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (62 mg, 75).

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, DMS0 - d 6} ) δ ppm:

 8.14 (lH, bs), 7.16- 7.47 (12H, m), 5.59 (lH, s), 3.55-3.78 (4H, m), 3.67-3.42 (6H, m), 2.26- 2.41 (2H, m), 1.84-1.93 (2H, m).

Infrared absorption spectrum awake cm- ¹ (KBr): 3430, 3339, 3013, 2929, 2665, 2580, 172, 1669, 1508, 1401, 1224.

Mass vector (FAB) m / z 463 ((M + H) +, free form)

Elemental analysis (as _{C 30 H 30 N 2 0 6} F 2 (%))

 Calculated: C: 65.21; H: 5.47; N: 5.07; F: .6.88%

Found: C: 64.45; H: 5.56; N: 5.10; F: 6.38%. Example 13 1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4-piperidine] -2,2-dioxide and its oxalate (Exemplified Compound No. 481 )

(1 3 a) l- [2-Bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4, -piperidine] -2,2-dioxide

 Spiro [benzo [c] thiophene-1 (3H), 4, -piperidine-2,2-dioxide hydrochloride 138 mg (0.50 mmol) and bis (4-fluorophenyl) methyl as in Example (la) 2 150 mg (0.53 tmol) of monoethyl ether was used to obtain 153 mg (63%) of the title compound.

 (1 3 b) l- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4-dipyridine] -2,2-dioxide oxalate

 The compound obtained in Example (13a) was dissolved in ethyl acetate (3 ml), oxalic acid (29 mg, 0.32 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (170 mg, 93).

Nuclear magnetic resonance spectrum _{(400 MHz, DMSO- d 6)} δ ppm:

 7.15- 7.45 (12H, m), 5.58 (lH, s), 4.68 (2H, s), 3.63 (2H, m), 2.9-3.4 (6H, m), 2.2-2.6 (4H, m).

Infrared absorption spectrum max cm— ¹ (KBr): 1604, 1509, 1406, 1406, 1305, 1224. Mass spectrum (FAB) m / z 484 ((M + H) +, free form). Example 14

 8- [2-bis (4-fluorophenyl) methoxethyl] -1-oxa-3,8-dazaspiro [4.5] decane-2-one and its oxalate (Exemplified Compound No. 308)

 (14a) 8- [2-Bis (4-fluorophenyl) methoxethyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one

1-Oxa-3,8-dazaspiro [4.5] decane-2-one hydrochloride 800 mg (4.15 bandol) and bis (4-fluorophenyl) methyl 2-chloroethyl ether as in Example (1a) 1.29 g (4.56 tmol) of 8- [2-bis (4-fluorophenyl) methoxethyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one 1.24 g (74 %).

 (14 b) 8- [2-Bis (4-fluorophenyl) methoxethyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Example (14a) was dissolved in 50 ml of ethyl acetate, 277 mg (3.08 mmoi) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (1.52 g, 84%).

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, DMS0-d 6} ) d ppm:

 7.63 (1H, s), 7.39-7.44 (4H, m), 7.15-7.21 (4H, m), 5.56 (1H, s), 3.64 (2H, m), 3.29 (2H, s), 2.9-3.3 ( 6H, m), 1.9-2.1 (4H, m).

Infrared absorption spectrum v _m cm " ¹ (KBr): 1762, 1639, 1604, 1508, 1406, 1223. Mass spectrum (FAB) m / z 403 ((M + H) +, free form)

Elemental analysis value (as C ₂₄ H ₂₆ N ₂ 0 ₇ F ₂ (5)

 Calculated: C: 58.53; H: 5.32; N: 5.69; F: 7.72%

 Found: C: 58.58; H: 5.33; N: 5.69; F: 7.50%. Example 15

 8- [2-Bis (4-chlorophenyl) methoxethyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one and its oxalate (Exemplified Compound No. 648)

 (15a) 8- [2-Bis (4-chlorophenyl) methoxhetyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one

 1-Oxa-3,8-dazaspiro [4.5] decane-2-one hydrochloride 97 mg (0.50 t ol) and bis (4-chlorophenyl) methyl 2-cloethyl as in Example (la) Using 159 mg (0.50 ol) of the ether, 115 mg (52%) of 8- [2-bis (4-chlorophenyl) methoxhetyl] -1-oxoxa-3,8-diazaspiro [4.5] decane-2-one I got

(15b) 8-[2-Bis (4-chlorophenyl) methoxhetyl]-1-oxa-3,8-diazas Pyro [4.5] decane-2-one oxalate

 The compound obtained in Example (15a) was dissolved in 5 ml of ethyl acetate, 24 mg (0.27 liter) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound (105 mg, 76%) as white crystals.

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, DMS0-d 6} ) δ ppm:

 7.63 (1H, s), 7.39-7.43 (8H, m), 5.58 (1H, s), 3.65 (2H, m), 3.29 (2H, s), 2.9-3.3 (6H, m), 1.9-2.1 ( 4H, m).

Infrared absorption spectrum rise cm- ¹ (KBr): 1763, 1753, 1640, 1490, 1408, 1090. Mass spectrum (FAB) m / z 435 ((M + H) \ free form)

Elemental analysis _{(C 24 H 26 N 2 0} 7 C1 2 0)

 Calculated values: C: 54.87; H: 4.99; N: 5.33; C1: 13.50%

 Found: C: 54.48; H: 4.83; N: 5.32; C1: 13.80%. Example 16

 8- [3-bis (4-fluorophenyl) methoxypropyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one and its oxalate (Exemplified Compound No. 309)

 (16a) 8- [3-Bis (4-fluorophenyl) methoxypropyl] -1-oxa-3,8-diazaspiro [4,5] decane-2-one

 1-Oxa-3,8-diazaspi mouth [4.5] decane-2-amine hydrochloride 86 mg (0.45 mmol) and bis (4-fluorophenyl) methyl 3-chloro mouth propyl as in Example (1a) Using 146 mg (0.49 tmol) of ether, 8- [3-bis (4-fluorophenyl) methoxypropyl] _1_oxa_3,8-diazaspiro [4.5] decane-2-one 111 mg ( 60%).

(16b) 8- [3-Bis (4-fluorophenyl) methoxypropyl] -1-oxa-3,8-diazaspirate [4.5] decane-2-one oxalate

The compound obtained in Example (16a) was dissolved in 5 ml of ethyl acetate, 24 mg (0.27 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals are collected by filtration to give the title compound Was obtained as white crystals (86 mg, 64./.).

Nuclear magnetic resonance spectrum (400 MHz, DMS0-d ₆ ) δ ppm:

7.62 (1H, s), 7.37-7.2 (4H, m), 7.13-7.19 (4H, m), 5.49 (1H, s), 3.41 (2H, m), 3.30 (2H, s), 2.8- 3.3 (6H, m), 1.8-2.1 (6H, m).-Infrared absorption spectrum: cm- ¹ (KBr): 1766, 1604, 1508, 1222, 1088.

Mass spectrum (FAB) m / z 417 ((M + H) +, free form)

Elemental analysis value (as C ₂₅ H ₂₈ N ₂ 0 ₇ F ₂ (%))

 Calculated: C: 59.28; H: 5.57; N: 5.53; F: 7.50%

 Found: C: 58.92; H: 5.40; N: 5.60; F: 7.20%. Example 17

 8- [4-bis (4-fluorophenyl) methoxybutyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one and its oxalate (Exemplified Compound No. 310)

 (17a) 8_ [4-Bis (4-fluorophenyl) methoxybutyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one

 1-Oxa-3, diazaspiro [4.5] decane-2-one hydrochloride 97 mg (0.50 mmol) and bis (4-fluorophenyl) methyl 4-chlorobutyl ether 172 mg (0.55%) as in Example (la). ol) to give 59 mg (27%) of 8- [4-bis (4-fluorophenyl) methoxybutyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one.

 (17 b) 8- [4-Bis (4-fluorophenyl) methoxybutyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Example (17a) was dissolved in 5 ml of ethyl acetate, 12 mg (0.14 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (49 mg, 69%).

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 5} ) δ ppm:

7.65 (1H, s), 7.37-7.40 (4H, m), 7.14-7.19 (4H, m), 5.47 (1H, s), 3.38 (2H, m), 3.30 (2H, s), 2.8-3.4 (6H, m), 1.5-2.1 (8H, m).

Infrared absorption spectrum cm- ¹ (KBr): 1753, 1615, 1606, 1508, 1404, 1222, 1083. Mass spectrum (FAB) m / z 431 ((M + H) +, free form)

Elemental analysis value (as C ₂₆ H ₃₀ N ₂ 0 ₇ F ₂ -H ₂₀ (%))

 Calculated: C: 58.97; H: 5.90; N: 5.29; F: 7.18% '

Found: C: 59.28; H: 5.75 ; N: 5.24; F: 6.95 0 Example 1 8

8- [5-Bis (4-fluorophenyl) methoxypentyl] -1-oxa-3,8-diazaspiro [4.5] decane- ² -one oxalate (Exemplified Compound No. 311)

 (18a) 8- [5-Bis (4-fluorophenyl) methoxypentyl] -1-oxa-3,8-dazaspirate [4.5] decane-2-one

 1-Oxa-3,8-dazaspiro [4.5] decane-2-one hydrochloride 97 mg (0.50 tmol) and bis (4-fluorophenyl) methyl 5-clopentyl pentyl ester as in Example (1a) Using 180 mg (0.55 t ol) of ter, 8- [5-bis (4-fluorophenyl) methoxypentyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one 921¾ (41 %).

 (1 8 b) 8- [5-bis (4-fluorophenyl) methoxypentyl] -1 -oxa-3,8-diazaspiro [4,5] decane-2-one oxalate,

 The compound obtained in Example (18a) was dissolved in 5 ml of ethyl acetate, 19 mg (0.21 liter) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (70 mg, 63%).

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0- d 6)} δ ppm:

 7 · 65 (1Η, s), 7.35-7.39 (4H, m), 7.13-7.19 (4H, m), 5.46 (1H, s), 3.37 (2H, m), 3.23 (2H, s), 2.8- 3.4 (6H, m), 1.3-2.1 (10H, m).

Infrared absorption spectrum cm- ¹ (KBr): 1754, 1615, 1507, 1403, 1222, 1087. Mass spectrum (FAB) m / z 445 ((M + H) ⁺ , free form) Elemental analysis (as C ₂₇ H ₃₂ N ₂ 0 ₇ F _2. (¾))

 Calculated values: C: 60.67; H: 6.03; N: 5.24; F: 7.11%

 Found: C: 60.44; H: 6.13; N: 5.20; F: 7.10%. Example 19

 8- [6-Bis (4-fluorophenyl) methoxyhexyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one and its oxalate (Exemplified Compound No. 312)

 (1 9 a) 8- [6-Bis (4-fluorophenyl) methoxyhexyl] -1-oxa-3,8-diazaspirate [4.5] decane-2-one

 In the same manner as in Example (1a), 1-oxa-3,8-diazspiro [4.5] decane-2-one hydrochloride 97 mg (0.50 liter) and bis (6-fluorophenyl) methyl 4-chlorobutane Using 188 mg (0.56 t ol) of xyl ether, 8- [6-bis (4-fluorophenyl) methoxyhexyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one 75 mg (32) were obtained.

(1 9 b) 8- [6-Bis (4-fluorophenyl) methoxyhexyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one oxalate

 The compound obtained in Example (19b) was dissolved in 5 ml of ethyl acetate, 15 mg (0.16 t) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (58 mg, 64%).

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 6} ) S ppm:

 7.66 (1H, s), 7.35—7.39 (4H, m), 7.13-7.19 (4H, m), 5.45 (1H, s), 3.36 (2H, m), 3.3K2H, s), 2.8-3.3 (6H , m), 1.2- 2.1 (12H, m).

Infrared absorption spectrum n ^ cm- ¹ (KBr): 1754, 1604, 1508, 1404, 1222, 1088. Mass spectrum (FAB) m / z 459 ((M + H) ⁺ , free form)

Elemental analysis value (as C ₂₈ H ₃₄ N ₂ 0 ₇ F ₂ -0.5H ₂₀ (%))

 Calculated: C: 59.36; H: 6.40; N: 4.94; F: 6.70%

Found: C: 59.14; H: 6.15; N: 4.87; F: 6.53%. Example 20

 1- [2-Bis (4-fluorophenyl) methoxethyl] -4- (4-chlorobenzyl) piperidin-4-carboxylic acid methyl ester and its oxalate (Exemplified Compound No. 219) (20a) 1-[ 2-bis (4-fluorophenyl) methoxethyl] -4- (4-chlorobenzyl) piperidine-4-carboxylic acid methyl ester

 In the same manner as in Example (la), 3- (4-chlorobenzyl) piperidine-3-carboxylic acid methyl ester hydrochloride 305 mg (1.00 mol) and bis (4-fluorophenyl) methyl 2-chloroethyl ether Using 283 mg (1.00 t ol), 349 mg (68%) of the title compound was obtained.

 (20 b) l- [2-Bis (4-fluorophenyl) methoxhetyl] -4- (4-chlorobenzyl) piperidine-4-carboxylic acid methyl ester oxalate

 The compound obtained in Example (20a) was dissolved in 5 ml of ethyl acetate, 61 mg (0.68 t) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give 308 mg (75 ° / ») of the title compound as white crystals.

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 6} ) δ ppm:

 7.02- 7.37 (12H, m), 5.51 (lH, s), 3.55 (3H, s), 3.2-3.6 (2H, m), 2.4-3.1 (8H, m), 1.3-2.0 (4H, m ).

Infrared absorption spectrum _ax cm— ¹ (KBr): 1731, 1604, 1509, 1405, 1224.

Mass spectrum (FAB) m / z 515 ((M + H) ⁺ , free form)

Elemental analysis value (as C ₃₁ ¾ ₂ N0 ₇ C1F ₂ (%))

 Calculated value: C: 61.64; H: 5.34; N: 2.32; F: 6.29; C1: 5.87%

 Found: C: 61.42; H: 5.48; N: 2.33; F: 6.17; C1: 5.84%. Example 2 1

1- [2-bis (4-fluorophenyl) methoxethyl] piperidine-4-carboxylate Jilamide and its oxalate (Exemplary Compound No. 441)

 (21a) 1- [2-bis (4-fluorophenyl) methoxethyl] piperidine-4-carboxylate benzylamide

 In the same manner as in Example (la), piveridine-4-potassic acid benzylamide hydrochloride 255 mg (1.00 mmol) and bis (4-fluorophenyl) methyl 2-chloroethyl ether 283 mg (1.00 t ol) Used to afford 279 mg (60%) of the title compound.

 (2 1 b) 1- [2-bis (4-fluorophenyl) methoxethyl] piperidine-4-benzylsulfonic acid benzylamide oxalic acid, salt

 The compound obtained in Example (21a) was dissolved in ethyl acetate (5 ml), oxalic acid (54 mg, 0.60 tmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (303 mg, 91).

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 6} ) δ ppm:

 8.46 (1H, t, J = 5.9Hz), 7.15-7.43 (13H, m), 5.57 (lH, s), 4.27 (2H, d, J = 5.2Hz), 3.65 (2H, m), 3.2- 3.4 (4H, m), 2.88 (2H, m), 2.42 (lH, m), 1.7-2.0 (4H, m).

Infrared absorption spectrum cm- ¹ (KBr): 1657, 1604, 1536, 1509, 1223.

Mass vector (FAB) m / z 465 ((M + H) ⁺ , free form)

Elemental analysis (as _{C 30 H 32 N 2 0 6} C1F 2 (%))

 Calculated value: C: 64.97; H: 5.82; N: 5.05; F: 6.85%

 Found: C, 64.90; H, 6.02; N, 4.95; F, 6.69%. Example 22

 1- [2-Bis (4-fluorophenyl) methoxethyl] -4- [1- (4-fluorobenzyl) -1H-benzimidazol-2-yl] -4-hydroxypiperidine and its nitrates (eg Compound number 229)

(22a) 1- [2-Bis (4-fluorophenyl) methoxhetyl] -4- [1- (4-fluorobenzyl) -1H-benzimidazol-2-yl] -4-hydroxypiぺ lysine In the same manner as in Example (la), 4- [l- (4-fluorobenzyl) -1H-benzimidazol-2-yl] -4-hydroxypiperidine dihydrochloride 200 mg (0.50 mol) and bis ( Using 143 mg (0.51 mmol) of 4-fluorophenyl) methyl 2-chloroethyl ether, 172 mg (60%) of the title compound was obtained.

 (22 b) 1- [2-Bis (4-fluorophenyl) methoxethyl] -4- [1- (4-fluorobenzyl) -1H-benzoimidazole-2-yl] -4-hid Roxypiperidine Nisuccinic acid The compound obtained in Example (22a) was dissolved in 5 ml of ethyl acetate, 54 mg of oxalic acid (0.6 ol of oxalic acid) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give 156 mg (69%) of the title compound as white crystals.

Nuclear magnetic resonance spectrum _{(400 MHz, DMSO- d 6)} δ ppm:

7.12- 7.67 (16H, m), 5.81 (2H, s), 5.59 (lH, s), 3.2-3.8 (10H, m), 2.0-2.2 (2H, m) Infrared absorption spectrum cm- ¹ (KBr ): 1722, 1605, 1509, 1405, 1224.

Mass spectrum (FAB) m / z 572 '((M + Η) ⁺ , free form)

Elemental analysis value (as C ₃₈ H ₃₆ N ₃ 0 ₁₀ F ₃ (%)) ''

 Calculated values: C: 60.72; H: 4.83; N: 5.59; F: 7.58%

 Found: C: 60.82; H: 4.83; N: 5.57; F: 7.28%. Example 23

 8-[2-Bis (4-fluorophenyl) methoxethyl] -1-phenyl-1,3,8-triazaspire [4.5] decane-4-one and its oxalate (Exemplified Compound No. 367)

 (23a) 8- [2-Bis (4-fluorophenyl) methoxethyl] -1-phenyl-1,3,8-triazaspi [4.5] decane-4-one

1-Phenyl-1,3,8-triazaspiro [4.5] decane-4-one 180 mg (0.78 mmol) and bis (4-fluorophenyl) methyl 2-chloroethyl ether as in Example (1a) Using 200 mg (0.71 mol), 235 mg (70%) of the title compound was obtained. (23 b) 8- [2-Bis (4-fluorophenyl) methoxethyl] -1-phenyl-1,3,8-triazaspi [4.5] decane-4-one oxalate

 The compound obtained in Example (23a) was dissolved in 5 ml of methanol, 44 mg (0.49 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (167 mg, 42).

Nuclear magnetic resonance spectrum _{(400 MHz, DMS0-d 6} ) δ ppm:

 9.01 (1H, s), 7.43- 7.46 (4H, m), 7.15-7.26 (6H, m), 6.95 (2H, d, J = 8.4Hz), 6.79 (1H, dd, J = 7.2,7.2Hz) , 5.61 (lH, s), 4.62 (2H, bs), 3.6-3.8 (4H, m), 3.3-3.5 (4H, m), 2.7-2.9 (2H, m), 1.8-1.9 (2H, m) .

Infrared absorption spectrum cm- ¹ (KBr): 3234, 3068, 2876, 2572, 1717, 1601, 150 7, 1223.

Mass spectrum (FAB) m / z 478 ((M + H) +, free form)

Elemental analysis (as _{C 30 H 31 N 3 0 6} F 2 (%))

 Calculated: C: 63.48; H: 5.51; N: 7.40; F: 6.69%

 Found: C, 63.25; H, 5.43; N, 7.38; F, 6.52%. Example 24

 1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [isobenzofuran-1 (3H), 4, -piperidine] and its oxalate (Exemplified Compound No. 483)

 (24a) 1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [isobenzofuran-1 (3H), 4, -piperidine]

 Spiro [isobenzofuran-1 (3H), 4-piperidine] hydrochloride 114 mg (0.51 tmol) and bis (4-fluorophenyl) methyl 2-chloroethyl ether 150 as in Example (la) mg (0.53 tmol); 130 mg (59%) of the title compound was obtained.

(24 b) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [isobenzolaran-1 (3H), 4, -piperidine] oxalate The compound obtained in Example (24a) was dissolved in 5 ml of ethyl acetate, oxalic acid (27 mg, 0.30 tmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (102 mg, 65%).

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, DMS0-d 6} ) δ ppm:

7.17-7.45 (12H, m), 5.60 (lH, s), 5.03 (2H, s), 2.8-4.0 (8H, m), 1.7-2.3 (4H, m). Infrared absorption spectrum, αιΓ ¹ (KBr): 1720, 1633, 1604, 1508, 1405, 1223. Mass vector (FAB) m / z 436 ((M + H) ⁺ , free form). Example 2 5

 2- [l- [2-Bis (4-fluorophenyl) methoxethyl] -piperidine-4-ylidene] propionic acid ethyl ester (Exemplary Compound No. 491)

 0.661 g of 2-phosphonopropionic acid triethyl ester was dissolved in 6 ml of tetrahydrofuran, and a suspension of 0.125 g of 55% sodium hydrogen in 10 ml of tetrahydrofuran was added in a nitrogen stream. Then, the mixture was cooled with acetone-ice, and a solution of 0.959 g of 1- [2-bis (4-fluorophenyl) methoxethyl] -piperidone in 5 mi of tetrahydrofuran was added dropwise, followed by stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with dichloromethane and concentrated. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate: hexane = 1: 2) to give the title compound as a colorless oil (0.865 g). (73%). Example 26

 2- [1- [2-bis (4-fluorophenyl) methoxethyl] -piperidin-4-yl] propionic acid ethyl ester and its oxalate salt (Exemplary Compound No. 417)

 (26a) 2- [1- [2-Bis (4-fluorophenyl) methoxethyl] -piperidine-4-yl] propionate ethyl ester

0.784 g of the compound obtained in Example 25 was dissolved in 15 ml of ethanol, and 10 ° /. Parazi 0.03 g of calories were shaken in a stream of hydrogen for 4 hours. Then, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure to obtain 0.726 g (92%) of the title compound as a yellow liquid.

 (26b) 2- [1- [2-Bis (4-fluorophenyl) methoxethyl] -piperidin-4-yl] propionic acid ethyl ester oxalate

 The compound obtained in Example (26a) was dissolved in ethanol, oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound.

Melting point: 137-138 ° C. '' Example 2

 2- [1- [2-bis (4-fluorophenyl) methoxethyl] -piperidine-4-ylidene] -2-cyanoacetic acid methyl ester (Exemplary Compound No. 498)

 1- [2-bis (4-fluorophenyl) methoxethyl] -4-piperidone 1.14 g, cyanoacetic acid methyl ester 0.43 g, piperidine 0.03 ml and acetic acid 0.04 g in benzene 10 The mixture was dissolved in ml, and refluxed for 1 hour while removing generated water. After cooling, the mixture was washed with water, washed with a saturated solution of sodium hydrogen carbonate, and concentrated by dehydration. The remaining oil was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 3) to obtain 995 mg of the title compound as a yellow liquid. Example 2 8

 2- [1- [2-bis (4-fluorophenyl) methoxethyl] -piperidin-4-yl] -2-cyanoacetic acid methyl ester and its oxalate salt (Exemplary Compound No. 423)

(28a) 2- [1- [2-Bis (4-fluorophenyl) methoxethyl] -piperidine-4-y 609 mg of the compound obtained in Example 27 was dissolved in 20 ml of methanol, and ° /. 0.03 g of palladium-carbon was added, and the mixture was shaken under a stream of hydrogen for 1.5 hours. Then, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to obtain 609 mg (91%) of the title compound as a yellow liquid. (28b) 2_ [1- [2-bis (4-fluorophenyl) methoxethyl] -piperidin-4-yl] -2-cyanoacetic acid methyl ester oxalate

 The compound obtained in Example (28a) was dissolved in ethanol, oxalic acid was removed, and left at room temperature for 1 B. The precipitated crystals were collected by filtration to give the title compound.

Melting point: 141-144 ° C (decomposition). Example 2 9

 1_ [2-bis (4-fluorophenyl) methoxyl] -4-ethoxycarbonylpiperazine and its oxalate (Exemplary Compound No. 478)

 (29a) 1- [2-Bis (4-fluorophenyl) methoxethyl] -4-ethoxycarbonilpiperazine

 Using 1.19 g of 1-ethoxycarbonylpiperazine and 1.43 g of bis (4-fluorophenyl) methyl 2-chloroethyl ether in the same manner as in Example (la), 0.43 g (21 %).

 (29b) 1- [2-bis (4-fluorophenyl) methoxhetyl] -4-ethoxycarbonirubiperazine oxalate

 The compound obtained in Example (29a) was dissolved in ethanol, oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound.

Melting point: 154-156 ° C. Example 30

 1- [2-Bis (4-fluorophenyl) methoxyl] -piperidine-4-ylidene] -propionic acid methyl ester (Exemplary Compound No. 461)

50 ° / in 70 ml of anhydrous tetrahydrofuran in a nitrogen stream. 0.87 g of sodium hydrogen was added, and a solution of 3.6 g of dimethylphosphonopropionic acid methyl ester dissolved in 12 ml of tetrahydrofuran was added dropwise at 10 ° C. Then, 1- [2-bis (4-fluorophenyl) A solution dissolved in 12 ml of furan was added dropwise at 10 ° C. Next, a solution of 6.8 g of 1- [2-bis (4-fluorophenyl) methoxhetyl] -4-piperidone in 70 ml of tetrahydrofuran was added dropwise at 0 ° C. After stirring at room temperature for 2 hours, the solvent was distilled off, and the residue obtained by extraction with dichloromethane to which ice water was added was subjected to silica gel chromatography (developing solvent; ethyl acetate: hexane = 1: 1). Purification was performed in 2) to give 6.04 g (76) of the title compound as a colorless oil.

Nuclear magnetic resonance spectrum _{(400 MHz, CDC1 3) δ} ppm:

 2.30 (2H, t), 2.60 (4H, m), 2.98 (2H, t), 3.57 (2H, t), 3.68 (3H, s), 5.35 (1H, s),

5.65 (1H, s), 7.00 (4H, t), 7.30 (4H, dd).

Infrared absorption spectrum Li _{^{- 1 (CHC1 3): 1710}} , 1655, 1605. Test example 1

 Mouse T cell clone D10. G4.1 cells were cultured in RPMI medium (manufactured by Life Technologies) containing 10% fetal bovine serum and 52-mercaptoethanol at a cell concentration of 2500 cells / 0.2 ml. It was prepared and dispensed into a 96-well flat bottom plate (manufactured by Koningu Co., Ltd.) by 0.2 ml. At this time, IL-4 was produced in the culture supernatant after culturing for <24 hours to which the compound of the present invention was added at a predetermined concentration. IL-4 in the culture supernatant was quantified by IL-4 ELISA KIT (Genzyme).

 As a result, the compound of the present invention exhibited excellent IL-4 production inducing activity.

[Table 2] 'Example compound number (concentration) I L-14 production (pg / ml)

1 (2.5ug / ml) 1000 Test example 2

 The compound of the present invention was used by dissolving Celdegs (manufactured by Nippon Shokuhin Kako Co., Ltd.) in distilled water to prepare a 20% solution.

 Experimental encephalomyelitis (Experimental Autoimmune Encephalomyelitis: EAE) eliciting peptide (MOG35-55) dissolved in saline at 4 mg / ml and complete adjuvant (CFAH37Ra (Difco)) 8-fold concentrate A mixed solution of 1: 1.3 was prepared. 0.1 ml of this mixture was subcutaneously administered to 8-week-old female C57BL / 6 mice. Further, pertussis toxin (manufactured by List Biological Laboratories) was dissolved in physiological saline to make a 1 g / ml solution, and 0.2 ml of the solution was administered via the tail vein. Two days later, 0.2 ml of the above-mentioned pertussis toxin solution was administered again via the tail vein to cause EAE.

 The compound of the present invention was administered daily for 11 days from 1 day to 11 days after administration of the evoked peptide.

 Symptoms of EAE were scored according to the method of Sabelko et al. (The Journal of Immunolog 159: 3096 (1997)). Table 3 shows the obtained EAE onset date.

 The compounds of the present invention exhibited an excellent effect of delaying the onset of EAE.

[Table 3] Example compound number (Dose) EAE onset date

 (After administration of the peptide)

1 4 (30 mg / kg) 1 2 days

 Control control group 9 days

Claims

Claims General formula (I)

 [Where, R ¹ and R ² are the same or different and are selected from an aryl group, a heteroaryl group, an aryl group substituted by 1 to 3 groups selected from a substituent group a, or a substituent group a Represents a heteroaryl group substituted by 1 to 3 groups,  X represents an oxygen atom, a sulfur atom, or a group having the formula —NR—, wherein R is a hydrogen atom or a group selected from substituent group b. Y is, C -C ₈ alkylene group or a C ₂ - (indicates ₈ Aruke two alkylene groups, L is a group having the formula C (R ³ ) (R ⁴ )  [Where ' R ³ is an aryl group, a heteroaryl group, an aryl group substituted by 1 to 3 groups selected from substituent group a, or a heteroaryl group substituted by 1 to 3 groups selected from substituent group a. Represents a group, R ⁴ is a group having the formula: CO—R ⁵ (wherein, R ⁵ is an aryl group substituted by 1 to 3 groups selected from an amide residue, an aryl group, a heteroaryl group, and a substituent group a) Or a heteroaryl group substituted by 1 to 3 groups selected from a substituent group a.) And R ^{3! 4} together form a 5- to 8-membered saturated heterocycle or 1 to 3 substituted with a group selected from the group of substituents c, which includes the carbon atoms to which they are attached. An 8-membered saturated heterocyclic ring (provided that the saturated heterocyclic ring excludes tetrahydrofuran, imidazolidine or dioxepane), or R ³ and R ⁴ are linked together to form the carbon atom to which they are attached 3 A 3- to 10-membered saturated carbocycle substituted with 1 to 3 membered by a to 10-membered saturated carbocycle or a group selected from substituent groups a and c. ]. ] Or a pharmacologically acceptable salt thereof, an ester thereof, or another derivative ο  <Substituent group a> Halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxy group, hydroxyl group, lower aliphatic acyl group, lower aliphatic acylamino group, amino group, and cyano group Substituent group b> Lower alkyl group substituted with 1 to 3 groups selected from lower alkyl group, aryl group, aralkyl group, substituent group a, and 1 to 3 groups substituted with a group selected from substituent group a Aryl group, aralkyl group substituted with 1 to 3 groups selected from substituent group a, lower aliphatic acyl group, and lower alkylsulfonyl group <Substituent group c> An oxo group, or a group selected from substituent group b as a substituent on a nitrogen atom when there is a nitrogen atom. 2. Claims! In. A compound or a pharmacologically acceptable salt thereof, wherein R ¹ and R ² are the same or different and are an aryl group, a heteroaryl group or an aryl group substituted by 1 to 3 groups selected from a substituent group a. 3. In claim 1, A compound or a pharmacologically acceptable salt thereof, wherein R ¹ and R ^{2 are} the same or different and are an aryl group or an aryl group substituted by 1 to 3 groups selected from substituent group a. 4. In Claim 1, R ¹ and R ^{2 are the} same or different, aryl group, or 1 to 3 substituted aryl group (the substituent is selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group) Or a pharmacologically acceptable salt thereof. 5. In Claim 1, A compound or a pharmaceutically acceptable salt thereof, wherein R ¹ and: ² are the same or different and are an aryl group or an aryl group substituted by one halogen atom. 6. In Claim 1, A compound or a pharmacologically acceptable salt thereof, wherein R ¹ and R ² are the same aryl group substituted by one halogen atom. 7. In any one of the claims 1 to 6,  A compound or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom, a sulfur atom or a group having the formula —] Si H—. 8. In any one of claims 1 to 6,  X is an oxygen atom or a pharmacologically acceptable salt thereof. 9. In any one of the claims 1 to 8, A compound wherein Y is a C ₈ alkylene group or a pharmacologically acceptable salt thereof. 10. In any one of claims 1 to 8, A compound which is a Y-force ^s , C i -C ₅ alkylene group or a pharmacologically acceptable salt thereof. 1 1. In any one of claims 1 to 8, A compound or a pharmacologically acceptable salt thereof having a Y-force ^s , C ₂ -C ₃ alkylene group. 1 2. In any one of claims 1 to 8,  A compound wherein γ is an ethylene group or a pharmacologically acceptable salt thereof. 1 3. In any one of claims 1 to 12, L is a group having the formula C (R ³ ) (R ⁴ )  (Where R ³ is an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from the substituent group a, or a heteroaryl substituted 1 to 3 groups with a group selected from the substituent group a. Group, R ⁴ is a group having the formula CO—R ⁵ . ) Or a pharmaceutically acceptable compound thereof 1 4. In claim 13, A compound in which R ³ is an aryl group or a heteroaryl group or a pharmacologically acceptable 1 5. In claim 13, A compound wherein R ³ is a phenyl group or a pyridyl group, or a pharmacologically acceptable salt thereof. 1 6. In claim 13, A compound or a pharmaceutically acceptable salt thereof, wherein R ³ is a pyridyl group. 17. In any one of claims 13 to 16, A compound or a pharmacologically acceptable salt thereof, wherein R ⁵ is an amine residue. 18. In any one of claims 13 to 16, A compound wherein R ⁴ is a carbamoyl group or a pharmacologically acceptable salt thereof.  1 9. In any one of claims 1 to 12, L ^s is a group having the formula C (R ³ ) (R ⁴ ), wherein R ³ and R ⁴ are taken together to form the carbon atom to which they are attached, A compound or a pharmacologically acceptable salt thereof, which is an 8-membered saturated heterocyclic ring or a 5- to 8-membered saturated heterocyclic ring substituted by 1 to 3 substituent (s) selected from substituent group c. 20. In claim 19,  A compound or a pharmacologically acceptable salt thereof, wherein L is a 5- or 6-membered saturated heterocyclic ring or a 5- or 6-membered saturated heterocyclic ring substituted by 1 to 3 groups with a group selected from substituent group c. 2 1. In claim 19,  A compound or a pharmacologically acceptable salt thereof, wherein L is a 5- to 6-membered saturated heterocyclic ring substituted with 1 to 3 substituents selected from a group of substituents. 2 2. In claim 19,  A compound or a pharmacologically acceptable salt thereof, which is a 5- to 6-membered saturated heterocyclic ring which is substituted by one L-oxo group and may be further substituted by one or two groups selected from substituent group c. 23. In claim 19, L is the following formula (L-1) (Le 1)

 (Where  G and J are the same or different and each represent an oxygen atom, a sulfur atom or a group having the formula —NR—. However, G and J do not represent the same group having the formula NR—. Or a pharmacologically acceptable salt thereof. 2 4. In claim 23,  A compound or a pharmaceutically acceptable salt thereof, wherein G is an oxygen atom or a sulfur atom, and J is a group having -NH-. 25. In any one of claims 1 to 12, L ^s , a group having the formula C (R ³ ) (R ⁴ ) 1, wherein R ³ and R ⁴ together form the carbon atom to which they are attached; 10. A 10-membered saturated carbocycle or a 3- to 10-membered saturated carbocycle substituted with 1 to 3 substituents selected from groups a and c, or a pharmaceutically acceptable salt thereof. 2 6. In claim 25,  A compound or a pharmacologically acceptable salt thereof, wherein L is a 5- to 6-membered saturated carbocyclic ring or a 5- to 6-membered saturated carbocyclic ring substituted by 1 to 3 substituents with a group selected from substituent groups a and c. 2 7. In claim 25, A compound in which L is a 5- or 6-membered saturated carbocyclic ring condensed with a benzene ring (the 5- or 6-membered saturated carbocyclic ring has an oxo group or a hydroxyl group as a substituent), or a pharmaceutically acceptable salt thereof. 2 8. In claim 25,  A compound or a pharmaceutically acceptable salt thereof, wherein L is 2-hydroxyindane or 2-oxoindane II. 29. Any one compound selected from the following or a pharmacologically acceptable salt thereof. 1- [2-bis (4-fluorophenyl) methoxethyl] -4-phenylpiperidine-4-force rubonic acid amide,  1- [2-bis (4-fluorophenyl) methoxethyl] -4-phenylbiperidine-4 -force  1- [2-bis (4-fluorophenyl) methoxethyl] -4- (2-pyridyl) piperidine-4-butyric acid amide,  8-[2-Bis (4-fluorophenyl) methoxethyl] -1-oxa-3,8-diazaspirate [4.5] decane-2-one,  8-[3-Bis (4-fluorophenyl) methoxypropyl] -1-oxa_3,8-diazaspirate [4.5] decane-2-one,  8- [2-bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-oxa-3,8-dazaspiro [4.5] decane-2-one,  8- [2-bis (4-fluorophenyl) methoxethyl] -3-benzyl-1-oxa-3,8-diazaspiro [4.5] decane-2-one,  8-[2-Bis (4-fluorophenyl) methoxethyl]-1-thio-3,8-diazaspiro [4.5] decane-2-one,  8- [2-bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-thio-3,8-diazaspiro [4.5] de-2-one 1_ [2-bis (4-fluorophenyl) methoxethyl] spiro [2,3-dihydrobenzothi Offen-3,4-piperidine] -1-oxoxide,  1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4, -piperidine],  1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4, -piperidine] -2-oxoxide,  1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(1,4-dihydro-2H-isoquinolin-3-one) -1,4, -piperidine],  1_ [2-bis (4-fluorophenyl) methoxethyl] spiro [(indane) -1,4-dipyridine],  1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(indane-1-one) —3,4, -piperidine],  1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(2-hydroxy) indane-1,4, -piperidine],  1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4, -piperidine] -2,2-dioxide, and  8- [2-Bis (4-chlorophenyl) methoxhetyl] -1-oxa-3,8-dazaspiro [4.5] decane-2-one. 30. A pharmaceutical composition comprising the compound according to any one of claims 1 to 29, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof as an active ingredient. 31. Nitrogen-containing saturated heterocyclic compound having the general formula (II), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof as an active ingredient, and selectively inhibits the immunological activity of TH1 cells. Pharmaceutical compositions for (Π)

 [Where ' R ¹ and R ² are the same or different and are an aryl group, a heteroaryl group, an aryl group substituted by 1 to 3 groups selected from a substituent group a, or a group selected from a substituent group a Represents 1 to 3 substituted heteroaryl groups,  Represents an oxygen atom, a sulfur atom, or a group having the formula 1 N R— (wherein, R is a hydrogen atom or a group selected from the substituent group b); Y is, C ^ - C ₈ alkylene group or a C ₂ - 0 ₈ Aruke shows a two lens group, L ¹ is a group having the formula — C (R ^3a ) (R ^4a )  [Where, R ^3a is a hydrogen atom, an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from substituent group a, or 1 to 3 groups selected from substituent group a Represents a substituted heteroaryl group, R ^4a is a group having the formula: D—E—R ^{6 wherein} D represents a single bond or a group having the formula C (R ⁷ ) H— (where R ⁷ is a hydrogen atom or a group selected from substituent group a); E represents a single bond or a C ₈ alkylene group, R ⁶ is a hydrogen atom, a hydroxyl group, an amino group, a lower aliphatic acylamino group, an aromatic acylamino group, or a group having the formula CO—R ^5a (wherein R ^5a is a lower alkyl group, a lower alkoxy group, an amine residue, a hydroxyl group, an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from a substituent group a, or a substituent group a heteroaryl group substituted by 1 to 3 groups selected from a. ). ] R ^3a and R ^4a are taken together and include 1 to 3 substituted 5- to 8-membered saturated heterocycles or a group selected from substituent group c, including the carbon atom to which they are attached. 8 Form a membered saturated heterocycle, or R ^3a and R ^4a are taken together and are substituted by 1 to 3 3-membered saturated carbocycles or a group selected from substituent groups a and c, including the carbon atom to which they are attached. To form a 3- to 10-membered saturated carbocycle. ] -A group having the formula —N (R ^b ) one [Wherein, R ^4b represents a group having the formula D—E—R ⁶ (where D, E and R ⁶ have the same meanings as described above). ], Or A group having the formula — C (R ^4c ) one [Wherein, R ^4c represents a group having the formula = C (R ⁷ ) -E-R ⁵ (wherein, E, R ⁶ and R ⁷ have the same meanings as described above). ] <Substituent group 3> Halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxy group, hydroxyl group, lower aliphatic acyl group, lower aliphatic acylamino group, amino group, and cyano group  <Substituent group b> ' Lower alkyl group substituted with 1 to 3 groups selected from lower alkyl group, aryl group, aralkyl group, and substituent group a; aryl group substituted with 1 to 3 groups selected from substituent group a Groups, an aralkyl group substituted with 1 to 3 groups selected from a substituent group a, a lower aliphatic acyl group, and a lower alkylsulfonyl group  <Substituent group (:> An oxo group, or a group selected from substituent group b as a substituent on a nitrogen atom when there is a nitrogen atom. 3 2. In claim 31, A compound or a compound thereof wherein R ¹ and R ² are the same or different and are an aryl group, a heteroaryl group or an aryl group substituted by 1 to 3 groups selected from a substituent group a; A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a pharmacologically acceptable salt as an active ingredient. 3 3. In claim 31, R ¹ and R ² are the same or different and each contains, as an active ingredient, a compound or a pharmacologically acceptable salt thereof, which is an aryl group or an aryl group substituted by 1 to 3 groups selected from a substituent group a. A pharmaceutical composition for selectively suppressing the immune activity of TH1 cells. 3 4. In claim 31, R ¹ and R ² are the same or different and are an aryl group or an aryl group substituted by 1 to 3 (the substituent is selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group; Or a pharmacologically acceptable salt thereof as an active ingredient, and a pharmaceutical composition for selectively suppressing TH1 cell immune activity. 3 5. In claim 3, R ¹ and R ² are the same or different and each is an aryl group or an aryl group substituted with one halogen atom, or a pharmacologically acceptable salt thereof as an active ingredient. Pharmaceutical composition for suppressing immune activity of one cell. 3 6. In claim 31, R ¹ and R ² , which contain, as an active ingredient, a compound which is the same aryl group substituted by one halogen atom or a pharmacologically acceptable salt thereof, selectively inhibits the immunological activity of TH 1 cells Pharmaceutical compositions for 37. In any one selected from claims 31 to 36,  Pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising as an active ingredient a compound in which X is an oxygen atom, a sulfur atom or a group having the formula -NH- or a pharmaceutically acceptable salt thereof as an active ingredient. object. 38. In any one of claims 31 to 36,  A pharmaceutical composition for selectively suppressing the immune activity of TH1 cells, comprising a compound in which X is an oxygen atom or a pharmaceutically acceptable salt thereof as an active ingredient. 39. In any one of claims 31 to 38, Y is, c 'is c ₈ alkylene group compound or containing a pharmacologically acceptable salt thereof as an active Ingredient, selectively TH 1 cells pharmaceutical composition for inhibiting the immunological activity of. 40. In any one of claims 31 to 38, A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a compound in which Y is a C ₅ alkylene group or a pharmacologically acceptable salt thereof as an active ingredient. 4 1. In any one of claims 31 to 38, A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a compound in which Y is a C ₂ -C ₃ alkylene group or a pharmacologically acceptable salt thereof as an active ingredient. 4 2. In any one of claims 31 to 38,  A pharmaceutical composition for selectively suppressing the immunological activity of TH1 cells, comprising a compound in which γ is an ethylene group or a cryo-acceptable salt thereof as an active ingredient. 43. In any one selected from claims 31 to 42, L ¹ is a group having ^one of the formulas —C (R ^3a ) (R ^4a )  (Where  R is an aryl group, a heteroaryl group, an aryl group substituted with 1 to 3 groups selected from the substituent group a, or a heteroaryl substituted 1 to 3 groups with a group selected from the substituent group a. Group, R ^4a is a group having the force s ′ and the formula —D—E—R ⁶ . A pharmaceutical composition for selectively suppressing the immune activity of TH1 cells, comprising a compound or a pharmacologically acceptable salt thereof as an active ingredient. 44. In claim 43, A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a compound in which R ^3a is an aryl group or a heteroaryl group or a pharmaceutically acceptable salt thereof as an active ingredient. 4 5. In claim 43, A pharmaceutical composition for selectively suppressing the immune activity of TH1 cells, comprising a compound in which R ^3a is a phenyl group or a pyridyl group or a pharmaceutically acceptable salt thereof as an active ingredient. ;, 46. In claim 43, A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a compound in which R ^3a is a pyridyl group or a pharmacologically acceptable salt thereof as an active ingredient. 47. In any one of claims 43 to 46, A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a compound in which D and E are a single bond or a pharmacologically acceptable salt thereof as an active ingredient. 48. In any one of claims 43-47, A pharmaceutical composition for selectively suppressing the immune activity of TH1 cells, comprising a compound or a pharmacologically acceptable salt thereof, wherein R ⁶ is a group having the formula CO—R ^5a, as an active ingredient. 49. In claim 48, R ^5a is a compound which is an Amin residue or contain a pharmacologically acceptable salt thereof as an active ingredient, optionally TH 1 cells pharmaceutical composition for inhibiting the immunological activity of. 50. In claim 48, A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a compound in which ^R5a is an amino group or a pharmaceutically acceptable salt thereof as an active ingredient. 51. In any one of claims 31 to 42, L ¹ is a group having the formula: C (R ^3a ) (R ^4a )  (Where R ³³ is a hydrogen atom, R ^4a is a group having the formula D—E—R ⁶ . A pharmaceutical composition for selectively suppressing the immune activity of TH1 cells, comprising a compound or a pharmacologically acceptable salt thereof as an active ingredient. 52. In claim 51, A pharmaceutical composition for selectively suppressing the immunological activity of TH1 cells, comprising a compound that is a group having the formula D_C (R ⁷ ) H— or a pharmacologically acceptable salt thereof as an active ingredient. 53. In claim 52, A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a compound having R ⁷ , a cyano group or a lower alkyl group, or a pharmaceutically acceptable salt thereof as an active ingredient. . 54. In claim 51,  A pharmaceutical composition for selectively suppressing immune activity of TH1 cells, comprising a compound in which E is a single bond or a pharmacologically acceptable salt thereof as an active ingredient. ' 55. In claim 51, A pharmaceutical composition for selectively suppressing the immune activity of TH1 cells, comprising a compound or a pharmacologically acceptable salt thereof, wherein R ⁶ is a group having the formula CO—R ^5a, as an active ingredient. 56. In claim 55, A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a compound in which ^R5a is a lower alkoxy group or a pharmacologically acceptable salt thereof as an active ingredient. 57. In any one of claims 31 to 42, L ¹ is a group having the formula C (R ^3a ) (R ^a ) 1, wherein R ^3a and: ^4a are taken together to include those force-bonded carbon atoms, 5-8 Selected from the group consisting of a 5- to 8-membered saturated heterocyclic ring substituted with 1 to 3 membered saturated heterocycles or a group selected from substituent group c or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition for suppressing the immune activity of TH1 cells. 58. In claim 57, L ¹ , a 5- to 6-membered saturated heterocyclic ring or a compound which is a 5- or 6-membered saturated heterocyclic ring substituted by 1 to 3 groups with a group selected from substituent group c or a pharmacologically acceptable salt thereof as an active ingredient For selectively suppressing immune activity of TH 1 cells 5 9. In claim 57, Selectively containing a compound or a pharmacologically acceptable salt thereof, wherein L ¹ is a 5- to 6-membered saturated complex ring substituted by 1 to 3 groups selected from a substituent group c, as an active ingredient; A pharmaceutical composition for suppressing immune activity of TH1 cells. 60. In claim 57, L ¹ or a 5- to 6-membered saturated heterocyclic compound or a pharmacologically acceptable salt thereof, which is substituted with one oxo group and may be further substituted with one or two groups selected from substituent group c. A pharmaceutical composition for selectively suppressing the immune activity of TH1 cells, comprising as an active ingredient. 6 1. In Claim 57, L ^{1 force?,} The following formula (L one 1) (Le 1)

(Wherein G and J are the same or different and are an oxygen atom, a sulfur atom or a group having the formula —NR—) or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition for selectively suppressing the immune activity of TH1 cells, comprising: 62. In claim 61, G 1 ⁵ ', containing an oxygen or sulfur atom and J is a group having -NH- or a pharmacologically acceptable salt thereof as an active ingredient. Pharmaceutical composition to control. 63. In any one of the items i selected from claims 31 to 42, L ¹ is a group having the formula C (R ^3a ) (R ^4a ), wherein R ^3a and R ^4a are linked together to form a carbon atom to which they are bonded; Contains, as an active ingredient, a compound having a 3 to 10-membered saturated carbocyclic ring substituted with 1 to 3 10-membered saturated carbocycles or a group selected from substituent groups a and c, or a pharmacologically acceptable salt thereof. A pharmaceutical composition for selectively suppressing the immune activity of TH1 cells. 64. In claim 63, A compound or a pharmaceutically acceptable salt thereof, wherein L ¹ is a 5- to 6-membered saturated carbocyclic ring or a 5- to 6-membered saturated carbocyclic ring substituted by 1 to 3 substituents with a group selected from substituent groups a and c A pharmaceutical composition for selectively suppressing the immune activity of TH1 cells, comprising as an active ingredient. 65. In claim 63, A compound or a pharmaceutically acceptable salt thereof, wherein L ¹ is a 5- or 6-membered saturated carbocyclic ring condensed with a benzene ring (the 5- or 6-membered saturated carbocyclic ring has an oxo group or a hydroxyl group as a substituent) A pharmaceutical composition for selectively suppressing immune activity of TH1 cells, comprising as an active ingredient. 66. In claim 63, L ¹ is 2-hydroxy-indane or 2-Okisoindan a group compound or containing as an active ingredient salts pharmacologically acceptable of their selectively TH 1 cells pharmaceutical composition for inhibiting the immunological activity of. 67. In any one of claims 31 to 42, Pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising as an active ingredient a compound or a pharmaceutically acceptable salt thereof, wherein L ¹ is a group having the formula 1 N (R ^4b ) 1 . 68. In claim 67, R ^4b contains, as an active ingredient, a compound or a pharmaceutically acceptable salt thereof, which is a group having the formula: D—E—R ⁶ (wherein D is a single bond); A pharmaceutical composition for suppressing the immune activity of one cell. 69. In claim 68,  (F) A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a single bond compound or a pharmacologically acceptable salt thereof as an active ingredient. 70. In claim 68, R ⁶ force A pharmaceutical composition for selectively suppressing TH cell immune activity, comprising a compound having a formula of CO—R ^5a or a pharmaceutically acceptable salt thereof as an active ingredient. 71. In claim 68, A medicament for selectively suppressing TH1 cell immune activity, comprising a compound in which R ⁶ is a lower alkoxycarbonyl group or a pharmacologically acceptable salt thereof as an active ingredient. Composition. 72. In any one of claims 31 to 42, L ¹ is a group having the formula C (R ^4c ) —, and R ^4c is a group having the formula: = C (R ⁷ ) -ER ⁶ or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition for selectively suppressing the immune activity of TH1 cells. 73. In claim 72, A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a compound in which R ⁷ is a cyano group or a lower alkyl group or a pharmaceutically acceptable salt thereof as an active ingredient. 74. In claim 72,  A pharmaceutical composition for selectively suppressing immune activity of TH1 cells, comprising a compound in which E is a single bond or a pharmacologically acceptable salt thereof as an active ingredient. 75. In claim 72, A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a compound or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a group having the formula CO—R ^5a, as an active ingredient. 76. In claim 75, A pharmaceutical composition for selectively suppressing TH1 cell immune activity, comprising a compound in which ^R5a is a lower alkoxy group or a pharmacologically acceptable salt thereof as an active ingredient. 77. Any one compound selected from the following or a pharmacologically acceptable salt thereof A pharmaceutical composition for selectively suppressing TH1 cell immune activity, which is contained as an active ingredient.  1- [2-bis (4-fluorophenyl) methoxethyl] -4-phenylpiperidine-4-force 'rubonic acid amide,  1- [2-Bis (4-fluorophenyl) methoxethyl] -4-phenylpiperidine-4-forceRubonic acid morpholinamide, 1- [2-bis (4-fluorophenyl) methoxethyl] -4- (4-cyclobenzyl) piperidine-4-carboxylic acid methyl ester, 1- [2-bis (4-fluorophenyl) methoxethyl] -4- [1- (4-fluorobenzyl) -1H-benzoimidazole τ · 2-yl] -4-hydroxypiperidine,  1- [2-bis (4-fluorophenyl) methoxethyl] -4- (2-pyridyl) piperidine-4-carboxylic acid amide,  8- [2-bis (4-fluorophenyl) methoxethyl]-1-oxa-3,8-diazaspi [4.5] decane-2-one,  8- [3-bis (4-fluorophenyl) methoxypropyl] -1-oxa-3,8-diazaspirate [4.5] decane-2-one,  8- [2-bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-oxa-3,8-dazaspiro [4.5] decane-2-one,  8- [2-bis (4-fluorophenyl) methoxethyl] -3-benzyl-1-oxa-3,8-dazaspiro [4.5] decane-2-one,  8-[2-Bis (4-fluorophenyl) methoxethyl]-1-thio-3,8-diazaspiro [4.5] decane-2-one,  8-[2-bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-thio-3,8-diazaspirate [4.5] decane-2- 8- [2-Bis (4-fluorophenyl) methoxethyl]-1-phenyl-1,3,8-triaza spiro "4.5" decane-4-one, 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [2,3-dihydrobenzothiophene-3,4-dipyridine] -1-oxide,  1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4, -piperidine],  1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophene-1 (3H), 4, -piperidine] -2-oxide,  1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(1,4-dihydro-2H-isoquinolin-3-one) -1,4, -piperidine],  1- [2-bis (4-fluorophenyl) methoxhetyl] spiro [(indane) -1,4, -pyridine],  1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [(indane-1-one) -3,4piperidine],  1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(2-hydroxy) indane-1,4-piperidine],.  2- [1- [2-bis (4-fluorophenyl) methoxethyl] -piperidin-4-yl] propionic acid ethyl ester,  1- [2-bis (4-fluorophenyl) methoxethyl] -piperidine-4-ylidene] -p-methyl pionate,  1- [2-bis (4-fluorophenyl) methoxethyl] piperidine-4-carboxylic acid benzylamide,  1- [2-bis (4-fluorophenyl) methoxethyl] piperidine-4-ylideneacetate,  1- [2-bis (4-fluorophenyl) methoxethyl] -4-ethoxycarbonylpiperazine, 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4, -piperidine] -2,2-dioxide,. l- [2-bis (4-fluorophenyl) methoxethyl] spiro [isobenzofuran-1 (3H), 4, -piperidine], and  8- [2-Bis (4-chlorophenyl) methoxethyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one. ' 78. The pharmaceutical composition according to any one of claims 31 to 77, which promotes the production of IL-4. 79. The pharmaceutical composition according to any one of claims 31 to 77, which promotes the production of IL-10. 80. The pharmaceutical composition according to any one of claims 31 to 77 for prevention or treatment of an autoimmune disease. 81. The compound according to any one of claims 31 to 77 for producing a pharmaceutical composition for selectively suppressing the immune activity of TH1 cells, wherein the compound is pharmacologically acceptable. Use of salts, esters or other derivatives thereof. '