JP2005097125A - Medicine comprising oxazolidinone derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine comprising a compound having excellent TH1 selective immunosuppressive actions, its pharmacologically acceptable salt, an ester or other derivatives thereof. <P>SOLUTION: This medicine comprises an oxazolidinone derivative of formula (I) (wherein, R<SP>1</SP>and R<SP>2</SP>are each a substituted phenyl group; R<SP>3</SP>and R<SP>4</SP>are each hydrogen atom or a lower alkyl group, R<SP>5</SP>is a lower alkyl group, a lower alkylsulfinyl-lower alkyl group or a lower alkylsulfonyl-lower alkyl group; and (n) is an integer of 1-6), its pharmacologically acceptable salt, the ester or other derivatives thereof. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an oxazolidinone derivative having an inhibitory action on Th1 cell immune activity, a pharmacologically acceptable salt thereof, an ester or other derivative thereof, and a medicament containing them as an active ingredient.

  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 reactions. However, these are symptomatic treatments and not fundamental treatments.

  In addition, it has been reported that abnormalities of the immune system are involved in the onset of diabetes and nephritis (Non-patent Documents 1 and 2), but no drug has been developed to improve the abnormality.

  Helper T cells that play a central role in the immune response are two different subsets: type 1 helper T cells (hereinafter abbreviated as Th1 cells) and type 2 helper T cells (hereinafter abbreviated as Th2 cells). .)are categorized.

  Th1 cells produce cytokines such as interleukin 2 (hereinafter abbreviated as IL-2), interferon-γ (hereinafter abbreviated as IFN-γ), TNF-α, and are mainly involved in cellular immunity. On the other hand, Th2 cells produce cytokines such as interleukin 4 (hereinafter abbreviated as IL-4) and interleukin 10 (hereinafter abbreviated as IL-10), and are mainly involved in humoral immunity (non-). Patent Document 3). IFN-γ produced by Th1 cells 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 the living body.

  In recent years, it has become clear that abnormal balance of Th1 / Th2 cells is involved in the development of various immune-related diseases. The balance bias toward Th1 cells is due to rheumatoid arthritis, which is a chronic inflammatory disease, and organ-specific autoimmune diseases [eg, diabetes, multiple sclerosis, inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease) , Glomerulonephritis, hepatitis, liver damage, autoimmune hemolytic anemia, leukopenia, thrombocytopenia, allergic encephalitis, demyelinating disease, Hashimoto's thyroiditis, Addison's disease, hypoparathyroidism, pernicious anemia, Localized ileitis, atrophic gastritis, gluten intolerant enteropathy, Good Pasteur syndrome, post-streptococcal nephritis, myasthenia gravis, rheumatic fever, viral cardiomyopathy, uveitis, sympathetic ophthalmitis, vulgaris Pemphigus, bullous pemphigoid, psoriasis], and balance bias to Th2 cells has been reported to be involved in allergic diseases and systemic autoimmune diseases (Non-Patent Document 4, Non-Patent Document 5, Non-patent Document 6, Non-patent Document 7, Non-patent Document 8, Non-patent Document 9). Regarding immune-related diseases, the involvement of various cytokines produced by helper T cells for each disease state has been proven, and inducing or suppressing the production of these cytokines is considered to be effective in the treatment of immune-related diseases. It is done.

  In the studies up to now, for example, 1,25-dihydroxyvitamin D3 is known as a compound having an action of increasing IL-4 in the body, but its action is considered to be indirect ( Non-patent document 10). Gold and D-penicillamine are also known to have similar actions, but it has not been proved whether these actions are weak and direct IL-4 production-inducing actions (Non-patent Document 11). .

  On the other hand, as a compound having an action of increasing IL-10 in the body, for example, 2,4-dinitrochlorobenzene is known, but this action has also been proved to be a direct IL-10 production inducing action. (Non-patent document 12).

  From such a background, an attempt has been made to find a compound having an action of selectively inducing production of IL-4 and / or IL-10.

For example, Patent Document 1 discloses a compound having an action of selectively inducing production of IL-4 and / or IL-10. Although this document discloses a compound having a 1-oxa-3,8-diazaspiro [4.5] decan-2-one skeleton, the compound having a specific substituent in the skeleton is specifically described. Not disclosed.
Kidney International, 51, 94 (1997) Journal of Immunology, 157, 4691 (1996) Journal of Immunology, 136, 2348-2357 (1986) Immunol. Today, 16, 34-38 (1995) Science, 260, 547-549 (1993) Immunity, 3, 171-174 (1995) J. Exp. Med., 190, 995-1003 (1999) Kidney International, 52, 52-59 (1997) J. Exp. Med., 185, 65-70 (1997) Journal of Immunology, 160, 5314 (1998) Clinical Experimental Immunology, 438, 108 (1997) Immunology, 89, 502 (1996) JP 2001-11050 A

  The present inventors have conducted extensive research on derivatives having an action of selectively inducing the production of IL-4 and / or IL-10 produced from Th2 cells and selectively suppressing the immune activity of Th1 cells. As a result, the oxazolidinone derivative of the present invention has an excellent IL-4 and / or IL-10 production-inducing action, rheumatoid arthritis that is a chronic inflammatory disease, and organ-specific autoimmune diseases [for example, diabetes, Multiple sclerosis, inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease), glomerulonephritis, hepatitis, liver damage, autoimmune hemolytic anemia, leukopenia, thrombocytopenia, allergic encephalitis, prolapse Myelopathy, Hashimoto's thyroiditis, Addison's disease, hypoparathyroidism, pernicious anemia, localized ileitis, atrophic gastritis, gluten intolerant enteropathy, Good Pasteur syndrome, streptococcal nephritis, myasthenia gravis Disease, rheumatic fever, wi Cardiomyopathy, uveitis, sympathetic ophthalmitis, pemphigus vulgaris, bullous pemphigus, psoriasis] (preferably rheumatoid arthritis or organ-specific autoimmune disease, most preferably ulcer The compound of the present invention is more water-soluble than conventional IL-4 and / or IL-10 production inducers. High, oral absorbability, rapid onset of action, high transferability to target organs or cells, low transferability to brain, weak side effects, wide safety range (concentration difference between drug efficacy and toxicity expression), The inventors have found that the pharmacokinetics are excellent (long plasma half-life, large AUC, low tissue accumulation, etc.), and the present invention has been completed.

(1) The present invention relates to the general formula (I)

General formula (II)

Or general formula (III)

[Where:
R ¹ and R ² are the same or different and each independently represent 1 to 3 phenyl groups substituted with any group selected from the substituent group a,
R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a lower alkyl group, or R ³ and R ⁴ together represent an ethylene group,
R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkylsulfinyl lower alkyl group, a lower alkylsulfonyl lower alkyl group, a lower alkyl group having 1 to 3 oxygen atoms in the carbon chain, or 1 to 3 in the carbon chain. 1 to 3 lower alkyl groups having a sulfur atom, a lower alkyl group having 1 to 3 nitrogen atoms in the carbon chain, and a group selected from the substituent group b, and 1 to 3 in the carbon chain A lower alkyl group having one oxygen atom, sulfur atom or nitrogen atom or a group having the formula —CO—R ⁷ (wherein R ⁷ represents a group selected from the substituent group b);
R ⁶ represents a lower alkyl group or a lower alkyl group having one oxygen atom in the carbon chain;
m represents an integer of 0 to 2,
n represents an integer of 1 to 6,
Substituent group a represents a group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a halogeno lower alkoxy group, a lower alkylthio group, a hydroxy group, an amino group, a nitro group, and a cyano group,
Substituent group b was substituted with 1 to 3 aryl groups, heteroaryl groups, aryl groups substituted with 1 to 3 groups selected from substituent group a, and groups selected from substituent group a. Represents a group consisting of heteroaryl groups;
However, when it has the general formula (I) and R ³ and R ⁴ simultaneously represent a hydrogen atom, R ⁵ is other than a hydrogen atom, a lower alkyl group and a lower alkyl group having one oxygen atom in the carbon chain. The group of is shown. ]
And a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient.

Preferably,
(2) In (1), a pharmaceutical comprising a compound having the general formula (I), a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(3) In (1), a pharmaceutical comprising a compound having the general formula (II), a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(4) In (1) or (3),
a pharmaceutical comprising a compound wherein m is 0 or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(5) In (1) or (3),
a pharmaceutical agent comprising a compound wherein m is an integer of 1 or 2 or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(6) In any one item selected from (1) to (5),
A pharmaceutical comprising a compound wherein R ³ and R ⁴ are hydrogen atoms, or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(7) In any one item selected from (1) to (5),
A pharmaceutical comprising a compound wherein R ³ and R ⁴ together are an ethylene group, or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(8) In any one item selected from (1) to (5),
A pharmaceutical comprising a compound wherein R ³ and R ⁴ are the same or different and are a lower alkyl group, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient,
(9) In any one item selected from (1) to (5),
A pharmaceutical comprising a compound wherein R ³ and R ⁴ are the same or different and are a C ₁ -C ₂ alkyl group, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient,
(10) In any one item selected from (1) to (5),
R ³ and R ⁴ are the same or different and are a methyl group or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient,
(11) In any one item selected from (1) to (10),
A pharmaceutical comprising a compound in which R ⁵ is a hydrogen atom or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(12) In any one item selected from (1) to (10),
A pharmaceutical comprising a compound wherein R ⁵ is a lower alkyl group or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(13) In any one item selected from (1) to (10),
A pharmaceutical comprising a compound wherein R ⁵ is a C ₁ -C ₄ alkyl group or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(14) In any one item selected from (1) to (10),
A pharmaceutical comprising a compound in which R ⁵ is a methyl or ethyl group or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(15) In any one item selected from (1) to (10),
A drug containing a compound wherein R ⁵ is a lower alkyl group having one oxygen atom in the carbon chain, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient,
(16) In any one item selected from (1) to (10),
A pharmaceutical comprising a compound wherein R ⁵ is a C ₁ -C ₄ alkyl group having one oxygen atom in the carbon chain or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient,
(17) In any one item selected from (1) to (10),
A pharmaceutical comprising a compound wherein R ⁵ is a C ₂ -C ₃ alkyl group having one oxygen atom in the carbon chain, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient,
(18) In any one item selected from (1) to (10),
A pharmaceutical comprising a compound wherein R ⁵ is a methoxymethyl group or a 2-methoxyethyl group, or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(19) In any one item selected from (1) to (10),
A pharmaceutical comprising a compound wherein R ⁵ is a lower alkylsulfinyl lower alkyl group or a lower alkylsulfonyl lower alkyl group, or a pharmaceutically acceptable salt, ester or other derivative thereof as an active ingredient,
(20) In any one item selected from (1) to (10),
A compound wherein R ⁵ is a C ₁ -C ₂ alkylsulfinyl C ₁ -C ₂ alkyl group or a C ₁ -C ₂ alkylsulfonyl C ₁ -C ₂ alkyl group, or a pharmacologically acceptable salt, ester or other thereof A medicament containing a derivative as an active ingredient,
(21) In any one item selected from (1) to (10),
A pharmaceutical comprising a compound wherein R ⁵ is a methylsulfinylmethyl group or a methylsulfonylmethyl group, or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(22) In any one item selected from (1) to (10),
R ⁵ represents a lower alkyl group having 2 or 3 oxygen atoms in the carbon chain, a lower alkyl group having 1 to 3 sulfur atoms in the carbon chain, and 1 to 3 nitrogen atoms in the carbon chain. A compound having 1 to 3 lower alkyl groups or a lower alkyl group having 1 to 3 oxygen, sulfur or nitrogen atoms in the carbon chain, or a pharmacological thereof A pharmaceutical comprising as an active ingredient an above-acceptable salt, ester or other derivative thereof,
(23) In any one item selected from (1) to (10),
R ⁵ represents a lower alkyl group having 2 or 3 oxygen atoms in the carbon chain, a lower alkyl group having 1 to 3 sulfur atoms in the carbon chain, or 1 to 3 nitrogen atoms in the carbon chain. A pharmaceutical comprising a compound having a lower alkyl group or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(24) In any one item selected from (1) to (10),
R ⁵ is a C ₁ -C ₄ alkyl group having 2 or 3 oxygen atoms in the carbon chain, a lower alkyl group having 1 to 3 sulfur atoms in the carbon chain, or 1 to 3 in the carbon chain Or a pharmacologically acceptable salt thereof, an ester or other derivative thereof, which is a C ₁ -C ₄ alkyl group having a nitrogen atom, as an active ingredient,
(25) In any one item selected from (1) to (10),
R ⁵ is a C ₂ -C ₃ alkyl group having 2 or 3 oxygen atoms in the carbon chain or a C ₁ -C ₄ alkyl group having ₁ to 3 sulfur atoms in the carbon chain or in the carbon chain 1 C ₂ -C ₃ alkyl group compound or a pharmacologically acceptable salt thereof having three nitrogen atoms, medicaments containing the esters or other derivatives as an active ingredient,
(26) In any one item selected from (1) to (10),
A pharmaceutical comprising a compound wherein R ⁵ is a C ₂ -C ₃ alkyl group having 1 to 3 sulfur atoms in the carbon chain, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient,
(27) In any one item selected from (1) to (10),
A pharmaceutical comprising a compound wherein R ⁵ is a methylthiomethyl group or a 2-methylthioethyl group, or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(28) In any one item selected from (1) to (10),
A compound in which R ⁵ is a group having the formula —CO—R ⁷ (wherein R ⁷ represents a group selected from substituent group b), or a pharmacologically acceptable salt thereof, an ester thereof, or the like A pharmaceutical comprising a derivative of
(29) In (28),
Effective compounds wherein R ⁷ is an aryl group, a heteroaryl group or an aryl group substituted by 1 to 3 groups selected from substituent group a, or a pharmacologically acceptable salt, ester or other derivative thereof A medicine containing as an ingredient,
(30) In (28),
A compound, a pharmacologically acceptable salt, ester or other derivative thereof, wherein R ⁷ is a phenyl group, a phenyl group, a furyl group, a thienyl group or a phenyl group substituted by 1 to 3 groups selected from the substituent group a A medicine containing as an active ingredient,
(31) In (28),
R ⁷ is a phenyl group, a furyl group, a thienyl group or 1 to 3 substituted phenyl groups (the substituent is a group selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group). Or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient,
(32) In (28),
R ⁷ is a phenyl group or 1 to 3 substituted phenyl groups (the substituent is a group selected from the group consisting of a fluorine atom, a chlorine atom, a C ₁ -C ₂ alkyl group and a lower alkoxy group. Or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient,
(33) In (28),
A pharmaceutical comprising a compound wherein R ⁷ is a phenyl group substituted with 1 to 3 lower alkoxy groups, or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(34) In (1), a pharmaceutical comprising a compound having the general formula (III), a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(35) In (34),
Effective compounds wherein R ⁶ is a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkyl group having one oxygen atom in the carbon chain, or a pharmacologically acceptable salt, ester or other derivative thereof A medicine containing as an ingredient,
(36) In (34),
Effective compounds wherein R ⁶ is a C ₁ -C ₂ alkyl group or a C ₂ -C ₃ alkyl group having one oxygen atom in the carbon chain, or a pharmacologically acceptable salt, ester or other derivative thereof A medicine containing as an ingredient,
(37) In (34),
A drug comprising as an active ingredient a compound wherein R ⁶ is a methyl group, an ethyl group, a methoxymethyl group or a 2-methoxyethyl group, or a pharmacologically acceptable salt thereof, an ester or other derivative thereof;
(38) In any one item selected from (1) to (37),
R ¹ and R ² are the same or different and are selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a C ₁ -C ₂ alkoxy group, a C ₁ -C ₂ alkylthio group, a nitro group, and a cyano group. Or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient, which is a phenyl group substituted by 1 to 3 groups with
(39) In any one item selected from (1) to (37),
A compound in which R ¹ and R ² are the same or different and each is a phenyl group substituted with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a nitro group and a cyano group Or a pharmacologically acceptable salt, an ester or other derivative thereof as an active ingredient,
(40) In any one item selected from (1) to (37),
R ¹ and R ² are the same or different and are 1 to 3 groups selected from the group consisting of a halogen atom, a C ₁ -C ₂ alkyl group, a halogeno C ₁ -C ₂ alkyl group, a nitro group, and a cyano group. A pharmaceutical comprising a compound having a substituted phenyl group or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(41) In any one item selected from (1) to (37),
R ¹ and R ² are the same or different and each is a phenyl group substituted with 1 to 3 groups selected from the group consisting of fluorine atom, chlorine atom, methyl group, trifluoromethyl group, nitro group and cyano group A pharmaceutical comprising a certain compound or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(42) In any one item selected from (1) to (37),
R ¹ and R ² are the same or different and are 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 3-nitro Phenyl, 3,4-dimethylphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-ditrifluoro A pharmaceutical comprising a compound which is a methylphenyl, 3-cyanophenyl or 4-cyanophenyl group or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(43) In any one item selected from (1) to (37),
A compound in which R ¹ and R ² are the same or different and are 3-fluorophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-cyanophenyl or 4-cyanophenyl group, or A pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(44) In any one item selected from (1) to (43),
a pharmaceutical comprising a compound wherein n is 2, or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(45) In any one item selected from (1) to (43),
a pharmaceutical comprising a compound wherein n is 3, or a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
(46) In (1),
8- {2- [bis- (4-fluorophenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- {2- [Bis (4-fluorophenyl) methoxy] ethyl} -spiro [(8-azabicyclo [3.2.1] octane) -3,5 '-(3-methylthiomethyl) -oxazolidine] -2'- on,
8- {3- [Bis (4-fluorophenyl) methoxy] propyl} -spiro [(8-azabicyclo [3.2.1] octane) -3,5 '-(3-methylthiomethyl) -oxazolidine] -2'- on,
8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylsulfinylmethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one ,
8- {2-[(4-Cyanophenyl) (4'-trifluoromethylphenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one ,
8- [3- (4-fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- [3- (3-trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- [3- (3-trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) propyl] -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2- on,
8- {2- [bis (3-trifluoromethylphenyl) methoxy] ethyl} -spiro [(8-azabicyclo [3.2.1] octane) -3,5'-oxazolidine] -2'-one,
8- [3- (3-cyanophenoxy) -3- (3-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- [3- (4-cyanophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- [3- (3-cyanophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- [3- (4-cyanophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- [3- (2-fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and
From 8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-ethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one Examples thereof include a pharmaceutical comprising a compound selected from the group consisting of the above or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient.

In the above formula, “lower alkyl group” in the definition of R ³ , R ⁴ , R ⁵ , R ⁶ and substituent group a is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t- Butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 1 to 6 carbon atoms such as 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl group a linear or branched alkyl group, in R ^3, R ⁴ and substituent group a, preferably a C ₁ -C ₄ alkyl group, more Preferably a C ₁ -C ₂ alkyl group, most preferably a methyl group, R ⁵ and R ^6, preferably a C ₁ -C ₄ alkyl group, more preferably, a C ₁ -C ₂ alkyl group, most preferably a methyl or ethyl group.

In the above formula, “lower alkylsulfinyl lower alkyl group” in the definition of R ⁵ is a group in which the “lower alkyl group” is bonded to a sulfinyl group (for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, Isobutylsulfinyl, s-butylsulfinyl, t-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl, 2-methylbutylsulfinyl, neopentylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl or isohexylsulfinyl group) Group ", for example, methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, isopropylsulfinylmethyl Butylsulfinylmethyl, isobutylsulfinylmethyl, s-butylsulfinylmethyl, t-butylsulfinylmethyl, pentylsulfinylmethyl, isopentylsulfinylmethyl, 2-methylbutylsulfinylmethyl, neopentylsulfinylmethyl, 1-ethylpropylsulfinylmethyl, hexylsulfinyl Methyl, isohexylsulfinylmethyl, 2- (methylsulfinyl) ethyl, 2- (ethylsulfinyl) ethyl, 2- (propylsulfinyl) ethyl, 2- (isopropylsulfinyl) ethyl, 2- (butylsulfinyl) ethyl, 2- ( Isobutylsulfinyl) ethyl, 2- (s-butylsulfinyl) ethyl, 2- (t-butylsulfinyl) ethyl, 2- (pentylsulfinyl) ethyl 2- (isopentylsulfinyl) ethyl, 2- (2-methylbutylsulfinyl) ethyl, 2- (neopentylsulfinyl) ethyl, 2- (1-ethylpropylsulfinyl) ethyl, 2- (hexylsulfinyl) ethyl, 2- (isohexylsulfinyl) ethyl, 3- (methylsulfinyl) propyl, 3- (ethylsulfinyl) propyl or 3- (propylsulfinyl) propyl group, preferably C ₁ -C ₄ alkylsulfinyl C _1- A C ₄ alkyl group, more preferably a C ₁ -C ₂ alkylsulfinyl C ₁ -C ₂ alkyl group, and most preferably a methylsulfinylmethyl group or a 2- (methylsulfinyl) ethyl group.

In the above formula, the “lower alkylsulfonyl lower alkyl group” in the definition of R ⁵ is a group in which the “lower alkyl group” is bonded to a sulfonyl group (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, Isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, 2-methylbutylsulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl or isohexylsulfonyl group) is the above-mentioned “lower alkyl”. Group '', for example, methylsulfonylmethyl, ethylsulfonylmethyl, propylsulfonylmethyl, isopropylsulfonylmethyl, butylsulfonylmethyl, isobutylsulfo Methyl, s-butylsulfonylmethyl, t-butylsulfonylmethyl, pentylsulfonylmethyl, isopentylsulfonylmethyl, 2-methylbutylsulfonylmethyl, neopentylsulfonylmethyl, 1-ethylpropylsulfonylmethyl, hexylsulfonylmethyl, isohexylsulfonylmethyl 2- (methylsulfonyl) ethyl, 2- (ethylsulfonyl) ethyl, 2- (propylsulfonyl) ethyl, 2- (isopropylsulfonyl) ethyl, 2- (butylsulfonyl) ethyl, 2- (isobutylsulfonyl) ethyl, 2 -(S-butylsulfonyl) ethyl, 2- (t-butylsulfonyl) ethyl, 2- (pentylsulfonyl) ethyl, 2- (isopentylsulfonyl) ethyl, 2- (2-methylbutylsulfonyl) ethyl 2- (Neopentylsulfonyl) ethyl, 2- (1-ethylpropylsulfonyl) ethyl, 2- (hexylsulfonyl) ethyl, 2- (isohexylsulfonyl) ethyl, 3- (methylsulfonyl) propyl, 3- (ethyl sulfonyl) propyl or 3- (propyl-sulfonyl) propyl group, preferably a C ₁ -C ₄ alkylsulfonyl C ₁ -C ₄ alkyl group, more preferably, C ₁ -C ₂ alkylsulfonyl C ₁ a -C ₂ alkyl group, and most preferably a methylsulfonylmethyl group or 2- (methylsulfonyl) ethyl.

In the above formula, the “lower alkyl group having 1 to 3 oxygen atoms in the carbon chain” in the definition of R ⁵ is a group having 1 to 3 oxygen atoms in the carbon chain of the lower alkyl group (carbon chain end). Does not include a group having an oxygen atom.), For example, methoxymethyl, 2-methoxyethyl, 2-methoxypropyl, 3-methoxybutyl, ethoxymethyl, 2- (ethoxy) ethyl, 2- (ethoxy) A lower alkyl group having one oxygen atom in the carbon chain, such as propyl, 3- (ethoxy) butyl, propoxymethyl, 2- (propoxy) ethyl or 2- (propoxy) propyl group, 2- (methoxy) ethoxy A lower alkyl group having two oxygen atoms in the carbon chain, such as methyl, 2- (ethoxy) ethoxymethyl or 2- [2- (methoxy) ethoxy] ethyl group; A lower alkyl group having three oxygen atoms in the carbon chain, such as a [2- (methoxy) ethoxy] ethoxymethyl or 2- {2- [2- (methoxy) ethoxy] ethoxy} ethyl group; Preferred is a C ₁ -C ₄ alkyl group having ₁ to 3 oxygen atoms in the carbon chain, and more preferred is a C ₂ -C ₃ having 1 to 3 oxygen atoms in the carbon chain. an alkyl group, a C ₂ -C ₃ alkyl groups having one oxygen atom in the carbon chain, and most preferably a methoxymethyl group or a 2-methoxyethyl group.

In the above formula, the “lower alkyl group having 1 to 3 sulfur atoms in the carbon chain” in the definition of R ⁵ is a group having 1 to 3 sulfur atoms in the carbon chain of the lower alkyl group (carbon chain end). Does not include a group having a sulfur atom.), For example, methylthiomethyl, 2-methylthioethyl, 2-methylthiopropyl, 3-methylthiobutyl, ethylthiomethyl, 2- (ethylthio) ethyl, 2- (ethylthio) ) A lower alkyl group having one sulfur atom in the carbon chain such as propyl, 3- (ethylthio) butyl, ethylthiomethyl, 2- (ethylthio) ethyl or 2- (ethylthio) propyl group, 2- (methylthio) ) Two sulfur atoms in the carbon chain such as ethylthiomethyl, 2- (ethylthio) ethylthiomethyl or 2- [2- (methylthio) ethylthio] ethyl groups 3 sulfur atoms in the carbon chain such as a lower alkyl group having a 2- [2- (methylthio) ethylthio] ethylthiomethyl or 2- {2- [2- (methylthio) ethylthio] ethylthio} ethyl group A lower alkyl group, preferably a C ₁ -C ₄ alkyl group having ₁ to 3 sulfur atoms in the carbon chain, more preferably 1 to 3 sulfur atoms in the carbon chain. a C ₂ -C ₃ alkyl groups having a C ₂ -C ₃ alkyl groups having one sulfur atom in the carbon chain, and most preferably a methylthiomethyl group or a 2-methylthioethyl group.

In the above formula, the “lower alkyl group having 1 to 3 nitrogen atoms in the carbon chain” in the definition of R ⁵ is a group having 1 to 3 nitrogen atoms in the carbon chain of the lower alkyl group (carbon chain end). Does not include a group having a nitrogen atom.), For example, methylaminomethyl, 2-methylaminoethyl, 2-methylaminopropyl, 3-methylaminobutyl, ethylaminomethyl, 2- (ethylamino) ethyl 1 nitrogen atom in a carbon chain such as 2-, ethylamino) propyl, 3- (ethylamino) butyl, ethylaminomethyl, 2- (ethylamino) ethyl or 2- (ethylamino) propyl group. A lower alkyl group having two nitrogen atoms in a carbon chain such as a [2- (methylamino) ethyl] aminomethyl or 2- [2- (methylamino) ethyl] aminoethyl group A lower alkyl group having three groups in a carbon chain such as 2- [2- (methylamino) ethylamino] ethylaminomethyl or 2- {2- [2- (methylamino) ethylamino] ethylamino} ethyl group A lower alkyl group having 1 to 3 nitrogen atoms, preferably a C ₁ -C ₄ alkyl group having ₁ to 3 nitrogen atoms in the carbon chain, and more preferably 1 to 3 in the carbon chain. a C ₂ -C ₃ alkyl groups having a number of nitrogen atoms, a C ₂ -C ₃ alkyl groups having one nitrogen atom in the carbon chain, most preferably, methyl aminomethyl group or 2-methyl An aminoethyl group.

In the above formula, “lower alkyl group substituted with 1 to 3 groups selected from substituent group b and having 1 to 3 oxygen, sulfur or nitrogen atoms in the carbon chain” in the definition of R ⁵ Is the “lower alkyl group having 1 to 3 oxygen atoms in the carbon chain”, the “lower alkyl group having 1 to 3 sulfur atoms in the carbon chain” or the “lower alkyl group having 1 to 3 sulfur atoms in the carbon chain”. “A lower alkyl group having three nitrogen atoms” represents a group in which 1 to 3 groups selected from the substituent group b are substituted, such as 4-methoxybenzyloxymethyl, 4-methylthiobenzyloxymethyl, 4- Dimethylaminobenzyloxymethyl or 2- (4-methoxybenzyloxy) ethyl group.

In the above formula, the “lower alkyl group having one oxygen atom in the carbon chain” in the definition of R ⁶ is the “carbon chain of the lower alkyl group having 1 to 3 oxygen atoms in the carbon chain”. It has the same meaning as the “lower alkyl group having one oxygen atom”.

  In the above formula, the “halogen atom” in the definition of the substituent group a is a fluorine, chlorine, bromine or iodine atom, preferably a fluorine atom or a chlorine atom, and most preferably a fluorine atom.

In the above formula, the “halogeno lower alkyl group” in the definition of the substituent group a represents a group in which a halogen atom is substituted on the “lower alkyl group”, and examples thereof include trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, Dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4 A halogeno C ₁ -C ₆ alkyl group such as -fluorobutyl, 6-iodohexyl or 2,2-dibromoethyl group, preferably a halogeno C ₁ -C ₄ alkyl group, more preferably a halogeno C ₁ -C ₂ alkyl group, and more preferably, fluoro C ₁ -C ₂ alkyl group or chloro C ₁ -C ₂ alkyl group Ri, and most preferably a trifluoromethyl group.

In the above formula, the “lower alkoxy group” in the definition of the substituent group a represents a group in which the “lower alkyl group” is bonded to an oxygen atom. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, -Butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethylpropoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3 1 to 6 carbon atoms such as 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy group a linear or branched alkoxy group, preferably a C ₁ -C ₄ alkoxy group, Preferably the a C ₁ -C ₂ alkoxy group, most preferably a methoxy group.

In the above formula, the “halogeno lower alkoxy group” in the definition of the substituent group a represents a group in which a halogen atom is substituted on the “lower alkoxy group”, and examples thereof include trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, Dibromomethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 2-bromoethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2-iodoethoxy, 3-chloroprolo A halogeno C ₁ -C ₆ alkoxy group such as poxy, 4-fluorobutoxy, 6-iodohexyloxy or 2,2-dibromoethoxy group, preferably a halogeno C ₁ -C ₄ alkoxy group More preferably a halogeno C ₁ -C ₂ alkoxy group, more preferably fluoro C ₁ A —C ₂ alkoxy group or a chloro C ₁ -C ₂ alkoxy group, and most preferably a trifluoromethoxy group.

In the above formula, the “lower alkylthio group” in the definition of the substituent group a represents a group in which the “lower alkyl group” is bonded to a sulfur atom. For example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-Butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3-dimethylbutyl 1 to 6 carbon atoms such as thio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio or 2,3-dimethylbutylthio group a number of straight-chain or branched alkylthio group, preferably a C ₁ -C ₄ alkylthio groups More preferably a C ₁ -C ₂ alkylthio group, and most preferably a methylthio group.

  In the above formula, the aryl moiety of the “aryl group” and the “aryl group substituted with 1 to 3 groups selected from the substituent group a” in the definition of the substituent group b is, for example, An aromatic hydrocarbon group having 6 to 10 carbon atoms such as phenyl, indenyl or naphthyl, preferably a phenyl or naphthyl group, and most preferably a phenyl group.

  In the above formula, the heteroaryl moiety of the “heteroaryl group” in the definition of the substituent group b and the “heteroaryl group substituted with 1 to 3 groups selected from the substituent group a” is a sulfur atom, A 5- to 7-membered aromatic heterocyclic group containing 1 to 3 oxygen atoms and / or nitrogen atoms, such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2 , 3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, and the heteroaryl group may be another cyclic group such as a benzene ring. For example, benzothienyl, benzothiazolyl, benzoxazo Le, a group such as isobenzofuranyl, quinolinyl, indolyl or isoindolyl group, preferably, 5 to 6-membered heteroaryl - a group, most preferably a furyl or thienyl group.

In the above formula, specific examples of the “phenyl group independently substituted with one to three arbitrary groups selected from the substituent group a” in the definition of R ¹ and R ² include 2-fluorophenyl, 3 -Fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-methylthiophenyl, 3- Methylthiophenyl, 4-methylthiophenyl, 2-nitropheny 3-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3, 4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-ditrifluoromethylphenyl 2,4-ditrifluoromethylphenyl, 2,5-ditrifluoromethylphenyl, 3,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 3,4,5-trifluorophenyl, 3,4 , 5-trichlorophenyl, 2,4-dimethoxyphenyl or 3,5 A dimethoxyphenyl group, preferably a halogen atom, a lower alkyl group, a halogeno-lower alkyl group, halogeno C ₁ -C ₂ alkoxy group, C ₁ -C ₂ alkoxy group, C ₁ -C ₂ alkylthio group, a nitro group and A phenyl group substituted by 1 to 3 groups selected from the group consisting of cyano groups, more preferably selected from the group consisting of halogen atoms, lower alkyl groups, halogeno lower alkyl groups, nitro groups and cyano groups 1 to 3 substituted phenyl groups, and more preferably from the group consisting of halogen atoms, C ₁ -C ₂ alkyl groups, halogeno C ₁ -C ₂ alkyl groups, nitro groups, and cyano groups. A phenyl group substituted with 1 to 3 selected groups, and even more preferably a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a nitro group and a cyano group. A phenyl group substituted by 1 to 3 groups selected from the group consisting of 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3 -Methylphenyl, 3-trifluoromethylphenyl, 3-nitrophenyl, 3,4-dimethylphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl 3,5-difluorophenyl, 3,5-ditrifluoromethylphenyl, 3-cyanophenyl or 4-cyanophenyl group, most preferably 3-fluorophenyl, 4-fluorophenyl, 3-trifluoromethyl. Phenyl, 4-trifluoromethylphenyl, 3-cyanophenyl or 4-sia A phenyl group.

In the above formula, the “aryl group independently substituted with one to three arbitrary groups selected from the substituent group a” in the definition of the substituent group b is, for example, selected from the above-mentioned “substituent group a” 1 to 3 independently substituted phenyl groups by any group ", 5-fluoroinden-3-yl, 5-chloroinden-3-yl, 5-methylinden-3-yl, 5-methoxyindene-3 -Yl, 5-fluoroinden-2-yl, 5-chloroinden-2-yl, 5-methylinden-2-yl, 5-methoxyinden-2-yl, 5-fluoronaphthalen-2-yl, 5- Chloronaphthalen-2-yl, 5-methylnaphthalen-2-yl, 5-methoxynaphthalen-2-yl, 5-fluoronaphthalen-1-yl, 5-chloronaphthalen-1-yl, 5-methylnaphthalene 1-yl, 5-methoxynaphthalen-1-yl, 5-hydroxyinden-3-yl, 5-hydroxynaphthalen-2-yl or 5-hydroxynaphthalen-1-yl, preferably a group of substituents a phenyl group substituted by 1 to 3 groups with a group selected from a, more preferably a phenyl group substituted by 1 to 3 (the substituent is a halogen atom, a lower alkyl group or a lower alkoxy group; And more preferably 1 to 3 substituted phenyl groups (the substituent is a fluorine atom, a chlorine atom, a C ₁ -C ₂ alkyl group and a lower alkoxy group). A group selected from the group consisting of groups), and most preferably a phenyl group substituted by 1 to 3 lower alkoxy groups.

  “Pharmaceutically acceptable salt thereof” means that a compound having the general formula (I), (II) or (III) of the present invention has a basic group such as an amino group and is reacted with an acid. The salt, its ester or other derivative is shown.

  Such salts are preferably hydrofluoride, hydrochloride, hydrobromide, hydrohalide such as hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfonic acids such as benzene sulfonate and p-toluene sulfonate Salt, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate and other organic acid salts; and glycine salt, lysine salt, Amino acid salts such as arginine salt, ornithine salt, glutamate, aspartate can be mentioned, most preferably inorganic acid salt or organic acid salt (particularly preferably fumarate salt or maleate salt) ) .

  The compounds having the general formula (I), (II) or (III) of the present invention, pharmacologically acceptable salts, esters or other derivatives thereof have various asymmetric carbon atoms in the molecule. It has the isomer. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, ie the general formula (I), (II) or (III). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.

  The compound having the general formula (I), (II) or (III) of the present invention, a pharmacologically acceptable salt thereof, an ester or other derivative thereof should be left in the atmosphere or recrystallized. By absorbing water, adsorbed water may be attached or a hydrate may be formed, and such a hydrate is also included in the salt of the present invention.

  The “ester” in the above indicates the ester of the compound (I), (II) or (III) of the present invention, since it has a hydroxy group and can be esterified. Refers to 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 a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis.

  As the “general protecting group” for “ester of hydroxy group”, preferably formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, Alkaline such as 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, icosanoyl, heinacosanoyl Yl group, halogenated alkylcarbonyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, alkoxyalkylcarbonyl group such as methoxyacetyl, acryloyl, propioroyl, methacryloyl, crotonoyl, isocrotonoyl, (E) -2- A “substituted lower aliphatic acyl group” such as an unsaturated alkylcarbonyl group such as methyl-2-butenoyl (preferably a lower aliphatic acyl group having 1 to 6 carbon atoms); benzoyl, α- Naphthoyl, arylcarbonyl groups such as β-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl, lower groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl An alkylated arylcarbonyl group, 4- Lower alkoxylated arylcarbonyl groups such as nisoyl, 4-nitrobenzoyl, nitrated arylcarbonyl groups such as 2-nitrobenzoyl, lower alkoxycarbonylated aryls such as 2- (methoxycarbonyl) benzoyl “Substituted aromatic acyl group” such as carbonyl group, arylated arylcarbonyl group such as 4-phenylbenzoyl; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxy Lower alkoxycarbonyl substituted by lower alkoxycarbonyl group such as carbonyl, isobutoxycarbonyl, halogen such as 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or tri-lower alkylsilyl group An “alkoxycarbonyl group” such as a group; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran “Tetrahydropyranyl or tetrahydrothiopyranyl group” such as -4-yl; “tetrahydrofuranyl or tetrahydrothiofuranyl group” such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl , Tri-lower alkylsilyl groups such as isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, “Silyl group” such as lower alkylsilyl group substituted by 1 to 2 aryl groups such as diphenylisopropylsilyl, phenyldiisopropylsilyl; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl , Propoxymethyl, isopropoxymethyl, butoxymethyl, lower alkoxymethyl groups such as t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis “Alkoxymethyl groups” such as halogeno lower alkoxymethyl such as (2-chloroethoxy) methyl; lower alkoxylated ethyl groups such as 1-ethoxyethyl, 1- (isopropoxy) ethyl, 2,2,2-trichloro Such as ethyl halide groups such as ethyl Ethyl group "; substituted with 1 to 3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl Lower alkyl group, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4 -Substituted with 1 to 3 aryl groups in which the aryl ring is substituted with lower alkyl, lower alkoxy, nitro, halogen, cyano groups such as chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl “Aralkyl groups” such as lower alkyl groups; “aralkyl groups” such as vinyloxycarbonyl and allyloxycarbonyl 1 to 2 lower groups such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl An “aralkyloxycarbonyl group” in which the aryl ring may be substituted with an alkoxy or nitro group, preferably a substituted lower aliphatic acyl group.

“Protecting group that can be cleaved in vivo by a biological method such as hydrolysis” means a protecting group that is cleaved by a biological method such as hydrolysis in the human body to produce a free acid or a salt thereof. Whether it is a derivative or not, it is administered intravenously to laboratory animals such as rats and mice, and then the body fluids of the animals are examined to detect the original compound or a pharmacologically acceptable salt thereof. You can decide what you can,
As the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis”, “formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxy” is preferable. Methyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryl Oxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1 Pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivalo 1-("lower aliphatic acyl" oxy such as 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl ) “Lower alkyl group”, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxy 1-("cycloalkyl" carbonyloxy) "lower alkyl" such as propyl, 1-cyclopentylcarbonyloxybutyl, 1-cyclohexylcarbonyloxybutyl, 1-("aromatic acyl" oxy) such as benzoyloxymethyl 1- (acyloxy) “lower alkyl group” such as “lower alkyl group”; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, Pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (Isobutoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- (pentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1 -(Cyclopentyloxycarbonyloxy) propyl, 1- (cyclohexyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cycl Hexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) ) Propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1- (isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutene) (Lower alkoxycarbonyloxy) such as 1- (methoxycarbonyloxy) pentyl, 1- (methoxycarbonyloxy) hexyl, 1- (ethoxycarbonyloxy) hexyl An alkyl group; (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolen-4-yl] Methyl, [5- (4-chlorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, (2-oxo-1, 3-Dioxolen-4-yl) methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl) Methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-butyl-2) An oxodioxolenylmethyl group such as -oxo-1,3-dioxolen-4-yl) methyl; a "carbonyloxy lower alkyl group" such as; a "phthalidyl group such as phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl"; “Substituted lower aliphatic acyl group”; “Substituted aromatic acyl group”; “Succinic acid half ester residue”; “Phosphate salt residue”: “Amino acid etc.” A carbamoyl group; a carbamoyl group substituted with 1 to 2 lower alkyl groups; and a “1- (acyloxy) alkyloxycarbonyl group” such as pivaloyloxymethyloxycarbonyl; A substituted lower aliphatic acyl group or a succinic acid half ester salt residue is preferred.

  “Other derivative” refers to a derivative other than the above “pharmacologically acceptable salt” and the “ester thereof” when the compound (I), (II) or (III) of the present invention has an amino group. Derivatives are shown. Examples of such derivatives include amide derivatives such as lower alkylcarbonylamino, arylcarbonylamino or heteroarylcarbonylamino groups.

  Specific examples of the compound having the general formula (I), (II) or (III) of the present invention include, for example, compounds described in Tables 1 to 3 below. It is not limited to compounds. In addition, the compound of Table 1, Table 2, and Table 3 has structural formula of Formula (I), (II), and (III), respectively.

Furthermore, the abbreviations in the table are as follows.
Et: ethyl group;
Me: methyl group;
Ph: phenyl group;
Fur (2): Furan-2-yl group;
Fur (3): furan-3-yl group;
Thi (2): a thiophen-2-yl group;
Thi (3): a thiophen-3-yl group.
(Table 1)

No. R ¹ R ² R ³ R ⁴ R ⁵ n

1-1 3-F-Ph 3-F-Ph HH -CH ₂ -SOMe 2
1-2 3-F-Ph 3-F-Ph HH-(CH ₂ ) ₂ -SOMe 2
1-3 3-F-Ph 3-F-Ph HH -CH ₂ -SOMe 3
1-4 3-F-Ph 3-F-Ph HH-(CH ₂ ) ₂ -SOMe 3
1-5 3-F-Ph 3-F-Ph HH -CH ₂ -SO ₂ Me 2
1-6 3-F-Ph 3-F-Ph HH-(CH ₂ ) ₂ -SO ₂ Me 2
1-7 3-F-Ph 3-F-Ph HH -CH ₂ -SO ₂ Me 3
1-8 3-F-Ph 3-F-Ph HH-(CH ₂ ) ₂ -SO ₂ Me 3
1-9 3-F-Ph 3-F-Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 2
1-10 3-F-Ph 3-F-Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 3
1-11 3-F-Ph 3-F-Ph HH -CH ₂ -SMe 2
1-12 3-F-Ph 3-F-Ph HH -CH ₂ -SMe 3
1-13 3-F-Ph 3-F-Ph HH-(CH ₂ ) ₂ -SMe 2
1-14 3-F-Ph 3-F-Ph HH-(CH ₂ ) ₂ -SMe 3
1-15 3-F-Ph 3-F-Ph HH -CH ₂ -NHMe 2
1-16 3-F-Ph 3-F-Ph HH -CH ₂ -NHMe 3
1-17 3-F-Ph 3-F-Ph HH -CO-Ph 2
1-18 3-F-Ph 3-F-Ph HH -CO-Ph 3
1-19 3-F-Ph 3-F-Ph HH -CO- (2-MeO-Ph) 2
1-20 3-F-Ph 3-F-Ph HH -CO- (2-MeO-Ph) 3
1-21 3-F-Ph 3-F-Ph HH -CO- (3-MeO-Ph 2
1-22 3-F-Ph 3-F-Ph HH -CO- (3-MeO-Ph) 3
1-23 3-F-Ph 3-F-Ph HH -CO- (4-MeO-Ph) 2
1-24 3-F-Ph 3-F-Ph HH -CO- (4-MeO-Ph) 3
1-25 3-F-Ph 3-F-Ph HH -CO- (2,4-diMeO-Ph) 2
1-26 3-F-Ph 3-F-Ph HH -CO- (2,4-diMeO-Ph) 3
1-27 3-F-Ph 3-F-Ph HH -CO-Fur (2) 2
1-28 3-F-Ph 3-F-Ph HH -CO-Fur (2) 3
1-29 3-F-Ph 3-F-Ph HH -CO-Fur (3) 2
1-30 3-F-Ph 3-F-Ph HH -CO-Fur (3) 3
1-31 3-F-Ph 3-F-Ph HH -CO-Thi (2) 2
1-32 3-F-Ph 3-F-Ph HH -CO-Thi (2) 3
1-33 3-F-Ph 3-F-Ph HH -CO-Thi (3) 2
1-34 3-F-Ph 3-F-Ph HH -CO-Thi (3) 3
1-35 3-F-Ph 3-F-Ph Me Me H 2
1-36 3-F-Ph 3-F-Ph Me Me H 3
1-37 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ -H 2
1-38 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ -H 3
1-39 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CH ₂ -SMe 2
1-40 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CH ₂ -SMe 3
1-41 3-F-Ph 3- F-Ph - (CH 2) 2 - - (CH 2) 2 -SMe 2
1-42 3-F-Ph 3- F-Ph - (CH 2) 2 - - (CH 2) 2 -SMe 3
1-43 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CO-Ph 2
1-44 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CO-Ph 3
1-45 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CO- (2-MeO-Ph) 2
1-46 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CO- (2-MeO-Ph) 3
1-47 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CO-Fur (2) 2
1-48 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CO-Fur (2) 3
1-49 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CO-Thi (2) 2
1-50 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CO-Thi (2) 3
1-51 4-F-Ph 4-F-Ph HH -CH ₂ -SOMe 2
1-52 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -SOMe 2
1-53 4-F-Ph 4-F-Ph HH -CH ₂ -SOMe 3
1-54 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -SOMe 3
1-55 4-F-Ph 4-F-Ph HH -CH ₂ -SO ₂ Me 2
1-56 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -SO ₂ Me 2
1-57 4-F-Ph 4-F-Ph HH -CH ₂ -SO ₂ Me 3
1-58 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -SO ₂ Me 3
1-59 4-F-Ph 4-F-Ph HH -CH ₂ -O- (CH ₂ ) ₂ -Ome 2
1-60 4-F-Ph 4-F-Ph HH -CH ₂ -O- (CH ₂ ) ₂ -Ome 3
1-61 4-F-Ph 4-F-Ph HH -CH ₂ -SMe 2
1-62 4-F-Ph 4-F-Ph HH -CH ₂ -SMe 3
1-63 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -SMe 2
1-64 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -SMe 3
1-65 4-F-Ph 4-F-Ph HH -CH ₂ -NHMe 2
1-66 4-F-Ph 4-F-Ph HH -CH ₂ -NHMe 3
1-67 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -NHMe 2
1-68 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -NHMe 3
1-69 4-F-Ph 4-F-Ph HH -CO-Ph 2
1-70 4-F-Ph 4-F-Ph HH -CO-Ph 3
1-71 4-F-Ph 4-F-Ph HH -CO- (2-MeO-Ph) 2
1-72 4-F-Ph 4-F-Ph HH -CO- (2-MeO-Ph) 3
1-73 4-F-Ph 4-F-Ph HH -CO- (3-MeO-Ph) 2
1-74 4-F-Ph 4-F-Ph HH -CO- (3-MeO-Ph) 3
1-75 4-F-Ph 4-F-Ph HH -CO- (4-MeO-Ph) 2
1-76 4-F-Ph 4-F-Ph HH -CO- (4-MeO-Ph) 3
1-77 4-F-Ph 4-F-Ph HH -CO- (2,4-diMeO-Ph) 2
1-78 4-F-Ph 4-F-Ph HH -CO- (2,4-diMeO-Ph) 3
1-79 4-F-Ph 4-F-Ph HH -CO- (3,5-diMeO-Ph) 2
1-80 4-F-Ph 4-F-Ph HH -CO- (3,5-diMeO-Ph) 3
1-81 4-F-Ph 4-F-Ph HH -CO-Fur (2) 2
1-82 4-F-Ph 4-F-Ph HH -CO-Fur (2) 3
1-83 4-F-Ph 4-F-Ph HH -CO-Fur (3) 2
1-84 4-F-Ph 4-F-Ph HH -CO-Fur (3) 3
1-85 4-F-Ph 4-F-Ph HH -CO-Thi (2) 2
1-86 4-F-Ph 4-F-Ph HH -CO-Thi (2) 3
1-87 4-F-Ph 4-F-Ph HH -CO-Thi (3) 2
1-88 4-F-Ph 4-F-Ph HH -CO-Thi (3) 3
1-89 4-F-Ph 4-F-Ph Me Me H 2
1-90 4-F-Ph 4-F-Ph Me Me H 3
1-91 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ -H 2
1-92 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ -H 3
1-93 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CH ₂ -SMe 2
1-94 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CH ₂ -SMe 3
1-95 4-F-Ph 4- F-Ph - (CH 2) 2 - - (CH 2) 2 -SMe 2
1-96 4-F-Ph 4- F-Ph - (CH 2) 2 - - (CH 2) 2 -SMe 3
1-97 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CO-Ph 2
1-98 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CO-Ph 3
1-99 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CO- (2-MeO-Ph) 2
1-100 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CO- (2-MeO-Ph) 3
1-101 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CO-Fur (2) 2
1-102 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CO-Fur (2) 3
1-103 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CO-Thi (2) 2
1-104 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CO-Thi (2) 3
1-105 3-Cl-Ph 3-Cl-Ph HH -CH ₂ -SMe 2
1-106 3-Cl-Ph 3-Cl-Ph HH-(CH ₂ ) ₂ -SMe 2
1-107 3-Cl-Ph 3-Cl-Ph HH -CO-Ph 2
1-108 3-Cl-Ph 3-Cl-Ph HH -CO- (2-MeO-Ph) 2
1-109 3-Cl-Ph 3-Cl-Ph HH -CO-Fur (2) 2
1-110 3-Cl-Ph 3-Cl-Ph HH -CO-Thi (2) 2
1-111 3-Cl-Ph 3-Cl-Ph Me Me H 2
1-112 3-Cl-Ph 3-Cl-Ph-(CH ₂ ) ₂ -H 2
1-113 4-Cl-Ph 4-Cl-Ph HH -CH ₂ -SMe 2
1-114 4-Cl-Ph 4-Cl-Ph HH-(CH ₂ ) ₂ -SMe 2
1-115 4-Cl-Ph 4-Cl-Ph HH -CO-Ph 2
1-116 4-Cl-Ph 4-Cl-Ph HH -CO- (2-MeO-Ph) 2
1-117 4-Cl-Ph 4-Cl-Ph HH -CO-Fur (2) 2
1-118 4-Cl-Ph 4-Cl-Ph HH -CO-Thi (2) 2
1-119 4-Cl-Ph 4-Cl-Ph Me Me H 2
1-120 4-Cl-Ph 4-Cl-Ph-(CH ₂ ) ₂ -H 2
1-121 3-Me-Ph 3-Me-Ph HH -CH ₂ -SMe 2
1-122 3-Me-Ph 3-Me-Ph HH-(CH ₂ ) ₂ -SMe 2
1-123 3-Me-Ph 3-Me-Ph HH -CO-Ph 2
1-124 3-Me-Ph 3-Me-Ph HH -CO- (2-MeO-Ph) 2
1-125 3-Me-Ph 3-Me-Ph HH -CO-Fur (2) 2
1-126 3-Me-Ph 3-Me-Ph HH -CO-Thi (2) 2
1-127 3-Me-Ph 3-Me-Ph Me Me H 2
1-128 3-Me-Ph 3-Me-Ph-(CH ₂ ) ₂ -H 2
1-129 4-Me-Ph 4-Me-Ph HH -CH ₂ -SMe 2
1-130 4-Me-Ph 4-Me-Ph HH-(CH ₂ ) ₂ -SMe 2
1-131 4-Me-Ph 4-Me-Ph HH -CO-Ph 2
1-132 4-Me-Ph 4-Me-Ph HH -CO- (2-MeO-Ph) 2
1-133 4-Me-Ph 4-Me-Ph HH -CO-Fur (2) 2
1-134 4-Me-Ph 4-Me-Ph HH -CO-Thi (2) 2
1-135 4-Me-Ph 4-Me-Ph Me Me H 2
1-136 4-Me-Ph 4-Me-Ph-(CH ₂ ) ₂ -H 2
1-137 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -SOMe 2
1-138 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -SOMe 2
1-139 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -SOMe 3
1-140 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -SOMe 3
1-141 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -SO ₂ Me 2
1-142 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -SO ₂ Me 2
1-143 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -SO ₂ Me 3
1-144 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -SO ₂ Me 3
1-145 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 2
1-146 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 3
1-147 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -SMe 2
1-148 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -SMe 3
1-149 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -SMe 2
1-150 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -SMe 3
1-151 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -NHMe 2
1-152 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -NHMe 3
1-153 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -NHMe 2
1-154 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -NHMe 3
1-155 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -O-CH ₂ -Ph 2
1-156 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -O-CH ₂ -Ph 3
1-157 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -O-CH _2- (4-Cl-Ph) 2
1-158 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -O-CH _2- (4-Cl-Ph) 3
1-159 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Ph 2
1-160 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Ph 3
1-161 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (2-MeO-Ph) 2
1-162 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (2-MeO-Ph) 3
1-163 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (3-MeO-Ph) 2
1-164 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (3-MeO-Ph) 3
1-165 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (4-MeO-Ph) 2
1-166 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (4-MeO-Ph) 3
1-167 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (2,4-diMeO-Ph) 2
1-168 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (2,4-diMeO-Ph) 3
1-169 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Fur (2) 2
1-170 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Fur (2) 3
1-171 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Fur (3) 2
1-172 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Fur (3) 3
1-173 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Thi (2) 2
1-174 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Thi (2) 3
1-175 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Thi (3) 2
1-176 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Thi (3) 3
1-177 3-CF ₃ -Ph 3-CF ₃ -Ph Me Me H 2
1-178 3-CF ₃ -Ph 3-CF ₃ -Ph Me Me H 3
1-179 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ -H 2
1-180 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ -H 3
1-181 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CH ₂ -SMe 2
1-182 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CH ₂ -SMe 3
_{1-183 3-CF 3 -Ph 3-} CF 3 -Ph - (CH 2) 2 - - (CH 2) 2 -SMe 2
_{1-184 3-CF 3 -Ph 3-} CF 3 -Ph - (CH 2) 2 - - (CH 2) 2 -SMe 3
1-185 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Ph 2
1-186 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Ph 3
1-187 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CO- (2-MeO-Ph) 2
1-188 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CO- (2-MeO-Ph) 3
1-189 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Fur (2) 2
1-190 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Fur (2) 3
1-191 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Thi (2) 2
1-192 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Thi (2) 3
1-193 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -SOMe 2
1-194 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -SOMe 2
1-195 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -SOMe 3
1-196 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -SOMe 3
1-197 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -SO ₂ Me 2
1-198 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -SO ₂ Me 2
1-199 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -SO ₂ Me 3
1-200 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -SO ₂ Me 3
1-201 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 2
1-202 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 3
1-203 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -SMe 2
1-204 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -SMe 3
1-205 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -SMe 2
1-206 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -SMe 3
1-207 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -NHMe 2
1-208 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -NHMe 3
1-209 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -NHMe 2
1-210 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -NHMe 3
1-211 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Ph 2
1-212 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Ph 3
1-213 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (2-MeO-Ph) 2
1-214 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (2-MeO-Ph) 3
1-215 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (3-MeO-Ph) 2
1-216 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (3-MeO-Ph) 3
1-217 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (4-MeO-Ph) 2
1-218 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (4-MeO-Ph) 3
1-219 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (2,4-diMeO-Ph) 2
1-220 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (2,4-diMeO-Ph) 3
1-221 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Fur (2) 2
1-222 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Fur (2) 3
1-223 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Fur (3) 2
1-224 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Fur (3) 3
1-225 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Thi (2) 2
1-226 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Thi (2) 3
1-227 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Thi (3) 2
1-228 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Thi (3) 3
1-229 4-CF ₃ -Ph 4-CF ₃ -Ph Me Me H 2
1-230 4-CF ₃ -Ph 4-CF ₃ -Ph Me Me H 3
1-231 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ -H 2
1-232 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ -H 3
1-233 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CH ₂ -SMe 2
1-234 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CH ₂ -SMe 3
_{1-235 4-CF 3 -Ph 4-} CF 3 -Ph - (CH 2) 2 - - (CH 2) 2 -SMe 2
_{1-236 4-CF 3 -Ph 4-} CF 3 -Ph - (CH 2) 2 - - (CH 2) 2 -SMe 3
1-237 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Ph 2
1-238 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Ph 3
1-239 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CO- (2-MeO-Ph) 2
1-240 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CO- (2-MeO-Ph) 3
1-241 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Fur (2) 2
1-242 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Fur (2) 3
1-243 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Thi (2) 2
1-244 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Thi (2) 3
1-245 3-MeO-Ph 3-MeO-Ph HH -CH ₂ -SMe 2
1-246 3-MeO-Ph 3-MeO-Ph HH-(CH ₂ ) ₂ -SMe 2
1-247 3-MeO-Ph 3-MeO-Ph HH -CO-Ph 2
1-248 3-MeO-Ph 3-MeO-Ph HH -CO- (2-MeO-Ph) 2
1-249 3-MeO-Ph 3-MeO-Ph HH -CO-Fur (2) 2
1-250 3-MeO-Ph 3-MeO-Ph HH -CO-Thi (2) 2
1-251 3-MeO-Ph 3-MeO-Ph Me Me H 2
1-252 3-MeO-Ph 3-MeO-Ph-(CH ₂ ) ₂ -H 2
1-253 4-MeO-Ph 4-MeO-Ph HH -CH ₂ -SMe 2
1-254 4-MeO-Ph 4-MeO-Ph HH-(CH ₂ ) ₂ -SMe 2
1-255 4-MeO-Ph 4-MeO-Ph HH -CO-Ph 2
1-256 4-MeO-Ph 4-MeO-Ph HH -CO- (2-MeO-Ph) 2
1-257 4-MeO-Ph 4-MeO-Ph HH -CO-Fur (2) 2
1-258 4-MeO-Ph 4-MeO-Ph HH -CO-Thi (2) 2
1-259 4-MeO-Ph 4-MeO-Ph Me Me H 2
1-260 4-MeO-Ph 4-MeO-Ph-(CH ₂ ) ₂ -H 2
1-261 3-MeS-Ph 3-MeS-Ph HH -CH ₂ -SMe 2
1-262 3-MeS-Ph 3-MeS-Ph HH-(CH ₂ ) ₂ -SMe 2
1-263 3-MeS-Ph 3-MeS-Ph HH -CO-Ph 2
1-264 3-MeS-Ph 3-MeS-Ph HH -CO- (2-MeO-Ph) 2
1-265 3-MeS-Ph 3-MeS-Ph HH -CO-Fur (2) 2
1-266 3-MeS-Ph 3-MeS-Ph HH -CO-Thi (2) 2
1-267 3-MeS-Ph 3-MeS-Ph Me Me H 2
1-268 3-MeS-Ph 3-MeS-Ph-(CH ₂ ) ₂ -H 2
1-269 4-MeS-Ph 4-MeS-Ph HH -CH ₂ -SMe 2
1-270 4-MeS-Ph 4-MeS-Ph HH-(CH ₂ ) ₂ -SMe 2
1-271 4-MeS-Ph 4-MeS-Ph HH -CO-Ph 2
1-272 4-MeS-Ph 4-MeS-Ph HH -CO- (2-MeO-Ph) 2
1-273 4-MeS-Ph 4-MeS-Ph HH -CO-Fur (2) 2
1-274 4-MeS-Ph 4-MeS-Ph HH -CO-Thi (2) 2
1-275 4-MeS-Ph 4-MeS-Ph Me Me H 2
1-276 4-MeS-Ph 4-MeS-Ph-(CH ₂ ) ₂ -H 2
1-277 3-F-Ph 3-CN-Ph HH -CH ₂ -SMe 2
1-278 3-F-Ph 3-CN-Ph HH-(CH ₂ ) ₂ -SMe 2
1-279 3-F-Ph 3-CN-Ph HH -CO-Ph 2
1-280 3-F-Ph 3-CN-Ph HH -CO- (2-MeO-Ph) 2
1-281 3-F-Ph 3-CN-Ph HH -CO-Fur (2) 2
1-282 3-F-Ph 3-CN-Ph HH -CO-Thi (2) 2
1-283 3-F-Ph 3-CN-Ph Me Me H 2
1-284 3-F-Ph 3-CN-Ph Me Me H 3
1-285 3-F-Ph 3-CN-Ph-(CH ₂ ) ₂ -H 2
1-286 3-F-Ph 3-CN-Ph-(CH ₂ ) ₂ -H 3
1-287 4-F-Ph 4-CN-Ph HH -CH ₂ -SMe 2
1-288 4-F-Ph 4-CN-Ph HH-(CH ₂ ) ₂ -SMe 2
1-289 4-F-Ph 4-CN-Ph HH -CO-Ph 2
1-290 4-F-Ph 4-CN-Ph HH -CO- (2-MeO-Ph) 2
1-291 4-F-Ph 4-CN-Ph HH -CO-Fur (2) 2
1-292 4-F-Ph 4-CN-Ph HH -CO-Thi (2) 2
1-293 4-F-Ph 4-CN-Ph Me Me H 2
1-294 4-F-Ph 4-CN-Ph Me Me H 3
1-295 4-F-Ph 4-CN-Ph-(CH ₂ ) ₂ -H 2
1-296 4-F-Ph 4-CN-Ph-(CH ₂ ) ₂ -H 3
1-297 3-CF ₃ -Ph 3-CN-Ph HH -CH ₂ -SMe 2
1-298 3-CF ₃ -Ph 3-CN-Ph HH -CH ₂ -SMe 3
1-299 3-CF ₃ -Ph 3-CN-Ph HH-(CH ₂ ) ₂ -SMe 2
1-300 3-CF ₃ -Ph 3-CN-Ph HH -CO-Ph 2
1-301 3-CF ₃ -Ph 3-CN-Ph HH -CO- (2-MeO-Ph) 2
1-302 3-CF ₃ -Ph 3-CN-Ph HH -CO- (2-MeO-Ph) 3
1-303 3-CF ₃ -Ph 3-CN-Ph HH -CO- (4-MeO-Ph) 2
1-304 3-CF ₃ -Ph 3-CN-Ph HH -CO- (4-MeO-Ph) 3
1-305 3-CF ₃ -Ph 3-CN-Ph HH -CO-Fur (2) 2
1-306 3-CF ₃ -Ph 3-CN-Ph HH -CO-Fur (2) 3
1-307 3-CF ₃ -Ph 3-CN-Ph HH -CO-Thi (2) 2
1-308 3-CF ₃ -Ph 3-CN-Ph HH -CO-Thi (2) 3
1-309 3-CF ₃ -Ph 3-CN-Ph HH -CH ₂ -O-CH ₂ -Ph 2
1-310 3-CF ₃ -Ph 3-CN-Ph HH -CH ₂ -O-CH ₂ -Ph 3
1-311 3-CF ₃ -Ph 3-CN-Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 2
1-312 3-CF ₃ -Ph 3-CN-Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 3
1-313 3-CF ₃ -Ph 3-CN-Ph Me Me H 2
1-314 3-CF ₃ -Ph 3-CN-Ph Me Me H 3
1-315 3-CF ₃ -Ph 3-CN-Ph-(CH ₂ ) ₂ -H 2
1-316 3-CF ₃ -Ph 3-CN-Ph-(CH ₂ ) ₂ -H 3
1-317 4-CF ₃ -Ph 4-CN-Ph HH -CH ₂ -SMe 2
1-318 4-CF ₃ -Ph 4-CN-Ph HH-(CH ₂ ) ₂ -SMe 2
1-319 4-CF ₃ -Ph 4-CN-Ph HH -CO-Ph 2
1-320 4-CF ₃ -Ph 4-CN-Ph HH -CO- (2-MeO-Ph) 2
1-321 4-CF ₃ -Ph 4-CN-Ph HH -CO-Fur (2) 2
1-322 4-CF ₃ -Ph 4-CN-Ph HH -CO-Thi (2) 2
1-323 4-CF ₃ -Ph 4-CN-Ph Me Me H 2
1-324 4-CF ₃ -Ph 4-CN-Ph Me Me H 3
1-325 4-CF ₃ -Ph 4-CN-Ph-(CH ₂ ) ₂ -H 2
1-326 4-CF ₃ -Ph 4-CN-Ph-(CH ₂ ) ₂ -H 3
1-327 3-F-Ph 3-NO ₂ -Ph HH -CH ₂ -SMe 2
1-328 3-F-Ph 3-NO ₂ -Ph HH-(CH ₂ ) ₂ -SMe 2
1-329 3-F-Ph 3-NO ₂ -Ph HH -CO-Ph 2
1-330 3-F-Ph 3-NO ₂ -Ph HH -CO- (2-MeO-Ph) 2
1-331 3-F-Ph 3-NO ₂ -Ph HH -CO-Fur (2) 2
1-332 3-F-Ph 3-NO ₂ -Ph HH -CO-Thi (2) 2
1-333 3-F-Ph 3-NO ₂ -Ph Me Me H 2
1-334 3-F-Ph 3-NO ₂ -Ph Me Me H 3
1-335 3-F-Ph 3-NO ₂ -Ph-(CH ₂ ) ₂ -H 2
1-336 3-F-Ph 3-NO ₂ -Ph-(CH ₂ ) ₂ -H 3
1-337 4-F-Ph 4-NO ₂ -Ph HH -CH ₂ -SMe 2
1-338 4-F-Ph 4-NO ₂ -Ph HH-(CH ₂ ) ₂ -SMe 2
1-339 4-F-Ph 4-NO ₂ -Ph HH -CO-Ph 2
1-340 4-F-Ph 4-NO ₂ -Ph HH -CO- (2-MeO-Ph) 2
1-341 4-F-Ph 4-NO ₂ -Ph HH -CO-Fur (2) 2
1-342 4-F-Ph 4-NO ₂ -Ph HH -CO-Thi (2) 2
1-343 4-F-Ph 4-NO ₂ -Ph Me Me H 2
1-344 4-F-Ph 4-NO ₂ -Ph Me Me H 3
1-345 4-F-Ph 4-NO ₂ -Ph-(CH ₂ ) ₂ -H 2
1-346 4-F-Ph 4-NO ₂ -Ph-(CH ₂ ) ₂ -H 3
1-347 3-CF ₃ -Ph 3-NO ₂ -Ph HH -CH ₂ -SMe 2
1-348 3-CF ₃ -Ph 3-NO ₂ -Ph HH-(CH ₂ ) ₂ -SMe 2
1-349 3-CF ₃ -Ph 3-NO ₂ -Ph HH -CO-Ph 2
1-350 3-CF ₃ -Ph 3-NO ₂ -Ph HH -CO- (2-MeO-Ph) 2
1-351 3-CF ₃ -Ph 3-NO ₂ -Ph HH -CO-Fur (2) 2
1-352 3-CF ₃ -Ph 3-NO ₂ -Ph HH -CO-Thi (2) 2
1-353 3-CF ₃ -Ph 3-NO ₂ -Ph Me Me H 2
1-354 3-CF ₃ -Ph 3-NO ₂ -Ph Me Me H 3
1-355 3-CF ₃ -Ph 3-NO ₂ -Ph-(CH ₂ ) ₂ -H 2
1-356 3-CF ₃ -Ph 3-NO ₂ -Ph-(CH ₂ ) ₂ -H 3
1-357 4-CF ₃ -Ph 4-NO ₂ -Ph HH -CH ₂ -SMe 2
1-358 4-CF ₃ -Ph 4-NO ₂ -Ph HH-(CH ₂ ) ₂ -SMe 2
1-359 4-CF ₃ -Ph 4-NO ₂ -Ph HH -CO-Ph 2
1-360 4-CF ₃ -Ph 4-NO ₂ -Ph HH -CO- (2-MeO-Ph) 2
1-361 4-CF ₃ -Ph 4-NO ₂ -Ph HH -CO-Fur (2) 2
1-362 4-CF ₃ -Ph 4-NO ₂ -Ph HH -CO-Thi (2) 2
1-363 4-CF ₃ -Ph 4-NO ₂ -Ph Me Me H 2
1-364 4-CF ₃ -Ph 4-NO ₂ -Ph Me Me H 3
1-365 4-CF ₃ -Ph 4-NO ₂ -Ph-(CH ₂ ) ₂ -H 2
1-366 4-CF ₃ -Ph 4-NO ₂ -Ph-(CH ₂ ) ₂ -H 3
1-367 3-CF ₃ O-Ph 3-CF ₃ O-Ph HHH 2
.
(Table 2)

No. R ¹ R ² R ³ R ⁴ R ⁵ nm

2-1 3-F-Ph 3-F-Ph HHH 2 0
2-2 3-F-Ph 3-F-Ph HHH 3 0
2-3 3-F-Ph 3-F-Ph HH -CH ₂ -SOMe 2 0
2-4 3-F-Ph 3-F-Ph HH-(CH ₂ ) ₂ -SOMe 2 0
2-5 3-F-Ph 3-F-Ph HH -CH ₂ -SOMe 3 0
2-6 3-F-Ph 3-F-Ph HH-(CH ₂ ) ₂ -SOMe 30
2-7 3-F-Ph 3-F-Ph HH -CH ₂ -SO ₂ Me 2 0
2-8 3-F-Ph 3-F-Ph HH-(CH ₂ ) ₂ -SO ₂ Me 2 0
2-9 3-F-Ph 3-F-Ph HH -CH ₂ -SO ₂ Me 3 0
2-10 3-F-Ph 3-F-Ph HH-(CH ₂ ) ₂ -SO ₂ Me 3 0
2-11 3-F-Ph 3-F-Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 2 0
2-12 3-F-Ph 3-F-Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 3 0
2-13 3-F-Ph 3-F-Ph HH -CH ₂ -SMe 2 0
2-14 3-F-Ph 3-F-Ph HH -CH ₂ -SMe 3 0
2-15 3-F-Ph 3-F-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-16 3-F-Ph 3-F-Ph HH-(CH ₂ ) ₂ -SMe 3 0
2-17 3-F-Ph 3-F-Ph HH -CH ₂ -NHMe 2 0
2-18 3-F-Ph 3-F-Ph HH -CO-Ph 2 0
2-19 3-F-Ph 3-F-Ph HH -CO-Ph 3 0
2-20 3-F-Ph 3-F-Ph HH -CO- (2-MeO-Ph) 2 0
2-21 3-F-Ph 3-F-Ph HH -CO- (2-MeO-Ph) 3 0
2-22 3-F-Ph 3-F-Ph HH -CO- (3-MeO-Ph) 2 0
2-23 3-F-Ph 3-F-Ph HH -CO- (3-MeO-Ph) 3 0
2-24 3-F-Ph 3-F-Ph HH -CO- (4-MeO-Ph) 2 0
2-25 3-F-Ph 3-F-Ph HH -CO- (4-MeO-Ph) 3 0
2-26 3-F-Ph 3-F-Ph HH -CO- (2,4-diMeO-Ph) 2 0
2-27 3-F-Ph 3-F-Ph HH -CO- (2,4-diMeO-Ph) 3 0
2-28 3-F-Ph 3-F-Ph HH -CO-Fur (2) 2 0
2-29 3-F-Ph 3-F-Ph HH -CO-Fur (2) 3 0
2-30 3-F-Ph 3-F-Ph HH -CO-Fur (3) 2 0
2-31 3-F-Ph 3-F-Ph HH -CO-Fur (3) 3 0
2-32 3-F-Ph 3-F-Ph HH -CO-Thi (2) 2 0
2-33 3-F-Ph 3-F-Ph HH -CO-Thi (2) 3 0
2-34 3-F-Ph 3-F-Ph HH -CO-Thi (3) 2 0
2-35 3-F-Ph 3-F-Ph HH -CO-Thi (3) 3 0
2-36 3-F-Ph 3-F-Ph Me Me H 2 0
2-37 3-F-Ph 3-F-Ph Me Me H 3 0
2-38 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ -H 2 0
2-39 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ -H 3 0
2-40 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CH ₂ -SMe 2 0
2-41 3-F-Ph 3- F-Ph - (CH 2) 2 - - (CH 2) 2 -SMe 2 0
2-42 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CO-Ph 2 0
2-43 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CO- (2-MeO-Ph) 2 0
2-44 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CO-Fur (2) 2 0
2-45 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ --CO-Thi (2) 2 0
2-46 3-F-Ph 3-F-Ph HHH 2 1
2-47 3-F-Ph 3-F-Ph Me Me H 2 1
2-48 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ -H 2 1
2-49 4-F-Ph 4-F-Ph HHH 2 0
2-50 4-F-Ph 4-F-Ph HHH 3 0
2-51 4-F-Ph 4-F-Ph HH -CH ₂ -SOMe 2 0
2-52 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -SOMe 2 0
2-53 4-F-Ph 4-F-Ph HH -CH ₂ -SOMe 3 0
2-54 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -SOMe 3 0
2-55 4-F-Ph 4-F-Ph HH -CH ₂ -SO ₂ Me 2 0
2-56 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -SO ₂ Me 2 0
2-57 4-F-Ph 4-F-Ph HH -CH ₂ -SO ₂ Me 3 0
2-58 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -SO ₂ Me 3 0
2-59 4-F-Ph 4-F-Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 2 0
2-60 4-F-Ph 4-F-Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 3 0
2-61 4-F-Ph 4-F-Ph HH -CH ₂ -SMe 2 0
2-62 4-F-Ph 4-F-Ph HH -CH ₂ -SMe 3 0
2-63 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-64 4-F-Ph 4-F-Ph HH-(CH ₂ ) ₂ -SMe 3 0
2-65 4-F-Ph 4-F-Ph HH -CH ₂ -NHMe 2 0
2-66 4-F-Ph 4-F-Ph HH -CO-Ph 2 0
2-67 4-F-Ph 4-F-Ph HH -CO-Ph 3 0
2-68 4-F-Ph 4-F-Ph HH -CO- (2-MeO-Ph) 2 0
2-69 4-F-Ph 4-F-Ph HH -CO- (2-MeO-Ph) 3 0
2-70 4-F-Ph 4-F-Ph HH -CO- (3-MeO-Ph) 2 0
2-71 4-F-Ph 4-F-Ph HH -CO- (3-MeO-Ph) 3 0
2-72 4-F-Ph 4-F-Ph HH -CO- (4-MeO-Ph) 2 0
2-73 4-F-Ph 4-F-Ph HH -CO- (4-MeO-Ph) 3 0
2-74 4-F-Ph 4-F-Ph HH -CO- (2,4-diMeO-Ph) 2 0
2-75 4-F-Ph 4-F-Ph HH -CO- (2,4-diMeO-Ph) 3 0
2-76 4-F-Ph 4-F-Ph HH -CO-Fur (2) 2 0
2-77 4-F-Ph 4-F-Ph HH -CO-Fur (2) 3 0
2-78 4-F-Ph 4-F-Ph HH -CO-Fur (3) 2 0
2-79 4-F-Ph 4-F-Ph HH -CO-Fur (3) 3 0
2-80 4-F-Ph 4-F-Ph HH -CO-Thi (2) 2 0
2-81 4-F-Ph 4-F-Ph HH -CO-Thi (2) 3 0
2-82 4-F-Ph 4-F-Ph HH -CO-Thi (3) 2 0
2-83 4-F-Ph 4-F-Ph HH -CO-Thi (3) 3 0
2-84 4-F-Ph 4-F-Ph Me Me H 2 0
2-85 4-F-Ph 4-F-Ph Me Me H 3 0
2-86 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ -H 2 0
2-87 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ -H 3 0
2-88 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ -Me 2 0
2-89 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ -Me 3 0
2-90 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CH ₂ -SMe 2 0
2-91 4-F-Ph 4- F-Ph - (CH 2) 2 - - (CH 2) 2 -SMe 2 0
2-92 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CO-Ph 2 0
2-93 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CO- (2-MeO-Ph) 2 0
2-94 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CO-Fur (2) 2 0
2-95 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ --CO-Thi (2) 2 0
2-96 4-F-Ph 4-F-Ph HHH 2 1
2-97 4-F-Ph 4-F-Ph Me Me H 2 1
2-98 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ -H 2 1
2-99 3-Cl-Ph 3-Cl-Ph HHH 2 0
2-100 3-Cl-Ph 3-Cl-Ph HH -CH ₂ -SMe 2 0
2-101 3-Cl-Ph 3-Cl-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-102 3-Cl-Ph 3-Cl-Ph HH -CO-Ph 2 0
2-103 3-Cl-Ph 3-Cl-Ph HH -CO- (2-MeO-Ph) 2 0
2-104 3-Cl-Ph 3-Cl-Ph HH -CO-Fur (2) 2 0
2-105 3-Cl-Ph 3-Cl-Ph HH -CO-Thi (2) 2 0
2-106 3-Cl-Ph 3-Cl-Ph Me Me H 2 0
2-107 3-Cl-Ph 3-Cl-Ph-(CH ₂ ) ₂ -H 2 0
2-108 3-Cl-Ph 3-Cl-Ph HHH 2 1
2-109 3-Cl-Ph 3-Cl-Ph Me Me H 2 1
2-110 3-Cl-Ph 3-Cl-Ph-(CH ₂ ) ₂ -H 2 1
2-111 4-Cl-Ph 4-Cl-Ph HHH 2 0
2-112 4-Cl-Ph 4-Cl-Ph HH -CH ₂ -SMe 2 0
2-113 4-Cl-Ph 4-Cl-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-114 4-Cl-Ph 4-Cl-Ph HH -CO-Ph 2 0
2-115 4-Cl-Ph 4-Cl-Ph HH -CO- (2-MeO-Ph 2 0
2-116 4-Cl-Ph 4-Cl-Ph HH -CO-Fur (2) 2 0
2-117 4-Cl-Ph 4-Cl-Ph HH -CO-Thi (2) 2 0
2-118 4-Cl-Ph 4-Cl-Ph Me Me H 2 0
2-119 4-Cl-Ph 4-Cl-Ph-(CH ₂ ) ₂ -H 2 0
2-120 4-Cl-Ph 4-Cl-Ph HHH 2 1
2-121 4-Cl-Ph 4-Cl-Ph Me Me H 2 1
2-122 4-Cl-Ph 4-Cl-Ph-(CH ₂ ) ₂ -H 2 1
2-123 3-Me-Ph 3-Me-Ph HHH 2 0
2-124 3-Me-Ph 3-Me-Ph HH -CH ₂ -SMe 2 0
2-125 3-Me-Ph 3-Me-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-126 3-Me-Ph 3-Me-Ph HH -CO-Ph 2 0
2-127 3-Me-Ph 3-Me-Ph HH -CO- (2-MeO-Ph) 2 0
2-128 3-Me-Ph 3-Me-Ph HH -CO-Fur (2) 2 0
2-129 3-Me-Ph 3-Me-Ph HH -CO-Thi (2) 2 0
2-130 3-Me-Ph 3-Me-Ph Me Me H 2 0
2-131 3-Me-Ph 3-Me-Ph-(CH ₂ ) ₂ -H 2 0
2-132 3-Me-Ph 3-Me-Ph HHH 2 1
2-133 3-Me-Ph 3-Me-Ph Me Me H 2 1
2-134 3-Me-Ph 3-Me-Ph-(CH ₂ ) ₂ -H 2 1
2-135 4-Me-Ph 4-Me-Ph HHH 2 0
2-136 4-Me-Ph 4-Me-Ph HH -CH ₂ -SMe 2 0
2-137 4-Me-Ph 4-Me-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-138 4-Me-Ph 4-Me-Ph HH -CO-Ph 2 0
2-139 4-Me-Ph 4-Me-Ph HH -CO- (2-MeO-Ph) 2 0
2-140 4-Me-Ph 4-Me-Ph HH -CO-Fur (2) 2 0
2-141 4-Me-Ph 4-Me-Ph HH -CO-Thi (2) 2 0
2-142 4-Me-Ph 4-Me-Ph Me Me H 2 0
2-143 4-Me-Ph 4-Me-Ph-(CH ₂ ) ₂ -H 2 0
2-144 4-Me-Ph 4-Me-Ph HHH 2 1
2-145 4-Me-Ph 4-Me-Ph Me Me H 2 1
2-146 4-Me-Ph 4-Me-Ph-(CH ₂ ) ₂ -H 2 1
2-147 3-CF ₃ -Ph 3-CF ₃ -Ph HHH 2 0
2-148 3-CF ₃ -Ph 3-CF ₃ -Ph HHH 3 0
2-149 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -SOMe 2 0
2-150 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -SOMe 2 0
2-151 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -SOMe 3 0
2-152 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -SOMe 3 0
2-153 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -SO ₂ Me 2 0
2-154 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -SO ₂ Me 2 0
2-155 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -SO ₂ Me 3 0
2-156 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -SO ₂ Me 3 0
2-157 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 2 0
2-158 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 3 0
2-159 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -SMe 2 0
2-160 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -SMe 3 0
2-161 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-162 3-CF ₃ -Ph 3-CF ₃ -Ph HH-(CH ₂ ) ₂ -SMe 3 0
2-163 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CH ₂ -NHMe 2 0
2-164 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Ph 2 0
2-165 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Ph 3 0
2-166 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (2-MeO-Ph 2 0
2-167 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (2-MeO-Ph) 3 0
2-168 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (3-MeO-Ph) 2 0
2-169 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (3-MeO-Ph) 3 0
2-170 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (4-MeO-Ph) 2 0
2-171 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (4-MeO-Ph) 3 0
2-172 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (2,4-diMeO-Ph) 2 0
2-173 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO- (2,4-diMeO-Ph) 3 0
2-174 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Fur (2) 2 0
2-175 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Fur (2) 3 0
2-176 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Fur (3) 2 0
2-177 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Fur (3) 3 0
2-178 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Thi (2) 2 0
2-179 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Thi (2) 3 0
2-180 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Thi (3) 2 0
2-181 3-CF ₃ -Ph 3-CF ₃ -Ph HH -CO-Thi (3) 3 0
2-182 3-CF ₃ -Ph 3-CF ₃ -Ph Me Me H 2 0
2-183 3-CF ₃ -Ph 3-CF ₃ -Ph Me Me H 3 0
2-184 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ -H 2 0
2-185 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ -H 3 0
2-186 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CH ₂ -SMe 2 0
_{2-187 3-CF 3 -Ph 3-} CF 3 -Ph - (CH 2) 2 - - (CH 2) 2 -SMe 2 0
2-188 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Ph 2 0
2-189 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CO- (2-MeO-Ph) 2 0
2-190 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Fur (2) 2 0
2-191 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Thi (2) 2 0
2-192 3-CF ₃ -Ph 3-CF ₃ -Ph HHH 2 1
2-193 3-CF ₃ -Ph 3-CF ₃ -Ph Me Me H 2 1
2-194 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ -H 2 1
2-195 4-CF ₃ -Ph 4-CF ₃ -Ph HHH 2 0
2-196 4-CF ₃ -Ph 4-CF ₃ -Ph HHH 3 0
2-197 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -SOMe 2 0
2-198 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -SOMe 2 0
2-199 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -SOMe 3 0
2-200 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -SOMe 3 0
2-201 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -SO ₂ Me 2 0
2-202 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -SO ₂ Me 2 0
2-203 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -SO ₂ Me 3 0
2-204 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -SO ₂ Me 3 0
2-205 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 2 0
2-206 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 3 0
2-207 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -SMe 2 0
2-208 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -SMe 3 0
2-209 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-210 4-CF ₃ -Ph 4-CF ₃ -Ph HH-(CH ₂ ) ₂ -SMe 3 0
2-211 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CH ₂ -NHMe 2 0
2-212 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Ph 2 0
2-213 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Ph 3 0
2-214 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (2-MeO-Ph) 2 0
2-215 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (2-MeO-Ph) 3 0
2-216 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (3-MeO-Ph) 2 0
2-217 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (3-MeO-Ph) 3 0
2-218 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (4-MeO-Ph) 2 0
2-219 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (4-MeO-Ph) 3 0
2-220 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (2,4-diMeO-Ph) 2 0
2-221 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO- (2,4-diMeO-Ph) 3 0
2-222 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Fur (2) 2 0
2-223 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Fur (2) 3 0
2-224 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Fur (3) 2 0
2-225 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Fur (3) 3 0
2-226 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Thi (2) 2 0
2-227 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Thi (2) 3 0
2-228 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Thi (3) 2 0
2-229 4-CF ₃ -Ph 4-CF ₃ -Ph HH -CO-Thi (3) 3 0
2-230 4-CF ₃ -Ph 4-CF ₃ -Ph Me Me H 2 0
2-231 4-CF ₃ -Ph 4-CF ₃ -Ph Me Me H 3 0
2-232 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ -H 2 0
2-233 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ -H 3 0
2-234 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CH ₂ -SMe 2 0
_{2-235 4-CF 3 -Ph 4-} CF 3 -Ph - (CH 2) 2 - - (CH 2) 2 -SMe 2 0
2-236 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Ph 2 0
2-237 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CO- (2-MeO-Ph) 2 0
2-238 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Fur (2) 2 0
2-239 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ --CO-Thi (2) 2 0
2-240 4-CF ₃ -Ph 4-CF ₃ -Ph HHH 2 1
2-241 4-CF ₃ -Ph 4-CF ₃ -Ph Me Me H 2 1
2-242 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ -H 2 1
2-243 3-MeO-Ph 3-MeO-Ph HHH 2 0
2-244 3-MeO-Ph 3-MeO-Ph HH -CH ₂ -SMe 2 0
2-245 3-MeO-Ph 3-MeO-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-246 3-MeO-Ph 3-MeO-Ph HH -CO-Ph 2 0
2-247 3-MeO-Ph 3-MeO-Ph HH -CO- (2-MeO-Ph) 2 0
2-248 3-MeO-Ph 3-MeO-Ph HH -CO-Fur (2) 2 0
2-249 3-MeO-Ph 3-MeO-Ph HH -CO-Thi (2) 2 0
2-250 3-MeO-Ph 3-MeO-Ph Me Me H 2 0
2-251 3-MeO-Ph 3-MeO-Ph-(CH ₂ ) ₂ -H 2 0
2-252 3-MeO-Ph 3-MeO-Ph HHH 2 1
2-253 3-MeO-Ph 3-MeO-Ph Me Me H 2 1
2-254 3-MeO-Ph 3-MeO-Ph-(CH ₂ ) ₂ -H 2 1
2-255 4-MeO-Ph 4-MeO-Ph HHH 2 0
2-256 4-MeO-Ph 4-MeO-Ph HH -CH ₂ -SMe 2 0
2-257 4-MeO-Ph 4-MeO-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-258 4-MeO-Ph 4-MeO-Ph HH -CO-Ph 2 0
2-259 4-MeO-Ph 4-MeO-Ph HH -CO- (2-MeO-Ph) 2 0
2-260 4-MeO-Ph 4-MeO-Ph HH -CO-Fur (2) 2 0
2-261 4-MeO-Ph 4-MeO-Ph HH -CO-Thi (2) 2 0
2-262 4-MeO-Ph 4-MeO-Ph Me Me H 2 0
2-263 4-MeO-Ph 4-MeO-Ph-(CH ₂ ) ₂ -H 2 0
2-264 4-MeO-Ph 4-MeO-Ph HHH 2 1
2-265 4-MeO-Ph 4-MeO-Ph Me Me H 2 1
2-266 4-MeO-Ph 4-MeO-Ph-(CH ₂ ) ₂ -H 2 1
2-267 3-MeS-Ph 3-MeS-Ph HHH 2 0
2-268 3-MeS-Ph 3-MeS-Ph HH -CH ₂ -SMe 2 0
2-269 3-MeS-Ph 3-MeS-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-270 3-MeS-Ph 3-MeS-Ph HH -CO-Ph 2 0
2-271 3-MeS-Ph 3-MeS-Ph HH -CO- (2-MeO-Ph) 2 0
2-272 3-MeS-Ph 3-MeS-Ph HH -CO-Fur (2) 2 0
2-273 3-MeS-Ph 3-MeS-Ph HH -CO-Thi (2) 2 0
2-274 3-MeS-Ph 3-MeS-Ph Me Me H 2 0
2-275 3-MeS-Ph 3-MeS-Ph-(CH ₂ ) ₂ -H 2 0
2-276 3-MeS-Ph 3-MeS-Ph HHH 2 1
2-277 3-MeS-Ph 3-MeS-Ph Me Me H 2 1
2-278 3-MeS-Ph 3-MeS-Ph-(CH ₂ ) ₂ -H 2 1
2-279 4-MeS-Ph 4-MeS-Ph HHH 2 0
2-280 4-MeS-Ph 4-MeS-Ph HH -CH ₂ -SMe 2 0
2-281 4-MeS-Ph 4-MeS-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-282 4-MeS-Ph 4-MeS-Ph HH -CO-Ph 2 0
2-283 4-MeS-Ph 4-MeS-Ph HH -CO- (2-MeO-Ph) 2 0
2-284 4-MeS-Ph 4-MeS-Ph HH -CO-Fur (2) 2 0
2-285 4-MeS-Ph 4-MeS-Ph HH -CO-Thi (2) 2 0
2-286 4-MeS-Ph 4-MeS-Ph Me Me H 2 0
2-287 4-MeS-Ph 4-MeS-Ph-(CH ₂ ) ₂ -H 2 0
2-288 4-MeS-Ph 4-MeS-Ph HHH 2 1
2-289 4-MeS-Ph 4-MeS-Ph Me Me H 2 1
2-290 4-MeS-Ph 4-MeS-Ph-(CH ₂ ) ₂ -H 2 1
2-291 3-F-Ph 3-CN-Ph HHH 2 0
2-292 3-F-Ph 3-CN-Ph HHH 3 0
2-293 3-F-Ph 3-CN-Ph HH -CH ₂ -SMe 2 0
2-294 3-F-Ph 3-CN-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-295 3-F-Ph 3-CN-Ph HH -CO-Ph 2 0
2-296 3-F-Ph 3-CN-Ph HH -CO- (2-MeO-Ph) 2 0
2-297 3-F-Ph 3-CN-Ph HH -CO-Fur (2) 2 0
2-298 3-F-Ph 3-CN-Ph HH -CO-Thi (2) 2 0
2-299 3-F-Ph 3-CN-Ph Me Me H 2 0
2-300 3-F-Ph 3-CN-Ph-(CH ₂ ) ₂ -H 2 0
2-301 3-F-Ph 3-CN-Ph HHH 2 1
2-302 3-F-Ph 3-CN-Ph Me Me H 2 1
2-303 3-F-Ph 3-CN-Ph-(CH ₂ ) ₂ -H 2 1
2-304 4-F-Ph 4-CN-Ph HHH 2 0
2-305 4-F-Ph 4-CN-Ph HHH 3 0
2-306 4-F-Ph 4-CN-Ph HH -CH ₂ -SMe 2 0
2-307 4-F-Ph 4-CN-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-308 4-F-Ph 4-CN-Ph HH -CO-Ph 2 0
2-309 4-F-Ph 4-CN-Ph HH -CO- (2-MeO-Ph) 2 0
2-310 4-F-Ph 4-CN-Ph HH -CO-Fur (2) 2 0
2-311 4-F-Ph 4-CN-Ph HH -CO-Thi (2) 2 0
2-312 4-F-Ph 4-CN-Ph Me Me H 2 0
2-313 4-F-Ph 4-CN-Ph-(CH ₂ ) ₂ -H 2 0
2-314 4-F-Ph 4-CN-Ph HHH 2 1
2-315 4-F-Ph 4-CN-Ph Me Me H 2 1
2-316 4-F-Ph 4-CN-Ph-(CH ₂ ) ₂ -H 2 1
2-317 3-CF ₃ -Ph 3-CN-Ph HHH 2 0
2-318 3-CF ₃ -Ph 3-CN-Ph HHH 3 0
2-319 3-CF ₃ -Ph 3-CN-Ph HH -CH ₂ -SMe 2 0
2-320 3-CF ₃ -Ph 3-CN-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-321 3-CF ₃ -Ph 3-CN-Ph HH -CO-Ph 2 0
2-322 3-CF ₃ -Ph 3-CN-Ph HH -CO- (2-MeO-Ph) 2 0
2-323 3-CF ₃ -Ph 3-CN-Ph HH -CO-Fur (2) 2 0
2-324 3-CF ₃ -Ph 3-CN-Ph HH -CO-Thi (2) 2 0
2-325 3-CF ₃ -Ph 3-CN-Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 2 0
2-326 3-CF ₃ -Ph 3-CN-Ph HH -CH ₂ -O- (CH ₂ ) ₂ -OMe 3 0
2-327 3-CF ₃ -Ph 3-CN-Ph Me Me H 2 0
2-328 3-CF ₃ -Ph 3-CN-Ph-(CH ₂ ) ₂ -H 2 0
2-329 3-CF ₃ -Ph 3-CN-Ph-(CH ₂ ) ₂ -H 3 0
2-330 3-CF ₃ -Ph 3-CN-Ph HHH 2 1
2-331 3-CF ₃ -Ph 3-CN-Ph Me Me H 2 1
2-332 3-CF ₃ -Ph 3-CN-Ph-(CH ₂ ) ₂ -H 2 1
2-333 4-CF ₃ -Ph 4-CN-Ph HHH 2 0
2-334 4-CF ₃ -Ph 4-CN-Ph HH -CH ₂ -SMe 2 0
2-335 4-CF ₃ -Ph 4-CN-Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-336 4-CF ₃ -Ph 4-CN-Ph HH -CO-Ph 2 0
2-337 4-CF ₃ -Ph 4-CN-Ph HH -CO- (2-MeO-Ph) 2 0
2-338 4-CF ₃ -Ph 4-CN-Ph HH -CO-Fur (2) 2 0
2-339 4-CF ₃ -Ph 4-CN-Ph HH -CO-Thi (2) 2 0
2-340 4-CF ₃ -Ph 4-CN-Ph Me Me H 2 0
2-341 4-CF ₃ -Ph 4-CN-Ph-(CH ₂ ) ₂ -H 2 0
2-342 4-CF ₃ -Ph 4-CN-Ph HHH 2 1
2-343 4-CF ₃ -Ph 4-CN-Ph Me Me H 2 1
2-344 4-CF ₃ -Ph 4-CN-Ph-(CH ₂ ) ₂ -H 2 1
2-345 3-F-Ph 3-NO ₂ -Ph HHH 2 0
2-346 3-F-Ph 3-NO ₂ -Ph HH -CH ₂ -SMe 2 0
2-347 3-F-Ph 3-NO ₂ -Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-348 3-F-Ph 3-NO ₂ -Ph HH -CO-Ph 2 0
2-349 3-F-Ph 3-NO ₂ -Ph HH -CO- (2-MeO-Ph) 2 0
2-350 3-F-Ph 3-NO ₂ -Ph HH -CO-Fur (2) 2 0
2-351 3-F-Ph 3-NO ₂ -Ph HH -CO-Thi (2) 2 0
2-352 3-F-Ph 3-NO ₂ -Ph Me Me H 2 0
2-353 3-F-Ph 3-NO ₂ -Ph-(CH ₂ ) ₂ -H 2 0
2-354 3-F-Ph 3-NO ₂ -Ph HHH 2 1
2-355 3-F-Ph 3-NO ₂ -Ph Me Me H 2 1
2-356 3-F-Ph 3-NO ₂ -Ph-(CH ₂ ) ₂ -H 2 1
2-357 4-F-Ph 4-NO ₂ -Ph HHH 2 0
2-358 4-F-Ph 4-NO ₂ -Ph HH -CH ₂ -SMe 2 0
2-359 4-F-Ph 4-NO ₂ -Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-360 4-F-Ph 4-NO ₂ -Ph HH -CO-Ph 2 0
2-361 4-F-Ph 4-NO ₂ -Ph HH -CO- (2-MeO-Ph) 2 0
2-362 4-F-Ph 4-NO ₂ -Ph HH -CO-Fur (2) 2 0
2-363 4-F-Ph 4-NO ₂ -Ph HH -CO-Thi (2) 2 0
2-364 4-F-Ph 4-NO ₂ -Ph Me Me H 2 0
2-365 4-F-Ph 4-NO ₂ -Ph-(CH ₂ ) ₂ -H 2 0
2-366 4-F-Ph 4-NO ₂ -Ph HHH 2 1
2-367 4-F-Ph 4-NO ₂ -Ph Me Me H 2 1
2-368 4-F-Ph 4-NO ₂ -Ph-(CH ₂ ) ₂ -H 2 1
2-369 3-CF ₃ -Ph 3-NO ₂ -Ph HHH 2 0
2-370 3-CF ₃ -Ph 3-NO ₂ -Ph HH -CH ₂ -SMe 2 0
2-371 3-CF ₃ -Ph 3-NO ₂ -Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-372 3-CF ₃ -Ph 3-NO ₂ -Ph HH -CO-Ph 2 0
2-373 3-CF ₃ -Ph 3-NO ₂ -Ph HH -CO- (2-MeO-Ph) 2 0
2-374 3-CF ₃ -Ph 3-NO ₂ -Ph HH -CO-Fur (2) 2 0
2-375 3-CF ₃ -Ph 3-NO ₂ -Ph HH -CO-Thi (2) 2 0
2-376 3-CF ₃ -Ph 3-NO ₂ -Ph Me Me H 2 0
2-377 3-CF ₃ -Ph 3-NO ₂ -Ph-(CH ₂ ) ₂ -H 2 0
2-378 3-CF ₃ -Ph 3-NO ₂ -Ph HHH 2 1
2-379 3-CF ₃ -Ph 3-NO ₂ -Ph Me Me H 2 1
2-380 3-CF ₃ -Ph 3-NO ₂ -Ph-(CH ₂ ) ₂ -H 2 1
2-381 4-CF ₃ -Ph 4-NO ₂ -Ph HHH 2 0
2-382 4-CF ₃ -Ph 4-NO ₂ -Ph HH -CH ₂ -SMe 2 0
2-383 4-CF ₃ -Ph 4-NO ₂ -Ph HH-(CH ₂ ) ₂ -SMe 2 0
2-384 4-CF ₃ -Ph 4-NO ₂ -Ph HH -CO-Ph 2 0
2-385 4-CF ₃ -Ph 4-NO ₂ -Ph HH -CO- (2-MeO-Ph) 2 0
2-386 4-CF ₃ -Ph 4-NO ₂ -Ph HH -CO-Fur (2) 2 0
2-387 4-CF ₃ -Ph 4-NO ₂ -Ph HH -CO-Thi (2) 2 0
2-388 4-CF ₃ -Ph 4-NO ₂ -Ph Me Me H 2 0
2-389 4-CF ₃ -Ph 4-NO ₂ -Ph-(CH ₂ ) ₂ -H 2 0
2-390 4-CF ₃ -Ph 4-NO ₂ -Ph HHH 2 1
2-391 4-CF ₃ -Ph 4-NO ₂ -Ph Me Me H 2 1
2-392 4-CF ₃ -Ph 4-NO ₂ -Ph-(CH ₂ ) ₂ -H 2 1
2-393 3-F-Ph 4-F-Ph HHH 2 0
2-394 3-F-Ph 4-F-Ph HHH 2 1
2-395 3-F-Ph 4-F-Ph HHH 3 0
2-396 3-F-Ph 4-F-Ph HHH 3 1
2-397 3-F-Ph 4-CF ₃ -Ph HHH 2 0
2-398 3-F-Ph 4-CF ₃ -Ph HHH 2 1
2-399 3-F-Ph 4-CF ₃ -Ph HHH 3 0
2-400 3-F-Ph 4-CF ₃ -Ph HHH 3 1
2-401 4-F-Ph 2-F-Ph HHH 2 0
2-402 4-F-Ph 2-F-Ph HHH 2 1
2-403 4-F-Ph 2-F-Ph HHH 3 0
2-404 4-F-Ph 2-F-Ph HHH 3 1
2-405 4-F-Ph 3-F-Ph HHH 2 0
2-406 4-F-Ph 3-F-Ph HHH 2 1
2-407 4-F-Ph 3-F-Ph HHH 3 0
2-408 4-F-Ph 3-F-Ph HHH 3 1
2-409 4-F-Ph 4-Cl-Ph HHH 2 0
2-410 4-F-Ph 4-Cl-Ph HHH 2 1
2-411 4-F-Ph 4-Cl-Ph HHH 3 0
2-412 4-F-Ph 4-Cl-Ph HHH 3 1
2-413 4-F-Ph 3-CF ₃ -Ph HHH 2 0
2-414 4-F-Ph 3-CF ₃ -Ph HHH 2 1
2-415 4-F-Ph 3-CF ₃ -Ph HHH 3 0
2-416 4-F-Ph 3-CF ₃ -Ph HHH 3 1
2-417 4-F-Ph 4-CF ₃ -Ph HHH 2 0
2-418 4-F-Ph 4-CF ₃ -Ph HHH 2 1
2-419 4-F-Ph 4-CF ₃ -Ph HHH 3 0
2-420 4-F-Ph 4-CF ₃ -Ph HHH 3 1
2-421 4-F-Ph 3-CN-Ph HHH 2 0
2-422 4-F-Ph 3-CN-Ph HHH 2 1
2-423 4-F-Ph 3-CN-Ph HHH 3 0
2-424 4-F-Ph 3-CN-Ph HHH 3 1
2-425 3-CF ₃ -Ph 2-F-Ph HHH 2 0
2-426 3-CF ₃ -Ph 2-F-Ph HHH 2 1
2-427 3-CF ₃ -Ph 2-F-Ph HHH 3 0
2-428 3-CF ₃ -Ph 2-F-Ph HHH 3 1
2-429 3-CF ₃ -Ph 3-F-Ph HHH 2 0
2-430 3-CF ₃ -Ph 3-F-Ph HHH 2 1
2-431 3-CF ₃ -Ph 3-F-Ph HHH 3 0
2-432 3-CF ₃ -Ph 3-F-Ph HHH 3 1
2-433 3-CF ₃ -Ph 4-F-Ph HHH 2 0
2-434 3-CF ₃ -Ph 4-F-Ph HHH 2 1
2-435 3-CF ₃ -Ph 4-F-Ph HHH 3 0
2-436 3-CF ₃ -Ph 4-F-Ph HHH 3 1
2-437 3-CF ₃ -Ph 4-Cl-Ph HHH 2 0
2-438 3-CF ₃ -Ph 4-Cl-Ph HHH 2 1
2-439 3-CF ₃ -Ph 4-Cl-Ph HHH 3 0
2-440 3-CF ₃ -Ph 4-Cl-Ph HHH 3 1
2-441 3-CF ₃ -Ph 4-CF ₃ -Ph HHH 2 0
2-442 3-CF ₃ -Ph 4-CF ₃ -Ph HHH 2 1
2-443 3-CF ₃ -Ph 4-CF ₃ -Ph HHH 3 0
2-444 3-CF ₃ -Ph 4-CF ₃ -Ph HHH 3 1
2-445 3-CF ₃ -Ph 4-CN-Ph HHH 2 0
2-446 3-CF ₃ -Ph 4-CN-Ph HHH 2 1
2-447 3-CF ₃ -Ph 4-CN-Ph HHH 3 0
2-448 3-CF ₃ -Ph 4-CN-Ph HHH 3 1
2-449 3-CF ₃ -Ph 2,3-diF-Ph HHH 2 0
2-450 3-CF ₃ -Ph 2,4-diF-Ph HHH 2 0
2-451 3-CF ₃ -Ph 3,5-diF-Ph HHH 2 0
2-452 3-CF ₃ -Ph 3,4-diF-Ph HHH 2 0
2-453 3-CF ₃ -Ph 2,6-diF-Ph HHH 2 0
2-454 3-CF ₃ -Ph Ph HHH 2 0
2-455 3-CF ₃ -Ph 3-Cl-Ph HHH 2 0
2-456 2-F-Ph 4-CF ₃ -Ph HHH 2 0
2-457 4-F-Ph 2-Cl-Ph HHH 2 0
2-458 4-F-Ph Ph HHH 2 0
2-459 4-CN-Ph 3-CF ₃ -Ph HHH 2 0
2-460 4-CN-Ph 4-CF ₃ -Ph HHH 2 0
2-461 4-Cl-Ph 3-CF ₃ -Ph HHH 2 0
2-462 4-Cl-Ph 4-CN-Ph HHH 2 0
2-463 4-Cl-Ph 4-F-Ph HHH 2 0
2-464 4-Cl-Ph 3-F-Ph HHH 2 0
2-465 4-MeO-Ph 4-CN-Ph HHH 2 0
2-466 4-MeO-Ph 4-CF ₃ -Ph HHH 2 0
2-467 3-CF ₃ -Ph 4-CN-Ph HH Me 2 0
2-468 3-CF ₃ -Ph 4-CN-Ph HH Et 2 0
2-469 3-CF ₃ -Ph 4-CN-Ph HH -CH ₂ -SMe 2 0
.
(Table 3)

R ¹ R ² R ⁶ n

3-1 3-F-Ph 3-F-Ph Me 2
3-2 3-F-Ph 3-F-Ph Me 3
3-3 3-F-Ph 3-F-Ph Et 2
3-4 3-F-Ph 3-F-Ph Et 3
3-5 3-F-Ph 3-F-Ph -CH ₂ -OMe 2
3-6 3-F-Ph 3-F-Ph -CH ₂ -OMe 3
3-7 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ -OMe 2
3-8 3-F-Ph 3-F-Ph-(CH ₂ ) ₂ -OMe 3
3-9 4-F-Ph 4-F-Ph Me 2
3-10 4-F-Ph 4-F-Ph Me 3
3-11 4-F-Ph 4-F-Ph Et 2
3-12 4-F-Ph 4-F-Ph Et 3
3-13 4-F-Ph 4-F-Ph -CH ₂ -OMe 2
3-14 4-F-Ph 4-F-Ph -CH ₂ -OMe 3
3-15 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ -OMe 2
3-16 4-F-Ph 4-F-Ph-(CH ₂ ) ₂ -OMe 3
3-17 3-CF ₃ -Ph 3-CF ₃ -Ph Me 2
3-18 3-CF ₃ -Ph 3-CF ₃ -Ph Me 3
3-19 3-CF ₃ -Ph 3-CF ₃ -Ph Et 2
3-20 3-CF ₃ -Ph 3-CF ₃ -Ph Et 3
3-21 3-CF ₃ -Ph 3-CF ₃ -Ph -CH ₂ -OMe 2
3-22 3-CF ₃ -Ph 3-CF ₃ -Ph -CH ₂ -OMe 3
3-23 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ -OMe 2
3-24 3-CF ₃ -Ph 3-CF ₃ -Ph-(CH ₂ ) ₂ -OMe 3
3-25 4-CF ₃ -Ph 4-CF ₃ -Ph Me 2
3-26 4-CF ₃ -Ph 4-CF ₃ -Ph Me 3
3-27 4-CF ₃ -Ph 4-CF ₃ -Ph Et 2
3-28 4-CF ₃ -Ph 4-CF ₃ -Ph Et 3
3-29 4-CF ₃ -Ph 4-CF ₃ -Ph -CH ₂ -OMe 2
3-30 4-CF ₃ -Ph 4-CF ₃ -Ph -CH ₂ -OMe 3
3-31 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ -OMe 2
3-32 4-CF ₃ -Ph 4-CF ₃ -Ph-(CH ₂ ) ₂ -OMe 3
3-33 3-F-Ph 3-CN-Ph Me 2
3-34 3-F-Ph 3-CN-Ph Me 3
3-35 3-F-Ph 3-CN-Ph Et 2
3-36 3-F-Ph 3-CN-Ph Et 3
3-37 3-F-Ph 3-CN-Ph -CH ₂ -OMe 2
3-38 3-F-Ph 3-CN-Ph -CH ₂ -OMe 3
3-39 3-F-Ph 3-CN-Ph-(CH ₂ ) ₂ -OMe 2
3-40 3-F-Ph 3-CN-Ph-(CH ₂ ) ₂ -OMe 3
3-41 4-F-Ph 4-CN-Ph Me 2
3-42 4-F-Ph 4-CN-Ph Me 3
3-43 4-F-Ph 4-CN-Ph Et 2
3-44 4-F-Ph 4-CN-Ph Et 3
3-45 4-F-Ph 4-CN-Ph -CH ₂ -OMe 2
3-46 4-F-Ph 4-CN-Ph -CH ₂ -OMe 3
3-47 4-F-Ph 4-CN-Ph-(CH ₂ ) ₂ -OMe 2
3-48 4-F-Ph 4-CN-Ph-(CH ₂ ) ₂ -OMe 3
3-49 3-CF ₃ -Ph 3-CN-Ph Me 2
3-50 3-CF ₃ -Ph 3-CN-Ph Me 3
3-51 3-CF ₃ -Ph 3-CN-Ph Et 2
3-52 3-CF ₃ -Ph 3-CN-Ph Et 3
3-53 3-CF ₃ -Ph 3-CN-Ph -CH ₂ -OMe 2
3-54 3-CF ₃ -Ph 3-CN-Ph -CH ₂ -OMe 3
3-55 3-CF ₃ -Ph 3-CN-Ph-(CH ₂ ) ₂ -OMe 2
3-56 3-CF ₃ -Ph 3-CN-Ph-(CH ₂ ) ₂ -OMe 3
3-57 4-CF ₃ -Ph 4-CN-Ph Me 2
3-58 4-CF ₃ -Ph 4-CN-Ph Me 3
3-59 4-CF ₃ -Ph 4-CN-Ph Et 2
3-60 4-CF ₃ -Ph 4-CN-Ph Et 3
3-61 4-CF ₃ -Ph 4-CN-Ph -CH ₂ -OMe 2
3-62 4-CF ₃ -Ph 4-CN-Ph -CH ₂ -OMe 3
3-63 4-CF ₃ -Ph 4-CN-Ph-(CH ₂ ) ₂ -OMe 2
3-64 4-CF ₃ -Ph 4-CN-Ph-(CH ₂ ) ₂ -OMe 3
3-65 3-F-Ph 3-NO ₂ -Ph Me 2
3-66 3-F-Ph 3-NO ₂ -Ph Me 3
3-67 3-F-Ph 3-NO ₂ -Ph Et 2
3-68 3-F-Ph 3-NO ₂ -Ph Et 3
3-69 3-F-Ph 3-NO ₂ -Ph -CH ₂ -OMe 2
3-70 3-F-Ph 3-NO ₂ -Ph -CH ₂ -OMe 3
3-71 3-F-Ph 3-NO ₂ -Ph-(CH ₂ ) ₂ -OMe 2
3-72 3-F-Ph 3-NO ₂ -Ph-(CH ₂ ) ₂ -OMe 3
3-73 4-F-Ph 4-NO ₂ -Ph Me 2
3-74 4-F-Ph 4-NO ₂ -Ph Me 3
3-75 4-F-Ph 4-NO ₂ -Ph Et 2
3-76 4-F-Ph 4-NO ₂ -Ph Et 3
3-77 4-F-Ph 4-NO ₂ -Ph -CH ₂ -OMe 2
3-78 4-F-Ph 4-NO ₂ -Ph -CH ₂ -OMe 3
3-79 4-F-Ph 4-NO ₂ -Ph-(CH ₂ ) ₂ -OMe 2
3-80 4-F-Ph 4-NO ₂ -Ph-(CH ₂ ) ₂ -OMe 3
3-81 3-CF ₃ -Ph 3-NO ₂ -Ph Me 2
3-82 3-CF ₃ -Ph 3-NO ₂ -Ph Me 3
3-83 3-CF ₃ -Ph 3-NO ₂ -Ph Et 2
3-84 3-CF ₃ -Ph 3-NO ₂ -Ph Et 3
3-85 3-CF ₃ -Ph 3-NO ₂ -Ph -CH ₂ -OMe 2
3-86 3-CF ₃ -Ph 3-NO ₂ -Ph -CH ₂ -OMe 3
3-87 3-CF ₃ -Ph 3-NO ₂ -Ph-(CH ₂ ) ₂ -OMe 2
3-88 3-CF ₃ -Ph 3-NO ₂ -Ph-(CH ₂ ) ₂ -OMe 3
3-89 4-CF ₃ -Ph 4-NO ₂ -Ph Me 2
3-90 4-CF ₃ -Ph 4-NO ₂ -Ph Me 3
3-91 4-CF ₃ -Ph 4-NO ₂ -Ph Et 2
3-92 4-CF ₃ -Ph 4-NO ₂ -Ph Et 3
3-93 4-CF ₃ -Ph 4-NO ₂ -Ph -CH ₂ -OMe 2
3-94 4-CF ₃ -Ph 4-NO ₂ -Ph -CH ₂ -OMe 3
3-95 4-CF ₃ -Ph 4-NO ₂ -Ph-(CH ₂ ) ₂ -OMe 2
3-96 4-CF ₃ -Ph 4-NO ₂ -Ph-(CH ₂ ) ₂ -OMe 3
3-97 3,4-diF-Ph 3,4-diF-Ph Me 2
3-98 3,4-diF-Ph 3,4-diF-Ph Me 3
3-99 3,4-diF-Ph 3,4-diF-Ph Et 2
3-100 3,4-diF-Ph 3,4-diF-Ph Et 3
3-101 3,4-diF-Ph 3,4-diF-Ph -CH ₂ -OMe 2
3-102 3,4-diF-Ph 3,4-diF-Ph -CH ₂ -OMe 3
3-103 3,4-diF-Ph 3,4-diF-Ph-(CH ₂ ) ₂ -OMe 2
3-104 3,4-diF-Ph 3,4-diF-Ph-(CH ₂ ) ₂ -OMe 3
.

In Tables 1 to 3, preferably,
Exemplified compound numbers: 1-9 to 1-12, 1-19 to 1-34, 1-37 to 1-40, 1-43 to 1-50, 1-59 to 1-62, 1-65, 1- 66, 1-69 to 1-88, 1-91 to 1-94, 1-97 to 1-105, 1-107 to 1-110, 1-112, 1-113, 1-115 to 1-118, 1-120, 1-137, 1-139, 1-141, 1-143, 1-145 to 1-148, 1-151, 1-152, 1-155 to 1-176, 1-179 to 1- 182, 1-185 to 1-192, 1-201 to 1-204, 1-207, 1-208, 1-211 to 1-228, 1-231 to 1-234, 1-237 to 1-245, 1-277, 1-2791-282, 1-2851-292, 1-2951-298, 1-300-1-312, 1-315-1-317, 1-319-1- 322, 1-325 to 1-327, 1-329 to 1-332, 1-335 to 1-333, 1-339 to 1-342, 1-345 to 1-347, 1-349, 1-351, 1-352, 1-355 to 1-357, 1-359 to 1-362, 1-365, 1-366, 2-1, 2-2, 2-13, 2-14, 2-17 to 2- 35, 2-38 to 2-40, 2-42 to 2-45, 2-49, 2-50, 2-59 to 2-62, 2-65 to 2-83, 2-90, 2-92 to 2-95, 2-100, 2-102 to 2-105, 2-107, 2-111, 2-112, 2-114 to 2-117, 2-119, 2-147, 2-148, 2- 159, 2-160, 2-163 to 2-181, 2-184 to 2-186, 2-188 to 2-192, 2-195, 2-196, 2-205, 2-208, 2-212 to 2-227, 2-232 to 2-234, 2-236 to 2-239, 2-291 to 2-293, 2-295 to 2-300, 2-304 to 2-306, 2-308 to 2- 311, 2-317 2-319, 2-321 to 2-326, 2-328, 2-329, 2-333, 2-334, 2-336 to 2-339, 2-341, 2-345, 2-346, 2- 348 ~ 2-351, 2-353, 2-357, 2-358, 2-360 ~ 2-363, 2-365, 2-369, 2-370, 2-372 ~ 2-375, 2-377, 2-381, 2-382, 2-384 to 2-387, 2-389, 2-393, 2-395, 2-397, 2-399, 2-401, 2-403, 2-405, 2- 407, 2-409, 2-411, 2-413, 2-415, 2-417, 2-419, 2-421, 2-423, 2-425, 2-427, 2-429, 2-431, 2-433, 2-435, 2-437, 2-439, 2-441, 2-443, 2-445, 2-447, 3-1 to 3-64 and 3-97 to 3-104, Most preferably
Illustrative compound number 1-61: 8- {2- [bis- (4-fluorophenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one ,
Illustrative compound number 1-62: 8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one ,
Exemplified compound number 1-93: 8- {2- [bis (4-fluorophenyl) methoxy] ethyl} -spiro [(8-azabicyclo [3.2.1] octane) -3,5 '-(3-methylthiomethyl) -Oxazolidine] -2'-one,
Illustrative compound number 1-94: 8- {3- [bis (4-fluorophenyl) methoxy] propyl} -spiro [(8-azabicyclo [3.2.1] octane) -3,5 ′-(3-methylthiomethyl) -Oxazolidine] -2'-one,
Illustrative compound number 1-137: 8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylsulfinylmethyl-1-oxa-3,8-diazaspiro [4,5] decane- 2-on,
Illustrative compound number 1-147: 8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decane-2 -on,
Illustrative compound number 1-148: 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decane-2 -on,
Illustrative compound number 1-298: 8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4, 5] Decan-2-one,
Exemplified Compound No. 1-317: 8- {2-[(4-Cyanophenyl) (4'-trifluoromethylphenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4, 5] Decan-2-one,
Illustrative compound number 2-49: 8- [3- (4-fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
Illustrative compound number 2-147: 8- [3- (3-trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane- 2-on,
Illustrative compound number 2-159: 8- [3- (3-trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) propyl] -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4 , 5] decan-2-one,
Illustrative compound number 2-184: 8- {2- [bis (3-trifluoromethylphenyl) methoxy] ethyl} -spiro [(8-azabicyclo [3.2.1] octane) -3,5'-oxazolidine] -2 '-on,
Illustrative compound number 2-291: 8- [3- (3-cyanophenoxy) -3- (3-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
Illustrative compound number 2-304: 8- [3- (4-cyanophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
Illustrative compound number 2-317: 8- [3- (3-cyanophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2- on,
Illustrative compound number 2-333: 8- [3- (4-cyanophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2- on,
Illustrative compound number 2-401: 8- [3- (2-fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one, And Exemplified Compound No. 3-52: 8- {3-[(3-cyanophenyl) (3′-trifluoromethylphenyl) methoxy] propyl} -3-ethyl-1-oxa-3,8-diazaspiro [4, 5] Decan-2-one.

  The compound having the general formula (I), (II) or (III) of the present invention has an excellent IL-4 and / or IL-10 production-inducing action and is useful as a Th1-selective immunosuppressive agent. .

  The compound having the general formula (I), (II) or (III) of the present invention can be produced according to the method described below.

  Method A is a method for producing compounds (I), (II) and (III).

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , m and n are as defined above,
Other R ^1a and R ^2a is an amino group and / or hydroxy group contained as a substituent group of R ¹ and R ² is a protected amino group which may and / or hydroxy group, R ¹ and R ² A group similar to the group in the definition of the group of
R ^5a is a lower alkyl group, a lower alkylsulfinyl lower alkyl group, a lower alkylsulfonyl lower alkyl group, a lower alkyl group having 1 to 3 oxygen atoms in the carbon chain, or 1 to 3 sulfur atoms in the carbon chain. Or a lower alkyl group having 1 to 3 nitrogen atoms in the carbon chain, or 1 to 3 carbon atoms in the carbon chain substituted with 1 to 3 groups selected from the substituent group b. A lower alkyl group having an oxygen atom, a sulfur atom or a nitrogen atom [provided that, in the compound (Ia), when R ³ and R ⁴ are hydrogen atoms, R ^5a represents a lower alkyl group or one oxygen atom in the carbon chain; A group other than a lower alkyl group having an atom is shown. ],
R ^5b is a group having the formula —CO—R ⁷ (wherein R ⁷ has the same meaning as described above);
R ^5c is a lower alkyl group, a lower alkylsulfinyl lower alkyl group, a lower alkylsulfonyl lower alkyl group, a lower alkyl group having 1 to 3 oxygen atoms in the carbon chain, or 1 to 3 sulfur atoms in the carbon chain. 1 to 3 lower alkyl groups having 1 to 3 nitrogen atoms in the carbon chain, or 1 to 3 substituents selected from the substituent group b, and 1 to 3 carbon atoms in the carbon chain A lower alkyl group having an oxygen atom, a sulfur atom or a nitrogen atom,
Q is usually not particularly limited as long as it is a group capable of leaving as a nucleophilic residue, but is preferably a halogen atom such as chlorine, bromine or iodine; a trihalogenomethyloxy group such as trichloromethyloxy; Lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyl An arylsulfonyloxy group such as oxy, and most preferably a halogen atom or a lower alkanesulfonyloxy group,
X is a halogen atom.

In the above, the “protecting group” of the “optionally protected amino group” in the definition of R ^1a and R ^2a is not particularly limited as long as it is a protecting group of an amino group used in the field of organic synthetic chemistry. For example, “aliphatic acyl group”; “aromatic acyl group”; “alkoxycarbonyl group”; “alkenyloxycarbonyl group”; “aralkyloxycarbonyl group” in the “general protecting group for esters of hydroxy group” "Silyl group" or a group similar to "aralkyl group" or N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenyl “Substituted to form a Schiff base, such as methylene, (5-chloro-2-hydroxyphenyl) phenylmethylene Methylene group ”, preferably aliphatic acyls, alkoxycarbonyls or alkenyloxycarbonyls, more preferably alkoxycarbonyls, most preferably methoxycarbonyl or ethoxycarbonyl groups. is there.

In the above, the “protecting group” of the “hydroxy group that may be protected” in the definition of R ^1a and R ^2a is not particularly limited as long as it is a protecting group of a hydroxy group used in the field of organic synthetic chemistry. For example, it has the same meaning as the above-mentioned “general protecting group for esters of hydroxy group”, preferably aliphatic acyls, aromatic acyls or silyls, and more preferably silyls. Most preferably, it is a trimethylsilyl or triethylsilyl group.

  Step A1 is a step of producing a compound having the general formula (VI). In a inert solvent, in the presence of a base, the compound having the general formula (IV) is converted to a compound having the general formula (V) or a compound thereof. It is carried out by reacting with an acid addition salt (for example, a mineral acid salt such as hydrochloride, nitrate, sulfate).

  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, aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether. , Aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, ethyl formate, propyl acetate, acetic acid Esters such as butyl, diethyl carbonate, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethers such as diethylene glycol dimethyl ether, acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophor , Ketones such as cyclohexanone, nitro compounds such as nitroethane and nitrobenzene, nitriles such as acetonitrile and isobutyronitrile, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl -2-pyrrolidone, N-methylpyrrolidinone, amides such as hexamethylphosphoric triamide, dimethyl sulfoxide, sulfoxides such as sulfolane, preferably ketones, amides, ethers or nitriles Most preferred are ketones or amides.

  Examples of the base used in the above reaction include alkali metal iodides such as lithium iodide, sodium iodide and potassium iodide, alkali alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, and hydrogen carbonate. Alkali metal bicarbonates such as lithium, sodium bicarbonate, potassium bicarbonate, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, or lithium fluoride, sodium fluoride, fluoride Combination with inorganic bases such as alkali metal fluorides such as potassium, or N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, 4-pyrrolidinopyridine , Picoline, 4- (N, N-dimethyla Mino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,4-diazabicyclo [4.3.0] octane (DABCO), 1 , 8-diazabicyclo [5.4.0] -7-undecene, and is preferably a combination of a metal iodide and an alkali metal carbonate.

  While the reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of the base, it is generally 0 ° C. to 250 ° C. (preferably 70 ° C. to 170 ° C.).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of base, and the reaction temperature, it is generally 15 minutes to 48 hours (preferably 2 hours to 24 hours).

  After completion of the reaction, the target compound (VI) of this reaction is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, After washing with water and the like, it is obtained by drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate and the like and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.

In step (A2), in compound (I),
(I) R ⁵ is a lower alkyl group, a lower alkylsulfinyl lower alkyl group, a lower alkylsulfonyl lower alkyl group, a lower alkyl group having 1 to 3 oxygen atoms in the carbon chain, or 1 to 3 in the carbon chain A lower alkyl group having 1 to 3 sulfur atoms, a lower alkyl group having 1 to 3 nitrogen atoms in the carbon chain, or 1 to 3 in a carbon chain substituted with 1 to 3 groups selected from the substituent group b A lower alkyl group having three oxygen atoms, sulfur atoms or nitrogen atoms [provided that when R ³ and R ⁴ are hydrogen atoms, R ⁵ is a lower alkyl group or one oxygen atom in the carbon chain; A group other than a lower alkyl group having Compound (Ia) or (ii) Compound (Ib) in which R ⁵ is a group having the formula —CO—R ⁷ (wherein R ⁷ has the same meaning as described above).
Is a process of manufacturing.

(I) Production Method of Compound (Ia) Compound (Ia) is obtained by reacting Compound (VI) with a base, metal or organometallic reagent in the presence or absence (preferably in the presence) of an inert solvent. After reacting with the compound having the general formula (VIIa), it is produced by removing the amino and / or hydroxy protecting groups in R ^1a and R ^{2a as} desired.

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene chloride, and the like. Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran, Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether, bases such as pyridine and triethylamine, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, and preferably amides or A A Le class.

  Examples of the base used in the above reaction include alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, lithium carbonate and potassium carbonate. Alkali metal carbonates, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, pyridine, triethylamine, triisopropylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, picoline, 4-dimethylaminopyridine, 1 , 4-diazabicyclo [4.3.0] octane, 1,8-diazabicyclo [5.4.0] -7-undecene, and preferred are alkali metal hydrides.

  The metal used in the above reaction is preferably lithium, potassium or sodium.

  The organometallic reagent used in the above reaction is, for example, butyllithium, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, lithium diisopropylamide, ethylmagnesium bromide or isopropylmagnesium bromide. .

  In this step, for example, tetrabutylammonium iodide, potassium iodide or sodium iodide can be used as a catalyst to promote the reaction.

  The reaction temperature varies depending on the raw material compound, the inert solvent used, the base, the metal, and the organometallic reagent, but is usually −78 ° C. to 100 ° C. (preferably 0 ° C. to room temperature).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of base, metal, organometallic reagent, and reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 24 hours). .

  The removal of the protecting group of the amino group and / or hydroxy group varies depending on the type, but generally a method well known in the art of synthetic organic chemistry, such as TWGreen, (Protective Groups in Organic Synthesis), John Wiley & Sons: JFWMcOmis , (Protective Groups in Organic Chemistry), according to the method described in Plenum Press.

  When the amino-protecting group is a silyl group, it is usually treated with a compound that generates a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, or potassium fluoride. Is removed.

  The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether can be used. Is preferred.

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

  When the amino protecting group is an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group or a substituted methylene group forming a Schiff base, it is treated with an acid or a base in the presence of an aqueous solvent. Can be removed.

  The acid used in the above reaction is not particularly limited as long as it is an acid used for removing the amino-protecting group, and examples thereof include hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid, An inorganic acid such as phosphoric acid or nitric acid, preferably hydrochloric acid.

  The base used in the above reaction is not particularly limited as long as it is a base used for removing the amino-protecting group, but is preferably a lithium carbonate, sodium carbonate, potassium carbonate or the like. Alkali alkali metal carbonates; alkali alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide Or ammonia such as aqueous ammonia or concentrated ammonia-methanol.

  Examples of the inert solvent used in the above reaction include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, and isoamyl alcohol. , Diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; water; or water and the above A mixed solvent with an organic solvent, preferably alcohols (most preferably ethanol).

  The reaction temperature and reaction time vary depending on the raw material compound, the solvent and the acid or base used, and are not particularly limited. However, in order to suppress side reactions, the reaction temperature is usually 0 ° C. to 150 ° C. The time is 1 hour to 10 hours.

  When the amino-protecting group is an aralkyl group or an aralkyloxycarbonyl group, it is usually removed by contact with a reducing agent in an inert solvent (preferably catalytic reduction at room temperature under a catalyst). A method or a method of removing using an oxidizing agent is preferred.

  The inert solvent used for the removal by catalytic reduction is not particularly limited as long as it is inert to this reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; toluene, Aromatic hydrocarbons such as benzene and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether Ethers: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, Cyclohexanol, methyl cellosolve Alcohols; organic acids such as acetic acid; water; or a mixed solvent of the above solvent and water, preferably alcohols, ethers, organic acids or water (most preferably Alcohols or organic acids).

  The catalyst used for the removal by catalytic reduction is preferably palladium-carbon, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate.

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

  Although the reaction temperature and reaction time vary depending on the raw material compound, catalyst, inert solvent, etc., the reaction temperature is usually 0 ° C. to 100 ° C., and the reaction time is 5 minutes to 24 hours.

  The inert solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this 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, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane. Ethers such as diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; or sulfoxides such as dimethyl sulfoxide, sulfolane, Preferred are halogenated hydrocarbons, ethers or sulfoxides (most preferably halogenated hydrocarbons or sulfoxides).

  The oxidizing agent used in the above reaction is not particularly limited as long as it is an oxidizing agent used for removing the amino-protecting group, but preferably potassium persulfate, sodium persulfate, ammonium cerium nitrite. Late (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

  The reaction temperature and reaction time vary depending on the raw material compound, oxidizing agent, solvent, etc., but the reaction temperature is usually from 0 ° C. to 150 ° C., and the reaction time is from 10 minutes to 24 hours.

  In addition, when the amino-protecting group is an aralkyl group, the protecting group can be removed using an acid.

  The acid used in the reaction is not particularly limited as long as it is an acid used for removing the aralkyl group which is a protecting group for the amino group. For example, hydrochloric acid, hydrobromic acid, sulfuric acid, perchlorine Inorganic acids such as acids and phosphoric acids; Bronsted acids such as acetic acid, formic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc .; zinc chloride Or Lewis acid such as tin tetrachloride, boron trichloride, boron trifluoride, boron tribromide; or an acidic ion exchange resin, preferably an inorganic or organic acid (most preferably hydrochloric acid, acetic acid or tri Fluoroacetic acid).

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene, Aromatic hydrocarbons such as toluene and xylene; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride; such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and diethyl carbonate Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol -L, t-butanol, isoamyl amyl Alcohols such as alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; water; or a mixed solvent of the above solvents Preferred are ethers, alcohols or water (most preferably dioxane, tetrahydrofuran, ethanol or water).

  The reaction temperature varies depending on the raw material compound, the acid used, the solvent, and the like, but is usually −20 ° C. to boiling point temperature (preferably 0 ° C. to 100 ° C.).

  The reaction time varies depending on the raw material compound, the acid used, the inert solvent, the reaction temperature, etc., but is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours).

  When the amino protecting group is an alkenyloxycarbonyl group, the amino protecting group is usually a substituted methylene group that forms the aliphatic acyl group, aromatic acyl group, alkoxycarbonyl group or Schiff base. It is carried out by treating with a base in the same manner as in the removal reaction in some cases.

  In the case of an allyloxycarbonyl group, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with few side reactions.

  When the protecting group of the hydroxy group is a silyl group, it is usually treated with a compound that generates a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride, or Inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid It can be removed by treatment with an organic acid.

  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 this reaction, but preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether. Ethers such as: acetonitrile, nitriles such as isobutyronitrile; organic acids such as acetic acid; water; or a mixed solvent of the above solvents.

  Although the reaction temperature and reaction time vary depending on the raw material compound, catalyst, inert solvent, etc., the reaction temperature is usually 0 ° C. to 100 ° C. (preferably 10 ° C. to 50 ° C.), and the reaction time is 1 Hours to 24 hours.

  When the protective group for the hydroxy group is an aralkyl group or an aralkyloxycarbonyl group, it is usually removed by contacting with a reducing agent in an inert solvent (preferably catalytic reduction at room temperature under a catalyst). A method or a method of removing using an oxidizing agent is preferred.

  The inert solvent used for the removal by catalytic reduction is not particularly limited as long as it does not participate in this reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; toluene, benzene Aromatic hydrocarbons such as xylene; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; methanol; Alcohols such as ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve Class; formamide, Amides such as methylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide; fatty acids such as formic acid and acetic acid; water; or a mixed solvent of the above solvents, preferably alcohol -Ru (most preferably methanol or ethanol).

  The catalyst used for the removal by catalytic reduction is not particularly limited as long as it is used for removing the protective group of the hydroxy group by catalytic reduction. For example, palladium-carbon, palladium-black, lane- Nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride or palladium-barium sulfate, preferably palladium-carbon.

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

  The reaction temperature and reaction time vary depending on the raw material compound, catalyst, inert solvent, etc., but the reaction temperature is usually 0 ° C. to 100 ° C. (preferably 20 ° C. to 70 ° C.), and the reaction time is 5 Minutes to 48 hours (preferably 1 to 24 hours).

  The inert solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a water-containing organic solvent, for example, ketones such as acetone; methylene chloride, chloroform , Halogenated hydrocarbons such as carbon tetrachloride; nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide Or sulfoxides such as dimethyl sulfoxide.

  The oxidizing agent used in the reaction is not particularly limited as long as it is an oxidizing agent used for removing the protective group for the hydroxy group, but preferably potassium persulfate, sodium persulfate, ammonium cerium nitrite. Late (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) is used.

  The reaction temperature and reaction time vary depending on the raw material compound, oxidizing agent, inert solvent, etc., but the reaction temperature is usually 0 ° C. to 150 ° C. and the reaction time is 10 minutes to 24 hours.

  Further, in liquid ammonia or methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexane In alcohols such as hexanol and methyl cellosolve, it can be removed by reacting alkali metals such as metallic lithium and metallic sodium at −78 ° C. to 0 ° C.

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

  The inert solvent used in the above reaction is not particularly limited as long as it does not participate in this reaction, but preferably halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride; Nitriles; or a mixed solvent of the above solvents.

  The reaction temperature and reaction time vary depending on the raw material compound, inert solvent, etc., but the reaction temperature is usually 0 ° C. to 50 ° C. and the reaction time is 5 minutes to 72 hours.

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

  When the protecting group for the hydroxy group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it is removed by treatment with a base in an inert solvent.

  The base used in the reaction is not particularly limited as long as it is a base used for removing the protective group for the hydroxy group. For example, an alkali alkali metal carbonate such as lithium carbonate, sodium carbonate, or potassium carbonate is used. Salts; alkali alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; alkali alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium Metal alkoxides such as methoxide, sodium ethoxide, potassium tert-butoxide; or ammonia such as aqueous ammonia and concentrated ammonia-methanol, preferably alkali alkali metal hydroxides, metals Alkoxides or ammonia (most preferably alkaline A Li metal hydroxides or metal alkoxides).

  The inert solvent used in the above reaction is not particularly limited as long as it is used in a normal hydrolysis reaction. For example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether are used. Ethers: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclo Preferred are alcohols such as hexanol and methyl cellosolve; water; or a mixed solvent of the above solvents.

  Although the reaction temperature and reaction time vary depending on the raw material compound, the base used, an inert solvent, etc., in order to suppress side reactions, the reaction temperature is usually −20 ° C. to 150 ° C., and the reaction time is 1 to 10 hours.

  When the protecting group for a hydroxy group is an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group or a substituted ethyl group, it is usually treated with an acid in an inert solvent. It is removed by processing.

  The acid used in the above reaction is not particularly limited as long as it is an acid used for removing the protective group for the hydroxy group, and examples thereof usually include those used as Bronsted acid or Lewis acid. Preferably, hydrogen chloride; inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid; or Bronsted acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, organic acids such as p-toluenesulfonic acid: trifluoride A Lewis acid such as boron, and a strongly acidic cation exchange resin such as Dowex 50W can also be used.

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene, toluene, Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n- Butanol, isobutanol, t-butanol , Isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, alcohols such as methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; water; or a mixture of the above solvents Solvent, preferably ethers or alcohols (most preferably tetrahydrofuran or methanol).

  Although the reaction temperature and reaction time vary depending on the raw material compound, the acid used, the inert solvent, etc., the reaction temperature is usually −10 ° C. to 200 ° C. (preferably 0 ° C. to 150 ° C.). The time is 5 minutes to 48 hours (preferably 30 minutes to 10 hours).

  When the protecting group for a hydroxy group is an alkenyloxycarbonyl group, it is usually the same as the removal reaction conditions when the protecting group for a hydroxy group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group. This can be achieved by treatment with a base.

  In the case of an allyloxycarbonyl group, there is a method of removing it using palladium and triphenylphosphine or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) .hexafluorophosphate. It is simple and can be carried out with few side reactions.

  Moreover, the removal of the protecting group of an amino group and / or a hydroxy group can be carried out sequentially in the desired removal reaction in any order.

Further, in the compound (Ia), R ⁵ is a lower alkyl group having one sulfur atom in the carbon chain in an inert solvent (preferably water or ketones), and an oxidizing agent (for example, Manganese compounds such as potassium permanganate and manganese dioxide; chromic acid such as chromium oxide, dichromate, pyridinium chlorochromate and pyridinium dichromate; osmium-based oxidants such as osmium tetroxide; ruthenium tetroxide Ruthenium-based oxidants; hydrogen peroxide, t-butyl hydroperoxide, cumene hydroperoxide, peracetic acid, m-chloroperbenzoic acid, peracids such as dimethyldioxirane, peroxides; dimethyl sulfoxide, quinone, etc. Oxidation using various organic compounds; Oxidation using oxygen and ozone; Selenium dioxide, Sodium hypochlorite, Bromine, Chlorine Such as selenium, halogen-based oxidizing agent; oxidizing agent using microorganisms, preferably peracid or peroxide) and 5 at -78 ° C to 100 ° C (preferably -20 ° C to room temperature). By reacting for ⁵ minutes to 48 hours (preferably 15 minutes to 24 hours), a compound in which R ⁵ is a lower alkylsulfonyl lower alkyl group can be separately produced. This reaction can be carried out sequentially before and after the removal of the protective group for the amino group and / or hydroxy group, which is carried out as desired.

(Ii) Production Method of Compound (Ib) Compound (Ib) is obtained by using compound (VI) in the presence or absence (preferably in the presence) of an inert solvent using a base, an organometallic reagent or a metal. After reacting with a compound having the general formula (VIIb), it is produced by removing the amino and / or hydroxy protecting groups in R ^1a and R ^{2a as} desired.

  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 materials to some extent. For example, compound (VI) is converted to compound (VIIa) in the above-mentioned Method A, Step A2. Examples thereof include those similar to those used in the reaction with ether, preferably ethers, hydrocarbons or amides, and most preferably ethers.

  Examples of the organometallic reagent and metal used in the above reaction include the same ones as used when reacting compound (VI) with compound (VIIa) in the above-mentioned Method A, Step A2. Preferred is butyl lithium.

  The reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of reagent, but is usually -78 ° C to around room temperature (preferably -20 ° C to 0 ° C).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of reagent, and the reaction temperature, it is generally 5 minutes to 98 hours (preferably 5 minutes to 24 hours).

The method for removing the protecting group for amino group and / or hydroxy group in R ^1a and R ^{2a, which} is carried out as desired, is carried out in the same manner as the method for removing the protecting group for amino group and / or hydroxy group.

  After completion of the reaction, the target compound (Ia) or (Ib) of this reaction is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, After washing with water and the like, it is obtained by drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate and the like and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.

  Step A3 is a step of producing a compound having the general formula (IX). In the presence of a base in an inert solvent, the compound having the general formula (VIII) is converted to the compound (V) or an acid addition salt thereof. This step is carried out by reacting, and this step is carried out in the same manner as the above-mentioned Method A step A1.

In step A4, in compound (II),
(I) R ⁵ is a lower alkyl group, a lower alkylsulfinyl lower alkyl group, a lower alkylsulfonyl lower alkyl group, a lower alkyl group having 1 to 3 oxygen atoms in the carbon chain, or 1 to 3 in the carbon chain A lower alkyl group having 1 to 3 sulfur atoms, a lower alkyl group having 1 to 3 nitrogen atoms in the carbon chain, or 1 to 3 in a carbon chain substituted with 1 to 3 groups selected from the substituent group b Compound (IIa) which is a lower alkyl group having three oxygen atoms, sulfur atoms or nitrogen atoms, or (ii) Compound (IIb) wherein R ⁵ is a group having the formula —CO—R ⁷
Is a process of manufacturing.
(I) Production Method of Compound (IIa) Compound (IIa) is obtained by reacting compound (IX) with a base, metal or organometallic reagent in the presence or absence (preferably in the presence) of an inert solvent. After reacting with the compound having the general formula (VIIc), the amino group and / or hydroxy protecting group in R ^1a and R ^2a is optionally removed, and this step is the above-mentioned Method A, Step A2 In the same manner as in the production of compound (Ia).
(Ii) Method for producing compound (IIb) Compound (IIb) is obtained by using compound (IX) in the presence or absence (preferably in the presence of an inert solvent) using a base, metal or organometallic reagent. After reacting with the compound having the general formula (VIIb), it is optionally produced by removing the protecting group of the amino group and / or hydroxy group in R ^1a and R ^2a . In the same manner as in the production of compound (Ib).

Step A5 is a step of producing compound (IIc) in which R ⁵ is a hydrogen atom in compound (II), and protecting the amino group and / or hydroxy group in R ^1a and R ^2a of compound (IX). This step is carried out in the same manner as the method for removing the amino and / or hydroxy protecting group in the above-mentioned Method A, Step A2.

Step A6 is a step for producing compound (III). In compound (VI), a base, metal or organometallic reagent is used in the presence or absence (preferably in the presence) of an inert solvent. After reacting the compound (VIa) in which R ^1a and R ^2a are hydrogen atoms with the compound having the general formula (X), the amino and / or hydroxy protecting groups in R ^1a and R ^2a are optionally removed. This step is carried out in the same manner as the method for producing compound (Ib) in the above-mentioned Method A, Step A2.

  Method B is a method for producing compound (IV), which is a raw material compound of Method A.

In the above formula, R ^1a , R ^2a , n, Q and X are as defined above, and R ⁸ is a lower alkyl group, a halogeno lower alkyl group or phenyl, p-tolyl, p-nitrophenyl. Such a lower alkyl group or an aryl group which may be substituted with 1 to 3 of nitro is preferred, and a lower alkyl group is preferred.

  Step B1 is a step of producing a compound having the general formula (XIII), using a metal or organometallic reagent in the presence or absence (preferably in the presence) of an inert solvent, It is carried out by reacting a compound having the general formula (XI) with a compound having the general formula (XII).

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene, hexane , Aliphatic hydrocarbons such as heptane, ligroin and petroleum ether, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, and ethers are preferred.

  Examples of the metal and organometallic reagent used in the above reaction include the same as those used in the above-mentioned Method A, Step A2.

  While the reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of reagent, it is generally −100 ° C. to room temperature (preferably −90 ° C. to 0 ° C.).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of reagent, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 1 hour).

  Step B2 is a step of producing a compound having the general formula (XIV), and is performed by converting the hydroxyl group of compound (XIII) to a functional group leaving as a nucleophilic residue.

  The method of converting a hydroxyl group into a functional group varies depending on the target functional group, but can be generally performed as follows by a method well known in the art of organic synthetic chemistry.

  When the target functional group is a halogen atom, the reaction is performed by reacting compound (XIII) with a halogenating reagent in the presence or absence (preferably in the presence) of an inert solvent.

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene; organic acids such as acetic acid, formic acid, propionic acid; formamide, N, N-dimethylformamide, N, N Amides such as dimethylacetamide; water; preferably aromatic hydrocarbons, halogenated hydrocarbons or water.

  The halogenating reagent used in the above reaction includes, for example, inorganic acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid, halogen molecules such as bromine and chlorine; phosphorus trichloride, phosphorus tribromide, five Phosphorus reagents such as phosphorus bromide, phosphorus pentachloride, phosphorus oxychloride; sulfinic acids such as thionyl chloride, thionyl bromide, toluenesulfonic acid chloride; or sulfonic acid reagents, preferably phosphorus reagents It is.

  While the reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of halogenating reagent, it is generally -78 ° C to 200 ° C (preferably -78 ° C to 100 ° C).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the halogenating reagent, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 10 hours).

  When the target functional group is a lower alkanesulfonyloxy group, a halogeno lower alkanesulfonyloxy group or an arylsulfonyloxy group, the compound (XIII) is added to the compound (XIII) in the presence or absence (preferably in the presence) of an inert solvent. On the other hand, this reaction can be performed by reacting with a corresponding acid halide or acid anhydride using a base.

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene chloride, and the like. , Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether, organic bases such as pyridine and triethylamine, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, and preferably ,Halo A down hydrocarbons or organic bases.

  Examples of the base used in the above reaction include those similar to those used in the above-mentioned Method A, Step A2, and are preferably organic amines.

  Examples of the acid halide or acid anhydride used in the above reaction include fatty acid halides such as acetyl chloride, acetyl bromide, and propionyl chloride, fatty acid anhydrides such as acetic anhydride and propionic anhydride, and methanesulfonic acid chloride. , Sulfonyl acid halides such as toluenesulfonic acid chloride, methanesulfonic acid anhydride, sulfonic acid anhydride such as trifluoromethanesulfonic acid anhydride, and preferably acid chloride.

  The reaction temperature varies depending on the raw material compound, the inert solvent used, the acid halide, and the acid anhydride, but is usually -80 ° C to 100 ° C (preferably -80 ° C to room temperature).

  While the reaction time varies depending on the raw material compound, the inert solvent used, acid halide, acid anhydride, and reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 3 hours).

  Step B3 is a step for producing compound (IV). In the presence or absence (preferably in the presence) of an inert solvent, compound (XIV) is represented by the general formula (XV) using an acid as a catalyst. It is carried out by reacting with a compound having

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene, hexane , Aliphatic hydrocarbons such as heptane, ligroin and petroleum ether, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, and ethers are preferred.

  Examples of the acid used in the above reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid, acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid. Bronsted acids such as organic acids such as trifluoroacetic acid and trifluoromethanesulfonic acid, Lewis acids such as zinc chloride, tin tetrachloride, boron trifluoride, boron tribromide, and acidic ion exchange resins. Is an organic acid.

  While the reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of acid, it is generally 0 ° C. to 200 ° C. (preferably 20 ° C. to 150 ° C.).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the acid, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 30 minutes to 12 hours).

  The reaction may be accelerated by using a dehydrator such as Dean-Stark.

  Step B4 is a step for separately producing a compound having the general formula (IV), and using an acid as a catalyst in the presence or absence (preferably present) of an inert solvent, compound (XIII) Is reacted with compound (XV).

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene, hexane, Aliphatic hydrocarbons such as heptane, ligroin and petroleum ether, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, and aromatic hydrocarbons are preferred.

  Examples of the acid used in the above reaction include those similar to those used in the B method, step B3, and are preferably organic acids.

  While the reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of acid, it is generally 0 ° C. to 200 ° C. (preferably 20 ° C. to 150 ° C.).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of acid, and the reaction temperature, it is generally 15 minutes to 48 hours (preferably 30 minutes to 15 hours).

  The reaction may be accelerated by using a dehydrator such as Dean-Stark.

  Step B5 is a step for producing a compound having the general formula (XVII). In general, in the presence or absence (preferably in the presence) of an inert solvent, in the presence of a base, the compound (XIII) This is done by reacting a compound having the formula (XVI).

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene chloride, and the like. , Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane and diethylene glycol dimethyl ether, organic bases such as pyridine and triethylamine, amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, Ami It is a class or ethers.

  Examples of the base used in the above reaction include those similar to those used in the above-mentioned Method A, Step A2, and are preferably organic amines or alkali metal hydrides.

  While the reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of the base, it is generally −78 ° C. to 100 ° C. (preferably −50 ° C. to room temperature).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of base, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 1 hour).

  Step B6 is a step of producing a compound having the general formula (XVIII), and using compound (XVII) in the presence or absence (preferably in the presence) of an inert solvent, using a boration reagent. Boronation is followed by subsequent oxidative treatment.

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene Halogenated hydrocarbons such as chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and ethers are preferred.

  The boronation reagent used in the above reaction is, for example, a boronation reagent such as borane-dimethyl sulfide complex, borane-tetrahydrofuran complex, 9-borabicyclo [3.3.1] nonane (9-BBN), and preferably 9-borabicyclo [3.3.1] nonane (9-BBN).

  The oxidative treatment in the above reaction can be carried out by a well-known method in the ordinary organic synthesis technology, for example, hydrogen peroxide-hydroxylation as in the method described in Org. Syn. Coll. Vol. VII.259. Can be performed using sodium.

  The reaction temperature varies depending on the raw material compound, the inert solvent used, and the boronation reagent, but is usually -78 ° C to 100 ° C (preferably 0 ° C to room temperature).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the boronation reagent, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 24 hours).

  Step B7 is a step of producing a compound having the general formula (IVa). In the presence or absence (preferably in the presence) of an inert solvent, compound (XVIII) is treated in the presence of a base. It is carried out by reacting with a compound having the general formula (XIX).

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene chloride, and the like. , Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether, organic bases such as pyridine and triethylamine, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, and preferably ,Halo A down hydrocarbons or organic bases.

  Examples of the base used in the above reaction include those similar to those used in the above-mentioned Method A, Step A2, and are preferably organic amines.

  While the reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of the base, it is generally −78 ° C. to 100 ° C. (preferably −50 ° C. to room temperature).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the base, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 3 hours).

  After completion of the reaction, the target compound in each step of Method B is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, After washing with water and the like, it is obtained by drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate and the like and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.

  Method C is a method for producing compound (VIII), which is a raw material compound of Method A.

In the above formula, R ^1a , R ^2a , m, n, and Q are as defined above.

  Step C1 is a step of producing a compound having the general formula (XXI), and is performed by reducing the compound having the general formula (XX) in an inert solvent.

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene Halogenated hydrocarbons such as chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane and diethylene glycol dimethyl ether, bases such as pyridine and triethylamine, amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, and alcohols such as methanol and ethanol An Lumpur acids, and is preferably an alcohol.

  Examples of the reducing agent used in the above reaction include sodium borohydride, lithium borohydride, borohydride alkali metals such as cyanoborohydride, diisobutylaluminum hydride, lithium aluminum hydride, lithium ethoxylate hydride. Aluminum hydride compounds such as sodium aluminum, tellurium hydride, diisobutylaluminum hydride, hydride reagents of organoaluminum hydride reducing agents such as bismethoxyethoxyaluminum sodium hydride, alkali metals such as sodium and lithium Preferred are alkali metal borohydrides.

  While the reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of reducing agent, it is generally −20 ° C. to 80 ° C. (preferably 0 ° C. to room temperature).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of reducing agent, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 3 hours).

  Step C2 is a step for producing compound (VIII). In an inert solvent, compound (XXI) and compound having general formula (XXII) are reacted with Mitsunobu reaction using a phosphine reagent and an azodicarboxylic acid reagent. It is carried out by condensation.

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene Halogenated hydrocarbons such as chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane and diethylene glycol dimethyl ether, bases such as pyridine and triethylamine, amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, preferably aromatic hydrocarbon Or ethers.

  The phosphine reagent used in the above reaction is, for example, tributylphosphine or triphenylphosphine, and preferably triphenylphosphine.

  Examples of the azodicarboxylic acid reagents used in the above reaction include azodicarboxylic acid esters such as azodicarboxylic acid diethyl ester and azodicarboxylic acid diisopropyl ester, and azodicarboxylic acid such as 1,1′-azobis (dimethylformamide). Acid amides, preferably azodicarboxylic acid esters.

  While the reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of reagent, it is generally −78 ° C. to 120 ° C. (preferably 0 ° C. to room temperature).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of reagent, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 2 hours).

  After completion of the reaction, the target compound in each step of Method C is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, After washing with water and the like, it is obtained by drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate and the like and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.

Method D is a method of producing compound (Va) in which R ³ and R ⁴ are hydrogen atoms in compound (V) and compound (V), which are the raw material compounds of method A.

In the above formula, R ³ and R ⁴ have the same meaning as described above, and R ⁹ represents a lower alkoxycarbonyl group (a group in which the “lower alkoxy group” is bonded to a carbonyl group, such as methoxycarbonyl, Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl a group, preferably a C ₁ -C ₄ alkoxycarbonyl group, most preferably a t- butoxycarbonyl group.) indicates, R ¹⁰ is the field of the synthesis of protective group (organic chemistry carboxy group Generally used as a protecting group for carboxy group in Is not particularly limited as long as it is, preferably, a lower alkyl group.) Indicates, W is shown lithium, sodium or potassium.

  Step D1 is a method for producing a compound having the general formula (XXV), and in the presence or absence (preferably in the presence) of an inert solvent, using a metal or organometallic reagent, This is carried out by reacting a compound having (XXIII) with a compound having general formula (XXIV).

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene Halogenated hydrocarbons such as chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether, bases such as pyridine and triethylamine, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, and preferably amides Or It is ethers.

  Examples of the metal and organometallic reagent used in the above reaction include the same as those used in the above-mentioned Method A, Step A2.

  The reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of reagent, but is usually -120 ° C to room temperature (preferably -78 ° C to 0 ° C).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of reagent, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 1 hour).

  Step D2 is a method for producing a compound having the general formula (XXVI), which is carried out by removing the protecting group of the carboxy group, and is generally a method well known in the art of synthetic organic chemistry, such as TWGreen, ( Protective Groups in Organic Synthesis), John Wiley & Sons: JFWMcOmis, (Protective Groups in Organic Chemistry), Plenum Press.

  For example, when the protecting group for the carboxy group is a lower alkyl group, the compound (XXV) is treated with a base in the presence or absence (preferably in the presence) of an inert solvent to convert the ester group to a carboxy group. This is done by converting.

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene Halogenated hydrocarbons such as chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether, bases such as pyridine, triethylamine, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, methanol, ethanol, n-prop And alcohols such as diol, i-propanol, n-butanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve, water, water, or a mixed solvent of the above solvents, and the like, preferably , Alcohols or a mixed solvent of water and alcohols.

  Examples of the base used in the above reaction include those similar to those used in the above-mentioned Method A, Step A2, and are preferably alkali metal hydroxides.

  The reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of the base, but is usually −20 ° C. to boiling point temperature (preferably 0 ° C. to boiling point temperature).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of base, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 5 hours).

  Step D3 is a method for producing a compound having the general formula (XXVII) by Curtius reaction. In the presence or absence (preferably in the presence) of an inert solvent, compound (XXVI) It is carried out by treatment with an azide reagent in the presence.

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene chloride, and the like. Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran, Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether, bases such as pyridine and triethylamine, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, etc., preferably aromatic hydrocarbon It is.

  Examples of the base used in the above reaction include those similar to those used in the above-mentioned Method A, Step A2, and are preferably organic amines.

  The azide used in the above reaction is, for example, a diaryl phosphate azide derivative such as diphenyl phosphate azide; a trialkylsilyl azide such as trimethylsilyl azide or triethylsilyl azide, or an azide such as sodium azide or potassium azide. Alkali metal salts, preferably diphenyl phosphate azide.

  The reaction temperature varies depending on the raw material compound, the inert solvent used, the azide reagent, and the type of the base, but is usually −20 ° C. to boiling temperature (preferably 0 ° C. to boiling temperature).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the azide reagent, the type of base, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 1 hour).

Step D4 is a step for producing compound (V), and is performed by treating compound (XXVII) with an acid in an inert solvent and removing the R ⁹ group.

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene, toluene, Aromatic hydrocarbons such as xylene; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; Esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol , T-butanol, isoamyl Alcohols such as cholol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; water; water or a mixture of the above solvents Solvent, preferably alcohols, ethers, or a mixed solvent of alcohols and ethers.

  Examples of the acid used in the above reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid; acetic acid, formic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid Bronsted acids such as organic acids such as trifluoroacetic acid, trifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, boron tribromide; acidic ion exchange resins; Yes, preferably an inorganic or organic acid (most preferably hydrochloric acid, acetic acid or trifluoroacetic acid).

  The reaction temperature varies depending on the raw material compound, the acid used, the inert solvent, and the like, but is usually −20 ° C. to boiling point temperature (preferably 0 ° C. to 100 ° C.).

  The reaction time varies depending on the raw material compound, the acid used, the inert solvent, the reaction temperature and the like, but is usually 15 minutes to 48 hours (preferably 30 minutes to 25 hours).

Step D5 is a step for producing compound (Va), and is performed by treating a compound having the general formula (XXVIIa) with an acid in an inert solvent and removing the R ⁹ group. Performed in the same manner as in the B method, B4 step.

  After completion of the reaction, the target compound in each step of Method D is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, After washing with water and the like, it is obtained by drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate and the like and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.

  Method E is a method for producing compounds (Ia), (Ib), (IIa), (IIb) and (III) separately from Method A.

In the above formula, R ¹ , R ^1a , R ² , R ^2a , R ³ , R ⁴ , R ^5a , R ^5b , R ^5c , R ⁶ , m, n and Q are as defined above.

Step E1 is a step for producing compound (Ia) or (Ib) separately from Method A. Compound (IV) is converted to general formula (XXVIIIa) or (XXVIIIb) in the presence of a base in an inert solvent. ) Or an acid addition salt thereof (for example, a mineral acid salt such as hydrochloride, nitrate, sulfate, etc.), and optionally protecting the amino group and / or hydroxy group in R ^1a and R ^2a . This is done by removing.

The method of reacting compound (IV) with compound (XXVIIIa) or (XXVIIIb) or an acid addition salt thereof is carried out in the same manner as in the above-mentioned Method A, Step A1, and if desired, the amino group and / or hydroxy in R ^1a and R ^2a The method for removing the protecting group is carried out in the same manner as the method for removing the protecting group for the amino group and / or hydroxy group in the step A2 of the method A.

Step E2 is a step for preparing compound (IIa) or (IIb) separately from method A. In an inert solvent, compound (VIII) is converted to general formula (XXVIIIc) or (XXVIIIb) in the presence of a base. ), Or an acid addition salt thereof, and then, if desired, the amino group and / or hydroxy protecting group in R ^1a and R ^2a is removed.

The method of reacting compound (VIII) with compound (XXVIIIc) or (XXVIIIb) or an acid addition salt thereof is carried out in the same manner as in the above-mentioned Method A, Step A1, and if desired, the amino group and / or hydroxy in R ^1a and R ^2a The method for removing the protecting group is carried out in the same manner as the method for removing the protecting group for the amino group and / or hydroxy group in Step A2 of Method A.

Step E3 is a step for producing compound (III) separately from Method A. In the presence of a base in an inert solvent, compound (IV) is converted to compound having general formula (XXIX) or an acid addition thereof. After reacting with a salt, the amino group and / or hydroxy protecting group in R ^1a and R ^2a is optionally removed.

The method of reacting compound (IV) with compound (XXIX) or an acid addition salt thereof is carried out in the same manner as in the above-mentioned Method A, Step A1, and optionally protecting groups for the amino group and / or hydroxy group in R ^1a and R ^2a . The method for removing is carried out in the same manner as the method for removing the protecting group for the amino group and / or hydroxy group in the above-mentioned Method A, Step A2.

  After completion of the reaction, the target compound in each step of Method E is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, After washing with water and the like, it is obtained by drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate and the like and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.

  Method F is a method for producing compounds (XXVIIIa), (XXVIIIb), (XXVIIIc), and (XXIX), which are raw material compounds of Method E.

In the above formula, R ³ , R ⁴ , R ^5a , R ^5b , R ^5c , R ⁶ , R ⁹ and X are as defined above.

Step F1 is a step for producing compound (XXVIIIa), and using a base, metal, or organometallic reagent in the presence or absence (preferably in the presence) of an inert solvent, compound (XXVII) Is reacted with compound (VIIa) followed by removal of the R ⁹ group.

The method of reacting compound (XXVII) with compound (VIIa) is carried out in the same manner as the method of reacting compound (IV) with compound (VIIa) in the above-mentioned Method A, step A2, and the method for removing R ⁹ group is: This is carried out in the same manner as the D method, the D4 step.

Step F2 is a step for producing compound (XXVIIIb). In the presence or absence (preferably in the presence) of an inert solvent, compound (XXVII) is prepared using a base, metal or organometallic reagent. Is reacted with compound (VIIb) followed by removal of the R ⁹ group.

Method of compound (XXVII) with a compound (VIIb), said A method compounds of the A2 step (IV) compound is performed in the same manner as a method of reacting with (VIIb), a method of removing the R ⁹ groups are Performed in the same manner as the D method, the D4 step.

Step F3 is a step for producing compound (XXVIIIc), and using a base, metal, or organometallic reagent in the presence or absence (preferably in the presence) of an inert solvent, compound (XXVII) Is reacted with compound (VIIc) followed by removal of the R ⁹ group.

The method of reacting compound (XXVII) with compound (VIIc) is carried out in the same manner as the method of reacting compound (IV) with compound (VIIc) in Step A4 of Method A, and the method for removing the R ⁹ group is as follows: This is carried out in the same manner as the D method, the D4 step.

Step F4 is a step for producing compound (XXIX). In the presence or absence (preferably in the presence) of an inert solvent, compound (XXVIIa) is reacted with compound (X) using a base. Followed by removal of the R ⁹ group.

The method of reacting compound (XXVIIa) with compound (X) is carried out in the same manner as the method of reacting compound (VIa) with compound (X) in the above-mentioned Method A, Step A6, and the method for removing R ⁹ group is as follows: Performed in the same manner as in Method A, Step A6.
This step is carried out in the same manner as the method for producing compound (Ia) in the above-mentioned Method A, Step A2.

  After completion of the reaction, the target compound in each step of Method F is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, After washing with water and the like, it is obtained by drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate and the like and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.

  Method G is a method for producing compound (XXIa) wherein n is 2 in compound (XXI) which is an intermediate of method C.

In the above formula, R ^1a , R ¹⁰ , X and Q are as defined above.

  Step G1 is a method for producing a compound having the general formula (XXXII), and using a metal or organometallic reagent in the presence or absence (preferably in the presence) of an inert solvent, This is carried out by reacting a compound having (XXX) with a compound having the general formula (XXXI).

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene Halogenated hydrocarbons such as chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether, bases such as pyridine and triethylamine, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, and preferably amides Or It is ethers.

  Examples of the metal and organometallic reagent used in the above reaction include the same as those used in the above-mentioned Method A, Step A2.

  The reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of reagent, but is usually −120 ° C. to 120 ° C. (preferably room temperature to 100 ° C.).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of reagent, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 1 hour).

  Step G2 is a step of producing a compound having the general formula (XXXIII), and is performed by reducing compound (XXXII) with a reducing agent in an inert solvent.

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene Halogenated hydrocarbons such as chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane and diethylene glycol dimethyl ether, bases such as pyridine and triethylamine, amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, and alcohols such as methanol and ethanol An Lumpur acids, and is preferably an ether.

  Examples of the reducing agent used in the above reaction include sodium borohydride, lithium borohydride, borohydride alkali metals such as cyanoborohydride, diisobutylaluminum hydride, lithium aluminum hydride, lithium ethoxylate hydride. Aluminum hydride compounds such as sodium aluminum, tellurium hydride, diisobutylaluminum hydride, hydride reagents of organoaluminum hydride reducing agents such as bismethoxyethoxyaluminum sodium hydride, alkali metals such as sodium and lithium An aluminum hydride compound is preferable.

  While the reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of reducing agent, it is generally −20 ° C. to 80 ° C. (preferably 0 ° C. to room temperature).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of reducing agent, and the reaction temperature, it is generally 5 minutes to 48 hours (preferably 15 minutes to 24 hours).

  Step G3 is a step of converting the compound (XXXIII) into a compound having the general formula (XXIa) having a functional group capable of leaving as a nucleophilic residue, and this step is the same as the above-mentioned Method B, Step B2. It can be carried out.

  After completion of the reaction, the target compound in each step of the above Method G is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, After washing with water and the like, it is obtained by drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate and the like and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.

  Method H is a method for producing an optically active compound (XXI-asym) of compound (XXI), which is an intermediate of method C.

In the above formula, R ^1a and Q are as defined above.

  Step H1 is a step of producing a compound having the general formula (XXI-asym), and is performed by asymmetric reduction of the compound having the general formula (XX) in an inert solvent.

  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 materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene, methylene Halogenated hydrocarbons such as chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane and diethylene glycol dimethyl ether, bases such as pyridine and triethylamine, amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide, and alcohols such as methanol and ethanol An Lumpur ethers, preferably ethers.

  The asymmetric reducing agent used in the above reaction is not particularly limited as long as it is usually used as a reducing agent. For example, diisopinocanphenyl chloroborane, B-isopinocanphenyl-9- Organoborium reagents such as borabicyclo [3.3.1] nonane, oxazoborolidine, aluminum hydride compounds such as diisobutylaluminum hydride, lithium aluminum hydride, lithium ethoxide aluminum hydride, binaphthyldiol, 2,2 ' Asymmetrically reduced aluminum reagents modified with asymmetric ligands such as -bis (diphenylphosphino) -1,1'-binaphthyl, and rare earth metals such as ruthenium and rhodium with 2,2'-bis (diphenylphosphino) Metal catalysts modified with asymmetric ligands such as -1,1'-binaphthyl, enzymes such as baker's yeast, Is an organic boron reagents.

  While the reaction temperature varies depending on the raw material compound, the inert solvent used, the type of asymmetric reducing agent, and the like, it is generally −78 ° C. to 80 ° C. (preferably −25 ° C. to room temperature).

  While the reaction time varies depending on the raw material compound, the inert solvent used, the type of asymmetric reducing agent, the reaction temperature, etc., it is generally 5 minutes to 72 hours (preferably 15 minutes to 24 hours).

  After completion of the reaction, the target compound (XXI-asym) in the H1 step is collected from the reaction mixture according to a conventional method. For example, excess reagent or product is decomposed or treated with alcohol, amine, water, etc., and then the reaction mixture is appropriately neutralized, and if insolubles are present, removed by filtration, Add an immiscible organic solvent such as ethyl acetate, separate the organic layer containing the target compound, wash with water, etc., dry with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc., and then evaporate the solvent Can be obtained. If necessary, the obtained target compound can be eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.

  Raw material compounds (VIIa), (VIIb), (VIIc), (X) to (XII), (XV), (XVI), (XIX), (XX), (XXII) to (XXIV), (XXX) and (XXXI) is a known compound, or is easily produced according to a known method or a method similar thereto. [For example, J. Org. Chem., 58, 1109-1117 (1993); J. Org. Chem., 66, 2181-2182 (2001); JACS, 95, 3050 (1973), etc.].

  The oxazolidinone derivative having the general formula (I), (II) or (III) of the present invention, its pharmacologically acceptable salt, its ester or other derivative is an excellent derivative of IL-4 and / or IL-10. A Th1-selective immunosuppressive agent [particularly rheumatoid arthritis, which is a chronic inflammatory disease, organ-specific autoimmune diseases (for example, diabetes, multiple sclerosis), inflammatory bowel diseases (for example, ulcers) Colitis, Crohn's disease), glomerulonephritis, hepatitis, liver damage, autoimmune hemolytic anemia, leukopenia, thrombocytopenia, allergic encephalitis, demyelinating disease, Hashimoto's thyroiditis, Addison's disease, parathyroid Hypofunction, pernicious anemia, localized ileitis, atrophic gastritis, gluten intolerant enteropathy, Good Pasteur syndrome, post-streptococcal nephritis, myasthenia gravis, rheumatic fever, viral cardiomyopathy, uveitis , Sympathetic ophthalmitis, pemphigus vulgaris, bullous pemphigus, psoriasis] (preferably rheumatoid arthritis or organ-specific autoimmune disease, most preferably ulcerative colitis, Crohn's disease or hepatitis) In addition, the compound of the present invention has high water solubility, high oral absorption, and action as compared with conventional IL-4 and / or IL-10 production inducers. Fast expression, high transferability to target organs or cells, low brain transfer, low side effects, wide safety range (concentration difference between drug efficacy and toxic expression), excellent pharmacokinetics (in plasma Long half-life, large AUC, low tissue accumulation, etc.).

  When the oxazolidinone derivative having the general formula (I), (II) or (III) of the present invention, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative is used as the above therapeutic agent or prophylactic agent. Or mixed with excipients, diluents, etc. as such or appropriate pharmacologically acceptable, for example, orally or by injection, such as tablets, capsules, granules, powders or syrups It can be administered parenterally, such as with suppositories.

  These formulations include excipients (eg sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate magnesium phosphate; phosphates such as calcium hydrogen phosphate; Carbonates such as calcium; inorganic excipients such as sulfates such as calcium sulfate; and lubricants (eg, stearic acid, calcium stearate, metal stearate such as magnesium stearate) Salt; Talc; Colloidal silica; Veegum, Gay wax Such as wax; boric acid; adipic acid; sulfate such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; And silicic acids such as silicic acid hydrate; and the starch derivatives mentioned above), binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the above excipients) And the like, and disintegrants (for example, cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; Mention may be made of chemically modified starches and celluloses such as carboxymethyl starch, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone), stabilizers (paraoxybenzoates such as methylparaben and propylparaben; chlorobutanol; Alcohols such as benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.), Flavoring agents (for example, usually Examples thereof include sweeteners, acidulants, fragrances, etc.) and additives such as diluents.

  The amount used varies depending on symptoms, age, etc. In the case of oral administration, the lower limit of 0.1 mg (preferably 0.5 mg) and the upper limit of 4000 mg (preferably 400 mg) per day are administered intravenously. In the case of internal administration, the lower limit of 0.01 mg per day (preferably 0.05 mg) and the upper limit of 500 mg (preferably 300 mg) are given to adults 1 to 6 times per day depending on symptoms. Is desirable.

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

Example 1
8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3- (thiophen-2-ylcarbonyl) -1-oxa-3,8-diazaspiro [4,5] decane-2- ON and its oxalate (Exemplified Compound No. 1-173)
(1a) 8- [2-bis (3-trifluoromethylphenyl) methoxyethyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one 1-oxa-3 produced in Reference Example 1, 8-diazaspiro [4,5] decane-2-hydrochloride 150 mg (0.78 mmol), bis (3-trifluoromethylphenyl) methyl 2-chloroethyl ether prepared in Reference Example 298 mg (0.78 mmol), sodium carbonate 289 mg ( 2.72 mmol) and 12 mg (0.078 mmol) of sodium iodide were suspended in 8 ml of methyl isobutyl ketone and heated to reflux for 18 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated or evaporated. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 99: 1) to obtain 287 mg (73%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.76 (2H, s), 7.51-7.66 (6H, m), 5.65 (1H, s), 3.65 (2H, t, J = 5.6 Hz), 3.34 (2H, s), 2.53-2.80 (6H, m), 1.78-1.98 (4H, m)
Infrared absorption spectrum ν _max cm ⁻¹ (KBr): 3269, 2925, 2830, 1753, 1330, 1256, 1166, 1125, 1074.

(1b) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3- (thiophen-2-ylcarbonyl) -1-oxa-3,8-diazaspiro [4,5] decane 2- {1- [2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (1a) -Onion 0.25 g (0.498 mmol) was dissolved in tetrahydrofuran 5.0 ml, then 2-thenoyl chloride 0.11 ml (0.995 mmol) and n-butyl lithium (1.59 N, 0.47 ml (0.746 mmol) were added, After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. Purification by elution solvent: ethyl acetate / methanol = 10/1) gave 0.24 g (yield 82.8%) of the title compound as an oily substance.

(1c) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3- (thiophen-2-ylcarbonyl) -1-oxa-3,8-diazaspiro [4,5] decane 2-one oxalate 8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3- (thiophen-2-ylcarbonyl) -1-oxa prepared in Example (1b) -3,8-Diazaspiro [4,5] decan-2-one 0.24 g (0.411 mmol) was dissolved in 5 ml of ethyl acetate, 0.037 g (0.411 mmol) of oxalic acid was added, and the mixture was allowed to stand overnight. The precipitated crystals were collected by filtration to obtain 0.12 g (43.3%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.29-7.24 (m, 6H), 7.03-6.98 (m, 2H), 5.29 (s, 1H), 3.47-3.44 (m, 2H), 3.35-3.29 (m, 2H), 3.25 (s, 2H), 2.54-2.46 (m, 6H), 1.97-1.63 (m, 6H), 1.15 (t, 3H, J = 7.15Hz)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1748,1604,1507,1223
Mass spectrum (FAB) m / z 445 ((M + H) ⁺ , free form).

Example 2
8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate (Exemplary Compound No. 1-147)
(2a) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one 13.0 g of 2- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in mmol) in 130 ml of N, N-dimethylformamide, then 1.24 g of sodium hydride (content 60.0%, 31.1 mmol), 1.91 g (5.18 mmol) of tetrabutylammonium iodide, 3.25 ml (38.8 mmol) of chloromethyl methyl sulfide. ) And stirred at room temperature for 5 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate) to obtain 9.30 g (yield 63.7%) of the title compound as an oily substance.

(2b) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one fumaric acid Salt 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decane prepared in Example (2a) 9.30 g (16.6 mmol) of 2-one was dissolved in 50 ml of ethyl acetate, and 1.92 g (16.6 mmol) of fumaric acid was added and left overnight. The precipitated crystals were collected by filtration to obtain 9.25 g (82.4%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.76-7.54 (m, 8H), 5.73 (s, 1H), 3.80 (t, 2H, J = 5.34Hz), 3.52 (s, 2H), 3.33 -3.21 (m, 8H), 2.20-2.07 (m, 7H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1753, 1615, 1430, 1331, 1255, 1166, 1125, 1073, 984
Mass spectrum (FAB) m / z 563 ((M + H) ⁺ , free form).

Example 3
8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (thiophen-2-ylcarbonyl) -1-oxa-3,8-diazaspiro [4,5] decane-2- ON and its oxalate (Exemplified Compound No. 1-174)
(3a) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one 1-oxa produced in Reference Example 1 -3,8-diazaspiro [4.5] decan-2-one hydrochloride 89 mg (0.46 mmol) and bis- (3-trifluoromethylphenyl) methyl 3-chloropropyl ether 167 mg (0.42 mmol) prepared in Reference Example 3 After dissolving in 2 ml of N, N-dimethylformamide, 145 mg (1.05 mmol) of potassium carbonate and 6 mg (0.04 mmol) of sodium iodide were added, and the mixture was stirred at 130 ° C. for 4 hours. After cooling to room temperature, the solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried and concentrated. The residue was purified by preparative thin layer chromatography (developing solvent; methylene chloride: methanol = 10: 1) to obtain 156 mg (72%) of the title compound.

(3b) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (thiophen-2-ylcarbonyl) -1-oxa-3,8-diazaspiro [4,5] decane 2- {1- [3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (3a) The reaction was purified in the same manner as in Example (1b) using 200 mg (0.39 mmol) of 1-on and 62 μl (0.58 mmol) of 2-thenoyl chloride to obtain 235 mg (97%) of the title compound.

(3c) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (thiophen-2-ylcarbonyl) -1-oxa-3,8-diazaspiro [4,5] decane 2-one oxalate 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (thiophen-2-ylcarbonyl) -1-oxa prepared in Example (3b) -3,8-diazaspiro [4,5] decan-2-one 220 mg (0.35 mmol) was dissolved in 3 ml of ethyl acetate, oxalic acid 32 mg (0.35 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to obtain 122 mg (48%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400 MHz, DMSO-d ₆ ) δ ppm: 8.00-7.94 (2H, m), 7.79 (2H, m), 7.74-7.60 (6H, m), 7.22-7.19 (1H, m), 5.77 (1H, s), 3.96 (2H, s), 3.48 (2H, t, J = 5.9Hz), 3.21-2.87 (6H, m), 2.19-1.87 (6H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2493, 1786, 1651, 1330, 1123
Mass spectrum (FAB) m / z 627 ((M + H) ⁺ , free body)
Elemental analysis (as C ₃₂ H ₃₀ F ₆ N ₂ O ₈ S-1 / 2H ₂ O)
Calculated value: C: 52.97; H: 4.31; F: 15.71; N: 3.86; S: 4.42
Found: C: 52.75; H: 4.30; F: 15.44; N: 3.95; S: 4.31.

Example 4
8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decan-2-one and The oxalate salt (Exemplified compound number 1-162)
(4a) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decane-2 -ON 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in Example (3a) 200 mg (0.39 mmol) and 2-methoxybenzoyl chloride 80 μl (0.58 mmol) were reacted and purified in the same manner as in Example (1b) to obtain 250 mg (99%) of the title compound.

(4b) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decane-2 -On oxalate 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxybenzoyl) -1-oxa-3,8 prepared in Example (4a) -Diazaspiro [4,5] decan-2-one 240 mg (0.37 mmol) was dissolved in 3 ml of ethyl acetate, 33 mg (0.37 mmol) of oxalic acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 155 mg (62%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.79 (2H, s), 7.75-7.73 (2H, m), 7.68-7.60 (4H, m), 7.48-7.44 (1H, m), 7.33 -7.31 (1H, m), 7.08-6.99 (2H, m), 5.77 (1H, s), 3.96 (2H, s), 3.48 (2H, d, J = 5.9Hz), 3.32-2.97 (6H, m ), 2.16-1.91 (6H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2947, 2498, 1793, 1331, 1123
Mass spectrum (FAB) m / z 651 ((M + H) ⁺ , free form).

Example 5
8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-ethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one and its oxalate salt ( Exemplified compound number 3-20)
(5a) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-ethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one Examples 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in 3a) 200 mg (0.39 mmol) Then, the reaction mixture was purified in the same manner as in Example (2a) using 47 μl (0.58 mmol) of ethyl iodide to obtain 168 mg (80%) of the title compound.

(5b) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-ethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one oxalate 160 mg (0.29 mmol) of the compound prepared in Example (5a) was dissolved in 3 ml of ethyl acetate, 26 mg (0.29 mmol) of oxalic acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 145 mg (78%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δ ppm: 7.87 (2H, s), 7.74-7.59 (6H, m), 5.77 (1H, s) 3.47 (2H, t, J = 6.0Hz), 3.37 (2H, s), 3.19 (2H, q, J = 7.2Hz), 3.16-2.92 (6H, m), 2.03-1.87 (6H, m), 1.06 (3H, t, J = 7.2Hz)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2929, 2563, 1743, 1332, 1125
Mass spectrum (FAB) m / z 545 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₉ H ₃₂ F ₆ N ₂ O ₇ )
Calculated value: C: 54.89; H: 5.08; F: 17.96; N: 4.41
Found: C: 54.65; H: 4.82; F: 18.57; N: 4.46.

Example 6
8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxyethoxymethyl) -1-oxa-3,8-diazaspiro [4,5] decan-2-one And its fumarate (Exemplified Compound No. 1-146)
(6a) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxyethoxymethyl) -1-oxa-3,8-diazaspiro [4,5] decane- 2-one 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-prepared in Example (3a) The reaction was purified in the same manner as in Example (2a) using 300 mg (0.58 mmol) of ON and 80 μl (0.70 mmol) of 2-methoxyethoxymethyl chloride to obtain 165 mg (47%) of the title compound.

(6b) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxyethoxymethyl) -1-oxa-3,8-diazaspiro [4,5] decane- 2-one fumarate 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxyethoxymethyl) -1-oxa-3 prepared in Example (6a) , 8-diazaspiro [4,5] decan-2-one 155 mg (0.26 mmol) was dissolved in 3 ml of ethyl acetate, 30 mg (0.26 mmol) of fumaric acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to obtain 149 mg (80%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400 MHz, DMSO-d ₆ ) δ ppm: 7.77 (2H, s), 7.71-7.58 (6H, m), 6.61 (2H, s), 5.74 (1H, s), 4.64 (2H, s ), 3.52-3.39 (6H, m), 3.38 (2H, s), 3.24 (3H, s), 2.49-2.37 (6H, m), 1.82-1.67 (6H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2928, 2493, 1757, 1330, 1123
Mass spectrum (FAB) m / z 605 ((M + H) ⁺ , free body)
Elemental analysis (as C ₃₃ H ₄₀ F ₆ N ₂ O ₉ -1 / 2H ₂ O)
Calculated value: C: 54.17; H: 5.65; F: 15.58; N: 3.83
Found: C: 54.16; H: 4.95; F: 14.18; N: 3.75.

Example 7
8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (4-chloro-benzyloxymethyl) -1-oxa-3,8-diazaspiro [4,5] decane-2 -On and its fumarate (Exemplified Compound No. 1-158)
(7a) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (4-chlorobenzyloxymethyl) -1-oxa-3,8-diazaspiro [4,5] decane 2- {1- [3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (3a) The reaction product was purified in the same manner as in Example (2a) using 300 mg (0.58 mmol) of ON and 122 mg (0.64 mmol) of 4-chlorobenzyl chloromethyl ether to obtain 175 mg (45%) of the title compound.

(7b) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (4-chloro-benzyloxymethyl) -1-oxa-3,8-diazaspiro [4,5] Decan-2-one fumarate 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (4-chloro-benzyloxymethyl) -1 prepared in Example (7a) 160 mg (0.24 mmol) of -oxa-3,8-diazaspiro [4,5] decan-2-one was dissolved in 3 ml of ethyl acetate, 28 mg (0.24 mmol) of fumaric acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 112 mg (60%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.79 (2H, s), 7.77-7.58 (6H, m), 7.41 (2H, d, J = 8.4Hz), 7.36 (2H, d, J = 8.4Hz), 6.61 (2H, s), 5.74 (1H, s), 4.72 (2H, s), 4.47 (2H, s), 3.46 (2H, d, J = 6.2Hz), 3.37 (2H, s ), 2.47-2.35 (6H, m), 1.80-1.62 (6H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2930, 2492, 1759, 1330, 1124
Mass spectrum (FAB) m / z 671 ((M + H) ⁺ , free body)
Elemental analysis (as C ₃₇ H ₃₇ ClF ₆ N ₂ O ₈ -1 / 2H ₂ O)
Calculated value: C: 55.82; H: 4.81; Cl: 4.45; F: 14.32; N: 3.52
Found: C: 55.81; H: 4.43; Cl: 4.46; F: 14.12; N: 3.42.

Example 8
8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxyethoxymethyl) -1-oxa-3,8-diazaspiro [4,5] Decan-2-one and its oxalate salt (Exemplified Compound No. 1-312)
(8a) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one Reference Example 300 mg (0.89 mmol) of 3-[(3-cyanophenyl) (3′-trifluoromethylphenyl) methoxy] propanol prepared in 4 was dissolved in 3 ml of dichloromethane, and 187 μl (1.34 mmol) of triethylamine and methanesulfonyl chloride were cooled with ice 90 μl (1.16 mmol) was added. The mixture was stirred for 30 minutes under ice-cooling, and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. 370 mg (0.89 mmol) of the obtained methanesulfonic acid- {3- [3-cyanophenyl) (3′-trifluoromethylphenyl) methoxy] propyl} ester was dissolved in 5 ml of N, N-dimethylacetamide, and Reference Example 1 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride prepared in 207 mg (1.07 mmol), potassium carbonate 247 mg (1.87 mmol) and potassium iodide 15 mg (0.09 mmol) were added at 100 ° C. Stir for 10 hours. After completion of the reaction, the reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash chromatography (developing solvent; methanol: dichloromethane = 5: 95) to obtain 283 mg (67%) of the title compound.

(8b) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxyethoxymethyl) -1-oxa-3,8-diazaspiro [4 , 5] decan-2-one 8- {3-[(3-cyanophenyl) (3′-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8- prepared in Example (8a) The reaction was purified in the same manner as in Example (2a) using 300 mg (0.63 mmol) of diazaspiro [4,5] decan-2-one and 110 μl (0.95 mmol) of 2-methoxyethoxymethyl chloride, and 283 mg of the title compound ( 67%).

(8c) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxyethoxymethyl) -1-oxa-3,8-diazaspiro [4 , 5] decan-2-one oxalate 8- {3-[(3-cyanophenyl) (3′-trifluoromethylphenyl) methoxy] propyl} -3- (2- Methoxyethoxymethyl) -1-oxa-3,8-diazaspiro [4,5] decan-2-one 270 mg (0.48 mmol) is dissolved in 3 ml of ethyl acetate, and 43 mg (0.48 mmol) of oxalic acid is added. Left overnight. The precipitated crystals were collected by filtration to obtain 188 mg (60%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400 MHz, DMSO-d ₆ ) δ ppm: 7.94 (1H, s), 7.79-7.72 (4H, m), 7.67-7.56 (3H, m), 5.71 (1H, s) 4.66 (2H, s), 3.53 (2H, d, J = 4.0Hz), 3.49-3.42 (6H, m), 3.25 (3H, s), 3.19-2.93 (6H, m), 2.06-1.88 (6H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2928, 2496, 1757, 1329, 1122
Mass spectrum (FAB) m / z 562 ((M + H) ⁺ , free body)
Elemental analysis (as C ₃₁ H ₃₆ F ₃ N ₃ O ₉ -1 / 2H ₂ O)
Calculated value: C: 56.36; H: 5.65; F: 8.63; N: 6.36
Found: C: 56.51; H: 5.41; F: 8.79; N: 6.34.

Example 9
8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-benzyloxymethyl-1-oxa-3,8-diazaspiro [4,5] decane-2- ON and its fumarate (Exemplified Compound No. 1-310)
(9a) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-benzyloxymethyl-1-oxa-3,8-diazaspiro [4,5] decane 2- {1-one 8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4, prepared in Example (8a) 5] Reaction and purification in the same manner as in Example (2a) using 200 mg (0.42 mmol) of decan-2-one and 70 μl (0.51 mmol) of benzylchloromethyl ether gave 165 mg (66%) of the title compound. .

(9b) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-benzyloxymethyl-1-oxa-3,8-diazaspiro [4,5] decane 2-one fumarate 8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-benzyloxymethyl-1-oxa prepared in Example (9a) 160 mg (0.27 mmol) of -3,8-diazaspiro [4,5] decan-2-one was dissolved in 3 ml of ethyl acetate, 31 mg (0.27 mmol) of fumaric acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to obtain 87 mg (47%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400 MHz, DMSO-d ₆ ) δ ppm: 7.94 (1H, s), 7.77-7.70 (4H, m), 7.66-7.55 (3H, m), 7.37-7.27 (5H, m), 6.61 (2H, s), 5.68 (1H, s) 4.73 (2H, s), 4.48 (2H, s), 3.45 (2H, d, J = 6.7Hz), 3.37 (2H, s), 2.47-2.36 (6H , m), 1.79-1.62 (6H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2932, 2501, 1759, 1329, 1124
Mass spectrum (FAB) m / z 594 ((M + H) ⁺ , free body)
Elemental analysis (as C ₃₇ H ₃₈ F ₃ N ₃ O ₈ -H ₂ O)
Calculated value: C: 61.07; H: 5.54; F: 7.83; N: 5.77
Found: C: 60.89; H: 5.17; F: 7.94; N: 5.83.

Example 10
3-ethyl-8- {3-[(3-trifluoromethylphenyl) (3'-cyanophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one and Its fumarate (Exemplified Compound No. 3-52)
(10a) 3-Ethyl-8- {3-[(3-trifluoromethylphenyl) (3'-cyanophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 -ON 8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] prepared in Example (8a) The reaction was conducted in the same manner as in Example (2a) using 1030 mg (2.17 mmol) of decan-2-one and 336 μl (4.2 mmol) of ethyl iodide to obtain 869 mg (80%) of the title compound.

(10b) 3-Ethyl-8- {3-[(3-trifluoromethylphenyl) (3'-cyanophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 -On fumarate 3-ethyl-8- {3-[(3-trifluoromethylphenyl) (3'-cyanophenyl) methoxy] propyl} -1-oxa-3,8 prepared in Example (10a) -Diazaspiro [4,5] decan-2-one (469 mg, 0.95 mmol) was dissolved in ethyl acetate (10 ml), fumaric acid (108 mg, 0.95 mmol) was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 461 mg (80%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.95 (1H, s), 7.52-7.81 (7H, m), 6.60 (2H, s), 5.68 (1H, s), 3.45 (2H, t , J = 5Hz), 3.29 (2H, s), 3.17 (2H, q, J = 7Hz), 2.36-2.60 (8H, m), 1.65-1.86 (4H, m), 1.05 (3H, t, J = (7Hz)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1751, 1330, 1165, 1123, 1074
Mass spectrum (FAB) m / z 502 ((M + H) ⁺ , free body)
Elemental analysis (as C ₃₁ H ₃₄ F ₃ N ₃ O ₇ -0.5H ₂ O)
Calculated value: C: 59.44; H: 5.63; N: 6.71
Found: C: 59.17; H: 5.43; N: 6.40.

Example 11
8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylsulfonylmethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumaric acid Salt (Exemplified compound number 1-141)
(11a) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylsulfonylmethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (2a) -0.4 g (0.711 mmol) of ON was dissolved in 8 ml of acetone / water (1/1), and 0.44 g (0.711 mmol) of oxone was added with stirring under ice cooling, followed by stirring for 1 hour. After completion of the reaction, water was added to the reaction solution, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by basic silica gel chromatography (elution solvent: methylene chloride / methanol = 10/1) to obtain 0.145 g (yield 34.3%) of the title compound as an oily substance.

(11b) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylsulfonylmethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate Acid salt 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylsulfonylmethyl-1-oxa-3,8-diazaspiro [4,5] prepared in Example (11a) ] 0.145 g (0.244 mmol) of decan-2-one was dissolved in 5 ml of ethyl acetate, 0.028 g (0.244 mmol) of fumaric acid was added and left overnight. The precipitated crystals were collected by filtration to obtain 0.079 g (45.7%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.76-7.54 (m, 8H), 5.73 (s, 1H), 4.66 (s, 2H), 3.79 (t, 2H, J = 5.34 Hz), 3.73 (s, 2H), 3.33-3.21 (m, 8H), 2.99 (s, 3H), 2.20-2.03 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1756, 1435, 1331, 1166, 1126, 1073, 983
Mass spectrum (FAB) m / z 595 ((M + H) ⁺ , free form).

Example 12
8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylsulfinylmethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumaric acid Salt (Exemplary Compound No. 1-137)
(12a) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylsulfinylmethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (2a) -0.4 g (0.711 mmol) of ON was dissolved in 4 ml of acetone / water (1/1), and 0.219 g (0.356 mmol) of oxone was added with stirring under ice cooling, followed by stirring for 30 minutes. After completion of the reaction, water was added to the reaction solution, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by basic silica gel chromatography (elution solvent: methylene chloride / methanol = 50/1) to obtain 0.156 g (yield 38.0%) of the title compound as an oily substance.

(12b) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylsulfinylmethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate Acid salt 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylsulfinylmethyl-1-oxa-3,8-diazaspiro [4,5] prepared in Example (12a) ] 0.156 g (0.270 mmol) of decan-2-one was dissolved in 5 ml of ethyl acetate, 0.031 g (0.270 mmol) of fumaric acid was added and left overnight. The precipitated crystals were collected by filtration to obtain 0.090 g (48.1%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.76-7.54 (m, 8H), 5.72 (s, 1H), 4.57 (d, 1H, J = 13.6 Hz), 4.43 (d, 1H, J = 13.6 Hz), 3.78 (t, 2H, J = 5.16 Hz), 3.71 (q, 2H, J = 8.71 Hz), 3.22 (t, 4H, J = 5.16 Hz), 3.15-3.04 (m, 2H), 2.67 (s, 3H), 2.24-2.01 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1750, 1435, 1331, 1259, 1166, 1124, 1073, 983
Mass spectrum (FAB) m / z 579 ((M + H) ⁺ , free form).

Example 13
3-methyl-8- {2- [bis- (4-fluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its oxalate salt (exemplary compounds Number 3-9)
(13a) 8- [2-Bis (4-fluorophenyl) methoxyethyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one 1-oxa-3,8- prepared in Reference Example 1 Using diazaspiro [4.5] decan-2-one hydrochloride 800 mg (4.15 mmol) and bis (4-fluorophenyl) methyl 2-chloroethyl ether 1.29 g (4.56 mmol) prepared in Reference Example 5, the example (1a ) To give 1.24 g (74%) of the title compound.

(13b) 3-Methyl-8- {2- [bis- (4-fluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one Example (13a) -{2- [Bis- (4-fluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one 118 mg (0.29 mmol) and methyl iodide prepared in 20 μl (0.32 mmol) was used for reaction and purification in the same manner as in Example (2a) to obtain 75 mg (60%) of the title compound.

(13c) 3-Methyl-8- {2- [bis- (4-fluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one oxalate Examples 3-methyl-8- {2- [bis- (4-fluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in (13b) 75 mg ( 0.18 mmol) was dissolved in 5 ml of ethyl acetate, 16 mg (0.18 mmol) of oxalic acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 74 mg (80%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.34-7.46 (4H, m), 7.12-7.25 (4H, m), 5.56 (1H, s), 3.62 (2H, t, J = 5Hz) , 3.35 (2H, s), 2.92-3.38 (4H, m), 2.75 (3H, s), 2.50 (2H, t), 1.86-2.03 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1754, 1603, 1507, 1408,
Mass spectrum (FAB) m / z 417 ((M + H) ⁺ , free body)
Elemental analysis (C ₂₅ H ₂₈ F ₂ N ₂ O ₇ )
Calculated value: C: 59.28; H: 5.57; N: 5.53
Found: C: 58.52; H: 5.34; N: 5.48.

Example 14
8- {2- [bis (4-fluorophenyl) methoxy] ethyl} -spiro [(8-azabicyclo [3.2.1] octane) -3,5′-oxazolidine] -2′-one (Exemplary Compound No. 1- 91)
Spiro [(8-azabicyclo [3.2.1] octane) -3,5′-oxazolidine] -2′-one prepared in Reference Example 10 103 mg (0.47 mmol) and bis (4-fluorophenyl) prepared in Reference Example 5 ) Methyl 2-chloroethyl ether 133 mg (0.47 mmol) was used in the same manner as in Example (1a) for purification to give 110 mg (55%).
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.19-7.48 (4H, m), 6.96-7.10 (4H, m), 5.33 (1H, s), 5.30 (1H, s), 3.54 (2H , t, J = 6Hz), 3.18-3.54 (4H, m), 2.63 (2H, t, J = 5Hz), 1.84-2.22 (8H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1740, 1508, 1260, 1222, 1079
Mass spectrum (FAB) m / z 429 ((M + H) ⁺ , free form).

Example 15
8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -spiro [(8-azabicyclo [3.2.1] octane) -3,5'-oxazolidine] -2'-one (Exemplary compound Number 1-179)
Spiro [(8-azabicyclo [3.2.1] octane) -3,5′-oxazolidine] -2′-one prepared in Reference Example 10 1240 mg (1.32 mmol) and bis (3-tri The reaction was purified in the same manner as in Example (1a) using 600 mg (1.32 mmol) of fluoromethylphenyl) methyl 2-chloroethyl ether to obtain 622 mg (49%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.67-7.42 (m, 8H), 5.46 (s, 1H), 5.12 (s, 1H), 3.65-3.53 (m, 2H), 3.36-3.20 ( m, 4H), 2.73-2.58 (m, 2H), 2.24-1.81 (m, 8H)
Infrared absorption spectrum νmax cm ^-1 (CDCl ₃ ): 1750, 1489, 1449, 1420, 1331
Mass spectrum (FAB) m / z 529 ((M + H) ⁺ , free form).

Example 16
8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one and Its oxalate (Exemplified Compound No. 3-50)
(16a) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methyl-1-oxa-3,8-diazaspiro [4,5] decane-2 -ON 300 mg (0.90 mmol) of 3-[(3-cyanophenyl) (3′-trifluoromethylphenyl) methoxy] propanol prepared in Reference Example 4 was dissolved in 3 ml of dichloromethane, and 188 μl (1.35 mmol) of triethylamine under ice-cooling. And 90 μl (1.17 mmol) of methanesulfonyl chloride were added. The mixture was stirred for 30 minutes under ice-cooling, and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. 372 mg (0.90 mmol) of the obtained methanesulfonic acid- {3-[(3-cyanophenyl) (3′-trifluoromethylphenyl) methoxy] propyl} ester was dissolved in 5 ml of dimethylacetamide and prepared in Reference Example 6. Add 3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride 222 mg (1.07 mmol), potassium carbonate 248 mg (1.80 mmol) and potassium iodide 15 mg (0.01 mmol) and add 100 Stir at 6 ° C. for 6 hours. After completion of the reaction, the temperature was returned to room temperature, the reaction solution was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash chromatography (developing solvent; methanol: dichloromethane = 5: 95) to obtain 246 mg (56%) of the title compound.

(16b) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methyl-1-oxa-3,8-diazaspiro [4,5] decane-2 -On oxalate 8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methyl-1-oxa-3,8 prepared in Example (16a) -Diazaspiro [4,5] decan-2-one 240 mg (0.49 mmol) was dissolved in 3 ml of ethyl acetate, 44 mg (0.49 mmol) of oxalic acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 235 mg (82%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400 MHz, DMSO-d ₆ ) δ ppm: 7.94 (2H, m), 7.79-7.56 (6H, m), 5.70 (1H, s), 3.52-3.40 (2H, m), 3.36 (2H , s), 3.22-2.91 (6H, m), 2.75 (3H, s), 2.03-1.86 (6H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2501, 1756, 1405, 1329, 1121
Mass spectrum (FAB) m / z 488 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₈ H ₃₀ F ₃ N ₃ O ₇ )
Calculated value: C: 58.23; H: 5.24; F: 9.87; N: 7.28
Found: C: 58.00; H: 5.13; F: 9.89; N: 6.67.

Example 17
8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one and its oxalate salt ( Exemplified compound number 3-17)
(17a) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one Reference Example 2 Bis- (3-trifluoromethylphenyl) methyl 2-chloroethyl ether prepared in 1) 260 mg (0.68 mmol) was dissolved in 5 ml of dimethylacetamide and 3-methyl-1-oxa-3,8-diazaspiro prepared in Reference Example 6 was dissolved. [4,5] decan-2-one hydrochloride 168 mg (0.81 mmol), potassium carbonate 188 mg (1.36 mmol) and potassium iodide 15 mg (0.01 mmol) were added, and the mixture was stirred at 100 ° C. for 10 hours. After completion of the reaction, the temperature was returned to room temperature, the reaction solution was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash chromatography (developing solvent; methanol: dichloromethane = 5: 95) to obtain 318 mg (91%) of the title compound.

(17b) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one oxalate 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methyl-1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (17a) -310 mg (0.60 mmol) of ON was dissolved in 3 ml of ethyl acetate, 54 mg (0.60 mmol) of oxalic acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 311 mg (85%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.80 (2H, m), 7.73-7.60 (6H, m), 5.82 (1H, s), 3.67 (2H, t, J = 5.2Hz), 3.34 (2H, s), 3.14-2.87 (6H, m), 2.75 (3H, s), 1.97-1.85 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2928, 2501, 1755, 1331, 1123
Mass spectrum (FAB) m / z 517 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₇ H ₂₈ F ₆ N ₂ O ₇ )
Calculated value: C: 53.47; H: 4.65; F: 18.79; N: 4.62
Found: C: 53.33; H: 4.54; F: 20.39; N: 4.63.

Example 18
3- (2-methoxyethyl) -8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one and The oxalate (Exemplified Compound No. 3-23)
(18a) 3- (2-Methoxyethyl) -8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 -ON 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in Example (1a) The reaction and purification was conducted in the same manner as in Example (2a) using 158 mg (0.31 mmol) and 2-methoxyethyl bromide 58 μl (0.54 mmol) to obtain 85 mg (49%) of the title compound.

(18b) 3- (2-Methoxyethyl) -8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 -On oxalate 3- (2-methoxyethyl) -8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8 prepared in Example (18a) -85 mg (0.15 mmol) of diazaspiro [4,5] decan-2-one was dissolved in 5 ml of ethyl acetate, 14 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 obtain 77 mg (78%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.60-7.80 (8H, m), 5.82 (1H, s), 3.68 (2H, t, J = 5Hz), 3.46 (2H, t, J = 5Hz), 3.40 (2H, s), 3.31 (2H, t, J = 5Hz), 3.25 (3H, s), 2.90-3.25 (6H, m), 1.85-2.00 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1754, 1331, 1167, 1122
Mass spectrum (FAB) m / z 561 ((M + H) ⁺ , free body)
Elemental analysis (C ₂₉ H ₃₂ F ₆ N ₂ O ₇ )
Calculated value: C: 53.54; H: 4.96; N: 4.31
Found: C: 53.44; H: 4.90; N: 4.24.

Example 19
8- {3- [Bis- (4-fluorophenyl) methoxy] propyl} -3-ethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one and its oxalate salt (exemplary compounds Number 3-12)
(19a) 8- {3- [Bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one 1-produced in Reference Example 1 Oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 86 mg (0.45 mmol) and bis (4-fluorophenyl) methyl 3-chloropropyl ether prepared in Reference Example 146 mg (0.49 mmol) And purified in the same manner as in Example (1a) to obtain 111 mg (60%) of the title compound.

(19b) 8- {3- [Bis- (4-fluorophenyl) methoxy] propyl} -3-ethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one Example (19a) 8- {3- [Bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in 1) 0.15 g (0.36 mmol), iodinated The reaction was conducted in the same manner as in Example (2a) using 13.3 mg (0.036 mmol) of tetrabutylammonium and 0.0432 ml (0.54 mmol) of ethyl iodide to obtain 83 mg (51.8%) of the title compound.

(19c) 8- {3- [Bis- (4-fluorophenyl) methoxy] propyl} -3-ethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one oxalate Examples 8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -3-ethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in (19b) 83 mg ( 0.187 mmol) was dissolved in 3 ml of ethyl acetate, 17.8 mg (0.187 mmol) of oxalic acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 61 mg (59.5%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.40-7.33 (m, 4H), 7.09-7.01 (m, 4H), 5.42 (s, 1H), 3.61-3.30 (m, 3H), 3.45 ( s, 2H), 3.35-3.20 (m, 8H), 2.18-2.05 (m, 6H), 1.16 (t, 3H, J = 7.29 Hz)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1741, 1729, 1604, 1506, 1221
Mass spectrum (FAB) m / z 445 ((M + H) ⁺ , free form).

Example 20
8- {3- [Bis- (4-fluorophenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one and its oxalate salt Compound No. 1-62)
(20a) 8- {3- [Bis- (4-fluorophenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one Examples (19a ) 8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one 0.15 g (0.36 mmol) The reaction was purified in the same manner as in Example (2a) using 13.3 mg (0.036 mmol) of tetrabutylammonium bromide and 0.0453 ml (0.54 mmol) of chloromethyl methyl sulfide to obtain 60 mg (51.8%) of the title compound.

(20b) 8- {3- [Bis- (4-fluorophenyl) methoxy] propyl} -3-methylsulfanylmethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one oxalate 8- {3- [Bis- (4-fluorophenyl) methoxy] propyl} -3-methylsulfanylmethyl-1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (20a) -60 mg (0.126 mmol) of ON was dissolved in 3 ml of ethyl acetate, and 11.3 mg (0.126 mmol) of oxalic acid was added and left overnight at room temperature. The precipitated crystals were collected by filtration to obtain 39 mg (54.7%) of the title compound as colorless crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.39-7.33 (m, 4H), 7.09-7.02 (m, 4H), 5.43 (s, 1H), 4.42 (s, 2H), 3.63-3.45 ( m, 4H), 3.35-3.20 (m, 6H), 2.22-2.05 (m, 9H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1753, 1604, 1507, 1427, 1405, 1252, 1222
Mass spectrum (FAB) m / z 477 ((M + H) ⁺ , free form).

Example 21
8- {2- [Bis- (4-fluorophenyl) methoxy] ethyl} -3-ethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one (Exemplified Compound No. 3-11)
8- [2-bis (4-fluorophenyl) methoxyethyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one prepared in Example (13a) 0.15 g (0.37 mmol), iodinated The reaction was conducted in the same manner as in Example (2a) using 13.8 mg (0.037 mmol) of tetrabutylammonium and 0.045 ml (0.49 mmol) of ethyl iodide to obtain 123 mg (63.4%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.52-7.25 (m, 6H), 7.04-6.98 (m, 2H), 5.33 (s, 1H), 3.56 (t, 2H, J = 5.89 Hz), 3.32 (q, 2H, J = 7.28 Hz), 3.25 (s, 2H), 2.71 (t, 2H, J = 5.89 Hz), 2.62-2.55 (m, 4H), 1.95-1.72 (m, 4H), 1.15 (t, 3H, J = 7.28 Hz)
Infrared absorption spectrum νmax cm ^-1 (CDCl ₃ ): 1748, 1604, 1507, 1222
Mass spectrum (FAB) m / z 431 ((M + H) ⁺ , free form).

Example 22
3-methyl-8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its oxalate salt (exemplary compounds Number 3-10)
(22a) 3-Methyl-8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one Example (19a) 8- {3- [Bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in 197 mg (0.47 mmol) and methyl iodide 44 μl (0.71 mmol) was used for reaction and purification as in Example (2a) to give 122 mg (60%).

(22b) 3-Methyl-8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one oxalate Examples 122 mg of 3-methyl-8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in (22a) 0.28 mmol) was dissolved in 10 ml of ethyl acetate, 26 mg (0.28 mmol) of oxalic acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 95 mg (64%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.35-7.45 (4H, m), 7.12-7.23 (4H, m), 5.51 (1H, s), 3.42 (2H, t, J = 5Hz) , 3.38 (2H, s), 3.00-3.21 (4H, m), 2.76 (3H, s), 2.50 (2H, t, J = 5Hz), 1.90-2.10 (6H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1748, 1604, 1505, 1440, 1408
Mass spectrum (FAB) m / z431 ((M + H) ⁺ , free body)
Elemental analysis (C ₂₄ H ₂₈ F ₂ N ₂ O _3, 13 / 9C ₂ H ₂ O ₄ )
Calculated value: C: 57.62; H: 5.55; N: 5.00
Found: C: 57.78; H: 5.50; N: 4.59.

Example 23
3- (2-methoxyethyl) -8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its shu Acid salt (Exemplified Compound No. 3-16)
(23a) 3- (2-Methoxyethyl) -8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one 225 mg (0.54 mmol) of 8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in Example (19a) ) And 2-methoxyethyl bromide 56 μl (0.60 mmol) and purified in the same manner as in Example (2a) to obtain 50 mg (20%) of the title compound.

(23b) 3- (2-Methoxyethyl) -8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one Oxalate 3- (2-methoxyethyl) -8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4] prepared in Example (23a) , 5] decan-2-one 50 mg (0.11 mmol) was dissolved in 5 ml of ethyl acetate, 9 mg (0.11 mmol) of oxalic acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 48 mg (74%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.35-7.45 (4H, m), 7.12-7.20 (4H, m), 5.49 (1H, s), 3.46 (2H, t, J = 5Hz) , 3.36-3.42 (5H, m), 3.31 (2H, t, J = 5Hz), 3.26 (2H, s), 2.90-3.20 (6H, m), 2.51 (2H, t, J = 5Hz), 1.80- 1.98 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1746, 1728, 1506, 1221, 1117
Mass spectrum (FAB) m / z 475 ((M + H) ⁺ , free body)
Elemental analysis (C ₂₆ H ₃₂ F ₂ N ₂ O _4, 5 / 4C ₂ H ₂ O ₄ )
Calculated value: C: 58.31; H: 5.92; N: 4.77
Found: C: 58.60; H: 5.56; N: 4.75.

Example 24
8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one and its oxalate salt ( Exemplified compound number 3-18)
(24a) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one Examples 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in 19a) 300 mg (0.58 mmol) Then, the reaction mixture was reacted and purified in the same manner as in Example (2a) using 54 μl (0.87 mmol) of methyl iodide to obtain 253 mg (82%) of the title compound.

(24b) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one oxalate 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methyl-1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (24a) -240 mg (0.45 mmol) of ON was dissolved in 3 ml of ethyl acetate, and 41 mg (0.45 mmol) of oxalic acid was added and left overnight at room temperature. The precipitated crystals were collected by filtration to obtain 217 mg (77%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.87 (2H, s), 7.74-7.59 (6H, m), 5.76 (1H, s) 3.47 (2H, t, J = 5.8Hz), 3.36 (2H, s), 3.21-2.89 (6H, m), 2.75 (3H, s), 2.00-1.87 (6H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2926, 2505, 1755, 1330, 1123
Mass spectrum (FAB) m / z 531 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₈ H ₃₀ F ₆ N ₂ O ₇ )
Calculated value: C: 54.20; H: 4.87; F: 18.37; N: 4.51
Found: C: 53.78; H: 4.68; F: 18.08; N: 4.51.

Example 25
8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3- (furan-2-ylcarbonyl) -1-oxa-3,8-diazaspiro [4,5] decane-2- ON and its oxalate (Exemplified Compound No. 1-169)
(25a) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3- (furan-2-ylcarbonyl) -1-oxa-3,8-diazaspiro [4,5] decane 2- {1- [2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (1a) The reaction was purified in the same manner as in Example (1b) using 200 mg (0.39 mmol) of 1-one and 59 μl (0.58 mmol) of 2-furoyl chloride to obtain 234 mg (98%) of the title compound.

(25b) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3- (furan-2-ylcarbonyl) -1-oxa-3,8-diazaspiro [4,5] decane 2-one oxalate 8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3- (furan-2-ylcarbonyl) -1-oxa prepared in Example (25a) -3,8-diazaspiro [4,5] decan-2-one 220 mg (0.37 mmol) was dissolved in 3 ml of ethyl acetate, oxalic acid 33 mg (0.37 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to obtain 165 mg (65%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 8.00 (1H, d, J = 1.8Hz), 7.81 (2H, s), 7.74-7.61 (4H, m), 7.46 (1H, d, J = 3.5Hz), 6.71 (1H, dd, J = 1.8Hz, 3.5Hz), 5.83 (1H, s), 3.95 (2H, s), 3.69 (2H, t, J = 5.0Hz), 3.15-2.83 ( 6H, m), 2.14-1.96 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2499, 1789, 1667, 1330, 1123
Mass spectrum (FAB) m / z 597 ((M + H) ⁺ , free body)
Elemental analysis (as C ₃₁ H ₂₈ F ₆ N ₂ O ₉ )
Calculated value: C: 54.23; H: 4.11; F: 16.60; N: 4.08
Found: C: 53.85; H: 4.01; F: 16.37; N: 4.05.

Example 26
8- {2- [Bis- (3,4-difluorophenyl) methoxy] ethyl} -3-ethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one (Exemplary Compound No. 3- 99)
(26a) 8- {2- [Bis- (3,4-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one 1 prepared in Reference Example 1 -Oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 150 mg (0.78 mmol) and (3,4-difluorophenyl) phenylmethyl 2-chloroethyl ether 220 mg (0.78 mmol) prepared in Reference Example 8 ) And purified in the same manner as in Example (1a) to obtain 232 mg (74%) of the title compound.

(26b) 8- {2- [Bis- (3,4-difluorophenyl) methoxy] ethyl} -3-ethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one Examples 8- {2- [bis- (3,4-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in 26a) 0.20 g (0.45 mmol) ), Tetrabutylammonium iodide 16.8 mg (45.6 mmol) and ethyl iodide 0.055 ml (0.68 mmol) were reacted and purified in the same manner as in Example (2a) to obtain 130 mg (61.1%) of the title compound. It was.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.15-6.95 (m, 6H), 5.28 (s, 1H), 3.60 (br s, 2H), 3.32 (q, 2H, J = 7.27 Hz), 3.27 (s, 2H), 2.90-2.43 (m, 4H), 2.00-1.40 (m, 6H), 1.16 (t, 3H, J = 7.27 Hz)
Infrared absorption spectrum νmax cm ^-1 (CDCl ₃ ): 1749, 1611, 1515, 1434, 1279
Mass spectrum (FAB) m / z 467 ((M + H) ⁺ , free form).

Example 27
8- {2- [Bis- (3,4-difluorophenyl) methoxy] ethyl} -3-methoxymethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one (Exemplary Compound No. 3 -101)
8- {2- [Bis- (3,4-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in Example (26a) 20 g (0.45 mmol), tetrabutylammonium iodide 16.8 mg (45.6 mmol) and chloromethyl methyl ether 0.052 ml (0.68 mmol) were reacted and purified in the same manner as in Example (2a) to obtain 103 mg of the title compound ( 46.8%) was obtained.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.21-6.95 (m, 6H), 5.28 (s, 1H), 4.69 (s, 2H), 3.59 (br s, 2H), 3.39 (s, 3H) , 3.34 (s, 2H), 2.91-2.49 (m, 4H), 2.05-1.40 (m, 6H)
Infrared absorption spectrum νmax cm ^-1 (CDCl ₃ ): 1754, 1611, 1515, 1434, 1278
Mass spectrum (FAB) m / z 483 ((M + H) ⁺ , free form).

Example 28
8- {2- [Bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -3- (furan-2-ylcarbonyl) -1-oxa-3,8-diazaspiro [4 , 5] decan-2-one (Exemplified Compound No. 1-305)
(28a) 8- {2- [Bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one 204 mg (1.06 mmol) of 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride prepared in Reference Example 1 and (3-cyanophenyl) (3′-triphenyl) prepared in Reference Example 9 The reaction was purified in the same manner as in Example (1a) using 300 mg (0.88 mmol) of fluoromethylphenyl) methyl 2-chloroethyl ether to obtain 130 mg (32%) of the title compound.
Nuclear magnetic resonance spectrum _{(400MHz, CDCl 3) δ ppm} : 7.69 (1H, s), 7.60 (1H, s), 7.43-5.59 (6H, m), 5.34 (1H, s), 3.59 (2H, t, J = 5.7 Hz), 3.34 (2H, s), 2.71 (2H, t, J = 5.7 Hz), 2.55-2.67 (4H, m), 1.95-2.03 (2H, m), 1.75-1.84 (2H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 3268, 2923, 2330, 1750, 1328, 1126
Mass spectrum (FAB) m / z 460 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₄ H ₂₄ F ₃ N ₃ O ₅ )
Calculated value: C: 62.74; H: 5.27; N: 9.15; F: 12.40
Found: C: 62.52; H: 5.08; N: 8.60; F: 12.34.

(28b) 8- {2- [Bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -3- (furan-2-ylcarbonyl) -1-oxa-3,8- Diazaspiro [4,5] decan-2-one 8- {2- [bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -1-oxa prepared in Example (28a) -3,8-diazaspiro [4,5] decan-2-one 0.100 g (0.211 mmol), n-butyllithium (1.59 N) 0.20 ml (0.317 mmol) and 2-thenoyl chloride 0.041 ml (0.422 mmol) And purified in the same manner as in Example (1b) to obtain 65.0 mg (54.2%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.66-7.41 (m, 10H), 6.58-6.57 (m, 1H), 5.41 (s, 1H), 3.92 (s, 2H), 3.61-3.47 (m , 2H), 3.10-2.55 (m, 4H), 2.32-1.61 (m, 8H)
Infrared absorption spectrum νmax cm ^-1 (CDCl ₃ ): 1785, 1674, 1470, 1377, 1330, 1229, 1165, 1124
Mass spectrum (FAB) m / z 568 ((M + H) ⁺ , free form).

Example 29
3-ethyl-8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its oxalate salt ( Exemplified compound number 3-19)
(29a) 3-Ethyl-8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one Examples 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in 25a) 210 mg (0.42 mmol) Then, the reaction mixture was reacted and purified in the same manner as in Example (2a) using 67 μl (0.84 mmol) of ethyl iodide to obtain 196 mg (88%) of the title compound.

(29b) 3-Ethyl-8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one oxalate 3-Ethyl-8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (29a) -196 mg (0.38 mmol) of ON was dissolved in 2 ml of methanol, 33 mg (0.38 mmol) of oxalic acid and isopropanol were added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 180 mg (79%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.60-7.80 (8H, m), 5.83 (1H, s), 3.68 (2H, t, J = 5Hz), 3.35 (2H, s), 3.18 (2H, q, J = 7Hz), 2.90-3.20 (4H, m), 2.51 (2H, t, J = 5Hz), 1.87-2.00 (4H, m), 1.06 (3H, t, J = 7Hz)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1755, 1331, 1167, 1123, 1074
Mass spectrum (FAB) m / z 531 ((M + H) ⁺ , free body)
Elemental analysis (C ₂₇ H ₃₀ F ₆ N ₂ O ₇ )
Calculated value: C: 54.20; H: 4.87; N: 4.51
Found: C: 54.01; H: 4.61; N: 4.48.

Example 30
8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methoxymethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one and its oxalate salt (Exemplary compound number 3-22)
(30a) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methoxymethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in (3a) 0.30 g (0.581 mmol), 21.0 mg (58.1 mmol) of tetrabutylammonium iodide and 0.13 ml (1.74 mmol) of chloromethyl methyl ether were reacted and purified in the same manner as in Example (2a) to obtain 124 mg (38.1%). It was.

(30b) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methoxymethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one oxalic acid Salt 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methoxymethyl-1-oxa-3,8-diazaspiro [4,5] decane prepared in Example (30a) 124 mg (0.221 mol) of 2-one was dissolved in 5 ml of ethyl acetate, 19.9 mg (0.221 mmol) of oxalic acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 99 mg (68.8%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.75-7.53 (m, 8H), 5.66 (s, 1H), 4.87 (s, 3H), 4.67 (s, 2H), 3.64-3.47 (m, 6H), 3.38-3.21 (m, 4H), 2.25-2.08 (m, 6H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1759, 1617, 1435, 1404, 1332, 1280, 1256, 1166, 1123, 1093, 1074
Mass spectrum (FAB) m / z 561 ((M + H) ⁺ , free form).

Example 31
8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one and its oxalate salt (Exemplified compound number 1-148)
(31a) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in (3a) 0.30 g (0.581 mmol), tetrabutylammonium iodide 21.0 mg (58.1 mmol) and chloromethyl methyl sulfide 0.15 ml (1.74 mmol) were reacted and purified in the same manner as in Example (2a) to give 222 mg (66.3%) of the title compound. Got.

(31b) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one oxalic acid Salt 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decane prepared in Example (31a) -2-one 222 mg (0.385 mol) was dissolved in ethyl acetate 5 ml, oxalic acid 34.7 mg (0.385 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to obtain 157 mg (61.2%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.73-7.53 (m, 8H), 5.67 (s, 1H), 4.43 (s, 2H), 4.67 (s, 2H), 3.66-3.47 (m, 4H), 3.35-3.22 (m, 7H), 2.25-2.08 (m, 6H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1750, 1616, 1431, 1331, 1255, 1165, 1123, 1092, 1074
Mass spectrum (FAB) m / z 577 ((M + H) ⁺ , free form).

Example 32
8- {2- [Bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -3- (thiophen-2-ylcarbonyl) -1-oxa-3,8-diazaspiro [4 , 5] decan-2-one and its oxalate salt (Exemplified Compound No. 1-307)
(32a) 8- {2- [Bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -3- (thiophen-2-ylcarbonyl) -1-oxa-3,8- Diazaspiro [4,5] decan-2-one 8- {2- [bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -1-oxa prepared in Example (28a) -3,8-diazaspiro [4,5] decan-2-one 0.300 g (0.211 mmol), n-butyllithium (1.59 N), 0.60 ml (0.950 mmol) and 0.14 ml (1.27 mmol) of 2-thenoyl chloride And purified in the same manner as in Example (1b) to obtain 259 mg (70%) of the title compound.

(32b) 8- {2- [Bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -3- (thiophen-2-ylcarbonyl) -1-oxa-3,8- Diazaspiro [4,5] decan-2-one oxalate 8- {2- [bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl}-prepared in Example (32a) 259 mg (0.444 mol) of 3- (thiophen-2-ylcarbonyl) -1-oxa-3,8-diazaspiro [4,5] decan-2-one was dissolved in 5 ml of ethyl acetate, and 40.0 mg (0.444 mmol) of oxalic acid was dissolved. ) Was added and lyophilized. The precipitated crystals were collected by filtration to obtain 273 mg (91.3%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.97-7.50 (m, 10H), 7.18-7.13 (m, 1H), 5.65 (s, 1H), 4.02 (s, 2H), 3.70-3.50 ( m, 4H), 3.40-3.27 (m, 4H), 2.38-2.08 (m, 6H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1786, 1652, 1417, 1382, 1330, 1229, 1164, 1123
Mass spectrum (FAB) m / z 584 ((M + H) ⁺ , free form).

Example 33
8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (4-methoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decan-2-one and The oxalate salt (Exemplified compound number 1-166)
(33a) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (4-methoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decane-2 -ON 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in Example (30a) Using 0.300 g (0.581 mmol), n-butyllithium (1.59 N), 0.55 ml (0.871 mmol) and 4-methoxybenzoyl chloride 198 mg (0.871 mmol), the same reaction and purification as in Example (1b) was carried out. 360 mg (95.3%) were obtained.

(33b) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (4-methoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decane-2 -On oxalate 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (4-methoxybenzoyl) -1-oxa-3,8 prepared in Example (33a) -Diazaspiro [4,5] decan-2-one 360 mg (0.553 mol) was dissolved in ethyl acetate 5 ml, oxalic acid 49.8 mg (0.553 mmol) was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 220 mg (53.7%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.72-7.53 (m, 10H), 6.98-6.93 (m, 2H), 5.67 (s, 1H), 3.99 (s, 2H), 3.86 (s, 3H), 3.64-3.50 (m, 4H), 3.38-3.27 (m, 4H), 2.38-2.09 (m, 6H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1785, 1654, 1605, 1513, 1330, 1258, 1171, 1124
Mass spectrum (FAB) m / z 651 ((M + H) ⁺ , free form).

Example 34
8- {2- [Bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -3- (2-methoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5 ] Decan-2-one and its oxalate (Exemplified Compound No. 1-301)
(34a) 8- {2- [Bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -3- (2-methoxybenzoyl) -1-oxa-3,8-diazaspiro [ 4,5] decan-2-one 8- {2- [bis- (3-cyanophenyl) (3′-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3 prepared in Example (28a) , 8-diazaspiro [4,5] decan-2-one 0.30 g (0.211 mmol), n-butyllithium (1.59 N), 0.60 ml (0.950 mmol) and 2-methoxybenzoyl chloride 0.17 ml (1.27 mmol) And purified in the same manner as in Example (1b) to obtain 281 mg (72.3%) of the title compound.

(34b) 8- {2- [Bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -3- (2-methoxybenzoyl) -1-oxa-3,8-diazaspiro [ 4,5] Decan-2-one oxalate 8- {2- [bis- (3-cyanophenyl) (3′-trifluoromethylphenyl) methoxy] ethyl} -3-prepared in Example (34a) 281 mg (0.463 mol) of (2-methoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decan-2-one is dissolved in 5 ml of ethyl acetate, 41.6 mg (0.463 mmol) of oxalic acid is added, Lyophilized. The precipitated crystals were collected by filtration to obtain 268 mg (83.0%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.82-6.95 (m, 12H), 5.64 (s, 1H), 4.00 (s, 2H), 3.81 (s, 3H), 3.65-3.52 (m, 4H), 3.41-3.25 (m, 4H), 2.32-2.19 (m, 4H), 2.18-2.08 (m, 2H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1793, 1685, 1603, 1332, 1250, 1165, 1122
Mass spectrum (FAB) m / z 608 ((M + H) ⁺ , free form).

Example 35
8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2,4-dimethoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decane-2- ON and its oxalate (Exemplified Compound No. 1-168)
(35a) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2,4-dimethoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decane 2- {1- [3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (33a) -Reaction as in Example (1b) using 0.300 g (0.581 mmol), n-butyllithium (1.59 N), 0.55 ml (0.871 mmol) and 232 mg (0.871 mmol) of 2,4-dimethoxybenzoyl chloride To give 353 mg (89.3%) of the title compound.

(35b) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2,4-dimethoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decane 2-one oxalate 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2,4-dimethoxybenzoyl) -1-oxa prepared in Example (35a) 353 mg (0.519 mol) of 3,8-diazaspiro [4,5] decan-2-one was dissolved in 5 ml of ethyl acetate, 46.7 mg (0.519 mmol) of oxalic acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 52 mg (13.0%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.73-7.53 (m, 8H), 7.33 (d, 1H, J = 8.16 Hz), 6.59-6.54 (m, 2H), 5.67 (s, 1H) , 3.98 (s, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 3.65-3.58 (m, 4H), 3.38-3.27 (m, 4H), 2.31-2.08 (m, 6H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1789, 1673, 1608, 1331, 1165, 1123
Mass spectrum (FAB) m / z 681 ((M + H) ⁺ , free form).

Example 36
8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3- (2-methoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decan-2-one and The oxalate salt (Exemplified compound number 1-161)
(36a) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3- (2-methoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decane-2 -ON 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in Example (1a) The reaction was conducted in the same manner as in Example (1b) using 200 mg (0.40 mmol) and 2-methoxybenzoyl chloride 67 μl (0.44 mmol) to obtain 193 mg (76%) of the title compound.

(36b) 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3- (2-methoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5] decane-2 -On oxalate 8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3- (2-methoxybenzoyl) -1-oxa-3,8 prepared in Example (36a) -193 mg (0.30 mmol) of diazaspiro [4,5] decan-2-one was dissolved in 2 ml of methanol, 27 mg (0.30 mmol) of oxalic acid and isopropanol were added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 124 mg (56%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.60-7.75 (8H, m), 7.46 (1H, dt, J = 1.5Hz, 7Hz), 7.31 (1H, dt, J = 1.5Hz, 7Hz ), 7.07 (1H, d, 8Hz), 7.03 (1H, t, 8Hz), 5.83 (1H, s), 3.94 (2H, s), 3.75 (3H, s), 3.70 (2H, t, 5Hz), 2.95-3.25 (4H, m), 2.50 (2H, t, 5Hz), 2.00-2.15 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1792, 1331, 1252, 1166, 1123
Mass spectrum (FAB) m / z 637 ((M + H) ⁺ , free body)
Elemental analysis (as C ₃₂ H ₃₀ F ₆ N ₂ O ₅・ 1.6C ₂ H ₂ O ₄ )
Calculated value: C: 53.95; H: 4.27; N: 3.56
Found: C: 53.97; H: 4.37; N: 3.77.

Example 37
3-methoxymethyl-8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its oxalate salt (Exemplary compound number 3-21)
(37a) 3-Methoxymethyl-8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one 8- {2- [Bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in (1a) 206 mg (0.41 mmol ) And 62 μl (0.82 mmol) of chloromethyl methyl ether were reacted and purified in the same manner as in Example (2a) to obtain 160 mg (71%) of the title compound.

(37b) 3-Methoxymethyl-8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one oxalic acid Salt 3-methoxymethyl-8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane prepared in Example (37a) 2-one 160 mg (0.29 mmol) was dissolved in 2 ml of methanol, oxalic acid 26 mg (0.29 mmol) and isopropanol were added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to obtain 138 mg (74%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.60-7.77 (8H, m), 5.82 (1H, s), 4.73 (2H, s), 3.67 (2H, t, J = 5Hz), 3.44 (3H, s), 3.21 (2H, s), 2.88-3.17 (4H, m), 2.51 (2H, t, J = 5Hz), 1.90-2.05 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1703, 1331, 1165, 1120, 1074
Mass spectrum (FAB) m / z 547 ((M + H) ⁺ , free body)
Elemental analysis (C ₂₈ H ₃₀ F ₆ N ₂ O ₈ )
Calculated value: C: 52.83; H: 4.75; N: 4.40
Found: C: 52.73; H: 4.65; N: 4.44.

Example 38
3- (2-methoxyethyl) -8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one and Its oxalate (Exemplified Compound No. 3-24)
(38a) 3- (2-Methoxyethyl) -8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 -ON 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in Example (3a) The reaction was purified in the same manner as in Example (2a) using 165 mg (0.32 mmol) and 2-methoxyethyl bromide 60 μl (0.642 mmol) to obtain 90 mg (49%) of the title compound.

(38b) 3- (2-Methoxyethyl) -8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 -On oxalate 3- (2-methoxyethyl) -8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8 prepared in Example (38a) -90 mg (0.15 mmol) of diazaspiro [4,5] decan-2-one was dissolved in 2 ml of methanol, 14 mg (0.15 mmol) of oxalic acid and isopropanol were added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 81 mg (78%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.58-7.82 (8H, m), 5.76 (1H, s), 3.40-3.51 (4H, m), 3.41 (2H, s), 3.32 (2H , t, J = 5Hz), 3.26 (3H, s), 2.85-3.20 (4H, m), 2.51 (2H, t, J = 5Hz), 1.85-2.00 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1734, 1702, 1333, 1166, 1123
Mass spectrum (FAB) m / z 575 ((M + H) ⁺ , free body)
Elemental analysis (C ₃₀ H ₃₄ F ₆ N ₂ O ₈ )
Calculated value: C: 53.30; H: 5.30; N: 4.03
Found: C: 52.86; H: 5.07; N: 4.18.

Example 39
8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2-furoyl) -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its Oxalate (Exemplified Compound Number 1-170)
(39a) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2-furoyl) -1-oxa-3,8-diazaspiro [4,5] decane-2- ON 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in Example (3a) 470 mg (0.91 mmol) and 130 μl (1.09 mmol) of 2-furoyl chloride were reacted and purified in the same manner as in Example (1b) to obtain 490 mg (88%) of the title compound.

(39b) 8- {3- [Bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2-furoyl) -1-oxa-3,8-diazaspiro [4,5] decane-2- On-oxalate 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -3- (2-furoyl) -1-oxa-3,8-diazaspiro prepared in Example (39a) 490 mg (0.81 mmol) of [4,5] decan-2-one was dissolved in 5 ml of ethyl acetate, 72 mg (0.81 mmol) of oxalic acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 433 mg (77%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 8.01 (1H, d, J = 1Hz), 7.60-7.77 (8H, m), 7.46 (1H, d, 3.5Hz), 6.72 (1H, dd , J = 1Hz, J = 3.5Hz), 5.77 (1H, s), 3.96 (2H, s), 3.47 (2H, t, J = 5Hz), 2.90-3.25 (4H, m), 2.47-2.52 (4H , m), 1.90-2.20 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1791, 1331, 1229, 1166, 1123
Mass spectrum (FAB) m / z 611 ((M + H) ⁺ , free body)
Elemental analysis (as _{C 30 H 28 F 6 N 2} O 5 · 7 / 6C 2 H 2 O 4)
Calculated value: C: 54.27; H: 4.27; N: 3.91
Found: C: 54.47; H: 4.16; N: 4.01.

Example 40
8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one And its oxalate (Exemplified Compound No. 1-298)
(40a) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decane- 2-one 8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] prepared in Example (8a) The reaction was conducted in the same manner as in Example (2a) using 200 mg (0.42 mmol) of decan-2-one and 53 μl (0.63 mmol) of chloromethyl methyl sulfide to obtain 142 mg (63%) of the title compound.

(40b) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decane- 2-one oxalate 8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3 prepared in Example (40a) , 8-diazaspiro [4,5] decan-2-one (130 mg, 0.24 mmol) was dissolved in ethyl acetate (3 ml), oxalic acid (22 mg, 0.24 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to obtain 118 mg (78%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.94 (1H, m), 7.79-7.72 (4H, m), 7.67-7.56 (3H, m), 5.71 (1H, s) 4.42-4.36 ( 2H, m), 3.50-3.41 (4H, m), 3.34-2.91 (6H, m), 2.08 (3H, s), 2.04-1.88 (6H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2493, 1754, 1430, 1330, 1123
Mass spectrum (FAB) m / z 534 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₉ H ₃₂ F ₃ N ₃ O ₇ S)
Calculated value: C: 55.85; H: 5.17; F: 9.14; N: 6.72; S: 5.14
Found: C: 55.54; H: 4.95; F: 8.97; N: 6.72; S: 5.18.

Example 41
8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxyethyl) -1-oxa-3,8-diazaspiro [4,5] decane -2-one and its oxalate (Exemplified Compound No. 3-56)
(41a) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxyethyl) -1-oxa-3,8-diazaspiro [4, 5] Decan-2-one 8- {3-[(3-cyanophenyl) (3′-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro prepared in Example (8a) [4,5] decan-2-one 200 mg (0.42 mmol) and 2-bromoethyl methyl ether 60 μl (0.63 mmol) were reacted and purified in the same manner as in Example (2a) to give 161 mg (72 %).

(41b) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxyethyl) -1-oxa-3,8-diazaspiro [4, 5] Decan-2-one oxalate 8- {3-[(3-cyanophenyl) (3′-trifluoromethylphenyl) methoxy] propyl} -3- (2-methoxy) prepared in Example (41a) Ethyl) -1-oxa-3,8-diazaspiro [4,5] decan-2-one 150 mg (0.28 mmol) is dissolved in ethyl acetate 3 ml, oxalic acid 25 mg (0.28 mmol) is added, and the mixture is allowed to stand at room temperature overnight. did. The precipitated crystals were collected by filtration to obtain 97 mg (56%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.94 (1H, m), 7.85-7.72 (4H, m), 7.67-7.56 (3H, m), 5.71 (1H, s) 3.50-3.43 ( 4H, m), 3.41 (2H, s), 3.32 (2H, t, J = 5.3Hz), 3.26 (3H, s), 3.20-2.93 (6H, m), 2.03-1.87 (6H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2928, 2498, 1753, 1329, 1121
Mass spectrum (FAB) m / z 532 ((M + H) ⁺ , free body)
Elemental analysis (as C ₃₀ H ₃₄ F ₃ N ₃ O ₈ )
Calculated value: C: 57.97; H: 5.51; F: 9.17; N: 6.76
Found: C: 57.56; H: 5.16; F: 8.83; N: 6.48.

Example 42
8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methoxymethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one And its oxalate (Exemplified Compound No. 3-54)
(42a) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methoxymethyl-1-oxa-3,8-diazaspiro [4,5] decane- 2-one 8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] prepared in Example (8a) The reaction was conducted in the same manner as in Example (2a) using 500 mg (1.06 mmol) of decan-2-one and 120 μl (1.58 mmol) of chloromethyl methyl ether to obtain 225 mg (40%) of the title compound.

(42b) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methoxymethyl-1-oxa-3,8-diazaspiro [4,5] decane- 2-one oxalate 8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methoxymethyl-1-oxa-3 prepared in Example (42a) , 8-diazaspiro [4,5] decan-2-one 210 mg (0.40 mmol) was dissolved in ethyl acetate 3 ml, oxalic acid 36 mg (0.40 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to obtain 191 mg (78%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.94 (1H, m), 7.85-7.72 (4H, m), 7.67-7.56 (3H, m), 5.70 (1H, s), 4.59 (2H , s), 3.50-3.42 (4H, m), 3.22 (3H, s), 3.18-2.87 (6H, m), 2.06-1.83 (6H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2497, 1758, 1403, 1329, 1121
Mass spectrum (FAB) m / z 518 ((M + H) ⁺ , free form).
Elemental analysis (as C ₂₉ H ₃₂ F ₃ N ₃ O ₈ -H ₂ O)
Calculated value: C: 55.68; H: 5.48; F: 9.11; N: 6.72
Found: C: 55.68; H: 5.17; F: 9.21; N: 6.34.

Example 43
8- {2- [Bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -3- (4-methoxybenzoyl) -1-oxa-3,8-diazaspiro [4,5 ] Decan-2-one (Exemplified Compound No. 1-303)
8- {2- [Bis- (3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] prepared in Example (28a) Example (1b) with 0.100 g (0.211 mmol) decan-2-one, n-butyllithium (1.59 N), 0.20 ml (0.317 mmol) and 0.072 g (0.422 mmol) 4-methoxybenzoyl chloride Reaction and purification in the same manner gave 138 mg (100%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.70-7.42 (m, 10H), 6.96-6.88 (m, 2H), 5.43 (s, 1H), 3.91 (s, 2H), 3.87 (s, 3H ), 3.55 (s, 2H), 3.11-2.40 (m, 4H), 2.16-1.51 (m, 8H)
Infrared absorption spectrum νmax cm ^-1 (CDCl ₃ ): 1781, 1677, 1606, 1513, 1329, 1258, 1169, 1126
Mass spectrum (FAB) m / z 608 ((M + H) ⁺ , free form).

Example 44
8- [3- (4-Fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate (Exemplary compounds) Number 2-49)
(44a) 8- [3- (4-Fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Produced in Reference Example 12 3-chloro-1- (4-fluorophenyl) propyl 4-fluorophenyl ether 190 mg (0.67 mmol) was dissolved in dimethylacetamide 5 ml, and 1-oxa-3,8-diazaspiro [4, 5] Decan-2-one hydrochloride 155 mg (0.81 mmol), sodium bicarbonate 112 mg (1.34 mmol) and potassium iodide 15 mg (0.01 mmol) were added, and the mixture was stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (elution solvent: ethyl acetate / methanol = 9/1) to obtain 250 mg (92%) of the title compound.

(44b) 8- [3- (4-Fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate Examples 8- [3- (4-Fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in (44a) 240 mg ( 0.60 mmol) was dissolved in 3 ml of ethyl acetate, 69 mg (0.60 mmol) of fumaric acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 213 mg (69%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.47-7.41 (2H, m), 7.19-7.13 (2H, m), 7.07-7.00 (2H, m), 6.92-6.86 (2H, m) , 6.62 (2H, s), 5.36-5.33 (1H, m), 3.22 (2H, s), 2.56-2.45 (6H, m), 2.17-2.05 (1H, m), 1.96-1.88 (1H, m) , 1.87-1.70 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1753, 1505, 1260, 1207
Mass spectrum (FAB) m / z 403 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₆ H ₂₈ F ₂ N ₂ O ₇ )
Calculated value: C: 60.23; H: 5.44; F: 7.33; N: 5.40
Found: C: 59.90; H: 5.07; F: 7.21; N: 5.41.

Example 45
8- [3- (3-trifluoromethylphenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate ( Exemplified Compound No. 2-413)
(45a) 8- [3- (3-Trifluoromethylphenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Reference Example 22 3-chloro-1- (4-fluorophenyl) propyl 3-trifluoromethylphenyl ether prepared in 306 mg (0.92 mmol) and 1-oxa-3,8-diazaspiro [4,5] decane prepared in Reference Example 1 The reaction was carried out in the same manner as in Example (44a) using 212 mg (1.1 mmol) of 2-one hydrochloride, to obtain 358 mg (86%) of the title compound.

(45b) 8- [3- (3-Trifluoromethylphenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate 8- [3- (3-Trifluoromethylphenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (45a) -350 mg (0.77 mmol) of ON was dissolved in 3 ml of ethyl acetate, 90 mg (0.77 mmol) of fumaric acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 308 mg (70%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.48-7.42 (3H, m), 7.23-7.12 (5H, m), 6.63 (2H, s), 5.55-5.52 (1H, m), 3.23 (2H, s), 2.62-2.50 (6H, m), 2.21-2.12 (1H, m), 2.03-1.93 (1H, m), 1.87-1.70 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1751, 1329, 1226, 1127
Mass spectrum (FAB) m / z 453 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₇ H ₂₈ F ₄ N ₂ O ₇ )
Calculated value: C: 57.04; H: 4.96; F: 13.37; N: 4.93
Found: C: 56.38; H: 4.36; F: 13.40; N: 4.85.

Example 46
8- [3- (3-Cyanophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate ( Illustrative compound number 2-317)
(46a) 8- [3- (3-Cyanophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Reference Example 1 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride prepared in 150 mg (0.774 mmol), methanesulfonic acid 3- (3-cyanophenoxy) -3- (3 prepared in Reference Example 20 -Trifluoromethylphenyl) propyl 309 mg (0.774 mmol) was dissolved in 5 ml of N, N-dimethylacetamide, and stirred at room temperature, 214 mg (1.55 mmol) of potassium carbonate, 26 mg (0.155 mmol) of potassium iodide, 0.46 g of molecular sieve 4A And stirred at 100 ° C. for 16 hours. After completion of the reaction, the reaction solution was filtered through celite and washed several times with ethyl acetate. Thereafter, water was added to the organic layer, extracted with ethyl acetate, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 10/1) to obtain 172 mg (yield 99.7%) of the title compound as an oily substance.

(46b) 8- [3- (3-Cyanophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate 8- [3- (3-Cyanophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (46a) -Dissolved 172 mg (0.374 mmol) of ON in 5 ml of ethyl acetate, added 43 mg (0.374 mmol) of fumaric acid and allowed to stand overnight. The precipitated crystals were collected by filtration to obtain 93.0 mg (43.3%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.76-7.17 (m, 8H), 5.62-5.57 (m, 1H), 3.41 (s, 2H), 3.36-3.03 (m, 7H), 2.48- 2.35 (m, 1H), 2.35-2.22 (m, 1H), 2.19-1.97 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1759, 1329, 1256, 1166, 1127, 1074, 983
Mass spectrum (FAB) m / z 460 ((M + H) ⁺ , free form).

Example 47
8- [3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate (Exemplary compound number 2-445)
(47a) 8- [3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Reference Example 190 mg (1.01 mmol) of 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride prepared in 1 and 3- (4-cyanophenoxy) -3- (methanesulfonate) prepared in Reference Example 21 432 mg (0.774 mmol) of 3-trifluoromethylphenyl) propyl was dissolved in 5 ml of N, N-dimethylacetamide, and stirred at room temperature, potassium carbonate 278 mg (2.01 mmol), potassium iodide 33 mg (0.201 mmol), molecular sieve 4A 0.62 g was added and it stirred at 100 degreeC for 16 hours. After completion of the reaction, the reaction solution was filtered through celite and washed several times with ethyl acetate. Thereafter, water was added to the organic layer, extracted with ethyl acetate, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 10/1) to obtain 252 mg (yield 99.7%) of the title compound as an oily substance.

(47b) 8- [3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumaric acid Salt 8- [3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decane prepared in Example (47a) -2-one 252 mg (0.549 mmol) was dissolved in ethyl acetate 5 ml, fumaric acid 0.064 g (0.374 mmol) was added and left overnight. The precipitated crystals were collected by filtration to give 162 mg (51.3%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.75-7.52 (m, 6H), 7.05-7.00 (m, 2H), 5.65-5.60 (m, 1H), 3.41 (s, 2H), 3.37- 3.05 (m, 7H), 2.49-2.38 (m, 1H), 2.38-2.25 (m, 1H), 2.19-1.98 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1753, 1604, 1506, 1330, 1250, 1173, 1127, 1074, 983
Mass spectrum (FAB) m / z 460 ((M + H) ⁺ , free form).

Example 48
8- [3- (4-Chlorophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate ( Exemplified Compound No. 2-437)
(48a) 8- [3- (4-Chlorophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Reference Example 1 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride prepared in 137 mg (0.709 mmol), methanesulfonic acid 3- (4-chlorophenoxy) -3- (3 prepared in Reference Example 16 -Trifluoromethylphenyl) propyl 290 mg (0.709 mmol) was dissolved in 5 ml of N, N-dimethylacetamide, and stirred at room temperature, 196 mg (1.42 mmol) of potassium carbonate, 24 mg (0.142 mmol) of potassium iodide, 0.43 g of molecular sieve 4A And stirred at 100 ° C. for 16 hours. After completion of the reaction, the reaction solution was filtered through celite and washed several times with ethyl acetate. Thereafter, water was added to the organic layer, extracted with ethyl acetate, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 10/1) to obtain 280 mg (yield: 84.2%) of the title compound as an oily substance.

(48b) 8- [3- (4-Chlorophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate 8- [3- (4-Chlorophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (48a) -280 mg (0.597 mmol) of ON was dissolved in 5 ml of ethyl acetate, 0.069 g (0.597 mmol) of fumaric acid was added and left overnight. The precipitated crystals were collected by filtration to give 183 mg (52.4%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.72-7.52 (m, 4H), 7.20-7.14 (m, 2H), 6.89-6.82 (m, 2H), 5.50-5.43 (m, 1H), 3.41 (s, 2H), 3.37-3.03 (m, 7H), 2.42-2.32 (m, 1H), 2.32-2.21 (m, 1H), 2.19-2.00 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1758, 1490, 1329, 1235, 1168, 1127, 983
Mass spectrum (FAB) m / z 469 ((M + H) ⁺ , free form).

Example 49
8- [3- (2-Fluoro-phenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumaric acid Salt (Exemplary compound number 2-425)
(49a) 8- [3- (2-Fluoro-phenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Reference 142 mg (0.789 mmol) of 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride prepared in Example 1 and 3- (2-fluorophenoxy) -3-methanesulfonic acid prepared in Reference Example 17 290 mg (0.789 mmol) of (3-trifluoromethylphenyl) propyl was dissolved in 5 ml of N, N-dimethylacetamide, and stirred at room temperature, 204 mg (1.48 mmol) of potassium carbonate, 25 mg (0.148 mmol) of potassium iodide, molecular sieve 4A 0.43g was added and it stirred at 100 degreeC for 16 hours. After completion of the reaction, the reaction solution was filtered through celite and washed several times with ethyl acetate. Thereafter, water was added to the organic layer, extracted with ethyl acetate, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 10/1) to obtain 260 mg (yield 77.8%) of the title compound as an oily substance.

(49b) 8- [3- (2-Fluoro-phenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate Acid 8- [3- (2-Fluoro-phenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] prepared in Example (49a) Decan-2-one 260 mg (0.575 mmol) was dissolved in ethyl acetate 5 ml, fumaric acid 0.067 g (0.575 mmol) was added, and the mixture was allowed to stand overnight. The precipitated crystals were collected by filtration to give 262 mg (80.1%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.77-7.51 (m, 4H), 7.11-7.02 (m, 1H), 6.96-6.85 (m, 3H), 5.52-5.48 (m, 1H), 3.41 (s, 2H), 3.38-3.05 (m, 7H), 2.50-2.39 (m, 1H), 2.34-2.22 (m, 1H), 2.19-1.99 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1754, 1503, 1330, 1258, 1199, 1169, 1126, 1074
Mass spectrum (FAB) m / z 453 ((M + H) ⁺ , free form).

Example 50
8- [3- (3-Fluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate (Exemplary compound number 2-429)
(50a) 8- [3- (3-Fluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Reference Example 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride prepared in 1 113 mg (0.586 mmol), methanesulfonic acid 3- (3-fluorophenoxy) -3- (prepared in Reference Example 18 3-trifluoromethylphenyl) propyl 230 mg (0.586 mmol) was dissolved in N, N-dimethylacetamide 5 ml, and stirred at room temperature, potassium carbonate 162 mg (1.17 mmol), potassium iodide 19 mg (0.117 mmol), molecular sieve 4A 0.34 g was added and it stirred at 100 degreeC for 16 hours. After completion of the reaction, the reaction solution was filtered through celite and washed several times with ethyl acetate. Thereafter, water was added to the organic layer, extracted with ethyl acetate, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10/1) to give the title compound (165 mg, yield 62.2%) as an oil.

(50b) 8- [3- (3-Fluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumaric acid Salt 8- [3- (3-Fluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decane prepared in Example (50a) 165 mg (0.365 mmol) of 2-one was dissolved in 5 ml of ethyl acetate, 0.042 g (0.365 mmol) of fumaric acid was added and left overnight. The precipitated crystals were collected by filtration to give 113 mg (54.6%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.75-7.52 (m, 4H), 7.22-7.13 (m, 1H), 6.72-6.59 (m, 3H), 5.52-5.48 (m, 1H), 3.41 (s, 2H), 3.38-3.02 (m, 7H), 2.42-2.31 (m, 1H), 2.31-2.21 (m, 1H), 2.18-1.98 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1757, 1610, 1593, 1489, 1330, 1262, 1167, 1135, 983
Mass spectrum (FAB) m / z 453 ((M + H) ⁺ , free form).

Example 51
8- [3- (4-Trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate Acid salt (Exemplified Compound No. 2-441)
(51a) 8- [3- (4-Trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one 115 mg (0.599 mmol) of 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride prepared in Reference Example 1 and 3- (4-trifluoromethylphenoxy) methanesulfonate prepared in Reference Example 19 -3- (3-trifluoromethylphenyl) propyl 265 mg (0.599 mmol) was dissolved in N, N-dimethylacetamide 5 ml, and stirred at room temperature, potassium carbonate 166 mg (1.20 mmol), potassium iodide 20 mg (0.120 mmol), Molecular sieve 4A 0.38 g was added and stirred at 100 ° C. for 16 hours. After completion of the reaction, the reaction solution was filtered through celite and washed several times with ethyl acetate. Thereafter, water was added to the organic layer, extracted with ethyl acetate, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10/1) to give 254 mg (yield 84.4%) of the title compound as an oily substance.

(51b) 8- [3- (4-Trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Fumarate 8- [3- (4-trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4] prepared in Example (51a) , 5] decan-2-one 254 mg (0.506 mmol) was dissolved in 5 ml of ethyl acetate, and 0.059 g (0.506 mmol) of fumaric acid was added and left overnight. The precipitated crystals were collected by filtration to give 184 mg (58.8%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.78-7.47 (m, 6H), 7.05-7.00 (m, 2H), 5.62-5.58 (m, 1H), 3.42 (s, 2H), 3.42- 3.08 (m, 7H), 2.49-2.38 (m, 1H), 2.38-2.26 (m, 1H), 2.20-2.01 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1757, 1614, 1330, 1247, 1166, 1115, 1069, 983
Mass spectrum (FAB) m / z 503 ((M + H) ⁺ free form).

Example 52
8- [3- (4-Fluorophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate ( Exemplified Compound No. 2-433)
(52a) 8- [3- (4-Fluorophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Reference Example 23 Methanesulfonic acid 3- (4-fluorophenoxy) -3- [3- (trifluoromethyl) phenyl] propyl 270 mg (0.69 mmol) prepared in 1) and 1-oxa-3,8-diazaspiro prepared in Reference Example 1 The reaction was carried out in the same manner as in Example (44a) using 159 mg (0.83 mmol) of 4,5] decan-2-one hydrochloride to obtain 283 mg (91%) of the title compound.

(52b) 8- [3- (4-Fluorophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate 8- [3- (4-Fluorophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (52a) -270 mg (0.60 mmol) of ON was dissolved in 3 ml of ethyl acetate, and 69 mg (0.60 mmol) of fumaric acid was added and left overnight at room temperature. The precipitated crystals were collected by filtration to obtain 244 mg (72%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400 MHz, DMSO-d ₆ ) δ ppm: 7.76-7.57 (4H, m), 7.07-7.01 (2H, m), 6.96-6.89 (2H, m), 6.61 (2H, s), 5.50 -5.46 (1H, m), 3.22 (2H, s), 2.55-2.39 (6H, m), 2.17-2.06 (1H, m), 2.03-1.92 (1H, m), 1.87-1.67 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1755, 1505, 1329, 1204, 1126
Mass spectrum (FAB) m / z 453 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₇ H ₂₈ F ₄ N ₂ O ₇ )
Calculated value: C: 57.04; H: 4.96; F: 13.37; N: 4.93
Found: C: 56.38; H: 4.36; F: 13.40; N: 4.85.

Example 53
8- [3- (3-trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumaric acid Salt (Exemplary compound number 2-147)
(53a) 8- [3- (3-Trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Reference Methanesulfonic acid 3- [3- (trifluoromethyl) phenoxy] -3- [3- (trifluoromethyl) phenyl] propyl 287 mg (0.65 mmol) prepared in Example 24 and 1-oxa- prepared in Reference Example 1 The reaction was conducted in the same manner as in Example (44a) using 150 mg (0.78 mmol) of 3,8-diazaspiro [4,5] decan-2-one hydrochloride to obtain 286 mg (88%) of the title compound. .

(53b) 8- [3- (3-Trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate Acid salt 8- [3- (3-trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] prepared in Example (53a) ] Decan-2-one 280 mg (0.56 mmol) was dissolved in ethyl acetate 3 ml, fumaric acid 65 mg (0.56 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to obtain 245 mg (71%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.82 (1H, s), 7.78-7.73 (1H, m), 7.57-7.67 (2H, m), 7.49-7.43 (1H, m), 7.28 -7.20 (3H, m), 6.61 (2H, s), 5.72-5.65 (1H, m), 3.21 (2H, s), 2.55-2.37 (6H, m), 2.23-2.12 (1H, m), 2.06 -1.97 (1H, m), 1.83-1.65 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1756, 1328, 1167, 1125, 1072
Mass spectrum (FAB) m / z 503 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₈ H ₂₈ F ₆ N ₂ O ₇ )
Calculated value: C: 53.59; H: 4.66; F: 18.16; N: 4.46
Found: C: 53.61; H: 4.42; F: 17.68; N: 4.40.

Example 54
(3S) -8- [3- (4-Fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumaric acid Salt (optically active form of Exemplified Compound No. 2-49)
(54a) (3S) -8- [3- (4-Fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Reference 13.1 g (69 mmol) of (1R) -3-chloro-1- (4-fluorophenyl) -1-propanol prepared in Example 25 was dissolved in 130 ml of toluene, 9.3 g (83.0 mmol) of 4-fluorophenol, triphenylphosphine 21.8 g (83.1 mmol) and 36 ml (82.7 mmol) of a 40% diethyl azodicarboxylate toluene solution were added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane = 1/9) to give (1S) -3-chloro-1- (4-fluorophenyl). 14.3 g of propyl 4-fluorophenyl ether was obtained.

  14.3 g of the obtained compound was dissolved in 280 ml of dimethylacetamide, 11.7 g (60.7 mmol) of 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride prepared in Reference Example 1 and hydrogen carbonate Sodium 8.5g (101mmol) and potassium iodide 760mg (4.57mmol) were added and stirred at 100 ° C for 8 hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / methanol = 9/1) to obtain 17.1 g (84%) of the title compound.

(54b) (3S) -8- [3- (4-Fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate (3S) -8- [3- (4-Fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] prepared in Example (54a) ] 17.1 g (42.5 mmol) of decan-2-one was dissolved in 180 ml of ethyl acetate, 4.93 g (42.5 mmol) of fumaric acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 17.1 g (78%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.47-7.41 (2H, m), 7.19-7.13 (2H, m), 7.05-7.00 (2H, m), 6.91-6.86 (2H, m) , 6.61 (2H, s), 5.35-5.32 (1H, m), 3.21 (2H, s), 2.46-2.42 (6H, m), 2.13-2.05 (1H, m), 1.95-1.86 (1H, m) , 1.82-1.68 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1754, 1504, 1222, 1204
Mass spectrum (FAB) m / z 403 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₆ H ₂₈ F ₂ N ₂ O ₇ )
Calculated value: C: 60.23; H: 5.44; F: 7.33; N: 5.40
Found: C: 60.16; H: 5.23; F: 7.53; N: 5.46
Specific rotation [α] ²⁵ _D -0.37 ° (c 1.0, MeOH).

Example 55
(3S) -8- [3- (3-Trifluoromethylphenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its Fumarate (optically active form of Exemplified Compound No. 2-413)
(55a) (3S) -8- [3- (3-Trifluoromethylphenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2- On The synthesis was performed in the same manner as in Example 54 using 300 mg (1.59 mmol) of (1R) -3-chloro-1- (4-fluorophenyl) -1-propanol and 309 mg (2.03 mmol) of 3-trifluoromethylphenol. 221 mg (42%) of (1S) -3-chloro-1- (4-fluorophenyl) propyl 3-trifluoromethylphenyl ether was obtained.

  Synthesis was carried out using 221 mg (0.66 mmol) of the compound obtained and 153 mg (0.79 mmol) of 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride prepared in Reference Example 1. 241 mg (80%) of compound were obtained.

(55b) (3S) -8- [3- (3-Trifluoromethylphenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2- On fumarate (3S) -8- [3- (3-trifluoromethylphenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro prepared in Example (55a) 241 mg (0.53 mmol) of [4,5] decan-2-one was dissolved in 3 ml of ethyl acetate, 62 mg (0.53 mmol) of fumaric acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 236 mg (78%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.49-7.42 (3H, m), 7.22-7.15 (5H, m), 6.61 (2H, s), 5.55-5.52 (1H, m), 3.22 (2H, s), 2.48-2.33 (6H, m), 2.18-2.11 (1H, m), 1.99-1.91 (1H, m), 1.82-1.68 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1750, 1328, 1226, 1126
Mass spectrum (FAB) m / z 453 ((M + H) ⁺ , free body)
Specific rotation [α] ²⁵ _D + 5.14 ° (c 1.0, MeOH).

Example 56
8- [3- (2,3-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decan-2-one and its Fumarate (Exemplified Compound No. 2-449)
(56a) 8- [3- (2,3-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decane-2- ON 300 mg (1.01 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) -propyl methanesulfonate prepared in Reference Example 15 was dissolved in 6 ml of toluene, and 140 mg of 2,3-difluorophenol was stirred at room temperature. 1.11 mmol), 290 mg (1.11 mmol) of triphenylphosphine and 0.174 ml (1.11 mmol) of diethyl azodicarboxylate were added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 3- (2,3-difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl methanesulfonate 265 mg Got.

  265 mg of the obtained compound was dissolved in 5 ml of dimethylacetamide, and 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride prepared in Reference Example 1 124 mg (0.646 mmol), potassium carbonate 179 mg (1.29 mmol) and 21 mg (0.129 mmol) of potassium iodide were added, and the mixture was stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / methanol = 10/1) to obtain 205 mg (67.5%) of the title compound.

(56b) 8- [3- (2,3-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decane-2- On fumarate 8- [3- (2,3-difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa3,8-diaza-spiro prepared in Example (56a) 205 mg (0.436 mmol) of [4,5] decan-2-one was dissolved in 3 ml of ethyl acetate, 51 mg (0.436 mmol) of fumaric acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 159 mg (62.1%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.75 (s, 1H), 7.70 (d, 1H, J = 7.5 Hz), 7.65-7.55 (m, 2H), 6.96-6.68 (m, 3H) , 5.58 (dd, 1H, J = 3.9 Hz, 8.8 Hz), 3.42 (s, 2H), 3.40-3.06 (m, 7H), 2.54-2.42 (m, 1H), 2.37-2.25 (m, 1H), 2.20-2.00 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1745, 1620, 1511, 1479, 1330, 1254, 1168, 1127, 1073, 983, 804, 768, 728, 705, 648
Mass spectrum (FAB) m / z 471 ((M + H) ⁺ , free form).

Example 57
8- [3- (2,4-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decan-2-one and its Fumarate (Exemplified Compound No. 2-450)
(57a) 8- [3- (2,4-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decane-2- ON 300 mg (1.01 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) -propyl methanesulfonate prepared in Reference Example 15 was dissolved in 6 ml of toluene, and 140 mg of 2,4-difluorophenol ( 1.11 mmol), 290 mg (1.11 mmol) of triphenylphosphine and 0.174 ml (1.11 mmol) of diethyl azodicarboxylate were added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give 3- (2,4-difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl methanesulfonate 225 mg Got.

  225 mg of the obtained compound was dissolved in 5 ml of dimethylacetamide, and 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride prepared in Reference Example 1 106 mg (0.548 mmol), potassium carbonate 152 mg ( 1.10 mmol) and 18 mg (0.110 mmol) of potassium iodide were added, and the mixture was stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / methanol = 10/1) to obtain 185 mg (71.1%) of the title compound.

(57b) 8- [3- (2,4-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decane-2- On fumarate 8- [3- (2,4-difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa3,8-diaza-spiro prepared in Example (57a) 185 mg (0.393 mmol) of [4,5] decan-2-one was dissolved in 3 ml of ethyl acetate, 46 mg (0.393 mmol) of fumaric acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 105 mg (45.5%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.74 (s, 1H), 7.69 (d, 1H, J = 7.5 Hz), 7.65-7.54 (m, 2H), 6.99-6.87 (m, 2H) , 6.77-6.68 (m, 1H), 5.46 (dd, 1H, J = 3.9 Hz, 8.8 Hz), 3.42 (s, 2H), 3.40-3.07 (m, 7H), 2.53-2.40 (m, 1H), 2.36-2.23 (m, 1H), 2.20-2.01 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1756, 1508, 1330, 1258, 1208, 1168, 1127, 1074, 982, 966, 805, 706, 647
Mass spectrum (FAB) m / z 471 ((M + H) ⁺ , free form).

Example 58
8- [3- (3,5-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decan-2-one and its Fumarate (Exemplified compound number 2-451)
(58a) 8- [3- (3,5-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decane-2- On 300 mg (1.01 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) -propyl methanesulfonate prepared in Reference Example 15 was dissolved in 6 ml of toluene, and 140 mg of 3,5-difluorophenol was stirred at room temperature. 1.11 mmol), 290 mg (1.11 mmol) of triphenylphosphine and 0.174 ml (1.11 mmol) of diethyl azodicarboxylate were added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give methanesulfonic acid 3- (3,5-difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl 257 mg Got.

  257 mg of the obtained compound is dissolved in 5 ml of dimethylacetamide, and 121 mg (0.626 mmol) of 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride, 177 mg (1.29 mmol) of potassium carbonate and iodine 21 mg (0.125 mmol) of potassium was added and stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / methanol = 10/1) to obtain 201 mg (68.2%) of the title compound.

(58b) 8- [3- (3,5-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decane-2- On fumarate 8- [3- (3,5-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro prepared in Example (58a) [4,5] decan-2-one 201 mg (0.427 mmol) was dissolved in ethyl acetate 3 ml, fumaric acid 50 mg (0.427 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to obtain 164 mg (65.3%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.74 (s, 1H), 7.69 (d, 1H, J = 7.4 Hz), 7.66-7.56 (m, 2H), 6.58-6.44 (m, 3H) , 5.20 (dd, 1H. J = 4.1 Hz, 8.3 Hz), 3.41 (s, 2H), 3.36-3.21 (m, 3H), 3.21-3.01 (m, 4H), 2.44-2.32 (m, 1H), 2.32-2.21 (m, 1H), 2.18-1.99 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1739, 1624, 1600, 1471, 1329, 1170, 1146, 1118, 1073, 992, 966, 842, 805, 705, 647
Mass spectrum (FAB) m / z 471 ((M + H) ⁺ , free form).

Example 59
8- [3- (3,4-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decan-2-one and its Fumarate (Exemplified Compound No. 2-452)
(59a) 8- [3- (3,4-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decane-2- ON 300 mg (1.01 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) -propyl methanesulfonate prepared in Reference Example 15 was dissolved in 6 ml of toluene, and 140 mg of 3,4-difluorophenol was stirred at room temperature. 1.11 mmol), 290 mg (1.11 mmol) of triphenylphosphine and 0.174 ml (1.11 mmol) of diethyl azodicarboxylate were added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give methanesulfonic acid 3- (3,4-difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl 211 mg Got.

  211 mg of the obtained compound was dissolved in 5 ml of dimethylacetamide, 99.1 mg (0.514 mmol) of 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride prepared in Reference Example 1 and 142 mg of potassium carbonate (1.03 mmol) and 17 mg (0.103 mmol) of potassium iodide were added, and the mixture was stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / methanol = 10/1) to obtain 194 mg (80.2%) of the title compound.

(59b) 8- [3- (3,4-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diaza-spiro [4,5] decane-2- On fumarate 8- [3- (3,4-difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro prepared in Example (59a) 194 mg (0.412 mmol) of [4,5] decan-2-one was dissolved in 3 ml of ethyl acetate, 48 mg (0.412 mmol) of fumaric acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 150 mg (62.0%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.73 (s, 1H), 7.69 (d, 1H, J = 7.4 Hz), 7.65-7.55 (m, 2H), 7.13-7.03 (m, 1H) , 6.89-6.81 (m, 1H), 6.74-6.63 (m, 1H), 5.46 (dd, 1H, J = 4.1 Hz, 8.7 Hz), 3.42 (s, 2H), 3.38-3.23 (m, 3H), 3.23-3.04 (m, 4H), 2.43-2.32 (m, 1H), 2.32-2.21 (m, 1H), 2.19-2.01 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1756, 1515, 1330, 1256, 1210, 1159, 1126, 1074, 982, 803, 706, 647
Mass spectrum (FAB) m / z 471 ((M + H) ⁺ , free form).

Example 60
8- [3- (2,6-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decan-2-one and its Fumarate (Exemplified Compound No. 2-453)
(60a) 8- [3- (2,6-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decane-2- ON 300 mg (1.01 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) -propyl methanesulfonate prepared in Reference Example 15 was dissolved in 6 ml of toluene, and 140 mg of 2,6-difluorophenol ( 1.11 mmol), 290 mg (1.11 mmol) of triphenylphosphine and 0.174 ml (1.11 mmol) of diethyl azodicarboxylate were added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give 292 mg of 3- (2,6-difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl methanesulfonate. (Yield 70.1%) was obtained.

  292 mg (0.712 mmol) of the obtained compound was dissolved in 5 ml of dimethylacetamide, and 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride 137 mg (0.712 mmol), potassium carbonate 197 mg (1.42 mmol) ) And 24 mg (0.142 mmol) of potassium iodide were added, and the mixture was stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / methanol = 10/1) to obtain 225 mg (67.2%) of the title compound.

(60b) 8- [3- (2,6-Difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decane-2- On fumarate 8- [3- (2,6-difluorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa3,8-diaza-spiro prepared in Example (60a) 225 mg (0.478 mmol) of [4,5] decan-2-one was dissolved in 3 ml of ethyl acetate, 56 mg (0.478 mmol) of fumaric acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 155 mg (55.2%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.76 (s, 1H), 7.67 (d, 1H, J = 7.7 Hz), 7.61 (d, 1H, J = 7.7 Hz), 7.53 (t, 1H , J = 7.7Hz), 7.06-6.95 (m, 1H), 6.93-6.84 (m, 2H), 5.42 (dd, 1H, J = 4.3 Hz, 8.7 Hz), 3.42 (s, 2H), 3.40-3.25 (m, 3H), 3.25-3.07 (m, 4H), 2.63-2.52 (m, 1H), 2.34-2.24 (m, 1H), 2.20-2.01 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1756, 1495, 1476, 1330, 1291, 1168, 1126, 1074, 1006, 983, 780, 733, 705, 648
Mass spectrum (FAB) m / z 471 ((M + H) ⁺ , free form).

Example 61
8- {2- [Bis- (3-trifluoromethoxyphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate (Exemplified Compound No. 1) -367)
(61a) 8- {2- [Bis- (3-trifluoromethoxyphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one obtained in Reference Example 26 170 mg (0.41 mmol) of 2-chloroethyl- (3,3′-ditrifluoromethoxyphenyl) methyl ether was dissolved in 5 ml of dimethylacetamide, and 1-oxa-3,8-diazaspiro [4,5] prepared in Reference Example 1 was prepared. Decan-2-one hydrochloride 79 mg (0.41 mmol), potassium carbonate 113 mg (0.82 mmol) and potassium iodide 14 mg (820 μmol) were added and stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / methanol = 5/1) to obtain 220 mg (100%) of the title compound.

(61b) 8- {2- [Bis- (3-trifluoromethoxyphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate Example (61a) 8- {2- [bis- (3-trifluoromethoxyphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one 220 mg (0.41 mmol) Dissolved in 3 ml of ethyl acetate, added 48 mg (0.41 mmol) of fumaric acid, and allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 180 mg (67.4%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.47 (t, 2H, J = 2.0 Hz), 7.49 (d, 2H, J = 8.0 Hz), 7.34 (s, 2H), 7.22 (dd, 2H , J = 1.4 Hz, 8.0 Hz), 5.64 (s, 1H), 3.81 (t, 2H, J = 5.1 Hz), 3.41 (s, 2H), 3.39-3.25 (m, 4H), 3.25-3.14 (m , 2H), 2.19-2.01 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1760, 1259, 1215, 1165, 1082, 983
Mass spectrum (FAB) m / z 535 ((M + H) ⁺ , free form).

Example 62
8- [3- (phenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diaza-spiro [4,5] decan-2-one and its fumarate (examples) Compound number 2-454)
(62a) 8- [3- (Phenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diaza-spiro [4,5] decan-2-one In Reference Example 15 300 mg (1.01 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) -propyl methanesulfonate prepared was dissolved in 6 ml of toluene, and 99 mg (1.06 mmol) of phenol and 320 mg (1.21) of triphenylphosphine were stirred at room temperature. mmol) and 0.190 ml (1.21 mmol) of diethyl azodicarboxylate were added, followed by stirring at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to obtain 227 mg of 3- (phenoxy) -3- (3-trifluoromethylphenyl) -propyl methanesulfonate as an oily substance. It was.

  227 mg of the resulting compound is dissolved in 5 ml of dimethylacetamide, and 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride 117 mg (0.626 mmol), potassium carbonate 168 mg (1.21 mmol) and iodide 20 mg (0.121 mmol) of potassium was added and stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / methanol = 10/1) to obtain 124 mg (47.1%) of the title compound.

(62b) 8- [3- (Phenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diaza-spiro [4,5] decan-2-one fumarate 8- [3- (Phenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decan-2-one prepared in Example (62a) 124 mg (0.285 mmol) was dissolved in 3 ml of ethyl acetate, 33 mg (0.427 mmol) of fumaric acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 110 mg (70.1%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.73 (s, 1H), 7.69 (d, 1H, J = 7.2 Hz), 7.61-7.53 (m, 2H), 7.23-7.15 (m, 2H) , 6.92-6.85 (m, 3H), 5.49 (dd, 1H, J = 4.0 Hz, 8.7 Hz), 3.42 (s, 2H), 3.45-3.07 (m, 7H), 2.43-2.22 (m, 2H), 2.19-2.00 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1759, 1740, 1589, 1490, 1329, 1232, 1168, 1125, 1073, 982, 805, 756, 705, 648
Mass spectrum (FAB) m / z 435 ((M + H) ⁺ , free form).

Example 63
8- [3- (3-Chlorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decan-2-one and its fumaric acid Salt (Exemplified compound number 2-455)
(63a) 8- [3- (3-Chlorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diaza-spiro [4,5] decan-2-one Reference 300 mg (1.01 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) -propyl methanesulfonate prepared in Example 15 was dissolved in 6 ml of toluene, and 136 mg (1.21 mmol) of 3-chlorophenol was stirred at room temperature. After adding 320 mg (1.11 mmol) of triphenylphosphine and 0.190 ml (1.21 mmol) of diethyl azodicarboxylate, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 385 mg of 3- (3-chlorophenoxy) -3- (3-trifluoromethylphenyl) -propyl methanesulfonate as an oil Obtained as material.

  385 mg of the obtained compound was dissolved in 5 ml of dimethylacetamide, and 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride 189 mg (0.981 mmol), potassium carbonate 271 mg (1.96 mmol) and iodide Potassium (33 mg, 0.196 mmol) was added, and the mixture was stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / methanol = 10/1) to obtain 262 mg (57.0%) of the title compound.

(63b) 8- [3- (3-Chlorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diaza-spiro [4,5] decan-2-one fumarate Acid salt 8- [3- (3-Chlorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diaza-spiro [4,5] prepared in Example (63a) ] 262 mg (0.559 mmol) of decan-2-one was dissolved in 3 ml of ethyl acetate, 65 mg (0.559 mmol) of fumaric acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 220 mg (67.3%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.73 (s, 1H), 7.69 (d, 1H, J = 7.4 Hz), 7.64-7.55 (m, 2H), 7.19-7.14 (m, 1H) , 6.97-6.87 (m, 2H), 6.84-6.78 (m 1H), 5.56 (dd, 1H, J = 4.0 Hz Hz, 8.7 Hz), 3.41 (s, 2H), 3.38-3.05 (m, 7H), 2.43-2.22 (m, 2H), 2.20-2.00 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1739, 1591, 1477, 1329, 1240, 1167, 1124, 1072, 981
Mass spectrum (FAB) m / z 469 ((M + H) ⁺ , free body).

Example 64
8- [3- (4-Trifluoromethylphenoxy) -3- (2-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate ( Exemplified Compound No. 2-456)
(64a) 8- [3- (4-Trifluoromethylphenoxy) -3- (2-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Examples Similar to 3a), 373 mg (0.95 mmol) of 3- [4- (trifluoromethyl) phenoxy] -3- (2-fluorophenyl) propyl methanesulfonate prepared in Reference Example 30 and 1 prepared in Reference Example 1 Synthesis was performed using 212 mg (1.1 mmol) of -oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride to obtain 349 mg (82%) of the title compound.

(64b) 8- [3- (4-Trifluoromethylphenoxy) -3- (2-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate 8- [3- (4-Trifluoromethylphenoxy) -3- (2-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (64a) -349 mg (0.77 mmol) of ONE was dissolved in 3 ml of ethyl acetate, 89 mg (0.77 mmol) of fumaric acid was added, and left overnight at room temperature. The precipitated crystals were collected by filtration to obtain 365 mg (83%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.60 (2H, d, J = 9Hz), 7.49 (1H, s), 7.42-7.48 (1H, m), 7.32-7.38 (1H, m) , 7.16-7.28 (2H, m), 7.06 (2H, d, J = 9Hz), 6.63 (2H, s), 5.72-5.78 (1H, m), 3.22 (2H, s), 2.47-2.60 (6H, m), 2.12-2.22 (1H, m), 2.02-2.18 (1H, m), 1.67-1.85 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1750, 1329, 1249, 1164, 1068
Mass spectrum (FAB) m / z 453 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₃ H ₂₄ F ₄ N ₂ O ₃ -4 / 3C ₄ H ₄ O ₄ )
Calculated value: C: 56.05; H: 4.84; N: 4.61
Found: C: 56.28; H: 4.81; N: 4.85.

Example 65
8- [3- (2-Chlorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate (Exemplary compounds) Number 2-457)
(65a) 8- [3- (2-Chlorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Same as Reference Example 12 Was synthesized using 300 mg (1.59 mmol) of 3-chloro-1- (4-fluorophenyl) -1-propanol obtained in Reference Example 11 and 165 μl (1.59 mmol) of 2-chlorophenol. 319 mg of (4-fluorophenyl) propyl 2-chlorophenyl ether was obtained.
Synthesis was performed using 319 mg of the obtained compound and 246 mg (1.28 mmol) of 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride prepared in Reference Example 1, and the title compound 386 mg (86 %).

(65b) 8- [3- (2-Chlorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate Examples 8- [3- (2-chlorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in (65a) (386 mg) 0.92 mmol) was dissolved in 3 ml of ethyl acetate, and 107 mg (0.92 mmol) of fumaric acid was added and left at room temperature overnight. The precipitated crystals were collected by filtration to obtain 352 mg (71%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.49-7.44 (2H, m), 7.25-7.14 (3H, m), 6.99-6.85 (3H, m), 6.61 (2H, s), 5.48 -5.43 (1H, m), 3.22 (2H, s), 2.45-2.41 (6H, m), 2.14-2.05 (1H, m), 1.96-1.87 (1H, m), 1.82-1.69 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1751.1591.1226.1075.981
Mass spectrum (FAB) m / z 419 ((M + H) ⁺ , free form).

Example 66
8- [3-phenoxy-3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate (Exemplary Compound No. 2-458)
(66a) 8- [3-Phenoxy-3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one In Reference Example 11 as in Reference Example 12 Synthesis was performed using 300 mg (1.59 mmol) of 3-chloro-1- (4-fluorophenyl) -1-propanol and 150 mg (1.59 mmol) of phenol, and 3-chloro-1- (4-fluorophenyl) propyl phenyl was obtained. 230 mg of ether was obtained.

  Synthesis was performed using 230 mg of the obtained compound and 201 mg (1.04 mmol) of 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride prepared in Reference Example 1, and the title compound 286 mg (86 %).

(66b) 8- [3-Phenoxy-3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate Prepared in Example (66a) The obtained 8- [3-phenoxy-3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one (286 mg, 0.74 mmol) was added to 3 ml of ethyl acetate. Into the solution, 86 mg (0.74 mmol) of fumaric acid was added and left at room temperature overnight. The precipitated crystals were collected by filtration to obtain 271 mg (73%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.48-7.42 (2H, m), 7.22-7.13 (4H, m), 6.89-6.83 (3H, m), 6.61 (2H, s), 5.41 -5.37 (1H, m), 3.22 (2H, s), 2.48-2.43 (6H, m), 2.15-2.05 (1H, m), 1.96-1.87 (1H, m), 1.82-1.69 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1753, 1597, 1510, 1226, 1080
Mass spectrum (FAB) m / z 385 ((M + H) ⁺ , free form).

Example 67
8-[(3S) -3- (4-Chlorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its Fumarate (optically active substance of Exemplified Compound No. 2-437)
(67a) 8-[(3S) -3- (4-Chlorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2- ON 1.82 g (4.45 mmol) of 3- (4-chlorophenoxy) -3- (3-trifluoromethylphenyl) -propyl methanesulfonate prepared in Reference Example 51 was dissolved in 20 ml of dimethylacetamide, and 1-oxa-3 , 8-diazaspiro [4,5] decan-2-one hydrochloride 0.94 g (4.90 mol), sodium hydrogen carbonate 0.75 g (8.90 mmol) and potassium iodide 0.15 g (0.89 mmol) were added, and 8 at 100 ° C. was added. Stir for hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / methanol = 5/1) to obtain 1.45 g (69.3%) of the title compound.

(67b) 8-[(3S) -3- (4-Chlorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8-diazaspiro [4,5] decane-2- On fumarate 8-[(3S) -3- (4-Chlorophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diazaspiro prepared in Example (67a) 351 mg (0.748 mmol) of [4,5] decan-2-one was dissolved in 5 ml of ethyl acetate, and 87 mg (0.748 mmol) of fumaric acid was added and left overnight. The precipitated crystals were collected by filtration to give 204 mg (46.6%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.72 (s, 1H), 7.68 (d, 1H, J = 7.3 Hz), 7.66-7.56 (m, 4H), 7.18 (d, 1H, J = 8.6 Hz), 6.87 (d, 1H, J = 8.6 Hz), 5.48 (dd, 1H, J = 3.6 Hz, 8.5 Hz), 3.42 (s, 2H), 3.50-3.03 (m, 7H), 2.46-2.20 (m, 2H), 2.20-1.95 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1761, 1490, 1329, 1233, 1169, 1126, 1073, 981
Mass spectrum (FAB) m / z 469 ((M + H) ⁺ , free body)
Specific rotation [α] ²⁵ _D + 3.44 ° (c 0.30, MeOH).

Example 68
8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diaza-spiro [4,5] decan-2-one , Its fumarate and hydrochloride (optically active form of Exemplified Compound No. 2-445)
(68a) 8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa3,8-diaza-spiro [4,5] decane- 2-one Methanesulfonic acid (3S) -3- (4-cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl 2.66 g (6.66 mmol) prepared in Reference Example 53 was dissolved in 20 ml of dimethylacetamide. 1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride 1.41 g (7.33 mmol), sodium bicarbonate 1.12 g (13.3 mmol) and potassium iodide 0.22 g (1.33 mmol) The mixture was further stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / methanol = 5/1) to obtain 2.00 g (65.4%) of the title compound.

(68b) 8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diaza-spiro [4,5] decane- 2-one fumarate 8-[(3S) -3- (4-cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8 prepared in Example (68a) -308 mg (0.670 mmol) of diaza-spiro [4,5] decan-2-one was dissolved in 5 ml of ethyl acetate, and 78 mg (0.670 mmol) of fumaric acid was added and left overnight. The precipitated crystals were collected by filtration to give 222 mg (57.5%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.75 (s, 1H), 7.69 (d, 1H, J = 7.4 Hz), 7.64-7.53 (m, 4H), 7.07-7.01 (m, 2H) , 5.64 (dd, 1H, J = 4.0 Hz, 8.7 Hz), 3.42 (s, 2H), 3.45-3.07 (m, 7H), 2.50-2.37 (m, 1H), 2.37-2.27 (m, 1H), 2.20-2.02 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1761, 1604, 1506, 1329, 1250, 1172, 1127, 1074, 982, 837, 805, 706, 647
Mass spectrum (FAB) m / z 460 ((M + H) ⁺ , free body).

(68c) 8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa-3,8-diaza-spiro [4,5] decane- 2-one hydrochloride 8-[(3S) -3- (4-cyanophenoxy) -3- (3-trifluoromethoxyphenyl) -propyl] -1-oxa 3,8- prepared in Example (68a) Diaza-spiro [4,5] decan-2-one (100 mg, 0.218 mmol) was dissolved in ether (5 ml), 1N hydrochloric acid / ether solution (0.22 ml, 0.22 mmol) was added, and the mixture was allowed to stand overnight. The precipitated crystals were collected by filtration to give 97 mg (89.9%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.77 (s, 1H), 7.72 (d, 1H, J = 7.5 Hz), 7.64-7.53 (m, 4H), 7.08-7.02 (m, 2H) , 5.67 (dd, 1H, J = 3.8 Hz, 8.7 Hz), 3.45 (s, 2H), 3.75-3.15 (m, 7H), 2.56-2.32 (m, 2H), 2.34-2.06 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1759, 1604, 1506, 1329, 1250, 1172, 1126, 1074
Mass spectrum (FAB) m / z 460 ((M + H) ⁺ , free body)
Specific rotation [α] ²⁵ _D -10.4 ° (c 0.20, H ₂ O).

Example 69
8- [3- (3-trifluoromethylphenoxy) -3- (4-cyanophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate ( Exemplified compound number 2-459)
(69a) 8- [3- (3-Trifluoromethylphenoxy) -3- (4-cyanophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Examples As in 3a), 420 mg (1.05 mmol) of 3- [3- (trifluoromethyl) phenoxy] -3- (4-cyanophenyl) propyl methanesulfonate prepared in Reference Example 34 and 1-oxa-3,8 -Diazaspiro [4,5] decan-2-one Hydrochloride 233 mg (1.21 mmol) was used for the synthesis to give 409 mg (85%) of the title compound.

(69b) 8- [3- (3-Trifluoromethylphenoxy) -3- (4-cyanophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate 8- [3- (3-Trifluoromethylphenoxy) -3- (4-cyanophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (69a) -409 mg (0.89 mmol) of ONE was dissolved in 4 ml of ethyl acetate, and 103 mg (0.89 mmol) of fumaric acid was added and left overnight at room temperature. The precipitated crystals were collected by filtration to obtain 375 mg (73%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.83 (2H, d, J = 8Hz), 7.64 (2H, d, J = 8Hz), 7.43-7.50 (2H, m), 7.16-7.27 ( 3H, m), 6.61 (2H, s), 5.62-5.68 (1H, m), 3.21 (2H, s), 2.36-2.55 (6H, m), 2.06-2.17 (1H, m), 1.93-2.05 ( 1H, m), 1.64-1.80 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1758, 1452, 1328, 1126
Mass spectrum (FAB) m / z 460 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₄ H ₂₄ F ₃ N ₃ O ₃ -6 / 5C ₄ H ₄ O ₄ )
Calculated value: C: 57.77; H: 4.85; N: 7.02
Found: C: 57.93; H: 4.82; N: 7.18.

Example 70
8- [3- (4-Trifluoromethylphenoxy) -3- (4-cyanophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate ( Exemplified Compound No. 2-460)
(70a) 8- [3- (4-Trifluoromethylphenoxy) -3- (4-cyanophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Examples As in 3a), 391 mg of 3- [4- (trifluoromethyl) phenoxy] -3- (4-cyanophenyl) propyl methanesulfonate prepared in Reference Example 35 and 1-oxa-3,8-diazaspiro [4 , 5] decan-2-one hydrochloride 217 mg (1.13 mmol) was used for synthesis to give 323 mg (72%) of the title compound.

(70b) 8- [3- (4-Trifluoromethylphenoxy) -3- (4-cyanophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate 8- [3- (4-Trifluoromethylphenoxy) -3- (4-cyanophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (70a) -323 mg (0.71 mmol) of ONE was dissolved in 4 ml of ethyl acetate, and 82 mg (0.71 mmol) of fumaric acid was added and left overnight at room temperature. The precipitated crystals were collected by filtration to obtain 347 mg (86%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δ ppm: 7.83 (2H, d, J = 8Hz), 7.62 (2H, d, J = 8Hz), 7.58 (2H, d, J = 9Hz), 7.48 ( 1H, s), 7.08 (2H, d, J = 9Hz), 6.61 (2H, s), 5.62-5.68 (1H, m), 3.21 (2H, s), 2.36-2.56 (6H, m), 2.06- 2.17 (1H, m), 1.93-2.05 (1H, m), 1.64-1.80 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1759, 1328, 1178, 1113, 1068
Mass spectrum (FAB) m / z 460 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₄ H ₂₄ F ₃ N ₃ O ₃ -5 / 4C ₄ H ₄ O ₄ )
Calculated value: C: 57.62; H: 4.84; N: 6.95
Found: C: 57.74; H: 4.77; N: 7.20.

Example 71
8-{(3S) -3- (4-Chlorophenyl) -3- [3- (trifluoromethyl) phenoxy] propyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one and its fumarate Acid salt (optically active form of Exemplified Compound No. 2-461)
(71a) 8-{(3S) -3- (4-Chlorophenyl) -3- [3- (trifluoromethyl) phenoxy] propyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one 192.4 mg (0.5510 mmol) of (1S) -3-chloro-1- (4-chlorophenyl) propyl 3- (trifluoromethyl) phenyl ether prepared in Reference Example 37 and 1-oxa-3 prepared in Reference Example 1, 8-diazaspiro [4,5] decan-2-one hydrochloride 116.8 mg (0.6063 mmol) was used in the same manner as in Example (3a) to give 177.0 mg (yield 69%) of the title compound as a pale yellow oily substance. Obtained.

(71b) 8-{(3S) -3- (4-Chlorophenyl) -3- [3- (trifluoromethyl) phenoxy] propyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one Fumarate 8-{(3S) -3- (4-Chlorophenyl) -3- [3- (trifluoromethyl) phenoxy] propyl} -1-oxa-3,8-diazaspiro prepared in Example (71a) [4.5] 170.3 mg (0.3632 mmol) of decan-2-one was dissolved in methanol, 42.2 mg (0.364 mmol) of fumaric acid was added, isopropyl ether was added, and the precipitated crystals were collected by filtration to give 178.3 mg (yield) of the title compound. 83%) was obtained as a white powder.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.43-7.35 (m, 5H), 7.18 (d, 1H, J = 8.1 Hz), 7.14 (s, 1H), 7.10 (dd, 1H, J = 2.2 Hz, 8.1 Hz), 5.47 (dd, 1H, J = 4.1 Hz, 8.5 Hz), 3.41 (s, 2H), 3.31-3.30 (m, 2H), 3.16-2.91 (m, 4H), 2.39-2.31 (m, 1H), 2.27-2.20 (m, 1H), 2.15-2.11 (m, 2H), 2.07-1.96 (m, 2H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 3246, 2931, 2555, 1756, 1592, 1492, 1453, 1328, 1169, 1127, 983
Mass spectrum (FAB) m / z 469 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₇ H ₂₈ ClF ₃ N ₂ O ₇ )
Calculated value: C: 55.44; H: 4.82; Cl: 6.06; F: 9.74; N: 4.79
Found: C: 54.94; H: 4.62; Cl: 5.80; F: 9.29; N: 4.73.

Example 72
8-{(3S) -3- (4-Chlorophenyl) -3- [4-cyanophenoxy] propyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one and its fumarate Optically active compound of Compound No. 2-462)
(72a) 8-{(3S) -3- (4-Chlorophenyl) -3- [4-cyanophenoxy] propyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one
203.5 mg (0.6646 mmol) of (1S) -3-chloro-1- (4-chlorophenyl) propyl 4-cyanophenyl ether prepared in Reference Example 38 and 1-oxa-3,8-diazaspiro prepared in Reference Example 1 Using 4,7] decanonone hydrochloride (147 mg, 0.763 mmol), 224.9 mg (yield 79%) of the title compound was obtained as a pale yellow oily substance in the same manner as in Example (3a).

(72b) 8-{(3S) -3- (4-Chlorophenyl) -3- [4-cyanophenoxy] propyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one fumarate 8-{(3S) -3- (4-Chlorophenyl) -3- [4-cyanophenoxy] propyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one prepared in Example (72a) Dissolve 202.2 mg (0.4747 mmol) in methanol, add 55.1 mg (0.475 mmol) of fumaric acid, add isopropyl ether and collect the precipitated crystals by filtration to obtain 236.7 mg (yield 92%) of the title compound as a milky white powder. Obtained.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.58-7.55 (m, 2H), 7.41-7.36 (m, 4H), 7.03-7.00 (m, 2H), 5.50 (dd, 1H, J = 4.4 Hz, 8.1 Hz), 3.31-3.30 (m, 2H), 3.30-3.05 (m 6H), 2.35 (m, 1H), 2.23 (m, 1H), 2.14-2.11 (m, 2H), 2.07-1.99 ( m, 2H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 3248, 2930, 2556, 2225, 1757, 1604, 1505, 1250, 1173, 1088, 983
Mass spectrum (FAB) m / z 426 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₇ H ₂₈ ClN ₃ O ₇ )
Calculated value: C: 59.83; H: 5.21; Cl: 6.54; N: 7.75
Found: C: 58.87; H: 5.69; Cl: 6.20; N: 7.50.

Example 73
8-[(3S) -3- (4-Chlorophenyl) -3- (4-chlorophenoxy) propyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one and its fumarate Optically active compound of Compound No. 2-111)
(73a) 8-[(3S) -3- (4-Chlorophenyl) -3- (4-chlorophenoxy) propyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one In Reference Example 39 175.9 mg (0.5573 mmol) of (1S) -3-chloro-1- (4-chlorophenyl) propyl 4-chlorophenyl ether prepared and 1-oxa-3,8-diazaspiro [4,5] decane prepared in Reference Example 1 The title compound (164.7 mg, yield 68%) was obtained as a yellow oil in the same manner as in Example (3a) using 123 mg (0.639 mmol) of 2-one hydrochloride.

(73b) 8-[(3S) -3- (4-Chlorophenyl) -3- (4-chlorophenoxy) propyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one fumarate 8-[(3S) -3- (4-Chlorophenyl) -3- (4-chlorophenoxy) propyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one prepared in Example (73a) 153.7 mg (0.3531 mmol) was dissolved in methanol, 41.0 mg (0.353 mmol) of fumaric acid was added, isopropyl ether was added, and the precipitated crystals were collected by filtration to give 175.5 mg (yield 90%) of the title compound as a white powder. Obtained.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.39-7.36 (m, 4H), 7.35-7.16 (m, 2H), 6.86-6.82 (m, 2H), 5.35 (dd, 1H, J = 4.4 Hz, 8.5 Hz), 3.31-3.05 (m, 8H), 2.33-2.12 (m, 4H), 2.07-2.03 (m, 2H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 3236, 2932, 2533, 1752, 1703, 1582, 1489, 1235, 1172, 1090, 982
Mass spectrum (FAB) m / z 435 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₆ H ₂₈ Cl ₂ N ₂ O ₇ )
Calculated value: C: 56.63; H: 5.12; Cl: 12.86; N: 5.08
Found: C: 55.96; H: 5.09; Cl: 12.56; N: 5.04.

Example 74
8-[(3S) -3- (4-Chlorophenyl) -3- (4-fluorophenoxy) propyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one and its fumarate (examples) Optically active compound of Compound No. 2-463)
(74a) 8-[(3S) -3- (4-Chlorophenyl) -3- (4-fluorophenoxy) propyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one In Reference Example 40 161.9 mg (0.5412 mmol) of (1S) -3-chloro-1- (4-chlorophenyl) propyl 4-fluorophenyl ether prepared and 1-oxa-3,8-diazaspiro [4,5] prepared in Reference Example 1 Using decan-2-one hydrochloride 116 mg (0.602 mmol), 183.2 mg (yield 81%) of the title compound was obtained as a pale yellow oily substance in the same manner as in Example (3a).

(74b) 8-[(3S) -3- (4-Chlorophenyl) -3- (4-fluorophenoxy) propyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one fumarate 8-[(3S) -3- (4-Chlorophenyl) -3- (4-fluorophenoxy) propyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one prepared in Example (74a) Dissolve 174.3 mg (0.4161 mmol) in methanol, add 48.3 mg (0.416 mmol) of fumaric acid, add isopropyl ether and collect the precipitated crystals by filtration to obtain 190.4 mg (yield 86%) of the title compound as a white powder. It was.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.40-7.34 (m, 4H), 6.94-6.82 (m, 4H), 5.31 (dd, 1H, J = 4.4 Hz, 8.8 Hz), 3.33-3.05 (m, 8H), 2.40-2.03 (m, 6H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 3422, 3253, 2929, 2642, 2560, 1744, 1681, 1616. 1504, 1203, 1089, 983
Mass spectrum (FAB) m / z 419 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₆ H ₂₈ ClFN ₂ O ₇ )
Calculated value: C: 58.37; H: 5.28; Cl: 6.63; F: 3.55; N: 5.24
Found: C: 57.87; H: 4.88; Cl: 6.48; F: 3.59; N: 5.41.

Example 75
8-[(3S) -3- (4-Chlorophenyl) -3- (3-fluorophenoxy) propyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one and its fumarate (examples) Optically active compound of Compound No. 2-464)
(75a) 8-[(3S) -3- (4-Chlorophenyl) -3- (3-fluorophenoxy) propyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one In Reference Example 41 The prepared (1S) -3-chloro-1- (4-chlorophenyl) propyl 3-fluorophenyl ether 204.9 mg (0.6849 mmol) and the 1-oxa-3,8-diazaspiro [4,5] prepared in Reference Example 1 Using decan-2-one hydrochloride 146 mg (0.758 mmol), 232.9 mg (yield 81%) of the title compound was obtained as a pale yellow oily substance in the same manner as in Example (3a).

(75b) 8-[(3S) -3- (4-Chlorophenyl) -3- (3-fluorophenoxy) propyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one fumarate 8-[(3S) -3- (4-Chlorophenyl) -3- (3-fluorophenoxy) propyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one prepared in Example (75a) Dissolve 217.7 mg (0.5197 mmol) in methanol, add 48.3 mg (0.416 mmol) of fumaric acid, add isopropyl ether and collect the precipitated crystals by filtration to obtain 237.9 mg (yield 86%) of the title compound as a pale yellow powder. Obtained.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.41-7.35 (m, 4H), 7.20-7.14 (m, 1H), 6.70-6.60 (m, 3H), 5.39 (dd, 1H, J = 4.4 Hz, 8.1 Hz), 3.31-3.30 (m, 2H), 3.22-2.91 (m, 6H), 2.35-2.00 (m, 6H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 3403, 3237, 2931, 2560, 1754, 1610, 1592, 1489, 1263, 1136, 983
Mass spectrum (FAB) m / z 419 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₆ H ₂₈ ClFN ₂ O ₇ )
Calculated value: C: 58.37; H: 5.28; Cl: 6.63; F: 3.55; N: 5.24
Found: C: 57.85; H: 4.94; Cl: 6.04; F: 3.92; N: 5.37.

Example 76
8- [3- (4-Cyanophenoxy) -3- (4-methoxyphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate (Exemplary compounds) Number 2-465)
(76a) 8- [3- (4-Cyanophenoxy) -3- (4-methoxyphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Example (3a) In the same manner as described above, 200 mg of 3- (4-cyanophenoxy) -3- (4-methoxyphenyl) propyl methanesulfonate prepared in Reference Example 45 and 1-oxa-3,8-diazaspiro [4,5] decane-2 Synthesis was performed using 192 mg (1.00 mmol) of -one hydrochloride to obtain 185 mg (82%, 2 steps) of the title compound.

(76b) 8- [3- (4-Cyanophenoxy) -3- (4-methoxyphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate Examples 8- [3- (4-Cyanophenoxy) -3- (4-methoxyphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one prepared in (76a) 185 mg ( 0.40 mmol) was dissolved in 2 ml of ethyl acetate, 46 mg (0.40 mmol) of fumaric acid was added, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration to obtain 110 mg (47%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δ ppm: 7.66 (2H, d, J = 9Hz), 7.47 (1H, s), 7.33 (2H, d, J = 9Hz), 7.08 (2H, d, J = 9Hz), 6.90 (2H, d, J = 9Hz), 6.58 (2H, s), 5.45-5.52 (1H, m), 3.72 (3H, s), 3.21 (2H, s), 2.32-2.50 ( 6H, m), 2.08-2.20 (1H, m), 1.85-1.95 (1H, m), 1.64-1.84 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1756, 1603, 1506, 1250, 1173
Mass spectrum (FAB) m / z 422 ((M + H) ⁺ , free form).

Example 77
8- [3- (4-Trifluoromethylphenoxy) -3- (4-methoxyphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and its fumarate ( Exemplified Compound No. 2-466)
(77a) 8- [3- (4-Trifluoromethylphenoxy) -3- (4-methoxyphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one Examples As in 3a), 290 mg of 3- (4-trifluoromethylphenoxy) -3- (4-methoxyphenyl) propyl methanesulfonate prepared in Reference Example 48 and 1-oxa-3,8-diazaspiro [4,5 Synthesis was performed using 164 mg (0.85 mmol) of decan-2-one hydrochloride to give 224 mg (68%, 2 steps) of the title compound.

(77b) 8- [3- (4-Trifluoromethylphenoxy) -3- (4-methoxyphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one fumarate 8- [3- (4-Trifluoromethylphenoxy) -3- (4-methoxyphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decane-2 prepared in Example (77a) -224 mg (0.48 mmol) of ONE was dissolved in 2 ml of ethyl acetate, and 56 mg (0.48 mmol) of fumaric acid was added and left overnight at room temperature. The precipitated crystals were collected by filtration to give 230 mg (82%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δ ppm: 7.55 (2H, d, J = 9Hz), 7.48 (1H, s), 7.33 (2H, d, J = 9Hz), 7.06 (2H, d, J = 9Hz), 6.90 (2H, d, J = 9Hz), 6.61 (2H, s), 5.45-5.52 (1H, m), 3.72 (3H, s), 3.22 (2H, s), 2.32-2.50 ( 6H, m), 2.08-2.20 (1H, m), 1.85-1.95 (1H, m), 1.64-1.84 (4H, m)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1752, 1613, 1515, 1329, 1250
Mass spectrum (FAB) m / z 465 ((M + H) ⁺ , free body)
Elemental analysis (as C ₂₄ H ₂₇ F ₃ N ₂ O ₄ -6 / 5C ₄ H ₄ O ₄ )
Calculated value: C: 57.29; H: 5.31; N: 4.64
Found: C: 57.28; H: 5.21; N: 5.10.

Example 78
8- [3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -3-methyl-1-oxa 3,8-diaza-spiro [4,5] decan-2-one And its fumarate (Exemplified Compound No. 2-467)
(78a) 8- [3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -3-methyl-1-oxa3,8-diaza-spiro [4,5] decane- 2-one Methanesulfonic acid 3- (4-cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl 373 mg (0.934 mmol) prepared in Reference Example 21 was dissolved in 5 ml of dimethylacetamide. Produced 3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride 212 mg (1.03 mol), sodium hydrogen carbonate 157 mg (1.87 mmol) and potassium iodide 16 mg (93.4 μmol) And stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / methanol = 5/1) to obtain 441 mg (99.9%) of the title compound.

(78b) 8- [3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -3-methyl-1-oxa3,8-diaza-spiro [4,5] decane- 2-one fumarate 8- [3- (4-cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -3-methyl-1-oxa 3,8 prepared in Example (78a) -441 mg (0.931 mmol) of diaza-spiro [4,5] decan-2-one was dissolved in 5 ml of ethyl acetate, and 106 mg (0.931 mmol) of fumaric acid was added and left overnight. The precipitated crystals were collected by filtration to give 301 mg (54.8%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.80 (s, 1H), 7.76-7.56 (m, 5H), 7.13-7.07 (m, 1H), 5.69 (dd, 1H, J = 5.5 Hz, 14.0 Hz), 3.29 (s, 2H), 2.73 (s, 3H), 2.55-2.32 (m, 7H), 2.22-2.10 (m, 1H), 2.07-1.94 (m, 1H), 1.81-1.67 (m , 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1752, 1604, 1505, 1329, 1250, 1172, 1125, 1073, 1033, 983
Mass spectrum (FAB) m / z 474 ((M + H) ⁺ , free form).

Example 79
8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -3-ethyl-1-oxa-3,8-diaza-spiro [4,5] decane -2-one and its fumarate (an optically active form of Exemplified Compound No. 2-468)
(79a) 8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -3-ethyl-1-oxa-3,8-diaza-spiro [4, 5] Decan-2-one 8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8- prepared in Example 67 Diaza-spiro [4,5] decan-2-one 300 mg (0.653 mmol) was dissolved in dimethylformamide 6 ml, and stirred at room temperature, sodium hydride 0.029 g (content 60.0%, 0.718 mmol), tetrabutylammonium iodide 24 mg (65.3 μmmol) and 0.063 ml (0.784 mmol) of ethyl iodide were added and stirred at room temperature for 9 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate / methanol: 5/1) to obtain 230 mg (72.3%) of the title compound.

(79b) 8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -3-ethyl-1-oxa-3,8-diaza-spiro [4, 5] Decan-2-one fumarate 8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -3- prepared in Example (79a) Dissolve 230 mg (0.472 mmol) of ethyl-1-oxa-3,8-diaza-spiro [4,5] decan-2-one in 3 ml of ethyl acetate, add 55 mg (0.472 mmol) of fumaric acid, and let stand at room temperature overnight did. The precipitated crystals were collected by filtration to obtain 184 mg (64.6%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δ ppm: 7.81 (s, 1H), 7.75-7.57 (m, 5H), 7.13-7.07 (m, 2H), 5.70 (dd, 1H, J = 5.5 Hz , 14.0 Hz), 3.29 (s, 1H), 3.16 (q, 2H, J = 7.4 Hz), 2.60-2.35 (m, 7H), 2.22-2.10 (m, 1H), 2.08-1.95 (m, 1H) , 1.82-1.68 (m, 4H), 1.05 (t, 3H, J = 7.4 Hz)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1748, 1605, 1506, 1329, 1250, 1172, 1125, 1073, 983, 836, 803, 760, 706, 647
Mass spectrum (FAB) m / z 488 ((M + H) ⁺ , free form).

Example 80
8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -3-methylthiomethyl-1-oxa3,8-diaza-spiro [4,5] Decan-2-one and its fumarate (optically active form of Exemplified Compound No. 2-469)
(80a) 8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -3-methylthiomethyl-1-oxa3,8-diaza-spiro [4 , 5] decan-2-one 8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -1-oxa 3,8 prepared in Example 68 -Diaza-spiro [4,5] decan-2-one 300 mg (0.653 mmol) was dissolved in dimethylformamide 6 ml, then sodium hydride 29 mg (content 60.0%, 0.718 mmol), tetrabutylammonium iodide 0.024 g (65.3 μmol) and 0.066 ml (0.784 mmol) of chloromethyl methyl sulfide were added and stirred at room temperature for 9 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate) to obtain 200 mg (yield 59.0%) of the title compound as an oily substance.

(80b) 8-[(3S) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -3-methylthiomethyl-1-oxa3,8-diaza-spiro [4 , 5] decan-2-one fumarate 8-[(3S) -3- (4-cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl] -3 prepared in Example (80a) -Methylthiomethyl-1-oxa-3,8-diaza-spiro [4,5] decan-2-one 200 mg (0.385 mmol) was dissolved in 3 ml of ethyl acetate and 45 mg (0.385 mmol) of fumaric acid was added and left overnight. . The precipitated crystals were collected by filtration to obtain 191 mg (78.0%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δ ppm: 7.79 (s, 1H), 7.78-7.55 (m, 5H), 7.13-7.07 (m, 1H), 6.73-6.65 (m, 1H), 5.70 (dd, 1H, J = 5.50 Hz, 14.0 Hz), 4.37 (s, 2H), 3.37 (s, 1H), 2.58-2.34 (m, 7H), 2.22-2.10 (m, 1H), 2.05 (s, 3H), 2.10-1.95 (m, 1H), 1.82-1.65 (m, 4H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1754, 1604, 1506, 1431, 1329, 1251, 1173, 1127, 1073, 984
Mass spectrum (FAB) m / z 520 ((M + H) ⁺ , free form).

Reference example 1
1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride
2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t-synthesized according to the method described in J. Med. Chem., 38, 3772-3779 (1995) 2.50 g (9.75 mmol) of butyl ester was dissolved in 25 ml of ethanol, 2.8 ml of 4N hydrochloric acid / dioxane solution was added under ice cooling, and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol / diethyl ether to obtain 1.1 g (59%) of the title compound as white crystals.
Infrared absorption spectrum ν _max cm ^-1 (KBr): 3227, 2970, 1762, 1565, 1431, 1274
Mass spectrum (EI) m / z 156 (M ⁺ , free body)
Elemental analysis (C ₇ H ₁₂ N ₂ O ₂ -HCl (%))
Calculated value: C: 43.64; H: 6.80; N: 14.54; Cl: 18.40
Found: C: 43.59; H: 6.87; N: 14.65; Cl: 17.50.

Reference example 2
Bis- (3-trifluoromethylphenyl) methyl 2-chloroethyl ether 0.5 g (1.56 mmol) of bis- (3-trifluoromethylphenyl) methanol and 0.6 ml of 2-chloroethanol were dissolved in 5 ml of toluene, -Toluenesulfonic acid monohydrate was added and heated to reflux for 5 hours. After cooling to room temperature, the solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried and concentrated to give the title compound (0.55 g, 92%) as an oil.
Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 7.45-7.70 (8H, m), 5.52 (1H, s), 3.70-3.78 (4H, m).

Reference Example 3
Bis- (3-trifluoromethylphenyl) methyl 3-chloropropyl ether bis- (3-trifluoromethylphenyl) methanol 249 mg (0.78 mmol) and 3-chloro-1-propanol 2 ml were dissolved in toluene 4 ml Of p-toluenesulfonic acid monohydrate was added and heated to reflux for 12 hours. After cooling to room temperature, the solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 50: 1) to obtain 294 mg (92%) of the title compound as an oily substance.

Reference example 4
3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propanol Reference Example (4a) 3-Cyanophenyl-3'-trifluoromethylphenylmethanol
20 g (88.8 mmol) of 3-bromobenzotrifluoride was dissolved in 200 ml of tetrahydrofuran, and 62 ml of n-butyllithium (1.56 mol / l in hexane 97.7 mmol) was added dropwise at −78 ° C. over 1 hour. After stirring at −78 ° C. for 30 minutes, a tetrahydrofuran solution (50 ml) of 11.7 g (88.8 mmol) of 3-cyanobenzaldehyde was added dropwise over 30 minutes. The mixture was stirred at -78 ° C for 1 hour, then returned to room temperature and stirred for 1 hour. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (developing solvent; ethyl acetate: n-hexane = 15: 85) to give 3-cyanophenyl-3′-trifluoromethylphenylmethanol 16.3. g (66%) was obtained.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.71 (1H, s), 7.66 (1H, s), 7.54-7.72 (3H, m), 7.45-7.52 (3H, m), 5.92 (1H, s ).

Reference Example (4b) 3-[(3-Cyanophenyl) (3′-trifluoromethylphenyl) methoxy] propanol 16.3 g of 3-cyanophenyl-3′-trifluoromethylphenylmethanol prepared in Reference Example (4a) ( 58.8 mmol) was dissolved in 160 ml of N, N-dimethylformamide. Under ice-cooling, 2.8 g of sodium hydride (content 55%, 64.7 mmol) was added and stirred for 30 minutes, and then 8.9 ml (70.6 mmol) of allyl bromide was added dropwise over 5 minutes. The mixture was stirred for 30 minutes under ice cooling, then returned to room temperature and stirred for 1 hour. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 170 ml of tetrahydrofuran. Under ice cooling, 141 ml (70.6 mmol) of 9-borabicyclo [3,3,1] nonane (9-BBN) 0.5 mol / l tetrahydrofuran solution was added dropwise over 30 minutes, and the mixture was returned to room temperature and stirred for 16 hours. Under ice cooling, 27 ml of ethanol and 27 ml of 6N-sodium hydroxide aqueous solution were sequentially added, and 27 ml of 30% aqueous hydrogen peroxide was added dropwise over 30 minutes. The mixture was stirred for 30 minutes under ice cooling, poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash chromatography (developing solvent; ethyl acetate: n-hexane = 35: 65) to obtain 13.8 g (70%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.65 (1H, s), 7.55-7.59 (4H, m), 7.48-7.51 (3H, m), 5.42 (1H, s), 3.82 (2H, t , J = 6.0 Hz), 3.62 (2H, t, J = 6.0 Hz), 1.87-1.93 (2H, m).

Reference Example 5
Bis (4-fluorophenyl) methyl 2-chloroethyl ether 18.4 g (84 mmol) of bis- (4-fluorophenyl) methanol and 11.2 ml of 2-chloroethanol were reacted in the same manner as in Reference Example 2 and purified. 12.4 g of compound was obtained as an oily substance.

Reference Example 6
3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride Reference Example (6a): 8-t-butoxycarbonyl-3-methyl-1-oxa-3,8- Diazaspiro [4,5] decan-2-one
8-t-butoxycarbonyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one (5 g, 27.3 mmol) was dissolved in dimethylformamide (70 ml) and methyl iodide (2.55 ml, 41.0 mmol) was added. . Under ice cooling, 1.3 g (30.0 mmol) of sodium hydride was added. The mixture was stirred for 30 minutes under ice cooling and then stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (elution solvent ethyl acetate: n-hexane = 75: 25) to obtain 6.9 g (93%) of the title product as white crystals. .
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 3.88-3.73 (2H, m), 3.30-3.17 (4H, m), 2.85 (3H, m), 1.88-1.80 (2H, m), 1.67-1.56 (2H, m), 1.41 (9H, s).

Reference Example (6b): 3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one hydrochloride
6-g (22 mmol) of 8-t-butoxycarbonyl-3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one was dissolved in 60 ml of ethanol, and 55 ml of 4N-dioxane hydrochloride under ice-cooling. Was added dropwise over 5 minutes. The mixture was stirred for 30 minutes under ice cooling, then returned to room temperature and stirred for 4 hours. The solvent was distilled off under reduced pressure and recrystallized from methanol-diethyl ether to obtain 3.8 g (83%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 3.37 (2H, s), 3.20-3.13 (2H, m), 3.09-3.01 (2H, m), 2.73 (3H, m), 1.99-1.96 (4H, m).

Reference Example 7
Bis (4-fluorophenyl) 3-chloropropyl ether bis- (4-fluorophenyl) methanol 1.5 g (6.81 mmol) and 3-chloropropanol 1.14 ml were reacted and purified in the same manner as in Reference Example 2, This gave 2.02 g (99%) of the title compound as an oil.

Reference Example 8
(3,4-Difluorophenyl) phenylmethyl 2-chloroethyl ether
Purification was carried out in the same manner as in Reference Example 2 using 0.84 g (4.00 mmol) of (3,4-difluorophenyl) phenylmethanol and 0.54 ml of 2-chloroethanol to obtain 1.12 g (99%) of the title compound. .
Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 6.90-7.35 (8H, m), 5.39 (1H, s), 3.65-3.75 (4H, m).

Reference Example 9
(3-Cyanophenyl) (3'-trifluoromethylphenyl) methyl 2-chloroethyl ether Reference Example (9a): 3-cyanophenyl-3'-trifluoromethylphenylmethanol
The reaction was performed in the same manner as in Reference Example (4a) using 20 g (88.8 mmol) of 3-bromobenzotrifluoride and 2.9 g (88.8 mmol) of 3-cyanobenzaldehyde to obtain 16.3 g (66%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.71 (1H, s), 7.66 (1H, s), 7.54-7.72 (3H, m), 7.45-7.52 (3H, m), 5.92 (1H, s ).

Reference Example (9b): (3-Cyanophenyl) (3'-trifluoromethylphenyl) methyl 2-chloroethyl ether (3-Cyanophenyl) (3'-trifluoromethylphenyl) methanol prepared in Reference Example (9a) 576 mg (2.08 mmol) was dissolved in 5 ml of dichloromethane, 230 ml (3.12 mmol) of thionyl chloride was added, and then 1 drop of dimethylformamide was added. After stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure and azeotroped twice with diethyl ether. The obtained residue was dissolved in 5 ml of 2-chloroethanol, 40 mg (0.21 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at 120 ° C. for 48 hours. After completion of the reaction, the temperature was returned to room temperature, the reaction solution was poured into water, extracted with ethyl acetate, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash chromatography (developing solvent; ethyl acetate: n-hexane = 5: 95) to obtain 461 mg (65%) of the title compound.
Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 7.42-7.74 (8H, m), 5.50 (1H, s), 3.60-3.75 (4H, m).

Reference Example 10
Spiro [(8-azabicyclo [3.2.1] octane) -3,5 '-(oxazolidine)]-2'-one Reference Example (10a): 3-t-Butoxycarbonylmethyl-3-hydroxy-8-aza- Bicyclo [3.2.1] octane-8-carboxylic acid t-butyl ester
N-butoxycarbonylnortropin 7.2 g (32.0 g mmol) in 20 ml of toluene was added dropwise and stirred at the same temperature for 1 hour. After completion of the reaction, 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 5.89 g of the unpurified title compound as white crystals.

Reference Example (10b): 3-Carboxymethyl-3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid t-butyl ester 3-t-butoxycarbonylmethyl prepared in Reference Example (10a) -3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid t-butyl ester 5.89 g (about 17.3 mmol) is dissolved in 50 ml of ethanol, and 1N sodium hydroxide solution is added under stirring at room temperature. 50 ml was added. Thereafter, the mixture was stirred at 100 degrees for 1.5 hours. After completion of the reaction, the reaction system was weakly acidified with 1N hydrochloric acid with stirring on ice, and extracted with methylene chloride. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude title compound as white crystals (4.92 g).

Reference Example (10c): Spiro [(8-t-butoxycarbonyl-8-azabicyclo [3.2.1] octane) -3,5 ′-(oxazolidine)]-2′-one 3 prepared in Reference Example (10b) 4-Carboxymethyl-3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid t-butyl ester 4.92 g (about 17.3 mmol) was dissolved in toluene 90 ml, and stirred at room temperature, 4.8 ml of triethylamine ( 34.5 mmol) and 7.4 ml (34.5 mmol) of diphenylphosphoryl azide were added, and the mixture was heated to reflux for 30 minutes. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 1/4) to obtain 4.64 g (yield 95.3%) of the title compound as white crystals. It was.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 4.79 (1H, br.s.), 4.16-4.40 (2H, m), 3.27 (2H, s), 1.82-2.24 (8H, m), 1.46 ( 9H, s).

Reference Example (10d): Spiro [(8-azabicyclo [3.2.1] octane) -3,5 '-(oxazolidine)]-2'-one Spiro [(8-t-butoxy) prepared in Reference Example (10c) Carbonyl-8-azabicyclo [3.2.1] octane) -3,5 '-(oxazolidine)]-2'-one (734 mg, 2.6 mmol) is dissolved in 7.0 ml of methylene chloride, and 7 ml of trifluoroacetic acid is added with stirring at room temperature. Stir at room temperature for 1 hour. After completion of the reaction, the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate. The organic phase was extracted with a mixed solvent of chloroform / methanol = 3/1 to obtain 341 mg (yield 71.9%) of the title compound as white crystals.
Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 3.57-3.49 (m, 2H), 3.26 (s, 2H), 2.19-2.11 (m, 2H), 2.16 (s, 1H), 2.14 (s, 1H), 1.92-1.88 (m, 1H), 1.88-1.85 (m, 1H), 1.83-1.76 (m, 3H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1774,1484,1406,1385,1331,1259
Mass spectrum (FAB) m / z 182 ((M + H) ⁺ , free form).

Reference Example 11
3-chloro-1- (4-fluorophenyl) -1-propanol
2-Chloro-4′-fluoropropiophenone 2 g (10.7 mmol) was dissolved in 10 ml of tetrahydrofuran and 10 ml of ethanol, and 405 mg (10.7 mmol) of sodium borohydride was added under ice cooling. After stirring for 10 minutes, the mixture was returned to room temperature and stirred for 2 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate / n-hexane = 1/4) to obtain 1.75 g (87%) of the title compound.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.38-7.31 (2H, m), 7.08-7.02 (2H, m), 4.99-4.93 (1H, m), 3.78-3.70 (1H, m) , 3.59-3.51 (1H, m), 2.27-2.17 (1H, m), 2.11-2.02 (1H, m).

Reference Example 12
3-chloro-1- (4-fluorophenyl) propyl 4-fluorophenyl ether 200 mg (1.06 mmol) of 3-chloro-1- (4-fluorophenyl) -1-propanol prepared in Reference Example 11 was dissolved in 5 ml of toluene. 4-fluorophenol 118 mg (1.06 mmol) and triphenylphosphine 310 mg (1.06 mmol) were added. 186 μl (1.16 mmol) of diethyl azodicarboxylate was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent; ethyl acetate: n-hexane = 1: 9) to obtain 190 mg (64%) of the title compound.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.34-7.30 (2H, m), 7.06-7.01 (2H, m), 6.90-6.84 (2H, m), 6.79-6.75 (2H, m) , 5.30-5.25 (1H, m), 3.83-3.77 (1H, m), 3.61-3.55 (1H, m), 2.49-2.39 (1H, m) m 2.20-2.11 (1H, m).

Reference Example 13
3-hydroxy-3- (3-trifluoromethylphenyl) propionic acid ethyl ester
2-Trifluoromethylbenzaldehyde (25.0 g, 144 mmol) was dissolved in tetrahydrofuran (300 ml), and ethyl bromoacetate (23.9 ml, 215 mmol) and zinc powder (14.1 g, 215 mmol) were added with stirring at room temperature, followed by heating under reflux for 1 hour. After completion of the reaction, 1N hydrochloric acid was added to the reaction solution, and the organic layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 39.1 g of the title compound as an oily substance.

Reference Example 14
1- (3-trifluoromethylphenyl) -propane-1,3-diol 39.1 g (144 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) propionic acid ethyl ester prepared in Reference Example 13 was dissolved in diethyl ether. This was dissolved in 300 ml and added to a suspension of lithium aluminum hydride 8.17 g (144 mmol) -diethyl ether (100 ml) under ice-cooling and stirring. After stirring at room temperature for 1 hour, 8 ml of water, 8 ml of 1N aqueous sodium hydroxide solution and 16 ml of water were sequentially added with stirring under ice cooling, and the mixture was stirred at room temperature for 16 hours. Thereafter, the reaction solution was filtered through Celite and washed several times with ethyl acetate. The organic layer was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to obtain 23.6 g (yield 74.8%) of the title compound as an oily substance.

Reference Example 15
Methanesulfonic acid 3-hydroxy-3- (3-trifluoromethylphenyl) propyl
2.00 g (9.08 mmol) of 1- (3-trifluoromethylphenyl) propane-1,3-diol produced in Reference Example 14 was dissolved in 30 ml of methylene chloride, and 0.70 ml (9.08) of methanesulfonyl chloride was stirred at −40 ° C. mmol) and 2.54 ml (18.2 mmol) of triethylamine were added, and then the mixture was stirred for 9 hours under ice cooling. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to give the title compound (244 mg, yield 89.9%) as an oil.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.69-7.44 (m, 4H), 5.01-4.96 (m, 1H), 4.58-4.49 (m, 1H), 4.37-4.25 (m, 1H), 3.02 (s, 3H), 2.10-2.03 (m, 2H).

Reference Example 16
Methanesulfonic acid 3- (4-chlorophenoxy) -3- (3-trifluoromethylphenyl) propyl methanesulfonic acid 3-hydroxy-3- (3-trifluoromethylphenyl) propyl 300 mg (1.01 mmol) was dissolved in 6 ml of toluene, and 142 mg (1.11 mmol) of p-chlorophenol, 317 mg (1.21 mmol) of triphenylphosphine and 0.19 ml (1.21 mmol) of diethyl azodicarboxylate were added at room temperature with stirring at room temperature. Stir for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 290 mg (yield 70.5%) of the title compound as an oily substance.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.62-7.44 (m, 4H), 7.15-7.10 (m 1H), 6.92-6.88 (m 1H), 6.84-6.82 (m 1H), 6.72-6.69 ( m 1H), 5.39-5.35 (m, 1H), 4.58-4.42 (m, 1H), 4.38-4.32 (m, 1H), 2.97 (s, 3H), 2.41-2.03 (m, 2H).

Reference Example 17
Methanesulfonic acid 3- (2-fluorophenoxy) -3- (3-trifluoromethylphenyl) propyl
300 mg (1.01 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) propyl methanesulfonate prepared in Reference Example 15 was dissolved in 6 ml of toluene, and 124 mg (1.11 mmol) of o-fluorophenol was stirred at room temperature. After adding 317 mg (1.21 mmol) of triphenylphosphine and 0.19 ml (1.21 mmol) of diethyl azodicarboxylate, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 290 mg (yield 73.5%) of the title compound as an oily substance.

Reference Example 18
Methanesulfonic acid 3- (3-fluorophenoxy) -3- (3-trifluoromethylphenyl) propyl
300 mg (1.01 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) propyl methanesulfonate prepared in Reference Example 15 was dissolved in 6 ml of toluene, and 124 mg (1.11 mmol) of m-fluorophenol was stirred at room temperature. After adding 317 mg (1.21 mmol) of triphenylphosphine and 0.19 ml (1.21 mmol) of diethyl azodicarboxylate, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 230 mg (yield 58.3%) of the title compound as an oily substance.

Reference Example 19
Methanesulfonic acid 3- (4-trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) propyl
300 mg (1.01 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) propyl methanesulfonate prepared in Reference Example 15 was dissolved in 6 ml of toluene, and stirred at room temperature, 179 mg (1.11 mmol) of 4-hydroxybenzotrifluoride ), 317 mg (1.21 mmol) of triphenylphosphine and 0.19 ml (1.21 mmol) of diethyl azodicarboxylate were added, and then the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 265 mg (yield 59.6%) of the title compound as an oily substance.

Reference Example 20
Methanesulfonic acid 3- (3-cyanophenoxy) -3- (3-trifluoromethylphenyl) propyl
300 mg (1.01 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) propyl methanesulfonate prepared in Reference Example 15 was dissolved in 6 ml of toluene, and stirred at room temperature, 132 mg (1.11 mmol) of 3-cyanophenol, After adding 317 mg (1.21 mmol) of triphenylphosphine and 0.19 ml (1.21 mmol) of diethyl azodicarboxylate, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 309 mg (yield 76.9%) of the title compound as an oily substance.

Reference Example 21
Methanesulfonic acid 3- (4-cyanophenoxy) -3- (3-trifluoromethylphenyl) propyl
300 mg (1.01 mmol) of 3-hydroxy-3- (3-trifluoromethylphenyl) propyl methanesulfonate prepared in Reference Example 15 was dissolved in 6 ml of toluene, and stirred at room temperature, 132 mg (1.11 mmol) of 4-cyanophenol, After adding 317 mg (1.21 mmol) of triphenylphosphine and 0.19 ml (1.21 mmol) of diethyl azodicarboxylate, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 335 mg (yield 83.3%) of the title compound as an oily substance.

Reference Example 22
3-chloro-1- (4-fluorophenyl) propyl 3-trifluoromethylphenyl ether 200 mg (1.06 mmol) of 3-chloro-1- (4-fluorophenyl) -1-propanol prepared in Reference Example 11 and 3- The reaction was conducted in the same manner as in Reference Example 12 using 172 mg (1.06 mmol) of hydroxybenzotrifluoride to purify to give 306 mg (87%) of the title compound.
Nuclear magnetic resonance spectrum _{(400MHz, CDCl 3) δ ppm} : 7.57-7.52 (1H, m), 7.42-7.33 (3H, m), 7.10-7.03 (2H, m), 6.98-6.93 (1H, m), 6.83 -6.80 (1H, m), 5.56-5.50 (1H, m), 3.93-3.85 (1H, m), 3.66-3.59 (1H, m), 2.61-2.51 (1H, m), 2.27-2.17 (1H, m).
Reference Example 23
3- (4-Fluorophenoxy) -3- [3- (trifluoromethyl) phenyl] propyl methanesulfonate 3-hydroxy-3- [3- (trifluoromethyl) phenyl] methanesulfonate prepared in Reference Example 15 The reaction was purified in the same manner as in Reference Example 16 using propyl 360 mg (1.21 mmol) and 4-fluorophenol 149 mg (1.21 mmol) to obtain 294 mg (62%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.63-7.46 (4H, m), 6.94-6.74 (4H, m), 5.32-5.27 (1H, m), 4.57-4.49 (1H, m), 4.40 -4.33 (1H, m), 2.97 (3H, s), 2.42-2.22 (2H, m).

Reference Example 24
3- [3- (Trifluoromethyl) phenoxy] -3- [3- (trifluoromethyl) phenyl] propyl methanesulfonate 3-hydroxy-3- [3- (trifluoromethanemethane prepared in Reference Example 15 Methyl) phenyl] propyl 360 mg (1.21 mmol) and 3-hydroxybenzotrifluoride 149 mg (1.21 mmol) were reacted and purified in the same manner as in Reference Example 19 to obtain 326 mg (61%) of the title compound.
Nuclear magnetic resonance spectrum _{(400MHz, CDCl 3) δ ppm} : 7.65-7.49 (4H, m), 7.34-7.20 (1H, m), 7.22-7.16 (1H, m), 7.14-7.10 (1H, m), 6.99 -6.95 (1H, m), 5.45-5.49 (1H, m), 4.55-4.48 (1H, m), 4.39-4.34 (1H, m), 2.98 (3H, s), 2.45-2.26 (2H, m) .

Reference Example 25
(1R) -3-Chloro-1- (4-fluorophenyl) -1-propanol
20 g (107 mmol) of 3-chloro-4′-fluoropropiophenone was dissolved in 400 ml of tetrahydrofuran, and 40 g (125 mmol) of (+)-B-chlorodiisopinocinfeylborane was added at −78 ° C. The mixture was stirred at -78 ° C for 30 minutes and then allowed to stand at -20 ° C for 15 hours. Diethanolamine (21 ml, 219 mmol) was added, and the mixture was stirred at room temperature for 2 hours. 400 ml of diethyl ether was added to the reaction solution, the insoluble matter was filtered through Celite, the mother liquor was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent; toluene / n-hexane = 4/1). The obtained compound was recrystallized from n-hexane to obtain 13.1 g (65%) of the title compound.
Optical purity is determined by an optically active HPLC column for analysis [ChiralPak OJ (0.46 cm × 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol = 70/30, flow rate: 1.0 ml / min]. , 99.1% ee was confirmed.
Nuclear magnetic resonance spectrum _{(400MHz, CDCl 3) δ ppm} : 7.38-7.31 (2H, m), 7.08-7.02 (2H, m), 4.99-4.93 (1H, m), 3.78-3.70 (1H, m), 3.59 -3.51 (1H, m), 2.27-2.17 (1H, m), 2.11-2.02 (1H, m).

Reference Example 26
2-Chloroethyl- (3,3'-ditrifluoromethoxyphenyl) methyl ether
1.20 g (4.98 mmol) of 3-trifluoromethoxybromobenzene was dissolved in 24 ml of tetrahydrofuran, and 3.20 ml (4.98 mmol) of 1.57N normal butyl lithium (hexane solution) was added dropwise with stirring at −78 ° C. After stirring for 3 minutes, 1.20 g (3.32 mmol) of 3-trifluoromethoxybenzaldehyde was added, and the mixture was stirred for 3 hours under ice cooling. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 10/1) to give 765 mg (yield 43.5%) of the desired compound as an oil.

  765 mg (2.17 mmol) of the obtained compound was dissolved in 14 ml of tetrahydrofuran, and with stirring under ice cooling, 0.41 ml (4.34 mmol) of acetic anhydride, 0.90 ml (6.52 mmol) of triethylamine, and 0.13 g (1.09 mmol) of 4-dimethylaminopyridine were added. The mixture was further stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 15/1) to give 480 mg (yield 53.3%) of the target compound as an oil.

  480 mg (1.22 mmol) of the resulting compound was dissolved in 7.2 ml of toluene, 0.33 ml (4.87 mmol) of 2-chloroethanol and 23 mg (0.122 mmol) of paratoluenesulfonic acid monohydrate were added with stirring at room temperature, and the mixture was heated to 100 ° C. And stirred for 16 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 10/1) to give the desired compound (170 mg, yield 33.7%) as an oil.

Reference Example 27
3-Hydroxy-3- (2-fluorophenyl) -propionic acid ethyl ester In the same manner as in Reference Example 13, 4.55 g (36.7 mmol) of 2-fluorobenzaldehyde and 6.12 g (36.7 mmol) of ethyl bromoacetate were used to give 7.65 g of the title compound. Was obtained as an oil. Used in the next reaction without purification.

Reference Example 28
1- (2-Fluorophenyl) -propane-1,3-diol Same as Reference Example 14 using 7.65 g of 3-hydroxy-3- (2-fluorophenyl) -propionic acid ethyl ester prepared in Reference Example 27 Thus, 5.17 g (yield 83%, 2 steps) of the title compound was obtained as an oily substance.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.52-7.57 (m, 1H), 7.22-7.29 (m, 1H), 7.13-7.18 (m, 1H), 6.98-7.05 (m, 1H), 5.26 -5.32 (m, 1H), 3.86-3.93 (m, 2H), 2.91-2.97 (m, 1H), 2.13-2.17 (m, 1H), 2.01 (t, 2H, J = 5Hz).

Reference Example 29
3-hydroxy-3- (2-fluorophenyl) propyl methanesulfonate 5.00 g (29.4 mmol) of 1- (2-fluorophenyl) -propane-1,3-diol prepared in Reference Example 28 was used, and Reference Example 15 In the same manner, 6.82 g (93% yield) of the title compound was obtained as an oily substance.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.45-7.52 (m, 1H), 7.26-7.32 (m, 1H), 7.14-7.20 (m, 1H), 7.01-7.08 (m, 1H), 5.13 -5.23 (m, 1H), 4.48-4.55 (m, 1H), 4.30-4.37 (m, 1H), 3.02 (s, 3H), 2.10-2.26 (m, 3H).

Reference Example 30
Methanesulfonic acid 3- [4- (trifluoromethyl) phenoxy] -3- (2-fluorophenyl) propyl methanesulfonic acid 3-hydroxy-3- (2-fluorophenyl) propyl 315 mg (1.27 mmol) and 246 mg (1.52 mmol) of 4-hydroxybenzotrifluoride were used to obtain the title compound 373 mg (yield 75%).
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.47 (d, 2H, J = 9Hz), 7.27-7.38 (m 2H), 7.07-7.15 (m, 2H), 6.15 (d, 2H, J = 9Hz ), 5.58-5.73 (m, 1H), 4.46-4.54 (m, 1H), 4.34-4.42 (m, 1H), 2.97 (s, 3H), 2.35-2.47 (m, 2H).

Reference Example 31
3-hydroxy-3- (4-cyanophenyl) -propionic acid ethyl ester In the same manner as in Reference Example 13, 4-cyanobenzaldehyde 4.65 g (35.4 mmol) and ethyl bromoacetate 4.60 g (27.5 mmol) were used to give 5.06 g of the title compound. (65%) was obtained as an oil.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.66 (2H, d, J = 8Hz), 7.51 (2H, d, J = 8Hz), 5.15-5.21 (1H, m), 4.20 (2H, q, J = 7Hz), 3.56 (1H, d, J = 4Hz), 2.65-2.76 (2H, m), 1.27 (3H, t, J = 7Hz).

Reference Example 32
1- (4-Cyanophenyl) -propane-1,3-diol Same as Reference Example 14 using 5.06 g of 3-hydroxy-3- (4-cyanophenyl) -propionic acid ethyl ester prepared in Reference Example 31 Thus, 2.90 g (yield 71%) of the title compound was obtained as an oily substance.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.66 (2H, d, J = 8Hz), 7.45 (2H, d, J = 8Hz), 5.03-5.68 (1H, m), 3.85-3.95 (2H, m), 3.28-3.31 (1H, m), 1.93-2.03 (3H, m).

Reference Example 33
3-hydroxy-3- (4-cyanophenyl) propyl methanesulfonate 1.90 g (16.4 mmol) of 1- (4-cyanophenyl) -propane-1,3-diol prepared in Reference Example 32 was used, and Reference Example 15 In the same manner, 2.23 g (yield 54%) of the title compound was obtained as an oily substance.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.67 (2H, d, J = 9Hz), 7.51 (2H, d, J = 9Hz), 4.97-5.02 (1H, m), 4.51-4.59 (1H, m), 4.29-4.36 (1H, m), 3.05 (3H, s), 2.00-2.18 (3H, m).

Reference Example 34
3- [3- (trifluoromethyl) phenoxy] -3- (4-cyanophenyl) propyl methanesulfonate 3-hydroxy-3- (4-cyanomethanemethane prepared in Reference Example 33 in the same manner as Reference Example 16. Reaction was performed using 300 mg (1.17 mmol) of phenyl) propyl and 218 mg (1.34 mmol) of 3-hydroxybenzotrifluoride to obtain 420 mg (yield 89%) of the title compound.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.68 (2H, d, J = 9Hz), 7.50 (2H, d, J = 9Hz), 7.31 (1H, dd, J = 7 Hz, 8 Hz), 7.195 (1H, d, J = 7Hz), 7.09 (1H, s), 6.94 (1H, dd, J = 8Hz, 2Hz), 5.39-5.44 (1H, m), 4.47-4.55 (1H, m), 4.35 -4.22 (1H, m), 2.99 (3H, m), 2.26-2.42 (2H, m).

Reference Example 35
3- [4- (Trifluoromethyl) phenoxy] -3- (4-cyanophenyl) propyl methanesulfonate 3-hydroxy-3- (4-cyanomethanemethane prepared in Reference Example 33 in the same manner as Reference Example 16. Reaction was performed using 309 mg (1.21 mmol) of phenyl) propyl and 225 mg (1.39 mmol) of 4-hydroxybenzotrifluoride to obtain 391 mg of the title compound. Used in the next reaction without purification.

Reference Example 36
(1R) -3-Chloro-1- (4-chlorophenyl) propan-1-ol Similar to Reference Example 25, 5.51 g (27.1 mmol) of 3,4′-dichloropropiophenone, (+)-B-chloro Using 9.13 g (28.5 mmol) of diisopinocanphenylborane, 3.40 g (yield 61%) of the title compound was obtained as a colorless oil.
The optical purity was determined by an optically active HPLC column for analysis [ChiralPak OJ (0.46 cm × 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol = 90/10, flow rate: 0.7 ml / min]. 97.1% ee.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.34-7.29 (m, 4H), 4.94 (dt, 1H, J = 4.4 Hz, 8.1 Hz), 3.74 (ddd, 1H, J = 5.9 Hz, 8.5 Hz , 11.0 Hz), 3.54 (ddd, 1H, J = 5.1 Hz, 5.9 Hz, 11.0 Hz), 2.24-2.15 (m, 1H), 2.09-2.00 (m, 1H), 1.98 (d, 1H, J = 4.4 Hz)
Mass spectrum (EI) m / z 204 (M ⁺ , free form).

Reference Example 37
(1S) -3-Chloro-1- (4-chlorophenyl) propyl 3- (trifluoromethyl) phenyl ether (1R) -3-chloro-1- (4-chlorophenyl) propane-1-prepared in Reference Example 36 Using 201.4 mg (0.9821 mmol) of all in the same manner as in Reference Example 12, 241.4 mg (yield 70%) of the title compound was obtained as a colorless oil.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.34-7.26 (m, 5H), 7.16-7.10 (m, 2H), 6.95 (dd, 1H, J = 2.2 Hz, 8.1 Hz), 5.40 (dd, 1H, J = 4.4 Hz, 8.8 Hz), 3.79 (ddd, 1H, J = 5.1 Hz, 8.8 Hz, 11.0 Hz), 3.58 (ddd, 1H, J = 5.1 Hz, 5.9 Hz, 11.0 Hz), 2.50-2.41 (m, 1H), 2.22-2.14 (m, 1H)
Mass spectrum (EI) m / z 348 (M ⁺ , free body).

Reference Example 38
(1S) -3-Chloro-1- (4-chlorophenyl) propyl 4-cyanophenyl ether 204.7 mg of (1R) -3-chloro-1- (4-chlorophenyl) propan-1-ol prepared in Reference Example 36 In the same manner as in Reference Example 12, 245.1 mg (yield 80%) of the title compound was obtained as a colorless oily substance.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.50 (d, 2H, J = 8.8 Hz), 7.36-7.26 (m, 4H), 6.89 (d, 2H, J = 8.8 Hz), 5.44 (dd, 1H, J = 4.4 Hz, 8.1 Hz), 3.77 (ddd, 1H, J = 5.1 Hz, 8.8 Hz, 11.0 Hz), 3.58 (ddd, 1H, J = 5.1 Hz, 5.9 Hz, 11.0 Hz), 2.51-2.43 (m, 1H), 2.24-2.16 (m, 1H)
Mass spectrum (EI) m / z 305 (M ⁺ , free body).

Reference Example 39
(1S) -3-Chloro-1- (4-chlorophenyl) propyl 4-chlorophenyl ether (1R) -3-Chloro-1- (4-chlorophenyl) propan-1-ol 201.5 mg (0.9825) prepared in Reference Example 36 In the same manner as in Reference Example 12, 198.3 mg (yield 64%) of the title compound was obtained as a colorless oily substance.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.34-7.25 (m, 4H), 7.11 (d, 2H, J = 8.8 Hz), 6.75 (d, 2H, J = 8.8 Hz), 5.31 (dd, 1H, J = 4.4 Hz, 8.8 Hz), 3.78 (ddd, 1H, J = 5.1 Hz, 8.8 Hz, 11.0 Hz), 3.58 (ddd, 1H, J = 5.1 Hz, 5.9 Hz, 11.0 Hz), 2.46-2.38 (m, 1H), 2.19-2.11 (m, 1H)
Mass spectrum (EI) m / z 314 (M ⁺ , free body).

Reference Example 40
(1S) -3-Chloro-1- (4-chlorophenyl) propyl 4-fluorophenyl ether (1R) -3-chloro-1- (4-chlorophenyl) propan-1-ol 202.7 mg prepared in Reference Example 36 0.9884 mmol) was used in the same manner as in Reference Example 12 to obtain 189.7 mg (yield 64%) of the title compound as a colorless oil.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.34-7.25 (m, 4H), 6.89-6.85 (m, 2H), 6.77-6.74 (m, 2H), 5.27 (dd, 1H, J = 4.4 Hz , 8.8 Hz), 3.79 (ddd, 1H, J = 5.1 Hz, 8.8 Hz, 11.0 Hz), 3.58 (ddd, 1H, J = 5.1 Hz, 5.9 Hz, 11.0 Hz), 2.46-2.35 (m, 1H), 2.19-2.10 (m, 1H).

Reference Example 41
(1S) -3-Chloro-1- (4-chlorophenyl) propyl 3-fluorophenyl ether 218.1 mg of (1R) -3-chloro-1- (4-chlorophenyl) propan-1-ol prepared in Reference Example 36 In the same manner as in Reference Example 12, 224.8 mg (yield 71%) of the title compound was obtained as a colorless oily substance.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.34-7.30 (m, 2H), 7.04-6.99 (m, 2H), 6.77-6.71 (m, 4H), 5.24 (dd, 1H, J = 4.4 Hz , 8.8 Hz), 3.80 (ddd, 1H, J = 5.1 Hz, 8.8 Hz, 11.0 Hz), 3.59 (ddd, 1H, J = 5.1 Hz, 5.9 Hz, 11.0 Hz), 2.46-2.38 (m, 1H), 2.18-2.10 (m, 1H).

Reference Example 42
3- (t-Butyldimethylsilyloxy) -1- (4-methoxyphenyl) -propan-1-ol
1- (4-Methoxyphenyl) -propane-1,3-diol (Bioorg. Chem. Lett. 8, 1998, 2967-2972) 4.0 g (21.9 mmol), t-butyldimethylsilyl chloride 3.16 g (21.0 mmol) Then, 1.58 g (23.2 mmol) of imidazole was stirred in 100 mlc of methylene chloride at room temperature for 1 hour and 30 minutes. The reaction mixture was poured into water and extracted with a hexane-ethyl acetate mixture. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (75 g, 15% ethyl acetate-hexane) to obtain 4.71 g (67%) of the title compound as an oily substance.
Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δ ppm: 7.30 (2H, d, J = 9Hz), 6.90 (2H, d, J = 9Hz), 4.88-4.93 (1H, m), 3.80-3.87 ( 2H, m), 3.80 (3H, s), 1.87-1.97 (2H, m), 0.93 (9H, s), 0.09 (6H, s).

Reference Example 43
4-[(3-t-butyldimethylsilyloxy) -1- (4-methoxyphenyl) -propoxy] benzonitrile 3- (t-butyldimethylsilyloxy) -1- (4-methoxy) prepared in Reference Example 42 Phenyl) -propan-1-ol 260 mg (0.90 mmol) was dissolved in tetrahydrofuran-DMF (4: 1, 2.5 ml), and 39 mg (0.90 mmol) of sodium hydride was added under ice cooling. After stirring for 1 hour, 493 μl (1.5 mmol) of 4-fluorobenzonitrile was added at the same temperature, and further stirred at 80 ° C. for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and washed with water and saturated brine. After drying, it was concentrated to obtain 450 mg of an oily substance. Used in the next reaction without purification.

Reference Example 44
4-[(3-Hydroxy) -1- (4-methoxyphenyl) -propoxy] benzonitrile 4-[(3-t-butyldimethylsilyloxy) -1- (4-methoxyphenyl) prepared in Reference Example 43 450 mg of a mixture containing -propoxy] benzonitrile was dissolved in 10 ml of tetrahydrofuran, and 2 ml of 1M-tetrabutylammonium fluoride solution was added. After stirring for 1 hour, the reaction solution was poured into water. The mixture was extracted with ethyl acetate and washed with water and saturated brine. After drying, the mixture was concentrated, and the residue was purified by silica gel column chromatography (20 g, 45% ethyl acetate-hexane) to obtain 150 mg (59%, 2 steps) of the title compound as an oily substance.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.47 (2H, d, J = 9Hz), 7.26 (2H, d, J = 9Hz), 6.90 (2H, d, J = 9Hz), 6.87 ( 2H, d, J = 9Hz), 5.37-5.42 (1H, m), 3.82-3.88 (1H, m), 3.80 (3H, s), 3.71-3.78 (1H, m), 2.23-2.33 (1H, m ), 2.02-2.08 (1H, m).

Reference Example 45
3- [4-Cyanophenoxy) -3- (4-methoxyphenyl) propyl methanesulfonate 4-[(3-hydroxy) -1- (4-methoxyphenyl) -propoxy] benzonitrile 150 mg prepared in Reference Example 44 (0.53 mmol) was dissolved in 3 ml of methylene chloride, and 64 μl (0.79 mmol) of pyridine and 61 μl (0.79 mmol) of methanesulfonyl chloride were added under ice cooling. The mixture was stirred at the same temperature for 1 hour, and the reaction solution was poured into a 1N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate, and water and saturated carbonated water were washed successively with aqueous sodium solution and saturated brine. After drying, it was concentrated to obtain 200 mg of an oily substance. Used in the next reaction without purification.

Reference Example 46
t-butyl- [3- (4-methoxyphenyl) -3- (4-trifluoromethylphenoxy) propoxy] dimethylsilane In the same manner as in Reference Example 43, 3- (t-butyldimethylsilyloxy) -1- (4 Using 386 mg (1.30 mmol) of -methoxyphenyl) -propan-1-ol and 507 μl (4.0 mmol) of 4-trifluoromethylfluorobenzene, 514 mg of an oily substance was obtained. Used in the next reaction without purification.

Reference Example 47
3- (4-Methoxyphenyl) -3- (4-trifluoromethylphenoxy) -propan-1-ol In the same manner as in Reference Example 44, t-butyl- [3- (4-methoxyphenyl) prepared in Reference Example 46 was used. ) -3- (4-Trifluoromethylphenoxy) propoxy] dimethylsilane to give 231 mg (55%, 2 steps) of the title compound as an oil.
Nuclear magnetic resonance spectrum _{(400MHz, DMSO-d 6)} δ ppm: 7.43 (2H, d, J = 9Hz), 7.27 (2H, d, J = 9Hz), 6.91 (2H, d, J = 9Hz), 6.87 ( 2H, d, J = 9Hz), 5.36-5.41 (1H, m), 3.84-3.90 (1H, m), 3.78 (3H, s), 3.75-3.80 (1H, m), 2.24-2.30 (1H, m ), 2.02-2.11 (1H, m).

Reference Example 48
3- (4-Trifluoromethylphenoxy) -3- (4-methoxyphenyl) propyl methanesulfonate 3- (4-methoxyphenyl) -3- (4- Trifluoromethylphenoxy) -propan-1-ol was used to give 290 mg of oil. Used in the next reaction without purification.

Reference Example 49
3- (tert-butyldimethylsilanyloxy) -1- (3-trifluoromethylphenyl) -propan-1-one 1- (3-trifluoromethylphenyl) -propane-1,3 prepared in Reference Example 14 -Dissolve 4.00 g (18.2 mmol) of diol in 80 ml of methylene chloride, add 2.74 g (18.2 mmol) of t-butyldimethylchlorosilane and 1.48 g (21.8 mmol) of imidazole under ice-cooling and stir for 1 hour under ice-cooling. Stir. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 10/1) to obtain 4.44 g of a TBS ether as an oily substance.

2.00 g (5.98 mmol) of the obtained compound was dissolved in 12 ml of methylene chloride, and stirred with ice cooling, 105 mg (0.299 mmol) of tetrapropylammonium pearlatenate, 1.05 g (8.97 mol) of 4-methylmorpholine N-oxide, 3 g of molecular sieves 4A Was added at once and stirred for 1 hour under ice-cooling. After completion of the reaction, the reaction mixture was filtered through celite, and the residue was washed with methylene chloride. The solution was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 10/1) to obtain 1.76 g (yield: 88.4%) of the target compound as an oily substance.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 8.20 (s, 1H), 8.13 (d, 1H, J = 8.06), 7.79 (d, 1H J = 7.33 Hz), 7.58 (t, 1H, J = 7.70 Hz), 4.05 (t, 2H, J = 6.59 Hz), 3.18 (t, 2H, J = 6.59 Hz), 0.82 (s, 9H), 0.02 (s, 6H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2956, 2930, 2858, 1732, 1689, 1613, 1330, 1256, 1172, 1136, 1098, 836
Mass spectrum (FAB) m / z 333 ((M + H) ⁺ , free form).

Reference Example 50
(3S) -1- (tert-Butyldimethylsilanyloxy) -3- (4-chlorophenoxy) -3- (3-trifluoromethylphenyl) -propane
3- (tert-butyldimethylsilanyloxy) -1 prepared in Reference Example 49 in 10 ml of a THF solution of 3.93 g (12.2 mmol) of (+)-B-chlorodiisopinocinfeylborane was stirred at −78 ° C. 3.70 g (5.49 mmol) of-(3-trifluoromethylphenyl) -propan-1-one was added and the mixture was allowed to stand at −20 ° C. for 16 hours. After completion of the reaction, 2.57 ml (26.8 mmol) of diethanolamine was added with stirring under ice-cooling, and the mixture was stirred for 1 hour. The reaction solution was diluted with ether, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography. (Elution solvent: toluene / hexane = 5/1 to hexane / ethyl acetate = 5/1) was roughly purified to obtain 2.88 g of a reduced product as an oily substance.

2.88 g (8.61 mmol) of the produced reduced product was dissolved in 30 ml of toluene, and stirred at room temperature, 1.22 g (9.47 mmol) of 4-chlorophenol, 2.48 g (9.47 mol) of triphenylphosphine, 4.12 ml of diethyl azodicarboxylate ( 9.47 mol) was added, followed by stirring at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 7/1) to give 2.47 g (yield 64.4%) of the target compound as an oil.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.58 (s, 1H), 7.50 (d, 1H, J = 8.1 Hz), 7.43 (d, 1H, J = 7.3 Hz), 7.12 (d, 1H, J = 8.8 Hz), 5.36 (dd, 1H, J = 4.8 Hz, 8.4 Hz), 3.87-3.78 (m, 1H), 3.72-3.58 (m, 1H), 2.22-2.12 (m, 1H), 2.00- 1.75 (m, 1H), 0.87 (s, 9H), 0.01 (s, 3H), -0.02 (s, 3H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2955, 2930, 2858, 1490, 1330, 1237, 1169, 1132, 1094
Mass spectrum (FAB) m / z 445 ((M + H) ⁺ , free form).

Reference Example 51
Methanesulfonic acid (3S) -3- (4-chlorophenoxy) -3- (3-trifluoromethylphenyl) -propyl 1- (tert-butyldimethylsilanyloxy) -3- (4 -Chlorophenoxy) -3- (3-trifluoromethylphenyl) -propane 2.47 g (5.55 mmol) was dissolved in 25 ml of ether, and 10 ml of 4N hydrochloric acid aqueous solution was added with stirring at room temperature, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was neutralized with 4N aqueous sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 3/2) to obtain 1.81 g of a de-TBS product. 1.18 g (5.47 mmol) of the obtained compound was dissolved in 18 ml of methylene chloride, and 0.51 ml (6.57 mmol) of methanesulfonyl chloride and 1.2 ml (8.2 mmol) of triethylamine were added with stirring under ice cooling. Stir for 2 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give 1.82 g (yield 81.1%) of the desired compound as an oil.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.68-7.45 (m, 4H), 7.16 (d, 2H, J = 9.2 Hz), 6.76 (d, 2H, J = 9.2 Hz), 5.32 (dd, 1H, J = 4.0 Hz, 8.4 Hz), 4.56-4.47 (m, 1H), 4.40-34.31 (m, 1H), 2.97 (s, 3H), 2.39-2.21 (m, 2H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 1490, 1330, 1235, 1176, 1134
Mass spectrum (FAB) m / z 408 (M ⁺ , free body).

Reference Example 52
(3S) -1- (tert-Butyl-dimethyl-silanyloxy) -3- (4-cyanophenoxy) -3- (3-trifluoromethylphenyl) -propane
3- (tert-Butyldimethylsilanyloxy) -1 prepared in Reference Example 49 in 11 ml of a THF solution of 4.25 g (13.2 mmol) of (+)-B-chlorodiisopinocinfeylborane was stirred at −78 ° C. -(3-Trifluoromethylphenyl) -propan-1-one 4.00 g (12.0 mmol) was added and the mixture was allowed to stand at −20 ° C. for 16 hours. After completion of the reaction, 2.31 ml (24.1 mmol) of diethanolamine was added with stirring under ice-cooling, and the mixture was stirred for 1 hour. The reaction solution was diluted with ether, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography. (Elution solvent: toluene / hexane = 5/1 to hexane / ethyl acetate = 5/1) was roughly purified to obtain 3.46 g of a reduced product as an oily substance.

3.46 g (10.4 mmol) of the reduced form was dissolved in 17 ml of toluene, and 1.48 g (12.4 mmol) of 4-cyanophenol, 3.26 g (12.4 mol) of triphenylphosphine, 5.45 ml (12.4 mol) of diethyl azodicarboxylate with stirring at room temperature. ) And then stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 7/1) to give the desired compound (4.06 g, yield 89.9%) as an oil.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.61-7.45 (m, 6H), 6.92 (d, 1H, J = 8.8 Hz), 5.49 (dd, 1H, J = 4.8 Hz, 8.4 Hz), 3.89 -3.81 (m, 1H), 3.67-3.61 (m, 1H), 2.28-2.18 (m, 1H), 2.09-1.95 (m, 1H), 0.90 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2955, 2930, 2227, 1605, 1506, 1330, 1253, 1191, 1133
Mass spectrum (FAB) m / z 436 ((M + H) ⁺ , free form).

Reference Example 53
Methanesulfonic acid (3S) -3- (4-cyanophenoxy) -3- (3-trifluoromethylphenyl) -propyl prepared in Reference Example 52 (3S) -1- (tert-butyl-dimethylsilanyloxy) -3- (4-Cyanophenoxy) -3- (3-trifluoromethylphenyl) -propane 4.06 g (9.32 mmol) was dissolved in 40 ml of ether, and 20 ml of 4N hydrochloric acid aqueous solution was added with stirring at room temperature. Stir for 3 hours. After completion of the reaction, the reaction mixture was neutralized with 4N aqueous sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 1/1) to obtain 2.85 g of a de-TBS product. 2.68 g of the obtained compound was dissolved in 30 ml of methylene chloride, and 0.97 ml (12.5 mmol) of methanesulfonyl chloride and 2.1 ml (15.0 mmol) of triethylamine were added with stirring under ice cooling, followed by stirring for 2 hours under ice cooling. . After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give the title compound (2.66 g, yield 79.7%) as an oil.
Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.62-7.45 (m, 6H), 6.91 (d, 1H, J = 8.8 Hz), 5.49 (dd, 1H, J = 4.4 Hz, 8.8 Hz), 3.95 -3.86 (m, 1H), 3.78-3.71 (m, 1H), 2.33-2.22 (m, 1H), 2.13-2.02 (m, 1H)
Infrared absorption spectrum νmax cm ^-1 (KBr): 2228, 1732, 1605, 1506, 1330, 1254, 1171, 1133, 1073, 1048, 835
Mass spectrum (FAB) m / z 322 (M ⁺ , free).

Test example 1
IL-10 production inducing action on mouse T cell clone D10.G4.1 cells (1) Measurement of IL-10 production Mouse T cell clone D10.G4.1 cells were treated with 10% fetal bovine serum and 5 μM 2-mercaptoethanol. In an RPMI1640 medium containing Life Technologies (Life Technologies), 25000 cells / 0.2 ml were dispensed into 96-well flat bottom plates (Corning). At this time, a predetermined concentration of the compound was added. As a positive control for the IL-10 production inducing action, an anti-mouse CD3e antibody (BD Biosciences) was adsorbed to a 96-well flat bottom plate at a final concentration of 0.4 μg / ml, and D10.G4.1 cells were similarly adsorbed to 25000. Dispensing each piece / 0.2 ml. After culturing for 24 hours, IL-10 was produced in the culture supernatant. IL-10 in the culture supernatant was measured by ELISA KIT (Genzyme Techne).
(2) Evaluation of IL-10 production-inducing action Regarding the IL-10 production-inducing action of each compound, from a graph in which the concentration of each compound was semilogarithmically plotted against the amount of IL-10 produced, 30% of the positive control the concentration of the compound to induce the production amount of IL-10 was similarly calculated as ED _30. The results are shown in Table 4 below.
(Table 4)

Compound ED ₃₀ (μg / ml)

Example 2 0.021
Example 21 0.054
Example 52 0.030
Example 53 0.033

From the above results, it is clear that the compound of the present invention has an excellent IL-10 production inducing action.

Claims (46)

Formula (I)

General formula (II)

Or general formula (III)

[Where:
R ¹ and R ² are the same or different and each independently represent 1 to 3 phenyl groups substituted with any group selected from the substituent group a,
R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a lower alkyl group, or R ³ and R ⁴ together represent an ethylene group,
R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkylsulfinyl lower alkyl group, a lower alkylsulfonyl lower alkyl group, a lower alkyl group having 1 to 3 oxygen atoms in the carbon chain, or 1 to 3 in the carbon chain. 1 to 3 lower alkyl groups having a sulfur atom, a lower alkyl group having 1 to 3 nitrogen atoms in the carbon chain, and a group selected from the substituent group b, and 1 to 3 in the carbon chain A lower alkyl group having one oxygen atom, sulfur atom or nitrogen atom or a group having the formula —CO—R ⁷ (wherein R ⁷ represents a group selected from the substituent group b);
R ⁶ represents a lower alkyl group or a lower alkyl group having one oxygen atom in the carbon chain;
m represents an integer of 0 to 2,
n represents an integer of 1 to 6,
Substituent group a represents a group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a halogeno lower alkoxy group, a lower alkylthio group, a hydroxy group, an amino group, a nitro group, and a cyano group,
Substituent group b was substituted with 1 to 3 aryl groups, heteroaryl groups, aryl groups substituted with 1 to 3 groups selected from substituent group a, and groups selected from substituent group a. Represents a group consisting of heteroaryl groups;
However, when it has the general formula (I) and R ³ and R ⁴ simultaneously represent a hydrogen atom, R ⁵ is other than a hydrogen atom, a lower alkyl group and a lower alkyl group having one oxygen atom in the carbon chain. The group of is shown. ]
And a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient.   The medicament according to claim 1, comprising as an active ingredient a compound having the general formula (I), a pharmacologically acceptable salt thereof, an ester or other derivative thereof.   The medicament according to claim 1, comprising a compound having the general formula (II), a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active ingredient. In claim 1 or 3,
A pharmaceutical comprising a compound wherein m is 0 or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In claim 1 or 3,
A pharmaceutical comprising a compound wherein m is an integer of 1 or 2, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claim 1 thru | or 5,
A pharmaceutical comprising a compound in which R ³ and R ⁴ are hydrogen atoms, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claim 1 thru | or 5,
A pharmaceutical comprising a compound wherein R ³ and R ⁴ together are an ethylene group, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claim 1 thru | or 5,
A medicament comprising, as an active ingredient, a compound wherein R ³ and R ⁴ are the same or different and each is a lower alkyl group, or a pharmacologically acceptable salt, ester or other derivative thereof. In any one selected from Claim 1 thru | or 5,
A pharmaceutical comprising, as an active ingredient, a compound wherein R ³ and R ⁴ are the same or different and are a C ₁ -C ₂ alkyl group, or a pharmacologically acceptable salt, ester or other derivative thereof. In any one selected from Claim 1 thru | or 5,
A pharmaceutical comprising, as an active ingredient, a compound wherein R ³ and R ⁴ are the same or different and each is a methyl group, or a pharmacologically acceptable salt, ester or other derivative thereof. In any one selected from Claim 1 thru | or 10,
The pharmaceutical which contains the compound whose R < ⁵ > is a hydrogen atom, its pharmacologically acceptable salt, its ester, or another derivative as an active ingredient. In any one selected from Claim 1 thru | or 10,
A pharmaceutical comprising a compound wherein R ⁵ is a lower alkyl group or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claim 1 thru | or 10,
Pharmaceutical R ⁵ is, containing C ₁ -C ₄ alkyl group compound or a pharmacologically acceptable salt thereof, esters thereof or other derivatives as an active ingredient. In any one selected from Claim 1 thru | or 10,
The pharmaceutical which contains the compound whose R < ⁵ > is a methyl or ethyl group, its pharmacologically acceptable salt, its ester, or another derivative as an active ingredient. In any one selected from Claim 1 thru | or 10,
A pharmaceutical comprising a compound wherein R ⁵ is a lower alkyl group having one oxygen atom in the carbon chain or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claim 1 thru | or 10,
A pharmaceutical comprising a compound wherein R ⁵ is a C ₁ -C ₄ alkyl group having one oxygen atom in the carbon chain, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claim 1 thru | or 10,
A pharmaceutical comprising a compound wherein R ⁵ is a C ₂ -C ₃ alkyl group having one oxygen atom in the carbon chain or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claim 1 thru | or 10,
The pharmaceutical which contains the compound whose R < ⁵ > is a methoxymethyl group or 2-methoxyethyl group, its pharmacologically acceptable salt, its ester, or another derivative as an active ingredient. In any one selected from Claim 1 thru | or 10,
A pharmaceutical comprising a compound wherein R ⁵ is a lower alkylsulfinyl lower alkyl group or a lower alkylsulfonyl lower alkyl group, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claim 1 thru | or 10,
A compound wherein R ⁵ is a C ₁ -C ₂ alkylsulfinyl C ₁ -C ₂ alkyl group or a C ₁ -C ₂ alkylsulfonyl C ₁ -C ₂ alkyl group, or a pharmacologically acceptable salt, ester or other thereof A medicament containing a derivative as an active ingredient. In any one selected from Claim 1 thru | or 10,
A pharmaceutical comprising a compound wherein R ⁵ is a methylsulfinylmethyl group or a methylsulfonylmethyl group or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claim 1 thru | or 10,
R ⁵ represents a lower alkyl group having 2 or 3 oxygen atoms in the carbon chain, a lower alkyl group having 1 to 3 sulfur atoms in the carbon chain, and 1 to 3 nitrogen atoms in the carbon chain. A compound having 1 to 3 lower alkyl groups or a lower alkyl group having 1 to 3 oxygen, sulfur or nitrogen atoms in the carbon chain, or a pharmacological thereof A pharmaceutical comprising as an active ingredient an above-acceptable salt, ester or other derivative thereof. In any one selected from Claim 1 thru | or 10,
R ⁵ represents a lower alkyl group having 2 or 3 oxygen atoms in the carbon chain, a lower alkyl group having 1 to 3 sulfur atoms in the carbon chain, or 1 to 3 nitrogen atoms in the carbon chain. A pharmaceutical comprising a compound having a lower alkyl group or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claim 1 thru | or 10,
R ⁵ is a C ₁ -C ₄ alkyl group having 2 or 3 oxygen atoms in the carbon chain, a lower alkyl group having 1 to 3 sulfur atoms in the carbon chain, or 1 to 3 in the carbon chain Or a pharmacologically acceptable salt, ester or other derivative thereof, which is a C ₁ -C ₄ alkyl group having a nitrogen atom. In any one selected from Claim 1 thru | or 10,
R ⁵ is a C ₂ -C ₃ alkyl group having 2 or 3 oxygen atoms in the carbon chain or a C ₁ -C ₄ alkyl group having ₁ to 3 sulfur atoms in the carbon chain or in the carbon chain 1 C ₂ -C ₃ alkyl group, compound or a pharmacologically acceptable salt thereof having three nitrogen atoms, medicaments containing the esters or other derivatives as an active ingredient. In any one selected from Claim 1 thru | or 10,
A pharmaceutical comprising a compound wherein R ⁵ is a C ₂ -C ₃ alkyl group having 1 to 3 sulfur atoms in the carbon chain, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claim 1 thru | or 10,
The pharmaceutical which contains the compound whose R < ⁵ > is a methylthiomethyl group or 2-methylthioethyl group, its pharmacologically acceptable salt, its ester, or another derivative as an active ingredient. In any one selected from Claim 1 thru | or 10,
A compound in which R ⁵ is a group having the formula —CO—R ⁷ (wherein R ⁷ represents a group selected from substituent group b), or a pharmacologically acceptable salt thereof, an ester thereof, or the like A pharmaceutical comprising a derivative thereof as an active ingredient. In claim 28,
Effective compounds wherein R ⁷ is an aryl group, a heteroaryl group or an aryl group substituted by 1 to 3 groups selected from substituent group a, or a pharmacologically acceptable salt, ester or other derivative thereof Pharmaceuticals contained as an ingredient. In claim 28,
A compound, a pharmacologically acceptable salt, ester or other derivative thereof, wherein R ⁷ is a phenyl group, a phenyl group, a furyl group, a thienyl group or a phenyl group substituted by 1 to 3 groups selected from the substituent group a As an active ingredient. In claim 28,
R ⁷ is a phenyl group, a furyl group, a thienyl group or 1 to 3 substituted phenyl groups (the substituent is a group selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group). Or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In claim 28,
R ⁷ is a phenyl group or 1 to 3 substituted phenyl groups (the substituent is a group selected from the group consisting of a fluorine atom, a chlorine atom, a C ₁ -C ₂ alkyl group and a lower alkoxy group. Or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In claim 28,
A pharmaceutical comprising a compound wherein R ⁷ is a phenyl group substituted with 1 to 3 lower alkoxy groups or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient.   The medicament according to claim 1, comprising as an active ingredient a compound having the general formula (III), a pharmacologically acceptable salt thereof, an ester or other derivative thereof. In claim 34,
Effective compounds wherein R ⁶ is a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkyl group having one oxygen atom in the carbon chain, or a pharmacologically acceptable salt, ester or other derivative thereof Pharmaceuticals contained as an ingredient. In claim 34,
Effective compounds wherein R ⁶ is a C ₁ -C ₂ alkyl group or a C ₂ -C ₃ alkyl group having one oxygen atom in the carbon chain, or a pharmacologically acceptable salt, ester or other derivative thereof Pharmaceuticals contained as an ingredient. In claim 34,
The pharmaceutical which contains the compound whose R < ⁶ > is a methyl group, an ethyl group, a methoxymethyl group, or a 2-methoxyethyl group, its pharmacologically acceptable salt, its ester, or another derivative as an active ingredient. 38. Any one selected from claims 1-37,
R ¹ and R ² are the same or different and are selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a C ₁ -C ₂ alkoxy group, a C ₁ -C ₂ alkylthio group, a nitro group, and a cyano group. Or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. 38. Any one selected from claims 1-37,
A compound in which R ¹ and R ² are the same or different and each is a phenyl group substituted with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a nitro group and a cyano group Or the pharmaceutical which contains the pharmacologically acceptable salt, its ester, or another derivative as an active ingredient. 38. Any one selected from claims 1-37,
R ¹ and R ² are the same or different and are 1 to 3 groups selected from the group consisting of a halogen atom, a C ₁ -C ₂ alkyl group, a halogeno C ₁ -C ₂ alkyl group, a nitro group, and a cyano group. A pharmaceutical comprising a compound having a substituted phenyl group or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. 38. Any one selected from claims 1-37,
R ¹ and R ² are the same or different and each is a phenyl group substituted with 1 to 3 groups selected from the group consisting of fluorine atom, chlorine atom, methyl group, trifluoromethyl group, nitro group and cyano group A pharmaceutical comprising as an active ingredient a certain compound or a pharmacologically acceptable salt, ester or other derivative thereof. 38. Any one selected from claims 1-37,
R ¹ and R ² are the same or different and are 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 3-nitro Phenyl, 3,4-dimethylphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-ditrifluoro A pharmaceutical comprising a compound which is a methylphenyl, 3-cyanophenyl or 4-cyanophenyl group or a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof as an active ingredient. 38. Any one selected from claims 1-37,
A compound in which R ¹ and R ² are the same or different and are 3-fluorophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-cyanophenyl or 4-cyanophenyl group, or A medicament comprising a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claims 1 thru | or 43,
A pharmaceutical comprising a compound wherein n is 2 or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In any one selected from Claims 1 thru | or 43,
A pharmaceutical comprising a compound wherein n is 3 or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. In claim 1,
8- {2- [bis- (4-fluorophenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- {2- [Bis (4-fluorophenyl) methoxy] ethyl} -spiro [(8-azabicyclo [3.2.1] octane) -3,5 '-(3-methylthiomethyl) -oxazolidine] -2'- on,
8- {3- [Bis (4-fluorophenyl) methoxy] propyl} -spiro [(8-azabicyclo [3.2.1] octane) -3,5 '-(3-methylthiomethyl) -oxazolidine] -2'- on,
8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylsulfinylmethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- {2- [bis- (3-trifluoromethylphenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one ,
8- {2-[(4-Cyanophenyl) (4'-trifluoromethylphenyl) methoxy] ethyl} -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one ,
8- [3- (4-fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- [3- (3-trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- [3- (3-trifluoromethylphenoxy) -3- (3-trifluoromethylphenyl) propyl] -3-methylthiomethyl-1-oxa-3,8-diazaspiro [4,5] decan-2- on,
8- {2- [bis (3-trifluoromethylphenyl) methoxy] ethyl} -spiro [(8-azabicyclo [3.2.1] octane) -3,5'-oxazolidine] -2'-one,
8- [3- (3-cyanophenoxy) -3- (3-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- [3- (4-cyanophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- [3- (3-cyanophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- [3- (4-cyanophenoxy) -3- (3-trifluoromethylphenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one,
8- [3- (2-fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one and
From 8- {3-[(3-cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} -3-ethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one A pharmaceutical comprising a compound selected from the group consisting of the above or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient.