WO2002036122A1 - Preventive or therapeutic medicines for hepatitis and/or hepatopathy - Google Patents

Abstract

Preventive or therapeutic medicines for hepatitis and/or hepatopathy, containing as the active ingredient nitrogenous saturated heterocyclic compounds of the general formula (I), or their pharmacologically acceptable salts, esters or other derivatives: (I) [wherein R?1 and R2¿ are each aryl, heteroaryl, or the like; X is oxygen or the like; Y is C¿1-8? alkylene or the like; and L is C(R?3)(R4¿)- (wherein R?3 and R4¿ together with the carbon atom to which they are bonded form a five- to eight-membered saturated heterocyclic group), or the like].

Description

 Description Preventive or therapeutic agent for hepatitis and z or liver injury

 The present invention provides a prophylactic or therapeutic agent for hepatitis and Z or hepatic disorder, a hepatitis and Z or liver containing a nitrogen-containing saturated heterocyclic compound, a pharmaceutically acceptable salt thereof, an ester or other derivative thereof as an active ingredient. The use of the above-mentioned active ingredient for producing a pharmaceutical composition for the prevention or treatment of a disorder, or the administration of a pharmacologically effective amount of the above-mentioned active ingredient to a warm-blooded animal (particularly, a human). Or, a method for preventing or treating liver damage. Technology background

 Conventionally, in the treatment of hepatitis and Z or liver damage, antiviral agents such as compounds having an inhibitory effect on replication against viruses causing hepatitis and protein products such as interferon have been mainly used.

 However, although these antivirals have an inhibitory effect on the proliferation of hepatitis virus, they are poorly effective against inflammation after virus infection, so they have become a fundamental treatment for hepatitis and / or liver damage. In addition, it is known that Interferen preparation has side effects such as psychosuppressive effects.

 Therefore, no effective therapeutic agent with few side effects for hepatitis and / or liver damage has been found. Disclosure of the invention

The present inventors have conducted intensive studies on a prophylactic or therapeutic agent for hepatitis and / or hepatic disorder, and as a result, it has been found that a nitrogen-containing saturated heterocyclic compound is a prophylactic or therapeutic agent for hepatitis and / or hepatic disorder. The present invention has been found to be useful and has few side effects.

 The present application relates to a prophylactic or therapeutic agent for hepatitis and / or hepatic disorder, comprising the above-mentioned nitrogen-containing saturated heterocyclic compound, a pharmaceutically acceptable salt thereof, an ester or other derivative thereof as an active ingredient. z or use of the above active ingredient for producing a pharmaceutical composition for the prevention or treatment of liver injury, or administration of a pharmacologically effective amount of the above active ingredient to a warm-blooded animal (particularly a human) To provide a method for preventing or treating hepatitis and z or liver damage caused by the disease. '

(1) The prophylactic or therapeutic agent for hepatitis and / or liver damage of the present invention has the following general formula (I):

And a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient.

 Where:

R ¹ and R ² are the same or different, and are independently selected from an aryl group, a heteroaryl group, and an aryl group or a substituent group a substituted with 1 to 5 arbitrary groups selected from a substituent group a. Represents a heteroaryl group which is independently substituted with 1 to 3 arbitrary groups,

 X represents an oxygen atom, a sulfur atom, or a group having the formula —N R— (wherein, R represents a hydrogen atom or any group selected from substituent group b);

Y is one C ₈ alkylene group or a C ₂ - represents 0 ₈ Aruke two alkylene groups,

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

 [Where,

(i) R ³ is a hydrogen atom, an aryl group, an aralkyl group, a heteroaryl group, an aryl group or a substituent group a independently substituted with 1 to 3 arbitrary groups selected from a substituent group a An aralkyl group or a substituent independently substituted with 1 to 3 arbitrary groups selected from Represents an independently substituted 1 to 3 heteroaryl group with an arbitrary group selected from the group a, and R ⁴ is a group having the formula D—E—R ⁵ (wherein

R ^s represents a hydrogen atom, a hydroxyl group, an amino group, a lower aliphatic acylamino group, an aromatic acylamino group or a group having the formula CO—R ⁶ ;

R ⁶ is an arbitrary group selected from a lower alkyl group, a lower alkoxy group, an amine residue, a hydroxyl group, an aryl group, a 5- to 8-membered saturated heterocyclic group, and a substituent group a. A substituted or unsubstituted aryl group or a 5- to 8-membered saturated heterocyclic group independently substituted with an arbitrary group selected from the substituent group a,

D represents a single bond or a group having the formula C (R ⁷ ) H—,

R ⁷ represents a hydrogen atom or an arbitrary group selected from substituent group a,

E represents a single bond or a C ₈ alkylene group. ) Or

(ii) a 5- to 8-membered saturated heterocyclic group or any group selected from substituent group c formed by R ³ and R ⁴ being linked to each other and including the carbon atom to which they are bonded; Independently represents 1 to 3 substituted 5- to 8-membered saturated heterocyclic group,

(iii) R ³ and R ⁴ are taken together and include a carbon atom to which they are bonded, and are selected from a 3- to 10-membered saturated carbocyclic group or a substituent group a and a substituent group c. Represents a 3- to 10-membered saturated carbocyclic group independently substituted by 1 to 3 groups of any group represented by

(iv) R ³ and R ⁴ together form a group having the formula = C (R ⁷ ) —E—R ^s , wherein R ⁵ , R ⁷ and E are in agreement with the foregoing. Is shown). ] Or

A group having the formula N (R ⁴ ) —, wherein represents a group having the formula D—E—R ⁵ , wherein D, E and R ⁵ are in agreement with those described above. .)

 Substituent group a includes a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl group, a carbonyl group, a hydroxyl group, a lower aliphatic acyl group, a lower aliphatic acylamino group, and an amino group. Group, a cyano group and a nitro group.

Substituent group b is selected from lower alkyl group, aryl group, aralkyl group and substituent group a. A lower alkyl group independently substituted by 1 to 3 substituents with an arbitrary group selected, an aryl group independently substituted by 1 to 3 substituents with an arbitrary group selected from the substituent group a, or a substituent group a A group consisting of an aralkyl group, a lower aliphatic acyl group and a lower alkynolesulfonyl group, each independently substituted with 1 to 3 optional groups,

 Substituent group c is independently an oxo group or any group selected from an aryl group, an aralkyl group and a substituent group a as a substituent on the nitrogen atom when substituting for a nitrogen atom. A group selected from an aryl group substituted with 1 to 3 substituents and an aralkyl group substituted with 1 to 3 substituent (s); In the above, preferably,

 . (2) (1)

 X is an oxygen atom or a sulfur atom, a prophylactic or therapeutic agent for hepatitis and Z or liver damage,

(3) In (1),

 X is an oxygen atom, a prophylactic or therapeutic agent for hepatitis and Z or liver damage,

(4) In any one of the items selected from (1) to ( ³ ),

Y is a C ₈ alkylene group, hepatitis and / or liver failure prophylactic or therapeutic agent,

(5) In any one item selected from (1) to (3),

Y is C _: a C ₅ alkylene group, a prophylactic or therapeutic agent for hepatitis and / or ff disorder,

(6) In any one of (1) to (3),

Y is a C ₂ -C ₃ alkylene group, a prophylactic or therapeutic agent for hepatitis and / or liver damage

(7) In any one of (1) through (3),

γ is an ethylene group, a prophylactic or therapeutic agent for hepatitis and / or liver injury,

 (8) In any one item selected from (1) to (3),

 Υ is a trimethylene group, a prophylactic or therapeutic agent for hepatitis and / or liver injury,

(9) In any one of (1) through ( ⁸ ), L is a group having the formula —C (R ³ ) (R ⁴ ); R ³ is any group selected from a hydrogen atom, an aryl group, an aralkyl group, a heteroaryl group, and a substituent group a. Is an independently substituted 1 to 3 aryl group, any group selected from substituent group a, and 1 to 3 independently substituted aralkyl group or any group selected from substituent group a. Independently represents 1 to 3 substituted heteroaryl groups, R ⁴ is a group having the formula D-E-R ⁵ , a prophylactic or therapeutic agent for hepatitis and / or liver injury,

 (10) In (9),

R ³ is an aryl group or a heteroaryl group, a prophylactic or therapeutic agent for hepatitis and Z or hepatic disorder,

 (1 1) (9)

R ³ is a fuel group or a pyridyl group, a prophylactic or therapeutic agent for hepatitis and / or liver injury,

 (1 2) In (9),

R ³ is a pyridyl group, a prophylactic or therapeutic agent for hepatitis and / or liver injury,

(1 3) In any one selected from ( ⁹ ) ′ to (I ² ),

R ⁴ is a group having the formula one CO- R ^6, hepatitis and / or liver failure prophylactic or therapeutic agent,

 (14) In (13),

R ⁶ is an Amin residue, hepatitis and Z or hepatopathy prophylactic or therapeutic agent,

 (1 5) In any one selected from (1) to (8),

L is a group having the formula —C (R ³ ) (R ⁴ ), wherein R ³ and R ⁴ are taken together to form a carbon atom to which they are attached, a 5- to 8-membered member A prophylactic or therapeutic agent for hepatitis and Z or liver disorder, which is a 5- to 8-membered saturated heterocyclic group independently substituted with 1 to 3 saturated heterocyclic groups or an arbitrary group selected from substituent group c,

 (1 6) In any one selected from (1) to (8),

L is a group having the formula C (R ³ ) (R ⁴ ), wherein R ³ and R ⁴ are A 5- or 6-membered saturated heterocyclic ring independently formed by a 5- or 6-membered saturated heterocyclic group or an arbitrary group selected from substituent group c, which is formed including a carbon atom bonded to A prophylactic or therapeutic agent for hepatitis and Z or liver damage,

 (17) In any one selected from (1) to (8),

L is a group having the formula C (R ³ ) (R ⁴ ) 1, wherein R ³ and R ⁴ are linked to form a substituent group including the carbon atom to which they are bonded; a 5 to 6-membered saturated heterocyclic group independently substituted with 1 to 3 arbitrary groups selected from c, a prophylactic or therapeutic agent for menstritis and / or liver injury,

 (1 8) In any one selected from (1) to (8),

L is a group having the formula C (R ³ ) (R ⁴ ) 1, and R ³ and R ⁴ are taken together to form one oxo group including the carbon atom to which they are bonded ^ 5 to 5 of which may be independently substituted with any group selected from substituent group c.

A 6-membered saturated heterocyclic group, a prophylactic or therapeutic agent for hepatitis and / or liver damage,

 (1 9) In any one selected from (1) to (8),

L is the following general formula (L-1)

 [Wherein, G and J are the same or different and each represent an oxygen atom, a sulfur atom, or a group having the formula NR′— (wherein, R ′ represents a hydrogen atom, an aryl group, an aralkyl group, a substituent group a A group independently selected from an aryl group independently substituted with 1 to 3 substituents and an aralkyl group independently substituted with 1 to 3 optional groups selected from substituent group a. Is shown). A prophylactic or therapeutic agent for hepatitis and Z or hepatic disorder,

(20) In (1 9)

G is an oxygen atom or a sulfur atom, and is a group having J-NH-, a prophylactic or therapeutic agent for hepatitis and / or liver injury, (21) In (1 9),

 G force An oxygen atom, a group having J force —NH—, a prophylactic or therapeutic agent for hepatitis and Z or liver injury,

 (22) In any one of (1) to (8),

L is a group having the formula C (R ³ ) (R ⁴ ) —, wherein R ³ and R ⁴ together form a carbon atom to which they are attached, from 3 to 10 Hepatitis and / or hepatic disorder, which is a ^3- to 10-membered saturated carbocyclic group independently substituted with 1 to ³ membered saturated carbocyclic groups or an arbitrary group selected from substituent group a and substituent group c. Prophylactic or therapeutic agents,

 (23) In any one of (1) to (8),

L is a group having the formula C (R ³ ) (R ⁴ ) —, wherein R ³ and R ⁴ are taken together to form a carbon atom to which they are attached, a 5- or 6-membered A saturated carbocyclic group or a 5- to 6-membered saturated carbocyclic group independently substituted by 1 to 3 substituents selected from a substituent group a and a substituent group c; Prophylactic or therapeutic agents,

 (24) In any one item selected from (1) to (8),

L is a group having the formula C (R ³ ) (R ⁴ ) 1, and R ³ and R ⁴ are linked together to form a benzene ring including the carbon atom to which they are bonded. Or a 5- or 6-membered saturated carbocyclic group condensed with the above (the 5- or 6-membered saturated carbocyclic group has an oxo group or a hydroxyl group as a substituent). Agent,

 (25) In any one selected from (1) to (8),

L is a 2-hydroxyindane or 2-oxoindane group, a prophylactic or therapeutic agent for hepatitis and / or liver injury,

 (26) In any one selected from (1) to (8),

L is a group having the formula _C (R ³ ) ( ⁴ ), and R ³ and R ⁴ together form the formula = C

A prophylactic or therapeutic agent for hepatitis and / or liver damage, which is a group having (R ⁷ ) —E—R ⁵ ,

(27) In (26),

E is a single bond, a prophylactic or therapeutic agent for hepatitis and / or liver damage, (28) In subsection (26) or (27),

R ⁷ is a lower alkyl group or a cyano group, a prophylactic or therapeutic agent for hepatitis and / or liver injury,

 (29) In any one selected from (26) to (28),

R ⁵ is a group having the formula CO—R ⁶ , a prophylactic or therapeutic agent for hepatitis and / or liver injury,

 (30) In (29),

R ⁶ is a lower alkoxy group, a prophylactic or therapeutic agent for hepatitis and / or liver injury,

(3 1) In any one selected from (1) to (8),

Prophylactic or therapeutic agent for hepatitis and Z or hepatic disorder, which is a group having L force S, Formula I N (R ⁴ ) —

 (32) In (3 1),

R ⁴ is a group having the formula one D-R ^5, hepatitis and / or liver failure prophylactic or therapeutic agents

(33) In (3 1),

R ⁴ is a group having the formula _D- CO- R ^6, hepatitis and / or liver failure prophylactic or therapeutic agent,

 (34) In (33),

R ⁶ is a lower alkoxy group, a prophylactic or therapeutic agent for hepatitis and / or liver injury,

(3 5) In any one selected from (1) to (34),

R ¹ is an aryl group independently substituted with 1 to 5 aryl groups or an arbitrary group selected from substituent group a, a prophylactic or therapeutic agent for hepatitis and / or hepatic disorder,

 (36) In any one of (1) to (34),

R ¹ is an aryl group or an aryl group independently substituted with ¹ to 3 aryl groups or an arbitrary group selected from substituent group a, a prophylactic or therapeutic agent for hepatitis and / or liver injury,

(37) In any one selected from (1) to (34), R ¹ is any selected from the group consisting of an aryl group or a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, an amino group, a nitro group and a cyano group A prophylactic or therapeutic agent for hepatitis and / or hepatic disorder, which is an aryl group substituted by 1 to 3 groups with

 (38) In any one selected from (1) to (34),

Ri is an arbitrary group selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno, a lower alkylene group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, an amino group, a nitro group and a cyano group; A prophylactic or therapeutic agent for hepatitis and / or hepatic disorder, which is a monosubstituted aryl group;

 (39) In any one selected from (1) to (34),

A preventive agent for hepatitis and / or hepatic disorder, wherein Ri is an aryl group substituted with 1 to 3 arbitrary groups selected from a halogen atom, a lower alkyl group, a nitrogeno lower alkyl group, and an ethoxy group; Therapeutic agent, ''

 (40) In any one of (1) to (34),

R ¹ is an aryl group substituted with 1 to 3 groups selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group and a nitro group; Or therapeutic agents,

 (4 1) In any one selected from (1) to (34),

R ¹ is a phenyl group substituted by 1 to 3 groups selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group and a nitro group, wherein the agent is a prophylactic or therapeutic agent for hepatitis and / or liver injury. Agent,

 (4 2) In any one selected from (1) to (34),

R ¹ is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenol, 3-chlorophenol, 4-chlorophenol, 3-methylphenol, 3-trifluoro Methylphenyl, 3-Ethrophenyl, 3,4-Dimethylphenyl, 2,3-Difluorophenyl, 2,4-Difluorophenyl, 2,5-Difluoro Phenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-ditrifluoromethylphenyl, 3,4,5-trifluorophenol or? A prophylactic or therapeutic agent for hepatitis and / or liver injury, which is a 5-nitrophenyl group,

 (43) In any one selected from (1) to (34),

R ¹ is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenol, 4-chlorophenol, 3-methinophenol, 3-trifluoromethylphenol , 3-Trophenyl, 3,4-Dimethinolephenine, 2,3-Dibrolofenole, 2,4-Diphnoleolopheninole, 2,5-Diphneololophenine, 3,4-Difluorophenyl Hepatitis and / or 3,5-difluorophenyl, 3,5-ditrifluoromethylphenyl, 3,4,5-trifluoronorenophenylene or 2-chloro-5-nitropheninole group Prophylactic or therapeutic agent for liver damage,

 (44) In any one selected from (1) to (43),

R ² is Ariru group, a 1 to 5-substituted Ariru groups independently any group selected from Heteroariru group or substituent group a, hepatitis and / or liver failure prophylactic agent or therapeutic agent,

 (45) In any one of (1) through (43),

A preventive or therapeutic agent for hepatitis and Z or liver disorder, wherein R ² is an aryl group, a phenyl group or an aryl group independently substituted by 1 to 3 groups selected from a substituent group a,

 (46) In any one of (1) to (43),

R ² is an aryl group or an aryl group independently substituted with 1 to 3 aryl groups or an arbitrary group selected from substituent group a, a prophylactic or therapeutic agent for hepatitis and / or liver injury,

 (47) In any one of (1) to (43),

R ² represents an aryl group or a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, an amino group, a A prophylactic or therapeutic agent for hepatitis and hepatic disorder, which is an aryl group substituted with 1 to 3 arbitrary groups selected from the group consisting of

 (48) In any one of (1) to (43),

Hepatitis and Z, wherein R ² is an aryl group substituted with 1 to 3 aryl groups or an arbitrary group 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 prophylactic or therapeutic agent for liver damage,

 (49) In any one of (1) to (43),

R ² is an aryl group substituted with 1 to 3 aryl groups or any group selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a nitro group and a cyano group A prophylactic or therapeutic agent for hepatitis and Z or liver damage,

 (50) In any one selected from (1) to (43),

R ² is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of a phenyl group, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a nitro group and a cyano group A prophylactic or therapeutic agent for hepatitis and Z or liver damage,

 (51) In any one of (1) to (43),

R ² is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenol, 3-chlorophenol, 4-chlorophenol, 3-methinole Phenyl, 3-triphnoleolomethinolephenyl, 3-etropheninole, 2,3-difluo ore, 2,4-dibutanololopheninole, 2,5-difluorophenyl, 2,6- Difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-ditrifluoromethylphenyl, 3-cyanophenyl, 4-cyanophenyl or 2-chloro-5-nitrophenyl Prophylactic or therapeutic agent for hepatitis and Z or liver injury,

 (52) In any one selected from (1) to (43),

R ² is phenyl, 3-fluorophenylene, 4-fluorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 2,3-difluorophenyl, 2,4-diphenyl Heleitis and / or hepatic injury, which is a group of norelofer, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-ditrifluoromethylphenyl, .3-cyanophenyl or 4-cyanofur. Prophylactic or therapeutic agents,

 (53) In (1), the compound having the general formula (I) is

 8-[2-bis (3-fluorophenyl) methoxhetyl]-1-oxa- 3,8-diazaspiro [4.5] decane-2-one,

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

 8- [2-bis (3-trifluoromethylphenol) methoxhetyl] -1 -oxa-3,8-dazaspiro · [45] decane-2-one;

 8-{2-[(3-Coural phenyl) phenylmethoxy] ethyl}-1_oxa- 3,8-diazaspiro [5] decane-2-one,

 8-{2-[(3,4-Difluorophenyl) phenyl-methoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one,

 8- {2-[(3-Nitrofeuer) feelmethoxy] ethyl}-1-oxa- 3,8-diazaspiro [4.5] decane-2-one,

 8- {2-[(3-Methynolephen-phenyl) phenylmethoxy] ethyl}-1-oxa-3,8-diazaspiro [4.5] decane-2-one,

 . 8- {2-[(3,5-difluorophenyl) phenylmethoxy] dityloxa-3,8-diazaspiro [4.5] decane-2-one;

 8-[(2-Fluorophenyl) (4-fluorophenyl) methoxy] ethyl}-1-oxa-3,8-diazaspiro [4.5] decane-2-one,

 8-{2-[(2,5-difluorophenyl) pheninolemethoxy] ethyl}-1-oxa-3,8-diazaspiro [4.5] decane-2-one,

8- {2-[(2-Fluorophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [5] decane-2-one, 8- {2-[(2-kuguchi-5-ditrophenyl) feermethoxy] ethyl}-1-oxa-3,8-diazaspiro [4.5] decane-2-one,

 8- {2-[(3,4-Dimethylphenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one and

8- {2- [(3-triflate Ruo Russia methyl Hue - Le) Fuenirume butoxy] Echiru} - 1-Okisa - 3, ⁸ - Jiazasupiro ^[5] decane - 2-one

A prophylactic or therapeutic agent for hepatitis and / or hepatic disorder, which is one compound selected from the group consisting of:

 (54) In (1), the compound having the general formula (I) is

 8--[Bis- (3-trifluoromethylphenyl) methoxy] propyloxa-3, 8- diazaspiro [4.5] decane-2-one,

8 - {2- [(2-click every mouth Hue - Honoré) (4, - click every mouth phenylene Honoré) method butoxy] Echinore Okisa - 3, 8-Jiazasupiro ^[4, 5] decane - 2 - one,

 8--[Bis- (2,3-difluorophenyl) methoxy] ethyl}-1-oxa-3,8-diazaspiro [4,5] decane-2-one,

 8-{2- [Bis- (3,4-difluorophenyl) methoxy] ethyloxa-3,8-diazaspiro [4,5] decane-2-one;

 8- {2- [bis- (3,5-difluorophenyl) methoxy] ethyl} -1-oxa-3,8_diazaspiro [4,5] decane-2-one,

 8-{2- [Bis- (2,4-difluorophenyl) methoxy] ethyl]-1-oxa-3,8-diazaspiro [4,5] decane-2-one,

 8--[Bis- (3,5-ditrifluoromethylphenyl) methoxy] ethyl} -1 -oxa-3,8-diazaspiro [4,5] decane-2-one,

 8-{2-[(3,4,5-trifluorophenyl) phenylmethoxy] ethyloxa-3,8-diazaspiro [4,5] decane-2-one,

8-[(4-Cyanophenyl) (3 ', 4'-difluorophenyl) methoxy] ethyl} -1- Kisa-3,8-dazaspiro [4,5] decane-2-one,

 8- {2-[(3-Cyanophenyl) (3,4'-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-dazaspiro [4,5] decane-2-one,

 8- {2-[(3-Cyanophininole) (3, -trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one;

 8- {3- [bis- (3,4-difluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one,. '

 8- {3-[(3-cyanophenyl) (3 ', 4'-difluorophenyl) methoxy] propyl)-1-oxa-3,8-diazaspiro [4,5] decane-2-one,

 8- {3-[(4-Cyanophuel) (3 ', 4'-difluorophenyl) methoxy] -propyl}-1-year-old-3,8-diazaspiro. [4,5] decane-2-one as well as

8 - {3- [(3- Shianofueeru) (3, - triflumizole Ruo b methylphenylpolysiloxane We El) method butoxy] propyl Le} - 1-Okisa - ^3, 8-Jiazasupiro ^[5] decane - 2-one

A prophylactic or therapeutic agent for hepatitis and Z or hepatic disorder, which is any one compound selected from the group consisting of:

Can be mentioned. Also, in the above compound (I), (2) or (3); (4) to (8); (9) Noji (14), (15) to (21), (22) to (25), (26) to (30) or (31) to (33); (35) to (43); and (44) to (52). Also, a compound in which any one of them is arbitrarily combined is also suitable. Such compounds include, for example,

 (3), (7), (9), (40) and (49) Compounds combined in the group consisting of (3), (7), (10), (41) and (50) A) a compound combined in the group consisting of

(3), (7), (1 1), (1 3), (4 2) and (5 1) (3), (7), (1 2), (1 4), (4 3) and (52) compounds combined in the group

 A compound combined in the group consisting of (2), (4), (15), (35) and (44);

(2), (5), (16) (35) and (45) a compound combined in the group consisting of

A compound combined in the group consisting of (2), (5), (1 7) (3 6) and (46),

(2), (6), (18), (37) and (47) compounds combined in the group consisting of

A compound combined in the group consisting of (2), (6), (1 9) (3 8) and (4 7),

A compound combined in the group consisting of (2), (6), (19), (39) and (48);

A compound combined in the group consisting of (3), (6), (20), (40) and (49);

A compound combined in the group consisting of (3), (6), (20), (41) and (50);

A compound combined in the group consisting of (3), (6), (21), (42) and (51);

(3), (7), (21), (43) and (52) a compound combined in the group consisting of

(3), (8), (21), (43) and (52) a compound combined in the group consisting of

A compound combined in the group consisting of (3), (7), (22), (40) and (49);

A compound combined in the group consisting of (3), (7), (23), (41) and (50);

(3), (7), (24) a compound combined in the group consisting of (42) and (51),

(3), (7), (25) a compound combined in the group consisting of (43) and (52),

A compound combined in the group consisting of (3), (7), (26), (42) and (51);

Compounds combined in the group consisting of (3), (7), (2-7), (28), (29), (30), (43) and (52)

 (3), (7), (31) a compound combined in the group consisting of (41) and (50),

Compounds combined in the group consisting of (3), (7), (32), (42) and (51); and

Compounds combined in the group consisting of (3), (7), (33), (43) and (52) are preferred. In the above formula, R 2

\ R, R ³ , R ⁶ , R,, in the definition of substituent group b and substituent group c T JP01 / 09387

16

“Aryl group”, RRR ′, “aryl group independently substituted with 1 to 3 arbitrary groups selected from substituent group a” in the definition of substituent group b and substituent group c, and R ¹ and R ^In the definition of ² , "aryl group" of "aryl group independently substituted with 1 to 5 arbitrary groups selected from substituent group _a " is, for example, phenyl, indel or naphthyl It is an aromatic hydrocarbon group having 6 to 10 carbon atoms, and is preferably a phenol group. In the above formula, `` heteroaryl group '' in the definition of RR <sup>2</sup> and R <sup>3</sup> `` heteroaryl group '' and `` heteroaryl group independently substituted by 1 to 3 arbitrary groups selected from substituent group a '' are For example, furyl, chenyl, pyrrolyl, azepiel, pyrazolyl, imidazolyl, oxazolyl, isoxazoly ^, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranil, pyranyl, pyranyl, pyranyl Or an aromatic heterocyclic group containing one to three sulfur atoms, oxygen atoms and / or nitrogen atoms such as a pyrazur group, and the above heteroaryl group is condensed with another cyclic group such as a benzene ring. It may be a ring, for example, benzothienyl, benzothiazoli Λ \ benzoxazolyl Or an isobenzofuranyl group. In R ¹ and R ² , a 5- to 6-membered aromatic heterocyclic group is preferable, a 5-membered aromatic heterocyclic group is more preferable, and a phenyl group is more preferable. Most preferably, it is a 2-phenyl group, and in R ³ , preferably a 5- to 6-membered aromatic double-ring group, more preferably a pyridyl or pyrazur group, most preferably , 2-pyridyl group. In the above formula, “^ —C ₈ alkylene group” in the definition of Υ and ぴ is, for example, methylene, methynolemethylene, ethylene, propylene, trimethylene, 1-methynoleethylene, tetramethylene, 1-methyl ^ / trimethylene, 2-methylene Trimethylene, 3-methyltrimethylene, 1-methylpropylene, 1,1-dimethylethylene, pentamethyl Tylene, 1-methynoletetramethylene, 2-methyltetramethylene, 3-methynoletetramethylene, 4-methyltetramethylene, 1,1-dimethyltrimethylene, 2,2-dimethizoletrimethylene, 3,3-dimethinoletri Methylene, hexamethylene, 1-methinolepentamethylene, 2-methinolepentamethylene, 3-methinolepentamethylene, 4-methinolepentamethylene, 5-methizolepentamethylene, 1,1-dimethinoletetramethylene, 2,2-Dimethytetramethylene, 3,3-Dimethynoletetramethylene, 4,4-Dimethytetramethylene, Heptamethylene, 1-Methynolehexamethylene,

2-Methinolehexamethylene, 5-Methynolehexamethylene, 3-Ethynolepentamethylene, Ottamethylene, 2-Methynoleheptamethylene, 5-Methynoleheptamethylene, 2-Ethylhexamethylene, 2-Ethyl-3-methyl A linear or branched alkylene group having 1 to 8 carbon atoms such as a pentamethylene or 3-ethylpentamethylene group; and in Υ, preferably a C ₂ -C ₅ alkylene group And more preferably a C ₂ —C ₃ alkylene group, most preferably an ethylene or trimethylene group, and in E, preferably a C _: —G ₄ alkylene group, more preferably Is a —C ₂ alkylene group, most preferably a methylene group. In the above formula, "C ₂ -〇 ₈ Aruke two alkylene group" in the definition of Y, for example, Eteyure down, 2-propenylene, 1 Mechinore one 2-propenylene, 2-methyl-one 2- propenyl Yuren , 2-Echinolene 2-propenylene, 2-ptenylene, 1-methinole 2-ptenylene, 2-methynole-l-ptenylene, 1-ethynyl 2-butenylene, 3-butenylene, 1-methizole 3-buturene, 2—Mechinore 1—Pteeren, 1

3-pentenylene, 2-pentenylene, 1-methinolene 2-pentenylene, 2-methinole —2-pentenylene, 3-pentenylene, 1-methinolene 3-pentenylene, 2-pentenylene 3-pentenylene Nylene, 4-pentenylene, 1-methynolene 4-penteneulene, 2-methynolene 4-pentenelene, 2-hexenylene, 3-hexenelene, 4-hexenylene, 5-hexenylene or 9-hexadecelenene 2 to 8 carbon atoms such as groups A linear or branched alkenylene group, preferably a c ₂ -c ₅ alkenylene group, more preferably a C ₂ -C ₃ alkenylene group, most preferably And the Ethylen group. In the above formula, the “amine residue” in the definition of R ⁶ is, for example, an amino group; a “lower alkyl group” such as methylamino, ethylamino, isopropylamino, butylamino, dimethylamino, acetylamino, diisopropylamino or dibutylamino; Is an amino group substituted with 1 or 2 amino groups; an amino group substituted with 1 or 2 "cycloalkyl groups having 5 to 7 carbon atoms" such as cyclopentylamino, cyclohexylamino, dicyclopentylamino or dicyclohexylamino A saturated cyclic amine residue having a nitrogen atom in the ring such as pyrrolidino, piperidino, piperazino, N-methylbiperazino, morpholino or thiomorpholino; a-lino, benzylamino, N-methylylurino or N-methylbenzylamino Such a nitrogen atom is An arylamino or an aralkylamino group which may be substituted with a "alkyl group"; a nitrogen atom such as pyridylamino, N-methylpyridylamino or N-ethylpyridylamino may be substituted with a "lower alkyl group"; Preferable examples include an amine residue which is bonded by a nitrogen atom such as a good heteroarylamino group, and is preferably an amino group; an amino group substituted by one or two “lower alkyl groups”; pyrrolidino, piperidino, A saturated cyclic amine residue having a nitrogen atom in the ring, such as piperazino, N-methylbiperazino, morpholino or thiomorpholino, or aniline, benzylamino, N-methylanilino or N-methylbenzylamino; Such a nitrogen atom is an arylamino or aralkylamino group which may be substituted by a “lower alkyl group”, Preferably a § amino group. In the above formula, R ³ and R ⁴ are taken together to form a “5- to 8-membered saturated heterocyclic group” including the carbon atom to which they are bonded, and an optional group selected from “Substituent group c”. Based on Germany 5 to 8 membered saturated heterocyclic group substituted by 1 to 3 substituents '' and `` 5 to 8 membered saturated heterocyclic group J in the definition of R <sup>6</sup> and `` an arbitrary group selected from substituent group a The "5- to 8-membered saturated heterocyclic group" in the "1- to 3-substituted 5- to 8-membered saturated heterocyclic group" is a 5- to 8-membered saturated heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and nitrogen or nitrogen atoms. 8-membered saturated heterocyclic group, for example, tetrahydroviranyl, tetrahydrofuryl, imidazolidyl-, dioxepaael, morpholinyl-, thiomorpholinel, pyrrolidinyl, pyrrolyl, pyrazolidinyl, piridiel, pirazell, oxazolidizyl, nisoxazolidiel Or a pyrazolidinyl group, and may be further condensed with another cyclic group such as a benzene ring, for example, chromayur, isochromanyl, a Dori - a le or Isoindorieru group. In such a 5- to 8-membered saturated heterocyclic group, preferably, it is a 5- to 6-membered saturated heterocyclic group, more preferably, an oxazolidinyl or thiazolidyl group, and most preferably, an oxazolidinyl group. Group. In the above formula, R ³ and R ⁴ are linked to form a “3- to 10-membered saturated carbocyclic group” and R ³ and R ^{4 which} are formed including the carbon atom to which they are bonded. Together, they form together with the carbon atoms to which they are attached, and form 3 to 1 independently substituted with 1 to 3 arbitrary groups selected from substituent group a and substituent group c. The “3- to 10-membered saturated carbocyclic group” of the “0-membered saturated carbocyclic group” is, for example, cyclopropyl, cyclopentinole, cyclopentyl, cyclohexyl or cycloheptyl group, and further a benzene ring or a saturated carbon ring. It may be fused with another cyclic group such as a group, for example, a norbornyl, adamantyl or indanyl group. In such a 3- to 10-membered saturated carbocyclic group, preferably a 5- to 6-membered saturated carbocyclic group which may be condensed with a benzene ring, more preferably a condensed ring with a benzene ring A 5-membered saturated carbocyclic group, and most preferably an indanyl group. In the above formula, the “halogen atom” in the definition of the substituent group “a” is a fluorine atom, a chlorine atom , A bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and most preferably a fluorine atom. In the above formula, R ⁶ , a “lower alkyl group” in the definition of the substituent group a and the substituent group b, and “an arbitrary group selected from the substituent group a in the definition of the substituent group b, each independently having 1 to 3 The “lower alkyl group” of the “substituted lower alkyl group” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, s-butyl, t_butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, Ethyl propyl, hexinole, isohexyl, 4-methylenopentene, 3-methylopentyl / yl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylinobutylinole, 2,2-dimethylpentinole, 1, Such as 1'-dimethinoleptinole, 1,2-dimethinolebutyl, 1,3-dimethinolebutyl, 2,3-dimethylbutyl or 2-ethylbutyl group A linear or branched alkyl group having 1 to 6 carbon atoms, preferably is an C ₄ alkyl group, and more preferably is an C ₂ alkyl group, most preferably a methyl group It is. 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 has been substituted for the “lower alkyl group”, for example, trifluoromethyl, trichloromethinole, and diphnolethiomethine. , Dichloromethinole, dibromomethinole, fenolemethyl, 2,2,2-trif / leoloethinole, 2,2,2-trichloroethinole, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-odoethinole, 3-chloroethylpropyl, 4 is a halogeno-C ₆ alkyl group such as monofluorobutyl, 6-odohexyl or 2,2-dibromoethyl group, preferably a halogeno-C ₄ alkyl group, more preferably halogeno C! - a C ₂ alkyl group, and more preferably, Furuoro ^ _ 0 ₂ alkyl or black port d-C ₂ alkyl group There, preferably most, a triflate Ruo b methyl group. In the above formula, `` lower alkoxy group '' in the definition of R <sup>6</sup> and the substituent group a represents a group in which the above-mentioned `` lower alkyl group '' is bonded to an oxygen atom, for example, methoxy, ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethyl A straight-chain having 1 to 6 carbon atoms such as butoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy. A chain or branched chain alkoxy group, preferably —C ₄ alkoxy group, more preferably C ″ C ₂ alkoxy group, In the above formula, “lower alkylthio group” in the definition of the substituent group “a” indicates a group in which the above “lower alkyl group” is bonded to a sulfur atom, for example, methylthio, ethylthio , Pupinoletio, isopropylthio, ptinorethio, isobutinorethio, s-butinorethio, t-butylthio, pentylthio, isopentylthio, 2-methinolebutylthio, neopentylthio, hexinorethio, 4-methylpentylthio, 3-methylinolepentinole Thio, 2-methylinopentylthio, 3,3-dimethylinobutylthio, 2,2-dimethylinobutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio or A straight or branched chain of 1 to 6 carbon atoms such as a 2,3-dimethylbutylthio group A Kiruchio group, preferably a chromatography alkylthio group, more preferably a C one C ₂ alkylthio group, and most preferably a methylthio group. In the above formula, the `` lower alkoxycarboyl group '' in the definition of the substituent group a represents a group in which the above `` lower alkoxy group '' is bonded to a carboyl group, for example, methoxycarbonyl, ethoxycarbonyl, propoxycanolebonyl, Isopropoxy olevonil , P-toxcanoleponinole, isotopoxyka ^^ boninole, S-toptoxika ^^ bonyu Λt-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbol, 2-methylbutoxycarbol, neopentoxycarbonyl , Hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbol, 2-methylpentoxycarbol, 3,3-dimethylbutoxycarbol, 2,2-dimethylbutoxycarbonole (Ci-Ce alkoxy) carbol such as 1,1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycanoleboninole, 1,3-dimethylbutoxycanoleponyl or 2,3-dimethylbutoxycarbonyl group a group, preferably a (one C ₄ alkoxy) carbonyl group, more preferably, (- C ₂ Al co Xy) a carbonyl group, most preferably a methoxycarboyl group.

In the above formula, the `` lower aliphatic acyl group '' in the definition of the substituent group a and the substituent group b represents a group in which a hydrogen atom or a saturated or unsaturated chain hydrocarbon group is bonded to a carboxy group, For example, formyl, acetyl, propiol, petyryl, isoptyryl, palle! ; Norre, Isopareriru, pivaloyl, to Kisanoiru, Akuriroiru, C "C <sub>6</sub> aliphatic Ashiru groups such as methacrylonitrile I le or black Tonoiru group, preferably a -C <sub>4</sub> aliphatic Ashiru group, further preferably Is a C <sub>2</sub> -C <sub>3</sub> aliphatic acetyl group, more preferably an acetyl group or a propionyl group, most preferably an acetyl group, wherein R <sup>5</sup> and the substituent group a The term "lower aliphatic acylamino" in the definition of "" means a group in which the above "lower aliphatic acyl" is bonded to an amino group, for example, formylamino, acetylamino, propionylamino, petylinoleamino, isoptyrylamino, noklerylamino, Isovalerylamino, pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino or black A good UNA one C <sub>6</sub> aliphatic Ashiruamino group Noiruamino group, preferably one C <sub>4</sub> aliphatic Ashiruami And more preferably a C <sub>2</sub> -C <sub>3</sub> aliphatic acylamino group, more preferably an acetylamino or propioelamino group, and most preferably an acetylamino group. In the above formula, R <sup>3</sup> , R ′, the `` aralkyl group '' in the definition of the substituent group b and the substituent group c and `` 1 to 3 independently substituted with any group selected from the substituent group a '' The “aralkyl group” of the “aralkyl group” represents a group in which the above “aryl group” is bonded to the above “lower alkyl group”, for example, benzyl, 1-naphthylmethyl, / 3-naphthylmethyl, indenylmethyl, diphenyl 2-methyl, triphenylmethyl, 1-phenethyl, 2-phenethyl / le, 1-naphthyl / lethynole, 2-naphthinolethynole, 1-phenylpropynole, 2-phenylpropizole, 3-phenylpropyl, 1-naphthinole Propyl, 2-naphthinolepropynole, 3-naphthynolepropynole, 1-phenylenolebutinole, 2-phenyl / lebutyl, 3-phenylbutyl, 4-phenylbutyl, 1-phenylbutyl Naphtinoleptyl, 2-Naphtinoleptinole, 3-Naphtinoleptinole, 4-Naphthylleptinole, 1-Fenylpentinole, 2-Fenolepentinole, 3-Fenenolepentinole, 4-Feninolepentyl, 5-Fenolepentyl, 5-Fenolepentine , 1-naphthinolepentinole, 2-naphthizolepentinole, 3-naphthylpentyl, 4-naphthinolepentinole, 5-naphthinolepentinole, 1-naphthinolepentinole, 1-fue-norehexyl, 2 , 3-fenixole, 4-hexinole, 5-hexinole, 6-hexinole, 1-naphthylhexinole, 2-naphthinolehexyl, 3-naphthyl A C <sub>7</sub> -C <sub>16</sub> aralkyl group such as hexyl, 4-naphthylhexyl, 5-naphthylhexyl or 6-naphthylhexyl group; It is a C <sub>7</sub> -C <sub>12</sub> aralkyl group, most preferably a benzyl group. In the above formula, the “lower alkylsulfonyl group” in the definition of the substituent group b indicates a group in which the “lower alkyl group” is bonded to a sulfonyl group, for example, methylsulfur, ethylsulfonyl, propylsulfonyl, isopropyl Sulfonyl, butylsil Honyl, Isobutyls / Lephonyl, s-butylsulfonyl, t-butylsulfonel, pentinolesnorefoninole, isopentinolesnorethoninole, 2-methinoleptinolesnorethoninole, neopenty / les / leho- Nole, 1-ethynolepropinoresnorethonyl, hexinoles / levoninor, isohexenolesnorefole, 4-methinolepentinolesnorefonole, 3-methylpentylsulfonyl, 2-methylpentylsulfonyl, 2-methinolepentylsulfoel, 1-methinolepentylsulfonyl, 3, 3-dimethinolebutylsnolephonyl, 2,2-dimethinoleptino / resnorelephonyl, 1,1 dimethinolebutynolesnorlleol, 1,2-dimethinolebutyls / lephoninole, 1,2 Such as 3-dimethinoleptylsulfol, 2,3-dimethylbutylsulfol or 2-ethylbutylsulfol Is an C <sub>6</sub> alkylsulfonyl group, preferably a CI- C <sub>4</sub> Aruki Rusuruhoniru group, more preferably, C〗 is an C <sub>2</sub> alkylsulfonyl group, preferably most are Mechirusuruho - Le group It is. In the above formula, the “aromatic acylamino group” in the definition of R <sup>s</sup> represents a group in which the above “aryl group” is bonded to a carbo-amino group, for example, benzoylamino, 1-indancanolepo-noreamino, 2-indancarboamino or 1 one or 2-na Futoiruamino C <sub>7</sub> such as groups - a C <sub>u</sub> aromatic Ashiruamino group, preferably a Venn Zoiruamino group. In the above formula, specific examples of the “aryl group independently substituted with 1 to 5 arbitrary groups selected from the substituent group a” in the definition of R <sup>1</sup> and R <sup>2</sup> include, for example, 2—, 3- or 4-funoleolopheninole, 2-, 3- or 4-chlorophenol, 2-, 3- or 4-promophenyl, 2-, 3- or 4-phenol, 2 —, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-methoxycarberphenyl, 2-, 3- or 4-ethoxycarberfe 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-formylphenyl, 2-, 3- or 4-acetylphenyl, 2-, 3- or 4-propionylphenyl, 2-, 3- or 4- honoleminoleminaminophenyl, 2-, 3- or 4-acetylaminophenyl, 2-, 3- or 4-propionylaminophenyl L, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-cyanophenyl, 3,4-difluorophenynole, 3,4-dichlorophenol, 3,4-dibromophenyl, 3 , 4-Dimethylphenole, 2,3-Dimethoxyphenole, 3,4-Dimethoxyphenole, 3,5-Dimethoxyphenyl, 3,4,5-Trimethoxyphenyl, 3-Fluoro—4-Metone Toxifenino 、, .4-Methylenol 2-Methoxyphenole, 6-Fusleolo 4-Methyl-12-Methoxyphenyl, 2-, 3- or 412-Trophenyl, 2,3-Difluorophenol, 2,4-Difluorophenyl Nore, 2,5-difluoropheninole, 2,6-diphneololofeninole, 3,5-diphneololofeninole, 3,5-ditrifluoromethinolefeninole, 2-funoleo mouth—5-nitrophene Nore, 2-chloro-5-nitropheninole, 3,4,5—Trifleo-fene, 3,4,5 _ Triclofene, 3,4,5-Trimethinole, 2,3, 4,5,6-Pentamethylphenol-Nore, 2,3,4,5,6-Pentaethylphenyl, 5-Funolein-Indone 3-inole, 5-Fluoroindene 3-inole, 5-Methinolein-de-3 —Inore, 5—Metoki Indene-3 f, 5-Fluoroindene 2-inole, 5-cloin-in.den-2-yl, 5-methylindene_2-yl, 5-methoxyindene-2-yl, 5 — Fluoronaphthalene-1-yl, 5-Fluoronaphthalene-2-yl, 5-Methinole naphthalene-1-Inole, 5-Methoxynaphthalene-1-inole, 5-Fluoronaphthalene-1-1 , 5-Funoleronaphthalene 1-inole, 5-Methynolenaphthalene 1-yl, 5-Methoxynaphthalene 1-inole, 5-hydroxyindene 3-inole, 5-hydroxynaphthalene A 2-inole or 5-hydroxynaphthalene-11-inole group, and in R <sup>1</sup> , preferably independently an arbitrary group selected from substituent group a 1 to 3 substituted aryl groups, more preferably a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, an amino group, a nitro group and a cyano group An arylene group substituted with 1 to 3 arbitrary groups selected from the group consisting of, more preferably, an arbitrary group selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, and an ethoxy group. And more preferably 1 to 3 substituted with a group selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group and a -toro group. And more preferably 2-fluorophenyl, 3-fluorophenyl, 4-phenylphenol, 4-chlorophenol, 3-chlorophenol, 4-chlorophenyl, and 4-fluorophenyl. 2,3-Dimethinolephenyl, 2,3-Difluorophenyl, 2,4-Difluorophenyl, 2,5-Difluorophenyl, 2,5-Difluorophenyl, 2,5-Difluorophenyl, 2,3-Difluorophenyl, 2,3-Difluorophenyl -Difluorophenyl, 2,6-difluorophenyl, 3,4-difluorenol, 3,5-diphnoleolofenenole, 3,5-ditrifluoromethinolefeninole, 3,4, 5 is a triphenylphenol or 2-cyclopentyl 5-nitrophenyl group, most preferably 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenylphenol, 3-chlorophenylphenol, 3-chlorophenylphenol, 4-Mouth feninole, 3-Methinolefeninole, 3-Trifluorometinolefeninole, 3-Nitrophenol, 3,4-Dimethinolefeninole, 2,3-Diphnolenofeninole, 2 , 4—Ziff Fluorophenyl, 2,5-diphneololophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-ditrinoleo-methyl phenyl, 3,4,5-trihnoleo-phenyl, or 2-chloro-5 —Nitrophenyl group, and in R <sup>2</sup> , preferably an arylene group independently substituted with 1 to 3 arbitrary groups selected from substituent group a, more preferably a halogen atom, Aryl substituted with 1 to 3 arbitrary groups selected from the group consisting of a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, an amino group, a nitro group and a cyano group And more preferably a group 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. Is an aryl group substituted by 1 to 3 groups of interest, still more preferably selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a nitro group and a cyano group An aryl group substituted with 1 to 3 arbitrary groups, and more preferably, 2-fluorophenyl, 3-funoleolopheninole, 4-fluorophenyl, 2-chlorophenylenole, 3-chlorophenyl, 4-Mouth feninole, 3-methylphene, 3-trifnorenolomethinolefenore, 3-trofenenole, 2,3-diphnoolerofeninole, 2,4-diphnoleolofenenole, 2, 5-Difluorophenel, 2,6-Diphnoleolopheninole, 3,4-diph / leo mouth feninole, 3,5-Diphnoleolopheninole, 3,5-Ditrifonoleolomethinolephenyl, 3, —Sianofenino , 4-cyanophenyl or 2-chloro-5-nitrophenyl group, most preferably 3-fluorophenyl, 4-fluorophenyl, 4-cyclophenyl, 3-trifluoro Oromethylpheninole, 2,3-difluorofeninole, 2,4-difluoropheninole, 3,4-diphneoleolopheninole, 3,5-difluorophenyl, 3,5-ditrifluoromethyl It is a phenyl, a 3-cyanophenol or a 4-cyanophenol group. In the above formula, specific examples of “aryl group independently substituted by 1 to 3 arbitrary groups selected from substituent group a” in the definition of R <sup>3</sup> , RR ′, substituent group b and substituent group c For example, in the above-mentioned “aryl group independently substituted with 1 to 5 arbitrary groups selected from substituent group a”, any group selected from substituent group a is 1 to Represents three groups, for example, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-monophenyl, 2-, 3- or 4-promophenyl, 2-, 3- or 4-phenylphenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4 —Methoxyphenyl, 2—, 3— or 4—Ethoxyphenyl, 2—, 3—Young 4 main Toki Shikano levo sulfonyl phenylalanine, 2-, 3- or 4-ethoxycarbonyl butylphenyl, 2-, 3- or 4 one Karubokishifu Eniru, 2-, 3- or 4-arsenide Dorokishifueniru, 2-, 3- or 4-E Rumirufue - le, 2-, 3- or 4-§ cetyl phenylalanine, 2-, 3- or <sub>4</sub> - Puropioyuru Phenyl, 2-, 3- or 4-formylaminophenyl, 21, 3- or 4-acetylaminophenyl, 2-, 3_ or 4-propionylaminophenyl, 2-, 3- or 4-aminophenol,, 2-, 3- or 4-one cyanophenole, 3,4 diphnoleolopheninole, 3,4-dichloromouth feninole, 3,4 dipromophenol, 3,4 dimethy Noreffenore, 2,3-Dimethoxyphenole, 3,4-Dimethoxyphenole, 3,5-Dimethoxyphenole, 3,4,5-Trimethoxyphenole, 3-Fluoro-1-methoxyphenole, 4 —Methyl 1 2 Xifufenore, 6-funoroleau 4-methinoure, 2-methoxyphene, 2-, '3- or 41-etrophele, 2,3-difluorophuel, 2,4-diphnoleole 5-Difnoleolopheninole, 2,6-difluorophenyl, 3,5-difluorophenyl, 3,5-ditrifluoromethylphenyl, 2-fluoro-5-trofenolene, 2-chloro-5-di 3,4,5—Trifolene, 3,4,5—Triclofenol, 3,4,5—Trimethinolephenyl, 5—Fluoroindene 3-yl, 5-Fluoroindene 3-inole, 5-Methylindene 3-inole, 5-Methoxyindene 3-inole, 5-Henolein-indene 2-inole, 5-Chloroindene 1-2-inole, 5-Methylinolidene 2- Inore, 5-me Toxinindene 2-inole, 5-Funoleronaphthalene-1--2- ィ, 5-Funaleo-naphthalene-1 2-inole, 5-methyl./Lenaphthalene-12-yl, 5-methoxynaphthalene-1 2 —Yl, 5—fluoronaphthalene-1—yl, 5—funolelonalphthalene—1—1 1 1 1 1 ^ {Nore, 5—Methynolenaphthalene— 1—inole, 5—Methoxynaphthalene—1—inole, 5— hydroxycarboxylic <sub>inden-3</sub> one I le, 5-hydroxycarboxylic naphthalene one 2-I le or a 5-hydroxycarboxylic naphthalene one 1 Iru group, preferably a halogen atom, a lower Arukinore group, a halogeno-lower alkyl group And an aryl group substituted with 1 to 3 groups of an arbitrary group selected from a lower alkoxy group and, more preferably, 1 group substituted with a halogen atom. An aryl group, more preferably a phenyl group substituted by one fluorine atom or chlorine atom, and most preferably a 4-fluorophenyl or 41-chlorophenyl group. In the above formula, R <sup>3</sup> and R <sup>4</sup> are linked together to form a group including the carbon atom to which they are bonded. The `` substituted 5- to 8-membered saturated heterocyclic group '' is preferably a 5- or 6-membered saturated heterocyclic group substituted by 1 to 3 groups selected from a substituent group c, more preferably Is a 5- or 6-membered saturated heterocyclic group which is substituted with one oxo group and may be independently substituted with one or two arbitrary groups selected from the substituent group c. Preferably, the following formula (L-1) is used.

[Wherein, G and J are the same or different and each represent an oxygen atom, a sulfur atom, or a group having the formula NR′— (wherein, R is a hydrogen atom, an aryl group, an aralkyl group, a substituent group a A group selected from an aryl group independently substituted with 1 to 3 substituents with an arbitrary group selected and an aralkyl group independently substituted with 1 to 3 arbitrary groups selected from a substituent group a ). Even more preferably, in the above formula (L-11), G is an oxygen atom or a sulfur atom, and J is a group having -NH-, most preferably In the above formula (L-11), G is an oxygen atom, and J is a group having -NH-. In the above formula, R ³ and R ⁴ are linked together to form a group including the carbon atom to which they are bonded. As the `` 3-substituted 3- to 10-membered saturated carbocyclic group '', preferably 1 to 3 independently substituted by any group selected from Substituent Group a and Substituent Group c 5- or 6-membered saturated carbocyclic group More preferably, it is a 5- to 6-membered saturated carbocyclic group condensed with a benzene ring (the 5- or 6-membered saturated carbocyclic group has an oxo group or a hydroxyl group as a substituent), and is most preferably. , 2-hydroxyindan or 2-oxoindane group.

“Pharmacologically acceptable salt” means that the compound (I) of the present invention is reacted with an acid when it has a basic group such as an amino group, or when it has an acidic group such as a carboxy group. When the compound has a group, it can be converted into a salt by reacting with a base.

The salt based on a basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid Inorganic acid salts such as salts and phosphates; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, benzenesulfonates and p-toluenesulfonates; Organic acid salts such as reelsulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; and glycine Salts, lysine salts, algiene salts, orditin salts, glutamates, and amino salts such as aspartate can be mentioned. More preferred are inorganic or organic acid salts, most preferably Is Hydrohalide or an organic acid salt. On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, an aluminum salt, or an iron salt. Inorganic salts such as ammonium salts, octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, fugurglycine alkyl ester salts, ethylenediamine salts, N-methylgonolemate salts, guanidine salts, getylamine salts , Triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, Amine salts such as organic salts such as insalts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethinoleammonium salts, tris (hydroxymethylenole) aminoamino salts; and glycine salts; Amino acid salts such as lysine salt, arginine salt, ornithine salt, glutamate, and aspartate can be mentioned, and are preferably alkali metal salts. The compound (I) of the present invention has various isomers due to the presence of an asymmetric carbon atom in the molecule. In the compound of the present invention, all of these isomers and a mixture of these isomers are represented by a single formula, that is, a general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in any ratio. The compound (1) of the present invention, its pharmacologically acceptable salt, its ester or other derivative absorbs moisture by leaving it in the air or recrystallizing, thereby absorbing water. In some cases, the hydrate may form or become a hydrate, and such a hydrate is also included in the salt of the present invention. In the above, the “ester” refers to the ester of the compound (I) of the present invention because it can be converted to an ester. Examples of such an ester include “ester of hydroxyl group” and “ester of carboxy group”. And an ester wherein each ester residue is a “general protecting group” or “a protecting group that can be cleaved in vivo by a biological method such as hydrolysis”.

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

As the “general protecting group” for the “ester of a hydroxyl group”, preferably, forminole, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl , Valerinole, Isovaleryl, Octanoyl, Nonanoyl, Decanoyl, 3-Methylnonanoinole, 8-Methinolennonanole, 3-Echilotanotanyl, 3,7-Dimethyloctanoyl, Pendecanoyl, Dodecanoyl, Ledecano, Dodecanoyl Xadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanol, 15-methylhexadecanoyl, octadecanol, 1-methylheptadecanol Alkanoyl groups such as, nonadecanoyl, eicosanoyl, henikosanoyl, halogenated alkylcarboyl groups such as chloroacetylinole, dichloroacetyl Λ \ trichloroacetylinole, triflenoloroacetyl, methoxy Lower alkyloxycarbonyl groups such as alkenyl-quinolecarpinole groups such as cycetyl, acryloylole, propiolenole, methacryloylole, crotonyl, isocrotonyl, and (Ε) 12-methyl-12-ptenoyl; Aliphatic acyl group "(preferably a lower aliphatic acyl group having 1 to 6 carbon atoms); arylrecanolepo-nore group such as benzoyl, hynaphthoyl, β-naphthoinole, 2 —Bromobenzoyl, 4-halogenated arylcarbonyl groups such as benzobenzene, 2,4,6-trimethylbenzoyl, lower alkylated arylcarbonyl groups such as 4-toluoyl, 4— Lower alkoxylated arylcarbonyl groups such as anisyl, nitration such as 4-1-trobenzoyl and 2-nitrobenzoyl "Aromatic" such as arylcarbonyl group, lower alkoxycarbonylated arylcarbonyl group such as 2- (methoxycarboxy) benzoyl, arylalkylcarbonyl group such as 4-phenylbenzoyl Lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycanolebon, ptoxycanolepon, s-butoxycarbonyl, t-butoxycarbonyl, isotoxycarbonyl, and 2,2,2 "Alkoxycarbyl groups" such as lower alkoxycarboyl groups substituted by halogen or tri-lower alkylsilyl groups such as 2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbol; tetrahydropyran Yl, 3-promotetrahydrovilla Tetrahedro-villanole or Tetrahidrovillanole, such as 4--2-yl, 4-methoxytetrahydro-dropyran, 2-yl, 4-methoxytetrahydro-drochopyran, 4-yl A "tetrahydrofuran or tetrahydrothiofuranyl group" such as tetrahydrofuran-12-yl or tetrahydrothiofuran-12-yl; trimethylsilyl, triethylsilyl, isopropylidyl t-butylsilyl, triisopropylsilyl Tri-lower alkylsilyl groups such as tri-lower alkynylsilyl groups, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl groups substituted with one or two aryl groups "Silyl group", etc .; Lower alkoxymethyl groups such as methyl, 1,11-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl "Alkoxymethyl group" such as halogeno lower alkoxymethyl such as group, 2,2,2-trichloroethoxymethinole, bis (2-chloroethoxy) methinole; such as 1-ethoxyhexyl, 11- (isopropoxy) ethyl "Substituted ethyl groups" such as unsubstituted lower alkoxylated tyl groups and halogenated acetyl groups such as 2,2,2-trichloroethyl; benzinole, hiichinaphthinolemethinole,] 3-naphthinolemethinole, diphene Ninoremechinore, truffle Eerumechinore, _a one Nafuchinorejifu Eneolemethinole, lower alkyl group substituted with 1 to 3 aryl groups such as 9-anthrylmethyl, 4-monomethylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4 -Lower alkyl, lower alkoxy, such as methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-ethoxybenzyl, 4-nitrobenzinole, 4-cyclobenzinole, 4-promobenzinole, 4-cyanobenzinole An "aralkyl group" such as a lower alkyl group substituted by one to three aryl groups wherein the aryl ring is replaced by a toro, halogen or cyano group; a carbonyl group, an arylalkyl group or the like; Like "Arkeniroki" Shikanorepo-nore group ”; Penzinoleoxycanolepo-nore, 4-Methoxypentinoleoxycanolebonyl, 3,4-Dimethybenzylbenzyloxycarbonyl, 2-Nitrobenzoyloxycarbonyl, 4-Dutrobe And an `` aralkyloxycarbonyl group '' in which the aryl ring may be substituted with one or two lower anoreoxy or nitro groups such as benzyloxycarbonyl. It is an aliphatic or aromatic acyl group, most preferably a lower aliphatic acyl group.

As the “general protecting group” for the “ester of a carboxy group”, preferably, the above “lower alkyl group”; ethenyl, 1-propenyl, 2-propyl, 1-methyl-2 —Propenisle, 1-Mechinore 1—Prozenore, 2-Mechinore 1-Prono-Nore, 2-Metino / Reno 2-Propino-Nore, 2-Echinore 1 2-Prono-Nore, 1-Buteninore, 2 -Butul, 1-methyl-2-butul, 1-methyl-1 pturn, 3-methyl-2 one-pteninole, 1-ethynorre-one-buten-norre, 3-butynore, 1-methinol-one 3-pteninore, 2-methinolate 3-buthenolé , 1—Echinore 1—Pente Norre, 1—Pente Norre, 21—Pentenore, 1—Methinore 2—Pentenore, 2-Mechinore 1 2-Penteninore, 3—Pentenore, 1—Metinore 3 —Pentenora, 2 Mechinore _ 3—penthenore, 4—penthenore, 1—methinole 4—penthenore, 2—methinole 4—pentent-norle 1 hexenore, 2-hexeninole, 3-hexeninole, 4-hexeninole, 4-hexeninole "Lower alkenyl groups", such as, 5-hexeninole; ethur, 2-probule, 1-methyl-2-propenole, 2-methinole 2-propyninole, 2-ethynole 1-2-propynyl, 2-petinyl Nore, 1-methyl-1-butynyl, 2-methyl-2-butul, 1-ethyl-12-butyl, 3-butynyl, 1-methyl-3-butyl, 2-methyl-3-butynyl, 1-ethyl 3-Petinole, 2-pentylene, 1-methinole 2-pentine-leave, 2-pentinole, 3-pentulle, 1-methyl-3-pentulle, 2-methylen-pentyl 3-pentenele Nore, 4 pen - Honoré, 1 Mechinore 4 one pliers two Honoré, 2- Mechinore one 4-pentyl two Honoré, Kishunore to 2, Kishunore to 3, to 4 one Kishuru, the 5-key A “lower alkynyl group” such as a shell; the above “halogeno lower alkyl group”; 2-hydroxyshetinole, 2,3-dihydroxypropynole, 3-hydroxypropynole, 3,4-dihydroxybutyl, 4 —Hydroxy “lower alkyl group” such as hydroxybutyl; “lower aliphatic acyl” such as acetylmethyl— “lower alkyl group”; the above-mentioned aralkyl group; and the above-mentioned “silyl group”. A lower alkyl group or a halogeno lower alkyl group, most preferably a lower alkyl group.

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

As the “protecting group capable of being cleaved in vivo by a biological method such as hydrolysis” as the “ester of a hydroxyl group”, preferably, formyloxymethyl, acetoxmethyl, dimethylaminoacetoxymethyl , Propionyloxymethyl, ptyryloxy methine, pivaloyloxymethine / le, valeryloxymethyl, isopaleryloxymethyl, hexanoinoleoxymethinole, 1-honolemilyloxymethinele, 1-acetoxyethinole , 1-propioninoleoxycetinole, 1-butylinoleoxyeti 1-pivalo inoleoxyethyl, 1-valeryloxetil, 1-isopareryloxetil, 1-hexanoy Loxoshetyl, 1-formyloxypropyl, 1-acetoxip Mouth pill, 1-propionyloxypropyl, 1-butyryl Xypropyl, 1-pivalyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropinole, 1-hexanoinoleoxypropynole, 1-acetoxybutyl, 1-propioninoleoxybutyl , 1-Ptyryloxybutyl, 1-Bivaloyloxyptyl, 1-Acetoxypentinole, 1-Propylenoleoxypentinole, 1-Butyrinoleoxypentyl, 1-Pipalyloxypentyl, 1-Piva Like yloxyhexyl 1 (“Lower aliphatic acryl” oxy) “Lower alkyl group”, cyclopentyl carboxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentyl propyloxyl, 1-cyclohexylcarbonyl 1-("cycloalkyl" carbonyloxy) such as 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropinole, 1-cyclopentylcarboxy-loxybutyl, 1-cyclohexylcarbonylcarboxyloxybutyl ) "Lower alkyl group", 11-("aromatic acyl" oxy) such as benzoyloxymethyl 11- (Acyloxy) "lower alkyl group" such as "lower alkyl group"; methoxycarboxy-methoxymetholene , Ethoxycanoleboninoleoxymethinole, propo Xyloxycarbonyloxymethyl, isopropoxycarbonyloxytyl, butoxycarbonyloxymethyl, isobutoxy / leponinoleoxymethinole, pentinoleoxycanoleponinoleoxymethinole, hexyloxycarbonyloxymethyl , Hexoxy carboxy-methoxymethyl, cyclohexyl / reoxycarboninoleoxy (cyclohexynole) methyl /, 11-(methoxycarbonyloxy) ethyl, 11-(ethoxycarbonyloxy) ethyl 1- (propoxycarboxy) ethyl, 1- (isopropoxycarboxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 11- (isoptoxycarbonyloxy) ethyl, 11- (t-butoxycarbonyl) ethyl Kissi) Echil, 1-1 (Pentinoreoka) (Noroxy) ethinole, 1- (hexinoleoxycarboninoleoxy) ethyl, 1- (cyclopentyloxycarbonyl / reoxy) ethyl, 1- (cyclopentyloxycarbonyloxy) propyl, 1- (cyclohexyl) Xyloxy oxycarbonyl, propyl, 1- (cyclopentyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (eth ' Xycarberoxy) propyl, 1- (methoxycarburoxy) propyl, 1- (ethoxycarberoxy) propyl, 1- (propoxycarbonyloxy) propyl, 1- (isopropoxy-canoleponylo) Xy) propinole, 1- (butoxycanolebonyloxy) propyl, 1— (Isobutoxycarbonyl / reoxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) propyl, 1 _ (methoxycarbonylcarbonyl) butyl, 1— (Ethoxycarboxy) Petil, 11

(Propoxycarboxy) butyl, 1- (isopropoxycarboxy) butyl, 1- (butoxycarboxy) butyl, 1- (isoptoxycarboxy) butyl, 1- (methoxycarbonyloxy) pentyl (Lower alkoxycarbonyloxy) alkyl groups such as, 11- (ethoxycanoleponyloxy) pentinole, 11- (methoxycanolepo-noreoxy) hexyl, and 11- (ethoxycarponyloxy) hexyl; 2- (oxo-1,1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxolen-1-yl] methyl, [5- ( 4-methoxy-1) 2-oxo-1,3, -dioxolen-41-yl] methyl, [5- (4-fluorophenyl) 1-2-oxo-one

1,3-Dioxolen-1-4-inole] Methyl, [5- (4-chlorophenone) 1-2-oxo-1,3-dioxolen-4-yl] methinole, (2-oxo_1,3-dioxolene) (4-yl) methyl, (5-methyl-2-oxo-1,1,3-dioxolen-14-yl) methyl, (5-ethyl-12-oxo-1,1,3-dioxolen-14-methyl) methyl , (5-Propyl-2-oxo-1, 3-dioxolen-41-yl) methyl, (5-Isopropyl-2-oxo-1, 3-dioxolene-41-yl) methyl, (5- "Carbooxy lower alkyl group" such as oxodioxorenylmethyl group such as methyl; 2- (oxo-1,1,3-dioxolen-14yl): such as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl "Phthalidi / le group"

: The above-mentioned "lower aliphatic acyl group": The above-mentioned "aromatic acyl group": "The half ester salt residue of succinic acid": "The esterol phosphate residue": "The ester-forming residue of amino acid etc." Groups: carbamoyl groups substituted with one or two lower alkyl groups: and "1- (asyloxy) alkyloxycarboyl groups" such as vivaloyloxymethyloxycarbol, and the like. Preferably, carbonyloxy lower alkyl Group. On the other hand, as the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of a carboxy group”, preferably, methoxyethyl, 1-ethoxyxenole, and 1-methyl-1- 1- (isopropoxy) ethynole, 2-methoxyxenole, 2-ethoxyxenole, 1,1 dimethynole 1-methoxine ole, ethoxymethylinole, n-propoxymethylenole, isopropoxymethyl, n-butoxymethyl, t-butoxymethyl A lower alkoxy lower alkyl group such as 2-methoxymethoxyloxy, a lower alkoxy lower alkyl group such as 2-methoxyxetoxymethyl, an "aryl" oxy "lower alkyl group" such as phenoxymethyl, 2,2,2- Trichloroethoxymethyl, bis (2-chloroethoxy) methyl Such as “alkoxyalkyl group” such as lower alkoxy lower alkyl group; “lower alkoxy” carbonyl “lower alkyl group” such as methoxycarbonmethyl; “cyano lower alkyl” such as cyanomethyl and 2-cyanoethyl "" Lower alkyl "thiomethyl groups, such as methylthiomethyl and ethylthiomethyl;""aryl" thiomethyl groups, such as phenylthiomethyl and naphthylthiomethyl; 2-methanesulfonylonethiotinole, 2-trifluoromethanesnorehoni “Lower alkyl” sulfonyl “lower alkyl group” which may be substituted with halogen, such as Ruetinole; “Aryl” sulfonyl, such as 2-benzenesnorrefonyletyl, 2-toluenesulfonylechinole "Lower alkyl group" The above-mentioned "(a-yloxy)" lower alkyl group ""; the above-mentioned "phthalidyl group"; the above-mentioned "aryl group"; the above-mentioned "lower alkyl group";"carboxyalkylgroup" such as carboxymethyl; and phenylalanine. Examples of such a “amino acid amide-forming residue” include, preferably, an “alkoxyalkyl group”.

The “other derivative” may be a derivative other than the above “pharmacologically acceptable salts” and the above “esters thereof” when the compound (I) of the present invention has an amino group. I will show you the derivatives. Such derivatives include, for example, amide derivatives. Specific examples of the compound (I) of the present invention include, for example, the compounds shown in Table 1 below, but the present invention is not limited to these compounds. The compounds in Table 1 have the structural formula (II). In Table 1, the group having M has the following groups.

_Two

Dimension

89 L9

99

S9

179

S

.8C60 / T0df / X3d H-OAV Further, the groups having the above M and the abbreviations in Table 1 are as follows (Ac: acetinol group

 B z: benzyl group

 E t: ethyl group

 M e: methyl group

P h: feninole group.

【table 1】

-X-Y-

(Π)

Compd. Is Y

 Λ V I

 Sweet lambda No.

丄 rn ΓΠ ^ then π ₂ 2 \) o

Δ rn ΓΠ one Λ—

 Then 3

U then 2

rn D rLe nu 1 (L _z ) 2)

0 rn し 2 丄 D a 0 rn rxl 1 fp Π 3 1 UD

7 rnV, rn し_{4 4} R ■ Ti 丄 1 丄 1 — (—, 1

¹ 2 no

9 Ph .-0- Π ₂ no 2, in rll -0-, 1 ¾ no V 丄 0 no

11 Ph Ph 1 0--(CH ₂ ) _3- (18)

12 Ph Ph 1 o--(CH ₂ ) _2- (19)

13 Ph Ph 1 0--(CH ₂ ) _2- (20)

14 Ph Ph 1 0--(CH ₂ ) _2- (21)

15 Ph Ph-0--(CH ₂ ) _3- (21)

16. Ph Ph -0--(CH ₂ ) _2- (22)

17 Ph Ph _0--(C¾) _2- (23)

18 Ph Ph-0--(C¾) _2- (30)

19 Ph Ph 1 0—-(CH ₂ ) _3- (30) Ph Ph - 0 - • - ( CH 2) 4 - (30)

Ph Ph-0_-(C) _2- . (31)

Ph Ph-0--(CH ₂ ) _2- (32)

Ph Ph-0--(CH ₂ ) _3- (32)

Ph Ph-0--(CH ₂ ) _2- (33)

Ph Ph-0--(C¾) _3- (33)

Ph Ph-0_-(CH ₂ ) _2- (34)

Ph Ph-0--(C¾) _2- (35)

Ph Ph-0--(CH ₂ ) _2- (3.6)

Ph Ph 1 0—-(CH ₂ ) _3- (36)

Ph Ph-0--(c¾) _2- (37)

Ph Ph-0--(CH ₂ ) _2- (38)

Ph Ph-0--(c¾) _2- (59)

Ph Ph —. _-(CH ₂ ) _2- (73)

Ph Ph-0--(C¾) (74)

Ph Ph-0--(CH ₂ ) ₃ -'(74)

Ph Ph-0- ~ (CH ₂ ) _2- (75)

2-F-Ph 2-F-Ph-0--(c¾) _2- (1)

2-F-Ph 2-F-Ph-0--(CH ₂ ) _3- (1)

2-F-Ph 2-F -Ph - 0 - - (c¾) 4 - (1)

2-F-Ph 2-F-Ph-0--(CH ₂ ) _2- (2)

2-F-Ph 2-F-Ph-. -(2)

2-F-Ph 2-F-Ph-0--(CH ₂ ) _2- (3)

2-F-Ph 2-F-Ph-0--(CH ₂ ) _3- (3)

2-F-Ph 2-F-Ph-0--(CH ₂ ) _2- (4)

2-F-Ph 2-F-Ph -0—-(CH ₂ ) _2- (5) 2-F-Ph 2-F-Ph-0--(c) _2- (6)

2-F-Ph 2-F-Ph-0--(CH ₂ 2-(15)

2-F-Ph 2-F-Ph-0--(CH ₂ ) _3- (15)

2-F-Ph 2-F-Ph-. _{- - (CH 2) 4 -} (15)

2-F-Ph 2-F-Ph-S--(CH ₂ ) _2- (15)

2-F-Ph 2-F-Ph -NH--(C¾) _2- (15)

2-F-Ph 2-F-Ph-0--(CH ₂ ) _2- (16)

2-F-Ph 2-F-Ph-0--(C) _3- (16)

2-F-Ph 2-F-Ph 1 0--(CH _{2 2-} (17)

2-F-Ph 2-F-Ph — 0--(CH ₂ ) ₃ _ (17)

2-F-Ph 2-F-Ph-0--(CH ₂ ) _2- (18)

2-F-Ph 2-F-Ph-0--(CH ₂ ) _3- (18)

2-F-Ph 2-F -Ph one _{0- - (C¾) 4 - (} 18)

2-F-Ph 2-F-Ph-0--(CH ₂ ) _2- (19)

2-F-Ph 2-F-Ph one 0—-(C) _3- (19)

2-F-Ph 2-F-Ph one 0--(c) _2- (20)

2-F-Ph 2-F-Ph one 0-"(CH ₂ ) _3- (20)

2-F-Ph 2-F-Ph 1 0--(CH ₂ ) _2- (21)

2-F-Ph 2-F-Ph-0--(CH ₂ ) _3- (21)

2-F-Ph 2-F -Ph - 0 - - (C¾) 4 - (21)

2-F-Ph 2-F-Ph-0--(c) _2- (22)

2-F-Ph 2-F-Ph-0--(CH ₂ ) _3- (22)

2-F-Ph 2-F-Ph-0_-(CH ₂ ) _2- (23)

2-F-Ph 2-F-Ph "-0--(CH ₂ ) _3- (23)

2-F-Ph 2-F-Ph One. --(C¾) _2- (24)

2-F-Ph 2-F-Ph 1 0--(CH ₂ ) _2- (30) 72 2-F-Ph 2-F-Ph One. One-(c¾) _3- (30)

73 2-F-Ph 2- F-Ph - 0- - (C) 4 - (30)

74 2-F-Ph 2-F-Ph-S--(CH ₂ ) _2- (30)

75 2-F-Ph 2-F-Ph-NH--(c¾) _2- (30)

76 2-F-Ph 2-F-Ph-0--(C) _2- (31)

77 2-F-Ph 2-F-Ph-0--(C¾) _3- (31)

78 2-F-Ph 2-F-Ph-0--(c) _2- (32)

79 2-F-Ph 2-F-Ph 1 0--(c) _3- (32)

80 2-F-Ph 2- F-Ph one _{0 - (C¾) 4 - (} 32)

81 2-F-Ph 2-F-Ph one 0--(c) _2- (33)

82 2-F-Ph 2-F-Ph — 0--(CH ₂ ) _3- (33)

83 2-F-Ph 2- F-Ph one _{0 - - (c) 4 -} (33)

84 2-F-Ph 2-F-Ph -0--(CH ₂ ) _2- (34)

85 2-F-Ph 2-F-Ph — 0--(CH ₂ ) _3- (34)

86 2-F-Ph 2-F-Ph -0--(CH ₂ ) _2- (35)

87 2-F-Ph 2-F-Ph -0--(C) _3- (35)

88 2-F-Ph 2-F-Ph-0--(CH ₂ ) _2- (36)

89 2-F-Ph 2-F-Ph -0--(CH ₂ ) _3- (36)

90 2-F-Ph 2- F-Ph -0- - (C¾) 4 - (36)

91 2-F-Ph 2-F-Ph-0--(c) _2- (37)

92 2-F-Ph 2-F-Ph -0--(CH ₂ ) _3- (37)

93 2-F-Ph 2-F-Ph _0--(c¾) _2- (38)

94 2-F-Ph 2-F-Ph-0--(CH ₂ ) _3- (38)

95 2-F-Ph 2-F-Ph -0--(CH ₂ ) _2- (40)

96 2-F-Ph 2-F-Ph-0--(CH ₂ ) _2- (42)

97 2-F-Ph 2-F-Ph -0—-(CH ₂ ) _2- (55) oo

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150 3-F-Ph 3-F-Ph -NH--(c¾) _2- (30)

151 3-F-Ph 3-F-Ph one 0--(c) _2- (31)

152 3-F-Ph 3-F-Ph one 0--(c¾) _3- (31)

153 3-F-Ph 3-F-Ph one 0--(c¾) _2- (32)

154 3-F-Ph 3-F-Ph one 0--(CH ₂ ) ₃ _ (32)

155 3-F-Ph 3- F-Ph -0- - (c¾) 4 - (32)

156 3-F-Ph 3-F-Ph-0--(CH ₂ ) _2- (33)

157 3-F-Ph 3-F-Ph 0--(c¾) _3- (33)

158 3-F-Ph 3- F-Ph one _{0 - - (c¾) 4 -} (33)

159 3-F-Ph 3-F-Ph one 0--(C¾) _2- (34)

160 3-F-Ph 3-F-Ph one 0--(c) _3- (34)

161 3-F-Ph 3-F-Ph 1 0 _ (CH ₂ ) _2- (35)

162 3-F-Ph 3-F-Ph-0--(C¾) _3- (35)

163 3-F-Ph 3-F-Ph one 0--(CH ₂ ) _2- (36)

164 3-F-Ph 3-F-Ph-0— '-(CH ₂ ) 3 ~ (36)

165 3-F-Ph 3-F-Ph one 0--(C¾) (36)

166 3-F-Ph 3-F-Ph-0--(CH ₂ ) _2- (37)

167 3-F-Ph 3-F-Ph one 0--(CH ₂ (37)

168 3-F-Ph 3-F-Ph -0--(CH ₂ ) _2- (38)

169 3-F-Ph 3-F-Ph one 0--(CH ₂ ) _3- (38)

170 3-F-Ph 3-F-Ph-0--(CH ₂ ) _2- (40)

171 3-F-Ph 3-F-Ph-0--(CH ₂ ) _2- (42)

172 3-F-Ph 3-F-Ph one 0--(C¾) _2- (55)

173 3-F-Ph 3-F-Ph one 0--(CH ₂ ) _2- (56)

174 3-F-Ph 3-F-Ph-0--(CH ₂ ) _2- (57)

175 3-F-Ph 3-F-Ph 1 0-1 (C) _2- (58) 176 3-F-Ph 3-F-Ph -0--(c) _2- (59)

177 3-F-Ph 3- F-Ph - 0 - - (<¾ Roh ₃ - (59)

178 3-F-Ph 3-F-Ph-0--(c) _2- (60)

179 3-F-Ph. 3-F-Ph — 0--(CH ₂ ) _2- (73)

180 3-F-Ph 3-F-Ph 1 0—-(C) _3- (73)

181 3-F-Ph 3-F-Ph-0--(c) _2- (74)

182 3-F-Ph 3-F-Ph — 0--(C) _3- (74)

183 3-F-Ph 3- F-Ph - 0 - - (c¾) 4 - (74)

184 3-F-Ph 3-F-Ph -0--(CH ₂ ) _2- (75)

185 3-F-Ph 3-F-Ph-0--(C) ₃ _ (75)

186 3-F-Ph 3-F-Ph-0--(SCH ₂ ) _2- (78)

187 4-F-Ph 4-F-Ph — 0- -CH _2- (1)

188 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (1)

189 4-F-Ph 4-F-Ph-0--(C¾) _3- (1)

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

191 4-F-Ph 4-F-Ph — 0—-(c) _5- (1)

192 4-F-Ph. 4-F-Ph-S--(C¾) _2- (1)

193 4-F-Ph 4-F-Ph-S--(CH ₂ ) _3- (1)

194 4-F-Ph 4-F-Ph -NH--(CH ₂ ) _2- (1)

195 4-F-Ph--F-Ph -NH- (1)

196 4-F-Ph 4-F-Ph-0--(C) _2- (2)

197 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (2)

198 4-F-Ph 4- F-Ph -0 - - (C¾) 4 -. (2)

199 '• 4-F-Ph 4-F-Ph -S--(CH ₂ ) _2- (2)

200 4-F-Ph 4-F-Ph -NH--(C¾) _2- (2)

201 4-F-Ph 4-F-Ph one 0—-(CH ₂ ) _2- (3) 202 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _3- (3)

203 4-F-Ph 4- F-Ph one _{0 - - (c¾) 4 -} (3)

204 4-F-Ph 4-F-Ph-S--(CH ₂ ) _2- (3)

205 4-F-Ph 4-F-Ph -NH--(c¾) _2- (3)

206 4-F-Ph 4-F-Ph one 0--(c¾) _2- (4)

207 4-F-Ph 4-F-Ph 1 0--(CH ₂ ) _3- (4)

208 4-F-Ph 4- F-Ph one _{0 - - (c¾) 4 -} (4)

209 4-F-Ph 4-F-Ph one 0--(c¾) _2- (5)

210 4-F-Ph 4-F-Ph one 0—-(CH ₂ ) _3- (5)

211 4-F-Ph 4- F-Ph one _{0 - - (C¾) 4 -} (5)

212 4-F-Ph 4-F-Ph one 0--(c¾) _2- (6)

213 4-F-Ph 4-F-Ph-0--(c) _3- (6)

214 4-F-Ph 4- F-Ph -0- - (CH 2) 4 - (6)

215 4-F-Ph 4-F-Ph one 0-•-(C) _2- (7)

216 4-F-Ph 4-F-Ph _0--(CH ₂ ) _3- (7)

217 4-F-Ph 4-F-Ph one 0—-(c¾) _2- (8)

218 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (8)

219 4-F-Ph 4-F-Ph 1 0-_ (c) _2- (9)

220 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (9)

221 4-F-Ph. 4-F-Ph -0--(CH ₂ ) _2- (10)

222 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _3- (10)

223 4-F-Ph 4-F-Ph-0--(C) _2- (11)

224 4-F-Ph 4-F-Ph — 0--(CH ₂ ) _3- (11)

225 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (12)

226 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _3- (12)

227 4-F-Ph 4-F-Ph one 0—-(c) _2- (13) 228 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (13)

229 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _2- (14)

230 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _3- (14)

231 ■ 4-F-Ph-4-F-Ph -0--C¾-(15)

232 4-F-Ph 4-F-Ph one 0--(C) _2- (15)

233 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _3- (15)

234 4-F-Ph 4- F-Ph one _{0 - - (c) 4 -} (15)

235 4-F-Ph 4-F-Ph one 0—-(CH ₂ ) _5- (15)

236 4-F-Ph 4-F-Ph 1 0--(C) _6- (15)

237 4-F-Ph 4-F-Ph-S--(CH ₂ ) _2- (15)

238 4-F-Ph 4-F-Ph one S--(CH ₂ ) _3- (15)

239 4-F-Ph 4- F-Ph one _{S- - (C¾) 4 - (} 15)

240 4-F-Ph 4-F-Ph one S--(c¾) _5- (15)

241 4-F-Ph 4-F-Ph-NH--(C¾) _2- (15)

242 4-F-Ph 4-F-Ph-NH--(Ch ₂ ) 3-(15)

243 4-F-Ph 4- F-Ph - NH - - (c) 4 - (15)

244 4-F-Ph 4-F-Ph -NH--(C) ₅ _ (15)

245 4-F-Ph 4-F-Ph-0--(C¾) _2- (16)

246 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _3- (16)

247 4-F-Ph 4- F-Ph - 0 - - (c) 4 - (16)

248 4-F-Ph 4-F-Ph-S--(CH ₂ ) _2- (16)

249 4-F-Ph 4-F-Ph-NH- ~ (CH ₂ ) _2- (16)

250 4-F-Ph 4-F-Ph-0--(C¾) _2- (17)

251.4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (17)

252 4-F-Ph 4- F-Ph - 0 - - (C¾) 4 - (17)

253 4-F-Ph 4-F-Ph-S--(C) _2- (17) 254 4-F-Ph 4-F-Ph-NH--(CH ₂ ) _2- (17)

255 4-F-Ph 4-F-Ph One. --CH _2- (18)

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

257 4-F-Ph 4-F-Ph — 0--(C) _3- (18)

258 4-F-Ph 4- F-Ph one _{0 - - (c) 4 -} (18)

259 4-F-Ph 4-F-Ph one 0--(C¾) _5- (18)

260 4-F-Ph 4-F-Ph one S--(C¾) _2- (18)

261 4-F-Ph 4-F-Ph-S--(C) _3- (18)

262 4-F-Ph 4-F-Ph -NH--(C¾) _2- (18)

263 4-F-Ph 4-F-Ph '-NH--(CH ₂ ) _3- (18)

264 4-F-Ph 4-F-Ph one 0_-(C¾) ₂ _ (19)

265 4-F-Ph 4-F-Ph-0--(CH ₂ ) ₃ (19)

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

267 4-F-Ph 4-F-Ph-S--(CH ₂ ) _2- (19)

268 4-F-Ph 4-F-Ph-H--(C¾) _2- (19)

269 4-F-Ph 4-F-Ph-0--(Cn ₂ ) _2- (20)

270 4-F-Ph 4-F-Ph one 0--(Ch ₂ ) _3- (20)

271 4-F-Ph 4- F-Ph one _{0 - - (c¾) 4 -} (20)

272 4-F-Ph 4-F-Ph-S--(CH ₂ ) _2- (20)

273 4-F-Ph 4-F-Ph -NH--(CH ₂ ) _2- (20)

274 4-F-Ph 4-F-Ph-0--CH _2- (21)

275 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (21)

276 4-F-Ph 4-F-Ph-0--(CH ₂ ) ₃ _ (21)

277 4-F-Ph 4- F-Ph - 0 - - (c¾) 4 - (21)

278 4-F-Ph 4-F-Ph-0- _ (c¾) _5- (21)

279 4-F-Ph 4-F-Ph one S--(CH ₂ ) _2- (21) 280 4-F-Ph 4-F-Ph-S--(CH ₂ ) _3- (21)

281 4-F-Ph 4-F-Ph-NH--(c) _2- (21)

282 4-F-Ph 4-F-Ph-NH--(c¾) _3- (21)

283 4-F-Ph 4-F-Ph-0—-(CH ₂ ) _2- (22)

284 4-F-Ph 4-F-Ph — 0--(c¾) _3- (22)

285 4-F-Ph 4- F-Ph - 0- - (CH 2) 4 - (22)

286 4-F-Ph 4-F-Ph-s--(c) _2- (22)

287 4-F-Ph • 4-F-Ph-NH--(c¾) _2- (22)

288 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _2- (23)

289 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _3- (23)

290 4-F-Ph 4- F-Ph - 0- - (CH 2) 4 - (23)

291 4-F-Ph 4-F-Ph -S--(c) ₂ _ (23)

292 4-F-Ph 4-F-Ph -Thigh--(C) _2- (23)

293 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _2- (24)

294 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _3- (24)

295 4-F-Ph 4- F-Ph one _{0 - - (C¾) 4 -} (24)

296 4-F-Ph 4-F-Ph one 0--(c¾) _2- (25)

297 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (25)

298 4-F-Ph 4-F-Ph-0--(C¾) _2- (26)

299 4-F-Ph 4-F-Ph-0—-(C) _3- (26)

300 4-F-Ph 4-F-Ph--0--(CH ₂ ) _2- (27)

301 4-F-Ph 4-F-Ph One. One-(CH ₂ ) _3- (27)

302 4-F-Ph 4- F-Ph - 0 - - (CH 2) 4 - (27)

303 4-F-Ph 4-F-Ph-0--(C) _2- (28)

304 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (28)

305 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _2- (29) 306 4-F-Ph 4-F-Ph -0--(CH ₂ ) _3- (29)

307 4-F-Ph 4-F-Ph -o- -CH _2- (30)

308 4-F-Ph 4-F-Ph one 0--(C¾) _2- (30)

309 4-F-Ph 4-F-Ph — 0--(CH ₂ ) _3- (30)

310 4-F-Ph 4- F-Ph one _{0 - - (CH 2) 4} - (30)

311 4-F-Ph 4-F-Ph — 0--(C¾) ₅ _ (30)

312 4-F-Ph 4-F-Ph-0--(c¾) _6- (30)

313 4-F-Ph 4-F-Ph -S--(CH ₂ ) ₂ _ (30)

314 4-F-Ph 4-F-Ph-S--(c¾) _3- (30)

315 4-F-Ph 4- F-Ph - S - - (c) 4 - (30)

316 4-F-Ph 4-F-Ph-S--(C¾) _5- (30)

317 4-F-Ph 4-F-Ph -NH--(c¾) _2- (30)

318 4-F-Ph 4-F-Ph -NH--(c¾) _3- (30)

319 4-F-Ph 4- F-Ph -NH- - (c¾) 4 - (30)

320 4-F-Ph 4-F-Ph -NH--(CH ₂ ) _5- (30)

321 4-F-Ph 4-F-Ph one 0--c¾- (31)

322 4-F-Ph 4-F-Ph-0--(C¾) _2- (31)

323 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (31)

324 4-F-Ph 4- F-Ph - 0- - (c¾) 4 - (31)

325 4-F-Ph 4-F-Ph one 0—-(c¾) _5- (31)

326 4-F-Ph 4-F-Ph -S--(CH ₂ ) _2- (31)

327 4-F-Ph 4-F-Ph -S--(CH ₂ ) _3- (31)

328 4-F-Ph 4-F-Ph -NH--(CH ₂ ) _2- (31)

329 4-F-Ph 4-F-Ph -NH--(CH ₂ ) _3- (31)

330 4-F-Ph 4-F-Ph-0--C-(32)

331 4-F-Ph 4-F-Ph 1 0--(C¾) _2- (32) 332 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (32)

333 4-F-Ph 4- F-Ph - 0 - - (C¾) 4 - (32)

334 4-F-Ph 4-F-Ph -o--(C¾) _5- (32)

335 4-F-Ph 4-F-Ph-s--(CH ₂ ) _2- (32)

336 4-F-Ph 4-F-Ph-s--(C¾) _3- (32)

337 4-F-Ph 4-F-Ph-NH--. (C¾) ₂ _ (32)

338 4-F-Ph 4-F-Ph '-NH--(CH ₂ ) _3- (32)

339 4-F-Ph 4-F-Ph-0-(33)

340 4-F-Ph 4-F-Ph -o--(CH ₂ ) _2- (33)

341 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (33)

342 4-F-Ph 4- F-Ph one _{0- - (c¾) 4 - (} 33)

343 4-F-Ph 4-F-Ph-0--(c¾) _5- (33)

344 4-F-Ph 4-F-Ph-S--(C) _2- (33)

345 4-F-Ph 4-F-Ph-S--(CH ₂ ) _3- (33)

346 4-F-Ph 4-F-Ph -NH--(CH ₂ ) _2- (33)

347 4-F-Ph 4-F-Ph -NH--(C) _3- (33)

348 4-F-Ph 4-F-Ph one 0--(c¾) _2- (34)

349 4-F-Ph 4-F-Ph one 0--(c) _3- (34)

350 4-F-Ph 4- F-Ph - 0 - - (C¾) 4 - (34)

351 4-F-Ph 4-F-Ph-S--(C¾) _2- (34)

352 4-F-Ph 4-F-Ph -NH--(c) _2- • (34)

353 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (35)

354 4-F-Ph 4-F-Ph-0-'-(CH ₂ ) _3- (35)

355 4-F-Ph 4- F-Ph - 0 - - (C¾) 4 - (35)

356 4-F-Ph 4-F-Ph-S--(C¾) _2- (35)

357 4-F-Ph 4-F-Ph -NH--(CH ₂ ) _2- (35) 358 4-F-Ph 4-F-Ph-0--c¾-(36)

359 4-F-Ph 4-F-Ph-. One-(C No _2- (36)

360 4-F-Ph 4-F-Ph 1 0--(CH _{2 3-} (36)

361 4-F-Ph 4-F-Ph one 0-(36)

362 4-F-Ph 4-F-Ph 1 0-(36)

363 4-F-Ph 4-F-Ph-S--(C) ₂ _ (36)

364 4-F-Ph 4-F-Ph one S--(CH ₂ ) _3- (36)

365 4-F-Ph 4-F-Ph -NH--(c¾) _2- (36)

366 4-F-Ph 4-F-Ph -NH--(C¾) _3- (36)

367 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _2- (37)

368 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _3- (37)

369 4-F-Ph 4-F-Ph-0--(CH ₂ ) _r (37)

370 4-F-Ph 4-F-Ph-S--(C¾) _2- (37)

371 4-F-Ph 4-F-Ph -NH--(c¾) _2- (37)

372 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (38)

373 4-F-Ph 4-F-Ph-0--(C¾) _s- (38)

374 4-F-Ph 4- F-Ph - 0 - - (C¾) 4 - (38)

375 4-F-Ph 4-F-Ph-S--(Cn ₂ ) _2- (38)

376 4-F-Ph 4-F-Ph -NH--(CH ₂ ) _2- (38)

377 4-F-Ph 4-F-Ph-0--(C) _2- (39)

378 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (39)

379 4-F-Ph 4-F-Ph--0--(CH ₂ ) _2- (40)

380 4-F-Ph 4-F-Ph 0--(CH ₂ ) _3- (40)

381 4-F-Ph 4- F-Ph - 0 - - (c> 4 - (40)

382 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (41)

383 4-F-Ph 4-F-Ph-0--(C) _3- (41) 384 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (42)

385 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (42)

386 4-F-Ph 4- F-Ph - 0 - - (c¾) 4 - (42)

387 4-F-Ph 4-F-Ph-0--(Ch ₂ ) 2-(43)

388 4-F-Ph 4-F-Ph-0_-(c) _3- (43)

389 4-F-Ph 4-F-Ph — 0--(c¾) _2- (44)

390 4-F-Ph 4-F-Ph 1 0--(c¾) _3- (44)

391 4-F-Ph 4-F-Ph one 0--(C¾) _2- (45)

392 4-F-Ph 4-F-Ph one 0--(CH ₂ ') _3- (45)

393 4-F-Ph 4-F-Ph-0_- _2- (46)

394 4-F-Ph 4-F-Ph-0- one (c¾) _3- . (46)

395 4-F-Ph 4-F-Ph one 0--(Cn ₂ ) 2-(47)

396 4-F-Ph 4-F-Ph-0-_ (CH ₂ ) _3- (47)

397 4-F-Ph 4-F-Ph-0--(C) _2- (48)

398 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _3- (48)

399 4-F-Ph 4-F-Ph -0--(CH ₂ ) _2- (49)

400 4-F-Ph 4-F-Ph — 0--(CH ₂ ) _3- (49)

401 4-F-Ph 4-F-Ph-0--(C¾) _2- (50)

402 4-F-Ph 4-F-Ph -0--(CH ₂ ) _3- (50)

403 • 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (51)

404 4-F-Ph 4-F-Ph -0- _ (CH ₂ ) _3- (51)

405 4-F-Ph 4-F-Ph-0--(C) _2- (52)

406 4-F-Ph 4-F-Ph-0--(C¾) _3- (52)

407 4-F-Ph 4-F-Ph .- 0--(C) _2- (53)

408 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (53)

409 4-F-Ph 4-F-Ph one 0---(C¾) ₂ ~ (54) 410 .4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (54)

411 4-F-Ph '4-F-Ph-0--(C¾) _2- (55)

412 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (55)

413 4-F-Ph 4- F-Ph one _{0 - - (c¾) 4 -} (55)

414 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (56)

415 4-F-Ph 4-F-Ph One. --(C¾) _3- (56)

416 4-F-Ph 4- F-Ph -. 0 - - (C¾) 4 - (56)

417 4-F-Ph 4-F-Ph one 0--(c¾) _2- (57)

418 4-F-Ph 4-F-Ph one 0--(c¾) _3- (57)

. 419 4-F-Ph 4 -F-Ph one _{0 - - (c) 4 -} (57)

420 4-F-Ph 4-F-Ph one 0--(C¾) _2- (58)

421 • 4-F-Ph 4-F-Ph .- 0--(CH ₂ ) _3- (58)

422 4-F-Ph 4- F-Ph one _{0 - - (c¾) 4 -} (58)

423 4-F-Ph 4-F-Ph one 0--(C) _2- (59)

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

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

426 4-F-Ph 4-F-Ph-S--(C¾) _2- (59)

427 4-F-Ph 4-F-Ph-H--(CH ₂ ) _2- (59)

428 4-F-Ph 4-F-Ph -0--(C) _2- (60)

429 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (60)

430 4-F-Ph 4- F-Ph - 0- - (c) 4 - (60)

431 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (61)

432 4-F-Ph 4-F-Ph-0--(c¾) _3- (61)

433 4-F-Ph 4-F-Ph-0--(C) _2- (62)

434 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (62)

435 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _2- (63) 436 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (63)

437 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (64)

438 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (64)

439 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (65)

440 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (65)

441 4-F-Ph 4-F-Ph-0--(c¾) _2- (66)

442 4-F-Ph 4-F-Ph-0--(C¾) _3- (66)

443 4-F-Ph 4-F-Ph-0--(c¾) _2- (67)

444 4-F-Ph 4-F-Ph One. One-(c¾) _3- (67)

445 4-F-Ph 4-F-Ph-0--(C¾) _2- (68)

446 4-F-Ph 4-F-Ph 1 0--(c) _3- (68)

447 4-F-Ph 4-F-Ph one 0--(C) _2- (69)

448 4-F-Ph 4-F-Ph-0--(C¾) _3- (69)

449 '4-F-Ph 4-F-Ph-0—-(CH ₂ ) _2- (70)

450 4-F-Ph4-F-Ph one 0--(CH ₂ ) _3- (70)

451 4-F-Ph 4-F-Ph one 0-.- (CH ₂ ) _2- (71)

452 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (71)

453 4-F-Ph 4-F-Ph-0--(CH ₂ 2-(72)

454 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _3- (72)

455 4-F-Ph 4-F-Ph-0--(C) _2- (73)

456 4-F-Ph 4-F-PK -0--(CH ₂ ) _3- (73)

457 4-F-Ph 4- F-Ph one _{0 - - (C¾) 4 -} (73)

458 4-F-Ph 4-F-Ph-S--(CH ₂ ) _2- (73)

459 4-F-Ph 4-F-Ph -NH--(c) _2- (73)

460 4-F-Ph 4-F-Ph one 0--CH _2- (74)

461 4-F-Ph 4-F-Ph One 0 One (CH ₂ ) _2- (74) 462 4-F-Ph 4-F-Ph -o--(c¾) _3- (74)

463 4-F-Ph 4- F-Ph - 0 - - (CH 2) 4 - (74)

464 4-F-Ph 4-F-Ph-0--(C¾) _5- (74)

465 4-F-Ph 4-F-Ph-s--(CH ₂ ) _2- (74)

466 4-F-Ph 4-F-Ph -S--(c) _3- (74)

467 4-F-Ph 4-F-Ph .-NH--(c¾) _2- (74)

468 4-F-Ph 4-F-Ph-NH--(C) _3- (74)

469 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _2- (75)

470 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (75)

471 4-F-Ph 4- F-Ph -0- - (c¾) 4 - (75)

472 4-F-Ph 4-F-Ph -S--(Cn ₂ ) _2- (75)

473 4-F-Ph 4-F-Ph -NH--(C¾) _2- (75)

474 4-F-Ph '4-F-Ph-0_-(CH ₂ ) _2- (76)

475 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (76)

476 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (77)

477 4-F-Ph 4-F-Ph one 0--(Cn ₂ ) _3- (77)

478 4-F-Ph 4-F-Ph -0--(c¾) _2- (78)

479 4-F-Ph 4-F-Ph ー 0--(C¾) _3- (78)

480 4-F-Ph 4- F-Ph one _{0 - - (c) 4 -} (78)

481 4-F ~ Ph 4-F-Ph-0--(c¾) _2- (79)

482 4-F-Ph 4-F-Ph-0--(c¾) _3- (79)

483 4-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (80)

484 4-F-Ph 4-F-Ph — 0--(c¾) _3- (80)

485 4-F-Ph 4-F-Ph-0--(c¾) _2- (81)

486 4-F-Ph 4-F-Ph -0--(CH ₂ ) _3- (81)

487 4-F-Ph 4- F-Ph one _{0 - - (CH 2) 4} - (81) 488 4-F-Ph 4-F-Ph -0--(CH ₂ ) _2- (82)

489 4-F-Ph 4-F-Ph .- 0--(CH ₂ ) _3- (82)

490 4-F-Ph 4- F-Ph - 0 - - (C¾) 4 - (82)

491 4-F-Ph 4-F-Ph-0_-(CH ₂ ) _2- (83)

492 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (83)

493 4-F-Ph 4-F-Ph-. _{- - (c¾) 4 - (} 83)

494 4-F-Ph 4-F-Ph-0_-(C¾) _5- (83)

495 4-F-Ph 4-F-Ph-0-(84)

496 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (84)

497 4-F-Ph 4- F-Ph one _{0- - 1 (C¾) 4 -} (84)

498 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _2- (85)

499 4-F-Ph 4-F-Ph one 0--(C) _3- (85)

500 4-F-Ph 4- F-Ph - 0 - - (c¾) 4 - (85)

501 4-F-Ph 4- F-Ph -0- - (CH 2) 4 - (85)

502 4-F-Ph 4-F-Ph-0--(C) _2- (86)

503 4-F-Ph 4-F-Ph-0--(CH ₂ ) _3- (86)

504 4-F-Ph 4- F-Ph - 0- _ (c¾) 4 - (86)

505 2-Cl-Ph 2-Cl-Ph-0_-(c¾) _2- (1)

506 2-Cl-Ph 2-Cl-Ph 1 0--(CH ₂ ) ₃ _ (1)

507 2-Cl-Ph 2-Cl-Ph — 0—-(c¾) _2- (2)

508 2-Cl-Ph 2-Cl-Ph-0--(c) _2- (3)

509 2-Cl-Ph 2-Cl-Ph 1 0--(CH ₂ ) _2- . (15)

510 2-Cl-Ph 2-Cl-Ph-0--(CH ₂ ) _3- (15)

511 2-Cl-Ph 2- Cl-Ph - 0_ - (c) 4 - (15)

512 2-Cl-Ph 2-Cl-Ph-0--(C) _2- (16)

513 2-Cl-Ph 2-Cl-Ph 1 0--(CH ₂ ) _2- (17) 514 2-CI- Ph 2-Cl-Ph-0--(C¾) _2- (18)

515 2-Cl-Ph 2-CI- Ph 1 0--(CH ₂ ) _3- (18)

516 2-Cl-Ph '2-CI-Ph 1 0--(c¾) _2- (19)

517 2-Cl-Ph 2- CI-Ph 1 0--(CH ₂ ) _2- (20)

518 2-CI-Ph '2-Cl-Ph 1 0--(c) _2- (21)

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

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

521 2- CI-Ph 2-Cl-Ph 1 0--(C¾) _2- (23)

522 2-CI- Ph 2-Cl-Ph 1 0--(c¾) ₂ _ (30)

523 2-Cl-Ph 2-Cl-Ph -0--(C) _3- (30)

524 2- CI - Ph 2- CI - Ph one _{0 - '- (c¾) 4} - (30)

525 2- CI- Ph 2-Cl-Ph-0--(CH ₂ ) _2- (31)

526 2-Cl-Ph 2-Cl-Ph-0--(CH ₂ ) _2- (32)

527 2-Cl-Ph 2-CI- Ph-0--(C¾) _3- (32)

528 2- CI-Ph 2-Cl-Ph-0—-(C¾) _2- (33)

529 2-CI- Ph 2-Cl-Ph one 0--(C¾) _s- (33)

530 2-Cl-Ph 2-Cl-Ph 1 0-_ (CH ₂ ) _2- (34)

531 2-CI- Ph 2-Cl-Ph 1 0--(CH ₂ ) _2- (35)

532 2-Cl-Ph 2-Cl-Ph-0— _ (C¾) _2- (36)

533 2-CI-Ph 2-Cl-Ph-0--(CH ₂ ) _3- (36)

534 2- CI-Ph 2-Cl-Ph-0--(CH ₂ ) _2- (37)

535 2-Cl-Ph 2-CI- Ph 1 0--(C¾) _2- (38)

536 2-Cl-Ph 2-Cl-Ph-0--(C) _2- (59)

537 2-Cl-Ph 2-CI- Ph • 1 0--(CH ₂ ) _2- (73)

538 2-Cl-Ph 2-Cl-Ph-0--(CH ₂ ) _2- (74)

539 2-CI- Ph 2--Ph 1 0--(CH ₂ ) _3- (74) 540 2-Cl-Ph 2-C1- -Ph -0--(c) _2- (75)

541 3-Cl-Ph 3-C1--Ph-0--(CH ₂ ) _2- (1)

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

543 3- CI-Ph 3-C1--Ph-0--(CH ₂ ) ₂ _ (2)

544 3-Cl-Ph 3-C1--Ph -0--(CH ₂ ) _2- (3)

545 3-Cl-Ph 3-Cl--Ph-0--(CH ₂ ) _2- (15)

546 3-Cl-Ph 3-C1--Ph -0--(c¾) _3- (15)

547 3-Cl-Ph 3- C1- -Ph -o- - (c¾) 4 - (15)

548 3-Cl-Ph 3-C1- -Ph -o--(C¾) _2- (16)

549 3-Cl-Ph 3-C1- -Ph-0--(CH ₂ ) _2- (17)

550 3-Cl-Ph 3-C1--Ph -0--(CH ₂ ) _2- (18)

551 3-Cl-Ph 3-C1--Ph-0--(CH ₂ ) _3- (18)

552 3- CI- Ph 3-C1- -Ph-0—-(C ノ_2- (19)

553 3- CI-Ph 3-C1- -Ph-0--(CH ₂ ) _2- (20)

554 3-Cl-Ph 3-Cl- -Ph-(C) _2- (21)

555 3- CI - Ph 3- CI- - Ph - 0 - - CH 2 Bruno ₃ - (21)

556 3-Cl-Ph 3-C1--Ph-0-1 ii _{2 2} 1 (22)

557 3-Cl-Ph 3-CI- -Ph-0--(CH ₂ ) _2- (23)

558 3-Cl-Ph 3-C1- -Ph-0--(C¾) _2- (30)

559 3-Cl-Ph 3-C1- -Ph-0--(c¾) _3- (30)

560 3-Cl-Ph 3- C1- -Ph - 0- - (CH 2) 4 - (30)

561 3-Cl-Ph 3-C1- -Ph — 0-no 21 (31)

562 3-Cl-Ph 3-C1- -Ph -0--(CH ₂ ) _2- (32)

563 3-Cl-Ph 3-C1- -Ph-0--(C) _3- (32)

564 3-Cl-Ph 3-CI- -Ph-0--(CH ₂ ) _2- (33)

565 3-Cl-Ph 3-CI- -Ph 1 0--(CH ₂ ) _3- (33) 566 3-Cl-Ph 3-Cl-Ph-0--(C¾ ノ_2- (34)

567 3-Cl-Ph 3-Cl-Ph-0--(CH ₂ ) _2- (35)

568 3-Cl-Ph 3-Cl-Ph-0--(CH ₂ ) _¾- (36)

569 3-Cl-Ph 3-Cl-Ph -0--(CH ₂ ) _3- (36)

570 3-Cl-Ph 3-Cl-Ph 1 0--(CH ₂ ) _2- (37)

571 3-Cl-Ph 3-Cl-Ph-0- (38)

572 3-Cl-Ph 3-Cl-Ph 1 0--(CH ₂ ) _2- (59)

573 3-Cl-Ph '3-Cl-Ph-0--(c¾) _2- (73)

574 3-Cl-Ph 3-Cl-Ph 1 0--(CH ₂ ) ₂ _ '(74)

575 3-Cl-Ph 3-Cl-Ph-0--(C) (74)

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

577 4-Cl-Ph 4-Cl-Ph one 0--(C¾) _2- (1)

578 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _3- (1)

579 4-Cl-Ph 4- Cl-Ph - 0- - (C) 4 -. (1)

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

581 4-Cl-Ph 4-Cl-Ph -NH--(CH ₂ ) _2- (1)

582 4-Cl-Ph 4-Cl-Ph-0--(C¾) _2- (2)

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

584 4-Cl-Ph 4- Cl-Ph _0 - - (C¾) 4 - (2)

585 4-Cl-Ph 4-Cl-Ph One. One-(CH ₂ ) (3)

586 4-Cl-Ph 4-Cl-Ph one 0--(CH ₂ ) _3- (3)

587 4-Cl-Ph 4- Cl-Ph -0 - - (CH 2) 4 - (3)

588 4-Cl-Ph 4-Cl-Ph-0--(c) _2- (4)

589 4-Cl-Ph 4-Cl-Ph..-0--(C¾) _3- (4)

590 4-Cl-Ph 4-Cl-Ph-0--(C) _2- (5)

591 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _3- (5) 592 4-Cl-Ph 4-Cl-Ph-0—-(c) _2- (6)

593 4-Cl-Ph 4-Cl-Ph one 0--(CH ₂ ) _3- (6)

594 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (7)

595 4-Cl-Ph 4-Cl-Ph 1 0--(c¾) _2- (8)

596 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (9)

597 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (10)

598 4-Cl-Ph 4-Cl-Ph-0— (11)

599 4-Cl-Ph 4-Cl-Ph 1 0--(C) _2- (12)

600 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (13)

601 4-Cl-Ph 4-Cl-Ph-0--i (CH ₂ ) _2- (14)

602 4-Cl-Ph 4-Cl-Ph-0--CH _2- (15)

603 4-Cl-Ph 4-Cl-Ph one 0-(15)

604 4-Cl-Ph 4-Cl-Ph one 0-.- (c¾) _3- (15)

605 4-Cl-Ph 4- Cl-Ph - 0 - - (C¾) 4 - (15)

606 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) ₅ _ (15)

607 4-Cl-Ph 4-Cl-Ph-S--(C¾) _2- (15)

608 4-Cl-Ph 4-Cl-Ph-S--(C) ₃ _ (15)

609 4-Cl-Ph 4-Cl-Ph -NH--(C¾) _2- (15)

610 4-Cl-Ph 4-Cl-Ph-NH--(CH ₂ ) _3- (15)

611 4-Cl-Ph 4-Cl-Ph — 0--(CH ₂ ) _2- (16)

612 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) ₃ _. (16)

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

614 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (17)

615 4-Cl-Ph 4-Cl-Ph — 0--(C¾) _3- (17)

616 4-Cl-Ph 4- Cl-Ph - 0- - (CH 2) 4 - (17)

617 4-Cl-Ph 4-Cl-Ph one 0_-(C〉 _2- (18) 618 4-Cl-Ph 4-CI-Ph -o--(C) _3- (18)

619 4-Cl-Ph 4- Cl-Ph - 0 - - (c¾) 4 - (18)

620 4-Cl-Ph 4-Cl-Ph-s--(c¾) _2- (18)

621 4-Cl-Ph 4-Cl-Ph-NH--(CH ₂ ) _2- (18)

622 4-Cl-Ph 4-Cl-Ph 1 0--(c) _2- (19)

623 4-Cl-Ph 4-Cl-Ph one 0--(c) _3- (19)

624 4-Cl-Ph 4- Cl-Ph - 0- - (c¾) 4 - (19)

625 4-Cl-Ph 4-Cl-Ph one 0--(CH ₂ ) _2- (20)

626 4-Cl-Ph 4-Cl-Ph One. —-(CH ₂ ) _3- (20)

627 4-Cl-Ph 4- Cl-Ph one _{0 - - (c) 4 -} (20)

628 4-Cl-Ph • 4-Cl-Ph one 0--(C¾) ₂ _ • (21)

629 4-Cl-Ph 4-Cl-Ph —0—-(C¾) _3- (21)

630 4-Cl-Ph 4- Cl-Ph -0- - (C¾) 4 - (21)

631 4-Cl-Ph 4-Cl-Ph--S-'-(CH ₂ ) _2- (21)

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

633 4-Cl-Ph 4-Cl-Ph 1 0--(C) _2- (22)

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

635 4-Cl-Ph 4 - CI - Ph - 0 - - (c) 4 - (22)

636 4-Cl-Ph 4-Cl-Ph-0--(C¾) _2- (23)

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

638 4-Cl-Ph 4- Cl-Ph -0- - (c) 4 - (23)

639 4-Cl-Ph 4-Cl-Ph-0--(C) _2- (24)

640 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _3- (24)

641 4-Cl-Ph 4- CI-Ph-0—-(c¾) _2- (25)

642 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (26)

643 4-Cl-Ph 4-Cl-Ph 1 0--(CH ₂ ) _2- (27) 644 4-Cl-Ph 4-Cl-Ph — 0--(C¾) _3- (27)

645 4-Cl-Ph 4-Cl-Ph 1 0--(CH ₂ ) _2- (28)

646 4-Cl-Ph 4-Cl-Ph — 0--(C¾) _2- (29)

647 4-Cl-Ph 4-Cl-Ph 1 0--CH _2- (30)

648 4-Cl-Ph 4-Cl-Ph 1 0--(c) _2- (30)

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

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

651 4-Cl-Ph 4-Cl-Ph -0--(c¾) _5- (30)

652 4-Cl-Ph 4-Cl-Ph i S-_ (CH ₂ ) _2- (30)

653 4-Cl-Ph 4-Cl-Ph-S-1-(c) _3- (30) o

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

 ί

655 4-Cl-Ph 4-Cl-Ph -O--(C¾) _3- (30)

656 4-Cl-Ph 4-Cl-Ph one 0--(CH ₂ ) ₂ -'(31)

657 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _3- (31)

658 4-Cl-Ph 4- Cl-Ph - 0 - - (CH 2) 4 - (31)

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

660 4-Cl-Ph 4-Cl-Ph -NH--(CH ₂ ) _2- (31)

661 4-Cl-Ph 4-Cl-Ph 1 0--(C) _2- (32)

662 4-Cl-Ph 4-Cl-Ph one 0--(CH ₂ ) _3- (32)

663 4-Cl-Ph 4- Cl-Ph - 0- - (c) 4 - (32)

664 4-Cl-Ph 4-Cl-Ph -S- '(32)

665 4-Cl-Ph 4-Cl-Ph -NH--(c¾) _2- (32)

666 4-Cl-Ph 4-Cl-Ph-0--(c) _2- (33)

667 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _3- (33)

668 4-Cl-Ph 4-Cl-Ph-0--(c) _r (33)

669 4-Cl-Ph 4-Cl-Ph -S--(C〉 _2- (33) 670 4-Cl-Ph 4-Cl-Ph-NH--(CH ₂ ) _2- (33)

671 4-Cl-Ph 4- CI-Ph 1 0--(c) _2- (34)

672 4-Cl-Ph 4-Cl-Ph 1 0--(C¾) _3- (34)

673 4-Cl-Ph 4- Cl-Ph - 0 - - (CH 2) 4 - (34)

674 4-Cl-Ph 4-Cl-Ph 1 0-_ (C) _2- (35)

675 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) ₃ _ (35)

676 4-Cl-Ph 4- Cl-Ph one _{0 - - (c) 4 -} (35)

677 4-Cl-Ph 4-Cl-Ph 1 0--(CH ₂ ) _2- (36)

678 4-Cl-Ph 4-Cl-Ph 1 0--(CH ₂ ) _3- (36)

679 4-Cl-Ph 4- CI-Ph 1 0--(CH ₂ ) (36)

680 4-Cl-Ph 4-Cl-Ph-S--(c¾) _2- (36)

681 4-Cl-Ph 4-Cl-Ph-NH--(c) _2- (36)

682 4-Cl-Ph 4-Cl-Ph "-0--(C¾) _2- (37)

683 4-CI- Ph. 4-CI- Ph 1 0--(CH ₂ ) _3- (37)

684 4-Cl-Ph 4- Cl-Ph -. 0 - - (CH 2) 4 - (37)

685 4-Cl-Ph 4-Cl-Ph -0--(CH ₂ ) _2- (38)

686 4-Cl-Ph 4-Cl-Ph-0--(C¾) _3- (38)

687 4 - CI - Ph 4- Cl-Ph one _{0 - - (c) 4 -} (38)

688 4-Cl-Ph 4-CI-Ph — 0—-(C¾) _2- (39)

689 • 4-Cl-Ph 4-CI-Ph .-0--(CH ₂ ) _2- (40)

690 4-CI-Ph '-Cl-Ph-0--(c) _3- (40)

691 4-Cl-Ph 4-Cl-Ph-0--(C¾) _2- (41)

692 4 - CI - Ph 4- Cl-Ph one 0- - (c Bruno ₂ - (42)

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

694 4-Cl-Ph '4-Cl-Ph-0--(C) _2- (43)

695 4-Cl-Ph 4-CI- Ph — 0--(CH ₂ ) _2- (44) 696 4-Cl-Ph 4-Cl-Ph 1 0--(CH ₂ ) _2- (45)

697 4-Cl-Ph 4-Cl-Ph-0--(c¾) _2- (46)

698 4-Cl-Ph 4-Cl-Ph-0--(c¾) _2- (47)

699 4-Cl-Ph 4-Cl-Ph-. --(CH ₂ ) _2- (48)

700 4-Cl-Ph 4-Cl-Ph 1 0--(CH ₂ ) _2- (49)

701 4-Cl-Ph 4- CI-Ph 1 0--(C¾) _2- (50)

702 4-Cl-Ph 4-Cl-Ph-0--(C¾) _2- (51)

703 4-Cl-Ph 4-Cl-Ph one 0--(CH ₂ ) _2- (52)

704 4-Cl-Ph 4- CI- Ph 1 0--(C) _2- (53)

705 4-Cl-Ph 4-Cl-Ph — 0—-(c¾) _2- (54)

706 4-Cl-Ph 4-Cl-Ph -0--(c) _2- (55)

707 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _3- (55)

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

709 4-Cl-Ph 4- CI-Ph-0--(CH ₂ no _3- (56)

710 4-Cl-Ph 4-CI- Ph 1 0--(CH ₂ ) _2- (57)

711 4-Cl-Ph 4-Cl-Ph-0-(57)

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

713 4-CI-Ph 4-CI- Ph -0--(C¾) _3- (58)

714 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) (59)

715 4-CI- Ph 4- CI- Ph-0--(CH ₂ ) _3- (59)

716 4 - CI - Ph · 4 -Cl-Ph - 0_ "(CH 2) 4 - (59)

717 4-Cl-Ph 4--Ph-0--(C) _2- (60)

718 4-Cl-Ph 4-Cl-Ph 1 0--(CH ₂ ) _3- (60)

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

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

721 4 CI-Ph 4-CI- Ph 1 0--(CH ₂ ) _2- (63) 722 4-Cl-Ph 4-Cl-Ph one 0--(CH ₂ ) _2- (64)

723 4-Cl-Ph 4-Cl-Ph-0--(c¾) _2- (65)

724 4-Cl-Ph 4-Cl-Ph-0--(c) _2- (66)

725 4-Cl-Ph 4-Cl-Ph 1 0--(c¾) _2- (67)

726 4-Cl-Ph 4-Cl-Ph one 0--(CH ₂ ) _2- (68)

727 4-Cl-Ph 4-Cl-Ph-0--(C¾) _2- (69)

728 4-Cl-Ph 4-Cl-Ph -0--(C¾) _2- (70)

729 4-Cl-Ph 4-Cl-Ph-0--(c¾) ₂ --(71)

730 4-Cl-Ph 4-CI-Ph -0--(C¾) _2- (72)

731 4-Cl-Ph 4-Cl-Ph 1 0--(CH ₂ ) _2- (73)

732 4-Cl-Ph 4- CI- Ph 1 0-1 (C) ₃ — (73)

733 4-Cl-Ph 4- Cl-Ph one _{0 - - (C¾) 4 -} (73)

734 4-Cl-Ph 4-Cl-Ph-0--(C¾) _2- (74)

735 4-Cl-Ph 4-Cl-Ph one 0--(C¾) _3- (74)

736 4-Cl-Ph 4- Cl-Ph - 0- - (C¾) 4 - (74)

737 4-Cl-Ph 4-Cl-Ph-S--(C) _2- (74)

738 4-Cl-Ph 4- CI-Ph -NH--(CH ₂ ) _2- (74)

739 4-Cl-Ph '4-Cl-Ph-0-(75)

740 4-Cl-Ph 4- CI-Ph — 0-"(CH ₂ ) _3- (75)

741 4-Cl-Ph 4- Cl-Ph - 0 - - (C¾) 4 - (75)

742 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (76)

743 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (77)

744 4-Cl-Ph 4-Cl-Ph-0—-(CH ₂ ) _2- (78)

745 4-Cl-Ph 4-Cl-Ph one 0--(c¾) _3- (78)

746 4-Cl-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (79)

747 4-1 Cl-Ph 4-Cl-Ph — 0—-(CH ₂ ) _2- (80) 748 2-Br-Ph 2-Br-Ph-0--(c) _2- (1)

749 2-Br-Ph 2-Br-Ph-o--. (CH ₂ ) _2- (15)

750 2-Br-Ph 2-Br-Ph 1 0--(c¾) _3- (15)

751 2-Br-Ph 2-Br-Ph-0--(CH ₂ ) _2- (18)

752 2-Br-Ph 2-Br-Ph 1 0-(21)

753 2-Br-Ph2-Br-Ph-0--(c) _2- (30)

754 2-Br-Ph 2-Br-Ph-0--(CH ₂ ) _3- (30)

755 2-Br-Ph 2-Br-Ph-0--(c¾) _2- (32)

756 2-Br-Ph 2-Br-Ph 1 0--(CH ₂ ) _2- (33)

757 2-Br-Ph 2-Br-Ph 1 0-_ (CH ₂ ) _2- (36)

758 2-Br-Ph 2-Br-Ph 1 0--(C) _2- (74)

759 3-Br-Ph 3-Br-Ph 1 0--(c) _2- (1)

760 3-Br-Ph 3-Br-Ph-0--(CH ₂ ) _2- (15)

761 3-Br-Ph 3-Br-Ph 1 0--(CH ₂ ) _3- (15)

762 3-Br-Ph 3-Br-Ph 1 0-_ (CH ₂ ) _2- (18)

763 3-Br-Ph 3-Br-Ph-0--(CH ₂ ) _2- (21)

764 3-Br-Ph 3-Br-Ph -0--(c¾) _2- (30)

765 3-Br-Ph 3-Br-Ph -0--(CH ₂ ) _3- (30)

766 3-Br-Ph 3-Br-Ph-0-"(CH ₂ ) _2- (32)

767 3-Br-Ph 3-Br-Ph-0--(C) _2- (33)

768 3-Br-Ph 3-Br-Ph-0--(C _2- (36)

769 3-Br-Ph 3-Br-Ph-0--(c¾) _2- (74)

770 4-Br-Ph 4-Br-Ph one 0--(CH ₂ ) _2- (1)

771 4-Br-Ph 4-Br-Ph-0-_ (CH ₂ ) _3- (1)

772 4-Br-Ph 4- Br-Ph - 0 - - (CH 2) 4 - (1)

773 4-Br-Ph 4-Br-Ph-0--(C) _2- (2) One HJ)-One U-One Ha-* ^ ^l V

 ττ τ

 l) σ

-(IID)-One LH 4d— One ¹⁷ ool ε / ヽ

 (Ϊ2)-(HO)-One J One LbL ヽ

 (12)-(HO)-one (J— 4d— τπ—

Ζ)-ΊΏ)-One Hd one ¹ ^ ^L U-7

 -(HO)-— ϋ— π 7bi

(6 Τΐ ヽ)-(H)-— ϋ 一 ϊ ΓΤ 4d— ^L H- eight 1

(6ΐ) ^-S CEO)--0-

(81)-(HO)-— 0-

(8ΐ)-(Η つ)-one 0-

(8ΐ)-(¾0)--0-

(LI)-(HO)-one 0-

-(HO) one -0- Ha one " ^L u ~ V

(9T)-(HD)-1 0-ττ-— Ha1 ”τ ^L πa-7

 /,

 (91)-("HO)-I 0--8-

^{(ST) - Ζ (Ή0)} - -H - - 8 -

^{(31) - ζ (¾0)} - one S - Hd ¾-

(ST)-(HO)-One 0—

 π Τ

-(HO)--0-4d-y "-4a ^L or ~ v

 (ST) One HO; One one 一 — Ha one ^ Ding

 ιη ~ ν σ— no f

(9) One (HJ-One U— 4a— ΤΠ

 Lo ~ v 4 α OLL

(S) one (, ΉΟ) - one ϋ- T HTa- ^L ay ττ τπ 0 one (HO) - one 0 - 4d - U- ττ ILL

^{(ε) - ε (¾ο)} - -0- - g- - jg - 9LL

(ε) ^-3 (¾0)--0- n-

^(Ζ) - ε (one ¾) - one 0- L .8C60 / I0df / X3d ^ Thus ίθ OAV 800 4-Br-Ph 4-Br-Ph one 0--(C¾) _3- (22)

801 4-Br-Ph 4-Br-Ph-0--(CH ₂ ) _2- (23)

802 4-Br-Ph 4-Br-Ph i 0--(c) _3- (23)

803 4-Br-Ph 4-Br-Ph One. --(C) _2- (24)

804 4-Br-Ph 4-Br-Ph 1 0- ~ (CH ₂ ) _2- (30)

805 4-Br-Ph 4-Br-Ph-0--(CH ₂ ) _3- (30)

806 4-Br-Ph 4- Br-Ph one _{0 - - (CH 2) 4} - (30)

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

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

809 4-Br-Ph 4-Br-Ph one 0--(C no (31)

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

811 4-Br-Ph 4-Br-Ph -0--(c¾) _2- (32)

812 4-Br-Ph 4-Br-Ph-0--(c¾) _3- (32)

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

814 4-Br-Ph 4-Br-Ph -0--(c¾) _2- (33)

815 '4-Br-Ph 4-Br-Ph-0--(C (33)

816 4-Br-Ph 4- Br-Ph - 0 - - (C) 4 - (33)

817 4-Br-Ph 4-Br-Ph-0--(c¾) _2- (34)

818 4-Br-Ph 4-Br-Ph •-0--(c¾) _3- (34)

819 4-Br-Ph 4-Br-Ph-0--(CH ₂ ) _2- (35)

820 4-Br-Ph 4-Br-Ph-0--(CH ₂ ) _3- (35)

821 4-Br-Ph 4-Br-Ph-0--(CH ₂ ) _2- (36)

822 4-Br-Ph 4-Br-Ph-0--(CH ₂ ) _3- (36)

823 4-Br-Ph 4-Br-Ph 1 0--(c¾) ₄ -'(36)

824 4-Br-Ph 4-Br-Ph-0--(C¾) _2- (37)

825 4-Br-Ph 4-Br-Ph 1 0--(CH ₂ ) _3- (37) 826 4- Br- Ph 4-Br-Ph — o_-(c¾) _2- (38)

827 4-Br-Ph 4-Br-Ph — 0--(c) _3- (38)

828 4-Br-Ph 4-Br-Ph-0_-(c) _2- (40)

829 4-Br-Ph 4-Br-Ph — 0--(c) ₂ -'(42)

830 4-Br-Ph 4-Br-Ph-0--(CH ₂ ) _2- (55)

831 4-Br-Ph 4-Br-Ph -o- _ (c¾) _2- (56)

832 4-Br-Ph 4-Br-Ph -0--(CH ₂ ) _2- (57)

833 4-Br-Ph 4-Br-Ph-0--(c¾) _2- (58)

834 4-Br-Ph 4-Br-Ph -0--(c¾) _2- (59)

835 4-Br-Ph 4-Br-Ph-0--(c¾) _3- (59)

836 4-Br-Ph 4-Br-Ph -0--(C¾) _2- (60)

837 4-Br-Ph 4-Br-Ph — 0--(CH ₂ ) _2- (73)

838 4-Br-Ph 4-Br-Ph-0--(c¾) _3- (73)

839 4-Br-Ph 4-Br-Ph. ー 0--(c¾) _2- (74)

840 4-Br-Ph 4-Br-Ph-0--(C¾) _3- (74)

841 4-Br-Ph 4- Br-Ph - 0 -. - (CH 2) 4 - (74)

842 4-Br-Ph 4-Br- Ph-0--(CH ₂ ) _2- (75)

843 4-Br-Ph 4-Br-Ph -0--(CH ₂ ) _3- (75)

844 4-Br-Ph 4-Br-Ph -0--(CH ₂ ) ₂ _ (78)

845 2- Me-Ph 2-Me-Ph-0--(CH ₂ ) _2- (1)

846 2- Me- Ph 2- Me Ph-0--(CH ₂ ) _2- (15)

847 2-Me-Ph 2-Me-Ph-0--(C¾) _3- (15)

848 2- Me- Ph 2-Me-Ph — 0--(CH ₂ ) _2- (18)

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

850 2-Me-Ph 2-Me-Ph-0--(CH ₂ ) _2- (30)

851 2-Me- Ph 2-Me-Ph 1 0-1 (CH ₂ ) _3- (30) 852 2-Me-Ph 2-Me-Ph-0--(c) _2- (32)

853 2-Me-Ph 2-Me-Ph-0--(c¾) _2- (33)

854 2-Me-Ph 2-Me-Ph-0--(c¾) _2- (36)

855 2-Me-Ph 2-Me-Ph 1 0--(CH ₂ ) _2- (74)

856 3-Me-Ph 3-Me-Ph-0--(CH ₂ ) _2- (1)

857 3- Me- Ph 3-Me-Ph-0--(c¾) _2- (15)

858 3- Me- Ph 3-Me-Ph-0--(CH ₂ ) _3- (15)

859 3-Me-Ph 3-Me-Ph one 0--(c) _2- (18)

860 3-Me-Ph 3-Me-Ph one 0--(CH ₂ ) _2- (21)

861 3-Me-Ph 3-Me-Ph one 0--(CH ₂ ) ₂ (30)

862 3-Me-Ph 3-Me-Ph-0--(c¾) _3- (30)

863 3-Me-Ph 3-Me-Ph-0--(C¾) _2- (32)

864 3-Me-Ph 3-Me-Ph-0--(c¾) _2- (33)

865 3-Me-Ph 3-Me-Ph — 0--(C¾) _2- (36)

866 3-Me-Ph 3-Me-Ph -0--(C) _2- (74)

867 4-Me-Ph 4-Me-Ph-0--(CH ₂ ) _2- (1)

868 4-Me-Ph 4-Me-Ph -0--(C¾) _3- (1)

869 4-Me-Ph 4-Me-Ph-0--(CH ₂ ) ₂ _ (2)

870 4-Me-Ph 4-Me-Ph _0--(c¾) _2- (3)

871 4-Me-Ph 4-Me-Ph-0--(C¾) _2- (15)

872 4-Me-Ph 4-Me-Ph-0--(C) _3- (15)

873 4-Me-Ph 4- Me-Ph - 0- - (CH 2) 4 - (15)

874 4-Me-Ph 4-Me-Ph-0--(CH ₂ ) _2- (16)

875 4-Me-Ph 4-Me-Ph -0--(CH ₂ ) 2-(17)

876 4-Me-Ph 4-Me-Ph -0--(CH ₂ ) _2- (18)

877 4-Me-Ph 4-Me-Ph — 0--(CH ₂ ) _3- (18) 878 4-Me-Ph 4-Me-Ph -o--(c) _2- (19)

879 4-Me-Ph 4-Me-Ph -o--(c¾) _2- (20)

880 4-Me-Ph 4-Me-Ph -0--(c) ₂ -'(21)

881 4-Me-Ph 4-Me-Ph one 0--(c¾) _3- (21)

882 4-Me-Ph 4-Me-Ph one 0--(CH ₂ ) _2- (22)

883 4-Me-Ph 4-Me-Ph-0--(c¾) _2- (23)

884 4-Me-Ph 4-Me-Ph one 0--(CH ₂ ) ₂ _ (30)

885 4-Me-Ph 4-Me-Ph 1 0-1 (c¾) _3- (30)

886 4-Me-Ph 4- Me-Ph one _{0 - - (CH 2) 4} - (30)

887 4-Me-Ph 4-Me-Ph i 0—-(C¾ ノ_2- (31)

888 4-Me-Ph 4-Me-Ph one 0--(CH ₂ ) ₂ _ (32)

889 4-Me-Ph 4-Me-Ph-0--(C¾) _3- (32)

890 4-Me-Ph • 4-Me-Ph one 0--(.¾ ノ_2- (33),

891 4-Me-Ph 4-Me-Ph-0--(c¾) ₃ _ (33)

892 4-Me-Ph 4-Me-Ph one 0--(c) _2- (34)

893 4-Me-Ph 4-Me-Ph one 0-- ~ (CH ₂ ) _2- (35)

894 4-Me-Ph 4-Me-Ph-0--(C¾) _2- (36)

895 4-Me-Ph 4-Me-Ph-0--(CH _{2 3-} (36)

896 4-Me-Ph 4-Me-Ph one 0--(C¾) _2- (37)

897 4-Me-Ph 4-Me-Ph-0--(CH ₂ ) _2- (38)

898 4-Me-Ph 4-Me-Ph-0-(C¾) _2- (59)

899 4-Me-Ph 4-Me-Ph 1 0-1 (CH ₂ 2-(73)

900 4-Me-Ph 4-Me-Ph-0--(C¾) _2- (74)

901 4-Me-Ph 4- Me-Ph 10 - A (C¾ Bruno ₃ one (74)

902 4-Me-Ph 4- Me-Ph - 0- one (C¾ Bruno ₂ one (75)

_{903 2-CF 3 -Ph 2 -} CF 3 - Ph one _{0- - (c) 2 - (} 1) 904 2-CF ₃ -Ph 2-CF ₃ -Ph-0--(c¾) _2- (15)

905 2-CF ₃ -Ph 2-CF ₃ -Ph-. 1-(CH ₂ ) _3- (15)

906 2-CF ₃ -Ph 2- CF ₃ -Ph-0--(c¾) _2- (18)

907 2-CF ₃ -Ph 2- CF ₃ -Ph-0--(c¾) _2- (21)

908 2-CF ₃ -Ph 2-CF ₃ -Ph — 0-"(CH ₂ ) _2- (30)

_{909 '2-CF 3 -Ph 2} - CF 3 - Ph - 0- - (CH 2) 3 "(30)

_{910 2 - CF 3 - Ph 2} -CF 3 -Ph - 0- - (c¾) 2 - (32)

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

_{912 2 - CF 3 - Ph 2} -CF 3 -Ph - 0 - - (c¾) 2 - - (36)

913 2-CF ₃ -Ph 2-CF ₃ -Ph -0--(CH ₂ ) _2- (74)

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

915 3-CF ₃ -Ph 3- CF ₃ -Ph-0--(c¾) _2- (15)

916 3- CF ₃ -Ph 3- CF ₃ -Ph-0--(c¾) _3- (15)

_{917 3 - CF 3 - Ph 3} -CF 3 -Ph - 0 - - (CH 2) 2 - (18)

918 3- CF ₃ -Ph '3-CF ₃ -Ph 1 0--(C¾) _2- (21)

919 3- CF ₃ -Ph 3- CF ₃ -Ph-0--(C) _2- (30)

_{920 3-CF 3 -Ph 3 -} CF 3 - Ph -0- - (CH 2) 3 - (30)

921 3-CF ₃ -Ph 3- CF ₃ -Ph -0--(CH ₂ ) _2- (32)

922 3-CF ₃ -Ph 3-CF ₃ -Ph -0--(c¾) _2- (33)

923 3_CF ₃ -Ph 3-CF ₃ -Ph-0--(C¾) ₂ -'(36)

924 3-CF ₃ -Ph 3-CF ₃ -Ph -0--(c¾) _2- (74)

925 4- CF ₃ -Ph 4-CF ₃ -Ph 1 0--(Cr¾) _2- (1)

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

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

928 4-CF ₃ -Ph 4-CF ₃ -Ph _0--(CH ₂ ) _2- (3)

929 4-CF ₃ -Ph 4-CF ₃ -Ph '—0—-((¾) _2- (15) _{930 4 - CF 3 - Ph 4} -CF 3 -Ph - 0 - - (c) 3 - (15) 931 4- CF 3 - Ph 4- CF 3 - Ph - 0 - - (c¾) 4 - (15) _{932 4- CF 3 - Ph 4-} CF, -Ph - 0 - - (c¾) 2 - (16) 933 4 - CF 3 - Ph 4-CF 3 -Ph - 0 - - (c) 2 - (17) 934 4-CF ₃ -Ph 4-CF ₃ -Ph 1 0--(CH ₂ ) _2- (18) 935 4-CF ₃ -P 4-CF ₃ -Ph-0--(CH ₂ ) _3- ( 18) 936 4-CF ₃ -Ph 4-CF ₃ -Ph-0--(CH ₂ ) _2- (19) 937 4-CF ₃ -Ph 4-CF ₃ -Ph-0--(CH ₂ ) ₂ -(20) 938 4-CF ₃ -Ph 4-CF-Ph-0--(C¾) _2- (21) 939 4-CF ₃ -Ph 4-CF ₃ -Ph-0--(CH ₂ ) ₃ -(21) 940 4-CF ₃ -Ph 4-CF ₃ -Ph 1 0--(c¾) _z- (22) 941 4-CF ₃ -Ph 4- CF ₃ -Ph 1 0--(CH ₂ ) _2- (23) 942 4-CF ₃ -Ph 4- CF ₃ -Ph 1 0--(CH ₂ ) _2- (30) 943 4-CF ₃ -Ph 4 CF ₃ -Ph 1 0--(C¾ _{) 3 - (30) 944 4} -CF 3 -Ph 4-CF 3 -Ph one _{0 - - (c¾) 4 -} (30) 945 4- CF 3 - Ph 4 - CF 3 -Ph -0- - (CH ₂ ) _2- (31) 946 4-CF ₃ -Ph 4- CF ₃ -Ph -0--(c¾) _2- (32) 947 4- CF ₃ -Ph 4-CF ₃ -Ph 1 0--( (CH ₂ ) (32) 948 4-CF ₃ -Ph 4-CF ₃ -Ph -0--(C¾) _2- (33) 949 4-CF ₃ -Ph 4-C F ₃ -Ph one. —-(CH ₂ ) _3- (33) 950 4-CF ₃ -Ph 4-CF ₃ -Ph 1 0—-(c¾) _2- (34) 951 4-CF ₃ -Ph 4-CF ₃ -Ph 1 0-"(CH ₂ ) _2- (35) 952 4-CF ₃ -Ph 4- CF ₃ -Ph 1 0--(c¾) _2- (36) 953 4-CF ₃ -Ph 4-CF ₃ -Ph -0-'(C¾) _3- (36) 954 4-CFj-Ph 4-CF ₃ -Ph-0-• (CH ₂ ) _2- (37) 955 4-CF ₃ -Ph 4- CF ₃ -Ph — 0 one ■ (C¾) _2- (38) 956 4- CF ₃ -Ph 4- CF ₃ -Ph-0--(CH ₂ ) _2- (59)

957 ■ 4-CF ₃ -Ph 4-CF ₃ -Ph-0--(C¾) _2- (73)

958 4-CF ₃ -Ph 4-CF ₃ -Ph-0--(CH ₂ ) _2- (74)

959 4-CF ₃ -Ph 4-CF ₃ -Ph-0--(CH ₂ ) _3- (74)

_{960 4 - CF 3 - Ph 4} -CF 3 -Ph one _{0- - (c¾) 2 - (} 75)

961 3-Cl-Ph Ph-0--(CH _{2 2-} (30)

962 3, 4-diF-Ph Ph ■ 1 0--(c¾) _2- (30)

_{963 3- N0 2 - Ph Ph -} . --(C¾) _2- (30)

964 3-Me-Ph Ph-0--(CH ₂ ) _2- (30)

 1

 965 3, 5-diF-Ph Ph-0-1 (30)

966 2-F-Ph 4-F-Ph one 0--(c¾) _2- (30)

 1

967 2, 5-diF-Ph Ph-0--(c¾) _2- (30)

968 2-F-Ph Ph I. One-(c¾) _2- (30)

969 2-CI- 5- N0 ₂ -Ph Ph -0--(CH ₂ ) _2-

970 3-F-Ph Ph-0--(C¾) _2- (30)

971 3, -diMe-Ph Ph — 0--(c¾) _2- (30)

972 4-F-Ph 4-F-Ph one 0--(CH ₂ ) _2- (87)

973 2-F-Ph 3-F-Ph -0— (30)

974 2-F-Ph 2- Cl-Ph -0- -. (0¾ Bruno ₂ - (30)

975 2-F-Ph 3-CI- Ph -0--(c¾) _2- (30)

976 2-F-Ph 4-Cl-Ph-0--(CH ₂ ) _2- (30)

977 2-F-Ph 3-Me-Ph _0--(CH ₂ ) _2- (30)

978 2-F-Ph 3- CF ₃ -Ph -0--(c¾) _2- (30)

979. 2-F-Ph 3-N0 ₂ -Ph — 0--(CH ₂ ) _2- (30)

980 3-F-Ph 4-F-Ph-0--(CH ₂ ) _2- (30)

981 3-F-Ph 2-CI one Ph — 0— one (c¾) _2- (30) 982 3-F-Ph 3-CI-Ph 1 0--(c¾) _2- (30)

983 3-F-Ph 4- CI-Ph-0—-(c¾) _2- (30)

984 3-F-Ph 3-Me-Ph-0--(c¾) _2- (30)

985 3-F-Ph 3-CF ₃ -Ph-0--(C) 2-(30)

986 3-F-Ph 3-N0 ₂ -Ph-0--(c¾) _2- (30)

987 2-Cl-Ph Ph-0--(CH ₂ ) ₂ -'(30)

988 2-Cl-Ph 3-CI-Ph. One-(c¾) _2- (30)

989 2-Cl-Ph 4-CI-Ph-0--(c¾) _2- (30)

990 2-Cl-Ph 3-Me-Ph -0--(c¾) _2- (30)

991 2-Cl-Ph 3-CF ₃ -Ph-0-1

-(c) _2- (30)

992 2-Cl-Ph 3- N0 2 -Ph -0- - (c) 2 - (30)

993 3-Cl-Ph 4-Cl-Ph .- 0--(c) _2- (30)

994 3-Cl-Ph 3-Me-Ph-0--(CH ₂ ) _2- (30)

995 3-Cl-Ph 3-CF ₃ -Ph one 0-(30)

996 3-Cl-Ph 3-N0 ₂ -Ph -0--(c¾) _2- (30)

997 3-Me-Ph 4-F-Ph-0--((¾) 2-(30)

998 3-Me-Ph 4- CI- Ph -0--(c¾) _2- (30)

999 3-Me-Ph 3- CF ₃ -Ph -0--(c) _2- (30)

1000 3-Me-Ph 3- N0 ₂ -Ph _0--(c¾) _2- (30)

1001 3-CF ₃ -Ph Ph-0--(c¾) _2- (30)

1002 3-CF ₃ -Ph 4-F-Ph-0--(c) _2- (30)

1003 3-CF ₃ -Ph 4-Cl-Ph 1 0--(c¾) _2- (30)

1004 3-CF ₃ -Ph 3-Me-Ph-0--(CH ₂ ) _2- (30)

_{1005 3-CF 3 -Ph 3-} N0 2 -Ph - 0- - (c) 2 - (30)

_{1006 3- N0 2 - Ph 4-} F-Ph scratch. —-(C¾) _2- (30)

1007 3-N0 ₂ -Ph 4-Cl-Ph —0— one (c) _2- (30) 1008 3-N0 ₂ -Ph 4-CF ₃ -Ph 1 0--(CH ₂ ) _2- (30)

1009 2, 3-diF-Ph Ph -0--(CH ₂ ) _2- (30)

1010 2, 3-diF-Ph 2, 3-diF-Ph — 0--(c¾) _2- (30)

1011 2, 4-diF-Ph Ph One. One-(c¾) _2- (30)

1012 2, -diF-Ph 2, 3-diF-Ph one 0--(c¾) _2- (30)

1013 2,5-diF-Ph 2, 5-diF-Ph-0--(Cr¾) 2-(30)

1014 2, 6-diF-Ph Ph-0--(c¾) _2- (30)

1015 2, 6-diF-Ph 2, 6-diF-Ph — 0--(CH ₂ ) _2- (30)

1017 3, 5-diF-Ph 3, 5-diF-Ph — 0--(c¾) _2- (30)

1018 2-F-Ph Ph 1 0--(CH ₂ ) _3- (30)

1019 2-F-Ph 3-F-Ph one 0--(c¾) _3- (30)

1020 2-F-Ph 4-F-Ph one 0--(CH ₂ ) _3- (30)

1021 3-F-Ph Ph 1 0--(C¾) _3- (30)

1022 2-Cl-Ph 4-Cl-Ph -0--(Cn ₂ ) 3-(30)

1023 3-Cl-Ph Ph _0--(c¾) _3- (30)

1024 3- Me- Ph Ph — 0—-(C¾) _3- (30)

1025 3-N0 ₂ -Ph Ph-0--(C¾ ノ_3- (30)

1026 2, 4-diF-Ph 2, 4-diF-Ph-0--(CH ₂ ) _2- (30)

1027 3, 5-diCF ₃ -Ph 3, 5- diCF ₃ -Ph-0--(c¾) _2- (30)

1028 3, 4, 5-triF-Ph Ph-0--(C¾) _2- (30)

1029 3, 4-diF-Ph 4-CN-Ph one 0--(CH ₂ ) _2- (30)

1030 3, 4-diF-Ph 3-CN-Ph-0-"(CH ₂ ) _2- (30)

1031 3- CF ₃ -Ph 3-CN-Ph — 0--(CH ₂ ) _2- (30)

1032 2, 3, 4, 5, 6-pentaMe-Ph Thi (2)-0--(CH ₂ ) _2- ■ (30)

1033 2,4-diF-Ph 2, 4-diF-Ph-0--(CH ₂ ) _3- (30)

1034 3,4-diF-Ph 3, 4-diF-Ph 1 0--(CH ₂ ) _3- (30) 1035 3, 4-diF-Ph 3-CN-Ph -0--(CH ₂ ) _3- (30)

1036 3, 4-diF-Ph 4-CN-Ph-. --(C) _3- (30)

1037 3- CF ₃ — Ph 3-CN-Ph 1 0—-(C¾) _3- (30)

In the above table, preferred compounds include

Compound number: 146, 188-214, 231-357, 377-398, 481, 482, 577-593, 602-676, 688-699, 746, 919, 920 and 961-1037,

 Further preferred compounds include

Compound number: 146, 188-191, 196-198, 201-203, 206-214, 231-236, 245-247, 250-252, 255-259, 264-266, 269-271, 274-278, 283-285, 288-290, 293-312, 321-325, 330-334, 339-343, 348-350, 353-355, 377-398, 481, 482, 648, 919, 920 and 961-1037 Can be mentioned,

 '' More preferred compounds include

Compound number: 146, 188, 196, 201, 206, 209, 212, 215, 217, 219, 221, 223, 225, 227, 229, 232, 245, 250, 256, 264, 269, 275, 283, 288 , 293, 296, 298, 300, 303, 305, 308, 322, 331,. 340, 348, 353, 359, 367, 372, 377, 379, 382, 384, 387, 389, 391, 393, 395, 397, 399, 401, 403, 405, 407, 409, 411, 414, 417, 420, 423, 428, 431, 433, 435, 437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 461, 469, 474, 476, 478, 481, 483, 485, 488, 491, 495, 498, 502, 919, 920 and 961-1037,

 Even more preferred compounds include

Compound No. 146: 8- [2-bis (3-fluorophenyl) methoxethyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one,

Compound No. 1δ8: 1- [2-bis (4-fluorophenyl) methoxhetyl] -4-phenylbiperidine-4-carboxylic acid amide,

Compound No. 212: 1- [2-bis (4-fluorophenyl) methoxhetyl] -4 -phenylene ぺ lysine-4-carboxylic acid morpholine amide,

Compound No. 229: 1- [2-bis (4-fluorophenyl) methoxyethyl] -4- [1- (4-fluorobenzyl) -1H-benzimidazol-2-yl] -4-hydroxy; t. Peridine, Compound No. 232: 1- [2-bis (4-fluorophenyl) methoxethyl] -4- (2-pyridyl) piperidine-4-carboxylic acid amide,

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

Compound number 309: 8- [3-bis (4-fluorophenyl) methoxypropyl] -1-oxa-3,8-dazaspiro [4.5] decane-2-one,

Compound number 322: 8- [2-bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-oxa-3,8-diazaspiro [4.5] decane-2-one,

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

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

Compound No. 348: 8- [2- bis (4-Furuorofu - sulfonyl) method Tokishechiru] - 3 - Hue - Le - 1 - Chio - ^{3, 8} - Jiazasupiro ^[5] decane - 2-one,

Compound No. 367: 8- [2-bis (4-fluorophenyl) methoxhetyl] -1-phenenole-1,3,8-triazaspiro [4.5] decane-4-one,

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

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

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

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

Compound No. 393: 1- [2-bis (4-fluorophenyl) methoxhetyl] spiro [(indane) -1,4'-piperidine],

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

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

Compound No. 417: 2- [1- [2-bis (4-fluoropheninole) methoxhetyl] -piperidine_4-yl] p-mouth ethyl pionate,

Compound number 423: Methylester 2- [1- [2- [2-bis (4-fluorophenyl) methoxethyl] -piperidine-4-yl] -2-cyanoacetate,

Compound No. 441: 1- [2-bis (4-fluorophenyl) methoxhetyl] piperidine-4-benzyl sulfonic acid,

Compound number 461: 1- [2-bis (4-fluorophenyl) methoxethyl] -piperidine-4-ylidene] -propionic acid methyl ester,

Compound No. 478: 1- [2-bis (4-fluorophenyl) methoxhetyl] -4-ethoxyxanolorenorinobiperazine,

Compound number 481: 1- [2-bis (4-fluorophenyl) methoxyethyl] spiro [benzo [c] thiophen-1 (3H), 4, -piperidine] -2,2-dioxide,

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

Compound No. 6: 8- [2-bis (4-octaphenyl) methoxyl] -1-oxa-3,8-diazaspiro [ ⁵ ] decane-2-one,

Compound No. 919: 8- [2-bis (3-trifluoromethylphenyl) methoxethyl] -1-oxa-3,8-diazaspiro [45] decane-2-one,

Compound No. 920: 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propane } -8-Methyl-1-oxa-3-aza-8-azonia-spiro [4,5] decane-2-one, Compound No. 961: 8- {2-[(3-chlorophenyl) phenylmethoxy] 1-oxa-3,8-diazaspiro [4.5] decane-2-one,

Compound No. 962: 8- {2-[(3,4-difluorophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one,

Compound No. 9: 8- {2-[(3-nitrophenyl) phenylmethoxy] ethyl} -1-oxa'-3,8-diazaspiro [4.5] decane- ² -one,

Compound No. 964: 8- {2-[(3-methylphenyl) phenylmethoxy] ethyloxa_3, 8-diazaspiro [4.5] decane-2-one,

Compound No. 965: 8 2-[(3,5-difluorophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one,

Compound No. 966: 8- {2 _ [(2-fluorophenyl) (4-fluorophenyl) methoxy] ethyloxa- 3,8-diazaspiro [4: 5] decane-2-one,

Compound No. 967: 8- {2-[(2,5-difluorophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspirate [4.5] decane-2-one,

Compound No. 968: 8- {2-[(2-fluorophenyl) phenylmethoxy] ethyl} -1-oxo-3,8-diazaspiro [4.5] decane-2-one,

Compound No. 969: 8- {2- [(2 - Black port - 5 - Two Torofueniru) Fuenirume butoxy] E Chi le} - 1-Okisa - 3, ⁸ - Jiazasupiro [4.5] decane - ² _ one,

Compound No. 971: 8-{2 _ [(3,4-dimethylphenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one;

Compound No. 972: 1- [2-bis (4-fluorophenyl) methoxethyl] -4- (4-cyclobenzyl) piperidine-4-carboxylic acid methyl ester,

Compound No. 989: 8- {2-[(2-chlorophenyl) (4, -chlorophenyl; methoxy] ethyl] -1-oxoxa-3,8-diazaspiro [4,5] decane-2 On,

Compound number 1001: 8-[(3-trifluoromethylphenyl) phenylmethoxy] ethy Nore}-1-oxa- ³ , ⁸ -dazaspiro [5] decane- ² -one,

Compound No. 1010: 8- {2- [bis - (2, 3 - difluoromethyl O Lof enyl) method butoxy] Echiru} - 1-O hexa - 3, ⁸ - Jiazasupiro [4, ^5] decane - ² - one,

Compound No. 1016: 8-{2_ [bis- (3,4-difluorofluoro) methoxy] ethyl) -1 -oxa-3,8-diazaspiro [4,5] decane-2-one;

Compound No. 1017: 8- {2- [bis- (3,5-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one,

Compound No. 1026: 8- {2_ [bis- (2,4-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [5] decane-2-one,

Compound No. 1027: 8- {2- [bis- (3,5-ditrifluoromethylphenyl) methoxy] ethyloxa-3,8-diazaspiro [4,5] decane-2-one,

Compound No. 1028: 8- {2-[(3,4,5-trifluorophenyl; nyl) phenylmethoxy] ethylenoxa-3,8-dazaspiro [4,5] decane-2-one,

Compound No. 1029: 8- {2-[(4-Cyanophenyl) (3,4, -difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2 -On,

Compound No. 1030: 8- {2-[(3-Cyanophenyl) (3,4'-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one ,

Compound No. 1031: 8- {2-[(3-Cyanophenyl) (3, -trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one ,

Compound number 1032: 8- {2-[(2,3,4,5,6-pentamethylphenyl) (2'-thiophene) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4 , 5] decane-2-one,

Compound No. 1034: 8- {3- [bis- (3,4-difluorophenyl) methoxy] propyl 1-oxa-3,8-diazaspiro [4,5] decane-2-one, '

Compound No. 10 ³ 5: ⁸ - {3- [(3- Shianofueniru) (3 ', 4, - Jifuruoro' phenyl) method butoxy] propyl Okisa -3, 8 Jiazasupiro [4, 5] decane - 2-one,

Compound No. 1036: 8--[(4-Cyanobundyl) (3,4, -difluorophenyl) methoxy] Propyloxa-3,8-diazaspiro [4,5] decan-2-one and compound number 1037: 8-{3-[(3-Cyanophenyl) (3, -trifluoromethylfuunyl) methoxy] propyl ) -1-Oxa-3,8-dazaspiro [4,5] decane-2-one

The most preferred compound is

Compound No. 146: 8- [2-bis (3-fluorophenyl) methoxhetyl] -oxa-3,8-diazaspiro [4.5] decane-2-one,

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

Compound No. 919: 8- [2-bis (3-trifluoromethylphenyl) methoxethoxyl] -1-oxoxa-3,8-diazaspiro [4.5] decane-2-one,

Compound number 920: 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one,

Compound No. 961: 8--[(3-chlorophenyl) phenylmethoxy] ethyl}-1-oxa-3,8-diazaspiro [4.5] decane-2-one,

Compound No. 962: 8--[(3,4-difluorophenyl) phenylmethoxy] ethyl}-1-oxa-3, 8-diazaspiro [4.5] decane-2-one,

Compound No. 963: 8- {2-[(3-ditrophenyl) furmethoxy] ethyl) -1-oxa-3,8-diazaspiro [4,5] decane-2-one,

Compound No. 964: 8- {2-[(3-methylphenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2_one;

Compound No. 965: 8- {2-[(3,5-difluorophenyl) phenylmethoxy] ethyl) -1-oxa-3,8-diazaspiro [4.5] decane-2-one,

Compound No. 966: 8- {2-[(2-fluorophenyl) (4-fluorophenyl) methoxy] ethyl}-1-oxa-3,8-diazaspiro [4.5] decane-2-one,

Compound No. 967: 8--[(2,5-difluorophenyl) phenylmethoxy] ethyl}-1-oxa-3, 8-diazaspiro [4.5] decane-2-one, Compound No. 968: 8- {2-[(2-Fluorophenyl) phenylmethoxy] ethyl} -1-oxo-3,8-diazaspiro [4,5] decane-2-one,

Compound No. 969: 8- {2- [(2-Black mouth - 5- Etorofu enyl) Hue - Rume butoxy] E Chi le} - 1-Okisa - ^{3, 8} _ Jiazasupiro ^[5] decane - ² - one.

Compound No. 971: 8- {2-[(3,4-dimethylphenyl) phenylmethoxy] ethyl} -toxa-3,8-diazaspiro [4,5] decane-2-one;

Compound No. 989: 8- {2-[(2-chlorophenyl) (4'-chlorophenyl) methoxy] ethynole} -1-oxoxa-3,8-diazaspiro [ ⁵ ] decane- ² -one;

Compound No. 1001: 8- {2-[(3-trifluoromethylphenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diaza, spiro [4.5] decane-2- On,

Compound No. 1010: 8- {2- [bis- (2,3-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one,

Compound number 1016: 8- {2- [bis- (3,4-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-dazaspiro [4,5] decane-2-one,

Compound number 1017: 8- {2- [bis_ (3,5-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one,

Compound No. 1026: 8- ^{2 - [bis - ^{(2, 4} - difluoro Fe - Le) method butoxy] Echiru} - 1 - O hexa - 3, 8-Jiazasupiro [4, 5] decane - 2-one,

Compound No. 10 ² §: 8- {2 - [bis - (3, 5 - di Full O b methyl phenylalanine) method butoxy] We chill Okisa -3, 8 Jiazasupiro [4, 5] decane - 2-one,

Compound No. 1028: 8- {2-[(3,4,5-trifluorophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one,

Compound No. 1029: 8--[(4-Cyanophenyl) (3 ', 4, -difluorophenyl) methoxy] ethyl}-1-oxa-3,8-diazaspiro [4,5] decane-2-one ,

Compound No. 1030: 8 - [(3-Shianofuweniru) (3 ', 4' - difluorenylamino O Lof enyl) method butoxy] Echiru) - Bok Okisa - ^3, 8-Jiazasupiro ^[4, 5] decane - 2-one, Compound No. 1031: 8- {2 - [(3-Shianofueniru) (3, - triflumizole Ruo B methyl fuel) method butoxy] Echiru} - Okisa _3, 8 Jiazasupi port [4, 5] decane - 2-one,

Compound No. 1034: 8- {3- [bis (3,4-difluorophenyl) methoxy] propyloxa-3,8-diazaspiro [4,5] decane-2-one,

Compound number 1035: 8- {3-[(3-Cyanophenyl) (3,4'-difluorophenyl) methoxy] propyloxa-3,8-diazaspiro [4,5] decane-2-one,

Compound No. 1036: 8- {3-[(4-Cyanophenyl) (3,4, -difluorophenyl) methoxy] propyl: oxa-3,8-diazaspiro [4,5] decane-2-one and

Compound No. 1037: 8- {3-[(3_cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl}-1-oxa-3,8-diazaspiro [4,5] decane-2- On

Can be mentioned.

BEST MODE FOR CARRYING OUT THE INVENTION

Compound (I) of the present invention can be produced according to the method described below ₍ Method A is a method for producing compound (I)).

Method A

 (IV)

In the above formula, RR ^2, X, Y and L have the same meanings as described above, R ^la, R ^2a and L _a is amino contained as substituents group I ^1, R ²及Pi L group, a hydroxyl及Pi Z or a carboxyl group with each protected or an amino group, other is a hydroxyl group and / or carboxyl sheet group. indicate the same groups in the definition of group R \ R ² and L And Q are not particularly limited as long as they are usually a group capable of leaving as a nucleophilic residue, but are preferably halogen atoms such as chlorine, bromine and iodine; and trihalogenomethyl such as trichloromethyloxy. Lower alkyl groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno lower alkyl groups such as trifluoromethanesulfonyloxy and pentafluoronorsulfonoloxy groups; / Lephonyloxy group Or an arylsulfonyloxy group such as benzenesulfonyloxy, p-tonolenesnorefony / reoxy, p-nitrobenzenesulfonyloxy, and preferably a halogen atom and a lower alkanesulfonyloxy group. A xy group, and most preferably a nitrogen atom or a logogen atom. In the above, R ^la, "protecting group" in "protected amino group which may be" in the definition of R ^2a and L _a., The particularly limited as long as it is a protecting group of Amino groups used in the field of organic synthetic chemistry For example, halogeno C ₂ such as C, 1 CJ aliphatic acyl group, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc. Is c ₁₀ § reel to a carbonyl group - a c _6; one C ₇ alkylcarbonyl El group, "aliphatic Ashiru such" of such C- and alkoxy in replacement has been c ₂ -c ₇ alkylcarbonyl group as main Tokishiasechiru bound C ₇ - C _u aromatic Ashiru group, 2 one Puromopenzoiru, 4 one black orifice halogeno C ₇ such as Benzoiru - C _u aromatic Ashiru group, 2, 4, 6-Application Benefits methylbenzoyl I le, 4 one C ₇ one C _u aromatic Ashiru group substituted with one C ₆ alkyl, such as toluoyl, C ₇ substituted by Cj-Ce alkoxy, such as 4 Anisoiru - C "aromatic Ashiru group, 4 twelve Torobe C ₇ -C „aromatic radicals, such as benzoyl, 2-nitrobenzoyl, and C ₂ -C ₇ alkoxy radicals, such as 2- (methoxycarbonyl) benzoyl, C ₇ substituted with alkoxycarbonyl — C u aromatic group, 4-phenyl C _6, such as Le base Nzoiru -. An “aromatic acyl” such as a C ₇ —C „aromatic acyl group substituted with aryl; the C ₂ —C ₇ alkoxycarbonyl group, 2,2, '2-trichloroethoxycanoleponinole, 2 trimethylolpropane Honoré silica Honoré ethoxy force / repurchase dihalide or tri C such as Le - C ₆ C ₂ substituted by an alkyl silyl - C ₇ alcohol Kishikarubo - such as Le group "alkoxycarbonyl - Le acids", vinyl “Alkyloxycarbonyls” such as oxycarbonyl and aryloxycarbonyl; benzyloxy force / repotinole, 4-methoxypentinoleoxycanolepo / re, 3,4-dimethoxybenzinole oxy Kano levo sulfonyl, 2 Torobe Njinore old carboxymethyl Kano levo Nino les, 4-nitro base, such as Nji Ruo alkoxycarbonyl, "1 to two C - C ₆ alkoxy or - § reel ring substituted by Toro Which may § Lal Kill O alkoxycarbonyl such "; trimethylsilyl, Toryechirushiriru, isopropyl dimethylsilyl, t one heptyl dimethyl silyl, methyl Jie Seo professional building silyl, Mechiruji t- butylsilyl, tri one such as triisopropylate Rushiriru C ₆ alkylsilyl group, diphenyl methyl silyl, diphenyl E sulfonyl-butylsilyl, Jifue two Le isopropyl building silyl, phenyl 'Jiisopurobirushi § Lil及Pi 〇 such as Lil, was three substituted with a group selected from a C ₆ alkyl "Silyls" such as silyl group; benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethinole, | 3-naphthylmethyl, diphenylmethinole, triphenylmethinole, a; —a C, 1C ₆ alkyl group substituted with 1 to 3 aryl groups such as naphthyldiphenylmethyl, 9—anthrylmethyl, 4-methylbenzyl, 2,4,6-tri Methylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 41-methoxyphenis-lezinenolemethinele, 2-nitrobenzinole, 4-nitrobenzinole, 4-chlorobenzinole, 4 1 C ₆ alkyl, C ₆ alkoxy, Etro, halogen, cyano, such as 1-bromobenzinole, 4-cyanobenzyl 7-, 4-cyanobenzyldiphenyl-methyl, bis (2-diphenyl) methyl, pyridine "Aralkyls" such as a 1-alkyl group substituted with 1 to 3 aryl groups substituted with an aryl ring; or N, N-dimethylaminoaminomethylene, benzylidene, Methoxy be Substituted to form "Schiff bases" such as dilydene, 4-122 benzylidene, salicylidene, 5-chlorosalicylidene, dipheninolemethylene, (5-chloro-2-hydroxyphenynole) pheninolemethylene A methylene group '', preferably an aliphatic acyl, an alkoxycarbonyl or an alkenyloxycarbonyl, more preferably an alkoxycarbonyl, most preferably a C ₂ -C ₇ alkoxy It is a carbonyl group.

In the above, R ^la, "protecting group" in "protected which may be hydroxy group" in the definition of R ^2a and L _a is not particularly limited as long as it is a protecting group for hydroxyl group used in the field of organic synthetic chemistry For example, it has the same meaning as the above-mentioned "general protecting group for an ester of a hydroxyl group", and is preferably an aliphatic acyl group or an aromatic acyl group, and most preferably an aliphatic acyl group. . In the above, R ^la, "protecting group" of the "protected may be carboxy group" in the definition of R ^2a and L _a is., Especially if Re protecting groups der carboxy groups used in the field of organic synthetic chemistry Although it is not limited, for example, it has the same meaning as the above “general deprotection group for ester of carboxy group”, preferably, lower alkyl group or halogeno lower alkyl. And more preferably a ^ alkyl group, most preferably a methyl or ethyl group.

Step A1 is a step for producing the compound (I) of the present invention. The compound having the general formula (IV) is prepared by converting the compound having the general formula (III) into a compound having the general formula (IV) in an inert solvent in the presence of a base. After reacting with acid addition salts (eg, mineral salts such as hydrochloride, nitrate, sulfate), protection of amino, hydroxyl and Z or carboxyl groups in R ^la , R ^2a and 1 ^ if desired This is done by removing the group. ,

 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 a certain extent. Examples of the inert solvent include hexane, heptane, ligwin, and petroleum ether. Aliphatic hydrocarbons such as benzene, toluene, xylene; Aromatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, and dichlorobenzene Esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycolone resin methinoleate. Ethers such as Tenoré; acetone, methyl ethyl ketone, 4- Ketones such as methyl-2-pentanone, isophorone and cyclohexanone; nitrated compounds such as nitroethane and -trobenzene; nitriles such as acetonitrile and isoptimouth etryl; formamide, N, N-dimethyl Amides such as formamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphoric triamide; or sulfoxides such as dimethyl sulfoxide and sulfolane And preferably ketones, amides, ethers or -tolyls, more preferably ketones (most preferably 4-methinole-2 ^ tantanone).

The base used in the above reaction is used as a base in a normal reaction. Although there is no particular limitation, for example, alkali metal iodides such as lithium iodide, sodium iodide, and potassium iodide; and alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; lithium hydrogen carbonate, Alkali / recali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride, and lithium hydride; lithium hydroxide, sodium hydroxide, and hydroxide Alkali metal hydroxides such as potassium; or a combination with inorganic bases such as alkali metal fluorides such as lithium fluoride, sodium fluoride and fluorinated lime, or N-methylmorpholine, triethylamine , Tripropylamine, Tryptinoleamine, Disopropylethylamine, Dishik mouth Xylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethinoleamino) pyridine, 2,6-di (t-p-tinole) 14-methylpyridine, quinoline, N, N— Dimethylaniline, N, N-Jetylaniline, 1,5-Diazabicyclo [4.3.0] Noner 5-ene (DBN), 1,4-Diazabicyclo mouth [2.2.2] octane (DAB CO ), 1,8-diazabicyclo [5.4.0] —7- organic amines, such as pendene (DBU), preferably in combination with inorganic bases and inorganic bases. Yes, more preferably, a combination of an alkali metal iodide and an alkali metal carbonate, and most preferably, a combination of sodium iodide and sodium carbonate. 'The reaction temperature varies depending on the starting compound, the reagent used, the solvent, etc., but is usually 120. C to 250 ° C (preferably 0 ° C to 170 ° C).

The reaction time varies depending on the starting compound, the reagent used, the solvent, the reaction temperature and the like, but is usually 15 minutes to 50 hours (preferably 1 hour to 24 hours). Removal of protecting groups for amino group, hydroxyl group and carboxy group depends on the type thereof. Methods generally known in the art of organic synthetic chemistry, for example, TWGreen, (Protective Groups in Organic Synthesis), John Wiley &'Sons: FW McOmis, (Protecti ve Groups in Organic Chemistry), Plenum Press. When the protecting group of the amino group is a silyl, usually, a compound that generates a fluorine ion such as tetrabutylammonium fluoride, hydrofluoric acid, monopyridine hydrofluoride, or potassium fluoride. And is removed by treating with

 The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethinoleate. Ethers are preferred.

 The reaction temperature and the 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 protecting group for the amino group is an aliphatic acyl, an aromatic acyl, an alkoxycarbinole, or a substituted methylene group forming a Schiff base, the acid or the acid may be added in the presence of an aqueous solvent. It can be removed by treating with a base.

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

The base used in the above reaction is not particularly limited as long as it is generally used as a base and does not inhibit the reaction. Preferably, an alkali metal such as lithium carbonate, sodium carbonate, and potassium carbonate is used. Carbonates; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium methoxide, potassium-t-butoxide; Or ammonia such as aqueous ammonia or concentrated ammonia-methanol. The solvent used in the above reaction is not particularly limited as long as it is used in a usual hydrolysis reaction. For example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t—Ptanol, isoamyl alcohol—Nore, diethylene glycol, glycerin, octanol, cyclohexanol, methyl socole alcohols, such as sozolev; Ether; water; or a mixed solvent of water and the above organic solvent, preferably ethers (most preferably dioxane).

The reaction temperature and reaction time vary depending on the starting compound, the solvent, and the acid or base used, and are not particularly limited. However, in order to suppress a side reaction, the reaction temperature is usually from o ° C to 150 ° C. ° C, and the reaction time is 1 hour to 10 hours. In the case of aralkyls or aralkyloxycarbols, the protective group is usually brought into contact with a reducing agent in an inert solvent (preferably at room temperature under a catalyst at room temperature). A method of removing by catalytic reduction) or a method of removing with an oxidizing agent is preferable. The inert solvent used for the removal by catalytic reduction is not particularly limited as long as it is inert to the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether. Aromatic hydrocarbons such as toluene, benzene, and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane Ethers such as dimethoxetane, diethylene glycol dimethyl ether; methanol, ethanol, n-prono. Alcohols such as phenol, isopropanol, 'η-butanol, isoptanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, otatanol, cyclohexanol, and methyl acetate; organic such as acetic acid 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 to be used for the removal by catalytic reduction is not particularly limited as long as it is generally used for the catalytic reduction reaction, but is preferably palladium monocarbon, Raney nickel, platinum oxide , Platinum black, rhodium aluminum monoxide, triphenylphosphine rhodium monochloride, and palladium monosulfate barium.

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

 The reaction temperature and reaction time vary depending on the starting compound, the catalyst, the inert solvent, etc., and are usually from 0 ° C to 100 ° C, and the reaction time is from 5 minutes to 24 hours. It is.

 The inert solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the reaction, but is preferably a water-containing organic solvent. Such organic solvents include, for example, ketoform, dichloromethane, 1,2-dichloroethane, halogenated hydrocarbons such as carbon tetrachloride; nitriles such as acetoetrile, getyl ether, diisopropyl ether, Ethers such as tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether: ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphate triamide; or Sulfoxides such as dimethyl sulfoxide and sulfolane, preferably halogenated hydrocarbons, ethers or sulfoxides (most preferably halogenated hydrocarbons or sulfoxides).

 The oxidizing agent used is not particularly limited as long as it is a compound used for the oxidation, but is preferably potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3-dichloromethane.口 一 5 and 6-dicyanor ρ-benzoquinone (DDQ).

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent, and the like, but the reaction temperature is usually 0. C to 150 ° C., and the reaction time is 10 minutes to 24 hours. Further, when the protecting group of the amino group is an aralkyl, the protecting group can be removed using an acid.

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

The inert solvent used in the first-stage reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether Aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichlorotan, and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate; Esters such as butyl acetate and getyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethyleneglyconoresinmethinole ether; methanol, ethanol, n-propanol, and iso Propanol, _n -butanol, isobutanol, t-butano Alcohols such as alcohol, isoaminophenol, diethylene glycol, glycerin, octanol, hexanol hexanol, and methyl sorbet; formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide. And water; or a mixed solvent of the above solvents, preferably ethers, alcohols or water (most preferably dioxane, tetrahydrofuran, ethanol or water). The reaction temperature varies depending on the starting compound, the acid used, the solvent, and the like. The reaction time varies depending on the starting compound, the acid used, the inert solvent, the reaction temperature and the like. The reaction time is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours). When the protecting group for the amino group is an alkenyloxycarbol, the protecting group for the amino group is usually the same as the above-mentioned aliphatic acyls, aromatic acyls, alkoxycarbols or Schiff bases. It is carried out by treating with a base in the same manner as the conditions for the removal reaction when the substituted methylene group is formed.

 It should be noted that the aryloxycarbol group can be easily removed by using palladium, triphenylphosphine or Eckeltetracarbol, and the reaction can be carried out with few side reactions. . When a silyl group is used as a protecting group for a hydroxyl group, it is usually treated with a compound that generates fluorine cation such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or lithium fluoride. Or an inorganic acid 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 treating with an organic acid such as

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

 The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction, but is preferably dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl. Ethers such as ether; nitriles such as aceto-tolyl and isobutyronitrile; organic acids such as acetic acid; water;

The reaction temperature and the reaction time vary depending on the starting compound, the catalyst, the inert solvent and the like, but the reaction temperature is usually 0. C to 100 ° C (preferably 10 ° C to 50 ° C) The time is from 1 hour to 24 hours.

When the protecting group for the hydroxyl group is an aralkyl group or an aralkyloxycarbonyl group, it is usually contacted with a reducing agent in an inert solvent (preferably by catalytic reduction at room temperature under a catalyst at room temperature). A method of removing or a method of removing with 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 the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; Aromatic hydrocarbons such as toluene, benzene, and xylene; esters such as ethyl acetate and propyl acetate; such as getyl ether, disop pirate ethere, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether Ethers such as methanol, ethanol, _n- propanol, isopropanol, n-butanol, isoptanol, t-butanol, isoamyl alcohol, diethylene glycolone, glycerin, octanol, cyclohexanol, and methyl sorbanol Like al Amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, and hexamethylphosphate triamide; fatty acids such as formic acid and acetic acid; water; It is a mixed solvent of solvents, and is preferably an alcohol (most preferably methanol).

 The catalyst used for the removal by catalytic reduction is not particularly limited as long as it is usually used for the catalytic reduction reaction.For example, palladium-carbon, palladium-black, Raney nickel, platinum oxide, platinum black, platinum black, Rhodium aluminum monoxide, tri-phosphine phosphine rhodium monochloride or palladium monophosphate sulfate, preferably palladium monocarbon.

Although the pressure is not particularly limited, it is usually 1 to 10 atm. '' The reaction temperature and reaction time vary depending on the starting compound, catalyst, inert solvent, etc., but usually, the reaction temperature is 0 ° C to 100 ° C (preferably 20 ° C to 70 ° C). C) and the reaction The time is 5 minutes to 48 hours (preferably 1 hour to 24 hours).

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

 The oxidizing agent to be used is not particularly limited as long as it is a compound used for the oxidation. Preferably, potassium persulfate, sodium persulfate, ammonium permeate nitrate (CAN) or 2, 3 is used. —Dichro-5,6-dicyan-1-p-benzoquinone (DDQ) is used. .

 The reaction temperature and reaction time vary depending on the starting compound, catalyst, inert solvent, etc., but usually the reaction temperature is 0 ° C to 150 ° C, and the reaction time is 10 minutes to 24 hours. It is.

In liquid ammonia or in methanol, ethanol, n-propanol, isopropanol, _n -butanol, isoptanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorbanol In such alcohols, it can also be removed by the action of alkali metals such as lithium metal and sodium at -78 ° C7b 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 is not particularly limited as long as it does not take part in the reaction, but is preferably a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride; and acetonitrile. Nitriles; or a mixed solvent of the above solvents. The reaction temperature and the reaction time vary depending on the starting compound, the inert solvent and the like, but usually the reaction temperature is 0 ° C to 50 ° C, and the reaction time is 5 minutes to 72 hours.

 When the reaction substrate has a sulfur atom, sodium hydroxide-sodium iodide is preferably used. When the protecting group for a hydroxyl group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it is removed by treating with a base in an inert solvent.

The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound. For example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; lithium hydrogen carbonate Alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide, sodium ethoxide, Metal alkoxides, such as potassium-t-butoxide; or ammonia, such as ammonia water and concentrated ammonium hydroxide, preferably alkali metal hydroxides, metal alkoxides or ammonia (most preferred) Include alkali metal hydroxides or metal alkoxy It is a class). The inert solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and examples thereof include getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethyleneglycol dimethinole. Ethers such as aethenole; methanol, ethanol, η-propanol, isopropanol, η-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octananol, siglohexano Alcohols such as methyl and methyl cellosolve; water; or mixed solvents of the above solvents are preferred. The reaction temperature and reaction time vary depending on the starting compound, the base used, the inert solvent and the like, and are not particularly limited. However, in order to suppress a side reaction, the reaction temperature is usually set at about 120 ° C. The reaction time is from 1 hour to 10 hours. When the protecting group for the hydroxyl group is an anolexoxymethyl group, a tetrahydrobilanyl group, a tetrahydrothiolpyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofurayl group or a substituted ethyl group, usually, an acid is used in an inert solvent. It is removed by processing.

 The acid used is not particularly limited as long as it is usually used as Brenstead acid or Lewis acid, but is preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid; or acetic acid or trifluoroacetic acid. Prested acid such as organic acid such as methanesulfonic acid, p-toluenesulfonic acid, etc .: Lewis acid such as boron trifluoride, and strongly acidic cation exchange resin such as Dowex 5OW Can be.

 The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; benzene , Toluene, xylene; aromatic hydrocarbons such as methylene chloride, chlorophonolem, tetrachlorosilane, halogenated hydrocarbons such as dichloroethane, dichlorobenzene, dichlorobenzene; ethyl formate, dimethyl acetate, acetic acid Esters such as propyl, butyl acetate, getyl carbonate; ethers such as getyl ether, diisopropene pinoleatene, tetrahydrofuran, dioxane, dimethyloxetane, and dimethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol , N-butanol Alcohols, such as isobutanol, isobutanol, isobutanol, isoaminophenol, glycerol, diethyleneglycol, glycerol, octanol, cyclohexanol, and methyl sorbent; acetone, methinoolethinoketone, methinoleisobutylene Ketones such as noreketone, isophorone and cyclohexanone; water; or a mixed solvent of the above solvents, preferably ethers or alcohols (most preferably tetrahydrofuran or methanol). .

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

When the protecting group for the hydroxyl group is an alkenyloxycarbonyl group, it is usually the same as the removal reaction conditions when the protecting group for the hydroxyl group is the above-mentioned aliphatic acyls, aromatic acyls or alkoxycarbonyls. , And a base. In the case of an aryloxycarbel group, in particular, palladium, triphenylphosphine, or bis (methinoresiphenylenolephosphine) (1,5-cyclooctadiene) iridium (I) .hexafluorophosphine The removal method using a paint is simple and can be performed with few side reactions. When the protecting group of the carboxyl group is a lower alkyl group, a lower alkyl group or a lower alkyl group,

When it is a benzyl group, it can be removed by treating with an acid or a base. The acid used in the above reaction is, for example, hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid. The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound. For example, alkali metal carbonates such as sodium carbonate and carbonated carbonate; sodium hydroxide, water Alkali metal hydroxides such as lium oxide; or concentrated ammonia-methanol solution. It should be noted that isomerization may occur in hydrolysis with a base.

 The solvent used in the above reaction is not particularly limited as long as it is used in a usual hydrolysis reaction and does not inhibit the reaction. Water or alcohols such as methanol, ethanol, and n-propanol; Ethers such as tetrahydrofuran and dioxane; or mixed solvents of the above organic solvents and water are preferred.

The reaction temperature and reaction time vary depending on the starting compound, the solvent, the reagents used, and the like, and are not particularly limited.However, the reaction temperature is generally 0 ° C to 150 ° C in order to suppress side reactions. The reaction time is from 1 hour to 10 hours. When the protecting group of the carboxy group is an aralkyl group or a halogeno lower alkyl group, it is usually removed by reduction in a solvent.

 As the reduction method, when the protecting group for the carboxy group is a halogeno lower alkyl group, a method by chemical reduction such as zinc monoacetic acid is preferable, and when the protecting group for the carboxy group is an aralkyl group, palladium carbon or platinum It is carried out by a method of performing a method of catalytic reduction using a catalyst such as described above, or a method of performing chemical reduction using an alkali metal sulfide such as potassium sulfide or sodium sulfide.

 The solvent used is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; fatty acids such as acetic acid; or A mixed solvent of the above organic solvent and water is preferred.

 The reaction temperature and the reaction time vary depending on the starting compound, the solvent, the reduction method and the like, but usually the reaction temperature is from 0 ° C to around room temperature, and the reaction time is from 5 minutes to 12 hours. .

 The removal of the protecting group for the amino, hydroxy and / or carboxy groups can be carried out in any order and the desired removal reaction can be carried out sequentially.

 After completion of the reaction, the target compound (I) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture. If necessary, the obtained target compound can be used in a conventional manner, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for the separation and purification of organic compounds, applying chromatography and applying an appropriate dissolution agent. Can be separated and purified.

The method B is a method for producing the compound (I) of the present invention separately from the method A. ' B method

 (IV)

In the above formula, RR ^la , R \ R ^2a , X, Y, L and L _a have the same meanings as described above, and Y ′ is “C” C ₈ alkylene group or C ₂ —C ₈ alkenylene group ”means an alkylene group or an alkenylene group having one less carbon atom than the“ C ₈ alkenylene group ”. Step B1 is a step for producing the compound (I) of the present invention. The compound having the general formula (V) is reacted with a compound (IV) or an acid addition salt thereof (for example, hydrochloric acid salt) in an inert solvent. , nitrates, removed after t this is reacted, optionally R ^la, the amino group in R ^2a and L _a, the hydroxyl-protecting group and Z or a carboxy group by reductive amino reduction and mineral) such as sulfate This is done by:

 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. Examples thereof include ethanol, methanol, ethanol, and propanol. Or ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether, and preferably alcohols (most preferably methanol or ethanol). .

The reducing agent used in the above reaction is not particularly limited as long as it is usually used as a reducing agent, and examples thereof include sodium borohydride, lithium borohydride, and sodium cyanoborohydride. Alkali metal hydrogen hydrides; aluminum hydride compounds such as diisobutylaluminum hydride, lithium aluminum hydride, lithium trimethoxide aluminum hydride; tenorelnadium hydride; or di (isobutyl) aluminum Hydride, bis (methoxhetoxy) It is a hydride reagent such as an organoaluminum hydride reducing agent such as sodium lumidium hydride, and is preferably an alkali metal borohydride.

The reaction temperature varies depending on the starting compound, the reagent used, the solvent and the like, but is usually from 120 ° C to 100 ° C (preferably from room temperature to 80 ^DC ). '

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

The method for removing the protecting group for the amino group, hydroxyl group and / or carboxy group in R ^la , R ^2a and 1 ^ as required can be carried out by the method described in the above-mentioned Method A, Step A1, Step A1. In the same manner as the method for removing the protecting group of

 After completion of the reaction, the target compound (I) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture. If necessary, the obtained target compound can be used in a conventional manner, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for the separation and purification of organic compounds, applying chromatography and applying an appropriate dissolution agent. Can be separated and purified.

C method, in the compounds of the present invention (I), L is the formula - CH (R ⁴⁾ - a group having a, R ⁴ is a group having the formula one ^{C (R 7) H- E- R} 5 Compound (Ia), a compound (lb) wherein L is a group having the formula C (= C (R ⁷ ) -ER ⁵ ) — and a compound (I) wherein L is a group having the formula CH (OH) 1 c).

Law

 (IVa)

(VI) (Ic) In the above formula, ΚR ^la R ² R ^2a R ⁵ R ⁷ Xs YE and Q are as defined above, and R ^5a and R ^7a are R ⁵ and R ⁷ Wherein the amino group, hydroxyl group and / or carboxy group in the definition of In addition to being a boxy group, they represent the same groups as in the definition of the groups R ⁵ and R ⁷ , and R ⁸ represents a lower alkyl group (having the same meaning as described above). Step C1 is a step for producing a compound having the general formula (VI), wherein the compound having the general formula (III) has the general formula (IVa) in an inert solvent in the presence of a base. This step is carried out in the same manner as the above-mentioned Method A, Step A1 by reacting with a compound or an acid addition salt thereof (for example, a mineral acid salt such as hydrochloride, nitrate and sulfate). Step C2 is a step for producing a compound having the general formula (VII), and is carried out by bringing the compound (VI) into contact with an oxidizing agent in an inert solvent.

The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. Examples thereof include aliphatic solvents such as hexane, heptane, ligroin, and petroleum ether. Hydrocarbons; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated carbons such as methylene chloride, chloroform, methane, 1,2-dichloroethane, 1,2-dichloroethane, and benzene Hydrogens; ethers such as getyl ether, disopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethyleneglycol / resimethinoleate ether; methanol, ethanol, n-propanol, isopropanol, n-butanol , Isoptanol, t-butanol, isoamylal Alcohols such as alcohol, diethylene glycol, glycerin, otano monol, cyclohexanol, methinoleserosonoleb; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-1 Amides such as pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphoric triamide; acids such as acetic acid and propionic acid; sulfoxides such as dimethyl sulfoxide and snoreholane; or a mixed solvent of the above solvents, Preferably, it is a halogenated hydrocarbon (most preferably, dichloromethane). The oxidizing agent used in the above reaction is not particularly limited as long as it is usually used in the oxidizing reaction. Examples thereof include manganese oxides such as potassium permanganate and manganese dioxide; and ruthenium tetroxide. ruthenium oxide, such as; Zeren compounds such as dioxide Zeren; Osumiumu compounds such as tetroxide Osumiumu, Osumin acid Kariu-time dihydrate _{(K 2 0s (V 2 0} ); iron compounds such as iron chloride; Silver compounds such as silver oxide; mercury compounds such as mercury acetate; lead oxide compounds such as lead oxide and lead tetraacetate; chromium such as potassium chromate, chromate monosulfate complex, and oxalate-pyridine complex Inorganic metal oxidizing agents such as acid compounds, cerium compounds such as ammonium cerium nitrate (CAN); halogen molecules such as chlorine, bromine and iodine molecules; Periodic acids such as sodium; ozone; aqueous hydrogen peroxide; nitrites such as nitrous acid; chlorites such as potassium chlorite and sodium chlorite; potassium persulfate; Inorganic oxidizing agents such as persulfate compounds such as sodium sulfate; reagents used for DM SO oxidation (complex of dimethyl sulfoxide and dicyclohexylcarbodiimide, oxalyl chloride, acetic anhydride or phosphorus pentoxide, or pyridine) A combination of a peroxide such as t-butyl hydroperoxide and a vanadium or molybdenum complex; a stable cation such as a triphenylmethyl cation; an N-promosuccinic acid imid. Combination of succinimides and alkalis; oxolanes such as dimethyldioxylan; t-butyl hypochlorite Chlorous acid oxide compounds; azodicarboxylic acid compounds such as azodicarboxylic acid esters; peracids such as m-chloroperbenzoic acid and perphthalic acid; Di / lephosphine; nitrites such as methyl nitrite; or tetrahalogenated carbons such as methane tetrabromide, such as 2,3-dichloro-1,5,6-dicyanor p-benzoquinone (DDQ) It is an organic oxidizing agent such as a quinone compound, and is preferably a reagent used for DMSO oxidation (most preferably, dimethylsulfoxide and oxalyl chloride). The reaction temperature varies depending on the starting compound, the oxidizing agent used, the solvent, and the like. 100 ° C. to 50 ° C. (preferably, −80 ° C. to 40 ° C.).

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

 After the completion of the reaction, the reaction ^ target compound (VII) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. It is obtained by washing with water, etc., drying with anhydrous magnesium sulfate, aluminum, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent. If necessary, the target compound obtained may be combined with a conventional method, for example, recrystallization, reprecipitation, etc., as appropriate, using a method commonly used for separation and purification of organic compounds. Can be separated and purified. Step C3 is a step of producing a compound having the general formula (IX) by the HORNER-EMMONS reaction, and treating the compound having the general formula (VIII) with a base in an inert solvent in a stream of nitrogen. This is achieved by generating = · on and then reacting with compound (VII).

 The inert solvent used when reacting compound (VIII) with a base is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. For example, hexane, heptane, ligroin Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; or getyl ether, disopropy / leate / re, tetrahydrofuran, dioxane, dimethyloxetane and dimethylene glycol dimethyl ether Such ethers, preferably ethers

(Most preferably, tetrahydrofuran).

The base used for reacting compound (VIII) with a base is not particularly limited as long as it is used as a base in a usual reaction. And the like, and preferably, alkali gold Hydrides (most preferably, sodium hydride).

 The reaction temperature for reacting compound (VIII) with a base varies depending on the starting compound, the base used, the solvent and the like, but it is usually from -70 to 80 (preferably from -20 to 50 ° C). is there.

 The reaction time for reacting compound (VIII) with a base varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 50 hours (preferably 1 hour to 25 hours). It is.

 The inert solvent used when reacting compound (VII) with compound (VIII) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. The same inert solvents as those used when reacting with a base can be used.

 The reaction temperature at which the compound (VII) is reacted with the compound (VIII) varies depending on the starting compound, the solvent and the like, but is usually from -100 ° C to 50 ° C (preferably from 0 ° C to room temperature). ).

 The reaction time for reacting the compound (VII) with the compound (VIII) depends on the starting compound, the solvent, the reaction temperature and the like, but is usually 30 minutes to 50 hours (preferably 1 hour to 25 hours). is there.

After completion of the reaction, the target compound (IX) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. It is obtained by washing with water, etc., drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the desired compound obtained can be combined with conventional methods, such as recrystallization and reprecipitation, etc., as appropriate, using methods commonly used for the separation and purification of organic compounds. Can be separated and purified. The step C4 is a step for producing the compound (la). The compound (IX) is subjected to a catalytic reduction reaction in an inert solvent, and then, if necessary, the amino acid at R ^la , R ^2a , R ^5a and R ^7a is prepared. This is carried out by removing the protective groups of the amino group, the hydroxyl group and the Z or carboxy group. The inert solvent used in the catalytic reduction reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but examples thereof include hexane, heptane, rig-in, and petroleum ether. Aliphatic hydrocarbons; Aromatic hydrocarbons such as toluene, benzene, and xylene; Esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, disopropyl ether, tetrahi Ethers such as drofuran, dioxane, dimethoxetane, and diethylene glycol dimethinoleate ether; methanol, ethanol, _n -pronanol, isopropanol, n-butanol, isobutanol, t-butanol, isoaminoreanolone, diethylene glycolone The guri Alcohols such as serine, octanol, cyclohexanol, and methyl sorbate; organic acids such as acetic acid; water; or a mixed solvent of the above solvent and water; Preferably, it is ethanol.

 The catalyst used in the catalytic reduction reaction is not particularly limited as long as it is usually used in the catalytic reduction reaction, but is preferably palladium monocarbon, Raney nickel, platinum oxide, platinum black, rhodium aluminum monoxide, Trifluorophenylphosphine monochloride or palladium monosulfate, most preferably palladium monocarbon.

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

 The reaction temperature and reaction time in the catalytic reduction reaction vary depending on the starting compound, catalyst, solvent and the like, but usually the reaction temperature is 0 ° C to 100 ° C, and the reaction time is 5 minutes to 5 minutes. 24 hours.

The method for removing the protecting group of the amino group, hydroxyl group and / or phenolic group in R ^la , R ^2a , R ^5a and R ^7a , which is carried out as desired, is as follows. It is carried out in the same manner as the method for removing the protecting group for the group and / or the carboxy group.

After completion of the reaction, the target compound (Ia) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture. If necessary, the desired compound obtained can be combined with a conventional method, for example, recrystallization, reprecipitation, or the like, which is usually used for the separation and purification of organic compounds. Separation and purification can be achieved by elution. Step C5 is a step of preparing compound (lb), and in a solvent such as an amino group, a hydroxyl group and a protecting group for Z or carboxy group of ^la , R ² R ^5a and R ^7a in an inert solvent. This step is carried out in the same manner as in the above-mentioned method A method step A1 step of removing the protecting group for the amino, hydroxyl and Z or carboxy groups. -Step C6 is a step of producing compound (Ic), in which an amino group, a hydroxyl group and / or a carboxy group of R ^la and R ^2a of compound (VI) are removed in an inert solvent. This step is carried out by the amino group, hydroxyl group and

It is performed in the same manner as the method of removing the protecting group of Z or carboxy group. The starting compounds (111), (IV), (IVa), (V) and (VIII) are known compounds or are easily produced according to known methods or methods similar thereto. For example, compound (III) can be produced according to the method described in J. Med. Chem. 23, 149 (1980) and the like, and (IV), (IVa) and (V) can be produced according to EP 47068 9A, It can be produced according to the method described in EP 776893 A, US Pat.

Method D is a method for producing compound (IIIa) in which X is an oxygen atom in compound (III). D method

 (X) (XI) (Ilia)

In the above formula, R ^la , R ² Y and Q have the same meanings as described above. Step Dl is a step for producing a compound (Ilia), in the presence or absence (preferably in the presence) of an inert solvent, using an acid as a catalyst to form a compound having the general formula (X) The reaction is carried out by reacting the compound with a compound having the general formula (XI).

 The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; Aliphatic hydrocarbons such as acetylene, heptane, ligroin, petroleum ether; or ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, diethylene glycol dimethyl ether, and preferably And aromatic hydrocarbons (most preferably, toluene).

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

 The reaction temperature varies depending on the type of the starting compound, the inert solvent used, and the acid, but is usually from 0 ° C to 200 ° C (preferably from 20 ° C to 150 ° C). ).

 The reaction time varies depending on the starting compound, the inert solvent used, the type of acid and the reaction temperature, but is usually from 15 minutes to 48 hours (preferably from 30 minutes to 12 hours). The reaction may be accelerated by using a dehydrator such as Dean-Stark.

 After completion of the reaction, the target compound (Ilia) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is removed. It is obtained by separating, washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent. If necessary, the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for the separation and purification of organic compounds, applying chromatography and applying an appropriate eluent. Can be separated and purified. The step D2 is a step of producing a compound having the compound (XII), which is carried out by converting the hydroxyl group of the compound (X) into a functional group capable of leaving as a nucleophilic residue. The method of converting a hydroxyl group into a functional group varies depending on the intended functional group, but can be generally carried out 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 carried out by reacting compound (X) 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 hinder the reaction and dissolves the starting materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride , Black mouth form, carbon tetrachloride, dichlorome Halogenated hydrocarbons such as tan, 1,2-dichloroethane and dichlorobenzene; organic acids such as acetic acid, formic acid and propionic acid; formamide, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide And water, preferably aromatic hydrocarbons, halogenated hydrocarbons or water (most preferably halogenated hydrocarbons).

 The halogenating reagent used in the above reaction is not particularly limited as long as it is a halogenating reagent used in a usual reaction.For example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, bromine, Halogen molecules such as chlorine; phosphorus reagents such as phosphorus trichloride, phosphorus tribromide, phosphorus pentabromide, phosphorus pentachloride, and phosphorus oxychloride; thiol chloride, chlorobromide, toluenesulfonic acid Sulfinic acids such as lids; or sulfonic acid reagents, preferably phosphorus reagents.

 The reaction temperature depends on the type of the starting compound, the inert solvent used, and the type of the halogenating reagent, but is usually from −78 ° C. to 200 ° C. (preferably, from −78 ° C. to 100 ° C.). ° C).

The reaction time varies depending on the starting compound, the inert solvent used, the halogenating reagent, and the reaction temperature. The reaction time is usually 5 minutes to 48 hours (preferably 15 minutes to 3 hours). When the target functional group is a lower alkane sulfonyloxy group, a halogeno lower alkane sulfonyloxy group or an arylsulfonyloxy group, in the presence or absence (preferably in the presence) of an inert solvent This reaction can be carried out by reacting the compound (X) with the corresponding acid phenol or anhydride in the presence of a base. The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride Halogenated hydrocarbons such as chlorophonolem, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and dichlorobenzene; aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; dimethyl ether, diisopropyl ether , Tetrahydrofuran, dioxane, dime Ethers such as toxetane and diethylene glycol dimethyl ether; organic bases such as pyridine and triethylamine; or amides such as formamide, N, N-dimethylformamide and N, N-dimethylacetamide. And are preferably halogenated hydrocarbons or organic bases.

 The base used in the above reaction is not particularly limited as long as it is a commonly used base. For example, metal hydrides such as sodium hydride and potassium hydride; sodium hydroxide, potassium potassium hydroxide Metal carbonates such as lithium carbonate and potassium carbonate; metal bicarbonates such as sodium bicarbonate and potassium hydrogen carbonate; or pyridine, triethylamine, triisopropylamine, and dipyropenpyletylamine. Hexylamine, N-methylpiperidine, picoline, 4-, dimethylaminopyridine, 1,4-diazabicyclo [4.3.0] octane, 1,8-diazabicik [5.4.0] —7-indene Such organic amines, preferably organic amines.

 The acid halide or acid anhydride used in the above reaction is not particularly limited as long as it is a commonly used acid halide or acid anhydride, and examples thereof include acetyl chloride, acetyl chloride, and propionyl chloride. Fatty acid halides; fatty acid anhydrides such as acetic anhydride and propionic anhydride; sulfonyl acid halides such as methanesulfonic acid chloride and toluenesulfonic acid chloride; or methanesulfonic anhydride and trifluoromethanesulfone It is a sulfonic anhydride such as an acid anhydride, and is preferably a fatty acid halide.

 The reaction temperature varies depending on the type of the starting compound, the inert solvent used, the acid halide, and the acid anhydride, but it is usually −78 ° C. to 100 ° C. (preferably, Room temperature).

The reaction time varies depending on the starting compound, the inert solvent used, the acid halide, the acid anhydride, and the reaction temperature, but is usually 5 minutes to 48 hours (preferably 15 minutes to 3 hours). is there. After completion of the reaction, the target compound (XII) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. It is obtained by washing with water, etc., drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent. If necessary, the desired compound obtained can be combined with conventional methods, such as recrystallization and reprecipitation, etc., as appropriate, using methods commonly used for the separation and purification of organic compounds. Can be separated and purified. · Step D3 is a step of producing compound (I lia). Compound (XII) is converted to compound (XI) in the presence or absence (preferably in the presence) of an inert solvent using an acid as a catalyst. ).

 The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like; Aliphatic hydrocarbons such as hexane, heptane, lignoin, petroleum ether; or like getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and methylenglycol dimethyl ether Ethers, and preferably ethers.

 The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a normal reaction.For example, the same acids as those used in Method A, Step A1 may be used. Preferably, it is an organic acid.

 The reaction temperature varies depending on the type of the starting compound, the inert solvent used, and the acid, but is usually from 0 ° C to 200 ° C (preferably from 20 ° C to 150 ° C). C).

 The reaction time varies depending on the starting compound, the inert solvent used, the acid and the reaction temperature, but is usually 5 minutes to 48 hours (preferably 30 minutes to 12 hours).

It should be noted that the reaction is accelerated by using a dehydrator such as Dean-Stark. There is.

 After completion of the reaction, the target compound (III'a) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is removed. It is obtained by separating, washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent. If necessary, the obtained target compound may be appropriately combined with a conventional method, such as recrystallization and reprecipitation, if necessary, by commonly used methods commonly used for the separation and purification of organic compounds. Separation and purification can be performed by eluting with an eluent.

Method E is a method for producing a compound (IVb) in which L in the compound (IV) is a 2-oxoxazodindin ring.

E method

In the above formula, R ⁹ represents a lower alkoxycarbonyl group (preferably a C—C ₄ alkoxycarbonyl group, most preferably a t-butoxycarbonyl group). Step E1 is a step for producing a compound (IVb), which is carried out by treating a compound having the general formula (III) with an acid in an inert solvent.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. However, for example, aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether are used. Hydrogens; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as chlorophonolem, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; Methyl acetate, ethyl acetate, propyl acetate, acetic acid Petil, carbonated Esters such as getyl; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; methanol, ethanol, η-propanol, isopropanol, _η -butanol, Alcohols such as isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl sorbet; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphate triamide Water; or water or a mixed solvent of the above solvents, preferably alcohols, ethers or a mixed solvent of alcohols and ethers (most preferably, A mixed solvent) of alcohol and ethers.

 The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a normal reaction, and examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid. Acids: Prensted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, organic acids such as p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid; zinc chloride, tin tetrachloride, boron trichloride A Lewis acid such as lid, boron trifluoride, boron tribromide; or an acidic ion exchange resin, preferably an inorganic or organic acid (most preferably hydrochloric acid, acetic acid or trifluoroacetic acid). is there.

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

The reaction time varies depending on the starting compound, the acid used, the inert solvent, the reaction temperature and the like. The reaction time is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours). After completion of the reaction, the target compound (IVb) of the reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After washing with water, etc., anhydrous magnesium sulfate, anhydrous sodium sulfate It can be obtained by drying over anhydrous sodium bicarbonate or the like and then distilling off the solvent. If necessary, the desired compound obtained can be combined with conventional methods, such as recrystallization and reprecipitation, etc., as appropriate, using methods commonly used for the separation and purification of organic compounds. Can be separated and purified. The starting compound (XIII) is a known compound or is easily produced according to a known method or a method similar thereto. For example, compound (XIII) can be produced according to the method described in J. Med. Chem., 38, 3772-3779 (1995) and the like.

Method F is a method for producing compound (X) which is a starting material of the above-mentioned Method D.

F method.

In the above formula, R ^la and R ^2a are in agreement with those described above, and W is a halogen atom.

 Step F1 is a step of producing compound (X), and using a reagent of a base, a metal or an organometallic reagent in the presence or absence (preferably in the presence) of an inert solvent, using a general formula This is performed by reacting a compound having the formula (XIV) with a compound having the general formula (XV). .

The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like; Luminous aliphatic hydrocarbons such as hexane, heptane, lignoin, petroleum ether; or getyl ether, disopropyl ether, tetrahydric furan, dioxane, dimethoxetane, diethylene glycolone dimethyl ether Such ethers, preferably ethers (most preferably tetrahydrogen Mouth franc).

 The base used in the above reaction is not particularly limited as long as it is used as a base in a usual reaction, but is preferably a metal alkoxide such as potassium butoxide, sodium methoxide, and sodium methoxide. is there.

 The metal used in the above reaction is not particularly limited as long as it is a metal used in a normal reaction, but is preferably lithium, potassium or sodium.

 The organometallic reagent used in the above reaction is not particularly limited as long as it is used as an organometallic reagent in a usual reaction. For example, n-butyllithium, sodium hexamethyldisilazide, potassium hexamethyl Disilazide, lithium hexamethyldisilazide, lithium diisopropylamide, ethylmagnesium bromide, or isopropylmagnesium bromide, and preferably n-butyllithium.

 The reagent used in this step is preferably an organometallic reagent.

 The reaction temperature varies depending on the starting compound, the inert solvent used, and the seed teeth of the reagent, but is usually from 120 ° C to room temperature (preferably, from −100 ° C to 0 ° C). .

The reaction time varies depending on the starting compound, the inert solvent used, the type of reagent, and the reaction temperature, but is usually 5 minutes to 48 hours (preferably 5 minutes to 1 hour). In addition, R ^la of compound (XIV) is R ² . And the compound of formula (XV) wherein the R ^2a moiety of R ^la is R ^la , and reacted in the same manner as in this step, to obtain the desired compound (X).

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

Method G is a method for producing a compound (I) in which X is an oxygen atom and Y is a trimethylene group.

G method

 (XVIII) (XIX) (XX)

 (IV)

In the above formula, R ^la , R ² , R ^2a , Q, W, L and 1 ^ have the same meanings as described above, and R ¹ . Represents a lower alkyl group, a halogeno lower alkyl group or a lower alkyl group such as phenyl, p-tolyl or p-nitrophenyl, or a aryl group which may be substituted by 1 to 3 substituents; Is a lower alkyl group.

Step G1 is a method for producing a compound having the general formula (XVII), which is carried out by using a base in the presence or absence (preferably in the presence) of an inert solvent and a compound (X). The reaction is carried out by reacting a compound having the general formula (XVI).

The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but examples thereof include benzene, toluene, and xylene. Aromatic hydrocarbons; halogenated hydrocarbons such as methylene chloride, carbon form, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, dichlorobenzene; hexane, heptane, ligroin, petroleum ether Aliphatic hydrocarbons; ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; organic bases such as pyridine, triethylamine; or formamide, N, N-dimethylformamide; Amides such as Ν, Ν-dimethylacetamide, preferably amides or ethers (most preferably amides).

 The base used in the above reaction is not particularly limited as long as it is a base used in a usual reaction. For example, metal hydrides such as sodium hydride and lithium hydride; sodium hydroxide, water Metal hydroxides such as lithium oxide; metal carbonates such as lithium carbonate and carbon dioxide; metal bicarbonates such as sodium hydrogen carbonate and hydrogen carbonate; or pyridine, triethylamine, triisopropylamine , Diisopropinoleethynoleamine, dicyclohexynoleamine, Ν-methylpiperidine, picoline, 4-dimethylaminopyridine, 1,4-diazabicyclo [4.3.0] octane, 1,8-diazabicyclo [5.4.0] Organic amines such as 7-indene, preferably organic amines or alkali metal hydrides (most preferred). Suitable is an alkali metal hydride.

 The reaction temperature varies depending on the type of the starting compound, the inert solvent used and the base, but is usually from −78 ° C. to 100 ° C. (preferably from 0. C. to room temperature).

The reaction time varies depending on the starting compound, the inert solvent used, the type of base and the reaction temperature, but is usually from 5 minutes to 48 hours (preferably from 15 minutes to 1 hour). After completion of the reaction, the target compound (XVII) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is removed. Separate and wash with water etc., then anhydrous magnesium sulfate, anhydrous sodium sulfate It is obtained by drying with urea, anhydrous sodium hydrogencarbonate and the like, and then distilling off the solvent. If necessary, the target compound obtained may be used in a conventional manner, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for the separation and purification of organic compounds, applying chromatography, and applying a suitable eluent. Can be separated and purified. Step G2 is a step of producing a compound having the general formula (XVIII), and the compound (XVII) is reacted with a boration reagent in the presence or absence (preferably in the presence) of an inert solvent. This is done by boration followed by oxidative treatment.

 The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and methylene chloride. Halogenated hydrocarbons such as carbon dioxide, carbon tetrachloride, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and dichlorobenzene; aliphatic hydrocarbons such as hexane, heptane, rig-mouth, petroleum ether; Or ethers such as jetinole ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane and diethylene glycol dimethyl ether, and preferably ethers (most preferably tetrahydrofuran).

 The boration reagent used in the above reaction is not particularly limited as long as it is used as a boration reagent in an ordinary reaction.For example, a borane-dimethylsulfide complex, a borane-tetrahydrofuran complex, or a 91-borabicycle port [3.3 .1] nonane (9-BBN), preferably 9-borabicyclo [3.3.1] nonane (9-BBN).

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

The reaction temperature varies depending on the raw material compound, the 'inert solvent used', and the 'boronating reagent', but is usually from 178 ° C to 100 ° C (preferably from 0 ° C to room temperature). The reaction time varies depending on the starting compound, the inert solvent used, the boration reagent and the reaction temperature, but is usually 5 minutes to 48 hours (preferably 15 minutes to 24 hours). .

 After completion of the reaction, the target compound (XVIII) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent. If necessary, the target compound obtained is eluted with a suitable eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified. Step G3 is a step for producing a compound having the general formula (XX), and in the presence or absence (preferably, in the presence) of an inert solvent, compound (XVIII) 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 hinder 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 chlorobenzene, heptane, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, and dicyclomethane; aliphatic hydrocarbons such as hexane, heptane, rig mouth, petroleum ether Ethers such as dimethyl ether, dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; organic bases such as pyridine and triethylamine; or formamide, Ν, Ν-dimethinoleformamide, Amides such as Ν-dimethylacetamide And a, preferably, '' halogenated hydrocarbons or organic bases (most preferably, halogenated hydrocarbons) is. The base used in the above reaction is not particularly limited as long as it is a base used in a usual reaction.For example, the same bases as those in Step E1 of Method E can be used. (Most preferably, triethylamine).

 The reaction temperature varies depending on the starting compound and the inert solvent used. The reaction temperature is usually −78 ° C. to 100 ° C. (preferably 0 ° C. to room temperature).

 The reaction time varies depending on the starting compound, the inert solvent used and the reaction temperature, but is usually 5 minutes to 48 hours (preferably 15 minutes to 3 hours).

After completion of the reaction, the target compound (XX) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the target compound obtained may be appropriately combined with conventional methods, for example, recrystallization, reprecipitation, etc., which are commonly used for the separation and purification of organic compounds. Separation and purification can be achieved by elution with an agent. The step G4 is a step for producing a compound having the compound (Id). In step G4, the compound (XX) is reacted with the compound (IV) or an acid addition salt thereof (for example, in an inert solvent in the presence of a base). hydrochloride, nitrate, is reacted with a mineral acid) such as sulfate, optionally R ^la, R ^{2 a}及Pi 1 ^ amino group in the child removing the protecting group of the hydroxyl and / or carboxy group This step is performed in the same manner as in the A method A1 step. The starting compounds (XI), (XIV), (XV), (XVI) and (XIX) can be easily produced according to a known compound or a known method or a method similar thereto [for example, J. Org Chem., 6, 489 (1941); Chem. Ber., 1199 (1989), etc.]. The invention's effect

 The nitrogen-containing saturated heterocyclic compound having the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, and an esthetic / ester or other derivative thereof can be used to treat a warm-blooded animal (particularly, a human) with lupus Or, it is useful as a prophylactic or therapeutic agent for liver damage and has few side effects. Industrial applicability

 When the nitrogen-containing saturated heterocyclic compound having the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof is used as the above-mentioned prophylactic or therapeutic agent, the compound itself may be used. Alternatively, it is mixed with an appropriate pharmacologically acceptable excipient, diluent, or the like. For example, tablets, capsules, granules, powders, syrups, etc., orally, injections or suppositories, etc. It can be administered orally.

These preparations may contain excipients (eg, sugar derivatives such as lactose, lactose, sucrose, dextrose, mannitol, sorbitol); starch derivatives such as corn starch, potato starch, starch, dextrin; Organic excipients such as gum arabic; dextran; pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium metasilicate aluminate; phosphoric acid Inorganic excipients such as phosphates such as calcium hydrogen; carbonates such as calcium carbonate; sulfates such as calcium sulfate, etc.), lubricants (eg, stearic acid, calcium stearate, Metal stearate such as magnesium stearate; talc; colloidal silica; Gums, gays, etc .; boric acid; adipic acid; sulfuric acid salts such as sodium sulfate; glycol; fuma / leic acid; sodium benzoate; DL leucine; fatty acid sodium salt; sodium radium sulfate; Lauryl sulfates such as magnesium; silicic acids such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives.), Binders (eg, hydroxypropylcellulose, hydroxypropyl) Methylcellulose, Polybierpyrrolidone, Macrogol, Compounds can be mentioned. ), Disintegrants (eg, cellulose derivatives such as low-substituted hydroxypropylcellulose, canoleboxymethinoresenorelose, canoleboxymethinoresenolerose kanoresum, internally cross-linked carboxymethylcellulose sodium; Chemically modified starch and celluloses such as carboxymethyl starch, sodium carboxymethyl starch, cross-linked polybutylpyridone, etc.), stabilizers (p-hydroxybenzoic acid esters such as methylparaben and propylparaben) Alcohols such as chloroptanol, benzyl alcohol and phenylethyl alcohol; benzalcodium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. .. To that), flavoring agent (e.g., the commonly used sweeteners, acidulants, can be mentioned perfumes), prepared in a known manner with additives such as diluents; ^ Ru. The dosage varies depending on symptoms, age, etc.For oral administration, the lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 4000 mg (preferably 400 mg) per dose per day. In the case of intravenous administration, the lower limit of 0.1 mg (preferably 0.05 mg) and the upper limit of 500 mg (preferably 300 mg) per day should be 1 to 6 times daily for adults. It is desirable to administer according to.

BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Production Examples, Reference Examples, and Test Examples, but the scope of the present invention is not limited thereto. Production Example 1

 8- [2-Bis (4-funenole) methoxytin] 3-benzinole-1-oxa-3,8-diazaspiro [4.5] decane-2-one and its oxalate (exemplified compound (Number 331)

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

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

(l b) 8- [2-bis (4-fluorophenyl) methoxethyl] -3-benzyl-1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

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

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, DMS0-d 6} ) δ ppra:

 7.14-7.42 (13 m), 5.55 (lH, s), 4.37 (2H, s), 3.61 (2H, m), 3.25 (2H, s), 2.9-3.2 (6H, m), 1.9-2. L (4H, m).

Infrared absorption spectrum ,, _iax cm- ¹ (KBr): 1752, 1729, 1604, 1509, 1224. Mass vector (FAB) m / z 493 ((M + H) +, free form)

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

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

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

 8- [2-bis (4-fluorophenyl) methoxethyl] -3-pheninole-1-oxa-3,8-diazaspiro [4,5] decane-2-one and its oxalate ( (Exemplary compound number 322)

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

 Production example 3-phenyl-1-oxa-3,8-dazaspiro [4.5] decane-2-one hydrochloride 269 mg (1.00 mmol) and bis (4-fluorophenyl) methyl 2-chloro Using 283 mg (1.00 mmol) of ethyl ether, 318 mg (66%) of the title compound was obtained.

(2b) 8- [2-Bis (4-fluorophenyl) methoxethyl] -3-phenyl-1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate.

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

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

 7.12-7.58 (13H, m), 5.58 (1H, s), 3.93 (2H, s), 3.64 (2H, m), 2.9-3.3 (6H, m), 2.0-2.2 (4H, m).

Infrared absorption spectrum! ^ _Ax cnf ¹ (KBr): 1756, 1602, 1507, 1409, 1224.

Mass vector (FAB) m / z 479 ((M + H). ⁺ , Free form)

Elemental analysis (as _{C 30 H 30 N 2 0 7} F 2 (%))

Calculated: C: 63.37; H: 5.32; N: 4.93; F: 6.68% Found: C: 63.48; H: 5.42; N: 4.84; F: 6.40%. Production Example 3

 1- [2-bis (4-fluorophenyl) methoxethyl] -4-phenylpiperidine-4-carboxylic acid amide and its oxalate (Exemplified Compound No. 188)

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

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

(3 b) 1- [2-Bis (4-fluorophenyl) methoxethyl] -4-f: birubiperidin-4-carboxylic acid amide oxalate

 The compound obtained in Production Example (3a) was dissolved in 5 ml of ethyl acetate, 83 mg (0.92 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give 407 rag (82%) of the title compound as white crystals.

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

 7.16-7.42 (13H, m), 5.56 (1H, s), 3.64 (2H, m), 3.2-3.5 (4H, m), 2.9-3.1 (2H, m), 2, 5-2, 8 (2H, m), 1.9-2.2 (2H, m).

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

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

Elemental analysis value (as C _2g 0 ₆ F ₂ (%)) ·

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

Found: C, 63.79; H, 5.73; N, 5.08; F, 6.78%. Production Example 4 1- [2-bis (4-fluorophenyl) methoxhetyl] -4-phenylpiperidine-4-capronic acid morpholinamide and its oxalate salt (Exemplary Compound No. 212)

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

 Production example 4-phenylbiperidine-4-carboxylic acid morpholine amide hydrochloride 311 rag (1.00 mraol) and bis (4-fluorophenyl) methyl 2-chloroethyl ether 283 mg (1,00 hall) ol) to give 390 rag (75%) of the title compound.

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

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

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

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

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

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

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

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

 1- [2-Bis (4-funolylphenyl) methoxethyl] -4- (2-pyridyl) pyridine-4-carboxylic acid amide and its oxalate (Exemplified Compound No. 232)

(5a) 1- [2-Bis (4_fluorene) methoxhetyl] -4- (2-pyridyl) pyridine-4-carboxylic acid amide Production Example 4- ( ² -pyridyl) piperidine- ⁴ -carboxylic acid amide dihydrochloride 139 mg (0.50 mmol) and bis (4-fluorophenyl) methyl 2-chloroethynole ether 141 Using rag (0.50 orchid ol), 204 mg (90%) of the title compound was obtained.

(5 b) 1- [2-Bis (4-fluorophenyl) methoxhetyl] -4- (2-pyridyl) pyridine-4-aminosulfonic acid oxalate

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

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

8.57 (IH, m), 7.82 (IH, m), 7.12- 7.47 (10H, m), 5.55 (1H, s), 3.64 (2H, m), 3.0-3.5 (6H, m), 2.2-2.8 ( 4H, m)-Infrared absorption spectrum v _max cnf ¹ (KBr): 1669, 1605, 1508, 1220.

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

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

 Calculation: C: 62.10; H: 5.40; N: 7.76; F: 7.02%

 Found: C: 61.62; H: 5.50; N: 7,63; F: 6.73%. Production Example 6

 1- [2-Bis (4-fluoropropyl) methoxicetyl] spiro [(2-hydroxy) indane-1,4, -piperidine] and its oxalate salt (Exemplified Compound No. 397)

 (6a) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(2-hydroxy) indane-1,4'-piperidine]

Spiro [(2-hydroxy) indane-1,4'-piperidine] hydrochloride 187 mg (0.78 mmol) and bis (4-fluorophenyl) methyl 2-chloroethynole ether 200 mg as in Production Example (la) (0.71 mmol) to give 256 mg (81%) of the title compound. (6b) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(2-hydroxy

) Indan - 1, ⁴ '- piperidine] Shuu salt

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

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, DMS0-d 6} ) 6 ppm:

 7.42-7.45 (4H, m), 7.17—7.22 (8H, m), 5.60 (1H, s), 4.3—4.4 (1H, m), 3.71 (2H, t, J = 4.9Hz), 3.1-3.4 ( 7H, m), 2.7-2.8 (1H, m), 1.8-2.2 (3H, m), 1.6-1.7 (lH, m).

Infrared absorption spectrum v _max cm— ¹ (KBr): 3364, 2938, 2676, 1721, 1604, 1509, 1224. Mass spectrum (FAB) m / z 450 ((M + H) +, free form)

Elemental analysis (C _{3, as} H ₃₁ N0 ₆ F ₂ (% :)) ''

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

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

 1: [2-bi ^ :( 4-fluorophenyl) methoxetinole] spiro [2,3-dihydrobenzothiophene-3,4'-piperidine] -1-oxide and its oxalate (Exemplary Compound No. 379)

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

 172 mg (0.78 mmol) of spiro [2,3-dihydrobenzothiophene-3,4'-pyridin] -1-oxide and bis (4-fluorophenyl) methyl 2- Using chloroethyl ether (200 mg, 0.71 reference), 243 mg (73%) of the title compound was obtained.

(7 b) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [2,3-dihydro Benzothiophene-3,4'-piperidine]-1-oxide citrate

 The compound obtained in Production Example (7a) was dissolved in 5 ml of ethyl acetate, 47 mg (0.52 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (261 mg, 66%).

Nuclear magnetic resonance scan Bae-vector _{^{(4 00 MHz, DMSO- d 6}} ) δ ppra:

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

17-7.21 (4H, m), 5.60 (IH, s), 3.69 (2H, t, J = 5.OHz), 3.50 (IH, d, J = 14.2Hz), 3.34 (

IH, d, J = 14.2Hz), 2.9-3.5 (6H, m), 2.0-2.5 (3H, m), 1.6-1.7 (IH, m).

Infrared absorption spectrum v _raax cm— ¹ (KBr): 3436, 2927, 2572, 1721, 1604, 1508, 1223. Mass spectrum (EI) m / z 467 ((M) ⁺ , free form)

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

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

 Found: C: 62, 30; H: 5.36; N: 2.3; S: 5.65; F: 6.70%. Production Example 8

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

 (8a) 1- [2-Bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4'-piperidine] -2-oxide

 Spiro [benzo [c] thiophen-1 (3H), 4, -piperidine] -2-oxide hydrochloride 182 mg (0.71 mmol) and bis (4-fluorophene) were prepared in the same manner as in Production Example (la). B) Using 200 mg (0.71 mmol) of methyl 2-chloroethyl ether, 132 mg (45%) of the title compound was violent.

(8 b) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4'-piperidine] -2-oxoxide oxalate The compound obtained in Production Example (8a) was dissolved in 3 ml of ethyl acetate, and 20 mg of oxalic acid was added.

(0.22 mmol) was added and left overnight at room temperature. The precipitated crystals were collected by filtration to give the title compound as white crystals (75 mg, 63%).

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

 7.36-7.45 (8Η, ιη), 7.19 (4H, t, J = 8.9Hz), 5.58 (1H, s), 4.63 (1H, d, J = 7.0Hz), 4.04

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

.97 (2H, m), 2.57 (1H, m), 2.20 (1H, m), 2.06 (l¾ m), 1.90 (lH, m).

Infrared absorption spectrum v _max cm— ¹ (KBr): 3438, 2903, 2540, 1720, 1604, 1508, 1223. Mass spectrum (FAB) m / z 468 ((M + H) +, free form)

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

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

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

 1 ^ [2-bis- (4-le-phenyl) methoxchetyl] spiro [benzo [c] thiophene-U 3H), 4'-piperidine] and its oxalate (Exemplified Compound No. 382)

 (9a) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4, -piperidine]

 Spiro [benzo [c] thiophen-1 (3Η), 4'-piperidine] hydrochloride 171 rag (0.71 mmol) and bis (4-fluorophenyl) methyl 2-chloro Using 200 mg (0.71 ol) of mouth ethyl ether, 222 mg (80%) of the title compound was obtained.

(9 b) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3Η), 4'-piperidine] oxalate

The compound obtained in Production Example (9a) was dissolved in 3 ml of ethyl acetate, 41 mg (0.44 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated L crystals were collected by filtration, and the title compound was purified. 205 mg (87%) were obtained as white crystals.

Nuclear magnetic resonance scan Bae-vector _{^{(4 00 MHz, DMSO- d 6}} ) δ ppm:

 7.42-7.45 (4H, m), 7.28-7.33 (4H, m), 7, 16-7.21 (4H, m), 5.59 (IH, s), 4.21 (2H, s), 3.68 (2H, t, J = 5.0Hz), 3.45 (2H, m), 3.23 (2H, brs), 2.95 (2H, m), 2.48 (2H, m), 1 • 92 (2H, m).

Infrared absorption spectrum v _max cm ^-1 (KBr): 3436, 3012, 2562, 1719, 1655, 1604, 1507, 1224.

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

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

 (10a) 1- [2-bis (4-fluorophenyl) methoxethyl] spiro [(indane) -1,4'-piperidine]

 Spiro [(indane) -1,4'-piperidine] hydrochloride 79 mg (0.35 t ol) and bis (4-fluorophenyl) methyl 2-cloguchiethyl ether 100 mg as in Production Example (1a) (0.35 mmol) to give 43 mg (28%) of the title compound.

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

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

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, DMSO- d 6)} δ ppm:

7.13-7.46 (12H, m), 5.60 (lH, s), 3.66-3.74 (2H, m), 3.31-3.48 (4H, m), 3.00-3.18 (2H, m), 2.88-2.94 (2H, m ), 1.98-2.16 (4H, m), 1.58-1.67 (2H, m). Infrared absorption spectrum v _max cm— ¹ (KBr): 3427, 2941, 2648, 2568, 1721, 1702, 163

4, 1604, 1508, 1405, 1223, 1155, 835, 721.

Mass vector (FAB) m / z 434 ((M + H) ⁺ , free form)

Elemental analysis value (as C ₃₀ H ₃₁ N0 ₅ F ₂ + ¾0 (%;))

 Calculation 畲: C: 66.53; H: 6.14; N: 2.59; F: 7.02%

 Found: C: 65.91;. H: 5.86; N: 2.6; F: 6.78%. Production example 1 1

 1 2 -Bi (4-L tP feninole) methoxicetyl] spiro [(indan-1-one) -3,4'-piperidine] and its oxalate (Exemplified Compound No. 395)

 (1 1a) 1- [2-bis (4-phenyl / leo-phenyl) methoxhetyl] spiro [(indan-1-one) -3,4'-piperidine]

 Spiro [(indan-1-one) -3,4, -piperidine] hydrochloride 84 mg (0.35 mmol) and bis (4-fluorophenyl) methyl 2-chloro Using 100 mg (0.35 mmol) of ethyl ether, 50 mg (32%) of the title compound was obtained.

(l i b) 1- [2-Bis (4-fluorophenyl) methoxhetyl] spiro [(indan-1-one) -3,4, -piperidine] oxalate

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

Nuclear magnetic resonance scan Bae-vector ⁽⁴ 00丽_{z, DMS0-d 6) δ} ppm:

 7.15-7.77 (12H, m), 5.61 (1H, s), 3.67-3.73 (2H, m), 3.22-3.48 (4H, m), 2.87-3.11 (2H, m), 2.71 (2H, s), 2.18-2.33 (2H, ra), 1.63-1.74 (2H, m).

Infrared absorption spectrum, „ _ax cm" ¹ (KBr): 3412, 2927, 2568, 1715, 1635, 1603, 1508, 1404, 1223, 1156, 1097, 837. Mass vector (FAB) m / z 448 ((M + H) +, free form)

Elemental analysis value (as C ₃₀ H ₂₉ N0 ₆ F ₂ + 1 / 2H ₂₀ (%))

 Calculated: C: 65.93; H: 5.53; N: 2.56; F: 6.95%

 Found: C: 65.73; H: 5.12; N: 2.55; F: 6.40%. Production example 1 2

[^ Bis- (4- ^ leonyl) methoxhetyl] spiro [(1,4-dihydro-2H-isoquinolin-3-one) -1,4, -piperidine] and its oxalic acid Salt (Exemplary Compound No. 389)

(12a) 1- [2-Bis (4-fluoropheel) methoxhetyl] spiro [(1,4-dihydrido-2H-isoquinolin-3-one) -1,4'-piperidine]

 Spiro [(1,4-dihydro-2H-isoquinolin-3-one) -1,4'-piperidine] 63 mg (0.29 mmol) and bis (4-fluorophenyl) were prepared in the same manner as in Production Example (1a). ) Using 100 mg (0.35 mmol) of methyl 2-chloroethyl ether, 69 mg (42%) of the title compound was obtained.

(1 2 b) 1- [2-Bis (4-fluorophenyl) methoxhetyl] spiro [(1,4-dihydrofuran-2H-isoquinoline-3-one) -1,4'-piperidine ] Salt

 The compound obtained in Production Example (12a) was dissolved in 5 ml of ethyl acetate, 13.4 mg (0.15 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (62 mg, 75%).

Nuclear magnetic resonance scan Bae spectrum ⁽⁴ 00丽_{z, DMSO- d 6) δ ppm} :

 8.14 (lH, bs), 7.16-7.47 (12H, m), 5.59 (1H, s), 3.55-3.78 (4H, m), 3.67-3.42 (6H, m), 2.26-2.41 (2H, m), 1.84-1.93 (2H, m).

Infrared absorption spectrum v _max cnf ¹ (KBr): 3430, 3339, 3013, 2929, 2665, 2580, 172 2, 1669, 1508, 1401, 1224.

Mass vector (FAB) m / z 463 ((M + H) ⁺ , free form)

Elemental analysis (C ₃ .H ₃ as _{.N 2 0 6 F 2 (%} )) True statement

 Arithmetic

Direct

Production example 1 3

[2-bis (4-fluorophenyl) methoxyethyl] spi [benzo [c] thiophen-1 (3H), 4'-piperidine] -2,2-dioxide and its oxalate (Exemplified Compound No. 481)

(13a) 1- [2-Bis (4-fluorofurnyl) methoxicetyl] spiro [benzo [c] thiophen-1 (3H), 4'-piperidine] -2,2-dioxide

 '' Spiro [benzo [c] thio66-phen-1 (3H), 4'-piperidine-2,2-dioxide hydrochloride 138 mg (0.50 ol) and bis ( Using 150 mg (0.53 mmol) of 4-fluorophenyl) methyl 2-chloroethyl ether, 153 mg (63%) of the title compound was obtained.

(13b) 1_ [2-bis (4-fluorophenyl) methoxethyl] spiro [benzo [c] thiophen-1 (3H), 4'-piperidine] -2,2-dioxide oxalate

 The compound obtained in Production Example (13a) was dissolved in 3 ml of ethyl acetate, 29 mg (0.32 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (0 mg, 93%).

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

 7 15-7.45 (12H, m), 5.58 (1H, s), 4.68 (2H, s), 3.63 (2H, m), 2.9-3.4 (6H, m), 2.2-2.6 (4H, m).

Infrared absorption spectrum v cm— ¹ (KBr): 1604, 1509, 1406 1406, 1305, 1224. Mass spectrum (FAB) m / z 484 ((M + H) +, free form).

Production Example 14

8-[2-Bis (4-fluorophenyl) methoxyethynole] -1-oxa-3,8-diazaspiro [4.5] Decane-2-one and its oxalate salt (Exemplary Compound No. 308)

 (14 a) 8- [2-Bis (4-fluorophenyl) methoxethyl] -1-oxa-3,8-diazaspiro [4,5] decane-2-one

 1-oxa-3,8-dazaspiro [4.5] decane-2-one hydrochloride 800 mg (4.15 g ol) and bis (4-fluorophenyl) methyl 2-chloroethyl as in Production Example (1a) Using 1.29 g (4.56 mmol) of ether, 1.24 g of 8- [2-bis (4-fluorophenyl) methoxethyl] -1-oxoxa-3,8-diazaspiro [4.5] decane-2-one ( 74%).

(14 b) 8- [2-Bis (4-fluorophenyl) methoxethyl]-1-oxa-3,8-diazaspi [4.5] de-2-one-oxalate

 The compound obtained in Production Example (14a) was dissolved in 50 ral of ethyl acetate, 277 mg (3.08 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (1.52 g, 84%).

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

 7.63 (1H, s), 7.39-7.44 (4H, m), 7.15-7.21 (4H, m), 5.56 (1H, s), 3.64 (2H, m), 3.29 (2H, s), 2.9- 3.3 ( 6H, m), 1.9- 2.1 (4H, m).

Infrared absorption spectrum v _max cnf ¹ (KBr): 1762, 1639, 1604, 1508, 1406, 1223. Mass spectrum (FAB) m / z 403 ((M + H) +, free form)

Elemental analysis value (as C ₂₄ ¾ ₆ N ₂ 0 ₇ F ₂ (%))

 Calculated: C: 58.53; H: 5.32; N: 5.69; F: 7.72%

 Found: C, 58.58; H, 5.33; N, 5.69; F, 7.50%. Production example 1 5

 8-2- [2-bis (4-octaphenyl) -toxityl]-1-oxa-3,8-diazaspiro 4.5] decane-2-one and its oxalate (Exemplified Compound No. 648)

(1 5a) 8- [2-bis (4-chloropheninole) methoxhetyl]-1-oxa-3,8-diaza 387

147 Spiro [4.5] decane-2-one

 Preparation example 1-Oxa-3,8-diazspiro [4.5] decane-2-one hydrochloride 97 mg (0.50 mmol) and bis (4-cloguchi feninole) methyl 2-chloro Using 159 mg (0.50 mmol) of mouth ethyl ether, 8- [2-bis (4-chloromethyl) methoxhetyl] -1-oxoxa-3,8-diazaspiro [4.5] decane-2-one 115 mg (52%) were obtained.

(1 5 b) 8- [2-Bis (4-chlorophene) methoxeti-oxa-3,8-dazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Production Example (15a) was dissolved in 5 ml of ethyl acetate, oxalic acid (24 mg, 0.27 sulfuric acid) was added, and the mixture was allowed to stand at room temperature for one hour. The precipitated crystals were collected by filtration to give the title compound (105 mg, 76%) as white crystals.

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

 7.63 (1H, s), 7.39-7.43 (8H, m), 5.58 (1H, s), 3.65 (2H, m), 3.29 (2H, s), 2, 9-3.3 (6H, ra), 1.9— 2.1 (4H, m).

Infrared absorption spectrum v _raax era ^-1 (KBr): 1763, 1753, 1640, 1490, 1408, 1090. _Mass spectrum (FAB) m / z 435 ((M + H) +, free form)

Elemental analysis (as _{C 24 H 26 N 2 0 7} C1 2 (%))

 Calculated: C: 54.87; H: 4.99; N: 5.33; C1: 13.50%

 Found: C: 54.48; H: 4.83; N: 5.32; C1: 13.80%. Production Example 16

8- [1,3-bis (4-Furuorofueniru) method Tokishipuropiru] - Tokisa two ^3, 8 Nijiaza peak π

[4.5] Decane-2-one and its oxalate (Exemplified Compound No. 309)

 (16a) 8- [3-bis (4-fluorophenyl) methoxypropyl-oxa-3,8-diazaspiro [4.5] decane-2-one

1-Oxa-3,8-dazaspiro [4.5] decane-2-one hydrochloride as in Preparation Example (la) Using 86 mg (0.45 mmol) and 146 mg (0.49 mmol) of bis (4-fluorophenyl) methyl 3-chloropropyl propyl ether, give 8- [3-bis (4-fluorophenyl) methoxypropyl]- 1-oxa-3,8-dazaspiro [4.5] decan-2-one 111 rag (60%) was obtained.

(16b) 8- [3-Bis (4-fluorophenyl) methoxypropyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Production Example (16a) was dissolved in 5 ml of ethyl acetate, 24 mg (0.27 ol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give 86 mg (64%) of the title compound as white crystals.

Nuclear magnetic resonance scan Bae spectrum ^{(4 00 MHz, DMS0-d} 6) 6 ppm:

 7.62 (1H, s), 7.37-7.42 (4H, m), 7.13-7.19 (4H, m), 5.49 (1H, s), 3.41 (2H, m),

3.30 (2H, s), 2.8-3.3 (6H, m), 1.8-2.1 (6H, m).

Infrared absorption spectrum v _raax cm- ¹ (KBr): 1766, 1604, 1508, 1222, 1088.

Mass spectrum (FAB) m / z 417 ((M + H) +, free form)

Elemental analysis value (as C ₂₅ H ₂₈ N ₂ 0 ₇ F ₂ (%))

 Calculated: C: 59.28; H: 5.57; N: 5.53; F: 7.50%

 Found: C, 58.92; H, 5.40; N, 5.60; F, 7.20%. Production Example 1 7

 8- [4-bis (4-fluorophenyl) methoxybutyl] -toxa-3,8-diazaspiro [4.5] decane-2-one and its oxalate (Exemplified Compound No. 310)

 (17a) 8- [4-Bis (4-fluorophenyl) methoxybutyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one

1-Oxa-3,8-diazspiro [4.5] decane-2-one hydrochloride 97 mg (0.50 tmol) and bis (4-fluorophenyl) methyl 4-chlorobutyl ether were prepared in the same manner as in Production Example (la). mg (0.55 mmol) to give 8- [4-bis (4-fluorophenyl) methoxypeptide. 1] -Oxa-3,8-dazaspiro [4,5] decane- ² -one ⁵⁹ mg (27%).

(17 b) 8- [4-Bis (4-fluorophenyl) methoxybutyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Production Example (17a) was dissolved in 5 ml of ethyl acetate, 12 mg (0.14 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (49 mg, 69%).

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

 7.65 (1H, s), 7.37-7.40 (4H, m), 7.14- 7.19 (4H, m), 5.47 (1H, s), 3.38 (2H, ra), 3.30 (2H, s), 2.8-3.4 ( 6H, m), 1.5—2.1 (8H, m).

Infrared absorption spectrum v _max cm " ¹ (KBr): 1753, 1615, 1606, 1508, 1404, 1222, 1083. Mass spectrum (FAB) m / z 431 ((M + H) +, free form)

Elemental analysis (C ₂₆ H _3, N ₂ 0 ₇ F ₂ -¾0 (%))

 Calculated: C: 58.97; H: 5.90; N: 5.29; F: 7.18%

 Found: C, 59.28; H, 5.75; N, 5.24; F, 6.95%. Production example 1 8

 8- [5-Bis (4-fluorophenylene) meth ¾cinpentinole]-1-oxa-3,8-diazaspiro

[4.5] Decane-2-one and its oxalate salt (Exemplary Compound No. 311)

 (18a) 8- [5-Bis (4-fluorophenyl) methoxypentyl]-1-oxa-3,8-diazaspiro [4.5] decane-2-one

Toxa-3,8-dazaspiro [4.5] decane-2-one hydrochloride 97 mg (0.50 mmol) and bis (4-chlorofluoro) methyl 5-chloropentylate as in Preparation Example (1a) Ter 180 mg (0.55 t ol) was used to prepare 8- [5-bis (4-fluorophenyl) methoxypentyl] -1-oxa-3,8-diazaspiro [4.51decane-2-one 92 mg ( 41%). (18b) 8- [5-bis (4-fluorophenyl) methoxypentyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Production Example (18a) was dissolved in 5 ml of ethyl acetate, 19 mg (0.21 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (70 mg, 63%).

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

 7.65 (IH, s), 7.35-7.39 (4H, m), 7.13-7.19 (4H, m), 5.46 (IH, s), 3.37 (2 m), 3.23 (2H, s), 2.8-3.4 (6H , m), 1.3-2.1 (10H, m).

Infrared absorption spectrum _m3X cm— ¹ (KBr): 1754, 1615, 1507, 1403, 1222, 1087. Mass spectrum (FAB) m / z 445 ((M + H) +, free form)

Elemental analysis value (as C ₂₇ N ₂ 0 ₇ F ₂ (%))

 Calculated: C: 60.67; H: 6.03; N: 5.24; F: 7.11%

 Found: C: 60.4; H: 6.13; N: 5.20; F: 7.10%. Production example 1 9

 8-[6-bi (4-? Luofue: ^) methoxyhexyl]-1-oxa-3, 8- diazaspiro

[4.5] Decane-2-one and its oxalate salt (Exemplary Compound No. 312)

 (1 9a) 8- [6-Bis (4-fluorophenyl) methoxyhexyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one

Tokisa in the same manner as described in Example (la) - 3,8-Jiazasupiro ^{[4 5.]} Decane - ² - one hydrochloride 97 mg (0.50謹ol) and bis (6-Furuorofu sulfonyl) Kishirue ether to methyl 4- black port Using 188 mg (0.56 mmol), 8- [6-bis (4-fluorophenyl) methoxyhexyl] -1-oxa_3,8-diazaspiro [4.5] decane-2-one 75 mg (32% ) Was obtained.

(1 9 b) 8- [6-bis (4-fluorophenyl) methoxyhexyl] -1 -oxa-3,8-diazspiro [4.5] decane-2-one oxalate The compound obtained in Production Example (19b) was dissolved in 5 ml of ethyl acetate, 15 mg (0.16 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (58 mg, 64%).

Nuclear magnetic resonance scan data Torr _{(400 MHz, DMSO- d 6)} δ ppm: ·

 7.66 (1H, s), 7.35-7.39 (4H, m), 7.13-7.19 (4H, m), 5.45 (1H, s), 3.36 (2H, m), 3.31 (2H, s), 2.8-3.3 ( 6H, m), 1.2-2.1 (12H, m).

Infrared absorption spectrum v _max cm— ¹ (KBr): 1754, 1604, 1508, 1404, 1222, 1088. Mass spectrum (FAB) m / z 459 ((M + H) ⁺ , free form)

Elemental analysis _{(C 28 H 34 N 2 0} 7 F 2 - as 0 · 5¾0 (%;))

 Calculated: C: 59.36; H: 6.40; N: 4.94; F: 6.70%

 Found: C: 59; 14; H: 6.15; N: 4.87; F: 6.53%. Production Example 20

 1- [2-Bis (4-fluorophenyl) methoxethyl] -4- (4-chlorobenzyl) piperidine-4-carboxylic acid methyl ester and its oxalate salt (Exemplary Compound No. 972)

(20a) 1- [2-Bis (4-fluorophenyl) methoxetinole] -4- (4-chlorobenzyl) piperidine-4-methyl carbonyl ester

 Production Example 3-(4-Mouth benzyl) piperidine-3-carboxylic acid methyl ester hydrochloride 305 mg (1.00 mmol) and bis (4_fluorophenyl) methyl 2-chloride as in (1a) 283 mg (1.00 t ol) of loroethyl ether was used to obtain 349 mg (68%) of the title compound.

(20 b) 1- [2-Bis (4-funolelophenyl) methoxetinole] -4- (4-chlorobenzene) piperidine 4-carboxylic acid methylester oxalate

The compound obtained in Production Example (20a) was dissolved in 5 ml of ethyl acetate, and 61 mg (0.68 mmol) of oxalic acid was added thereto. The precipitated crystals were collected by filtration to give the title compound. Was obtained as white crystals (308 mg, 75%).

Nuclear magnetic resonance spectrum (400 MHz, 丽 SO-d ₆ ) δ ppm:

 7.02-7.37. (12H, m), 5.51 (lH, s), 3.55 (3H, s), 3.2-3.6 (2H, m), 2; 4-3.1 (8H, m), 1.3-2.0 ( 4H, m).

Infrared absorption spectrum v _nax cm ¹ (KBr): 1731, 1604, 1509, 1405, 1224.

Mass spectrum (FAB) m / z 515 ((M + H) free body)

Elemental analysis value (as C ₃₁ H ₃₂ N0 ₇ C1F ₂ (%))

 Calculated: C: 61.64; H: 5.34; N: 2.32; F: 6.29; C1: 5.87%

 Found: C: 61.42; H: 5.48; N: 2.33; F: 6.17; C1: 5.84%. Production example 21 '

1- [2-Bis (4-fluorophenyl) methoxethyl] piperidine-4-benzylamide and its oxalate (Exemplary Compound No. 441)

 (21 a) '1- [2-Bis (4-fluorophenyl) me'toxityl] piperidine-4-carbonic acid benzinoleamide

 In the same manner as in Production Example (la), 255 mg (1.00 mmol) of piperidine-4-carboxylic acid benzylamide hydrochloride and 283 mg (1.00 mmol) of bis (4-fluorophenyl) methyl 2-chloroethyl ether As a result, 279 rag (60%) of the title compound was obtained.

(21 b) 1- [2-bis (4-fluorophenyl) methoxethyl] piperidine-4-carboxylate benzylamide oxalate

 The compound obtained in Production Example (21a) was dissolved in 5 ml of ethyl acetate, 54 mg (0.60 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (303 mg, 91%).

Nuclear magnetic resonance spectrum (00 MHz, DMS0-d ₆ ) δ ppm:

8.46 (IH, t, J = 5.9Hz), 7.15-7.43 (13H, m), 5.57 (IH, s), 4.27 (2H, d, J = 5.2Hz), 3.6 5 (2H, m), 3.2-3.4 (4H, m), 2.88 (2H, m), 2.42 (lH, m), 1.7-2.0 (4H, m).

Infrared absorption spectrum cm- ¹ (KBr): 1657, 1604, 1536, 1509, 1223.

Mass vector (FAB) m / z 465 ((M + H) +, free form)

Elemental analysis (as _{C 30 H 32 N 2 0 6} C1F 2 (%;))

 Calculated: C: 64.97; H: 5.82; N: 5.05; F: 6.85%

 Found: C: 64.90; H: 6.02; N: 4.95; F: 6.69% Production Example 22

 1 [2-bis (4-_full; ^ mouth_phenyl) methoxhetyl] -4- [1- (4-fluorobenzyl)-1H

-^ ^ Midazol-2-yl] -4-hydroxypiperidine and its oxalate (Example Compound No. 229) '

 (22a) 1- [2-Bis (4-fluorophenyl) methoxhetyl] -4- [1- (4-fluorobenzyl) -1H-benzoimidazole-2-inole] -4-hydroxypitanium Lysine

In the same manner as described in Example ^{(la) 4 - [1- (} 4- Furuo port benzyl) - 1H-benzo I Mi indazole - 2 - I le] -4 - hydroxy piperidine dihydrochloride 200 mg (0.50 mmol)及172 mg (60%) of the title compound was obtained using 143 mg (0.51 ramol) of ぴ bis (4-fluoropheninole) methinole 2-chloroethyl ether.

(22 b) 1- [2-bis (4-fluorophenyl) methoxethyl] -4- [1- (4-fluorobenzyl) -1H-benzimidazol-2-yl "1-4-h Droxypiperidine Nisshu The compound obtained in Production Example (22a) was dissolved in 5 ml of ethyl acetate, 54 mg (0.60 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature, and the precipitated crystals were collected by filtration. This gave 156 rag (69%) of the title compound as white crystals.

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

7 12-7 7 (16H, m), 5.81 (2H, s), 5.59 (IH, s), 3.2-3.8 (10H, m), 2.0-2.2 (2H, m) Infrared absorption spectrum v _max cm- ¹ (KBr): 1722, 1605, 1509, 1405, 1224.

Mass vector (FAB) m / z 572 ((M + H) +, free form)

Elemental analysis value (as C ₃₈ H ₃₆ N ₃ 0 ₁₀ F ₃ (%))

 Calculated: C: 60.72; H: 4.83; N: 5.59; F: 7.58%

 Found: C, 60.82; H, 4.83; N, 5.57; F, 7.28%. Production Example 23

 8- [2-Bis (4-fluorophenyl) methoxethyl] -1-phenyl-1,3,8-triazaspiro [4.5] decane-4-one and its oxalate salt (Exemplified Compound No. 367)

 (23a) 8- [2-Bis (4-fluorophenyl) methoxethyl] -1-phenyl-1,3,8-triazaspiro [4.5] decane-4-one

 1-Phenyl-1,3,8-triazaspiro [4.5] decane-4-one 180 mg (0.78 mmol) and bis (4-fluorophenyl) methyl 2-chloroethyl ether 200 mg as in Production Example (la) (0.71 mmol) to give 235 mg (70%) of the title compound.

(2 3 b) 8- [2-Bis (4-fluorophenyl) methoxetinole] -1 -Fuel-1,3,8-triazaspiro [4.5] decane-4-one oxalate

 The compound obtained in Production Example (23a) was dissolved in 5 ml of metafur, and oxalic acid (44 mg, 0.49 benzyl) was added thereto. The precipitated crystals were collected by filtration to give 167 mg (42%) of the title compound as white crystals.

Nuclear magnetic resonance scan Bae-vector (400顧_{z, DMS0 - d 6) δ} ppra:

 9.0K1H, s), 7.43-7.46 (4H, m), 7.15-7.26 (6H, m), 6.95 (2H, d, J = 8.4Hz), 6.79 (1H, dd, J = 7.2, 7, 2Hz) , 5.61 (1H, s), 4.62 (2H, bs), 3.6-3.8 (4H, m), 3.3-3.5 (4H, m), 2.7-2.9 (2H, m), 1.8-1.9 (2H, m) .

Infrared absorption spectrum v, „ _ax cm— ¹ (KBr): 3234, 3068, 2876, 2572, 1717, 1601, 150 7, 1223. Mass vector (FAB) m / z 478 ((M + H) +, free form)

Elemental analysis (as _{C 30 H 31 N 3 0 6} F 2 (%;))

 Calculated: C: 63.48; H: 5.51; N: 7.40; F: 6.69%

 Found: C: 63.25; H: 5.43; N: 7.38; F: 6.52%. Production Example 24

 〗-[2-Bis (4-ruth-mouth) methoxicetyl] spiro [isobenzofuran-1 (3H), 4'-piperidine] and its oxalate salt (Exemplified Compound No. 483)

 (24 a) 1- [2-Bis (4-fluorophenyl) methoxetinole] spiro [isobenzofuran-1 (3H), 4'-piperidine]

 Spiro [isobenzofuran-1 (3H), 4, -piperidine] hydrochloride 114 mg (0.51 ol) and bis (4-fluorophenyl) methyl 2-chloro 130 mg (59%) of the title compound was obtained using 150 mg (0.53 mol) of ethyl ether.

(24 b) 1- [2-bis (4-fluorophenyl) methoxyl] spiro [isobenzofuran-1 (3H), 4'-piperidine] oxalate

 The compound obtained in Production Example (24a) was dissolved in 5 ml of ethyl acetate, oxalic acid (27 mg, 0.30 armol) was added, and the mixture was allowed to stand at room temperature at room temperature. The precipitated crystals were collected by filtration to give the title compound as white crystals (102 mg, 65%).

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

7.17-7.45 (12H, m) ₎ 5.60 (1H, s), 5.03 (2H, s), 2.8— 4.0 (8H, m), 1.7-2.3 (4H, m). Infrared absorption spectrum v _raax cm— ¹ (KBr): 1720, 1633, 1604, 1508, 1405, 1223. Mass spectrum (FAB) m / z 436 ((M + H) free form). Production Example 25

2-[1- [2-Bis (4-fluorophenyl) methoxethyl] -piperidine-4-ylidene] p Ethyl lopionate (Exemplary Compound No. 4-1)

 0.61 g of 2-phosphonopropionic acid triethyl ester was dissolved in 6 ml of tetrahydrofuran, and a suspension of 0.125 g of 55% sodium hydrogen hydrogen in 10 ml of tetrahydrofuran was added in a nitrogen stream. Then, the reaction mixture was cooled with acetone-ice, 0.95 g of 1- [2-bis (4-fluorophenyl) methoxethyl] -4-piperidone was added dropwise in 5 ml of tetrahydrofuran, and the mixture was added dropwise at room temperature for 3 hours. Stirred. The mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with dichloromethane and concentrated. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate: hexane = 1: 2) to give the title compound as a colorless oil. 865 g (73%) were obtained. Production Example 2 6

 2- [1- [2-Bis (4-fluorophenyl) methoxethyl] -piperidin-4-yl] propionate ethyl ester and its oxalate salt (Exemplary Compound No. 417)

 (26a) 2- [1- [2-Bis (4-fluorophenyl) methoxyl] -piperidine-4-inole] ethylethyl propionate

 0.784 g of the compound obtained in Production Example 25 was dissolved in 15 ml of ethanol, 0.03 g of 10% palladium-carbon was added, and the mixture was shaken in a stream of hydrogen for 4 hours. Then, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to obtain 0.726 g (92%) of the title compound as a yellow liquid.

(26b) 2- [1- [2-Bis (4-fluorophenyl) methoxethyl] -piperidine-4-yl] propionate ethyl oxalate

 The compound obtained in Production Example (26a) was dissolved in ethanol, oxalic acid was added, and the mixture was allowed to stand at room temperature at room temperature. The precipitated crystals were collected by filtration to give the title compound.

Melting point: 137-138 ° C. Production Example 2 7 ^ [1- [2- ^ S (4-fluorophenyl) methoxchetyl] -piperidine-4-ylidene] -2-methylesterenole 2-cyanoacetate (Exemplified Compound No. 498)

 1- [2-Bis (4-fluorophenyl) methoxethyl] -4-piperidone 1.14 g, cyanoacetic acid methyl ester 0.43 g, piperidine 0.03 ml, and acetic acid 0.04 g in benzene 10 The mixture was dissolved in ml, and refluxed for 1 hour while removing generated water. After cooling, the mixture was washed with water, washed with a saturated solution of sodium bicarbonate, and concentrated by dehydration. The residual oil was purified by silica gel gel chromatography (Bisolvent; ethyl acetate: hexane = 1: 3) to give 995 mg of the title compound as a yellow liquid. Production Example 2 8

 2-Jl- [2, -S- (fluo-Zell) methoxchetyl] -piperidine-4-yl] -2-cyanoacetic acid methyl ester and its oxalate salt (Exemplary Compound No. 423) '

 (28a) Methylester 2- [1- [2-bis (4-fluorophenyl) methoxethyl] -piperidine-4-yl] -2-cyanoacetate. Compound obtained in Production Example 27. mg was dissolved in methanol (20 ml), 10% palladium-carbon (0.03 g) was added, and the mixture was shaken under a hydrogen stream for 1.5 hours. Then, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to obtain 609 mg (91%) of the title compound as a yellow liquid.

(28b) 2- [1- [2-Bis (4-fluorophenyl) methoxethyl] -piperidine-4-yl] -2-methyl cyanoacetate oxalate

 The compound obtained in Production Example (28a) was dissolved in ethanol, oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound.

Melting point: 141-144 ° C (decomposition). Production Example 2 9

1-[2-bis (4-fluorophenyl) methoxyethyl]-4-ethoxycarbonylbiperazine And its oxalate (Exemplary Compound No. 478)

 (29 a) 1- [2-Bis (4-fluorophenyl) methoxethyl] -4-ethoxycarbinolinolepiperazine

 In the same manner as in Production Example (la), 0.43 g (21%) of the title compound was prepared using 1.19 g of triethoxycarbonirubiperazine and 1,43 g of bis (4-fluoropheninole) methyl 2-chloroethyl ether. Obtained.

(29 b) 1- [2-Bis (4-fluororazinyl) methoxhetyl] -4-ethoxycarbonylpyrazine, oxalate

 The compound obtained in Production Example (29a) was dissolved in ethanol, oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound. '

Melting point: 154-156 ° C ₀ Production example 30

 1- [2-Bis (4-fluorophenyl) methoxhetyl] -piperidine-4-ylidene] -propionic acid methyl ester (Exemplary Compound No. 461)

 0.87 g of 50% sodium hydrogen was added to 70 ml of anhydrous tetrahydrofuran in a stream of nitrogen, and a solution of 3.6 g of methyl dimethylphosphonopropionate in 12 ml of tetrahydrofuran was added dropwise at 10 ° C. Next, a solution prepared by dissolving 6.8 g of 1- [2-bis (4-fluorophenyl) methoxethyl] -4-piperidone in 70 ml of tetrahydrofuran was added dropwise at 0 ° C. After stirring at room temperature for 2 hours, the solvent was distilled off and ice water was added. The residue obtained by extraction with dichloromethane was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1 ': 2), and the title compound was converted into 6.04 g (76%) as a colorless oil. %).

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, CDC1 3) δ} ppm:

2.30 (2H, t), 2.60 (4H, m), 2.98 (2H, t), 3.57 (2H, t), 3.68 (3H, s), 5.35 (1H, s), 5.65 (1H, s), 7.00 (4H, t), 7.30 (4¾dd).

Infrared absorption spectrum ^{_{v max cm- 1 (CHC1 3)}} : 1710, 1655, 1605. Production example 3 1

 8- · ί2-Κ5-c-mouth phenyl) phen-methoxy 1-ethyloxa-3,8-diazaspiro

[4.5 Decane-2-one and its oxalate (Exemplary Compound No. 961)

 (31a) 8- {2-[(3-chlorophenyl) phenylmethoxy] ethyloxa-3,8-diazaspiro [4.5] decane-2-one

 1-oxa-3,8-dazaspiro [4.5] decane-2-one hydrochloride synthesized in Reference Example 1 150 mg (0.78 mmol) and (3-chlorophenyl) phenylmethyl 2-chloroethylethyl 199 mg (0.71 mmol) of ter were dissolved in 8 ml of 4-methyl-2-pentanone, then 263 mg (2.48 mmol) of sodium carbonate and 11 mg (0.07 mmol) of sodium iodide were added, The mixture was heated and refluxed at 130 ° C for 16 hours. After cooling to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; methylene chloride: methanol = 10: 1) to give 8- {2-[(3-chlorophenyl) phenylmethoxy] ethyl} -1-oxoxa-3,8. -Diazaspiro [4.5] decane-2-one was obtained in an amount of 181 mg (64%).

(31b) 8- {2-[(3-chlorophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Production Example (31a) was dissolved in 10 ml of ethyl acetate, 41 mg (0.46 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature at room temperature. The precipitated crystals were collected by filtration to give the title compound as white crystals (200 mg, 90%).

Nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ ppm:

7.25-7.45 (9H, m), 5.52 (1H, s) ₃ 3.77-3.86 (2H, m), 3.30-3.57 (8H, m), 2.08-2.24 (4H, m).

Infrared absorption spectrum _max cm ' ¹ (Br): 3235, 2929, 2558, 1762, 1749, 1638, 1406, 1279, 1077, 719. Production example 3 2

 8-Γ2-bis (3-fluorophenol) methoxiltilt 1-oxa-3,8-diazaspiro “4.51decane-2-one and its oxalate salt (Exemplary Compound No. 146)

 (32a) 8- [2-Bis (3-funoreo mouth) -methoxhetinole] -1-oxa-3,8-diazaspiro [4.5] decane-2-year

 1-Oxa-3,8-diazaspiro [4.5] decane-2-one hydrochloride 150 (0.78 mmol) and bis (3-fluorophenyl) methyl 2-chloroethyl as in Production Example (31a) The reaction was performed using 220 mg (0.78 mmol) of ether, and 8- [2-bis (3-fluorophenyl) methoxethyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-one 151 mg (48%).

(32b) 8- [2-Bis (3-fluorophenyl) methoxyl] -1-oxa-3,8-diazaspiro [4.5] decane-2-year oxalate

 The compound obtained in Production Example (32a) was dissolved in ethyl acetate, oxalic acid (34 mg, 0.38 mniol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (135 mg, 73%).

Nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ ppm:

 7.33-7.41 (2H, m), 7.14-7.23 (4H, m), 6.98-7.06 (2H, m), 5.56 (1H, s), 3.82 (2H, t, J = 5.0 Hz), 3.30-3.57 ( 8H, m), 2.09-2.25 (4H, m).

Infrared absorption spectrum v _max cm " ¹ (Br): 3241, 2931, 2564, 1761, 1750, 1591, 1486, 1450, 1244, 1075. Production Example 33

8-12-[(3,4-difluorophenyl) phenylmethoxy 1-ethyl 1-oxa-3,8-diazas Pyro [4.51 decane-2-one and its oxalate (Exemplary Compound No. 962)

(33a) 8- {2-[(3,4-difluorophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one

 1-Oxa-3,8-diazspiro [4.5] decane-2-one hydrochloride 150 mg (0.78 mmol) and (3,4-difluorophenyl) phenylmethyl as in Production Example (31a) The reaction was carried out using 220 mg (0.78 mmol) of 2-chloroethyl ether to give 8- {2-[(3,4-difluorophenyl / re) phenylmethoxy] ethyl 1-oxa-3,8- Diazaspi [4.5] decane-2-one 232 mg (74%) was obtained.

(33b) 8- {2-[(3,4-difluorophenyl) phenylmethoxy] ethyl 1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Production Example (33a) was dissolved in ethyl acetate, oxalic acid (52 mg, 0.58 mniol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give 198 mg (70%) of the title compound as white crystals.

Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm:

 7.33-7.44 (3H, m), 6.97-7.22 (5H, m), 5.54 (1H, s), 3.81 (2H, t, J = 4.9 Hz), 3.30- 3.58 (8H, m), 2.09-2.25 ( 4H, m).

Infrared absorption spectrum v _max cm " ¹ (KBr): 3248, 2929, 2564, 1759, 1615, 1509, 1405,

Production example 3 4

 8- {2a (3-ditrophenyl) phenino.remethoxy 1ethyl 1-oxa-3,8-diazaspiro 4.51 decane-2-one and its oxalate (Exemplified Compound No. 963)

 (34a) 8- {2-[(3-Nitrophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspi [4.5] decane-2-one

1-Oxa-3,8-dazaspiro [4.5] decane-2-one salt as in Production Example (31a) The reaction was carried out using 150 mg (0.78 mmol) of the acid salt and 227 mg (0.78 rmnol) of (3--trophenyl) phenylmethyl 2-chloroethyl ether to give 8- {2-[(3-nitrophenyl) phenylmethoxy] ethynole} 247 mg (77%) of 1-oxa-3,8-diazaspiro [4.5] decane-2-one was obtained.

(34b) 8- {2-[(3-Ditrophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Production Example (34a) was dissolved in ethyl acetate, 50 mg (0.56 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature at room temperature. The precipitated crystals were collected by filtration to give the title compound as white crystals (211 mg, 70%).

Nuclear magnetic resonance spectrum (400MHz, CD ₃ OE>) δ ppm:

 8.28 (1H, d, J = 1.9 Hz), 8.14 (1H, dd, J- 8.0, 1.9 Hz), 7.78 (1H, d, J = 8.0 Hz), 7.59 (1H, dd, J = 8.0, 8.0 Hz) ), 7.29-7.46 (5H, m), 5.68 (1H, s), 3.29-3.42 (2H, m) 3.30-3.62 (8H, m), 2.09-2.25 (4H, m).

Infrared absorption spectrum v _max cm " ¹ (KBr): 3284, 2928, 1742, 1650, 1529, 1403, 1351,

Production example 3 5

 8- {2- (3-methylphenyl) phenylmethoxy 1-ethyl-l-oxa-3,8-diazaspiro [4.51 decane-2-one and its oxalate (Exemplified Compound No. 964)

 (35a) 8- {2-[(3-methylphenyl) phenylmethoxy] ethyloxa-3,8-diazaspiro [4.5] decane-2-one

1-Oxa-3,8-dazaspiro [4.5] decane-2-one hydrochloride 150 (0.78 mmol) and (3-methylphenyl) phenylmethyl 2-chloro The reaction was carried out using 203 mg (0.78 mmol) of ethyl ether, and 8- {2-[(3-methylphenyl) phenylmethoxy] ethyl 1-oxa-3,8-diazaspiro [4.5] decane-2-one 159 mg (54Q / ₀ ) Got

(35b) 8-[(3-Methylphenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Production Example (35a) was dissolved in ethyl acetate, 38 mg (0.42 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (141 mg, 72%).

Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm:

 7.07- 7.41 (9H, m), 5.46 (1H, s), 3.80 (2H, t, J = 5.0 Hz), 3.30-3.57 (8H, m), 2.31 (3H, s), 2.07-2.24 (4H, m).

Infrared absorption spectrum v _max cm ' ¹ (KBr): 3422, 3242, 2925, 2564, 1749, 1636, 1404,

Production example 3 6

 8- {2 (3,5-difluorophenyl) ferrmethoxy 1-ethyloxa-3,8-diazaspiro [4.51 decane-2-one and its oxalate (Exemplary Compound No. 965)

 (36a) 8- {2-[(3,5-difluorophenyl) phenylmethoxy] ethyl 1-oxa-3,8-diazaspiro [4.5] decane-2-one

 1-Oxa-3,8-diazaspiro [4.5] decane-2-one hydrochloride 150 mg (0.78 mmol) and (3,5-difluorophenyl) phenylmethyl 2- The reaction was carried out using 220 mg (0.78 mmol) of chloroethyl ether, and 8- {2-[(3,5-difluorophenyl) phenylmethoxy] ethyl} small oxa-3,8-diazaspiro [4.5] .decane-2 246 mg (79%) were obtained.

(36b) 8- {2-[(3,5-difluorophenyl) phenylethoxy] ethyloxa-

3.8-Diazaspiro [4.5] decane-2-one oxalate The compound obtained in Production Example (36a) was dissolved in ethyl acetate, 55 mg (0.61 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (233 mg, 77%).

Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm:

 7.28-7.44 (5H, m), 6.98-7.05 (2H, m), 6.80-6.87 (IH, m), 5.54 (IH, s), 3.76-3.88 (2H, m), 3.30-3.58 (8H, m ), 2.08-2.24 (4H, m).

Infrared absorption spectrum V max Cm— ¹ (KBr): 3430, 2930, 2566, 1744, 1625, 1599, 1455, 1404, 1119, 720ο Production example 3 7 '

8- [2-bis (3-trifluoromethylphenyl) methoxhetyl 1-1-oxa-3,8-diazaspiro 4.51 decane-2-one (exemplified compound number 919)

 1-Oxa-3,8-diazaspiro [4.5] decane-2-one hydrochloride 150 mg (0.78 mmol) and bis (3-trifluoromethylphenyl) methyl in the same manner as in Production Example (3 la) The reaction was carried out using 298 mg (0.78 mmol) of 2-ethyl mouth ether to give 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 (IH, 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 true cm ⁴ (KBr): 3269, 2925, 2830, 1753, 1330, 1256, 1166, 1125, 1074. Production example 3 8.

 8- {2a (2-fluorophenyl) (4-fluorophenyl) methoxy 1-ethyl 1-oxa-3,8-diazaspiro [4.51decane-2-one and its oxalate (Exemplified Compound No. 966)

(38a) 8- {2-[(2-fluorophenyl) (4-fluorophenyl) methoxy] ethyl} -1- Oxa-3,8-dazaspiro [4.5] decane -2 "on

 As in Production Example (31a), 1-oxa-3,8-diazaspiro [4.5] decane-2-one hydrochloride 100 mg (0.52 mmol) and (2-fluorophenyl) (4-fluorophen- The reaction was carried out using 135 mg (0.48 mmol) of methyl 2-chloroethyl ether, to give 8- {2-[(2-fluorophenyl) (4-fluorophenyl) methoxy] ethyl} -1-oxa-3 , 8-Zazaspi mouth

[4.5] Decane-2-one 71 mg (37%) was obtained.

(38b) 8- {2-[(2-fluorophenyl) (4-fluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The obtained compound was dissolved in ethyl acetate, oxalic acid (16 mg, 0.18 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (69 mg, 79%).

Nuclear magnetic resonance spectrum (400MHz, DMSO-de) δ ppm:

7.51-7.63 (2H, m), 7.33-7.44 (3H _; m), 7.14-7.28 (4H, m), 5.79 (1H, s), 3.66 (2H, t, J = 5.0 Hz), 3.28 (2H, s), 2.90-3.20 (6H, m), 1.85-2.00 (4H, m).

Infrared absorption spectrum v _max cm " ¹ Br): 3234, 2934, 2560, 1763, 1639, 1509, 1409,

Production example 3 9

 8- {2-[(2,5-Difluorophenyl) phenylethoxy] ethyl}-1-oxa- 3, 8-diazaspiro [4.5] decane-2-one and its oxalate (example) (Compound No. 967)

 (39a) 8- {2-[(2,5-Difluorophenyl) phenylmethoxy] ethyl)-1-oxo-3,8-diazaspiro [4.5] decane-2-one

In the same manner as in Production Example (31a), 1-oxaco 3,8-dazaspiro [4.5] decan-2-one hydrochloride 150 mg (0.78 t ol) and (2,5-difluorofuran) were used. The reaction was carried out using 220 mg (0.78 t ol) of (phenyl) phenylmethyl 2-chloroethyl ether, and 8--[(2,5-difluoro Mouth phenyl) phenylmethoxy] ethyl} -1-oxoxa-3,8-dazaspiro [4.5] decane-2-one 193 mg (62%) was obtained.

(39 b) 8- {2-[(2,5-difluorophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-dazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Production Example (39a) was dissolved in ethyl acetate, 43 rag (0.48 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (170 mg, 72%).

Nuclear magnetic resonance's Bae vector _{^{(4 00MHz, CD 3 0D)}} δ ppm:

 7.27-7.45 (6H, m), 7.00-7.13 (2H, m), 5.79 (1H, s), 3.78-3.90 (2H, m), 3.30-3.60 (8H, m), -2.07-2.24 (4H, m m).

Infrared absorption spectrum v _max cm " ¹ (KBr): 3423, 3247, 2928, 2564, 1747, 1636, 1492, 1404, 1243, 721. Production Example 40

 8- {2-[(2-Fluorophenyl) phenylmethoxane] ethyl} -1-oxo-3,8-diazaspiro [4.5] decane-2-one and its oxalate (Exemplified Compound No. 968)

 (40a) 8- {2-[(2-Fluorophenyl) phenylmethoxy] ethyl}-1-oxa- 3,3-diazaspiro [4.5] decane-2-one

 1-Oxa-3,8-dazaspiro [4.5] decane-2-one hydrochloride 100 mg (0.52 mmol) and (2-fluorophenyl) phenylmethyl 2-chloroethyl ether 125 The reaction was carried out using rag (0.47 mraol), and 8-[(2-fluorophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspi [4.5] decane-2-one 87 mg ( 48%). ,

(40 b) 8- {2-[(2-fluorophenyl) phenylmethoxy] ethyl} -1-oxa- 3, 8-dazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Production Example (40a) was dissolved in ethyl acetate, oxalic acid (20 mg, 0.22 ol) was added, and the mixture was allowed to stand at room temperature at room temperature. The precipitated crystals were collected by filtration to give the title compound as white crystals (92 mg, 85%).

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, DMSO- d 6)} 8 ppm:

7.61 (1H, s), 7.54 (1H, dt, J = 1.6 and 7.5 Hz), 7.14-7.37 (7H, m), 5.78 (1H, s), 3.68 (2H, t, J = 5.1 Hz), 3.28 (2H, s), 2.91-3.15 (6H, m), 1,87–1.99 (4H, m). Infrared absorption spectrum _raax cm ^-1 (KBr): 3236, 1750, 1637, 1404, 1226 . Production Example 41

 8-{_2- [(2-clo-low 5-nitrophen) phenenomethoxy] ethyl) -1-oxa-3,8-diazaspiro [4.5] decane-2-one and its oxalate (Exemplified Compound No. 969)

 (41a) 8- {2-[(2-Chloro-5-ditrophenyl) phenylmethoxy] ethynole} — 1-oxa-3,8-diazaspiro [4,5] decane-2-one

 As in Production Example (31a), 1-oxa-3,8-diazaspiro [4.5] decane-2-one hydrochloride 100 mg (0.52 acetyl) and (2-chloro-5-nitrophenyl) phenyl The reaction was carried out using 155 mg (0.47 ramol) of -methyl 2-chloroethynole ether, and 8- {2-[(2_chloro-5-nitrophenenyl) phenylmethoxy] ethyl oxa-3,8-diazaspiro [4.5 123 mg (58%) of decane-2-one was obtained.

(41 b) 8- {2-[(2-Chloro-5-nitrophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The obtained compound was dissolved in ethyl acetate, oxalic acid (25 mg, 0.28 alcohol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (10 mg, 74%).

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, DMSO- d 6)} δ ppm: 8.42 (1H, d, J = 2.9 Hz), 8.19 (1H, dd, J = 2.9 and 8.8 Hz), 7.76 (1H, d, J = 8.8 Hz), 7.30-7.42 (5H, m), 5.87 (1H , s), 3.61-3.74 (2H, m), 3.25 (2H, s), 2.88-2.97 (2H, m), 2.72-2.87 (4H, m), 1.78-1.91 (4H, m).

Infrared absorption spectrum ^{_{v mx cm "1 (KBr)}} : 3413, 1745, 1610, 1525, 1347. Production Example 42

 8--f2-[(3-trypnoreo-methylphenyl) phenyl methoxy "I-ethyl 1-oxa-3,8-diazspiro" 4.51 decane-2-one and its oxalate (Exemplified Compound No. 1001)

 (42a) 8- {2-[(3-Trifluoromethylphenyl) furmethoxy] ethyl} -1-oxa-3,8-diazaspis [4.5] decane-2-one

 Preparation example 1-Oxa-3,8-diazaspiro [4.5] decane-2-one hydrochloride 150 mg (0.78 mmol) and (3-trifluoromethylphenyl) phenylmethyl 2- The reaction was carried out using 245 mg (0.78 mmol) of octaethyl ether, and 8- {2-[(3-trifluoromethylphenyl) phenylethoxy] ethyl 1-oxa-3,8-diazaspiro [4.5] decane-2-one 245 mg (72%) were obtained.

(42 b) 8- {2-[(3-Trifluoromethylphenyl) phenylethoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The compound obtained in Production Example (42a) was dissolved in ethyl acetate, oxalic acid (51 mg, 0.57 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound (180 mg, 61%) as white crystals.

Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) 5ppm:

7.64-7.70 (2H, m), 7.52-7.60 (2H, m) ₎ 7.28-7.44 (5H ₎ m), 5.63 (lH, s) _> 3.78-3.88 (2H, m) ₎ 3.30-3.58 (8H, m ) _> 2.07-2.23 (4H ₎ m).

Infrared absorption spectrum V _max cn ^ CKBr): 3248, 2931, 2563, 1750, 1637, 1405, 1330, 1166, 1123, 1074. Production example 4 3

 8- {2- `` (3,4-dimethylphenyl) phenyl methoxy 1-ethyl 1-oxa-3,8-dazaspirate 4.51 decane-2-one and its oxalate (Exemplified Compound No. 971)

 (43 a) 8- {2-[(3,4-dimethylphenyl) phenylmethoxy] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one

 1-Oxa-3,8-diazaspiro [4.5] decane-2-one hydrochloride 150 mg (0.78 mmol) and (3,4-dimethylphenyl) phenylmethyl 2-chloroethyl ester as in Production Example (31a) —Reaction was carried out using 214 mg (0.78 minol) of ter, and 169 mg of 8- {2-[(3,4-dimethylphenyl) phenylmethoxy] ethyloxa-3,8-diazaspiro [4.5] decan-2-one (55%). "

(43b) 8- {2-[(3,4-Dimethylphenyl) phenylmethoxy] ethyl 1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The obtained compound was dissolved in chill acetate, 39 mg (0.43 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature. The precipitated crystals were collected by filtration to give the title compound as white crystals (31 mg, 63%). '

Nuclear magnetic resonance spectrum (400MHz, DMSO- _ds ) S ppm:

7.6 l (lH, s), 7.2 l-7.39 (5H, m), 7.06-7.14 (3H, m) _; 5.42 (lH, s), 3.62 (2H, t, J = 5.lHz), 3.29 (2H , s), 2.97-3.22 (6H, m), 2.19 (3H, s), 2.17 (3H, s) ₎ 1.87-2.04 (4H, m).

Infrared absorption spectrum v _max cn ^ CKBr): 3235, 2923, 2562, 1750, 1639, 1406, 1280, 1103, 1075. Production Example 4 4

8- {2Ibis- (3,4-difluorophenyl) methoxy 1-ethyloxa-3,8-diazaspirate [4,5] decane-2-one and its oxalate (Exemplified Compound No. 1016) (44a) 8- {2- [bis- (3,4-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one

 Production Example 31 1-oxa-3,8-diazaspiro [4,5] decane-2-one hydrochloride

The reaction was carried out using 243 mg (1.26 mmol) and 420 mg (1.32 nmol) of bis- (3,4-difluorophenyl) methyl 2-octylethyl ether to obtain the title compound.

(44b) 8- {2- [Bis- (3,4-difluorophenyl) methoxy] ethyl] -1-oxa-3,8-diazaspiro [4,5] decane-2-one oxalate

 The compound obtained in Production Example (44a) was dissolved in 10 ml of ethyl acetate, 77 mg (0.85 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature at room temperature. The precipitated crystals were collected by filtration to give 217 mg (48%) of the title compound as white crystals.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, DMSO-d 6)} δ ppm:

 7.62 (1H, s), 7.16-7.50 (6H, m), 5.85 (1H, s), 3.71 (2H, t, J = 5Hz), 3.29 (2H, s), 2.90- 3.22 (6H, m), 1.85-2.03 (4H, m)

Infrared absorption spectrum v max cn ^ C Br): 1763, 1748, 1518, 1488, 1279

Mass vector (FAB) m / z 439 ((M + H) free integrated)

Elemental analysis value (as C ₂₄ H ₂₄ F ₄ N ₂ O ₇ -0.5H ₂ O)

Calculated: C: 53.62; H: 4.69; N: 5.21

Obtained value: C: 54.00; H: 4.44; N: 5.28 Production example 45

 8- {2- [bis- (3,5-difluorophenyl) methoxy 1-ethyl 1-oxa-3,8-diazaspiro "4,51-decane-2-one and its oxalate (Exemplified Compound No. 1017)

 (45 a) 8- {2- [bis- (3,5-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one

Production Example 31 1-oxa-3,8-diazaspiro [4,5] decane-2-one hydrochloride as in Preparation Example 1 The reaction was carried out using 243 mg (1.26 nunol) and 420 mg (1.32 mmol) of bis- (3,5-difluorophenyl) methyl 2-chloroethyl ether to obtain 280 mg (72%) of the title compound.

(45 b) 8- {2- [bis- (3,5-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one oxalate

 The compound obtained in Production Example (45a) was dissolved in 10 ml of ethyl acetate, 57 mg (0.6 in. Inol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (250 mg, 74%).

Nuclear magnetic resonance spectrum (400MHz, DMSO-de) δ ppm:

 7.62 (1H, s), 7.10-7.28 (6H, m), 5.61 (1H, s), 3.68 (2H, t, J = 5Hz), 3.30 (2H, s), 2.87-3.27 (6H, m), 1.86-2.06 (4H, m)

Infrared absorption spectrum v max cn ^ C Br): 1763, 1749, 1622, 1599, 1120

Mass spectrum (FAB) m / z 439 ((M + H) ⁺ , free integrated)

Elemental analysis _{(C 24 H 24 F 4 N} 2 O 7)

Calculated: C: 54.55; H: 4.58; N: 5.30

Obtained: C: 54.41; H: 4.49; N: 5.33 Production Example 4 6

 8- {2- "bis- (2,3-difluorophenyl) methoxy 1-ethyl 1-oxa-3,8-diazaspiro" 4,51-decane-2-one and oxalate thereof (Exemplified Compound No. 1010 )

 (46a) 8- {2- [bis- (2,3-difluorophenyl) methoxy] ethyloxa-3,8-diazaspiro [4,5] decane-2-one

 Production Example 31 1-oxa-3,8-diazaspiro [4,5] decane-2-one hydrochloride

The reaction was carried out using 491 mg (2.55 mmol) and 847 mg (2.66 mmol) of bis- (2,3-diflu'orofiel) methyl 2-chloroethyl ether to obtain 761 mg (68%) of the title compound. (46b) 8- {2- [bis- (2,3-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one oxalate

 The compound obtained in Production Example (46a) was dissolved in 10 ml of ethyl acetate, 156 mg (1.73 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (596 mg, 65%).

Nuclear magnetic resonance spectrum (400MHz, DMSO-de) δ ppm:

 7.60 (1H, s), 7.20-7.45 (6H, m), 6.10 (lH, s), 3.65-3.80 (2H, m), 3.28 (2H, s), 2.85-3.25 (6H, m), 1.82- 2.03 (4H, m)

IR absorption spectrum v max cn ^ CKBr) ::!? ^ 1630, 1491, 1404, 1276

Mass spectrum (FAB) m / z 439 ((+ H) Free integrated)

Elemental analysis _{(C 24 H 24 F 4 N} 2 0 7)

Calculated: C: 54.55; H: 4.58; N: 5.30

Obtained value: C: 54.34; H: 4.31; N: 5.26 Production example 4 7

 Bis-(^ 4-full-mouthed 1-methoxy-1-ethyl / 1-oxa-3,8-diazaspiro 4,51-decane-2-one and its oxalate (Exemplary Compound No. 1026)

 (47a) 8- {2- [bis- (2,4-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one

 Preparation Example 31 1-Oxa-3,8-dazaspiro [4,5] decane-2-one hydrochloride

Using 244 mg (1.26 mmol) and bis- (2,4-difluorophenyl) methyl 2-chloroethyl: d, 425 mg (1.33 mmol), 446 mg (80%) of the title compound were obtained.

(47 b) 8- {2- [bis- (2,4-difluorophenyl) methoxy] ethyl 1-oxa-3,8-diazaspiro [4,5] decane-2-one oxalate

The compound obtained in Production Example (15a) was dissolved in 10 ml of ethyl acetate, and 91 mg of oxalic acid was dissolved. (l. Olmmol) was added and left at room temperature for 10 minutes. The precipitated crystals were collected by filtration to give 322 mg (60%) of the title compound as white crystals.

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

 7.61 (1H, s), 7.47-7.58 (2H, m), 7.08-7.30 (4H, m), 5.95 (1H, s), 3.70 (2H, t, J = 5Hz),

3.28 (2H, s), 2.86-3.2086H, m), 1.84-2.04 (4H, m)

Infrared absorption spectrum v max cm ' ¹ (Br): 1765, 1752, 1614, 1503, 1271

Mass toque (FAB) m / z 439 ((M + H) free)

Elemental analysis _{(C 24 H 24 F 4 N} 2 0 7)

Calculated values: C: 54.55; H: 4.58; N: 5.30

Obtained: C: 54.61; H: 4.50; N: 5.30 Production Example 48

 842-[(3-Sia J_enyl) (3, -triphenylolemethinorefle) methoxy 1ethyl} -1-oxa-3,8-diazaspiro [4,51-decane-2-one ( (Exemplary compound number 1031)

 Production Example 31 1-oxa-3,8-diazspiro [4,5] decane-2-one hydrochloride 204 mg (1.06 mmol) and (3-cyanophenyl) (3′-trifluoromethylphene) L) Methyl 2-chloroethyl ether was reacted with 300 mg (0.88 mmol) to obtain 130 mg (32%) of the title compound.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 7.69 (lH, 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 v max cm ' ¹ (Br): 3268, 2923, 2330, 1750, 1328, 1126 Mass spectrum (FAB) m / z 460 ((M + H) +, free integrated)

Elemental analysis (as _{C 24 H 24 F 3 N 3} 0 5)

Calculated: C: 62.74; H: 5.27; N: 9.15; F: 12.40

Obtained: C: 62.52; H: 5.08; N: 8.60; F: 12.34 Production example 4 9

 8 2-“(4-Cyanophenoinole) (3 ′, 4, -difluoropheninole) methoxy 1-ethyl 1-oxa-3,8-diazaspiro 4,51-decane-2-one and its oxalate ( (Exemplary Compound No. 1029)

(49a) 8- {2-[(4-Cyanophane) (3 ', 4'-difluorophenyl) methoxy] ethyl 1-oxa-3,8-diazaspiro [4,5] decane- 2-on

 Production Example 31 1-oxa-3,8-diazaspiro [4,5] decane-2-one hydrochloride 187 mg (0.97 mmol) and (4-cyanophenyl) (3 ′, 4-difluoro Using 250 mg (0.81 mmol) of phenyl) methyl 2-chloroethyl ether gave 220 mg (51%) of the title compound.

(49b) 8- {2-[(4-Cyanophenyl) (3,4, -difluorophenyl) methoxy] ethyl 1-oxa-3,8-diazaspiro [4,5] decane-2 -On oxalate

 The compound obtained in Production Example (49a) was dissolved in 2 ml of ethyl acetate, 46 mg (0.51 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give 210 mg (79%) of the title compound as white crystals.

Nuclear magnetic resonance spectrum (400MHz, DMSO- _ds ) δ ppm:

 7.84 (2H, d, J = 8.3 Hz), 7.61 (2H, d, J = 8.3 Hz), 7.39-7.53 (2H, m), 7.23-7.26 (lH, m), 5.67 (lH, s), 3.65 (2H, d, J = 5.1 Hz), 3.28 (2H, s), 2.90-3.17 (6H, m), 1.87-1.99 (4H, m).

Infrared absorption spectrum v max cm ^-1 (Br): 3241, 2555, 1764, 1515, 1279, 1098 Mass spectrum (FAB) m / z 428 ((M + H) free integrated)

Elemental analysis (as _{C 25 H 25 F 2 N 3} 0 7)

Calculated values: C: 57.03; H: 4.87; N: 8.12; F: 7.34

Obtained: C: 57.85; H: 4.84; N ": 7.78; F: 7.27 Production Example 50 8- {2-[(3-Cyanophenyl) (3,4'-difluorophenyl) methoxy 1-ethyloxa-3,8-diazaspiro 4,51-decane-2-one and its oxalate (Exemplified Compound No. 1030)

(50a) 8- {2-[(3-Cyanophenyl) (3 ', 4'-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane- 2-on

 Production Example 31 1-oxa-3,8-diazaspiro [4,5] decane-2-one hydrochloride

React with 150 mg (0.78 mmol) and 200 mg (0.65 minol) of (3-cyanophenol) (3 ', 4, -difluorophenyl) methyl 2-chloroethyl ether to give the title compound

191 mg (68%) were obtained.

(50b) 8- {2-[(3-Cyanophenyl) (3,4, -difluorophenyl) methoxy] ethyl 1-oxa-3,8-diazaspiro [4,5] decane-2- On oxalate

 The compound obtained in Production Example (50a) was dissolved in 2 ml of ethyl acetate, and oxalic acid was added.

38 mg (0.42 nmol) was added, and the mixture was left at room temperature for 10 minutes. The precipitated crystals were collected by filtration to give 180 mg (78%) of the title compound as white crystals.

Nuclear magnetic resonance spectrum (400MHz, DMSO-de) δ ppm:

7.91 (1H, m), 7.73-7.78 (2H, m), 7.51-7.60 (2H ₃ m), 7.39-7.46 (lH, m), 7.25-7.28 (lH, m) _; 5.67 (lH _; s), 3.6.7 (2H, t, J = 5.1 Hz), 3.29 (2H, s), 2.90-3.17 (6H, m), 1.87-1.99 (4H, m).

Infrared absorption spectrum v max cm ' ¹ (KEr): 3240, 2560, 1753, 1515, 1279, 1113 Mass spectrum (FAB) m / z 428 ((M + H) free integrated)

Elemental analysis (as _{C 25 H 25 F 2 N 3} 0 7)

Calculated: C: 58.03; H: 4.87; N: 8.12; F: .7.34

Obtained: C: 57.86; H: 4.87; N: 7.80; F: 6.97 Production Example 51

8- {2 bis-^-ditrifluoromethylphenyl methoxy 1-ethyl oxalate-3, -di Azaspiro "4,51 decane-2-one and its oxalate salt (Exemplary Compound No. 1027)

 (51a) 8- {2- [Bis- (3,5-ditrifluoromethylphenyl) methoxy] ethyloxa-3,8-diazaspiro [4,5] decane-2-one

 Production Example 31 1-oxa-3,8-diazaspiro [4,5] decane-2-one hydrochloride

The reaction was carried out using 276 mg (1.43 mmol) and 770 mg (1.48 nmol) of bis- (3,5-ditrifluoromethylphen: methyl) 2-methylethyl ether, and 733 mg (78%) of the title compound was obtained. Obtained.

(51b) 8- {2- [bis- (3,5-ditrifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2- On oxalate

 The compound obtained in Production Example (51a) was dissolved in ethyl acetate, and oxalic acid was dissolved.

103 mg (1.14 mmol) was added, and the mixture was allowed to stand at room temperature. The precipitated crystals were collected by filtration to give 543 mg (65%) of the title compound as white crystals.

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

 8.23 (4H, s), 8.07 (2H, s), 7.60 (1H, s), 6.04 (1H, s), 3.74 (2H, t, J = 5Hz), 3.27 (2H, s), 2.85-3.21 ( 6H, m), 1.87-2.01 (4H, m)

Infrared absorption spectrum v max cm ' ¹ (KBr): 1767, 1376, 1282, 1175, 1132

Mass vector (FAB) m / z 639 ((M + H) +, free form)

Elemental analysis _{(C 28 H 24 F 12 N} 2 0 7)

Calculated values: C: 46.17; H: 3.32; N: 3.85

Obtained: C: 46.39; H: 3.39; N: 3.74 Production Example 52

8- {2-[(2,3,4,5,6-pentamethylphenyl) (2, -thiophene) methoxy "| ethyl 1-oxa-3,8-diazaspiro 4,51-decane-2- And its oxalate (Exemplary Compound No. 1032) (52a) 8- {2-[(2,3,4,5,6-pentamethylphenyl) (2'-thiophene) methoxy] ethyl } -1-oxa-3,8-dazaspiro [4,5] decane-2-one

 As in Production Example 31, 1-oxa-3,8-diazaspiro [4,5] decane-2-one hydrochloride 150 mg (0.78 mmol) and [(2,3,4,5,6-pentane) Methylphenyl) (2′-thiophene)] methyl 2-chloroethyl ether was reacted with 228 mg (0.71 mmol) to obtain 224 mg (72%) of the title compound.

(52b) 8- {2-[(2,3,4,5,6-pentamethylphenyl) (2, -phenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one oxalate

 The compound obtained in Production Example (52a) was dissolved in ethyl acetate, oxalic acid (46 mg, 0.51 mmol) dissolved in methanol was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (114 mg, 42%).

Nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ ppm:

7.30 (d, IH, J = 5.2 Hz), 6.87 (dd, IH, J = 5.2, 3.4 Hz), 6.50 (d, IH, J =

3.4Hz), 6.24 (s, IH), 3.86-3.76 (m, IH), 3.60-3.49 (m, IH), 3.49-3.10 (m, 6H), 3.41 (s, 2H), 2.26 (s, 3H ), 2.21 (s, 12H), 2.20-2.04 (m, 4H)

Infrared absorption spectrum max cm " ¹ (Br): 3251, 2924, 2642, 2557, 1752, 1614, 1438, 1404, 1310, 1255, 1229, 1102, 1077, 973, 766, 722, 701, 504

Mass petrol (FAB) m / z 443 ((M + H) +, free integrated) Production example 5 3

 8- ·? 2-Γ (2-octanol) (4, -octenyl) methoxy “Iethyl 1-oxa-3,8-diazaspiro [4,51-decane-2-one andぴ Its oxalate (Exemplary Compound No. 989)

 (53a) 8- {2-[(2-chlorophenyl) (4'-chlorophenyl) methoxy] ethyl 1-oxa-3,8-diazaspiro [4,5-decane-2- ON ·

Production Example 31 1-oxa-3,8-diazaspiro [4,5] decane-2-one hydrochloride 351 mg (1.82 mmol) and (2-chlorophenyl) (4, -chlorophenyl) methyl 2 -Black mouth The reaction was carried out using 530 mg (1.68 mmol) of ethyl ether to obtain 206 mg (28%) of the title compound.

(53b) 8- {2-[(2-Chlorophenyl) (4, -chlorophenyl) methoxy] ethyloxa-3,8-diazaspiro [4,5] decane-2-one oxalate

 The compound obtained in Production Example (53a) was dissolved in 2 ml of ethyl acetate, 43 mg (0.47 mmol) of oxalic acid was added, and the mixture was allowed to stand at room temperature for one hour. The precipitated crystals were collected by filtration to give the title compound as white crystals. 175 mg (70%).

Nuclear magnetic resonance spectrum (400MHz, DMSO-de) δ ppm:

 7.61-7.63 (2H, m), 7.33-7.46 (6H, m), 5.83 (1H, s), 3.62-3.60 (2H, m), 3.28 (2H, m), 2.97-3.18 (6H, m), 1.86-1.99 (4H, m).

Infrared absorption spectrum v max cm ¹ (Br): 3240 2559 1749 1637 1404 1089 Mass spectrum (FAB) m / z 435 ((M + H) ⁺ , free form)

Elemental analysis value (as C ₂₄ H ₂₆ Cl ₂ N ₂ O _v -2H ₂₀ )

Calculated values: C: 51.35; H: 5.39; N: 4.99; C1: 12.63

Obtained: C: 51.39; H: 4.51; N: 5.39; C1: 12.97 Production Example 54

 8- {2a (3,4,5-trifluorophenyl) phenylmethoxy 1-ethyl 1-oxa-3,8-diazaspiro "4,51-decane-2-one and its oxalate (Exemplified Compound No. 1028 )

 (54a) 8- {2-[(3,4,5-trifluorophenyl) phenylmethoxy] ethyloxa-3,8-diazaspiro [4,5] decane-one

Production Example 31 1-oxa-3,8-diazaspiro [4,5] decane-2-one hydrochloride 385 mg (2.00 mmol) and (3,4,5-trifluorophenyl) phenylmethyl 2- The reaction was carried out using 601 mg (2.00 minol) of chloroethyl ether to obtain 656 mg (78%) of the title compound. (54b) 8- {2-[(3,4,5-Trifnorelolophenylinole) pheninolemethoxy] ethyloxa-3,8-diazaspiro [4,5] decane-2-one oxalate

 The compound obtained in Production Example (54a) was dissolved in ethyl acetate (20 ml), oxalic acid (140 mg, 1.56 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound as white crystals (577 mg, 57%).

Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm:

 7.30-7.43 (5H, m), 7.12-7.22 (2H, m), 5.51 (1H, s), 3.74-3.87 (2H, m), 3.43 (2H, s), 3.28-3.58 (6H, m), 2.09-2.19 (4H, m)

Infrared absorption spectrum v max cm ¹ (KBr): 3241, 3166, 2933, 2559, 1762, 1749,

1637, 1622, 1528, 1449, 1414, 1075, 1046, 710

Mass spectrum (FAB) m / z 421 ((M + H) +, free form)

Elemental analysis (as _{C 22 H 23 F 3 N 2} 0 3 -C 2 H 2 O 4)

Calculated values: C: 56.47; H: 4.94; N: 5.49, F: 11.17

Obtained: C: 56.20; H: 4.83; N: 5.62, F: 10.78 Production Example 55

 8- {3-"(3-sia_7-eninole) (3,3-trifluoroethyl) methoxy 1-propyl 1-year-old -3,8-diazaspiro" 4,51-decane-2-one and its oxalate (Exemplary Compound No. 1037)

 (55a) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl} small oxa-3,8-diazaspiro [4,5] decane-2-one

Dissolve 300 mg (0.89 mmol) of 3-[(3-cyanophenyl) (3, -trifluoromethylphenyl) methoxy] propanol in 3 ml of dichloromethane, and add 187 μl (1.334ηιηιο1) of triethylamine under ice cooling. 90 l (1.16 mmol) of methanesulfoel chloride were added. After stirring for 30 minutes under ice-cooling, the mixture was washed with water and saturated saline in this order. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. The obtained methanesulfonic acid--[3-Cyanofue ) (3'-Trifluoromethylphenyl) methoxy] propyl} estenole (370 mg, 0.89 mmol) was dissolved in Ν, Ν-dimethylacetoamide (5 ml), and 1-oxa-3,8-diazaspiro [4 , 5] Decan-2-one hydrochloride 207mg (1.07mmol), lithium carbonate

247 mg (1.87 mmol) and 15 mg (0.09 mmol) of potassium iodide were added, and the mixture was stirred at 100 ° C for 10 hours. After the 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 sequentially with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by flash chromatography (developing solvent; methanol: dichloromethane = 5: 95) to obtain 283 mg (67%) of the title compound.

(55b) 8- {3-[(3-Cyanophenyl) (3'-trifluoromethylphenyl) methoxy] propyl oxa-3,8-diazaspiro [4,5] decane-2-one oxalate

 The compound obtained in Production Example (55a) was dissolved in 2 ml of ethyl acetate, and oxalic acid was added.

54 mg (0.60 mmol) was added, and the mixture was left overnight at room temperature. The precipitated crystals were collected by filtration to give 282 mg (84%) of the title compound as white crystals.

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

 7.94 (1H, s), 7,70-7.81 (4H, m), 7.56-7.68 (3H, m), 5.70 (1H, s), 3.42-3.51 (2H, m), 3.29 (2H, s), 2.92-3.21 (6H, m), 1.85-2.03 (6H, m).

Infrared absorption spectrum max cm " ¹ (KBr): 3248 2930 2563 1764 1330 1124 Mass spectrometer (FAB) m / z 474 ((M + H) +, free integrated)

Elemental analysis (as _{C 27 H 28 F 3 N 3} 0 7)

Calculated values: C: 57.55; H: 5.01; N: 7.46; F: 10.11

Obtained: C: 57.58; H: 4.89; N: 7.22; F: 9.87 Production Example 5 6

8- {3a ( ⁴ -cyanophenyl) (3,4'-difluoromethyl) methoxy 1-propyl} -1-oxa-3, ^ azaspiro {4,51-decane-2-one and its oxalic acid Salt (Exemplary Compound No. 1036) (56a) 8- {3-[(4-Cyanophenyl) (3,4, -difluorophenyl) methoxy] propanoloxa-3,8-diazaspiro [4,5] decane-2-one

 As in Production Example (55a), 300 mg (0.99 mmol) of 3-[(4-cyanophenyl) (3 ′, 4′-difluorophenyl) methoxy] propanol and 1-oxa-3,8-diazaspiro [ The reaction was carried out using 228 mg (1.18 mmol) of 4,5] decan-2-one hydrochloride to obtain 236 mg (54%) of the title compound.

(56b) 8- {3-[(4-cyanophenyl) (3,4'-difluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5 ] Decan-2-one oxalate

 The compound obtained in Production Example (56a) was dissolved in 2 ml of ethyl acetate, 48 mg (0.54 mmol) of oxalic acid was added, and the mixture was released overnight at room temperature. The precipitated crystals were collected by filtration to give the title compound as white crystals (242 mg, 85%).

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

7.82 (2H, d, J = 8.4 Hz), 7.60 (2H, d, J = 8.4 Hz) ₃ 7.38-7.51 (2H, m), 7.22-7.25 (lH, m), 5.61 (1H, s), 3.44 (2H, t, J = 6.0 Hz), 3.28 (2H, s), 2.83-3.10 (6H, m), 1.83- 1.98 (6H, m).

Red, external absorption spectrum V max cm ' ¹ (Br): 3246, 2558, 1754, 1609, 1516, 1279, 1093

Mass vector (FAB) m / z 442 ((M + H) +, free form)

Elemental analysis (as _{C 26 H 27 F 2 N 3} 0 7)

Calculated: C: 58.75; H: 5.12; N: 7.91; F: 7.15

Obtained: C: 59.63; H: 5.23; N: 7.53; F: 7.30 Production Example 57

8- {3-Γ (3-cyanophenyl) (3 ', 4'-difluorophenyl) methoxy 1-propyl 1-oxa- 3.-diazaspiro [4,51-decane-2-one and its oxalate (exemplified compound (Number 1035) (57a) 8- {3-[(3_Cyanophenyl) (3,4'-difluoropheninole) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decane- 2-on

 In the same manner as in Production Example (55a), 345 mg (1.13 mmol) of 3-[(3-cyanophenyl) (3 ', 4'-difluorophenyl) methoxy] propanol and 1-oxa-3,8-propanol were used. The reaction was carried out using 263 mg (1.36 nmol) of diazaspiro [4,5] decan-2-one hydrochloride to obtain 220 mg (44%) of the title compound.

(57b) 8- {3- [3-Cyanophenyl) (3,4, -difluorophenyl) methoxy] propinole}-: L-oxa_3,8-diazaspiro [4,5] decane- 2-one oxalate

 The compound obtained in Production Example (57a) was dissolved in 2 ml of ethyl acetate, and oxalic acid was added.

45 mg (0.50 nmol) was added, and the mixture was left at room temperature for one hour. The precipitated crystals were collected by filtration to give the title compound as white crystals (214 mg, 81%).

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

7.89 (1H, m), 7.71-7.77 (2H, m), 7.49-7.59 (2H, m), 7.38-7.45 (lH, m), 7.24-7.27 (lH, m), 5.58 (1H, s), 3.44 (2H, t, J = 5.9 Hz), 3.30 (2H ₎ s), 3.13-3.27 (2H, m), 2.95-3.09 (4H, m), 1.88-2.05 (6H, m).

Infrared absorption spectrum v max cm ' ¹ (Br): 3247, 2563, 1761, 1515, 1279, 1081 Mass spectrum (FAB) m / z 442 ((M + H) +, free form)

Elemental analysis value (as C ₂₆ H ₂₇ F ₂ N ₃ O ₇ -0.5H ₂ O)

Calculated values: C: 57.78; H: 5.22; N: 7.77; F: 7.03

Obtained: C: 57.75; H: 5.06; N: 7.14; F: 7.10 Production Example 58

8- ・ ί ^ Bis-shi 3-trifluoromethylphenyl) methoxy 1-propyl 8-methyl-1-o サ _S-3-aza- 8-Azourea-spiro 4,51-decane-2-one And its oxalate (Exemplary Compound No. 9201 ′ (58a) 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one

 Oxa-3,8-diazaspiro [4.5] decane-2-one hydrochloride synthesized in Reference Example 1

89 mg (0.46 mmol) and 167 mg (0.42 mmol) of bis- (3-trifluoromethylphenyl) methinole 3-chloromethyl propyl ether synthesized in Reference Example 28 were dissolved in 2 ml of Ν, Ν-dimethylformamide. Then, 145 mg (1.05 mmol) of potassium carbonate and 6 mg (0.04 inmol) 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 saline, 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.

(58b) 8- {3- [bis- (3-trifluoromethylphenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4.5] decane-2-one oxalate

 The compound synthesized in Production Example (58a) was dissolved in methanol, and oxalic acid was added.

27 mg (0.30 mmol) was added, and the mixture was concentrated. The obtained solid was washed with hexane and collected by filtration to give 177 mg (97%) of the title compound as white crystals.

Nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ ppm:

 7.53-7.74 (8H, m), 5.66 (IH, s), 3.50-3.65 (4H, m), 3.43 (2H, s), 3.20-3.40 (4H, m), 2.05-2.25 (6H, m)

Infrared absorption spectrum v _max cm ' ¹ (Br): 3248, 2929, 2565, 2525, 1755, 1633, 1404, 1331, 1166, 1124, 1074, 721, 709 Production Example 5 9

 8- {3 ibis- (3,4-difluorophenyl) methoxy 1-propyl 1-oxa-3,8-dazaspirate 4,51-decane-2-one and its oxalate (Exemplified Compound No. 1034)

(59a) 8- {3- [bis- (3,4-difluorophenyl) methoxy] propyl} small oxade-3,8- Diazaspiro [4,5] decane-2-one

 As in Production Example (55a), 200 mg (0.64 mmol) of 3- [bis- (3,4-difluorophenyl) methoxy] propanol and 1-oxa-3,8-diazaspiro [4,5] Using 147 mg (0.76 mmol) of decane-2-one hydrochloride, 8- {2- [bis- (3,4-difluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4, 5] 65 mg (23%) of decane-2-one was obtained.

(59 b) 8- {3- [bis- (3,4-difluorophenyl) methoxy] propyloxa-3,8-diazaspiro [4,5] decane-2-one oxalate

 The reaction was carried out using the compound synthesized in Production Example (59a) in the same manner as in Production Example (57b) to obtain 38 mg (46%) of the title compound as white crystals.

Nuclear magnetic resonance spectrum (400MHz, DMSO-de) δ ppm:

 7.37-7.52 (4H, m), 7.20-7.26 (2H, m), 5.51 (1H, s), 3.43 (2H, t, J = 5.9 Hz), 3.30 (2H, s), 2.91-3.19 (6H, m m), 1.83-2.05 (6H, m).

Infrared absorption spectrum v max cm ' ¹ (Br): 3308, 2512, 1757, 1514, 1277, 1112 Mass spectrum (FAB) m / z 453 ((M + H) ⁺ , free integrated)

High resolution Masusu Bae-vector calculated value _{(C 23 H 25 O 3 N} 2 F 4) (M + H) + 453.1801

 Measurement value 453.1794 Reference example 1

 1-oxa-3,8-dazaspiro 4.51 decane-2-one hydrochloride

 It was synthesized according to the method described in J. Med. Chem., 38, 3772-3779 (1995).

Dissolve 2.50 g (9.75 mmol) of 2-oxo-1-oxa-3,8-diazaspiro [4,5] decane-8-carboxylic acid t-butyl ester in 25 ml of ethanol, and add 4N hydrochloric acid under ice-cooling. 2.8 ml of a dioxane solution was added, 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 dimethyl ether to obtain 1.1 g of the title compound as white crystals.

(59%). Infrared absorption spectrum _max cm " ¹ (Br): 3227, 2970, 1762, 1565, 1431, 1274.

Mass Vector (EI) m / z 156 (M ⁺ , free)

Elemental analysis (as _{C 7 H 12 N 2 0 2} -HC1 (%))

 Calculated: C: 43.64; H: 6.80; N: 14.54; C1: 18.40.

 Found: C: 43.59; H: 6.87; N: 14.65; C1: 17.50. Reference example 2

Bis-(-trif-noreo methinorefle)-methinole 2-chloroethynole

 Dissolve 0.5 g (1.56 nmol) of bis- (3-trifluoromethylphenyl) methanol and 0.6 ml of ethanol in 5 ml of toluene, and add a catalytic amount of p-toluenesulfonic acid monohydrate. 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 saline, dried and concentrated to give 0.55 g (92%) of the title compound as an oil.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 7.45-7.70 (8H, m), 5.52 (lH, s), 3.70-3.78 (4H, m) Reference Example 3

 (3-black mouth fenole) feninole methinole 2-chloroethinole

 In the same manner as in Reference Example 2, the reaction was carried out using 1.03 g (471 mmol) of (3-chlorophenyl) phenylmethanol to obtain 1.31 g (99%) of the title compound.

Nuclear magnetic resonance spectrum _{(500MHz, CDC1 3) δ ppm} : 7.10-7.40 (9H, m) 3 5.39 (lH, s), 3.65-3.75 (4H, m) Reference Example 4

Bis (3-fluorophenyl, methyl 2-chloroethyl)

As in Reference Example 2, bis (3-fluorophenyl) methanol 0.85 g (3.86 imnol) was used. To give 1.08 g (99%) of the title compound.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 6.95-7.35 (8H, m), 5.40 (IH, s), 3.65-3.75 (4H, m) Reference Example 5

 Gibunoleolofeel) Feenoremel 2-Chloroechinore Ethenole

 As in Reference Example 2, (3,4-difluorophenyl) phenol methanol

Using 0.88 g (4.00 mmol), 1.12 g (99%) of the title compound was obtained.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 6.90-7.35 (8H, m), 5.39 (1H, s), 3.65-3.75 (4H, m) Reference Example 6

 3-Nitrofeninore) Fee / Remethinole 2-Chlorochinenoet

In the same manner as in Reference Example 2, the reaction was carried out using 0.83 g (3.66 mmol) of (3-nitrophenyl) phenol methanol to obtain 1.06 g (99 ^Q / ₀ ) of the title compound.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 8.25 (IH, dd, J = 2.0, 2.0 Hz), 8.10-8.15 (IH, m), 7.15-7.55 (7H, m), 5.51 ( 1H, s), 3.65-3.80 (4H, m) Reference example 7

 <3-methinolephenole) pheninolemethinole

 In the same manner as in Reference Example 2, the reaction was carried out using 0.92 g (4.64 mmol) of (3-methylphenyl) phenylmethanol to obtain 1.20 g (99%) of the title compound.

Nuclear magnetic resonance spectrum (400 MHz, CDCI3) δ ppm: 7.05-7.40 (9H, m), 5.39 (1H, s), 3.65-3.75 (4H, m) Reference Example 8 2,5-difluorophenyl) phenylmethyl 2-chloroethynole

 As in Reference Example 2, (2,5-difluorophenyl) fuelmethanol

Using 0.47 g (2.13 mmol), 0.55 g (91%) of the title compound was obtained.

Nuclear magnetic resonance spectrum _{(400MHz, CDC1 3) δ ppm} : 7.22-7.42 (6H, m), 6..88-7.00 (2H, m), 5.72 (1H, s), 3.65-3.80 (4H, m) Reference Example 9

 3,5-diphnoleolopheninole) pheninolemethinole 2-chloroethinole ethenole

 As in Reference Example 2, (3,5-difluorophenyl) phenylmethanol

The reaction was carried out using 0.47 g (2.13 mmol) to obtain 0.59 g (98%) of the title compound.

Nuclear magnetic resonance spectrum _{(400MUz, CDC1 3) δ ppm} : 7.25-7.40 (5H, m), 6.88-6.95 (2H, m), 6.65-6.72 (1H, m), 5.37 (1H, s), 3.65-3.75 (4H, m) Reference example 10

 (2-Fluorofeninole) Phenylmethinole 2-c

 In the same manner as in Reference Example 2, the reaction was carried out using 0.98 g (4.85 mmol) of (2-fluorophenyl) phenol methanol to obtain 1.0 g (79 ° /.) Of the title compound.

Nuclear magnetic resonance spectrum (400 MHz, CDCI3) δ ppm: 6.99-7.52 (9H, m), 5.78 (lH, s), 3.66-3.77 (4H, m). Reference Example 11

 (2-.Fluorophenyl) (4, -fluorophenyl) methyl 2-chloroethyl ether In the same manner as in Reference Example 2, 480 mg (2.18 mmol) of (2-fluorophenyl) (4'-fluorophenyl) methanol was added. The reaction was carried out using the above compound to obtain 536 mg (87%) of the title compound.

Nuclear magnetic resonance spectrum (400MHz, CDCI3) δ ppm: 6.99-7.51 (8H, m), 5.76 (1H, s), 3.66-3.77 (4H, m). Reference Example 12

 (2-chloro-5-2-2 _trofeninole feninolemethyl 2-chloroethyl ether

 The reaction was carried out in the same manner as in Reference Example 2 using 400 mg (1.52 mniol) of (2-chloro-5-utrophenyl) phenylmethanol to obtain 398 mg (80%) of the title compound.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 8.55-8.56 (lH, m), 8.07- 8.10 (1H, m), 7.31-7.52 (6H, m), 5.83 (lH, s), 3.66-3.78 (4H, m). Reference Example 13

Bis-^ _ 4-difluo mouth)

 Reference Example (13a) Bis- (3,4-difluorophenyl) methanol

 1.12 g (5.80 mmol) of 1-bromo-3,4-difluorobenzene was dissolved in 10 ml of tetrahydrofuran, and -78. After cooling to C, 3.82 ml (5.80 minol) of n-butyllithium (1.52 M tetrahydrofuran solution) was added dropwise over 10 minutes. Thereafter, 640 μl (5.80ππηο1) of 3,4-difluorobenzoaldehyde was added dropwise over 5 minutes. After the reaction was completed, the solution was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried and concentrated. The residue was purified by silica gel gel chromatography (developing solvent: 15 (Ethyl acetate-hexane) to give 720 mg (49%) of the title compound as an oil.

Nuclear magnetic resonance spectrum _{(400MHz, CDC1 3) δ ppm} : 6.97-7.26 (6H, m), 6.07 (1H, s) Reference Example (13b) bis - (3,4-difluorophenyl) methyl 2- Kuroroechiru ether Reference Example Bis- (3,4-difluorophenyl) methanol synthesized in (13a)

700 mg (2.73 nmol) was dissolved in pyridine (5 ml), acetic anhydride (2.5 ml) was added, and the mixture was stirred at room temperature with stirring at room temperature. The reaction solution was concentrated, dissolved in 2-chloroethanol (20 ml), and a catalytic amount of camphorsulfonic acid was added. After cooling to room temperature, the solution was poured into saturated aqueous sodium hydrogen carbonate. Extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried and concentrated. The residue was purified by silica gel gel chromatography (developing solvent: 10% ethyl acetate-hexane) to give the title compound. 420 mg (49%) were obtained as an oil.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 7.20-7.32 (3H, m), 6.82- 6.95 (3H, m), 6.24 (1H, s), 3.83 (2H, t, J = 5Hz ), 3.68 (2H ₃ , J = 5Hz) Reference example 14 '

Bis _ (^ 5-difluoro mouth methyl) 2-chloroethynole

 Reference example (14a) Bis- (3,5-difluorophenyl) methanol

 As in Reference Example (13a), the reaction was carried out using 1.39 g (7.20 mmol) of 1-promo-3,5-difluorobenzene and 782 μl of 3,5-difluorobenzaldehyde (7.20ιηηιο1), 1.50 g (81%) of the title compound were obtained as an oil.

Nuclear magnetic resonance spectrum (400 MHz, CDCI3) δ ppm: 6.84-7.04 (4H ₃ m), 6.68- 6.79 (2H, m), 5.745 (lH, d, J = 4 Hz), 2.455 (1H, d, (J = 4Hz) Reference Example (14b) Bis- (3,5-difluorophenyl) methyl 2-chloroethyl ether The same as Reference Example (13b), bis- (3,5-difluoro) synthesized in Reference Example (14a). The reaction was carried out using 370 mg (1.44 minol) of (phenyl) methanol to obtain 295 mg (64%) of the title compound as an oil.

Nuclear magnetic resonance spectrum (400 MHz, CDCI3) δ ppm: 6.83-7.02 (4H _; m), 6.69-6.80 (2H, m), 5.33 (1H, s), 3.50-3.81 (4H, m) Reference example Fifteen

Bis-(^ 3-difluoro_phenyl) methyl 2-chloroethynole

 Reference Example (15a) Bis- (2,3-difluorophenyl) methanol

As in Reference Example (13a), 1-bromo-2,3-difluorobenzene 2.25 g (11.6 mmol) and 2, Using 1.26 ml (11.6 rmnol) of 3-difluorobenzaldehyde, the title compound

2.90 g (90%) were obtained as an oil.

Nuclear magnetic resonance scan Bae spectrum _{(400MHz, CDC1 3) δ ppm} : 7.04-7.32 (6H, m), 6.435 (1H, d, J = 5Hz), 2.50 (1H, d, J = 5Hz) Reference Example (15b) Bis- (2,3-difluoropheninole) methyl 2-chloroethyl ether 850 mg (3.32 mmol) of bis- (2,3-difluorophenyl) methanol synthesized in Reference Example (15a) in the same manner as Reference Example (13b) To give 847 mg (80%) of the title compound as an oil.

Nuclear magnetic resonance spectrum (400MHz, CDClg) δ ppm: 7.04-7.31 (6H, m), 6.06 (1H, m), 3.79 (2H, t, J = 6Hz), 3.68 (2H, t, J = (6Hz) Reference example 16

Bis-(^^ 4-difluorophenylmethyl 2- ^ loroethyl)

 Reference Example (16a) bis- (2,4-difluorophenyl) methanol

 As in Reference Example (13a), 1-p π-mo-2,4-difluorobenzene 2.51 g (13.0 mmol) and 2,

Using 1.41 ml (13.0 imnol) of 4-difluorobenzaldehyde, give the title compound

2.65 g (83%) were obtained as an oil.

Nuclear magnetic resonance spectrum _{(400MHz, CDC1 3) δ ppm} : 7.18-7.32 (2H; m), 6.79- 6.96 (4H, m), 6.47-6.55 (lH, m), 3.49-3.66 (lH, m) Reference Example (16b) bis- (2,4-difluorophenyl) methyl 2-chloroethyl ether As in Reference Example (13b), 2.65 g of bis- (2,4-difluorophenyl) methanol synthesized in Reference Example (16a) Using 10.3 mmol), 1.83 g (53%) of the title compound was obtained as an oil.

Nuclear magnetic resonance spectrum _{(400MHz, CDC1 3) δ ppm} : 7.17-7.28f2H, m); 6.73- 6.91 (4H, m), 6.18-6.21 (1H, m), 3.77 (2H, t, J = 6Hz), 3.62 (2H, t, J = 6Hz) Reference example 17

 <3-Cyanophenole, -trifnoroleolomethinolepheninole) methinole 2-chloroethyl ether Reference Example (17a) 3-Cyanophenyl-3′-trifluoromethylphenylmethanol Similar to Reference Example (13a), 3- The reaction was carried out using 20 g (88.8 mmol) of bromobenzotrifluoride and 2.9 g (88.8 mmol) of 3-cyanobenzaldehyde, and 16.3 g of the title compound was obtained.

(66%).

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 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 (17b) (3-Cyanophenyl) (3'-Trifluoromethinolepheninole) methinole

 576 mg (2.08 minol) of (3-cyanophenyl) (3'-trifluoromethylphenyl) methanol synthesized in Reference Example (17a) was dissolved in 5 ml of dichloromethane, and 230 m 1 (3.12 mmol) of thionyl chloride was added. Thereafter, one drop of dimethylformamide was added. After stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure, and the mixture was azeotroped twice with diethyl ether. The obtained residue is dissolved in 5 ml of 2-chloroethanol, and p-toluenesulfonic acid monohydrate is dissolved.

40 mg (0.21 mmol) was added, and the mixture was stirred at 120 ° C for 48 hours. After the completion of the reaction, the temperature was returned to room temperature, the reaction solution was poured into water, extracted with ethyl acetate, washed sequentially with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained 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 scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 7.42-7.74 (8H, m), 5.50 (1H, s), 3.60-3.75 (4H, m). Reference Example 18

 <4-Cyanophenyl) (3 ′, 4, -difluoropheninole) methinole 2-chloromethylethyl ether Reference Example (18a) 4-Cyanophenyl-3 ′, 4′-difluorophenylmethanol

 As in Reference Example (13a), 1-bromo-3,4-difluorobenzene 10.0 g (51.8 nmol) and

The reaction was performed using 6.4 g (51.8 mmol) of 4-cyanobenzaldehyde, and 4.8 g of the title compound was obtained.

(38%).

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 7.65 (2H, d, J = 8.3 Hz), 7.49 (2H, d, J = 8.3 Hz), 7.05-7.21 (3H, m), 5.84 (1H, s). Reference example (18b) (4-Cyanophenoline) (3 ', 4'-difluorophenol) methyl 2-octanol ether

 In the same manner as in Reference Example (17b), the reaction was carried out using 620 mg (2.53 mmol) of (4-cyanophenyl) (3 ′, 4, -difluoromouth phenol) methanol synthesized in Reference Example (18a), and 485 mg of the title compound was obtained. (62%).

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 7.65 (2H, d, J = 8.1 Hz), 7.47 (2H, d, J = 8.1 Hz), 7.05-7.19 (3H, m), 5.42 (1H, s), 3.64-3.73 (4H, m). Reference Example 19

 (3-Cyanophenyl) (3 ', 4'-difluorophenyl) methyl 2-chloroethyl ether Reference Example (19a) 3-Cyanophenyl-3,, 4'-difluorophenylmethanol

 As in Reference Example (13a), 1-promo-3,4-difluorobenzene 10.0 g (51.8 mmol) and

6.4 g (51.8 mmol) of 3-cyanobenzaldehyde was subjected to a square T reaction to give 10.5 g (83%) of the title compound.

Nuclear magnetic resonance spectrum (400MHz, CDCI3) δ ppm: 7.68 (1H, s), 7.57-7.60 (2H, m), 7.44-7.48 (lH, m) ₅ 7.05-7.23 (3H, m), 5.81 (1H, s). Reference example (19b) (3-Cyanophuel) (3,4'-difluorophenyl) methyl 2-chloroethyl ether

 In the same manner as in Reference Example (17b), the reaction was carried out using 1.9 g (7.75 mmol) of (3-cyanophenyl) (3,4′-difluoromethylphenyl) methanol synthesized in Reference Example (19a), and the title compound was obtained.

1.6 g (67%) were obtained.

Nuclear magnetic resonance scan Bae spectrum _{(400MHz, CDC1 3) δ ppm} : 7.65 (1H, s), 7.54-7.61 (2H, m), 7.43-7.49 (lH, m), 7.02-7.21 (3H, m), 5.40 (1H, s), 3.67-3.74 (4H _; m) Reference example 20

Bis-5-ditriphenole methyl phenylmethinole-2-chloroethynole ether

 In the same manner as in Reference Example 13 (b), the reaction was carried out using 1.38 g (3.02 mniol) of bis- (3,5-ditrifluoromethylphenyl) methanol to obtain 775 mg (49%) of the title compound as an oil. Was. .

Nuclear magnetic resonance spectrum (400MHz, CDCI3) δ ppm: 7.86 (2H, s), 7.82 (4H, s), 7.26 (lH, s), 3.69-3.82 (4H, m) Reference example 21 '

[(2,3,4,5,6-pentamethylphenyl) (2, -chenyl)} methyl 2-chloroethyl ether;

Reference Example (21a) [(2,3,4,5,6-pentamethylphenyl) (2'-Che / y)] methanol Dissolved in 40 ml of anhydrous tetrahydrofuran (2,3,4,5,6) Lithium aluminum hydride (220 mg, 5.80 mmol) suspended in 2.95 g (11.42 mmol) of (2-Cheninole) methanone in 10 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere and ice cooling. Then, the mixture was stirred for 30 minutes at room temperature under ice-cooling for 2 days. On the way, 228 mg (6.01 mmol) of lithium aluminum hydride was added. After stirring, add water under ice-cooling 0.45 ml, 15% (w / v) aqueous sodium hydroxide solution (0.45 ml) and water (1.35 ml) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through celite, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 20: 1, V / V) to obtain 980 mg (yield: 33.0%) of the title compound.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 7.24 (dd, 1H, J = 4.8, 1.2 Hz), 6.91 (dd, 1H, J = 4.8, 3.6Hz), 6.62 (dd, 1H, J = 3.6, 1.2Hz), 6.56 (d, 1H, J = 4.0Hz), 2.42 (d, 1H, J = 4.0Hz), 2.27 (s, 3H), 2.26 (s, 6H), 2.23 (s, 6H) Reference example (21b) [(2,3,4,5,6-pentamethylphenyl) (2'-phenyl)] methyl 2-chloroethynole ether

 In the same manner as in Reference Example 2, the reaction was carried out using 902 mg (3.46 mmol) of [(2,3,4,5,6-pentamethylphenyl) (2, -chel)] methanol to obtain 977 mg of the title compound ( 87%) as an oil.

Nuclear magnetic resonance scan Bae spectrum _{(400MHz, CDC1 3) 8 ppm} : 7.24 (d, 1H, J = 4.8Hz), 6.88 (dd, 1H, J = 4.8, 3.6Hz), 6.50 (d, IH, J = 3.6 Hz), 6.19 (s, IH), 3.72-3.56 (m, 4H), 2.27 (s, 3H), 2.23 (s, 6H), 2.22 (s, 6H) Reference example 22

 (2-Chloro-Feninole ^ 4 Chloro-Feninole Chinole 2-ChloroEchinoleethenore

 Reference Example (22a) (2-fluorophenyl) (4'-fluorophenyl) methanol

 The reaction was carried out in the same manner as in Reference Example 23 (a) using 500 mg (1.86 nmol) of 2,4′-dichlorobenzozophenone to obtain 487 mg (89%) of the title compound.

Nuclear magnetic resonance spectra _{(400Mtfz, (¾C1 3) δ} ppm:. 7.53-7.57 (lH, m), 7.21- 7.36 (7H, m), 6.19 (1H, s) Reference Example (22b) (2-Kurorofuweniru) (4'-chlorophenyl) methyl 2-chloroethylene, Tell

 In the same manner as in Reference Example 2, the reaction was carried out using 470 mg (1.86 mmol) of (2-fluorophenyl) (4, -fluorophenyl) methanol to obtain 522 mg (& 9%) of the title compound.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 7.54-7.56 (lH, m), 7.20- 7.36 (7H, m), 5.84 (1H, s), 3.65-3.75 (4H, m). Reference Example 23 '<3,4,5-Trifluorophenyl ”Nino methylino 2-chloroethino

 Reference example (23a) (3,4,5-trifluorophenyl) phenyl methanol

 Dissolve 1.5 g (6.3 mmol) of Fuunil (3,4,5-trifluorophenyl) methanone in 30 ml of methanol, cool to -30 ° C and add 240 mg (6.3 mmol) of sodium borohydride. And stirred for one hour at the same temperature. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The extract was washed with saturated saline, dried and concentrated, and the residue was purified by column chromatography (developing solvent: 15% ethyl acetate-hexane) to obtain 1.52 g (99 ° / o) of the title compound as an oil. .

Nuclear magnetic resonance scan Bae spectrum _{(400MHz, CDC1 3) δ ppm} : 7.29-7.40 (5H, m), 7.01 (2H, t, J = 8Hz), 5.74 (1H, s), 2.26-2.30 (lH, br. s) Reference example (23b) (3,4,5-trifluorophenyl) phenylmethyl 2-octylethyl ether

In the same manner as in Reference Example 2, the reaction was carried out using 1.00 g (4.20 mmol) of (3,4,5-trifluorophenyl) phenylmethanol synthesized in Reference Example (23a), and 1.15 g (91% ). Nuclear magnetic resonance scan Bae spectrum _{(500MHz, CDC1 3) δ ppm} : 7.28-7.42 (5H, m), 6.95-7.04 (2H, m), 5.33 (1H, s), 3.65-3.75 (4H, m) Reference Example twenty four 3-[(3-Cyanophenyl X3, -trifnoroleolomethylphenyl) methoxy 1-propanol 16.3 g (58.8mniol) of 3-cyanofur-3'-trifluoromethylphenylethanol obtained in Reference Example (17a) ) Was dissolved in 160 ml of Ν, Ν-dimethylformamide. Under ice-cooling, 2.8 g of sodium hydride (content 55%, 64.7 mmol) was added, and after stirring for 30 minutes, 8.9 ml (70.6 nmol) of aryl bromide was added dropwise over 5 minutes. After stirring for 30 minutes under ice cooling, the mixture was returned to room temperature and stirred for 1 hour. The reaction solution was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed sequentially with water and saturated saline, and dried over sodium sulfate.

The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in 170 ml of tetrahydrofuran. Under ice-cooling, 9-boravish mouth [3,3,1] nonane (9-ΒΒΝ) 0.5ιηο11 1 tetrahydrofuran solution (141 ml, 70.6 imnol) 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. After stirring for 30 minutes under ice cooling, the mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed sequentially with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained 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 scan Bae spectrum _{(400MHz, CDC1 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.25 '3-4 -Cyanofel) (3', 4'- Difluorophenino _ methoxy 1 propanol

 Similarly to Reference Example 24, the reaction was carried out using 560 mg (2.28 mmol) of 4-cyanophenyl-3 ′, 4 difluorophenylmethanol obtained in Reference Example (18a) to give the title compound.

497 mg (72 ° /.) Were obtained.

Nuclear magnetic resonance scan Bae spectrum _{(400MHz, CDC1 3) δ ppm} : 7.63 (2H, d, J = 8.3 Hz), 7.43 (2H, d, J = 8.3 Hz), 7.13-7.19 (2H, m), 7.05- 7.09 (lH, m), 5.33 (1H, s), 3.80 (2H, t, J = 5.9 Hz), 3.58-3.63 (2H, m), 1.86-1.94 (2H, m).

 3-Γ (3-cyanophenyl) (3 ', 4, -difluorophenyl) methoxy 1-propanol

 Similarly to Reference Example 24, the reaction was carried out using 370 mg (1.50 mmol) of 3-cyanophenyl-3 ′, 4′-difluorophenylmethanol obtained in Reference Example (19a) to give the title compound.

331 mg (72%) were obtained.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 7.43-7.62 (4H, m), 7.11-7.18 (2Η, m), 7.01-7.04 (1Η, m), 5.32 (1Η, s), 3.81 (2Η, t, J = 5.9 Hz), 3.61 (2H, t, J = 5.9 Hz), 1.88-1.95 (211, m) .Reference example 27

 3J bis (^ _4-diflurofeninole) methoxy 1 propanol

 In the same manner as in Reference Example 24, the reaction was carried out using 560 mg (2.28 mmol) of bis (3,4-difluorophenyl) methanol obtained in Reference Example (13a), and 3- [bis (3,4-difluorophene- 497 mg (72%) of methoxy] propanol was obtained.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} : 7.10-7.15 (4H, m), 7.00- 7 · 02 (2Η, m), 5.25 (1H, s), 3.80 (2H, t, J = 5.9 Hz), 3.60 (2H, t _; J = 5.9 Hz), 1.88-1.93 (2H, m).

Bis- (3-triphnoleo methinolepheninole) methinole 3-chloropropyl ether

Dissolve 249 mg (0.78 mmol) of bis- (3-trifluoromethylphenyl) methanol and 2 ml of 3-chloro-1-propanol in 4 ml of toluene, and add a catalytic amount of p-toluenesulfonic acid monohydrate. The mixture was heated under 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 saline, dried and concentrated. The residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate-50: 1) to give 294 mg (92%) of the title compound as an oil. Test example 1

 Effects on liver injury caused by administration of Piopionibacteiium Acnes (P. Acnes) and lipopolysaccharide

 Five AKR mice (female, 8 weeks old) were grouped into one group, and a suspension in which R Acnes was suspended in physiological saline was intravenously administered at a dose of 0.3 mg / kg. Seven days later, 1 μg of lipopolysaccharide (manufactured by SIGMA) was intravenously administered to cause liver injury.

 The compound of the present invention was prepared by dissolving Celdettas (manufactured by Nippon Shokuhin Kako Co., Ltd.) in distilled water and dissolving it in a 20% solution. Intravenous administration of 30 mg Z kg daily for 7 days from 1 day after intravenous administration of P. Acnes (Group A). Separately, a group in which distilled water containing 20% Celdettas was intraperitoneally administered instead of the compound of the present invention (Group B), and a group in which physiological saline was intravenously administered instead of the lipopolysaccharide solution (Group C) Was provided. Eight hours after administration of lipopolysaccharide, plasma was collected, and the levels of glutamic acid oxaloacetate transaminase (AST) and glutamate pyruvate transaminase (ALT) in the plasma were measured by a UV rate method (Pharmacol. Exp. Ther. Vol. .264, 496-500, 1993).

 From the obtained measured values, the inhibition rate against the increase in each of AST and ALT due to the administration of lipopolysaccharide was calculated according to the following formula.

Inhibition rate (%) = {1— (A-C) / (B—C)} X I 00

A: Average of AST or ALT of group A

B: Average value of AST or ALT of group B

C: Average value of AST or ALT of group C

Table 2 shows the results. The compounds of the present invention are excellent in inhibiting AST and ALT elevation. Showed for

 [Table 2]

AST υ / L) (suppression rate./.) ALT u / L) (suppression rate./.)

A: Compound of Production Example 14 270 (80%) 90 (75%) B: Non-administration group 910 330

C: Non-liver disorder group 130 14

Test Example 2-Effect on liver injury due to administration of Galactosamine and lipopolysaccharide (1)

Groups of 5 C57BL / 6 mice (female 9 weeks old) were treated with a solution of Galactosamine and lipopolysaccharide in physiological saline at a dose of Galactosamine 60 Omg / kg, lipopolysaccharide 5 Administration was performed intraperitoneally at a concentration of μg / kg to cause liver damage (Biochem. Pharmacol., Vol. 40, 1601-1603, 1990). The compound of the present invention is prepared by dissolving Celdex (manufactured by Nippon Shokuhin Kako Co., Ltd.) in distilled water to make a 20% solution. It was administered intraperitoneally (Group A). Further, as in Test Example 1, a group in which distilled water containing 20 ° / ₀ celldex was intraperitoneally administered instead of the compound of the present invention (Group B), and a saline solution instead of the Galactosamine / lipopolysaccharide solution. Was administered intraperitoneally (Group C). Galactosamine. Lipopolysaccharide administration 5 hours after the plasma was collected to measure the AS T, the value of ALT in the plasma (J. Pharmacol. Exp. Ther. Vol.264, 496-500, 1993) 0 In addition, 24 The number of surviving mice after time was counted. From the obtained measured values, the inhibition rate against the increase in AST and ALT values due to administration of Galactosamine 'lipopolysaccharide was calculated according to the formula of Test Example 1. [Table 3]

AST υ / L) (suppression rate./.) ALT υ / L) (suppression rate./.)

A: Compound of Production Example 14 110 (74%) 51 (87%) B: Non-administered group 340 290

C: Non-liver disorder group 32 1 6

[Table 4] Number of dead mice Mortality

A: Compound of Production Example 14 0 (out of 5) 0%

B: non-administration group 5 animals (out of 5) 00%

C: Non-liver disorder group 0 (out of 5) 0%

Test example 3

 Effect on liver injury by administration of Galactosamine and lipopolysaccharide (2)

Groups of 5 C57BL / 6 mice (female, 8 weeks old) were treated with a solution of Galactosamine and lipopolysaccharide in saline, and the dosage was Galactosamine 60 Omg_kg, lipopolysaccharide g / It was administered intraperitoneally to the body weight to cause liver damage (Biochem. Pharmacol., Vol. 40, 1601-1603, 1990). The compound of the present invention is obtained by dissolving carboxymethylcellulose (Wako Pure Chemical Industries) in distilled water and preparing a 0.5% solution intraperitoneally with Galactosamine 'lipopolysaccharide. Before that, 3 OmgZkg was orally administered (group A). Further, similarly to Test Example 1, a group (group B) was administered in which distilled water containing 0.5% carboxymethylcellulose was orally administered instead of the compound of the present invention. ^Five hours after administration of Galactosamine-lipopolysaccharide, plasma was collected and AST (IU / L) and ALT (IU / L) levels in plasma were measured (J. Pharmacol. Exp. Ther. Vol. 264, 496 -500, 1993). From the measured values obtained, according to the following formula,

The inhibition rate against the increase in AST and ALT due to administration of Galactosamine 'lipopolysaccharide was calculated.

Suppression rate (%) = {1 -A / B} X 100

A: Average value of AST or ALT of group A

B: Average value of AST or ALT of group B

 [Table 5]

AST inhibition rate (%) Compound of Production Example 14 Compound 74 9

 Production Example 38 Compound 80 7

 Compound of Preparation Example 40 82 8

 Compound 693 of Production Example 44

 Compound 65 6 of Production Example 46

 Compound 54 3 of Production Example 47

Production Example 55 Compound 53 9 [Table 6]

ALT inhibition (%) Compound of Preparation Example 14 79.9

 Preparation Example 38 Compound 82.1

 Compound of Production Example 40 89.6

 Compound of Production Example 44 85.0

From the above results, in the liver injury model, P. Acnes · lipopolysaccharide-induced liver injury, Galactosamine * lipopolysaccharide-induced liver injury, the compound of the present invention is an index of liver injury, AST value and It clearly inhibits the elevation of ALT level and is useful as a preventive or therapeutic agent for hepatitis and Z or liver damage.

Claims

Claims General formula (I)

 [Where,

R ¹ and R ² are the same or different, and are independently selected from an aryl group, a heteroaryl group, and an aryl group or a substituent group a substituted with 1 to 5 arbitrary groups selected from a substituent group a. A heteroaryl group which is independently substituted by 1 to 3 arbitrary groups;

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

Y is one C ₈ alkylene group or a C ₂ - C ₈ Aruke - indicates Len group,

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

 [Where,

(i) R ³ is independently selected from a hydrogen atom, an aryl group, an aralkyl group, a heteroaryl group, an aryl group substituted with 1 to 3 substituents and an arbitrary group selected from the substituent group a, and a substituent group a Represents an aralkyl group independently substituted by 1 to 3 groups or an aryl group independently substituted by 1 to 3 groups by an arbitrary group selected from substituent group a, and R ⁴ represents , group (wherein having the formula _ D-E- R ^5,

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

R ⁶ is an arbitrary group selected from a lower alkyl group, a lower alkoxy group, an amine residue, a hydroxyl group, an aryl group, a 5- to 8-membered saturated heterocyclic group, and a substituent group a. A substituted or unsubstituted aryl group or a 5- to 8-membered saturated heterocyclic group independently substituted with an arbitrary group selected from the substituent group a, D represents a single bond or a group having the formula C (R ⁷ ) H—, R ⁷ represents a hydrogen atom or any group selected from substituent group a,

E represents a single bond or a Ci—C ₈ alkylene group. ) Or

(il) R ³ and R ⁴ together form the carbon atom to which they are attached

, A 5 to 8 membered saturated heterocyclic group or an arbitrary group selected from substituent group c independently represents 1 to

Represents a 3- to 5-membered saturated heterocyclic group substituted by 3

(iii) R ³ and R ⁴ are taken together and include a carbon atom to which they are bonded, and are selected from a 3- to 10-membered saturated carbocyclic group or a substituent group a and a substituent group c. A 3- to 10-membered saturated carbocyclic group independently substituted by 1 to 3 arbitrary groups, or

(iv) R ³ and R ⁴ are taken together to form a group having the formula —C (R ⁷ ) —E—R ⁵ , wherein R ⁵ , R ⁷ and E are in agreement with the foregoing. ). ] Or

'A group having the formula N (R ⁴ ) —, wherein R ⁴ represents a group having the formula D—E—R ⁵ , wherein D, E and R ^s are as defined above. ).

 Substituent group a includes a halogen atom, a lower alkyl group, a halog / lower alkyl group, a lower anolexoxy group, a lower alkylthio group, a lower alkoxycarboyl group, a carbonyl group, a hydroxyl group, a lower aliphatic acyl group, and a lower aliphatic acylamino group. , An amino group, a cyano group and a nitro group.

 Substituent group b is selected from a lower alkyl group, an aryl group, an aralkyl group, a lower alkyl group independently substituted by 1 to 3 groups selected from substituent group a, and a substituent group a An aryl group independently substituted with 1 to 3 arbitrary groups, an aralkyl group, a lower aliphatic acyl group and a lower alkyl independently substituted with 1 to 3 arbitrary groups selected from the substituent group a. A group consisting of a sulfonyl group;

Substituent group c is independently an oxo group or any group selected from an aryl group, an aralkyl group and a substituent group a as a substituent on the nitrogen atom when substituting for a nitrogen atom. A group selected from an aryl group substituted with 1 to 3 substituents and an aralkyl group substituted with 1 to 3 substituent (s); ] A prophylactic or therapeutic agent for hepatitis and / or hepatic disorder, comprising a compound having the following formula:

2. In Claim 1,

 X is an oxygen atom or a sulfur atom; a prophylactic or therapeutic agent for hepatitis and / or liver injury.

3. In claim 1,

 X is an oxygen atom; a prophylactic or therapeutic agent for hepatitis and Z or liver damage.

4. In any one of claims 1 to 3,

A preventive or therapeutic agent for hepatitis and / or hepatic disorder, wherein Y is a C ₈ alkylene group.

5. In any one of claims 1 to 3,

The preventive or therapeutic agent for hepatitis and Z or liver damage, wherein γ is a 1 c ₅ alkylene group.

6. In any one of claims 1 to 3,

γ is a c ₂ -c ₃ alkylene group, a prophylactic or therapeutic agent for hepatitis and Z or liver damage

7. In any one of claims 1 to 3,

The preventive or therapeutic agent for hepatitis and / or liver damage, wherein γ is an ethylene group.

8. In any one of claims 1 to 3,

 Y is a trimethylene group, a prophylactic or therapeutic agent for hepatitis and / or liver damage

9. In any one of the claims 1 to 8, L is a group having the formula C (R ³ ) (R ⁴ ) —, wherein R ³ is independently any group selected from a hydrogen atom, an aryl group, an aralkyl group, a heteroaryl group, and a substituent group a. 1 to 3 substituted aryl groups, arbitrary groups selected from substituent group a, and 1 to 3 independently substituted aralkyl groups or arbitrary groups selected from substituent group a. A prophylactic or therapeutic agent for hepatitis and / or hepatic disorder, wherein R ⁴ is a group having the formula: D-E-R ⁵ independently representing a substituted or unsubstituted heteroaryl group.

10. In claim 9,

A prophylactic or therapeutic agent for hepatitis and / or hepatic disorder, wherein R ³ is an aryl group or a heteroaryl group.

1 1. In claim 9,

A prophylactic or therapeutic agent for hepatitis and Z or liver damage, wherein R ³ is a fuel group or a pyridyl group.

1 2. In claim 9,

A prophylactic or therapeutic agent for hepatitis and / or liver injury, wherein R ³ is a pyridyl group.

1 3. In any one of claims 9 to 12,

A preventive or therapeutic agent for hepatitis and Z or liver damage, wherein R ⁴ is a group having the formula CO—R ⁶ .

1 4. In claim 13,

A prophylactic or therapeutic agent for hepatitis and / or liver damage, wherein R ⁶ is an amine residue.

15. In any one of claims 1 to 8, L is a group having the formula C (R ³ ) (R ⁴ ) —, wherein R ³ and R ⁴ together form the carbon atom to which they are attached, a 5- to 8-membered A preventive or therapeutic agent for hepatitis and / or hepatic disorder, which is a 5- to 8-membered saturated heterocyclic group independently substituted with 1 to 3 saturated heterocyclic groups or an arbitrary group selected from substituent group c. ,

1 6. In any one of the claim 1 to 8,

L is a group having the formula C (R ³ ) (R ⁴ ) 1, wherein R ³ and R ⁴ together form a carbon atom to which they are attached, a 5- or 6-membered A preventive or therapeutic agent for hepatitis and Z or liver damage, which is a 5- to 6-membered saturated heterocyclic group independently substituted by 1 to 3 saturated heterocyclic groups or an arbitrary group selected from substituent group c.

17. In any one of claims 1 to 8,

L is a group having the formula C (R ³ ) (R ⁴ ) —, and R ³ and R ⁴ together form a substituent group c including the carbon atom to which they are bonded; A prophylactic or therapeutic agent for hepatitis and / or hepatic disorder, which is a 5- or 6-membered saturated heterocyclic group independently substituted with 1 to 3 arbitrary groups selected from:

18. In any one of claims 1 to 8,

L is a group having the formula C (R ³ ) (R ⁴ ) —, wherein R ³ and R ⁴ are linked together to form a single bond including the carbon atom to which they are attached; Is a 5- or 6-membered saturated heterocyclic group which is substituted with an oxo group and may be independently substituted with one or two arbitrary groups selected from the substituent group c. Agent or therapeutic agent.

1 9. In any one of claims 1 to 8,

L is the following general formula (L-1) (Le 1)

 [In the above formula, G and J are the same or different and are an oxygen atom, a sulfur atom, or a group having one of the formulas —NR ′ (wherein, R is selected from an aryl group, an aralkyl group, and a substituent group a. And a group independently selected from an aralkyl group independently substituted with 1 to 3 substituents and an arbitrary group selected from the substituent group a with 1 to 3 substituents. ). ] A preventive or therapeutic agent for hepatitis and / or hepatic disorder.

20. In claim 19,

 An agent for preventing or treating hepatitis and Z or liver damage, wherein G is an oxygen atom or a sulfur atom, and J is a group having one NH—.

2 1. In claim 19,

 A preventive or therapeutic agent for hepatitis and / or hepatic disorder, wherein G is an oxygen atom and J is a group having one NH—.

2 2. In any one of claims 1 to 8,

L is a group having the formula C (R ³ ) (R ⁴ ) —, wherein R ³ and R ⁴ together form the carbon atom to which they are attached, from 3 to 10 A 3- to 10-membered saturated carbocyclic group independently substituted with 1 to 3 membered saturated carbocyclic groups or substituents selected from group a and optional group c, hepatitis and / or An agent for preventing or treating liver damage.

23. In any one of claims 1 to 8,

L is a group having the formula C (R ³ ) (R ⁴ ) —, wherein R ³ and R ⁴ are combined to form a carbon atom to which they are bonded, 6-membered saturated carbocyclic group or substituent group a prophylactic or therapeutic agent for hepatitis and Z or hepatic disorder, which is a 5- to 6-membered saturated carbocyclic group independently substituted with 1 to 3 arbitrary groups selected from a and substituent group c.

2 4. In any one of claims 1 to 8,

L is a group having the formula C (R ³ ) (R ⁴ ) 1, wherein R ³ and R ⁴ together form a benzene ring, including the carbon atom to which they are bonded, A preventive or therapeutic agent for hepatitis, Z or liver injury, which is a 5- or 6-membered saturated carbocyclic group (the 5- or 6-membered saturated carbocyclic group has an oxo group or a hydroxyl group as a substituent).

25.In any one of claims 1 to 8,

 A preventive or therapeutic agent for hepatitis and / or liver injury, wherein L is a 2-hydroxyindane or 2-oxoindane group.

26. In any one of claims 1 to 8,

L power S, wherein one C (R ³⁾ (R ⁴⁾ is a group having one, it becomes R ³ and R ⁴ gar cord, the formula ^{= C (R 7) -E- R} 5 a group having a A prophylactic or therapeutic agent for hepatitis and Z or liver damage.

27. In claim 26:

The agent for preventing or treating hepatitis and Z or liver injury, wherein E is a single bond.

28. In Claim 26 or Claim 27,

R ⁷ is lower alkyl group or Shiano group, prophylactic or therapeutic agents of liver及Pi Z or liver damage.

29. In any one of claims 26 to 28,

R ⁵ is a group having the formula —CO—R ⁶ ; a prophylactic or therapeutic agent for hepatitis and / or liver injury Agent.

30. In claim 29,

A prophylactic or therapeutic agent for hepatitis and / or liver injury, wherein R ⁶ is a lower alkoxy group.

3 1. In any one of claims 1 to 8,

L is a group having the formula N (R ⁴ ) 1, a prophylactic or therapeutic agent for hepatitis and Z or hepatic disorder.

3 2. In claim 31,

R ⁴ is a group having the formula D—R ⁵ , wherein the agent is a prophylactic or therapeutic agent for hepatitis and Z or hepatic disorder.

3 3. In claim 31,

A prophylactic or therapeutic agent for hepatitis and / or hepatic disorder, wherein R ⁴ is a group having the formula: D—CO—R ⁶ .

3 4. In claim 33,

A prophylactic or therapeutic agent for hepatitis and / or liver injury, wherein R ⁶ is a lower alkoxy group.

35. In any one of the claims 1 to 34,

A prophylactic or therapeutic agent for hepatitis and Z or liver injury, wherein R ¹ is an aryl group or an aryl group independently substituted with ¹ to 5 aryl groups or any group selected from substituent group a.

36. In any one of claims 1 to 34,

R ¹ is an aryl group or an arbitrary group selected from substituent group a, and is independently 1 to 3 A prophylactic or therapeutic agent for hepatitis and Z or liver damage, which is an substituted aryl group.

37. In any one of the claims 1 to 34,

R ¹ is an arbitrary group selected from the group consisting of a halogen group, a halogen atom, a lower alkyl group, a halogeno lower alkynole group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, an amino group, a -toro group and a cyano group. A prophylactic or therapeutic agent for hepatitis, Z or liver injury, which is an aryl group substituted with 1 to 3 amino acids.

38. In any one of claims 1 to 34,

1 to 3 substitutions of Ri with an arbitrary group selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, an amino group, a nitro group and a cyano group A preventive or therapeutic agent for hepatitis and Z or liver damage, which is an aryl group obtained. +

39. In any one of claims 1 to 34,

R ¹ is an aryl group substituted with 1 to 3 arbitrary groups selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a nitro group; Agent.

40. In any one of claims 1 to 34,

R ¹ is an aryl group substituted by 1 to 3 groups selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group and a dinitro group, or a hepatitis and / or liver injury preventing agent or Therapeutic agent.

4 1. In any one of claims 1 to 34,

R ¹ is selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group and a nitro group A prophylactic or therapeutic agent for hepatitis and / or hepatic disorder, which is a phenyl group substituted with one to three phenyl groups.

42. In any one of claims 1 to 34,

R ¹ is 2-fuenore rofuenore, 3_fluorophenyl, 4-funoreolofeel, 2-kuronofu-nore, 3-kuronofuenoren, 4-kuronofuenoren, 3-methinorefue 2-ino, 3-trifluoromethylphenyl, 3-nitrophenyl, 3,4-, dimethylphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-diphneololophenol, 3,4-diphneololophenol, 3,5-difluorophenyl, 3,5-ditrinoleolomethynolephenyl, 3,4,5-trifluorophenyl or 2-chloro- A prophylactic or therapeutic agent for hepatitis, Z or liver damage, which is a 5-nitrophenyl group.

43. In any one of claims 1 through 34,

R ¹ is 2-fluorophenyl, 3_fluorophenyl, 4-fluorophenyl, 3-chlorophene / le, 4-clofene / n-, 3-meth / lefeninole, 3-triphnoleolomethine / norn 3,2-difluorophenol, 2,4-difluorophenol, 2,4-difluorophenol, 2,5-difluorophenyl, 3,4-difluorophenyl, Hepatitis and / or liver which is 3,5-difluorophenyl, 3,5-ditrifluoromethylphenyl, 3,4,5-trifluorophenyl or 2-chloro-5-nitrophenyl; An agent for preventing or treating disorders.

44. In any one of claims 1 through 43,

A preventive or therapeutic agent for hepatitis and / or hepatic disorder, wherein R ² is an aryl group, a heteroaryl group, or an aryl group independently substituted with 1 to 5 arbitrary groups selected from substituent group a.

In 4 5. Any one selected from claims 1 to 4 3, R ² is Ariru group, substituted 1 to 3 independently any group selected from thienyl group, or a substituent group a An agent for the prevention or treatment of hepatitis and Z or liver damage, which is an aryl group.

46. In any one of claims 1 to 43,

A prophylactic or therapeutic agent for hepatitis and Z or hepatic disorder, wherein R ² is an aryl group or an aryl group independently substituted with 1 to 3 aryl groups or an arbitrary group selected from substituent group a.

47. In any one of claims 1 through 43,

R ² is an aryl group or any group selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, an amino group, a nitro group and a cyano group. A preventive or therapeutic agent for hepatitis and / or hepatic disorder, which is an aryl group substituted by 1 to 3 amino acids.

48. In any one of claims 1 to 43,

R ² is an aryl group substituted with 1 to 3 aryl groups or any group selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a nitro group and a cyano group; Or a prophylactic or therapeutic agent for liver damage.

49. In any one of claims 1 to 43,

R ² is an aryl group or an aryl group selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a nitro group, and a cyano group; An agent for preventing or treating hepatitis and / or liver injury.

50. In any one of claims 1 to 43, R ² is a group consisting of a fuel group or a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a nitro group and a cyano group. A preventive or therapeutic agent for hepatitis, Z or liver injury, which is a phenyl group substituted by 1 to 3 arbitrary groups selected from the group consisting of:

5 1. In any one of claims 1 to 43,

R ² is Hue-Nore, 2-Funore, Rohu-Nore, 3-Funoleo-Fue-Nore, 4-Funole-Lofe-Nore, 2-Fro-No-Fuenore, 3-Fro-No-Fune, and 4-Fro-No-Fen Nore, 3-methinolefeninole, 3-trifluoromethinolepheninole, 3-nitropheninole, 2,3-diphnoleo oral feninole, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,, 6-Diphnoleolofenolene, 3,4-difluorophenyl, 3,5-difluorophenolene, 3,5-ditrifluoromethylphenyl, 3-cyanophenyole, 4-cyanophenyole or 2 A prophylactic or therapeutic agent for hepatitis and / or liver damage, which is a 5-nitrophenyl group. '

5 2, In any one selected from claims 1 to 43,

R ² is phenole, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, A preventive agent for hepatitis and / or hepatic injury, which is 3,4-diphnoleolophenyl, 3,5-dibutenoleophenyl, 3,5-ditriflenole mouth methylpheninole, 3-cyanophene or 4-cyanophenine group Or therapeutic agents.

53. In Claim 1, the compound having the general formula (I) is:

 8-[2-Bis (3-fluorophenyl) methoxil)-.1-oxa-3,8-dazaspiro '[4.5] decane-2-one,

8- [2-bis (4-fluorophenyl) methoxyethyl Ί-toloxa-3,8-diazaspiro [4.5] Decane-2-one,

8- [2- bis (3-triflate Ruo Russia methyl phenylalanine) method Tokishechiru] - 1 - Okisa -3, 8-di Azasupiro ^[4 5.] Decane - ² - one,

 8-{2-[(3-co-mouth phenyl) phenylethoxy] ethyl} -1 -oxa-3,8-diazapyro [4.5] decane-2-one,

 8-{2-[(3,4-difluorophenyl) phenylmethoxy] ethyloxa-3,8-dazaspiro [4.5] decane-2-one,

 8-{2-[(3-Nitrofeuer) phenylmethoxy] ethyloxa-3,8-diazaspiro [4.5] decane-2-one, ■

 8- {2-[(3-Methylphenyl) phenylmethoxy] ethyl} _1-oxa-3,8-diazaspiro [4.5] decane-2-one,

 8-{2-[(3,5-difluoromethyl) phenylmethoxy] ethyl) -1 -oxa-3,8-diazaspiro [4.5] decane-2-one;

 8- {2-[(2-fluorophenyl) (4-fluorophenyl) methoxy] ethyl}-1-oxa-3,8-diazaspiro [4.5] decane-2-one,

 8- {2-[(2,5-difluorophenyl) phenylmethoxy] ethynole} -1-oxa-3,8-diazaspiro [4.5] decane-2-one,

 8- {2-[(2-Fluorophenyl) phenylmethoxy] ethyl} -1-oxa-3,8-dazaspi [4.5] decane-2-one,

 8-{2-[(2-Couguchi-5-ditrophenyl) phenylmethoxy] ethynole :)-1-oxa-3,8-diazaspiro [4.5] decane-2-one,

 8- {2-[(3,4-dimethylphenyl) phenylmethoxy] ethyl} -toxa-3,8-diazaspiro [4.5] decane-2-one and

 8-{2-[(3-Trifluoromethylphenyl) 'phenylmethy.shi] ethyl}-1-oxa-3,8-diazaspiro [4.5] decane-2-one

Hepatitis and any one compound selected from the group consisting of: And z or a prophylactic or therapeutic agent for liver damage.

54. In claim 1, the compound having the general formula (I) is

 8- {3- [bis- (3-trifluoromethylphenyl) .methoxy] propyl) -1-oxa-3,8-diazaspiro [4.5] decane-2-one,

 8— {2 — [(2-— 口 口 ふ エ-ノ レ) (4 ,， 口 口 ふ 口 二 ノ レ) methoxy] ethyloxa- 3,8-diazaspiro [4,5] decane-2-one;

8--[Bis_ (2,3-difluorophenyl) methoxy] ethyl]-1-oxa-3,8-diazaspiro [ ⁵ ] decane-2-one,

 8-{2- [bis- (3,4-difluorophenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one,

 8- {2- [Bis- (3,5-difluorophenyl) methoxy] ethyl}-1-oxa-3,8-dazaspiro [4,5] decane-2-one,

 8- {2- [bis_ (2,4-difluorophenyl) methoxy] ethyl}-1-oxo- 3,8-diazaspiro [4,5] decane-2-one,

 8- {2- [bis- (3,5-ditrifluoromethylphenyl) methoxy] ethyl] 1-oxa-3,8-diazaspiro [4,5] decane-2-one;

 8- {2-[(3,4, '5-Trifluorophenyl) phenylmethoxy] ethyl}-1-oxa-3,8-diazaspiro [4,5] decane-2-one,

 8- {2 _ [(4-Cyanophenyl) (3 ', 4'-difluorophenyl) methoxy] ethynole} -1-oxa-3,8-diazaspiro [4,5] decane-2-one,

8- {2 - [(3-Shianofueyuru) (3 ', 4'-difluorophenyl) method butoxy] Echiru} - 1 - O hexa - 3, 8-Jiazasupiro ^[4, 5] decane - 2-one,

 8- {2-[(3-Cyanophenyl) (3-trifluoromethylphenyl) methoxy] ethyl} -1-oxa-3,8-diazaspiro [4,5] decane-2-one;

8--[Bis- (3,4-difluorophenyl) methoxy] propyl}-1-oxa- 3,8-dia Zaspi mouth [4,5] decane-2-one,

 8- {3-[(3-Cyanophenyl) (3,4, -difluorophenyl) methoxy] propyl} -1-oxa-3,8-diazaspiro [4,5] decan-2-one,

 8- {3-[(4-Cyanophuel) (3,4'-difluorophenyl) methoxy] propyl) -1_oxa-3,8-diazaspiro [4,5] decane-2-one and

8 - {3 - [(3- Shianofueniru) (3, - triflumizole Ruo B methyl phenylalanine) method butoxy] propyl Le} - 1-hexa - ^{3, 8} - Jiazasupiro [4, 5] decane - ² - one

A prophylactic or therapeutic agent for hepatitis and / or hepatic disorder, which is selected from the group consisting of at least one compound or a pharmacologically acceptable salt thereof.

55. The prophylactic or therapeutic agent for hepatitis according to any one of claims 1 to 54.

56. The preventive or therapeutic agent for liver damage according to any one of claims 1 to 54.