JP2000178231A - New production intermediate of fluorine-containing 1,4- disubstituted piperidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having a highly selective muscarine M3 receptor antagonism, slight adverse effect and safety, effective for treating and preventing diseases related to muscarine M3 receptor such as chronic closed pulmonary disease, chronic bronchitis, etc. SOLUTION: This derivative is (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2- hydroxy-2-phenylacetic acid. The compound is shown by formula I [Ar is an aryl, a heteroaryl or the like; R1 is a (substituted) 3-6C cycloalkyl; R2 is a (substituted) 5-15C (un)saturated aliphatic hydrocarbon or the like; X is O or NH]. The compound is obtained by reacting a carboxylic acid of formula II [R10 is a (substituted) 3-6C cycloalkyl or the like] or its reactive derivative with a compound of formula III [R20 is a (substituted) 5-15C aliphatic hydrocarbon] or its salt and removing the protecting group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel fluorine-containing 1,4-disubstituted piperidine derivative, a process for producing the same, a medicament containing the same, and a use thereof as a medicament, particularly various respiratory diseases and urinary diseases. Or a use for the treatment or prevention of digestive disorders.

[0002]

2. Description of the Related Art It has long been known that antagonism to muscarinic receptors causes effects such as bronchodilation, gastrointestinal motility suppression, acid secretion suppression, dry mouth, mydriasis, bladder contraction suppression, sweat reduction, and tachycardia. [Basic and Clinic
al Pharmacology 4th Ed. , (A
PPLETON & LANGE) PP83-PP9
2, (1989) and Drug News & Per
selective, 5 (6), PP345-PP352
(1992) etc.].

In recent years, muscarinic receptors have at least three
There are species subtypes, M ₁ receptor mainly in the brain, M ₂ receptors in the heart or the like, and M ₃ receptors was found to be present in smooth muscle and glandular tissue. However, any of a large number of existing compounds having an antagonistic action on the muscarinic receptor to date will non-selectively antagonize these three subtypes. So, for example,
When used as a therapeutic or prophylactic agent for respiratory diseases, in addition to side effects such as dry mouth, nausea and mydriasis, M ₁
Serious side effects related to the heart, such as heart palpitations due to the central nervous system and the M ₂ receptor of dementia, such as due to the receptor becomes a problem, the improvement has been strongly demanded.

[0004] The present inventors have proposed such a drug as:
1,4-disubstituted piperidine derivatives have been disclosed (PCT
WO96 / 33973). However, creation of even better drugs is desired.

[0005]

The object of the present invention is to solve the above, by creating more excellent drug than said known compounds, highly selective muscarinic M ₃ receptors have antagonistic activity, reduced side effects safe and effective Do muscarinic M ₃ diseases receptor is involved, such as chronic obstructive pulmonary disease, chronic bronchitis,
Respiratory diseases such as asthma and rhinitis; irritable bowel syndrome, spastic colitis, diverticulitis, and gastrointestinal diseases such as pain associated with digestive system smooth muscle spasm; It is an object of the present invention to provide a therapeutic or preventive agent for urinary diseases such as urinary incontinence and frequent urination in diseases such as unstable bladder, bladder spasticity and chronic cystitis; and motion sickness.

[0006]

According to the present invention, there is provided a compound represented by the general formula [I]:

[0007]

Embedded image Wherein Ar is an aryl group or a heteroaryl group having 1-2 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (a ring of the aryl group and the heteroaryl group) The optional 1 to 3 hydrogen atoms above are a lower alkyl group, a trifluoromethyl group, a cyano group, a hydroxyl group, a nitro group, a lower alkoxycarbonyl group, a halogen atom,
It may be substituted with a lower alkoxy group, an amino group or a lower alkylamino group. ) Wherein R ¹ is any 1 to
4 hydrogen atoms represent a cycloalkyl group having 3 to 6 carbon atoms which may be substituted by a fluorine atom, and R ² may have any 1 to 6 hydrogen atoms substituted by a fluorine atom A saturated or unsaturated aliphatic hydrocarbon group having 5 to 15 carbon atoms, an aralkyl group, an arylalkenyl group or a nitrogen atom, selected from the group consisting of an oxygen atom and a sulfur atom;
A heteroarylalkyl group or a heteroarylalkenyl group having two heteroatoms (the aralkyl group,
Any one to three hydrogen atoms on the ring of the arylalkenyl group, heteroarylalkyl group and heteroarylalkenyl group may be a lower alkyl group, a trifluoromethyl group, a cyano group, a hydroxyl group, a nitro group, a lower alkoxycarbonyl group, or a halogen atom. It may be substituted with an atom, lower alkoxy group, amino group or lower alkylamino group. ) And X represents O or NH. However, at least one of R ¹ and R ² has one or more fluorine atoms. And a pharmaceutically acceptable salt thereof.

[0008] The formula [I] provided by the present invention
The compound is an effective selective muscarin M _ThreeReceptor antagonism
Has excellent oral activity, long-lasting action and body
Because it shows pharmacokinetics, it is safe with few side effects,
For obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis
Irritable bowel syndrome, spastic colitis, diverticulitis and extinction
Gastrointestinal disorders such as pain associated with gastrointestinal smooth muscle spasm;
Frequent urination, neuropathic bladder, nocturnal enuresis, unstable bladder, bladder spasm,
Urology such as urinary incontinence and pollakisuria in diseases such as chronic cystitis
System diseases; and extremely for the treatment or prevention of motion sickness
Useful.

Hereinafter, the meaning of the terms used in the specification will be described, and the present invention will be described in more detail.

An aryl group (arbitrary 1 to 3 hydrogen atoms on the ring of the aryl group may be a lower alkyl group, a trifluoromethyl group, a cyano group, a hydroxyl group, a nitro group, a lower alkoxycarbonyl group, a halogen atom, a lower May be substituted with an alkoxy group, an amino group or a lower alkylamino group.) ”Means an unsubstituted or substituted aryl group having 6 to 11 carbon atoms, and is, for example, an unsubstituted or the above-mentioned substituent. Examples include a substituted phenyl group and a naphthyl group.

A heteroaryl group having one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (arbitrary one to three on the ring of the heteroaryl group)
Each hydrogen atom may be substituted with a lower alkyl group, a trifluoromethyl group, a cyano group, a hydroxyl group, a nitro group, a lower alkoxycarbonyl group, a halogen atom, a lower alkoxy group, an amino group or a lower alkylamino group. ) "Is, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 2-thienyl, 3-thienyl unsubstituted or substituted with the above substituents. Group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 3-pyrazolyl group,
4-pyrazolyl group, 2-furyl group, 3-furyl group, 2-
Pyrrolyl group, 3-pyrrolyl group, 2-pyrimidinyl group, 4
-Pyrimidinyl group, 5-pyrimidinyl group, 2-pyrazinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-
Examples thereof include a quinolinyl group, a 2-benzothienyl group and a 2-indolyl group.

"A cycloalkyl group having 3 to 6 carbon atoms, in which 1 to 4 hydrogen atoms may be substituted by a fluorine atom"
Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 1-fluorocyclopropyl group, a 1-fluorocyclobutyl group,
-Fluorocyclopentyl group, 1-fluorocyclohexyl group, 2-fluorocyclopropyl group, 2-fluorocyclobutyl group, 2-fluorocyclopentyl group, 2-
Fluorocyclohexyl group, 3-fluorocyclobutyl group, 3-fluorocyclopentyl group, 3-fluorocyclohexyl group, 4-fluorocyclohexyl group, 2,2
-Difluorocyclopropyl group, 2,2-difluorocyclobutyl group, 2,2-difluorocyclopentyl group,
2,2-difluorocyclohexyl group, 3,3-difluorocyclobutyl group, 3,3-difluorocyclopentyl group, 3,3-difluorocyclohexyl group, 4,4-
Difluorocyclohexyl group, 3,3,4,4-tetrafluorocyclopentyl group, 3,3,4,4-tetrafluorocyclohexyl group, 2,3 difluorocyclobutyl group, 2,3 difluorocyclopentyl group, 3,4
Difluorocyclopentyl group, 2,3 difluorocyclohexyl group, 3,4 difluorocyclohexyl group, 2,2,3,3-tetrafluorocyclobutyl group,
A 2,2,3,3-tetrafluorocyclopentyl group is exemplified.

"A saturated or unsaturated aliphatic hydrocarbon group having 5 to 15 carbon atoms, in which arbitrary 1 to 6 hydrogen atoms may be substituted with a fluorine atom" is defined as having 5 to 15 carbon atoms. Linear or branched, for example, having 5 to 5 carbon atoms in which any 1 to 6 hydrogen atoms may be replaced by a fluorine atom
~ 15 alkyl groups, alkenyl groups, alkynyl groups,
A cycloalkylidenealkyl group, a cycloalkylalkyl group, a cycloalkylalkenyl group or a cycloalkylalkynyl group in which any hydrogen atom on the cycloalkyl ring may be substituted with a lower alkyl, or any hydrogen atom on the cycloalkenyl ring is a lower alkyl group; It includes a cycloalkenylalkyl group and a cycloalkenylalkenyl group which may be substituted with alkyl.

Specific examples of such aliphatic hydrocarbon groups include, for example, 2-methylbutyl, 3-methylbutyl, pentyl, neopentyl, 2-methylpentyl, 3-methylpentyl, and 4-methylpentyl. Pentyl group, hexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group,
2,4-dimethylpentyl group, 2-ethylhexyl group,
4,5-dimethylhexyl group, 4,4-dimethylpentyl group, heptyl group, 4-methylheptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group,
Tridecyl group, tetradecyl group, pentadecyl group, 3-
Fluoromethylbutyl group, 1-fluoropentyl group, 4
-Fluoropentyl group, 5-fluoropentyl group, 1,
1 difluoropentyl group, 4,4 difluoropentyl group, 5,5,5-trifluoropentyl group, 1,1,
4,4-tetrafluoropentyl group, 1,1,5,5
5-pentafluoropentyl group, 1-fluorohexyl group, 5-fluorohexyl group, 6-fluorohexyl group, 1,1 difluorohexyl group, 5,5 difluorohexyl group, 6,6,6-trifluorohexyl Group,
1,1,5,5-tetrafluorohexyl group, 1,1,
6,6,6-pentafluorohexyl group, 1-fluoro-4-methylpentyl group, 2-fluoro-4-methylpentyl group, 3-fluoro-4-methylpentyl group, 4-fluoro-4-methylpentyl group, 4-fluoromethylpentyl group, 1,1-difluoro-4-methylpentyl group, 4-trifluoromethylpentyl group, 5,5,5-trifluoro-4-trifluoromethylpentyl group,
1,1-difluoro-4-trifluoromethylpentyl group, 1,1,5-trifluoro-4-methylpentyl group, 1-fluoro-4-methylhexyl group, 4-fluoro-4-methylhexyl group, 5-fluoro-4-methylhexyl group, 6-fluoro-4-methylhexyl group,
1,1-difluoro-4-methylhexyl group, 5,5-difluoro-4-methylhexyl group, 4-trifluoromethylhexyl group, 6,6,6-trifluoro-4-methylhexyl group, 6,6,6-trifluoro-4-trifluoromethylhexyl group, 1,1-difluoro- Unsubstituted and fluorine-substituted alkyl groups such as 4-trifluoromethylhexyl group and 1,1-difluoro-6,6,6-trifluoro-4-methylhexyl group; 3-methyl-2
-Butenyl group, 2-pentenyl group, 3-pentenyl group,
4-pentenyl group, 3-methyl-2-pentenyl group, 3
-Methyl-3-pentenyl group, 4-methyl-2-pentenyl group, 4-methyl-3-pentenyl group, 4-methyl-
4-pentenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 4-methyl-2-hexenyl group, 4-methyl-3-hexenyl group, 4-methyl-4-
Hexenyl group, 5-methyl-2-hexenyl group, 5-methyl-3-hexenyl group, 5-methyl-4-hexenyl group, 5-methyl-2-heptenyl group, 5-methyl-3-
Heptenyl group, 5-methyl-4-heptenyl group, 5-methyl-5-heptenyl group, 3,4-dimethyl-2-pentenyl group, 3,4-dimethyl-3-pentenyl group, 4,
5-dimethyl-2-hexenyl group, 4,5-dimethyl-
3-hexenyl group, 4,5-dimethyl-4-hexenyl group, octenyl group, nonenyl group, decenyl group, undecenyl group, dodecenyl group, tridecenyl group, tetradecenyl group, pentadecenyl group, 1-fluoro-4-methyl-3-pentenyl group, 2-fluoro- 4-methyl-3-pentenyl group, (E) -4-fluoromethyl-3-pentenyl group, (Z) -4-fluoromethyl-3-pentenyl group, 1,1-difluoro-4-methyl-3-pentenyl group, 2,2 difluoro-4-methyl-3-pentenyl group Group, (E) -4-trifluoromethyl-3-pentenyl group, (Z) -4-trifluoromethyl-3-pentenyl group, (E) -1,1-difluoro-4-trifluoromethyl-3-pentenyl group, (Z) -1 , 1 difluoro-4-trifluoro Methyl-3 over-pentenyl group, 5,
5,5-trifluoro-4-trifluoromethyl-3-pentenyl group, 1-fluoro-4-methyl-2-pentenyl group, 4-fluoro-4-methyl-2-pentenyl group, 4-fluoromethyl-2-pentenyl group, 1,1-difluoro-4-methyl-2-pentenyl group, 4- A trifluoromethyl-2-pentenyl group, a 4-fluoro-1,1-difluoro-4-methyl-2-pentenyl group,
1,1-difluoro-4-trifluoromethyl-2-pentenyl group, 1-fluoro-4-methyl-4-pentenyl group, 2-fluoro-4-methyl-4-pentenyl group,
3-fluoro-4-methyl-4-pentenyl group, 4-fluoromethyl-4-pentenyl group, 1,1 difluoro-4-methyl-4-pentenyl group, 2,2 difluoro-4-methyl-4-pentenyl group, 3,3 difluoro-4-methyl-4-pentenyl group, 4-trifluoro L-methyl-4-pentenyl group, 1,1-difluoro-4-trifluoromethyl-4-pentenyl group, 1,1,3,3
-Tetrafluoro-4-methyl-4-pentenyl group, 1
-Fluoro-4-methyl-3-hexenyl group, 2-fluoro-4-methyl-3-hexenyl group, 4-fluoromethyl-3-hexenyl group, 6-fluoro-4-methyl-3-hexenyl group, 4-trifluoromethyl-3-hexenyl group, 1,1-difluoro-4-methyl-3-hexenyl group A 2,2-difluoro-4-methyl-3-hexenyl group, a 4-trifluoromethyl-3-hexenyl group, a 5,5-difluoromethyl-3-hexenyl group,
6,6,6-trifluoro-4-methyl-3-hexenyl group, 1,1 difluoro-4-trifluoromethyl-3-hexenyl group, 1,1 difluoro-6,6,6-trifluoromethyl-3-hexenyl group, 6,6,6-trifluoro-4- Unsubstituted and fluorine-substituted alkenyl groups such as trifluoromethyl-3-hexenyl group;
Pentynyl group, 3-pentynyl group, 4-pentynyl group,
4-methyl-2-pentynyl group, octynyl group, noninyl group, decynyl group, undecynyl group, dodecynyl group, tridecynyl group, tetradecynyl group, pentadecynyl group and the like, and arbitrary 1 to 6 hydrogen atoms thereof are substituted by fluorine atoms Alkynyl group; cyclopropylethyl group, cyclopropylpropyl group, cyclopropylbutyl group, cyclopropylpentyl group, cyclopropylhexyl group,
Cyclopropylheptyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclobutylpropyl group, cyclobutylbutyl group, cyclobutylpentyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclopentylpropyl group, cyclopentylbutyl group, cyclohexylmethyl group, Cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl, cycloheptylethyl, cycloheptylpropyl, cycloheptylbutyl, cyclooctylmethyl, cyclooctylethyl, cyclooctylpropyl, cyclooctylbutyl Group, 1-methylcyclopentylmethyl group, 2-methylcyclopentylmethyl group,
3-methylcyclopentylmethyl group, 1-ethylcyclopentylmethyl group, 2-ethylcyclopentylmethyl group, 3-ethylcyclopentylmethyl group, 2-cyclopentylethyl group, 2- (1-methylcyclopentyl) ethyl group, 2- (2- Methylcyclopentyl) ethyl group,
2- (3-methylcyclopentyl) ethyl group, 2- (1
-Ethylcyclopentyl) ethyl group, 2- (2-ethylcyclopentyl) ethyl group, 2- (3-ethylcyclopentyl) ethyl group, 1-methylcyclohexylmethyl group, 2-methylcyclohexylmethyl group, 3-methylcyclohexylmethyl group, 4-methylcyclohexylmethyl group, 1-ethylcyclohexylmethyl group, 2-ethylcyclohexylmethyl group, 3-ethylcyclohexylmethyl group, 4-ethylcyclohexylmethyl group, cyclohexylethyl group, 2- (1-methylcyclohexyl) ethyl group, 2- (2-methylcyclohexyl) ethyl group,
2- (3-methylcyclohexyl) ethyl group, 2- (4
-Methylcyclohexyl) ethyl group, 2- (1-ethylcyclohexyl) ethyl group, 2- (2-ethylcyclohexyl) ethyl group, 2- (3-ethylcyclohexyl)
Ethyl group, 2- (4-ethylcyclohexyl) ethyl group, 1-methylcycloheptylmethyl group, 2-methylcycloheptylmethyl group, 3-methylcycloheptylmethyl group, 4-methylcycloheptylmethyl group, 1-ethylcyclo Heptylmethyl group, 2-ethylcycloheptylmethyl group, 3-ethylcycloheptylmethyl group, 4-ethylcycloheptylmethyl group, 2-cycloheptylethyl group, 2- (1-methylcycloheptyl) ethyl group, 2-
(2-methylcycloheptyl) ethyl group, 2- (3-methylcycloheptyl) ethyl group, 2- (4-methylcycloheptyl) ethyl group, 2- (1-ethylcycloheptyl) ethyl group, 2- (2 -Ethylcycloheptyl) ethyl group, 2- (3-ethylcycloheptyl) ethyl group, 2
-(4-ethylcycloheptyl) ethyl group, 1-methylcyclooctylmethyl group, 2-methylcyclooctylmethyl group, 3-methylcyclooctylmethyl group, 4-methylcyclooctylmethyl group, 5-methylcyclooctylmethyl group , 1-ethylcyclooctylmethyl group, 2-ethylcyclooctylmethyl group, 3-ethylcyclooctylmethyl group, 4-ethylcyclooctylmethyl group, 5-
Ethylcyclooctylmethyl group, 2- (1-methylcyclooctyl) ethyl group, 2- (2-methylcyclooctyl) ethyl group, 2- (3-methylcyclooctyl) ethyl group, 2- (4-methylcyclooctyl) ) Ethyl group, 2
-(5-methylcyclooctyl) ethyl group, 2- (1-
Ethylcyclooctyl) ethyl group, 2- (2-ethylcyclooctyl) ethyl group, 2- (3-ethylcyclooctyl) ethyl group, 2- (4-ethylcyclooctyl) ethyl group, 2- (5-ethylcyclo Octyl) ethyl group,
1-fluoro-1-cyclohexylmethyl group, 2-fluorocyclohexylmethyl group, 3-fluorocyclohexylmethyl group, 4-fluorocyclohexylmethyl group,
1,1-difluoro-1-cyclohexylmethyl group,
2,2 difluorocyclohexylmethyl group, 3,3 difluorocyclohexylmethyl group, 4,4 difluorocyclohexylmethyl group, 1-fluoro-1-cycloheptylmethyl group, 2-fluorocycloheptylmethyl group, 3-fluorocycloheptylmethyl Group, 4-fluorocycloheptylmethyl group, 1,1 difluoro-1-cycloheptylmethyl group, 2,2 difluorocycloheptylmethyl group, 3,3 difluorocycloheptylmethyl group, 4,4 difluorocycloheptylmethyl group ,
1-fluoro-1- (3-methylcyclohexyl) methyl group, 2-fluoro-3-methylcyclohexylmethyl group, 3-fluoro-3-methylcyclohexylmethyl group, 4-fluoro-3-methylcyclohexylmethyl group, 1,1-difluoro-1- (3-methyl Cyclohexyl) methyl group, 2,2-difluoro-3-methylcyclohexylmethyl group, 3-trifluoromethylcyclohexylmethyl group, 4,4-difluoro-3-methylcyclohexylmethyl group, 1-fluoro-2-cyclopentylethyl group, 2- (2-fluoro A cyclopentyl) ethyl group, a 2- (3-fluorocyclopentyl) ethyl group,
1,1-difluoro-2-cyclopentylethyl group, 2
-(2,2 difluorocyclopentyl) ethyl group, 2
-(3,3 difluorocyclopentyl) ethyl group,
1,1 difluoro-2- (2,2 difluorocyclopentyl) ethyl group, 1,1 difluoro-2- (3,
An unsubstituted or fluorine-substituted cycloalkylalkyl group in which any hydrogen atom on a cycloalkyl ring such as a 3-difluorocyclopentyl) ethyl group may be substituted with a lower alkyl; a cyclopropylideneethyl group, a cyclopropylidenepropyl group , Cyclopropylidenebutyl, cyclopropylidenepentyl, cyclobutylideneethyl, cyclobutylidenepropyl, cyclobutylidenebutyl, cyclobutylidenepentyl, cyclopentylideneethyl, cyclopentylidenepropyl, cyclopropyl Pentylidenebutyl, cyclopentylidenepentyl, cyclohexylideneethyl, cyclohexylidenepropyl, cyclohexylidenebutyl, cyclohexylidenepentyl, cycloheptylideneethyl, cycloheptylidene A pill group, a cycloheptylidenebutyl group, a cycloheptylidenepentyl group, a cyclooctylideneethyl group, a cyclooctylidenepropyl group, a cyclooctylidenebutyl group, a cyclooctylidenepentyl group, and any one to six thereof. A cycloalkylidenealkyl group in which a hydrogen atom of the above is substituted by a fluorine atom; a cyclopropylpropenyl group, a cyclopropylbutenyl group, a cyclopropylpentenyl group in which any hydrogen atom on the cycloalkyl ring may be substituted by a lower alkyl group , Cyclopropylhexenyl group, cyclopropylheptenyl group,
Cyclobutylpropenyl group, cyclobutylbutenyl group,
Cyclobutylpentenyl group, cyclopentylpropenyl group, cyclopentylbutenyl group, cyclopentylpentenyl group, cyclohexylpropenyl group, cyclohexylbutenyl group, cyclohexylpentenyl group, cycloheptylpropenyl group, cyclooctylpropenyl group, and any 1 to 6 of these; A cycloalkylalkenyl group in which a hydrogen atom of the above is substituted with a fluorine atom; a cyclopropylpropynyl group, a cyclopropylbutynyl group or a cyclopropylpentynyl in which any hydrogen atom on the cycloalkyl ring may be substituted with a lower alkyl group Group, cyclopropylhexynyl, cyclopropylheptynyl, cyclobutylpropynyl, cyclobutylbutynyl, cyclobutylpentynyl, cyclopentylpropynyl, cyclopentylbutynyl Group, cyclopentyl pentynyl group,
Cyclohexylpropynyl group, cyclohexylbutynyl group, cyclohexylpentynyl group and the like and a cycloalkylalkynyl group in which 1 to 6 hydrogen atoms are substituted with a fluorine atom; cyclopropenylethyl group, cyclopropenylpropyl group, cyclopropenyl Butyl, cyclopropenylpentyl, cyclopropenylhexyl, cyclopropenylheptyl, cyclobutenylmethyl, cyclobutenylethyl, cyclobutenylpropyl, cyclopentenylmethyl, cyclohexenylmethyl, cyclohexenylethyl , Cycloheptenylmethyl group, cycloheptenylethyl group, cyclooctenylmethyl group, cyclooctenylethyl group, (1-methyl-2-cyclopentenyl) methyl group, (1-methyl-3
-Cyclopentenyl) methyl group, (2-methyl-1-cyclopentenyl) methyl group, (2-methyl-2-cyclopentenyl) methyl group, (2-methyl-3-cyclopentenyl) methyl group, (5-methyl -2-cyclopentenyl) methyl group, (5-methyl-1-cyclopentenyl)
A methyl group, a (3-methyl-1-cyclopentenyl) methyl group, a (3-methyl-2-cyclopentenyl) methyl group, a (3-methyl-3-cyclopentenyl) methyl group,
(4-methyl-2-cyclopentenyl) methyl group, (4
-Methyl-1-cyclopentenyl) methyl group, (1-methyl-2-cyclohexenyl) methyl group, (1-methyl-3-cyclohexenyl) methyl group, (2-methyl-1
-Cyclohexenyl) methyl group, (2-methyl-2-cyclohexenyl) methyl group, (2-methyl-3-cyclohexenyl) methyl group, (6-methyl-3-cyclohexenyl) methyl group, (6-methyl -2-cyclohexenyl) methyl group, (6-methyl-1-cyclohexenyl)
A methyl group, a (3-methyl-1-cyclohexenyl) methyl group, a (3-methyl-2-cyclohexenyl) methyl group, a (3-methyl-3-cyclohexenyl) methyl group,
(5-methyl-3-cyclohexenyl) methyl group, (5
-Methyl-2-cyclohexenyl) methyl group, (5-methyl-1-cyclohexenyl) methyl group, (4-methyl-1-cyclohexenyl) methyl group, (4-methyl-2
-Cyclohexenyl) methyl group, (4-methyl-3-cyclohexenyl) methyl group, (1-methyl-2-cycloheptenyl) methyl group, (1-methyl-3-cycloheptenyl) methyl group, (1-methyl-4 -Cycloheptenyl) methyl group, (2-methyl-1-cycloheptenyl)
A methyl group, a (2-methyl-2-cycloheptenyl) methyl group, a (2-methyl-3-cycloheptenyl) methyl group, a (2-methyl-4-cycloheptenyl) methyl group,
(7-methyl-3-cycloheptenyl) methyl group, (7
-Methyl-2-cycloheptenyl) methyl group, (7-methyl-1-cycloheptenyl) methyl group, (3-methyl-1-cycloheptenyl) methyl group, (3-methyl-2
-Cycloheptenyl) methyl group, (3-methyl-3-cycloheptenyl) methyl group, (3-methyl-4-cycloheptenyl) methyl group, (6-methyl-3-cycloheptenyl) methyl group, (6-methyl-2-cycloheptenyl) ) Methyl group, (6-methyl-1-cycloheptenyl)
A methyl group, a (4-methyl-1-cycloheptenyl) methyl group, a (4-methyl-2-cycloheptenyl) methyl group, a (4-methyl-3-cycloheptenyl) methyl group,
(4-methyl-4-cycloheptenyl) methyl group, (5
-Methyl-3-cycloheptenyl) methyl group, (5-methyl-2-cycloheptenyl) methyl group, (5-methyl-1-cycloheptenyl) methyl group, (1-methyl-2
-Cyclooctenyl) methyl group, (1-methyl-3-cyclooctenyl) methyl group, (1-methyl-4-cyclooctenyl) methyl group, (2-methyl-1-cyclooctenyl) methyl group, (2-methyl-2-cyclooctenyl) ) Methyl group, (2-methyl-3-cyclooctenyl)
A methyl group, a (2-methyl-4-cyclooctenyl) methyl group, a (8-methyl-4-cyclooctenyl) methyl group, a (8-methyl-3-cyclooctenyl) methyl group,
(8-methyl-2-cyclooctenyl) methyl group, (8
-Methyl-1-cyclooctenyl) methyl group, (3-methyl-1-cyclooctenyl) methyl group, (3-methyl-2-cyclooctenyl) methyl group, (3-methyl-3
-Cyclooctenyl) methyl group, (3-methyl-4-cyclooctenyl) methyl group, (7-methyl-4-cyclooctenyl) methyl group, (7-methyl-3-cyclooctenyl) methyl group, (7-methyl-2-cyclooctenyl) ) Methyl group, (7-methyl-1-cyclooctenyl)
A methyl group, a (4-methyl-1-cyclooctenyl) methyl group, a (4-methyl-2-cyclooctenyl) methyl group, a (4-methyl-3-cyclooctenyl) methyl group,
(4-methyl-4-cyclooctenyl) methyl group, (6
-Methyl-4-cyclooctenyl) methyl group, (6-methyl-2-cyclooctenyl) methyl group, (6-methyl-1-cyclooctenyl) methyl group, (5-methyl-1
-Cyclooctenyl) methyl group, (5-methyl-2-cyclooctenyl) methyl group, (5-methyl-3-cyclooctenyl) methyl group, (5-methyl-4-cyclooctenyl) methyl group, and any of these 1-6 A hydrogen atom on a cycloalkenyl ring in which two hydrogen atoms have been replaced with a fluorine atom, a cycloalkyl group optionally substituted with a lower alkyl; a hydrogen atom on the cycloalkenyl ring is substituted with a lower alkyl group Cyclopropenylpropenyl group, cyclopropenylbutenyl group, cyclobutenylbutenyl group, cyclopentenylpropenyl group, cyclopentenylbutenyl group, cyclopropenylpentenyl group, cyclopropenylhexenyl group, cyclopropenylheptenyl group, which may be Cyclobutenylpropenyl group, cyclo Hexenyl Le propenyl group, cyclohexenyl butenyl group and cycloalkenyl cycloalkenyl group such as 1 to 6 hydrogen atoms of these optional is substituted with a fluorine atom.

An aralkyl group (arbitrary 1 to 3 hydrogen atoms on the ring of the aralkyl group may be a lower alkyl group, a trifluoromethyl group, a cyano group, a hydroxyl group, a nitro group, a lower alkoxycarbonyl group, a halogen atom, a lower May be substituted with an alkoxy group, an amino group or a lower alkylamino group.)) "Is an unsubstituted or substituted carbon atom having 7-1.
It means two aralkyl groups and includes, for example, a benzyl group, a phenethyl group, a phenylpropyl group, a naphthylmethyl group and the like, which are unsubstituted or substituted with the above substituents.

An arylalkenyl group (arbitrary 1 to 3 hydrogen atoms on the ring of the arylalkenyl group may be a lower alkyl group, a trifluoromethyl group, a cyano group, a hydroxyl group, a nitro group, a lower alkoxycarbonyl group, a halogen atom ,
It may be substituted with a lower alkoxy group, an amino group or a lower alkylamino group. ) "Means an unsubstituted or substituted arylalkenyl group having 8 to 12 carbon atoms,
For example, there may be mentioned a phenylpropenyl group, a naphthylpropenyl group and the like, which are unsubstituted or substituted with the above substituents.

A heteroarylalkyl group having one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (an arbitrary one to three hydrogen atoms on the ring of the heteroarylalkyl group) May be substituted with a lower alkyl group, a trifluoromethyl group, a cyano group, a hydroxyl group, a nitro group, a lower alkoxycarbonyl group, a halogen atom, a lower alkoxy group, an amino group or a lower alkylamino group.) For example, a 2-pyridylmethyl group, a 3-pyridylmethyl group, a 4-pyridylmethyl group, a 2-thiazolylmethyl group, a 4-thiazolylmethyl group, a 2-thienylmethyl group, an unsubstituted or substituted with the above substituents,
3-thienylmethyl group, 1-imidazolylmethyl group, 2
-Imidazolylmethyl group, 2-imidazolylmethyl group,
4-imidarylmethyl group, 3-pyrazolylmethyl group, 4
-Pyrazolylmethyl group, 2-furylmethyl group, 3-furylmethyl group, 2-pyrrolylmethyl group, 3-pyrrolylmethyl group, 2-pyrimidinylmethyl group, 4-pyrimidinylmethyl group, 5-pyrimidinylmethyl group, pyrazinylmethyl group, 3- Pyridazinylmethyl group, 4-pyridazinylmethyl group, 3-quinolylmethyl group, 4-quinolylmethyl group,
5-quinolylmethyl group, 6-quinolylmethyl group, 7-quinolylmethyl group, 8-quinolylmethyl group, 1-isoquinolylmethyl group, 3-isoquinolylmethyl group, 4-isoquinolylmethyl group, 5-isoquinolylmethyl Group, 6-isoquinolylmethyl group, 7-isoquinolylmethyl group, 8-isoquinolylmethyl group, 2-benzothienylmethyl group, 3
-Benzothienylmethyl group, 4-benzothienylmethyl group, 5-benzothienylmethyl group, 6-benzothienylmethyl group, 7-benzothienylmethyl group, 2-indolylmethyl group, 3-indolylmethyl group, 4- Indolylmethyl group, 5-indolylmethyl group, 6-indolylmethyl group, 7-indolylmethyl group, 2-benzimidazolylmethyl group, 4-benzimidazolylmethyl group, 5-
Benzimidazolylmethyl group, 2-benzothiazolylmethyl group, 4-benzothiazolylmethyl group, 5-benzothiazolylmethyl group, 6-benzothiazolylmethyl group, 7
-Benzothiazolylmethyl group, 2-benzooxazolylmethyl group, 4-benzooxazolylmethyl group, 5-benzooxazolylmethyl group, 6-benzooxazolylmethyl group, 7-benzoxazolyl group Methyl group, 2-benzofuranylmethyl group, 3-benzofuranylmethyl group, 4-benzofuranylmethyl group, 5-benzofuranylmethyl group,
6-benzofuranylmethyl group, 7-benzofuranylmethyl group, 2-pyridylethyl group, 2-pyridylpropyl group, 3-pyridylethyl group, 4-pyridylethyl group, 2
-Thiazolylethyl group, 2-thienylethyl group, 3-thienylethyl group, 1-imidazolylethyl group, 2-imidazolylethyl group, 3-pyrazolylethyl group, 4-pyrazolylethyl group, 2-furylethyl group, 3-furylethyl Group, 2-pyrrolylethyl group, 3-pyrrolylethyl group,
2-pyrimidinylethyl group, 4-pyrimidinylethyl group, 5-pyrimidinylethyl group, pyrazinylethyl group,
3-pyridazinylethyl group, 4-pyridazinylethyl group, 2-quinidylethyl group, 2-benzothienylethyl group, 3-benzothienylethyl group, 4-benzothienylethyl group, 5-benzothienylethyl group 6-benzothienylethyl group, 7-benzothienylethyl group, 2-indolylethyl group, 3-indolylethyl group, 4-indolylethyl group, 5-indolylethyl group, 6-indolylethyl group, 7-indolylethyl group, 2-benzimidazolylethyl group, 4-benzimidazolylethyl group, 5-benzimidazolylethyl group, 2-benzothiazolylethyl group, 4-benzothiazolylethyl group, 5-
Benzothiazolylethyl group, 6-benzothiazolylethyl group, 7-benzothiazolylethyl group, 2-benzooxazolylethyl group, 4-benzooxazolylethyl group,
5-benzoxazolylethyl group, 6-benzoxazolylethyl group, 7-benzoxazolylethyl group, 2-
Examples include a benzofuranylethyl group, a 3-benzofuranylethyl group, a 4-benzofuranylethyl group, a 5-benzofuranylethyl group, a 6-benzofuranylethyl group, and a 7-benzofuranylethyl group. it can.

A heteroarylalkenyl group having one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (an arbitrary one to three hydrogen atoms on the ring of the heteroarylalkenyl group) Is a lower alkyl group,
Trifluoromethyl group, cyano group, hydroxyl group, nitro group,
It may be substituted with a lower alkoxycarbonyl group, a halogen atom, a lower alkoxy group, an amino group or a lower alkylamino group. ) "Means, for example, a 2-pyridylpropenyl group, a 3-pyridylpropenyl group, a 4-pyridylpropenyl group, a 2-thiazolylpropenyl group, a 2-thienylpropenyl group, an unsubstituted or substituted with the above-mentioned substituents.
-Thienylpropenyl group, 1-imidazolylbutenyl group, 2-imidazolylpropenyl group, 3-pyrazolylpropenyl group, 4-pyrazolylpropenyl group, 2-furylpropenyl group, 3-furylpropenyl group, 2-pyrrolylpropenyl group, 3 -A pyrrolylpropenyl group, a 2-pyrimidinylpropenyl group, a 4-pyrimidinylpropenyl group,
5-pyrimidinylpropenyl group, pyrazinylpropenyl group, 3-pyridazinylpropenyl group, 4-pyridazinylpropenyl group, 2-quinidylpropenyl group, 2-benzothienylpropenyl group or 2-indolylpropenyl group And the like.

The term "halogen" includes fluorine, chlorine, bromine and iodine.

The term "lower alkyl group" refers to a group having 1 to 1 carbon atoms.
Represents six linear or branched alkyl groups, for example,
Examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, a pentyl group, an isopentyl group, a hexyl group, and an isohexyl group.

The term "lower alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy. Group, isobutoxy group, t-butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group or isohexyloxy group.

The term "lower alkoxycarbonyl group" means a linear or branched alkoxycarbonyl group having 1 to 7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Butoxycarbonyl group, sec-butoxycarbonyl group, isobutoxycarbonyl group, t-
Butoxycarbonyl group, pentyloxycarbonyl group,
Examples thereof include an isopentyloxycarbonyl group, a hexyloxycarbonyl group, and an isohexyloxycarbonyl group.

The “aralkyloxycarbonyl group” is
It means an aralkyloxycarbonyl group having 7 to 10 carbon atoms, such as a benzyloxycarbonyl group and a phenethyloxycarbonyl group.

The term "lower alkylamino group" represents a linear or branched alkylamino group having 1 to 6 carbon atoms, such as methylamino, ethylamino, propylamino, isopropylamino, Butylamino group,
Examples thereof include a sec-butylamino group, a t-butylamino group, a pentylamino group, an isopentylamino group, a hexylamino group, an isohexylamino group, a dimethylamino group, a diethylamino group, and a dipropylamino group.

The term "protected hydroxyl group" means an acyl group such as an acetyl group, an alkylsilyl group such as a trimethylsilyl group and a t-butyldimethylsilyl group, an aralkyl group such as a benzyl group and a trityl group, and an ether group such as a methoxymethyl group. Group, a hydroxy group protected in the form of an alkylidene ketal such as isopropylidene ketal.

The term "protected oxo group" means an oxo group protected in the form of an acetal such as ethylene ketal, trimethylene ketal, dimethyl ketal, or a ketal.

The term "protected amino group or lower alkylamino group" means, for example, an aralkyl group such as a benzyl group, a p-methoxybenzyl group, a p-nitrobenzyl group, a benzhydryl group or a trityl group; Alkenyl groups such as phenylacetyl group and phenoxyacetyl group; lower alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, isobutoxycarbonyl group and t-butoxycarbonyl group; An alkenyloxycarbonyl group such as a 2-propenyloxycarbonyl group; an aralkyloxycarbonyl group such as a benzyloxycarbonyl group and a p-nitrobenzyloxycarbonyl group; a trimethylsilyl group;
means an amino group or a lower alkylamino group protected with a lower alkylsilyl group such as a t-butyldimethylsilyl group; particularly, an amino group or a lower alkylamino group protected with a t-butoxycarbonyl group or a benzyloxycarbonyl group; Groups are preferred. The term "deprotection" means removal of a protecting group by, for example, hydrolysis or hydrogenolysis, which is usually used in the field of organic chemistry. In the general formula [I], (1) Ar is an aryl group or a heteroaryl group having one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (the aryl group) And any one to three hydrogen atoms on the ring of the heteroaryl group are a lower alkyl group, a trifluoromethyl group, a cyano group, a hydroxyl group, a nitro group, a lower alkoxycarbonyl group, a halogen atom, a lower alkoxy group, an amino group Or a phenyl group which may be unsubstituted or substituted with the above substituent. (2) R ¹ represents a cycloalkyl group having 3 to 6 carbon atoms which may have ¹ to 4 fluorine atoms on a ring, and among them, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and 2-fluorocyclo Butyl group, 3-fluorocyclobutyl group, 2,2-difluorocyclobutyl group, 3,3
Difluorocyclobutyl group, 2-fluorocyclopentyl group, 3-fluorocyclopentyl group, 2,2 difluorocyclopentyl group, 3,3 difluorocyclopentyl group, 2,2,3,3-tetrafluorocyclopentyl group, 3,3 , 4,4-tetrafluorocyclopentyl, 2-fluorocyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl, 2,
A 2-difluorocyclohexyl group, a 3,3-difluorocyclohexyl group, and a 4,4-difluorocyclohexyl group are preferred.

Further, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 2-fluorocyclopentyl, 3-fluorocyclopentyl, and 2,2-difluorocyclopentyl group, 3,3-difluorocyclopentyl group, 2,2,3,3-tetrafluorocyclopentyl group, 3,3,4,4-tetrafluorocyclopentyl group, 2-fluorocyclohexyl group, 3-fluoro Cyclohexyl group, 4-fluorocyclohexyl group, 2,2-difluorocyclohexyl group,
A 3,3 difluorocyclohexyl group and a 4,4 difluorocyclohexyl group are preferred, and a 3,3 difluorocyclopentyl group is particularly preferred. (3) X represents O or NH, and among them, NH is preferable. (4) R ² is a saturated or unsaturated aliphatic hydrocarbon group having 5 to 15 carbon atoms, in which any 1 to 6 hydrogen atoms may be substituted by a fluorine atom, an aralkyl group, an arylalkenyl group or A heteroarylalkyl group or a heteroarylalkenyl group having one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (the aralkyl group, the arylalkenyl group, the heteroarylalkyl group and the heteroarylalkenyl group); Any 1 to 3 hydrogen atoms on the ring are a lower alkyl group, trifluoromethyl group, cyano group, hydroxyl group, nitro group, lower alkoxycarbonyl group, halogen atom, lower alkoxy group, amino group or lower alkylamino group In which 1 to 6 hydrogen atoms are replaced by fluorine atoms. Also a good following formula have been [II]

[0029]

Embedded image [In the formula, Q represents a methylene group, an ethylene group, a trimethylene group or a tetramethylene group, and R ^a and R ^c each represent a hydrogen atom, or R ^a and R ^c together form a single bond. And R ^b , R ^d and R ^e are the same or different and each represent a hydrogen atom, a lower alkyl group or
Or represents 8 amino cycloalkyl group or cycloalkenyl group, or R ^b and R ^d, or R ^d and R ^e are each taken together form a number of 3 to 8 cycloalkyl group or cycloalkenyl group having a carbon I do. A benzyl group, a phenethyl group, a phenylpropyl group, a phenylpropenyl group or a 2-pyridylmethyl group, a 2-pyridylethyl group, a 2-pyridylpropyl group, a 3-pyridylmethyl group, a 4-pyridylmethyl group; 2-thiazolylmethyl group,
2-thienylmethyl group, 3-thienylmethyl group, 1-imidazolylmethyl group, 2-imidazolylmethyl group, 4-
Imidazolylmethyl group, 2-furylmethyl group, 3-furylmethyl group, 2-pyrrolylmethyl group, 3-pyrrolylmethyl group (provided that the benzyl group, phenethyl group, phenylpropyl group, phenylpropenyl group and heteroarylalkyl group Any one to three hydrogen atoms are a lower alkyl group, a trifluoromethyl group, a cyano group, a hydroxyl group, a nitro group, a lower alkoxycarbonyl group, a halogen atom,
It may be substituted with a lower alkoxy group, an amino group or a lower alkylamino group. ) Is preferred.

Further, a 2-thienylmethyl group, 3-thienylmethyl group, 2-furylmethyl group, 3-furylmethyl group, 2-pyridylmethyl group or benzyl group (provided that the thienylmethyl group, furylmethyl group, Any one to three hydrogen atoms on the ring of the pyridylmethyl group and the benzyl group may be a lower alkyl group, a trifluoromethyl group, a cyano group, a hydroxyl group, a nitro group, a lower alkoxycarbonyl group, a halogen atom, an amino group, a lower alkyl group. Which may be substituted with an amino group or a lower alkoxy group.)
An -aminopyridin-2-ylmethyl group is preferred.

The compound of the present invention may exist in stereoisomers such as optical isomers, diastereoisomers, and geometric isomers depending on the mode of substitution. It also includes the body and mixtures thereof.

The compounds of the present invention can also exist in the form of pharmaceutically acceptable salts, such as hydrochloride, sulfate, nitrate, phosphate, perchlorate Inorganic salts such as acid salts; organic carboxylate salts such as maleate, fumarate, succinate, tartrate, citrate, ascorbate; methanesulfonate, isethionate, benzenesulfonate And organic sulfonates such as p-toluenesulfonate.

The compound of the general formula [I] of the present invention can be prepared by, for example, (a)

[0034]

Embedded image Wherein Ar is an aryl group or a heteroaryl group having 1-2 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (a ring of the aryl group and the heteroaryl group) The optional 1 to 3 hydrogen atoms above are a lower alkyl group, a trifluoromethyl group, a cyano group, a hydroxyl group, a nitro group, a lower alkoxycarbonyl group, a halogen atom,
It may be substituted with a lower alkoxy group, an amino group or a lower alkylamino group. ) Wherein R ¹⁰ is any 1 to
A cycloalkyl group having 3 to 6 carbon atoms which may be substituted with 4 hydrogen atoms by a fluorine atom, or a 3 to 6 carbon atom having 1 to 2 unprotected or protected hydroxyl or oxo groups; Represents a cycloalkyl group. A carboxylic acid represented by the general formula [IV]

[0035]

Embedded image [Wherein, R ²⁰ represents a saturated or unsaturated aliphatic hydrocarbon group having 5 to 15 carbon atoms, in which any 1 to 6 hydrogen atoms may be substituted with a fluorine atom, an unprotected or protected 5 to 1 carbon atoms having 1 to 2 hydroxyl groups or oxo groups
5 saturated or unsaturated aliphatic hydrocarbon groups, aralkyl groups, arylalkenyl groups or heteroarylalkyl groups having 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur An arylalkenyl group (provided that any one to three hydrogen atoms on the ring of the aralkyl group, the arylalkenyl group, the heteroarylalkyl group, and the heteroarylalkenyl group are a lower alkyl group, a trifluoromethyl group, a cyano group, a hydroxyl group, , Nitro group, lower alkoxycarbonyl group,
It may be substituted with a halogen atom, a lower alkoxy group, an unprotected or protected amino group, an unprotected or protected lower alkylamino group or an aralkyloxycarbonyl group. ) And X represents NH or O. When R ¹⁰ or R ²⁰ has one or two unprotected or protected hydroxyl groups or oxo groups, the hydroxyl group or Converting an oxo group to a fluorine atom,
In the case of having a protected amino group or a protected lower alkylamino group, the protecting group is removed, and in the case of having a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, a conversion reaction to an amino group is performed, or (b) The carboxylic acid of the general formula [III] or a reactive derivative thereof is converted to a compound of the general formula [V]

[0036]

Embedded image [Wherein, E represents an imino group-protecting group, and X has the above-mentioned meaning] or a salt thereof, and obtained by the general formula [VI]

[0037]

Embedded image [Wherein, Ar, R ¹⁰ , X and E have the above-mentioned meanings]
After deprotection of the compound represented by the general formula [VII]

[0038]

Embedded image [Wherein L represents a leaving group, and R ²⁰ has the above-mentioned meaning], and if necessary, in the presence of a base. ¹⁰ and R ²⁰ are converted, or (c) the above general formula [V
After deprotection of the compound of formula I], the compound of the general formula [VIII]

[0039]

Embedded image [Wherein, R ²¹ is a saturated or unsaturated aliphatic hydrocarbon group having 4 to 14 carbon atoms, in which arbitrary 1 to 6 hydrogen atoms may be substituted with a fluorine atom, unprotected or protected 4 to 1 carbon atoms having 1 to 2 hydroxyl groups or oxo groups
1 to 4 saturated or unsaturated aliphatic hydrocarbon groups, aryl groups, aralkyl groups, arylalkenyl groups or nitrogen, oxygen and sulfur atoms
A heteroaryl group, a heteroarylalkyl group, or a heteroarylalkenyl group having two heteroatoms (provided that the aryl, aralkyl, arylalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl groups Any of 1-3
Hydrogen atoms are lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, unprotected or protected amino, unprotected or protected lower It may be substituted with an alkylamino group or an aralkyloxycarbonyl group. ). Compounds represented by] and subjected to reductive alkylation reactions, and can be produced by performing conversion reaction of R ¹⁰ and R ²¹ similar to the above as necessary.

In the above formula [VII], the "leaving group" represented by L includes, for example, a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; an alkylsulfonyloxy group such as a methanesulfonyloxy group; and an arylsulfonyloxy group such as a p-toluenesulfonyloxy group.

In the above formulas [V] and [VI], the term "protecting group for imino group" represented by E means the same protecting group as the above-mentioned protecting group for amino group.

In the production step (a), the compound represented by the formula [II]
The carboxylic acid of the formula [IV] is reacted with a compound of the formula [IV] or a salt thereof in the presence of a suitable condensing agent to obtain a compound of the following general formula [IX]

[0043]

Embedded image [Wherein Ar, R ¹⁰ , X and R ²⁰ have the above-mentioned meanings].

In the above-mentioned condensation reaction, the carboxylic acid of the formula [III] used as a starting material can be produced, for example, by the method described in the following Reference Examples.

Examples of the condensing agent used in the above reaction include N, N'-dicyclohexylcarbodiimide and 1-N-N-dicyclohexylcarbodiimide which are commonly used in the field of organic synthetic chemistry in the condensation reaction between a carboxyl group and a hydroxyl group or an amino group. Ethyl-3- (3-dimethylaminopropyl)
Carbodiimide, diphenylphosphoryl azide, dipyridyl disulfide-triphenylphosphine and the like are mentioned, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide is particularly preferred.

The amount of these condensing agents is not strictly limited, but is usually in the range of 1 to 5 equivalents, especially 1 to 2 equivalents, per 1 mol of the compound of the formula [III]. it can.

The condensation reaction can be carried out, if necessary, in the presence of a base. Examples of usable bases include aliphatic tertiary amines such as triethylamine and diisopropylethylamine; pyridine; Examples thereof include aromatic amines such as dimethylaminopyridine and quinoline, and 4-dimethylaminopyridine is particularly preferable.

The condensation reaction is preferably performed in an inert solvent. Examples of such an inert organic solvent include diethyl ether, tetrahydrofuran, N, N-
Dimethylformamide, dioxane, benzene, toluene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, or a mixture of the above solvents, especially diethyl ether,
Tetrahydrofuran, N, N-dimethylformamide,
Dioxane is preferred.

The reaction temperature can be generally from -70 ° C to the boiling point of the solvent used in the reaction, preferably from -20 ° C to 100 ° C.
It can be completed in 5 minutes to 7 days, preferably in 10 minutes to 24 hours.

Formula [IV] for the compound of formula [III]
The use ratio of the compound of the formula (I) or a salt thereof is not strictly limited, and can be changed according to the kind of the compound and the reaction conditions to be used. IV] or a salt thereof,
It can be used in the range of -5 mol, preferably 1-2 mol.

The coupling compound of the formula [IX] can also be obtained by converting a carboxylic acid of the formula [III] into a reactive derivative and then condensing it with a compound of the formula [IV] or a salt thereof. it can.

The reactive derivative of the carboxylic acid of the formula [III] includes, for example, mixed acid anhydrides which are commonly used in the field of organic synthetic chemistry for the activation of carboxyl groups in esterification or amidation reactions, for example, Active ester,
Active amide and the like.

The mixed acid anhydride of the carboxylic acid of the formula [III] can be obtained by converting a carboxylic acid of the formula [III] into an alkyl chlorocarbonate such as ethyl chlorocarbonate; The active ester can be obtained by reacting a carboxylic acid of the formula [III] according to a conventional method.
For example, N, N'-dicyclohexylcarbodiimide, 1
In the presence of a condensing agent such as -ethyl-3- (3-dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyl disulfide-triphenylphosphine, for example, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole and the like N-hydroxy compounds; 4-nitrophenol,
The amide can be reacted with a phenol compound such as 2,4-dinitrophenol, 2,4,5-trichlorophenol, pentachlorophenol and the like. ,
It can be obtained by reacting with 1′-carbonyldiimidazole, 1,1′-carbonylbis (2-methylimidazole) and the like.

The condensation reaction between the reactive derivative of the carboxylic acid of the formula [III] and the compound of the formula [IV] or a salt thereof is preferably carried out in an inert solvent. For example, diethyl ether, tetrahydrofuran, N, N-dimethylformamide, dioxane, benzene, toluene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene or a mixture of the above-mentioned solvents can be mentioned. In particular, diethyl ether, chloroform, tetrahydrofuran , N, N-dimethylformamide, dioxane and the like are preferred.

The reaction temperature can be generally from -70 ° C to the boiling point of the solvent used in the reaction, preferably from -20 ° C to 100 ° C.

The ratio of the compound of the formula [IV] or a salt thereof to the reactive derivative of the carboxylic acid of the formula [III] is not strictly limited, and varies depending on the type of the reactive derivative. But typically have the formula [II
Per mole of the reactive derivative of the carboxylic acid of formula [I]
V] or a salt thereof is 1 to 5 mol, preferably 1 to 5 mol.
It can be used within a range of 2 moles.

In the condensed compound represented by the general formula [IX],
When R ¹⁰ is an unprotected or protected 1 to 2 hydroxy group or a cycloalkyl group having 3 to 6 carbon atoms having an oxo group, or R ²⁰ is an unprotected or protected 1 to 2 hydroxy group or In the case of an aliphatic hydrocarbon group having an oxo group, the hydroxyl group or the oxo group is converted into a fluorine atom as it is or by removing the protecting group.

For example, the removal of the protecting group from the hydroxyl group and the oxo group protected in the form of a ketal in the compound of the formula [IX] is usually carried out in an aqueous solvent using an inorganic acid, an organic acid, a weak acid salt or the like. Examples of the inorganic acid include hydrochloric acid and sulfuric acid, and examples of the organic acid include paratoluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, and acetic acid. As the salt, for example, ammonium chloride, pyridinium
P-toluenesulfonate; As the hydrated solvent, hydrated methanol, hydrated ethanol, hydrated tetrahydrofuran, hydrated dioxane and the like are preferable. The reaction is usually carried out at 0 ° C. to 100 ° C., preferably at room temperature to 80 equivalents, using a catalytic amount to 5 equivalents, preferably a catalytic amount to 1 equivalent of the acid or salt.
It can be performed at a temperature of ° C.

The conversion of the hydroxyl group or oxo group to a fluorine atom is usually carried out in an inert solvent which does not adversely affect the reaction of, for example, methylene chloride, chloroform, tetrahydrofuran, methanol, acetonitrile, dimethylsulfoxide, pyridine or the like. In the absence, for example, fluorine such as sulfur tetrafluoride, diethylaminosulfuric acid, cesium fluoride, cesium fluoride, tetrabutylammonium fluoride, tris (dimethylamino) sulfonium difluorotrimethylsilicate, hydrogen fluoride, and tosyl fluoride 1 agent
The reaction can be carried out by using an equivalent to excess amount, preferably 1 to 2 equivalents, and preferably in the range of -80 ° C to 180 ° C for 10 minutes to 72 hours.

When R ²⁰ has a protected amino group or a protected lower alkylamino group in the compound represented by the general formula [IV] or [IX], the protecting group is removed if necessary. , Lower alkoxycarbonyl group or ally
If a ruoxycarbonyl group is present, appropriate functional group conversion to an amino group is performed. The removal of the amino protecting group can be carried out by a method known per se, for example, Protective Groups.
In Organic Synthesis (Protective
e Groups in Organic Synth
esis), T.M. W. Green (TW Green)
e) Author, John Wiley & Sons (198
1 year) etc., or a method equivalent thereto,
For example, it can be carried out by solvolysis using an acid or a base, chemical reduction using a metal hydride complex, catalytic reduction using a palladium-carbon catalyst, Raney nickel catalyst, or the like.

The solvolysis with an acid is usually carried out, for example, in an inert solvent such as methylene chloride, anisole, tetrahydrofuran, dioxane, methanol, ethanol or a mixed solvent thereof with water, or in the absence of a solvent. Using an acid such as formic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or the like, preferably at a temperature in the range of about 0 ° C to about 100 ° C,
It can be performed by treating for 0 minute to 24 hours.

The solvolysis with a base is usually carried out in an inert solvent which does not adversely affect the reaction of, for example, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or the like, or a mixed solvent thereof with water, for example, lithium hydroxide, hydroxide or the like. Alkali metal hydroxides such as sodium and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate;
It is performed by operating at a temperature in the range of 0 ° C. for 10 minutes to 24 hours.

The catalytic reduction is usually carried out, for example, with methanol,
Inert solvent such as tanol, water, acetic acid or a mixed solvent thereof
In, for example, palladium-carbon catalyst, palladium hydroxide,
Using a catalyst such as Raney nickel or platinum oxide catalyst,
About 1 to about 20 kg / cm ^TwoUnder the hydrogen pressure of
Or at a temperature in the range of about 0 ° C to about 40 ° C for 10 minutes to 24 hours.
This is carried out by catalytic reduction over time.

Conversion of a lower alkoxycarbonyl group or an aryloxycarbonyl group to an amino group can be carried out by reacting hydrazine to form an acid hydrazide and then forming an acid azide, or forming a carboxylic acid by hydrolysis to form an acid azide; Subsequently, transfer and hydrolysis can be performed.

In the production process (b), the condensation reaction between the carboxylic acid of the formula [III] or a reactive derivative thereof and the piperidine derivative of the formula [V] in the first step is carried out according to the formula [A] in the production process (a). It can be carried out in the same manner as in the condensation reaction of the carboxylic acid of III] or its reactive derivative with the compound of the formula [IV].

The above formula [V] obtained by this condensation reaction
The compound of I] is then freed of the protecting group for the imino group.

The removal of the imino protecting group from the compound of the formula [VI] can be carried out in the same manner as the removal of the amino protecting group.

The thus obtained general formula [X]

[0069]

Embedded image [Wherein, Ar, R ¹⁰ and X have the above-mentioned meanings. In the second step, the compound represented by the formula [VII] is reacted with a compound of the formula [VII], if necessary, in the presence of a base.

The reaction of the compound of the formula [X] with the compound of the formula [VII] is usually carried out in a suitable solvent in an approximately equimolar amount or in a slight excess of either one (for example, the compound 1 of the formula [X] It is carried out using a compound of the formula [VII] in a ratio of 1 to 1.3 mol per mol), but it is also possible to carry out using one of them in a large excess if necessary. Further, if necessary, the reaction can be carried out using a suitable base or a reaction aid.

As the solvent, for example, diethyl ether,
Ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; aprotic polar solvents such as dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, and hexamethylphosphoric triamide; And the like.

Examples of usable bases include: alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; for example, trimethylamine, triethylamine, N, N-diisopropyl Ethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DB
U), 1,5-diazabicyclo [4.3.0] nona-5
Tertiary aliphatic amines such as -ene (DBN); for example, aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline, and isoquinoline; preferable.

The reaction aids that can be used in the above reaction include:
Examples thereof include alkali metal iodides such as lithium iodide, sodium iodide, and potassium iodide, and potassium iodide is particularly preferred.

Usually, the reaction temperature is from about 0 ° C. to the boiling point of the solvent, and the reaction time can be from 10 minutes to 48 hours. It can also be used.

If necessary, the conversion reaction of R ¹⁰ and R ²⁰ described in the production step (a) is carried out.

Furthermore, the reductive alkylation reaction of the compound of the formula [X] with the aldehyde of the formula [VIII] according to the production step (c) is usually carried out in an inert solvent which does not adversely influence the reaction. Examples of the inert solvent include alcohols such as methanol and ethanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; and a mixed solvent thereof, particularly methanol. , Ethanol, tetrahydrofuran, toluene and the like are preferred.

The reaction temperature is usually about -30 ° C to about 200 ° C.
° C, preferably from about 0 ° C to about 100 ° C,
The reaction time can be generally from 10 minutes to 7 days, preferably from 10 minutes to 24 hours.

The above-mentioned reductive alkylation reaction is preferably carried out under weak acidity in which a Schiff base is easily formed.
Acids that can be used to adjust the pH include, for example, p-
Examples include toluenesulfonic acid, hydrochloric acid, acetic acid, and trifluoroacetic acid.

The reductive alkylation is carried out using, for example, a metal hydride complex such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride, or a palladium-carbon catalyst. It can be performed by catalytic reduction using a Raney nickel catalyst or the like, and is preferably performed using a metal hydride complex such as sodium borohydride or sodium cyanoborohydride. In particular, in the case where the reduction reaction is performed under weak acidity in which a Schiff base is easily generated, it is preferable to use sodium cyanoborohydride which is relatively stable under acidity.

When a metal hydride complex is used as the reducing agent, the amount of the reducing agent to be used is generally 1 mol to excess mol, preferably 1 to 10 mol, per 1 mol of the compound of the formula [X]. Can be.

If necessary, the conversion reaction of R ¹⁰ and R ²¹ described in the production step (a) is carried out.

The compound of the formula [I] obtained in the above-mentioned production steps (a), (b) and (c) can be obtained by a method known per se, for example, column chromatography using silica gel, an adsorption resin or the like, liquid chromatography Purification and isolation can be performed using conventional separation means such as chromatography, thin-layer chromatography, solvent extraction, or recrystallization / reprecipitation.

The compounds and intermediates of the present invention exist as stereoisomers such as enantiomers, diastereoisomers, and geometric isomers. However, the compounds of the present invention are in a stereoisomerically pure form. And mixtures thereof. Optical resolution in the case where the compounds and intermediates of the present invention are in a racemic form can be achieved by ordinary means such as high performance liquid chromatography using a chiral carrier or fractional crystallization of diastereomeric salts.

The compound of the general formula [I] obtained by the above method can be converted into a pharmaceutically acceptable salt by a conventional method, and conversely, the conversion of a salt to a free amine can be carried out according to a conventional method. Can be.

The compound of the formula [I] of the present invention has potent and selective muscarinic receptor binding inhibitory action and in vitro
and has a receptor antagonism in ro
o showed a strong and sustained bronchodilator effect.
Such effects of the compounds of the present invention are demonstrated by the following muscarinic receptor binding inhibition tests and various muscarinic receptor antagonistic tests. Muscarinic Receptor Binding Inhibition Test Hargreaves et al.'S method [B
r. J. Pharmacol. , 107, 494-5
01 (1992)]. That is,
M1-m5 muscarinic acetylcholine receptors expressed in CHO cells (Receptor Biolo)
gy), 0.2 nM [ ³ H] -N-methylscopolamine (84 Ci / mmol, New England)
Nuclear) and the test compound in 0.5 ml of 50
mM Tris-HCl, 10 mM MgCl ₂ , 1 mM E
Room temperature (about 20-25) in DTA solution (pH 7.4)
C)) and incubated for 120 minutes, followed by a glass filter (Packard Unifilter Plate GF /
The solution was suction-filtered in C) and washed four times with 1 ml of ice-cold Tris-HCl buffer. After the filter was dried at 50 ° C. for 1 hour, the radioactivity of [ ³ H] -N-methylscopolamine adsorbed on the filter by adding a scintillator (Packard micro scintillator 0) was measured with a microplate scintillation counter (Packard top count). The receptor non-specific binding of [ ³ H] -N-methylscopolamine was determined by adding 1 μM N-methylscopolamine. The binding affinity of the compounds of the present invention for muscarinic receptors was determined by Chen and Prusov (Che).
ng and Prusoff) [Bioche
m. Pharmacol. , Volume 22, 3099-310
8 (1973)], and is a labeled ligand [
^The dissociation constant (K _i ) calculated from the concentration (IC ₅₀ ) of the test compound that inhibits the binding of ³ H] -N-methylscopolamine by 50% was determined.

[0086]

[Table 1] As is clear from the results shown in Table 1, the compounds of the present invention showed a much stronger binding inhibitory activity against m ₃ receptors than muscarinic m ₂ receptors. Muscarinic receptor antagonist test (in vitro) 1) M ₂ receptor antagonistic Test This test method in isolated rat right atrium was carried out according to a conventional method. SD male rats (30
0-500 g) was bled to death and the right atrium was excised. Specimens were placed in a 20 ml Krebs-Henseleit nutrient solution (95%
The suspension was isometrically suspended at an initial tension of 0.5 g in a Magnus tube filled with O ₂ , 5% CO ₂ aeration, 32 ° C.). Beat rate was recorded using a heart rate monitor. After equilibration for 30 minutes, carbachol (10 ^-9 to 10 ^-6 M) was cumulatively administered from a low concentration to a three-fold dose, and the decrease in the pulse rate was measured to obtain a dose response curve of the control. Was. After the pulsation was recovered by washing with a fresh solution, the test compound was administered, and 10 minutes later, carbachol was cumulatively administered again. The response to carbachol was expressed as the number of beats before carbachol administration was taken as 100%. From the degree of shift of the dose response curve by the compound treatment of the present invention to determine the antagonistic potency of the test compound (K _B value). 2) airway M ₃ receptor antagonistic Test This test method in isolated rat trachea was performed according to a conventional method. SD male rats (30
0-500 g) was bled to death and the trachea was removed. After the trachea was formed into a ring shape with a width of 2 mm, the abdominal cartilage was cut open to prepare a transection specimen. Specimens were treated with 5 ml of Krebs-Henseleit nutrient solution (95% O ₂ , 5% CO ₂ aeration, 32
° C) and suspended at an initial tension of 1.0 g and a static tension of 0.6 g. Specimen tension was recorded isometrically. After equilibration for 1 hour, the cells were contracted twice with 10 ^-4 M carbachol, and the second carbachol contraction was taken as the reference contraction. After washing with a fresh solution and returning to the baseline, the test compound was administered (or no treatment), and 10 minutes later, carbachol (10 ^-8 to 10 ^-3 M) was cumulatively administered in a three-fold dose. Dose response curves were obtained. The dose-response curves were expressed with the contraction of the reference in each specimen as 100%. From the degree of shift of the dose-response curve by the test compound treatment was determined antagonistic potency of the test compound (K _B value).

[0087]

[Table 2] As is clear from the results shown in Table 2, the compounds of the present invention antagonized much stronger than the right atrium M ₂ to receptors of the trachea M _3. Thus, the compounds of the invention into the trachea M ₃ receptor, which is more selective compounds. Muscarinic M ₃ receptor antagonist test (in vivo) 1-A) bronchodilation in rats (i. V) 8-11 weeks old (380-420g) Sprague dough Ryi based male rats urethane (750 mg / kg , I.
p. ) And α-chloralose (37.5 mg / kg,
i. p. ), And the trachea was cannulated. A cannula was inserted into the right common jugular vein for drug administration. Succinylcholine (5 mg / body, s.
c. )), After completely suppressing spontaneous breathing,
nary Mechanics Model 6 (B
uxco) was used to measure airway resistance under artificial ventilation. The airway resistance induced by acetylcholine (50 μg / kg, iv) was measured 5 minutes before and 5 minutes after administration of the test substance, and the airway resistance 5 minutes after administration to the airway resistance 5 minutes before administration of the test substance was measured. The percentage of airway resistance was calculated. As a control group, a physiological saline solution was used in place of the test substance, and the same operation was performed to calculate the ratio of the airway resistance value.
00%. The dose that suppressed the acetylcholine-induced increase in airway resistance in the control group to 50% was defined as the ED ₅₀ value, and the ED ₅₀ value was calculated from the dose-response curve of the test substance using probit analysis. 1-B) Bronchodilator effect in rats (po) The test substance was orally administered, 8-11 weeks old (380-42)
0 g) of Sprague-Dawley male rats
Minutes later i. v. The same treatment as in the test was performed, and airway resistance was measured. Acetylcholine (50 μg / kg, iv) -induced airway resistance was measured 60 minutes after the administration of the test substance. As a control group, physiological saline was used in place of the test substance, and the same operation was performed to measure the airway resistance value, which was set to 100%. The dose that suppressed the acetylcholine-induced airway resistance in the control group to 50% was defined as the ED ₅₀ value, and the ED ₅₀ value was calculated from the dose-response curve of the test substance using probit analysis.

[0088]

[Table 3] 2) Bronchodilator effect (PO) in dogs A 12-24 month old (10-15 kg) male beagle dog was anesthetized with pentobarbital (30 mg / kg, iv) and a tracheal cannula was inserted. Then, by using a methacholine inhalation provocation test, airway sensitivity (methacholine inhalation threshold) was measured at least twice at two-week intervals, and dogs exhibiting a reproducible methacholine response threshold ¹⁾ were selected. Oral administration of test substance to dogs with a defined methacholine response threshold (1 m
g / kg), and a methacholine inhalation provocation test was performed again 4 hours after the administration, whereby a methacholine reaction threshold ²⁾ after the administration of the test substance was measured. The bronchodilator effect of the test substance was determined by the following equation.

[0089]

(Equation 1) The mesacholine inhalation induction test was performed using Astragraph TCK-6100H manufactured by Chest. Inhalation inducers
Using mesacholine chloride in physiological saline, 40000μ
g / ml from 20000, 10,000, 5000,
2500, 1250, 625, 312.5, 156, 7
It was diluted to 10 concentrations of 8 μg / ml. This mesacholine aerosol was inhaled from the low concentration for 1 minute, and the respiratory resistance was continuously described. The methacholine concentration at which the respiratory resistance was twice the initial value was defined as the methacholine threshold.

[0090]

[Table 4] As is clear from the results shown in Table 4 above, the compounds of the present invention exhibited a strong bronchodilator effect and sustainability.

As described above, the compound of the formula [I] of the present invention is characterized by the introduction of a fluorine atom, exhibits potent and selective muscarinic M ₃ receptor antagonism, and has excellent oral activity and sustained action. Shows sex and pharmacokinetics. Therefore, as a safe medicine with few side effects, in particular, respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis; irritable bowel syndrome, spastic colitis, diverticulitis and digestive system smooth muscle Gastrointestinal disorders such as pain associated with spasm; urinary disorders such as urinary incontinence and pollakisuria in diseases such as neurogenic pollakiuria, neuropathic bladder, nocturnal enuresis, unstable bladder, bladder spasticity, chronic cystitis; and vehicles It can be administered orally or parenterally to patients for the treatment or prevention of sickness.

When the compound of the present invention is actually used for treating or preventing the above-mentioned diseases, it is formulated into a dosage form suitable for administration together with pharmaceutically acceptable additives according to a conventional method. be able to. As the additive, various additives commonly used in the field of pharmaceutical preparations can be used, such as gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch, and microcrystalline wax. , White petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester,
Examples include polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, acacia, propylene glycol, polyalkylene glycol, cyclodextrin or hydroxypropylcyclodextrin.

[0093] Dosage forms formulated using these additives include solid preparations such as tablets, capsules, granules, powders and suppositories; liquid preparations such as syrups, elixirs and injections. These can be prepared according to a usual method in the field of pharmaceuticals. The liquid preparation may be in the form of being dissolved or suspended in water or another suitable medium at the time of use. In particular, the injection may be in the form of being dissolved or suspended in a physiological saline or glucose solution in advance, or in the form of a powder to be dissolved or suspended in a physiological saline or glucose solution before use. And a buffer or a preservative may be contained in some cases.

Examples of the preparation for oral administration include ordinary tablets, capsules, granules, powders and the like, as well as aerosol or dry powder inhalation forms, or elixirs or suspensions containing flavors or coloring agents. It can be.

These preparations may contain the compound of the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 60% by weight of the whole drug. These formulations may also contain other therapeutically effective compounds.

When the compound of the present invention is used as a drug, the dose and frequency of administration vary depending on the sex, age, body weight, degree of symptoms and the kind and range of the intended therapeutic effect of the patient. In the case of administration, 0.1 to 100 mg / kg is divided into 1 to several times per day for adults, and in the case of parenteral administration, 0.001 to 10 mg / kg is divided into 1 to several times. Is preferred.

[0097]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.

[0098]

EXAMPLES Example 1 (2R) -N- [1- (4-methyl-3-pentenyl)
Piperidin-4-yl] -2-[(1R) -3,3
Fluorocyclopentyl] -2-hydroxy-2-fe
Nylacetamide structural formula

[0099]

Embedded image Step 1. 1- (4-methyl-3-pentenyl) -4-pi
Synthesis of Peridone To a solution of 2.5 g of 4-piperidone monohydrochloride monohydrate in 150 ml of acetonitrile, 11 g of potassium carbonate, 2.62 g of 5-bromo-2-methyl-2-pentene and 800 mg of potassium iodide were sequentially added, and the mixture was heated under reflux for 3 hours.
The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.24 g of the title compound as a white solid. Step 2. 4-amino-1- (4-methyl-3-penteni
L) Synthesis of piperidine 1.1 g of ammonium acetate and 860 mg of sodium cyanoborohydride were sequentially added to a solution of 2.2 g of 1- (4-methyl-3-pentenyl) -4-piperidone in 60 ml of methanol at room temperature, and the same temperature was maintained overnight. Stirred. After methanol was distilled off under reduced pressure, the mixture was adjusted to pH = 3 with 1N hydrochloric acid and washed with diethyl ether. The aqueous layer was made alkaline with a 1N aqueous sodium hydroxide solution and extracted with chloroform. Water the organic layer,
After washing with a saturated saline solution, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.9 g of the title compound as a colorless oily substance. Step 3. (2R) -N- [1- (4-methyl-3-pen
Tenyl) piperidin-4-yl] -2-[(1R)-
3,3-difluorocyclopentyl] -2-hydroxy
Synthesis of 2-phenylacetamide (2R)-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetic acid 75 mg in N, N-dimethylformamide 3 ml solution at room temperature,
55 mg of 1,1'-carbonyldiimidazole was added, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was further added with 4-amino-1- (4-methyl-3-pentenyl) piperidine (60 mg),
5 mg of 4-dimethylaminopyridine was sequentially added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with diethyl ether, washed sequentially with saturated aqueous sodium hydrogen carbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to preparative thin-layer chromatography (Kieselgel ^™).
60F ₂₅₄ , Art 5744 (manufactured by Merck) chloroform / methanol = 10/1) to give the title compound 2
3 mg was obtained as an oil.

¹ H-NMR (CDCl ₃ , δ ppm):
1.32-1.50 (2H, m), 1.60 (3H,
s), 1.68 (3H, s), 1.58-2.34 (1
2H, m), 2.43-2.49 (1H, m), 2.7
3-2.82 (3H, m), 3.23-3.36 (1
H, m), 3.48 (1H, brs), 3.62-3.
73 (1H, m), 5.03-5.08 (1H, m),
6.29-6.33 (1H, m), 7.25-7.39
(3H, m), 7.54 over 7.57 (2H, m) low resolution FAB-MS (m / e, (C 24 H 34 F 2 N 2 O 2
+ H) ⁺ ): 421 Example 2 ( 2R) -N- [1- (4-methyl-3-pentenyl)
Piperidin-4-yl] -2-[(1S) -3,3
Fluorocyclopentyl] -2-hydroxy-2-fe
Nylacetamide structural formula

[0101]

Embedded image The title compound was produced in the same manner as in Step 3 of Example 1 using (2R)-[(1S) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetic acid.

¹ H-NMR (CDCl ₃ , δ ppm):
1.60 (3H, s), 1.68 (3H, s), 1.3
5-2.48 (15H, m), 2.75-2.86 (3
H, m), 3.22-3.36 (1H, m), 3.48
(1H, brs), 3.61-3.76 (1H, m),
5.03-5.08 (1H, m), 6.27 (1H,
d, J = 8.0 Hz), 7.26-7.40 (3H,
m), 7.55 over 7.58 (2H, m) low resolution FAB-MS (m / e, (C 24 H 34 F 2 N 2 O 2
+ H) ⁺ ): 421 Example 3 ( 2R) -N- [1- (4-methyl-3-pentenyl)
Piperidin-4-yl] -2-[(1S, 3S) -3-
Fluorocyclopentyl] -2-hydroxy-2-fe
Nylacetamide and (2R) -N- [1- (4-methyl
Rou-3-pentenyl) piperidin-4-yl] -2-
[(1S, 3R) -3-fluorocyclopentyl] -2
-Hydroxy-2-phenylacetamide structural formula

[0103]

Embedded image (2R)-[(1S) -3-fluorocyclopentyl]
Example 1 using 2-hydroxy-2-phenylacetic acid
The title compound was produced in the same manner as in Step 3, and separated in the final step. ( 2R) -N- [1- (4-methyl-3-pentenyl)
Piperidin-4-yl] -2-[(1S, 3S) -3-
Fluorocyclopentyl] -2-hydroxy-2-fe
Nylacetamide ¹ H-NMR (CDCl ₃ , δ ppm): 1.60 (3
H, s), 1.68 (3H, s), 1.31-2.33.
(15H, m), 2.44-2.49 (1H, m),
2.69-2.81 (2H, m), 3.19-3.30
(1H, m), 3.62-3.74 (1H, m), 3.
90 (1H, brs), 5.03-5.28 (2H,
m), 5.87-5.91 (1H, m), 7.25-7.40 (3H, m), 7.53-7.57 (2H,
m) Low resolution FAB-MS (m / e, (C ₂₄ H ₃₅ FN ₂ O ₂ +
H) ⁺ ): 403 (2R) -N- [1- (4-methyl-3-pentenyl)
Piperidin-4-yl] -2-[(1S, 3R) -3-
Fluorocyclopentyl] -2-hydroxy-2-fe
Nylacetamide ¹ H-NMR (CDCl ₃ , δ ppm): 1.61 (3
H, s), 1.68 (3H, s), 1.37-2.26.
(14H, m), 2.32-2.37 (2H, m),
2.75-2.90 (2H, m), 3.43-3.56
(1H, m), 3.63-3.76 (1H, m), 5.
04-5.13 (2H, m), 6.91-6.95 (1
H, m), 7.23-7.35 (3H, m), 7.67.
Over 7.71 (2H, m) low resolution FAB-MS (m / e, (C 24 H 35 FN 2 O 2 +
H) ⁺ ): 403 Example 4 (2R) -N- [1- (4-methyl-3-pentenyl)
Piperidin-4-yl] -2-[(1R, 3S) -3-
Fluorocyclopentyl] -2-hydroxy-2-fe
Nylacetamide and (2R) -N- [1- (4-methyl
Rou-3-pentenyl) piperidin-4-yl] -2-
[(1R, 3R) -3-fluorocyclopentyl] -2
-Hydroxy-2-phenylacetamide structural formula

[0104]

Embedded image (2R)-[(1R) -3-fluorocyclopentyl]
Example 1 using 2-hydroxy-2-phenylacetic acid
The title compound was produced in the same manner as in Step 3, and separated in the final step. (2R) -N- [1- (4-methyl-3-pentenyl)
Piperidin-4-yl] -2-[(1R, 3S) -3-
Fluorocyclopentyl] -2-hydroxy-2-fe
Nylacetamide ¹ H-NMR (CDCl ₃ , δ ppm): 1.60 (3
H, s), 1.70 (3H, s), 1.38-2.17
(14H, m), 2.27-1.32 (2H, m),
2.70-2.81 (2H, m), 3.19-3.32
(1H, m), 3.63-3.74 (1H, m), 3.
93 (1H, brs), 5.00-5.21 (2H,
m), 5.96-6.02 (1H, m), 7.26-7.38 (3H, m), 7.55-7.58 (2H,
m) Low resolution FAB-MS (m / e, (C ₂₄ H ₃₅ FN ₂ O ₂ +
H) ⁺ ): 403 (2R) -N- [1- (4-me
Chill-3-pentenyl) piperidin-4-yl] -2-
[(1R, 3R) -3-fluorocyclopentyl] -2
-Hydroxy-2-phenylacetamide ¹ H-NMR (CDCl ₃ , δ ppm): 1.60 (3
H, s), 1.68 (3H, s), 1.38-2.32.
(6H, m), 2.74-2.88 (2H, m), 3.
41-3.52 (1H, m), 3.63-3.74 (1
H, m), 5.02-5.21 (2H, m), 6.90.
(1H, d, J = 8.2 Hz), 7.23-7.35
(3H, m), 7.66-7.69 (2H, m) Low-resolution FAB-MS (m / e, (C ₂₄ H ₃₅ FN ₂ O ₂ +
H) ⁺ ): 403 Example 5 N- [1-[(3Z) -4-trifluoromethyl-3-]
Pentenyl] piperidin-4-yl] -2-cyclopen
Cyl-2-hydroxy-2-phenylacetamide structural formula

[0105]

Embedded image Step 1. N- (piperidin-4-yl) -2-cyclope
Of ethyl 2-hydroxy-2-phenylacetamide
Synthetic 2-cyclopentyl-2-hydroxy-2-phenylacetic acid 3.51 g of N, N-dimethylformamide 40 ml
2.61 g of 1,1′-carbonyldiimidazole was added to the solution.
Was added and stirred at room temperature for 2 hours. 4-amino-1- (t-butoxycarbonyl) piperidine monohydrochloride 3.96
g, 4-dimethylaminopyridine (200 mg) and diisopropylethylamine (6.9 ml) were added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to obtain 2.84 g of a white solid.
I got This solid was dissolved in 10% hydrochloric acid-methanol (30 ml) and stirred at room temperature overnight. The residue obtained by distilling off methanol under reduced pressure was diluted with water and washed with diethyl ether. The aqueous layer was made alkaline with sodium hydroxide and extracted with chloroform. The organic layer was washed successively with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.15 g of the title compound as a white solid. Step 2. (3Z) -4-trifluoromethyl-3-pen
Synthesis of thenyl t-butyldiphenylsilyl ether To a solution of 2.94 g of (3-tert-butyldiphenylsilyloxypropyl) triphenylphosphonium bromide in 40 ml of tetrahydrofuran, 2.5 ml of a 1.7 M hexane solution of n-butyllithium was added dropwise at -78 ° C. -20 ℃
And stirred for 1 hour. The mixture was cooled again to -78 ° C, 0.5 ml of trifluoroacetone was added dropwise, and the mixture was stirred overnight while raising the temperature to room temperature. Dilute the reaction solution with hexane,
After washing with 10% hydrochloric acid, water and saturated saline in this order, the extract was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1) to obtain 1.44 g of the title compound. Step 3. (3Z) -4-trifluoromethyl-3-pen
Synthesis of Tenol (3Z) -4-trifluoromethyl-3-pentenyl
To a solution of 1.44 g of t-butyldiphenylsilyl ether in 8 ml of tetrahydrofuran was added 4.4 ml of a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with diethyl ether, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure is subjected to silica gel column chromatography (developing solvent:
The residue was purified by ethyl acetate to give 414 mg of the title compound. Step 4. (3Z) -4-trifluoromethyl-3-pen
Synthesis of thenyl p-toluenesulfonate To a solution of (3Z) -4-trifluoromethyl-3-pentenol (414 mg) in pyridine (6 ml) was added 565 mg of p-toluenesulfonyl chloride under ice-cooling, and the mixture was stirred at room temperature for 16 hours. Dilute the reaction solution with diethyl ether and water,
After washing with a saturated saline solution sequentially, it was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1) to obtain 412 mg of the title compound. Step 5. N- [1-[(3Z) -4-trifluoromethyl
Rue-3-pentenyl] piperidin-4-yl] -2-cy
Clopentyl-2-hydroxy-2-phenylacetoa
Synthesis of amide A solution of 77 mg of N- (piperidin-4-yl) -2-cyclopentyl-2-hydroxy-2-phenylacetamide in 3 ml of N, N-dimethylformamide at room temperature was
(3Z) -4-trifluoromethyl-3-pentenyl
74 mg of p-toluenesulfonate, potassium carbonate 10
2 mg and 43 mg of potassium iodide were sequentially added, and the mixture was refluxed for 3 hours. Dilute the reaction solution with diethyl ether, add water,
After washing with a saturated saline solution sequentially, it was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by preparative thin-layer chromatography (Kieselgel ^™ 60F ₂₅₄ , A
Purification was performed using rt5744 (manufactured by Merck, Inc., chloroform / methanol = 9/1) to obtain 27 mg of the title compound as an oil.

¹ H-NMR (CDCl ₃ , δ ppm):
1.12-1.88 (16H, m), 1.83 (3H,
s), 2.01-2.13 (2H, m), 2.68-2.80 (2H, m), 2.97-3.10 (1H,
m), 3.13 (1H, brs), 3.62-3.76.
(1H, m), 5.65-5.72 (1H, m), 6.
32 (1H, d, J = 8.5 Hz), 7.23-7.3
6 (3H, m), 7.59 (2H, d, J = 7.3H
z) Low-resolution FAB-MS (m / e, (C ₂₄ H ₃₃ F ₃ N ₂ O ₂₎
+ H) ⁺ ): 439 Example 6 N- [1-[(3Z) -4-fluoromethyl-3-pen
Tenyl] piperidin-4-yl] -2-cyclopentyl
-2-Hydroxy-2-phenylacetamide structural formula

[0107]

Embedded image The title compound was produced in the same manner as in Step 2-5 of Example 5 using fluoroacetone.

¹ H-NMR (CDCl ₃ , δ ppm):
1.04-2.16 (14H, m), 1.79 (3H,
s), 2.16-2.28 (2H, m), 2.28-2.40 (2H, m), 2.66-2.86 (2H, m)
m), 2.94-3.24 (2H, m), 3.62-3.78 (1H, m), 4.86 (2H, d, J = 4)
7.5Hz), 5.34-5.44 (1H, m), 6.
36 (1H, d, J = 8.3 Hz), 7.22-7.4
0 (3H, m), 7.56-7.64 (2H, m) Example 7 N- [1-[(3E) -4-fluoromethyl-3-pen]
Tenyl] piperidin-4-yl] -2-cyclopentyl
-2-Hydroxy-2-phenylacetamide structural formula

[0109]

Embedded image Step 1. (2E) -5-bromo-2-methyl-2-pen
Synthesis of Tenol To a solution of 681 mg of selenium dioxide in 10 ml of dichloromethane was added 2.5 ml of t-butyl peroxide at room temperature, stirred at the same temperature for 30 minutes, added with 2.0 g of 5-bromo-2-methyl-2-pentene, and further stirred for 2 hours. The reaction solution was diluted with diethyl ether, and an aqueous solution of sodium thiosulfate was added.
% Potassium hydroxide solution and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 20/1 to 4/1) to obtain 1.24 g of the title compound. Step 2. (2E) -5-bromo-2-methyl-2-pen
Synthesis of thenyl t-butyldimethylsilyl ether (2E) To a solution of 300 mg of 5-bromo-2-methyl-2-pentenol in 10 ml of N, N-dimethylformamide were added 302 mg of chlorot-butyldimethylsilane and 137 mg of imidazole, and the mixture was stirred at room temperature for 1 hour. .
The reaction solution was diluted with diethyl ether, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 604 mg of the title compound. Step 3. N- [1-[(3E) -4-t-butyl dimethyl]
Lucylyloxymethyl-3-pentenyl] piperidine-
4-yl] -2-cyclopentyl-2-hydroxy-2
Synthesis of 2 -phenylacetamide (2E) -5-bromo-2-methyl-2-pentenyl
Example 5 using t-butyldimethylsilyl ether
The title compound was produced in the same manner as in Step 5. Step 4. N- [1-[(3E) -4-fluoromethyl-
3-pentenyl] piperidin-4-yl] -2-cyclo
Pentyl-2-hydroxy-2-phenylacetamide
Molecular sieves 4 in tetrahydrofuran 3ml solution of synthetic tetrabutylammonium fluoride trihydrate 59mg of
A 200 mg, N- [1-[(3E) -4-tert-butyldimethylsilyloxymethyl-3-pentenyl] piperidin-4-yl] -2-cyclopentyl-2-hydroxy-2-phenylacetamide 31 mg, and fluorinated p-toluenesulfonate 22 mg The mixture was added sequentially, and heated and refluxed at 80 ° C. overnight. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to preparative thin-layer chromatography (Kie
The product was purified by selgel ^™ 60F ₂₅₄ , Art 5744 (manufactured by Merck), chloroform / methanol = 20/1) to obtain 11 mg of the title compound as an oil.

¹ H-NMR (CDCl ₃ , δ ppm):
1.10-1.76 (10H, m), 1.70 (3H,
s), 1.76-1.95 (2H, m), 1.95-2.42 (6H, m), 2.72-2.88 (2H,
m), 2.94-3.24 (2H, m), 3.62-3.78 (1H, m), 4.69 (2H, d, J = 4)
7.8 Hz), 5.44-5.54 (1H, m), 6.
37 (1H, d, J = 8.0 Hz), 7.22-7.4
0 (3H, m), 7.56 over 7.64 (2H, m) low resolution FAB-MS (m / e, (C 24 H 35 FN 2 O 2 +
H) ⁺ ): 403 Example 8 (2R) -N- (1-cycloheptylmethylpiperidine)
-4-yl) -2-[(1R) -3,3-difluorosi
Clopentyl] -2-hydroxy-2-phenylaceto
Amide structural formula

[0111]

Embedded image Using (2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetic acid and cycloheptylmethyl methanesulfonate, the title compound was produced in the same manner as in Steps 1 and 5 of Example 5. did.

¹ H-NMR (CDCl ₃ , δ ppm):
1.03-2.27 (27H, m), 2.63-2.7
1 (2H, m), 3.21-3.33 (1H, m),
3.49 (1H, brs), 3.61-3.72 (1
H, m), 6.23 (1H, d, J = 8.3 Hz),
7.27-7.39 (3H, m), 7.53-7.57
(2H, m) low resolution FAB-MS (m / e, (C 26 H 38 F 2 N 2 O 2
+ H) ⁺ ): 449 Example 9 (2R) -N- [1-[(3E) -4-fluoromethyl
-3-pentenyl] piperidin-4-yl] -2-
[(1R) -3,3-difluorocyclopentyl] -2
-Hydroxy-2-phenylacetamide structural formula

[0113]

Embedded image The title compound was produced in the same manner as in Example 7 using (2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetic acid.

¹ H-NMR (CDCl ₃ , δ ppm):
1.34 to 1.52 (2H, m), 1.69 (3H,
s), 1.75-2.31 (12H, m), 2.31-2.46 (2H, m), 2.72-2.86 (2H, m).
m), 3.24-3.38 (1H, m), 3.43 (1
H, brs), 3.62-3.78 (1H, m), 4.
69 (2H, d, J = 47.8 Hz), 5.42-5.
52 (1H, m), 6.34 (1H, d, J = 7.9H)
z), 7.24 over 7.42 (3H, m), 7.52 over 7.60 (2H, m) low resolution FAB-MS (m / e, (C 24 H 33 F 3 N 2 O 2
+ H) ⁺ ): 439 Example 10 (2R) -N- [1- (6-methylpyridin-2-yl)
Methyl) piperidin-4-yl] -2-[(1R)-
3,3-difluorocyclopentyl] -2-hydroxy
-2-phenylacetamide structural formula

[0115]

Embedded image Step 1. (2R) -N- (piperidin-4-yl) -2
-[(1R) -3,3-difluorocyclopentyl]-
Synthesis of 2-hydroxy-2-phenylacetamide Using (2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetic acid, the title compound was produced in the same manner as in Step 1 of Example 5 did.

Step 2. (2R) -N- [1- (6-methyl
Rupyridin-2-ylmethyl) piperidin-4-yl]
-2-[(1R) -3,3-difluorocyclopentene
L] -2-Hydroxy-2-phenylacetamide
Adult (2R) -N chromatography (piperidin -4 Iru) -2 chromatography [(1
R) -3,3-Difluorocyclopentyl] -2-hydroxy-2-phenylacetamide (17 mg) was added to a solution of tetrahydrofuran (2 ml) at room temperature in the order of 3 μl of acetic acid, 12 mg of 6-methylpyridine-2-carbaldehyde and 21 mg of sodium triacetoxyborohydride. And stirred at room temperature overnight. Dilute the reaction solution with ethyl acetate,
After washing with a saturated saline solution, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to preparative thin-layer chromatography (Kieselgel ^™ 60F ₂₅₄ , Ar
t5744 (manufactured by Merck) chloroform / methanol =
10/1) to give 9 mg of the title compound as a solid.

¹ H-NMR (CDCl ₃ , δ ppm):
1.35-1.50 (2H, m), 1.72-2.23
(10H, m), 2.53 (3H, s), 2.70-
2.80 (2H, m), 3.21-3.35 (1H,
m), 3.59 (2H, s), 3.60-3.78 (1
H, m), 6.31 (1H, d, J = 8.5 Hz),
7.02 (1H, t, J = 7.6 Hz), 7.18 (1
H, d, J = 7.6 Hz), 7.28-7.39 (3
H, m), 7.50 (1H, d, J = 7.6 Hz),
7.53-7.59 (2H, m) Example 11 (2R) -N- [1- (3-thienylmethyl) piperidi
N-4-yl] -2-[(1R) -3,3-difluoro
Cyclopentyl] -2-hydroxy-2-phenylace
Toamide structural formula

[0118]

Embedded image Example 10 Step 2 Using Thiophene-3-aldehyde
The title compound was produced in the same manner as in.

¹ H-NMR (CDCl ₃ , δ ppm):
1.30-1.50 (2H, m), 1.56-1.30
(10H, m), 2.66-2.82 (2H, m),
3.22-3.37 (1H, m), 3.40 (1H,
s), 3.49 (2H, s), 3.61-3.78 (1
H, m), 6.25 (1H, d, J = 8.2 Hz),
7.02 (1H, dd, J = 1.1 Hz, 7.6H
z), 7.06-7.12 (1H, m), 7.22-7.42 (4H, m), 7.50-7.60 (2H,
m) Low resolution FAB-MS (m / e, (C 23 H 28 F 2 N 2 O 2
S + H) ⁺ ): 435 Example 12 (2R) -N- [1- (3-furylmethyl) piperidine
-4-yl] -2-[(1R) -3,3-difluorosi
Clopentyl] -2-hydroxy-2-phenylaceto
Amide structural formula

[0120]

Embedded image The title compound was produced in the same manner as in Step 2 of Example 10 using furan-3-aldehyde.

¹ H-NMR (CDCl ₃ , δ ppm):
1.32-1.47 (2H, m), 1.73-2.27
(10H, m), 2.70-2.78 (2H, m),
3.24-3.35 (1H, m), 3.33 (2H,
s), 3.42 (1H, s), 3.62-3.75 (1
H, m), 6.26 (1H, d, J = 7.2 Hz),
6.34 (1H, s), 7.27-7.40 (5H,
m), 7.52 over 7.57 (2H, m) low resolution FAB-MS (m / e, (C 23 H 28 F 2 N 2 O 3
+ H) ⁺ ): 419 Example 13 (2R) -N- [1- (2-furylmethyl) piperidine
-4-yl] -2-[(1R) -3,3-difluorosi
Clopentyl] -2-hydroxy-2-phenylaceto
Amide structural formula

[0122]

Embedded image The title compound was produced in the same manner as in Step 2 of Example 10 using furan-2-aldehyde.

¹ H-NMR (CDCl ₃ , δ ppm):
1.35-1.49 (2H, m), 1.73-2.25
(10H, m), 2.70-2.80 (2H, m),
3.23-3.35 (1H, m), 3.48 (1H,
s), 3.49 (2H, s), 3.61-3.73 (1
H, m), 6.17 (1H, d, J = 3.0 Hz),
6.27-6.31 (2H, m), 7.27-7.38
(4H, m), 7.52 over 7.56 (2H, m) low resolution FAB-MS (m / e, (C 23 H 28 F 2 N 2 O 3
+ H) ⁺ ): 419 Example 14 (2R) -N- [1- (2-pyridylmethyl) piperidi
N-4-yl] -2-[(1R) -3,3-difluoro
Cyclopentyl] -2-hydroxy-2-phenylace
Toamide structural formula

[0124]

Embedded image The title compound was produced in the same manner as in Step 2 of Example 10 using pyridine-2-aldehyde.

¹ H-NMR (CDCl ₃ , δ ppm):
1.39-1.52 (2H, m), 1.75-2.25
(10H, m), 2.70-2.80 (2H, m),
3.24-3.36 (1H, m), 3.58 (1H,
s), 3.61 (2H, s), 3.67-3.77 (1
H, m), 6.32 (1H, d, J = 7.8 Hz),
7.15 (1H, ddd, J = 1.2Hz, 4.8H
z, 7.6 Hz), 7.27-7.39 (4H, m),
7.53-7.57 (2H, m), 7.63 (1H, t
d, J = 1.8 Hz, 7.6 Hz), 8.52 (1H,
ddd, J = 1.2 Hz, 1.8 Hz, 3.0 Hz) Low-resolution FAB-MS (m / e, (C ₂₄ H ₂₉ F ₂ N ₃ O ₂₎
+ H) ⁺ ): 430 Example 15 (2R) -N- [1- (3-methoxybenzyl) piperi
Gin-4-yl] -2-[(1R) -3,3 difluor
Rocyclopentyl] -2-hydroxy-2-phenyla
Cetamide structural formula

[0126]

Embedded image (2R) -N- (piperidin-4-yl) -2-[(1
R) -3,3 Difluorocyclopentyl] -2-hydroxy-2-phenylacetamide (71 mg), 3-methoxybenzyl chloride (74 mg) and potassium carbonate (80 mg) were added to a solution of N, N-dimethylformamide (2 ml) at room temperature and stirred for about 12 hours. . The reaction solution was diluted with diethyl ether, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to preparative thin-layer chromatography (Kieselgel ^™).
60F ₂₅₄ , Art 5744 (manufactured by Merck) chloroform / methanol = 9/1) to give the title compound 75
mg was obtained as a white solid.

¹ H-NMR (CDCl ₃ , δ ppm):
1.32-1.54 (2H, m), 1.65-2.30
(10H, m), 2.68-2.85 (2H, m),
3.21-3.39 (1H, m), 3.42 (1H,
s) 3.45 (2H, s), 3.63-3.78 (1
H, m), 3.80 (3H, s), 6.27 (1H,
d, J = 8.2 Hz), 6.76-6.83 (1H,
m), 6.84-6.90 (2H, m), 7.21 (1
H, t, J = 8.0 Hz), 7.24-7.40 (3
H, m), 7.51 over 7.59 (2H, m) low resolution FAB-MS (m / e, (C 26 H 32 F 2 N 2 O 3
+ H) ⁺ ): 459 Example 16 (2R) -N- (1-benzylpiperidin-4-yl)
-2-[(1R) -3,3 difluorocyclopentene
Ru] -2-Hydroxy-2-phenylacetamide structural formula

[0128]

Embedded image The title compound was produced in the same manner as in Example 15 using benzyl bromide.

¹ H-NMR (CDCl ₃ , δ ppm):
1.35-1.52 (2H, m), 1.70-2.23
(10H, m), 2.70-2.81 (2H, m),
3.22-3.34 (1H, m), 3.41 (1H,
s) 3.48 (2H, s), 3.60-3.80 (1
H, m), 6.27 (1H, d, J = 8.0 Hz),
7.24-7.39 (8H, m), 7.54-7.56
(2H, m) low resolution FAB-MS (m / e, (C 25 H 30 F 2 N 2 O 2
+ H) ⁺ ): 429 Example 17 (2R) -N- [1- (3-fluorobenzyl) piperi
Gin-4-yl] -2-[(1R) -3,3 difluor
Rocyclopentyl] -2-hydroxy-2-phenyla
Cetamide structural formula

[0130]

Embedded image The title compound was produced in the same manner as in Example 15 using 3-fluorobenzyl chloride.

¹ H-NMR (CDCl ₃ , δ ppm):
1.34-1.52 (2H, m), 1.52-2.30
(10H, m), 2.65-2.80 (2H, m),
3.22-3.38 (1H, m), 3.40 (1H,
s) 3.72 (2H, s), 3.60-3.80 (1
H, m), 6.28 (1H, d, J = 7.7 Hz),
6.88-6.97 (1H, m), 7.00-7.10.
(2H, m), 7.20-7.42 (4H, m), 7.
51 over 7.60 (2H, m) low resolution FAB-MS (m / e, (C 25 H 29 F 3 N 2 O 2
+ H) ⁺ ): 447 Example 18 (2R) -N- [1- (3-chlorobenzyl) piperidi
N-4-yl] -2-[(1R) -3,3-difluoro
Cyclopentyl] -2-hydroxy-2-phenylace
Toamide structural formula

[0132]

Embedded image The title compound was produced in the same manner as in Example 15 using 3-chlorobenzyl chloride.

¹ H-NMR (CDCl ₃ , δ ppm):
1.33-1.50 (2H, m), 1.60-2.25
(10H, m), 2.67-2.77 (2H, m),
3.24-3.38 (1H, m), 3.44 (2H,
s) 3.63-3.76 (1H, m), 6.29 (1
H, d, J = 8.0 Hz), 7.13-7.40 (7
H, m), 7.53 over 7.57 (2H, m) low resolution FAB-MS (m / e, (C 25 H 29 ClF 2 N 2
Example 4 ( O ₂ + H) ⁺ ): 463 Example 19 (2R) -N- [1- (2-thienylmethyl) piperidi
N-4-yl] -2-[(1R) -3,3-difluoro
Cyclopentyl] -2-hydroxy-2-phenylace
Toamide structural formula

[0134]

Embedded image The title compound was produced in the same manner as in Example 15 using 2-thienylmethyl chloride.

¹ H-NMR (CDCl ₃ , δ ppm):
1.32-1.50 (2H, m), 1.52-2.30
(10H, m), 2.70-2.82 (2H, m),
3.22-3.36 (1H, m), 3.41 (1H,
s) 3.62-3.76 (1H, m), 3.68 (2
H, s), 6.26 (1H, d, J = 7.9 Hz),
6.87 (1H, dd, J = 3.2 Hz, 4.8H
z), 6.92 (1H, dd, J = 3.2 Hz, 4.8)
Hz) 7.21 (1H, dd, J = 1.5 Hz, 4.8)
Hz), 7.24 over 7.40 (3H, m), 7.50 over 7.58 (2H, m) low resolution FAB-MS (m / e, (C 23 H 28 F 2 N 2 O 2
S + H) ⁺ ): 435 Example 20 (2R) -N- [1- (6-aminopyridin-2-yl)
Methyl) piperidin-4-yl] -2-[(1R)-
3,3-difluorocyclopentyl] -2-hydroxy
-2-phenylacetamide dihydrochloride structural formula

[0136]

Embedded image The compound of Example 20 was produced by the following production methods-1, 2 and 3. Production Method-1 Step 6-tert-butyldiphenylsilyloxy
Synthesis of methylpyridine-2-carboxylic acid To a solution of 1.8 g of ethyl 6-hydroxymethylpyridine-2-carboxylate in 55 ml of N, N-dimethylformamide, 1.4 g of imidazole and 3.9 g of tert-butyldiphenylsilane chloride were added sequentially under ice-cooling. Stir at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in methanol (60 ml). A 4N aqueous sodium hydroxide solution (7.5 ml) was added, and the mixture was stirred at room temperature for 20 hours and further at 60 degrees for 2 hours. The residue obtained by distilling off methanol under reduced pressure was acidified with 1N hydrochloric acid, extracted with chloroform, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (developing solvent: hexane /
The residue was purified by ethyl acetate = 4/1) to give 895 m of the title compound.
g was obtained as a white solid. Step 2. 6-tert-butyloxycarbonylamino
Pyridin-2-ylmethyl tert-butyldiphenyl
At room temperature, a solution of 890 mg of 6-tert-butyldiphenylsilyloxymethylpyridine-2-carboxylic acid in 30 ml of toluene was added with 0.6 ml of triethylamine at room temperature.
3 ml, tert-butanol 3.2 ml, and diphenylphosphoryl azide 887 mg were successively added, and 100
The mixture was heated and stirred for 6 hours. Dilute the reaction solution with ethyl acetate,
The extract was washed successively with a saturated aqueous solution of sodium bicarbonate, a 10% aqueous citric acid solution, water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 4/1).
And 863 mg of the title compound was obtained as an oil. Step 3. 6-tert-butyloxycarbonylamino
Using 6-tert-butyloxycarbonylaminopyridin-2-ylmethyl tert-butyldiphenylsilyl ether obtained in pyridine-2-methanol synthesis step 2 in the same manner as in step 3 of Example 5, the title compound was produced. Step 4. 6-tert-butyloxycarbonylamino
0.19 ml of triethylamine was added to a solution of 61 mg of 6-tert-butyloxycarbonylaminopyridine-2-methanol obtained in synthesis step 3 of pyridin-2-ylmethyl methanesulfonate in 2 ml of chloroform under ice-cooling.
Add 0.032 ml of methanesulfonyl chloride and add 1 at the same temperature.
Stirred for hours. The reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated saline, and dried over anhydrous magnesium sulfate.
g were obtained as an oil. Step 5. (2R) -N- [1- (6-tert-butyl)
Oxycarbonylaminopyridin-2-ylmethyl) pi
Peridin-4-yl] -2-[(1R) -3,3-diph
Fluorocyclopentyl] -2-hydroxy-2-phenyl
The title compound was produced in the same manner as in Example 15 using 6-tert-butyloxycarbonylaminopyridin-2-ylmethyl methanesulfonate obtained in the synthesis step 4 of lucacetamide. Step 6. (2R) -N- [1- (6-aminopyridine-
2-ylmethyl) piperidin-4-yl] -2-[(1
R) -3,3 Difluorocyclopentyl] -2-hydrido
(2R) -N- [1- (6-tert-butyloxycarbonylaminopyridin-2-ylmethyl) piperidin-4-yl] -2-[(1R) -3,3 obtained in synthesis step 5 of roxy-2-phenylacetamide
[Difluorocyclopentyl] -2-hydroxy-2-phenylacetamide was treated with hydrochloric acid according to a conventional method to give the title compound as a white solid.

¹ H-NMR (CD ₃ OD, δ ppm):
1.76-2.14 (10H, m), 3.20-3.6
3 (5H, m), 3.85-4.00 (1H, m),
4.44 (2H, s), 7.07-7.34 (2H,
m), 7.25-7.34 (3H, m), 7.58-7.60 (2H, m), 7.89-7.94 (1H,
m) Low resolution FAB-MS (m / e, (C 24 H 30 F 2 N 4 O 2
+ H) ⁺ ): 445 Production Method-2 Step 1. 6-tert-butyloxycarbonylamino
Synthesis of ethyl pyridine-2-carboxylate Using 6-ethoxycarbonylpyridine-2-carboxylic acid, the title compound was produced in the same manner as in Step 2 of Production Method-1. Step 2. 6-tert-butyloxycarbonylamino
Synthesis of pyridine-2-methanol To a solution of 500 mg of calcium chloride in 10 ml of ethanol was added 150 mg of sodium borohydride under ice-cooling, followed by stirring at the same temperature for 15 minutes. The 6-ter obtained in step 1 was added to the reaction solution.
1.1 g of ethyl t-butyloxycarbonylaminopyridine-2-carboxylate was added, and the mixture was stirred at room temperature for 13 hours. After ethanol was distilled off under reduced pressure, the residue was suspended in a mixed solution of chloroform and water, and insolubles were removed by filtration. The organic layer was washed successively with water and saturated saline and dried over anhydrous magnesium sulfate to give the title compound 99
6 mg was obtained as a pale yellow oil. Step 3. 4-tert-butyloxycarbonylamino
-1- (6-tert-butyloxycarbonylamino
Production method using 6-tert-butyloxycarbonylaminopyridine-2-methanol and 4-tert-butyloxycarbonylaminopiperidine obtained in Step 2 of synthesizing pyridin-2-ylmethyl) piperidine
The title compound was produced in the same manner as in Steps 4-5 of 1. Step 4. (2R) -N- [1- (6-aminopyridine-
2-ylmethyl) piperidin-4-yl] -2-[(1
R) -3,3 Difluorocyclopentyl] -2-hydrido
163 mg of 4-tert-butyloxycarbonylamino-1- (6-tert-butyloxycarbonylaminopyridin-2-ylmethyl) piperidine obtained in the synthesis step 3 of roxy-2-phenylacetamide
Was dissolved in 5 ml of 10% hydrochloric acid-methanol,
Stir for 3 hours. Methanol was distilled off under reduced pressure. To a suspension of the residue obtained in 15 ml of chloroform was added 0.16 ml of triethylamine and 86 mg of (2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetic acid under ice-cooling. , Hydroxybenzotriazole 1
14 mg and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (75 mg) were sequentially added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was diluted with diethyl ether, washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 50/1 to 20/1) to obtain 101 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , δ ppm):
1.35-1.51 (2H, m), 1.70-2.25
(10H, m), 2.68-2.80 (2H, m),
3.21-3.35 (1H, m), 3.41 (2H,
s), 3.52 (1H, brs), 3.62-3.77.
(1H, m), 4.40 (2H, brs), 6.28
(1H, d, J = 8.2 Hz), 6.36 (1H, d,
J = 8.2 Hz), 6.67 (1H, d, J = 7.3H)
z), 7.27-7.40 (4H, m), 7.53-7.57 (2H, m). (2R) -N- [1- (6-aminopyridine-
2-ylmethyl) piperidin-4-yl] -2-[(1
R) -3,3 Difluorocyclopentyl] -2-hydrido
(2R) -N- [1- (6-aminopyridin-2-ylmethyl) piperidin-4-yl] -2 obtained in synthesis step 4 of roxy-2-phenylacetamide dihydrochloride
-[(1R) -3,3-Difluorocyclopentyl] -2-hydroxy-2-phenylacetamide was treated with hydrochloric acid in a conventional manner to give the title compound. Production Method-3 Step 2-tert-butyloxycarbonylamino
Synthesis of 6-methylpyridine 2 g of chloroform 3 of 2-methyl-2-aminopyridine
5 g of di-tert-butyloxydicarbonate was added to the 0 ml solution at room temperature, then heated to 70 ° C., 2.5 g of 4-dimethylaminopyridine was added, and the mixture was stirred at the same temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 20/1) to obtain 4.1 g of the title compound as a white solid. Step 2. (2R) -N- [1- (6-aminopyridine-
2-ylmethyl) piperidin-4-yl] -2-[(1
R) -3,3 Difluorocyclopentyl] -2-hydrido
Synthesis of roxy-2-phenylacetamide dihydrochloride 100 mg of 2-tert-butyloxycarbonylamino-6-methylpyridine obtained in Step 1 of carbon tetrachloride 3 m
90 mg of N-bromosuccinimide to the solution at room temperature
10 mg of benzoyl peroxide was sequentially added and the mixture was stirred under reflux for 6 hours. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The residue obtained and 4-tert-butyloxycarbonylaminopyridine were used to prepare step 5 of production method-1 and step 4 of production method-2.
The title compound was produced in the same manner as in -5. Example 21 (2R) -N- [1- (6-amino-4-methoxypyri)
Zin-2-ylmethyl) piperidin-4-yl] -2-
[(1R) -3,3-difluorocyclopentyl] -2
-Hydroxy-2-phenylacetamide dihydrochloride structural formula

[0139]

Embedded image The title compound was produced in the same manner as in Example 20 using ethyl 6-hydroxymethyl-4-methoxypyridine-2-carboxylate.

¹ H-NMR (CD ₃ OD, δ ppm):
1.69-2.21 (10H, m), 3.10-3.7
0 (5H, m), 3.83-3.97 (1H, m),
3.98 (3H, s), 4.30-4.46 (2H,
m), 6.39-6.47 (1H, m), 6.74-6.89 (1H, m), 7.20-7.38 (3H,
m), 7.58 (2H, d , J = 6.9Hz) low resolution FAB-MS (m / e, (C 25 H 32 F 2 N 4 O 3
+ H) ⁺ ): 475 Example 22 (2R) -N- [1- (3-amino-5-methylbenzyl)
Le) piperidin-4-yl] -2-[(1R) -3,3
Difluorocyclopentyl] -2-hydroxy-2-
Phenylacetamide dihydrochloride structural formula

[0141]

Embedded image Step 1 . N- (tert-butyloxycarbonyl)-
Synthesis of 3,5-dimethylaniline 1.2 g of 3,5-dimethylaniline in 20 m of dioxane
l Add 10 ml of a 10% aqueous sodium hydroxide solution
2.7 g of tert-butyl dicarbonate were added and 10
The mixture was heated and stirred at 0 ° for 1.5 hours. The reaction solution was diluted with diethyl ether, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure is subjected to silica gel column chromatography (developing solvent:
Hexane / ethyl acetate = 9/1) to give 1.8 g of the title compound as an oil. Step 2. 3- (tert-butyloxycarbonyl)
1.5 g of N-bromosuccinimide was added to a solution of 1.8 g of N- (tert-butyloxycarbonyl) -3,5-dimethylaniline obtained in the synthesis step 1 of l-amino) -5-methylbenzyl in 20 ml of carbon tetrachloride,
53 mg of 2,2′-azobis (isobutyronitrile) was sequentially added, and the mixture was heated and stirred at 100 ° C. for 3 hours. The reaction solution was diluted with hexane and filtered, and the solvent was distilled off under reduced pressure to obtain 2.8 g of the title compound as an oil. Step 3. (2R) -N- [1- (3-amino-5-methyl
Rubenzyl) piperidin-4-yl] -2-[(1R)
-3,3-difluorocyclopentyl] -2-hydroxy
Example 2 Using 3- (tert-butyloxycarbonylamino) -5-methylbenzyl bromide obtained in Step 2 of Synthesis of C-2-phenylacetamide dihydrochloride
The title compound was produced in the same manner as in Steps 5 and 6 of Production Method-1 of Preparation 0.

¹ H-NMR (CD ₃ OD, δ ppm):
1.66-2.11 (12H, m), 2.99-3.4
8 (3H, m), 3.26 (3H, s), 3.78-3.98 (1H, m), 4.28 (2H, s), 7.1
8-1 7.60 (8H, m) low resolution FAB-MS (m / e, (C 26 H 33 F 2 N 3 O 2
+ H) ⁺ ): 458 Example 23 (2R) -N- [1- (3-aminobenzyl) piperidi
N-4-yl] -2-[(1R) -3,3-difluoro
Cyclopentyl] -2-hydroxy-2-phenylace
Toamide structural formula

[0143]

Embedded image Step 1. (2R) -N- [1- (3-nitrobenzyl)
Piperidin-4-yl] -2-[(1R) -3,3
Fluorocyclopentyl] -2-hydroxy-2-fe
Synthesis of Nylacetamide The title compound was produced in the same manner as in Example 15 using 3-nitrobenzyl chloride. Step 2. (2R) -N- [1- (3-aminobenzyl)
Piperidin-4-yl] -2-[(1R) -3,3
Fluorocyclopentyl] -2-hydroxy-2-fe
(2R) -N- [1- (3-nitrobenzyl) piperidin-4-yl] -2-[(1R) -3,3 obtained in synthesis step 1 of nylacetamide
6.5 mg of difluorocyclopentyl] -2-hydroxy-2-phenylacetamide was heated to 60 ° C. together with 2 mg of iron powder in aqueous ethanol, 1 drop of concentrated hydrochloric acid was added, and the mixture was further stirred at 100 ° C. for about 1 hour. The reaction solution was made basic with a 4N aqueous sodium hydroxide solution, and then extracted with chloroform. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 4.8 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , δ ppm):
1.30-1.48 (2H, m), 1.50-2.25
(10H, m), 2.68-2.78 (2H, m),
3.24-3.40 (1H, m), 3.38 (2H,
s), 3.43 (1H, s), 3.52-3.80 (1
H, m), 6.26 (1H, d, J = 7.9 Hz),
6.57 (1H, dd, J = 1.5 Hz, 7.8H
z), 6.65 (1H, d, J = 1.5 Hz), 6.6
6 (1H, d, J = 7.8 Hz), 7.08 (1H,
t, J = 7.8 Hz), 7.28-7.39 (3H,
m), 7.53 over 7.57 (2H, m) low resolution FAB-MS (m / e, (C 25 H 31 F 2 N 3 O 2
+ H) ⁺ ): 444 Example 24 (2R) -N- [1- (2-aminobenzyl) piperidi
N-4-yl] -2-[(1R) -3,3-difluoro
Cyclopentyl] -2-hydroxy-2-phenylace
Toamide dihydrochloride structural formula

[0145]

Embedded image The title compound (free base) was obtained in the same manner as in Example 23 using 2-nitrobenzyl chloride, and the title compound was obtained by treatment with hydrochloric acid.

¹ H-NMR (CD ₃ OD, δ ppm):
1.50-1.95 (10H, m), 2.92-3.0
7 (2H, m), 3.07-3.20 (1H, m),
3.24-3.38 (2H, m), 3.67-3.80
(1H, m), 4.15-4.27 (2H, m), 7.
05 over 7.45 (9H, m) low resolution FAB-MS (m / e, (C 25 H 31 F 2 N 3 O 2
+ H) ⁺ ): 444 Example 25 (2R) -N- [1- (4-aminobenzyl) piperidi
N-4-yl] -2-[(1R) -3,3-difluoro
Cyclopentyl] -2-hydroxy-2-phenylace
Toamide structural formula

[0147]

Embedded image The title compound was produced in the same manner as in Example 23 using 4-nitrobenzyl chloride.

¹ H-NMR (CDCl ₃ , δ ppm):
1.35-1.52 (2H, m), 1.70-2.23
(10H, m), 2.70-2.82 (2H, m),
3.23-3.35 (1H, m), 3.41 (2H,
s), 3.30-3.70 (3H, m), 3.65-3.75 (1H, m), 6.29 (1H, d, J = 7.
4Hz), 6.63 (2H, d, J = 8.5Hz),
7.06 (2H, d, J = 8.5 Hz), 7.28-7.39 (3H, m), 7.52-7.56 (2H,
m) Low resolution FAB-MS (m / e, (C 25 H 31 F 2 N 3 O 2
+ H) ⁺ ): 444 Example 26 (2R) -N- [1- (4-amino-3-methoxybenz)
Jill) piperidin-4-yl] -2-[(1R) -3,
3-difluorocyclopentyl] -2-hydroxy-2
-Phenylacetamide structural formula

[0149]

Embedded image The title compound was produced in the same manner as in Example 23 using 3-methoxy-4-nitrobenzyl chloride.

¹ H-NMR (CDCl ₃ , δ ppm):
1.35-1.60 (2H, m), 1.70-2.30
(10H, m), 2.70-2.90 (2H, m),
3.22-3.38 (1H, m), 3.44 (2H,
s), 3.40-3.60 (1H, m), 3.62-3.85 (3H, m), 3.85 (3H, s), 6.3
6 (1H, d, J = 7.9 Hz), 6.60-6.70
(2H, m), 6.81 (1H, s), 7.24-7.
40 (3H, m), 7.51 over 7.58 (2H, m) low resolution FAB-MS (m / e, (C 26 H 33 F 2 N 3 O 3
+ H) ⁺ ): 474 Example 27 (2R) -N- [1- (3,5-diaminobenzyl) pi
Peridin-4-yl] -2-[(1R) -3,3-diph
Fluorocyclopentyl] -2-hydroxy-2-phenyl
Ruacetamide structural formula

[0151]

Embedded image The title compound was produced in the same manner as in Example 23 using 3,5-dinitrobenzyl chloride.

¹ H-NMR (CDCl ₃ , δ ppm):
1.30-2.20 (12H, m), 2.70-2.8
0 (2H, m), 3.23-3.36 (1H, m),
3.28 (2H, s), 3.44 (1H, s), 3.6
0-3.73 (1H, m), 5.93 (1H, t, J =
2.0 Hz), 6.07 (2H, d, J = 2.0H)
z), 6.23 (1H, d, J = 7.5 Hz), 7.2
9-7.40 (3H, m), 7.53-7.57 (2
H, m) low resolution FAB-MS (m / e, (C 25 H 32 F 2 N 4 O 2
+ H) ⁺ ): 459 Example 28 (2R) -N- [1- (5-methylfuran-2-ylmeth)
Tyl) piperidin-4-yl] -2-[(1R) -3,
3-difluorocyclopentyl] -2-hydroxy-2
-Phenylacetamide structural formula

[0153]

Embedded image Step 1. 4- (tert-butyloxycarbonylamido
No) -1- (5-methyl-2-furylmethyl) piperidi
To a solution of 4- (tert-butyloxycarbonylamino) piperidine (200 mg) in tetrahydrofuran (5 ml) at room temperature was added 5-methylfuran-3-aldehyde (0.1 ml), acetic acid (0.06 ml) and sodium triacetoxyborohydride (318 mg), and the mixture was stirred for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate / n-hexane to obtain 198 mg of the title compound. Step 2. (2R) -N- [1- (5-methyl-2-free)
Rumethyl) piperidin-4-yl] -2-[(1R)-
3,3-difluorocyclopentyl] -2-hydroxy
To 2- mg of 4- (tert-butyloxycarbonylamino) -1- (5-methyl-2-furylmethyl) piperidine obtained in the synthesis step 1 of 2-phenylacetamide, 2 ml of a 10% hydrochloric acid methanol solution is added at room temperature, and the mixture is stirred for about 12 hours Then, the solvent was distilled off under reduced pressure.
(2R) -2 was added to 4 ml of a chloroform solution of the obtained residue.
-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetic acid 59 mg, hydroxybenzotriazole 93 mg, triethylamine 0.1 mg
2 ml and 66 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide were sequentially added at room temperature, followed by stirring for 2 hours. Water was added to the reaction solution, and extracted with chloroform. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 50/1) to give the title compound (63 mg).
Was obtained as a white solid.

¹ H-NMR (CDCl ₃ , δ ppm):
1.35-1.54 (2H, m), 1.60-2.25
(10H, m), 2.27 (3H, s), 2.71-2.86 (2H, m), 3.22-3.36 (1H,
m), 3.40 (1H, s), 3.45 (2H, s),
3.60-3.76 (1H, m), 5.85-5.90
(1H, m), 6.05 (1H, d, J = 3.0H
z), 6.25 (1H, d, J = 7.9 Hz), 7.2
6-7.40 (3H, m), 7.50-7.56 (2
H, m) Low-resolution FAB-MS (m / e, (C ₂₄ H ₃₀ F ₂ N ₂ O ₃₎
+ H) ⁺ ): 433 Example 29 (2R) -N- [1- (3-methylbenzyl) piperidi
N-4-yl] -2-[(1R) -3,3-difluoro
Cyclopentyl] -2-hydroxy-2-phenylace
Toamide structural formula

[0155]

Embedded image Step 1. 4- (tert-butyloxycarbonylamido
No) Synthesis of 1- (3-methylbenzyl) piperidine The title compound was produced in the same manner as in Example 15 using 4- (tert-butyloxycarbonylamino) piperidine and 3-methylbenzyl bromide. Step 2. (2R) -N- [1- (3-methylbenzyl)
Piperidin-4-yl] -2-[(1R) -3,3
Fluorocyclopentyl] -2-hydroxy-2-fe
The title compound was produced in the same manner as in Example 28 using 4- (tert-butyloxycarbonylamino) -1- (3-methylbenzyl) piperidine obtained in the synthesis step 1 of nylacetamide.

¹ H-NMR (CDCl ₃ , δ ppm):
1.24 to 1.50 (2H, m), 1.50 to 2.25
(10H, m), 2.33 (3H, s), 2.60-2.82 (2H, m), 3.20-3.55 (3H,
m), 3.42 (2H, s), 6.25 (1H, d, J
= 8.1 Hz), 7.00-7.14 (3H, m),
7.19 (1H, t, J = 7.6 Hz), 7.23-7.42 (3H, m), 7.50-7.60 (2H,
m) Low resolution FAB-MS (m / e, (C 26 H 32 F 2 N 2 O 2
+ H) ⁺ ): 443 Example 30 (2R) -N- [1- (4-methoxybenzyl) piperi
Gin-4-yl] -2-[(1R) -3,3 difluor
Rocyclopentyl] -2-hydroxy-2-phenyla
Cetamide structural formula

[0157]

Embedded image The title compound was produced in the same manner as in Step 2 of Example 10 using p-anisaldehyde.

¹ H-NMR (CDCl ₃ , δ ppm):
1.32-1.47 (2H, m), 1.75-2.23
(10H, m), 2.65-2.76 (2H, m),
3.22-3.36 (1H, m), 3.42 (2H,
s), 3.46 (1H, s), 3.63-3.76 (1
H, m), 3.79 (3H, s), 6.27 (1H,
d, J = 8.2 Hz), 6.84 (2H, d, J = 8.
6 Hz), 7.19 (2H, d, J = 8.6 Hz),
7.28-7.39 (3H, m), 7.52-7.56
(2H, m) low resolution FAB-MS (m / e, (C 26 H 32 F 2 N 2 O 3
+ H) ⁺ ): 459 Example 31 (2R) -N- [1- (3-amino-5-methoxybenz)
Jill) piperidin-4-yl] -2-[(1R) -3,
3-difluorocyclopentyl] -2-hydroxy-2
-Phenylacetamide dihydrochloride structural formula

[0159]

Embedded image Step 1. 3-tert-butyloxycarbonylamino
Synthesis of methyl 5-methoxybenzoate In a solution of 864 mg of methyl 3-methoxy-5-nitrobenzoate in 15 ml of methanol, 1.0 g of ditert-butyl dicarbonate, 912 m of 10% palladium-carbon.
g was added and stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure.
28 g were obtained as a white solid. Step 2. 3-tert-butyloxycarbonylamino
Synthesis of -5 -methoxybenzyl alcohol 1.28 g of methyl 3-tert-butoxycarbonylamino -5-methoxybenzoate obtained in Step 1 of toluene 8
At -78 ° C, 12.1 ml of a 1.0 M diisobutylaluminum hydride tetrahydrofuran solution was added to the ml solution, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (developing solvent: hexane /
The residue was purified by ethyl acetate (7/3) to give 262 m of the title compound.
g were obtained as an oil. Step 3. 3-tert-butyloxycarbonylamino
1.89 g of manganese dioxide was added to a solution of 194 mg of 3-tert-butyloxycarbonylamino-5-methoxybenzyl alcohol obtained in the synthesis step 2 of -5-methoxybenzaldehyde in 10 ml of chloroform at room temperature, followed by stirring for 2 hours. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure to obtain 132 mg of the title compound as an oil. Step 4. (2R) -N- [1- (3-amino-5-met
[Xybenzyl) piperidin-4-yl] -2-[(1
R) -3,3 Difluorocyclopentyl] -2-hydrido
Example 1 using 3-tert-butyloxycarbonylamino-5-methoxybenzaldehyde obtained in the synthesis step 3 of roxy-2-phenylacetamide dihydrochloride
The title compound was prepared in the same manner as in Step 0 and Step 6 of Production Method-1 of Example 20.

¹ H-NMR (CD ₃ OD, δ ppm):
1.74-2.14 (10H, m), 3.00-3.1
5 (2H, m), 3.27-3.52 (3H, m),
3.82-3.92 (1H, m), 3.89 (3H,
s) 4.32 (2H, s), 7.01 (1H, s),
7.18-7.35 (5H, m), 7.56-7.60
(2H, m) low resolution FAB-MS (m / e, (C 26 H 33 F 2 N 3 O 3
+ H) ⁺ ): 474. Example 32 (2R) -N- [1- (4-amino-3-fluorobenzene
Jill) piperidin-4-yl] -2-[(1R) -3,
3-difluorocyclopentyl] -2-hydroxy-2
-Phenylacetamide structural formula

[0161]

Embedded image Example 22 using 3-fluoro-4-aminotoluene
The title compound was produced in the same manner as in.

¹ H-NMR (CDCl ₃ , δ ppm):
1.28-1.50 (2H, m), 1.50-2.32.
(10H, m), 2.60-2.80 (2H, m),
3.20-3.38 (1H, m), 3.33 (2H,
s), 3.45 (1H, s), 3.55-376 (3
H, m), 6.25 (1H, d, J = 8.2 Hz),
6.69 (1H, dd, J = 8.1, 8.9 Hz),
6.82 (1H, dd, J = 1.6, 8.1 Hz),
6.93 (1H, dd, J = 1.6, 12.0 Hz),
7.24-7.40 (3H, m), 7.50-7.58
(2H, m) low resolution FAB-MS (m / e, (C 25 H 30 F 3 N 3 O 2
+ H) ⁺ ): 462 Example 33 ( 2R) -N- [1- (6-amino-4-methylpyridyl)
2-2-yl) piperidin-4-yl] -2-[(1
R) -3,3 Difluorocyclopentyl] -2-hydrido
Roxy-2-phenylacetamide structural formula

[0163]

Embedded image Step 1. 6-chloromethyl-4-methyl-2-acetyl
Synthesis of aminopyridine To a solution of 23 mg of 6-acetylamino-4-methylpyridine-2-methanol in 2 ml of chloroform was added 0.05 ml of thionyl chloride at room temperature, and the mixture was stirred under reflux for 15 minutes.
The solvent was distilled off under reduced pressure to obtain the title compound. Step 2. (2R) -N- [1- (6-acetylamino-
4-methylpyridin-2-yl) piperidine-4-y
Ru] -2-[(1R) -3,3-difluorocyclopen
Tyl] -2-hydroxy-2-phenylacetamide
Using 6-chloromethyl-4-methyl-2-acetylaminopyridine obtained in Synthesis Step 1, the title compound was produced in the same manner as in Example 15. Step 3. (2R) -N- [1- (6-amino-4-methyl)
Rupyridin-2-yl) piperidin-4-yl] -2-
[(1R) -3,3-difluorocyclopentyl] -2
(2R) -N- [1- (6-acetylamino-4-methylpyridin-2-yl) piperidin-4-yl] -2-[(1R) -3,3 obtained in the synthesis step 2 of 1-hydroxy-2-phenylacetamide To a solution of 16.5 mg of [difluorocyclopentyl] -2-hydroxy-2-phenylacetamide in 1 ml of methanol was added 0.5 ml of a 3M aqueous sodium hydroxide solution, and the mixture was heated with stirring at 60 ° C. for 1.5 hours. The reaction solution was diluted with diethyl ether, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to preparative thin-layer chromatography (Kieselgel ^™ 60).
F ₂₅₄ , Art 5744 (manufactured by Merck) chloroform /
(Methanol = 10/1) to give 14 m of the title compound.
g were obtained as an oil.

¹ H-NMR (CDCl ₃ , δ ppm):
1.30-1.50 (2H, m), 1.71-2.30
(10H, m), 2.33 (3H, s), 2.62-2.76 (2H, m), 3.21-3.38 (1H,
m), 3.29 (2H, s), 3.60-3.78 (1
H, m), 4.35-4.51 (2H, m), 6.26.
(1H, s), 6.35 (1H, d, J = 8.1H
z), 6.45 (1H, s), 7.25-7.40 (3
H, m), 7.52 over 7.60 (2H, m) low resolution FAB-MS (m / e, (C 25 H 32 F 2 N 4 O 2
+ H) ⁺ ): 459 Example 34 (2R) -N- [1- (3-amino-4-fluoroben)
Jill) piperidin-4-yl] -2-[(1R) -3,
3-difluorocyclopentyl] -2-hydroxy-2
-Phenylacetamide dihydrochloride structural formula

[0165]

Embedded image Example 22 using 2-fluoro-5-methylaniline
The title compound was produced in the same manner as in.

¹ H-NMR (CD ₃ OD, δ ppm):
1.68-2.11 (10H, m), 3.00-3.5
0 (5H, m), 3.79-3.90 (1H, m),
4.32 (2H, s), 7.18-7.30 (3H,
m), 7.43 (1H, d, J = 8.4 Hz), 7.5
2-7.56 (2H, m), 7.57-7.65 (1
H, m), 7.73 over 7.78 (1H, m) low resolution FAB-MS (m / e, (C 25 H 30 F 3 N 3 O 2
+ H) ⁺ ): 462 Example 35 ( 2R) -N- [1- (5-amino-2-fluorobenz)
Jill) piperidin-4-yl] -2-[(1R) -3,
3-difluorocyclopentyl] -2-hydroxy-2
-Phenylacetamide structural formula

[0167]

Embedded image Example 22 using 2-fluoro-5-nitrotoluene
The title compound was produced in the same manner as in Step 2 and Example 23.

¹ H-NMR (CDCl ₃ , δ ppm):
1.36-1.49 (2H, m), 1.57-2.26
(10H, m), 2.71-2.78 (2H, m),
3.24-3.36 (1H, m), 3.42-3.57
(5H, m), 3.66-3.75 (1H, m), 6.
24 (1H, d, J = 8.1 Hz), 6.51-6.5
6 (1H, m), 6.65-6.68 (1H, m),
6.82 (1H, t, J = 9.0 Hz), 7.29-7.40 (3H, m), 7.53-7.57 (2H,
m) Low resolution FAB-MS (m / e, (C 25 H 30 F 3 N 3 O 2
+ H) ⁺ ): 462 Example 36 (2R) -N- [1- (2-amino-4-chloropyridi)
N-6-ylmethyl) piperidin-4-yl] -2-
[(1R) -3,3-difluorocyclopentyl] -2
-Hydroxy-2-phenylacetamide structural formula

[0169]

Embedded image The title compound was produced in the same manner as in Production Method-2 of Example 20 using methyl 4-chloro-6-hydroxymethylpyridine-2-carboxylate.

¹ H-NMR (CDCl ₃ , δ ppm):
1.42 to 1.54 (2H, m), 1.78 to 2.26
(10H, m), 2.76-2.79 (2H, m),
3.28-3.38 (1H, m), 3.42-3.47
(3H, m), 3.67-3.75 (1H, m), 4.
53-4.56 (2H, m), 6.36 (1H, d, J
= 7.2 Hz), 6.38 (1H, d, J = 1.6H)
z), 6.72 (1H, d, J = 1.6 Hz), 7.2
5-7.39 (3H, m), 7.53-7.57 (2
H, m) Low-resolution FAB-MS (m / e, (C ₂₄ H ₂₉ ClF ₂ N ₄
(As O ₂ + H) ⁺ ): 479 Example 37 (2R) -N- [1- (3-amino-5-chlorobenzyl)
Le) piperidin-4-yl] -2-[(1R) -3,3
Difluorocyclopentyl] -2-hydroxy-2-
Phenylacetamide structural formula

[0171]

Embedded image Step 1. 3-chloro-5-nitrobenzyl methanesul
Synthesis of phonate 0.3 ml of triethylamine and 0.1 ml of chloromethanesulfonate were added at room temperature to a solution of 92 mg of 3-chloro-5-nitrobenzyl alcohol in 3 ml of chloroform, and the mixture was stirred for 40 minutes. The reaction solution was diluted with diethyl ether, washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 119 mg of the title compound as an oil. Step 2. (2R) -N- [1- (3-amino-5-chrome
Robenzyl) piperidin-4-yl] -2-[(1R)
-3,3-difluorocyclopentyl] -2-hydroxy
The title compound was produced in the same manner as in Example 23, using 3-chloro-5-nitrobenzyl methanesulfonate obtained in the synthesis step 1 of C-2-phenylacetamide .

¹ H-NMR (CDCl ₃ , δ ppm):
1.30-1.44 (2H, m), 1.73-2.22
(10H, m), 2.68-2.73 (2H, m),
3.24-3.36 (1H, m), 3.32 (2H,
s), 3.44 (1H, brs), 3.61-3.77
(3H, m), 6.28 (1H, d, J = 8.4H
z), 6.49 (1H, d, J = 1.9 Hz), 6.5
5 (1H, dd, J = 1.7, 1.9 Hz), 6.66
(1H, d, J = 1.7 Hz), 7.29-7.39
(3H, m), 7.53 over 7.56 (2H, m) low resolution FAB-MS (m / e, (C 25 H 30 ClF 2 N 3
O ₂ + H) as a ^+): 459 Example 38 (2R) over N-[1 chromatography (4-amino-3,5 Jifuruo
Robenzyl) piperidin-4-yl] -2-[(1R)
-3,3-difluorocyclopentyl] -2-hydroxy
Sea 2-phenylacetamide structural formula

[0173]

Embedded image The title compound was produced in the same manner as in Step 2 of Example 10 using 4-amino-3,5-difluorobenzaldehyde.

¹ H-NMR (CDCl ₃ , δ ppm):
1.24-2.22 (12H, m), 2.66-2.7
2 (2H, m), 3.27-3.41 (4H, m),
3.66-3.71 (3H, m), 6.28 (1H,
d, J = 7.8 Hz), 6.77 (2H, d, J = 8.
3Hz), 7.28-7.39 (3H, m), 7.54
Over 7.56 (2H, m) low resolution FAB-MS (m / e, (C 25 H 29 F 4 N 3 O 2
+ H) ⁺ ): 480 Example 39 (2R) -N- [1- (benzimidazol-5-yl)
Methyl) piperidin-4-yl] -2-[(1R)-
3,3-difluorocyclopentyl] -2-hydroxy
-2-phenylacetamide structural formula

[0175]

Embedded image The title compound was prepared in the same manner as in Step 2 of Example 10 using benzimidazole-5-carbaldehyde.

¹ H-NMR (CD ₃ OD, δ ppm):
1.45-2.25 (10H, m), 2.25-2.4
8 (2H, m), 2.90-3.10 (2H, m),
3.20-3.42 (1H, m), 3.56-3.75
(1H, m), 3.82 (2H, s), 7.18-7.
40 (4H, m), 7.51-7.75 (4H, m),
8.17 (1H, s) low resolution FAB-MS (m / e, (C 26 H 30 F 2 N 4 O 2
+ H) ⁺ ): 469 Example 40 (2R) -N- [1- (6-aminopyridin-2-yl)
Methyl) piperidin-4-yl] -2- (3,3 diph
(Fluorocyclobutyl) -2-hydroxy-2-phenyl
Acetamide structural formula

[0177]

Embedded image Using (2R)-(3,3-difluorocyclobutyl) -2-hydroxyphenylacetic acid and 4-amino-1- (6-aminopyridin-2-ylmethyl) piperidine.3 hydrochloride, the production method-2 of Example 20 The title compound was produced in the same manner as in Step 4.

¹ H-NMR (CDCl ₃ , δ ppm):
1.20-1.52 (2H, m), 1.60-1.86
(2H, m), 2.08-2.22 (2H, m), 2.
40-2.82 (6H, m), 3.07-3.21 (1
H, m), 3.41 (2H, s), 3.60-3.80.
(1H, m), 3.84 (1H, brs), 4.40
(2H, brs), 6.01 (1H, d, J = 8.1H)
z), 6.36 (1H, d, J = 8.2 Hz), 6.6
6 (1H, d, J = 8.2 Hz), 7.28-7.42
(4H, m), 7.43 over 7.50 (2H, m) low resolution FAB-MS (m / e, (C 23 H 28 F 2 N 4 O 2
+ H) ⁺ ): 431 Example 41 (2R) -N- [1- (6-aminopyridin-2-yl)
Methyl) piperidin-4-yl] -2- (4,4 diph
Fluorocyclohexyl) -2-hydroxy-2-phenyl
Ruacetamide structural formula

[0179]

Embedded image (2R)-(4,4-difluorocyclohexyl) -2
Using -hydroxyphenylacetic acid and 4-amino-1- (6-aminopyridin-2-ylmethyl) piperidine-3 hydrochloride, the title compound was produced in the same manner as in Step 4 of Production Method-2 of Example 20.

¹ H-NMR (CDCl ₃ , δ ppm):
1.20-1.97 (10H, m), 1.97-2.2
2 (4H, m), 2.44-2.68 (1H, m),
2.70-2.92 (3H, m), 3.42 (2H,
s), 3.62-3.80 (1H, m), 4.42 (2
H, brs), 6.36 (1H, d, J = 8.2H)
z), 6.62 (1H, d, J = 7.9 Hz), 6.6
7 (1H, d, J = 8.2 Hz), 7.24-7.42
(4H, m), 7.55 over 7.62 (2H, m) low resolution FAB-MS (m / e, (C 25 H 32 F 2 N 4 O 2
+ H) ⁺ ): 459 Example 42 (2R) -N- [1- (6-aminopyridin-2-yl)
Methyl) piperidin-4-yl] -2-[(1R)-
3,3-difluorocyclopentyl] -2- (4-fur
Orophenyl) -2-hydroxyacetamide structural formula

[0181]

Embedded image (2R)-(3,3 difluorocyclopentyl) -2
The title compound was produced in the same manner as in Production Method-1 of Example 20 using-(4-fluorophenyl) -2-hydroxyacetic acid.

¹ H-NMR (CDCl ₃ , δ ppm):
1.39-1.55 (2H, m), 1.70-2.22
(10H, m), 2.73-2.81 (2H, m),
3.23-3.36 (1H, m), 3.43 (2H,
s), 3.65-3.77 (1H, m), 4.43 (2
H, brs), 6.31 (1H, d, J = 7.6H)
z), 6.37 (1H, d, J = 8.2 Hz), 6.6
7 (1H, d, J = 7.4 Hz), 7.01-7.08
(2H, m), 7.37 (1H, dd, J = 7.4,
8.2 Hz), 7.51 over 7.58 (2H, m) low resolution FAB-MS (m / e, (C 24 H 29 F 3 N 4 O 2
+ H) ⁺ ): 463 Reference Example 1 ( 2R)-[(1R) -3-oxocyclopentyl]-
2-hydroxy-2-phenylacetic acid step 1. (2R, 5R) -2- (t-butyl) -5-
[(1R) -3-oxocyclopentyl] -5-phenyl
Roux 1,3-dioxolan-4-one and (2R, 5
R) -2- (t-butyl) -5-[(1S) -3-oki
Socyclopentyl] -5-phenyl-1,3-dioxo
Synthesis of run-4-one Seebach et al. [Tetr
ahedron, 40, 1313-1324 (19
(84))] (2R, 5R) -2- (t
-Butyl) -5-phenyl-1,3-dioxolane-4
A 1.5M solution of lithium diisopropylamide in 1.5M hexane was added to a mixture of 510mg of -on (510mg) and 20ml of tetrahydrofuran-1ml of hexamethylphosphoric triamide at -78 ° C.
ml, and after stirring for 30 minutes, cyclopentenone 2
85 mg of a 1.5 ml solution of tetrahydrofuran was added,
The mixture was further stirred for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed successively with a saturated aqueous solution of ammonium chloride, water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was subjected to medium pressure silica gel column chromatography (developing solvent: hexane / ethyl acetate = 15/1 to 1).
10/1) and the title compound was 150 m each.
g, 254 mg obtained as an oil. Each configuration was determined by NMR NOE. Step 2. ( 2R)-[(1R) -3-oxocyclopene
Synthesis of tyl] -2-hydroxy-2-phenylacetic acid (2R, 5R) -2- (t-butyl) -5-[(1R)
-3-oxocyclopentyl] -5-phenyl-1,3
-Dioxolan-4-one 61mg methanol 3ml
1 ml of a 1N aqueous sodium hydroxide solution was added to the solution, and the mixture was stirred at room temperature for 3 hours. After methanol was distilled off under reduced pressure, the residue was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether, and the organic layer was dried over anhydrous magnesium sulfate to obtain 48 mg of the title compound. Reference Example 2 (2R)-[(1S) -3-oxocyclopentyl]-
2-hydroxy-2-phenylacetic acid (2R, 5R) -2- (t-butyl) -5-[(1S)
-3-oxocyclopentyl] -5-phenyl-1,3
The title compound was produced in the same manner as in Step 2 of Reference Example 1 using -dioxolan-4-one. Reference Example 3 (2R)-[(1R) -3,3-difluorocyclopen
Tyl] -2-hydroxy-2-phenylacetic acid (2R, 5R) -2- (t-butyl) -5-
[(1R) -3,3-difluorocyclopentyl] -5
Synthesis of -phenyl-1,3-dioxolan-4-one (2R, 5R) -2- (t-butyl) -5-[(1R)
-3-oxocyclopentyl] -5-phenyl-1,3
-Dioxolan-4-one 256mg of chloroform 3
0.34 ml of a solution of diethylaminosulfuric acid in ice-cooled solution
Then, the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with diethyl ether, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 20/1) to obtain 115 mg of the title compound. Step 2. (2R)-[(1R) -3,3-difluorosi
Clopentyl] -2-hydroxy-2-phenylacetic acid
Synthesis (2R, 5R) -2- (t-butyl) -5-[(1R)
Using [-3,3-difluorocyclopentyl] -5-phenyl-1,3-dioxolan-4-one, the title compound was produced in the same manner as in Step 2 of Reference Example 1. Reference Example 4 (2R)-[(1S) -3,3-difluorocyclopen
Tyl] -2-hydroxy-2-phenylacetic acid (2R, 5R) -2- (t-butyl) -5-[(1S)
-3-oxocyclopentyl] -5-phenyl-1,3
The title compound was produced in the same manner as in Reference Example 3 using -dioxolan-4-one. Reference Example 5 (2R)-[(1S) -3-hydroxycyclopentene
2-hydroxy-2-phenylacetic acid step 1. (2R, 5R) -2- (t-butyl) -5-
[(1S) -3-hydroxycyclopentyl] -5-f
Synthesis of enyl-1,3-dioxolan-4-one (2R, 5R) -2- (t-butyl) -5-[(1S)
-3-oxocyclopentyl] -5-phenyl-1,3
-Dioxolan-4-one 169mg methanol 2m
To the 1 solution, 71 mg of sodium borohydride was added under ice cooling, followed by stirring at the same temperature for 30 minutes. The reaction solution was diluted with diethyl ether, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound 15
7 mg were obtained as a colorless oil. Step 2. (2R)-[(1S) -3-hydroxycyclo
Synthesis of Pentyl] -2-hydroxy-2-phenylacetic acid (2R, 5R) -2- (t-butyl) -5-[(1S)
Using [-3-hydroxycyclopentyl] -5-phenyl-1,3-dioxolan-4-one, the title compound was produced in the same manner as in Step 2 of Reference Example 1. Reference Example 6 (2R)-[(1R) -3-hydroxycyclopentene
Ru] -2-hydroxy-2-phenylacetic acid (2R, 5R) -2- (t-butyl) -5-[(1R)
-3-oxocyclopentyl] -5-phenyl-1,3
The title compound was produced in the same manner as in Reference Example 5 using -dioxolan-4-one. Reference Example 7 (2R)-[(1S) -3-fluorocyclopentyl]
The title compound was produced in the same manner as in Reference Example 3 using -2-hydroxy- 2-phenylacetic acid (2R)-[(1S) -3-hydroxycyclopentyl] -2-hydroxy-2-phenylacetic acid. Reference Example 8 (2R)-[(1R) -3-fluorocyclopentyl]
The title compound was produced in the same manner as in Reference Example 3 using -2-hydroxy- 2-phenylacetic acid (2R)-[(1R) -3-hydroxycyclopentyl] -2-hydroxy-2-phenylacetic acid. Reference Example 9 2-cyclopentyl-2-hydroxy-2-phenyl vinegar
To a solution of 23.5 g of ethyl phenylglyoxylate in 200 ml of tetrahydrofuran was added dropwise 70 ml of a 2.0 M cyclopentylmagnesium chloride-diethyl ether solution under ice-cooling, followed by stirring at the same temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 30 / 1-20 / 1) to give 2-cyclopentyl-2-hydroxy-2-phenylethyl acetate 11
g was obtained. This was dissolved in methanol (40 ml), 4N aqueous sodium hydroxide solution (20 ml) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours and at 50 ° C for 1 hour. After methanol was distilled off under reduced pressure, the aqueous layer was made weakly acidic with 4N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was washed with diethyl ether / hexane = 1/1 to obtain 8.7 g of the title compound. Reference Example 10 (2R)-[(1R) -3,3-difluorocyclopen
Tyl] -2-hydroxy-2-phenylacetic acid (2R, 5R) -2- (t-butyl) -5-
[(1S, 2R, 5R, 6S, 7R) -3-oxotri
Cyclo [5.2.1.0 ^2,6 ] dec-8-en-5-
Il] -5-phenyl-1,3-dioxolan-4-o
Down of the synthesis (2R, 5R) was added dropwise over 2-(t-butyl) -5-phenyl-1,3 Jiokisoran 4 On 32g of tetrahydrofuran 1.1l solution over 78 ° C. under lithium diisopropylamide 1.5M hexane solution 105 ml, 3
After stirring for 0 minutes, (1S, 2R, 6S, 7R) -tricyclo [5.2.1.0 ^2,6 ] dec-4,8-diene-
A solution of 23.4 g of 3-one in 300 ml of tetrahydrofuran was added, and the mixture was further stirred for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed successively with a saturated aqueous solution of ammonium chloride, water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was recrystallized from hexane-ethyl acetate to obtain 36.9 g of the title compound as a white solid. Step 2. (2R, 5R) -2- (t-butyl) -5-
[(1S) -4-oxo-2-cyclopentenyl] -5
(2R, 5R) -2- (t-butyl) -5 obtained in synthesis step 1 of 1- phenyl-1,3-dioxolan-4- one
-[(1S, 2R, 5R, 6S, 7R) -3-oxo-8-tricyclo [5.2.1.0 ^2,6 ] dec-8-en-5-yl] -5-phenyl-1,3-dioxolan-4-one 25.6 g 1,2-dichlorobenzene 35
The 0 ml solution was heated and stirred at 175 ° C. for 7 hours under a nitrogen atmosphere. The precipitated solid was filtered and washed with hexane to obtain 14 g of the title compound as a white solid. Step 3. (2R, 5R) -2- (t-butyl) -5-
[(1R) -3-oxocyclopentyl] -5-phenyl
(2R, 5R) -2- (t-butyl) -5 obtained in synthesis step 2 of 1,3-dioxolan-4-one
-[(1S) -4-oxo-2-cyclopentenyl] -5-phenyl-1,3-dioxolan-4-one 19.
2.0 g of 10% palladium-carbon was added to a solution of 1 g of ethyl acetate in 700 ml, and the mixture was stirred under a hydrogen atmosphere at normal temperature and normal pressure for 2 hours. After removing the catalyst by filtration, the solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from hexane-ethyl acetate to give the title compound 14
g was obtained as a white solid. Step 4. ( 2R)-[(1R) -3,3-difluorosi
Clopentyl] -2-hydroxy-2-phenylacetic acid
(2R, 5R) -2- (t-butyl) -5 obtained in synthesis step 3
The title compound was produced in the same manner as in Reference Example 3 using-[(1R) -3-oxocyclopentyl] -5-phenyl-1,3-dioxolan-4-one. Reference Example 11 (2R)-(3,3 difluorocyclopentyl) -2
Using 1- (4-fluorophenyl) -2-hydroxyacetic acid (R) -4 -fluoromandelic acid, the title compound was produced in the same manner as in Reference Example 1, Step 1 and Reference Example 3. Reference Example 12 (2R)-(3,3 difluorocyclobutyl) -2-
Hydroxy-2-phenylacetic acid step 1. (2R, 5R) -2- (t-butyl) -5-
(3-benzyloxy-1-hydroxycyclobutyl)
The combination of -5-phenyl-1,3-dioxolan-4-one
With formation 3 over benzyloxy cyclobutanone The title compound was prepared in the same manner as in Reference Example 1 Step 1. Step 2. (2R, 5R) -2- (t-butyl) -5-
(3-benzyloxycyclobutyl) -5-phenyl-
(2R, 5R) -2- (t-butyl) -5 obtained in synthesis step 1 of 1,3-dioxolan-4- one
2.6 g of 4-dimethylaminopyridine was added to a solution of 2.82 g of-(3-benzyloxy-1-hydroxycyclobutyl) -5-phenyl-1,3-dioxolan-4-one in 80 ml of chloroform under ice-cooling, followed by stirring at the same temperature for 1 hour. . Add 1 ml of methylchloroglyoxylate to the reaction solution.
Was added and the mixture was further stirred for 1 hour. The reaction solution was diluted with chloroform, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and a hexane / ethyl acetate = 1/1 mixed solution of the residue obtained was filtered through a silica gel column. The solvent of the filtrate was distilled off under reduced pressure, 56 mg of 2,2′-azobis (isobutyronitrile) and 2.3 ml of tri-n-butyltin hydride were added to a solution of the residue obtained in 80 ml of toluene at room temperature, and the mixture was heated at 110 ° C. for 4 hours. The mixture was heated and stirred. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 8/1) to obtain 1.82 g of the title compound as an oil. Step 3. (2R, 5R) -2- (t-butyl) -5-
(3-oxocyclobutyl) -5-phenyl-1,3-
(2R, 5R) -2- (t-butyl) -5 obtained in synthesis step 2 of dioxolan-4-one
-(3-benzyloxycyclobutyl) -5-phenyl-1,3-dioxolan-4-one 1.82 g of palladium hydroxide-carbon (430 mg) in ethanol (40 ml)
Was added and the mixture was stirred at normal temperature and normal pressure for 6 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. A solution of the residue obtained in 5 ml of dichloromethane was treated with dimethyl sulfoxide 1.1.
0.63 ml of oxalyl chloride was added to a solution of 50 ml of dichloromethane at −78 ° C., and the mixture was stirred at room temperature for 5 minutes, and added dropwise at −78 ° C., and stirred at the same temperature for 15 minutes.
0.5 ml of triethylamine was further added to the reaction solution, and the mixture was stirred for 30 minutes while warming to room temperature. The reaction solution was diluted with chloroform, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 8/1) to obtain 1.36 g of the title compound as an oil. Step 4. (2R)-(3,3 difluorocyclobuty)
(2R, 5R) -2- (t-butyl) -5 obtained in Step 3 of the synthesis of l) -2-hydroxy-2-phenylacetic acid.
-(3-oxocyclobutyl) -5-phenyl-1,3
The title compound was produced in the same manner as in Reference Example 3 using -dioxolan-4-one. Reference Example 13 (2R)-(4,4-difluorocyclohexyl) -2
-Hydroxy-2-phenylacetic acid step 1. (2R, 5R) -2- (t-butyl) -5-
(1,4-dioxaspiro [4.5] decal 8-yl)
The combination of -5-phenyl-1,3-dioxolan-4-one
The title compound was produced in the same manner as in Steps 1 and 2 of Reference Example 12 using 1,4-dioxa-8-oxospiro [4.5] decane. Step 2. ( 2R, 5R) -2- (t-butyl) -5-
(4-oxocyclohexyl) -5-phenyl-1,3
(2R, 5R) -2- (t-butyl) -5 obtained in synthesis step 1 of -dioxolan-4- one
-(1,4-Dioxaspiro [4.5] dec-8-yl) -5-phenyl-1,3-dioxolan-4-one 52 mg of p-toluenesulfonic acid was added to a mixture of 83 mg of acetone, 4 ml of water and 0.4 ml of water at room temperature, and added at 50 ° C.
Stirred for hours. Acetone was distilled off under reduced pressure, and the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 70 mg of the title compound as an oil. Step 3. (2R)-(4,4 difluorocyclohexyl
(2) (2R, 5R) -2- (t-butyl) -5 obtained in the synthesis step 2 of 2 -hydroxyphenylacetic acid.
-(4-oxocyclohexyl) -5-phenyl-1,
The title compound was produced in the same manner as in Reference Example 3 using 3-dioxolan-4-one. Reference Example 14 (2R)-[(1R) -3,3-difluorocyclopen
Tyl] -2-hydroxy-2-phenylacetic acid (2R, 5R) -2- (t-butyl) -5-
[(1R) -3-hydroxyiminocyclopentyl]-
Synthesis of 5-phenyl-1,3-dioxolan-4-one (2R, 5R) -2- (t-butyl) -5-[(1R)
-3-oxocyclopentyl] -5-phenyl-1,3
-Dioxolan-4-one 46 mg of pyridine 1.5 m
To the solution was added 85 mg of hydroxyamine hydrochloride at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 55 mg of the title compound. Step 2. ( 2R, 5R) -2- (t-butyl) -5-
[(1R) -3,3-difluorocyclopentyl) -5
Synthesis of 2-phenyl-1,3-dioxolan-4-one A mixture of 20 mg of nitrosonium boron tetrafluoride and 0.5 ml of 70% hydrogen fluoride-pyridine was cooled under ice cooling (2R, 5
R) -2- (t-butyl) -5-[(1R) -3-hydroxyiminocyclopentyl] -5-phenyl-1,3
-Dioxolan-4-one (34 mg) in dichloromethane (0.5 ml) was added, and the mixture was added at 0 ° C. for 10 minutes and at room temperature for 5 minutes.
Stirred for hours. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 35 mg of the title compound. Step 3. (2R)-[(1R)-(3,3-difluoro
Cyclopentyl] -2-hydroxy-2-phenylacetic acid
Synthesis of (2R, 5R) -2- (t-butyl) -5-[(1R)
Using -3,3-difluorocyclopentyl) -5-phenyl-1,3-dioxolan-4-one, the title compound was produced in the same manner as in Step 2 of Reference Example 1.

[0183]

The fluorinated 1,4-disubstituted piperidine derivatives of the present invention have selective muscarinic M ₃ receptor antagonism and exhibit excellent oral activity, long-lasting action and pharmacokinetics, and therefore have side effects. Less and safe and effective respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis; irritable bowel syndrome, spastic colitis, diverticulitis and pain associated with digestive smooth muscle spasm Gastrointestinal disorders such as urinary incontinence and urinary frequency in diseases such as neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, bladder spasticity, chronic cystitis; and treatment or prevention of motion sickness Useful as an agent.

[0184]

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Kumiko Kawakami 3, Okubo Tsukuba, Ibaraki Pref. Within Tsukuba Research Laboratories (72) Inventor Kenji Owaki 3, Okubo Tsukuba, Ibaraki Pref. Within the Tsukuba Research Laboratory (72) Inventor: Yu Nishikibe 3 Okubo, Tsukuba City, Ibaraki Pref.

Claims (1)

[Claims] (1) (2R) -2-[(1R) -3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetic acid