JP2014001142A - Cycloalkane compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel cycloalkane compound or a pharmaceutically acceptable salt thereof that powerfully suppresses production of Aβ42 and has a regulatory effect on the function of γ-secretase and that is useful particularly as a prophylactic and therapeutic agent for alzheimer disease.SOLUTION: In a compound (I), a carboxy group or a tetrazole group is bound to a cycloalkane part through a linker. An amine is bound to the cycloalkane part directly or through a linker.

Description

  The present invention relates to a novel cycloalkane compound or a pharmaceutically acceptable salt thereof useful as a pharmaceutical, particularly an agent for preventing or treating Alzheimer's disease.

  Alzheimer's disease (AD) is a progressive cerebral degenerative disease whose chief complaint is cognitive impairment, and the quality of life (QOL) of patients who develop the disease is significantly reduced. In the future, the number of patients is expected to increase rapidly with the aging of the world, and the establishment of treatment is urgently required by society. Currently, acetylcholinesterase inhibitors and NMDA-type glutamate receptor antagonists are used for the treatment of AD, but both are symptomatic treatments that only improve symptoms, and the development of fundamental treatments that lead to the suppression of the progression of the disease Is strongly demanded.

  In AD patients' brains, there are abnormal pathological structures such as senile plaques and neurofibrillary tangles, in addition to brain atrophy due to synaptic loss and neuronal loss in the cerebral cortex. Senile plaques are amyloid β peptides (Aβ40 or Aβ42) consisting of 40 or 42 residues that form aggregates extracellularly and are considered to be pathological changes that occur in the early stages of AD. The amount of Aβ40 produced in vivo is higher than Aβ42, but Aβ42 is more aggregated than Aβ40, and the genes for amyloid β precursor protein (APP) and presenilin protein that cause early-onset familial AD Since many of the mutations increase the production of Aβ42, not Aβ40, Aβ42 has come to be considered as a causative agent for the onset of AD (Non-patent Document 1).

  In Aβ40 and Aβ42, amyloid β precursor protein (APP) is first cleaved from the extracellular region by β-site APP cleaving enzyme 1 (BACE1), and then the C-terminal fragment left in the membrane is cleaved by γ-secretase. To be generated. Therefore, it is considered that the production of Aβ42 can be suppressed by regulating the function of γ-secretase. In fact, the effect has been confirmed with a plurality of compounds. For example, γ-411575, a γ-secretase inhibitor, decreased Aβ40 and Aβ42 in the brain of APP transgenic mice, which are AD model animals, and suppressed senile plaque formation (Non-patent Document 2). Some non-steroidal anti-inflammatory drugs have been reported to regulate only the amount of Aβ42 without changing the amount of Aβ40 produced by regulating the function of γ-secretase (Non-patent Document 3). Moreover, it is known that the γ-secretase function regulator described in Patent Documents 1 to 6 reduces Aβ42 without affecting the amount of Aβ40 (Non-patent Documents 4 and 5). Since Aβ42 is considered to be a causative agent of the onset of AD, a compound that lowers Aβ42 is expected to be a therapeutic drug that suppresses the progression of AD pathology.

（式中の記号は当該公報参照。） In Patent Document 1, it is reported that the compound of the formula (A) which is piperidine and related compounds selectively inhibits the production of Aβ (1-42) and is useful for treatment of Alzheimer's disease and the like. .

(See the official gazette for symbols in the formula.)

（式中の記号は当該公報参照。） In Patent Document 2, it is reported that the compound of formula (B) has a γ-secretase function-modulating action and is useful for treatment of Alzheimer's disease and the like.

(See the official gazette for symbols in the formula.)

（式中の記号は当該公報参照。） In Patent Document 3, it is reported that the compound of the formula (C) has a γ-secretase function regulating action and is useful for treatment of Alzheimer's disease and the like.

(See the official gazette for symbols in the formula.)

（式中の記号は当該公報参照。） In Patent Document 4, it is reported that the compound of the formula (D) has a γ-secretase function regulating action and is useful for treatment of Alzheimer's disease and the like.

(See the official gazette for symbols in the formula.)

（式中の記号は当該公報参照。） Patent Document 5 reports that the compound of the formula (E) selectively inhibits the production of Aβ (1-42) and is useful for treatment of Alzheimer's disease and the like.

(See the official gazette for symbols in the formula.)

（式中の記号は当該公報参照。） Patent Document 6 reports that the compound of the formula (F) selectively inhibits the production of Aβ (1-42) and is useful for treatment of Alzheimer's disease and the like.

(See the official gazette for symbols in the formula.)

（式中の記号は当該公報参照。） Patent Document 7 discloses a compound of formula (G) which is a tachykinin receptor antagonist. Further, in the background art of the patent document, it is reported that tachykinin receptor antagonists are useful for prevention and / or treatment of Alzheimer's disease together with a number of disease names. The compound group is characterized in that ring A is essential.

(See the official gazette for symbols in the formula.)

International Publication No. 2006/043064 Pamphlet International Publication No. 2007/110667 Pamphlet International Publication No. 2007/116228 Pamphlet International Publication No. 2007/125364 Pamphlet International Publication No. 2008/030391 Pamphlet International Publication No. 2008/085301 Pamphlet US Patent No. 575049

"Physiological reviews", 2001, 81, p.741-766 “J Pharmacol Experimental Therapeutics”, 2008, 327, p.411-424 `` Nature '', 2001, volume 414, p .: 212-216 Bioorganic & Medicinal Chemistry Letters, 2010, 20, p. 1306-1311 “Bioorganic & Medicinal Chemistry Letters”, 2010, 20, 755-758

  An object of the present invention is to provide a pharmaceutical composition, in particular, a compound having a gamma secretase function-modulating action useful as a preventive and / or therapeutic agent for diseases associated with amyloid β peptide deposition in the brain.

  As a result of intensive studies on compounds having an inhibitory effect on Aβ42 production, the present inventors have found that a carboxylic acid or a tetrazole group is bonded to a cycloalkane moiety via a linker, and that the amine is directly or via a linker to the cycloalkane moiety. It was found that the compound (I) of the present invention or a pharmaceutically acceptable salt thereof, to which is bound, strongly suppresses the production of Aβ42. Furthermore, they found that these compounds have an excellent γ-secretase function-modulating action, and completed the present invention.

（式中、
R¹¹、R¹²、R¹³及びR¹⁴は、互いに同一又は異なって、H、又は、ハロゲン、あるいは、
R¹¹とR¹²若しくはR¹³とR¹⁴が一体となってオキソ(=O)であり、
R¹及びR²は、互いに同一又は異なって、置換されていてもよい低級アルキル、O-(置換されていてもよい低級アルキル)、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよいシクロアルキル、O-(置換されていてもよいシクロアルキル)、置換されていてもよいアリール、O-(置換されていてもよいアリール)、置換されていてもよいヘテロ環基、又は、O-(置換されていてもよいヘテロ環基)であり、
R³及びR⁵は、互いに同一又は異なって、H、OH、ハロゲン、置換されていてもよい低級アルキル、O-(置換されていてもよい低級アルキル)、又は、低級アルキル（この低級アルキルはハロゲンで置換されていてもよい）で置換されていてもよいアミノであり、
R⁴は、置換されていてもよい低級アルキル、置換されていてもよいシクロアルキル、置換されていてもよいアリール、又は、置換されていてもよいヘテロ環基であり、
Wは、単結合、又は、-CR^W1R^W2-であり、
R^W1及びR^W2は、互いに同一又は異なって、H、OH、ハロゲン、置換されていてもよい低級アルキル、O-(置換されていてもよい低級アルキル)、又は、低級アルキル（この低級アルキルはハロゲンで置換されていてもよい）で置換されていてもよいアミノであり、
Xは、-(CR^X1R^X2)_n-であり、
R^X1及びR^X2は、互いに同一又は異なって、H、ハロゲン、又は、置換されていてもよい低級アルキルであり、
nは、1、2、又は、3、
Lは、置換されていてもよい低級アルキレン、O-置換されていてもよい低級アルキレン*、NH-置換されていてもよい低級アルキレン*、又は、N(置換されていてもよい低級アルキル)-置換されていてもよい低級アルキレン*であり、
*は、当該部分でZと結合することを意味し、
Zは、-C(=O)-OH、又は、置換されていてもよいテトラゾール基であり、
p及びqは、互いに同一又は異なって、0、1、2、又は、3であり、
Yは、単結合、又は、-CH₂-、
ただし、Wが単結合、かつ、R¹及びR²の一方が置換されていてもよい低級アルキルのとき、もう一方は、置換されていてもよいアリール、又は、置換されていてもよいヘテロ環基ではない。） That is, the present invention contains a cycloalkane compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof and a cycloalkane compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. It relates to a composition.

(Where
R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are the same or different from each other, and H, halogen, or
R ¹¹ and R ¹² or R ¹³ and R ¹⁴ together are oxo (= O),
R ¹ and R ² are the same or different from each other, and may be substituted lower alkyl, O- (optionally substituted lower alkyl), optionally substituted lower alkenyl, optionally substituted. Lower alkynyl, optionally substituted cycloalkyl, O- (optionally substituted cycloalkyl), optionally substituted aryl, O- (optionally substituted aryl), optionally substituted A good heterocyclic group or O- (optionally substituted heterocyclic group),
R ³ and R ⁵ are the same or different from each other, and H, OH, halogen, optionally substituted lower alkyl, O- (optionally substituted lower alkyl), or lower alkyl (this lower alkyl is Amino optionally substituted with halogen),
R ⁴ is an optionally substituted lower alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heterocyclic group;
W is a single bond or -CR ^W1 R ^W2-
R ^W1 and R ^W2 are the same or different from each other, and H, OH, halogen, optionally substituted lower alkyl, O- (optionally substituted lower alkyl), or lower alkyl (this lower alkyl is Amino optionally substituted with halogen),
X ^is- (CR ^X1 R ^X2 ) _n-
R ^X1 and R ^X2 are the same or different from each other and are H, halogen, or optionally substituted lower alkyl,
n is 1, 2, or 3,
L is optionally substituted lower alkylene, O-optionally substituted lower alkylene *, NH-optionally substituted lower alkylene *, or N (optionally substituted lower alkyl)- An optionally substituted lower alkylene *,
* Means to combine with Z at that part,
Z is -C (= O) -OH or an optionally substituted tetrazole group;
p and q are the same or different from each other, and are 0, 1, 2, or 3.
Y is a single bond, or -CH _2- ,
However, when W is a single bond and ^one of R ¹ and R ² is optionally substituted lower alkyl, the other is optionally substituted aryl or optionally substituted heterocycle Not a group. )

  Unless otherwise specified, when a symbol in a chemical formula in this specification is also used in another chemical formula, the same symbol indicates the same meaning.

Furthermore, the present invention relates to a pharmaceutical composition for preventing and / or treating a disease associated with amyloid β peptide deposition in the brain, comprising a compound of formula (I) or a salt thereof, ie a compound of formula (I) or a salt thereof The present invention relates to a preventive and / or therapeutic agent for a disease associated with amyloid β peptide deposition in a brain containing salt.
The invention also relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of diseases associated with amyloid β peptide deposition in the brain, amyloid β peptide deposition in the brain. Use of a compound of formula (I) or a salt thereof for the prevention and / or treatment of a disease associated with the disease, a compound of formula (I) for the prevention and / or treatment of a disease associated with amyloid β peptide deposition in the brain, or a method thereof And a method for the prevention and / or treatment of diseases associated with amyloid β peptide deposition in the brain comprising administering to a patient an effective amount of a compound of formula (I) or a salt thereof.

  Since the compound of the present invention strongly suppresses the production of Aβ42 and has an excellent γ-secretase function regulating action, Alzheimer's disease (AD), mild cognitive impairment (MCI), cerebral amyloid angiopathy, Dutch hereditary cerebral hemorrhage It is useful as a preventive and / or therapeutic agent for diseases related to amyloid β peptide deposition in the brain such as (HCHWA-D), multiple infarct dementia, fighting dementia, or Down's syndrome.

  Hereinafter, the present invention will be described in detail. Hereinafter, the “compound of formula (I) or a salt thereof” may be referred to as “the compound (I) of the present invention” or “compound (I)”.

In the present specification, “lower alkyl” means linear or branched alkyl having 1 to 6 carbon atoms (hereinafter abbreviated as C _1-6 ), such as methyl, ethyl, n-propyl, isopropyl, n -Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. Another embodiment is C _1-4 alkyl, and yet another embodiment is C _1-3 alkyl.

“Linear lower alkyl” means linear C _1-6 alkyl among the above “lower alkyl”, and includes methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl. It is. In another embodiment, it is linear C _1-4 alkyl, and in another embodiment, it is linear C _1-3 alkyl.

“Branched lower alkyl” means a branched C _3-6 alkyl among the above “lower alkyl”, for example, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl. , Isohexyl and the like. In another embodiment, it is branched C _3-5 alkyl, and in another embodiment, it is branched C _3-4 alkyl.

The “lower alkyl having a quaternary carbon” means a C _4-6 alkyl having a quaternary carbon among the above “branched lower alkyl”, and examples thereof include tert-butyl, neopentyl, tert-pentyl and the like. In another embodiment, tert-butyl.

“Lower alkenyl” refers to straight or branched C _2-6 alkenyl such as vinyl, propenyl, butenyl, pentenyl, 1-methylvinyl, 1-methyl-2-propenyl, 1,3-butadienyl, 1 , 3-pentadienyl and the like. Another embodiment is C _2-4 alkenyl, and yet another embodiment is C _2-3 alkenyl.

“Lower alkynyl” means linear or branched C _2-6 alkynyl, such as ethynyl, propynyl, butynyl, pentynyl, 1-methyl-2-propynyl, 1,3-butadiynyl, 1,3-pentadiynyl Etc. In another embodiment, C _2-4 alkynyl. It is.

“Lower alkylene” means linear or branched C _1-6 alkylene such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethyl. Ethylene, 1,1,2,2-tetramethylethylene and the like. Another embodiment is C _1-4 alkylene, and yet another embodiment is C _1-3 alkylene.

“Cycloalkyl” is a C _3-10 saturated hydrocarbon ring group which may have a bridge. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like. Another embodiment is C _3-8 cycloalkyl, and yet another embodiment is C _5-7 cycloalkyl.

The “aryl” is a C _6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and includes a cyclic group condensed with a C _5-8 cycloalkene at its double bond site. For example, phenyl, naphthyl, 5-tetrahydronaphthyl, 4-indenyl, 1-fluorenyl and the like.

“Heterocycle” group refers to i) a 3-8 membered, alternatively 5-7 membered monocyclic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, and Ii) The monocyclic heterocycle is condensed with one or two rings selected from the group consisting of a monocyclic heterocycle, a benzene ring, a C _5-8 cycloalkane and a C _5-8 cycloalkene. A ring group selected from bi to tricyclic heterocycles containing 1 to 5 heteroatoms selected from oxygen, sulfur and nitrogen (these bi to tricyclic heterocycles include spirocycles) Means. Ring atoms such as sulfur or nitrogen may be oxidized to form oxides or dioxides.

In the present specification, other embodiments of the “heterocyclic” group include the following embodiments.
(1) Monocyclic saturated heterocyclic groups (a) those containing 1 to 4 nitrogen atoms, such as azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl, hexamethyleneimino , Homopiperazinyl, etc .;
(B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl and the like;
(C) those containing 1 to 2 sulfur atoms, such as tetrahydrothiopyranyl;
(D) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, such as oxathiolanyl;
(E) those containing 1 to 2 oxygen atoms, such as oxiranyl, oxetanyl, dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl and the like;

(2) monocyclic unsaturated heterocyclic group (a) containing 1 to 4 nitrogen atoms, for example, pyrrolyl, 2-pyrrolinyl, imidazolyl, 2-imidazolinyl, pyrazolyl, 2-pyrazolinyl, pyridyl, dihydropyridyl , Tetrahydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl, azepinyl and the like;
(B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, Oxazinyl and the like;
(C) those containing 1 to 2 sulfur atoms, such as thienyl, thiepinyl, dihydrodithiopyranyl, dihydrodithionyl, 2H-thiopyranyl and the like;
(D) one containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, specifically dihydrooxathiopyranyl and the like;
(E) those containing 1 to 2 oxygen atoms, such as furyl, dihydrofuryl, pyranyl, 2H-pyranyl, oxepinyl, dioxolyl and the like;

(3) a condensed polycyclic saturated heterocyclic group (a) one containing 1 to 5 nitrogen atoms, such as quinuclidinyl, 7-azabicyclo [2.2.1] heptyl, 3-azabicyclo [3.2.2] nonanyl, 2,8-diazaspiro [4.5] dec-8-yl, 2,3,6,8-tetraazaspiro [4.5] decan-8-yl, etc .;
(B) those containing 1 to 4 nitrogen atoms, and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as trithiadiazaindenyl, dioxoleumidazolidinyl, 6- Oxa-2,8-diazaspiro [4.5] decan-8-yl, 6-thia-2,8-diazaspiro [4.5] decan-8-yl and the like;
(C) those containing 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as 2,6-dioxabicyclo [3.2.2] oct-7-yl, 2-oxa-6- Thiaspiro [4.5] decan-8-yl, etc .;

(4) condensed polycyclic unsaturated heterocyclic group (a) one containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, dihydrobenzoimidazolyl, tetrahyzolobenzoimidazolyl, quinolyl, tetrahydro Quinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, imidazopyridyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl, dihydroindazo Ryl, benzopyrimidinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pyridopyrrolidinyl, triazolopiperidinyl, 9, 10-dihydroacridine, 2,8-diazaspiro [4.5] dec-3-en-8-yl, 2, 3,6,8 -Tetraazaspiro [4.5] dec-1-en-8-yl and the like;
(B) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as benzothiazolyl, dihydrobenzothiazolyl, benzothiadiazolyl, imidazothia Zolyl, imidazothiadiazolyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, benzoxiadiazolyl, benzisothiazolyl, benzisoxazolyl, thiazolopiperidinyl, 10H-phenothiazine 6-oxa-2,8-diazaspiro [4.5] dec-3-en-8-yl, 6-thia-2,8-diazaspiro [4.5] dec-3-en-8-yl;
(C) those containing 1 to 3 sulfur atoms, such as benzothienyl, benzodithiopyranyl, chromanyl, dibenzo [b, d] thienyl, etc .;
(D) those containing 1 to 3 sulfur atoms and 1 to 3 oxygen atoms, such as benzooxathiopyranyl, phenoxazinyl, 2-oxa-6-thiaspiro [4.5] dec-3-en-8- Ill etc .;
(E) those containing 1 to 3 oxygen atoms, such as benzodioxolyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromenyl, dibenzo [b, d] furanyl, methylenedioxy Phenyl, ethylenedioxyphenyl, xanthenyl, etc .;
Such.

  The above “aryl”, “cycloalkyl” and “heterocyclic” groups are described as monovalent groups, but in some cases they may represent divalent or higher groups.

  The “nitrogen-containing heterocycle” group is one of the above “heterocycle” groups (1) (a), (1) (b), (2) (a), (2) (b), (3) A material containing 1 to 5 nitrogen atoms, such as (a), (3) (b), (4) (a) and (4) (b).

  The “nitrogen-containing monocyclic saturated heterocycle” group is a group of the above “monocyclic saturated heterocycle” groups such as (1) (a), (1) (b), etc. It contains 5 nitrogen atoms.

  The “nitrogen-containing monocyclic unsaturated heterocycle” group is a group of 1 to 5 of the above “heterocycle” groups such as (2) (a), (2) (b), etc. The thing containing a nitrogen atom.

  The “nitrogen-containing polycyclic saturated heterocycle” group is a group of 1 to 5 of the above “heterocycle” groups, such as (3) (a), (3) (b), etc. The thing containing a nitrogen atom.

  The “nitrogen-containing fused polycyclic unsaturated heterocycle” group is 1 to 5 of the above “heterocycle” groups as in (4) (a) and (4) (b) Containing nitrogen atoms.

  “Halogen” means F, Cl, Br, I, preferably F, Cl.

  “Disease related to amyloid β peptide deposition in the brain” is a concept including a disease related to production and / or deposition of Aβ42, and is not particularly limited. For example, Alzheimer's disease (AD), mild cognitive impairment ( MCI), cerebral amyloid angiopathy, Dutch hereditary cerebral hemorrhage (HCHWA-D), multiple infarct dementia, fighting dementia, or Down syndrome.

  “Aβ1-42” is an abbreviation of amyloid β protein that is excised as a molecular species of amino acid 42 residues, and is an insoluble cell composed of proteins, lipids, carbohydrates and salts in the brains of Alzheimer and Down syndrome patients It is the central component of external deposits (senile or neuritic plaques) (CLMasters et al. PNAS 82, 4245-4249, 1985).

  “Aβx-42” means a molecular species in which the N-terminal side is deleted from “Aβ1-42”.

  “Aβ42” means a generic name including Aβ1-42 and Aβx-42.

In the present specification, “optionally substituted” means unsubstituted or substituted with 1 to 5 substituents. In addition, when it has a some substituent, those substituents may be the same or may mutually differ. For example, —N (lower alkyl) ₂ includes an ethylmethylamino group.

Examples of the substituents allowed in the “optionally substituted aryl”, “optionally substituted cycloalkyl” and “optionally substituted heterocycle” groups in R ⁴ include the following (a ) To (j) and oxo (= O).
(A) Halogen.
(B) -OH, -O-lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens), -O-cycloalkyl (this cycloalkyl is 1 to 3 Optionally substituted with halogen).
(C) amino or nitro optionally substituted with 1 or 2 lower alkyls.
(D) -SH, -S-lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens).
(E) Sulfomoyl optionally substituted with —SO ₂ -lower alkyl, —SO ₂ -cycloalkyl, —SO ₂ -heterocyclic group, —SO ₂ -aryl, 1 or 2 lower alkyls.
(F) -CHO, -CO-lower alkyl, -CO-cycloalkyl (which may be substituted with one or more -O-lower alkyl), -CO-monocyclic saturated heterocycle Group, cyano.
(G) Aryl. The aryl may be substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens).
(H) a heterocyclic group. The heterocyclic group may be substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens).
(I) Cycloalkyl. The cycloalkyl may be substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens).
(J) Lower alkyl which may be substituted with one or more groups selected from the substituents shown in the above (a) to (i).

In R ^4, as the aspect of the substituents allowed in the "optionally substituted lower alkyl", for example, group and oxo shown in the above (a) ~ (i) ( = O) and the like . Another embodiment includes the group shown in the above (a).

As an embodiment of the substituent allowed in the “optionally substituted aryl”, “optionally substituted cycloalkyl” and “optionally substituted heterocycle” groups in R ¹ and R ² , For example, the group shown by said (a)-(j) and oxo (= O) are mentioned. Another embodiment includes the groups shown in the above (a), (b), (f) and (j).

As an embodiment of the substituents allowed in “optionally substituted lower alkyl”, “optionally substituted lower alkenyl” and “optionally substituted lower alkynyl” in R ¹ and R ² , For example, the group shown by said (a)-(i) and oxo (= O) are mentioned. Another embodiment includes the groups shown in the above (a) to (b) and (g) to (i). Still another embodiment includes the groups shown in the above (a) and (g).

The aspect of the substituents allowed in the "optionally substituted lower alkyl" for R ^5, for example, groups represented by the above (a) ~ (i). Another embodiment includes the group shown in the above (a).

  As an aspect with the substituent accept | permitted in "lower alkylene which may be substituted" in L, group shown by said (a)-(h) is mentioned, for example. Another embodiment includes the group shown in the above (b).

  As an aspect with the substituent accept | permitted in "the lower alkyl which may be substituted" in L, group shown by said (a)-(h) is mentioned, for example. Another embodiment includes the group shown in the above (a).

As an aspect with the substituent accept | permitted in "lower alkyl which may be substituted" in R ^{< X1>} and R ^<X2>, group shown by said (a) is mentioned, for example.

The R ^3, R ^5, R ^W1 and aspects of the substituents allowed in the "optionally substituted lower alkyl" for R ^W2, for example, groups represented by the above (a).

  As an aspect with the substituent accept | permitted in "the tetrazole group which may be substituted" in Z, group shown by said (g)-(j) is mentioned, for example.

Moreover, another aspect of this invention compound (I) is shown below.
(1) A compound in which R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are H.
(2) R ¹ and R ² are the same or different from each other, and may be substituted lower alkyl, O- (optionally substituted lower alkyl), optionally substituted lower alkenyl, substituted A compound which is an optionally substituted cycloalkyl, O- (optionally substituted cycloalkyl), optionally substituted aryl, or optionally substituted heterocyclic group.
(3) R ¹ and R ² are the same or different from each other and may be substituted with a halogenated branched lower alkyl, a linear lower alkyl substituted with a halogen, a halogen or a lower alkyl (this lower alkyl) Is optionally substituted with 1 to 3 halogens, optionally substituted with cycloalkyl, halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) Aryl) optionally substituted with O- (cycloalkyl), halogen or lower alkyl optionally substituted with 1 to 3 halogens, which may be substituted with 1 to 3 halogens, Or a heterocyclic group which may be substituted with halogen or lower alkyl (which may be substituted with 1 to 3 halogens) Compound.
(4) R ¹ and R ² are the same or different from each other and may be substituted with a halogenated branched lower alkyl, a linear lower alkyl substituted with a halogen, a halogen or a lower alkyl (this lower alkyl Is optionally substituted with 1 to 3 halogens) C _5-7 cycloalkyl optionally substituted with halogen, O- (C _5-7 cycloalkyl) _optionally substituted with halogen, A compound which is phenyl optionally substituted by halogen or lower alkyl (this lower alkyl may be substituted by 1 to 3 halogens), or tetrahydropyran optionally substituted by halogen.
(5) R ¹ is lower alkyl having a quaternary carbon which may be substituted with halogen, and R ² is lower alkyl having a quaternary carbon which may be substituted with halogen, or halogen or lower A compound which is C _5-7 cycloalkyl _optionally substituted with alkyl (this lower alkyl may be substituted with 1 to 3 halogens).
(6) A compound wherein R ¹ is lower alkyl having a quaternary carbon and R ² is lower alkyl having a quaternary carbon or C _5-7 cycloalkyl.
(7) The compound in which R ¹ and R ² are the same or different from each other and may be substituted cycloalkyl.
(8) R ¹ is the same as or different from R ¹ and R ^{2, and} is substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) A compound that is a good cycloalkyl.
(9) R ¹ is the same as or different from R ¹ and R ^{2, and} is substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) A compound that may be C _5-7 cycloalkyl.
(10) R ¹ is the same as or different from R ¹ and R ^{2, and} is substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) Cyclopentyl, halogen, or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) optionally substituted with cyclohexyl, or halogen or lower alkyl (this lower alkyl is A compound which is optionally substituted with 1 to 3 halogens).
(11) Cyclopentyl in which R ¹ and R ² are the same or different from each other and may be substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens), Cyclohexyl optionally substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens), or halogen or lower alkyl (this lower alkyl is 1 to 3 A compound which is optionally substituted with a halogen).
(12) R ¹ and R ² are the same or different from each other, and may be cyclohexyl which may be substituted with halogen or lower alkyl (which may be substituted with 1 to 3 halogens). A compound.
(13) The compound wherein R ¹ is cyclopentyl and R ² is 4,4-dimethylcyclohexyl.
(14) The compound in which R ¹ and R ² are the same or different from each other and are cyclopentyl, cyclohexyl, or cycloheptyl.
(15) The compound wherein R ¹ is cyclopentyl and R ² is cyclopentyl.
(16) The compound wherein R ¹ is cyclopentyl and R ² is cyclohexyl.
(17) The compound wherein R ¹ is cyclohexyl and R ² is cyclohexyl.
(18) The compound wherein R ¹ is cyclohexyl and R ² is cycloheptyl.
(19) The compound wherein R ¹ is cycloheptyl and R ² is cycloheptyl.
(20) The compound wherein R ¹ and R ² are the same or different from each other and optionally substituted aryl.
(21) R ¹ and R ² may be the same or different from each other and may be substituted with halogen, cyano or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) A compound that is aryl.
(22) R ¹ and R ² may be the same or different from each other and may be substituted with halogen, cyano or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens). A compound that is phenyl.
(23) The compound wherein R ¹ and R ² are the same or different from each other and are phenyl optionally substituted with F or trifluoromethyl.
(24) The compound wherein R ¹ and R ² are the same or different from each other and are phenyl or 4-trifluorophenyl.
(25) The compound wherein R ¹ and R ² are the same or different from each other and optionally substituted lower alkyl.
(26) A compound in which R ¹ and R ² are the same or different from each other and are branched lower alkyl optionally substituted with halogen, or linear lower alkyl substituted with halogen.
(27) The compound wherein R ¹ and R ² are the same or different from each other and are trifluoromethyl, isopropyl or tert-butyl.
(28) The compound wherein R ¹ and R ² are isopropyl.
(29) The compound wherein R ¹ is isopropyl and R ² is trifluoromethyl.
(30) R ¹ is lower alkyl having a quaternary carbon which may be substituted by halogen, and R ² is substituted by lower alkyl having a quaternary carbon which may be substituted by halogen, or halogen And a straight chain lower alkyl.
(31) The compound wherein R ¹ and R ² are the same or different from each other and are lower alkyl having a quaternary carbon which may be substituted with halogen.
(32) The compound wherein R ¹ and R ² are tert-butyl.
(33) The compound wherein R ¹ is optionally substituted lower alkyl and R ² is optionally substituted cycloalkyl.
(34) R ¹ is a branched lower alkyl which may be substituted with halogen, or linear lower alkyl substituted with halogen, and R ² is halogen or lower alkyl (this lower alkyl is Compound which is cycloalkyl optionally substituted with 1 to 3 halogens.
(35) R ¹ is a branched lower alkyl which may be substituted with halogen, or linear lower alkyl substituted with halogen, and R ² is halogen or lower alkyl (this lower alkyl is A compound which is C _5-7 cycloalkyl _optionally substituted with 1 to 3 halogens.
(36) The compound wherein R ¹ is branched lower alkyl optionally substituted with halogen, and R ² is cyclopentyl, cyclohexyl or cycloheptyl.
(37) The compound wherein R ¹ is isopropyl or tert-butyl and R ² is cyclopentyl, cyclohexyl or cycloheptyl.
(38) The compound wherein R ¹ is isopropyl and R ² is cyclohexyl.
(39) The compound wherein R ¹ is lower alkyl having a quaternary carbon which may be substituted with halogen, and R ² is cyclopentyl, cyclohexyl or cycloheptyl.
(40) The compound wherein R ¹ is tert-butyl and R ² is cyclopentyl, cyclohexyl or cycloheptyl.
(41) The compound wherein R ¹ is tert-butyl and R ² is cyclohexyl.
(42) R ¹ is a branched lower alkyl which may be substituted with halogen, or linear lower alkyl substituted with halogen, and R ² is halogen or lower alkyl (this lower alkyl is A compound which is aryl optionally substituted with 1 to 3 halogens.
(43) R ¹ is a branched lower alkyl which may be substituted with halogen, or linear lower alkyl substituted with halogen, and R ² is halogen or lower alkyl (this lower alkyl is A compound which is phenyl optionally substituted with 1 to 3 halogens.
(44) The compound wherein R ¹ is trifluoromethyl or isopropyl and R ² is phenyl (this phenyl may be substituted with tert-butyl, methyl, trifluoromethyl or cyano).
(45) R ¹ is isopropyl, and R ² is phenyl, 4-methylphenyl, 4-tert-butylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, or 4-trifluoro A compound that is methylphenyl.
(46) The compound wherein R ¹ is trifluoromethyl and R ² is phenyl (this phenyl may be substituted with tert-butyl, methyl, trifluoromethyl or cyano).
(47) The compound wherein R ¹ is trifluoromethyl and R ² is phenyl or 4-trifluoromethylphenyl.
(48) A compound wherein q and p are the same or different from each other and are 1 or 2.
(49) A compound wherein q and p are the same or different from each other and are 2 or 3.
(50) The compound wherein q is 1 or 2, and p is 0 or 1.
(51) The compound wherein q is 1, 2 or 3, and p is 0.
(52) The compound wherein q is 2 or 3, and p is 1.
(53) The compound wherein q is 0 and p is 1, 2, or 3.
(54) The compound wherein q is 2 and p is 1 or 2.
(55) The compound wherein q and p are 1.
(56) The compound wherein q and p are 2.
(57) The compound wherein q is 2 and p is 1.
(58) The compound wherein W is a single bond.
(59) The compound wherein W is -CR ^W1 R ^W2- .
(60) The compound in which R ^W1 and R ^W2 are the same or different from each other and are H, halogen, or lower alkyl optionally substituted with halogen.
(61) The compound wherein R ^W1 and R ^W2 are H.
(62) The compound wherein R ³ is H, halogen, or lower alkyl optionally substituted with halogen.
(63) The compound wherein R ³ is H.
(64) R ⁴ may be substituted with lower alkyl optionally substituted with halogen, halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) Aryl optionally substituted with cycloalkyl, halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens), or halogen or lower alkyl (this lower alkyl is 1 A compound which is a heterocyclic group which may be substituted with 1 to 3 halogen atoms.
(65) R ⁴ may be substituted with lower alkyl optionally substituted with halogen, halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) Aryl, halogen or lower alkyl optionally substituted with cycloalkyl, halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) A compound which is a nitrogen-containing heterocyclic group which may be substituted with (optionally substituted with 3 halogens).
(66) The compound wherein R ⁴ is phenyl which may be substituted with halogen or lower alkyl (the lower alkyl may be substituted with 1 to 3 halogens).
(67) R ⁴ is phenyl, 4-methylphenyl, 4-isopropylphenyl, 4-isobutylphenyl, 4-tert-butylphenyl, 4-tert-pentylphenyl, 4-tert-hexylphenyl, 4- (2- Cyclopropylethyl) phenyl, 4-cyclopentylphenyl, 4-cyclohexylphenyl, 4- (tetrahydro-2H-pyran-4-yl) phenyl, 3,5-dimethylphenyl, 2-methoxyphenyl, 4-fluoro-2- Methylphenyl, 4-fluoro-3-methylphenyl, 3-fluoro-4-methylphenyl, 3-chloro-4-methylphenyl, 5-chloro-2-fluoro-4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2,6-difluorophenyl, 2, 3,4- Lifluorophenyl, 2,4,5-trifluorophenyl, 3,4,5-trifluorophenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-fluoro-3-trifluoromethyl, 4-cyanophenyl, 4-methylsulfonylphenyl, or 4- (pentafluoro A compound which is -λ ⁶ -sulfanyl) phenyl.
(68) The compound wherein R ⁴ is 4-trifluoromethylphenyl.
(69) The compound wherein R ⁵ is H, halogen, or lower alkyl optionally substituted with halogen.
(70) The compound wherein R ⁵ is H.
(71) The compound wherein R ^X1 and R ^X2 are the same or different from each other and are H, halogen, or lower alkyl optionally substituted with halogen.
(72) The compound wherein R ^X1 and R ^X2 are H.
(73) The compound wherein n is 2.
(74) The compound wherein n is 3.
(75) The compound wherein Y is a single bond.
(76) The compound wherein Y is -CH _2- .
(77) The compound wherein L is optionally substituted lower alkylene.
(78) The compound wherein L is methylene.
(79) The compound wherein Z is -C (= O) -OH.
(80) The compound wherein Z is tetrazolyl.
Further, another embodiment of the compound (I) of the present invention is a compound comprising a combination of two or more of the groups described in the above (1) to (80), and specifically includes the following compounds: It is done.
(81) The compound according to (2) to (47), wherein R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are H.
(82) The compound described in (1) to (47) or (81), wherein q and p are the same or different from each other and are 1 or 2.
(83) The compounds according to (1) to (47) or (81), wherein q and p are the same or different from each other and are 2 or 3.
(84) The compound according to (1) to (47) or (81), wherein q is 1 or 2, and p is 0 or 1.
(85) The compound described in (1) to (47) or (81), wherein q is 1, 2 or 3, and p is 0.
(86) The compound described in (1) to (47) or (81), wherein q is 2, or 3, and p is 1.
(87) The compound described in (1) to (47) or (81), wherein q is 0, and p is 1, 2, or 3.
(88) The compound described in (1) to (47) or (81), wherein q is 2, and p is 1, or 2.
(89) The compound according to (1) to (47) or (81), wherein q and p are 1.
(90) The compound according to (1) to (47) or (81), wherein q and p are 2.
(91) The compound described in (1) to (47) or (81), wherein q is 2 and p is 1.
(92) The compound according to (1) to (57) or (81) to (91), wherein W is a single bond.
(93) The compounds described in (1) to (57) or (81) to (91), wherein W is -CR ^W1 R ^W2- .
(94) R ^W1 and R ^W2 are the same or different from each other and are H, halogen, or lower alkyl optionally substituted with halogen (1) to (57), (59), (81) to (91) or the compound according to (93).
(95) The compound according to (1) to (57), (59), (81) to (91), or (93), wherein R ^W1 and R ^W2 are H.
(96) The compound described in (1) to (61) or (81) to (95), wherein R ³ is H, halogen, or lower alkyl optionally substituted with halogen.
(97) The compound described in (1) to (61) or (81) to (95), wherein R ³ is H.
(98) R ⁴ may be substituted with lower alkyl optionally substituted with halogen, halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) Aryl optionally substituted with cycloalkyl, halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens), or halogen or lower alkyl (this lower alkyl is 1 The compound according to (1) to (63) or (81) to (97), which is a heterocyclic group which may be substituted with 1 to 3 halogen atoms.
(99) R ⁴ may be substituted with lower alkyl optionally substituted with halogen, halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) Aryl, halogen or lower alkyl optionally substituted with cycloalkyl, halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) The compound according to (1) to (63) or (81) to (97), which is a nitrogen-containing heterocyclic group which may be substituted with (optionally substituted with three halogens).
(100) R ⁴ is phenyl optionally substituted with halogen or lower alkyl (this lower alkyl may be substituted with 1 to 3 halogens) (1) to (63), Or the compound of (81)-(97) description.
(101) R ⁴ is phenyl, 4-methylphenyl, 4-isopropylphenyl, 4-isobutylphenyl, 4-tert-butylphenyl, 4-tert-pentylphenyl, 4-tert-hexylphenyl, 4- (2- Cyclopropylethyl) phenyl, 4-cyclopentylphenyl, 4-cyclohexylphenyl, 4- (tetrahydro-2H-pyran-4-yl) phenyl, 3,5-dimethylphenyl, 2-methoxyphenyl, 4-fluoro-2- Methylphenyl, 4-fluoro-3-methylphenyl, 3-fluoro-4-methylphenyl, 3-chloro-4-methylphenyl, 5-chloro-2-fluoro-4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2,6-difluorophenyl, 2, 3,4 -Trifluorophenyl, 2,4,5-trifluorophenyl, 3,4,5-trifluorophenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluoro Phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-fluoro-3-trifluoromethyl, 4-cyanophenyl, 4-methylsulfonylphenyl, or 4- (penta The compound according to (1) to (63) or (81) to (97), which is fluoro-λ ⁶ -sulfanyl) phenyl.
(102) The compounds according to (1) to (63) or (81) to (97), wherein R ⁴ is 4-trifluoromethylphenyl.
(103) The compound described in (1) to (68) or (81) to (102), wherein R ⁵ is H, halogen, or lower alkyl optionally substituted with halogen.
(104) The compound according to (1) to (68) or (81) to (102), wherein R ⁵ is H.
(105) (1) to (70) or (81) to (104) wherein R ^X1 and R ^X2 are the same or different from each other and are H, halogen, or lower alkyl optionally substituted with halogen. ) Described compounds.
(106) The compounds according to (1) to (70) or (81) to (104), wherein R ^X1 and R ^X2 are H.
(107) The compound described in (1) to (72) or (81) to (106), wherein n is 2.
(108) The compound according to (1) to (72) or (81) to (106), wherein n is 3.
(109) The compound according to (1) to (74) or (81) to (108), wherein Y is a single bond.
(110) The compound according to (1) to (74) or (81) to (108), wherein Y is —CH ₂ —.
(111) The compounds according to (1) to (76) or (81) to (110), wherein L is optionally substituted lower alkylene.
(112) The compounds according to (1) to (76) or (81) to (110), wherein L is methylene.
(113) The compound described in (1) to (78) or (81) to (112), wherein Z is —C (═O) —OH.
(114) The compounds according to (1) to (78) or (81) to (112), wherein Z is tetrazolyl.

Examples of specific compounds included in the present invention include the following compounds or salts thereof.
{(1R ^* , 3S ^* , 4R ^* )-4- [bis (cyclohexylmethyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid,
{(1R ^* , 3S ^* , 4R ^* )-{4-[(cyclohexylmethyl) (3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid,
{(1R ^* , 3S ^* , 4R ^* )-4- [bis (3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid,
{(1R ^* , 3S ^* , 4R ^* )-4-[(3 methylbutyl) (3,3,3-trifluoropropyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid,
rac-[(1R, 3S, 4R) -4- [bis (cyclohexylmethyl) amino] -3- (4-chlorophenyl) cyclohexyl] acetic acid,
rac-{(1R, 3S, 4R) -4-[(2-cyclopentylethyl) (4,4-dimethylcyclohexyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid,
rac-[(1R, 3S, 4R) -4- [bis (cyclohexylmethyl) amino] -3- (3,5-difluorophenyl) cyclohexyl] acetic acid,
rac-[(1R, 3S, 4R) -4- [bis (cyclohexylmethyl) amino] -3- (3-fluorophenyl) cyclohexyl] acetic acid,
[(1R ^* , 3S ^* , 4R ^* )-4-[(cyclohexylmethyl) (3,3-dimethylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid,
{(1R ^* , 2S ^* , 3R ^* )-3- [bis (cyclohexylmethyl) amino] -2- (2-fluorophenyl) cyclohexyl} acetic acid,
{(1R ^* , 2S ^* , 3R ^* )-3- [bis (cyclohexylmethyl) amino] -2- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid,
{(1R ^* , 2S ^* , 3R ^* )-3-[(cyclohexylmethyl) (3-methylbutyl) amino] -2- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid,
{(1R ^* , 2S ^* , 3R ^* )-3-[(cyclohexylmethyl) (3,3-dimethylbutyl) amino] -2- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid,
{(1R ^* , 2S ^* , 3R ^* )-3- [bis (3,3-dimethylbutyl) amino] -2- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid,
rac-[(1R, 3S, 4R) -4- [bis (cyclohexylmethyl) amino] -3- (3,4,5-trifluorophenyl) cyclohexyl] acetic acid,
rac-[(1R, 3S, 4R) -4- [bis (cyclohexylmethyl) amino] -3- (3,4-difluorophenyl) cyclohexyl] acetic acid, or
{(1R ^* , 2S ^* , 3R ^* )-3- [Bis (3,3-dimethylbutyl) amino] -2- [4-fluoro-3- (trifluoromethyl) phenyl] cyclohexyl} acetic acid.

  Examples of specific compounds included in the present invention include the following compounds. “Rac-” means a racemate of the described compound and its enantiomer.

In the compound of the formula (I), tautomers and geometric isomers may exist depending on the type of substituent. In the present specification, the compound of the formula (I) may be described in only one form of an isomer, but the present invention includes other isomers, separated isomers, or those isomers. And mixtures thereof.
In addition, the compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers based on these may exist. The present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.

  Furthermore, this invention also includes the pharmaceutically acceptable prodrug of the compound shown by a formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.

  The salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. is there. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine and ammonium salts Etc.

  Furthermore, the present invention also includes various hydrates and solvates of the compound of formula (I) and salts thereof, and polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

ABS-SINGLE-2：製造例606の方法で合成される左施性(-)を有する化合物、もしくは、当該化合物を原料として製造される化合物であり、シクロヘキサン環上の置換基が以下のいずれかの立体構造を有する化合物を意味する。ABS-SINGLE-1の鏡像異性体を意味する、

ABS-SINGLE-3：ABS-SINGLE-5の化合物を原料として製造され、シクロヘキサン環上の置換基が以下のいずれかの立体構造を有する化合物、

ABS-SINGLE-4：ABS-SINGLE-6の化合物を原料として製造され、シクロヘキサン環上の置換基が以下のいずれかの立体構造を有する化合物、

ABS-SINGLE-5：シクロヘキサン環上の置換基が以下のいずれかの立体構造を有する化合物であり、当該化合物が得られる反応においてこれらのうちで優先的に得られる化合物、

ABS-SINGLE-6：シクロヘキサン環上の置換基が以下のいずれかを立体構造を有する化合物であり、当該化合物が得られる反応においてこれらのうちで優先的に得られる化合物、

Structure：構造式、
Syn：製造法（数字の前にEがある場合は同様に製造した実施例番号を、数字の前にRがある場合は同様に製造した製造例番号をそれぞれ示す。）、
Acid：構造式記載の化合物が記載された酸と塩を形成していることを示し、酸の前の数字は酸の比を意味し、例えば、2HClは、2塩酸塩を形成することを意味する、
HCl：塩酸、
BA：ベンゼンスルホン酸、
DMSO：ジメチルスルホキシド、
THF：テトラヒドロフラン、
EtOAc：酢酸エチル、
DMF：N,N-ジメチルホルムアミド、
M：mol/L。 In the present specification, the following symbols are used.
Rf: Production example number (when a or b is written after the number, it means that two products were obtained in one reaction),
Ex: Example number (when a or b is written after the number, it means that two products were obtained in one reaction),
Data: Physicochemical data,
FAB +: Shows m / z value in FAB-MS (positive ion), and shows [M + H] ⁺ peak unless otherwise specified.
FAB-: FAB-MS showed the m / z value in (anion) Unless otherwise specified [MH] ^- a peak,
ESI +: Shows m / z value in ESI-MS (positive ion), and shows [M + H] ⁺ peak unless otherwise specified.
ESI-: ESI-MS showed the m / z value in (anion) Unless otherwise specified [MH] ^- a peak,
EI: Shows m / z value in EI-MS (positive ion), and shows M ⁺ peak unless otherwise specified.
CI +: Shows m / z value in CI-MS (positive ion), and shows [M + H] ⁺ peak unless otherwise specified.
APCI / ESI +: Shows the m / z value in APCI / ESI (positive ion), showing [M + H] ⁺ peak unless otherwise specified,
NMR1: δ (ppm) of a typical peak in ¹ H NMR in CDCl ₃ ,
NMR2: δ (ppm) of a typical peak in ¹ H NMR in pyridine-d6,
NMR3: δ (ppm) of a typical peak in ¹ H NMR in CD ₃ OD,
RT: Retention when CHIRALPAK AD-H is used for the column and hexane / EtOH / Et ₂ NH (80: 20: 0.1) eluate is run at a flow rate of 0.8 mL / min and detected by UV absorption (254 nm) Indicates time (min),
Configuration: means the three-dimensional structure of the compound
rac: means racemic,
-: Means the structure as described,
ABS-SINGLE-1: A compound having right applicability (+) synthesized by the method of Production Example 606, or a compound produced using the compound as a raw material, and the substituent on the cyclohexane ring is one of the following: Means a compound having the following three-dimensional structure. Means the enantiomer of ABS-SINGLE-2,

ABS-SINGLE-2: A compound having a left application property (-) synthesized by the method of Production Example 606, or a compound produced using the compound as a raw material, and the substituent on the cyclohexane ring is any of the following: Means a compound having the following three-dimensional structure. Means the enantiomer of ABS-SINGLE-1,

ABS-SINGLE-3: A compound produced from ABS-SINGLE-5 as a raw material, and the substituent on the cyclohexane ring has one of the following three-dimensional structures,

ABS-SINGLE-4: A compound produced from ABS-SINGLE-6 as a raw material, the substituent on the cyclohexane ring has any of the following three-dimensional structures,

ABS-SINGLE-5: a compound in which a substituent on the cyclohexane ring has any one of the following three-dimensional structures, and a compound obtained preferentially among these in a reaction to obtain the compound,

ABS-SINGLE-6: a compound in which the substituent on the cyclohexane ring has a steric structure with any of the following, and a compound obtained preferentially among these in a reaction to obtain the compound,

Structure:
Syn: Production method (when E is preceded by a number, an example number produced in the same manner is indicated, and when R is preceded by a number, a production example number produced in the same manner is indicated),
Acid: Indicates that the compound represented by the structural formula forms a salt with the described acid, the number before the acid means the ratio of the acid, for example, 2HCl means the formation of the dihydrochloride salt To
HCl: hydrochloric acid,
BA: benzenesulfonic acid,
DMSO: dimethyl sulfoxide,
THF: tetrahydrofuran,
EtOAc: ethyl acetate,
DMF: N, N-dimethylformamide,
M: mol / L.

(Production method)
The compound of the formula (I) and a salt thereof can be produced by applying various known synthesis methods utilizing characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protective group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There is a case. In particular, among the following production examples and example compounds, when a compound having OH is used, it may be desirable to introduce an appropriate protecting group so that the OH group does not cause a side reaction, so that the reaction proceeds. . Examples of such protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected according to the reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.
Also, the prodrug of the compound of formula (I) introduces a specific group at the stage from the raw material to the intermediate, or reacts further using the obtained compound of formula (I), as in the case of the protecting group. Can be manufactured. The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
Hereinafter, typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description. In addition, the manufacturing method of this invention is not limited to the example shown below.

本発明化合物（Ｉ）は、化合物（２７）とアルデヒド類若しくはケトン類との反応により得ることができる。
この反応では、化合物（２７）とアルデヒド類若しくはケトン類とを等量若しくは一方を過剰量用い、これらの混合物を、還元剤の存在下、反応に不活性な溶媒中、-45℃から加熱還流下、好ましくは0℃〜室温において、通常0.1時間〜5日間撹拌する。ここで用いられる溶媒の例としては、特に限定されないが、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、及びこれらの混合物が挙げられる。還元剤としては、シアン化水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム等が挙げられる。モレキュラーシーブス等の脱水剤、又は酢酸、塩酸等の酸、チタニウム（IV）イソプロポキシド錯体等の添加剤存在下で反応を行うことが好ましい場合がある。また、前記還元剤での処理の代わりに、メタノール、エタノール、酢酸エチル等の溶媒中、酢酸、塩酸等の酸の存在下又は非存在下で、還元触媒（例えば、パラジウム炭素、ラネーニッケル等）を用いて反応を行うこともできる。この場合、反応を常圧から50気圧の水素雰囲気下で、冷却下から加熱下で行うことが好ましい。
また、本反応は、化合物（２７）とR²-(CR¹³R¹⁴)_p-Lvとの反応によっても得ることができる。ここでLvは、脱離基を表し、例えば、ハロゲン、メタンスルホニルオキシ、p-トルエンスルホニルオキシ基等が含まれる。本反応は、化合物（２７）とR²-(CR¹³R¹⁴)_p-Lvとを等量もしくは一方を過剰量用い、これらの混合物を塩基の存在下、反応に不活性な溶媒中、-45℃から加熱還流下、好ましくは0℃から80℃において、通常0.1時間〜5日間する。ここで用いられる溶媒の例としては、特に限定されないが、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル及びこれらの混合物が挙げられる。また、ここで用いられる塩基としては、炭酸セシウム、リン酸カリウム、炭酸カリウム、炭酸ナトリウム若しくは水酸化カリウム等の無機塩基、又は、トリエチルアミン、N,N-ジイソプロピルエチルアミン若しくはN-メチルモルホリン等の有機塩基が挙げられる。また、ナトリウムヨージド、テトラブチルアンモニウムヨージド等の添加剤の存在下で反応を行うのが、反応を円滑に進行させる上で有利な場合がある。
〔文献〕
A. R. Katritzky及びR. J. K. Taylor著、「Comprehensive Organic Functional Group Transformations II」、第2巻、Elsevier Pergamon、2005年
日本化学会編「実験化学講座(第5版)」14巻(2005年)(丸善) (First manufacturing method)

The compound (I) of the present invention can be obtained by reacting the compound (27) with aldehydes or ketones.
In this reaction, an equal amount or an excess amount of compound (27) and aldehydes or ketones are used, and a mixture thereof is heated to reflux from −45 ° C. in a solvent inert to the reaction in the presence of a reducing agent. Under stirring, preferably at 0 ° C. to room temperature, usually for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, but halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like. And ethers thereof, and mixtures thereof. Examples of the reducing agent include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like. It may be preferable to carry out the reaction in the presence of a dehydrating agent such as molecular sieves, or an acid such as acetic acid or hydrochloric acid, or an additive such as a titanium (IV) isopropoxide complex. Further, instead of the treatment with the reducing agent, a reduction catalyst (for example, palladium carbon, Raney nickel, etc.) is used in a solvent such as methanol, ethanol, ethyl acetate, in the presence or absence of an acid such as acetic acid or hydrochloric acid. Can also be used to carry out the reaction. In this case, it is preferable to carry out the reaction under a hydrogen atmosphere at normal pressure to 50 atm and under cooling to heating.
This reaction can also be obtained by reacting compound (27) with R ^2- (CR ¹³ R ¹⁴ ) _p -Lv. Here, Lv represents a leaving group and includes, for example, halogen, methanesulfonyloxy, p-toluenesulfonyloxy group and the like. In this reaction, the compound (27) and R ^2- (CR ¹³ R ¹⁴ ) _p -Lv are used in an equal amount or in an excess amount, and a mixture of these in a solvent inert to the reaction in the presence of a base, The reaction is carried out at 45 ° C. under heating and reflux, preferably at 0 ° C. to 80 ° C., usually for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, but halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N, N- Examples include dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof. The base used here is an inorganic base such as cesium carbonate, potassium phosphate, potassium carbonate, sodium carbonate or potassium hydroxide, or an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine. Is mentioned. In addition, it may be advantageous to carry out the reaction in the presence of an additive such as sodium iodide, tetrabutylammonium iodide, etc., in order to facilitate the reaction.
[Reference]
AR Katritzky and RJK Taylor, `` Comprehensive Organic Functional Group Transformations II '', Volume 2, Elsevier Pergamon, 2005 Chemical Society of Japan, `` Experimental Chemistry Course (5th Edition) '', Volume 14 (2005) (Maruzen)

本発明化合物（Ｉ）のうち化合物（Ｉａ）は、化合物（２６）とアミン類との反応により得ることができる。本反応は、前述の（第１製法）と同様の反応条件を用いて行うことができる。 (Second manufacturing method)

Among the compounds (I) of the present invention, compound (Ia) can be obtained by reacting compound (26) with amines. This reaction can be carried out using the same reaction conditions as in the aforementioned (first production method).

（式中、R^Prは、低級アルキル、アリールなどの反応後にカルボン酸の保護基となる置換基を、TMSは、トリメチルシリル基を示す。）
化合物（２）は、化合物（１）とアルコール類もしくはフェノール類（２８）との反応により得ることができる。
この反応では、化合物（２）と等量若しくは過剰量のアルコール類もしくはフェノール類（２８）とを用い、これらの混合物を、反応に不活性な溶媒中、又は無溶媒下、冷却下から加熱還流下、好ましくは0℃から80℃において、通常0.1時間〜5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル及びこれらの混合物が挙げられる。硫酸、塩酸、塩化チオニル等の酸の存在下で反応を行うのが、反応を円滑に進行させる上で有利な場合がある。
また、上記反応は、縮合剤の存在下で行うこともできる。ここで用いられる縮合剤の例としては、特に限定されないが、ジシクロヘキシルカルボジイミド、ジイソプロピルカルボジイミド、1-エチル-3-（3-ジメチルアミノプロピル）カルボジイミド塩酸塩(WSC・HCl)等を用いることができる。
〔文献〕
S. R. Sandler及びW. Karo著、「Organic Functional Group Preparations」、第2版、第1巻、Academic Press Inc.、1991年
日本化学会編「実験化学講座(第5版)」14巻(2005年)(丸善)
次に、化合物（３）は、化合物（２）と化合物（２３）とのディールス-アルダー（Diels-Alder）反応により合成できる。
この反応では、化合物（２）と等量若しくは過剰量の化合物（２９）との混合物を、反応に不活性な溶媒中、又は無溶媒下、冷却下から加熱下、好ましくは・・・℃から15・℃、更に好ましくは0〜13・℃で、通常1時間から10日間、好ましくは1〜3日間程度反応させる。これらの工程で用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類が挙げられる。 (Raw material synthesis 1)

(In the formula, R ^Pr represents a substituent that becomes a protective group for carboxylic acid after the reaction of lower alkyl, aryl, etc., and TMS represents a trimethylsilyl group.)
Compound (2) can be obtained by reacting compound (1) with alcohols or phenols (28).
In this reaction, the compound (2) is used in an equal or excessive amount of an alcohol or phenol (28), and the mixture is heated to reflux in a solvent inert to the reaction or in the absence of solvent and from under cooling. Under stirring, preferably at 0 ° C. to 80 ° C., usually for 0.1 hour to 5 days. Examples of the solvent used here include, but are not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dichloromethane and 1,2-dichloroethane. Halogenated hydrocarbons such as chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof. It may be advantageous to carry out the reaction in the presence of an acid such as sulfuric acid, hydrochloric acid, thionyl chloride, etc., to facilitate the reaction.
The above reaction can also be carried out in the presence of a condensing agent. Examples of the condensing agent used here are not particularly limited, and dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl) and the like can be used.
[Reference]
SR Sandler and W. Karo, “Organic Functional Group Preparations”, 2nd edition, 1st volume, Academic Press Inc. (Maruzen)
Next, the compound (3) can be synthesized by a Diels-Alder reaction between the compound (2) and the compound (23).
In this reaction, a mixture of the compound (2) and an equal amount or an excess amount of the compound (29) is heated in a solvent inert to the reaction or in the absence of solvent, from cooling to heating, preferably from .degree. The reaction is carried out at 15 ° C., more preferably 0 to 13 ° C., usually for 1 hour to 10 days, preferably 1 to 3 days. Examples of the solvent used in these steps include, but are not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, and diethyl ether. , Ethers such as tetrahydrofuran, dioxane, dimethoxyethane and the like.

（R^X1a及びR^X2aは、H以外のR^X1の及びR^X2の基を、Lvは脱離基を、Qは、-(CR^X1R^X2)_n-1-を示す。）
化合物（５）は、化合物（４）とR^X1a-Lvとの付加反応により得ることができる。ここで、脱離基の例には、ハロゲン、メタンスルホニルオキシ、p-トルエンスルホニルオキシ基等が含まれる。
この反応は、、塩基の存在下、化合物（４）と等量若しくは過剰量のR^X1a-Lvとを用い、これらの混合物を、反応に不活性な溶媒中、又は無溶媒下、冷却下から加熱還流下、好ましくは0℃から80℃において、通常0.1時間〜5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル及びこれらの混合物が挙げられる。ここで用いられる塩基としては、リチウムジイソプロピルアミド(LDA)、リチウムテトラメチルジシラジド(LHMDS)等の金属アミド、又は、炭酸セシウム、リン酸カリウム、炭酸カリウム、炭酸ナトリウム若しくは水酸化カリウム等の無機塩基が挙げられる。
続いて、化合物（６）は、化合物（５）とR^X2a-Lvとの付加反応により得ることができる。本反応は、化合物（３）とR^X1a-Lvと同様の反応条件を用いて行うことができる。 (Raw material synthesis 2)

(R ^X1a and R ^X2a represent R ^X1 and R ^X2 groups other than H, Lv represents a leaving group, and Q represents-(CR ^X1 R ^X2 ) _n-1- .)
Compound (5) can be obtained by addition reaction of compound (4) and R ^X1a -Lv. Here, examples of the leaving group include halogen, methanesulfonyloxy, p-toluenesulfonyloxy group and the like.
In this reaction, compound (4) and an equal amount or excess amount of R ^X1a -Lv are used in the presence of a base, and a mixture thereof is cooled in a solvent inert to the reaction or in the absence of solvent. The mixture is stirred for 0.1 hour to 5 days under heating and reflux, preferably at 0 to 80 ° C. Examples of the solvent used here include, but are not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dichloromethane and 1,2-dichloroethane. Halogenated hydrocarbons such as chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof. The base used here is a metal amide such as lithium diisopropylamide (LDA) or lithium tetramethyldisilazide (LHMDS), or an inorganic substance such as cesium carbonate, potassium phosphate, potassium carbonate, sodium carbonate or potassium hydroxide. A base.
Subsequently, compound (6) can be obtained by addition reaction of compound (5) and R ^X2a -Lv. This reaction can be carried out using the same reaction conditions as for compound (3) and R ^X1a -Lv.

（式中、R^Crは、低級アルキル、アリールなどの反応後にカルボン酸の保護基になる置換基を、R^Pは、低級アルキルを示す。）
化合物（８）は、化合物（７）の加水分解反応により得ることができる。本反応は前述のグリーンらの文献を参照して実施することができる。
化合物（９）は、化合物（８）をアシルアジドへ変換後、クルティウス（Curtius）転位反応によりイソシアナートとした後に、化合物（３０）との付加反応により得ることができる。
アジド化の工程は、反応に不活性な溶媒中、冷却下から加熱下、好ましくは0℃から100℃、更に好ましくは25〜35℃で、化合物（８）を等量若しくは過剰量のジフェニルホスホリルアジド等のアジ化試薬と通常0.1から10時間、好ましくは3〜6時間程度反応させることにより行われる。又は、（８）を酸塩化物等の反応性誘導体とし、アジ化ナトリウム等のアジ化物塩と反応させることによっても製造できる。
転位反応の工程では、アシルアジドを反応に不活性な溶媒中、冷却下から加熱下、好ましくは0℃から100℃、更に好ましくは70〜90℃で、通常0.1から10時間、好ましくは1〜4時間程度反応させることにより行われる。
付加反応の工程では、反応混合物を等量若しくは過剰量の化合物（３０）に加熱下、好ましくは0℃から100℃、更に好ましくは70〜90℃で加えた後通常0.1から10時間、好ましくは1〜3時間程度反応させる。
尚、中間体であるアシルアジド又はイソシアナート体が安定である場合には、これを一旦単離した後に次の反応を行っても良い。
これらの工程で用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、アセトニトリル等が挙げられる。
次に、化合物（１０）は、化合物（９）とリン酸エステル化合物（３１）もしくはホスホニウム塩との反応により得ることができる。本反応は、特に限定はされないが、例えば、ホーナー-エモンズ（Horner-Emmons）反応やウィティッヒ（Wittig）反応により行うことができる。
この反応では、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃から80℃で、化合物（９）を等量若しくは過剰量のリン酸エステル化合物（３１）の存在下で、通常0.1時間〜3日間処理する。ここで用いられる溶媒の例としては、特に限定されないが、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド或いはこれらの混合物が挙げられる。ナトリウムビス(トリメチルシリル)アミド、n-ブチルリチウム、tert-ブトキシカリウム、ナトリウムエトキシド、ナトリウムメトキシド、水素化ナトリウム等の塩基の存在下で反応を行うのが、反応を円滑に進行させる上で有利な場合がある。リン酸エステル化合物（３１）の例としては、ホスホノ酢酸トリエチル等が挙げられる。
化合物（１１）は、化合物（１０）の水素添加反応及び脱保護反応により得ることができる。
この反応では、水素雰囲気下、反応に不活性な溶媒中、化合物（１０）を金属触媒存在下で、通常1時間〜5日間撹拌する。この反応は、通常、冷却下から加熱下、好ましくは室温で行われる。ここで用いられる溶媒の例としては、特に限定されないが、メタノール、エタノール、2-プロパノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、水、酢酸エチル、N,N-ジメチルホルムアミド、ジメチルスルホキシド及びこれらの混合物が挙げられる。金属触媒としては、パラジウム炭素、パラジウム黒、水酸化パラジウム等のパラジウム触媒、白金板、酸化白金等の白金触媒、還元ニッケル、ラネーニッケル等のニッケル触媒、テトラキストリフェニルホスフィンクロロロジウム等のロジウム触媒、還元鉄等の鉄触媒等が好適に用いられる。水素ガスの代わりに、化合物（１０）に対し等量〜過剰量のシクロヘキセン、ギ酸またはギ酸アンモニウム等を水素源として用いることもできる。
また、本反応は、化合物（１０）をメタノールの存在下でマグネシウムと接触させることによっても行える場合がある。この反応は、通常、冷却下から加熱下、好ましくは室温で行われる。ここで用いられる溶媒の例としては、特に限定されないが、メタノール、エタノール、2-プロパノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、水、酢酸エチル、N,N-ジメチルホルムアミド、ジメチルスルホキシド及びこれらの混合物が挙げられる。 (Raw material synthesis 3)

(In the formula, R ^Cr represents a substituent that becomes a protecting group for carboxylic acid after the reaction of lower alkyl, aryl, etc., and R ^P represents lower alkyl.)
Compound (8) can be obtained by hydrolysis reaction of compound (7). This reaction can be carried out with reference to the aforementioned Green et al.
The compound (9) can be obtained by converting the compound (8) into an acyl azide and then converting it into an isocyanate by a Curtius rearrangement reaction, followed by an addition reaction with the compound (30).
The azidation step is carried out in a solvent inert to the reaction from cooling to heating, preferably from 0 ° C. to 100 ° C., more preferably from 25 to 35 ° C., and an equivalent or excess amount of diphenylphosphoryl of compound (8). The reaction is usually carried out by reacting with an azide reagent such as azide for about 0.1 to 10 hours, preferably about 3 to 6 hours. Or it can also manufacture by making (8) into reactive derivatives, such as an acid chloride, and making it react with azide salts, such as sodium azide.
In the rearrangement reaction step, the acyl azide is cooled to heated in a solvent inert to the reaction, preferably 0 to 100 ° C., more preferably 70 to 90 ° C., usually 0.1 to 10 hours, preferably 1 to 4 It is carried out by reacting for about an hour.
In the addition reaction step, the reaction mixture is added to an equal or excess amount of compound (30) under heating, preferably at 0 ° C. to 100 ° C., more preferably at 70 to 90 ° C., and usually for 0.1 to 10 hours, preferably React for about 1 to 3 hours.
When the intermediate acyl azide or isocyanate is stable, it may be isolated and then subjected to the next reaction.
Examples of the solvent used in these steps include, but are not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, and diethyl ether. , Ethers such as tetrahydrofuran, dioxane and dimethoxyethane, acetonitrile and the like.
Next, compound (10) can be obtained by reacting compound (9) with phosphate ester compound (31) or phosphonium salt. Although this reaction is not specifically limited, For example, it can carry out by Horner-Emmons (Horner-Emmons) reaction or Wittig (Wittig) reaction.
In this reaction, in a solvent inert to the reaction, from cooling to heating, preferably from −20 ° C. to 80 ° C., the compound (9) is added in the presence of an equivalent amount or an excess amount of the phosphate ester compound (31). Process usually 0.1 hours to 3 days. Examples of the solvent used here are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, N, N-dimethylformamide and dimethyl Examples thereof include sulfoxide or a mixture thereof. It is advantageous to carry out the reaction in the presence of a base such as sodium bis (trimethylsilyl) amide, n-butyllithium, tert-butoxypotassium, sodium ethoxide, sodium methoxide, sodium hydride, etc., in order to facilitate the reaction. There are cases. Examples of the phosphate ester compound (31) include triethyl phosphonoacetate.
Compound (11) can be obtained by hydrogenation reaction and deprotection reaction of compound (10).
In this reaction, compound (10) is usually stirred for 1 hour to 5 days in the presence of a metal catalyst in a hydrogen inert atmosphere in a solvent inert to the reaction. This reaction is usually carried out under cooling to heating, preferably at room temperature. Examples of the solvent used here are not particularly limited, but alcohols such as methanol, ethanol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, water, ethyl acetate, N, N- Examples include dimethylformamide, dimethyl sulfoxide, and mixtures thereof. As metal catalysts, palladium catalysts such as palladium carbon, palladium black and palladium hydroxide, platinum catalysts such as platinum plate and platinum oxide, nickel catalysts such as reduced nickel and Raney nickel, rhodium catalysts such as tetrakistriphenylphosphine chlororhodium, reduction An iron catalyst such as iron is preferably used. Instead of hydrogen gas, an equivalent amount to an excess amount of cyclohexene, formic acid, ammonium formate, or the like relative to the compound (10) can be used as a hydrogen source.
This reaction may also be performed by bringing compound (10) into contact with magnesium in the presence of methanol. This reaction is usually carried out under cooling to heating, preferably at room temperature. Examples of the solvent used here are not particularly limited, but alcohols such as methanol, ethanol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, water, ethyl acetate, N, N- Examples include dimethylformamide, dimethyl sulfoxide, and mixtures thereof.

まず、化合物（３８）は、化合物（７）の加水分解により得られるカルボン酸体若しくはその反応性誘導体とNH₃とのアミド化反応により得ることができる。
化合物（７）のカルボン酸体を用いる場合、カルボン酸体と等量若しくは過剰量のNH₃を用い、これらの混合物を、縮合剤の存在下、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃〜60℃において、通常0.1時間〜5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン若しくはキシレン等の芳香族炭化水素類、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル又は水、及びこれらの混合物が挙げられる。縮合剤の例としては、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド、ジシクロヘキシルカルボジイミド、1,1'-カルボニルジイミダゾール、ジフェニルリン酸アジド、オキシ塩化リンが挙げられるが、これらに限定されるものではない。添加剤（例えば1-ヒドロキシベンゾトリアゾール）を用いることが反応に好ましい場合がある。トリエチルアミン、N,N-ジイソプロピルエチルアミン若しくはN-メチルモルホリン等の有機塩基、又は炭酸カリウム、炭酸ナトリウム若しくは水酸化カリウム等の無機塩基の存在下で反応を行うことが、反応を円滑に進行させる上で有利な場合がある。
また、本反応は、カルボン酸体の反応性誘導体を用い、NH₃と反応させる方法も用いることができる。カルボン酸の反応性誘導体の例としては、オキシ塩化リン、塩化チオニル等のハロゲン化剤と反応して得られる酸ハロゲン化物、クロロギ酸イソブチル等と反応して得られる混合酸無水物、1-ヒドロキシベンゾトリアゾール等と縮合して得られる活性エステル等が挙げられる。これらの反応性誘導体とNH₃との反応は、ハロゲン化炭化水素類、芳香族炭化水素類、エーテル類等の反応に不活性な溶媒中、冷却下〜加熱下、好ましくは、-20℃〜60℃で行うことができる。
〔文献〕
S. R. Sandler及びW. Karo著、「Organic Functional Group Preparations」、第2版、第1巻、Academic Press Inc.、1991年
日本化学会編「実験化学講座(第5版)」16巻(2005年)(丸善)
次に、化合物（１２）は、化合物（１１）の還元反応により得ることができる。
この反応では、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃から80℃で、化合物（１１）を等量若しくは過剰量の還元剤で、通常0.1時間〜3日間処理する。ここで用いられる溶媒の例としては、特に限定されないが、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、メタノール、エタノール、2-プロパノール等のアルコール類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル及びこれらの混合物が挙げられる。還元剤としては、リチウムアルミニウムヒドリド若しくはジイソブチルアルミウムヒドリド等のヒドリド還元剤、ナトリウム、亜鉛、鉄等の金属還元剤、その他、下記文献中の還元剤が好適に用いられる。
〔文献〕
M. Hudlicky著、「Reductions in Organic Chemistry, 2nd ed (ACS Monograph :188)」、ACS、1996年
R. C. Larock著、「Comprehensive Organic Transformations」、第2版、VCH Publishers, Inc.、1999年
T. J. Donohoe著、「Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)」、Oxford Science Publications、2000年
日本化学会編「実験化学講座(第5版)」14巻(2005年)(丸善)
化合物（１４）は、前述のグリーン(Greene)らの文献を参照して、化合物（１２）に保護基を導入して化合物（１３）に変換後に、酸化反応に付することで得ることができる。
この反応では、前述のラーロック(Larock)らの文献を参照して、水酸基の酸化を行うことにより得ることが出来る。本反応は、特に限定はされないが、例えば、化合物（１３）と等量若しくは過剰量のジメチルスルホキシドを適切な活性化剤および塩基の存在下、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃から80℃で、通常0.1時間〜3日間処理する。ここで用いられる溶媒の例としては、特に限定されないが、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、水或いはこれらの混合物が挙げられる。ここで、活性化剤としては、塩化オキサリル、無水トリフルオロ酢酸、無水酢酸、三硫化硫黄-ピリジン錯体などが用いられ、また、塩基としてはトリエチルアミン、N,N-ジイソプロピルエチルアミン、N-メチルモルホリンもしくはピリジン等の有機塩基などが用いられる。また、別の例として、テトラプロピルアンモニウムパールテネートを触媒として用い、N-メチルモルホリン-N-オキシドを再酸化剤として用い、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃から80℃で、通常0.1時間〜3日間処理する。ここで用いられる溶媒の例としては、特に限定されないが、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、或いはこれらの混合物が挙げられる。さらに別の例としては、デスマーチン(Dess-Martin)試薬のような過原子価ヨウ素試薬や、クロロクロム酸ピリジニウム、二クロム酸ピリジニウムなどのクロム酸試薬などを用いて行うこともできる。
化合物（１５）は、化合物（１４）と化合物（）との反応により得ることができる。本反応は、例えば、前述の（原料合成３）記載のホーナー-エモンズ（Horner-Emmons）反応やウィティッヒ（Wittig）反応と同様の条件で行うことができる。
化合物（１６）は、化合物（１５）の水素添加反応により得ることができる。本反応は、（原料合成３）記載の水素添加反応と同様の条件を用いて行うことができる。 (Raw material synthesis 4)

First, the compound (38) can be obtained by amidation reaction of NH ₃ with a carboxylic acid form obtained by hydrolysis of the compound (7) or a reactive derivative thereof.
When the carboxylic acid form of compound (7) is used, NH ₃ is used in the same amount or in excess of the carboxylic acid form, and the mixture is heated in the presence of a condensing agent in a solvent inert to the reaction from under cooling. Under stirring, preferably at -20 ° C to 60 ° C, usually for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, but are aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, diethyl ether, tetrahydrofuran. , Ethers such as dioxane and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile or water, and mixtures thereof. Examples of condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole, diphenyl phosphate azide, and phosphorus oxychloride. Is not to be done. It may be preferred for the reaction to use an additive (eg 1-hydroxybenzotriazole). Performing the reaction in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide can facilitate the reaction. May be advantageous.
Further, the reaction is with a reactive derivative of the carboxylic acid form, a method of reacting with NH ₃ can also be used. Examples of reactive derivatives of carboxylic acids include acid halides obtained by reacting with halogenating agents such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, 1-hydroxy Examples include active esters obtained by condensation with benzotriazole and the like. The reaction of these reactive derivatives with NH ₃ is carried out in a solvent inert to the reaction of halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc., under cooling to heating, preferably from −20 ° C. Can be performed at 60 ° C.
[Reference]
SR Sandler and W. Karo, “Organic Functional Group Preparations”, 2nd edition, 1st volume, Academic Press Inc. (Maruzen)
Next, compound (12) can be obtained by the reduction reaction of compound (11).
In this reaction, compound (11) is treated with an equal amount or an excess amount of a reducing agent, usually for 0.1 hour to 3 days, in a solvent inert to the reaction under cooling to heating, preferably at -20 ° C to 80 ° C. To do. Examples of the solvent used here are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol and 2-propanol, and aromatics such as benzene, toluene and xylene. Examples include hydrocarbons, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, and mixtures thereof. As the reducing agent, a hydride reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride, a metal reducing agent such as sodium, zinc, or iron, and the reducing agents described in the following documents are preferably used.
[Reference]
M. Hudlicky, "Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)", ACS, 1996
RC Larock, "Comprehensive Organic Transformations", 2nd edition, VCH Publishers, Inc., 1999
TJ Donohoe, `` Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6) '', Oxford Science Publications, 2000 The Chemical Society of Japan, `` Experimental Chemistry Course (5th Edition) '' Volume 14 (2005) (Maruzen)
The compound (14) can be obtained by referring to the aforementioned Greene et al. Document, introducing a protecting group into the compound (12) and converting it into the compound (13), followed by an oxidation reaction. .
This reaction can be obtained by oxidizing the hydroxyl group with reference to the aforementioned Larock et al. Although this reaction is not particularly limited, for example, compound (13) and an equivalent amount or an excess amount of dimethyl sulfoxide in the presence of a suitable activator and base, in a solvent inert to the reaction, from cooling to heating. The treatment is preferably performed at -20 ° C to 80 ° C, usually for 0.1 hour to 3 days. Examples of the solvent used here include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, N, N-dimethyl Examples include formamide, dimethyl sulfoxide, ethyl acetate, water, or a mixture thereof. Here, as the activator, oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, sulfur trisulfide-pyridine complex and the like are used, and as the base, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine or An organic base such as pyridine is used. As another example, tetrapropylammonium pearlate is used as a catalyst, N-methylmorpholine-N-oxide is used as a reoxidant, and in a solvent inert to the reaction, from cooling to heating, preferably- It is usually treated at 20 to 80 ° C. for 0.1 hour to 3 days. Examples of the solvent used here include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, or a mixture thereof. Can be mentioned. As another example, it can be carried out using a pervalent iodine reagent such as Dess-Martin reagent or a chromic acid reagent such as pyridinium chlorochromate or pyridinium dichromate.
Compound (15) can be obtained by reacting compound (14) with compound (). This reaction can be performed, for example, under the same conditions as the Horner-Emmons reaction and the Wittig reaction described in (Raw Material Synthesis 3) above.
Compound (16) can be obtained by hydrogenation reaction of compound (15). This reaction can be performed using the same conditions as the hydrogenation reaction described in (Raw Material Synthesis 3).

（式中、Halは、ハロゲンを、R^Aは、低級アルキル、アリールなどの反応後にカルボン酸の保護基になる置換基、R^S1、R^S2及びR^S3は、低級アルキルを示す。）
化合物（１８）は、化合物（１７）と化合物（３４）とのカップリング反応に付することにより得ることができる。
この反応は、化合物（１７）と等量若しくは過剰量の化合物（３４）の混合物を、反応に不活性な溶媒中、又は無溶媒下、冷却下から加熱還流下、好ましくは0℃から80℃において、通常0.1時間〜5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジメチルエーテル、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル及びこれらの混合物が挙げられる。トリエチルアミン、N,N-ジイソプロピルエチルアミン若しくはN-メチルモルホリン等の有機塩基、又は炭酸セシウム、炭酸カリウム、炭酸ナトリウム、リン酸カリウム、水酸化カリウム、フッ化セシウム、フッ化カリウム等の無機塩基の存在下で反応を行うのが、反応を円滑に進行させる上で有利な場合がある。
また、上記反応は、特に限定されないが、例えば鈴木-宮浦クロスカップリング反応に使用されるような触媒を用いて行うこともできる。ここで用いられる触媒は、特に限定はされないが、テトラキス（トリフェニルホスフィン）パラジウム(0)、酢酸パラジウム(II)、ジクロロ[1,1’-ビス(ジフェニルホスフェニルホスフィノ)フェロセン]パラジウム(II)、塩化ビストリフェニルホスフィンパラジウム(II)、ビス(トリシクロヘキシルホスフィン)パラジウム(II)ジクロリド等を用いることができる。また、金属パラジウム（0）を用いてカップリング反応を行うこともできる。
次に、化合物（１９）は、化合物（１８）と化合物（３５）の付加反応及びそれに引き続く脱シリル化反応により得ることができる。
この反応は、化合物（１８）と等量若しくは過剰量の化合物（３５）の混合物を、反応に不活性な溶媒中、又は無溶媒下、冷却下から加熱還流下、好ましくは0℃から80℃において、通常0.1時間〜5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジメチルエーテル、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル及びこれらの混合物が挙げられる塩化チタン(IV)、塩化鉄(III)、塩化アルミニウム、三フッ化ホウ素等のルイス酸の存在下で反応を行うのが、反応を円滑に進行させる上で有利な場合がある。脱シリル化反応は、前述のグリーンらの文献を参照して実施することができる。
化合物（２０）は、化合物（１９）とR⁴-Lvとの付加反応により得ることができる。本反応は前述の（原料合成２）と同様の反応条件を用いて実施できる。 (Raw material synthesis 5)

(In the formula, Hal represents halogen, R ^A represents a substituent that becomes a protecting group for carboxylic acid after the reaction, such as lower alkyl or aryl, and R ^S1 , R ^S2, and R ^S3 represent lower alkyl.)
Compound (18) can be obtained by subjecting compound (17) and compound (34) to a coupling reaction.
In this reaction, a mixture of the compound (17) and an equal amount or an excess amount of the compound (34) is heated in a solvent inert to the reaction or without solvent, from cooling to heating under reflux, preferably from 0 ° C to 80 ° C. The mixture is usually stirred for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, but aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, 1,2 -Halogenated hydrocarbons such as dichloroethane and chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile and mixtures thereof. In the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, or an inorganic base such as cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium hydroxide, cesium fluoride or potassium fluoride. It may be advantageous to carry out the reaction in order to make the reaction proceed smoothly.
The above reaction is not particularly limited, but it can also be carried out using a catalyst such as that used in the Suzuki-Miyaura cross-coupling reaction. The catalyst used here is not particularly limited, but tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, dichloro [1,1′-bis (diphenylphosphenylphosphino) ferrocene] palladium (II ), Bistriphenylphosphine palladium (II) chloride, bis (tricyclohexylphosphine) palladium (II) dichloride, and the like. In addition, a coupling reaction can be performed using metal palladium (0).
Next, compound (19) can be obtained by addition reaction of compound (18) and compound (35) and subsequent desilylation reaction.
In this reaction, a mixture of the compound (18) and an equal amount or an excess amount of the compound (35) is heated in a solvent inert to the reaction or without solvent, from cooling to heating under reflux, preferably from 0 ° C to 80 ° C. The mixture is usually stirred for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, but aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, 1,2 -Halogenated hydrocarbons such as dichloroethane and chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile and mixtures thereof include titanium chloride (IV), iron chloride (III), aluminum chloride, trifluoride. It may be advantageous to carry out the reaction in the presence of a Lewis acid such as boron fluoride in order to facilitate the reaction. The desilylation reaction can be carried out with reference to the aforementioned Green et al.
Compound (20) can be obtained by addition reaction of compound (19) and R ⁴ -Lv. This reaction can be carried out using the same reaction conditions as in the above (Raw material synthesis 2).

化合物（２１）は、化合物（２０）とニトロメタンとの縮合反応により得ることができる。例えば、この反応は、化合物（２０）と等量若しくは過剰量のニトロメタンの混合物を、反応に不活性な溶媒中、又は無溶媒下、冷却下から加熱還流下、好ましくは0℃から80℃において、通常0.1時間〜5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジメチルエーテル、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル及びこれらの混合物が挙げられる。また、ナトリウムビス(トリメチルシリル)アミド、n-ブチルリチウム、tert-ブトキシカリウム、ナトリウムエトキシド、ナトリウムメトキシド、水素化ナトリウム等の塩基の存在下で反応を行うのが、反応を円滑に進行させる上で有利な場合がある。
化合物（２２）は、化合物（２１）の水素添加反応により得ることができる。本反応は、（原料合成３）記載の水素添加反応と同様の条件を用いて行うことができる。 (Raw material synthesis 6)

Compound (21) can be obtained by a condensation reaction of compound (20) and nitromethane. For example, in this reaction, a mixture of the compound (20) and an equal amount or an excess amount of nitromethane is reacted in a solvent inert to the reaction or in the absence of a solvent, from cooling to heating under reflux, preferably at 0 ° C. to 80 ° C. Stir usually for 0.1 hours to 5 days. Examples of the solvent used here are not particularly limited, but aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, 1,2 -Halogenated hydrocarbons such as dichloroethane and chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile and mixtures thereof. In addition, the reaction is carried out in the presence of a base such as sodium bis (trimethylsilyl) amide, n-butyllithium, tert-butoxypotassium, sodium ethoxide, sodium methoxide, sodium hydride, etc. in order to facilitate the reaction. May be advantageous.
Compound (22) can be obtained by hydrogenation reaction of compound (21). This reaction can be performed using the same conditions as the hydrogenation reaction described in (Raw Material Synthesis 3).

化合物（２０）は、（原料合成５）の方法のほか、本方法によっても製造できる。
化合物（２３）は、化合物（１８）と化合物（３６）との反応により得ることができる。
この反応は、化合物（１８）と等量若しくは過剰量の化合物（３６）の混合物を、反応に不活性な溶媒中、又は無溶媒下、冷却下から加熱還流下、好ましくは0℃から80℃において、通常0.1時間〜5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ジメチルエーテル、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、2-プロパノール、tert-ブタノール等のアルコール類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル及びこれらの混合物が挙げられる。tert-ブトキシカリウム、ナトリウムエトキシド、ナトリウムメトキシド、水素化ナトリウム等の塩基もしくは塩化チタン(IV)、塩化鉄(III)、塩化アルミニウム、三フッ化ホウ素等のルイス酸の存在下で反応を行うのが、反応を円滑に進行させる上で有利な場合がある。
化合物（２４）は、化合物（２３）を前述のグリーンらの文献を参照して加水分解反応もしくは脱アルキル化反応に付することによって製造できる。
化合物（２５）は、化合物（２４）の脱炭酸反応により得ることができる。
この反応は、化合物（２４）を無溶媒もしくは反応に不活性な溶媒中、加熱下、好ましくは30℃から200℃で、通常0.1時間〜3日間処理する。ここで用いられる溶媒の例としては、特に限定されないが、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、水、アセトニトリル或いはこれらの混合物が挙げられる。酸化銅(I)等の銅触媒の存在下で反応を行うのが、反応を円滑に進行させる上で有利な場合がある。
化合物（２０）は、化合物（２５）を前述のグリーンらの文献を参照して保護反応に付すことによって製造できる。 (Raw material synthesis 7)

Compound (20) can be produced by this method in addition to the method of (Raw material synthesis 5).
Compound (23) can be obtained by reacting compound (18) with compound (36).
In this reaction, a mixture of the compound (18) and an equal amount or an excess amount of the compound (36) is heated to reflux in a solvent inert to the reaction or without solvent, preferably from 0 ° C. to 80 ° C. The mixture is usually stirred for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, but ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, methanol And alcohols such as ethanol, 2-propanol and tert-butanol, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile and mixtures thereof. The reaction is carried out in the presence of a base such as tert-butoxy potassium, sodium ethoxide, sodium methoxide, sodium hydride, or a Lewis acid such as titanium (IV) chloride, iron (III) chloride, aluminum chloride, boron trifluoride. This may be advantageous for allowing the reaction to proceed smoothly.
Compound (24) can be produced by subjecting compound (23) to a hydrolysis reaction or a dealkylation reaction with reference to the aforementioned Green et al.
Compound (25) can be obtained by decarboxylation of compound (24).
In this reaction, compound (24) is treated with no solvent or in a solvent inert to the reaction under heating, preferably at 30 ° C. to 200 ° C., usually for 0.1 hour to 3 days. Examples of the solvent used here include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, N, N-dimethyl Examples include formamide, dimethyl sulfoxide, ethyl acetate, water, acetonitrile, or a mixture thereof. It may be advantageous to carry out the reaction in the presence of a copper catalyst such as copper (I) oxide in order to facilitate the reaction.
Compound (20) can be produced by subjecting compound (25) to a protection reaction with reference to the aforementioned Green et al.

化合物（２７）は、化合物（３７）とアルデヒド類若しくはケトン類との反応により得ることができる。本反応は、前述の（第１製法）と同様の反応条件を用いて実施できる。 (Raw material synthesis 8)

Compound (27) can be obtained by reacting compound (37) with aldehydes or ketones. This reaction can be carried out using the same reaction conditions as in the above-mentioned (first production method).

The compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates or polymorphic substances. The salt of the compound of the formula (I) can also be produced by subjecting it to a conventional salt formation reaction.
Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.

The pharmacological activity of Compound (I), which is an active ingredient of the medicament of the present invention, was confirmed by the following test.
Test Example 1: Evaluation of inhibitory action of compounds on Aβ1-42 production ability of SK-N-BE (2) cells (1) Seeding of SK-N-BE (2) cells SK-N-, a human neuroblastoma BE (2) cells were seeded in a 96-well plate (Biocoat REF356640) coated with poly-D-lysine at a density of 3 × 10 ⁵ cells / cm ² . After sowing, the cells were cultured for 24 hours in RPMI1640 medium (containing Penicillin / Streptomycin and 10% fetal bovine serum).
(2) ELISA plate coating
An anti-rabbit IgG antibody (Novus Biologicals NB7180) solution diluted 100-fold with 20 mM HEPES buffer (pH 7.4) was treated in a 384-well plate (Greiner # 781061) at 35 μl / well and incubated at 4 ° C. for 24 hours. After washing this plate with 50 mM sodium phosphate buffer (pH 7.4), anti-Aβ42 antibody (Immunobiological Laboratories # 18582F) solution diluted 30-fold with 20 mM HEPES buffer (pH 7.4) was 35 μl / well. Each was treated and again incubated at 4 ° C. for 24 hours. The plate was washed with 50 mM sodium phosphate buffer (pH 7.4), and then subjected to blocking treatment at 4 ° C. for 6 hours using Block Ace solution (Snow Brand Milk Products UK-B80). The block ace solution was extracted from the plate, and after drying, the plate was stored at 4 ° C.
(3) Measurement of the amount of Aβ1-42 in the medium A dimethyl sulfoxide solution in which a test compound having a specified concentration was dissolved was diluted 200-fold with RPMI1640 medium (containing Penicillin / Streptomycin and 10% fetal bovine serum). The medium was extracted from the 96-well plate after the culture, a medium containing the test compound was added by 50 μl / well and incubated at 37 ° C. for 6 hours. The medium was collected in an amount of 35 μl / well and applied to the ELISA plate prepared in (2) and reacted at 4 ° C. overnight. The ELISA plate was washed with 50 mM sodium phosphate buffer (pH 7.4) and then diluted 1000-fold with Phosphate buffered saline (Invitrogen 12720-017) containing 1% Bovine serum albumin and 0.05% Tween-20. (Aβ N-terminal recognition; IBL # 10326) The solution was treated with 35 μl / well and reacted at 4 ° C. for 1 hour. After washing, Streptavidin-HRP conjugate (Invitrogen SA100-01) solution diluted 5000 times with Phosphate buffered saline containing 1% Bovine serum albumin and 0.05% Tween-20 was treated with 35 μl / well and allowed to react at room temperature for 15 minutes. . After washing again, Tetra methyl benzidine solution (attached to Wako Pure Chemicals # 292-64501) was treated at 35 μl / well and allowed to react at room temperature for 30 minutes. After stopping the reaction by treating each with 35 μl / well of 0.5 M sulfuric acid, the absorbance at 750 nm was measured with SpectraMax (Nippon Molecular Device), and simultaneously measured Aβ1-42 standard solution (Wako Pure Chemical # 292- The amount of Aβ1-42 was calculated based on a calibration curve prepared from the absorbance of (attached to 64501). Separately, cell viability was measured using CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega G7571) on the plate after collecting the medium, and the amount of Aβ1-42 in the same well measured by the above method was measured as cell viability. Standardized.
The inhibition rate of Aβ1-42 production by the compounds in each experiment was defined as 0% inhibition when the dimethyl sulfoxide alone was added to the medium, and 100% inhibition when the value was measured only in the unused medium. The index IC ₅₀ was calculated.
As a result, the compound of the present invention showed Aβ1-42 production inhibitory activity. Table 1 shows IC ₅₀ values of typical compounds of the present invention. Ex represents an example compound number described later.

試験例２：SK-N-BE(2)細胞のAβx-42産生能に対する化合物の阻害作用評価
（１）SK-N-BE(2)細胞の播種
ヒト神経芽細胞腫であるSK-N-BE(2)細胞を密度3×10⁵ cells/cm²でpoly-D-lysineコーティングされた96穴プレート（Biocoat REF356640）に播種した。播種後、RPMI培地（Penicillin/Streptomycinおよび10% FCS含有）により24時間培養を行った。
（２）培地中Aβx-42量の測定
規定濃度の被験化合物を溶解させたジメチルスルホキシド溶液をRPMI1640培地（Penicillin/Streptomycinおよび10% fetal bovine serum含有）で200倍希釈した。培養後の96穴プレートから培地を抜き取り、被験化合物を含む培地を50μl/wellずつ加え、37℃で6時間インキュベーションした。培地を回収し、Human/Rat βAmyloid(42) ELISA Kit, High-Sensitive（和光純薬 #292-64501）を用いてAβx-42量を測定した。測定はキット付属の説明書に従った。具体的には、培地を抗体固相化マイクロプレートに添加し、4℃で一晩反応させた。プレートを洗浄後、標識抗体溶液を添加し、4℃で1時間反応させた。プレートを洗浄後、Tetra methyl benzidine溶液を添加し、室温で30分間反応させた。反応停止液を添加後、吸収波長750 nmの吸光度を測定し、同時に測定したAβ1-42スタンダード溶液の吸光度から作成した検量線を基にAβx-42量を算出した。別途、培地回収後のプレートに対して、CellTiter-Glo Luminescent Cell Viability Assayキット（Promega G7571）を用いて細胞生存率を測定し、上記方法で測定した同一ウエルのAβx-42量を細胞生存率で規格化した。
各実験における化合物によるAβx-42産生抑制率は、ジメチルスルホキシドのみを培地に加えた時に測定される値を0%抑制、未使用の培地のみで測定される値を100%抑制とし、薬理活性の指標であるIC₅₀を算出した。
その結果、本発明化合物は、Aβx-42産生抑制活性を示した。本発明化合物の代表的な化合物のIC₅₀値を表１に示す。Exは後記実施例化合物番号を示す。

Test Example 2: Evaluation of inhibitory effect of compounds on Aβx-42 production ability of SK-N-BE (2) cells (1) Seeding of SK-N-BE (2) cells SK-N-, a human neuroblastoma BE (2) cells were seeded in a 96-well plate (Biocoat REF356640) coated with poly-D-lysine at a density of 3 × 10 ⁵ cells / cm ² . After sowing, the cells were cultured for 24 hours in RPMI medium (containing Penicillin / Streptomycin and 10% FCS).
(2) Measurement of Aβx-42 amount in medium A dimethyl sulfoxide solution in which a test compound having a specified concentration was dissolved was diluted 200-fold with RPMI1640 medium (containing Penicillin / Streptomycin and 10% fetal bovine serum). The medium was extracted from the 96-well plate after the culture, a medium containing the test compound was added by 50 μl / well and incubated at 37 ° C. for 6 hours. The medium was collected, and the amount of Aβx-42 was measured using Human / Rat βAmyloid (42) ELISA Kit, High-Sensitive (Wako Pure Chemicals # 292-64501). The measurement followed the instructions attached to the kit. Specifically, the medium was added to an antibody-immobilized microplate and allowed to react overnight at 4 ° C. After washing the plate, a labeled antibody solution was added and reacted at 4 ° C. for 1 hour. After washing the plate, Tetra methyl benzidine solution was added and reacted at room temperature for 30 minutes. After adding the reaction stop solution, the absorbance at an absorption wavelength of 750 nm was measured, and the amount of Aβx-42 was calculated based on a calibration curve created from the absorbance of the Aβ1-42 standard solution measured at the same time. Separately, cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Assay kit (Promega G7571) on the plate after collecting the medium, and the amount of Aβx-42 in the same well measured by the above method was measured as cell viability. Standardized.
The inhibition rate of Aβx-42 production by the compound in each experiment was defined as 0% inhibition when the dimethyl sulfoxide alone was added to the medium, and 100% inhibition with the value measured only in the unused medium. The index IC ₅₀ was calculated.
As a result, the compound of the present invention showed Aβx-42 production inhibitory activity. Table 1 shows IC ₅₀ values of typical compounds of the present invention. Ex represents an example compound number described later.

尚、試験例１及び試験例２は共にAβ42産生抑制に関する試験であり、試験例１のみ、若しくは、試験例２のみ実施された化合物であっても、他方の試験でも同様に抑制作用を示すものと考えられる。

試験例３：マウス脳内Aβx-42量の化合物による低下作用評価
（１）動物投与および組織採取
5週齢の雄性ddY系マウス（日本エスエルシー）を1群4〜5例使用した。被験化合物を0.5%メチルセルロース水溶液で懸濁させ、この液を体重1kgにつき10 mlになるようにマウスに経口投与した。投与3時間後に頚椎脱臼を施し、速やかに脳を摘出した後、氷上で海馬を分離、採取した。採取した海馬は速やかに液体窒素中で凍結させ、測定まで-80℃で保存した。
（２）海馬内Aβx-42量の測定
海馬の重量を測定し、10倍量のTris buffered saline（和光純薬 #317-90175）を加え、氷上でホモジナイズした。ホモジネートを遠心チューブに移し、100,000 gで1時間遠心した上清中のAβx-42量を、Human/Rat βAmyloid(42) ELISA Kit, High-Sensitive（和光純薬 #292-64501）を用いて測定した。測定はキット付属の説明書に従った。具体的には、上清を抗体固相化マイクロプレートに添加し、4℃で一晩反応させた。プレートを洗浄後、標識抗体溶液を添加し、4℃で1時間反応させた。プレートを洗浄後、Tetra methyl benzidine溶液を添加し、室温で30分間反応させた。反応停止液を添加後、吸収波長750 nmの吸光度を測定し、同時に測定したAβ42スタンダード溶液の吸光度から作成した検量線を基にAβx-42量を算出した。
各実験において、溶媒のみを投与した対象群で測定される値の平均値に対し、化合物投与群で測定される値の比を算出し、その差を化合物による脳内Aβx-42低下作用の指標とした。
その結果、本発明化合物は、有効なAβx-42低下作用を示した。本発明化合物の代表的な化合物の低下率(%)を表３に示す。Exは後記実施例化合物番号を示す。

Both Test Example 1 and Test Example 2 are tests related to inhibition of Aβ42 production, and even if only the test example 1 or the test example 2 is a compound, the other test shows the same inhibitory action. it is conceivable that.

Test Example 3: Evaluation of the effect of reducing the amount of Aβx-42 in the mouse brain by a compound (1) Animal administration and tissue collection
Four to five male ddY mice (Nihon SLC) aged 5 weeks were used. The test compound was suspended in a 0.5% aqueous methylcellulose solution, and this solution was orally administered to mice so as to be 10 ml per 1 kg body weight. Three hours after administration, cervical dislocation was performed, and the brain was quickly removed, and the hippocampus was separated and collected on ice. The collected hippocampus was immediately frozen in liquid nitrogen and stored at −80 ° C. until measurement.
(2) Measurement of the amount of Aβx-42 in the hippocampus The hippocampus was weighed, 10 times the amount of Tris buffered saline (Wako Pure Chemicals # 317-90175) was added, and the mixture was homogenized on ice. Transfer the homogenate to a centrifuge tube and centrifuge at 100,000 g for 1 hour to measure the amount of Aβx-42 using the Human / Rat βAmyloid (42) ELISA Kit, High-Sensitive (Wako Pure Chemicals # 292-64501) did. The measurement followed the instructions attached to the kit. Specifically, the supernatant was added to an antibody-immobilized microplate and allowed to react overnight at 4 ° C. After washing the plate, a labeled antibody solution was added and reacted at 4 ° C. for 1 hour. After washing the plate, Tetra methyl benzidine solution was added and reacted at room temperature for 30 minutes. After adding the reaction stop solution, the absorbance at an absorption wavelength of 750 nm was measured, and the amount of Aβx-42 was calculated based on a calibration curve prepared from the absorbance of the Aβ42 standard solution measured at the same time.
In each experiment, the ratio of the value measured in the compound-administered group to the average value of the value measured in the subject group administered with the solvent alone was calculated, and the difference was used as an index of the Aβx-42 lowering effect in the brain by the compound. It was.
As a result, the compound of the present invention showed an effective Aβx-42 lowering action. Table 3 shows the reduction rate (%) of typical compounds of the compound of the present invention. Ex represents an example compound number described later.

  From the above, it was confirmed that the compound of the formula (I) has an excellent amyloid β peptide deposition inhibitory action and an excellent γ-secretase function regulating action. Therefore, it can be used as a preventive or therapeutic agent for diseases associated with amyloid β peptide deposition.

A pharmaceutical composition containing one or more of the compounds of formula (I) or a salt thereof as an active ingredient is an excipient usually used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier. Can be prepared by a commonly used method.
Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.

As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.

  Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Non-aqueous solvents include alcohols such as ethanol. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

  External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.

  Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane or carbon dioxide.

  In general, in the case of oral administration, the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses. In the case of intravenous administration, the daily dose is appropriately about 0.0001 to 10 mg / kg per body weight, and is administered once a day or divided into multiple times. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

  The compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.

  Hereinafter, based on an Example, the manufacturing method of the compound of a formula (I) is demonstrated in detail. In addition, this invention is not limited only to the manufacturing method of the specific Example and manufacturing example which are shown below, The compound of a formula (I) is a combination of these manufacturing methods, or is obvious to those skilled in the art. It can also be produced by a method.

Production Example 1
Using the compound of Production Example 606b as a raw material, the compound was produced in the same manner as in Production Example 141 described later.

Production Example 6
Using the compound of Production Example 3 as a raw material, the compound was produced in the same manner as in Production Example 188 described later.

Production Example 11
Using the compound of Production Example 606b as a raw material, the compound was produced in the same manner as in Production Example 536 described later.

Production Example 12
Using the compound of Production Example 606b as a raw material, the compound was produced in the same manner as in Production Example 532 described later.

Production Example 13
Using the compound of Production Example 3 as a raw material, the compound was produced in the same manner as in Production Example 555 described later.

Production Example 14
Using the compound of Production Example 632 as a raw material, the salt of the raw material was treated with an aqueous solution containing a base such as sodium bicarbonate or sodium hydroxide, extracted with an appropriate organic solvent, and dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, or the like. Thereafter, desalting was carried out by distilling off the solvent.

Production Example 18
Using the compound of Production Example 606a as a raw material, the compound was produced in the same manner as in Production Example 141 described later.

Production Example 22
Using the compound of Production Example 20a as a raw material, the compound was produced in the same manner as in Production Example 188 described later.

Production Example 24
Using the compound of Production Example 20a as a raw material, the compound was produced in the same manner as in Production Example 555 described later.

Production Example 25
Ethyl rac-{(1R, 2R) -3-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexyl} (trimethylsilyl) acetate (8.9 g) in methanol (100 mL) in water (25 mL) and Potassium fluoride (2.6 g) was added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane to obtain ethyl rac-{(1R, 2R) -3-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (6.46 g).

Production Example 35
rac- (1R, 2R) -4-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexanecarboxylic acid (15 g) was added with toluene (225 ml), triethylamine (11 ml) and diphenyl phosphate azide (19 g) was added. The reaction mixture was stirred at room temperature for 30 minutes, benzyl alcohol (15 ml) was added, and the mixture was stirred at 110 ° C. for 4 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from acetonitrile. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate / chloroform = 45: 45: 10). The compound purified by recrystallization and silica gel column chromatography was combined to obtain benzyl rac-{(1R, 2S) -4-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexyl} carbamate as a colorless powder. (16.2 g).

Production Example 57
Add 2- (trimethylsiloxy) -1,3-butadiene (60 g) to a solution of pentafluorophenyl (2E) -3- [4- (trifluoromethyl) phenyl] acrylate (38 g) in xylene (190 mL). Stir at 130 ° C. for 3 days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with chloroform (380 mL), trifluoroacetic acid (38 ml) was added under ice cooling, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10: 1-4: 1-3: 1) and pentafluorophenyl rac- (1R, 2R) -4-oxo-2- [4- (tri Fluoromethyl) phenyl] cyclohexanecarboxylate was obtained as a pale yellow amorphous (35 g)

Production Example 74
2- (Trimethylsiloxy) -1,3-butadiene (14.8 g) was added to pentafluorophenyl (2E) -3- (4-fluorophenyl) acrylate (8.2 g), and the mixture was stirred at 130 ° C. for 4 days. The reaction mixture was cooled to room temperature, diluted with tetrahydrofuran, 1M aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred for 4 hr. Concentrated hydrochloric acid was added to make it acidic, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0 to 4: 1) to obtain a crude product. The crude product was concentrated by adding an aqueous ammonia solution, and the residue was purified by silica gel column chromatography (chloroform / methanol / acetic acid = 100: 0: 0 to 4: 1: 0 to 90: 10: 0.1). Rac- (1R, 2R) -2- (4-fluorophenyl) -4-oxocyclohexanecarboxylic acid was obtained as a pale yellow amorphous (2.13 g)

Production Example 78
The compound of Production Example 173 was used as a raw material, and the compound was produced in the same manner as in Production Example 141 described later. The compound was converted to a hydrochloride and purified by recrystallization.

Production Example 79
A solution of 2- [4- (trifluoromethyl) phenyl] cyclohex-2-en-1-one (700 mg) in dichloromethane (17.5 ml) was cooled to -70 ° C., and 1M titanium tetrachloride in dichloromethane (3.5 ml) was added and stirred for 5 minutes. Methyltrimethylsilyldimethylketene acetal (630 mg) was added, and the mixture was stirred at -70 ° C for 3 hours. After adding a saturated aqueous sodium hydrogen carbonate solution, the temperature was raised to room temperature, the precipitated solid was filtered through celite, and the filtrate was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (10 ml), sodium methoxide (3.0 mg) was added, and the mixture was stirred overnight. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 70:30), and methyl rac-2-methyl-2-{(1R, 2R) -3- Oxo-2- [4- (trifluoromethyl) phenyl] cyclohexyl} propanoate was obtained as a colorless oil (801 mg).

Production Example 80
Triethyl phosphonoacetate (8.9 g) was added to a suspension of 55% sodium hydride (1.6 g) in tetrahydrofuran (196 mL) under ice cooling. The reaction mixture was stirred for 15 minutes under ice-cooling, and then benzyl rac-{(1R, 2S) -4-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexyl} carbamate (13 g) was added. The reaction mixture was further stirred for 1 hour under ice cooling, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with a 2: 1 mixed solvent of hexane and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from 2-propanol (80 mL), the mother liquor was concentrated, and the residue was further recrystallized from 2-propanol (40 mL). The solids obtained by these operations were combined with ethyl rac-{(3R, 4S) -4-{[(benzyloxy) carbonyl] amino} -3- [4- (trifluoromethyl) phenyl] cyclohexylidene. } Acetate was obtained as a colorless powder (12.8 g).

Production Example 102
Ethyl rac-{(1R, 3S, 4R) -4-[(3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (52 mg) in dichloromethane (2 mL) Di-tert-butyl dicarbonate was added and stirred at room temperature for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 10: 1 to 1: 1), and ethyl rac-{(1R, 3S, 4R) -4-[(tert-butoxy Carbonyl) (3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate was obtained as a colorless oil (61 mg).

Production Example 103
Isopropyl rac-{(1R, 2S, 3E) -3- (benzylimino) -2- [4- (trifluoromethyl) phenyl] cycloheptyl} acetate (99 mg) in 1,2-dichloroethane (4 ml) To the mixture, 3-methylbutyraldehyde (57 mg) and ground molecular sieves 3A (250 mg) were added, and the mixture was stirred at room temperature for 45 minutes, and then sodium triacetoxyborohydride (140 mg) was added. After stirring at room temperature for 24 hours, the insoluble material was filtered off and washed with ethyl acetate. The filtrate and washings were concentrated under reduced pressure, basified with saturated aqueous sodium hydrogen carbonate solution and 1M aqueous sodium hydroxide solution (0.2 ml), and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / chloroform = 95: 5-85: 15), and isopropyl rac-{(1R, 2S, 3S) -3- [benzyl (3-methylbutyl) amino]- 2- [4- (Trifluoromethyl) phenyl] cycloheptyl} acetate was obtained (107 mg).

Production Example 104
Methyl rac-{(1R, 2S) -3-oxo-2- [4- (trifluoromethyl) phenyl] cycloheptyl} acetate (200 mg) and benzylamine (131 mg) were mixed with titanium tetraisopropoxide ( 554 mg) was added. The reaction mixture was stirred at 60 ° C. for 3 hr, cooled to room temperature, diluted with 1,2-dichloroethane (3 ml), sodium triacetoxyborohydride (258 mg) was added, and the mixture was stirred at room temperature overnight. Celite and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the insoluble material was filtered off through celite, and washed with a 10: 1 mixture of chloroform / methanol. The filtrate was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / chloroform = 90: 10 to 72:28), and isopropyl rac-{(1R, 2S, 3E) -3- (benzylimino) -2- [4- (Trifluoromethyl) phenyl] cycloheptyl} acetate was obtained (200 mg).

Production Example 105
A solution of 2- [4- (trifluoromethyl) phenyl] cyclohex-2-en-1-one (1.0 g) in dichloromethane (30 mL) was cooled to −78 ° C., and 1M titanium tetrachloride in dichloromethane (5 mL) ) Was added, followed by trimethylsilylketene ethyl trimethylsilyl acetal (1.16 mg). After stirring at the same temperature for 6 hours, an aqueous potassium carbonate solution was added, and the temperature was raised to room temperature. The insoluble material was filtered through celite, washed with ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 95: 5-85: 15) and ethyl rac-{(1R, 2R) -3-oxo-2- [4- (trifluoromethyl) phenyl ] Cyclohexyl} (trimethylsilyl) acetate was obtained (979 mg)

Production Example 115
The compound of Production Example 317 was used as a raw material, and the same process as in Production Example 105 and Production Example 25 was continuously carried out.

Production Example 135
To a tert-butanol solution (10 mL) of 2- [4-fluorophenyl] cyclohex-2-en-1-one (1.0 g) and dibenzyl malonate (2.8 gl) was added potassium tert-butoxide (91 mg), After stirring at 60 ° C. for 3 hours, the mixture was stirred overnight at room temperature. Acetic acid (0.2 ml) was added to stop the reaction, the solvent was distilled off under reduced pressure, and the mixture was acidified with aqueous potassium dihydrogen phosphate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 90: 10-76: 24), and dibenzyl rac-[(1R, 2R) -2- (4-fluorophenyl) -3-oxocyclohexyl] malonate (1.8 g) was obtained.

Production Example 141
Ethyl rac-{(1R, 3S, 4R) -4-amino-3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (200 mg) and 3-methylbutyraldehyde (73 mg) 1,2- Sodium triacetoxyborohydride (193 mg) was added to a dichloroethane (2.4 mL) solution. The reaction mixture was stirred at room temperature overnight, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0 to 10: 1), and ethyl rac-{(1R, 3S, 4R) -4-[(3-methylbutyl) amino] -3- [ 4- (Tolufluoromethyl) phenyl] cyclohexyl} acetate as a colorless oil (133 mg), ethyl rac-{(1R, 3S, 4R) -4- [bis (3-methylbutyl) amino] -3- [4 -(Turfluoromethyl) phenyl] cyclohexyl} acetate was obtained as a colorless oil (69 mg), respectively.

Production Example 185
By stirring rac-[(1R, 2R) -2- (4-fluorophenyl) -3-oxocyclohexyl] malonic acid (1.1 g) under an argon atmosphere at 170 ° C. for 15 minutes, rac-[(1R, 2S) -2- (4-Fluorophenyl) -3-oxocyclohexyl] acetic acid was obtained (799 mg).

Production Example 188
Ethyl rac-{(1R, 3S, 4R) -4-[(3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (100 mg) and cyclohexanecarboxaldehyde (56 mg) Sodium triacetoxyborohydride (110 mg) was added to a dichloromethane solution (3.4 mL). The reaction mixture was stirred at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 10: 1 to 1: 1), and ethyl rac-{(1R, 3S, 4R) -4-[(cyclohexylmethyl) (3-Methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate was obtained as a colorless oil (125 mg).

Production Example 258
The compound of Production Example 303 was used as a raw material and produced in the same manner as in Production Example 188.

Production Example 290
Methyl rac-{(1R, 2S) -3-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (500 mg) in methanol (10 mL) and acetic acid (0.27 ml), 3-methyl Butylamine (416 mg) and ground molecular sieves 3A (1.0 g) were added and stirred at room temperature for 45 minutes, and then sodium cyanoborohydride (300 mg) was added. After stirring at room temperature for 20 hours, the insoluble material was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / chloroform = 85: 15 to 65:35), and methyl rac-{(1R, 2S, 3R) -3-[(3-methylbutyl) amino] -2- [ 4- (Trifluoromethyl) phenyl] cyclohexyl} acetate was obtained as a white solid (219 mg).

Production Example 304
Ethyl rac-{(1R, 2S) -3-oxo-2- [4- (pentafluoro-λ ⁶ -sulfanyl) phenyl] cyclohexyl} acetate (0.15 g), cyclohexylmethylamine (0.15 ml), titanium tetraethoxy (0.25 ml) was sequentially added and stirred at 60 ° C. for 4 hours. The reaction mixture was cooled to 0 ° C., toluene (1 ml), ethanol (4 ml) and sodium borohydride (0.05 g) were sequentially added, and the mixture was stirred at room temperature for 17 hours. A 1 M aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) and ethyl rac-{(1R, 2S, 3R) -3-[(cyclohexylmethyl) amino] -2- [4- (pentafluoro-λ ^6- Sulfanyl) phenyl] cyclohexyl} acetate was obtained as a pale yellow solid (0.086 g).

Production Example 305
To a solution of rac-[(1R, 2R) -2- (4-fluorophenyl) -3-oxocyclohexyl] malonic acid (3.49 g) in acetonitrile (180 mL) was added copper (I) oxide (116 mg), The mixture was heated to reflux for 17 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain rac-{(1R, 2S) -3-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid (3.0 g)

Production Example 308
Methyl rac-{(1R, 2S) -3-oxo-2- [4- (trifluoromethyl) phenyl] cycloheptyl} acetate (307 mg) and 3-methylbutylamine (245 mg) were mixed with titanium tetraisopropoxy (797 mg) was added. The reaction mixture was stirred at 60 ° C. for 3 hr, cooled to room temperature, diluted with methanol (3 mL), sodium borohydride (106 mg) was added, and the mixture was stirred overnight at room temperature. Celite and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the insoluble material was filtered off through Celite, and washed with a 10: 1 mixed solution of chloroform / methanol. The filtrate was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / chloroform = 92: 8 to 72:28), and isopropyl rac-{(1R, 2S, 3S) -3-[(3-methylbutyl) amino] -2 -[4- (trifluoromethyl) phenyl] cycloheptyl} acetate (94 mg) and isopropyl rac-{(1R, 2S, 3R) -3-[(3-methylbutyl) amino] -2- [4- ( Trifluoromethyl) phenyl] cycloheptyl} acetate (216 mg) was obtained.

Production Example 313
Using the compound of Production Example 348 as a raw material, the compound was produced in the same manner as in Production Example 354 described later.

Production Example 315
To a solution of 2-iodocyclohex-2-en-1-one (3.13 g) in 1,4-dioxane (60 mL), add cesium carbonate (8.0 g), water (12 mL) and [4- (trifluoromethyl ) Phenyl] boric acid (4.7 g) was added, and dichlorobis (tricyclohexylphosphine) palladium (II) (208 mg) was added under an argon atmosphere. The reaction mixture was stirred at 100 ° C. for 2 hours under an argon atmosphere, cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 90: 10-80: 20) to obtain 2- [4- (trifluoromethyl) phenyl] cyclohex-2-en-1-one (2.96). g)

Production Example 343
Using the compound of Production Example 314 as a raw material, the compound was produced in the same manner as in Production Example 397 described later.

Production Example 345
The compound of Production Example 26 was used as a starting material, and in the same manner as in Production Example 412 described later, (R) -1-phenylethylamine was used instead of (S) -1-phenylethylamine.

Production Example 346
The compound of Production Example 25 was used as a starting material, and in the same manner as in Production Example 49 described later, (R) -1-phenylethylamine was used instead of (S) -1-phenylethylamine.

Production Example 347
5% Palladium carbon (650 mg) was added to a methanol solution (30 mL) of ethyl (3,3,5,5-tetramethylcyclohexylidene) acetate (1.45 g). The reaction mixture was stirred at room temperature for 4 days under a hydrogen atmosphere, and then filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100: 0-20: 1), and ethyl (3,3,5,5-tetramethylcyclohexyl) acetate was colorless. Obtained as an oil (1.21 g).

Production Example 348
Using the compound of Production Example 345 as a raw material, the compound was produced in the same manner as in Production Example 470 described later.

Production Example 350
Ethyl {(1R ^* , 2S ^* , 3R ^* )-3- [bis (cyclohexylmethyl) amino] -2- (3-chlorophenyl) cyclohexyl} acetate (377 mg) in 50% aqueous solution in ethanol (10 ml) 20% Palladium hydroxide carbon (100 mg) and ammonium formate (600 mg) were added, and the mixture was stirred under an argon atmosphere for 2 hours. The solid was filtered off, the filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 90:10), and ethyl {(1R ^* , 2S ^* , 3R ^* )-3- [bis (cyclohexylmethyl) amino] -2 -Phenylcyclohexyl} acetate was obtained as a colorless amorphous (251 mg).

Production Example 351
{(1R ^* , 2S ^* , 3R ^* )-3- [Bis (cyclohexylmethyl) amino] -2- (4-methoxyphenyl) cyclohexyl} acetic acid Hydrochloride (272 mg) in dichloromethane (3 ml) at 0 ° C After cooling to 1, 1M boron tribromide in dichloromethane (1.0 ml) was added and stirred at room temperature overnight. Ethanol (1 ml) was added to the reaction mixture and stirred for 30 minutes, and then water was added and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl {(1R ^* , 2S ^* , 3R ^* )-3- [bis (cyclohexylmethyl) amino] -2- (4-hydroxyphenyl) cyclohexyl} acetate as a colorless amorphous substance. (220 mg).

Production Example 352
Ethyl {(1R ^* , 2S ^* , 3R ^* ) -3- [Bis (cyclohexylmethyl) amino] -2- (4-hydroxyphenyl) cyclohexyl} acetate (220 mg) in N, N-dimethylformamide (3 ml) Then, N, N-bis (trifluoromethanesulfonyl) aniline (220 mg) and N, N-diisopropylethylamine (0.17 ml) were added under ice cooling, and the mixture was warmed to room temperature and stirred for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 80:20), and ethyl {(1R ^* , 2S ^* , 3R ^* )-3- [ Bis (cyclohexylmethyl) amino] -2- (4-{[(trifluoromethyl) sulfonyl] oxy} phenyl) cyclohexyl} acetate was obtained as a colorless oil (292 mg).

Production Example 353
Of ethyl {(1R ^* , 2S ^* , 3R ^* )-3- [bis (cyclohexylmethyl) amino] -2- (4-{[(trifluoromethyl) sulfonyl] oxy} phenyl) cyclohexyl} acetate (120 mg) Cyclopropylboronic acid (100 mg) and cesium carbonate (130 mg) were added to 1,4-dioxane (6 ml) solution, water (1.5 ml) was added, argon gas was extracted, and dichlorobis (tricyclohexylphosphine) was added. ) Palladium (II) (150 mg) was added and stirred at 90 ° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 50:50), and ethyl {(1R ^* , 2S ^* , 3R ^* )-3- [bis (cyclohexylmethyl) amino] -2 -(4-Cyclopropylphenyl) cyclohexyl} acetate was obtained as a colorless oil (40 mg).

Production Example 354
The compound of Production Example 468 was used as a raw material and produced in the same manner as in Production Example 141.

Production Example 397
Using the compound of Production Example 381b as a raw material, the compound was produced in the same manner as in Production Example 188.

Production Example 412
Acetic acid (130 mg), (1S) -1-phenyl in a methanol (5 ml) solution of ethyl rac-[(1R, 2S) -2- (4-fluorophenyl) -3-oxocyclohexyl] acetate (300 mg) Ethylamine (262 mg) and powdered molecular sieves 3A (450 mg) were sequentially added, and the mixture was stirred at room temperature for 15 hours, and then sodium borohydride (136 mg) was added. The reaction mixture was further stirred at room temperature for 24 hours, and then the solid was filtered off. A saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 70:30), and ethyl (1R ^* , 2S ^* , 3R ^* )-[2- (4-fluorophenyl) -3 -{[(1S) -1-Phenylethyl] amino} cyclohexyl] acetate was obtained as colorless amorphous (107 mg).

Production Example 415
Ethyl rac-{(1R, 2S) -2- [4-fluoro-3- (trifluoromethyl) phenyl] -3-oxocyclohexyl} acetate (2.3 g), (1S) -1-phenylethanamine, titanium Tetraisopropoxide (1.6 g) was sequentially added, and the mixture was stirred at 60 ° C. for 1 hr. After cooling to 0 ° C. and diluting with methanol (45 ml), sodium borohydride (251 mg) was added and stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the precipitated solid was filtered through celite. The filtrate was extracted with chloroform, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The residue was dissolved in methanol (45 ml), 28% sodium methoxide in methanol (1.28 g) was added, and the mixture was stirred at 60 ° C. for 4 hr. After cooling to 0 ° C., saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 75:25), and methyl (1R ^* , 2S ^* , 3R ^* )-(2- [4-fluoro-3- (trifluoro Methyl) phenyl] -3-{[(1S) -1-phenylethyl] amino} cyclohexyl) acetate was obtained as a colorless oil (0.85 g).

Production Example 419
The compound of Production Example 31 was used as a starting material, and in the same manner as in Production Example 415, (S) -1- (4-methoxyphenyl) ethylamine was used instead of (S) -1-phenylethylamine.

Production Example 422
Ethyl rac-{(1R, 2S) -3-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (3.6 g) was added to (S) -1-phenylethylamine (4.0 ml) and titanium tetra Ethoxide (6.5 ml) was successively added and stirred at 60 ° C. for 2 hours. After cooling to 0 ° C., toluene (10 ml), ethanol (40 ml) and sodium borohydride (1.2 g) were successively added and stirred for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the precipitated solid was filtered through celite. The filtrate was extracted with chloroform and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate = 95: 5-90: 10), and ethyl (1R ^* , 2S ^* , 3R ^* )-(3-{[(1S) -1- Phenylethyl] amino} -2- [4- (trifluoromethyl) phenyl] cyclohexyl) acetate was obtained as a light brown solid (1.9 g).

Production Example 433
The compound of Production Example 117 was used as a starting material, and in the same manner as in Production Example 422, (S) -1- (4-methoxyphenyl) ethylamine was used instead of (S) -1-phenylethylamine.

Production Example 439
Ethyl rac-{(1R, 2S) -3-oxo-2- [4- (trifluoromethyl) phenyl] cycloheptyl} acetate (600 mg) and (S) -1-phenylethylamine (664 mg) Titanium tetraisopropoxide (1.6 g) was added. The reaction mixture was stirred at 60 ° C. for 3 hr, cooled to room temperature, diluted with methanol (5.9 mL), sodium borohydride (207 mg) was added, and the mixture was stirred at room temperature for 4 hr. Celite and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the insoluble material was filtered off through Celite, and washed with a 10: 1 mixed solution of chloroform / methanol. The filtrate was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate = 96: 4-87: 13), and isopropyl (1R ^* , 2S ^* , 3R ^* )-(3-{[(1S) -1- Phenylethyl] amino} -2- [4- (trifluoromethyl) phenyl] cyclohexyl) acetate was obtained as a white solid (270 mg).

Production Example 440
Ethyl (1R ^* , 2S ^* , 3R ^* )-[3-amino-2- (2,4,5-trifluorophenyl) cyclohexyl] acetate (100 mg) in 1,2-dichloroethane (5 mL) in 4 , 4-Dimethyl-2-pentynal (105 mg) and sodium triacetoxyborohydride (202 mg) were added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol, water-containing 10% palladium-carbon catalyst was added, and the mixture was stirred at room temperature for 4 hours under a normal pressure hydrogen atmosphere. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10: 1) to obtain ethyl (1R ^* , 2S ^* , 3R ^* )-{3- [ Bis (4,4-dimethylpentyl) amino] -2- (2,4,5-trifluorophenyl) cyclohexyl} acetate was obtained as a colorless oil (72 mg).

Production Example 441
To a solution of ethyl (1R ^* , 2S ^* , 3R ^* )-[3-amino-2- (4-chloro-3-fluorophenyl) cyclohexyl] acetate (314 mg) in 1,2-dichloroethane (10 mL), 4-Dimethyl-2-pentynal (154 mg) and sodium triacetoxyborohydride (424 mg) were added, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Next, the residue was dissolved in ethanol (10 ml), 5% rhodium-carbon catalyst (50 mg) was added, and the mixture was stirred at room temperature for 6 hours under a normal pressure hydrogen atmosphere. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10: 1 to 1: 2) and purified by ethyl (1R ^* , 2S ^* , 3R ^* ). -{2- (4-Chloro-3-fluorophenyl) -3-[(4,4-dimethylpentyl) amino] cyclohexyl} acetate was obtained as a pale orange semi-solid (366 mg).

Production Example 442
Isopropyl (1R ^* , 2S ^* , 3R ^* )-(3-{[(1S) -1-phenylethyl] amino} -2- [4- (trifluoromethyl) phenyl] cyclohexyl) acetate (260 mg) ethanol (15 mL) To the solution was added 20% palladium hydroxide (90 mg) and ammonium formate (733 mg) under an argon atmosphere, and the mixture was stirred at 85 ° C. for 2 hr. The reaction mixture was filtered using celite, washed with ethanol, and the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate = 80: 20-50: 50), and isopropyl (1R ^* , 2S ^* , 3R ^* )-{3-amino-2- [4- ( Trifluoromethyl) phenyl] cyclohexyl} acetate was obtained (182 mg).

Production Example 460
Dibenzyl rac-[(1R, 2R) -2- (4-fluorophenyl) -3-oxocyclohexyl] malonate (1.81 g) in ethyl acetate (24 mL) was added ethanol (2 mL), 20% palladium hydroxide. (187 mg) was added, and the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere of 1 atm. The reaction mixture was filtered through celite and washed with ethyl acetate, and then the filtrate was concentrated under reduced pressure to give rac-[(1R, 2R) -2- (4-fluorophenyl) -3-oxocyclohexyl] malonic acid. (1.12 g) was obtained.

Production Example 466
Ethyl (1R ^* , 2S ^* , 3R ^* )-[2- (3-chloro-4-methylphenyl) -3-{[(1S) -1- (4-methoxyphenyl) ethyl] amino} cyclohexyl] acetate ( To a solution of 680 mg) in trifluoroacetic acid (3 mL) was added methylphenyl ether (169 mg), and the mixture was stirred with heating under reflux for 3 days. The reaction solution was cooled, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 4: 1 to 1: 1), and ethyl (1R ^* , 2S ^* , 3R ^* )-[3-amino-2- (3-Chloro-4-methylphenyl) cyclohexyl] acetate was obtained as a pale yellow oil (271 mg).

Production Example 470
Using the compound of Production Example 435 as a raw material, the compound was produced in the same manner as in Production Example 442.

Production Example 472
Methyl (1R ^* , 2S ^* , 3R ^* )-[2- (4-chlorophenyl) -3-{[(1S) -1- (4-methoxyphenyl) ethyl] amino} cyclohexyl] acetate (690 mg) and acetonitrile To a mixture of (10 ml) and water (2 ml) was added diammonium cerium (IV) nitrate (1.4 g), and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice-cooling, and the mixture was warmed to room temperature. The precipitated solid was filtered through celite, and the filtrate was extracted with chloroform. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, 1M hydrochloric acid (10 ml) was added to the residue, and the mixture was stirred at room temperature for 15 hr. Ethyl acetate was added to the reaction mixture and stirred, and the organic layer was removed. A saturated aqueous sodium hydrogen carbonate solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain methyl (1R ^* , 2S ^* , 3R ^* )-[3-amino-2- (4-chlorophenyl) cyclohexyl] acetate as a colorless oil (395 mg).

Production Example 476
Ethyl rac-[(3R, 4S) -4-{[(Benzyloxy) carbonyl] amino} -3- (4-bromophenyl) cyclohexylidene] acetate (500 mg) in 1,2-dimethoxyethane (5 mL ) 1-cyclohexen-1-yl-boronic acid pinacol ester (305 mg), cesium fluoride (500 mg) and tetrakis (triphenylphosphine) palladium (60 mg) were added to the solution. The reaction system was depressurized and purged with nitrogen, and then stirred at 85 ° C. overnight. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0 to 20: 1), and ethyl rac-{(3R, 4S) -4-{[(benzyloxy) carbonyl] amino} -3- [ 4- (Cyclohex-1-en-1-yl) phenyl] cyclohexylidene} acetate was obtained as a pale yellow amorphous (391 mg).

Production Example 483
Using the compound of Production Example 484 as a raw material, the compound was produced in the same manner as in Production Example 518.

Production Example 484
Benzyl rac-({(1R, 2R) -4-hydroxy-2- [4- (trifluoromethyl) phenyl] cyclohexyl} methyl) carbamate (660 mg) in 1,2-dichloroethane (10 mL) in tetrapropyl Ammonium pearlate (57 mg) and 4-methylmorpholine-4-oxide (380 mg) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was directly purified by silica gel column chromatography (chloroform / methanol = 20: 0 to 10: 1), and rac-({(1R, 2R) -4-oxo-2- [4- (trifluoromethyl) phenyl ] Cyclohexyl} methyl) carbamate was obtained as a colorless oil (211 mg).

Production Example 485
A solution of rac- (1R, 2R) -4-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexanecarboxamide (1.1 g) in tetrahydrofuran (20 mL) and 1M borane tetrahydrofuran complex in tetrahydrofuran (20 mL) Was added under ice cooling. The reaction mixture was stirred at 60 ° C. for 4 hours, and methanol was added under ice cooling. The reaction mixture was stirred for 30 minutes under ice-cooling, and saturated aqueous sodium hydrogen carbonate solution (5.6 mL), chloroform (5.6 mL) and benzyl chloroformate (1.3 g) were added. The reaction mixture was stirred at room temperature for 5 days and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10: 1), and benzyl rac-({(1R, 2R) -4-hydroxy-2- [4- (trifluoromethyl) phenyl] cyclohexyl} methyl) The carbamate was obtained as colorless amorphous (660 mg).

Production Example 486
To a solution of rac- (1R, 2R) -4-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexanecarboxylic acid (1.1 g) in chloroform (10 ml) was added N- [3- (dimethylamino) propyl. ] -N′-ethylcarbodiimide hydrochloride (1.1 g), 1-hydroxybenzotriazole (505 mg), and ammonium chloride (400 mg) were sequentially added. The reaction mixture was stirred at room temperature for 5 days, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 10: 1) to obtain rac- (1R, 2R) -4-oxo-2. -[4- (Trifluoromethyl) phenyl] cyclohexanecarboxamide was obtained as a pale yellow oil (1.1 g).

Production Example 487
Ethyl rac-{(1R, 3S, 4R) -4-amino-3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (150 mg) in methanol solution (6 mL) and 5% rhodium alumina (150 mg ) Was added. The reaction mixture was stirred at room temperature for 3 days under a hydrogen atmosphere of 3.5 atm, and then filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 10: 1 to 4: 1), and ethyl rac-[(1R, 1's, 3S, 4'S, 6S) -6- Amino-4 '-(trifluoromethyl) -1,1'-bi (cyclohexyl) -3-yl] acetate was obtained as a colorless oil (87 mg).

Production Example 488
2- (Trimethylsilyloxy) -1,3-butadiene (11 g) was added to a toluene solution (50 mL) of ethyl (2E) -3- (cyclohexyl) acrylate (6.8 g), and N- (trimethylsilyl) was cooled under ice cooling. ) -Bis (trifluoromethanesulfonyl) imide (1.3 g) was added slowly. The reaction mixture was stirred at 0 ° C. for 3 days, and saturated aqueous sodium hydrogen carbonate solution was added. The reaction mixture was stirred at room temperature overnight, the insoluble material was filtered through celite, and the filtrate was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4: 1), and ethyl rac- (1R, 2S) -5-oxo- 1,1′-bi (cyclohexyl) -2-carboxylate was obtained as an orange oil (1.88 g,).

Production Example 489
The compound of Production Example 490 was used as a raw material and produced in the same manner as in Production Example 188.

Production Example 490
Using the compound of Production Example 491 as a raw material, the compound was produced in the same manner as in Production Example 141.

Production Example 491
Using the compound of Production Example 492 as a raw material, the compound was produced in the same manner as in Production Example 631 described later.

Production Example 492
The compound of Production Example 35 was used as a raw material, and in the same manner as in Production Example 518, diethyl (cyanomethylphosphonate was used instead of triethyl phosphonoacetate).

Production Example 493
Using the compound of Production Example 631 as a raw material, this was produced by successively carrying out the same methods as in Production Example 141 and Example 16 described later.

Production Example 494
Using the compound of Production Example 495a as a raw material, the compound was produced in the same manner as in Production Example 188.

Production Example 495
Using the compound of Production Example 497 as a raw material, the compound was produced in the same manner as in Production Example 141.

Production Example 497
Using the compound of Production Example 483 as a raw material, the compound was produced in the same manner as in Production Example 631 described later.

Production Example 498
Using the compound of Production Example 514 as a raw material, the same method as Production Example 141 was performed, and triethylamine was added to the reaction mixture.

Production Example 511
Using the compound of Production Example 521 as a raw material, the salt of the raw material was desalted and then produced in the same manner as in Production Example 631 described later.

Production Example 513
The compound of Production Example 94 was used as a raw material, and the mixture was desalted after completion of the reaction in the same manner as in Production Example 603 described later.

Production Example 514
Using the compound of Production Example 93 as a raw material, the compound was produced in the same manner as in Production Example 631 described later.

Production Example 515
Ethyl [6-amino-4 '-(trifluoromethyl) biphenyl-3-yl] acetate (0.43 g) in methanol (12 ml), 4M hydrogen chloride in 1,4-dioxane (0.4 ml), platinum dioxide (0.08 g) was added, and the mixture was stirred under a hydrogen atmosphere of 3.4 atm for 20 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol). Methanol (5 ml) and sodium methoxide (0.1 g) were added to the obtained brown oil (0.32 g), and the mixture was stirred for 13 hours. Water was added to the reaction mixture, extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and methyl rac-{(1R, 3S, 4S) -4-amino-3- [4- (Trifluoromethyl) phenyl] cyclohexyl} acetate was obtained as a light brown oil (0.28 g).

Production Example 516
Ethyl (4-oxocyclohexyl) acetate (4.0 g) to 1-bromo-4- (trifluoromethyl) benzene (2.5 ml), tripotassium phosphate (5.0 g), toluene (40 ml), 4,5-bis (Diphenylphosphino) -9,9-dimethylxanthene (0.63 g) and tris (dibenzylideneacetone) dipalladium (0) (0.50 g) were sequentially added, and the mixture was stirred at 80 ° C. for 2 days in an argon atmosphere. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain ethyl rac- {4-oxo-3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate as a brown liquid (5.5 g).

Production Example 517
Ethyl rac- {4-oxo-3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (5.47 g) in dichloromethane (80 ml), 3-methylbutylamine (3 ml) and anhydrous magnesium sulfate (10 g) Were sequentially added and stirred at room temperature for 17 hours. After filtering the reaction mixture, sodium triacetoxyborohydride (6.0 g) was added to the filtrate, and the mixture was stirred at room temperature for 1 day. A 1 M aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) and ethyl rac-{(1R, 3R, 4R) -4-[(3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl ] Cyclohexyl} acetate was obtained (0.35 g).

Production Example 518
1-iodo-4- (pentafluoro-λ ⁶ -sulfanyl) benzene (1.0 g) to 1,4-dioxane (15 ml), bis (pinacolato) diboron (0.85 g), [1,1'-bis (diphenyl) Phosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (0.12 gl) and potassium acetate (0.62 g) were sequentially added, and the mixture was heated and stirred at 90 ° C. for 4 hours under nitrogen atmosphere. To the reaction mixture was added 2-iodocyclohex-2-en-1-one (1.0 g), cesium carbonate (2.0 g), water (3 ml) and bis (tricyclohexylphosphine) palladium (II) dichloride (0.10 g). The mixture was added successively and stirred at 90 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 2- [4- (pentafluoro-λ ⁶ -sulfanyl) phenyl] cyclohex-2-en-1-one as a brown liquid (0.24 g ).

Production Example 519
Using the compound of Production Example 101 as a raw material, the same process as in Production Example 631 was carried out for production. The product was isolated without desalting after the reaction.

Production Example 528
Methyl rac-{(1R, 2S, 3R) -3- (benzylamino) -2- [4- (trifluoromethyl) phenyl] cyclohexyl) acetate (122 mg), triethylamine (91 mg) and benzyl chloroformate ( 4- (dimethylamino) pyridine (5.5 mg) was added to a dichloromethane solution of 77 mg), and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure and diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 95: 5-80: 20) and methyl rac-{(1R, 2S, 3R) -3- {benzyl [(benzyloxy) carbonyl] amino} -2- [4- (Trifluoromethyl) phenyl] cyclohexyl) acetate was obtained (75 mg).

Production Example 529
Ethyl rac-{(3R, 4S) -4-amino-3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (825 mg) in toluene (8 mL) was added to iodobenzene (567 mg), palladium Acetate (60 mg), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (220 mg) and potassium tert-butoxide (425 mgl) were added. The reaction system was purged with nitrogen, and then stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform / methanol = 100: 0 to 4: 1) and ethyl rac-{(1R, 3R, 4S) -4-anilino-3- [4- (trifluoromethyl). ) Phenyl] cyclohexyl} acetate as a colorless oil (180 mg), ethyl rac-{(1R, 3S, 4R) -4-anilino-3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate as a colorless oil Obtained as a product (67 mg).

Production Example 532
Using the compound of Production Example 520 as a raw material, sodium iodide was added to the reaction mixture in the same manner as in Production Example 536 described later.

Production Example 536
Ethyl rac-{(1R, 3S, 4R) -4-amino-3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (120 mg) in acetonitrile (3 mL) in (2-bromoethyl) cyclohexane ( 98 mg) and sodium carbonate (120 mg) were added. The reaction mixture was stirred at 70 ° C. for 1 day, cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 10: 1) to obtain ethyl rac-{(1R , 3S, 4R) -4-[(2-cyclohexylethyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate as a colorless oil (114 mg), ethyl rac-{(1R, 3S, 4R) -4- [Bis (2-cyclohexylethyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate was obtained as a colorless oil (31 mg).

Production Example 547
Ethyl rac-{(1R, 3S, 4R) -4-[(3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (133 mg) in acetonitrile (2 mL) solution 1-Chloro-3-methylbut-2-ene (174 mg) and sodium carbonate (176 mg) were added. The reaction mixture was stirred at 50 ° C. for 7 hours, cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane / ethyl acetate = 10: 0 to 10: 1) to obtain ethyl rac-{(1R , 3S, 4R) -4-[(3-Methylbut-2-en-1-yl) (3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate as a colorless oil Obtained (140 mg).

Production Example 555
Using the compound of Production Example 183 as a raw material, sodium iodide was added to the reaction mixture in the same manner as in Production Example 547.

Production Example 556
(2E) -3- [4- (trifluoromethyl) phenyl] acrylic acid (25 g) and pentafluorophenol (23 g) were suspended in chloroform (200 mL), and N- [3- (dimethylamino) Propyl] -N′-ethylcarbodiimide hydrochloride (26 g) was added. The reaction mixture was stirred at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from 2-propanol to give pentafluorophenyl (2E) -3- [4- (trifluoromethyl) phenyl] acrylate as a colorless powder (38 g).

Production Example 577
After thionyl chloride (1.1 g) was added dropwise to methanol (17 mL) under ice cooling, this solution was added to rac-{(1R, 2S) -3-oxo-2- [4- (trifluoromethoxy) phenyl] cyclohexyl. ) Acetic acid (2.0 g) in methanol (16 mL). The reaction mixture was stirred overnight, diluted with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 90: 5-80: 20) and methyl rac-{(1R, 2S) -3-oxo-2- [4- (trifluoromethoxy) phenyl ] Cyclohexyl) acetate was obtained (1.3 g).

Production Example 580
rac-{(1R, 2S) -3-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexyl) acetic acid (3.0 g) in N, N-dimethylformamide (20 mL) solution in potassium bicarbonate (2.0 g) and methyl iodide (5.7 g) were added. The reaction mixture was stirred overnight, diluted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 75: 25-65: 35) and methyl rac-{(1R, 2S) -3-oxo-2- [4- (trifluoromethyl) phenyl ] Cyclohexyl) acetate was obtained (2.1 g).

Production Example 583
Ethyl rac-{(1R, 3S, 4R) -4-[(3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (100 mg) in ethanol (2 mL) solution 1-oxaspiro [2.5] octane (200 mg) was added, and the mixture was stirred overnight with heating under reflux. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 10: 1) to obtain ethyl rac-{(1R, 3S, 4R ) -4-{[(1-Hydroxycyclohexyl) methyl] (3-methylbutyl) amino} -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate was obtained as a colorless oil (48 mg).

Production Example 584
A solution of diisopropylamine (430 mg) in anhydrous tetrahydrofuran (1 ml) was cooled to −78 ° C., a 1.57M hexane (2.6 mL) solution of n-butyllithium was added dropwise, and the mixture was stirred at −78 ° C. for 1 hour. Ethyl rac-{(1R, 3S, 4R) -4- [bis (3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate in anhydrous tetrahydrofuran (3 mL) was added to -78 The mixture was cooled to 0 ° C., an adjusted tetrahydrofuran diisopropylamide solution in anhydrous tetrahydrofuran (2.1 mL) was added, and the mixture was stirred at −78 ° C. for 45 minutes. To the reaction mixture was added iodomethane (228 mg), and the mixture was stirred for 1 hour while gradually warming to 0 ° C. 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The same operation was repeated twice for the obtained residue, and the obtained residue was purified by basic silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 10: 1) to give ethyl rac- { (1R, 3S, 4R) -4- [Bis (3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} -2-methylpropanoate was obtained as a pale yellow oil ( 37 mg).

Production Example 585
Pentafluorophenyl rac- (1R, 2R) -4-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexanecarboxylate (35 g) in tetrahydrofuran (151 mL) in 3M aqueous sodium hydroxide solution (76 mL ) Was added. The reaction mixture was stirred at room temperature for 3 hours, and concentrated hydrochloric acid was added under ice cooling until acidic. The reaction mixture was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10: 1 to 6: 1), and rac- (1R, 2R) -4-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexanecarboxyl. The acid was obtained as a colorless powder (18 g).

Production Example 602
Using the compound of Production Example 488 as a raw material, the compound was produced in the same manner as in Production Example 585.

Production Example 603
Ethyl rac-[(3R, 4S) -4-{[(benzyloxy) carbonyl] amino} -3- (4-chlorophenyl) cyclohexylidene] acetate (2.0 g), ethanol (40 ml), tetrahydrofuran (20 ml), 1,4-dioxane solution (1.2 ml) of 4M hydrogen chloride and 10% palladium carbon (0.2 g) were sequentially added, and the mixture was stirred for 1 hour in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. Ethanol (60 ml) and platinum dioxide (0.2 g) were added to the residue, and the mixture was stirred for 30 minutes in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. Ethanol was added to the residue and allowed to stand overnight. The precipitated solid was collected by filtration, and ethyl rac-[(1R, 3S, 4R) -4-amino-3- (4-chlorophenyl) cyclohexyl] acetate hydrochloride was obtained as a white solid. (0.17 g,).

Production Example 605
A tetrahydrofuran solution (15 ml) of ethyl (3,3,5,5-tetramethylcyclohexyl) acetate (1.2 g) was cooled to −78 ° C., and a 1.01 M toluene solution (12 mL) of diisobutylaluminum hydride was added. The mixture was stirred for 1 hour while gradually raising the temperature to −40 ° C., 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100: 0-10: 1) to give 2- (3,3,5,5-tetramethylcyclohexyl) ethanol as a colorless oil (953 mg ).

Production Example 606
Ethyl rac-{(1R, 3S, 4R) -4-amino-3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (1.2 g) in methanol solution was added D-tartaric acid (556 g) at room temperature. After stirring for 30 minutes, the solvent was distilled off under reduced pressure. The residue was recrystallized twice from ethanol, and the obtained crystal was dissolved in methanol. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and ethyl (+)-{(1R ^* , 3S ^* , 4R ^* )-4-amino-3- [4- (trifluoromethyl) phenyl] Cyclohexyl} acetate was obtained as a colorless oil (165 mg). Further, the solvent was distilled off from the recrystallized mother liquor under reduced pressure, and the resulting residue was treated with a saturated aqueous sodium hydrogen carbonate solution and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was similarly optically resolved using L-tartaric acid, and ethyl (-)-{(1R ^* , 3S ^* , 4R ^* )-4-amino-3- [4- (trifluoromethyl) phenyl] Cyclohexyl} acetate was obtained as a pale yellow oil (166 mg).

Production Example 608
Ethyl rac-[(3R, 4S) -4-amino-3- (4-fluorophenyl) cyclohexyl] acetate (372 mg) in ethyl acetate (3 mL) was mixed with 4M hydrogen chloride in ethyl acetate (330 μL). In addition, the resulting precipitate was collected by filtration. The obtained colorless powder was dissolved in methanol, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain ethyl rac-[(1R, 3S, 4R) -4-amino-3- (4-fluorophenyl) cyclohexyl] acetate as a colorless oil. Obtained (158 mg).

Production Example 615
The compound of Production Example 622 was used as a raw material and was produced in the same manner as in Production Example 608 using benzenesulfonic acid instead of hydrogen chloride.

Production Example 617
2- (3,3,5,5-tetramethylcyclohexyl) ethanol (950 mg) in dichloromethane solution was added sodium bicarbonate (480 mg) and (1,1,1-triacetoxy) -1,1-dihydro-1 Then, 2-benziodoxol-3 (1H) -one (2.4 g) was added and stirred at room temperature for 3 hours. A saturated aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100: 0-20: 1) to give 2- (3,3,5,5-tetramethylcyclohexyl) acetaldehyde as a colorless oil (295 mg).

Production Example 618
Ethyl rac-[(3R, 4S) -4-{[(Benzyloxy) carbonyl] amino} -3- (4-methylphenyl) cyclohexylidene] acetate (1.16 g) in 2: 1 ethanol-tetrahydrofuran (75 mL ) 5% palladium barium sulfate (1.2 g) was added to the solution. The reaction mixture was stirred at room temperature for 1 day under a hydrogen atmosphere, and then filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane / ethyl acetate = 100: 0 to 3: 1), and ethyl rac-[(3R, 4S) -4-amino-3- (4-Methylphenyl) cyclohexyl] acetate was obtained as a colorless oil (606 mg).

Production Example 625
Using the compound of Production Example 83 as a raw material, the same method as in Production Example 618 was performed, and halogen was also reduced at the same time.

Production Example 626
Using the compound of Production Example 481 as a raw material, the same method as in Production Example 618 was performed, and the double bond part was also reduced at the same time.

Production Example 631
Using the compound of Production Example 80 as a raw material, the same process as in Production Example 618 and Production Example 608 was continuously performed.

Production Example 633
Using the compound of Production Example 477 as a raw material and using the same method as in Production Example 631, the double bond part was also reduced at the same time.

  It carried out similarly to the method of the said manufacture example, and manufactured the manufacture example compound shown in the following table | surface using the corresponding raw material, respectively. The following table shows the structure, production method and physicochemical data of the production example compounds.

Example 1
Ethyl {(1R ^* , 3S ^* , 4R ^* )-4- [bis (cyclohexylmethyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (395 mg) in 1: 1 methanol-tetrahydrofuran To the (6 mL) solution was added 1 M aqueous sodium hydroxide solution (2 mL). The reaction mixture was stirred at room temperature overnight, 1M hydrochloric acid (2 mL) was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0 to 4: 1), and {(1R ^* , 3S ^* , 4R ^* )-4- [bis (cyclohexylmethyl) amino] -3- [ 4- (Trifluoromethyl) phenyl] cyclohexyl} acetic acid was obtained as a colorless oil (347 mg).

Example 9
Using the compound of Production Example 13 as a raw material, the compound was produced in the same manner as in Example 16 described later.

Example 12
Using the compound of Example 3 as a raw material, the compound was produced in the same manner as in Example 236 described later.

Example 19
Using the compound of Production Example 24 as a raw material, the compound was produced in the same manner as in Example 84 described later.

Example 21
Using the compound of Example 306 as a raw material, the compound was produced in the same manner as in Example 236 described later.

Example 24
rac-{(1R, 3S, 4R) -4- [Bis (2-phenylethyl) amino] -3-cyclopentylcyclohexyl} acetic acid (131 mg) in ethanol (15 mL) in platinum dioxide (55 mg) and acetic acid (4 mL) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere of 3 atm. The reaction mixture was filtered through celite and washed with ethanol, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1: 1) to obtain the desired product as a colorless oil (105 mg). This compound (100 mg) was dissolved in ethyl acetate, 4M hydrogen chloride in ethyl acetate (0.3 ml) was added, and the resulting solid was collected by filtration and washed with hexane to give rac-{(1R, 3S, 4R) -4- [Bis (2-cyclohexylethyl) amino] -3-cyclopentylcyclohexyl} acetic acid hydrochloride was obtained as a colorless powder (94 mg).

Example 26
Using the compound of Production Example 344 as a raw material, the compound was produced in the same manner as in Example 84 described later.

Example 27
Using the compound of Example 309 as a raw material, the compound was produced in the same manner as in Example 236 described later.

Example 29
Using the compound of Production Example 355b as a raw material, the compound was produced in the same manner as in Example 84 described later.

Example 49
Using the compound of Production Example 313 as a raw material, the compound was produced in the same manner as in Example 236 described later.

Example 78
rac-{(1R, 3S, 4R) -4-[(cyclohexylmethyl) (3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetonitrile (100 mg) in toluene (2 mL ) Sodium azide (72 mg) and triethylamine hydrochloride (153 mg) were added to the solution, and the mixture was stirred at 100 ° C. overnight. The reaction solution is cooled and then purified by silica gel column chromatography (chloroform / methanol = 10: 1 to 4: 1), and rac- (1R, 2S, 4R) -N- (cyclohexylmethyl) -N- (3- Methylbutyl) -4- (1H-tetrazol-5-ylmethyl) -2- [4- (trifluoromethyl) phenyl] cyclohexaneamine was obtained as a colorless oil. This compound was dissolved in ethyl acetate (5 mL), 4M hydrogen chloride in ethyl acetate (0.2 ml) was added, and the mixture was concentrated to give rac- (1R, 2S, 4R) -N- (cyclohexylmethyl)- N- (3-methylbutyl) -4- (1H-tetrazol-5-ylmethyl) -2- [4- (trifluoromethyl) phenyl] cyclohexaneamine hydrochloride was obtained as a colorless amorphous substance (49 mg).

Example 79
Methyl rac-{(1R, 2S) -3-oxo-2- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (250 mg) and 3-methylbutylamine (139 mg) and titanium tetraisopropoxide (226 mg) was added. The reaction mixture was stirred at 60 ° C. for 3 hr, diluted with 1,2-dichloromethane (3 mL), and sodium triacetoxyborohydride (337 mg) was added. The reaction mixture was stirred at room temperature for 6 hr, celite and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was filtered through celite. The filtrate was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in acetonitrile (3 mL) and sodium carbonate (169 mg) and 4- (trifluoromethyl) benzyl bromide (190 mg) were added. The reaction mixture was stirred at 60 ° C. for 2 days, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10: 1 to 4: 1) to obtain a crude product. The composition organism was dissolved in tetrahydrofuran (1 mL), 12 M aqueous sodium hydroxide solution (1 ml) was added, and the mixture was stirred at 60 ° C. overnight. To this mixture was added 4M hydrogen chloride in ethyl acetate (4 mL), and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10: 1), and the target carboxylic acid was diastereomer. Obtained as a mixture (73 mg). This mixture (73 mg) was dissolved in ethyl acetate (5 mL), 4M hydrogen chloride in ethyl acetate (0.2 mL) was added, and the solvent was evaporated under reduced pressure to obtain the diastereomeric mixture hydrochloride. (65 mg). This mixture (60 mg) was purified by liquid chromatography, and each diastereomer was separated, and each was converted to the hydrochloride in the same manner as described above, and rac-{(1R, 2R, 3R) -3-{( 3-methylbutyl) [4- (trifluoromethyl) benzyl] amino} -2- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid hydrochloride as a colorless powder (4.1 mg), rac-{((1R, 2S, 3S) -3-{(3-Methylbutyl) [4- (trifluoromethyl) benzyl] amino} -2- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid hydrochloride was obtained as a colorless solid ( 9.6 mg).

Example 81
of rac-{(1R, 3S, 4R) -4-[(2,8-dimethylnon-5-yl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid hydrochloride (24.8 g) Formic acid (7 mg) and 37% aqueous formaldehyde solution (0.05 ml) were added to a THF (2 mL) solution. The reaction mixture was stirred at 60 ° C. for 6 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 6: 1), and rac-{(1R, 3S, 4R) -4-[(2,8-dimethylnon-5-yl) (methyl) amino]- 3- [4- (Trifluoromethyl) phenyl] cyclohexyl} acetic acid was obtained (21 mg). This was dissolved in ethyl acetate, 4M hydrogen chloride in ethyl acetate (0.1 ml) was added, and concentrated to give rac-{(1R, 3S, 4R) -4-[(2,8-dimethylnona-5- Yl) (methyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetic acid hydrochloride was obtained as a colorless powder (22 mg).

Example 82
Using the compound of Production Example 494 as a raw material, the compound was produced in the same manner as in Example 84 described later.

Example 85
Ethyl rac-{(1R, 3S, 4R) -4-[(2-cyclohexylethyl) (3-methylbutyl) amino] -3- [4- (trifluoromethyl) phenyl] cyclohexyl} acetate (62 mg) 1 M aqueous solution of sodium hydroxide (500 μL) was added to a methanol-tetrahydrofuran (3 mL) solution. The reaction mixture was stirred at room temperature overnight, 1M hydrochloric acid (500 μL) was added, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0 to 6: 1), and rac-{(1R, 3S, 4R) -4-[(2-cyclohexylethyl) (3-methylbutyl) amino ] -3- [4- (Trifluoromethyl) phenyl] cyclohexyl} acetic acid was obtained as colorless amorphous (56 mg).

Example 84
Using the compound of Production Example 543b as a raw material, the same method as in Example 85 and Example 236 was carried out successively.

Example 202
The compound of Production Example 277 was used as a raw material and was produced in the same manner as in Example 84.

Example 236
To a solution of rac-[(1R, 3S, 4R) -4-[(cyclohexylmethyl) (3-methylbutyl) amino] -3- (4-fluorophenyl) cyclohexyl] acetic acid (42 mg) in ethyl acetate (2 mL) Add 4M hydrogen chloride in ethyl acetate (30 μL) and concentrate to rac-[(1R, 3S, 4R) -4-[(cyclohexylmethyl) (3-methylbutyl) amino] -3- (4-fluorophenyl) [Cyclohexyl] acetic acid hydrochloride was obtained as a colorless amorphous substance (45 mg).

Example 306
The compound of Production Example 22 was used as a raw material and produced in the same manner as in Example 84.

Example 309
The compound of Production Example 313 was used as a raw material and was produced in the same manner as in Example 85.

Example 311
Using the compound of Production Example 403 as a raw material, the compound was produced in the same manner as in Example 85.

  In the same manner as in the above Examples, the Example compounds shown in the following table were produced using the corresponding raw materials. The following table shows the structures, production methods and physicochemical data of the example compounds.

  Since the compound of the present invention has an excellent inhibitory effect on amyloid β peptide deposition, Alzheimer's disease (AD), cerebral amyloid angiopathy, Dutch hereditary cerebral hemorrhage (HCHWA-D), multiple infarct dementia, fighting dementia Or, it is useful as an agent for preventing or treating diseases associated with amyloid β peptide deposition in the brain such as Down's syndrome.

Claims (1)

A compound of formula (I) or a salt thereof.

(Where
R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are the same or different from each other, and H, halogen, or
R ¹¹ and R ¹² or R ¹³ and R ¹⁴ together are oxo (= O),
R ¹ and R ² are the same or different from each other, and may be substituted lower alkyl, O- (optionally substituted lower alkyl), optionally substituted lower alkenyl, optionally substituted. Lower alkynyl, optionally substituted cycloalkyl, O- (optionally substituted cycloalkyl), optionally substituted aryl, O- (optionally substituted aryl), optionally substituted A good heterocyclic group or O- (optionally substituted heterocyclic group),
R ³ and R ⁵ are the same or different from each other, and H, OH, halogen, optionally substituted lower alkyl, O- (optionally substituted lower alkyl), or lower alkyl (this lower alkyl is Amino optionally substituted with halogen),
R ⁴ is an optionally substituted lower alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heterocyclic group;
W is a single bond or -CR ^W1 R ^W2-
R ^W1 and R ^W2 are the same or different from each other, and H, OH, halogen, optionally substituted lower alkyl, O- (optionally substituted lower alkyl), or lower alkyl (this lower alkyl is Amino optionally substituted with halogen),
X ^is- (CR ^X1 R ^X2 ) _n-
R ^X1 and R ^X2 are the same or different from each other and are H, halogen, or optionally substituted lower alkyl,
n is 1, 2, or 3,
L is optionally substituted lower alkylene, O-optionally substituted lower alkylene *, NH-optionally substituted lower alkylene *, or N (optionally substituted lower alkyl)- An optionally substituted lower alkylene *,
* Means to combine with Z at that part,
Z is -C (= O) -OH or an optionally substituted tetrazole group;
p and q are the same or different from each other, and are 0, 1, 2, or 3.
Y is a single bond, or -CH _2- ,
However, when W is a single bond and ^one of R ¹ and R ² is optionally substituted lower alkyl, the other is optionally substituted aryl or optionally substituted heterocycle Not a group. )