Novel cycloalkenone compounds or salts thereof

Abstract

A compound represented by General Formula (I) or a salt thereof; a nerve growth promoter comprising the compound or the salt thereof as an active ingredient; a pharmaceutical composition comprising the compound or the salt thereof; a therapeutic agent for neurodegenerative diseases comprising the compound or the salt thereof as an active ingredient; a therapeutic agent for amyotrophic lateral sclerosis comprising the compound or the salt thereof as an active ingredient; a therapeutic agent for pain comprising the compound or the salt thereof as an active ingredient; and a therapeutic agent for lower urinary tract dysfunction comprising the compound or the salt thereof as an active ingredient.

Description

Technical Field

[0001] The present disclosure relates to a novel cycloenone compound or a salt thereof having a nerve growth stimulating effect, and a pharmaceutical composition comprising the compound or the salt thereof as an active ingredient. Background Art

[0002] According to the location of the damaged nerves, neurodegenerative diseases are broadly divided into central and peripheral diseases. Typical central nervous system diseases include Alzheimer's disease, amyotrophic lateral sclerosis and cerebral spinal cord injury. Typical diseases involving peripheral nerve damage include sensory neuropathy such as neuropathic pain and hypoesthesia, and autonomic dysfunction with constipation or dysuria. Although the pathogenesis of neurodegenerative diseases varies, it is believed that these diseases involve degeneration or atrophy of neurites and neuronal cell death. For these diseases, there is currently a lack of basic therapeutic drugs to improve neuropathy.

[0003] Patent Document 1 discloses that 3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one has a nerve growth-stimulating effect and can be used as a medical drug for preventing or treating brain diseases such as dementia. Patent Document 2 discloses that the same compound can be used as a therapeutic agent for dysuria. However, the pharmacokinetics of 3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one are generally unsatisfactory when prescribed (Patent Document 3).

[0004] Citation List

[0005] Patent Literature

[0006] Patent Document 1: WO1999 / 008987A;

[0007] Patent Document 2: WO2002 / 066024A;

[0008] Patent document 3: WO2013 / 147072A. Summary of the Invention

[0009] Technical issues

[0010] The present disclosure aims to provide a novel compound or a salt thereof having excellent neurite outgrowth effect and a pharmaceutical composition comprising the compound or the salt thereof.

[0011] Problem Solution

[0012] The present inventors have conducted extensive research to achieve this purpose and have found that the cycloenone compound represented by formula (I) has a nerve growth stimulating effect (neurite growth effect and / or an effect of increasing the proportion of neurite-containing cells) and can be used as a medical drug for treating diseases that can be improved by promoting nerve growth (including neurodegenerative diseases), pain and / or lower urinary tract dysfunction.

[0013] Specifically, the present disclosure provides the following [1] to

[15] .

[0014] [1] A compound represented by the following formula (I) or a salt thereof:

[0015]

[0016] in

[0017] X represents -CH2-, -CH(CH3)-, -CH2-CH2- or -CH=CH-,

[0018] R1 represents -CH2OR4, -CH2OCON(R5)2, -CONHR6 or cyano,

[0019] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0020] R3 represents a hydrogen atom, a methyl group, -CH2OR7 or a halogen atom,

[0021] R4 represents C m H 2m+1 ,

[0022] R5 are the same or different and each represents a hydrogen atom or a methyl group,

[0023] R6 represents a hydrogen atom or a methyl group,

[0024] R7 represents a C1-C3 alkyl group,

[0025] m represents an integer from 1 to 14, and

[0026] n represents an integer from 1 to 15,

[0027] Provided that when R4 is a linear alkyl group, the sum of m and n is an integer from 12 to 17, and when R4 is a branched alkyl group, m b The sum of m and n is an integer from 12 to 17, where m b is the number of carbon atoms in the longest straight chain of a branched alkyl group.

[0028] [2] A compound represented by the following formula (I) or a salt thereof:

[0029]

[0030] in

[0031] X represents -CH2-, -CH(CH3)-, -CH2-CH2- or -CH=CH-,

[0032] R1 represents -CH2OR4, -CH2OCON(R5)2, -CONHR6 or cyano,

[0033] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0034] R3 represents a hydrogen atom, a methyl group, -CH2OR7 or a halogen atom,

[0035] R4 represents C m H 2m+1 ,

[0036] R5 are the same or different and each represents a hydrogen atom or a methyl group,

[0037] R6 represents a hydrogen atom or a methyl group,

[0038] R7 represents a C1-C3 alkyl group,

[0039] m represents an integer from 1 to 14, and

[0040] n represents an integer from 1 to 14,

[0041] Provided that when R4 is a linear alkyl group, the sum of m and n is an integer from 12 to 15, and when R4 is a branched alkyl group, m b The sum of m and n is an integer from 12 to 15, where m b is the number of carbon atoms in the longest straight chain of a branched alkyl group.

[0042] [3] A compound represented by the following formula (I) or a salt thereof:

[0043]

[0044] in

[0045] X represents -CH2-, -CH(CH3)-, -CH2-CH2- or -CH=CH-,

[0046] R1 represents -CH2OR4, -CH2OCON(CH3)2, -CONHR6 or cyano,

[0047] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms, and

[0048] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0049] Provided that when R2 are the same or different and each represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom, and when two R2 together with adjacent carbon atoms form a cyclopropyl group, R3 represents a methyl group, -CH2OCH3 or an iodine atom,

[0050] R4 represents a methyl group, an ethyl group, an n-propyl group or an isopropyl group, provided that when R4 is a methyl group, n represents an integer from 11 to 14, when R4 is an ethyl group or an isopropyl group, n represents an integer from 11 to 13, and when R4 is an n-propyl group, n is 11 or 12, and

[0051] R6 represents a hydrogen atom or a methyl group.

[0052] [4] The compound according to any one of [1] to [3] or a salt thereof, wherein X in formula (I) represents -CH2-, -CH2-CH2- or -CH=CH-.

[0053] [5] The compound according to any one of [1] to [4] or a salt thereof,

[0054] In formula (I),

[0055] R1 represents -CH2OR4, -CONH2 or cyano,

[0056] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0057] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom, provided that when R3 is a hydrogen atom, R2 is a hydrogen atom, and when R3 is a methyl group, -CH2OCH3 or an iodine atom, R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 can form a cyclopropyl group together with adjacent carbon atoms, and

[0058] R4 represents a methyl group, an ethyl group, an n-propyl group or an isopropyl group, provided that when R4 is a methyl group, n represents an integer from 11 to 14, when R4 is an ethyl group or an isopropyl group, n represents an integer from 11 to 13, and when R4 is an n-propyl group, n is 11 or 12.

[0059] [6] The compound or a salt thereof according to any one of [1] to [5], wherein in formula (I),

[0060] X represents -CH2- or -CH2-CH2-,

[0061] R1 represents -CH2OR4 or -CONH2,

[0062] R2 represents a methyl group,

[0063] R3 represents a methyl group or -CH2OCH3, and

[0064] R4 represents a methyl group, an ethyl group or an isopropyl group, provided that when R4 is a methyl group, n represents an integer of 11 to 14, and when R4 is an ethyl group or an isopropyl group, n represents an integer of 11 to 13.

[0065] [7] The compound or a salt thereof according to any one of [1] to [6], wherein X in formula (I) represents -CH2-CH2-.

[0066] [8] The compound or salt thereof according to any one of [1] to [7], which is any one of the following compounds (1) to (10):

[0067] (1) 3-(12-methoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0068] (2) 3-(12-ethoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0069] (3) 3-(12-isopropoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0070] (4) 3-(13-methoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0071] (5) 3-(13-ethoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0072] (6) 3-(13-isopropoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0073] (7) 3-(14-methoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0074] (8) 3-(14-ethoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0075] (9) 3-(14-isopropoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one, and

[0076] (10) 3-(15-Methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one.

[0077] [9] The compound or a salt thereof according to any one of [1] to [8], wherein the compound is 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one.

[0078]

[10] A nerve growth promoter comprising the compound or a salt thereof according to any one of [1] to [9] as an active ingredient.

[0079]

[11] A therapeutic agent for a neurodegenerative disease, comprising the compound of any one of [1] to [9] or a salt thereof as an active ingredient.

[0080]

[12] A therapeutic agent for amyotrophic lateral sclerosis, comprising the compound or a salt thereof according to any one of [1] to [9] as an active ingredient.

[0081]

[13] A therapeutic agent for pain, comprising the compound or a salt thereof according to any one of [1] to [9] as an active ingredient.

[0082]

[14] A therapeutic agent for lower urinary tract dysfunction, comprising the compound or a salt thereof according to any one of [1] to [9] as an active ingredient.

[0083]

[15] A pharmaceutical composition comprising

[0084] The compound of any one of [1] to [9] or a salt thereof, and

[0085] Pharmaceutical carrier.

[0086] Advantageous Effects of the Invention

[0087] The present disclosure provides a novel compound represented by formula (I) or a salt thereof, which can be used as a compound having a nerve growth stimulating effect. The present disclosure also provides a novel compound represented by formula (I) or a salt thereof, which can be used as a compound having excellent pharmacokinetics and / or an effect of improving urination function. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1 : Graph of residual urine volume in each group. These values ​​represent the mean ± SE. The numbers in each group are 10, 10, 12, and 12 from left to right.

[0089] *: p < 0.05, significantly different from vehicle in Dunnett's test;

[0090] NS: not significantly different from vehicle in Dunnett's test;

[0091] #: p < 0.05, significantly different from compound 24 in Student t-test;

[0092] ##: p < 0.01, significantly different from vehicle in Student's t-test. DETAILED DESCRIPTION

[0093] The compound represented by formula (I) according to the present disclosure is a novel compound not disclosed in any previous document.

[0094] In the compound represented by formula (I) of the present disclosure, X represents -CH2-, -CH(CH3)-, -CH2-CH2-, or -CH=CH-, and is preferably -CH2-, -CH(CH3)-, or -CH2-CH2-.

[0095] In an embodiment of the present disclosure, in the compound represented by formula (I) of the present disclosure, X represents -CH2-, -CH2-CH2-, or -CH=CH-, preferably -CH2- or -CH2-CH2-, more preferably -CH2-CH2-.

[0096] In the compound represented by formula (I) of the present disclosure, R1 represents -CH2OR4, -CH2OCON(R5)2, -CONHR6 or cyano. R1 preferably represents -CH2OR4, -CH2OCON(CH3)2, -CONHR6 or cyano, more preferably -CH2OR4, -CONH2 or cyano, more preferably -CH2OCH3, -CH2OC2H5, -CH2OCH(CH3)2, -CH2OCH2CH2CH3, -CONH2 or cyano, more preferably -CH2OCH3, -CH2OC2H5, -CH2OCH(CH3)2 or -CH2OCH2CH2CH3, and most preferably -CH2OCH3.

[0097] In the compounds represented by formula (I) of the present disclosure, R2 are identical or different and each represents a hydrogen atom or a methyl group, or two R2 can form a cyclopropyl group together with adjacent carbon atoms. R2 are preferably identical or different and each represents a hydrogen atom or a methyl group, more preferably a methyl group.

[0098] In the compound represented by formula (I) of the present disclosure, R3 represents a hydrogen atom, a methyl group, -CH2OR8 or a halogen atom.

[0099] The halogen atom represented by R3 is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and is preferably an iodine atom.

[0100] R3 is preferably a hydrogen atom, a methyl group, -CH2OCH3 or a halogen atom, more preferably a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom, more preferably a methyl group, -CH2OCH3 or an iodine atom, more preferably a methyl group or -CH2OCH3, and most preferably a methyl group.

[0101] In an embodiment of the present disclosure, when R2 is the same or different and each represents a hydrogen atom or a methyl group, R3 is a hydrogen atom, a methyl group, -CHOCH3, or an iodine atom. In another embodiment of the present disclosure, when two R2 together with adjacent carbon atoms form a cyclopropyl group, R3 is a methyl group, -CHOCH3, or an iodine atom; and when R2 is the same or different and each represents a hydrogen atom or a methyl group, R3 is preferably a hydrogen atom, a methyl group, -CHOCH3, or an iodine atom. In another embodiment of the present disclosure, when two R2 together with adjacent carbon atoms form a cyclopropyl group, R3 is a methyl group.

[0102] In the compound represented by formula (I) of the present disclosure, R4 is C m H 2m+1 R4 is preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group, more preferably a methyl group, an ethyl group or an isopropyl group, and still more preferably a methyl group.

[0103] In the compound represented by formula (I) of the present disclosure, m represents an integer of 1 to 14, and preferably an integer of 1 to 3.

[0104] In the compounds represented by formula (I) of the present disclosure, n represents an integer from 1 to 15, preferably an integer from 1 to 14, and more preferably an integer from 11 to 14. Preferably, when R4 is a methyl group, n is an integer from 11 to 14. Preferably, when R4 is an ethyl group or an isopropyl group, n is an integer from 11 to 13. Preferably, when R4 is an n-propyl group, n is 11 or 12.

[0105] In the compound represented by formula (I) of the present disclosure, when R4 is a straight-chain alkyl group, the sum of m and n is an integer from 12 to 17; when R4 is a branched-chain alkyl group, m b The sum of m and n is an integer from 12 to 17, where m b More preferably, when R4 is a straight-chain alkyl group, the sum of m and n is an integer from 12 to 15; when R4 is a branched-chain alkyl group, m b The sum of m and n is an integer from 12 to 15, where m b is the number of carbon atoms in the longest straight chain of a branched alkyl group.

[0106] In the compound represented by formula (I) of the present disclosure, when R4 is a branched alkyl group, m b represents an integer indicating the number of carbon atoms in the longest straight chain of a branched alkyl group. For example, when m is 3 and R4 is isopropyl, m b When m is 4 and R4 is sec-butyl or isobutyl, m b When m is 4 and R4 is tert-butyl, m b is 2.

[0107] In the compounds represented by formula (I) of the present disclosure, R5 is the same or different and each represents a hydrogen atom or a methyl group. Each R5 is preferably a methyl group.

[0108] In the compounds represented by formula (I) of the present disclosure, R6 represents a hydrogen atom or a methyl group. R6 is preferably a hydrogen atom.

[0109] In the compounds represented by formula (I) of the present disclosure, R7 represents a C1-C3 alkyl group, preferably a methyl group, an ethyl group or an isopropyl group, and more preferably a methyl group.

[0110] Preferred compounds among those represented by formula (I) satisfy the following conditions:

[0111] X represents -CH2-, -CH2-CH2- or -CH=CH-,

[0112] R1 represents -CH2OR4, -CH2OCON(CH3)2, -CONHR6 or a cyano group,

[0113] R2 is the same or different and each represents a hydrogen atom or a methyl group, or both R2 can form a cyclopropyl group together with the adjacent carbon atom, and

[0114] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0115] provided that

[0116] when R2 is the same or different and each represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0117] when both R2 form a cyclopropyl group together with the adjacent carbon atom, R3 represents a methyl group, -CH2OCH3 or an iodine atom,

[0118] R4 represents a methyl group, an ethyl group, an n-propyl group or an isopropyl group,

[0119] provided that

[0120] when R4 is a methyl group, n represents an integer of 11 to 14,

[0121] when R4 is an ethyl group or an isopropyl group, n represents an integer of 11 to 13,

[0122] when R4 is an n-propyl group, n is 11 or 12, and

[0123] R6 represents a hydrogen atom or a methyl group.

[0124] More preferred compounds among those represented by formula (I) satisfy the following conditions:

[0125] X represents -CH2-, -CH2-CH2- or -CH=CH-,

[0126] R1 represents -CH2OR4, -CONH2 or cyano,

[0127] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0128] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0129] The condition is

[0130] When R3 is a hydrogen atom, R2 is a hydrogen atom,

[0131] When R3 is a methyl group, -CH2OCH3 or an iodine atom, R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0132] R4 represents methyl, ethyl, n-propyl or isopropyl,

[0133] The condition is

[0134] When R4 is a methyl group, n represents an integer from 11 to 14,

[0135] When R4 is ethyl or isopropyl, n represents an integer from 11 to 13, and

[0136] When R4 is n-propyl, n is 11 or 12.

[0137] More preferred compounds among those represented by formula (I) satisfy the following conditions:

[0138] X represents -CH2- or -CH2-CH2-,

[0139] R1 represents -CH2OR4, -CONH2 or cyano,

[0140] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0141] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0142] The condition is

[0143] When R3 is a hydrogen atom, each R2 is a hydrogen atom,

[0144] When R3 is a methyl group, -CH2OCH3 or an iodine atom, R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0145] R4 represents methyl, ethyl, n-propyl or isopropyl,

[0146] The condition is

[0147] When R4 is a methyl group, n represents an integer from 11 to 14,

[0148] When R4 is ethyl or isopropyl, n represents an integer from 11 to 13, and

[0149] When R4 is n-propyl, n is 11 or 12.

[0150] More preferred compounds among those represented by formula (I) satisfy the following conditions:

[0151] X represents -CH2-CH2-,

[0152] R1 represents -CH2OR4, -CONH2 or cyano,

[0153] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0154] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0155] The condition is

[0156] When R3 is a hydrogen atom, each R2 is a hydrogen atom, and when R3 is a methyl group, -CH2OCH3 or an iodine atom, R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0157] R4 represents methyl, ethyl, n-propyl or isopropyl,

[0158] The condition is

[0159] When R4 is a methyl group, n represents an integer from 11 to 14,

[0160] When R4 is ethyl or isopropyl, n represents an integer from 11 to 13, and

[0161] When R4 is n-propyl, n is 11 or 12.

[0162] More preferred compounds among those represented by formula (I) satisfy the following conditions:

[0163] X represents -CH2-CH2-,

[0164] R1 represents -CH2OR4 or -CONH2,

[0165] Each R2 represents a methyl group,

[0166] R3represents a methyl group,

[0167] R4represents a methyl group, an ethyl group or an isopropyl group,

[0168] provided that

[0169] when R4is a methyl group, n represents an integer of 11 to 14, and

[0170] when R4is an ethyl group or an isopropyl group, n represents an integer of 11 to 13.

[0171] More preferred compounds among those represented by formula (I) satisfy the following conditions:

[0172] X represents -CH2-CH2-,

[0173] R1represents -CH2OR4,

[0174] each R2represents a methyl group,

[0175] R3represents a methyl group,

[0176] R4represents a methyl group, an ethyl group or an isopropyl group,

[0177] provided that

[0178] when R4is a methyl group, n represents an integer of 11 to 14, and

[0179] when R4is an ethyl group or an isopropyl group, n represents an integer of 11 to 13.

[0180] In an embodiment of the present disclosure, preferred compounds represented by formula (I) satisfy the following conditions:

[0181] X represents -CH2-CH2-,

[0182] R1represents -CH2OR4, -CH2OCON(CH3)2, -CONHR6or a cyano group,

[0183] R2are the same or different and each represents a hydrogen atom or a methyl group, or two R2may form a cyclopropyl group together with the adjacent carbon atom,

[0184] R3represents a hydrogen atom, a methyl group, -CH2OR7or a halogen atom,

[0185] provided that

[0186] when R2are the same or different and each represents a hydrogen atom or a methyl group, R3represents a hydrogen atom, a methyl group, -CH2OR7or a halogen atom, and when two R2form a cyclopropyl group together with the adjacent carbon atom, R3represents a methyl group, -CH2OR7or a halogen atom,

[0187] R4 represents C m H 2m+1 ,

[0188] R6 represents a hydrogen atom or a methyl group,

[0189] R7 represents a C1-C3 alkyl group,

[0190] m represents an integer from 1 to 14,

[0191] n represents an integer from 1 to 14,

[0192] The condition is

[0193] When m is an integer from 1 to 14, and R4 is a linear alkyl group, the sum of m and n is an integer from 12 to 15, and

[0194] When m is an integer from 1 to 14, and R4 is a branched alkyl group, m b The sum of m and n is an integer from 12 to 15, where m b is the number of carbon atoms in the longest straight chain of a branched alkyl group.

[0195] In the embodiments of the present disclosure, the preferred compound represented by formula (I) satisfies the following conditions:

[0196] X represents -CH2-CH2-,

[0197] R1 represents -CH2OR4, -CH2OCON(CH3)2, -CONHR6 or cyano,

[0198] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0199] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0200] The condition is

[0201] When R2 are the same or different and each represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom, and

[0202] When two R2 together with adjacent carbon atoms form a cyclopropyl group, R3 represents a methyl group, -CH2OCH3 or an iodine atom,

[0203] R4 represents C m H 2m+1 ,

[0204] R6 represents a hydrogen atom or a methyl group,

[0205] m represents an integer from 1 to 14,

[0206] n represents an integer from 1 to 14,

[0207] The condition is

[0208] When m is an integer from 1 to 14, and R4 is a linear alkyl group, the sum of m and n is an integer from 12 to 15, and

[0209] When m is an integer from 1 to 14, and R4 is a branched alkyl group, m b The sum of m and n is an integer from 12 to 15, where m b is the number of carbon atoms in the longest straight chain of a branched alkyl group.

[0210] In the embodiments of the present disclosure, the preferred compound represented by formula (I) satisfies the following conditions:

[0211] X represents -CH2-CH2-,

[0212] R1 represents -CH2OR4, -CH2OCON(CH3)2, -CONHR6 or cyano,

[0213] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0214] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0215] The condition is

[0216] When R2 are the same or different and each represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom, and

[0217] When two R2 together with adjacent carbon atoms form a cyclopropyl group, R3 represents a methyl group, -CH2OCH3 or an iodine atom,

[0218] R4 represents methyl, ethyl, n-propyl or isopropyl,

[0219] The condition is

[0220] When R4 is a methyl group, n represents an integer from 11 to 14,

[0221] When R4 is ethyl or isopropyl, n represents an integer from 11 to 13,

[0222] When R4 is n-propyl, n is 11 or 12, and

[0223] R6 represents a hydrogen atom or a methyl group.

[0224] In the embodiments of the present disclosure, more preferably the compound represented by formula (I) satisfies the following conditions:

[0225] X represents -CH2-CH2-,

[0226] R1 represents -CH2OR4, -CONH2 or cyano,

[0227] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0228] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0229] The condition is

[0230] When R3 is a hydrogen atom, each R2 is a hydrogen atom,

[0231] When R3 is a methyl group, -CH2OCH3 or an iodine atom, R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms, and

[0232] R4 represents methyl, ethyl, n-propyl or isopropyl,

[0233] The condition is

[0234] When R4 is a methyl group, n represents an integer from 11 to 14,

[0235] When R4 is ethyl or isopropyl, n represents an integer from 11 to 13, and

[0236] When R4 is n-propyl, n is 11 or 12.

[0237] In the embodiments of the present disclosure, the preferred compound represented by formula (I) satisfies the following conditions:

[0238] X represents -CH2-, -CH(CH3)-, -CH2-CH2- or -CH=CH-,

[0239] R1 represents -CH2OR4, -CH2OCON(CH3)2, -CONHR6 or cyano,

[0240] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0241] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0242] The condition is

[0243] When R2 are the same or different and each represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom, and

[0244] When two R2 together with adjacent carbon atoms form a cyclopropyl group, R3 represents a methyl group, -CH2OCH3 or an iodine atom,

[0245] R4 represents methyl, ethyl, n-propyl or isopropyl,

[0246] The condition is

[0247] When R4 is a methyl group, n represents an integer from 11 to 14,

[0248] When R4 is ethyl or isopropyl, n represents an integer from 11 to 13,

[0249] When R4 is n-propyl, n is 11 or 12, and

[0250] R6 represents a hydrogen atom or a methyl group.

[0251] In the embodiments of the present disclosure, the preferred compound represented by formula (I) satisfies the following conditions:

[0252] X represents -CH2-, -CH(CH3)-, -CH2-CH2- or -CH=CH-,

[0253] R1 represents -CH2OR4, -CONH2 or cyano,

[0254] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0255] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0256] The condition is

[0257] When R3 is a hydrogen atom, each R2 is a hydrogen atom,

[0258] When R3 is a methyl group, -CH2OCH3 or an iodine atom, R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0259] R4 represents methyl, ethyl, n-propyl or isopropyl,

[0260] The condition is

[0261] When R4 is a methyl group, n represents an integer from 11 to 14,

[0262] When R4 is ethyl or isopropyl, n represents an integer from 11 to 13, and

[0263] When R4 is n-propyl, n is 11 or 12.

[0264] In the embodiments of the present disclosure, the preferred compound represented by formula (I) satisfies the following conditions:

[0265] X represents -CH2-, -CH(CH3)- or -CH2-CH2-,

[0266] R1 represents -CH2OR4, -CONH2 or cyano,

[0267] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0268] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0269] The condition is

[0270] When R3 is a hydrogen atom, each R2 is a hydrogen atom,

[0271] When R3 is a methyl group, -CH2OCH3 or an iodine atom, R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0272] R4 represents methyl, ethyl, n-propyl or isopropyl,

[0273] The condition is

[0274] When R4 is a methyl group, n represents an integer from 11 to 14,

[0275] When R4 is ethyl or isopropyl, n represents an integer from 11 to 13, and

[0276] When R4 is n-propyl, n is 11 or 12.

[0277] Examples of specific compounds disclosed herein include, but are not limited to, the compounds prepared in the following examples.

[0278] Examples of preferred compounds of the present disclosure are as follows:

[0279] (1) 3-(12-methoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0280] (2) 3-(12-ethoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0281] (3) 3-(12-isopropoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0282] (4) 3-(13-methoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0283] (5) 3-(13-ethoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0284] (6) 3-(13-isopropoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0285] (7) 3-(14-methoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0286] (8) 3-(14-ethoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0287] (9) 3-(14-isopropoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0288] (10) 3-(15-Methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one.

[0289] Among the compounds represented by formula (I), the most preferred compound is 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one.

[0290] The following describes the preparation methods of the compounds according to the present disclosure.

[0291] The compound (I) of the present disclosure can be produced, for example, according to the following production methods or the methods described in Examples. However, the production method of the compound (I) is not limited to these reaction examples.

[0292] Reaction Scheme 1

[0293]

[0294] In Reaction Scheme 1, X, R2, R3, R4 and n are as defined above, and L1 represents a leaving group.

[0295] In the method shown in Reaction Scheme 1, the hydroxyl group of the compound having a hydroxyl group represented by Formula (1a) reacts with the compound having a leaving functional group represented by Formula (1b) to induce the ether derivative (1c).

[0296] Specifically, L1 in compound (1b) may be any group as long as it is a leaving functional group. Examples include a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a benzenesulfonyloxy group, and a p-toluenesulfonyloxy group.

[0297] At -50°C to 100°C, preferably -20°C to 80°C, in a suitable solvent, per mole of the hydroxy compound represented by formula (1a), 0.5 to 50 mol, preferably 0.8 to 20 mol, of the compound represented by formula (1b) is allowed to react in the presence of 0.5 to 10 mol, preferably 0.8 to 5 mol of a base (relative to each mole of the compound represented by formula (1a)) to obtain the ether compound represented by formula (1c).

[0298] There are no particular restrictions on suitable solvents, as long as the solvent does not affect the reaction. Examples include dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. These can be used alone or in combination.

[0299] Examples of the base used include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride; and organic bases such as pyridine, lutidine, collidine, 4-(N,N-dimethylamino)pyridine, triethylamine, diisopropylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide, sodium tert-butoxide, silver oxide and silver carbonate.

[0300] Reaction Scheme 2

[0301]

[0302] In Reaction Scheme 2, X, R2, R3 and n are as defined above, L2 represents a halogen atom, R 11 represents a C1-C7 alkyl group, R 12 represents R4 as defined above or a protecting group for hydroxyl group.

[0303] In the method shown in Reaction Scheme 2, a compound having an enol ether represented by formula (2a) reacts with a compound having a halogen atom represented by formula (2b) in the presence of a metal to induce an enone derivative (2c).

[0304] Specifically, L2 in compound (2b) may be any halogen atom. Examples include chlorine atom, bromine atom and iodine atom.

[0305] R 11 is a C1-C7 alkyl group. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0306] R 12represents R4 as defined above or a protecting group for a hydroxyl group. Examples of the protecting group for a hydroxyl group include a methoxymethyl group, a tetrahydropyranyl group, a benzyl group, a tert-butyldimethylsilyl group and a tert-butyldiphenylsilyl group.

[0307] At 0°C to 150°C, preferably 20°C to 120°C, in a suitable solvent, per mol of the enol ether compound represented by formula (2a), 0.5 to 50 mol, preferably 0.8 to 10 mol, of the compound represented by formula (2b) is allowed to react in the presence of 0.5 to 100 mol, preferably 0.8 to 30 mol of metal (relative to each mol of the compound represented by formula (2a)) to obtain the enone compound represented by formula (2c).

[0308] Suitable solvents are not particularly limited as long as the solvent does not affect the reaction. Examples include benzene, toluene, chlorobenzene, xylene, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, n-hexane, n-heptane, cyclohexane, acetonitrile, hexamethylphosphoric triamide and sulfolane. These can be used alone or in combination.

[0309] The metal is, for example, lithium, sodium, strontium, magnesium or zinc, preferably lithium or magnesium.

[0310] Reaction Scheme 3

[0311]

[0312] In Reaction Scheme 3, X, R2, R3, R5 and n are as defined above. In the method shown in Reaction Scheme 3, a compound having a hydroxyl group represented by formula (3a) or an active substance thereof is condensed with an amine compound represented by formula (3b) or a salt thereof according to a conventional method to induce a carbamate derivative (3c).

[0313] Specifically, in the condensation reaction, it is preferred to use an active substance having a leaving group, which is prepared by allowing, for example, triphosgene, 1,1'-carbonyldiimidazole (CDI), phenyl chloroformate, 4-nitrophenyl chloroformate or ethyl chloroformate to act on a compound having a hydroxyl group represented by formula (3a) in the presence or absence of an organic base such as triethylamine, diisopropylethylamine or pyridine at -20°C to 150°C, preferably 0°C to 100°C, in a solvent inert to the reaction (such as dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate or N,N-dimethylacetamide).

[0314] The active substance of formula (3a) can be, for example, an active substance having a leaving group. Such an active substance having a leaving group can be isolated for use in the reaction, or prepared in a reaction system and used in the reaction without isolation. Examples of leaving groups include a chlorine atom, an imidazole group, a phenoxy group, a 4-nitrophenoxy group, and an ethoxy group.

[0315] Examples of the salt of the amine compound represented by formula (3b) include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid or sulfuric acid or with organic acids such as carbonic acid or methanesulfonic acid.

[0316] When the condensing agent is used in an amount of 0.5 to 100 mol, preferably 0.8 to 50 mol, of the amine compound represented by formula (3b) or its salt per mol of the compound having a hydroxyl group represented by formula (3a) or its active substance, the amount of the condensing agent used is 0.5 to 20 mol, preferably 0.8 to 3 mol, per mol of the compound having a hydroxyl group represented by formula (3a) or its salt.

[0317] The reaction can be generally carried out at -20°C to 150°C, preferably 0°C to 100°C, in a solvent inert to the reaction, for example, a halogenated hydrocarbon such as dichloromethane or chloroform; an aromatic hydrocarbon such as toluene, an ether such as tetrahydrofuran, an ester such as ethyl acetate, an alcohol such as methanol or ethanol, water, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or pyridine, although the reaction differs depending on the active substance or condensing agent used.

[0318] The reaction can proceed smoothly when it is carried out in the presence of 0.5 to 20 mol, preferably 0.8 to 5 mol, of a base (per mol of the compound having a hydroxyl group represented by formula (3a) or its active substance) such as triethylamine, diisopropylethylamine, N-methylmorpholine, N,N-diethylaniline, 4-(N,N-dimethylamino)pyridine or pyridine.

[0319] Reaction Scheme 4

[0320]

[0321] In Reaction Scheme 4, X, R2, R3, R6, and n are as defined above. In the method shown in Reaction Scheme 4, in step 1, the hydroxyl group in the compound having a hydroxyl group represented by formula (4a) is oxidized to a carboxylic acid to form a carboxylic acid derivative represented by formula (4b). Then, in step 2, the carboxylic acid derivative (4b) is condensed with an amine compound represented by formula (4c) to induce an amide derivative (4d). In step 3, the amide derivative (4d) is further dehydrated to induce a nitrile derivative (4e).

[0322] Step 1

[0323] Specifically, the method for oxidizing the hydroxyl group of the compound represented by formula (4a) to a carboxylic acid can be a method of reacting the compound having a hydroxyl group represented by formula (4a) with 0.5 to 30 mol, preferably 0.8 to 20 mol of a commonly used appropriate oxidizing agent in a suitable solvent at a temperature of about -80 to 150° C., preferably about -80 to 120° C., per mol of the compound having a hydroxyl group represented by formula (4a), although the aldehyde is separated for use or directly oxidized to a carboxylic acid in some cases.

[0324] Examples of oxidizing agents include manganese reagents such as activated manganese dioxide and potassium permanganate, chromium reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC) and chromium trioxide, sodium hypochlorite- or calcium hypochlorite-2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO), dimethyl sulfoxide (DMSO) oxidation (DMSO-acetic anhydride, DMSO-trifluoroacetic anhydride, DMSO-oxalyl chloride, DMSO-dicyclohexylcarbodiimide (DCC), DMSO-1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and DMSO-sulfur trioxide pyridine complex).

[0325] There are no particular restrictions on suitable solvents, as long as the solvent does not affect the reaction. Examples include water, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, dimethyl sulfoxide, tert-butyl alcohol, pyridine, and triethylamine. These can be used alone or in combination.

[0326] Step 2

[0327] This step is a method of obtaining an amide compound represented by formula (4d) by amidation between the carboxyl group of the compound represented by formula (4b) and an amine compound (4c), which may be a commercially available product or a compound prepared according to a known method.

[0328] Amidation can be carried out according to known methods. Examples include a method in which the reaction is carried out in the presence of a condensing agent, and a method in which the carboxylic acid moiety is activated according to a known method to form a reactive derivative, followed by amidation of the derivative using an amine (for these methods, see Peptide gosei no kiso to jikken, Nobuo Izumiya et al., Maruzen Publishing Co., Ltd., 1983).

[0329] Examples of the condensing agent include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC), diphenylphosphoryl azide (DPPA), benzotriazol-1-yloxytrisdimethylaminophosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-1-yloxytripyrrolidinylphosphonium phosphate, (PyAOP), bromotripyrrolidinylphosphonium hexafluorophosphate (BroP), chlorotris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyCroP), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) and 4-(5,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM). Examples of additives used herein include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and N-hydroxysuccinimide (HOSu). These are generally used in an amount of about 1 to 100 mol, preferably about 1 to 10 mol, per mol of the compound represented by formula (4b).

[0330] A base may also be optionally added. Examples of the base include organic amines (e.g., trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, and N,N-dimethylaniline), alkali metal salts (e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide), metal hydrides (e.g., potassium hydride and sodium hydride), and alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide). The amount of the base used is generally about 1 to 100 mol, preferably about 1 to 10 mol, per mol of the compound represented by formula (4b).

[0331] The solvent for the reaction can be any solvent that does not adversely affect the reaction. The example of the solvent used includes alcohol (such as methanol), hydrocarbon (such as benzene, toluene and xylene), halogenated hydrocarbon (such as dichloromethane, chloroform and 1,2-dichloroethane), nitrile (such as acetonitrile), ether (such as dimethoxyethane and tetrahydrofuran), aprotic polar solvent (such as N, N-dimethylformamide, dimethyl sulfoxide and hexamethylphosphoramide), and mixtures thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is in the range of 0 DEG C to the temperature at which the solvent boils, preferably in the range of 0 DEG C to 100 DEG C.

[0332] Step 3

[0333] This step is a method for obtaining a nitrile compound represented by formula (4e) by dehydration reaction of an amide compound represented by formula (4d).

[0334] Specifically, one example of a method for performing dehydration is to allow, for example, trifluoroacetic anhydride, acetic anhydride, triphosgene, Burgess reagent, p-toluenesulfonyl chloride, benzenesulfonyl chloride, thionyl chloride or phosphorus oxychloride to act on a compound having an amide bond represented by formula (4d) in the presence or absence of an organic base such as triethylamine, diisopropylethylamine or pyridine in a solvent inert to the reaction (such as dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate or N,N-dimethylacetamide) at a temperature of -20°C to 150°C, preferably 0°C to 100°C.

[0335] When a dehydrating agent is used, the amount of the dehydrating agent used is 0.5 to 20 mol, preferably 0.8 to 5 mol, per mol of the compound having an amide bond represented by the formula (4d).

[0336] The reaction can be generally carried out at -20°C to 150°C, preferably 0°C to 100°C, in a solvent inert to the reaction, for example, halogenated hydrocarbons such as dichloromethane or chloroform, aromatic hydrocarbons such as toluene, ethers such as tetrahydrofuran, esters such as ethyl acetate, alcohols such as methanol or ethanol, water, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or pyridine, although the reaction differs depending on the base or dehydrating agent used.

[0337] When the reaction is carried out in the presence of 0.5 to 20 mol, preferably 0.8 to 5 mol (per mol of the compound having an amide bond represented by formula (4d)) of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, N,N-diethylaniline, 4-(N,N-dimethylamino)pyridine or pyridine, the reaction can proceed smoothly.

[0338] Reaction Scheme 5

[0339]

[0340] In Reaction Scheme 5, R2, R3, R4 and n are as defined above, and L3 represents a leaving functional group, such as phenylselenyl.

[0341] In the method shown in Reaction Scheme 5, in step 1, a functional group is introduced into the α position of the keto group of the compound having a keto group represented by formula (5a) to form a compound represented by formula (5b). Then, in step 2, compound (5b) is oxidized to induce a diene ketone compound (5c).

[0342] Step 1

[0343] Specifically, a method for introducing a functional group into the α-position of the keto group of the compound represented by formula (5a) can be a method of reacting the compound having a keto group represented by formula (5a) with 0.5 to 30 mol, preferably 0.8 to 10 mol, of a conventional appropriate base in an appropriate solvent at a temperature of about -100 to 120° C., preferably about -80 to 100° C., per mol of the compound having a keto group represented by formula (5a), although the enol ether is isolated for use or prepared in the reaction system and used for the reaction without isolation in some cases.

[0344] Examples of the base include organic amines (e.g., trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, and N,N-dimethylaniline), alkali metal salts (e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide), metal hydrides (e.g., potassium hydride and sodium hydride), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide), and metal reagents (e.g., methyllithium, n-butyllithium, lithium diisopropylamide, and lithium hexamethyldisilazide).

[0345] There are no particular restrictions on suitable solvents, as long as the solvent does not affect the reaction. Examples include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, dioxane, benzene, toluene, xylene, chlorobenzene, dimethyl sulfoxide, pyridine, and triethylamine. These can be used alone or in combination.

[0346] Examples of the functional group to be introduced include phenylselenyl group, and examples of the reagent to be used include phenylselenyl chloride and phenylselenyl bromide.

[0347] Step 2

[0348] This step is a method for obtaining a dienone compound represented by formula (5c) by subjecting the compound represented by formula (5b) to an extraction reaction. This step can be carried out by reacting the compound represented by formula (5b) having a leaving functional group with 0.5 to 30 mol, preferably 0.8 to 10 mol, of a conventional suitable oxidizing agent in a suitable solvent at a temperature of about -50 to 120°C, preferably about -20 to 100°C.

[0349] Examples of the oxidizing agent include hydrogen peroxide solution, m-chloroperbenzoic acid, and peracetic acid.

[0350] There are no particular restrictions on suitable solvents, as long as the solvent does not affect the reaction. Examples include water, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, benzene, toluene, xylene, chlorobenzene, dimethyl sulfoxide, pyridine, and triethylamine. These can be used alone or in combination.

[0351] Reaction Scheme 6

[0352]

[0353] In Reaction Scheme 6, X, R2, R3, R4 and n are as defined above, and Y represents a halogen atom.

[0354] In the method shown in Reaction Scheme 6, a halogen atom is introduced into the compound having an enone group represented by Formula (6a) to induce the compound represented by Formula (6b). The method using a halogenating agent can be carried out, for example, by a method using fluorine, chlorine, bromine, iodine, or the like, or by a method using N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide.

[0355] The amount of the halogenating agent used is 0.5 to 30 mol, preferably about 0.8 to 10 mol, per mol of the compound having an enone group represented by the formula (6a).

[0356] The solvent may be any solvent that does not adversely affect the reaction. Examples include hydrocarbons (e.g., benzene, toluene, and xylene), halogenated hydrocarbons (e.g., chloroform and 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane and tetrahydrofuran), alcohols (e.g., methanol and ethanol), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoramide), pyridine, triethylamine, and water. These may be used alone or in combination.

[0357] The reaction temperature is in the range of -20°C to the boiling temperature of the solvent, preferably in the range of 0°C to 100°C. The reaction can proceed smoothly when it is carried out in the presence of 0.1 to 10 mol, preferably 0.2 to 5 mol, of a reagent reactant (such as potassium carbonate, 4-(N,N-dimethylamino)pyridine or trimethylsilyl azido) per mol of the compound having an enone group represented by formula (6a).

[0358] Reaction Scheme 7

[0359]

[0360] In Reaction Scheme 7, X, R2, R4, R7 and n are as defined above, L2 represents a halogen atom, and R 13 represents a hydrogen atom or a C1-C4 alkyl group.

[0361] In the method shown in Reaction Scheme 7, in step 1, a compound having an enol ether represented by formula (7a) is reacted with a compound having a halogen atom represented by formula (7b) in the presence of a metal to induce an enone derivative (7c). In step 2, the hydroxyl group of the compound represented by formula (7c) is further etherified to induce an ether derivative (7d).

[0362] Step 1

[0363] L2 of compound (7b) may be any halogen atom. Examples include chlorine atom, bromine atom and iodine atom.

[0364] R 13 represents a hydrogen atom or a C1-C4 alkyl group. Examples include a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group.

[0365] The reaction is carried out in a suitable solvent at 0°C to 150°C, preferably 20°C to 120°C, by using 0.5 to 50 mol, preferably 0.8 to 10 mol, of the compound represented by formula (7b) per mol of the enol ether compound represented by formula (7a), in the presence of 0.5 to 100 mol, preferably 0.8 to 30 mol of a metal (per mol of the compound represented by formula (7a)) to obtain an enone compound represented by formula (7c).

[0366] Suitable solvents are not particularly limited as long as they do not affect the reaction. Examples include benzene, toluene, chlorobenzene, xylene, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, n-hexane, n-heptane, cyclohexane, acetonitrile, hexamethylphosphonium triamide, and sulfolane. These can be used alone or in combination.

[0367] The metal is, for example, lithium, sodium, strontium, magnesium or zinc, and preferably lithium or magnesium.

[0368] Step 2

[0369] Examples of the reagent for etherifying the compound having a hydroxyl group represented by formula (7c) include trimethyloxonium tetrafluoroborate and triethyloxonium hexafluoroborate.

[0370] The reaction is carried out in a suitable solvent at -50°C to 120°C, preferably -20°C to 100°C, using 0.5 to 50 mol, preferably 0.8 to 20 mol, of an etherifying agent per mol of the compound having a hydroxyl group represented by formula (7c) to obtain an ether compound represented by formula (7d).

[0371] There are no particular restrictions on suitable solvents, as long as the solvent does not affect the reaction. Examples include dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. These can be used alone or in combination.

[0372] When the reaction is performed in the presence of 0.5 to 20 mol, preferably 0.8 to 10 mol, of a reagent such as 1,8-bis(dimethylamino)naphthalene per mol of the compound having a hydroxyl group represented by formula (7c), the reaction can proceed smoothly.

[0373] The compounds of the present disclosure can be readily isolated and purified according to typical separation methods. Examples of these methods include solvent extraction, recrystallization, preparative reverse-phase high performance liquid chromatography, column chromatography, and preparative thin layer chromatography.

[0374] When the compounds of the present disclosure have isomers such as optical isomers, stereoisomers, rotational isomers or tautomers, unless otherwise specified, the compounds of the present disclosure include any isomers and mixtures thereof. For example, when the compounds of the present disclosure have optical isomers, unless otherwise specified, the scope of the compounds of the present disclosure includes optical isomers separated from racemates. These isomers can be obtained separately as single compounds according to known synthesis techniques or separation techniques (such as condensation, solvent extraction, column chromatography or recrystallization).

[0375] Compound of the present disclosure or its salt can be amorphous and / or crystalline. The scope of compound of the present disclosure or its salt includes the mixture of single crystal form, multiple polymorphic forms and the mixing of these forms with amorphous form. Crystal can be produced by using known crystallization method to carry out crystallization. Compound of the present disclosure or its salt can be solvate (for example, hydrate) or ansolvate, and both are included in compound of the present disclosure or its salt. Compounds labeled with isotopes (for example 3H, 14C, 35S and 125I) are also included in compound of the present disclosure or its salt.

[0376] The salts of the compounds disclosed herein or salts of their production intermediates refer to salts commonly used in the field of organic chemistry. The salts of the compounds disclosed herein are preferably pharmaceutically acceptable salts.

[0377] The salts of the compounds of the present disclosure or salts of their production intermediates are, for example, salts such as base addition salts at a carboxyl group when a carboxyl group is present in the compound, or acid addition salts at an amino group or a basic heterocyclic group when an amino group or a basic heterocyclic group is present in the compound.

[0378] Examples of base addition salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; and organic amine salts such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt and N,N'-dibenzylethylenediamine salt.

[0379] Examples of acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates and perchlorates; organic acid salts such as acetates, formates, maleates, fumarates, tartrates, citrates, ascorbates and trifluoroacetates; and sulfonates such as methanesulfonates, isethionates, benzenesulfonates and p-toluenesulfonates.

[0380] Included within the scope of the present disclosure are any pharmaceutically acceptable modification products (prodrugs) that are converted in vivo into the compounds of the present disclosure.

[0381] Due to their excellent nerve growth stimulating effects, such as neurite growth and / or increasing the proportion of neurite-containing cells, the compounds of the present disclosure or their salts can be used as medical drugs for preventing or treating diseases (including neurodegenerative diseases), pain and / or lower urinary tract dysfunction that can be improved by promoting nerve growth.

[0382] The pathogenesis of pathological conditions that can be improved by promoting nerve growth (including neurodegenerative diseases), pain, and / or lower urinary tract dysfunction is different. One of the causes is the degeneration or atrophy of neurites or the death of neuronal cells. Therefore, promoting nerve growth can prevent or treat these diseases.

[0383] In the present specification, diseases that are improved by promoting nerve growth include neurodegenerative diseases and traumatic neurological diseases caused by accidents etc. (eg, brain contusion and spinal cord injury), or mental illnesses (eg, schizophrenia, depression, and bipolar disorder).

[0384] In the present specification, neurodegenerative diseases are, for example, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's dementia, Lewy body dementia, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis and neuromyelitis optica; preferably amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's dementia or Lewy body dementia; more preferably amyotrophic lateral sclerosis.

[0385] In the present specification, the pain is, for example, peripheral neuropathic pain (e.g., diabetic pain, post-herpetic neuralgia, fibromyalgia, and chemotherapy-induced peripheral neuropathy), or central neuropathic pain (e.g., post-stroke pain and post-spinal cord injury pain); preferably peripheral neuropathic pain (e.g., diabetic pain, post-herpetic neuralgia, fibromyalgia, and chemotherapy-induced peripheral neuropathy); more preferably diabetic pain or chemotherapy-induced peripheral neuropathy.

[0386] In the present specification, the lower urinary tract dysfunction is, for example, stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, overactive bladder, underactive bladder, neurogenic bladder, unstable bladder, detrusor sphincter dyssynergia (DSD), detrusor hyperactivity with impaired contractility (DHIC), or urinary frequency caused by cystitis or prostatitis; preferably stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, overactive bladder, underactive bladder, or neurogenic bladder; more preferably overactive bladder or underactive bladder.

[0387] The compound of the present disclosure or a salt thereof used as a medical drug can optionally contain a pharmaceutical carrier, and can exist in various dosage forms according to the purpose of prevention or treatment. For example, the dosage form can be any one of the following: oral medicine, injection medicine, suppository, ointment, and patch, preferably oral medicine. These dosage forms can be produced according to the formulation method known and commonly used by those skilled in the art.

[0388] The pharmaceutical carrier used can be various organic or inorganic carrier substances commonly used as formulation materials. The pharmaceutical carrier is, for example, added as an excipient, a binder, a disintegrant, a lubricant, or a colorant in solid preparations, or as a solvent, a solubilizer, a suspending agent, a tonicity agent, a buffer, or a soothing agent in liquid preparations. In addition, formulation additives such as a preservative, an antioxidant, a colorant, a sweetener, and a stabilizer can be optionally used.

[0389] In the preparation of solid preparations for oral use, for example, an excipient, a binder, a disintegrant, a lubricant, a colorant, and / or an odor masking agent is added to the compound of the present disclosure as needed, and then tablets, coated tablets, granules, powdered medicines, capsules, etc. can be prepared according to ordinary methods.

[0390] Examples of excipients include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and silicic anhydride. Examples of binders include water, ethanol, 1-propanol, 2-propanol, simple syrup, glucose solution, α-starch solution, gelatin solution, D-mannitol, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, and polyvinyl pyrrolidone. Examples of disintegrants include dry starch, sodium alginate, powdered agar, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Examples of lubricants include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol. Examples of colorants include titanium oxide and iron oxide. Examples of odor masking agents include sucrose, orange peel, citric acid, and tartaric acid.

[0391] When preparing liquid preparations for oral use, flavoring agents, buffers, stabilizers and / or odor-masking agents, for example, are added to the compounds of the present disclosure to prepare internal fluid medicines, syrup medicines, elixirs, etc. according to common methods.

[0392] Odor masking agents may be those listed above. Buffering agents may be, for example, sodium citrate. Stabilizers may be, for example, gum tragacanth, gum arabic, or gelatin. Optionally, an enteric coating or a coating for prolonged efficacy may be added to the oral formulation according to known methods. Examples of such coating agents include hydroxypropyl methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropyl cellulose, polyoxyethylene glycol, and Tween 80 (registered trademark).

[0393] In the preparation of injectable drugs, for example, pH adjusters, buffers, stabilizers, tonicity agents and / or local anesthetics are added to the compounds of the present disclosure to produce subcutaneous, intramuscular or intravenous injection drugs according to conventional methods.

[0394] Examples of pH adjusters and buffers include sodium citrate, sodium acetate, and sodium phosphate. Examples of stabilizers include sodium metabisulfite, EDTA, thioglycolic acid, and thiolactic acid. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of tonicity agents include sodium chloride, glucose, D-mannitol, and glycerol.

[0395] Generally, the amount of the compound of the present disclosure contained in each unit dosage form is preferably 0.05 to 1000 mg for oral drugs, 0.01 to 500 mg for injections, and 1 to 1000 mg for suppositories, although the amount varies depending on, for example, the symptoms of the patient to be treated with the compound or its dosage form.

[0396] Although the daily dose of the drug in the above dosage form cannot be universalized due to differences in patient symptoms, weight, age, sex, etc., the daily dose of the compound of the present invention for an adult (weight: 50 kg) can generally be 0.05 to 5000 mg, preferably 0.1 to 1000 mg. This dose of the drug can be administered once a day or divided into about two to three doses a day.

[0397] The present disclosure also relates to the following embodiments.

[0398] [1] A compound represented by the following formula (I) or a salt thereof:

[0399]

[0400] in

[0401] X represents -CH2-, -CH(CH3)-, -CH2-CH2- or -CH=CH-,

[0402] R1 represents -CH2OR4, -CH2OCON(R5)2, -CONHR6 or cyano,

[0403] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0404] R3 represents a hydrogen atom, a methyl group, -CH2OR7 or a halogen atom,

[0405] R4 represents C m H 2m+1 ,

[0406] R5 are the same or different and each represents a hydrogen atom or a methyl group,

[0407] R6 represents a hydrogen atom or a methyl group,

[0408] R7 represents a C1-C3 alkyl group,

[0409] m represents an integer from 1 to 14, and

[0410] n represents an integer from 1 to 15,

[0411] Provided that when R4 is a linear alkyl group, the sum of m and n is an integer from 12 to 17, and when R4 is a branched alkyl group, m b The sum of m and n is an integer from 12 to 17, where m b is the number of carbon atoms in the longest straight chain of a branched alkyl group.

[0412] [2] A compound represented by the following formula (I) or a salt thereof:

[0413]

[0414] in

[0415] X represents -CH2-, -CH(CH3)-, -CH2-CH2- or -CH=CH-,

[0416] R1 represents -CH2OR4, -CH2OCON(R5)2, -CONHR6 or cyano,

[0417] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0418] R3 represents a hydrogen atom, a methyl group, -CH2OR7 or a halogen atom,

[0419] R4 represents C m H 2m+1 ,

[0420] R5 are the same or different and each represents a hydrogen atom or a methyl group,

[0421] R6 represents a hydrogen atom or a methyl group,

[0422] R7 represents a C1-C3 alkyl group,

[0423] m represents an integer from 1 to 14, and

[0424] n represents an integer from 1 to 14,

[0425] Provided that when R4 is a linear alkyl group, the sum of m and n is an integer from 12 to 15, and when R4 is a branched alkyl group, m b The sum of m and n is an integer from 12 to 15, where m b is the number of carbon atoms in the longest straight chain of a branched alkyl group.

[0426] [3] A compound represented by the following formula (I) or a salt thereof:

[0427]

[0428] in

[0429] X represents -CH2-, -CH(CH3)-, -CH2-CH2- or -CH=CH-,

[0430] R1 represents -CH2OR4, -CH2OCON(CH3)2, -CONHR6 or cyano,

[0431] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms, and

[0432] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom,

[0433] Provided that when R2 are the same or different and each represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom, and when two R2 together with adjacent carbon atoms form a cyclopropyl group, R3 represents a methyl group, -CH2OCH3 or an iodine atom,

[0434] R4 represents a methyl group, an ethyl group, an n-propyl group or an isopropyl group, provided that when R4 is a methyl group, n represents an integer from 11 to 14, when R4 is an ethyl group or an isopropyl group, n represents an integer from 11 to 13, when R4 is an n-propyl group, n is 11 or 12, and

[0435] R6 represents a hydrogen atom or a methyl group.

[0436] [4] The compound according to any one of [1] to [3] or a salt thereof, wherein X in formula (I) represents -CH2-, -CH2-CH2- or -CH=CH-.

[0437] [5] The compound according to any one of [1] to [4] or a salt thereof,

[0438] In formula (I),

[0439] R1 represents -CH2OR4, -CONH2 or cyano,

[0440] R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 may form a cyclopropyl group together with adjacent carbon atoms,

[0441] R3 represents a hydrogen atom, a methyl group, -CH2OCH3 or an iodine atom, provided that when R3 is a hydrogen atom, each R2 is a hydrogen atom, and when R3 is a methyl group, -CH2OCH3 or an iodine atom, R2 are the same or different and each represents a hydrogen atom or a methyl group, or two R2 can form a cyclopropyl group together with adjacent carbon atoms, and

[0442] R4 represents a methyl group, an ethyl group, an n-propyl group or an isopropyl group, provided that when R4 is a methyl group, n represents an integer from 11 to 14, when R4 is an ethyl group or an isopropyl group, n represents an integer from 11 to 13, and when R4 is an n-propyl group, n is 11 or 12.

[0443] [6] The compound or a salt thereof according to any one of [1] to [5], wherein in formula (I),

[0444] X represents -CH2- or -CH2-CH2-,

[0445] R1 represents -CH2OR4 or -CONH2,

[0446] Each R2 represents a methyl group,

[0447] R3 represents a methyl group or -CH2OCH3, and

[0448] R4 represents a methyl group, an ethyl group or an isopropyl group, provided that when R4 is a methyl group, n represents an integer of 11 to 14, and when R4 is an ethyl group or an isopropyl group, n represents an integer of 11 to 13.

[0449] [7] The compound or a salt thereof according to any one of [1] to [6], wherein X in formula (I) represents -CH2-CH2-.

[0450] [8] The compound or salt thereof according to any one of [1] to [7], which is any one of the following compounds (1) to (10):

[0451] (1) 3-(12-methoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0452] (2) 3-(12-ethoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0453] (3) 3-(12-isopropoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0454] (4) 3-(13-methoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0455] (5) 3-(13-ethoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0456] (6) 3-(13-isopropoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0457] (7) 3-(14-methoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0458] (8) 3-(14-ethoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one,

[0459] (9) 3-(14-isopropoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one, and

[0460] (10) 3-(15-Methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one.

[0461] [9] The compound or a salt thereof according to any one of [1] to [8], wherein the compound is 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one.

[0462]

[10] A nerve growth promoter comprising the compound or a salt thereof according to any one of [1] to [9] as an active ingredient.

[0463]

[11] A therapeutic agent for a neurodegenerative disease, comprising the compound of any one of [1] to [9] or a salt thereof as an active ingredient.

[0464]

[12] A therapeutic agent for amyotrophic lateral sclerosis, comprising the compound or a salt thereof according to any one of [1] to [9] as an active ingredient.

[0465]

[13] A therapeutic agent for pain, comprising the compound or a salt thereof according to any one of [1] to [9] as an active ingredient.

[0466]

[14] A therapeutic agent for lower urinary tract dysfunction, comprising the compound or a salt thereof according to any one of [1] to [9] as an active ingredient.

[0467]

[15] A pharmaceutical composition comprising

[0468] The compound of any one of [1] to [9] or a salt thereof, and

[0469] Pharmaceutical carrier.

[0470]

[16] The compound or salt thereof according to any one of [1] to [9], for use in treating a disease that can be improved by promoting nerve growth.

[0471]

[17] Use of the compound or salt thereof according to any one of [1] to [9] in the preparation of a nerve growth promoter.

[0472]

[18] A method for treating a disease that can be improved by promoting nerve growth, comprising administering an effective dose of the compound of any one of [1] to [9] or a salt thereof to a subject in need thereof.

[0473]

[19] The pharmaceutical composition according to

[15] , which is used for treating a disease that can be improved by promoting nerve growth.

[0474]

[20] The compound of any one of [1] to [9] or a salt thereof, for use in treating a neurodegenerative disease.

[0475]

[21] The compound according to any one of [1] to [9] or a salt thereof, which is used for preparing a therapeutic agent for a neurodegenerative disease.

[0476]

[22] A method for treating a neurodegenerative disease, comprising administering an effective dose of the compound of any one of [1] to [9] or a salt thereof to a subject in need thereof.

[0477]

[23] The pharmaceutical composition according to

[15] , which is used for treating neurodegenerative diseases.

[0478]

[24] The compound according to any one of [1] to [9] or a salt thereof, for use in treating amyotrophic lateral sclerosis.

[0479]

[25] Use of the compound or a salt thereof according to any one of [1] to [9] for preparing a therapeutic agent for amyotrophic lateral sclerosis.

[0480]

[26] A method for treating amyotrophic lateral sclerosis, comprising administering an effective dose of the compound or salt thereof according to any one of [1] to [9] to a subject in need thereof.

[0481]

[27] The pharmaceutical composition according to

[15] , which is used for treating amyotrophic lateral sclerosis.

[0482]

[28] The compound according to any one of [1] to [9] or a salt thereof, which is used for treating pain.

[0483]

[29] Use of the compound or salt thereof according to any one of [1] to [9] for preparing a therapeutic agent for pain.

[0484]

[30] A method for treating pain, comprising administering an effective dose of the compound of any one of [1] to [9] or a salt thereof to a subject in need thereof.

[0485]

[31] The pharmaceutical composition according to

[15] , which is used for treating pain.

[0486]

[32] The compound according to any one of [1] to [9] or a salt thereof, which is used for treating lower urinary tract dysfunction.

[0487]

[33] Use of the compound or salt thereof according to any one of [1] to [9] for the preparation of a therapeutic agent for lower urinary tract dysfunction.

[0488]

[34] A method for treating lower urinary tract dysfunction, comprising administering an effective dose of the compound or salt thereof according to any one of [1] to [9] to a subject in need thereof.

[0489]

[35] The pharmaceutical composition according to

[15] , which is used for treating lower urinary tract dysfunction.

[0490] Example

[0491] The following reference examples describe embodiments of the present invention in more detail. However, the present disclosure is not limited to the examples. Although the embodiments of the present invention are fully described by the examples, it will be understood by those skilled in the art that various variations and modifications are available. Therefore, such variations and modifications are included in the present disclosure unless they depart from the spirit and main concepts of the present disclosure.

[0492] Unless otherwise specified, the reagents used in the examples are commercially available products. Silica gel column chromatography was performed using Wakosil C-300 (registered trademark) manufactured by Wako Pure Chemical Industries, Ltd., Wakogel C-300 (registered trademark) manufactured by Wako Pure Chemical Industries, Ltd., SNAP-Ultra (registered trademark) silica pre-packed columns manufactured by Biotage, or KP-NH (registered trademark) pre-packed columns manufactured by Biotage. NMR spectra were obtained using an AL400 NMR spectrometer (400 MHz; manufactured by JEOL), a Mercury 400 NMR spectrometer (400 Hz; manufactured by Agilent Technologies, Inc.), a 400-MHz Bruker Avance NEO 400 NMR spectrometer (400-MHz; manufactured by Bruker), or a 500-MHz Brucer Avance III HD NMR spectrometer (500 MHz; manufactured by Bruce). When the deuterated solvent contained tetramethylsilane, tetramethylsilane was used as an internal reference. Otherwise, the NMR solvent was used as an internal reference for the measurements. All δ values ​​are expressed in ppm. Microwave reactions were performed using initiators manufactured by Biotage.

[0493] The LCMS spectrum was obtained using Acquity SQD (quadrupole) manufactured by Waters Corporation under the following conditions.

[0494] Column: Acquity UPLC (registered trademark) BEH C18, 2.1×50 mm, 1.7 μm (manufactured by Waters Corporation)

[0495] MS detection: ESI positive

[0496] UV detection: 254 and 280 nm

[0497] Column flow rate: 0.5 mL / min

[0498] Mobile phase: water / acetonitrile (0.1% formic acid)

[0499] Injection volume: 1 μL

[0500] Gradient (Table 1)

[0501]

[0502] Preparative reverse-phase HPLC purification was performed using a preparative separation system provided by Gilson, Inc. under the following conditions.

[0503] Column: Xselect CSH Prep C18 5μm OBD (19×50mm)+(19×100mm), manufactured by Waters Corporation

[0504] UV detection: 254nm

[0505] Column flow rate: 18 mL / min

[0506] Mobile phase: water / acetonitrile (0.1% formic acid)

[0507] Injection volume: 0.1 to 0.5 mL

[0508] These symbols represent the following.

[0509] s: single weight

[0510] d: double

[0511] t: triple

[0512] q: quadruple

[0513] m: multiple

[0514] br: Broad

[0515] DMSO: dimethyl sulfoxide

[0516] With respect to compounds 1 to 8, for example, compounds 1 to 5 can be synthesized according to the preparation method disclosed in WO99 / 08987, compound 6 can be synthesized according to the manufacturing method disclosed in WO2017 / 125087, and compounds 7 and 8 can be synthesized according to the preparation method disclosed in Tetrahedron (1998), 54 (27), pp.7735-7748. Alternatively, they can also be synthesized according to the method shown below. Compound 4 is 3-(15-hydroxypentadecanyl)-2,4,4-trimethylcyclohex-2-ene-1-one, which differs from the compound of formula (I) of the present disclosure in that R1 represents -CH2OH.

[0517] Synthesis of 3-(12-hydroxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 1)

[0518] A solution of 5.5 mL of 3,4-dihydro-2H-pyran in 10 mL of chloroform and 1.01 g of pyridinium p-toluenesulfonate were added to a solution of 10.6 g of 12-bromododecan-1-ol in 100 mL of chloroform, and the mixture was stirred at room temperature for 1 hour. Under ice-cooling temperature, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the residue was evaporated under reduced pressure to obtain a residue.

[0519] Tetrahydrofuran (40 mL) is added to 694 mg of lithium, and the mixture is heated to 37 ° C. Then, 30 mL of a tetrahydrofuran solution of the residue obtained above and 4.20 g of 3-isobutoxy-2,6,6-trimethylcyclohex-2-ene-1-one are added dropwise thereto, and the mixture is stirred at 50 ° C for 2 hours. After the reaction mixture is cooled on ice, 20 mL of water is added thereto, and the mixture is stirred at room temperature for 2 hours. After filtering out the insoluble matter with diatomaceous earth (Celite), the filtrate is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after reduced pressure evaporation is dissolved in 40 mL of methanol and 20 mL of tetrahydrofuran. Then, 380 mg of p-toluenesulfonic acid monohydrate is added thereto, and the mixture is stirred at room temperature for 2 hours. At ice-cooling temperature, a saturated sodium bicarbonate aqueous solution is added thereto, and the solvent is removed by reduced pressure evaporation. Then, the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate.After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 4.76 g of the title compound.

[0520] Physical properties: m / z[M+H] + 324.8 [M+Na] + 345.2

[0521] NMR (CDCl3) δppm 1.15 (s, 6H), 1.20-1.65 (m, 21H), 1.76 (s, 3H), 1.80 (t, J = 6.9Hz, 2H), 2.12-2.25 (m, 2H), 2.37-2.52 (m, 2H), 3.58-3.70 (m, 2H).

[0522] Synthesis of 3-(13-hydroxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 2)

[0523] A solution of 2.7 mL of 3,4-dihydro-2H-pyran in 5 mL of chloroform and 502 mg of pyridinium p-toluenesulfonate were stirred at room temperature for 1 hour. A sodium bicarbonate aqueous solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the mixture was evaporated under reduced pressure to obtain a residue.

[0524] Tetrahydrofuran (20 mL) was added to 347 mg of lithium, and the mixture was heated to 32 ° C. Then, 15 mL of a tetrahydrofuran solution of the residue obtained above and 2.10 g of 3-isobutoxy-2,6,6-trimethylcyclohex-2-ene-1-one were added dropwise thereto, and the mixture was stirred at 70 ° C for 2 hours. After the reaction mixture was cooled on ice, 10 mL of water was added thereto, and the mixture was stirred at room temperature for 1 hour. After filtering out the insoluble matter with diatomaceous earth, the filtrate was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after reduced pressure evaporation was dissolved in 20 mL of methanol and 10 mL of tetrahydrofuran. Then, 190 mg of p-toluenesulfonic acid monohydrate was added thereto, and the mixture was stirred at room temperature for 2 hours. At ice-cooling temperature, a saturated sodium bicarbonate aqueous solution was added thereto, and the solvent was removed by reduced pressure evaporation. Then, the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 2.57 g of the title compound.

[0525] Physical properties: m / z[M+H] + 338.8 [M+Na] + 359.3

[0526] NMR (CDCl3) δppm 1.15 (s, 6H), 1.20-1.65 (m, 23H), 1.76 (s, 3H), 1.80 (t, J = 6.9Hz, 2H), 2.10-2.23 (m, 2H), 2.40-2.52 (m, 2H), 3.55-3.73 (m, 2H).

[0527] Synthesis of 3-(14-hydroxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 3)

[0528] A solution of 2.7 mL of 3,4-dihydro-2H-pyran in 5 mL of chloroform and 502 mg of pyridinium p-toluenesulfonate were stirred at room temperature for 2 hours. An aqueous sodium bicarbonate solution was added to the reaction mixture at an ice cooling temperature, and the mixture was extracted with chloroform, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent, evaporation under reduced pressure was performed to obtain a residue.

[0529] Tetrahydrofuran (20 mL) was added to 347 mg of lithium, and the mixture was heated to 32°C. Then, 15 mL of a tetrahydrofuran solution of the above-obtained residue and 2.10 g of 3-isobutoxy-2,6,6-trimethylcyclohex-2-en-1-one were added dropwise thereto, and the mixture was stirred at 80°C for 2 hours. After cooling the reaction mixture on ice, 10 mL of water was added thereto, and the mixture was stirred at room temperature for 1 hour. After filtering off the insoluble matter with celite, the filtrate was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the residue obtained after evaporation under reduced pressure was dissolved in 20 mL of methanol and 10 mL of tetrahydrofuran. Then, 190 mg of p-toluenesulfonic acid monohydrate was added thereto, and the mixture was stirred at room temperature for 2 hours. An aqueous saturated sodium bicarbonate solution was added thereto at an ice cooling temperature, and the solvent was removed by evaporation under reduced pressure. Then, the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 2.98 g of the title compound.

[0530] Physical properties: m / z [M+H] + 352.7 [M+Na] + 373.3

[0531] NMR (CDCI3) δ ppm 1.15 (s, 6H), 1.20-1.65 (m, 25H), 1.76 (s, 3H), 1.80 (t, J=6.8 Hz, 2H), 2.10-2.23 (m, 2H), 2.38-2.52 (m, 2H), 3.58-3.72 (m, 2H).

[0532] Synthesis of 3-(16-hydroxyhexadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 5)

[0533] A solution of 2.7 mL of 3,4-dihydro-2H-pyran in 5 mL of chloroform and 502 mg of pyridinium p-toluenesulfonate were stirred at room temperature for 3 hours. A sodium bicarbonate aqueous solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the mixture was evaporated under reduced pressure to obtain a residue.

[0534] Tetrahydrofuran (20 mL) was added to 347 mg of lithium, and the mixture was heated to 32 ° C. Then, 15 mL of a tetrahydrofuran solution of the residue obtained above and 2.10 g of 3-isobutoxy-2,6,6-trimethylcyclohex-2-ene-1-one were added dropwise thereto, and the mixture was stirred at 50 ° C for 3 hours. After the reaction mixture was cooled on ice, 10 mL of water was added thereto, and the mixture was stirred at room temperature for 1 hour. After filtering out the insoluble matter with diatomaceous earth, the resulting filtrate was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after reduced pressure evaporation was dissolved in 20 mL of methanol and 10 mL of tetrahydrofuran. Then, 190 mg of p-toluenesulfonic acid monohydrate was added thereto, and the mixture was stirred at room temperature for 5 hours. At ice-cooling temperature, a saturated sodium bicarbonate aqueous solution was added thereto, and the solvent was removed by reduced pressure evaporation. Then, the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 3.02 g of the title compound.

[0535] Physical properties: m / z[M+H] + 379.6 [M+Na] + 401.4

[0536] NMR(CDCl3)δppm 1.15(s,6H),1.20-1.65(m,29H),1.75(s,3H),1.73-1.85(m,2H),2.10-2.23(m,2H),2.40-2.53(m,2H),3.55-3.70(m,2H).

[0537] Synthesis of 2,4,4-trimethyl-3-(15-((tetrahydro-2H-pyran-2-yl)oxy)pentadecyl)cyclohex-2-en-1-one (Compound 6)

[0538] Pyridinium p-toluenesulfonate (50mg) and 0.27mL 3,4-dihydro-2H-pyrans are added to 729mg 3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (compound 4, Taiho Pharmaceutical Co., Ltd.) in a solution of 7mL dichloromethane, and the mixture is stirred for 3 hours. Under ice-cooling temperature, saturated sodium bicarbonate aqueous solution is added to the reaction mixture, and the gained mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 811mg title compound.

[0539] Physical properties: m / z[M+H] + 449.5

[0540] NMR(CDCl3)δppm 1.17(s,6H),1.20-1.90(m,37H),2.10-2.25(m,2H),2.45-2.52(m,2H),3.35-3.45( m,1H),3.48-3.60(m,1H),3.70-3.82(m,1H),3.85-3.98(m,1H),4.57-4.63(m,1H).

[0541] Synthesis of 3-(15-hydroxypentadecyl)-2-methylcyclohex-2-en-1-one (Compound 7)

[0542] A solution of 1.4 mL of 3,4-dihydro-2H-pyran in 5 mL of chloroform and 251 mg of pyridinium p-toluenesulfonate, and the mixture were stirred at room temperature for 3 hours. At ice-cooling temperature, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, it was evaporated under reduced pressure to obtain a residue (4.1 g). Then, 95 mg of lithium was added to 8 mL of a tetrahydrofuran solution consisting of 1.17 g of the obtained residue and 273 mg of 3-isobutoxy-2-methylcyclohex-2-ene-1-one, and the mixture was stirred at 70 ° C for 4 hours. After the reaction mixture was cooled on ice, water was added thereto, and the mixture was stirred at room temperature for 0.5 hours, extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after reduced pressure evaporation was dissolved in 2 mL of methanol and 4 mL of tetrahydrofuran. Then, 29mg of p-toluenesulfonic acid monohydrate is added thereto, and at room temperature the mixture is stirred for 4 hours.Saturated sodium bicarbonate aqueous solution is added in the reaction mixture, and the gained mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate.After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 244mg title compound.

[0543] Physical properties: m / z[M+H] + 337.2

[0544] NMR(CDCl3)δppm 1.20-1.83(m,32H),1.88-2.02(m,2H),2.23-2.50(m,2H),3.57-3.72(m,2H).

[0545] Synthesis of 3-(15-hydroxypentadecyl)-4,4-dimethylcyclohex-2-en-1-one (Compound 8)

[0546] A solution of 1.4 mL of 3,4-dihydro-2H-pyran in 5 mL of chloroform and 251 mg of pyridinium p-toluenesulfonate, and the mixture were stirred at room temperature for 3 hours. At ice-cooling temperature, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, it was evaporated under reduced pressure to obtain a residue (4.1 g). Then, 95 mg of lithium was added to 8 mL of a tetrahydrofuran solution consisting of 1.17 g of the obtained residue and 294 mg of 3-isobutoxy-6,6-dimethylcyclohex-2-ene-1-one, and the mixture was stirred at 70 ° C for 2 hours. After the reaction mixture was cooled on ice, water was added thereto, and the mixture was stirred at room temperature for 0.5 hours, extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after reduced pressure evaporation was dissolved in 2 mL of methanol and 4 mL of tetrahydrofuran. Then, 29mg of p-toluenesulfonic acid monohydrate is added thereto, and at room temperature the mixture is stirred for 4 hours.Saturated sodium bicarbonate aqueous solution is added in the reaction mixture, and the gained mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate.After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 366mg title compound.

[0547] Physical properties: m / z[M+H] + 351.5

[0548] NMR (CDCl3) δppm 1.18 (s, 6H), 1.20-1.63 (m, 27H), 1.86 (t, J = 6.8Hz, 2H), 2.15-2.28 (m, 2H), 2.43-2.50 (m, 2H), 3.57-3.72 (m, 2H), 5.81 (s, 1H).

[0549] Intermediate 1: Synthesis of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecanal

[0550] At -70 DEG C, dimethyl sulfoxide (2.0mL) is added into the solution of 1.1mL oxalyl chloride in 30mL dichloromethane, and the mixture is stirred for 15 minutes. Subsequently, in 10 minutes, 3.79g 3- (15- hydroxypentadecanyl) -2,4,4- trimethylcyclohex-2-ene-1-one (compound 4, Taiho Pharmaceutical Co., Ltd.) is added dropwise into wherein in 10mL dichloromethane. By removing dry ice-acetone bath, internal temperature is increased to -30 DEG C in 20 minutes, then is cooled to -70 DEG C again, and 7.0mL triethylamine is added into wherein, then at room temperature stirred 2 hours. Under ice-cooling temperature, salt water is added into reaction mixture, and gained mixture is extracted with the mixed solvent of ethyl acetate and normal hexane, with 1mol / L hydrochloric acid, saturated sodium bicarbonate, water, salt water washing, and use anhydrous sodium sulfate drying. After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 3.04 g of the title compound.

[0551] Physical properties: m / z[M+H] + 363.9

[0552] NMR(CDCl3)δppm 1.15(s,6H),1.24-1.51(m,22H),1.53-1.65(m,2H),1.75(s,3H),1.73-1 .88(m,2H),2.15-2.24(m,2H),2.38-2.53(m,4H),9.76(t,J=2.0Hz,1H).

[0553] Intermediate 2: Synthesis of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecanoic acid

[0554] Under ice-cooling temperature, 4mL 2-methyl-2-butene and 1.02g potassium dihydrogen phosphate are added to the mixed solutions of 1.81g 15-(2,6,6-trimethyl-3-oxocyclohex-1-ene-1-yl) pentadecanal (i.e. intermediate 1) in 6mL tert-butyl alcohol and 2mL water.A solution of 1.71g 79% sodium chlorite in 5mL water is added dropwise to reaction mixture, and at room temperature the mixture is stirred 1 hour.Then, under ice-cooling temperature, 1mol / L hydrochloric acid is added to reaction mixture, and gained mixture is extracted with ethyl acetate, water and salt water washing, and with anhydrous sodium sulfate drying.After filtering out desiccant, the residue obtained after reduced pressure evaporation passes through silica gel column chromatography (methanol / chloroform) purifying, to obtain 1.69g title compound.

[0555] Physical properties: m / z[M+H] + 379.8

[0556] NMR(CDCl3)δppm 1.15(s,6H),1.20-1.45(m,22H),1.55-1.65(m,2H),1.76(s,3H),1.75-1. 85(m,2H),2.13-2.26(m,2H),2.35(t,J=7.4Hz,2H),2.46(t,J=6.8Hz,2H).

[0557] Intermediate 3: Synthesis of 4-nitrophenyl (15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl) pentadecyl) carbonate

[0558] Under ice-cooling temperature, 0.43mL triethylamine and 443mg 4-nitrophenyl chloroformate are added to 729mg 3-(15-hydroxypentadecanyl)-2,4,4-trimethylcyclohex-2-ene-1-one (compound 4, Taiho Pharmaceutical Co., Ltd.) in a solution of 10mL dichloromethane, and at ice-cooling temperature, the mixture is stirred for 1 hour, stirred at room temperature for 5 hours.Then, under ice-cooling temperature, water is added in the reaction mixture, and the gained mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 1.03g title compound.

[0559] Physical properties: m / z[M+H] + 530.6

[0560] NMR(CDCl3)δppm 1.15(s,6H),1.25-1.56(m,24H),1.75(s,3H),1.70-1.90(m,4H),2.10-2.25(m,2H),2. 45(t,J=6.8Hz,2H), 4.29(t,J=6.7Hz,2H), 7.39(d,J=9.3Hz,2H), 8.29(d,J=9.3Hz,2H).

[0561] Intermediate 4: Synthesis of 15-methoxypentadecan-1-ol

[0562] Pyridinium p-toluenesulfonate (251 mg) and 1.35 mL of 3,4-dihydro-2H-pyran were added to a solution of 3.07 g of 15-bromopentadecan-1-ol in 30 mL of chloroform, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling temperature, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after reduced pressure evaporation was dissolved in 40 mL of tetrahydrofuran. Then, 10 mL of sodium methoxide (5 M methanol solution) and 250 mg of sodium iodide were added thereto, and the mixture was stirred at 70 ° C for 2 hours. Under ice-cooling temperature, a saturated ammonium chloride solution was added to the residue obtained after reduced pressure evaporation, and the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after reduced pressure evaporation was dissolved in 10 mL of methanol and 5 mL of tetrahydrofuran. Then, 95mg of p-toluenesulfonic acid monohydrate is added thereto, and at room temperature the mixture is stirred for 3 hours. Under ice-cooling temperature, aqueous sodium bicarbonate solution is added in the reaction mixture, and the residue obtained after evaporation under reduced pressure is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 2.15g title compound.

[0563] Intermediate 5: Synthesis of 1-bromo-15-methoxypentadecane

[0564] Under ice-cooling temperature, 2.92g carbon tetrabromide and 2.52g triphenylphosphine are added in the solution of 2.07g 15-methoxy pentadecan-1-alcohol (i.e. intermediate 4) in 25mL dichloromethane, and the mixture is stirred 1 hour.Sodium bicarbonate aqueous solution is added in the reaction mixture, and products therefrom is extracted with ethyl acetate, water and salt water washing, and use anhydrous sodium sulfate drying.After filtering out desiccant, the residue obtained after reduced pressure evaporation passes through silica gel column chromatography (chloroform / hexane) purifying, to obtain the 2.28g title compound.

[0565] Physical properties:

[0566] NMR (CDCl3) δppm 1.18-1.58 (m, 24H), 1.78-1.95 (m, 2H), 3.33 (s, 3H), 3.36 (t, J = 6.8Hz, 2H), 3.41 (t, J = 6.8Hz, 2H).

[0567] Intermediate 6: Synthesis of 6,6-dimethyl-4,6,7,8-tetrahydro-5H-benzo[d][1,3]dioxol-5-one

[0568] At -78 ° C, lithium hexamethyldisilazide (1.3M tetrahydrofuran solution) (14.37 mL) was added to a solution of 1.25 g of 4,6,7,8-tetrahydro-5H-benzo[d][1,3]dioxol-5-one in 40 mL of tetrahydrofuran, and the mixture was stirred for 20 minutes. Then, 1.45 mL of iodomethane was added to the reaction mixture, and the mixture was stirred for 80 minutes at the same temperature and 80 minutes at -45 ° C. The reaction mixture was cooled to -78 ° C, 3.80 mL of lithium hexamethyldisilazide (1.3M tetrahydrofuran solution) and 0.28 mL of iodomethane were added thereto, and then stirred at -45 ° C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 173.1 mg of the title compound.

[0569] Intermediate 7: Synthesis of 2-(hydroxymethyl)-3-(15-methoxypentadecyl)-4,4-dimethylcyclohex-2-en-1-one

[0570] Lithium (0.11g) is added to a solution of 0.20g 6,6-dimethyl-4,6,7,8-tetrahydro-5H-benzo [d] [1,3] dioxo-5-ketone (i.e., intermediate 6) and 0.42g 1-bromo-15-methoxypentadecane (i.e., intermediate 5) in 8.0mL tetrahydrofuran, and the mixture is stirred at 70°C for 85 minutes. After the reaction mixture is cooled on ice, 32mL 0.5M hydrochloric acid is added thereto, and the mixture is stirred at room temperature for 30 minutes. The resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 276mg of the title compound.

[0571] Physical properties: m / z[M+H] + 395.4

[0572] NMR(CDCl3)δppm 1.21(s,6H),1.22-1.67(m,26H),1.80-1.93(m,2H),2.20-2.34(m,2H),2.45-2.55(m, 2H), 3.03 (t, J = 6.8Hz, 1H), 3.35 (s, 3H), 3.39 (t, J = 6.6Hz, 2H), 4.32 (d, J = 7.0Hz, 2H).

[0573] Intermediate 8: Synthesis of 6-isobutoxyspiro[2,5]oct-5-en-4-one

[0574] Isobutanol (0.54 g) and 31 mg of p-toluenesulfonic acid monohydrate were added to a solution of 0.50 g of spiro [2,5] octane -4,6- dione in 6.5 mL of cyclohexane, and the mixture was stirred at 70 ° C for 6 hours. Then, 1.0 g of molecular sieve 4A was added to the reaction mixture, and the mixture was heated and stirred for 16 hours. After cooling to room temperature, the insoluble matter was filtered off with ethyl acetate, and a saturated aqueous sodium bicarbonate solution was added. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 0.51 g of the title compound.

[0575] Intermediate 9: Synthesis of 5-methylspiro[2,5]octane-4,6-dione

[0576] Spiro[2,5]octane-4,6-dione (1.0 g) and 2.0 g of potassium hydroxide were dissolved in 10 mL of methanol and 20 mL of water and then heated to 70 ° C. Then, 2 mL of iodomethane was added four times at intervals of 40 minutes and stirred. After cooling to room temperature, a saturated aqueous ammonium chloride solution was added to the residue obtained after evaporation under reduced pressure, and the mixture was extracted with dichloromethane, washed with brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 0.3 g of the title compound.

[0577] Intermediate 10: Synthesis of 6-isobutoxy-5-methylspiro[2,5]oct-5-en-4-one

[0578] 5-Methylspiro [2,5] octane -4,6-dione (200 mg) (i.e., intermediate 9) was dissolved in toluene, 2.0 equivalents of isobutanol and 0.043 equivalents of p-toluenesulfonic acid monohydrate were added thereto, and then stirred at 70 ° C for 1 day. Then, 400 mg of molecular sieve 4A was added to the reaction mixture, and the mixture was stirred at 120 ° C for 1 day. After cooling to room temperature, the insoluble matter was filtered off with ethyl acetate, and a saturated aqueous sodium bicarbonate solution was added. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 73.8 mg of the title compound.

[0579] Intermediate 11: Synthesis of 3-isobutoxy-2,4,5-trimethylcyclopent-2-en-1-one

[0580] At -78 ℃, lithium hexamethyldisilazide (1.3M tetrahydrofuran solution) (9.60mL) is added to a solution of 1.00g 3-isobutoxy-2-methylcyclopent-2-ene-1-one in 50mL tetrahydrofuran, and the mixture is stirred for 10 minutes. Then, 0.78mL iodomethane is added to the reaction mixture, and the mixture is stirred for 10 minutes at the same temperature, and stirred for 3 hours at -45 ℃. After the reaction mixture is cooled to -78 ℃, 1.20mL lithium hexamethyldisilazide (1.3M tetrahydrofuran solution) and 0.10mL iodomethane are added thereto, and the mixture is stirred for 40 minutes at the same temperature, and stirred for 1 hour at -45 ℃. Under ice-cooling temperature, saturated ammonium chloride aqueous solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 419mg title compound.

[0581] Intermediate 12: Synthesis of methyl 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecanoate

[0582] 1-Hydroxybenzotriazole monohydrate (168mg), 230mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.4mL methanol are added to 379mg 15-(2,6,6-trimethyl-3-oxocyclohex-1-ene-1-yl) pentadecanoic acid (i.e. intermediate 2) in 5mL acetonitrile and 1mL N, in N-dimethylformamide, and at room temperature the mixture is stirred for 1 hour.Then, 0.21mL triethylamine solution is added in the reaction mixture, and at room temperature the mixture is stirred for 16 hours.Under ice-cooling temperature, sodium bicarbonate solution is added in the reaction mixture, the gained mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate.After filtering out desiccant, evaporated under reduced pressure, to obtain 386mg title compound.

[0583] Intermediate 13: Synthesis of methyl 1,5-(3-((tert-butyldimethylsilyl)oxy)-2,6,6-trimethylcyclohex-1-en-1-yl)pentadecanoate

[0584] Under ice-cooling temperature, 34mg sodium borohydride is added to a solution of 118mg 15-(2,6,6-trimethyl-3-oxocyclohex-1-ene-1-yl) pentadecanoic acid methyl esters (i.e. intermediate 12) in 2mL tetrahydrofuran and 1mL methanol, and the mixture is stirred for 2 hours. Saturated aqueous ammonium chloride solution is added to the reaction mixture, and the resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the remaining product obtained after reduced pressure evaporation is dissolved in 3mL dichloromethane. Then, 126 μL triethylamine, 90mg tert-butyldimethylchlorosilane and 7mg 4-dimethylaminopyridine are added thereto, and the mixture is stirred for 2 hours at room temperature. Water is added to the reaction mixture, and the resulting mixture is extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after reduced pressure evaporation is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 116mg title compound.

[0585] Intermediate 14: Synthesis of 1,6-3-((tert-butyldimethylsilyl)oxy)-2,6,6-trimethylcyclohex-1-en-1-yl)-2-methylmethylhexadecane-2-ol

[0586] Under ice-cooling temperature, the tetrahydrofuran solution of 2.2mL 0.96mol / L methylmagnesium bromide is added to 108mg15-3-((tert-butyldimethylsilyl) oxygen base)-2,6,6-trimethylcyclohex-1-ene-1-yl) solution of pentadecanoic acid methyl esters (i.e. intermediate 13) in 2mL tetrahydrofuran, and the mixture is stirred 1 hour.Saturated aqueous ammonium chloride solution is added in reaction mixture, gained mixture is extracted with ethyl acetate, water and salt water washing, and with anhydrous sodium sulfate drying.After filtering out desiccant, the residue obtained after reduced pressure evaporation passes through silica gel column chromatography (ethyl acetate / hexane) purifying, to obtain 89mg title compound.

[0587] Intermediate 15: Synthesis of tert-butyl((3-(15-methoxy-15-methylhexadecyl)-2,4,4-trimethylcyclohex-2-en-1-yl)oxy)dimethylsilane

[0588] Under ice-cooling temperature, 130mg 55% sodium hydride is added to 509mg 16-3-((tert-butyldimethylsilyl) oxygen base)-2,6,6-trimethylcyclohex-1-ene-1-yl)-2-methylmethyl hexadecane-2-ol (i.e. intermediate 14) in 10mL tetrahydrofuran, and the mixture is stirred at room temperature for 1 hour. Then, 125 μL iodomethane is added to the reaction mixture, and the mixture is stirred at room temperature for 2 days. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, and the resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (chloroform / hexane) to obtain 435mg title compound.

[0589] Intermediate 16: Synthesis of 3-(15-bromopentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one

[0590] Under ice-cooling temperature, 3.65 g of carbon tetrabromide and 3.15 g of triphenylphosphine were added to a solution of 3.64 g of 3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (Compound 4, Taiho Pharmaceutical Co., Ltd.) in 40 mL of dichloromethane, and the mixture was stirred for 3 hours. A sodium bicarbonate aqueous solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, a mixed solution of diethyl ether: hexane (1: 1) was added to the residue obtained after evaporation under reduced pressure, and the insoluble matter was filtered out. The residue obtained after evaporation under reduced pressure was then purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain 4.18 g of the title compound.

[0591] Physical properties: m / z[M+H] + 427.1,429.2

[0592] NMR (CDCl3) δppm 1.15 (s, 6H), 1.20-1.52 (m, 24H), 1.76 (s, 3H), 1.70-1.85 (m, 4H), 2.10-2.23 (m, 2H), 2.38-2.51 (m, 2H), 3.41 (t, J = 6.9Hz, 2H).

[0593] Intermediate 17: Synthesis of 3-isobutoxy-2,5,5-trimethylcyclopent-2-en-1-one

[0594] Lithium diisopropylamide (1M hexane-tetrahydrofuran solution) (120mL) is added in 400mL tetrahydrofuran.Then, in dry ice-acetone bath, add the solution of 20.0g 3-isobutoxy-2-methylcyclopent-2-ene-1-one in 100mL tetrahydrofuran.Then, 7.36mL iodomethane is added in the reaction mixture, and the temperature is raised to 20 ℃, then stirred 10 minutes. The reaction mixture is cooled in dry ice-acetone bath, and 120mL lithium diisopropylamide (1M hexane-tetrahydrofuran solution) and 7.36mL iodomethane are added wherein.Then the temperature is raised to 15 ℃, then stirred 15 minutes.Under ice cooling temperature, water is added in the reaction mixture, the gained mixture is extracted with diisopropyl ether, with 10% sodium chloride solution and salt water washing, and used anhydrous sodium sulfate drying. After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 14.6 g of the title compound.

[0595] Physical properties: m / z[M+H] + 197.2

[0596] NMR (CDCl3) δppm 1.01 (d, J = 6.8 Hz, 6H), 1.15 (s, 6H), 1.64 (t, J = 1.8 Hz, 3H), 1.95-2.15 (m, 1H), 2.48 (q, J = 1.8 Hz, 2H), 3.89 (d, J = 6.8 Hz, 2H).

[0597] Intermediate 18: Synthesis of 3-(12-hydroxydodecyl)-2,4,4-trimethylcyclopent-2-en-1-one

[0598] Pyridinium p-toluenesulfonate (361mg) and 1.97mL 3,4-dihydro-2H-pyrans are added to a solution of 3.81g 12-bromododecan-1-ol in 39.6mL chloroform, and the mixture is stirred at room temperature for 1 hour. After this, 180mg pyridinium p-toluenesulfonate and 985 μL 3,4-dihydro-2H-pyrans are added thereto, and the mixture is stirred at room temperature for 30 minutes. Under ice-cooling temperature, saturated sodium bicarbonate aqueous solution is added to the reaction mixture, and the resulting mixture is extracted with chloroform, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, evaporated under reduced pressure to obtain residue.

[0599] Tetrahydrofuran (10.8 mL) was added to 249 mg of lithium and the mixture was heated to 40°C. Then, 10.8 mL of a tetrahydrofuran solution of the above obtained residue and 1.41 g of 3-isobutoxy-2,5,5-trimethylcyclopent-2-en-1-one (i.e. intermediate 17) were added dropwise thereto and the mixture was stirred at 50°C for 2 hours. After the reaction mixture was cooled on ice, 7 mL of water was added thereto and the mixture was stirred at room temperature for 30 minutes. After insoluble matters were filtered off with celite, the filtrate was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the residue obtained after evaporation under reduced pressure was dissolved in 14.4 mL of methanol and 10.8 mL of tetrahydrofuran. Then, 137 mg of p-toluenesulfonic acid monohydrate was added thereto and the mixture was stirred at room temperature for 49 minutes. At an ice cooling temperature, saturated aqueous sodium bicarbonate solution was added thereto and the solvent was removed by evaporation under reduced pressure. Then, the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 1.88 g of the title compound.

[0600] Physical properties: m / z [M+H] + 309.4

[0601] NMR (CDCI3) δ ppm 1.20 (s, 6H), 1.23-1.75 (m, 21H), 1.70 (s, 3H), 2.28 (s, 2H), 2.20-2.40 (m, 2H), 3.66 (t, J=6.6 Hz, 2H).

[0602] Synthesis of intermediate 19: 3-(14-hydroxytetradecyl)-2,4,4-trimethylcyclopent-2-en-1-one

[0603] Pyridinium p-toluenesulfonate (171 mg) and 931 μL of 3,4-dihydro-2H-pyran were added to a solution of 1.99 g of 14-bromotetradecan-1-ol in 20.8 mL of chloroform and the mixture was stirred at room temperature for 45 minutes. Thereafter, 85 mg of pyridinium p-toluenesulfonate and 466 μL of 3,4-dihydro-2H-pyran were added thereto and the mixture was stirred at room temperature for 30 minutes. At an ice cooling temperature, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, the resulting mixture was extracted with chloroform, washed with water and brine, and dried over anhydrous sodium sulfate. After the drying agent was filtered off, evaporation under reduced pressure was performed to obtain a residue.

[0604] Tetrahydrofuran (5.66 mL) was added to 131 mg of lithium, and the mixture was heated to 40 ° C. Then, 5.66 mL of a tetrahydrofuran solution of the above-obtained residue and 740 mg of 3-isobutoxy-2,5,5-trimethylcyclopent-2-ene-1-one (i.e., intermediate 17) were added dropwise thereto, and the mixture was stirred at 50 ° C for 2 hours. After the reaction mixture was cooled on ice, 3.7 mL of water was added thereto, and the mixture was stirred at room temperature. After filtering out the insoluble matter with diatomaceous earth, the filtrate was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after reduced pressure evaporation was dissolved in 7.55 mL of methanol and 3.77 mL of tetrahydrofuran. Then, 72 mg of p-toluenesulfonic acid monohydrate was added thereto, and the mixture was stirred at room temperature for 1 hour. At ice-cooling temperature, a saturated sodium bicarbonate aqueous solution was added thereto, and the solvent was removed by reduced pressure evaporation. Then, the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 832 mg of the title compound.

[0605] Physical properties: m / z[M+H] + 337.5

[0606] NMR(CDCl3)δppm 1.21(s,6H),1.23-1.65(m,25H),1.70(s,3H),2.28(s,2H),2.20-2.40(m,2H),3.60-3.70(m,2H).

[0607] Intermediate 20: Synthesis of 3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclopent-2-en-1-one

[0608] Pyridinium p-toluenesulfonate (361mg) and 1.97mL 3,4-dihydro-2H-pyrans are added to a solution of 4.42g 15-bromopentadecan-1-ol in 39.6mL chloroform, and the mixture is stirred at room temperature for 45 minutes. After this, 180mg pyridinium p-toluenesulfonate and 985 μL 3,4-dihydro-2H-pyrans are added thereto, and the mixture is stirred at room temperature for 1 hour. Under ice-cooling temperature, saturated sodium bicarbonate aqueous solution is added to the reaction mixture, the resulting mixture is extracted with chloroform, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, evaporated under reduced pressure to obtain residue.

[0609] Tetrahydrofuran (10.8 mL) was added to 249 mg of lithium, and the mixture was heated to 40 ° C. Then, 10.8 mL of a tetrahydrofuran solution of the above-obtained residue and 1.41 g of 3-isobutoxy-2,5,5-trimethylcyclopent-2-ene-1-one (i.e., intermediate 17) were added dropwise thereto, and the mixture was stirred at 50 ° C for 2 hours. After the reaction mixture was cooled on ice, 7.19 mL of water was added thereto, and the mixture was stirred at room temperature. After filtering out the insoluble matter with diatomaceous earth, the filtrate was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after reduced pressure evaporation was dissolved in 14.4 mL of methanol and 7.19 mL of tetrahydrofuran. Then, 137 mg of p-toluenesulfonic acid monohydrate was added thereto, and the mixture was stirred at room temperature for 1 hour. At ice-cooling temperature, a saturated sodium bicarbonate aqueous solution was added thereto, and the solvent was removed by reduced pressure evaporation. Then, the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate.After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 2.08 g of the title compound.

[0610] Physical properties: m / z[M+H] + 351.5

[0611] NMR(CDCl3)δppm 1.20(s,6H),1.23-1.68(m,27H),1.70(s,3H),2.28(s,2H),2.20-2.40(m,2H),3.60-3.70(m,2H).

[0612] Intermediate 21: Synthesis of 15-(2,5,5-trimethyl-3-oxocyclopent-1-en-1-yl)pentadecanal

[0613] Dimethyl sulfoxide (3.18mL) is added to a solution of 1.00g 3-(15-hydroxypentadecanyl)-2,4,4-trimethylcyclopent-2-ene-1-one (i.e. intermediate 20) in 7.98mL dichloromethane. Then, under ice-cooling temperature, 3.18mL triethylamine and 1.82g sulfur trioxide pyridine complex are added thereto, and at room temperature the mixture is stirred for 30 minutes. Under ice-cooling temperature, water is added to the reaction mixture, the mixed solvent of gained mixture ethyl acetate and normal heptane is extracted, with 0.1mol / L hydrochloric acid, saturated aqueous ammonium chloride solution, water and salt water washing, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / heptane), to obtain 530mg title compound.

[0614] Intermediate 22: Synthesis of 15-(2,5,5-trimethyl-3-oxocyclopent-1-en-1-yl)pentadecanoic acid

[0615] Under ice-cooling temperature, 1.22mL 2-methyl-2-butene and 310mg potassium dihydrogen phosphate are added to the mixed solutions of 530mg 15-(2,5,5-trimethyl-3-oxocyclopent-1-ene-1-yl) pentadecanal (i.e. intermediate 21) in 1.83mL tert-butyl alcohol and 0.609mL water.A solution of 515mg80% sodium chlorite in 1.52mL water is added dropwise to reaction mixture, and at room temperature the mixture is stirred 1 hour.Then, under ice-cooling temperature, 1mol / L hydrochloric acid is added to reaction mixture, gained mixture is extracted with ethyl acetate, with the mixture of saturated sodium thiosulfate aqueous solution and salt solution and salt water washing, and use anhydrous sodium sulfate drying.After filtering out desiccant, the residue obtained after evaporation under reduced pressure passes through silica gel column chromatography (methanol / chloroform) purifying, to obtain 505mg title compound.

[0616] Physical properties: m / z[M+H] + 365.5

[0617] NMR(CDCl3)δppm 1.21(s,6H),1.23-1.55(m,22H),1.58-1.73(m,2H),1.70(s,3H),2.29(s,2H),2.25-2.45(m,4H).

[0618] Example 1: Synthesis of 3-(12-methoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 11)

[0619] Under ice-cooling temperature, 72mg sodium tert-butoxide is added to 161mg 3- (12- hydroxydodecyl) -2,4,4- trimethylcyclohex-2-ene-1-one (compound 1) in 2.0mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 62 μL iodomethane is added to the reaction solution, and the mixture is stirred for 0.5 hour under ice-cooling temperature, stirred at room temperature for 2 hours. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 114mg title compound.

[0620] Example 2: Synthesis of 3-(12-ethoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 12)

[0621] Under ice-cooling temperature, 43mg 55% sodium hydride is added to a solution of 161mg 3- (12- hydroxydodecyl) -2,4,4- trimethylcyclohex-2-ene-1-one (compound 1) in 2.0mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 80 μL of iodoethane is added to the reaction mixture, and the mixture is stirred for 1 hour at ice-cooling temperature and stirred at room temperature for 24 hours. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 57mg title compound.

[0622] Example 3: Synthesis of 3-(12-isopropoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 13)

[0623] Silver oxide (232mg) is added to a solution of 161mg 3-(12-hydroxydodecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (compound 1) in 0.57mL 2-iodopropane, and at room temperature the mixture is stirred for 7 days. The reaction mixture is diluted in tert-butyl methyl ether, and insoluble matter is filtered off with diatomaceous earth. After this, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 106mg title compound.

[0624] Example 4: Synthesis of 2,4,4-trimethyl-3-(12-propoxydodecyl)cyclohex-2-en-1-one (Compound 14)

[0625] Under ice-cooling temperature, 86mg 55% sodium hydride is added to 323mg 3- (12- hydroxy dodecyl) -2,4,4- trimethyl cyclohex-2-ene-1-one (compound 1) in 5.0mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 0.20mL 1- iodopropane is added to the reaction mixture, and the mixture is stirred for 1 hour under ice-cooling temperature, stirred at room temperature for 2 days. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 102mg title compound.

[0626] Example 5: Synthesis of 3-(12-butoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 15)

[0627] At ice-cooling temperature, 86 mg of 55% sodium hydride was added to a solution of 323 mg of 3-(12-hydroxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 1) in 5.0 mL of tetrahydrofuran, and the mixture was stirred for 30 minutes. Then, 0.23 mL of 1-iodobutane was added to the reaction mixture, and the mixture was stirred at ice-cooling temperature for 1 hour, at room temperature for 2 days. At ice-cooling temperature, saturated ammonium chloride solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give 101 mg of the title compound.

[0628] Example 6: Synthesis of 3-(13-methoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 16)

[0629] At ice-cooling temperature, 72 mg of sodium tert-butoxide was added to a solution of 168 mg of 3-(13-hydroxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 2) in 3.0 mL of tetrahydrofuran, and the mixture was stirred for 30 minutes. Then, 62 μL of iodomethane was added to the reaction mixture, and the mixture was stirred at ice-cooling temperature for 0.5 hour, at room temperature for 30 hours. At ice-cooling temperature, saturated ammonium chloride solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give 119 mg of the title compound.

[0630] Example 7: Synthesis of 3-(13-ethoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 17)

[0631] At ice-cooling temperature, 43 mg of 55% sodium hydride was added to a solution of 168 mg of 3-(13-hydroxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 2) in 3.0 mL of tetrahydrofuran, and the mixture was stirred for 30 minutes. Then, 80 μL of iodoethane was added to the reaction mixture, and the mixture was stirred at ice-cooling temperature for 1 hour, at room temperature for 4 days. At ice-cooling temperature, saturated ammonium chloride solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give 72 mg of the title compound.

[0632] Example 8: Synthesis of 3-(13-isopropoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 18)

[0633] Silver oxide (232mg) is added to a solution of 161mg 3-(13-hydroxytridecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (compound 2) in 0.57mL 2-iodopropane, and at room temperature the mixture is stirred for 5 days. The reaction mixture is diluted in tert-butyl methyl ether, and insoluble matter is filtered off with diatomaceous earth. After this, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 71mg title compound.

[0634] Example 9: Synthesis of 2,4,4-trimethyl-3-(13-propoxytridecyl)cyclohex-2-en-1-one (Compound 19)

[0635] Under ice-cooling temperature, 86mg 55% sodium hydride is added to 337mg 3- (13- hydroxy tridecyl) -2,4,4- trimethylcyclohex-2-ene-1-one (compound 2) in 5.0mL tetrahydrofuran, and the mixture is stirred for 30 minutes. 0.20mL 1- iodopropane is added to the reaction mixture, and the mixture is stirred for 1 hour under ice-cooling temperature, stirred at room temperature for 5 days. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 76mg title compound.

[0636] Example 10: Synthesis of 3-(13-butoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 20)

[0637] Under ice-cooling temperature, 86mg 55% sodium hydride is added to 337mg 3- (13- hydroxy tridecyl) -2,4,4- trimethylcyclohex-2-ene-1-one (compound 2) in a solution in 5.0mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 0.23mL 1- iodobutane is added to the reaction mixture, and the mixture is stirred for 1 hour under ice-cooling temperature, stirred at room temperature for 5 days. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 71mg title compound.

[0638] Example 11: Synthesis of 3-(14-methoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 21)

[0639] Under ice-cooling temperature, 72mg sodium tert-butoxide is added to 175mg 3- (14- hydroxytetradecyl) -2,4,4- trimethylcyclohex-2-ene-1-one (compound 3) in 3.0mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 62 μL iodomethane is added to the reaction mixture, and the mixture is stirred for 0.5 hour under ice-cooling temperature, stirred at room temperature for 24 hours. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 133mg title compound.

[0640] Example 12: Synthesis of 3-(14-ethoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 22)

[0641] Under ice-cooling temperature, 43mg 55% sodium hydride is added to a solution of 175mg 3- (14- hydroxytetradecyl) -2,4,4- trimethylcyclohex-2-ene-1-one (compound 3) in 3.0mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 80 μL iodoethane is added to the reaction mixture, and the mixture is stirred for 1 hour under ice-cooling temperature and stirred at room temperature for 3 days. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 66mg title compound.

[0642] Example 13: Synthesis of 3-(14-isopropoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 23)

[0643] Silver oxide (232mg) is added to a solution of 175mg 3-(14-hydroxytetradecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (compound 3) in 0.57mL 2-iodopropane, and at room temperature the mixture is stirred for 6 days. The reaction mixture is diluted in tert-butyl methyl ether, and insoluble matter is filtered off with diatomaceous earth. After this, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 43mg title compound.

[0644] Example 14: Synthesis of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 24)

[0645] Under ice-cooling temperature, 30mg 55% sodium hydride is added to 95mg 3- (15- hydroxypentadecanyl) -2,4,4- trimethylcyclohex-2-ene-1-one (compound 4, Taiho Pharmaceutical Co., Ltd.) in a solution in 0.8mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 50 μL iodomethane is added to the reaction mixture, and the mixture is stirred for 1 hour under ice-cooling temperature, stirred at room temperature for 15 hours. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 47mg title compound.

[0646] Example 15: Synthesis of 3-(15-ethoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 25)

[0647] Under ice-cooling temperature, 33mg 55% sodium hydride is added to 109mg 3- (15- hydroxypentadecanyl) -2,4,4- trimethylcyclohex-2-ene-1-one (compound 4, Taiho Pharmaceutical Co., Ltd.) in a solution in 1.5mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 72 μL iodoethane is added to the reaction mixture, and the mixture is stirred for 1 hour under ice-cooling temperature, stirred at room temperature for 2 days. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 55mg title compound.

[0648] Example 16: Synthesis of 3-(15-isopropoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 26)

[0649] Silver oxide (139mg) is added to 109mg 3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (compound 4, Taiho Pharmaceutical Co., Ltd.) in a solution in 0.30mL 2-iodopropane, and at room temperature the mixture is stirred for 6 days.Reactant mixture is diluted in diethyl ether, insoluble matter is filtered off with diatomite.After this, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 65mg title compound.

[0650] Example 17: Synthesis of 3-(15-(methoxy-d3)pentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 27)

[0651] Under ice-cooling temperature, 55mg 55% sodium hydride is added to 182mg 3- (15- hydroxypentadecanyl) -2,4,4- trimethylcyclohex-2-ene-1-one (compound 4, Taiho Pharmaceutical Co., Ltd.) in a solution in 3.0mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 93 μL iodomethane-d3 is added to the reaction mixture, and the mixture is stirred for 1 hour under ice-cooling temperature, stirred at room temperature for 5 hours. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the gained mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 151mg title compound.

[0652] Example 18: Synthesis of 3-(15-methoxypentadecyl-15,15-d2)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 28)

[0653] Under ice-cooling temperature, 0.98mL triethylamine and 0.59mL ethyl chloroformate are added to 717mg 15-(2,6,6-trimethyl-3-oxocyclohex-1-ene-1-yl) pentadecanoic acid (i.e. intermediate 2) in 15mL tetrahydrofuran, and the mixture is stirred for 30 minutes.A solution of 544mg sodium deuterium borate in 3.0mL deuterium oxide is added to the reaction mixture, and the mixture is stirred for 0.5 hour at the same temperature.Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the gained mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate.After filtering out desiccant, the residue obtained after reduced pressure evaporation passes through silica gel column chromatography (ethyl acetate / hexane) purification, to obtain 548mg 3-(15-hydroxypentadecanyl-15,15-d2)-2,4,4-trimethylcyclohex-2-ene-1-one. Under ice-cooling temperature, 43mg55% sodium hydride is added to 183mg of the obtained 3- (15- hydroxypentadecanyl -15,15-d2) -2,4,4- trimethylcyclohex-2-ene-1-one in 3.0mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 93 μL of iodomethane is added to the reaction mixture, and the mixture is stirred for 1 hour at ice-cooling temperature and stirred at room temperature for 3 days. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, and the resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 100mg of the title compound.

[0654] Example 19: Synthesis of 3-(16-methoxyhexadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 29)

[0655] Under ice-cooling temperature, 72mg sodium tert-butoxide is added to a solution of 189mg 3-(16-hydroxy hexadecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (compound 5) in 3.0mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 62 μL iodomethane is added to the reaction mixture, and the mixture is stirred for 0.5 hour under ice-cooling temperature, and stirred for 9 hours at room temperature. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 127mg title compound.

[0656] Example 20: Synthesis of 3-(16-ethoxyhexadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 30)

[0657] Under ice-cooling temperature, 44mg 55% sodium hydride is added to a solution of 189mg 3- (16- hydroxy hexadecyl) -2,4,4- trimethylcyclohex-2-ene-1-one (compound 5) in 3.0mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 80 μL of iodoethane is added to the reaction mixture, and the mixture is stirred for 1 hour at ice-cooling temperature and stirred at room temperature for 4 days. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 46mg title compound.

[0658] Example 21: Synthesis of 3-(16-isopropoxyhexadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 31)

[0659] Silver oxide (232mg) is added to a solution of 189mg 3-(16-hydroxy hexadecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (compound 5) in 0.57mL 2-iodopropane, and at room temperature the mixture is stirred for 5 days. The reaction mixture is diluted in tert-butyl methyl ether, and insoluble matter is filtered off with diatomaceous earth. After this, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 106mg title compound.

[0660] Example 22: Synthesis of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecanamide (Compound 32)

[0661] 1-Hydroxybenzotriazole monohydrate (168mg) and 230mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to 379mg 15-(2,6,6-trimethyl-3-oxocyclohex-1-ene-1-yl) pentadecanoic acid (i.e. intermediate 2) solution in 5mL acetonitrile, and at room temperature the mixture was stirred 15 minutes.Then, 0.5mL 28% ammoniacal liquor is added in the reaction mixture, and at room temperature the mixture was stirred 18 hours.Under ice-cooling temperature, sodium bicarbonate solution is added in the reaction mixture, precipitation is collected by filtration, then dried under reduced pressure, to obtain the 299mg title compound.

[0662] Example 23: Synthesis of N-methyl-15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecanamide (Compound 33)

[0663] 1-Hydroxybenzotriazole monohydrate (168mg) and 230mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added into the solution of 379mg 15-(2,6,6-trimethyl-3-oxocyclohex-1-ene-1-yl) pentadecanoic acid (i.e. intermediate 2) in 5mL acetonitrile, and at room temperature mixture was stirred 15 minutes.Then, 1mL 2mol / L methylamine tetrahydrofuran solution is added in reaction mixture, and at room temperature mixture was stirred 14 hours.Under ice-cooling temperature, sodium bicarbonate solution is added in reaction mixture, precipitate is collected by filtering, then dry under reduced pressure, to obtain the 340mg title compound.

[0664] Example 24: Synthesis of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecanitrile (Compound 34)

[0665] Burgess reagent (108 mg) was added to a solution of 113 mg of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecanamide (Example 22) in 2 mL of dichloromethane, and the mixture was stirred for 2 hours. The residue obtained after the reaction mixture was evaporated under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give 104 mg of the title compound.

[0666] Example 25: Synthesis of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecylcarbamate (Compound 35)

[0667] 28% ammonia (0.5 mL) was added to a solution of 265 mg of 4-nitrophenyl (15- (2,6,6-trimethyl-3-oxocyclohex-1-ene-1-yl) pentadecyl) carbonate (i.e., intermediate 3) in 5 mL of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 169 mg of the title compound.

[0668] Example 26: Synthesis of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecyl dimethylcarbamate (Compound 36)

[0669] Under ice-cooling temperature, 0.2mL 2mol / L dimethylamine tetrahydrofuran solution is added to 159mg 4-nitrophenyl (15-(2,6,6-trimethyl-3-oxocyclohex-1-ene-1-yl) pentadecyl) carbonate (i.e. intermediate 3) in 3mL tetrahydrofuran, and at room temperature the mixture is stirred for 3 hours. Under ice-cooling temperature, saturated aqueous ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 113mg title compound.

[0670] Example 27: Synthesis of 3-(15-methoxypentadecyl)cyclohex-2-en-1-one (Compound 37)

[0671] Lithium (694mg) is added to a solution of 1.40g 3-ethoxycyclohex-2-ene-1-one and 3.86g 1-bromo-15-methoxypentadecane (i.e. intermediate 5) in 50mL tetrahydrofuran, and the mixture is stirred at 70°C for 22 hours. After the reaction mixture is cooled on ice, 0.5M hydrochloric acid is added thereto, and the mixture is stirred at room temperature for 30 minutes. The gained mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 2.10g title compound.

[0672] Example 28: Synthesis of 3-(15-methoxypentadecyl)-2-methylcyclohex-2-en-1-one (Compound 38)

[0673] Sodium tert-butoxide (43mg) and 34 μ L iodomethane are added to a solution of 101mg 3-(15-hydroxypentadecyl)-2-methylcyclohex-2-ene-1-one (compound 7) in 2.0mL tetrahydrofuran, and at room temperature the mixture is stirred 44 hours. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the gained mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 38mg title compound.

[0674] Example 29: Synthesis of 3-(15-methoxypentadecyl)-4,4-dimethylcyclohex-2-en-1-one (Compound 39)

[0675] Lithium (80mg) is added to a solution of 154mg 3-methoxy-6,6-dimethylcyclohex-2-ene-1-one and 642mg 1-bromo-15-methoxypentadecane (i.e., intermediate 5) in 6mL tetrahydrofuran, and the mixture is stirred at 70°C for 8 hours. After the reaction mixture is cooled on ice, 0.5M hydrochloric acid is added thereto, and the mixture is stirred at room temperature for 30 minutes. The resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 224mg title compound.

[0676] Example 30: Synthesis of 2-iodo-3-(15-methoxypentadecyl)-4,4-dimethylcyclohex-2-en-1-one (Compound 40)

[0677] Under ice-cooling temperature, 0.63mL trimethylsilazide is added to 729mg 3- (15- methoxy pentadecyl) -4,4- dimethylcyclohex-2-ene-1-one (embodiment 29) in a solution in 5mL chloroform, and the mixture is stirred for 3 hours. Under ice-cooling temperature, a solution of 2.03g iodine and 2mL pyridine in 2mL chloroform is added to the reaction mixture, and the mixture is stirred for 3 days at room temperature. Then, 10% sodium sulfite aqueous solution is added thereto, the resulting mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 693mg title compound.

[0678] Example 31: Synthesis of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohexa-2,5-dien-1-one (Compound 41)

[0679] To a solution of 200 mg of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2- en-1-one (Example 14) in 4.0 mL of tetrahydrofuran was added 609 μL of lithium hexamethyldisilazide (1.3 M solution in tetrahydrofuran) at ice-cooled temperature and the mixture was stirred for 30 minutes. Then, 100 μL of chlorotrimethylsilane was added to the reaction mixture and the mixture was stirred at room temperature for 1 hour. Aqueous sodium bicarbonate solution was added to the reaction solution and the resulting mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the residue obtained after evaporation under reduced pressure was dissolved in 5.0 mL of tetrahydrofuran and 609 μL of lithium hexamethyldisilazide (1.3 M solution in tetrahydrofuran) was added thereto at -78°C and then stirred for 30 minutes. A solution of 102 mg of phenylselenyl chloride in 5.0 mL of tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at the same temperature for 30 minutes and then warmed to room temperature. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane). To a solution of 155 mg of 3-(15-methoxypentadecyl)-2,4,4-trimethyl-6-(phenylseleno)cyclohex-2-en-1-one thus obtained in 16 mL of dichloromethane was added 71.5 mg of m-chloroperbenzoic acid and the mixture was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate solution was added to the reaction mixture and the resulting mixture was extracted with dichloromethane, washed with brine and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give 65.2 mg of the title compound.

[0680] Example 32: Synthesis of 2-(methoxymethyl)-3-(15-methoxypentadecyl)-4,4- dimethylcyclohex-2-en-1-one (Compound 42)

[0681] To a solution of 60 mg of 2-(hydroxymethyl)-3-(15-methoxypentadecyl)-4,4- dimethylcyclohex-2-en-1-one (i.e., Intermediate 7) in 1.0 mL of dichloromethane were added 212 mg of 1,8-bis(dimethylamino)naphthalene and 146 mg of trimethyloxonium tetrafluoroborate at ice-cooled temperature and the mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was neutralized with 1 M hydrochloric acid, extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to give 50 mg of the title compound.

[0682] Example 33: Synthesis of 4-(15-methoxypentadecyl)spiro[2,5]oct-4-en-6-one (Compound 43)

[0683] Lithium (0.1 g) was added to a solution of 0.2 g of 6-isobutoxyspiro[2,5]oct-5-ene-4-one (i.e., intermediate 8) and 0.5 g of 1-bromo-15-methoxypentadecane (i.e., intermediate 5) in 8 mL of tetrahydrofuran, and the mixture was stirred at 70 ° C for 3 hours. After the reaction mixture was cooled on ice, 0.5 M hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 0.36 g of the title compound.

[0684] Example 34: Synthesis of 4-(15-methoxypentadecyl)-5-methylspiro[2,5]oct-4-en-6-one (Compound 44)

[0685] Lithium (14 equivalents) was added to a tetrahydrofuran solution of 73.8 mg of 6-isobutoxy-5-methylspiro[2,5]oct-5-ene-4-one (i.e., intermediate 10) and 1.2 equivalents of 1-bromo-15-methoxypentadecane (i.e., intermediate 5), and the mixture was stirred at 70 ° C for 4 hours. After the reaction mixture was cooled on ice, 0.5M hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 77.9 mg of the title compound.

[0686] Example 35: Synthesis of 3-(15-methoxypentadecyl)-2-methylcyclopent-2-en-1-one (Compound 45)

[0687] Lithium (38.3 mg) is added to a solution of 63.6 mg 3-isobutoxy-2-methylcyclopent-2-ene-1-one and 232.1 mg 1-bromo-15-methoxypentadecane (i.e., intermediate 5) in 3.0 mL tetrahydrofuran, and the mixture is stirred at 70 ° C for 4 hours. After the reaction mixture is cooled on ice, 0.5 M hydrochloric acid is added thereto, and the mixture is stirred at room temperature for 30 minutes. The resulting mixture is extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 89.0 mg of the title compound.

[0688] Example 36: Synthesis of 3-(15-methoxypentadecyl)-2,4,5-trimethylcyclopenta-2- en-1-one (Compound 46)

[0689] Lithium (35.5 mg) was added to a solution of 75.6 mg of 3-isobutoxy-2,4,5- trimethylcyclopenta-2-en-1-one (i.e. Intermediate 11) and 230 mg of 1-bromo-15- methoxypentadecane (i.e. Intermediate 5) in 3.0 mL of tetrahydrofuran and the mixture was stirred at 70 °C for 3.5 hours. After cooling the reaction mixture on ice, 0.5 M hydrochloric acid was added thereto and the mixture was stirred at room temperature for 20 minutes. The resulting mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the residue obtained after evaporation under reduced pressure was purified by column chromatography on silica gel (ethyl acetate / heptane) to give 112.5 mg of the title compound.

[0690] Example 37: Synthesis of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclopenta-2-en-1- one (Compound 69)

[0691] Lithium (156 mg) was added to a solution of 981 mg of 3-isobutoxy-2,5,5- trimethylcyclopenta-2-en-1-one (i.e. Intermediate 17) and 2.89 g of 1-bromo-15- methoxypentadecane (i.e. Intermediate 5) in 15 mL of tetrahydrofuran and the mixture was stirred at 70 °C for 5 hours. After cooling the reaction mixture on ice, 1 M hydrochloric acid was added thereto and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the residue obtained after evaporation under reduced pressure was purified by column chromatography on silica gel (ethyl acetate / hexane) to give 1.68 g of the title compound.

[0692] Example 38: Synthesis of 3-(12-methoxydodecyl)-2,4,4-trimethylcyclopenta-2-en-1-one (Compound 70)

[0693] Under ice-cooling temperature, 140mg sodium tert-butoxide is added to 300mg 3- (12- hydroxydodecyl) -2,4,4- trimethylcyclopent-2-ene-1-one (intermediate 18) in 3.9mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 122 μL iodomethane is added to the reaction mixture, and the mixture is stirred for 0.5 hour under ice-cooling temperature, stirred at room temperature for 1 hour. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / heptane), to obtain 199mg title compound.

[0694] Example 39: Synthesis of 2,4,4-trimethyl-3-(12-propoxydodecyl)cyclopent-2-en-1-one (Compound 71)

[0695] Under ice-cooling temperature, 141mg 55% sodium hydride is added to 500mg 3- (12- hydroxy dodecyl) -2,4,4- trimethylcyclopent- 2- ene- 1- ketone (intermediate 18) in 8.09mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 323 μ L 1- iodopropane is added to the reaction mixture, and the mixture is stirred for 1 hour under ice-cooling temperature, stirred at room temperature for 44 hours. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / heptane), to obtain 119mg title compound.

[0696] Example 40: Synthesis of 3-(14-methoxytetradecyl)-2,4,4-trimethylcyclopent-2-en-1-one (Compound 72)

[0697] Under ice-cooling temperature, 107mg sodium tert-butoxide is added to 250mg 3- (14- hydroxytetradecyl) -2,4,4- trimethylcyclopent-2-ene-1-one (intermediate 19) in 2.98mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 122 μL iodomethane is added to the reaction mixture, and the mixture is stirred for 30 minutes under ice-cooling temperature, stirred at room temperature for 3 hours. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / heptane), to obtain 174mg title compound.

[0698] Example 41: Synthesis of 2,4,4-trimethyl-3-(14-ethoxytetradecyl)cyclopent-2-en-1-one (Compound 73)

[0699] Under ice-cooling temperature, 130mg 55% sodium hydride is added to a solution of 500mg 3- (14- hydroxytetradecyl) -2,4,4- trimethylcyclopent-2-ene-1-one (intermediate 19) in 5.95mL tetrahydrofuran, and the mixture is stirred for 30 minutes. Then, 246 μL iodoethane is added to the reaction mixture, and the mixture is stirred for 1 hour at ice-cooling temperature and stirred at room temperature for 21 hours. Under ice-cooling temperature, saturated ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 274mg title compound.

[0700] Example 42: Synthesis of 15-(2,5,5-trimethyl-3-oxocyclopent-1-en-1-yl)pentadecanamide (Compound 74)

[0701] 1-Hydroxybenzotriazole monohydrate (115mg) and 158mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to a solution of 250mg 15-(2,5,5-trimethyl-3-oxocyclopent-1-ene-1-yl) pentadecanoic acid (i.e., intermediate 22) in 3.44mL acetonitrile, and the mixture is stirred at room temperature for 16 minutes. Then, 343 μL 28% ammonia water is added to the reaction mixture, and then stirred at room temperature for 17 hours. Then, 170 μL 28% ammonia water is added thereto, and then stirred at room temperature for 4 hours. In addition, 343 μL 28% ammonia water is added, and then stirred at room temperature for 20 hours. Under ice-cooling temperature, saturated sodium bicarbonate solution is added to the reaction mixture, and the solvent is evaporated under reduced pressure. After this, ethyl acetate and water are added thereto, the mixture is extracted, heptane is added to the organic layer, the mixture is washed with 10% sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (methanol / chloroform) to obtain 146 mg of the title compound.

[0702] Example 43: Synthesis of 15-(2,5,5-trimethyl-3-oxocyclopent-1-en-1-yl)pentadecanitrile (Compound 75)

[0703] Burgess reagent (71 mg) was added to a solution of 73 mg of 15-(2,5,5-trimethyl-3-oxocyclopent-1-ene-1-yl)pentadecanamide (Example 42) in 2 mL of dichloromethane, and the mixture was stirred for 2 hours. The residue obtained after the reaction mixture was evaporated under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give 51 mg of the title compound.

[0704] Reference Example 1: Synthesis of 3-(15-methoxy-15-methylhexadecyl)-2,4,4-trimethylcyclohex-2-en-1-ol (Compound 47)

[0705] A 1 mol / L tetrabutylammonium fluoride solution in tetrahydrofuran (1.4 mL) was added to a solution of 366 mg of tert-butyl ((3-(15-methoxy-15-methylhexadecyl)-2,4,4-trimethylcyclohex-2-en-1-yl)oxy)dimethylsilane (i.e., Intermediate 15) in 5 mL of tetrahydrofuran, and the mixture was stirred at room temperature for 2 days. The residue obtained after evaporation of the reaction mixture under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give 272 mg of the title compound.

[0706] Reference Example 2: Synthesis of 3-(15-methoxy-15-methylhexadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 48)

[0707] Activated manganese dioxide (435 mg) was added to a solution of 204 mg of 3-(15-methoxy-15-methylhexadecyl)-2,4,4-trimethylcyclohex-2-en-1-ol (Reference Example 1) in 10 mL of chloroform, and the mixture was stirred for 4 days. After filtering off insoluble matter with celite, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 199 mg of the title compound.

[0708] Reference Example 3: Synthesis of 2,4,4-trimethyl-3-(15-(trifluoromethoxy)pentadecyl)-cyclohex-2-en-1-one (Compound 49)

[0709] Ethyl acetate (5mL) is added to 365mg 3-(15-hydroxypentadecanyl)-2,4,4-trimethylcyclohexane-2-ene-1-one (compound 4, Taiho Pharmaceutical Co., Ltd.), 514mg silver trifluoromethanesulfonate, 531mg N-fluoro-N '-(chloromethyl) triethylenediamine bis(tetrafluoroborate) and 174mg potassium fluoride.Then, at room temperature, 172 μ L 2-fluoropyridine and 295 μ L (trifluoromethyl) trimethylsilane are added thereto, then stirred 25 hours.Reactant mixture is diluted in ethyl acetate, insoluble matter is filtered off with diatomite.After this, the residue obtained after reduced pressure evaporation passes through silica gel column chromatography (ethyl acetate / hexane) purifying, to obtain 212mg title compound.

[0710] Reference Example 4: Synthesis of 3-(15-(tert-butyldimethylsilyl)oxy)pentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 50)

[0711] Imidazole (102mg) and 151mg tert-butyldimethylchlorosilane are added to 182mg3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (compound 4, Taiho Pharmaceutical Co., Ltd.) in a solution of 1mL N,N-dimethylformamide, and at room temperature the mixture is stirred for 2 hours. Water is added to the reaction mixture, and the resulting mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 226mg title compound.

[0712] Reference Example 5: Synthesis of 3-(15-phenoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 51)

[0713] Under ice-cooling temperature, 144mg triphenylphosphine and 0.12mL diisopropyl azodicarboxylate are added to 182mg3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (compound 4, Taiho Pharmaceutical Co., Ltd.) and 52mg phenol in 4mL tetrahydrofuran, and the mixture is stirred for 1 hour. Then, the resulting mixture is stirred at room temperature for 22 hours. The reaction mixture is diluted in ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 125mg title compound.

[0714] Reference Example 6: Synthesis of 3-(15-(benzyloxy)pentadecyl)-2,4,4- trimethylcyclohex-2-en-1-one (Compound 52)

[0715] At an ice-cooling temperature, 55 mg of 55% sodium hydride was added to a solution of 182 mg of 3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 4, Taiho Pharmaceutical Co., Ltd.) in 3 mL of tetrahydrofuran, and the mixture was stirred for 30 minutes. Then, 178 μL of benzyl bromide was added to the reaction mixture, and the mixture was stirred for 1 hour at an ice-cooling temperature and for 3 days at room temperature. At an ice-cooling temperature, a saturated ammonium chloride solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give 107 mg of the title compound.

[0716] Reference Example 7: Synthesis of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1- yl)pentadecyl benzoate (Compound 53)

[0717] At an ice-cooling temperature, 1.05 mL of triethylamine and 0.64 mL of benzoyl chloride were added to a solution of 1.82 g of 3-(15-hydroxypentadecyl)-2,4,4- trimethylcyclohex-2-en-1-one (Compound 4, Taiho Pharmaceutical Co., Ltd.) in 20 mL of dichloromethane, and the mixture was stirred for 2 days at room temperature. At an ice-cooling temperature, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give 2.34 g of the title compound.

[0718] Reference Example 8: Synthesis of N,N-dimethyl-15-(2,6,6-trimethyl-3-oxocyclohex-1- en-1-yl)pentadecanamide (Compound 54)

[0719] 1-Hydroxybenzotriazole monohydrate (168mg) and 230mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to the solution of 379mg 15-(2,6,6-trimethyl-3-oxocyclohex-1-ene-1-yl) pentadecanoic acid (i.e. intermediate 2) in 5mL acetonitrile, and at room temperature the mixture was stirred 15 minutes.Then, 1mL 2mol / L dimethylamine-tetrahydrofuran solution is added in the reaction mixture, and at room temperature the mixture was stirred 14 hours.Under ice-cooling temperature, sodium bicarbonate solution is added in the reaction mixture, the gained mixture is extracted with ethyl acetate, water and salt water washing, and with anhydrous sodium sulfate drying.After filtering out desiccant, the residue obtained after reduced pressure evaporation passes through silica gel column chromatography (ethyl acetate / chloroform) purifying, to obtain 338mg title compound.

[0720] Reference Example 9: Synthesis of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecylmethylcarbamate (Compound 55)

[0721] Under ice-cooling temperature, 0.3mL 2mol / L methylamine-tetrahydrofuran solution is added to 265mg 4-nitrophenyl (15-(2,6,6-trimethyl-3-oxocyclohex-1-ene-1-yl) pentadecyl) carbonate (i.e. intermediate 3) in 5mL tetrahydrofuran, and at room temperature the mixture is stirred for 1 hour. Under ice-cooling temperature, saturated aqueous ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 177mg title compound.

[0722] Reference Example 10: Synthesis of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecylethylcarbamate (Compound 56)

[0723] Under ice-cooling temperature, 0.2mL 2mol / L ethylamine-tetrahydrofuran solution is added to 159mg 4-nitrophenyl (15-(2,6,6-trimethyl-3-oxocyclohex-1-ene-1-yl) pentadecyl) carbonate (i.e. intermediate 3) in 3mL tetrahydrofuran, and at room temperature the mixture is stirred for 3 hours. Under ice-cooling temperature, saturated aqueous ammonium chloride solution is added to the reaction mixture, the resulting mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate. After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 101mg title compound.

[0724] Reference Example 11: Synthesis of (15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecyl)ethyl carbonate (Compound 57)

[0725] Ethanol (175 μL) and 67 μL of 1,8-diazabicyclo [5.4.0] undec-7-ene were added to a solution of 159 mg of 4-nitrophenyl (15- (2,6,6-trimethyl-3-oxocyclohex-1-ene-1-yl) pentadecyl) carbonate (i.e., intermediate 3) in 3 mL of tetrahydrofuran, and the mixture was stirred at room temperature for 22 hours. Under ice-cooling temperature, saturated aqueous ammonium chloride solution was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 36 mg of the title compound.

[0726] Reference Example 12: Synthesis of 2,4,4-trimethyl-3-(15-(methylamino)pentadecyl)cyclohex-2-en-1-one (Compound 58)

[0727] 2mol / L methylamine-tetrahydrofuran solution (1mL) is added to 214mg 3-(15-bromopentadecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (i.e. intermediate 16) in 5mL tetrahydrofuran, and at room temperature the mixture is stirred for 4 days.Water is added in reaction mixture, gained mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate.After filtering out desiccant, the residue obtained after evaporation under reduced pressure passes through NH silica gel column chromatography (ethyl acetate / chloroform) purification, to obtain 98mg title compound.

[0728] Reference Example 13: Synthesis of 3-(15-(dimethylamino)pentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Compound 59)

[0729] 2mol / L dimethylamine-tetrahydrofuran solution (1mL) is added to 214mg 3-(15-bromopentadecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (i.e. intermediate 16) in 5mL tetrahydrofuran, and at room temperature the mixture is stirred for 3 days.Water is added in reaction mixture, gained mixture is extracted with ethyl acetate, washed with water and salt water, and dried over anhydrous sodium sulfate.After filtering out desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (methanol / chloroform), to obtain 162mg title compound.

[0730] Reference Example 14: Synthesis of 2-ethyl-3-(15-methoxypentadecyl)-4,4-dimethylcyclohex-2-en-1-one (Compound 60)

[0731] Potassium hydroxide (1 equivalent), 8 mL of water and 1.5 equivalents of iodoethane were added to a solution of 1.0 g of 4,4-dimethylcyclohexane-1,3-dione in 20 mL of ethanol, and the mixture was stirred at 70 ° C for 1 day. The reaction mixture was dried under reduced pressure and filtered with ethyl acetate. Thereafter, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (acetone / heptane) to obtain 221 mg of 2-ethyl-4,4-dimethylcyclohexane-1,3-dione. The obtained 2-ethyl-4,4-dimethylcyclohexane-1,3-dione (221 mg) was dissolved in toluene, 2.0 equivalents of isobutanol and 0.043 equivalents of p-toluenesulfonic acid monohydrate were added thereto, and then stirred at 70 ° C for 1 day. Then, molecular sieves 4A (2.0 equivalents) were added to the reaction mixture, and the mixture was stirred at 120 ° C for 1 day. After cooling to room temperature, the insoluble matter was filtered off with ethyl acetate, and 0.5 mol / L sodium hydroxide aqueous solution was added. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 143.8 mg of 2-ethyl-3-isobutoxy-6,6-dimethylcyclohex-2-ene-1-one. Lithium (14 equivalents) was added to a tetrahydrofuran solution of 143.8 mg of the obtained 2-ethyl-3-isobutoxy-6,6-dimethylcyclohex-2-ene-1-one and 1.2 equivalents of 1-bromo-15-methoxypentadecane (intermediate 5), and the mixture was stirred at 70 ° C for 4 hours. After the reaction mixture was cooled on ice, 0.5 mol / L hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 84.6 mg of the title compound.

[0732] Reference Example 15: Synthesis of 3-(15-methoxypentadecyl)-4,4-dimethyl-2-propylcyclohex-2-en-1-one (Compound 61)

[0733] Potassium hydroxide (1 equivalent), 24 mL of water and 1.5 equivalents of 1-iodopropane were added to a solution of 3.0 g of 4,4-dimethylcyclohexane-1,3-dione in 24 mL of ethanol, and the mixture was stirred at 70 ° C for 1 day. The reaction mixture was dried under reduced pressure and filtered with ethyl acetate. Thereafter, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (acetone / heptane) to obtain 868.5 mg of 4,4-dimethyl-2-propylcyclohexane-1,3-dione. Then, 868.5 mg of the obtained 4,4-dimethyl-2-propylcyclohexane-1,3-dione was dissolved in toluene, and 2.0 equivalents of isobutanol and 0.043 equivalents of p-toluenesulfonic acid monohydrate were added thereto, and then stirred at 70 ° C for 1 day. Then, molecular sieves 4A (2.0 equivalents) were added to the reaction mixture, and the mixture was stirred at 120 ° C for 1 day. After cooling to room temperature, the insoluble matter was filtered off with ethyl acetate, and 0.5 mol / L sodium hydroxide aqueous solution was added. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 723 mg of 3-isobutoxy-6,6-dimethyl-2-propylcyclohex-2-ene-1-one. Lithium (14 equivalents) was added to a tetrahydrofuran solution of 723 mg of the obtained 3-isobutoxy-6,6-dimethyl-2-propylcyclohex-2-ene-1-one and 1.2 equivalents of 1-bromo-15-methoxypentadecane (intermediate 5), and the mixture was stirred at 70 ° C for 4 hours. After the reaction mixture was cooled on ice, 0.5 mol / L hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain 78.1 mg of the title compound.

[0734] Reference Example 16: Synthesis of 2-isopropyl-3-(15-methoxypentadecyl)-4,4-dimethylcyclohex-2-en-1-one (Compound 62)

[0735] Potassium hydroxide (1 equivalent), 24 mL of water and 1.5 equivalents of 2-iodopropane were added to a solution of 3.0 g of 4,4-dimethylcyclohexane-1,3-dione in 44 mL of ethanol, and the mixture was stirred at 70°C for 1 day. The reaction mixture was dried under reduced pressure and filtered with ethyl acetate. Thereafter, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (acetone / heptane) to give 168.5 mg of 2-isopropyl-4,4-dimethylcyclohexane-1,3-dione. The obtained 2-isopropyl-4,4-dimethylcyclohexane-1,3-dione (168.5 mg) was dissolved in toluene, 2.0 equivalents of isobutanol and 0.043 equivalents of p-toluenesulfonic acid monohydrate were added thereto, and then stirred at 70°C for 1 day. Thereafter, molecular sieves 4A (2.0 equivalents) were added to the reaction mixture, and the mixture was stirred at 120°C for 1 day. After cooling to room temperature, the insoluble matter was filtered off with ethyl acetate, and 0.5 mol / L aqueous sodium hydroxide solution was added. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to give 70.2 mg of 3-isobutoxy-2-isopropyl-6,6-dimethylcyclohex-2-en-1-one. Lithium metal (14 equivalents) was added to a tetrahydrofuran solution of 70.2 mg of the obtained 3-isobutoxy-2-isopropyl-6,6-dimethylcyclohex-2-en-1-one and 1.2 equivalents of 1-bromo-15-methoxypentadecane (intermediate 5), and the mixture was stirred at 70°C for 4 hours. After cooling the reaction mixture on ice, 0.5 mol / L hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate / heptane) to give 28.5 mg of the title compound.

[0736] Reference Example 17: Synthesis of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohexan-1-one (Compound 63)

[0737] Carbon-supported palladium (10 mg) was added to a solution of 100 mg of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one (Example 14) in 5 mL of ethanol, and the mixture was stirred under a hydrogen gas atmosphere for 4 hours. The reaction mixture was filtered with celite, and evaporated under reduced pressure to give 68.9 mg of the title compound.

[0738] Reference Example 18: Synthesis of 2-(15-methoxypentadecyl)-1,3,3-trimethylcyclohex-1-ene (Compound 64)

[0739] Under ice-cooling temperature, 240mg sodium borohydride is added in the mixed solution of 1mL acetonitrile, 1mL trifluoroacetic acid and 1mL acetic acid.Then, add 200mg 3-(15-methoxy pentadecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (embodiment 14) in 0.4mL dichloromethane, and under ice-cooling temperature, mixture is stirred 2 hours.Saturated sodium bicarbonate aqueous solution is added in reaction mixture, mixture is extracted with dichloromethane, then uses anhydrous sodium sulfate drying.After filtering out desiccant, the residue obtained after reduced pressure evaporation passes through silica gel column chromatography (chloroform / hexane) purifying, to obtain 138mg title compound.

[0740] Reference Example 19: Synthesis of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-ol (Compound 65)

[0741] Under ice-cooling temperature, 148mg of cerium chloride heptahydrate and 15mg of sodium borohydride are added to a solution of 150mg of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (Example 14) in 3mL of methanol, and the mixture is stirred for 30 minutes, then stirred at room temperature. Saturated aqueous ammonium chloride solution is added to the reaction mixture, and the resulting mixture is extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering out the desiccant, the residue obtained after evaporation under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 130mg of the title compound.

[0742] Reference Example 20: Synthesis of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-amine (Compound 66)

[0743] Phthalimide (154mg) and 275mg triphenylphosphine are added to a solution of 200mg 3- (15- methoxypentadecyl) -2,4,4- trimethylcyclohex-2-ene-1-ol (reference example 19) in 4mL tetrahydrofuran. Then, at ice-cooling temperature, 204 μL diisopropyl azodicarboxylate are added thereto, and the mixture is stirred overnight at room temperature. The residue obtained after the reaction mixture is evaporated under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane). Then, 4mL ethanol and 107 μL hydrazine monohydrate are added thereto, the mixture is stirred and heated overnight. After the reaction mixture is cooled to room temperature, the precipitate is filtered off, and the residue obtained by evaporating the filtrate under reduced pressure is purified by silica gel column chromatography (ethyl acetate / hexane), to obtain 69.1mg title compound.

[0744] Reference Example 21: Synthesis of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one oxime (Compound 67)

[0745] Water (4 mL), 550 mg of hydroxylamine hydrochloride and 1.09 g of potassium carbonate were added to a solution of 500 mg of 3- (15-methoxypentadecyl) -2,4,4-trimethylcyclohex-2-ene-1-one (Example 14) in 8 mL of ethanol, and the mixture was stirred in a microwave apparatus at 70 ° C for 2 hours and 30 minutes. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by NH silica gel column chromatography (ethyl acetate / dichloromethane) to obtain 361 mg of the title compound.

[0746] Reference Example 22: Synthesis of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one O-methyloxime (Compound 68)

[0747] O-methylhydroxylamine hydrochloride (198 mg) and 329 mg of potassium carbonate were added to a solution of 300 mg of 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-ene-1-one (Example 14) in 3 mL of ethanol, and the mixture was stirred in a microwave apparatus at 70 ° C for 2 hours and 30 minutes. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the residue obtained after evaporation under reduced pressure was purified by silica gel column chromatography (dichloromethane / hexane) to obtain 151 mg of the title compound.

[0748] Table 1

[0749]

[0750] Table 2

[0751]

[0752] Table 3

[0753]

[0754] Table 4

[0755]

[0756] Table 5

[0757]

[0758] Table 6

[0759]

[0760] Table 7

[0761]

[0762] Test Example 1: Pharmacokinetics

[0763] The required amount of compound was weighed and a drug suspension was prepared in 0.5% hydroxypropylmethylcellulose. The number of rats in each group was 2, and each drug suspension was orally administered to each male rat (Crl:CD(SD)) using an oral probe (the dose of the compound was 10 mg / kg). At each blood sampling point (0.5, 1, 2, 4, 8, and 24 hours after administration), blood was collected from the jugular vein using a syringe and needle (the anticoagulant was sodium heparin). The collected blood was centrifuged (13000 rpm, 2 minutes, 4°C) to prepare plasma, and then deproteinized. Thereafter, the concentration of the compound in plasma was measured by LC / MS / MS (LCMS-8040 (Shimadzu Corporation) or API 4000 (ABSciex), LC:30-A and 20-A series (Shimadzu Corporation) or Waters Acquity (Waters Corporation)).

[0764] As shown in Table 8, the area under the curve (AUC) of compound 24 was confirmed to be more than 1900 times higher than that of compound 4, and the maximum blood concentration C max In addition, compared with compound 4, it was confirmed that the AUC of the compound wherein R1 is -CH2OR4, the compound wherein R1 is -CH2OCON(CH3)2, the compound wherein R1 is -CONHR6, and the compound wherein R1 is cyano were increased by at least 100 times, 1000 times, 10 times, and 1900 times, respectively. max The pharmacokinetics of the compounds represented by formula (I) are unexpectedly high compared to the known compound 4.

[0765] Table 8

[0766] The AUC and C of each compound max

[0767]

[0768] Experimental Example 2: Evaluation of drug efficacy in a diabetic rat model

[0769] To examine the effects of the compound in a diabetic model, bladder function was analyzed by cystometry according to the method of Saitoh et al. (European Journal of Pharmacology 501 (2004) 143-149).

[0770] A streptozotocin (STZ) solution was prepared by dissolving STZ in a citrate buffer solution (0.1 M citric acid, pH 4.2) to a concentration of 32.5 mg / mL and intraperitoneally administered (65 mg / kg) to SD rats to induce a DM model. The same procedure was performed on sham rats, except that a citrate buffer solution was used instead of the STZ solution.

[0771] On the second day after model preparation and after 4 weeks, blood samples were collected from the tail vein under the condition that the rats were awake to measure blood glucose levels. Blood glucose levels were measured using AntSense III (Horiba Corporation). On the second day after model preparation and after 4 weeks, individuals with blood glucose levels above 300 mg / dL were determined to be DM models established and used for subsequent operations.

[0772] The administration of the test substance (compound 4 or 24) starts from the second day after model preparation. The vehicle or solution for administering the compound was orally administered twice every day in the morning and evening with a volume of 10mL / kg for 4 weeks. On the second day of the last administration of the test substance, the abdomen of each rat was incised under isoflurane anesthesia, and a catheter (PE-90, Becton Dickinson and Company) was inserted into the bladder top for intravesical pressure measurement. After closing the abdomen, the rat was placed in a cage. At least 30 minutes after releasing isoflurane anesthesia, urethane solution (0.8g / kg) was subcutaneously injected.

[0773] A pressure transducer (DX-360, Nihon Kohden Kogyo Co., Ltd.) and an infusion pump (TE-331S, Terumo Corporation) were connected to the other end of the catheter inserted into the bladder via a three-way valve. The intravesical pressure during continuous intravesical infusion of saline solution (infusion rate: 12 mL / hr) was measured using a pressure transducer and a polygraph (AP-641G, Nihon Kohden Kogyo Co., Ltd.) and continuously recorded on a computer using a PowerLab (ML866, AD Instruments) (sampling rate: 20 / second). Urinary output was automatically measured using an electronic balance (GX-200, A&D Co., Ltd.) directly below the holding cage and continuously recorded on a computer using a PowerLab (sampling rate: 20 / second). Urinary function parameters were recorded and analyzed using PowerLab analysis software Chart 5 (version 5.5.6, AD Instruments).

[0774] Immediately after urethane anesthesia, a continuous intravesical infusion of saline solution (infusion rate: 3 mL / hr) was performed for approximately 1.5 hours to familiarize the rats with the cystometry environment. After acclimation to the cystometry environment, urinary function (intravesical bladder pressure, voided volume, and residual urine volume) was measured by cystometry (infusion rate: 12 mL / hr).

[0775] like Figure 1 As shown, compared with compound 4, compound 24 was found to have significant pharmaceutical efficacy.

[0776] Test Example 3: Measurement of nerve growth stimulation effect

[0777] To evaluate the nerve growth stimulating effect, neurite content (ratio of cells containing neurites) and neurite length (neurite length) were analyzed according to the method of Topalli et al. (Brain Research 1030 (2004), pp. 116-124).

[0778] ND3 neuronal cell line (European Collection of Authentic Cell Cultures) was seeded in 24-well plates containing 10% fetal bovine serum (0.6 x 10 4 The cells were cultured in a DMEM culture medium containing 100 cells / 1 mL). After 24 hours, the culture medium of the inoculated cells was removed, and a solution in which the compound of the present invention diluted sequentially in dimethyl sulfoxide (DMSO) was adjusted to a final concentration of 0.1% in DMEM containing 0.1% bovine serum albumin was added to the cells (evaluated repeatedly). After being added to 6 hours, the ratio of neurite-containing cells (the number of cells with neurites longer than the cell body diameter / the number of total cells) and the neurite length of each cell were analyzed. The number of total cells, the ratio of neurite-containing cells, and the neurite length of each cell were analyzed using the MetaMorph neurite growth application module (Molecular Devices Japan K.K.). The number of cells was defined as the relative cell number, and the number of cells in each well containing DMSO was taken as 1. When the maximum activity of 3-(15-methoxypentadecanyl)-2,4,4-trimethylcyclohex-2-ene-1-one (compound 24) in each test was defined as 1, the relative activity of each compound was as shown in Table 9. For compounds tested multiple times, average values ​​are shown. Data where the number of cells was 0.5 or more were also used. Therefore, if the number of cells was less than 0.5, the neurite length per cell and the ratio of neurite-containing cells were defined as "-".

[0779] As shown in Table 9, when Compound 24 was added in an amount of 1 to 100 μM, the relative cell number was 0.5 or more.

[0780] Table 9

[0781] Relative cell number at each concentration of compound 24

[0782]

[0783] As shown in Tables 10 to 13, the compounds of the present disclosure were confirmed to have excellent nerve growth stimulating effects. In addition, some compounds were confirmed to have nerve growth stimulating effects equal to or greater than that of Compound 24.

[0784]

[0785]

[0786]

[0787]

[0788] The results of this test indicate that the compounds of the present disclosure have a nerve growth stimulating effect.

Claims

1. A compound represented by the following formula (I) or a salt thereof: in X represents -CH2-CH2, R1 represents -CH2OR4, -CH2OCON(R5)2, -CONHR6 or cyano, R2 are the same or different and each represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom or a methyl group, R4 represents C m H 2m+1 , R5 are the same or different and each represents a hydrogen atom or a methyl group, R6 represents a hydrogen atom or a methyl group, m represents an integer from 1 to 14, and n represents an integer from 11 to 15, Provided that when R4 is a linear alkyl group, the sum of m and n is an integer from 12 to 17, and when R4 is a branched alkyl group, m b The sum of m and n is an integer from 12 to 17, where m b is the number of carbon atoms in the longest straight chain of a branched alkyl group.

2. A compound represented by the following formula (I) or a salt thereof: in X represents -CH2-CH2, R1 represents -CH2OR4, -CH2OCON(R5)2, -CONHR6 or cyano, R2 are the same or different and each represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom or a methyl group, R4 represents C m H 2m+1 , R5 are the same or different and each represents a hydrogen atom or a methyl group, R6 represents a hydrogen atom or a methyl group, m represents an integer from 1 to 14, and n represents an integer from 11 to 14, Provided that when R4 is a linear alkyl group, the sum of m and n is an integer from 12 to 15, and when R4 is a branched alkyl group, m b The sum of m and n is an integer from 12 to 15, where m b is the number of carbon atoms in the longest straight chain of a branched alkyl group.

3. A compound represented by the following formula (I) or a salt thereof: in X represents -CH2-CH2, R1 represents -CH2OR4, -CH2OCON(CH3)2, -CONHR6 or cyano, R2 are the same or different and each represents a hydrogen atom or a methyl group, and R3 represents a hydrogen atom or a methyl group, n represents an integer from 11 to 14, R4 represents a methyl group, an ethyl group, an n-propyl group or an isopropyl group, provided that when R4 is a methyl group, n represents an integer from 11 to 14, when R4 is an ethyl group or an isopropyl group, n represents an integer from 11 to 13, and when R4 is an n-propyl group, n is 11 or 12, and R6 represents a hydrogen atom or a methyl group.

4. The compound according to claim 1 or a salt thereof, Wherein in formula (I), R1 represents -CH2OR4, -CONH2 or cyano, R2 are the same or different and each represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom or a methyl group, provided that when R3 is a hydrogen atom, each R2 is a hydrogen atom, and when R3 is a methyl group, R2 are the same or different and each represents a hydrogen atom or a methyl group, n represents an integer from 11 to 14, and R4 represents a methyl group, an ethyl group, an n-propyl group or an isopropyl group, provided that when R4 is a methyl group, n represents an integer from 11 to 14, when R4 is an ethyl group or an isopropyl group, n represents an integer from 11 to 13, and when R4 is an n-propyl group, n is 11 or 12.

5. The compound or salt thereof according to claim 1, wherein in formula (I), X represents -CH2-CH2-, R1 represents -CH2OR4 or -CONH2, Each R2 is a methyl group, R3 represents a methyl group, n represents an integer from 11 to 14, and R4 represents a methyl group, an ethyl group or an isopropyl group, provided that when R4 is a methyl group, n represents an integer of 11 to 14, and when R4 is an ethyl group or an isopropyl group, n represents an integer of 11 to 13.

6. The compound or a salt thereof according to claim 1, which is any one of the following compounds (1) to (10): (1) 3-(12-methoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one, (2) 3-(12-ethoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one, (3) 3-(12-isopropoxydodecyl)-2,4,4-trimethylcyclohex-2-en-1-one, (4) 3-(13-methoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one, (5) 3-(13-ethoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one, (6) 3-(13-isopropoxytridecyl)-2,4,4-trimethylcyclohex-2-en-1-one, (7) 3-(14-methoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one, (8) 3-(14-ethoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one, (9) 3-(14-isopropoxytetradecyl)-2,4,4-trimethylcyclohex-2-en-1-one, and (10) 3-(15-Methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one. 7 . The compound or a salt thereof according to claim 1 , wherein the compound is 3-(15-methoxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one. A neurite growth agent comprising the compound or a salt thereof according to any one of claims 1 to 7 as an active ingredient. 9 . A therapeutic agent for a neurodegenerative disease, comprising the compound or a salt thereof according to claim 1 as an active ingredient. 10 . A therapeutic agent for lower urinary tract dysfunction, comprising the compound or a salt thereof according to claim 1 as an active ingredient.

11. A pharmaceutical composition comprising The compound or salt thereof according to any one of claims 1 to 7, and Pharmaceutical carrier.

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