JP2019055913A - Lithocholic acid derivative having vitamin D activity - Google Patents

Abstract

To provide a novel lithocholic acid derivative having vitamin D activity, and to provide medicines, vitamin D receptor activating agents, and prophylactic and/or therapeutic agents of vitamin D receptor associated diseases which comprise the lithocholic acid derivative.SOLUTION: The present invention provides a lithocholic acid derivative having a hydroxyalkyl group at a position 3, a salt thereof, or a prodrug thereof.SELECTED DRAWING: None

Description

  The present invention relates to a lithocholic acid derivative having vitamin D activity. The present invention further relates to a pharmaceutical, a vitamin D receptor activator, and a preventive and / or therapeutic agent for vitamin D receptor-related diseases comprising the lithocholic acid derivative.

  In vitamin D, 1α, 25-dihydroxyvitamin D3, which is a metabolic activator, binds to vitamin D receptor (VDR) and controls the expression of specific genes. By controlling the expression of this gene, vitamin D plays important physiological functions such as maintaining calcium concentration in the blood, bone formation, immune function, and cell differentiation / proliferation control. So far, a large number of VDR ligands have been developed for the purpose of developing therapeutic agents for osteoporosis, psoriasis and cancer, and some of them have been clinically applied as pharmaceuticals. Many of the existing VDR ligands have a secosteroid skeleton in the same manner as natural 1α, 25-dihydroxyvitamin D3. The secosteroid skeleton is useful for the development of derivatives having high activity, but generally has low chemical stability, requires complicated synthesis, and has a limited variety of pharmaceutical applications for vitamin D action. Therefore, development of a VDR ligand having a non-secosteroid type skeleton is desired, but there are few reports on such a non-secosteroid type VDR ligand.

  Lithocholic acid has been found to be an endogenous ligand for VDR, but the VDR affinity of lithocholic acid is very weak and the physiological significance is unknown. Patent Document 1 describes that lithocholic acid propionate, which is a lithocholic acid derivative, can activate CDR, and Non-Patent Document 1 describes lithocholic acid acetate and lithocholic acid propionate.

Japanese Patent No. 5283043

Masuno et al, Journal of Lipid Research, Volume 54, 2013, pages 2206-2213

  As described above, there are reports of lithocholic acid derivatives having vitamin D3 activity, but existing lithocholic acid derivatives have weak affinity for vitamin D3 receptors, and vitamin D3 activity is not sufficient. An object of the present invention is to provide a novel lithocholic acid derivative having sufficient vitamin D3 activity. Furthermore, this invention makes it the subject which should be solved to provide the pharmaceutical containing the said lithocholic acid derivative, a vitamin D receptor activator, and the prevention and / or treatment agent of a vitamin D receptor related disease.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors are a lithocholic acid derivative having a hydroxyalkyl group at the 3-position, and the main chain of the hydroxyalkyl group at the 3-position has 2 or more carbon atoms. The lithocholic acid derivative was found to have excellent vitamin D3 activity, and the present invention was completed.

（式中、Ｒ¹及びＲ²はそれぞれ独立して、水素原子又は炭素数１から６のアルキル基を示す。Ｒ³、Ｒ⁴、Ｒ⁵及びＲ⁶はそれぞれ独立して、水素原子又は炭素数１から６のアルキル基を示す。ｎは１から３の整数を示す。）
［２］ Ｒ¹及びＲ²がメチル基である、［１］に記載の化合物、その塩、又はそのプロドラッグ。
［３］ Ｒ³、Ｒ⁴、Ｒ⁵及びＲ⁶が水素原子である、［１］又は［２］に記載の化合物、その塩、又はそのプロドラッグ。
［４］ ｎが１である、［１］から［３］の何れか一に記載の化合物、その塩、又はそのプロドラッグ。
［５］ 下記の何れかの化合物、その塩、又はそのプロドラッグ。

［６］ ［１］から［５］の何れか一に記載の化合物、その塩、又はそのプロドラッグを含む医薬。
［７］ ［１］から［５］の何れか一に記載の化合物、その塩、又はそのプロドラッグを含む、ビタミンＤ受容体活性化剤。
［８］ ［１］から［５］の何れか一に記載の化合物、その塩、又はそのプロドラッグを含む、ビタミンＤ受容体関連疾患の予防及び／又は治療剤。 According to the present invention, the following inventions are provided.
[1] A compound represented by the following general formula (I), a salt thereof, or a prodrug thereof.

(In the formula, R ¹ and R ² each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R ³ , R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom or carbon. And represents an alkyl group of 1 to 6. n represents an integer of 1 to 3.)
[2] The compound according to [1], a salt thereof, or a prodrug thereof, wherein R ¹ and R ² are methyl groups.
[3] The compound, salt or prodrug thereof according to [1] or [2], wherein R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen atoms.
[4] The compound according to any one of [1] to [3], wherein n is 1, a salt thereof, or a prodrug thereof.
[5] Any of the following compounds, salts thereof, or prodrugs thereof.

[6] A medicament comprising the compound according to any one of [1] to [5], a salt thereof, or a prodrug thereof.
[7] A vitamin D receptor activator comprising the compound according to any one of [1] to [5], a salt thereof, or a prodrug thereof.
[8] A preventive and / or therapeutic agent for a vitamin D receptor-related disease, comprising the compound according to any one of [1] to [5], a salt thereof, or a prodrug thereof.

The present invention further provides the following inventions.
[9] A method for activating a vitamin D receptor, comprising administering the compound according to any one of [1] to [5], a salt thereof, or a prodrug thereof to a mammal including a human.
[10] Prevention and / or prevention of a vitamin D receptor-related disease, comprising administering the compound according to any one of [1] to [5], a salt thereof, or a prodrug thereof to a mammal including a human. Method for treatment.
[11] The compound according to any one of [1] to [5], a salt thereof, or a prodrug thereof for use in activation of a vitamin D receptor.
[12] The compound according to any one of [1] to [5], a salt thereof, or a prodrug thereof for use in the prevention and / or treatment of a vitamin D receptor-related disease.
[13] Use of the compound according to any one of [1] to [5], a salt thereof, or a prodrug thereof for the manufacture of a medicament.
[14] Use of the compound according to any one of [1] to [5], a salt thereof, or a prodrug thereof for the production of a vitamin D receptor activator.
[15] Use of the compound according to any one of [1] to [5], a salt thereof, or a prodrug thereof for the manufacture of an agent for preventing and / or treating a vitamin D receptor-related disease.

  The compounds of the present invention are novel lithocholic acid derivatives having sufficient vitamin D3 activity. The compound of the present invention is useful as a pharmaceutical agent such as a vitamin D receptor activator and a preventive and / or therapeutic agent for vitamin D receptor-related diseases. In addition, since the compound of the present invention does not have a secosteroid skeleton, it generally has higher chemical stability than a compound having a secosteroid skeleton.

FIG. 1 shows a dose response curve of differentiation-inducing action on HL-60 cells.

（式中、Ｒ¹及びＲ²はそれぞれ独立して、水素原子又は炭素数１から６のアルキル基を示す。Ｒ³、Ｒ⁴、Ｒ⁵及びＲ⁶はそれぞれ独立して、水素原子又は炭素数１から６のアルキル基を示す。ｎは１から３の整数を示す。）
ステロイド骨格の３位の置換基（即ち、ＨＯＣ（Ｒ¹）（Ｒ²）（ＣＨ₂）_n−で示される基）の立体配置は特に限定されず、α置換体又はβ置換体の何れでもよい。 Hereinafter, the present invention will be described more specifically.
The compound of the present invention is represented by the following general formula (I).

(In the formula, R ¹ and R ² each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R ³ , R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom or carbon. And represents an alkyl group of 1 to 6. n represents an integer of 1 to 3.)
The configuration of the substituent at the 3-position of the steroid skeleton (that is, the group represented by HOC (R ¹ ) (R ² ) (CH ₂ ) _n —) is not particularly limited, and any of α-substituted or β-substituted Good.

  In the present specification, the alkyl group having 1 to 6 carbon atoms may be linear, branched, cyclic, or a combination thereof. The alkyl group having 1 to 6 carbon atoms is not particularly limited, but is methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropylmethyl group, n-butyl group, sec-butyl group, tert-butyl group, cyclobutyl. Group, cyclobutylmethyl group, cyclopentyl group, cyclohexyl group and the like. Among them, a methyl group and an ethyl group can be preferably exemplified, and a methyl group is particularly preferable.

R ¹ and R ² may independently be the same group or different groups, but are preferably the same group. It is particularly preferred that both R ¹ and R ² are methyl groups.
R ³ , R ⁴ , R ⁵ and R ⁶ may each independently be the same group or different groups. R ³ , R ⁴ , R ⁵ and R ⁶ are particularly preferably all hydrogen atoms.
n represents an integer of 1 to 3, preferably 1 or 2, and more preferably 1.

  Specific examples of the compound of the present invention include the following compound 2 and compound 3, and among them, compound 2 is more preferable from the viewpoint of differentiation inducing action on HL-60 cells.

  The compound represented by the general formula (I) may have one or more asymmetric carbons, but any optically active substance based on the asymmetric carbon, a stereoisomer such as a diastereoisomer, a stereo Any mixture of isomers, racemates and the like are included in the scope of the present invention.

  The compound represented by the general formula (I) may exist in the form of a salt such as an acid addition salt or a base addition salt, and these are also included in the scope of the present invention. Examples of acid addition salts include mineral salts such as hydrochloride, hydrobromide, sulfate, and nitrate, p-toluenesulfonate, methanesulfonate, oxalate, tartrate, maleate, and the like. Examples of base addition salts include metal salts such as sodium salt, potassium salt, magnesium salt and calcium salt, organic amine salts such as ammonium salt, triethylamine salt and ethanolamine salt. Can be mentioned. In addition to these, amino acid salts such as glycine salts are also included in the scope of the present invention.

  The compound represented by formula (I) may be a prodrug. After being administered to a living body, the prodrug becomes a pharmaceutically active compound by the action of an enzyme or metabolic hydrolysis. The prodrug may be any acid derivative known to those skilled in the art, for example, an ester produced by the reaction of a compound represented by the general formula (I) with an appropriate alcohol, represented by the general formula (I) Examples of reduced forms of amides and carbosyl groups produced by reacting a compound with an appropriate amine include 24-alcohol compounds, but are not particularly limited.

  The compound represented by the general formula (I), a salt thereof and a prodrug thereof may exist in the form of an adduct (hydrate or solvate) with water or various solvents. It is within the scope of the present invention. Examples of the solvent in the solvate include methanol, ethanol, acetonitrile and the like, but are not particularly limited. The adduct (hydrate or solvate) may be a single product or a mixture of plural types.

  Arbitrary crystalline forms of the compounds of general formula (I), their salts and their prodrugs are also within the scope of the present invention.

  The production methods of typical compounds (the above compound 2 and the above compound 3) included in the general formula (I) are described in detail and specifically in the examples of the present specification. A person skilled in the art refers to the specific production methods described in the examples, appropriately selects raw material compounds, reaction conditions, reagents, etc., and adds appropriate modifications or alterations to these methods as necessary. It is possible to produce compounds encompassed by general formula (1).

  For example, the synthesis of compound 2 is not particularly limited, but can be carried out according to the method described in Example 1 described later. Compound 11 used as a starting material in Example 1 is described in Reference Example 1 described later. According to this method, lithocholic acid can be synthesized as a starting material. Compound 11 is obtained by reacting compound 11 with sodium borohydride (61.3 mg, 1.62 mmol) in a suitable solvent (eg, anhydrous methanol). Compound 16 is obtained by reacting compound 16 with p-toluenesulfonyl chloride such as pyridine. Compound 17 is obtained by reacting compound 17 with sodium cyanide in an appropriate solvent (for example, DMSO and the like).

Compound 18 is reacted with methyllithium in an appropriate solvent (for example, diethyl ether and the like), and further, hydrochloric acid is added to obtain compound 19. Here, by using another alkyl lithium instead of methyl lithium, a compound in which R ¹ and / or R ² in the general formula (I) is other than a methyl group can be synthesized.

Compound 19 is reacted with methyllithium in an appropriate solvent (for example, diethyl ether and the like), and further ammonium chloride is added to obtain compound 20. Here, a compound in which R ¹ or R ² is other than a methyl group in the general formula (I) is synthesized by using a reducing agent such as sodium borohydride or other alkyl lithium instead of methyl lithium. be able to.

  Compound 21 is obtained by reacting compound 20 with palladium hydroxide in an appropriate solvent (for example, methanol and the like) and replacing with hydrogen. Compound 21 can be obtained by reacting Jones reagent (chromium oxide (VI) dissolved in water and concentrated sulfuric acid) in a suitable solvent (for example, acetone).

  Similarly, the synthesis of Compound 3 is not particularly limited, but can be performed according to the method described in Example 2 described later.

  The compounds of the invention can bind to vitamin D receptor (VDR) and activate VDR. Whether the compound of the present invention binds to and activates the vitamin D receptor (VDR) can be verified by assaying the cell differentiation inducing action on human acute promyelocytic leukemia cells HL-60. . The assay for cell differentiation induction is described in Test Example 1 below, as described in “4.3.1. Assay of HL-60 cell differentiation-inducing” in Fujii et al. Bioorg. Med. Chem. 22 (2014) 5891-5901. It can be performed by a method according to the method described in “activity”.

  In addition to VDR, lithocholic acid has the effect of activating farnesoid X receptor (FXR) and G protein-coupled bile acid receptor (GPBAR1) (also referred to as TGR5), which are nuclear receptors. It is known. Therefore, the compound of the present invention may bind to FXR and / or GPBAR1 and activate them in addition to VDR.

  As described above, the compound represented by the formula (I) of the present invention has an action of activating VDR, and may further have an action of activating FXR and GPBAR1. Therefore, a medicament containing the compound of the present invention represented by formula (I), a salt thereof, or a prodrug thereof as an active ingredient is useful as a vitamin D receptor activator or a vitamin D agonist. The compound of the present invention represented by the formula (I), a salt thereof, or a prodrug thereof can be used as a prophylactic and / or therapeutic agent for vitamin D receptor-related diseases. Vitamin D receptor related diseases include, for example, rickets, osteomalacia, osteoporosis, bone diseases based on kidney disorders, hypoparathyroidism, skin diseases such as psoriasis, cancer (leukemia, breast cancer, prostate cancer, Colorectal cancer), autoimmune diseases (such as rheumatoid arthritis, systemic lupus lupus erythematosis), and infectious diseases (such as tuberculosis), but are not particularly limited.

  FXR has been identified as a nuclear receptor that responds to farnesol, an intermediate in cholesterol biosynthesis, and bile acid molecules such as chenodeoxycholic acid bind to FXR and recruit transcriptional coupling factors, thereby transcribing the FXR target gene. Has been reported to enhance. As a FXR target gene, BSEP (bile salt export pump) responsible for excretion of bile acids into bile is known. FXR is thought to improve the intrahepatic cholestasis by promoting the excretion of bile acids from the liver by enhancing the gene expression of BSEP. Further, FXR is considered to play an important function in lipid metabolism and sugar metabolism. FXR-related diseases include dyslipidemia, cholesterol absorption disease, atherosclerosis, peripheral obstructive disease, ischemic stroke, diabetes (particularly type II diabetes), metabolic syndrome, diabetic nephropathy, obesity, cholesterol gallstone disease Intrahepatic cholestasis / hepatic fibrosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, psoriasis, cancer, osteoporosis, Parkinson's disease, Alzheimer's disease, etc. are not particularly limited. The medicament of the present invention can be used as a preventive and / or therapeutic agent for the FXR-related diseases described above.

The biological effects of GPBAR1 include monocyte / macrophage migration / activation, control of dendritic cell differentiation, control of lymphocyte activation, control of inflammation growth and differentiation, control of cytokine production and / or release, pro-inflammation Control of production and / or release of sex mediator, control of immune response, GLP (glucagon-like peptide) -1 secretion, insulin secretion, appetite, pancreas regeneration, pancreatic β-cell differentiation, pancreatic β-cell proliferation, insulin resistance, energy consumption, etc. It has been known. GPBAR1-related diseases include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, transplant rejection, cancer, neurological disorders, cardiovascular disorders, type II diabetes, obesity and the like.
The medicament of the present invention can also be used as a preventive and / or therapeutic agent for the above-described GPBAR1-related diseases.

  As an active ingredient of the medicament, vitamin D receptor activator and vitamin D receptor-related disease of the present invention, a compound represented by the general formula (I), a salt thereof, or a prodrug thereof is used. Can be used. As the medicament, vitamin D receptor activator and vitamin D receptor related disease preventive and / or therapeutic agent of the present invention, the active ingredient may be administered as it is. It is desirable to prepare and administer a pharmaceutical composition containing one or more pharmaceutical additives.

  The administration route of the medicament, the vitamin D receptor activator and the preventive and / or therapeutic agent for vitamin D receptor related diseases of the present invention is not particularly limited. Oral administration or parenteral administration may be used. Examples of parenteral administration include, but are not limited to, intravenous, intramuscular, subcutaneous or intradermal injection, rectal administration, and transmucosal administration.

Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups.
Examples of the pharmaceutical composition suitable for parenteral administration include injections, drops, suppositories, inhalants, nasal drops, transdermal absorption agents, ointments, creams, and patches.

  Examples of the additives for preparation include excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or solubilizers, isotonic agents, A pH adjuster, a stabilizer, a propellant, an adhesive, and the like can be used, and an appropriate one can be selected and used according to the form of the pharmaceutical composition.

  Pharmaceutical additives that can be used in the preparation of formulations for oral administration include, for example, excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; carboxymethylcellulose, starch, carboxymethylcellulose calcium, etc. Disintegrating agents or disintegrating aids; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; coatings such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, or titanium oxide Agents: Bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat can be used.

  Examples of pharmaceutical additives that can be used for the preparation of pharmaceutical preparations for injection or infusion include aqueous solutions such as distilled water for injection, physiological saline, propylene glycol, surfactants, etc. Agents or solubilizers; isotonic agents such as glucose, sodium chloride, D-mannitol, glycerin; pharmaceutical additives such as pH regulators such as inorganic acids, organic acids, inorganic bases or organic bases can be used .

The medicament, vitamin D receptor activator and vitamin D receptor-related disease preventive and / or therapeutic agent of the present invention can be administered to mammals such as humans.
The dosage of the medicament, vitamin D receptor activator and vitamin D receptor related disease preventive and / or therapeutic agent of the present invention is appropriately determined according to conditions such as patient age, sex, weight, symptoms, and administration route. Generally, the amount of active ingredient per day for an adult is in the range of about 10 μg / kg to 5000 mg / kg, preferably in the range of about 100 μg / kg to 1000 mg / kg. . The above dose of the drug may be administered once a day, or may be divided into several times (for example, about 2 to 4 times).

  In addition, the compound represented by the general formula (I) of the present invention, a salt thereof or a prodrug thereof can also be used as an experimental reagent. By treating a cell, tissue, organ or animal individual having a vitamin D receptor with a compound represented by the general formula (I) of the present invention, a salt thereof or a prodrug thereof, the vitamin D receptor can be activated. it can. Examples of cells having a vitamin D receptor include, but are not limited to, kidney, intestinal mucosa, bone marrow, bone, mammary gland, skin, and nerve-derived cells. In addition, recombinant cells obtained by introducing a vitamin D receptor gene into established animal cells can also be used. Examples of tissues and organs having vitamin D receptors include, but are not limited to, kidney, intestinal mucosa, bone marrow, lymphoid tissue, bone, mammary gland, skin, nerve and the like. Examples of animal individuals include mice, rats, hamsters, rabbits and chickens, but are not particularly limited. The activation of the vitamin D receptor can be confirmed by measuring expression induction of a VDR target gene (for example, CYP24), but is not particularly limited.

  The present invention will be specifically described by the following examples, but the present invention is not limited to the examples.

The abbreviations mean the following:
THF: Tetrahydrofuran DMF: N, N-dimethylformamide AcOEt: Ethyl acetate DMSO: Dimethyl sulfoxide DIBAL: Diisobutylaluminum hydride

Reference Example 1: Synthesis of Compound 1 Compound 1 was synthesized from lithocholic acid according to Scheme 1.

(1) Synthesis of Compound 4 Under an argon atmosphere, a solution of lithocholic acid (4.78 g, 0.013 mol) and p-toluenesulfonic acid monohydrate (237.6 mg, 1.4 mmol) in anhydrous dichloromethane (60.0 mL) at 0 ° C. The mixture was cooled, 3,4-dihydro-2H-pyran (4.0 mL, 0.044 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour and 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with dichloromethane, and the organic layer was washed with brine. After drying over anhydrous MgSO ₄ , the solvent was distilled off to obtain a mixture (8.90 g) of compound 4 and 4 ′ as a yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ4.72 (m, 1 H), 3.92 (m, 1 H), 3.62 (m, 1 H), 3.48 (m, 1 H), 2.40 (ddd, J = 15.7, 10.4, 5.2 Hz, 1 H), 2.26 (ddd, J = 15.8, 9.6, 6.4 Hz, 1 H), 2.00-0.95 (m, 32 H), 0.92 (d, J = 7.8 Hz, 3 H) , 0.91 (s, 3 H), 0.64 (s, 3 H).

(2) Synthesis of compound 5 In a THF (30 mL) solution containing lithium aluminum hydride (696.3 mg, 0.018 mol) in an argon atmosphere, a mixture of compound 4 and 4 '(equivalent to 8.38 g, 0.012 mol) in THF (60 mL) The solution was added and refluxed at 90 ° C. for 1 hour. The reaction solution was cooled to 0 ° C., ethyl acetate and water were added, the mixture was filtered through celite, extracted, and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (7.63 g). Purification by silica gel column chromatography (AcOEt / n-hexane = 1/6 → 1/4 → 1/0) gave colorless oily compound 5 (5.36 g, 0.012 mmol, quant. In 2 steps) .
¹ H NMR (400 MHz, CDCl ₃ ) δ4.72 (m, 1 H), 3.92 (m, 1 H), 3.61 (m, 3 H), 3.48 (m, 1 H), 1.96 (dt, J = 12.4, 3.2 Hz, 1 H), 1.91-0.85 (m, 33 H), 0.92 (d, J = 7.3 Hz, 3 H), 0.91 (s, 3 H), 0.64 (s, 3 H).

(3) Synthesis of Compound 6 Sodium hydride (60%, 1.41 g, 35.2 mmol) was washed with hexane, DMF (10.0 mL) was added, and the mixture was cooled to 0 ° C. A solution of compound 5 (2.24 g, 5.0 mmol) in DMF (15.0 mL) was added thereto, and the mixture was stirred at 0 ° C. for 30 minutes. Benzyl bromide (3.4 mL, 28.6 mmol) was added, and the mixture was stirred at 0 ° C. for 30 minutes, and then stirred at room temperature for 6 hours and 30 minutes. The reaction solution was cooled to 0 ° C., methanol was added and the mixture was stirred at 0 ° C. for 30 minutes, and then the solvent was distilled off. Ethyl acetate, saturated aqueous sodium hydrogen carbonate solution and water were added for extraction, and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (3.86 g). Purification by silica gel column chromatography (CHCl ₃ ) gave pale yellow oily compound 6 (2.07 g, 3.9 mmol, 77%).
¹ H NMR (400 MHz, CDCl ₃ ) δ7.34 (d, J = 4.6 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.72 (m, 1 H), 4.50 (s, 2 H) , 3.92 (m, 1 H), 3.62 (m, 1 H), 3.48 (m, 1 H), 3.44 (t, J = 6.6 Hz, 2 H), 1.95 (dt, J = 12.4, 3.2 Hz, 1 H), 1.91-0.85 (m, 33 H), 0.91 (s, 3 H), 0.91 (d, J = 6.4 Hz, 3 H), 0.63 (s, 3 H).

(4) Synthesis of Compound 7 To a mixed solution of Compound 6 (2.07 g, 3.9 mmol) in dichloromethane (5.0 mL) and methanol (15.0 mL), p-toluenesulfonic acid monohydrate (50.8 mg, 0.27 mmol) was added. The mixture was further stirred at room temperature for 7 hours. The solvent of the reaction solution was distilled off, ethyl acetate was added, and neutralized with 2 M aqueous sodium hydroxide solution. After adding water, the organic layer was taken and washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (1.44 g). Purification by silica gel column chromatography (AcOEt / n-hexane = 1/14 → 1/7 → 1/4) gave Compound 7 (1.28 g, 2.8 mmol, 73%) as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.34 (d, J = 4.6 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.62 (m, 1 H) , 3.44 (t, J = 6.6 Hz, 2 H), 1.96 (d, J = 11.9 Hz, 1 H), 1.91-0.86 (m, 27 H), 0.92 (s, 3 H), 0.91 (d, J = 5.5 Hz, 3 H), 0.64 (s, 3 H).

(5) Synthesis of compound 8
Recrystallized p-toluenesulfonyl chloride (3.09 g, 0.016 mol) was added to a solution of compound 7 (4.89 g, 0.011 mol) in anhydrous pyridine (40.0 mL) cooled to 0 ° C and stirred at 0 ° C for 1 hour 30 minutes. And stirred at room temperature for 4 hours. After cooling to 0 ° C., p-toluenesulfonyl chloride (2.06 g, 0.010 mol) was added, and the mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 16 hours and 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with water, 2 M hydrochloric acid and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain Compound 8 (5.98 g, 9.9 mmol, 91%) as a pale yellow solid.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 4.1 Hz, 4 H), 7.32 (d, J = 7.8 Hz, 2 H) , 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 4.46 (m, 1 H), 3.43 (t, J = 6.4 Hz, 2 H), 2.44 (s, 3 H), 2.05- 1.91 (m, 2 H), 1.89-0.85 (m, 26 H), 0.90 (d, J = 6.4 Hz, 3 H), 0.88 (s, 3 H), 0.62 (s, 3 H).

(6) Synthesis of Compound 9 Sodium cyanide (0.523 g, 10.7 mmol) was added to a solution of Compound 8 (2.07 g, 3.4 mmol) in anhydrous DMSO (20.0 mL), and the mixture was stirred at 80 ° C. for 6 hours and 30 minutes. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (1.58 g). Purification by silica gel column chromatography (CHCl ₃ / n-hexane = 1/1 → 3/2) gave Compound 9 (1.11 g, 2.4 mmol, 71%) as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.34 (d, J = 4.1 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.43 (dt, J = 6.6 , 2.1 Hz, 2 H), 3.01 (br, 1 H), 2.10-0.95 (m, 28 H), 1.00 (s, 3 H), 0.91 (d, J = 6.4 Hz, 3 H), 0.64 (s , 3 H).

(7) Synthesis of compound 10 Under an argon atmosphere, a solution of compound 9 (500.1 mg, 1.1 mmol) in anhydrous dichloromethane (25.0 mL) was cooled to -71 ° C, and 1.0 M DIBAL (hexane solution, 1.9 mL, 1.9 mmol) was added. In addition, the mixture was stirred at -68 ° C for 1 hour and 10 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (502.0 mg). Purification by flash column chromatography (CHCl ₃ / n-hexane = 3/4, 4/5) gave colorless oily compound 10 (263.4 mg, 0.57 mmol, 53%).
¹ H NMR (400 MHz, CDCl ₃ ) δ9.72 (s, 1 H), 7.34 (d, J = 4.6 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H) , 3.44 (dt, J = 6.6, 1.7 Hz, 2 H), 2.45 (br, 1 H), 2.10-0.80 (m, 28 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.88 (s , 3 H), 0.64 (s, 3 H).

(8) Synthesis of Compound 11 To a mixed solution of Compound 10 (856.0 mg, 1.7 mmol) in anhydrous THF (16.0 mL) and anhydrous methanol (20.0 mL) was added potassium carbonate (649.5 mg, 4.7 mmol), and the mixture was stirred at room temperature for 7 hours. did. The reaction solution was evaporated under reduced pressure, and extracted with chloroform and water. The organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (1.00 g). Purification by flash column chromatography (CHCl ₃ / n-hexane = 2/3) gave colorless oily compound 11 (497.5 mg, 1.07 mmol, 62% in 2 steps).
¹ H NMR (500 MHz, CDCl ₃ ) δ9.64 (d, J = 1.4 Hz, 1 H), 7.34 (d, J = 4.6 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 ( s, 2 H), 3.43 (dt, J = 6.7, 1.4 Hz, 2 H), 2.27 (dt, J = 12.5, 1.1 Hz, 1 H), 2.00-0.80 (m, 28 H), 0.96 (s, 3 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.64 (s, 3 H).

(9) Synthesis of Compound 12 Sodium dihydrogen phosphate dihydrate (380.0 mg, 2.4 mmol) and sodium chlorite (254.4 mg, 2.8 mmol) were dissolved in water (3.5 mL) to prepare an oxidation solution. To a mixed solution of compound 11 (111.1 mg, 0.24 mmol) 2-methyl-2-butene (2.0 mL) and t-butanol (8.0 mL) cooled to 0 ° C, an oxidizing solution (3.5 mL) was added, and The mixture was stirred at room temperature for 1 hour and 40 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a crude product (140.2 mg). Purification by silica gel column chromatography (AcOEt / n-hexane = 1/5 → 1/1 → 1/0) gave Compound 12 (101.6 mg, 0.21 mmol, 88%) as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.34 (d, J = 4.6 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.43 (t, J = 6.6 Hz, 2 H), 2.37 (tt, J = 12.4, 3.7 Hz, 1 H), 2.00-0.80 (m, 28 H), 0.94 (s, 3 H), 0.91 (d, J = 6.4 Hz, 3 H ), 0.64 (s, 3 H).

(10) Synthesis of Compound 13 A mixed solution of Compound 12 (70.9 mg, 0.15 mmol) in chloroform (0.6 mL) and methanol (4.0 mL) was cooled to 0 ° C., concentrated sulfuric acid (0.6 mL) was added, and 2 at 80 ° C. Reflux for hours. The reaction solution was evaporated under reduced pressure, water was added, extraction was performed with dichloromethane, and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain Compound 13 (66.6 mg, 0.13 mmol, 91%) as a yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.34 (d, J = 4.1 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.67 (s, 3 H) , 3.44 (t, J = 6.6 Hz, 2 H), 2.32 (tt, J = 12.4 3.9 Hz, 1 H), 2.00-0.80 (m, 28 H), 0.93 (s 3 H), 0.91 (d, J = 6.9 Hz, 3 H), 0.63 (s, 3 H).

(11) Synthesis of Compound 14 Under an argon atmosphere, a THF (4.0 mL) solution of Compound 13 (24.2 mg, 0.049 mmol) was cooled to −69 ° C., and 1.08 M methyllithium (diethyl ether solution, 0.10 mL, 0.108 mmol). And stirred at -69 ° C. for 1 hour and 20 minutes. 1.08 M tillithium (diethyl ether solution, 0.20 mL, 0.216 mmol) was added again, and the mixture was stirred at -69 ° C for 55 minutes. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was allowed to reach room temperature, water was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (23.1 mg). Purification by silica gel column chromatography (AcOEt / n-hexane = 1/5 → 1/0) gave Compound 14 (16.4 mg, 0.033 mmol, 68%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.34 (d, J = 4.1 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.43 (t, J = 6.6 , 1.4 Hz, 2 H), 2.00-1.93 (d, J = 11.9 Hz, 1 H), 1.93-1.75 (m, 3 H), 1.75-0.80 (m, 25 H), 1.18 (s, 6 H) , 0.93 (s, 3 H), 0.91 (d, J = 6.4 Hz, 3 H), 0.64 (s, 3 H).

(12) Synthesis of Compound 15 To a solution of compound 14 (9.8 mg, 0.020 mmol) in methanol (2.5 mL) was added palladium hydroxide (2 mg), followed by hydrogen substitution, and the mixture was stirred at room temperature for 1 hour and 50 minutes. The reaction solution was filtered through celite, and the solvent was evaporated to obtain white solid compound 15 (7.5 mg, 0.019 mmol, 94%).
¹ H NMR (400 MHz, CDCl ₃ ) δ3.61 (dt, J = 6.6, 2.5 Hz, 2 H), 1.96 (dt, J = 11.7, 2.9 Hz, 1 H), 1.94-1.77 (m, 3 H ), 1.71-0.85 (m, 25 H), 1.18 (s, 6 H), 0.93 (s, 3 H), 0.92 (d, J = 6.9 Hz, 3 H), 0.65 (s, 3 H).

(13) Synthesis of Compound 1 Chromium (VI) oxide (1.06 g) was dissolved in water (3.1 mL), and concentrated sulfuric acid (0.92 mL) was added under ice cooling to prepare Jones reagent. Jones reagent (0.1 mL) was added to a solution of compound 15 (11.4 mg, 0.028 mmol) in anhydrous acetone (6.0 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and acetone was distilled off, followed by extraction with diethyl ether, and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (12.6 mg). Purification by GPC (CHCl ₃ ) gave Compound 1 (7.9 mg, 0.019 mmol, 69%) as a white solid.
¹ H NMR (600 MHz, CDCl ₃ ) δ 2.39 (ddd, J = 15.6, 10.5, 5.1 Hz, 1 H), 2.24 (ddd, J = 16.1, 9.8, 6.2 Hz, 1 H), 1.95 (dt, J = 12.0, 3.2 Hz, 1 H), 1.91-1.76 (m, 4 H), 1.60-0.80 (m, 22 H), 1.18 (s, 6 H), 0.92 (s, 3 H), 0.91 (d , J = 5.4 Hz, 3 H), 0.64 (s, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) ・ ・ 179.82, 73.21, 56.58, 56.02, 49.86, 43.76, 42.87, 40.77, 40.26, 37.49, 35.96, 35.45, 35.03, 31.02, 30.89, 28.32, 28.02, 27.77, 27.28, 27.21, 26.65, 24.32, 24.12, 22.09, 20.95, 18.39, 12.20.

Example 1: Synthesis of Compound 2 Compound 2 was synthesized from Compound 11 according to Scheme 2.

(1) Synthesis of compound 16 A solution of compound 11 (330.5 mg, 0.71 mmol) in anhydrous methanol (60.0 mL) was cooled to 0 ° C, sodium borohydride (61.3 mg, 1.62 mmol) was added, and the mixture was stirred at 0 ° C for 40 min Stir. After the reaction solution was distilled off under reduced pressure, ethyl acetate and water were added for extraction, and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain colorless oily compound 16 (280.1 mg, 0.60 mmol, 84%).
¹ H NMR (500 MHz, CDCl ₃ ) δ7.34 (d, J = 4.6 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.48 (d, J = 6.0 Hz, 2 H), 3.43 (dt, J = 6.7, 2.6 Hz, 2 H), 1.95 (d, J = 12.3 Hz, 1 H), 1.93-1.77 (m, 3 H), 1.75-1.64 (m, 1 H), 1.64-0.85 (m, 24 H), 0.94 (s, 3 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.64 (s, 3 H).

(2) Synthesis of Compound 17 A solution of Compound 16 (48.4 mg, 0.10 mmol) in anhydrous pyridine (5.0 mL) was cooled to 0 ° C., and recrystallized p-toluenesulfonyl chloride (42.6 mg, 0.22 mmol) was added. The mixture was stirred at 30 ° C. for 30 minutes and at room temperature for 1 hour and 10 minutes. The reaction solution was cooled to 0 ° C., p-toluenesulfonyl chloride (43.0 mg, 0.23 mmol) was added, and the mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 6 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with water, 2 M hydrochloric acid and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain colorless oily compound 17 (60.5 mg, 0.098 mmol, 94%).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (dd, J = 7.3, 1.8 Hz, 2 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 4.1 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.84 (d, J = 6.4 Hz, 2 H), 3.43 (dt, J = 6.6, 1.4 Hz, 2 H), 2.45 (s, 3 H), 1.94 (d, J = 11.9 Hz, 1 H), 1.90-1.74 (m, 3 H), 1.74-1.60 (m, 2 H), 1.60-0.82 (m, 29 H), 0.62 (s, 3 H).

(3) Synthesis of Compound 18 Sodium cyanide (67.2 mg, 1.37 mmol) was added to a solution of Compound 17 (273.9 mg, 0.44 mmol) in anhydrous DMSO (17.5 mL), and the mixture was stirred at 80 ° C. for 2 hours and 30 minutes. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (213.6 mg). Purification by flash column chromatography (AcOEt / n-hexane = 1/14) gave Compound 18 (176.2 mg, 0.37 mmol, 84%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.34 (d, J = 4.6 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.44 (dt, J = 6.5 , 1.1 Hz, 2 H), 2.26 (d, J = 6.9 Hz, 2 H), 1.96 (dt, J = 11.9, 2.7 Hz, 1 H), 1.93-1.76 (m, 3 H), 1.76-1.64 ( m, 2 H), 1.64-0.96 (m, 23 H), 0.94 (s, 3 H), 0.91 (d, J = 6.9 Hz, 3 H), 0.64 (s, 3 H).

(4) Synthesis of Compound 19 Under an argon atmosphere, a solution of Compound 18 (96.1 mg, 0.20 mmol) in diethyl ether (7.0 mL) was cooled to 0 ° C., and 1.08 M methyllithium (diethyl ether solution, 0.90 mL, 0.97 mmol). And stirred at 0 ° C. for 40 minutes. 2 M hydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 40 minutes. To the reaction solution was added 28% aqueous ammonia, extracted with dichloromethane, and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (95.5 mg). Purification by silica gel column chromatography (AcOEt / n-hexane = 1/8, 1/9) and flash column chromatography (AcOEt / n-hexane = 1/19) gave colorless oily compound 19 (76.2 mg, 0.15 mmol, 77%).
¹ H NMR (400 MHz, CDCl ₃ ) δ7.34 (d, J = 4.6 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.43 (dt, J = 6.8 , 1.5 Hz, 2 H), 2.32 (d, J = 6.9 Hz, 2 H), 2.12 (s, 3 H), 1.95 (d, J = 11.9 Hz, 1 H), 1.91-1.62 (m, 5 H ), 1.62-0.88 (m, 23 H), 0.92 (s, 3 H), 0.91 (d, J = 6.4 Hz, 3 H), 0.63 (s, 3 H).

(5) Synthesis of Compound 20 Under an argon atmosphere, a solution of Compound 19 (62.6 mg, 0.13 mmol) in diethyl ether (5.0 mL) was cooled to −69 ° C., and 1.08 M methyllithium (diethyl ether solution, 0.30 mL, 0.32 mmol). ) Was added, and the mixture was stirred at -69 ° C for 2 hours and 30 minutes. 1.08 M methyl lithium (diethyl ether solution, 0.10 mL, 0.11 mmol) was added again, and the mixture was stirred at -69 ° C for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was brought to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (59.8 mg). Purification by flash column chromatography (AcOEt / n-hexane = 1/9) gave Compound 20 (46.4 mg, 0.09 mmol, 72%) as a colorless oil.
¹ H NMR (500 MHz, CDCl ₃ ) δ7.34 (d, J = 4.3 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.44 (dt, J = 6.7 , 2.6 Hz, 2 H), 1.95 (d, J = 11.7 Hz, 1 H), 1.90-0.85 (m, 30 H), 1.22 (s, 6 H), 0.91 (d, J = 6.3 Hz, 3 H ), 0.91 (s, 3 H), 0.63 (s, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ) δ138.83, 128.48, 127.78, 127.60, 72.97, 71.88, 71.21, 56.72, 56.35, 51.42, 43.77, 42.85, 40.68, 40.38, 37.63, 36.10, 36.01, 35.73, 35.17, 34.87, 32.33, 30.17, 30.14, 29.96, 28.45, 27.62, 26.66, 26.44, 24.38, 24.15, 20.98, 18.75, 12.19.

(6) Synthesis of Compound 21 Palladium hydroxide (5.4 mg) was added to a solution of compound 20 (24.3 mg, 0.048 mmol) in methanol (4.0 mL), and after hydrogen substitution, the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through Celite, and then the solvent was distilled off to obtain a white solid compound 21 (20.6 mg, 0.048 mmol, quant.).
¹ H NMR (400 MHz, CDCl ₃ ) δ3.61 (m, 2 H), 1.95 (dd, J = 11.4, 3.7 Hz, 1 H), 1.90-1.79 (m, 2 H), 1.75 (d, J = 13.3 Hz, 1 H), 1.70-0.85 (m, 27 H), 1.22 (s, 6 H), 0.92 (d, J = 7.3 Hz, 3 H), 0.91 (s, 3 H), 0.64 (s , 3 H).

(7) Synthesis of Compound 2 Chromium (VI) oxide (266.3 mg) was dissolved in water (0.77 mL), and concentrated sulfuric acid (0.23 mL) was added under ice cooling to prepare Jones reagent. To a solution of compound 21 (7.6 mg, 0.018 mmol) in anhydrous acetone (5.0 mL) was added Jones reagent (0.1 mL), and the mixture was stirred at room temperature for 40 minutes. Water was added to the reaction solution, and acetone was distilled off, followed by extraction with diethyl ether, and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (10.5 mg). Purification by GPC (CHCl ₃ ) gave Compound 2 (4.3 mg, 0.010 mmol, 55%) as a white solid.
¹ H NMR (600 MHz, CDCl ₃ ) δ 2.40 (ddd, J = 15.8, 10.4, 5.3 Hz, 1 H), 2.26 (ddd, J = 15.9, 9.9, 6.3 Hz, 1 H), 1.94 (dd, J = 12.0, 3.6 Hz, 1 H), 1.88-1.77 (m, 3 H), 1.74 (d, J = 13.8 Hz, 1 H), 1.60-0.80 (m, 24 H), 1.22 (s, 6 H ), 0.92 (d, J = 6.6 Hz, 3 H), 0.91 (s, 3 H), 0.64 (s, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ) δ179.59, 71.94, 56.67, 56.05, 51.38, 43.73, 42.89, 40.63, 40.32, 37.60, 36.06, 35.98, 35.46, 35.14, 34.85, 30.97, 30.91, 30.16, 30.11, 29.94, 28.34, 27.57, 26.62, 24.34, 24.14, 20.96, 18.39, 12.20.

Example 2: Synthesis of Compound 3 Compound 3 was synthesized from Compound 10 according to Scheme 2.
(1) Synthesis of Compound 22 A solution of compound 10 (310.1 mg, 0.69 mmol) in anhydrous methanol (60.0 mL) was cooled to 0 ° C., sodium borohydride (61.6 mg, 1.63 mmol) was added, and then at 0 ° C. for 40 minutes Stir. After the reaction solution was distilled off under reduced pressure, ethyl acetate and water were added for extraction, and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (320.0 mg). Purification by silica gel column chromatography (AcOEt / n-hexane = 1/4) gave pale yellow oily compound 22 (296.0 mg, 0.63 mmol, 95%).
¹ H NMR (400 MHz, CDCl ₃ ) δ7.34 (d, J = 4.1 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.67 (m, 2 H) , 3.43 (dt, J = 6.6, 1.2 Hz, 2 H), 2.05-1.76 (m, 5 H), 1.76-0.98 (m, 24 H), 0.92 (s, 3 H), 0.91 (d, J = 6.4 Hz, 3 H), 0.64 (s, 3 H).

(2) Synthesis of Compound 23 A solution of Compound 22 (281.2 mg, 0.60 mmol) in anhydrous pyridine (22.0 mL) was cooled to 0 ° C., and recrystallized p-toluenesulfonyl chloride (230.9 mg, 1.21 mmol) was added. Stir at 30 ° C. for 30 minutes and at room temperature for 2 hours. The reaction solution was cooled to 0 ° C., p-toluenesulfonyl chloride (230.6 mg, 1.21 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 4 hours and 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with water, 2 M hydrochloric acid and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (358.5 mg). Purification by silica gel column chromatography (AcOEt / n-hexane = 1/8, 1/10) gave Compound 23 (325.9 mg, 0.52 mmol, 87%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 9.2 Hz, 2 H), 7.34 (d, J = 4.6 Hz, 4 H) , 7.31-7.25 (m, 1 H), 4.49 (s, 2 H), 4.05 (m, 2 H), 3.43 (dt, J = 6.6, 1.9 Hz, 2 H), 2.45 (s, 3 H), 2.10 (br, 1 H), 1.99-1.87 (m, 2 H), 1.87-1.62 (m, 3 H), 1.62-0.94 (m, 22 H), 0.90 (d, J = 6.4 Hz, 3 H) , 0.84 (s, 3 H), 0.79 (dt, J = 14.2, 4.1 Hz, 1 H), 0.61 (s, 3 H).

(3) Synthesis of Compound 24 Sodium cyanide (12.0 mg, 0.245 mmol) was added to a solution of Compound 23 (51.9 mg, 0.084 mmol) in anhydrous DMSO (4.0 mL), and the mixture was stirred at 80 ° C. for 22 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (39.2 mg). Purification by GPC (CHCl ₃ ) gave Compound 24 (29.9 mg, 0.063 mmol, 75%) as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.34 (d, J = 4.1 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.43 (dt, J = 6.6 , 1.8 Hz, 2 H), 2.44 (d, J = 8.2 Hz, 2 H), 2.27 (br, 1 H), 2.11 (dt, J = 14.0, 5.0 Hz, 1 H), 1.97 (dd, J = 12.1, 3.0 Hz, 1 H), 1.94-1.76 (m, 2 H), 1.76-1.63 (m, 2 H), 1.63-0.97 (m, 22 H), 0.94 (s, 3 H), 0.91 (d , J = 6.9 Hz, 3 H), 0.64 (s, 3 H).

(4) Synthesis of Compound 25 Under an argon atmosphere, a solution of Compound 24 (160.5 mg, 0.34 mmol) in diethyl ether (9.0 mL) was cooled to 0 ° C., and 1.08 M methyllithium (diethyl ether solution, 1.40 mL, 1.51 mmol). And stirred at 0 ° C. for 30 minutes. 2 M hydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 40 minutes. To the reaction solution was added 28% aqueous ammonia, extracted with dichloromethane, and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (153.0 mg). Purification by flash column chromatography (AcOEt / n-hexane = 1/19) gave colorless oily compound 25 (133.5 mg, 0.27 mmol, 80%).
¹ H NMR (400 MHz, CDCl ₃ ) δ7.34 (d, J = 4.6 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.43 (dt, J = 6.6 , 1.4 Hz, 2 H), 2.52 (d, J = 7.3 Hz, 2 H), 2.39 (br, 1 H), 2.13 (s, 3 H), 2.03 (dt, J = 13.6, 5.3 Hz, 1 H ), 1.96 (d, J = 11.9 Hz, 1 H), 1.91-1.76 (m, 2 H), 1.76-0.95 (m, 24 H), 0.93 (s, 3 H), 0.91 (d, J = 6.9 Hz, 3 H), 0.63 (s, 3 H).

(5) Synthesis of Compound 26 Under an argon atmosphere, a solution of Compound 25 (69.7 mg, 0.14 mmol) in diethyl ether (5.0 mL) was cooled to −69 ° C. and 1.08 M methyllithium (diethyl ether solution, 0.50 mL, 0.54 mmol). ) Was added, and the mixture was stirred at -69 ° C for 2 hours. 1.08 M methyllithium (diethyl ether solution, 0.25 mL, 0.27 mmol) was added again, and the mixture was stirred at -69 ° C for 1 hour 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was allowed to reach room temperature, water was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (69.9 mg). Purification by flash column chromatography (AcOEt / n-hexane = 1/9) gave colorless oily compound 26 (61.4 mg, 0.12 mmol, 85%).
¹ H NMR (400 MHz, CDCl ₃ ) δ7.34 (d, J = 4.1 Hz, 4 H), 7.31-7.25 (m, 1 H), 4.50 (s, 2 H), 3.43 (dt, J = 6.6 , 1.4 Hz, 2 H), 2.06-1.92 (m, 3 H), 1.92-1.76 (m, 2 H), 1.76-0.98 (m, 26 H), 1.22 (s, 6 H), 0.92 (s, 3 H), 0.91 (d, J = 6.9 Hz, 3 H), 0.64 (s, 3 H).

(6) Synthesis of Compound 27 Palladium hydroxide (11 mg) was added to a solution of Compound 26 (52.2 mg, 0.10 mmol) in methanol (7.0 mL), and after hydrogen substitution, the mixture was stirred at room temperature for 2 hours 30 minutes. The reaction solution was filtered through celite, and then the solvent was distilled off to obtain a crude product (43.2 mg). Purification by silica gel column chromatography (AcOEt / n-hexane = 1/3) gave white solid compound 27 (38.0 mg, 0.091 mmol, 89%).
¹ H NMR (400 MHz, CDCl ₃ ) δ3.61 (br, 2 H), 2.06-1.92 (m, 3 H), 1.92-1.76 (m, 2 H), 1.60-0.98 (m, 26 H), 1.22 (s, 6 H), 0.92 (d, J = 6.4 Hz, 3 H), 0.92 (s, 3 H), 0.65 (s, 3 H).

(7) Synthesis of Compound 3 Chromium (VI) oxide (266.3 mg) was dissolved in water (0.77 mL), and concentrated sulfuric acid (0.23 mL) was added under ice cooling to prepare Jones reagent. Jones reagent (0.1 mL) was added to a solution of compound 27 (25.7 mg, 0.061 mmol) in anhydrous acetone (10.0 mL), and the mixture was stirred at room temperature for 40 minutes. Jones reagent (0.1 mL) was added again, and the mixture was stirred at room temperature for 40 minutes. Water was added to the reaction solution, and acetone was distilled off, followed by extraction with diethyl ether, and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a crude product (31.2 mg). Purification by GPC (CHCl ₃ ) gave Compound 3 (24.1 mg, 0.056 mmol, 91%) as a white solid.
¹ H NMR (600 MHz, CDCl ₃ ) δ2.40 (ddd, J = 15.8, 10.4, 5.2 Hz, 1 H), 2.26 (ddd, J = 15.9, 9.9, 6.3 Hz, 1 H), 2.04-1.92 ( m, 3 H), 1.90-1.76 (m, 3 H), 1.61-0.98 (m, 23 H), 1.22 (s, 6 H), 0.92 (s, 3 H), 0.92 (d, J = 6.6 Hz , 3 H), 0.64 (s, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ) δ179.37, 72.26, 56.71, 56.05, 46.30, 42.89, 40.36, 40.06, 37.89, 35.87, 35.46, 35.18, 32.95, 31.62, 31.01, 30.91, 29.70, 29.64, 29.43, 28.34, 27.48, 27.07, 26.55, 24.42, 24.33, 21.09, 18.38, 12.20.

Test Example 1: Cell differentiation induction assay in HL-60 cells With respect to Compound 1, Compound 2, and Compound 3, the cell differentiation induction action on human acute promyelocytic leukemia cells HL-60 was examined. For comparison, active vitamin D ₃ was used.

  The assay for cell differentiation induction was performed in the same manner as described in “4.3.1. Assay of HL-60 cell differentiation-inducing activity” in Fujii et al. Bioorg. Med. Chem. 22 (2014) 5891-5901. It was. Specifically, it is as follows.

HL-60 cells were cultured in RPMI-1640 medium supplemented with 5% FBS (fetal bovine serum), penicillin G and streptomycin at 37 ° C., 5% CO ₂ . The cells were diluted with RPMI-1640 (5% FBS) to 8.0 × 10 ⁴ cells / mL, and an ethanol solution of the test compound was added to a final concentration of 10 ⁻¹⁰ to 10 ⁻⁵ M. Control cells were treated with the same amount of ethanol only. 1α, 25-dihydroxyvitamin D3 was assayed simultaneously as a positive control. Cells were incubated for 4 days at 37 ° C., 5% CO ₂ . The proportion of differentiated cells was measured by measuring the reducing ability of nitro blue tetrazolium (NBT). Cells were treated with the same amount of phosphate buffered physiology containing RPMI-1640 (5% FBS) and NBT (0.2%) and 12-O-tetradecanoylphorbol 13-acetate (TPA; 200 ng / mL). Incubated for 20 minutes at 37 ° C. in saline (PBS). The percentage of cells containing dark indigo formazan was measured in a minimum of 200 cells.
The percentage (%) of differentiated cells calculated from NBT reducing ability is shown in Table 1 and FIG.

  As can be seen from the results in Table 1 and FIG. 1, Compound 2 and Compound 3 of the present invention have higher differentiation-inducing action on HL-60 cells than Compound 1 for reference.

Claims (8)

A compound represented by the following general formula (I), a salt thereof, or a prodrug thereof.

(In the formula, R ¹ and R ² each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R ³ , R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom or carbon. And represents an alkyl group of 1 to 6. n represents an integer of 1 to 3.) The compound according to claim 1, a salt thereof, or a prodrug thereof, wherein R ¹ and R ² are methyl groups. The compound, its salt, or its prodrug of Claim 1 or 2 whose R < ³ >, R < ⁴ >, R < ⁵ > and R < ⁶ > are hydrogen atoms. The compound according to any one of claims 1 to 3, wherein n is 1, a salt thereof, or a prodrug thereof. Any of the following compounds, salts thereof, or prodrugs thereof.

A medicament comprising the compound according to any one of claims 1 to 5, a salt thereof, or a prodrug thereof. A vitamin D receptor activator comprising the compound according to any one of claims 1 to 5, a salt thereof, or a prodrug thereof. A preventive and / or therapeutic agent for a vitamin D receptor-related disease comprising the compound according to any one of claims 1 to 5, a salt thereof, or a prodrug thereof.

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