TW201406380A - Therapeutic agent for secondary hyperparathyroidism - Google Patents

Abstract

The present invention provides a therapeutic agent for secondary hyperparathyroidism which comprises as an active component a vitamin D3 derivative represented by formula (1) or a medically acceptable solvate thereof.

Description

Secondary hyperthyroid hyperthyroidism therapeutic agent

The present invention relates to a secondary hyperthyroid hyperthyroidism therapeutic agent containing a 23-acetylene-vitamin D ₃ derivative or a pharmaceutically acceptable solvate thereof as an active ingredient.

The measured value of parathyroid hormone (hereinafter referred to as PTH) in the blood is a good indicator of parathyroid function, so the treatment of secondary hyperthyroidism in patients with chronic renal failure is to reduce the concentration of PTH in the blood. Implemented as a goal. Moreover, PTH is generally measured in the form of a complete PTH (hereinafter abbreviated as iPTH).

The active vitamin D derivative has an effect of inhibiting the production and secretion of PTH. Therefore, the active vitamin D derivative is considered to be useful for treating PTH-dependent bone lesions (for example, renal bone lesions) in patients with renal failure, and it can be used as a therapeutic agent for secondary secondary hyperthyroidism. Typical examples include Paricalcitol which is an active vitamin D ₂ derivative.

On the other hand, patients with secondary parathyroidism are not only used in most elderly patients, but also in the treatment of renal failure, para-cortical steroids are often used, so they are accused of PTH-independent bone lesions (such as osteoporosis). Pine disease). Even in patients with renal failure who are at risk of renal bone disease, the cause of the fracture is mostly caused by postmenopausal osteoporosis or elderly osteoporosis (Non-Patent Document 1). It is known that fractures caused by osteoporosis increase mortality and become a cause of bed rest. However, the osteoporosis therapeutic agent used clinically has a lack of clinical evidence for patients with renal failure, and thus it is not possible to use it in patients with renal failure (Non-Patent Document 2). Further, in the case of using a therapeutic agent for osteoporosis in a patient with renal failure, a patient whose blood-free PTH concentration cannot be controlled to a target range should not be administered (Non-Patent Document 3). Therefore, there is an urgent need to treat not only secondary parathyroid hyperthyroidism but also osteoporosis agents, but there are almost no satisfactory therapeutic drugs in the current situation.

Advanced technical literature

Non-Patent Document 1: Miller, "Cleve. Clin. J. Med", 2009, 76, p.715-723

Non-Patent Document 2: Kansal, "Adv. Chronic. Kidney. Dis", 2010, Vol. 17, p.e41-e51

Non-Patent Document 3: Miller, "Bone", 2011, 49, p.77-81

It is an object of the present invention to provide a novel therapeutic agent for secondary secondary hyperthyroidism.

Another object of the present invention is to provide a new therapeutic effect with bone lesions A therapeutic agent for secondary hyperthyroidism.

The present inventors have conducted detailed studies on the results of the above objects to achieve the following invention.

In other words, the present invention is a therapeutic agent for secondary hyperparathyroidism containing a vitamin D ₃ derivative represented by the following formula (1) or a pharmaceutically acceptable solvate thereof as an active ingredient.

Wherein R ₁ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkylcarbonyloxyalkyl group (having a carbon number of 1 to 6 in each alkyl group), or an arylcarbonyloxyalkyl group (carbon of an aryl group) The number is 6 to 10, and the carbon number of the alkyl group is 1 to 6). R ₂ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or may form a cyclic alkyl group having 3 to 6 carbon atoms together with other R ₂ and a carbon atom to which they are bonded. R ₃ represents an alkyl group having 1 to 6 carbon atoms or may form a cyclic alkyl group having 3 to 6 carbon atoms together with other R ₃ and a carbon atom to which they are bonded. X represents an oxygen atom or a methyl group, and n represents an integer of 1 or 2.

Moreover, the present invention is a therapeutic agent for secondary hyperparathyroidism containing as an active ingredient a vitamin D ₃ derivative represented by the following formula (17) or a pharmaceutically acceptable solvate thereof.

Wherein, R ₁ , R ₂ and R _{3 have} the same definitions as in the formula (1).

The present invention provides a therapeutic agent for novel secondary parathyroid hyperthyroidism.

Fig. 1 is a graph showing the results of an experiment for inhibiting the secretion of PTH in the para-thyroid organ culture of the rat of Example 17.

Fig. 2 is a graph showing the results of an experiment for inhibiting the secretion of PTH in the rat kidney failure (5/6 renal artery ligation) model of Example 18.

Figure 3 shows the bone of the lumbar spine in the rat kidney failure model of Example 19. A graph of the test results of the effect of density increase.

Fig. 4 is a graph showing the results of an experiment for increasing the bone density of the femur bone in the rat kidney failure model of Example 19.

Form of implementing the invention

The terms used in the present invention are as defined below.

The alkyl group is a linear, branched or cyclic aliphatic hydrocarbon group. Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, an isopentyl group, a hexyl group, and a cyclopropyl group. A group, a cyclopropylmethyl group, and a cyclohexyl group are mentioned as a specific group.

The alkylcarbonyloxyalkyl group may, for example, be a t-butylcarbonyloxymethyl group.

The arylcarbonyloxyalkyl group is exemplified by a phenylcarbonyloxymethyl group.

In the above formula (1), R ₁ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkylcarbonyloxyalkyl group (the number of carbon atoms of each alkyl group is 1 to 6), or an arylcarbonyloxyalkyl group. (The carbon number of the aryl group is 6 to 10, and the carbon number of the alkyl group is 1 to 6). Among them, a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a t-butyl group is preferred, and a hydrogen atom or an isopropyl group is particularly preferred. As the alkylcarbonyloxyalkyl group, t-butylcarbonyloxymethyl group is preferred. Further, as the arylcarbonyloxyalkyl group, a phenylcarbonyloxyalkyl group is preferred.

In the above formula (1), R ₂ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or may form a cyclic alkyl group having 3 to 6 carbon atoms together with other R ₂ and a carbon atom to which they are bonded. Among them, when R ₂ is a hydrogen atom or a methyl group, or a ring-form alkyl group is formed with other R ₂ and a carbon atom to which they are bonded, a cyclopropyl group is preferred.

In the above formula (1), R ₃ represents an alkyl group having 1 to 6 carbon atoms, or a cyclic alkyl group may be formed together with other R ₃ and a carbon atom to which they are bonded. As the alkyl group having 1 to 6 carbon atoms, a methyl group or an ethyl group is preferred. Further, when a ring alkyl group is formed together with other R ₃ and the carbon atom to which they are bonded, a cyclopentyl group is preferred.

Further, in the above formula (1), X represents an oxygen atom or a methyl group.

Further, in the above formula (1), n represents an integer of 1 or 2, and particularly preferably n = 1.

Preferred examples of the vitamin D ₃ derivative represented by the formula (1) of the present invention include the compounds shown in the following tables.

The vitamin D ₃ derivative of the present invention can be converted to the pharmaceutically acceptable solvate as necessary. Examples of such a solvent include water, methanol, ethanol, 1-propanol, 2-propanol, butanol, t-butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, and diethyl. Ether, t-butyl methyl ether, benzene, toluene, DMF, DMSO, and the like. In particular, water, methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, acetone, methyl ethyl ketone or ethyl acetate is preferred.

The synthesis of the vitamin D ₃ derivative represented by the above formula (1) can be carried out by any method, and for example, it can be carried out as shown in the following Scheme 1. That is, after coupling the compound (2) and the compound (3), the protecting group of the hydroxyl group is deprotected, and if necessary, the ester group is hydrolyzed to obtain the object (1).

In the above formula (2), R ₂ , X and n are the same as the above formula (1). Further, R ₄ in the above formula (2) represents R ₁ in the above formula (1), or represents a methoxymethyl group, a methoxyethoxymethyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, or a benzene group. Methyloxymethyl. Among them, methyl, ethyl, propyl, isopropyl or t-butyl, t-butylcarbonyloxymethyl, phenylcarbonyloxyalkyl or benzyloxymethyl is also preferred.

Further, R ₅ in the above formula (2) represents a protective group of a hydroxyl group. Examples of the protective group of the hydroxyl group include a methoxymethyl group, a fluorenyl group having 1 to 3 carbon atoms (having a carbonyl carbon in a carbon number), a trimethylcarbinyl group, a triethylmethane group, and a t-butyl group. Dimethylformamidinyl, t-butyldiphenylcarbamyl, and the like. Among them, preferred examples of triethylcarbinyl group and t-butyldimethylformamidinyl group are mentioned.

Further, in the above formula (2), n represents an integer of 1 or 2, and particularly preferably n=1.

The same as R ₃ in the compound (3) of the formula R in the above formula (1) is _3. Further, OPG in the compound (3) represents a protected hydroxyl group. Specific examples thereof include trimethylmethane alkyl, triethylmethylalkyl, and methoxymethyl.

In the above Scheme 1, when R ₂ is a hydrogen atom, the compound (2) can be, for example, from the literature (Vitamin D Analog in Cancer Prevention and Therapy, Recent Results in Cancer Research, Vol. 164, Springer), pages 289-317, The enyne compound (4) described in 2003 and the like is synthesized according to the following Scheme 2. That is, the protecting group of the first-order hydroxyl group of (4) (t-butyldimethylformamidinyl group; TBS group) is selectively deprotected to obtain a compound (5), which is oxidized to form a carboxyl group, followed by After the esterification, the objective (2) (R ₂ = TBS) can be obtained.

On the other hand, in the above Scheme 1, when R ₃ is a methyl group, the compound (3) can be synthesized by the following Scheme 3.

That is, the compound (6) described in the literature (for example, the specification of U.S. Patent No. 4,804,502) can be obtained by dibromide-forming.

Further, among the vitamin D ₃ derivatives represented by the above formula (1), the compound wherein R ₂ is a hydrogen atom may be synthesized by the method shown in the following Scheme 4 except for the above Scheme 1. That is, the compound (5) in the scheme 2 is protected with a neopentyl group to obtain a compound (7), which is coupled with the compound (3) in the scheme 1 and then subjected to a hydroxyl group at the terminal of the second substituent of the ring A. Compound (8) is obtained after deprotection. The hydroxy group of the obtained compound is oxidized to a carboxylic acid, and finally all the hydroxy protecting groups are obtained by deprotection.

Further, in the above Scheme 1, when R ₂ is substituted, in the compound (2), for example, when R ₂ forms a cycloalkyl group with another R ₂ and a carbon atom to which they are bonded, the literature (Vitamin D Analog in The alkyne compound (4) described in Cancer Prevention and Therapy, Recent Results in Cancer Research, Vol. 164, Springer, 289-317, 2003, etc., similarly, 4,6-O-benzene Methyl-α-D-methyl-glucopyranoside (9) is used as a starting material, and after epoxidation, ring opening of an epoxide is carried out under basic conditions to obtain a compound (10). After the compound (11) is obtained by the protection of a hydroxyl group, ring opening of the benzylidene ring is carried out, and further reduction of the first position of the glucose is carried out to obtain a compound (12). The compound (13) is obtained by forming an epoxide by a diol, and the compound (14) introduced into the bonded portion is obtained by reacting an epoxide with acetylene. Compound (15) can be obtained by performing appropriate protection of a hydroxyl group. The coupling reaction of the compound (15) with the CD ring intermediate (3) described in the above Scheme 1 is carried out, followed by selective deprotection to obtain the compound (16), and further oxidizing the first-stage hydroxyl group to a carboxylic acid. The desired compound (1) can be obtained after deprotection.

Further, the present invention is to contain the following formula (17) vitamin D ₃ derivative or a pharmaceutically solvate may be permitted as an active ingredient of therapeutic doses of idiopathic hyperparathyroidism FIG.

Wherein, R ₁ , R ₂ and R _{3 have} the same definitions as in the formula (1).

Among the vitamin D ₃ derivatives represented by the formula (17) or a pharmaceutically acceptable solvate thereof, R ₁ , R ₂ and R _{3 are} preferred, and preferred combinations thereof are the same as those of the formula (1).

The synthesis of the formula (17) can be carried out by any method, for example, the following Scheme 6 can be carried out. That is, after the compound (2) described in the first embodiment is subjected to a coupling reaction with the compound (18), the protecting group of the hydroxyl group is deprotected, and if necessary, the ester group is hydrolyzed to obtain the object (17).

In the above Scheme 6, the compound (18) can be synthesized, for example, by the following Scheme 7. That is, the compound (19) described in the literature (for example, International Publication WO95/33716) can be obtained by reacting the acetylene compound (20) in the presence of n-butyllithium.

In the secondary hyperparathyroidism of the present invention, the condition of the bone lesion is complicated. Bone lesions contain PTH-dependent bone lesions and PTH-independent bone lesions. There are renal bone lesions as PTH-dependent bone lesions, and specific examples of renal bone lesions include osteoporosis caused by high-grade osteoporosis, bone formation, and osteoporosis PTH. Examples of the PTH-independent bone lesion include osteoporosis which is not dependent on renal failure, and specific examples include osteoporosis after menopause, osteoporosis of the elderly, and steroid-induced osteoporosis.

The therapeutic agent for the secondary parathyroid hyperthyroidism containing the vitamin D ₃ derivative or the pharmaceutically acceptable solvate thereof as an active ingredient of the present invention can be used as a carrier or an excipient which is generally used for formulation. Modulated with other additives. The carrier or excipient used for the preparation may be either solid or liquid, and examples thereof include lactose, magnesium stearate, starch, talc, gelatin, cold weather, pectin, gum arabic, olive oil, sesame oil, and cocoa fat. , ethylene glycol, etc. or other common people. The administration may be oral administration by a tablet, a pill, a capsule, a granule, a powder, a liquid, or the like, or a parenteral injection, a suppository, a transdermal injection or the like by intravenous injection or rib injection. With either form.

The therapeutically effective amount of the active ingredient in the therapeutic agent of the present invention varies depending on the administration route, the age, sex, and degree of the disease, and is generally 0.01 to 10 μg/day, and the number of administrations is generally 1 to 3 times per day to 1 ~3 times/week, it is preferred to prepare a preparation that satisfies the conditions.

Example

The present invention will be described in more detail below based on the examples, but the invention is not limited thereto. Further, the abbreviation in the present invention is as follows.

TBS=t-butyldimethylformamidin

TES=Triethylcarbamidine

TESCl=chlorotriethyl decane

TMS = trimethylmethanyl

TMSCl=chlorotrimethyl decane

Piv=新戊醯基

PivCl = neopentyl chloride

TBAF = tetrabutylammonium fluoride

CSA=(+/-)-camphor-10-sulfonic acid

PDC = dichromate pyridine

TBSOTf=t-butyldimethylformamidine triflate

DIBAL=Dibutylaluminum hydride

DMF=N,N-dimethylformamide

THF = tetrahydrofuran

TsCl=p-toluenesulfonyl chloride

Ts=p-toluenesulfonyl

[Example 1] (5Z,7E)-(1R,2S,3R,20R)-2-(2-carboxyethoxy)-23-yne-9,10-broken-5,7,10(19)-cholestrietene Manufacture of -1,3,25-triol (Compound C-1)

(1) Compound A-1 (2.29 g, 4.11 mmol) known from the literature (for example, The Journal of Organic Chemistry (J. Org. Chem.), 2004, 69, pp. 7463-7471). Dissolved in ethanol (20 (mL), (+/-)-camphor-10-sulfonic acid (954 mg, 4.11 mmol) was added under ice cooling, and stirred at 0 ° C for 1 hour. The reaction was quenched by the addition of a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was diluted with ethyl acetate. This was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (n-hexane/ethyl acetate=9/1) to afford compound A-2 (1.64 g, yield: 90%).

¹ H-NMR (CDCl ₃ ) δ: 5.96-5.88 (1H, m), 5.27-5.21 (2H, m), 4.29 (1H, dd, J = 6.8, 3.9 Hz), 3.88-3.72 (5H, m) , 3.45 (1H, dd, J = 5.4, 4.1 Hz), 3.00 (1H, t, J = 6.0 Hz), 2.50-2.46 (1H, m), 2.38-2.33 (1H, m), 2.01 (1H, t , J = 2.6 Hz), 1.85-1.68 (2H, m), 0.91 (9H, s), 0.91 (9H, s), 0.10 (9H, s), 0.07 (3H, s).

(2) Compound A-2 (1.0 g, 2.26 mmol) obtained in (1) was dissolved in pyridine (10 mL), and then added at room temperature at 0 ° C (0.69 mL, 5.65 mmol) at room temperature Stir. Anhydrous methanol (3 mL) was added, and the mixture was further stirred at room temperature for 30 minutes. Toluene was added and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with brine, and then evaporated. The residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (n-hexane/ethyl acetate = 9/1) to afford Compound A-3 (1.072 g, yield: 90%).

¹ H-NMR (CDCl ₃ ) δ: 5.95 (1H, ddd, J = 17.0, 11.0, 6.0 Hz), 5.21. (1H, ddd, J=17, 2.0, 1.0 Hz), 5.14 (1H, ddd, J = 11.0, 2.0, 1.0 Hz), 4.32-4.28 (1H, m), 4.18-4.10 (2H, m), 3.86 (1H, q, J = 5.6 Hz), 3.81-3.74 (1H, m), 3.68-3.60 (1H, m), 3.39 (1H, dd, J = 5.4, 3.4 Hz), 2.49 (1H, dq, J = 17.0, 2.7 Hz), 2.35 (1H, dq, J = 16.9, 2.8 Hz), 1.96 ( 1H, t, J = 2.7 Hz), 1.87 (2H, dt, J = 14.0, 7.0 Hz), 1.19 (9H, s), 0.90 (9H, s), 0.89 (9H, s), 0.10 (3H, s ), 0.08 (3H, s), 0.07 (5H, s), 0.03 (3H, s).

(3) (Bromomethyl)triphenylphosphonium bromide (1.25 g, 2.87 mmol) was dissolved in tetrahydrofuran (7 mL), and cooled to 0 ° C under nitrogen atmosphere. Sodium bis(trimethyldecane) decylamine (1.0 M tetrahydrofuran solution, 2.90 mL, 2.87 mmol) was added thereto, and stirred under ice cooling for 30 minutes. The reaction solution was cooled to -78 ° C, and Compound B-1 (200 mg, 0.574 mmol) known from the literature (for example, U.S. Patent No. 4,804,502, to Uskokovic) was dissolved in tetrahydrofuran (1.5 mL) and added. After stirring at -78 ° C for 1 hour, the mixture was further stirred at 0 ° C for 1 hour. To the reaction mixture, crepe (2.5 g) was added, and the mixture was vigorously stirred at room temperature for 10 minutes, and then filtered through Celite. The obtained filtrate was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (n-hexane/ethyl acetate=9/1) to afford compound B-2 (161 mg, yield 67%).

¹ H-NMR (CDCl ₃ ) δ: 5.65 (1H, s), 2.90-2.86 (1H, m), 2.28-1.24 (20H, m), 1.08 (3H, d, J = 6.3 Hz), 0.58 (3H) , s), 0.18 (9H, s).

(4) Compound B-2 (1.2 g, 2.82 mmol) obtained in (3) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 4.23 mL, 4.23 mmol) was added at 50 ° C. Stir for 30 minutes. Ethyl acetate was added and washed with water, and the organic layer was dried over anhydrous magnesium sulfate. through The residue obtained after concentration under reduced pressure was purified by silica gel chromatography (n-hexane/ethyl acetate = 19/1). The purified material was dissolved in anhydrous pyridine (10 mL) and cooled to 0 ° C under nitrogen atmosphere. Chlorotriethyldecane (0.944 mL, 5.70 mmol) was added thereto, and the mixture was warmed to room temperature and stirred for 2.5 hours. The reaction solution was cooled to 0 ° C, a saturated aqueous solution of ammonium chloride and water were added, and extracted with toluene. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue obtained by concentrating under reduced pressure was purified by silica gel chromatography (n-hexane/ethyl acetate=99/1) to afford compound B-3 (783 mg, yield 88%).

¹ H-NMR (CDCl ₃ ) δ: 5.65 (1H, s), 2.92-2.85 (1H, m), 2.23 (1H, dd, J = 16.5, 3.4 Hz), 2.07-1.24 (19H, m), 1.08 (3H, d, J = 6.6 Hz), 0.96 (9H, t, J = 7.9 Hz), 0.66 (6H, q, J = 7.9 Hz), 0.57 (3H, s).

(5) Compound B-3 (783 mg, 1.67 mmol) obtained in (4) and Compound A-3 (733 mg, 1.39 mmol) obtained in (2) were dissolved in anhydrous toluene/triethylamine (1/1, 11.1). (mL), triphenylphosphine palladium (289 mg, 0.25 mmol) was added, and the mixture was stirred at 105 ° C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, diamine gum (6 g of Fuji SILYSIA Co., Ltd.) and n-hexane (20 mL) were added, and the mixture was stirred at room temperature for 1 hour, and then filtered with ethyl acetate. The obtained filtrate was concentrated under reduced pressure, and the residue was purified by chromatography (n-hexane/ethyl acetate=100/0→95/5). The obtained purified product was dissolved in anhydrous tetrahydrofuran (5.5 mL), anhydrous methanol (4.6 mL), and sodium sulfate and a methanol solution (0.91 mL, 5.46 mmol), and refluxed for 1 hour. Add saturated aqueous ammonium chloride solution to reduce concentration Shrink. Ethyl acetate was added to the residue, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained after concentration under reduced pressure was purified by silica gel chromatography (n-hexane/ethyl acetate=100/0→50/50) to afford compound AB-1 (609 mg, yield 67%).

¹ H-NMR (CDCl ₃ ) δ: 6.18 (1H, d, J = 11.2 Hz), 6.02 (1H, d, J = 11.2 Hz), 5.30 (1H, brs), 5.00 (1H, brs), 4.46 ( 1H, brs), 4.05 (1H, m), 3.88-3.69 (4H, m), 3.36 (1H, brs), 2.94 (1H, brs), 2.83-2.77 (1H, m), 2.62-2.56 (1H, m), 2.24 (1H, dd, J = 16.5, 3.4 Hz), 2.10 (1H, dd, J = 13.9, 4.4 Hz), 2.06-1.21 (21H, m), 1.07 (3H, d, J = 6.6 Hz) ), 0.96 (9H, t, J = 7.9 Hz), 0.93 (9H, s), 0.87 (9H, s), 0.67 (6H, q, J = 7.9 Hz), 0.55 (3H, s), 0.10 (3H) , s), 0.10 (3H, s), 0.08 (3H, s), 0.07 (3H, s).

(6) The compound AB-1 (427 mg, 0.514 mmol) obtained in (5) was dissolved in anhydrous dichloromethane (5.2 mL), cooled to 0 ° C, and then added to the Dess-Martin reagent (523 mg, 1.23 mmol), under ice cooling After stirring for 2 hours, the mixture was heated to room temperature and stirred for 1 hour. A saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogencarbonate were added and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate The obtained residue was dissolved in t-butanol (21 mL), and tetrahydrofuran (37 mL) and 2-methyl-2-butene (6.47 mL) were added and ice-cooled. Add sodium hypochlorite (purity 80%, 580mg, 5.14mmol) and sodium hydrogen phosphate. An aqueous solution of hydrate (400 mg, 2.57 mmol) (7.3 mL) was stirred for 45 min. Add saturated aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogencarbonate solution. Extract with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating under reduced pressure was purified by silica gel chromatography (n-hexane/ethyl acetate=100/0→80/20) to afford compound AB-2 (341 mg, yield 78%).

¹ H-NMR (CDCl ₃ ) δ: 6.22 (1H, d, J = 11.2 Hz), 6.00 (1H, d, J = 11.2 Hz), 5.27 (1H, brs), 4.99 (1H, brs), 4.45 ( 1H, brs), 4.07 (1H, m), 3.91 (2H, t, J = 6.1 Hz), 3.36 (1H, brs), 2.84-2.77 (1H, m), 2.64 (2H, d, J = 6.1, 1.5Hz), 2.60-2.53(1H,m), 2.24(1H,dd,J=16.5,3.4Hz), 2.13(1H,dd,J=13.9,5.4Hz),2.07-1.21(19H,m), 1.07(3H,d,J=6.3Hz), 0.96(9H,t,J=7.9Hz), 0.90(9H,s),0.87(9H,s),0.67(6H,q,J=7.9Hz), 0.55 (3H, s), 0.09 (3H, s), 0.09 (6H, s), 0.07 (3H, s).

(7) The compound AB-2 (140 mg, 0.165 mmol) obtained in (6) was dissolved in acetone (1.65 mL), and then cooled to 0 ° C, and then a mixture of hydrochloric acid (6 eq, 0.332 mL) in acetone (1.65 mL) was added. Stirring was carried out for 4 hours at room temperature. N-hexane (3.3 mL) was added, and crude purification was carried out by silica gel chromatography (n-hexane/acetone = 1/1) and thin layer chromatography (n-hexane/acetone = 4/5). Further reverse phase HPLC (A = 0.1% formic acid / 1% methanol / 4% acetonitrile / water; B = 0.1% formic acid / 5% water / 19% methanol / acetonitrile; 0 - 2 min.: B = 20%, 2- 20 min.: B = 20% → 98%, 20-25 min.: B = 98%, 25-30 min.: B = 20%) After purification, Compound C-1 (34.9 mg, yield 42%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 6.42 (1H, d, J = 11.2 Hz), 6.00 (1H, d, J = 11.2 Hz), 5.39 (1H, d, J = 1.9 Hz), 5.09 (1H, d, J = 1.9 Hz), 4.50 (1H, d, J = 2.9 Hz), 4.36-3.58 (6H, m), 3.35 (1H, dd, J = 8.1, 3.2 Hz), 2.86-2.79 (1H, m ), 2.72-2.57 (3H, m), 2.29-2.19 (2H, m), 2.04-1.20 (19H, m), 1.06 (3H, d, J = 6.6 Hz), 0.54 (3H, s).

[Embodiment 2] (5Z,7E)-(1R,2S,3R,20R)-2-(2-methoxycarbonylethoxy)-23-yne-9,10-broken-5,7,10(19)-biliary Manufacture of ninhydrene-1,3,25-triol (Compound C-2)

(1) The compound A-2 (1.45 g, 3.27 mmol) obtained in Example 1 (1) was dissolved in anhydrous dimethylformamide (15 mL), and pyridine dichromate (6.17 g, 16.4 mmol) was added and carried out. Stir for 12 hours. Water was added, and the mixture was extracted with diethyl ether. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (20% ethyl acetate/n-hexane) to afford compound A-4 (0.82 g, yield 55%).

¹ H-NMR (CDCl ₃ ) δ: 5.90 (1H, ddd, J = 17.0, 6.0, 11.0 Hz), 5.30 - 5.20 (2H, m), 4.33 (1H, ddt, J = 7.0, 3.0, 1.0 Hz) , 3.96 (2H, td, J = 6.0, 1.2 Hz), 3.85-3.75 (1H, m), 3.55 (1H, dd, J = 6.3, 3.7 Hz), 2.63 (2H, td, J = 5.9, 1.9 Hz) ), 2.50-2.32 (2H, m), 2.02 (1H, t, J = 2.7 Hz), 0.91 (9H, s), 0.90 (9H, s), 0.11 (3H, s), 0.10 (3H, s) , 0.09 (3H, s), 0.08 (3H, s).

(2) The compound A-4 (0.82 g, 1.79 mmol) obtained in (1) was dissolved in anhydrous methanol (8 mL), and concentrated sulfuric acid (74 μL, 1.5 mmol) was added thereto, followed by stirring for 2.5 hours. After cooling to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added and ethyl acetate was evaporated. The obtained organic layer was dried over anhydrous sodium sulfate. The residue was concentrated in anhydrous dichloromethane. EtOAc (EtOAc, m. After 7.2 mmol), the mixture was stirred at room temperature for 1 hour. Anhydrous methanol (1.5 mL) was added and the mixture was further stirred at room temperature for 10 minutes. After adding n-hexane/ethyl acetate (9/1) and washing with water, the obtained organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (yield: EtOAc/EtOAc) to afford Compound A-5 (683.4mg, yield 81%).

¹ H-NMR (CDCl ₃ ) δ: 5.94 (1H, ddd, J = 10.0, 17.2, 6.5 Hz), 5.21. (1H, dt, J = 17.3, 1.3 Hz), 5.14 (1H, dt, J = 10.0, 1.3 Hz), 4.30 (1H, dd, J = 6.8, 3.4 Hz), 4.00-3.97 (1H, m), 3.88-3.82 (2H, m), 3.68 (3H, s), 3.40 (1H, dd, J =5.5, 3.5 Hz), 2.57 (2H, t, J = 6.6 Hz), 2.48 (1H, dq, J = 16.8, 2.7 Hz), 2.35 (1H, dq, J = 17.0, 2.8 Hz), 1.96 (1H) , t, J = 2.6 Hz), 0.90 (9H, s), 0.89 (9H, s), 0.09 (3H, s), 0.08 (3H, s), 0.07 (3H, s), 0.03 (3H, s) .

(3) Compound A-5 (47.0 mg, 0.1 mmol) obtained in (2) and Compound B-2 (46.2 mg, 0.11 mmol) obtained in Example 1 (3) were dissolved in toluene/triethylamine (1) /1,2 mL), palladium triphenylphosphine palladium (12.5 mg, 0.0108 mmol) was added, and the mixture was stirred at 110 ° C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, it was concentrated under reduced pressure. The residue was crudely purified by thin layer chromatography (n-hexane/ethyl acetate = 19/1). The obtained crude purified product was dissolved in anhydrous dichloromethane / acetonitrile (1/1, 1 mL), and then, at 0 ° C, lithium tetrafluoroborate (78 mg, 0.8 mmol), sulfuric acid (1 M acetonitrile solution, 0.08 mL) was added at 0 ° C. , 0.08 mmol) and stirred for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added, and the obtained organic layer was washed with ethyl acetate. The residue obtained by concentration under reduced pressure was purified by EtOAc (t-hexane/ethyl acetate = 1/2) and further purified by reverse phase HPLC (A=95% water/acetonitrile; B=0.5) After purification by % water/40% methanol/acetonitrile; B = 75%), Compound C-2 (6.8 mg, 13%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 6.42 (1H, d, J = 11.2 Hz), 6.03 (1H, d, J = 11.2 Hz), 5.40 (1H, d, J = 1.2 Hz), 5.09 (1H, d, J = 2.2 Hz), 4.45 (1H, t, J = 3.3 Hz), 4.06-3.79 (3H, m), 3.73 (3H, s), 3.36 (1H, dd, J = 7.7, 3.3 Hz), 2.85-2.60(7H,m), 2.24(2H,dt,J=18.8,5.9Hz), 2.02-1.96(3H,m),1.89-1.82(2H,m),1.72-1.54(6H,m), 1.51 (6H, s), 1.47-1.24 (4H, m), 1.06 (3H, d, J = 6.3 Hz), 0.54 (3H, s).

MS m/z 537.2 (M+23) + 523.3 (M+18)+

[Example 3] (5Z,7E)-(1R,2S,3R,20R)-2-(2-propoxycarbonylethoxy)-23-yne-9,10-broken-5,7,10(19)-biliary Manufacture of ninhydrene-1,3,25-triol (compound C-4)

(1) The compound A-4 (240 mg, 0.525 mmol) obtained in Example 2 (1) was used as a starting material, and methanol was substituted with propanol in the same manner as in Example 2 (2) to give Compound A- 6 (18.5 mg, yield 27%).

(2) Compound A-6 (40.5 mg, 0.081 mmol) obtained in (1) and Compound B-2 (47 mg, 0.11 mmol) obtained in Example 1 (3) were used as a starting material, and Example 2 (3) In the same manner, Compound C-4 (6.8 mg, 15%).

¹ H-NMR (CDCl 3 ) δ: 6.42 (1H, d, J = 11.2 Hz), 6.03 (1H, d, J = 11.2 Hz), 5.39 (1H, d, J = 1.2 Hz), 5.09 (1H, d , J = 2.2 Hz), 4.45 (1H, t, J = 3.5 Hz), 4.08 (2H, t, J = 6.7 Hz), 4.06-3.95 (2H, m), 3.85-3.77 (1H, m), 3.36 (1H, dd, J = 7.8, 3.2 Hz), 2.85-2.82 (1H, m), 2.79 (1H, d, J = 4.1 Hz), 2.70-2.62 (4H, m), 2.26-2.22 (2H, m ), 2.03-1.98 (3H, m), 1.90- 1.80 (3H, m), 1.70- 1.64 (7H, m), 1.58-1.53 (4H, m), 1.51 (6H, s), 1.48-1.45 (2H) , m), 1.40-1.20 (4H, m), 1.06 (3H, d, J = 6.6 Hz), 0.94 (4H, t, J = 7.4 Hz), 0.54 (3H, s).

[Example 4] (5Z,7E)-(1R,2S,3R,20R)-2-(2-(1-methyl)ethoxycarbonylethoxy)-23-yne-9,10-broken-5,7, Manufacture of 10(19)-cholestrylene-1,3,25-triol (compound C-5)

(1) The compound A-4 (240 mg, 0.525 mmol) obtained in Example 2 (1) was used as a starting material, and methanol was substituted with isopropyl alcohol in the same manner as in Example 2 (2) to obtain Compound A. -7 (157.4 mg, yield 60%).

(2) Compound A-7 (35 mg, 0.07 mmol) obtained in (1) and Compound B-2 (44 mg, 0.11 mmol) obtained in Example 1 (3) were used as a starting material, and Example 2 (3) In the same manner, Compound C-5 (6.8 mg, 17%) was obtained.

¹ H-NMR (CDCl 3 ) δ: 6.42 (1H, d, J = 11.0 Hz), 6.03 (1H, d, J = 11.5 Hz), 5.39 (1H, d, J = 1.5 Hz), 5.09-5.02 (2H , m), 4.45 (1H, t, J = 3.5 Hz), 4.05-3.78 (3H, m), 3.35 (1H, dd, J = 7.7, 3.3 Hz), 2.85-2.58 (6H, m), 2.28- 1.53 (18H, m), 1.51 (6H, s), 1.46-1.30 (5H, m), 1.26 (3H, d, J = 1.7 Hz), 1.24 (3H, d, J = 1.5 Hz), 1.06 (3H) , d, J = 6.3 Hz), 0.54 (3H, s).

[Example 5] (5Z,7E)-(1S,2S,3R,20R)-2-(2-carboxypropyl)-23-yne-9,10-broken-5,7,10(19)-cholestrietene- Manufacture of 1,3,25-triol (Compound D-1)

(1) From literature (eg Saito's tetrahedron (Tetrahedron), 2004 Known compound (3R, 4R, 5S)-3,5-bis[(t-butyldimethylcyclodecane)oxy]-4-[3-{(, 60, 7751-7961)) The compound A-8 (0.72 g, 1.69 mmol) obtained in the same manner as in Example 1 (1) was dissolved in t-butyldimethylsulfonyloxy}propyl]oct-1-ene-7-yne. Triethylamine (0.47 mL, 3.37 mmol), trimethylamine hydrochloride (16 mg, 0.169 mmol), p-toluenesulfonyl chloride (0.48 g, 2.53) were added to dichloromethane (6.8 mL) at 0 °C. Methyl) was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added, and ethyl acetate was evaporated. The residue obtained by concentration under reduced pressure was dissolved in dimethylmethaneamine (3mL), sodium hydride (199 mg, 4.06 mmol), sodium iodide (380 mg, 2.53 mmol) was added, and the mixture was stirred at 50 ° C for 2 hours. After adding water, the mixture was extracted with EtOAc. This was dissolved in tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 5.07 mL, 5.07 mmol) was added, and the mixture was stirred at 60 ° C for 1 hour. After adding ethyl acetate, it was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained after concentration under reduced pressure was dissolved in dimethylformamide (5mL), and then, at 0 ° C, imidazole (460 mg, 6.76 mmol), dimethylamine pyridine (21 mg, 0.169 mmol), chlorotriethyl decane ( 0.851 mL, 5.07 mmol), stirred at 50 ° C for 40 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added, and ethyl acetate was evaporated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (1% ethyl acetate / n-hexane - 2% ethyl acetate / n-hexane - 5% ethyl acetate / n - hexane → 10 Purification with % ethyl acetate / n-hexane) gave compound A-10 (531.3 mg, yield 72%).

¹ H-NMR (CDCl ₃ ) δ: 5.82 (1H, ddd, J = 17.0, 10.0, 7.0 Hz), 5.17 (1H, dd, J = 17.2, 1.1 Hz), 5.11 (1H, ddd, J = 10.0, 2.0, 1.0 Hz), 4.00-3.95 (1H, m), 2.42 - 2.37 (2H, m), 2.32 (2H, t, J = 7.8 Hz), 1.97 (1H, t, J = 2.6 Hz), 1.85- 1.65 (3H, m), 1.43-1.29 (2H, m), 1.26 (2H, t, J = 7.2 Hz), 0.89 (19H, s), 0.09 (3H, s), 0.06 (3H, s), 0.06 (3H, s), 0.03 (3H, s).

(2) Compound A-10 (449.4 mg, 1.03 mmol) obtained in (1) was dissolved in dichloromethane (5 mL), and di-butylaluminum hydride (1 M toluene solution, 2.08 mL) was added under cooling at -78 °C. 2.08 mmol), stirred at -78 °C for 50 minutes. Anhydrous methanol (0.3 mL) was added, and the mixture was stirred at room temperature for 20 minutes, and a saturated aqueous solution of sodium potassium tartrate was further added thereto, followed by stirring for 10 minutes. After adding ethyl acetate, it was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was dissolved in tetrahydrofuran (6.9 mL), and t-butanol (6.9 mL) and 2-methyl ^- 2-butene (4.5 g) were added to ice-cool. An aqueous solution (6.9 mL) of sodium hypochlorite (931 mg, 10.3 mmol) and sodium hydrogen phosphate (803 mg, 5.15 mmol) was added, and the mixture was stirred for 1 hour. A saturated aqueous solution of sodium thiosulfate was added, and aq. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (n-hexane/ethyl acetate=100/1→50/1→20/1→10/1→5/1→2/1). Compound A-11 (220 mg, 47%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 5.82 (1H, ddd, J = 17.0, 10.0, 7.0 Hz), 5.17 (1H, dd, J = 17.2, 1.1 Hz), 5.11 (1H, ddd, J = 10.0, 2.0, 1.0 Hz), 4.00-3.95 (1H, m), 2.42 - 2.37 (2H, m), 2.32 (2H, t, J = 7.8 Hz), 1.97 (1H, t, J = 2.6 Hz), 1.85- 1.65 (3H, m), 1.43-1.29 (2H, m), 1.26 (2H, t, J = 7.2 Hz), 0.89 (19H, s), 0.09 (3H, s), 0.06 (3H, s), 0.06 (3H, s), 0.03 (3H, s).

(3) Compound A-11 (126.6 mg, 0.278 mmol) obtained in (2) was dissolved in dimethylformamide (1.2 mL), and triethylamine (0.126 mL, 0.9 mmol) was added under cooling at 0 °C. And stir for 40 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added, and ethyl acetate was evaporated. The residue obtained by concentrating under reduced pressure was purified by silica gel chromatography (n-hexane/ethyl acetate=95/5) to afford Compound A-12 (126.5mg, 79%).

¹ H-NMR (CDCl ₃ ) δ: 5.82 (1H, ddd, J = 17.0, 10.0, 7.0 Hz), 5.17 (1H, dd, J = 17.2, 1.1 Hz), 5.11 (1H, ddd, J = 10.0, 2.0, 1.0 Hz), 4.00-3.95 (1H, m), 2.42 - 2.37 (2H, m), 2.32 (2H, t, J = 7.8 Hz), 1.97 (1H, t, J = 2.6 Hz), 1.85- 1.65 (3H, m), 1.43-1.29 (2H, m), 1.26 (2H, t, J = 7.2 Hz), 0.89 (19H, s), 0.09 (3H, s), 0.06 (3H, s), 0.06 (3H, s), 0.03 (3H, s).

(4) Compound A-12 (46 mg, 0.08 mmol) obtained in (3) and Compound B-2 (47 mg, 0.1 mmol) obtained in Example 1 (3) were dissolved in toluene/triethylamine (1/1). 2 mL), palladium triphenylphosphine palladium (12 mg, 0.01 mmol) was added, and the mixture was stirred at 110 ° C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, it was concentrated under reduced pressure. The residue was crudely purified by thin layer chromatography (n-hexane/ethyl acetate = 19/1). The obtained crude purified product was dissolved in acetone, and hydrochloric acid (6N, 0.1 mL, 0.6 mmol) was added thereto, and 50 minutes at 0 ° C. After stirring, hydrochloric acid (6N, 0.2 mL, 1.2 mmol) was added and stirred at room temperature for 40 minutes. After adding a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted with ethyl acetate. The residue obtained by concentration under reduced pressure was crude purified by EtOAc EtOAc (EtOAc: EtOAc: The crude product was purified by reverse phase HPLC (A = 95% water / acetonitrile; B = 0.5% acetic acid / 5% water / acetonitrile; B = 65%) to give compound D-1 (14.6 mg, 36%) .

¹ H-NMR (CDCl ₃ ) δ: 6.40 (1H, d, J = 11.5 Hz), 6.00 (1H, d, J = 11.2 Hz), 5.27 (1H, d, J = 1.5 Hz), 4.99 (1H, d, J = 2.0 Hz), 4.39 (1H, t, J = 4.0 Hz), 3.92-3.84 (1H, m), 2.86-2.79 (1H, m), 2.65 (1H, dd, J = 13.3, 4.3 Hz ), 2.30-2.20 (4H, m), 2.05-1.96 (3H, m), 1.88 (2H, t, J = 10.0 Hz), 1.81-1.64 (8H, m), 1.56 (6H, dt, J = 15.3) , 4.5 Hz), 1.51 (6H, s), 1.49-1.46 (3H, m), 1.45 (9H, s), 1.40-1.24 (5H, m), 1.06 (3H, d, J = 6.6 Hz), 0.54 (3H, s), 0.54 (3H, s).

[Embodiment 6] (5Z,7E)-(1S,2S,3R,20R)-2-(2-(1,1-dimethyl)ethoxycarbonylpropyl)-23-yne-9,10-broken-5, Manufacture of 7,10(19)-cholestrylene-1,3,25-triol (Compound D-6)

(1) The compound A-9 (565 mg, 1.29 mmol) obtained in Example 5 (1) was dissolved in methylene chloride, and then, under cooling at -78 ° C, diisobutylaluminum hydride (1 M toluene, 2 mL, 2 mmol) was added. ), stirring at -78 degrees for 2 hours. Anhydrous methanol (1 mL) was added, and the mixture was stirred at room temperature for 20 minutes, and then a saturated aqueous solution of sodium potassium tartrate was added thereto, followed by stirring for 10 minutes. Ethyl acetate was added, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was dissolved in tetrahydrofuran (18.3 mL), and t-butanol (18.3 mL) and 2-methyl-2-butene (6 mL) were added and allowed to cool. An aqueous solution (5 mL) of sodium hypochlorite (1.47 g, 13 mmol) and sodium hydrogen phosphate (1.01 g, 6.5 mmol) was added and stirred for 1 hour. A saturated aqueous solution of sodium thiosulfate was added, and aq. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (n-hexane/ethyl acetate=9/1→7/1→5/1) to afford compound A-13 (233.7) Mg, 38%).

¹ H-NMR (CDCl ₃ ) δ: 5.82 (1H, ddd, J = 17.0, 10.0, 7.0 Hz), 5.17 (1H, dd, J = 17.2, 1.1 Hz), 5.11 (1H, ddd, J = 10.0, 2.0, 1.0 Hz), 4.00-3.95 (1H, m), 2.42 - 2.37 (2H, m), 2.32 (2H, t, J = 7.8 Hz), 1.97 (1H, t, J = 2.6 Hz), 1.85- 1.65 (3H, m), 1.43-1.29 (2H, m), 1.26 (2H, t, J = 7.2 Hz), 0.89 (19H, s), 0.09 (3H, s), 0.06 (3H, s), 0.06 (3H, s), 0.03 (3H, s).

(2) Compound A-13 (228.4 mg, 0.5 mmol) obtained in (1) was added toluene (5 mL), and N,N-dimethylformamide dit-butyl acetal (1.1 mL, 4 mmol) was added. The mixture was stirred at 80 ° C for 1 hour. After ethyl acetate was added and washed with saturated brine, the organic layer was dried over magnesium sulfate. The residue was purified by EtOAc (EtOAc:EtOAc)

¹ H-NMR (CDCl ₃ ) δ: 5.83 (1H, ddd, J = 17.0, 10.0, 7.0 Hz), 5.15 (1H, dq, J = 17.2, 1.0 Hz), 5.10 (1H, dq, J = 10.0, 1.0 Hz), 4.12 (1H, dd, J = 8.0, 5.0 Hz), 4.00 (1H, td, J = 6.2, 3.8 Hz), 2.39 (2H, dd, J = 6.1, 2.7 Hz), 2.17 (2H, t, J = 8.0 Hz), 1.79-1.63 (3H, m), 1.44 (9H, s), 1.40-1.20 (4H, m), 0.89 (18H, s), 0.09 (3H, s), 0.06 (3H) , s), 0.05 (3H, s), 0.03 (3H, s).

(3) Compound A-14 (59.6 mg, 0.12 mmol) obtained in (2) and Compound B-2 (60 mg, 0.14 mmol) obtained in Example 1 (3) were dissolved in toluene/triethylamine (1/ 1,2 mL), adding triphenylphosphine palladium (17 mg, 0.0147 mmol), and stirring at 110 ° C for 3.5 hours under a nitrogen atmosphere. mix. After cooling to room temperature, it was concentrated under reduced pressure. The residue was crudely purified by thin layer chromatography (n-hexane/ethyl acetate = 19/1). The obtained crude purified product was dissolved in tetrahydrofuran, and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 0.84 mL, 0.84 mmol) was added, and the mixture was stirred at 60 ° C for 2 hours. Ethyl acetate was added and washed with water, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by EtOAc (t-hexane/ethyl acetate = 1/1), and then reverse phase HPLC (A = 95% water / acetonitrile; B = 0.5) After purification by % water / 40% methanol / acetonitrile; B = 85%), Compound D-6 (5.0 mg, 7%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 6.40 (1H, d, J = 11.5 Hz), 6.00 (1H, d, J = 11.2 Hz), 5.27 (1H, d, J = 1.5 Hz), 4.99 (1H, d, J = 2.0 Hz), 4.39 (1H, t, J = 4.0 Hz), 3.92-3.84 (1H, m), 2.86-2.79 (1H, m), 2.65 (1H, dd, J = 13.3, 4.3 Hz ), 2.30-2.20 (4H, m), 2.05-1.96 (3H, m), 1.88 (2H, t, J = 10.0 Hz), 1.81-1.64 (8H, m), 1.56 (6H, dt, J = 15.3) , 4.5 Hz), 1.51 (6H, s), 1.49-1.46 (3H, m), 1.45 (9H, s), 1.40-1.24 (5H, m), 1.06 (3H, d, J = 6.6 Hz), 0.54 (3H, s), 0.54 (3H, s).

[Embodiment 7] (5Z,7E)-(1R,2S,3R,20R)-2-((t-butylcarbonyloxy)methoxycarbonylethoxy)-23-yne-9,10-broken-5,7 ,10(19)-manufacturing of cholestrin-1,3,25-triol (compound C-7)

(1) Compound A-4 (164.3 mg, 0.360 mmol) obtained in Example 2 (1) was dissolved in anhydrous N,N-dimethylformamide (1.2 mL), cooled at 0 ° C, and triethyl Amine (0.15 mL, 1.08 mmol) and neopentyloxymethyl chloride (0.104 mL, 0.719 mmol) were stirred at room temperature for 1 hour. After 1 hour, sodium iodide (150 mg, 1.008 mmol) and potassium carbonate (140 mg, 1.008 mmol) were added, and the mixture was stirred and stirred at 50 ° C for 30 minutes. It was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (d-hexane/ethyl acetate=5/1) to afford Compound A-15 (158.0mg, yield 77%).

¹ H-NMR (CDCl ₃ ) δ: 5.98-5.90 (1H, m), 5.76 (2H, s), 5.21. (1H, dt, J = 17.32, 1.46 Hz), 5.14 (1H, dt, J = 10.37, 1.10 Hz), 4.30 (1H, dd, J = 8.00, 3.00 Hz), 4.02-3.82 (3H, m), 3.42 (1H, dd, J = 5.61, 3.41 Hz), 2.62 (2H, t, J = 6.71) Hz), 2.47 (1H, ddd, J = 16.83, 2.68, 5.50 Hz), 2.34 (1H, ddd, J = 16.83, 2.76, 5.50 Hz), 1.96 (1H, t, J = 2.68 Hz), 1.21 (9) H, s), 0.90 (9H, s), 0.89 (9H, s), 0.09 (3H, s), 0.08 (3H, s), 0.07 (3H, s), 0.03 (3H, s).

(2) Compound A-15 (40 mg, 0.07 mmol) obtained in (1) and Compound B-2 (36 mg, 0.085 mmol) obtained in Example 1 (3) were used as a starting material, and Example 2 (3) In the same manner, Compound C-7 (7.8 mg, 18%) was obtained.

¹ H-NMR (CDCl 3 ) δ: 6.42 (1H, d, J = 11.47 Hz), 6.02 (1H, d, J = 11.22 Hz), 5.81-5.76 (2H, m), 5.39 (1H, d, J = 1.46 Hz), 5.09 (1H, d, J = 2.20 Hz), 4.44 (1H, s), 4.04-3.95 (2H, m), 3.85-3.80 (1H, m), 3.36 (1H, dd, J = 7.56) , 3.17Hz), 2.85-2.57(6H,m), 2.28-1.81(8H,m), 1.59-1.24(16H,m),1.23(9H,s),1.06(3H,d,J=6.59Hz) , 0.54 (3H, s).

[Embodiment 8] (5Z,7E)-(1R,2S,3R,20R)-2-((phenylcarbonyloxy)methoxycarbonylethoxy)-23-yne-9,10-broken-5,7,10 (19) Manufacture of cholestrin-1,3,25-triol (compound C-8)

The compound A-4 (175 mg, 0.383 mmol) obtained in Example 2 (1) was used as a starting material, and the neopentyloxymethyl chloride in Example 7 (1) was substituted with benzhydryloxymethyl. The base chloride was subjected to the same procedure as in Example 7 (1) to give the compound A-16 (41.3 mg, 0.07 mmol) and the compound B-2 obtained in Example 1 (3) (34 mg). , 0.08 mmol) was obtained as the starting material in the same manner as in Example 7 (2) to give Compound C-8 (4.9 mg, 11%).

¹ H-NMR (CDCl 3 ) δ: 8.09-8.07 (2H, m), 7.62-7.44 (3H, m), 6.41 (1H, d, J = 10.98 Hz), 6.05-6.01 (3H, m), 5.38 ( 1H,d,J=1.46Hz),5.07(1H,d,J=1.95Hz),4.44(1H,d,J=2.93 Hz),4.05-3.97(2H,m),3.87-3.82(1H,m ), 3.36 (1H, dd, J = 7.56, 3.17 Hz), 2.85-2.64 (4H, m), 2.32-2.18 (2H, m), 2.05-1.53 (9H, m), 1.49-1.24 (4H, m ), 1.06 (3H, d, J = 6.34 Hz), 0.55 (3H, s).

[Embodiment 9] (5Z,7E)-(1R,2S,3R,20R)-2-((2-carboxy-2,2-ethanol)ethoxy)-23-yne-9,10-broken-5,7,10 (19) Manufacture of cholestrin-1,3,25-triol (Compound E-1)

(1) Dissolving Compound A-17 (6.03 g, 22.8 mmol) described in the literature (for example, Kittaka, The Journal of Organic Chemistry (J. Org. Chem.), 2004, 69, pp. 7463-7471) To the N-methylpyrrolidone (60 mL), potassium t-butoxide (11.88 g, 114 mmol) was added, and the mixture was stirred at 130 °C for 4 hours. Cool to room temperature, add water (240 mL), add Diaion HP-20SS (Mitsubishi Chemical Prepared, 30 g (dry weight)), stirred overnight at room temperature. After filtration, the solid was washed with saturated aqueous ammonium chloride (100 mL) and water (200 mL) and evaporated. The extract was concentrated under reduced pressure and diluted with ethyl acetate. The residue obtained by concentrating the organic layer EtOAc (EtOAc m.)

¹ H NMR (CDCl ₃ ) δ: 7.51 - 7.36 (5H, m), 5.54 (1H, s), 4.61 (1H, s), 4.40 - 4.29 (2H, m), 4.08 (1H, t, J = 4.27 Hz), 4.01 (1H, dd, J=9.27, 2.68 Hz), 3.93 (1H, br s), 3.83-3.75 (3H, m), 3.60-3.50 (3H, m), 3.41 (3H, s), 0.59-0.41 (3H, m).

(2) The compound A-18 (2.97 g, 8.10 mmol) obtained in (1) was dissolved in anhydrous pyridine (30 mL), and cooled at 0 ° C, and then pentyl chloride (1.15 mL, 9.32 mmol) was added at Stir for 1 hour at the same temperature. Anhydrous methanol (3 mL) was added, stirred at room temperature for 5 min and concentrated. After dissolving in toluene and washing with saturated brine, the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and dried. This crude was dissolved in anhydrous dichloromethane (20 mL), cooled at 0 <0>C, <""&&&&&&&&&&&&&& The ester (2.14 mL, 9.32 mmol) was stirred at room temperature for 1 hour. After adding anhydrous methanol (5 mL), it was concentrated under reduced pressure. After dissolving in toluene and washing with water, the organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (5% ethyl acetate / n-hexane - 10% ethyl acetate / n-hexane) to give compound A-19 (3.19 g, yield The rate is 69%).

¹ H NMR (CDCl ₃ ) δ: 7.49-7.34 (5H, m), 5.56 (1H, s), 4.45 (1H, s), 4.29-4.25 (2H, m), 4.18 (1H, d, J = 11.22) Hz), 3.98-3.92 (3H, m), 3.75 (1H, t, J = 12.08 Hz), 3.65 (1H, t, J = 2.68 Hz), 3.56 (2H, dd, J = 29.76, 9.51 Hz), 3.35 (3H, s), 1.19 (9H, s), 0.91 (9H, s), 0.61 - 0.51 (4H, m), 0.10 (3H, s), 0.10 (3H, s).

(3) A-19 (3.17 g, 5.61 mmol) obtained in (2) was dissolved in cyclohexane (63 mL), and cesium carbonate (775 mg, 3.92 mmol) and benzamyl peroxide (136 mg, 0.56 mmol) were added. N-bromosuccinimide (1.21 g, 6.73 mmol) was heated and refluxed for 1 hour. After cooling, it was filtered with celite, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give crude (4.0 g). This crude product was dissolved in a mixed solvent of 1-propanol (36 mL) and water (4 mL), and activated zinc (7.38 g, 112.2 mmol) and sodium cyanoborohydride (1.42 g, 22.4 mmol) were added and carried out. Heat back to reflux. After cooling, it was filtered with diatoms, and the solid was washed with 1-propanol, and the liquid was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate and washed with brine, The residue obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→80/20) to afford compound A-20 (1.50 g, yield 50%) .

¹ H NMR (CDCl ₃ ) δ: 8.05-8.02 (2H, m), 7.59-7.43 (3H, m), 6.11 (1H, ddd, J = 11.00, 17.32, 6.00 Hz), 5.78-5.75 (1H, m ), 5.41 (1H, dt, J = 17.32, 1.34 Hz), 5.30 (1H, dt, J = 10.49, 1.22 Hz), 4.17 (1H, d, J = 11.47 Hz), 3.96-3.93 (2H, m) , 3.81 (1H, dd, J = 11.47, 5.12 Hz), 3.73 - 3.68 (2H, m), 3.64 (1H, d, J = 9.76 Hz), 3.50 (1H, d, J = 9.76 Hz), 1.18 ( 9H, s), 0.90 (9H, s), 0.55 (4H, t, J = 1.95 Hz), 0.09 (3H, s), 0.07 (3H, s).

(4) A-20 (2.41 g, 4.5 mmol) obtained in (3) was dissolved in acetonitrile (25 mL), triethylamine (1.26 mL, 9 mmol), trimethylamine hydrochloride (86 mg, 0.9 mmol) ), p-toluenesulfonyl chloride (1.30 g, 6.8 mmol) was added in the order, and stirred at room temperature for 1 hour. After adding a saturated aqueous solution of sodium hydrogencarbonate, the mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. This crude product (3.31 g) was dissolved in tetrahydrofuran (18 mL), and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 13.5 mL, 13.5 mmol) was added, and the mixture was heated under reflux for 1.5 hours. After cooling, the organic layer was dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10) to afford Compound A-21 (851 mg, yield 47%).

¹ H NMR (CDCl ₃ ) δ: 8.06-8.02 (2H, m), 7.61-7.44 (3H, m), 6.10-6.01 (1H, m), 5.67-5.64 (1H, m), 5.42 (1H, dt , J = 17.24, 1.34 Hz), 5.32 (1H, dt, J = 10.57, 1.22 Hz), 4.04 (2H, dd, J = 27.32, 11.22 Hz), 3.65 (1H, d, J = 10.24 Hz), 3.53 (1H, d, J = 10.24 Hz), 3.17 (1H, dd, J = 7.32, 5.37 Hz), 3.10-3.06 (1H, m), 2.75 (1H, t, J = 4.39 Hz), 2.60 (1H, Dd, J = 4.88, 2.93 Hz), 1.19 (9H, s), 0.55 (4H, s).

(5) A solution of trimethyldecyl acetylene (1.62 mL, 11.5 mmol) in tetrahydrofuran (3 mL) was cooled with dry ice-acetone under nitrogen. An n-butyl lithium hexane solution (2.64 M, 3.97 mL, 10.5 mmol) was added thereto and stirred for 45 minutes. (4) The obtained compound A-21 (846 mg, 2.1 mmol) in tetrahydrofuran (6 mL), trifluoro boron-diethyl ether (0.343 mL, 2.73 mmol) was added to dry ice-acetone cooling. After 2 hours, stirring was carried out at 0 ° C for 1 hour. Saturated aqueous ammonium chloride solution was added and the mixture was returned to room temperature and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate and brine, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The obtained residue was dissolved in anhydrous methanol (10 mL), sodium sulfate (870 mg, 6.3 mmol) was added, and the mixture was stirred at 50 ° C for 1 hour. After cooling, it was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with brine, and then evaporated. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→50/50→35/65) to give compound A-22 (311.5mg) , yield 62%).

¹ H NMR (CDCl ₃ ) δ: 5.57 (1H, ddd, J = 17.00, 11.00, 6.00 Hz), 4.88 (1H, dt, J = 17.00, 1.70 Hz), 4.73 (1H, dt, J = 11.00, 1.70) Hz), 3.85-3.81 (1H, m), 3.51 (1H, ddd, J = 8.42, 5.73, 2.07 Hz), 3.16 (1H, d, J = 9.50 Hz), 3.05 (1H, d, J = 9.50 Hz) ), 2.85 (2H, dd, J = 4.63, 2.20 Hz), 2.12.1.22 (2H, m), 1.85 (1H, t, J = 2.68 Hz).

(6) Compound A-22 (534.4 mg, 2.26 mmol) obtained in (5) was dissolved in anhydrous pyridine (7.5 mL), and neopentyl chloride (0.276) was added at 0 °C. mL, 2.26 mmol), stirred at the same temperature for 45 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The obtained residue was dissolved in anhydrous dichloromethane (10 mL), and 2,6-dimethylpyridine (1.1 mL, 9.22 mmol), t-butyl dimethyl decyl trifluoromethanesulfonate ( 1.7 mL, 7.55 mmol), stirred at the same temperature for 1.5 hours. Ethyl acetate was added, and the mixture was washed with EtOAc. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=99/1→85/15) to afford Compound A-23 (1.08 g, yield 91%).

¹ H-NMR (CDCl ₃ ) δ: 6.00-5.91 (1H, m), 5.21. (1H, d, J = 17.32 Hz), 5.13 (1H, d, J = 11.00 Hz), 4.32 (1H, dd, J =7.07,3.90 Hz), 4.03 (2H, dd, J=19.03, 11.22 Hz), 3.94 (1H, dd, J = 10.73, 5.85 Hz), 3.64 (1H, d, J = 9.76 Hz), 3.45 (1H) , d, J = 9.76 Hz), 3.39 (1H, t, J = 4.27 Hz), 2.51 (1H, ddd, J = 16.83, 6.00, 3.00 Hz), 2.36 (1H, ddd, J = 16.71, 6.10, 2.56 Hz), 1.95 (1H, t, J = 2.56 Hz), 1.19 (9H, s), 0.90 (9H, s), 0.88 (9H, s), 0.55-0.483H, m), 0.11 (3H, s) , 0.09 (3H, s), 0.06 (3H, s), 0.03 (3H, s).

(7) The compound A-23 (70 mg, 0.15 mmol) obtained in (6) and the compound B-3 (69 mg, 0.16 mmol) obtained in Example 1 (4) were used as starting materials, and Example 1 (5) The same reaction gave compound AB-3 (48.1 mg, 37.4%).

¹ H-NMR (CDCl ₃ ) δ: 6.18 (1H, d, J = 10.98 Hz), 6.02 (1H, d, J = 11.47 Hz), 5.32 (1H, s), 5.01 (1H, s), 4.47 ( 1H, s), 4.03 (1H, q, J = 4.15 Hz), 3.91 (1H, d, J = 9.03 Hz), 3.58 (1H, dd, J = 11.10, 4.03 Hz), 3.46-3.39 (2H, m ), 3.32 (1H, d, J = 9.51 Hz), 3.21 (1H, br s), 2.80 (1H, t, J = 7.81 Hz), 2.61 (1H, d, J = 13.42 Hz), 2.24 (1H, Dd, J = 16.34, 3.42 Hz), 2.10 (1H, dd, J = 13.66, 4.15 Hz), 2.05-1.84 (4H, m), 1.66-1.49 (12H, m), 1.43-1.30 (4H, m) , 1.07 (4H, d, J = 6.59 Hz), 0.98-0.83 (36H, m), 0.82-0.81 (2H, m), 0.70-0.64 (9H, m), 0.57-0.54 (6H, m), 0.51 -0.36 (6H, m), 0.11 (3H, s), 0.10 (3H, s), 0.08 (3H, s), 0.07 (3H, s).

(8) The compound AB-3 (48.1 mg, 0.056 mmol) obtained in (7) was used as a material, and was treated in the same manner as in Example 1 (6). This reaction product (28.5 mg, 0.0327 mmol) was dissolved in a mixed solvent of anhydrous dichloromethane / acetonitrile (1/11 mL), and after cooling at 0 ° C, p-toluenesulfonic acid monohydrate (31 mg, 0.163 mmol) and lithium were added. Tetrafluoroborate (30 mg, 0.327 mmol) was stirred at the same temperature for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added, and ethyl acetate was evaporated. The residue obtained by concentration under reduced pressure was purified by a thin layer chromatography (ethyl acetate / acetone = 9 / 1 + 0.5% acetic acid) and then reverse phase HPLC (A = 95% water / acetonitrile; B = After purification by 0.5% water/40% methanol/acetonitrile; B = 85%), compound E-1 (4.9 mg, 16.6%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 6.41 (1H, d, J = 11.22 Hz), 6.01 (1H, d, J = 10.98 Hz), 5.37 (1H, s), 5.08 (1H, d, J = 1.46) Hz), 4.48 (1H, d, J = 2.68 Hz), 4.06-3.82 (2H, m), 3.55-3.25 (2H, m), 2.88-2.60 (2H, m), 2.28-1.54 (13H, m) , 1.42-1.20 (10H, m), 1.10-1.08 (1H, m), 1.06 (3H, d, J = 6.59 Hz), 0.91 (3H, d, J = 4.88 Hz), 0.54 (3H, s).

[Embodiment 10] (5Z,7E)-(1R,2S,3R,20R)-2-(2-carboxyethoxy)-26,27-dimethyl-23-yne-9,10-broken-5,7,10 (19) Manufacture of cholestrin-1,3,25-triol (compound F-1)

(1) Trimethyldecyl acetylene (1.84 mL, 13.0 mmol) was dissolved in 1,4-dioxane (15 mL), and n-butyl was added dropwise thereto over 10 minutes while cooling in an ice bath under an argon atmosphere. Lithium (1.59 M n-hexane solution, 8.18 mL, 13.0 mmol). Compound B-4 (1.91 g, 4.33 mmol) synthesized by the method of Tanaka (International Publication WO98/58909) was dissolved therein. 1,4-Dioxane (10 mL) was added and heated at 110 ° C for 24 hours under reflux. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added and stirred, and then extracted with n-hexane. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was dissolved in tetrahydrofuran-methanol (1:1, 20 mL), and potassium carbonate ( 718 mg, 5.20 mmol) was added and stirred at room temperature overnight. After the water was added to the reaction mixture, the mixture was extracted with EtOAc. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (n-hexane) to afford Compound B-5 (1.14 g, yield: 89%).

¹ H-NMR (CDCl ₃ ) δ: 5.65 (1H, s), 2.90-2.86 (1H, m), 2.25 (1H, dt, J = 16.6, 3.0 Hz), 2.10-1.88 (5H, m), 1.72 - 1.25 (9H, m), 1.11 (3H, d, J = 6.6 Hz), 0.58 (3H, s) ppm.

(2) Compound B-5 (301 mg, 1.02 mmol) obtained in (1) was dissolved in tetrahydrofuran (10 mL), and n-butyllithium (1.59 M) was added dropwise while cooling at -78 ° C under an argon atmosphere. N-hexane solution, 0.673 mL, 1.02 mmol) was stirred for 30 min. Hereto, 3-pentanone (0.216 mL, 2.04 mmol) was added, and the mixture was stirred at -78 ° C for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was warmed to room temperature. The reaction mixture was extracted with EtOAc. The residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (n-hexane/ethyl acetate=9/1) to afford compound B-6 (205 mg, yield 53%).

¹ H-NMR (CDCl ₃ ) δ: 6.42 (1H, d, J = 11.2 Hz), 6.02 (1H, d, J = 11.2 Hz), 5.39 (1H, s), 5.10 (1H, s), 4.44 ( 1H,t,J=3.9 Hz),4.11-4.07(1H,m),3.84-3.81(1H,m),3.75-3.68(2H,m),3.39(1H,dd,J=7.4,3.3Hz) , 2.84-2.81(1H,m), 2.68(1H,dd,J=13.7,4.4Hz),2.52(2H,t,J=6.8Hz), 2.29-2.20(3H,m),2.15-1.83(6H m), 1.70-1.22 (14H, m), 1.08-1.01 (9H, m), 0.55 (3H, s) ppm.

(3) Compound B-6 (396 mg, 1.04 mmol) obtained in (2) was dissolved in anhydrous N,N-dimethylformamide (4 mL), and chlorotriethyl decane (0.283 mL, 1.68 mmol), Imidazole (152 mg, 2.23 mmol) and 4-dimethylaminopyridine (27 mg, 0.22 mmol) were heated and stirred at 50 ° C for 1 hour. After cooling to room temperature, anhydrous methanol (1 mL) was added and stirred for 30 min. The mixture was diluted with toluene, washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the organic layer EtOAc (EtOAc m.

¹ H-NMR (CDCl ₃ ) δ: 5.65 (1H, s), 2.91-2.85 (1H, m), 2.24 (1H, dd, J = 16.46, 3.54 Hz), 2.10 (1H, dd, J = 16.58, 6.83 Hz), 2.02-1.88 (4H, m), 1.71-1.58 (9H, m), 1.54-1.24 (7H, m), 1.08 (3H, d, J = 8.00 Hz), 0.98-0.91 (22H, m ), 0.73-0.64 (9H, m), 0.58 (3H, s), 0.52 (2H, q, J = 7.97 Hz).

(4) The compound A-4 (457 mg, 1 mmol) obtained in Example 2 (1) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and triethylamine (0.421 mL, 3 mmol), Chloromethylbenzyl ether (0.276 mL, 2 mmol) was stirred at 0 ° C for 1 hour and 45 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate and washed with brine. will have The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=95/5) to afford Compound A-24 (485 mg, yield 84%).

(5) The compound B-7 (44 mg, 0.09 mmol) obtained in (3) and the compound A-24 (43 mg, 0.075 mmol) obtained in (4) are used as starting materials, according to the method described in Example 5 (4). , the coupling reaction and the deprotection reaction are carried out. The obtained reaction crude was subjected to crude purification by a thin layer of silica gel chromatography (ethyl acetate/acetone = 4/1 + acetic acid (1.5 v/v%)), followed by reverse phase HPLC (A = 95% water / Acetonitrile; B = 0.5% water / 40% methanol / acetonitrile; B = 75%) was purified to afford compound F-1 (4.7 mg, 12%).

¹ H-NMR (CDCl ₃ ) δ: 6.42 (1H, d, J = 10.98 Hz), 6.00 (1H, d, J = 10.98 Hz), 5.37 (1H, d, J = 1.46 Hz), 5.08 (1H, d, J = 1.95 Hz), 4.47 (1H, d, J = 2.93 Hz), 4.08-3.94 (2H, m), 3.82-3.74 (1H, m), 3.33 (1H, dd, J = 8.17, 3.05 Hz) ), 2.83 (1H, d, J = 12.20 Hz), 2.69-2.60 (3H, m), 2.30-2.20 (2H, m), 1.98 (2H, d, J = 11.71 Hz), 1.91-1.80 (1H, m), 1.72-1.24 (16H, m), 1.07 (3H, d, J = 6.34 Hz), 1.03 (8H, t, J = 7.44 Hz), 0.54 (3H, s).

[Example 11] (5Z,7E)-(1R,2S,3R,20R)-2-(2-carboxyethoxy)-26,27-nor-25-cyclopentyl-23-yne-9,10-broken-5 Manufacture of 7,10(19)-cholestrylene-1,3,25-triol (compound F-2)

(1) The compound B-5 (442 mg, 1.5 mmol) obtained in Example 10 (1) was used as a starting material, and a mixture of compound B-8 and cyclopentanone was obtained in the same manner as in Example 10 (2). (427.2 mg). The crude material was used as a starting material, using anhydrous N,N-dimethylformamide (4.5 mL), chlorotriethyl decane (0.283 mL, 1.68 mmol), imidazole (152 mg, 2.23 mmol), 4-di Methylaminopyridine (27 mg, 0.22 mmol) was obtained in the same manner as in Example 10 (3) to give Compound B-9 (506.2mg, yield 68%).

¹ H-NMR (CDCl ₃ ) δ: 5.65 (1H, s), 2.92-2.85 (1H, m), 2.24 (1H, dd, J = 16.46, 3.29 Hz), 2.08 (1H, dd, J = 16.10, 6.83 Hz), 2.02-1.57 (19H, m), 1.54-1.26 (7H, m), 1.07 (4H, d, J = 7.56 Hz), 0.98-0.91 (15H, m), 0.73-0.63 (8H, m ), 0.57 (3H, s), 0.52 (3H, q, J = 7.97 Hz).

(2) Compound B-9 (44 mg, 0.09 mmol) obtained in (1) and carried out The compound A-24 (43 mg, 0.075 mmol) obtained in Example 10 (4) was used as a starting material to give Compound F-2 (2.0 mg, yield 5%).

¹ H-NMR (CDCl ₃ ) δ: 6.41 (1H, d, J = 10.98 Hz), 6.00 (1H, d, J = 10.98 Hz), 5.36 (1H, s), 5.07 (1H, s), 4.46 ( 1H, s), 4.10-3.93 (2H, m), 3.78 (1H, br s), 3.30 (1H, d, J = 6.59 Hz), 3.07-2.62 (9H, m), 2.30-2.19 (2H, m ), 2.05-1.24 (25H, m), 1.06 (3H, d, J = 6.59 Hz), 0.54 (3H, s).

[Example 12] (5Z, 7E)-(1R, 2S, 3R, 20R)-2-(2-carboxyethoxy)-23-yne-9,10-broken-5,7,10(19) -manufacturing of cholestyrene-1,3-diol (compound G-1)

(1) 3-methyl-1-butyne (2.14 mL, 21 mmol) was dissolved in 1,4-dioxane (20 mL), and added dropwise to the mixture under an argon atmosphere for 15 minutes while cooling in an ice bath. -butyl lithium (2.64 M n-hexane solution, 7.95 mL, 21.0 mmol). Compound B-9 (3.19 g, 7.00 mmol) synthesized by the method of Tanaka (International Publication WO98/58909) was dissolved in 1,4-dioxane (10 mL) and added at 110 ° C. Heat reflux at 24 hours. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added and stirred, and then extracted with n-hexane. The obtained organic layer was washed with brine, dried over anhydrous sodium The residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (n-hexanes: 3% ethyl acetate/n-hexane) to afford compound B-10 (1.66 g, yield 70%).

¹ H-NMR (CDCl ₃ ) δ: 5.65 (1H, s), 2.89-2.86 (1H, m), 2.54-2.52 (1H, m), 2.22 (1H, ddd, J = 16.4, 3.4, 2.4 Hz) , 2.02-1.86 (4H, m), 1.71-1.26 (9H, m), 1.11 (9H, ddd, J = 21.3, 11.7, 4.9 Hz), 0.57 (3H, s) ppm.

(2) Compound B-10 (236 mg, 0.7 mmol) obtained in (1) and Compound A-3 (262.0 mg, 0.496 mmol) obtained in Example 1 (2) were used as a starting material, and Example 1 (5) The compound AB-4 (199.4 mg, 57%) was obtained in the same manner, and then AB-4 (191.0 mg, 0.273 mmol) was used as a starting material, and compound AB- was obtained by the same procedure as in Example 2 (1). 5 (34.6 mg, 17.7%).

¹ H-NMR (CDCl ₃ ) δ: 6.21 (1H, d, J = 11.5 Hz), 6.00 (1H, d, J = 11.5 Hz), 5.28 (1H, s), 5.00 (1H, s), 4.46 ( 1H, s), 4.07 (1H, dd, J = 9.0, 5.1 Hz), 3.90 (2H, t, J = 6.0 Hz), 3.38 (1H, s), 2.80 (1H, dd, J = 10.0, 4.0 Hz) ), 2.65-2.62 (3H, m), 2.58-2.50 (3H, m), 2.22 (1H, dt, J = 15.0, 2.0 Hz), 2.14 (1H, dd, J = 14.1, 5.1 Hz), 2.01- 1.29 (26H, m), 1.15 (9H, d, J = 6.8 Hz), 1.07 (3H, d, J = 6.3 Hz), 0.90 (9H, s), 0.87 (9H, s), 0.55 (3H, s ), 0.10 (3H, s), 0.09 (6H, s), 0.07 (3H, s).

(3) The AB-5 (34.6 mg, 0.0485 mmol) obtained in (2) was dissolved in a mixed solvent of dichloromethane (1 mL) and anhydrous acetonitrile (1 mL), and lithium tetrafluoroborate was added with stirring at 0 ° C (46.9) Mg, 0.5 mmol), 1 M sulfuric acid / acetonitrile solution (0.039 mL, 0.039 mmol), stirred at 0 ° C for 1 hour. After neutralizing with a saturated aqueous solution of sodium hydrogencarbonate, ethyl acetate was evaporated. The obtained residue was subjected to crude purification by a thin layer of silica gel chromatography (ethyl acetate/acetone = 4/1 + acetic acid (1.5 v/v%)), followed by reverse phase HPLC (A = 95% water / acetonitrile; B = 0.5% water / 40% methanol / acetonitrile; B = 85%). After purification, compound G-1 (4.5 mg, 19%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 6.42 (1H, d, J = 11.0 Hz), 6.00 (1H, d, J = 11.7 Hz), 5.38 (1H, d, J = 1.5 Hz), 5.09 (1H, d, J = 2.0 Hz), 4.48 (1H, d, J = 2.9 Hz), 4.08-3.96 (2H, m), 3.82-3.76 (1H, m), 3.34 (1H, dd, J = 8.1, 3.2 Hz ), 2.83 (1H, d, J = 12.9 Hz), 2.68-2.48 (4H, m), 2.27-2.19 (2H, m), 2.01-1.21 (16H, m), 1.15 (8H, d, J = 6.8) Hz), 1.06 (4H, d, J = 6.6 Hz), 0.54 (3H, s).

[Example 13] VDR affinity assessment

The evaluation of the VDR is to evaluate the kit by the purchased assay, for example, using POLARSCREEN VITAMIN D RECEPTOR COMPETITOR ASSAY, RED (invitrogen) Cat. No. PV4569 sold by Invitrogen, in the following order.

10 μL of the compound solution was added to each of the 384-square black plates. Each of the VDR/Fluoromone VDR Complex contained in the kit was added to each well at 10 μL, and the reaction was carried out for 2 hours at room temperature. The affinity was evaluated after measuring the fluorescence polarization after 2 hours.

Moreover, the affinity-based 1,25- (OH) 2- vitamin D ₃ affinity as the relative values of (1 / X) 1 at the time of the assessment.

It was confirmed that the compound obtained by the present invention has strong VDR affinity. In particular, it was confirmed that the compound C-1 and the compound D-1 have a very strong VDR affinity.

[Embodiment 14] VDR transcriptional activity in human bone bud cells (HOS cells)

(1) The message vector is obtained by using the pGL3 vector (promega), which is known in the literature upstream of the luciferase gene (The Journal of Biological Chemistry, Vol. 265, pp. 21881-21888, 1990). The sequence of the human osteocalcin gene promoter portion was cloned by cDNA obtained from HOS cells (started by ATCC) and constructed by insertion. The expression vector was constructed by inserting a DNA sequence encoding human VDR and human RXR into the pCDNA3 vector (Invitrogen). HOS cells were cultured in DMEM medium containing 10% FBS at 37 ° C, 5% CO ₂ , and subcultured every 2 or 3 days.

(2) The subcultured cells were collected by centrifugation, dispersed in a serum-free and phenol red-free DMEM medium at a density of 4 × 10 ⁵ cells/ml, and seeded at 0.1 mL/div in a 96-plate dish. In this system, various carriers described in (1) were tested using Lipofectamine 2000 (Invitrogen), and 0.05 mL was added to each cell. After incubating at 37 ° C for 3 hours, 2 μL of each concentration of the test compound ethanol solution or the control ethanol was added to each cell. After incubating at 37 ° C for 24 hours, the medium was taken out, washed once with PBS (-), and luciferase activity was measured by a luminometer (Berthold's) using a DualGlo-Luciferase Assay kit (Promega).

As a result, it was found that the compounds of the present invention all have a transcriptional activity with an EC ₅₀ value of 20 nM or less. Further, for the compounds C-1, C-2, D-1, E-1, F-1, and F-2, it was found that the EC ₅₀ value has a transcription activity of 0.2 nM or less. Particularly, for the compounds D-1, F-1 and F-2, it was found that the transcription activity was EC ₅₀ value of 0.02 nM or less.

[Example 15] Bone mineral density enhancement in rats with osteoporosis model (ovarian excision) (comparative test)

The ovary on both sides of a 12-week-old SD female rat (Nippon Charles River) was removed, and after 4 weeks, the compound of the present invention and 2α-(3-hydroxypropyl group) described in the manual of WO 01/62723 were released. Oxy-1α,25-dihydroxyvitamin D ₃ was orally administered by 5 times a week for 4 weeks. After 24 hours of final administration, blood was collected under ether anesthesia and euthanized. The bone density of the fourth and fifth lumbar vertebrae was measured under anesthesia using a double X-ray bone salt amount measuring device (QDR-2000, HOLOGIC). For comparison, for the sham group (although laparotomy is performed but the ovaries are not removed, the administration of the test compound is not performed) and the ovarian extract (OVX) group (although the ovary is removed but the test compound is not administered), The bone density of the lumbar spine was measured at the time of dissection. Further, the measurement of the calcium concentration in the serum of each group was also carried out.

By performing the operation, the bone density of the OVX group was confirmed to be lower than that of the sham group. The recovery of bone density was confirmed by administration of a vitamin D derivative. However, the 2α-(3-hydroxypropyl)oxy-1α,25-dihydroxyvitamin D ₃ administration group described in the International Publication WO01/62723 manual increases the calcium value in the blood as the bone density increases. In order to make the bone density more than the sham group, it is confirmed that the increase in serum calcium value is greatly increased to 1 mg/dL or more for the necessary dose (25 ng/kg).

On the other hand, the compound of the present invention was confirmed to have a range in which the increase in serum calcium value was in the range of 1 mg/dL or less in comparison with the serum calcium value of OVX, and the bone density was increased to a bone density equal to or higher than that of the sham group.

From the above results, it is known that the vitamin D ₃ derivative of the present invention or a pharmaceutically acceptable solvate thereof has a more excellent bone action than the vitamin D ₃ derivative reported in the past.

[Example 16] Inhibition of PTH secretion concentration in adenine kidney disease model rats

For 8-week-old Wistar male rats (Nippon Charles River Co., Ltd.), adenine solution of 160 mg/kg/day for 14 days was administered orally once a day to cause kidney disease. The compound solution of the present invention was administered orally on the 8th day from the adenine and administered orally once a day for 7 days. On the 7th day after adenine administration and the second day of the final administration of adenine, blood was collected from the tail vein, and serum iPTH concentration, serum calcium concentration, and serum phosphorus concentration were measured. The obtained data is a measurement value obtained by administering adenine on the seventh day as a measurement value before administration of the compound C-1, and the measurement value of the second day after the final administration of adenine is administered as the compound C-1. It is expressed as a measured value. For comparison, serum iPTH concentration is also performed for the normal group (solvent of the adenine solution and the solvent of the compound solution of the present invention) and the kidney disease group (the administration of the adenine solution and the solvent of the compound solution of the present invention). Determination of serum calcium concentration and serum phosphorus concentration.

By administering the adenine solution orally, the serum iPTH concentration of the kidney disease group was confirmed to increase as compared with the normal group. In the kidney disease group, on the 7th day after the adenine administration and the second day of the final administration of adenine, although the serum iPTH concentration difference was not observed, it was seen in the group of the compound solution to which the present invention was administered. A decrease in serum iPTH concentration. On the other hand, an increase in the serum calcium concentration and an increase in the serum phosphorus concentration depending on the administration of the compound solution of the present invention were not observed.

[Example 17] Inhibition of PTH secretion in rat parathyroid organ culture

The parathyroid gland was taken from a 12-week-old SD female rat (Nippon Charles River), and organ culture was carried out on a dish using a medium having a high phosphorus concentration. The culture was carried out for 21 hours as a preculture, and the concentration of PTH in the culture solution was used as a group. After the medium exchange, the compound of the present invention was added to the medium to 10 pM, 100 pM, 1 nM, and cultured for 48 hours. The culture medium was added at a time point 24 hours after the start of the culture, and the culture liquid was taken 24 hours to 48 hours after the start of the culture at 48 hours after the start of the culture 24 hours later. The PTH secretion inhibition rate was calculated using the amount of PTH secreted in the culture solution.

After the parathyroid gland was taken, the PTH secretion amount of each parathyroid gland when cultured for 21 hours before the culture in the high phosphorus concentration was used as the PTH value (pre) before the compound was added. The amount of PTH secreted 24 hours after the start of the culture of the added compound from 24 hours to 48 hours was taken as the PTH value (post) after the addition of the compound. Calculate the start of the culture for the added compound by the following formula The PTH secretion inhibition rate of PTH values before 24 hours of compound addition for 24 hours to 48 hours is expressed as mean ± standard error.

PTH%(post/pre)=(Amount of PTH secreted 24 hours after 24 hours to 48 hours after the start of the culture of the compound C-1) ×100/PTH amount in the medium before the compound C-1 was added

The result is shown in Figure 1. By culturing under high phosphorus conditions, an increase in PTH was confirmed after 48 hours of culture in the vehicle group to which no compound was added. In the group to which the compound of the present invention was added, inhibition of PTH secretion was observed in a dose-dependent manner, and the inhibition rate was a significant value of 100 pM and 1 nM (Kruskal-Wallis assay).

[Embodiment 18] Inhibition of PTH secretion in a rat model of renal failure (5/6 renal artery ligation)

The renal artery of the left kidney of a 12-week-old SD female rat (Nippon Charles River) was ligated, and the 2/3 region was presented with an ischemic image, and the whole right kidney was removed to prepare a 5/6 renal artery ligation model. After 4 weeks of breeding, the compound C-1 of the present invention was administered in an IV method in which the amount of the compound C-1 was increased by 4 times per week for 4 weeks, and a total of 12 times were administered to the tail vein. The administration amount of the compound of the present invention is started from 0.005 nmol/kg. Blood was collected 24 hours after the final administration from 1 week per week, and serum iPTH concentration was measured. In addition, for comparison, for the sham group (no left renal artery ligation, right kidney excision, and administration of a liquid solvent after laparotomy) and a 5/6 renal artery ligation group (5) /6 renal artery ligation surgery and administration of liquid solvent), also performed one week per week Blood was collected 24 hours later, and serum iPTH concentration was measured.

For the rat kidney failure model, the amount of PTH secreted prior to administration of Compound C-1 was approximately 2.6-fold higher for the sham group. The amount of PTH secreted before administration of each body was taken as 100%, and the % secretion of PTH after administration of Compound C-1 was calculated and expressed as mean value ± standard error. As shown in the results of Fig. 2, in the compound of the present invention, significant PTH secretion inhibitory action at the first week was confirmed, and PTH secretion was significantly inhibited after administration of the second (Student's t test).

From the above results, it was found that the vitamin D ₃ derivative of the present invention or a pharmaceutically acceptable solvate thereof has an excellent PTH secretion inhibiting action.

[Embodiment 19] Increased bone density in a rat model of renal failure

The renal artery of the left kidney of a 12-week-old SD female rat (Nippon Charles River) was ligated, and after 2/3 region showed an ischemic appearance, the whole right kidney was removed to prepare a 5/6 renal artery ligation model. . After 4 weeks of breeding, the compound C-1 of the present invention was administered three times a week, and the administration amount was increased to four times every one week, and the growth method was carried out for 4 weeks, and the total amount of the tail vein was 12 times. Cast. The dose of the compound C-1 of the present invention is started from 0.005 nmol/kg. Blood was collected and anesthetized under pentobarbital anesthesia 24 hours after the final administration. The lumbar spine and the thigh bone were taken at the time of the necropsy, and the bone density of the fourth and fifth lumbar vertebrae and the bone density of the distal femur were measured using a small animal bone density measuring device (PIXImus 2). In addition, as a comparison, the 4th and 5th lumbar vertebrae are also performed for the sham group and the vehicle group. Bone density and determination of bone density in the distal thigh bone.

The bone density (BMD) of the vehicle group was taken as 100%, and the bone density % of the sham group and the compound C-1 administration group was calculated and expressed as mean value ± standard error. The results are shown in Figures 3 and 4. For the rat kidney failure model, the bone density of the vehicle group was confirmed to be not reduced compared with the sham group. Even for a pathological condition different from the osteoporosis model such as the OVX model, it was confirmed that the compound of the present invention can significantly increase the bone density (Student's t test).

From the above results, it is known that the vitamin D3 derivative of the present invention or a pharmaceutically acceptable solvate thereof has an excellent effect on bone.

The vitamin D ₃ derivative used in the present invention not only can increase the serum calcium concentration, but also can rapidly reduce the serum PTH concentration which is abnormal due to renal failure, and can inhibit the increase of serum calcium concentration, and is enhanced in renal failure-independent Reduce the effect of bone density. The vitamin D ₃ derivative used in the present invention can be used as a therapeutic drug for secondary hyperthyroidism with PTH secretion hyperactivity, especially for concurrent PTH-dependent bone lesions or PTH-independent bone lesions. It is useful for the treatment of hyperparathyroidism.

Industrial availability

The agent containing the vitamin D ₃ derivative of the present invention or a pharmaceutically acceptable solvate thereof as an active ingredient can be used as a therapeutic agent for secondary parathyroidism.

Claims (13)

A therapeutic agent for secondary hyperparathyroidism, which comprises a vitamin D ₃ derivative represented by the following formula (1) or a pharmaceutically acceptable solvate thereof as an active ingredient; Wherein R ₁ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkylcarbonyloxyalkyl group (having a carbon number of 1 to 6 in each alkyl group), or an arylcarbonyloxyalkyl group (carbon of an aryl group) The number is 6-10, the carbon number of the alkyl group is 1~6); R ₂ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or forms a carbon number together with other R ₂ and the carbon atoms to which they are combined. a cyclic alkyl group of 3 to 6; R ₃ represents an alkyl group having 1 to 6 carbon atoms, or may form a cyclic alkyl group having 3 to 6 carbon atoms together with other R ₃ and a carbon atom to which they are bonded; X represents An oxygen atom or a methyl group, and n represents an integer of 1 or 2. A therapeutic agent for secondary hyperparathyroidism according to claim 1, wherein X represents an oxygen atom. A therapeutic agent for secondary parathyroidism according to claim 1, wherein X represents a methyl group. A therapeutic agent for secondary parathyroidism according to any one of claims 1 to 3, wherein n is 1. A therapeutic agent for secondary parathyroidism according to any one of claims 1 to 4, wherein R ₂ represents a hydrogen atom. A therapeutic agent for secondary parathyroidism according to any one of claims 1 to 5, wherein R ₁ represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, or a t-butyl group. Carbocarbonyloxymethyl or phenylcarbonyloxymethyl. The request to any of items 1 to 6 times onset hyperparathyroidism of a therapeutic agent, wherein R ₂ represents a hydrogen atom, n is 1. A therapeutic agent for secondary parathyroidism according to claim 1, wherein R ₁ represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, a t-butylcarbonyloxymethyl group. Or phenylcarbonyloxymethyl, R ₂ represents a hydrogen atom or forms a cyclopropyl group with other R ₂ and the carbon atom to which they are bonded, and R ₃ represents a methyl group, an ethyl group or a combination with other R ₃ and the like. The carbon atom forms a cyclopropyl group, and X represents an oxygen atom or a methyl group, and n=1. A therapeutic agent for secondary hyperparathyroidism characterized by containing any of the following vitamin D ₃ derivatives or a pharmaceutically acceptable solvate thereof as an active ingredient; (5Z, 7E)-(1R ,2S,3R,20R)-2-(2-carboxyethoxy)-23-yne-9,10-broken-5,7,10(19)-cholestriet-1,3,25-three Alcohol (5Z,7E)-(1R,2S,3R,20R)-2-(2-methoxycarbonylethoxy)-23-yne-9,10-broken-5,7,10(19)- Choletriene-1,3,25-triol (5Z,7E)-(1R,2S,3R,20R)-2-(2-ethoxycarbonylethoxy)-23-yne-9,10 -broken-5,7,10(19)-cholestrylene-1,3,25-triol (5Z,7E)-(1R,2S,3R,20R)-2-(2-propoxycarbonyl Ethoxy)-23-yne-9,10-broken-5,7,10(19)-cholestrylene-1,3,25-triol (5Z,7E)-(1R,2S,3R, 20R)-2-(2-(1-methyl)ethoxycarbonylethoxy)-23-yne-9,10-broken-5,7,10(19)-cholestriet-1,3 ,25-triol (5Z,7E)-(1R,2S,3R,20R)-2-(2-(1,1-dimethyl)ethoxycarbonylethoxy)-23-yne-9, 10-But-5,7,10(19)-cholestrylene-1,3,25-triol (5Z,7E)-(1R,2S,3R,20R)-2-((t-butyl) Carbonyloxy)methoxycarbonylethoxy)-23-yne-9,10-broken-5,7,10(19)-cholestrylene-1,3,25-triol (5Z,7E) -(1R,2S,3R,20R)-2-((phenylcarbonyl) Methoxycarbonyl ethoxy)-23-yne-9,10-broken-5,7,10(19)-cholestriet-1,3,25-triol (5Z,7E)-( 1S,2S,3R,20R)-2-(2-carboxypropyl)-23-yne-9,10-broken-5,7,10(19)-cholestriet-1,3,25-three Alcohol (5Z,7E)-(1S,2S,3R,20R)-2-(2-methoxycarbonylpropyl)-23-yne-9,10-broken-5,7,10(19)-dan Terpenetriene-1,3,25-triol (5Z,7E)-(1S,2S,3R,20R)-2-(2-ethoxycarbonylpropyl)-23-yne-9,10-broken -5,7,10(19)-cholestrins-1,3,25-triol (5Z,7E)-(1S,2S,3R,20R)-2-(2-propoxycarbonylpropyl )-23-yne-9,10-broken-5,7,10(19)-cholestrylene-1,3,25-triol (5Z,7E)-(1S,2S,3R,20R)- 2-(2-(1-methyl)ethoxycarbonylpropyl)-23-yne-9,10-broken-5,7,10(19)-cholestriet-1,3,25-three Alcohol (5Z,7E)-(1S,2S,3R,20R)-2-(2-(1,1-dimethyl)ethoxycarbonylpropyl)-23-yne-9,10-broken-5 ,7,10(19)-cholestrylene-1,3,25-triol (5Z,7E)-(1R,2S,3R,20R)-2-((2-carboxy-2,2-ethanol Ethoxy)-23-yne-9,10-broken-5,7,10(19)-cholestrylene-1,3,25-triol (5Z,7E)-(1R,2S,3R ,20R)-2-((2-carboxy-2,2-dimethyl)ethoxy)-23-yne-9,10-broken-5,7,10(19)-cholestriet-1 ,3,25-triol (5Z,7E)-(1R,2S,3R,20R)-2-(2-carboxyethoxy)-26,27 -Dimethyl-23-yne-9,10-broken-5,7,10(19)-cholestrylene-1,3,25-triol (5Z,7E)-(1R,2S,3R, 20R)-2-(2-carboxyethoxy)-26,27-nor-25-cyclopentyl-23-yne-9,10-broken-5,7,10(19)-cholestrietene- 1,3,25-triol. A therapeutic agent for secondary hyperparathyroidism, which comprises a vitamin D ₃ derivative represented by the following formula (17) or a pharmaceutically acceptable solvate thereof as an active ingredient; Wherein R ₁ , R ₂ and R _{3 have} the same meanings as in the formula (1). The therapeutic agent for secondary hyperparathyroidism according to any one of claims 1 to 10, wherein the secondary hyperthyroidism is a concurrent bone lesion. The therapeutic agent for secondary parathyroidism according to claim 11, wherein the bone lesion is osteoporosis. A therapeutic agent for secondary parathyroidism according to claim 12, wherein the osteoporosis is not dependent on renal failure.