A long-acting derivative of dutasteride and its preparation method and use

Abstract

The present application relates to the compound shown in formula (I) or its salt or its solvate, the present application also relates to the preparation method of formula I compound, the pharmaceutical composition containing formula I compound, and the purposes of formula I compound or the pharmaceutical composition containing formula I compound in the preparation of treating alopecia and benign prostatic hyperplasia drugs. The present application can maintain the administration effect for a long time by injection administration, and has the ideal pharmaceutical properties of long-acting drugs.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a compound based on a modified dutasteride structure, its preparation method, a pharmaceutical composition comprising the same, and its pharmaceutical uses. Background Technology

[0002] 5-α-reductase is a biological catalyst that reduces male hormones (i.e., testosterone) in the prostate, hair follicles, sebaceous glands, etc., to dehydrotestosterone (DHT). DHT is known to be associated with hair loss, benign prostatic hyperplasia (BPH), and other conditions. Therefore, 5-α-reductase inhibitors that inhibit the production of DHT in tissues have been used as therapeutic agents for BPH and can also be used to prevent and treat hair loss.

[0003] Benign prostatic hyperplasia (BPH) is a representative disease of the elderly, referring to the enlarged prostate gland that compresses the urethra at the base of the bladder, causing difficulty in urination. Causes of BPH include advanced age and the effects of androgens. Dehydrotestosterone, converted from testosterone by 5-α-reductase in the prostate, affects prostate development and enlargement, thus leading to BPH. This disease can be treated surgically by removing prostate tissue, but the number of eligible patients is limited because the majority of target patients are elderly. Therefore, due to postoperative side effects, recurrence, and other issues, simple drug therapy is preferred. As a drug therapy, 5-α-reductase inhibitors can alleviate urination difficulties by selectively inhibiting the production of dehydrotestosterone, activating anti-androgen effects, and reducing prostate enlargement.

[0004] Furthermore, hair loss refers to a condition where the amount of hair loss exceeds the average level, and it occurs due to a variety of reasons, including genetic factors, nutritional deficiencies, and stress. Male pattern baldness is the most common type of hair loss and is known to be caused by an excess of dehydrotestosterone (DHEA). In particular, DHEA leads to decreased energy production and inhibition of protein synthesis around hair follicles, suppressing the proliferation of hair follicle cells and inducing proteins that cause hair loss, thus resulting in male pattern baldness. In addition, tissues in bald areas are known to have higher 5-α-reductase activity than other scalp tissues. Therefore, 5-α-reductase inhibitors can effectively prevent and treat male pattern baldness by inhibiting the production of DHEA.

[0005] Among 5-alpha reductase inhibitors, dutasteride inhibits all types I and II 5-alpha reductases and is used to treat benign prostatic hyperplasia, male pattern baldness, etc., by taking 0.5 mg orally once daily. Dutasteride does not affect testosterone, which exhibits androgenic effects, but selectively inhibits the production of dehydrotestosterone, thus it is considered a relatively safe therapeutic agent. However, it is characterized by its effectiveness only after continuous use for several months. Furthermore, benign prostatic hyperplasia or male pattern baldness requires long-term or lifelong use of this medication. Therefore, although commercial products only require once-daily dosing, patient adherence remains low. The following are the basic properties of dutasteride:

[0006] Table 1. Basic properties of dutasteride

[0007] Dutasteride is a well-known and effective drug developed by GlaxoSmithKline and administered orally in the form of soft gelatin capsules under the brand name "Avodart". ® Branded product, 0.5 mg once daily, for the treatment of benign prostatic hyperplasia and male pattern baldness (androgenetic alopecia). The absolute bioavailability of oral dutasteride is only about 60%.

[0008] Optimizing drug bioavailability has many potential benefits. For patient convenience and improved adherence, it is generally believed that the frequency of dosing needs to be reduced. By prolonging the duration of drug release, the duration of action per dose is expected to be longer. This will lead to an overall improvement in dosing parameters, such as taking the drug once daily instead of four times daily, or once weekly, or even less when daily dosing was previously required. Many drugs are currently administered once daily, but not all of these drugs have pharmacokinetic properties suitable for an exact 24-hour dosing interval. Prolonging the release period of these drugs is also beneficial.

[0009] Despite these advantages, the design and development of prodrugs requires a thorough understanding of the pharmacokinetics, pharmacodynamics, and metabolism of the parent drug. Furthermore, the chemical structure of the parent drug itself can severely limit the design and feasibility of prodrugs.

[0010] One of the fundamental considerations in drug therapy involves the relationship between blood levels and therapeutic activity. For most drugs, maintaining serum levels between the minimum effective concentration and the potential toxic level is of paramount importance. From a pharmacokinetic perspective, the peaks and troughs of drug blood levels ideally fit within the therapeutic window of serum concentration. For some therapeutic agents, this window is so narrow that dosage formulation becomes crucial.

[0011] Non-oral administration routes (e.g., parenteral routes) have been explored for use in other classes of drugs. However, to date, there is no extended-release injectable prodrug formulation of dutasteride.

[0012] In addition to the benefits of improved medication adherence from long-acting injectable formulations, injectable formulations can also increase the bioavailability of 5α-reductase inhibitors, particularly dutasteride. This increased bioavailability of injectable formulations can provide therapeutic plasma concentrations, which can be administered intramuscularly or subcutaneously daily, every three days, weekly, every two weeks, every three weeks, monthly, every two months, every three months, or every six months. The total injectable dose can be significantly lower than the daily oral dose required over the same period, thereby reducing toxicity and improving patient adherence.

[0013] Therefore, given the advantages of long-acting formulations, there is an unmet need to develop long-acting parenteral formulations of dutasteride that would provide higher adherence rates while maintaining therapeutic levels of the drug in patients for extended periods (days, weeks, or even years) for the treatment of patients with alopecia and benign prostatic hyperplasia as described in this article. Summary of the Invention

[0014] This invention modifies the structure of dutasteride to prepare a prodrug with long-acting properties. This type of drug is formulated into a preparation suitable for intramuscular, subcutaneous, or intravenous injection. After intramuscular, subcutaneous, or intravenous injection, it forms a drug reservoir in the body, from which the drug is slowly, continuously, and stably released and converted into dutasteride, thereby exerting a long-acting effect. This invention is achieved using the following technical solution:

[0015] The purpose of this invention is to overcome the shortcomings of the prior art and provide a compound of formula (I) or a salt thereof or a solvate thereof: ,

[0016] Where R is C3~C 20 Straight-chain or branched alkyl groups.

[0017] As an ester group, R can be a straight-chain or branched saturated or unsaturated C1-C2 group. 20 Aliphatic groups or optionally C6-C 10 Aryl group. Preferably, R is a straight-chain or branched C1-C1 group. 20 The alkyl group may be optionally replaced with an aryl group. More preferably, R is a straight-chain or branched C1-C2 group. 20 alkyl.

[0018] In a preferred embodiment of the present invention, the compound salt represented by formula (I) is any of the following compounds: ,

[0019] In another aspect of the present invention, a method for preparing the compound of formula (I) or its salt or solvate thereof is provided, comprising the following steps:

[0020] Step 1: Dutasteride and paraformaldehyde are reacted with a catalyst and solvent to prepare intermediate 1 (hydroxymethyl dutasteride).

[0021] Step 2: The product from Step 1 and C3~C 20 Straight-chain or branched alkyl acyl chlorides are prepared under the action of solvent and acid-binding agent to form formula (I); ,

[0022] Where R is C3~C 20 Straight-chain or branched alkyl groups.

[0023] The solvents used in this invention may be selected from, but are not limited to, hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, and xylene; ether solvents such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-methoxyethyl ether, and 1,4-dioxane; ester solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, n-butyl acetate, and tert-butyl acetate; and polar aprotic solvents such as dimethyl ethyl ether. Amides, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.; chlorinated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile, etc.; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol or isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol, etc.; polar solvents such as water, formic acid, acetic acid, etc., or mixtures of any of the above solvents.

[0024] In some embodiments, the reaction solvent in step 1 is selected from one or more combinations of N,N-dimethylformamide, N,N-dimethylacetamide, DMSO, acetonitrile, and tetrahydrofuran, preferably N,N-dimethylformamide;

[0025] In some embodiments, the catalyst in step 1 is selected from cesium carbonate, pyridine DMAP, and preferably 4-dimethylaminopyridine (DMAP).

[0026] In some embodiments, the reaction solvent in step 2 is selected from one or more of n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, xylene, dimethyl ether, diethyl ether, isopropyl ether, tetrahydrofuran, methyl acetate, ethyl acetate, dichloromethane, dichloroethane, and chloroform, preferably dichloromethane;

[0027] In some embodiments, the acid-binding agent in step 2 is selected from one or more of triethylamine, diisopropylamine, pyridine, sodium acetate, sodium carbonate, potassium carbonate, cesium carbonate, and DBU, preferably triethylamine.

[0028] The compounds synthesized by the above method have been identified by basic analyses including nuclear magnetic resonance (NMR), mass spectrometry (MS), infrared spectroscopy (IR), X-ray powder diffraction (XRD), thermogravimetric analysis (TG), differential scanning spectroscopy (DSC), and high-performance liquid chromatography (HPLC). The HPLC chromatographic analysis conditions are as follows:

[0029] Table 2 Chromatographic conditions ,

[0030] The typical chromatograms and spectra are shown in the attached figure.

[0031] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) of the present invention, a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.

[0032] The pharmaceutical composition of the present invention is formulated for intramuscular, intradermal, or subcutaneous injection.

[0033] Preferably, the injectable formulation is prepared by the active compound of the present invention and related pharmaceutical excipients according to general pharmaceutical methods. The excipients include pharmaceutically necessary components such as suspending agents, antioxidants, stabilizers, wetting agents, and preservatives.

[0034] Furthermore, according to the present invention, the synthetic compound of formula I, or its salt or solvate, can also be formulated into different pharmaceutical preparations to provide a prolonged therapeutic effect. In this regard, the compound represented by formula (I) can be mixed with a selected oil carrier to form a parenteral formulation, whereby the release rate of the target drug, namely dutasteride, may be slowed down at the time of administration due to factors such as increased solubility of the target drug in oil. Therefore, longer dosing intervals can be set due to the prolonged duration of action of the target drug.

[0035] Gelders reported in International Clinical Psychopharmacology, (1986) Vol. 1, 1-11, and CN Hinko et al. reported in Neuropharmacology, (1988) Vol. 27, 475-483, that the controlled-release formulation of haloperidol decyl ester in injectable oils (such as sesame oil or soybean oil) prolongs its antipsychotic effect, making it possible to extend the dosing interval from 2-4 times per day to 1-2 times per month.

[0036] TR Norman reported the preparation of fluphenazine decyl ester from fluphenazine in International Clinical Psychopharmacology, (1987) Vol. 2, 299-305. CN Hinko reported the preparation of lactoferrate in Neuropharmacology (1988), Vol. 27, 475-483. CL Broekkamp reported the preparation of nicotinylmorphine ester from morphine in the Journal of Pharmacy and Pharmacology (1988) Vol. 40, 434-437. JV Joshi et al. reported a prodrug of testosterone enanthate in Steroids, (1989) Vol. 53, 751-761, with a dosing interval of up to two months.

[0037] However, due to unknown factors in nature, the target drug may sometimes be released rapidly from the oil base. For example, it has been found that intramuscularly injected testosterone suspensions release testosterone rapidly (T Tanaka (1974), Chemical & Pharmaceutical Bulletin, Vol. 22, pp. 1275-1284). HAC Titulaer reported the addition of artemisinin to parenteral oils to form various dosage forms for intramuscular, intravenous, oral, or rectal administration. However, the drug is rapidly released from these dosage forms (Journal of Pharmacy and Pharmacology (1990), Vol. 42, pp. 810-813). Z. Zuidema et al. reported in the International Journal of Pharmaceutics (1994), Vol. 105, pp. 189-207 that the release rate and extent of parenteral administration dosage forms are highly unstable and variable.

[0038] Based on the above studies, dosage forms containing drug compositions suspended or dissolved in an oil carrier will certainly not exhibit a longer duration of therapeutic effect. Generally, any attempt to add a target drug to an oil carrier to obtain a long-acting dosage form requires consideration of the target drug's physical solubility, stability, and rate of release from the carrier.

[0039] In view of the above, in order to prolong the duration of action of dutasteride, the applicant provides a pharmaceutical composition in the application, which contains the compound shown in formula (I) above, or a salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier.

[0040] Suitable oil carriers for use in this invention are injectable formulations, including, for example, vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil (early peanut oil), poppy seed oil, tea seed oil, and soybean oil, and combinations thereof. Furthermore, the compositions according to this invention may optionally include pharmaceutically acceptable excipients commonly used in the manufacture of pharmaceuticals. The use of such excipients will be apparent to those skilled in the art. Preferably, if present, the excipients may be selected from benzyl alcohol, benzyl benzoate, or combinations thereof. The formulated compositions are intended for intramuscular, intradermal, or subcutaneous injection.

[0041] Another aspect of the present invention provides the use of the compound of formula (I) described herein, or its salt or solvate thereof, in the preparation of a medicament for treating hair loss and benign prostatic hyperplasia.

[0042] The key points of this invention are:

[0043] The compounds of this invention can be formulated into suspensions or oil-based injections for intramuscular or subcutaneous injection, forming a drug reservoir in the body and prolonging the drug release rate, thus achieving a long-lasting therapeutic effect. Furthermore, the compounds of this invention have moderate melting points, moderate particle sizes, low solubility, good stability, and are essentially non-toxic, supporting further clinical trials. Attached Figure Description

[0044] Figure 1 The 1H NMR spectrum of compound I-1 hexanodotalamine.

[0045] Figure 2 This is the carbon spectrum of compound I-1 hexanodotalamine.

[0046] Figure 3 MS for compound I-1 hexanodutasteride.

[0047] Figure 4 The HPLC chromatogram of compound I-2-decanoic acid dutasteride is shown.

[0048] Figure 5 The 1H NMR spectrum of compound I-2-decanoic acid dutasteride.

[0049] Figure 6 This is the carbon spectrum of compound I-2-decanoic acid dutasteride.

[0050] Figure 7 MS for compound I-2-decanoic acid dutasteride.

[0051] Figure 8 The 1H NMR spectrum of compound I-3-lauric acid dutasteride.

[0052] Figure 9 This is the carbon spectrum of compound I-3-lauric acid dutasteride.

[0053] Figure 10 MS for compound I-3-lauric acid dutasteride.

[0054] Figure 11 The results are from in vivo pharmacokinetic studies of formulations 1-6. Detailed Implementation

[0055] The following implementations, including preferred embodiments, are intended to illustrate the practice of the invention. It is understood that the details shown are illustrative discussions of preferred embodiments of the invention by way of example and purpose, and are intended to demonstrate what is considered most useful and readily understood in the description of the development process and aspects of the invention's principles and concepts. It will be apparent to those skilled in the art that the invention is not limited to the details of the following illustrative examples, and that the invention may be embodied in other specific forms without departing from its essential attributes. Therefore, it is intended that these embodiments and examples be considered illustrative rather than restrictive in all respects.

[0056]

[0057] Example 1: Preparation of compound I-1 (hexanodidurandide).

[0058] 100.00 g dutasteride, 125.00 g paraformaldehyde, 4.62 g DMAP, and 500 ml DMF were added to a 1000 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000 ml dichloromethane and 500 ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 400 ml methanol, and cooled to 0–5 °C for 2 hours to allow crystals to precipitate. The mixture was then filtered to give 90.23 g of a white solid (hydroxymethyl dutasteride), with a yield of 85.38%.

[0059] 5.0 g of hydroxymethyldutasteride, 2.72 g of triethylamine, and 100 ml of dichloromethane were added to a 250 ml reaction flask, and the mixture was cooled to 0–5 °C. 2.41 g of hexanoyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 100 ml of dichloromethane was added, and the mixture was washed three times with 50 ml of water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 4.30 g of the target product (hexanoyldutasteride), with a yield of 73.19%.

[0060] Example 2: Preparation of compound I-1 (hexanodidurandramide).

[0061] 100.00 g dutasteride, 125.00 g paraformaldehyde, 4.62 g DMAP, and 500 ml DMF were added to a 1000 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000 ml dichloromethane and 500 ml water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, dissolved in 400 ml methanol, and cooled to 0–5 °C for 2 hours to crystallize. The mixture was then filtered to give 90.23 g of a white solid (hydroxymethyl dutasteride), with a yield of 85.38%.

[0062] 5.0 g of hydroxymethyldutasteride, 2.73 g of DBU, and 100 ml of dichloromethane were added to a 250 ml reaction flask, and the mixture was cooled to 0–5 °C. 2.41 g of hexanoyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 100 ml of dichloromethane was added, and the mixture was washed three times with 50 ml of water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 3.18 g of the target product (hexanoyldutasteride), with a yield of 54.13%.

[0063] Example 3: Preparation of compound I-1 (hexanodidurandramide).

[0064] 100.00 g dutasteride, 125.00 g paraformaldehyde, 4.62 g DMAP, and 500 ml DMF were added to a 1000 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000 ml dichloromethane and 500 ml water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, dissolved in 400 ml methanol, and cooled to 0–5 °C for 2 hours to crystallize. The mixture was then filtered to give 90.23 g of a white solid (hydroxymethyl dutasteride), with a yield of 85.38%.

[0065] 5.0 g of hydroxymethyldutasteride, 2.31 g of DIPEA, and 100 ml of dichloromethane were added to a 250 ml reaction flask, and the mixture was cooled to 0–5 °C. 2.41 g of hexanoyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 100 ml of dichloromethane was added, and the mixture was washed three times with 50 ml of water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 2.87 g of the target product (hexanoyldutasteride), with a yield of 48.85%.

[0066] Example 4: Preparation of compound I-1 (hexanodidurandramide).

[0067] 100.00 g dutasteride, 125.00 g paraformaldehyde, 4.62 g DMAP, and 500 ml DMF were added to a 1000 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000 ml dichloromethane and 500 ml water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, dissolved in 400 ml methanol, and cooled to 0–5 °C for 2 hours to crystallize. The mixture was then filtered to give 90.23 g of a white solid (hydroxymethyl dutasteride), with a yield of 85.38%.

[0068] 5.0 g of hydroxymethyldutasteride, 2.12 g of pyridine, and 100 ml of dichloromethane were added to a 250 ml reaction flask, and the mixture was cooled to 0–5 °C. 2.41 g of hexanoyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 100 ml of dichloromethane was added, and the mixture was washed three times with 50 ml of water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 2.35 g of the target product (hexanoyldutasteride), with a yield of 40.00%.

[0069] MS (ESI): M-H + 655.2

[0070] 1 H NMR (400 MHz, Chloroform-d): δ 8.82 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.60~7.46 (m, 2H), 6.88 (d, J = 10.0 Hz, 1H), 5.95 (d, J = 9.9 Hz, 1H), 5.86 (d, J = 10.8 Hz, 1H), 5.32 (s, 1H), 3.55 (dd, J = 12.7, 3.3 Hz, 1H), 2.46~2.27 (m, 4H), 2.17 (d, J = 11.2 Hz, 1H), 2.03~1.77 (m, 5H), 1.72~1.57(m, 5H), 1.50~1.38 (m, 3H), 1.34 (m, J = 4.7 Hz, 4H), 1.12 (t, J = 14.4 Hz, 2H), 1.00 (s, 3H), 0.93 (t, J = 6.7 Hz, 3H), 0.84 (s, 3H).

[0071] 13 C NMR (151MHz, CDCl3): δ 172.82, 170.85, 165.57, 150.51, 135.89, 134.66, 126.34, 126.30, 123.90, 122.10, 119.99, 119.91, 119.89, 65.67, 62.33, 57.82, 55.19, 47.17, 44.25, 39.09, 37.38, 34.38, 33.71, 30.76, 29.23, 24.00, 23.67, 23.19, 23.08, 21.79, 20.78, 13.40, 12.93, 11.72.

[0072] Example 5: Preparation of compound I-2 (decanoyl dutasteride).

[0073] 100.00 g dutasteride, 125.00 g paraformaldehyde, 4.62 g DMAP, and 500 ml DMF were added to a 1000 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000 ml dichloromethane and 500 ml water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, dissolved in 400 ml methanol, and cooled to 0–5 °C for 2 hours to crystallize. The mixture was then filtered to give 90.23 g of a white solid (hydroxymethyl dutasteride), with a yield of 85.38%.

[0074] 5.0 g of hydroxymethyldutasteride, 2.72 g of triethylamine, and 100 ml of dichloromethane were added to a 250 ml reaction flask, and the mixture was cooled to 0–5 °C. 3.41 g of decanoyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 100 ml of dichloromethane was added, and the mixture was washed three times with 100 ml of water (3 times). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 3.20 g of a colorless, transparent oil (decanoyldutasteride), with a yield of 50.18%.

[0075] Example 6: Preparation of compound I-2 (decanoyl dutasteride).

[0076] 100.00 g dutasteride, 125.00 g paraformaldehyde, 4.62 g DMAP, and 500 ml DMF were added to a 1000 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000 ml dichloromethane and 500 ml water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, dissolved in 400 ml methanol, and cooled to 0–5 °C for 2 hours to crystallize. The mixture was then filtered to give 90.23 g of a white solid (hydroxymethyl dutasteride), with a yield of 85.38%.

[0077] 5.0 g of hydroxymethyldutasteride, 2.31 g of DIPEA, and 100 ml of dichloromethane were added to a 250 ml reaction flask, and the mixture was cooled to 0–5 °C. 3.41 g of decanoyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 100 ml of dichloromethane was added, and the mixture was washed three times with 100 ml of water (3 times the volume of dichloromethane). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 2.55 g of a colorless, transparent oil (decanoyldutasteride), with a yield of 39.99%.

[0078] Example 7: Preparation of compound I-2 (decanoyl dutasteride).

[0079] 100.00 g dutasteride, 125.00 g paraformaldehyde, 4.62 g DMAP, and 500 ml DMF were added to a 1000 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000 ml dichloromethane and 500 ml water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, dissolved in 400 ml methanol, and cooled to 0–5 °C for 2 hours to crystallize. The mixture was then filtered to give 90.23 g of a white solid (hydroxymethyl dutasteride), with a yield of 85.38%.

[0080] 5.0 g of hydroxymethyldutasteride, 2.12 g of pyridine, and 100 ml of dichloromethane were added to a 250 ml reaction flask, and the mixture was cooled to 0–5 °C. 3.41 g of decanoyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 100 ml of dichloromethane was added, and the mixture was washed three times with 50 ml of water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 2.53 g of a colorless, transparent oil (decanoyldutasteride), with a yield of 39.67%.

[0081] Example 8: Preparation of compound I-2 (decanoyl dutasteride).

[0082] 100.00 g dutasteride, 125.00 g paraformaldehyde, 4.62 g DMAP, and 500 ml DMF were added to a 1000 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000 ml dichloromethane and 500 ml water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, dissolved in 400 ml methanol, and cooled to 0–5 °C for 2 hours to crystallize. The mixture was then filtered to give 90.23 g of a white solid (hydroxymethyl dutasteride), with a yield of 85.38%.

[0083] 5.0 g of hydroxymethyldutasteride, 2.73 g of DBU, and 100 ml of dichloromethane were added to a 250 ml reaction flask, and the mixture was cooled to 0–5 °C. 3.41 g of decanoyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 100 ml of dichloromethane was added, and the mixture was washed three times with 500 ml of water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 1.99 g of a colorless, transparent oil (decanoyldutasteride), with a yield of 31.21%. HPLC: 97.3% (see attached image). Figure 4 )

[0084] MS (ESI): M-H + 711.3

[0085] 1 H NMR (400 MHz, Chloroform-d): δ 8.81 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.61~7.43 (m, 2H), 6.87 (d, J = 10.0 Hz, 1H), 5.94 (d, J = 9.9 Hz, 1H), 5.85 (d, J = 10.6 Hz, 1H), 5.32 (s, 1H), 3.54 (dd, J = 12.7, 3.3 Hz, 1H), 2.48~2.27 (m, 4H), 2.21~2.09 (m, 1H), 2.02~1.74 (m, 5H), 1.72~1.39 (m,8H), 1.30 (d, J = 8.1 Hz, 12H), 1.11 (ddd, J = 19.4, 11.6, 3.3 Hz, 2H), 0.99(s, 3H), 0.91 (t, J = 6.7 Hz, 3H), 0.84 (s, 3H).

[0086] 13C NMR (151MHz, CDCl3): δ 172.85, 170.80, 165.57, 150.45, 135.89, 134.74, 126.33, 126.30, 123.94, 122.16, 119.96, 119.83, 119.80, 65.69, 62.34,57.89, 55.23, 47.21, 44.27, 39.11, 37.42, 34.40,33.79, 31.40, 29.27, 28.97,28.79, 28.65, 24.35, 23.69, 23.21, 23.10, 22.18, 20.80, 13.63, 12.96, 11.76.

[0087] Example 9: Preparation of compound I-3 (lauroyl dutasteride).

[0088] 4.00 g dutasteride, 5.00 g paraformaldehyde, 0.18 g DMAP, and 20 ml DMF were added to a 50 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was complete, the mixture was filtered, and the filtrate was washed three times with 80 ml of water (3 x 80 ml), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 1:1) to give 2.81 g of a white solid (hydroxymethyl dutasteride), with a yield of 66.47%.

[0089] 2.80 g of hydroxymethyldutasteride, 1.52 g of triethylamine, and 56 ml of dichloromethane were added to a 100 ml reaction flask, and the mixture was cooled to 0–5 °C. 2.19 g of lauroyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete, 56 ml of dichloromethane was added, and the mixture was washed three times with 56 ml of water (3 x 5 ml), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 2.33 g of a colorless, transparent oil (lauroyldutasteride), with a yield of 67.56%.

[0090] Example 10: Preparation of compound I-3 (lauroyl dutasteride).

[0091] 4.00 g dutasteride, 5.00 g paraformaldehyde, 7.40 g cesium carbonate, and 20 ml DMF were added to a 50 ml reaction flask and heated to 50–60 °C for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was washed three times with 80 ml of dichloromethane and 80 ml of water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 1:1) to give 2.12 g of a white solid (hydroxymethyl dutasteride), with a yield of 50.15%.

[0092] 2.10 g of hydroxymethyldutasteride, 1.14 g of triethylamine, and 42 ml of dichloromethane were added to a 100 ml reaction flask, and the mixture was cooled to 0–5 °C. 1.64 g of lauroyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete, 42 ml of dichloromethane was added, and the mixture was washed three times with 42 ml of water (3 times). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to give 1.81 g of a colorless, transparent oil (lauroyldutasteride), with a yield of 64.98%.

[0093] Example 11: Preparation of compound I-3 (lauroyl dutasteride).

[0094] 4.00 g dutasteride, 5.00 g paraformaldehyde, 2.39 g pyridine, and 20 ml DMF were added to a 50 ml reaction flask and heated to 50–60 °C for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was washed three times with 80 ml of dichloromethane and 80 ml of water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 1:1) to give 1.94 g of a white solid (hydroxymethyl dutasteride), with a yield of 45.89%.

[0095] 1.9 g of hydroxymethyldutasteride, 1.03 g of triethylamine, and 38 ml of dichloromethane were added to a 100 ml reaction flask, and the mixture was cooled to 0–5 °C. 1.49 g of lauroyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete, 38 ml of dichloromethane was added, and the mixture was washed three times with 38 ml of water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to give 1.56 g of a colorless, transparent oil (lauroyldutasteride), with a yield of 61.90%.

[0096] Example 12: Preparation of compound I-3 (lauroyl dutasteride)

[0097] 4.00 g dutasteride, 3.41 g paraformaldehyde, 0.18 g DMAP, and 20 ml DMF were added to a 50 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was complete, the mixture was filtered, and the filtrate was washed three times with 80 ml of water (3 x 80 ml), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 1:1) to give 2.11 g of a white solid (hydroxymethyl dutasteride), with a yield of 49.91%.

[0098] 2.10 g of hydroxymethyldutasteride, 1.38 g of triethylamine, and 38 ml of dichloromethane were added to a 100 ml reaction flask, and the mixture was cooled to 0–5 °C. 1.86 g of lauroyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete, 38 ml of dichloromethane was added, and the mixture was washed three times with 38 ml of water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 1.44 g of a colorless, transparent oil (lauroyldutasteride), with a yield of 57.14%.

[0099] Example 13: Preparation of compound I-3 (lauroyl dutasteride).

[0100] 20.00 g dutasteride, 25.00 g paraformaldehyde, 0.92 g DMAP, and 100 ml DMF were added to a 250 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was complete, the mixture was filtered, and the filtrate was washed three times with 200 ml of water (3 times each), dried over anhydrous sodium sulfate, concentrated, and recrystallized from 80 ml of methanol to give 17.20 g of a white solid (hydroxymethyl dutasteride), with a yield of 81.38%.

[0101] 17.00 g of hydroxymethyldutasteride, 9.24 g of triethylamine, and 340 ml of dichloromethane were added to a 1000 ml reaction flask, and the mixture was cooled to 0–5 °C. 13.32 g of lauroyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 340 ml of dichloromethane was added, and the mixture was washed three times with 340 ml of water (3 x 3 ml). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 15.60 g of a colorless, transparent oil (lauroyldutasteride), with a yield of 69.18%.

[0102] Example 14: Preparation of compound I-3 (lauroyl dutasteride).

[0103] 20.00 g dutasteride, 25.00 g paraformaldehyde, 0.92 g DMAP, and 100 ml DMF were added to a 250 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was complete, the mixture was filtered, and the filtrate was washed three times with 200 ml of water (3 times each), dried over anhydrous sodium sulfate, concentrated, and recrystallized from 120 ml of methanol to give 12.19 g of a white solid (hydroxymethyl dutasteride), with a yield of 57.67%.

[0104] 12.1 g of hydroxymethyldutasteride, 6.58 g of triethylamine, and 242 ml of dichloromethane were added to a 500 ml reaction flask, and the mixture was cooled to 0–5 °C. 9.48 g of lauroyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 242 ml of dichloromethane was added, and the mixture was washed three times with 242 ml of water (3 x 10 ml). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 10.00 g of a colorless, transparent oil (lauroyldutasteride), with a yield of 62.31%.

[0105] Example 15: Preparation of compound I-3 (lauroyl dutasteride).

[0106] 35 g dutasteride, 43.75 g paraformaldehyde, 1.62 g DMAP, and 175 ml DMF were added to a 500 ml reaction flask and heated to 50–60 °C for 48 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 350 ml of dichloromethane and 350 ml of water. The solution was dried over anhydrous sodium sulfate, concentrated, dissolved in 140 ml of methanol, and cooled to 0–5 °C for 2 hours to allow crystals to precipitate. The mixture was then filtered to give 31.04 g of a white solid (hydroxymethyl dutasteride), with a yield of 83.92%.

[0107] 30 g of hydroxymethyldutasteride, 21.74 g of triethylamine, and 300 ml of dichloromethane were added to a 1000 ml reaction flask, and the mixture was cooled to 0–5 °C. 23.50 g of lauroyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 300 ml of dichloromethane was added, and the mixture was washed three times with 300 ml of water (3 x 3 ml). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 22.22 g of a colorless, transparent oil (lauroyldutasteride), with a yield of 55.84%.

[0108] MS (ESI): M-H + 739.3

[0109] 1H NMR (400 MHz, Chloroform-d): δ 8.80 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.58~7.43 (m, 2H), 6.86 (d, J = 10.0 Hz, 1H), 5.93 (d, J = 10.0 Hz, 1H), 5.85 (d, J = 10.6 Hz, 1H), 5.34 (d, J = 21.4 Hz, 1H), 3.53 (dd, J =12.7, 3.3 Hz, 1H), 2.45~2.26 (m, 4H), 2.21~2.12 (m, 1H), 2.02~1.73 (m,6H), 1.69~1.57 (m, 3H), 1.55~1.38 (m, 4H), 1.34~1.25 (m, 16H), 1.17~1.02(m, 2H), 0.99 (s, 3H), 0.91 (t, J = 6.8 Hz, 3H), 0.83 (s, 3H).

[0110] 13 C NMR (151MHz, CDCl3): δ 173.20, 171.24, 165.95, 150.90, 136.28, 135.04, 126.73, 126.69, 124.29, 122.48, 120.37, 120.34, 120.32, 66.05, 62.72,58.19, 55.59, 47.57, 44.64, 39.48,37.76, 34.77, 34.14, 31.81, 29.63, 29.52,29.51, 29.39, 29.23, 29.16, 29.01, 24.72, 24.06, 23.58, 23.47, 22.57, 21.17, 13.99, 13.31, 12.11.

[0111] Example 16: Preparation of compound I-4 (palmitoyldutasteride).

[0112] 100.00 g dutasteride, 125.00 g paraformaldehyde, 4.62 g DMAP, and 500 ml DMF were added to a 1000 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000 ml dichloromethane and 500 ml water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, dissolved in 400 ml methanol, and cooled to 0–5 °C for 2 hours to crystallize. The mixture was then filtered to give 90.23 g of a white solid (hydroxymethyl dutasteride), with a yield of 85.38%.

[0113] 5.0 g of hydroxymethyldutasteride, 2.72 g of triethylamine, and 100 ml of dichloromethane were added to a 250 ml reaction flask, and the mixture was cooled to 0–5 °C. 4.92 g of palmitoyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 100 ml of dichloromethane was added, and the mixture was washed three times with 50 ml of water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to give 4.87 g of a colorless oil (palmitoyldutasteride), with a yield of 68.26%.

[0114] Example 17: Preparation of compound I-4 (palmitoyldutasteride).

[0115] 100.00 g dutasteride, 125.00 g paraformaldehyde, 4.62 g DMAP, and 500 ml DMF were added to a 1000 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000 ml dichloromethane and 500 ml water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, dissolved in 400 ml methanol, and cooled to 0–5 °C for 2 hours to crystallize. The mixture was then filtered to give 90.23 g of a white solid (hydroxymethyl dutasteride), with a yield of 85.38%.

[0116] 5.0 g of hydroxymethyldutasteride, 2.76 g of DBU, and 100 ml of dichloromethane were added to a 250 ml reaction flask, and the mixture was cooled to 0–5 °C. 4.92 g of palmitoyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 100 ml of dichloromethane was added, and the mixture was washed three times with 50 ml of water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to give 3.79 g of a colorless oil (palmitoyldutasteride), with a yield of 53.13%.

[0117] Example 18: Preparation of compound I-4 (palmitoyldutasteride).

[0118] 100.00 g dutasteride, 125.00 g paraformaldehyde, 4.62 g DMAP, and 500 ml DMF were added to a 1000 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000 ml dichloromethane and 500 ml water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, dissolved in 400 ml methanol, and cooled to 0–5 °C for 2 hours to crystallize. The mixture was then filtered to give 90.23 g of a white solid (hydroxymethyl dutasteride), with a yield of 85.38%.

[0119] 5.0 g of hydroxymethyldutasteride, 2.31 g of DIPEA, and 100 ml of dichloromethane were added to a 250 ml reaction flask, and the mixture was cooled to 0–5 °C. 4.92 g of palmitoyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 100 ml of dichloromethane was added, and the mixture was washed three times with 50 ml of water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to give 3.41 g of a colorless oil (palmitoyldutasteride), with a yield of 47.80%.

[0120] Example 19: Preparation of compound I-4 (palmitoyldutasteride).

[0121] 100.00 g dutasteride, 125.00 g paraformaldehyde, 4.62 g DMAP, and 500 ml DMF were added to a 1000 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000 ml dichloromethane and 500 ml water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, dissolved in 400 ml methanol, and cooled to 0–5 °C for 2 hours to crystallize. The mixture was then filtered to give 90.23 g of a white solid (hydroxymethyl dutasteride), with a yield of 85.38%.

[0122] 5.0 g of hydroxymethyldutasteride, 2.12 g of pyridine, and 100 ml of dichloromethane were added to a 250 ml reaction flask, and the mixture was cooled to 0–5 °C. 4.92 g of palmitoyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 100 ml of dichloromethane was added, and the mixture was washed three times with 50 ml of water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to give 2.77 g of a colorless oil (palmitoyldutasteride), with a yield of 38.83%.

[0123] MS (ESI): M-H + 795.9

[0124] 1H NMR (400 MHz, Chloroform-d): δ8.81 (s, 1H), 7.77 (d, J = 8.3 Hz,1H), 7.60~7.45 (m, 2H), 6.86 (d, J = 10.0 Hz, 1H), 5.95 (d, J = 9.9 Hz, 1H), 5.86 (d, J = 10.6 Hz, 1H), 5.32 (s, 1H), 3.55 (dd, J = 12.7, 3.3 Hz, 1H), 2.46~2.27 (m, 4H), 2.20~2.09 (m, 1H), 2.02~1.75 (m, 5H), 1.72~1.35 (m,8H), 1.30 (d, J = 8.1 Hz, 24H), 1.12 (ddd, J = 19.4, 11.6, 3.3 Hz, 2H), 0.99(s, 3H), 0.93 (t, J = 6.7 Hz, 3H), 0.84 (s, 3H).

[0125] 13 C NMR (151 MHz, CDCl3): δ173.22, 171.23, 165.98, 150.87, 136.35,135.16,126.92, 126.81, 124.33, 122.65, 120.67, 120.51, 120.43, 66.14, 62.84,58.37, 55.92, 47.77,44.86, 39.61, 37.83, 34.97, 34.44, 32.32,29.68, 29.63,29.54, 29.53,29.50, 29.48, 29.38, 29.24, 29.17, 29.11, 29.03, 24.87, 24.25, 23.88, 23.67, 22.87, 21.56, 14.22, 13.42, 12.15.

[0126] Comparative Example 1:

[0127] 40.00 g dutasteride, 50.00 g paraformaldehyde, 1.85 g DMAP, and 200 ml DMF were added to a 500 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was complete, the mixture was filtered, and the filtrate was washed three times with 200 ml of water (3 times each), dried over anhydrous sodium sulfate, concentrated, dissolved in 160 ml of methanol, and cooled to 0–5 °C for 2 hours to allow crystals to precipitate. The mixture was then filtered to give 35.75 g of a white solid (hydroxymethyl dutasteride), with a yield of 84.57%.

[0128] 10.00 g of hydroxymethyldutasteride, 5.45 g of DBU, and 200 ml of dichloromethane were added to a 500 ml reaction flask, and the mixture was cooled to 0–5 °C. 7.83 g of lauroyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 200 ml of dichloromethane was added, and the mixture was washed three times with 100 ml of water (3 times). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 3.68 g of a colorless, transparent oil (lauroyldutasteride), with a yield of 27.74%.

[0129] Comparative Example 2:

[0130] 40.00 g dutasteride, 50.00 g paraformaldehyde, 1.85 g DMAP, and 200 ml DMF were added to a 500 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was complete, the mixture was filtered, and the filtrate was washed three times with 200 ml of water (3 times each), dried over anhydrous sodium sulfate, concentrated, dissolved in 160 ml of methanol, and cooled to 0–5 °C for 2 hours to allow crystals to precipitate. The mixture was then filtered to give 35.75 g of a white solid (hydroxymethyl dutasteride), with a yield of 84.57%.

[0131] 10.00 g of hydroxymethyldutasteride, 4.25 g of pyridine, and 200 ml of dichloromethane were added to a 500 ml reaction flask, and the mixture was cooled to 0–5 °C. 7.83 g of lauroyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 200 ml of dichloromethane was added, and the mixture was washed three times with 100 ml of water (3 times). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 3.14 g of a colorless, transparent oil (lauroyldutasteride), with a yield of 23.67%.

[0132] Comparative Example 3:

[0133] 40.00 g dutasteride, 50.00 g paraformaldehyde, 1.85 g DMAP, and 200 ml DMF were added to a 500 ml reaction flask and heated to 50–60 °C for 24 hours. After the reaction was complete, the mixture was filtered, and the filtrate was washed three times with 200 ml of water (3 times each), dried over anhydrous sodium sulfate, concentrated, dissolved in 160 ml of methanol, and cooled to 0–5 °C for 2 hours to allow crystals to precipitate. The mixture was then filtered to give 35.75 g of a white solid (hydroxymethyl dutasteride), with a yield of 84.57%.

[0134] 10.00 g of hydroxymethyldutasteride, 4.63 g of DIPEA, and 200 ml of dichloromethane were added to a 500 ml reaction flask, and the mixture was cooled to 0–5 °C. 7.83 g of lauroyl chloride was slowly added dropwise, with the addition temperature not exceeding 10 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, 200 ml of dichloromethane was added, and the mixture was washed three times with 100 ml of water (3 times). The solution was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 4:1) to obtain 2.69 g of a colorless, transparent oil (lauroyldutasteride), with a yield of 20.28%.

[0135] Example 20: Preparation of a typical formulation.

[0136] All formulations below were prepared using a simple mixing method (see table below). In summary, a dutasteride solution (0.10 mg / mL) for oral administration was prepared immediately prior to administration. Compounds 1–4 (100 mg / g, dutasteride equivalent) were mixed with an organic phase consisting of benzyl benzoate and castor oil (6:4, v / v) for 3 h using a magnetic stirrer. All formulations were sterilized by filtration through a 0.2 μm PTFE syringe filter and confirmed by drug concentration measurement prior to in vivo studies.

[0137] Table 3 Composition of Formulations 1-6

[0138]

[0139] Example 21: Stability test.

[0140] The compounds of this invention may be used as active pharmaceutical ingredients (APIs) in the preparation of oil-based carrier injections; therefore, storage is crucial. Impurities may be introduced or generated during storage, affecting the use of the API. Therefore, the stability of the API of this invention is investigated. Following the ICH guideline "Stability Testing of New APIs and Formulations," influencing factor tests were conducted.

[0141] 1. Test conditions: The high humidity test of this product was conducted at 25℃±2℃, RH: 75%±5%, and high temperature (60℃) with the inner and outer packaging removed for 30 days. The light exposure (total illuminance not less than 1.2×106Lux·hr) was also conducted with the inner and outer packaging removed.

[0142] 2. Sampling and testing: High temperature samples were taken at 5, 10 and 30 days; high humidity samples were taken at 5 and 10 days; and light conditions samples were taken at 5 and 11 days.

[0143] 3. Observation results: See Table 4 below.

[0144] Table 4 Stability test results

[0145]

[0146] Conclusion: As shown in the table, the active pharmaceutical ingredient of the present invention is relatively stable under the relevant conditions and no obvious impurities are generated. Therefore, after the active pharmaceutical ingredient is prepared, it can be stored at room temperature.

[0147] Example 22: In vivo pharmacokinetic study.

[0148] The pharmacokinetic characteristics of dutasteride and its derivatives were evaluated in male SD rats (n = 4). All animals were acclimatized to a controlled environment for at least three days prior to administration. Animals were maintained on ad libitum feeding throughout the experiment. Administration was limited to rats weighing 200 ± 10 g. Formulation 1 was administered orally at a dose of 0.25 mg / kg once daily for 7 consecutive days. Blood samples were collected from rats at 0, 0.5, 1, 2, 4, and 6 h on days 1 and 7. Single blood samples were collected on days 2–6 prior to administration. Formulations 2–6 were administered intramuscularly as a single injection into the left thigh muscle at a dose of 7.5 mg / kg. Blood samples were collected at 0, 2, 4, and 6 h, and on days 1, 3, 5, 7, 10, 14, 21, 30, and 45.

[0149] Plasma sample preparation: The sample was prepared in an ice bath. Take 40 μL of acetonitrile, 15 μL of internal standard (EP impurity G, 1.5 μg / mL, dissolved in 50% acetonitrile), add 200 μL of plasma sample, vortex mix, add 5 mL of tetrahydrofuran, vortex mix, centrifuge at 9000g for 3 min, take the organic phase and evaporate to dryness under vacuum, redissolve in 150 μL of methanol, and inject 20 μL for analysis.

[0150] Data analysis: Samples were analyzed by LC-MS / MS. Based on the drug blood concentration data, the pharmacokinetic parameters were calculated using DAS 2.0 software.

[0151] Results: Pharmacokinetic assessments were performed in male Sprague Dawley rats to compare oral and intramuscular administration. Following daily oral administration of dutasteride solution (formulation 1), Cmax values ​​on day 1 and day 7 were 4.65 ± 1.04 and 6.02 ± 1.37 ng / mL, respectively (Table below). Corresponding AUC 0–1 Tianhe AUC 0-7 The day values ​​were 33.53 ± 9.65 and 30.62 ± 6.01 h·ng / mL, respectively. Tmax was consistently observed at 30 min at both time points, and no evidence of drug accumulation was observed during the 7-day repeated dosing period. In contrast, a single intramuscular injection of formulation 2 into the thigh muscle resulted in a Cmax of 8.29 ± 1.93 ng / mL, with Tmax occurring on day 3. Its AUC 0-45 The concentration was 3934.25 ± 457.45 h·ng / mL, compared with the theoretical cumulative AUC. 0-30 The dosage of formulation 3 increased 5.12-fold compared to formulation 1. Formulation 3 showed a Cmax of 3.88 ± 1.52 ng / mL, and Tmax was also on day 3. 0-45 The cumulative AUC was 1351.07 ± 120.25 h·ng / mL, compared to the theoretical cumulative AUC. 0-30 The dose of formulation 1 was 1.31 times higher on day 30. Furthermore, compared to formulation 1 normalized to 30 days, the mean residence time (MRT) of formulations 2 and 3 was 2.45 times and 2.56 times longer, respectively. These results indicate that both formulations 2 and 3 provide sustained systemic exposure, and formulation 3 appears to provide a more favorable outcome than formulation 2 in achieving and maintaining the expected systemic exposure. For formulation 4, although Cmax was slightly lower (3.15 ± 1.27 ng / mL), Tmax or AUC... 0-45 The time frame indicates that the physicochemical properties of the compound itself, rather than drug concentration, may play a dominant role in influencing systemic absorption. For formulation 6, Cmax was 10.77 ± 2.06 ng / mL, a 2.4-fold increase compared to formulation 4. Tmax was slightly delayed until day 5. Its AUC 0-45 The concentration of Hg / mL was 4196.94 ± 439.59 h·ng / mL, which was 2.84 times higher than that of formulation 3. This indicates that compounds 1–4 all achieved a long-acting release effect.

[0152] Table 5. Results of in vivo pharmacokinetic studies of formulations 1-6

[0153] Example 23: Toxicological and toxicokinetic (TK) studies in rats.

[0154] Methods: Compounds I-1 (dutasteride hexadecyl, hereinafter referred to as Compound 1) and I-4 (dutasteride palmityl, hereinafter referred to as Compound 4) were selected as representative compounds. This study aimed to evaluate the potential systemic toxicity, target organs, and TK profile of Compound 4 or Compound 1 administered twice intramuscularly (day 1 and day 14) at dose levels of Compound 4 (20, 100, and 200 mg / kg) or Compound 1 (20, 80, and 250 mg / kg). For each test item, a total of 41 male and 41 female Sprague Dawley rats were randomly assigned to four major groups (G1 to G4; 5 rats / sex / group) and four TK groups (carrier: 3 rats / sex / group and treatment test item: 6 rats / sex / group). The test sample was prepared using a carrier (0.5% CMC and 0.2% Tween 80 aqueous solution) and administered intramuscularly to the thigh muscle once on day 1 and day 14 at a dose of 0.7 mL / kg. Control groups received the same dose (0.5% CMC and 0.2% Tween 80 aqueous solution) on each day. Dosage formulations were prepared on day 1 and day 14 of the study, and the content of compound 1 or compound 4 was analyzed using a validated HPLC method. Observations included morbidity / mortality assessment, clinical signs of toxicity, detailed clinical examination, injection site assessment, body weight, and food consumption. Blood samples were collected from all TK groups at predetermined time points (samples from day 1 and day 14 were collected before administration (0 hours), and at 0.25, 1, 4, 24, 72, 120, 168, and 40 hours after administration) to determine plasma exposure and TK profiles of compound 1 and dutasteride or compound 4 and dutasteride. TK data analysis was performed in Phoenix WinNonlin (version 6.3). TK parameters, such as Tmax, Cmax, and AUC 0-240 Hours, AUC infusion, and terminal plasma half-life (t1 / 2). At the end of the treatment period (day 15), hematology, clinical chemistry, urinalysis, gross pathology, and organ weight measurements were performed. Histological examination was performed on all preserved organs for carrier control and high-dose groups, as well as injection sites (thigh muscle and skin, and subcutaneous tissue).

[0155] Results: In a 2-week non-GLP toxicology study of compound 1, male and female Sprague Dawley rats (5 / sex / group) were administered the carrier intramuscularly on days 1 and 14 at doses of 20, 80, or 250 mg / kg (equivalent to 16.1, 64.5, or 201.5 mg / kg dutasteride). Toxicity (TK) was assessed in the carrier group (3 animals / sex) and the compound 1 treatment group (6 animals / sex). There was no sex difference in compound 1 exposure. No clinical signs of toxicity (no mortality, weight loss, food consumption, etc.) were observed, and all animals survived to the end of the study. On day 15, very mild edema and slight swelling were observed at the injection site in female animals in the control group at doses ≥ 20 mg / kg. Mild to moderate inflammation at the injection site was characterized by the presence of mixed inflammatory cells (neutrophils, macrophages, lymphocytes, and / or giant cells), and occasional muscle degeneration / necrosis was observed at doses ≥ 80 mg / kg / day. Based on the study results, intramuscular injection did not result in any adverse findings. Therefore, the no-observed adverse reaction level (NOAEL) for compound 1 was determined to be 250 mg / kg (compared to 201 mg / kg for dutasteride), corresponding to a mean Cmax of 0.43 μg / mL for compound 1 (11.66 μg / mL dutasteride) and a mean AUC of 89.8 μg × hr / mL (2017 μg × hr / mL dutasteride) on day 14.

[0156] In another 2-week non-GLP rat toxicity study of compound 4, male and female Sprague-Dawley rats (5 sexes / groups) were intramuscularly injected with the carrier at doses of 20, 100, or 200 mg / kg of compound 4 (13.3, 66.4, or 132.8 mg / kg dutasteride) on days 1 and 14. Total kinematic toxicity (TK) was assessed in the carrier group (3 rats / sex) and the compound 4 group (6 rats / sex). There was no sex difference in compound 4 exposure. No clinical signs of toxicity were observed, and all animals survived to the end of the study. Microscopically, mild to moderate inflammation was observed at the injection site, characterized by the presence of mixed inflammatory cells (neutrophils, macrophages, lymphocytes, and / or giant cells), with occasional muscle degeneration / necrosis at doses ≥100 mg / kg / day. Skeletal muscle necrosis was observed in the left thigh muscle after the most recent injection (day 14), but not in the right thigh muscle after the earlier injection on day 1 in the 20 and 100 mg / kg dose groups, suggesting that this finding is reversible. Based on the results, intramuscular injection did not lead to any adverse findings. Therefore, the NOAEL for compound 4 is 200 mg / kg (compared to 132 mg / kg for dutasteride). At 200 mg / kg, the mean Cmax of compound 4 on day 14 was 3.93 μg / mL, and the mean AUC was 581.35 μg × hr / mL. Subsequently, at 200 mg / kg, the mean Cmax of dutasteride on day 14 was 2.99 μg / mL, and the mean AUC was 314.83 μg × hr / mL.

[0157] The therapeutic indices (TI) of compounds 1 and 4 were based on Cmax and C 最后 The effective concentration relative to 100 ng / ml is shown in the table below. Based on C max On day 14, the TIs for compound 1 were 35.4, 76.4, and 88.5 at concentrations of 20, 80, and 250 mg / kg. Similarly, the TIs for compound 4 were 2.7, 6.9, and 11.6 at 20, 100, and 200 mg / kg. Due to these safety and pharmacokinetic characteristics, the compounds of this invention can be advanced to a first-in-human clinical trial. Further evidence of the safety of this invention is provided.

[0158] Table 6 Treatment Indices (TI) in Rats During Two Weeks of IIM Study on Day 14

[0159]

[0160] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. The compound represented by formula (Ⅰ) or its salt: ， Where R is C3~C 20 Straight-chain or branched alkyl groups.

2. The compound of formula (I) as claimed in claim 1, characterized in that, The compound represented by formula (Ⅰ) is any of the following compounds: 。 3. A method for preparing the compound or its salt represented by formula (Ⅰ) according to claim 1, characterized in that: Includes the following steps: Step 1: Dutasteride and paraformaldehyde are reacted with a catalyst and solvent to prepare intermediate 1; Step 2: The product from Step 1 and C3~C 20 Straight-chain or branched alkyl acyl chlorides are used to prepare compounds of formula (Ⅰ) under the action of solvents and acid-binding agents; The reaction formula is as follows: ， Where R is C3~C 20 Straight-chain or branched alkyl groups.

4. The method for preparing the compound or its salt according to formula (I) as described in claim 3, characterized in that: The reaction solvent in step 1 is selected from one or more combinations of N,N-dimethylformamide, N,N-dimethylacetamide, DMSO, acetonitrile, and tetrahydrofuran.

5. The method for preparing the compound of formula (I) or its salt as described in claim 4, characterized in that: The reaction solvent in step 1 is selected from N,N-dimethylformamide.

6. The method for preparing the compound of formula (I) or its salt as described in claim 3, characterized in that: The catalyst is selected from cesium carbonate, pyridine, or DMAP; the reaction solvent in step 2 is selected from one or more of the following: n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, xylene, dimethyl ether, diethyl ether, isopropyl ether, tetrahydrofuran, methyl acetate, ethyl acetate, dichloromethane, dichloroethane, and chloroform.

7. The method for preparing the compound of formula (I) or its salt as described in claim 6, characterized in that: The catalyst is selected from DMAP; the reaction solvent in step 2 is selected from dichloromethane.

8. The method for preparing the compound of formula (I) or its salt as described in claim 3, characterized in that: The acid-binding agent is selected from one or more of triethylamine, diisopropylamine, pyridine, sodium acetate, sodium carbonate, potassium carbonate, cesium carbonate, and DBU.

9. The method for preparing the compound of formula (I) or its salt as described in claim 8, characterized in that: The acid-binding agent is selected from triethylamine.

10. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 2, or a salt thereof, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10, characterized in that, The pharmaceutical composition is formulated for intramuscular, intradermal, or subcutaneous injection.

12. Use of the compound of formula (I) according to any one of claims 1 to 2 or a salt thereof, or the pharmaceutical composition according to any one of claims 10 to 11, in the preparation of a medicament for treating hair loss and benign prostatic hyperplasia.

Images