A long-acting derivative of 5alpha-reductase and its preparation and use

Abstract

The application belongs to the field of medicine and relates to a 5alpha-reductase long-acting derivative, a preparation method and use thereof, a compound shown in formula (I) or a salt thereof, a preparation method of the compound of formula (I), and use of the compound of formula (I) or a pharmaceutical composition containing the compound of formula (I) in the preparation of a drug for treating alopecia and benign prostatic hyperplasia. The application can maintain the administration effect for a long time through injection administration, has the characteristics of significant long-acting and ideal pharmaceutical technical properties.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular to a long-acting ester derivative of finasteride and a crystal thereof, a preparation method thereof, a pharmaceutical composition containing the same and a medical use thereof. BACKGROUND

[0002] Drug delivery systems are generally critical for the safe and effective administration of biologically active agents. Perhaps the importance of these systems is best appreciated when considering patient compliance and consistent dosing. For example, reducing the dosage requirements of a drug from four times a day to once a day has significant value in ensuring patient compliance and optimizing therapy.

[0003] Optimizing the bioavailability of a drug has many potential benefits. There is a general desire to reduce the frequency of dosing for the convenience of the patient and to improve compliance. By extending the time period over which a drug is released, it is expected that the duration of action per dose will be longer. This will result in overall improvements in the dosage parameters, for example, taking a drug once a day instead of four doses a day as previously required, or once a week instead of daily dosing as previously required. Many drugs are currently dosed once a day, but not all of these drugs have pharmacokinetic properties that are well suited to a dosing interval of exactly 24 hours. It would be beneficial to extend the release period of these drugs as well.

[0004] Despite these advantages, the design and development of prodrugs requires a thorough understanding of the pharmacokinetics, pharmacodynamics, and metabolism of the parent drug. In addition, the chemical structure of the parent drug itself can place severe limitations on the design and feasibility of a prodrug.

[0005] Androgenetic alopecia (AGA) or male pattern hair loss (MPHL) is a genetic disease affecting approximately 50% of men over 50 years of age and a small percentage of women, but it remains an important genetic disease for women. AGA is a common form of hair loss in adult men and women. AGA patients typically exhibit progressive thinning and shortening of the hair in the affected areas. In men, the typical features of AGA are patterned hair loss, receding hairline, and balding on the top of the head. However, in women, AGA is characterized by overall thinning of the hair. AGA is a source of psychological stress for men and women, and can be more distressing for women. In addition, the prognosis of AGA severely impairs the quality of life of the affected individuals. AGA is a disease resulting from both genetic predisposition and the influence of androgens on the hair follicles of the scalp.

[0006] Currently, there are two drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of AGA, one of which is finasteride. Finasteride is a 5a-reductase inhibitor and is considered a synthetic steroid. It is reported that finasteride irreversibly inhibits 5a-reductase, preventing the conversion of testosterone to dihydrotestosterone (DHT) due to its structural similarity to testosterone. Currently, it is reported that a specific type of hair follicle reduces its anagen phase (growth phase) when it comes into contact with DHT. By preventing the formation of DHT, the anagen phase of the hair follicle can be enhanced, and the onset of androgenetic alopecia can be delayed for several years. However, this treatment must be applied continuously, because if finasteride administration is abandoned, DHT levels will rise and the hair that has grown will fall out again. In addition, finasteride is used to treat benign prostatic hyperplasia (BPH), also known as prostate enlargement, which can relieve symptoms associated with BPH, such as difficulty urinating, the need to get up at night to urinate, hesitation at the start of urination, and reduced urine flow.

[0007] Finasteride (Finasteride) is a well-known and useful drug for treating hair loss, and the formulation of finasteride is sold under the brand name "Propecia" at 1 mg once a day. In addition, finasteride is sold under the brand name "Proscar" at 5 mg once a day for the treatment of benign prostatic hyperplasia.

[0008] In a previous clinical study using 1 mg finasteride tablets, the bioavailability of finasteride was about 65%. In addition, the half-life of finasteride affects its long-term effect, so finasteride should be taken every day to maintain the necessary therapeutic drug concentration. Therefore, the inconvenience of having to take finasteride every day is considered a significant drawback of existing finasteride dosage forms.

[0009] The Chinese chemical name of finasteride is: N-tert-butyl-3-oxo-4-aza-5a-androst-1-ene-17b-carboxamide; the English chemical name is: N-tert-Butyl-3-oxo-4-aza-5a-androst-1-ene-17b-carboxamide; the molecular formula is: C 23 H 36 N2O2; the molecular weight is: 372.55; mp: about 258°C, and its structural formula is:

[0010] ,

[0011] Finasteride is described in US Patent Nos. US6046183, US5942519, US5571817, US5886184, US5945412, US6479063, US5547957, US4760071 and US5175155, which disclose the synthesis, dosage form, combination drug, etc. of finasteride.

[0012] Reports on N-derivatives of finasteride are disclosed in US5710275, GB2275050, WO2019108047, none of which report anything related to long-acting research.

[0013] In androgenetic alopecia, a phenomenon in which healthy hair gradually thins and shortens, hair becomes weak and is more easily broken. This phenomenon is called miniaturization. The hair follicle that has undergone miniaturization eventually thins, is less noticeable, and produces short and fine hair, resulting in hair loss. Therefore, many studies on the prevention and treatment of hair loss by inhibiting the activity of male hormones have recently been reported.

[0014] Testosterone is converted to the active androgen dihydrotestosterone (DHT) by 5α-reductase, and the activated dihydrotestosterone binds to the androgen receptor, thereby delaying protein synthesis in the hair follicle cell, shortening the anagen phase of the hair follicle, and causing the hair follicle to atrophy, resulting in hair loss. In addition, during androgenetic alopecia, sebum is excessively secreted, and thus, hair loss with inflammation can occur on the scalp (Dennis A. Holt, et. al., 1990). Finasteride and dutasteride are 5α-reductase inhibitors, which are known to effectively treat hair loss by inhibiting the conversion of testosterone to its active metabolite dihydrotestosterone (DHT) mediated by 5α-reductase.

[0015] Finasteride is a 5α-reductase inhibitor currently on the market, which is sold as an oral drug that must be taken every day, and thus, finasteride should be taken every day to prevent hair loss. If the administration of finasteride is stopped, the 5α-reductase inhibitory effect is stopped, and the symptoms of hair loss can reappear.

[0016] In order to solve the above problems, there is a need to develop a long-acting preparation of finasteride, which can exhibit the effect of preventing and treating hair loss for one month or more with a single dose.

[0017] Optimizing drug bioavailability has many potential benefits. For patient convenience and improved adherence, reducing dosing frequency is generally considered desirable. By prolonging the drug's release time, the duration of action per dose is expected to be longer. This then leads 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. However, not all of these drugs have pharmacokinetic properties suitable for an exact 24-hour dosing interval.

[0018] Extending the release period of these drugs would also be beneficial.

[0019] 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.

[0020] 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 finasteride.

[0021] 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 finasteride. 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.

[0022] Therefore, given the advantages of long-acting formulations, there is an unmet need to develop long-acting parenteral formulations of finasteride that would provide higher adherence rates while maintaining therapeutic levels 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

[0023] This invention modifies the structure of finasteride 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 finasteride, thereby exerting a long-acting effect. This invention is achieved using the following technical solution:

[0024] 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:

[0025] ,

[0026] Where R is C3~C 20 Straight-chain or branched alkyl groups.

[0027] In some embodiments, R is C3 to C 20 Straight-chain alkyl groups;

[0028] In some embodiments, R is C4 to C 19 Straight-chain or branched alkyl groups;

[0029] In some embodiments, R is C5 to C 18 Straight-chain or branched alkyl groups;

[0030] In some embodiments, R is C6 to C6. 17 Straight-chain or branched alkyl groups;

[0031] In some embodiments, R is C7 to C6. 16 Straight-chain or branched alkyl groups;

[0032] In some embodiments, R is C5 to C 15 Straight-chain or branched alkyl groups.

[0033] As an ester group, in a preferred embodiment of the present invention, the compound represented by formula (I) is any of the following compounds:

[0034] ,

[0035] 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:

[0036] Step 1: Finasteride and paraformaldehyde are reacted with a catalyst and solvent to prepare intermediate 1 (hydroxymethylfinasteride).

[0037] 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;

[0038] Step 3: The compound of formula (Ⅰ) is purified in a crystallization solvent, and the reaction formula is as follows:

[0039] ,

[0040] The definition of R is as described above.

[0041] 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. As a feature of this invention, 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; the catalyst is selected from cesium carbonate and pyridine (DMAP), preferably 4-dimethylaminopyridine (DMAP); the reaction solvent in step 2 is selected from one or more combinations 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; the alkaline acid-binding agent is selected from one or more combinations of triethylamine, diisopropylamine, pyridine, sodium acetate, sodium carbonate, potassium carbonate, cesium carbonate, and DBU, preferably triethylamine; the crystallization solvent in step 3 is selected from isopropanol or acetonitrile, and the crystallization temperature is 0 to -20°C, preferably 0 to -5°C.

[0042] 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:

[0043] Table 1 Chromatographic conditions for YPK-022

[0044] .

[0045] The typical chromatograms and spectra are shown in the attached figure.

[0046] 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.

[0047] The pharmaceutical composition of this invention is formulated for intramuscular, intradermal, or subcutaneous injection. The injectable formulation is prepared from the active compound of this invention and related pharmaceutical excipients according to pharmaceutically acceptable methods. The excipients include pharmaceutically necessary components such as suspending agents, antioxidants, stabilizers, wetting agents, and preservatives.

[0048] Furthermore, according to the present invention, compounds of formula (I), or their salts or solvates, can also be formulated into different pharmaceutical preparations to provide a prolonged therapeutic effect. In this regard, finasteride derivatives of formula (I) can be mixed with a selected oil carrier to form a parenteral formulation, whereby the release rate of the target drug, i.e., finasteride, may be slowed down 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.

[0049] 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.

[0050] 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.

[0051] 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 oil 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.

[0052] 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.

[0053] In view of the above, in order to prolong the duration of action of finasteride, this application provides a pharmaceutical composition comprising a compound of formula (I) or a solvate thereof and a pharmaceutically acceptable carrier.

[0054] 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.

[0055] The present invention also provides the use of the compound of formula (I) or its salt or solvate for the preparation of medicaments for treating hair loss and benign prostatic hyperplasia.

[0056] The present invention also provides the use of pharmaceutical compositions containing a compound of formula (I) or a salt thereof or a solvate thereof in the preparation of medicaments for treating hair loss and benign prostatic hyperplasia.

[0057] The key points of this invention are:

[0058] The compounds of this invention have moderate melting points, moderate particle sizes, and low solubility. They 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, this invention is essentially non-toxic, supporting further clinical research. Attached Figure Description

[0059] Figure 1 This is the HPLC chromatogram of compound I-3 finasteride lauryl acid.

[0060] Figure 2 This is the 1H NMR spectrum of compound I-3 finasteride lauryl acid.

[0061] Figure 3 This is the carbon spectrum of compound I-3 finasteride lauryl acid.

[0062] Figure 4 MS for compound I-3-finasteride lauryl acid.

[0063] Figure 5 DSC and TGA were performed on compound I-3 finasteride lauryl acid.

[0064] Figure 6 XRD pattern of compound I-3-finasteride lauryl acid.

[0065] Figure 7 IR for compound I-3-finasteride lauryl acid.

[0066] Figure 8 This is the 1H NMR spectrum of compound I-2-decanoic acid finasteride.

[0067] Figure 9 This is the carbon spectrum of compound I-2-decanoic acid finasteride.

[0068] Figure 10 MS for compound I-2-decanoic acid finasteride.

[0069] Figure 11 This is the 1H NMR spectrum of compound I-1 finasteride hexanoate.

[0070] Figure 12 This is the carbon spectrum of compound I-1 finasteride hexanoate.

[0071] Figure 13 MS for compound I-1 finasteride hexanoate.

[0072] Figure 14 This is a graph showing the change in in vivo drug concentration over time for a typical formulation. Detailed Implementation

[0073] Example 1: Preparation of compound I-3 (finasteride lauryl acid).

[0074] .

[0075] 2.0 g finasteride, 3.55 g paraformaldehyde, 0.13 g DMAP, and 10 ml DMF were added to a 50 ml reaction flask and heated to 50–60 °C for 6 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 purified by column chromatography (eluent: PE:EA = 2:1) to give 0.81 g of a white solid (intermediate 1), with a yield of 37.5%.

[0076] 0.80 g of intermediate 1, 0.22 g of triethylamine, and 20 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 0.48 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 1 hour. After the reaction was complete, the mixture was washed three times with 10 ml of water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 10:1) to give 0.6 g of a colorless, transparent oil (compound I-3), with a yield of 51.72%.

[0077] Example 2: Preparation of compound I-3 (finasteride lauryl acid).

[0078] 2.0 g finasteride, 3.55 g paraformaldehyde, 5.25 g cesium carbonate, and 10 ml DMF were added to a 50 ml reaction flask and heated to 50–60 °C for 10 hours. After the reaction was complete, the mixture was filtered, and the filtrate was washed three times with 200 ml of water (3 x 200 ml), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 2:1) to give 0.31 g of a white solid (intermediate 1), with a yield of 14.35%.

[0079] 0.30 g of hydroxymethylfinasteride (intermediate 1), 0.08 g of triethylamine, and 20 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 0.18 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, the mixture was washed three times with 10 ml of water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 10:1) to give 0.20 g of a colorless, transparent oil (compound I-3), with a yield of 46.51%.

[0080] Example 3: Preparation of compound I-3 (finasteride lauryl acid).

[0081] 2.0 g finasteride, 3.55 g paraformaldehyde, 1.13 g pyridine, and 10 ml DMF were added to a 50 ml reaction flask and heated to 50–60 °C for 5 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 purified by column chromatography (eluent: PE:EA = 2:1) to give 0.75 g of a white solid (hydroxymethylfinasteride, intermediate 1), with a yield of 34.72%.

[0082] 0.70 g of hydroxymethylfinasteride, 0.22 g of triethylamine, and 20 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 0.48 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 1 hour. After the reaction was complete, the mixture was washed three times with 10 ml of water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 10:1) to give 0.53 g of a colorless, transparent oil (compound I-3), with a yield of 52.47%.

[0083] Example 4: Preparation of compound I-3 (finasteride lauryl acid).

[0084] 2.0 g finasteride, 2.55 g paraformaldehyde, 0.13 g DMAP, and 10 ml DMF were added to a 50 ml reaction flask and heated to 50–60 °C for 5 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 purified by column chromatography (eluent: PE:EA = 2:1) to give 0.65 g of a white solid (hydroxymethylfinasteride, intermediate 1), with a yield of 46.29%.

[0085] 0.60 g of hydroxymethylfinasteride, 0.22 g of triethylamine, and 20 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 0.48 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 1 hour. After the reaction was complete, the mixture was washed three times with 10 ml of water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 10:1) to give 0.53 g of a colorless, transparent oil (compound I-3), with a yield of 60.91%.

[0086] Example 5: Preparation of compound I-3 (finasteride lauryl acid).

[0087] 20.0 g finasteride, 35.47 g paraformaldehyde, 1.31 g DMAP, and 100 ml DMF were added to a 500 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 300 ml of dichloromethane and 200 ml of water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, and recrystallized from 120 ml of methanol to give 6.81 g of a white solid (hydroxymethylfinasteride), with a yield of 31.51%.

[0088] 6.80 g of hydroxymethylfinasteride, 5.12 g of triethylamine, and 34 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 9.24 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, 400 ml of dichloromethane was added, and the mixture was washed three times with 300 ml of water (3 times each). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 10:1) to obtain 5.3 g of a colorless, transparent oil (compound I-3). 20 ml of isopropanol was added, and the mixture was cooled to -20–-10 °C and allowed to crystallize overnight. The crystals were filtered, dried, and yielded 3.30 g of a white solid, with a yield of 33.4% and a melting point of 40–42 °C.

[0089] Example 6: Preparation of compound I-3 (finasteride lauryl acid).

[0090] 20.0 g finasteride, 35.47 g paraformaldehyde, 1.31 g DMAP, and 100 ml DMF were added to a 500 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 300 ml of dichloromethane and 200 ml of water (3 times each). The solution was dried over anhydrous sodium sulfate, concentrated, and recrystallized from 100 ml of methanol to give 6.59 g of a white solid (hydroxymethylfinasteride), with a yield of 30.49%.

[0091] 6.50 g of hydroxymethylfinasteride, 4.90 g of triethylamine, and 30 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 8.84 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, 400 ml of dichloromethane was added, and the mixture was washed three times with 300 ml of water (3 x 3 ml). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 10:1) to obtain 5.12 g of a colorless, transparent oil (compound I-3). 20 ml of acetonitrile was added, and the mixture was cooled to 0–5 °C and allowed to crystallize overnight. The crystals were filtered, dried, and yielded 3.42 g of a white solid, with a yield of 36.22% and a melting point of 106–106.5 °C.

[0092] Example 7: Preparation of compound I-3 (finasteride lauryl acid).

[0093] 34.40 g finasteride, 61.00 g paraformaldehyde, 2.26 g DMAP, and 170 ml DMF were added to a 500 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 200 ml of water (3 times each), dried over anhydrous sodium sulfate, concentrated, dissolved in 500 ml of methanol, concentrated to approximately 150 ml, cooled to 0–5 °C for 2 hours to crystallize, and filtered to obtain 28.84 g of white crystalline solid (hydroxymethylfinasteride), with a yield of 77.59%.

[0094] 6.50 g of hydroxymethylfinasteride, 4.90 g of triethylamine, and 30 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 8.84 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, 400 ml of dichloromethane was added, and the mixture was washed three times with 300 ml of water (3 times each). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 10:1) to obtain 5.25 g of a colorless, transparent oil (compound I-3). 20 ml of acetonitrile was added, and the mixture was cooled to 0–5 °C and allowed to crystallize overnight. The crystals were filtered, dried, and yielded 3.53 g of a white solid, with a yield of 37.38% and a melting point of 106–106.5 °C. HPLC purity: 99.36%.

[0095] MS (ESI): M+H + 585.4;

[0096] 1 H NMR (400 MHz, Chloroform-d): δ6.86 (d, J = 10.0 Hz, 1H), 5.94 (d,J = 9.9 Hz, 1H), 5.87~5.31 (m, 2H), 5.12 (s, 1H), 3.53 (dd, J = 12.8, 3.4 Hz,1H), 2.33 (t, J = 7.5 Hz, 2H), 2.26~1.70 (m, 8H), 1.55~1.43 (m, 2H), 1.39(s, 9H), 1.31~1.29 (m, 20H), 1.19~0.96 (m, 7H), 0.92 (t, J = 6.7 Hz, 3H),0.74 (s, 3H).

[0097] 13C NMR (151 MHz, CDCl3): δ 173.27, 171.52, 166.02, 151.06, 122.54, 66.15, 62.84, 57.39, 55.57, 51.07, 47.76, 43.81, 39.57, 38.42, 34.82, 34.23,31.88, 29.74, 29.59, 29.58, 29.46, 29.30, 29.23, 29.08, 29.01, 24.79, 24.18,23.58, 23.28, 22.64, 21.28, 14.09, 13.23, 12.21.

[0098] DSC: This product is a crystalline compound that melts at 105.89℃~123.05℃;

[0099] TGA: This product begins to decompose at approximately 317.33°C;

[0100] XRD: This product is a crystalline compound; (Test conditions: XRD was performed on a Shimadzu 6100 diffractometer using Cu-Ka X-rays at a wavelength of 1.54 nm, 40 kV, and 30 mA. Before testing, the instrument's performance was checked using corundum. The test sample was placed on a non-reflective plate at room temperature. Test conditions: scan range 5-90°, 10° / min.) Its typical characteristic peaks are as follows:

[0101] Table 2 Typical characteristic peaks of crystals

[0102] ,

[0103] Infrared spectrum (IR):

[0104] Table 3 Infrared Spectra

[0105] .

[0106] Example 8: Preparation of compound I-2 (decanoylfinasteride).

[0107] .

[0108] 100g finasteride, 177.33g paraformaldehyde, 6.56g DMAP, and 6000ml DMF were added to a 1000ml reaction flask and heated to 50-60℃ for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000ml dichloromethane and 500ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 1000ml methanol, and concentrated to approximately 500ml. The solution was cooled to 0-5℃ for 2 hours to crystallize, and then filtered to obtain 69.26g of a white solid (hydroxymethylfinasteride), with a yield of 64.13%.

[0109] 5.0 g of hydroxymethylfinasteride, 3.76 g of triethylamine, and 25 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 5.92 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, 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 = 10:1) to give 4.1 g of a colorless, foamy solid (compound I-2), with a yield of 59.42%.

[0110] Example 9: Preparation of compound I-2 (decanoylfinasteride).

[0111] 100g finasteride, 177.33g paraformaldehyde, 6.56g DMAP, and 6000ml DMF were added to a 1000ml reaction flask and heated to 50-60℃ for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000ml dichloromethane and 500ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 1000ml methanol, and concentrated to approximately 500ml. The solution was cooled to 0-5℃ for 2 hours to crystallize, and then filtered to obtain 69.26g of a white solid (hydroxymethylfinasteride), with a yield of 64.13%.

[0112] 5.0 g of hydroxymethylfinasteride, 3.76 g of DIPEA, and 25 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 5.92 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, 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 = 10:1) to give 4.05 g of a colorless, foamy solid (compound I-2), with a yield of 58.69%.

[0113] Example 10: Preparation of compound I-2 (decanoylfinasteride).

[0114] 100g finasteride, 177.33g paraformaldehyde, 6.56g DMAP, and 6000ml DMF were added to a 1000ml reaction flask and heated to 50-60℃ for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000ml dichloromethane and 500ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 1000ml methanol, and concentrated to approximately 500ml. The solution was cooled to 0-5℃ for 2 hours to crystallize, and then filtered to obtain 69.26g of a white solid (hydroxymethylfinasteride), with a yield of 64.13%.

[0115] 5.0 g of hydroxymethylfinasteride, 3.16 g of pyridine, and 25 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 5.92 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, 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 = 10:1) to give 4.31 g of a colorless, foamy solid (compound I-2), with a yield of 61.69%.

[0116] Example 11: Preparation of compound I-2 (decanoylfinasteride).

[0117] 100g finasteride, 177.33g paraformaldehyde, 6.56g DMAP, and 6000ml DMF were added to a 1000ml reaction flask and heated to 50-60℃ for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000ml dichloromethane and 500ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 1000ml methanol, and concentrated to approximately 500ml. The solution was cooled to 0-5℃ for 2 hours to crystallize, and then filtered to obtain 69.26g of a white solid (hydroxymethylfinasteride), with a yield of 64.13%.

[0118] 5.0 g of hydroxymethylfinasteride, 3.22 g of DBU, and 25 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 5.92 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, 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 = 10:1) to give 3.96 g of a colorless, foamy solid (compound I-2), with a yield of 56.68%.

[0119] MS (ESI): M+H + 557.3;

[0120] 1 H NMR (400 MHz Chloroform-d) (attached Figure 8)δ 6.85(d, J = 10.0 Hz, 1H),5.93(d, J = 10.0 Hz, 1H), 5.86~5.32 (m, 2H),5.12 (s, 1H), 3.52 (dd, J = 12.8,3.4 Hz, 1H), 2.32 (t, J = 7.5 Hz, 2H), 2.24~2.14(m, 1H), 2.11~1.99 (m, 2H), 1.94~1.65 (m,6H), 1.51~1.45 (m,2H), 1.39 (s, 9H), 1.32~1.29 (m, 16H), 1.17~1.03(m, 3H), 0.98 (s, 3H), 0.91 (t, J = 6.7 Hz, 3H), 0.74 (s, 3H).

[0121] 13 C NMR (151MHz, CDCl3) (with appendix) Figure 9 )δ 172.83,171.11,165.61,150.66,122.06,65.69, 62.39, 56.93, 55.11, 50.64, 47.30, 43.37, 39.12, 37.95, 34.37, 33.77,31.38, 29.28, 28.95, 28.77, 28.63, 28.55, 24.33, 23.72, 23.12, 22.83, 22.17,20.82, 13.62, 12.78, 11.75.

[0122] Example 12: Preparation of compound I-1 (hexanofinasteride).

[0123] .

[0124] 100g finasteride, 177.33g paraformaldehyde, 6.56g DMAP, and 6000ml DMF were added to a 1000ml reaction flask and heated to 50-60℃ for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000ml dichloromethane and 500ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 1000ml methanol, and concentrated to approximately 500ml. The solution was cooled to 0-5℃ for 2 hours to crystallize, and then filtered to obtain 69.26g of a white solid (hydroxymethylfinasteride), with a yield of 64.13%.

[0125] 5.0 g of hydroxymethylfinasteride, 3.76 g of triethylamine, and 25 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 4.18 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, 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 = 10:1) to give 4.3 g of a colorless, foamy solid (compound I-1), with a yield of 69.13%.

[0126] Example 13: Preparation of compound I-1 (hexanofinasteride).

[0127] 100g finasteride, 177.33g paraformaldehyde, 6.56g DMAP, and 6000ml DMF were added to a 1000ml reaction flask and heated to 50-60℃ for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000ml dichloromethane and 500ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 1000ml methanol, and concentrated to approximately 500ml. The solution was cooled to 0-5℃ for 2 hours to crystallize, and then filtered to obtain 69.26g of a white solid (hydroxymethylfinasteride), with a yield of 64.13%.

[0128] 5.0 g of hydroxymethylfinasteride, 3.56 g of DBU, and 25 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 4.18 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, 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 = 10:1) to give 3.3 g of a colorless, foamy solid (compound I-1), with a yield of 53.05%.

[0129] Example 14: Preparation of compound I-1 (hexanofinasteride).

[0130] 100g finasteride, 177.33g paraformaldehyde, 6.56g DMAP, and 6000ml DMF were added to a 1000ml reaction flask and heated to 50-60℃ for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000ml dichloromethane and 500ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 1000ml methanol, and concentrated to approximately 500ml. The solution was cooled to 0-5℃ for 2 hours to crystallize, and then filtered to obtain 69.26g of a white solid (hydroxymethylfinasteride), with a yield of 64.13%.

[0131] 5.0 g of hydroxymethylfinasteride, 3.23 g of DIPEA, and 25 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 4.18 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, 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 = 10:1) to give 3.44 g of a colorless, foamy solid (compound I-1), with a yield of 55.30%.

[0132] Example 15: Preparation of compound I-1 (hexanofinasteride).

[0133] 100g finasteride, 177.33g paraformaldehyde, 6.56g DMAP, and 6000ml DMF were added to a 1000ml reaction flask and heated to 50-60℃ for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000ml dichloromethane and 500ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 1000ml methanol, and concentrated to approximately 500ml. The solution was cooled to 0-5℃ for 2 hours to crystallize, and then filtered to obtain 69.26g of a white solid (hydroxymethylfinasteride), with a yield of 64.13%.

[0134] 5.0 g of hydroxymethylfinasteride, 3.89 g of pyridine, and 25 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 4.18 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, 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 = 10:1) to give 3.88 g of a colorless, foamy solid (compound I-1), with a yield of 62.37%.

[0135] MS (ESI) (with appendix) Figure 13 ): M+H + 501.3;

[0136] 1 H NMR (400 MHz, Chloroform-d) (attached Figure 11)δ 6.86 (d, J =10.0 Hz, 1H), 5.94 (d, J = 9.9 Hz, 1H), 5.86~5.32 (m, 2H), 5.12 (s, 1H), 3.53 (dd, J = 12.8, 3.4Hz, 1H), 2.33 (t, J = 7.6 Hz, 2H), 2.21 (q, J = 10.5 Hz, 1H), 2.11~2.00 (m,2H), 1.98~1.66 (m, 6H), 1.55~1.43 (m, 2H), 1.39 (s, 9H), 1.36~1.28 (m, 6H),1.18~1.03 (m, 3H), 0.99 (s, 3H),0.92 (t, J = 6.8 Hz, 3H),0.74 (s, 3H).

[0137] 13 C NMR (151 MHz, CDCl3) (with appendix) Figure 12 )δ 172.77,171.10,165.56,150.69,121.99,65.66, 62.36, 56.85, 55.06, 50.58, 47.25, 43.34, 39.09, 37.89, 34.34, 33.68,30.73, 29.24, 28.52, 23.97, 23.70, 23.10, 22.80, 21.77, 20.79,13.40,12.76,11.72.

[0138] Example 16: Preparation of compound I-4 (palmitoylfinasteride).

[0139] .

[0140] 100g finasteride, 177.33g paraformaldehyde, 6.56g DMAP, and 6000ml DMF were added to a 1000ml reaction flask and heated to 50-60℃ for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000ml dichloromethane and 500ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 1000ml methanol, and concentrated to approximately 500ml. The solution was cooled to 0-5℃ for 2 hours to crystallize, and then filtered to obtain 69.26g of a white solid (hydroxymethylfinasteride), with a yield of 64.13%.

[0141] 5.0 g of hydroxymethylfinasteride, 3.76 g of triethylamine, and 25 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 6.18 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, 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 = 10:1) to give 5.3 g of a colorless oil (compound I-4), with a yield of 67.43%.

[0142] Example 17: Preparation of compound I-4 (palmitoylfinasteride).

[0143] 100g finasteride, 177.33g paraformaldehyde, 6.56g DMAP, and 6000ml DMF were added to a 1000ml reaction flask and heated to 50-60℃ for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000ml dichloromethane and 500ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 1000ml methanol, and concentrated to approximately 500ml. The solution was cooled to 0-5℃ for 2 hours to crystallize, and then filtered to obtain 69.26g of a white solid (hydroxymethylfinasteride), with a yield of 64.13%.

[0144] 5.0 g of hydroxymethylfinasteride, 3.56 g of DBU, and 25 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 5.88 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, 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 = 10:1) to give 3.56 g of a colorless oil (compound I-4), with a yield of 45.29%.

[0145] Example 18: Preparation of compound I-4 (palmitoylfinasteride).

[0146] 100g finasteride, 177.33g paraformaldehyde, 6.56g DMAP, and 6000ml DMF were added to a 1000ml reaction flask and heated to 50-60℃ for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000ml dichloromethane and 500ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 1000ml methanol, and concentrated to approximately 500ml. The solution was cooled to 0-5℃ for 2 hours to crystallize, and then filtered to obtain 69.26g of a white solid (hydroxymethylfinasteride), with a yield of 64.13%.

[0147] 5.0 g of hydroxymethylfinasteride, 3.23 g of DIPEA, and 25 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 4.18 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, 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 = 10:1) to give 3.44 g of a colorless oil (compound I-4), with a yield of 55.30%.

[0148] Example 19: Preparation of compound I-4 (palmitoylfinasteride).

[0149] 100g finasteride, 177.33g paraformaldehyde, 6.56g DMAP, and 6000ml DMF were added to a 1000ml reaction flask and heated to 50-60℃ for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was washed three times with 1000ml dichloromethane and 500ml water (3 times each). The filtrate was dried over anhydrous sodium sulfate, concentrated, dissolved in 1000ml methanol, and concentrated to approximately 500ml. The solution was cooled to 0-5℃ for 2 hours to crystallize, and then filtered to obtain 69.26g of a white solid (hydroxymethylfinasteride), with a yield of 64.13%.

[0150] 5.0 g of hydroxymethylfinasteride, 3.89 g of pyridine, and 25 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 6.88 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, 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 = 10:1) to give 3.66 g of a colorless oil (compound I-4), with a yield of 46.65%.

[0151] MS (ESI): M+H + 656.3;

[0152] 1H NMR (400 MHz, Chloroform-d) δ6.85 (d, J = 10.0 Hz, 1H), 5.93 (d, J =10.0 Hz, 1H), 5.86~5.33 (m, 2H), 5.12 (s, 1H), 3.52 (dd, J = 12.8, 3.4 Hz,1H), 2.31 (t, J = 7.5 Hz, 2H), 2.25~2.14(m, 1H), 2.11~1.98 (m, 2H), 1.93~1.65 (m,6H), 1.51~1.45 (m,2H), 1.39 (s, 9H),1.32~1.27 (m, 28H),1.17~1.03(m, 3H),0.98 (s, 3H),0.93 (t, J = 6.7 Hz, 3H),0.74 (s, 3H).

[0153] 13 C NMR (151MHz, CDCl3): δ 173.27,171.52,166.02,151.06,122.54,66.15,62.84,57.39, 55.57, 51.07, 47.76, 43.81, 39.57, 38.42, 34.82, 34.23, 31.88,29.74, 29.59, 29.58, 29.46, 29.30, 29.23, 29.13, 29.08,29.01,27.79,24.79,24.18,23.58,23.47,23.28,22.64,21.28, 20.59, 14.09, 13.23, 12.21.

[0154] Comparative Example 1:

[0155] 34.40 g finasteride, 61.00 g paraformaldehyde, 2.26 g DMAP, and 170 ml DMF were added to a 500 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 200 ml of water (3 times each), dried over anhydrous sodium sulfate, concentrated, dissolved in 500 ml of methanol, concentrated to approximately 150 ml, cooled to 0–5 °C for 2 hours to crystallize, and filtered to obtain 28.84 g of white crystalline solid (hydroxymethylfinasteride), with a yield of 77.59%.

[0156] 6.50 g of hydroxymethylfinasteride, 4.90 g of triethylamine, and 30 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 8.84 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, 400 ml of dichloromethane was added, and the mixture was washed three times with 300 ml of water (3 x 3 ml). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 10:1) to obtain 5.32 g of a colorless, transparent oil (lauroylfinasteride). 20 ml of acetone was added, and the mixture was cooled to -20–-10 °C and allowed to crystallize overnight; no solid precipitated.

[0157] Comparative Example 2:

[0158] 34.40 g finasteride, 61.00 g paraformaldehyde, 2.26 g DMAP, and 170 ml DMF were added to a 500 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 200 ml of water (3 times each), dried over anhydrous sodium sulfate, concentrated, dissolved in 500 ml of methanol, concentrated to approximately 150 ml, cooled to 0–5 °C for 2 hours to crystallize, and filtered to obtain 28.84 g of white crystalline solid (hydroxymethylfinasteride), with a yield of 77.59%.

[0159] 6.50 g of hydroxymethylfinasteride, 4.90 g of triethylamine, and 30 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 8.84 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, 400 ml of dichloromethane was added, and the mixture was washed three times with 300 ml of water (3 x 3 ml). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 10:1) to obtain 5.27 g of a colorless, transparent oil (lauroylfinasteride). 20 ml of methanol was added, and the mixture was cooled to -20–-10 °C and allowed to crystallize overnight; no solid precipitated.

[0160] Comparative Example 3:

[0161] 34.40 g finasteride, 61.00 g paraformaldehyde, 2.26 g DMAP, and 170 ml DMF were added to a 500 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 200 ml of water (3 times each), dried over anhydrous sodium sulfate, concentrated, dissolved in 500 ml of methanol, concentrated to approximately 150 ml, cooled to 0–5 °C for 2 hours to crystallize, and filtered to obtain 28.84 g of white crystalline solid (hydroxymethylfinasteride), with a yield of 77.59%.

[0162] 6.50 g of hydroxymethylfinasteride, 4.90 g of triethylamine, and 30 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 8.84 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, 400 ml of dichloromethane was added, and the mixture was washed three times with 300 ml of water (3 x 3 ml). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 10:1) to obtain 5.15 g of a colorless, transparent oil (lauroylfinasteride). 20 ml of ethanol was added, and the mixture was cooled to -20–-10 °C and allowed to crystallize overnight; no solid precipitated.

[0163] Comparative Example 4:

[0164] 34.40 g finasteride, 61.00 g paraformaldehyde, 2.26 g DMAP, and 170 ml DMF were added to a 500 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 200 ml of water (3 times each), dried over anhydrous sodium sulfate, concentrated, dissolved in 500 ml of methanol, concentrated to approximately 150 ml, cooled to 0–5 °C for 2 hours to crystallize, and filtered to obtain 28.84 g of white crystalline solid (hydroxymethylfinasteride), with a yield of 77.59%.

[0165] 6.50 g of hydroxymethylfinasteride, 4.90 g of triethylamine, and 30 ml of dichloromethane were added to a 50 ml reaction flask, and the mixture was cooled to 0–5 °C. 8.84 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, 400 ml of dichloromethane was added, and the mixture was washed three times with 300 ml of water (3 x 3 ml). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE:EA = 10:1) to obtain 5.10 g of a colorless, transparent oil (lauroylfinasteride). 20 ml of ethyl acetate was added, and the mixture was cooled to -20–-10 °C and allowed to crystallize overnight; no solid precipitated.

[0166] Example 20: Preparation of a typical formulation.

[0167] All formulations below were prepared using a simple mixing method (see table below). In summary, a finasteride solution (0.15 mg / mL) for oral administration was prepared immediately prior to administration. Compounds 1–4 (150 mg / g, finasteride 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.

[0168] Table 4 Composition of Formulations 1-7

[0169] .

[0170] Example 21: Stability test.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 3. Results of the investigation: See the table below.

[0175] Table 5 Results of stability test

[0176] .

[0177] 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.

[0178] Example 22: In vivo pharmacokinetic study.

[0179] The pharmacokinetic characteristics of finasteride 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 0.5 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 prior to administration on intermediate days (days 2–6). Formulations 2, 3, 4, 5, and 7 were administered via a single intramuscular injection into the left thigh muscle at a dose of 15 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.

[0180] Plasma sample preparation: The sample was prepared in an ice bath. Take 40 μL of acetonitrile, 15 μL of internal standard (ethinyl estradiol 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.

[0181] 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.

[0182] Results: Pharmacokinetic assessments were performed in male Sprague Dawley rats to compare oral and intramuscular administration (…). Figure 5 Following daily oral administration of finasteride solution (formulation 1), the Cmax values ​​on day 1 and day 7 were 8.76±1.25 and 11.35±1.64 ng / mL, respectively (see table below). Corresponding AUC 0–1 Tianhe AUC 0-7 The day values ​​were 63.26 ± 10.11 and 57.78 ± 6.15 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 15.65 ± 2.11 ng / mL, with Tmax occurring on day 3. Its AUC 0-45 The concentration was 7423.12 ± 863.12 h·ng / mL, compared with the theoretical cumulative AUC. 0-30 The dosage of formulation 3 increased 4.06-fold compared to formulation 1. Formulation 3 showed a Cmax of 7.32 ± 1.62 ng / mL, and Tmax was also on day 3. 0-45 The cumulative AUC was 2509.22 ± 227.28 h·ng / mL, compared to the theoretical cumulative AUC. 0-30 The dose of formulation 1 was 1.33 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 2.38 times and 2.47 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 (5.94 ± 1.01 ng / mL), Tmax or AUC... 0-45The 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 7, Cmax was 20.33 ± 2.41 ng / mL, indicating a 2.30-fold increase compared to formulation 2, while Tmax remained unchanged. However, the plasma concentration of formulation 7, upon reaching Cmax, will be comparable to that of formulation 3 by day 14. Its AUC... 0-45 The Cmax was 11.96 ± 2.04 h·ng / mL, approximately 1.3 times higher than formulation 3. For formulation 7 (compound 3 containing 0.3% BHT), the Cmax was 20.33 ± 2.41 ng / mL, a 2.30-fold increase compared to formulation 4. The Tmax was slightly delayed until day 5. Its AUC... 0-45 The concentration of Hg / mL was 77918.75 ± 829.42 h·ng / mL, which was 3.91 times higher than that of formulation 3. This indicates that compounds 1-4 all achieved a long-acting release effect.

[0183] Table 6 Results of in vivo pharmacokinetic studies

[0184] .

[0185] Example 23: Toxicological and toxicokinetic (TK) studies in rats.

[0186] Methods: Representative compounds 1 and 4 were selected. This study aimed to evaluate the potential systemic toxicity, target organs, and TK profile of either compound 4 or compound 1 when administered twice intramuscularly (day 1 and day 14) at dose levels of 20, 100, and 200 mg / kg of compound 4 or 20, 80, and 250 mg / kg of compound 1. 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 item was prepared using a carrier (0.5% CMC and 0.2% Tween 80 aqueous solution) and administered intramuscularly once in the thigh muscle at a dose of 0.7 mL / kg on days 1 and 14. Control groups received (0.5% CMC and 0.2% Tween 80 aqueous solution) on each day. Dosage formulations were prepared on days 1 and 14 of the study, and the content of compound 1 or compound 4 was analyzed using a validated HPLC method. Observations included morbidity / mortality screening, clinical signs of toxicity, detailed clinical examination, injection site assessment, body weight, and food consumption. Blood samples were collected at predetermined time points for all TK groups (samples on days 1 and 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 for either compound 1 (finasteride) or compound 4 (finasteride). TK data analysis was performed in Phoenix WinNonlin (version 6.3). TK parameters, such as Tmax, Cmax, and AUC, were analyzed. 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).

[0187] 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 14.8, 59.5, or 185 mg / kg finasteride). Toxicity (TK) was assessed in the carrier group (3 animals / sex) and the compound 4 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 (185 mg / kg finasteride) for compound 1, corresponding to a mean Cmax of 0.59 μg / mL for compound 1 (15.97 μg / mL finasteride) and a mean AUC of 123.06 μg × hr / mL (2763.2 μg × hr / mL finasteride) on day 14.

[0188] 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 (11.34, 56.7, or 113.4 mg / kg finasteride) 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 is >200 mg / kg for compound 4 (>113 mg / kg for finasteride). At 200 mg / kg, the mean Cmax of compound 4 at day 14 TK was 5.38 μg / mL, and the mean AUC was 796.37 μg × hr / mL. Subsequently, at 200 mg / kg, the mean Cmax of finasteride (derived from compound 4) at day 14 TK was 4.09 μg / mL, and the mean AUC was 431.27 μg × hr / mL.

[0189] 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 最后 On day 14, the TIs of compound 1 were 51, 104, and 126 at concentrations of 20, 80, and 250 mg / kg. Similarly, the TIs of compound 4 at 20, 100, and 200 mg / kg were 4, 9.5, and 16.5, respectively. 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.

[0190] Table 7 Treatment Index (TI) of Rats in the Two-Week IM Study on Day 14

[0191] .

[0192] 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 C5~C 15 Straight-chain 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. The method for preparing the compound or its salt as described in formula (I) of claim 1, characterized in that: Includes the following steps: Step 1: Finasteride and paraformaldehyde are reacted with a catalyst and solvent to prepare intermediate 1; Step 2: The product from Step 1 and C5~C 15 Straight-chain alkyl acyl chlorides are used to prepare compounds of formula (Ⅰ) under the action of solvents and acid-binding agents; Step 3: The compound of formula (Ⅰ) is purified in a crystallization solvent, and the reaction formula is as follows: ， Where R is C5~C 15 Straight-chain alkyl groups.

4. A method for preparing the compound of formula (I) or its salt 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; the catalyst is selected from cesium carbonate, pyridine, and DMAP; the reaction solvent in step 2 is selected from one or more combinations 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; the acid-binding agent is selected from one or more combinations of triethylamine, diisopropylamine, pyridine, sodium acetate, sodium carbonate, potassium carbonate, cesium carbonate, and DBU; the crystallization solvent in step 3 is selected from isopropanol or acetonitrile, and the crystallization temperature is 0 to -20℃.

5. 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.

6. The pharmaceutical composition of claim 5, formulated for intramuscular, intradermal, or subcutaneous injection.

7. Use of the compound of formula (I) according to claim 1 or a salt thereof, or the pharmaceutical composition according to claim 5 or 6, in the preparation of a medicament for treating hair loss and benign prostatic hyperplasia.

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