Therapeutic compounds, methods for producing the same, and uses thereof

Abstract

This disclosure provides pharmaceutical compositions, such as compounds of formula Ib or formula IIb or their hydrates, spray-dried pharmaceutical compositions containing compounds of formula Ib or formula IIb or their hydrates, as well as methods for preparing and using the same, for the treatment and / or prevention of one or more of the following functional disorders or disorders: sexual dysfunction, erectile dysfunction, ejaculatory dysfunction, hypoactive sexual desire disorder, mental disorders, and neurological disorders. [Formula 1] TIFF2026529136000063.tif56109

Description

[Technical Field]

[0001] This disclosure relates to compounds derived from or part thereof, novel pharmaceutical compositions containing such compounds, and their use in the treatment and / or prevention of sexual dysfunction. This disclosure also relates to methods for preparing the aforementioned compounds and compositions. [Background technology]

[0002] Any listing or discussion of documents that are clearly previously published in this specification should not necessarily be taken as an endorsement that the documents are part of the latest technology or common general knowledge.

[0003] Sexual dysfunction is very common in both men and women and has a significant impact on mood, self-esteem, interpersonal relationships, and overall quality of life.

[0004] Sexual dysfunction can result from a variety of causes and is often age-related. While physical conditions such as diabetes, heart disease, hypertension, and / or obesity can be triggered, psychological factors such as depression, anxiety, low self-esteem, stress, and relationship conflicts can also play a role. Neurological disorders, hormonal imbalances, and certain medications can also contribute, and lifestyle factors (e.g., smoking, excessive alcohol consumption, and lack of exercise) can also increase the risk of sexual dysfunction.

[0005] Most definitions of sexual dysfunction are based on a four-phase model of the sexual response cycle, which includes sexual desire, sexual arousal, orgasm / climax, and dissipation. Based on this model, four major categories of sexual dysfunction have been identified, including sexual desire disorder, sexual arousal disorder, orgasm disorder, and sexual pain disorder, which can occur in one or more of each of the four phases.

[0006] Hyposexuality disorder (HSDD) is characterized by a persistent lack of sexual fantasy or desire for any form of sexual activity. Often, HSDD is secondary to another sexual dysfunction. However, HSDD can also arise from medical and mental disorders (particularly chronic illnesses and depression), as well as relationship conflicts and loss of attraction.

[0007] Sexual arousal disorder is characterized by the inability to achieve sufficient physiological or subjective arousal during sexual stimulation. In women, this disorder is called female sexual arousal disorder (FSAD) and is characterized by the inability to achieve a proper lubrication-swelling response of the vagina and labia for completion of sexual activity, or by a lack of subjective arousal during sexual activity. The prevalence of FSAD increases with age and is associated with psychological factors such as anxiety and depression. In men, this disorder is called male erectile dysfunction (ED or MED), or more commonly known as erectile dysfunction or impotence, and is characterized by the inability to achieve or maintain an erection sufficient for sexual intercourse. The prevalence of ED also increases with age and is associated with physical conditions such as diabetes, heart disease, and hypertension, as well as psychological factors such as depression.

[0008] Orgasmic dysfunction in women and men is characterized by persistent or recurrent difficulty achieving orgasm despite adequate sexual stimulation. Situational or secondary orgasmic dysfunction is characterized by the inability to achieve orgasm during intercourse but the ability to achieve orgasm with self-harm or sexual prejudice with a partner. Primary orgasmic dysfunction or anorexia is characterized by the inability to achieve orgasm through any means of stimulation and is more common in women. The occurrence of rapid and uncontrolled ejaculation is called premature ejaculation (PE) and is the most frequent sexual complaint in men.

[0009] The introduction of the pharmaceutical drug sildenafil (Viagra®) in the 1990s was a major breakthrough in the treatment of erectile dysfunction. This drug is a so-called PDE5 inhibitor, i.e., an inhibitor of the enzyme phosphodiesterase 5. Further drugs that exert their activity via this mechanism of action have been developed, including tadalafil, vardenafil, and avanafil.

[0010] The development of these drugs has been a major advance in the field of sexual medicine and a clear improvement in the sexual health of many patients, and it has been reported that approximately one-third of all men suffering from ED do not respond to this treatment. Furthermore, the onset time of action and the duration of treatment require planning of sexual activity, and the treatment is not compatible, for example, with nitrate medication for treating angina.

[0011] Phytological extracts and pharmaceutical drugs have also been proposed for the treatment of sexual dysfunction.

[0012] WO2008 / 145996 (Patent Document 1) discloses extracts and pharmaceutical drugs from Neobeguea mahafalensis, their preparation procedures, and their use for inducing sexual enhancement effects and for the treatment of sexual dysfunction, particularly erectile dysfunction and hypoactive sexual desire disorder. This document describes that species of the genus Entandrophragma are useful sources as raw materials in the synthesis of the compounds described in this document. Entandrophragma cudatum is stated to be a rich source of fraxetin that can be used as a precursor in the semi-synthesis of a compound having structure R306. This document describes that compound R.306 can be hydrolyzed to provide compound R306AB.

[0013]

Chemical formula

[0014] WO2013 / 110744 (Patent Document 2) discloses novel limonoids, methods for their synthesis, and their use, inter alia, in the treatment of sexual dysfunction and / or in the synthesis of other compounds for inducing an enhancing effect on sexual behavior. Fragramarin is a preferred starting material for synthesis, and the synthesis is said to provide intramolecular lactonization. This document describes a process for preparing compounds from fragramarin, and it is described that fragramarin can be obtained from the bark and leaves of Endodrophragma coddatum. Further, this document discloses Compound 20 (also referred to as SAE5), which is reported to be an oil. The chemical structure of Compound 20 is the same as that of R306AB described above. SE2251130-7 (Patent Document 3), PCT / SE2023 / 050935 (Patent Document 4) and US Patent Application No. 18 / 469860 (Patent Document 5) disclose therapeutically active limonoids and improvements in the preparation of novel limonoid-type compounds.

Prior Art Documents

Patent Documents

[0015]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Summary of the Invention

Problems to be Solved by the Invention

[0016] One of the most significant challenges in the synthesis of compounds based on the chemical structure of fragrumin is the sheer complexity of its chemical structure, which contains multiple chiral centers, requiring precise stereochemical control at each synthetic step. Consequently, numerous process steps are required, and each step presents the possibility of side reactions, the need for purification of intermediate products, and material loss, often resulting in low overall yields.

[0017] For this reason, naturally occurring fragmarine-derived compounds are often used as starting materials because they provide most of the desired chemical structure, which can then be converted to the desired product in just a few steps.

[0018] However, reliance on natural product-derived starting materials can present its own challenges, particularly in terms of scalability. Natural products are typically isolated in trace amounts from their sources, making them impractical as starting materials for large-scale synthesis. Furthermore, the isolation and purification of starting materials are often difficult and time-consuming, especially due to the numerous compounds present in natural products, and frequently require advanced knowledge and skills in many different fields such as analytical chemistry, medicinal chemistry, and spectroscopy.

[0019] Therefore, there is a need for naturally derived compounds for treating sexual dysfunction that can be provided in satisfactory quantities and in satisfactory pure form, as well as improved methods for preparing such compounds. Furthermore, such compounds need to be provided in a form that exhibits satisfactory pharmaceutical properties as well as satisfactory physical and chemical properties, and that allows for easy handling and pharmaceutical formulation.

[0020] This disclosure describes an improved process for pharmaceutical formulations, including novel forms of SAE5 and its analogues that result in improved physicochemical and biological properties, mitigating problems and / or disadvantages associated with compound SAE5 and its analogues, their manufacturing methods, and providing advantages not previously provided or suggested by known art. [Brief explanation of the drawing]

[0021] [Figure 1A] The numbering of the carbon atoms in the compound of formula Ia is shown. [Figure 1B] This shows the numbering of the carbon atoms in the compound of formula Ib. [Figure 1C] The IUPAC numbering of compounds of formula IIc is shown. [Figure 1D] The IUPAC numbering of compounds in formula V1 is shown. [Figure 2] This outlines the preparation of methanol extract from Entandrophagma caudatum seeds. [Figure 3] This outlines the preparation of the extract composition of Entandrophagma caudatum. [Figure 4] The synthesis of a mixture of the compound of formula Ia1 and the compound of formula Ib1 is shown. [Figure 5] The synthesis of the compound of formula Ib1 is shown. [Figure 6] The IR spectrum of the monohydrate of formula VII1 is shown. [Figure 7] The dissolution plot of the solvent spike experiment, as described in Example 6, is shown. [Figure 8] The image shows a SEM micrograph of a spray-dried formulation containing 25% API + 75% Soluplus, as described in Example 7. [Figure 9] The dissolution plots of six spray-dried dispersions (SDDs) in FaSSIF, pH 6.5, as described in Example 7, are shown. [Figure 10] The XRP diffraction pattern of the monohydrate of formula VII1 or formula VII11 is shown. [Modes for carrying out the invention]

[0022] This disclosure is based on formula IIb:

[0023] [ka] The present invention provides a compound or hydrate thereof. In the formula, R 1 and R2 Each of these is independently a C1-C6 alkyl group optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F, and I, and the compound or its hydrate is essentially in solid form.

[0024] As used herein, the term C1-C6 alkyl refers to a linear, branched, or cyclic alkyl group containing 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl. Further examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0025] The term “solid” is understood by those skilled in the art to include any form of matter that, unless otherwise limited, retains its shape and density, and / or in which the molecules are generally compressed as strongly as intermolecular repulsion allows. Thus, “essentially in a solid form” means that the above compound or its hydrate is at least about 80%, for example at least about 90%, including, for example at least about 95% (or at least about 99%) of such form.

[0026] In particular, R 1 is methyl, and R 2 A compound of formula IIb is provided, wherein isopropyl is used.

[0027] Therefore, equation V:

[0028] [ka] The compound or hydrate thereof is provided. The compound or its hydrate is essentially in solid form.

[0029] As shown by the compound of formula VI, a hydrate of the compound of formula IIb is further provided, which is a combination of the compound of formula IIb and water in a ratio of 1:n.

[0030] [ka] In the formula, n has a value between 0.5 and 100, for example between 0.5 and 10, for example between 1.

[0031] When n is 1, the hydrate of formula VI is provided as the monohydrate of formula VII.

[0032] [ka]

[0033] The compounds of formula IIb described herein are those of formula IIc:

[0034] [ka]

[0035] It can be provided as a stereoisomer of . The stereochemistry of the compound of formula IIc can also be described as follows.

[0036] [ka]

[0037] In further examples, the compound of formula IIb may have stereoisomers as shown below.

[0038] [ka]

[0039] It will be understood that the starting materials for preparing the compounds of formula IIb described herein, such as the compound of formula IIa, and the compounds obtained from the processing of the starting materials, may have the same or essentially the same stereochemistry as that shown for the compound of formula IIb. For example, the compound of formula IIa may be provided as the stereoisomers shown below.

[0040] [ka]

[0041] In particular, this disclosure relates to formula VII1

[0042] [ka] It provides a monohydrate, and the monohydrate is taken in a 1:1 ratio for formula V:

[0043] [ka] It is a combination of a compound and water.

[0044] A stereoisomer of the monohydrate of formula VII1, which may be named the monohydrate of formula VII11, is also provided.

[0045] [ka] Compound V1 in which the monohydrate is taken in a 1:1 ratio:

[0046] [ka] It is a combination of water.

[0047] The IUPAC name of the compound of formula V1 was found to be methyl(3aR,4R,6aS,8S,9aR,11R,12S,12aS,12bR,12cR,14S,15R)-4-(3-furanylcarbonyl)decahydro-12a-hydroxy-4,8,11,15-tetramethyl-12-(2-methyl-1-oxopropoxy)-2-oxo-10H-8,12c-epoxy-11,6a,9a-ethanylylidenecyclopenta[dpyrano[2,3,4-fg][1,3]benzodioxosin-14-acetate.

[0048] The IUPAC name for the monohydrate of formula VII1 was found to be methyl(3aR,4R,6aS,8S,9aR,11R,12S,12aS,12bR,12cR,14S,15R)-4-(3-furanylcarbonyl)decahydro-12a-hydroxy-4,8,11,15-tetramethyl12-(2-methyl-1-oxopropoxy)-2-oxo-10H-8,12c-epoxy-11,6a,9a-ethanylylidenecyclopenta[d]pyrano[2,3,4-fg][1,3]benzodioxosin-14-acetate monohydrate.

[0049] It has been unexpectedly discovered that the compounds of formula IIb described herein, or their hydrates, such as the monohydrate of formula VII1, can be provided in essentially solid form, for example, in essentially crystalline solid form. Thus, the compounds of formula IIb described herein, or their hydrates, are provided, characterized by being substantially crystalline.

[0050] Naturally, the fact that compounds of formula IIb or their hydrates can be supplied in essentially solid forms, such as essentially crystalline forms, is a great advantage in facilitating product development, such as handling, storage, characterization, reduction of batch variability, and development of pharmaceutical formulations. For example, the degree of crystallinity clarifies this with respect to the melting point, which is beneficial, for example, for manufacturing tablets. Such substantially crystalline forms also improve physical and chemical properties and thus storage stability.

[0051] In particular, this disclosure provides monohydrates of formula VII1 or formula VIII1, characterized by having the XRP diffractogram shown in Figure 10. Furthermore, salts of formula VII11 may feature an XRP diffractogram containing one or more of the following peaks: about 19.41, about 10.92, and about 9.66 degrees 2θ, and optionally one or more of the following peaks: about 20.71, about 19.88, about 12.88, and about 11.16 degrees 2θ. The aforementioned values ​​are based on measurements described herein.

[0052] The methods described herein can produce compounds of formula IIb or their hydrates in a form that is crystalline at about 80% or more, for example, at about 85% or more, at about 90% or more, at about 95% or more, at about 99% or more, or at about 100%. "Substantially crystalline" includes crystallinity of more than about 60%, preferably more than about 75%, and more preferably more than about 80% (e.g., about 90%). The degree of crystallinity (%) can be determined by those skilled in the art using X-ray powder diffraction (XRPD). Other techniques such as solid-state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC), and microcalorimetry can also be used. In particular, the degree of crystallinity of compounds of formula IIb or their hydrates can be about 95% or more, for example, about 99% or more.

[0053] Surprisingly, it was found that the compound of formula IIb, or its hydrate, for example, the hydrate of formula VII1, can be prepared with very high chemical purity despite the need to prepare the compound from plant materials containing complex fragmarine derivatives and the associated purification challenges. Furthermore, it was unexpectedly discovered that the compound of formula V, or its hydrate, also possesses high chemical stability.

[0054] Therefore, when measured by a standardized chemical purity assay, for example, compounds of formula IIb or their hydrates, such as the hydrate of formula VII1, are provided with high chemical purity, such as about 95% or higher, for example, about 97%, about 98%, or about 99% or higher. High chemical purity enables the use of compounds of formula IIb or their hydrates in highly regulated products such as pharmaceuticals, where requirements and safety standards are very stringent.

[0055] Compounds of formula IIb, or their hydrates, such as the hydrate of formula VII1, also possess high chemical stability, for example, the amount of the compound or its hydrate after storage is about 90% or more of the amount at the start of storage, e.g., about 95% or more, e.g., about 99% or more. Storage may be carried out in isolated solid form when formulated into pharmaceutical formulations, spray-dried pharmaceutical compositions, or dosage forms. Measurement of chemical stability can be carried out using methods known in the art, such as HPLC. Chemical stability can be measured at a temperature of about 20°C to about 30°C, e.g., about 25°C, and / or at a relative humidity of about 40% to about 80%, e.g., about 60%. Chemical stability can be measured over a period of about 3 months to about 12 months, e.g., about 6 months. High chemical stability is a great advantage because it allows compounds of formula IIb or their hydrates to be stored with only slight degradation or decomposition so that they can be used at the desired appropriate time. For example, the compound of formula IIb or its hydrate may be stored before being used to prepare pharmaceutical compositions such as spray-dried pharmaceutical compositions or pharmaceutical formulations described herein.

[0056] Furthermore, the compound of formula Ib may possess the advantageous properties described for the compound of formula IIb, such as being a solid, such as a crystalline solid, and / or having high chemical purity. For example, the crystallinity of the compound of formula Ib may be about 95% or higher, for example, about 99% or higher, and / or the chemical purity may be greater than about 95%, for example, about 97%, about 98%, or about 99% or higher. Furthermore, the storage stability may be essentially equivalent to or higher than that of the compound of formula IIb. The compound of formula Ib may also be the compound of formula Ib1, i.e., R 1 It will be understood that the substituent may be methyl, as shown below. Furthermore, compounds of formula Ib may be provided as stereoisomers, such as the stereoisomers described herein, and / or as hydrates, such as monohydrates.

[0057] [ka]

[0058] The inventors have also surprisingly found that the physicochemical (e.g., solubility) properties of the above-mentioned compounds and hydrates can be greatly improved by spray-drying them together with polymers or copolymers that can form physicochemical interactions with such compounds or hydrates. This significant improvement in solubility is unexpected considering the very low solubility of the compounds and hydrates described herein.

[0059] This disclosure also relates to a spray-drying pharmaceutical composition, (a) Compounds of formula IIb, such as compounds of formula V or compounds of formula Ib, and (b) Excipients suitable for spray drying The present invention provides a spray-dryable pharmaceutical composition containing the compound of formula IIb. Excipients suitable for spray drying may include polymers or copolymers capable of forming physicochemical interactions with the compound of formula IIb.

[0060] For example, excipients suitable for spray drying may include one or more of the following: cellulose ester, N-vinylpyrrolidone-vinyl acetate copolymer, polyvinylcaprolactam polyvinyl acetate-polyethylene glycol graft copolymer, and methacrylate-methyl methacrylate copolymer.

[0061] Furthermore, excipients suitable for spray drying may include cellulose esters such as nonionic cellulose esters. The cellulose ester may include or consist of hydroxypropyl methylcellulose (HPMC) or its derivatives. For example, the derivatives of HPMC may include or consist of HPMC-AS and / or HPMC-P.

[0062] Additionally or alternatively, one or more of the following polymers may be used: hypromellose phthalate, polyvinylpyrrolidone-vinyl acetate (i.e., PVP-vinyl acetate), polymethacrylate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In yet another example, one or more of the following polymers may be used: PVP, PVP-vinyl acetate, crospovidone, PEG, methylcellulose, hydroxypropyl methylcellulose.

[0063] The ratio of compounds of formula Ib or formula IIb, or their hydrates, such as the hydrate of formula VII1, may be 1:5 to about 5:1, for example, about 1:4 to about 4:1, about 1:3 to about 3:1, about 1:2 to about 2:1, or about 1:1. For example, the ratio of compounds of formula IIb, or their hydrates, such as the hydrate of formula VII1, may be about 1.3.

[0064] Furthermore, it will be understood that the compound of formula Ib or formula IIb or its hydrate in the spray-dried pharmaceutical composition may be provided as a stereoisomer of formula IIc or its hydrate. For example, the spray-dried composition described herein includes a stereoisomer of the hydrate of formula VII1, such as the monohydrate of formula VII11 shown below.

[0065] [ka]

[0066] The spray-dried composition may contain particles having a particle size distribution with a Dv90 of 120 mm or less, for example, 100 mm or less, for example, 10 mm to 120 mm. Those skilled in the art will understand the parameters. As used herein, the term "Dv90" means the size (or diameter) in the particle size distribution that comprises 90% of the total volume of the material. The particle size distribution may be measured using methods used in the art. For example, the measurement may be carried out using laser diffraction, dynamic light scattering, scanning electron microscopy (SEM), sieving analysis, and any combination thereof.

[0067] Furthermore, the spray-dried composition may include, or consist of, powder, granules, pellets and / or beads.

[0068] The spray drying process conditions include volatile spray drying solvents (lower alkyl alcohols (e.g., methanol, isopropanol, or more particularly ethanol), hydrocarbons (e.g., C 5~10 Since spray drying results in the evaporation of one or more organic solvents, such as alkanes, haloalkanes (e.g., dichloromethane), dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetone, or mixtures thereof, or more preferably water, such as aqueous solvents, it will be understood that spray drying is considered to convert any hydrate of formula I(I)b, i.e., any hydrate of formula Ib or formula IIb, into a compound of formula I(I)b. Furthermore, spray drying conditions provide a spray-dried pharmaceutical composition containing a compound of formula I(I)b in a form that is completely or largely amorphous. For example, more than about 50% by weight, e.g., more than about 75% by weight, e.g., more than about 90% by weight, e.g., more than about 95% by weight, e.g., more than about 95% by weight, e.g., more than about 99% by weight of the spray-dried composition may be amorphous.

[0069] Pharmaceutical compositions can also be prepared in a manner that allows for the inclusion of compounds of formula Ib or formula IIb, or their hydrates, such as the hydrate of formula VII1, in pharmaceutical formulations suitable for administration to patients. Thus, pharmaceutical formulations containing compounds of formula Ib or formula IIb, or their hydrates, such as the hydrate of formula VII1, are provided.

[0070] The spray-dried pharmaceutical composition may contain a therapeutically effective amount of the compound of formula Ib or formula IIb, while the pharmaceutical preparation may contain a therapeutically effective amount of the compound of formula Ib or formula IIb or its hydrate.

[0071] As used herein, the term “therapeutic dose” refers to the amount of a compound that produces a therapeutic effect in a treated patient. The effect may be objective (i.e., measurable by several tests or markers) or subjective (i.e., the subject shows signs of an effect and / or feels an effect).

[0072] The amount of compound Ib or IIb, or its hydrate, administered may vary depending on factors such as age, weight, and the severity of the condition being treated. In one example, the compound Ib or IIb, or its hydrate, may be administered at a dose of approximately 1 microgram to 500 milligrams per day. In further examples, patients may be treated at a dose of approximately 1 mg to 100 mg per day.

[0073] therefore, A therapeutically effective amount of the compound of formula Ib and / or formula IIb described herein, or its hydrate, A spray-dried composition according to this specification, comprising a therapeutically effective amount of the compound of formula Ib and / or formula IIb described herein. A pharmaceutical formulation containing the following is provided.

[0074] This pharmaceutical preparation is a mixture of pharmaceutically acceptable excipients, carriers, and / or diluents.

[0075] Pharmaceutical formulations, such as pharmaceutical compositions containing spray-dried compositions, can be formulated for oral administration. For example, the pharmaceutical formulation may be provided as tablets, capsules, or lozenges. In further examples, the pharmaceutical formulation may be provided as a liquid, such as a syrup.

[0076] Accordingly, the compounds and / or spray-dried compositions described herein may, after their preparation (e.g., by spray-drying), be provided in the form of simple powder mixtures, powder microspheres, coated powder microspheres, lyophilized liposome dispersions, or combinations thereof.

[0077] Such pharmaceutical formulations and / or dosage forms may be provided in the form of single-unit dosage forms such as pills, capsules, cakes, films (e.g., intraoral films) or tablets.

[0078] Capsules can be prepared by directly filling the compounds or spray-dried compositions described herein into pharmaceutically acceptable capsules made from suitable materials designed for oral delivery, for example, or by mixing the compounds or spray-dried compositions with excipients and then filling such capsules, which may include a granulation step (described below) before filling the capsules for such delivery.

[0079] The compounds and / or spray-dried compositions described herein may be granulated into pellets or pills, but may also be formulated (i.e., provided for administration) in the form of a dry, free-flowing powder. "Dry" means essentially free of water and other liquid solvents, which includes less than 5%, or less than 4%, more preferably less than 3%, less than 2%, less than 1%, less than 10%, for example less than 6%, of which the formulation is a liquid such as water.

[0080] The fluidity of a powder composition can be measured by standard techniques known to those skilled in the art, including measurements performed with a powder flow analyzer (e.g., those sold by Stable Micro Systems or Meritics (both UK)), which may include bulk density measurement, powder flow rate dependence tests, caking tests, and agglomeration tests.

[0081] In the context of the present invention, the term “free flowability” may include the powder exhibiting an angle of repose of about 50° or less, for example, about 45° or less, including about 40° or less, for example, about 35° or less, and more specifically about 30° or less; a bulk density of about 0.3 g / mL or more, for example, about 0.4 g / mL or more, for example, about 0.5 g / mL or more, more specifically about 0.6 g / mL or more; and / or a tap density of about 0.5 g / mL or more, for example, about 0.6 g / mL or more, for example, about 0.7 g / mL or more, particularly about 0.8 g / mL or more.

[0082] Suitable techniques for producing dosage forms containing dry powder or granules include simple dry mixing, granulation (including dry granulation, wet granulation, melt granulation, thermoplastic pelletization, and spray granulation), extrusion / spheroidization, or more preferably freeze-drying or spray-drying (see below).

[0083] The compositions of the present invention may, in alternative terms, be provided in the form of tablets for oral use. Such tablets may be formed, for example, by direct compression / compression of the compositions of the present invention, after being mixed with one or more suitable excipients, such as diluents, disintegrants, flow enhancers, and / or lubricants, and may be achieved, for example, using techniques as described in Pharmaceutical Dosage Forms: Tablets. Volume 1,3 rd This can be achieved using techniques such as those described in Edition, Augsburger et al (eds.), CRC Press (2008) and the documents cited therein. Suitable compression equipment includes standard tablet presses such as the Kilian SP300 or Korsch EK0, XP1, XL100, and XL200.

[0084] Suitable disintegrants that can be used in tablets (e.g., Rowe et al, Handbook of Pharmaceutical Excipients, 6) th Examples of disintegrants (as defined in ed. (2009)) include cellulose derivatives such as hydroxypropyl cellulose (HPC), low-substituted HPC, methylcellulose, ethyl hydroxyethyl cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, and modified cellulose gum; starch derivatives, such as moderately crosslinked starch, modified starch, hydroxypropyl starch, and pregelatinized starch; and other disintegrants, such as calcium alginate, sodium alginate, alginic acid, chitosan, colloidal silicon dioxide, docusate sodium, guar gum, aluminum magnesium silicate, polariline potassium, and polyvinylpyrrolidone. Combinations of two or more disintegrants may be used.

[0085] Preferred disintegrants include so-called "super disintergrants" such as cross-linked polyvinylpyrrolidone, sodium starch glycolate, and croscarmellose sodium (e.g., Mohanachandran et al, International Journal of Pharmaceutical Sciences Review and Research, 6, 105 (2011)). A combination of two or more super disintergrants can be used.

[0086] When disintegrants and / or superdisintegrants are used in tablets, they may be used in amounts of 0.5 to 15% by weight (e.g., total) based on the total weight of the composition. A preferred range is 1 to 8% by weight, for example, about 2 to about 7% (e.g., about 5%, for example, about 4%).

[0087] If present, the binder is preferably used in an amount of 0.5 to 20% by weight based on the total weight of the tablet formulation. A preferred range is 1.0 to 15% by weight, for example, about 2.0 to about 12% (for example, about 10%). Suitable binders include cellulose gum and microcrystalline cellulose.

[0088] The spray-dried pharmaceutical composition may further contain enteric coatings, such as coatings, that help prevent the release of compounds, hydrates, or spray-dried compositions in the stomach.

[0089] Alternatively, the compounds described herein, or in particular the spray-dried pharmaceutical compositions, may be reconstituted with a liquid that is an orally administered vehicle, such as an oil-based or water-based vehicle. The vehicle may include cellulosic agents, such as nonionic cellulosic agents, such as carboxymethylcellulose (CMC), (microcrystalline cellulose)MC, hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), and / or hydroxyethylmethylcellulose (HEMC), or derivatives of any of the aforementioned cellulosic agents. In particular, the cellulosic agent may include or consist of HPMC, which may also be called hypromellose, or a derivative thereof. HPMC may be HPMC-AS, for example, grade M or grade USP / NF HPMC-AS. Additionally or alternatively, one or more of the following polymers may be used: hypromellose phthalate, PVP-vinyl acetate, polymethacrylate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In yet another example, one or more of the following polymers can be used: PVP (i.e., polyvinylpyrrolidone), PVP-vinyl acetate, crospoidone, PEG, methylcellulose, and hydroxypropyl methylcellulose.

[0090] The compounds of formula IIb described herein, or their hydrates, or pharmaceutical formulations or compositions may also be provided for parenteral administration, such as intramuscular, intravenous, and intradermal administration. For example, administration may be oral, sublingual, rectal, nasal, transdermal, vaginal, or by inhalation. In such situations, the compounds described herein, or in particular the spray-dried pharmaceutical compositions, may be reconstituted with a liquid that is an injection-suitable vehicle, such as an oil-based or water-based vehicle.

[0091] This disclosure also, Compounds of formula Ib and / or formula IIb described herein, or their hydrates, The spray-drying compositions described herein, or The pharmaceutical preparations described herein It is provided for use as a pharmaceutical in treatment.

[0092] Also, Compounds of formula Ib and / or formula IIb described herein, or their hydrates, The spray-drying compositions described herein, or The pharmaceutical preparations described herein It is provided for use in the treatment and / or prevention of one or more of the following functional disorders or disorders: sexual dysfunction, erectile dysfunction, ejaculatory dysfunction, hypoactive sexual desire disorder, mental disorders, and neurological disorders.

[0093] Also, Compounds of formula Ib and / or formula IIb described herein, or their hydrates, The spray-drying compositions described herein, or The pharmaceutical preparations described herein The following functional disorders or impairments are provided: use for the manufacture of medicines for the treatment and / or prevention of one or more of the following: sexual dysfunction, erectile dysfunction, ejaculatory dysfunction, hypoactive disorders, mental disorders, and neurological disorders.

[0094] Furthermore, a therapeutic and / or preventive method is provided for one or more of the following functional disorders or disorders: sexual dysfunction, erectile dysfunction, ejaculatory dysfunction, hypoactive sexual desire, mental disorders, and neurological disorders, in a therapeutically effective dose: Compounds of formula Ib and / or formula IIb described herein, or their hydrates, The spray-drying compositions described herein, or The pharmaceutical preparations described herein This includes administering it to patients who require it.

[0095] As used herein, the term prevention includes references to the prevention and / or avoidance of disease, disorder and / or condition. In particular, the term may mean that a patient (or healthy subject) achieves a reduction in the likelihood of developing a condition (e.g., a reduction of at least 10%, a reduction of at least 20%, 30%, or 40%, e.g., a reduction of at least 50%).

[0096] Sexual dysfunction may include, as described above, disorders relating to sexual desire, sexual arousal, orgasm / climax and / or dissipation phase, as well as sexual desire disorders, sexual arousal disorders, orgasm disorders and sexual pain disorders, which may occur in one or more of each of the four phases identified above and are described in detail above.

[0097] In particular, the functional impairments or disorders described herein may include erectile dysfunction and / or premature ejaculation. For example, the functional impairment or disorder may include or consist of erectile dysfunction. In further examples, the functional impairment or disorder may include or consist of premature ejaculation.

[0098] Compounds of formula Ib and / or formula IIb described herein, or their hydrates, The spray-drying compositions described herein, or The pharmaceutical preparations described herein are This drug may be administered to patients suffering from the functional impairment or disorder described herein.

[0099] The patient may be male or female. Furthermore, the patient may be an inadequate responder to treatment with PDE5 inhibitors, may have a condition that makes PDE5 inhibitors contraindicated, or may be exposed to medications that should not be administered with PDE5 inhibitors. Such conditions include, for example, vascular health problems such as hypertension, diabetes such as diabetes mellitus, hyperlipidemia, and blood glucose-related conditions such as smoking. Examples of medications that should not be administered with PDE5 inhibitors include alpha-blockers, soluble guanylate cyclase stimulants, or nitrate drugs such as isosorbide dinitrate or isosorbide dinitrate.

[0100] combination A compound of formula Ib and / or formula IIb or a hydrate thereof, or a pharmaceutical formulation comprising a compound of formula Ib and / or formula IIb or a hydrate thereof, can be combined with additional pharmaceuticals to achieve a greater beneficial effect with respect to the dysfunctions or disorders described herein. For example, a compound of formula Ib and / or a compound of formula IIb or a hydrate thereof, or a pharmaceutical formulation comprising a compound of formula Ib and / or a compound of formula IIb or a hydrate thereof, may be combined with a PDE5 inhibitor such as sildenafil, tadalafil, vardenafil or avanafil.

[0101] Salt Some compounds of the present disclosure can be provided as salts such as pharmaceutically acceptable salts. For example, a compound of formula III or a compound of formula IV, or a stereoisomer thereof, can be provided as a salt such as a metal salt or a base addition salt.

[0102] Isotope Compounds of the present disclosure such as a compound of formula Ib or formula IIb may contain atomic isotopes in one or more of the atoms constituting the compound, i.e., the compound may be labeled with isotopes. For example, a compound of formula V may be labeled with one or more isotopes, such as tritium ( 3 H), deuterium ( 2 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). In one example, the compound is labeled with one or more deuterium atoms. All isotope modifications of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0103] Preparation method The compounds of the present disclosure or hydrates thereof can be prepared as described herein. For example, the compounds of the present disclosure can be prepared as shown in Scheme 1.

[0104]

Chemical formula

[0105] Furthermore, the starting material of formula Ib may be prepared from the compound of formula IIa, or from a mixture of the compound of formula IIa and the compound of formula IIb. For example, the compound of formula IIa, the compound of formula IIb, or a mixture thereof may be converted into a mixture of the compounds of formula Ia and formula Ib, and subsequently separated as shown in scheme 2, where R 1 O - M + This refers to metal alkoxides such as sodium methoxide, and R 1 OH indicates an alcohol such as methanol, and acid (aq.) indicates an acidic aqueous solution such as an aqueous solution of acetic acid.

[0106] [ka]

[0107] Therefore, equation IIb

[0108] [ka] The present invention provides a method for preparing the compound or its hydrate, The following steps: a) A step of providing a compound of formula IIa, a compound of formula IIb, or a mixture thereof,

[0109] [ka] (In the formula, R 1 , R 2 and R 3 (These are C1-C6 alkyl groups that are independently and optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F, and I.) b) The mixture from step a) is given by formula R 1 O - M + Alkoxide of formula R 1 Alcohols of OH (where R is used in the formula) 1 As defined for compounds of formula IIa and / or formula IIb, M+ is Li + kaNa+ or K + A step of providing a mixture containing a compound of formula Ia and a compound of formula Ib by subjecting it to a metal cation such as, and an aqueous acid,

[0110] [ka] c) A step of separating the compound of formula Ia from the compound of formula Ib, d) A step of optionally converting the compound of formula Ia to the compound of formula Ib, e) A step of reacting a compound of formula Ib with a compound of formula X in the presence of an ester formation promoter such as a coupling reagent, to provide a compound of formula IIb.

[0111] [ka] (In the formula, Compound R of formula X 2 This is defined as for compounds of formula IIa and / or formula IIb, X is selected from the group consisting of halides such as OH and Cl, and OC(O)CH(CH3)2. f) optionally includes the step of combining the compound of formula IIb with water to provide the hydrate of formula VI,

[0112] [ka] The hydrate is a combination of the compound of formula IIb and water taken in a ratio of 1:n, where n has a value of 0.5 to 100, for example, 0.5 to 10, for example, 1.

[0113] In step e), an esterification promoter such as DMAP HCl salt and / or a compound of formula X such as isobutyryl chloride may be added in one or more parts and / or aliquots to form a compound of formula IIb that is free from or substantially free from impurities such as diester impurities, in which both hydroxyl groups of the compound of formula Ib are converted to ester groups.

[0114] The combination of the compound of formula IIb and water in step f) to form the hydrate of formula VI can be carried out using a mixture of acetone and water. Furthermore, the hydrate of formula VI can be subjected to a mixture of acetone and water to increase its purity.

[0115] The compound of formula Ia can be converted to the compound of formula Ib using a synthesis as shown in scheme 3.

[0116] [ka]

[0117] Therefore, a method is provided for converting a compound of formula Ia to a compound of formula Ib:

[0118] [ka] In the formula, R 1 is a C1-C6 alkyl group optionally substituted with one or more substituents selected from OH, Cl, Br, F, and I. This method, a) A step of subjecting the compound of formula Ia to lactone ring opening conditions, thereby providing the compound of formula III,

[0119] [ka] (In the formula, R 1 (This is as defined for compounds of formula Ia.) b) A step of oxidizing the compound of formula III to the compound of formula IV,

[0120] [ka] (In the formula, R 1 (This is as defined for compounds of formula Ia.) c) The carboxylic acid of the compound of formula III is reacted with the hydroxyl group of carbon 30, thereby producing formula Ib:

[0121] [ka]

[0122] The method includes the step of providing a compound of formula Ia and / or formula Ib, which will be understood to be prepared as described in steps a) to c) of the method for preparing a compound of formula IIb described herein.

[0123] Steps a), b), and / or c) in a method for converting a compound of formula Ia to a compound of formula Ib may be as follows: Step a) may include a base such as barium hydroxide octahydrate in the presence of a solvent such as methanol, and / or Step b) may include an oxidizing agent, such as Dess Martinperiodinane, and / or Step c) may include a coupling agent such as a carbodiimide-containing coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or its HCl salt, in the presence of a sterically hindered base such as N,N-diisopropylethylamine.

[0124] Preferably, step b) follows immediately after step a) without keeping the compound of formula III formed in step a) in solution for an extended period or isolating it. In this way, the risk of the compound of formula III cyclizing back to the compound of formula Ia is minimized.

[0125] The substituents of the compounds described herein, for example, the substituents of the compounds in the methods described herein, may have the following values: R 1 R may be methyl, and / or R 2 and R 3 R may be independently methyl, ethyl, or isobutyl. For example, R 1 R may be methyl, 2 R may be isopropyl, 3If present, it may be ethyl or isopropyl.

[0126] Furthermore, it will be understood that the compounds of formula IIa described herein may be fragmarine derivatives such as fragmarine 3,30-diisobutyrate, fragmarine 3-isobutyrate-30-propionate, and / or fragmarine 3-nicotinate-30-isobutyrate. Additionally or alternatively, the compounds of formula IIa may be provided in mixture with fragmarine-3-nicotinate-30-isobutyrate.

[0127] Furthermore, compounds of formula IIa, compounds of formula IIb, or mixtures thereof may be provided by plants or plant materials selected from the family Meliaceae, such as mangrove, Xylocarpus moluccensis, Pseudocedrela kotschyi, mahogany, Neobeuga mahafalensis, chucrasii, Entandrophaga caudatum, and any combination thereof. For example, the plant or plant material may be selected from the leaves, branches, roots and / or seeds of the plant or plant material. In particular, the plant or plant material may be provided by Entandrophaga caudatum seeds, such as crushed seeds or other disintegrating seeds.

[0128] A method for preparing the spray-dryable pharmaceutical compositions described herein is also provided, the method comprising spray-drying a compound of formula IIb, or a hydrate thereof such as a monohydrate of formula VIII, or a compound of formula Ib as described in claim 10, or a hydrate thereof, together with an excipient suitable for spray-drying.

[0129] A method for preparing a spray-dried pharmaceutical composition is: a) A step of providing a solution to a spray dryer comprising a compound of formula I or formula IIb, or a hydrate thereof, an excipient suitable for spray drying, and a solvent system comprising at least two polar solvents, wherein at least one of the polar solvents is miscible with water, and at least one solvent is aprotic and immiscible with water; b) The step of spray-drying the solution from step a) may include the following steps:

[0130] Furthermore, a method for preparing a spray-dryable pharmaceutical composition may include the additional steps of dissolving a compound or hydrate in a water-immiscible solvent, dissolving an excipient in a water-miscible solvent, and mixing them to provide a solution for a spray dryer.

[0131] The solvents in the solvent system for the method of preparing a spray-dried pharmaceutical composition may be as follows: The non-aqueous miscible polar aprotic solvent may optionally be halogenated. For example, the non-aqueous miscible polar aprotic solvent may include or consist of dichloromethane. Additionally or alternatively, the water-miscible polar solvent may be selected from polar aprotic solvents and protic solvents, preferably methanol and / or acetone. It will be understood that the water-miscible polar solvent and the non-aqueous miscible polar aprotic solvent may be mixed in various ratios, such as various volume ratios. For example, the water-miscible polar solvent and the non-aqueous miscible polar aprotic solvent may be mixed in ratios of about 1:5 to about 5:1, for example, about 1:4 to about 4:1, about 1:3 to about 3:1, about 1:2 to about 2:1, or about 1:1.

[0132] Whenever the word “about” is used herein in the context of quantities, such as absolute quantities like dose, weight, volume, size, diameter, aspect ratio, angle, pH value, or relative quantities (e.g., percentages) of individual components in a composition or components of a composition (including concentration and ratio), time frame, and parameters such as temperature, pressure, relative humidity, it will be understood that such variables are approximations and can therefore vary by ±10%, e.g., ±5%, preferably ±2% (e.g., ±1%) from the actual number specified herein. This is true even if such a number is initially presented as a percentage (e.g., “about 10%” can mean ±10% of the number 10, which is any between 9% and 11%).

[0133] The compounds of this disclosure have the advantage of being able to be stored over a wide range of temperatures and / or relative humidity (in appropriate pharmaceutical packaging, the packaging may or may not provide a barrier to moisture). The compounds of this disclosure may also have the advantage of being more physically and chemically stable over a wide range of storage temperatures.

[0134] The compounds, uses, and methods described herein may also have advantages such as being more convenient for physicians and / or patients, being more effective, having lower toxicity, having a broader range of activity, being more potent, causing fewer side effects, having lower inter-patient variability, and / or having other useful pharmacological properties, whether the active ingredient is intended for use in the treatment of a known condition or otherwise, compared to compounds or methods (treatments) known in the prior art. [Examples]

[0135] This disclosure is illustrated by the following non-limiting examples.

[0136] material I purchased the seeds of Entandrophagma caudatum from Parceval Ltd, Wellington, South Africa.

[0137] Abbreviation Fig. Figure DCM Dichloromethane DIPEA Diisopropylethylamine DMAP 4-N,N-dimethylaminopyridine hydrochloride DMSO (Dimethyl Sulfoxide) DCS (Difference Scanning Calorimetry) DVS Dynamic Steam Adsorption EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HCl ethyl acetate eq. equivalent weight g grams h time HDPE (High-Density Polyethylene) HPLC (High-Pressure Liquid Chromatography) HPMC (Hydroxypropyl Methylcellulose, Hypromellose) HPMC-AS Hypromellose Acetate Succinate HPMC-P Hypromellose Phthalate kg (kilogram) LDPE (Low-density polyethylene) min. mm (millimeters) mL (milliliter) μg (microgram) MDSC Modulated Differential Scanning Calorimetry NLT or higher NMR nuclear magnetic resonance L (liters) LOD Loss on drying Ph.Eur. European Pharmacopoeia PLM Polarizing Microscopy PTFE (Polytetrafluoroethylene) RH (Relative Humidity) rpm (revolutions per minute) RRT (Relative Retention Time) SDI spray-dried intermediates SDD spray dried dispersion SEM (Scanning Electron Microscopy) Tc crystallization temperature Tg (glass transition temperature) TLC (Thin-Layer Chromatography) USP (United States Pharmacopeia) V represents the equivalent volume for the batch input (for example, a 5V and 2.5kg input yields 12.5L). Same meaning as vol. V XRD X-ray diffraction w / w weight / weight Å Angstrom

[0138] Example 1: Preparation of an extract composition from the seeds of Entandrophagma caudatum Step 1: Preparation of methanol extract from Entandrophagma caudatum seeds A schematic of the procedure for this process is shown in Figure 2.

[0139] In Figure 2, DCT001 represents the oil formed during the extraction process, and IBC represents the intermediate bulk container.

[0140] Methanol (approximately 800 L) was added to a nitrogen-filled glass reactor and stirred. Then, crushed seeds of Entandrophagma caudatum (approximately 100 kg) were added, the reaction vessel was evacuated, and nitrogen gas was refilled. The reactor temperature was set to 40°C, and the contents were stirred for at least 15-20 hours. The mixture was then filtered under a pressurized nitrogen atmosphere using a polyamide filter cloth (mesh size 25 μm), and the filtrate was collected in a container. Methanol was added to a feed container (100 L). From the feed container, methanol was filtered (twice, 50 L each time), bypassing the glass reactor, and the filtrate was collected in a container. The mixture was then filtered again through the polyamide filter cloth by repeating the procedure. The resulting filtrate cake was then dried under vacuum for at least 1 hour. The filtrate was then added to the glass reactor (approximately 800 L in total), and the contents were stirred. The methanol solvent was removed under vacuum at a jacket temperature of 40–70°C (the internal temperature during distillation was approximately 21–29°C). Distillation continued until approximately 200 L remained in the glass container. Care was taken not to remove excess methanol due to the high viscosity of the residual contents, which made removal from the glass container difficult. The jacket temperature was then adjusted to approximately 20–25°C, and the concentrated methanol extract was recovered.

[0141] Step 2: Preparation of an extract composition of Entandrofragma caudatum in ethyl acetate. This process is shown in Figure 3.

[0142] In Figure 3, DCT001 represents the oil formed during the extraction process, and IBC represents the intermediate bulk container.

[0143] The concentrated methanol extract prepared in Step 1 (approximately 400 L, i.e., two batches from Step 1) was added to a nitrogen-filled glass reactor. The reactor temperature was adjusted to 75°C and stirring was started. Methanol was distilled off under vacuum to obtain a dry mixture, and then the temperature was adjusted to 20°C. Ethyl acetate (siRNA) (approximately 400 L) was then added to the dry mixture in the reactor, followed by water (approximately 170 L). The reactor temperature was set to 40°C and the contents of the reactor were stirred for approximately 30 minutes, while maintaining the temperature at 40°C. Then, stirring was stopped and the two phases were separated for 30-60 minutes. The aqueous layer was then discarded. The reactor temperature was adjusted to 55-75°C, and the mixture remaining after water removal was concentrated under vacuum until its volume was reduced to approximately 50 L (i.e., when approximately 350 L of distillate had been distilled off and recovered). Next, the resulting extract of Entandrophagma caudatum in æ was collected as a dark yellow solution and stored at 5°C ± 3°C before further use.

[0144] The extract composition of Entandrofragma caudatum obtained in this manner contained a mixture of fragmarin-3,30-di-isobutyrate, fragmarin-3-isobutyrate-30-propionate, fragmarin-3-nicotinate-30-isobutyrate, and a precursor of the compound of formula Ib1. The chemical structure of the precursor was not established.

[0145] Example 2: Synthesis of compound V

[0146] [ka]

[0147] Step 1: Synthesis of the compound of formula Ia1 and the compound of formula Ib1

[0148] [ka]

[0149] Figure 4 shows an overview of the steps involved in this process.

[0150] The extract of Entandrofragma caudatum in siRNA from Example 1 (138 kg) was dissolved in methanol (690 L, 5 vol) and distilled until no more distillate was observed. Methanol (690 L, 5 vol) was added to the reactant, and the mixture was further distilled at 45°C until no more distillate was observed, thereby obtaining a solvent-free extract residue as a brown syrup (105 kg).

[0151] The extraction residue (105 kg, 1.0 equivalent) was dissolved in methanol (1050 L, 10.0 V) and cooled to 15°C ± 5°C. Sodium methoxide (15.75 kg, 0.15% w / w) was added in four equal amounts at 10-minute intervals at a temperature below 30°C (exothermic reaction of 5–10°C was observed during the addition of sodium methoxide). The reaction mixture was then stirred at 45°C ± 5°C for 40 hours.

[0152] Detailed examination: The pH of the reaction mixture was adjusted to 6.0–7.0 using aqueous acetic acid solution (approximately 15.75 kg, approximately 0.15% w / w) at 15°C ± 5°C, and purified water (315 L, 3.0 V) was added at a temperature below 30°C. The reaction mixture was concentrated under reduced pressure at a temperature below 45°C to remove methanol. The residue was diluted with toluene (1050 L, 10.0 V). Then, purified water (420 L, 4.0 V) was added, followed by sodium chloride (21 kg, 0.2% w / w), and the mixture was stirred for 15 minutes. The two phases were then separated, and the aqueous phase was re-extracted with toluene (735 L, 7.0 V). The combined organic layers were washed with a 10% sodium chloride solution (735 L, 7.0 V), separated, and dried over anhydrous sodium sulfate (approximately 21 kg, 0.2% w / w). The organic layer was concentrated under reduced pressure at a temperature below 45°C to obtain a crude mixture of compounds of formulas Ia1 and Ib1.

[0153] Hexane slurry, followed by column purification. Hexane (1050 L, 10.0 V) was added to the crude mixture, and the mixture was then heated to 40°C ± 5°C and stirred for 2 hours. The mixture was then cooled to 25°C ± 5°C and stirred for 8 hours. The precipitate was collected by filtration and washed with hexane (210 L, 2.0 V) to obtain a crude mixture of compounds of formulas Ia1 and Ib1 as a pale yellow solid (approximately 13.36 kg) (all nonpolar impurities were washed away by hexane purification). Compounds of formulas Ia1 and Ib1 were separated from the crude mixture by column chromatography on silica gel to obtain compound Ia1 (approximately 4.17 kg) and compound Ib1 (approximately 2.94 kg).

[0154] Purification of the compound of formula Ia1: Crude compound of formula Ia1 (4.17 kg) was stirred with isopropyl alcohol (IPA) (8.3 L, 2.0 V) at 50°C ± 5°C for 1 hour. The temperature was then slowly reduced to 25°C ± 5°C (over 1 hour), and the crude compound was allowed to continue stirring for 6 hours. The solid was recovered by filtration and washed with IPA (2.1 L, 0.5 V). The wet solid (2.32 kg) was dried under vacuum at 40°C ± 5°C to obtain compound of formula Ia1 (approximately 2.13 kg) as a solid.

[0155] Analysis data: Purity (HPLC): 98.4%.

[0156] Purification of the compound of formula Ib1: Crude compound of formula Ib1 (2.94 kg) was stirred with IPA (8.8 L, 3.0 V) at 50°C ± 5°C for 1 hour. Then, the temperature was slowly lowered to 25°C ± 5°C (over 1 hour), and the crude compound was left to stir for 6 hours. The solid was recovered by filtration and washed with IPA (2.9 L, 1.0 V).

[0157] A wet solid (1.53 kg (corrected for loss on drying (LOD))) was stirred with Depositphotos (4.6 L, 3.0 V) at 50°C ± 5°C for 1 hour. The temperature was then slowly reduced to 25°C ± 5°C, and the mixture was stirred for 6 hours. The solid was recovered by filtration and washed with Depositphotos (1.5 L, 1.0 V).

[0158] A wet solid (1.07 kg) was stirred with Depositphotos (4.6 L, 3.0 V) at 50°C ± 5°C for 1 hour. The temperature was then slowly reduced to 25°C ± 5°C, and the mixture was stirred for 6 hours. The solid was recovered by filtration and washed with Depositphotos (1.5 L, 1.0 V).

[0159] A wet solid (0.85 kg) was stirred with Depositphotos (1.7 L, 2.0 V) at 50°C ± 5°C for 1 hour. The temperature was then slowly reduced to 25°C ± 5°C, and the mixture was stirred for 6 hours. The solid was recovered by filtration and washed with Depositphotos (0.4 L, 0.5 V).

[0160] The wet solid (0.58 kg) was dried under vacuum at 40°C ± 5°C to obtain the compound of formula Ib1 (approximately 0.335 kg) as a solid.

[0161] Analysis data: Purity (HPLC): 99.5%.

[0162] Step 2: Three-step synthesis for the conversion of compound Ia1 to compound Ib1. This process is shown in Figure 5.

[0163] Step 2(a): Ring opening of the lactone ring: Conversion of the compound of formula Ia1 to the compound of formula III1

[0164] [ka]

[0165] A suspension of barium hydroxide octahydrate (1.16 kg, 1.0 equivalent) in methanol (10.3 L, 5.0 V) was cooled to 0–5°C, and compound Ia1 (2.06 kg, 1.0 equivalent) was added in four equal volumes over 15 minutes at 0–5°C. The resulting reaction mixture was stirred at 0–10°C for 2 hours (the reaction mixture became homogeneous as the reaction progressed). The progress of the reaction was monitored by thin-layer chromatography (TLC) (60% siRNA / hexane for consumption of starting materials, and 10% methanol / methylene chloride (MeOH / DCM) for elution of the product). Visualization: potassium permanganate (KMnO4) staining).

[0166] Detailed examination: After the starting material was completely consumed, the reaction mixture was acidified to pH 5-6 with a 10% aqueous acetic acid solution (approximately 8.24 L, 4.0 V), and the methanol was removed by concentrating the mixture at a temperature below 40°C. The residue (10.3 L) was then collected. * 2.5V * 2) The mixture was extracted twice. The combined organic layers were washed with brine solution (8.2 L, 4.0 V), dried over anhydrous sodium sulfate, and filtered.

[0167] Analysis data: Purity (HPLC): 99.5%.

[0168] Step 2(b): Oxidation: Conversion of compound III1 to compound IV1

[0169] [ka]

[0170] A suspension of dess-martin periodinane (1.72 kg, 1.1 equivalents) in DCM (16.5 L, 8V) was added to the organic layer of step 2(a) (i.e., the compound of formula III1) at 0-5°C with stirring. The resulting reaction mixture (white suspension) was stirred at 10-15°C for 3 hours. The progress of the reaction was monitored by TLC (5% MeOH / DCM + 1 drop of acetic acid; visualization: KMnO4 staining).

[0171] Detailed examination: After the compound of formula III1 was completely consumed, the reaction mixture was quenched with a 20% sodium thiosulfate solution in purified water (20.6 L, 10V) and stirred for 30 minutes (the reaction mixture became clear, and a clear separation of the organic and aqueous layers was observed). The layers were separated, and the aqueous layer was extracted with DCM (10.3 L, 5.0V). The combined organic layers were washed with brine solution (10.3 L, 5.0V), dried over anhydrous sodium sulfate, and filtered. The organic layers were concentrated to a volume level of 10.0 with respect to the compound of formula Ia1 at a temperature below 40°C.

[0172] Step 2(c): Ring formation: Conversion of compound IV1 to compound Ib1

[0173] [ka]

[0174] To the organic layer of step 2(b) (i.e., the compound of formula IV1), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC×HCl) (0.702 kg, 1.0 equivalent), followed by diisopropylethylamine (DIPEA) (0.957 L, 1.5 equivalent), was added with stirring at 10°C ± 5°C for 30 minutes. The resulting reaction mixture was stirred at 10°C ± 5°C for 2 hours. The progress of the reaction was monitored by TLC (10% MeOH / DCM for consumption of starting materials, 80% siRNA / hexane for elution of products; visualization: KMnO4 staining).

[0175] Detailed examination: After the compound of formula IV1 was completely consumed, the reaction mixture was quenched with water (20.6 L, 10.0 V). The layers were separated, and the aqueous layer was extracted with DCM (10.3 L, 5.0 V). The organic layer was washed with brine solution (10.3 L, 5.0 V). The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and filtered. The combined organic layers were concentrated under reduced pressure at 40°C until no distillates were observed.

[0176] Purification of the compound of formula Ib1: To the crude product of the compound of formula Ib1, dimethyl (12.3 L, 6.0 V) was added at a temperature below 40°C, and the mixture was concentrated to a volume level of 3.0 with respect to the compound of formula IIb1, and stirred at 50°C ± 5°C for 1 hour. The reaction mixture was gradually cooled to 25°C ± 5°C over 1 hour and stirred at 25°C ± 5°C for 6 hours. The solid was recovered by filtration and washed with dimethyl (2.1 L, 1.0 V) to obtain a wet solid (1.1 kg) of the compound of formula Ib1. The wet solid was dried under vacuum at 40°C ± 5°C to obtain the compound of formula Ib1 (0.85 kg) as a solid.

[0177] Analysis data: Purity (HPLC): 95.4%.

[0178] Step 3: Synthesis of the compound of formula V

[0179] [ka]

[0180] To a solution of compound Ib1 (obtained from both steps 1 and 2 above) (322 g, 1.0 equivalent) in dried dimethylformamide (DMF) (1.6 L, 5.0 V), 4-N,N-dimethylaminopyridine hydrochloride (DMAP × HCl) (91 g), followed by isobutyryl chloride (92 g, 1.5 equivalents), was added at 25°C ± 5°C. The reaction mixture was heated to 60°C ± 5°C and stirred for 6 hours. Then, DMAP × HCl (45.6 g) was added to the reaction mixture, followed by isobutyryl chloride (61.2 g, 1.0 equivalent), and the reaction was continued for a further 4 hours and monitored by HPLC.

[0181] Detailed examination: After the reaction was complete, the reaction mixture was cooled to 25°C ± 5°C, filtered through a Celite bed, and washed with DMF (320 mL, 1.0 V). The filtrate was passed through a 0.2 μm cartridge and washed with DMF (320 mL, 1.0 V).

[0182] Purified water (8.0 L, 25.0 V) was added to another reaction vessel and cooled to 15 °C ± 5 °C. Then, the filtrate was slowly added at 15 °C ± 5 °C over 1 hour (reverse quench). The reaction contents were allowed to reach a temperature of 25 °C ± 5 °C and stirred at the same temperature for 4 hours. The solid was collected by filtration and washed with purified water (0.65 L, 2.0 V).

[0183] The wet solid was stirred with purified water (1.6 L, 5 V) at 40 °C ± 5 °C for 2 hours, then collected by filtration and washed with purified water (0.65 L, 2 V).

[0184] The wet solid was dried under reduced pressure at 40 °C ± 5 °C for 12 hours to obtain a crude product (456 g) of the compound of formula V.

[0185] Analysis data: Purity (HPLC): 79.97%.

[0186] Ethyl acetate purification: Ethyl acetate slurry - 1: The crude product (456 g) was stirred with EtOAc (1.36 L, 3.0 V) at 50 °C ± 5 °C for 1 hour. The reaction mixture was gradually cooled to 25 °C ± 5 °C over 1 hour and stirred at 25 °C ± 5 °C for 4 hours. The solid was collected by filtration and washed with EtOAc (0.45 L, 1.0 V).

[0187] Wet solid weight: 295 g, after LOD correction: 249 g (LOD: 15.6% w / w). Purity by HPLC: 97.7%, impurity: RRT 0.68: 1.38%.

[0188] Ethyl acetate slurry - 2: The crude product (249 g) was stirred with EtOAc (373 mL, 1.5 V) at 50 °C ± 5 °C for 1 hour. The reaction mixture was gradually cooled to 25 °C ± 5 °C over 1 hour and stirred at 25 °C ± 5 °C for 4 hours. The solid was collected by filtration and washed with EtOAc (0.45 L, 1.0 V).

[0189] Wet solid weight: 236.6 g, after LOD correction: 230 g (LOD: 2.6% w / w). Purity by HPLC: 98.68%, impurity: RRT 0.68: 1.38%.

[0190] Ethyl Acetate Slurry - 3: The crude product (230 g) was stirred with EtOAc (460 mL, 2.0 V) at 50 °C ± 5 °C for 1 hour. The reaction mixture was gradually cooled to 25 °C ± 5 °C over 1 hour and stirred at 25 °C ± 5 °C for 4 hours. The solid was collected by filtration and washed with EtOAc (115 mL, 1.0 V).

[0191] Wet solid weight: 191.6 g. Purity by HPLC: 99.8%, Impurity: RRT 0.68: 0.12%.

[0192] The wet solid was dried under reduced pressure at 40 °C ± 5 °C for (NLT) 10 hours to obtain the crude product (185.4 g) of the compound of formula V.

[0193] Example 3: Synthesis of the monohydrate of formula VIII

[0194]

Chemical Structure

[0195] In this example, acetone / purified water purification was carried out to obtain the desired monohydrate form.

[0196] The crude product (181.4 g) of the compound of formula V was stirred with acetone (1.3 L, 7.0 V) at 45 °C ± � °C for 30 minutes to obtain a clear solution, Purified water (2.8 L, 1�.0 V) was added to the reaction mixture over 1 hour and stirred at 45 °C ± � °C for an additional 1 hour. The reaction mixture was gradually cooled to 25 °C ± � °C (over 1 hour) and stirred for 6 hours. The solid was collected by filtration and washed with acetone / purified water (278 mL, 1.0 V) to obtain the wet product of the monohydrate of the compound of formula V1, i.e., the monohydrate of formula VII1 (1८८ g). The wet solid was dried under reduced pressure at 40 °C ± � °C for 16 hours or more and sieved to obtain the monohydrate of formula VII1 (1७९ g). <図

[0197] Analysis data: Purity (HPLC): 99.9%.

[0198] Specific rotation: -49.8°.

[0199] The IR spectrum of the generated monohydrate of formula VII1 is shown in Figure 6.

[0200] NMR data of the monohydrate of formula VII1: 1 H-NMR (DMSO, 400MHz): δ8.64(s,1H),7.78(s,1H),6.75(dd,1H),5.09(s,1 H),4.69(s,1H),3.92(s,1H),3.41(s,3H),2.68(m,3H),2.35(m,2H),2.24 (m,3H),1.95(m,2H),1.67(m,1H),1.55(d,4H),1.42(s,3H),1.26(d,6H), 1.18 (m, 1H), 1.04 (s, 1H), 0.76 (s, 3H) LCMS: 629.4 [M+H], HPLC purity: 98.50%.

[0201] Example 4 The hydrate of formula VII1 was prepared as described herein, and its solubility was tested by checking its uptake in saturated solutions of several biomedical media at different pH values, as shown in Table 1 below.

[0202] [Table 1]

[0203] Therefore, the best solubility was found when using FaSSIF at pH 6.5.

[0204] Example 5 Based on research conducted at Thermo Fisher (Oregon, USA), we decided to attempt spray drying of the hydrate of formula VII1 using Thermo Fisher's in silico platform for solubilization technology selection. In the following examples, the abbreviation "API" is used for the hydrate of formula VII1.

[0205] Example 6 Set up the solvent spike evaluation, add approximately 100 mg of polymer / excipient (see the following list) to a scintillation vial, and dissolve it in 20 mL of FaSSIF medium at pH 6.5 using a magnetic stir bar. · Vinylpyrrolidone vinyl acetate copolymer (Kollidon VA 64, PVP-VA 64, BASF Corporation, 100 Park Avenue, Florham Park, New Jersey, USA) · Hypromellose (HPMC, Pharamacoat, Shin-Etsu Chemicals, Tokyo, Japan) · PEG 6000 / vinyl caprate / vinyl acetate, BASF Corporation, 100 Park Avenue, Florham Park, New Jersey, USA Hypromellose acetate succinate (HPMCAS-M, Harke Pharma, Muelheim a.d.Ruhr, Germany) · Methacrylic acid - ethyl acrylate copolymer (1:1), Evonik Operations GmbH Kirschenallee, 64293 Darmstadt, Germany · Hypromellose phthalate (HPMCP-HP55, Harke Pharma, Muelheim. d.Ruhr Germany)

[0206] A control prepared in 20 mL of FaSSIF medium (pH 6.5) was added to a scintillation vial without added excipient. 50 mg of API was weighed into a 10 mL volumetric flask, dissolved in DMSO, and then made up to a volume of 10 mL with DMSO to prepare a 5 mg / mL API stock solution. This is a concentrated dissolved stock drug solution. 1.0 mL of the stock solution thus prepared was added to each scintillation vial containing polymer / excipient and FaSSIF or FaSSIF only (i.e., the control).

[0207] The solutions were then stirred using a magnetic stirring plate for 15, 30, or 60 minutes. Aliquots of each solution were then transferred to a centrifuge tube and centrifuged at 10,000 rpm for at least 5 minutes, or until a clear supernatant was produced. The resulting supernatant was then analyzed by HPLC. Figure 7, showing the solubility plot of the solvent spike experiment, demonstrates a significant increase in the solubility of API hydrates observed for all excipients compared to the control sample (pure API).

[0208] Based on this data, six formulations with API and excipient (Soluplus®, HPMC-HP55, and HPMC-ASM) loadings were selected with 25% and 50% API loadings for spray-dry feasible batch production (Table 2).

[0209] [Table 2]

[0210] Example 7 The six formulations listed in Table 2 were prepared accordingly for the feasibility study of spray drying.

[0211] Since the hydrate (API) of formula VII1 is highly soluble in dichloromethane (DCM) and the excipient is highly soluble in acetone, it was decided to dissolve both the hydrate of formula VII1 and the excipient in a solvent mixture with a high solid-filling ratio using a 1:1 acetone-DCM mixture for the production of spray-dried solution formulations (see Table 3). The excipient described herein is equally soluble in methanol (MeOH). Spray drying with MeOH and DCM using the method of the present invention was also tested and confirmed to yield spray-dried formulation products with the same chemical and physical characteristics as formulations spray-dried using acetone and DCM (data not shown). Therefore, the spray-drying method of the present invention can be carried out using, for example, either acetone / DCM or methanol / DCM. Accordingly, the examples of acetone ratios, amounts, volumes, etc. described herein can be used interchangeably with MeOH.

[0212] To prepare each supply solution, the selected excipient was added to Duran containing the required mass of 1:1 w / w acetone:DCM and dissolved while mixing. After the excipient was completely dissolved, the required mass of API was added, and the solution was further stirred until the API was dissolved. The solutions were then spray-dried immediately after preparation.

[0213] The supply solution was spray-dried using a Buchi B-290 laboratory-scale spray dryer equipped with an inert loop. Nitrogen was used as the drying gas, and a Buchi two-fluid spray nozzle (tip diameter 0.7 mm) and a standard Buchi cyclone were used. The spray drying parameters were as follows: ·Drying outlet temperature 65℃ • 1.0 bar spray pressure • Solution supply rate of 6g / min • Tubing: Masterflex L / S pump with PTFE head, i.e., PTFE with peristaltic pump.

[0214] After spray drying, the bulk material was transferred to a stainless steel tray and vacuum-dried for 24 hours at 25°C under continuous vacuum using either a Gallenkamp vacuum oven or an Edwards freeze dryer equipped with a vacuum pump.

[0215] Table 3 shows the yields obtained from the prepared formulations and the spray-drying process. All formulations were successfully spray-dried.

[0216] [Table 3]

[0217] Observations: Formulations containing either Soluplus or HPMC-ASM produced a fine white powder with soft aggregates. Formulations containing HPMC-HP55 produced a slightly sticky white powder with soft aggregates.

[0218] Place all six powders obtained from spray drying into a stainless steel tray covered with foil with small holes, and place the tray in a 25-inch container. 0 The samples were placed in a vacuum oven at °C and a maximum vacuum was maintained for 24 hours (>1000 mbar). As shown in Table 4, the weight of all six powders was recorded before and after vacuum drying.

[0219] [Table 4]

[0220] DSC, XRD, and SEM analysis: DSC, XRD, and SEM analyses were performed on spray-dried powders from the six feasible formulations listed in Table 4 (data not shown). Analysis using these techniques revealed no evidence of API crystallization in any of the batches of spray-dried dispersions, indicating that all manufactured formulations were amorphous. Figure 8 shows SEM micrographs of spray-dried formulations containing 25% API + 75% Soluplus.

[0221] Dissolution analysis: Six spray-dried formulations were also tested in a two-step dissolution process in FaSSGF (pH 1.6, 30 min), followed by switching the dissolution to FaSSIF (pH 6.5, 90 min). Figure 9 shows the dissolution plots of the six spray-dried dispersions (SDDs) in FaSSIF, pH 6.5. The data indicate that the solubility of the API was significantly improved with the HPMC-HP55 formulation, providing the best dissolution. The dissolution tests were performed using a USP basket type I apparatus.

[0222] Tq vs %RH(MDSC) To test long-term stability, these six spray-dried intermediate (SDI) formulations were exposed to 75% RH for 4 hours using a dynamic vapor adsorption (DVS) system. The term "intermediate" is used because the formulations can be further processed into formulations such as tablets and capsules. All formulations absorbed moisture under these conditions. The humidity-equalized samples were sealed in a sealed pan and analyzed by modulated differential scanning calorimetry (MDSC). No significant changes were observed in the glass transition temperature (Tg) of the samples before and after exposure to humidity, indicating that all formulations were stable.

[0223] Based on the results of DSC, XRD, SEM, dissolution, and DVS tests, four lead formulations were selected for large-scale production (see Example 8).

[0224] long term stability Long-term stability testing was also performed on the spray-dried formulation containing 25% API + 75% HPMC-ASM by packaging the spray-dried intermediate powder in double LDPE bags, each bag being gooseneck-shaped and sealed with a cable tie. One 0.5 g desiccant was added between the LDPE bags, and the bags were then placed in a 75 cc HDPE bottle with a lid but not heat-sealed. After maintaining the bags at 25°C / 60% RH for up to 6 months, the stored formulations were analyzed. As can be seen in Table 5 below, the spray-dried formulation of the present invention exhibits good stability up to 6 months under the test conditions.

[0225] [Table 5-1]

[0226] [Table 5-2]

[0227] Suspension stability Four formulations (25% API + 75% Soluplus, 50% API + 50% Soluplus, 50% API / 50% HPMC-HP55, and 50% API / 50% HPMC-ASM) were formulated as small-batch-size suspensions in three oral suspension vehicles (a. 0.5% methylcellulose in water, b. corn oil, and c. Ora-Blend SF). Ora-Blend SF was obtained from Perrigo / Padagis (Grand Rapids, Michigan, USA) and is reported to contain water, sorbitol, glycerin, berry citrus flavor, microcrystalline cellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, and calcium sulfate. These suspensions were visually evaluated for homogeneity and injectability for oral gastric tube feeding, and were examined for recrystallization by polarizing microscope (PLM) up to 6 hours after preparation. The Ora-blend SF suspension formulation presented problems during high-performance liquid chromatography (HPLC) analysis of the material, and gelation of the material was observed during extraction of the suspension with methanol as the solvent. Therefore, Ora-blend SF was not selected as the administration vehicle. Subsequently, four suspension formulations (dose strength 21 mg / mL) were stabilized and tested for appearance and injectability (visual), amorphous properties (optical microscope), and potency. All four formulations passed the injectability test and showed no evidence of API crystallization under a microscope.

[0228] Formulation 1.25% w / w API: Soluplus SDD in 0.1% w / w hypromellose solution Formulation 2.50% w / w API: Soluplus in 0.1% w / w hypromellose solution Formulation 3.50% w / w API: HPMC-HP55 in oleic acid Formulation 4.50% w / w API: 0.1% w / w hypromellose solution containing HPMC-AS

[0229] All four formulations showed >95% assay values ​​at T=6 hours, indicating that the suspensions were stable in their respective administration vehicles. The pH of all suspensions was approximately pH 4, indicating that the suspensions were slightly acidic to the administration.

[0230] Therefore, all tested suspensions are physically and chemically stable for a period of at least 6 hours.

[0231] Example 8: Spray Drying - Scale-Up Experiment Of the six spray-dried formulations developed in the feasibility study (see Table 4), four were selected for scale-up testing aimed at producing more than 100 g of spray-dried powder.

[0232] The four formulations selected for scale-up were as follows: • 25% API + 75% Soluplus (registered trademark) • 50% API + 50% Soluplus (registered trademark) 50% API + 50% HPMC-HP55 50% API + 50% HPMC-ASM

[0233] Table 6 shows the amounts of API, excipients, and acetone:DCM mixed and then spray-dried at the settings presented above in this specification. Note that the nozzle cleaner was set to "1" for all scale-up batches.

[0234] [Table 6]

[0235] Observations: Formulations containing either Soluplus or HPMC-ASM produced a fine white powder with soft aggregates. Formulations containing HPMC-HP55 produced a slightly sticky white powder with soft aggregates.

[0236] A comparison with the results in Table 3 shows that scaling up yielded slightly lower yields in the trials using Soluplus. Furthermore, a comparison with Table 3 shows that scaling up provided higher yields for HPMC, as evidenced by the results in Table 6 for formulations using HPMC-HP55 and HPMC-AS M, respectively.

[0237] Particle size distribution: To determine the particle size distribution of the spray-dried particles of the present invention, a Malven Mastersizer 3000 equipped with an Aero S dispersion unit was used. The spray-dried powder was dispersed in nitrogen, with a hopper height set to 1.0 mm, a gas pressure of 1.0 bar, a feed rate of 50%, an occlusion limit of 0.1–6%, and a refractive index of 1.681.

[0238] The two batches were manufactured with HPMC-ASM as the excipient and under a 25% API load. The comparison between the two batches regarding particle size distribution, shown in Table 7, exhibits similar distributions regardless of batch size. Dv90 will be understood to be as described herein. Similarly, “Dv50” refers to the size (or diameter) in the particle size distribution that includes 50% of the total volume of the material, and “Dv10” refers to the size (or diameter) in the particle size distribution that includes 10% of the total volume of the material. D[4,3] is the average diameter based on volume-weighted average results.

[0239] [Table 7]

[0240] Example 9 The long-term stability of the compound of formula V and the hydrate of formula VII1 was studied. Storage was carried out at a temperature of 25°C and a relative humidity of 60%. The results are shown in Table 8. Area % was measured using HPLC. The total amount of related substances is reported if it is >0.1%.

[0241] [Table 8]

[0242] It was concluded that long-term storage of the hydrate of formula VII1, for example, equivalent to 6 months, resulted in lower amounts of so-called related substances (i.e., compounds other than the hydrate of formula VII1 or the compound of formula VII1 that is structurally related to the compound of formula V) than those formed for the compound of formula V. In fact, no related substances appeared to form during the storage of the hydrate of formula VII1, but an increase was observed for the compound of formula V.

[0243] Example 10 X-ray powder diffraction patterns were recorded for the hydrate of formula VII1. XRPD data were collected using a powder X-ray diffractometer with the following settings.

[0244] Radiation copper Kα, λ = 1.54060 Å, anode voltage: 45 kV, anode current: 40 mA, scanning axis: theta-2 theta, divergence slit: 1.00°, scattering slit: 1.00°, receiving slit: 0.15 mm.

[0245] Sampling pitch: 0.0140°, scanning speed: 6° / min, preset time: 0.14 seconds.

[0246] Scanning range (20): 3 to 35° on a 20-scale.

[0247] The obtained XRP diffraction pattern is shown in Figure 10. The positions and intensities of the main peaks in the X-ray powder diffraction pattern are shown in Table 9.

[0248] [Table 9]

Claims

1. Equation IIb 【Chemistry 1】 A compound or hydrate thereof, In the formula, R １ and R ２ C is independently and optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F, and I. １ ~C ６ A compound or its hydrate that is alkyl, and the compound or its hydrate is essentially in solid form.

2. R １ is methyl, R ２ It is isopropyl, and thereafter formula V 【Chemistry 2】 The compound according to claim 1, which provides the compound or a hydrate thereof.

3. The hydrate is a combination of the compound of formula IIb and water in a 1:n ratio, thereby providing the hydrate of formula VI. 【Transformation 3】 In the formula, n has a value from 0.5 to 100. The hydrate according to claim 1 or 2.

4. n is 1, and therefore equation VII 【Chemistry 4】 The hydrate according to claim 3, which provides a monohydrate of the product.

5. The compound of formula IIb is formula IIc: 【Transformation 5】 Provided as stereoisomers of, The compound or hydrate thereof according to claim 1 or 2, The hydrate according to claim 3 or 4.

6. Compounds of formula III: 【Transformation 6】 or salts thereof, for example, pharmaceutically acceptable salts and / or stereoisomers, In the formula, R １ is a C optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F, and I １ -C ６ alkyl, a compound or a salt thereof.

7. Formula IV 【Transformation 7】 Compounds of or salts thereof, for example, pharmaceutically acceptable salts and / or stereoisomers, In the formula, R １ C is optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F, and I. １ ~C ６ A compound or salt thereof that is alkyl.

8. Characterized by being essentially crystalline, A compound or hydrate thereof according to any one of claims 1, 2, or 5 to 7, or a hydrate according to claim 3 or 4.

9. Having a chemical purity of approximately 90% or more, for example, approximately 95%, for example, approximately 99%, and / or It has a chemical stability of approximately 90% or more, for example, approximately 95%, for example, approximately 99%. A compound or hydrate thereof according to any one of claims 1, 2, or 5 to 8, or a hydrate according to claim 3, 4, or 8, characterized in that...

10. A spray-drying pharmaceutical composition, (a) A compound or hydrate thereof according to any one of claims 1, 2, 5 to 7 or 9, or a hydrate according to any one of claims 3, 4 or 9, or formula Ib: 【Transformation 8】 Compounds or hydrates thereof, and (b) Excipients suitable for spray drying A spray-drying pharmaceutical composition containing the above.

11. The spray-drying composition according to claim 10, wherein the excipient suitable for spray drying comprises a polymer or copolymer that can form physicochemical interactions with the compound or hydrate thereof described in claim 1, 2, 5 to 7 or 9, or the hydrate described in claim 3, 4 or 9, and enables the resolubilization of the compound.

12. The spray-drying composition according to claim 11, wherein the excipient suitable for spray drying comprises one or more of the following: cellulose ester, N-vinylpyrrolidone-vinyl acetate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and methacrylate-methyl methacrylate copolymer.

13. The spray-drying composition according to any one of claims 10 to 12, wherein the excipient suitable for spray drying includes a cellulose ester such as a nonionic cellulose ester.

14. The spray-drying composition according to claim 13, wherein the cellulose ester is hydroxypropyl methylcellulose (HPMC) or a derivative thereof.

15. The spray-drying composition according to claim 14, wherein the derivative of HPMC is HPMC-AS or HPMC-P.

16. The spray-drying composition according to any one of claims 13 to 15, wherein the HPMC or derivative thereof is HPMC-AS, for example, grade M HPMC-AS.

17. The spray-drying composition according to any one of claims 10 to 16, wherein the ratio of the compound or hydrate to the excipient is about 1:5 to about 5:1, for example, about 1:4 to about 4:1, about 1:3 to about 3:1, about 1:2 to about 2:1, or about 1:

1.

18. The spray-drying composition according to claim 17, wherein the ratio of the compound or hydrate to the excipient is about 1:

3.

19. The spray-drying composition according to any one of claims 10 to 18, wherein the compound is the compound or a hydrate thereof according to claim 5, or the hydrate according to claim 4.

20. The spray-dried pharmaceutical composition according to any one of claims 10 to 19, wherein the particles in the composition have a particle size distribution having a Dv90 of 120 mm or less, for example, 100 mm or less, for example, 10 mm to 120 mm.

21. A pharmaceutical preparation comprising a therapeutically effective amount of the compound described in any one of claims 1, 2, or 5 to 9, or its hydrate, or the hydrate described in any one of claims 3, 4, 8, or 9, or the spray-dried composition described in any one of claims 10 to 20, or the compound of formula Ib described in claim 10, or its solvate, A pharmaceutical preparation comprising a therapeutically effective amount of the relevant compound, mixed with pharmaceutically acceptable excipients, carriers, and / or diluents.

22. The pharmaceutical formulation according to claim 21, wherein the composition is formulated for oral administration.

23. A pharmaceutical preparation according to claim 22, formulated as a tablet or capsule.

24. The pharmaceutical formulation according to claim 22 or 23, wherein the composition further comprises an enteric coating, such as a coating, which helps prevent the release of the compound, hydrate, or spray-dried composition in the stomach.

25. The pharmaceutical formulation according to claim 22, wherein the spray-dried composition according to claim 21 is reconstituted with a liquid which is an orally administered vehicle such as an oil-based or water-based vehicle.

26. The pharmaceutical formulation according to claim 22, wherein the vehicle further comprises a cellulose-based agent, for example, a nonionic cellulose-based agent, such as CMC, MC, HEC, HPMC, and / or HEMC.

27. For use as a medicine in treatment, A compound or hydrate thereof according to any one of claims 1, 2, or 5 to 9, A hydrate according to any one of claims 3, 4, 8, or 9, A spray-drying composition according to any one of claims 10 to 20, or A pharmaceutical preparation according to any one of claims 21 to 26, or The compound of formula Ib or its hydrate according to claim 10.

28. Used for the treatment and / or prevention of one or more of the following functional disorders or disorders: sexual dysfunction, erectile dysfunction, ejaculatory dysfunction, hypoactive sexual desire, mental disorders, and neurological disorders. A compound or hydrate thereof according to any one of claims 1, 2, or 5 to 9, A hydrate according to any one of claims 3, 4, 8, or 9, A spray-drying composition according to any one of claims 10 to 20, or A pharmaceutical preparation according to any one of claims 21 to 26, or The compound of formula Ib or its hydrate according to claim 10.

29. The compound, hydrate, composition, or formulation for use according to claim 28, wherein the functional impairment and / or impairment includes erectile dysfunction and / or premature ejaculation.

30. For the manufacture of pharmaceuticals for the treatment and / or prevention of one or more of the following functional disorders or disorders: sexual dysfunction, erectile dysfunction, ejaculatory dysfunction, hypoactive sexual desire disorder, mental disorders, and neurological disorders, A compound or hydrate thereof according to any one of claims 1, 2, or 5 to 9, A hydrate according to any one of claims 3, 4, 8, or 9, A spray-drying composition according to any one of claims 10 to 20, or A pharmaceutical preparation according to any one of claims 21 to 26, or The compound of formula Ib or its hydrate according to claim 10 Use.

31. The use according to claim 30, wherein the functional impairment and / or impairment includes erectile dysfunction and / or premature ejaculation.

32. Methods for the treatment and / or prevention of one or more of the following functional disorders or disorders: sexual dysfunction, erectile dysfunction, ejaculatory dysfunction, hypoactive sexual desire, mental disorders, neurological disorders, A compound or hydrate thereof according to any one of claims 1, 2, or 5 to 9, A hydrate according to any one of claims 3, 4, 8, or 9, A spray-drying composition according to any one of claims 10 to 20, or A pharmaceutical preparation according to any one of claims 21 to 26, or A compound of formula Ib or its hydrate according to claim 10, A method comprising administering to patients who require it.

33. The method according to claim 32, wherein the functional impairment and / or impairment includes erectile dysfunction and / or premature ejaculation.

34. Equation IIb: 【Chemistry 9】 A method for preparing a compound or hydrate thereof, In the formula, R １ and R ２ C is independently and optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F, and I. １ ~C ６ It is alkyl, This method, a) A step of providing a mixture containing a compound of formula IIa and optionally a compound of formula IIb, 【Chemistry 10】 (In the formula, R １ , R ２ and R ３ C is independently and optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F, and I. １ ~C ６ (It is alkyl) b) The compound of formula IIa from step a) and optionally the compound of formula IIb, １ O － M ＋ Alkoxide of formula R １ OH is subjected to alcohol, and in the formula, R １ This is as defined for the compound of formula IIa and / or the compound of formula IIb, where M+ is Li ＋ Na ＋ or K ＋ The process involves providing a compound of formula Ia and / or formula lb, which are metal cations such as the above, 【Chemistry 11】 c) A step of separating the compound of formula Ia from the compound of formula lb, d) Optionally, a step of converting the compound of formula Ia to the compound of formula lb, e) A step of reacting the compound of formula Ib with the compound of formula X in the presence of an ester formation promoter such as a coupling reagent, to provide the compound of formula IIb, 【Chemistry 12】 (In the formula, R in the compound of formula X ２ This is as defined for the compound of formula IIa and / or the compound of formula IIb, and X is a halide such as OH and Cl, and OC(O)CH(CH ３ ) ２ (Selected from the group consisting of) f) optionally, a step of combining the compound of formula IIb with water to provide a hydrate of formula VI, 【Chemistry 13】 The hydrate is a combination of the compound of formula IIb and water taken in a ratio of 1:n, where n has a value of 0.5 to 100, for example, 1.

35. Compound Ia is converted to compound Ib 【Chemistry 14】 A method for converting to a compound, wherein R １ C is optionally substituted with one or more substituents selected from OH, Cl, Br, F, and I. １ ~C ６ It is alkyl, This method, a) A step of subjecting the compound of formula Ia to lactone ring-opening conditions, thereby providing the compound of formula III, 【Chemistry 15】 (In the formula, R １ (This is as defined for the compound of formula Ia.) b) A step of oxidizing the compound of formula III to the compound of formula IV, 【Chemistry 16】 (In the formula, R １ (This is as defined for the compound of formula Ia.) c) The carboxylic acid of the compound of formula IV is reacted with the hydroxyl group of carbon 30, thereby producing formula lb 【Chemistry 17】 A step of providing the aforementioned compound, Methods that include...

36. The method according to claim 35, wherein the compound of formula Ia is provided by steps a), b) and c) of claim 34.

37. The method according to claim 35, wherein step a) comprises a base such as barium hydroxide octahydrate in the presence of a solvent such as methanol, and / or step b) comprises an oxidizing agent such as Dess Martin periodinane, and / or step c) comprises a coupling agent such as a carbodiimide such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or a carbodiimide HCl salt thereof in the presence of a sterically hindered base such as N,N-diisopropylethylamine.

38. The method of claim 34, wherein step d) is present and is carried out according to claim 35 and / or 37.

39. R １ but is methyl and / or R ２ and R ３ The method according to any one of claims 34 to 38, wherein is independently methyl, ethyl, or isobutyl.

40. R １ It is methyl, R ２ It is isopropyl, R ３ If present, it is ethyl or isopropyl. The method according to any one of claims 34 to 39.

41. The method according to any one of claims 34 to 40, wherein the compound of formula Ila comprises fragmarine 3,30 diisobutyrate and / or fragmarine 3-isobutyrate-30-propionate.

42. The method according to any one of claims 34 to 41, wherein the compound of formula IIa, the compound of formula IIb, or a mixture thereof is provided by a plant or plant material selected from the Meliaceae family, for example, a plant or plant material selected from the group consisting of mangrove tree, senegalensis, Xylocarpus moluccensis, Pseudocedrella kotschyi, mahogany, Neobeuga mahafalensis, chucrasi, Entandrophaga caudatum, and any combination thereof.

43. The method according to claim 42, wherein the plant or plant material comprises Entandrophragma caudatum or its seeds.

44. The method according to claim 42 or 43, wherein the compound of formula IIa, the compound of formula IIb, or a mixture thereof is provided by an extract from Entandrofragma caudatum seeds.

45. A method for preparing a spray-dryable pharmaceutical composition according to any one of claims 10 to 20, comprising spray-drying a solution containing the compound or hydrate thereof according to any one of claims 1, 2, 5 to 7, or 9, or the hydrate according to any one of claims 3, 4, or 9, or the compound of formula Ib or hydrate thereof according to claim 10, together with the excipient suitable for spray drying.

46. The method according to claim 45, a) A step of providing a solution containing the compound or hydrate and the excipient, and a solvent system containing at least two polar solvents to a spray dryer, wherein at least one of the polar solvents is miscible with water, and at least one solvent is aprotic and immiscible with water, b) A step of spray-drying the solution from step a), Methods that include...

47. The method according to claim 46, further comprising the additional step of dissolving the compound or hydrate in the water-immiscible solvent, dissolving the excipient in the water-miscible solvent, and mixing them to provide the solution for the spray dryer.

48. The method according to any one of claims 46 or 47, wherein the non-aqueous miscible polar aprotic solvent in the solvent system is optionally halogenated.

49. The method according to any one of claims 46 to 48, wherein the non-aqueous miscible polar aprotic solvent in the solvent system is dichloromethane.

50. The method according to any one of claims 46 to 49, wherein the water-miscible polar solvent is selected from polar aprotic solvents and protic solvents, preferably methanol and / or acetone.

51. The method according to any one of claims 46 to 50, wherein the water-miscible polar solvent and the non-water-miscible polar aprotic solvent are mixed in a ratio of about 1:5 to about 5:1, for example, about 1:4 to about 4:1, about 1:3 to about 3:1, about 1:2 to about 2:1, or about 1:1.

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