Method for producing (10s, 13s, 16r, 17r)-17-hydroxy-10,13,16-trimethyl-17-propanoyl-7,8,12,14,15,16-hexahydro-6н-cyclopenta[a]phenanthrene-3-one

Abstract

The group of inventions relates to the field of medicine, pharmacology and the chemical and pharmaceutical industry and includes an improved method for producing (10S, 13S, 16R, 17R)-17-hydroxy-10,13,16-trimethyl-17-propanoyl-7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthrene-3-one (compound of formula (I)) and the use thereof for industrial batch, semi-continuous and continuous chemical production. Also described is a method for producing an intermediate compound, Vamorolone Acetate. The method for producing the compound of formula (I) is carried out according to the schema depicted. The production method makes it possible to produce the compound of formula (I) with a purity suitable for the use thereof in a finished dosage form for subjects requiring treatment for Duchenne muscular dystrophy. Thus, the technical results of the present invention consist in an improved production method which results in: a high yield and chemical purity, including stereoisomeric purity, of the compound of formula (I) and intermediate products in the synthesis of the compound of formula (I), which are suitable for use in a finished dosage form for subjects requiring treatment for Duchenne muscular dystrophy; the adaptability of the synthesis of the compound of formula (I) to industrial production; environmentally-friendly production; and a decrease in the formation of undesirable by-products.

Description

METHOD FOR PRODUCING (10S, 13S, 16R, 17R)-17-HYDROXY-10,13,16-TRIMETHYL-17-PROPANOYL-7,8, 12, 14, 15, 16-HEXAHYDRO-6H-CYCLOPENTA[A]PHENANTHRENA-3-ONE Technical area

[0001] The group of inventions relates to the field of medicine, pharmacology and the chemical-pharmaceutical industry and includes an improved method for the preparation of (10S, 13S, 16R, 17R)-17 hydroxy-10,13,16-trimethyl-17-propanoyl-7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthrene-3-one (compound of formula (I)) and its use for periodic chemical industrial production, semi-continuous industrial production or continuous industrial production. A method for the preparation of the intermediate compound Vamorolone Acetate is also described. The method for the preparation of the compound of formula (1) is carried out according to the scheme:

[0002]

[0003] Moreover, the method of production allows to obtain a compound of formula (1) with a purity suitable for the use of such a compound in a finished dosage form in subjects who need treatment for Duchenne muscular dystrophy.

[0004] Thus, the technical results of the present invention are an improved method for producing, leading to a high yield and chemical purity, including stereoisomeric purity, of the compound of formula (1) and intermediate products in the synthesis of the compound of formula (I), suitable for use in a finished dosage form in subjects who need treatment for Duchenne muscular dystrophy, adapting the synthesis of the compound of formula (1) for industrial production, ensuring environmentally safe production and reducing the formation of unwanted by-products.

[0005] The invention relates to the field of medicine, pharmacology and the chemical-pharmaceutical industry, namely to a new improved method for producing (10S,13S, 16R, 17R)-17 hydroxy-10,13,16-trimethyl-17-propanoyl-7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthrene-3-one (compound of formula (I)), as well as a method for producing intermediate products intended for use in the method for producing a compound of formula (I). Prior art

[0006] Duchenne muscular dystrophy (DMD) is an X-linked inherited disorder that manifests in the first 3-5 years of life. It is characterized by deterioration and loss of muscle strength, which worsens over time, leading to severe impairment of mobility and internal organ function. In Russia, as elsewhere in the world, DMD is a rare disease, and its early diagnosis presents certain difficulties, especially when clinical symptoms have not yet fully manifested. This creates obstacles to prompt treatment and management of the condition. The following medications are registered in Russia for the treatment of Duchenne muscular dystrophy: Ataluren (international nonproprietary name) is the first therapeutic drug approved for the treatment of patients with Duchenne muscular dystrophy. In November 2020, Ataluren was registered in Russia for the treatment of Duchenne muscular dystrophy in children over 2 years of age.The drug is recommended for outpatients over 2 years of age whose molecular genetic testing has revealed a nonsense mutation (a substitution of a codon encoding an amino acid with a stop codon) for the purpose of pathogenetic therapy. Delandistrogene moxeparvovec (international nonproprietary name), Elevidys (trade name), is a gene therapy drug designed to slow or stabilize the progression of Duchenne muscular dystrophy by altering the disease trajectory toward a milder phenotype similar to Becker muscular dystrophy.

[0007] Despite some progress in specific therapy, the mainstay of treatment is corticosteroids. Prednisolone or deflazacort may be prescribed to slow the decline in muscle strength. These medications can help improve mobility and delay the need for wheelchair use. The most common side effects associated with corticosteroid use in Duchenne muscular dystrophy include:

[0008] Weight gain – Corticosteroids can cause increased appetite and fluid retention, which often leads to weight gain;

[0009] Growth impairment - Long-term use may slow growth in children;

[0010] Osteoporosis - Corticosteroids may lead to a decrease in bone mineral density, increasing the risk of fractures;

[0011] Muscle weakness – use of corticosteroids may sometimes worsen muscle weakness, especially with long-term use;

[0012] Cataracts and glaucoma – Long-term treatment with corticosteroids may increase the risk of developing cataracts and glaucoma;

[0013] Adrenal suppression - Corticosteroids can suppress the body's natural production of cortisol, making it less able to adapt to stress;

[0014] Increased risk of infections – Corticosteroids may weaken the immune system, increasing susceptibility to infections;

[0015] Behavioral and mood changes – including mood changes, increased irritability, or depression;

[0016] Hypertension – Corticosteroids may lead to increased blood pressure;

[0017] Hyperglycemia – drugs can increase blood sugar levels, which is especially dangerous for patients with diabetes.

[0018] (10S,13S,16R,17R)-17-hydroxy-10,13,16-trimethyl-17-propanoyl-7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthrena-3-one (the compound of formula (I)) stands out from traditional corticosteroids in several key ways that make it a potentially preferable option. The compound of formula (I) is described as having “dissociative glucocorticoid properties,” meaning that it may offer some of the positive effects of traditional glucocorticoids without their side effects. Unlike corticosteroids, the compound of formula (I) is a potent mineralocorticoid receptor antagonist, allowing it to have antimineralocorticoid properties. This may reduce or eliminate some of the side effects, such as water retention or high blood pressure. The compound of formula (I) does not contain the 11ẞ-hydroxycarbonyl group, which is different from conventional glucocorticoids.This change in structure may introduce differences in its interaction with receptors in the body and, consequently, in its pharmacological profile.

[0019]

[0020] (compound of formula (1)) Summary of the invention

[0021] When developing drugs, it is important that the active agent be readily available and meet quality requirements. The most optimal way to increase the availability and quality control of the active agent is to develop a unique synthetic protocol. Active agent synthesis allows for the regulation of such properties as the active agent's form (e.g., crystalline, amorphous, or their ratio); chemical purity, particularly the amount of related impurities or reagents used during chemical transformations; and the stereoisomeric purity of the active agent. This is especially true for innovative molecules that have not been sufficiently studied and tested for optimized industrial production.

[0022] Chemical purity is of great importance in the production of substances. It is known that the degree of purity of substances potentially affects their safety and efficacy in both human and veterinary medicine. Increasing the chemical purity of a substance improves its original biological properties and reduces potential side effects associated with the presence of impurities.

[0023] The development of new approaches to active agent synthesis opens up opportunities to improve the physicochemical and technological characteristics of pharmaceutical products. This expands the range of active agents available to drug developers when developing a new drug with an enhanced safety profile. Furthermore, the sustainable development of modern approaches to active agent synthesis enables the implementation of environmentally friendly, resource-efficient, and atom-saving innovative technologies in production, which contribute to economic development and minimize environmental impact.

[0024] Thus, there is currently a constant need to develop new, improved methods for synthesizing innovative molecules.

[0025] In connection with the Decree of the President of the Russian Federation of May 7, 2018 No. 204 "On the national goals and strategic objectives of the development of the Russian Federation for the period up to 2024" within the framework of the import substitution program "Pharma-2030", the authors of the present invention have made efforts to create an innovative method for producing the innovative compound (10S,13S, 16R, 17R)-17 hydroxy-10,13,16-trimethyl-17-propanoyl-7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthrene-3-one (compound of formula (1)).

[0026] One of the key roles in the synthesis of the compound of formula (I) is the intermediate compound of the formula Vamorolone acetate:

[0027] Vamorolone acetate

[0028] The prior art (international application WO2023016817 - SYNTHESIS OF DELTA 9,11 STEROIDS, priority dated 12.08.2021) discloses methods for producing (10S,13S,16R,17R)-17-hydroxy-10,13,16-trimethyl-17-propanoyl-7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthrene-3-one and its intermediate compounds.

[0029]

[0030] A disadvantage of the said synthesis of the compound of formula (1) is, among other things, the use of corrosive and toxic reagents, for example, a 57% aqueous solution of hydroiodic acid (HI) for obtaining the key intermediate Vamorolone acetate. In this case, such reagents form a mixture of vamorolone and vamorolone acetate during the synthesis, which complicates purification and requires an additional step of acylation of this mixture. In addition, when using a 57% aqueous solution of hydroiodic acid (HI), iodohydrin-acetyl-8-DM is formed as a by-product, which is converted back into the starting material (8-DM) during alkaline hydrolysis of the acetyl group and is present in the final product as an impurity, the purification of which presents significant difficulties. Technical challenge

[0031] The objective of the present invention is to develop a new, improved, environmentally friendly, safe method for preparing a compound of formula (1) with a high yield of the target product, which uses readily available reagents, starting compounds and reaction conditions, by means of which the synthesis can be reproduced on an industrial scale. Another objective of the present invention is to provide a new, improved synthesis of intermediate products useful in the synthesis of a compound of formula (I). Solution to the problem

[0032] As a result of research, the authors of the present invention have developed a new method for producing a compound of formula (I), which is improved compared to the method known in the prior art, comprising:

[0033] a) Acylation of 8-DM with acetic anhydride and DMAP;

[0034] b) Deoxygenation of the resulting intermediate using a Lewis acid and a source of iodide ions (ZrCl4 and Nal in acetonitrile);

[0035] c) Hydrolysis of the obtained vamorolone acetate to a compound of formula (1) using an alkali metal hydroxide or carbonate (K2CO3 in CH3OH);

[0036] d) Recrystallization of the obtained compound of formula (I) from a mixture of solvents. Positive effects of the invention

[0037] The inventors unexpectedly discovered that the process for preparing a compound of formula (1) according to the present invention allows for the production of the target product (a compound of formula (I)) with an overall yield across all stages exceeding the yield in the processes for preparing a compound of formula (I) described in the prior art. The inventors also, in the course of their research, were able to develop a new process for preparing an intermediate product, Vamorolone acetate, which resulted in obtaining a stereoisomerically pure substance in high yield without the formation of undesirable by-products. The new process also simplifies the synthesis of Vamorolone acetate by eliminating the stage of additional acylation and eliminating extraction, evaporation, and coevaporation with acetonitrile, and obtaining the product by direct precipitation of acetyl vamorolone with a sodium bisulfite solution from an acetonitrile solution.

[0038] Thus, the technical results of the present invention are an improved method for producing, leading to a high yield and chemical purity, including stereoisomeric purity, of the compound of formula (1) and intermediate products in the synthesis of the compound of formula (I), suitable for use in a finished dosage form in subjects who need the treatment or prevention of Duchenne muscular dystrophy, adapting the synthesis of the compound of formula (1) for industrial production, ensuring environmentally safe production and reducing the formation of unwanted by-products. Description of embodiments

[0039] Within the framework of the present invention, the stated problem is solved, and the claimed technical result is achieved by means of a new method for obtaining a compound of formula (1):

[0040]

[0041] And also obtaining an intermediate compound for the synthesis of a compound of formula (1) Vamorolone Acetate:

[0042] Vamorolone acetate

[0043] Preferably, the organic solvent in said reaction is selected from the group including, but not limited to: dimethylformamide, dimethylacetamide, acetonitrile, N-methylpyrrolidone, tetrahydrofuran.

[0044] More preferably, the organic solvent in said reaction is acetonitrile.

[0045] The preferred Lewis acid in said reaction is selected from the group including, but not limited to: AICI3, BF3, TICI4, ZrCI4, FeCl3, ZnCl2.

[0046] The preferred Lewis acid is ZrCl4.

[0047] Preferably, the source of iodide ions in said reaction is selected from a group including, but not limited to, iodides of alkali and alkaline earth metals, iodides of quaternary ammonium bases.

[0048] A more preferred source of iodide ions in this reaction is Nal

[0049] One embodiment of the invention is a method for producing a compound of formula (IV) by reaction at a temperature in the range from -50°C to 150°C.

[0050] More preferably, the reaction for producing the compound of formula (IV) according to the present invention is carried out at a temperature in the range of -40°C to 80°C.

[0051] More preferably, the reaction for producing the compound of formula (IV) according to the present invention is carried out at a temperature in the range of -30°C to 70°C.

[0052] More preferably, the reaction for producing the compound of formula (IV) according to the present invention is carried out at a temperature in the range of -20°C to 60°C.

[0053] More preferably, the reaction for producing the compound of formula (IV) according to the present invention is carried out at a temperature in the range of -10°C to 50°C.

[0054] More preferably, the reaction for producing the compound of formula (IV) according to the present invention is carried out at a temperature in the range of 25°C to 45°C.

[0055] The stated problem is solved, and the claimed technical result is achieved by means of a new method for obtaining a compound of formula (1), which includes the following stages:

[0056] 1. Acylation of 8-DM with acetic anhydride and DMAP

[0057] 2. Deoxygenation of the resulting intermediate using a Lewis acid and a source of iodide ions (ZrCl4 and Nal in acetonitrile)

[0058] 3. Hydrolysis of the obtained vamorolone acetate to vamorolone using an alkali metal hydroxide or carbonate (K2CO3 in CH3OH)

[0059] 4. Recrystallization of the obtained vamorolone from a mixture of solvents.

[0060] One embodiment of the invention is a pharmaceutical composition comprising a compound of formula (1) obtained by the method of the present invention for the treatment or prevention of Duchenne muscular dystrophy.

[0061] The following are examples of the invention, which illustrate the invention, but do not cover all possible variants of its implementation and do not limit the invention.

[0062] It will be clear to a person skilled in the art that other particular embodiments of the invention are also possible. Examples

[0063] Example 1. Method for producing 10S,13S,16R,17R)-17-hydroxy-10,13,16-trimethyl-17-propanoyl-7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthrena-3-one.

[0064] 100 liters of acetonitrile are loaded into the reactor, then acetyl-8-DM is added and stirred until dissolved at 25°C. Nal and ZrCl4 are added sequentially to the resulting solution at 25°C. The resulting reaction mass is stirred under an inert gas atmosphere at 45°C for 6 hours, then cooled to room temperature. Then 400 liters of a 5% Na2S2O3 solution are added to the reaction mass with stirring, the resulting suspension is stirred for an additional 2 hours at room temperature, and then at +5°C for 6 hours. The precipitated product is filtered and washed twice with 50 liters of an acetonitrile:water mixture in a ratio of 1:4 and dried under vacuum at a temperature of 45°C to constant weight. Yield 93%

[0065] The resulting acetylvamorolone is hydrolyzed with K2CO3 in methanol according to the method described earlier and recrystallized from a mixture of 2-propanol and water in a ratio of 10:1 and dried to constant weight. Yield 97%

[0066] Identification of the compound of formula (1) was carried out by analytical methods: 1H NMR, 13C NMR and mass spectral analysis.

[0067] As a result, a product was obtained in the form of a powder containing compound (I) with a chemical purity of more than 99.7% and its stereoisomeric purity of 100%.

[0068] The compound is suitable for use in a pharmaceutical product for the treatment and / or prevention of Duchenne muscular dystrophy.

Claims

Formula [Item 1] A method for producing a compound of formula (I) which includes the following stages: a) acylation of 8-DM; b) deoxygenation of the resulting intermediate compound using a Lewis acid and a source of iodide ions; c) hydrolysis of the obtained vamorolone acetate to a compound of formula (I) using an alkali metal hydroxide or carbonate; d) recrystallization of the obtained compound of formula (I) from a mixture of solvents. [Item 2] Use of the method according to item 1 for the periodic chemical industrial production, semi-continuous industrial production or continuous industrial production of a compound of formula (1) with a purity suitable for the use of such compound in a finished dosage form in subjects who need the treatment or prevention of Duchenne muscular dystrophy. [Item 3] A pharmaceutical composition for the treatment or prevention of Duchenne muscular dystrophy, comprising a compound of formula I obtained by the method specified in item 1.

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