KR20200101200A - Monomethyl fumarate derivatives and their pharmaceutical compositions - Google Patents

Abstract

The present invention provides a novel compound capable of producing monomethyl fumarate after administration, a pharmaceutical composition comprising the same as an active ingredient, and a pharmaceutical use thereof for the treatment or amelioration of immune system abnormalities, neurodegeneration and/or inflammatory diseases.

Description

Monomethyl fumarate derivatives and their pharmaceutical compositions

The present invention relates to Psoriasis, Multiple sclerosis, Atopy, Asthma, Arthritis, Inflammatory bowel disease, Lupus, and amyotrophic lateral sclerosis. lateral sclerosis), Huntington's disease, Alzheimer's disease, Parkinson's disease, macular degeneration, Sleep Apnea, Radiologically Isolated Syndrome, Scleroderma), Scleroderma) It relates to a novel precursor drug (Prodrug) of a monomethyl fumarate compound known to be useful in the treatment or improvement of various diseases such as cancer or tumor. The present invention also relates to a pharmaceutical composition comprising such a new precursor drug as an active ingredient. The present invention also relates to pharmaceutical applications using such precursor drugs.

Dimethyl fumarate (DMF) is a methyl ester compound of fumaric acid and is an active ingredient of Fumaderm (tablet) commercially available as a treatment for psoriasis and Tecfidera (capsule) commercially available as a treatment for multiple sclerosis. These products are oral medicines, and dimethyl fumarate is rapidly metabolized to monomethyl fumarate (MMF) after oral administration and exposed to the blood, and the substance that actually shows efficacy is known as monomethyl fumarate. That is, dimethyl fumarate can be said to be a precursor drug compound of monomethyl fumarate, an active metabolite.

The physiological mechanism of action of monomethyl fumarate has been studied in various aspects so far, and several research results have been reported to clarify the immunomodulatory function, antioxidant effect, neuronal protection, and anti-inflammatory effect. (Journal of Neuroinflammation, 2012, 9, 163.; Redox Biology, 2015, 169.; Critical Reviews in Immunology, 2013, 33(4), 307.; Journal of Immunology, 2011, 187(10), 5015.; Perspectives in Medicinal Chemistry, 2015, 7, 1.; Psoriasis: Targets and Therapy, 2015, 5, 9) In the case of already commercialized Fumaderm products, dimethyl fumarate, ethyl hydrogen fumarate calcium salt, ethyl hydrogen fumarate Magnesium salt and ethyl hydrogen zinc salt were developed as a combination of four fumaric acid esters (FAEs), and this drug was found to be effective in patients with severe psoriasis, and its mechanism was selective immunomodulation (Th2 selective cytokine). Secretion induction). (British Journal of Dermatology, 1999, 141, 424.)

In the case of Tecfidera products containing dimethyl fumarate as the main component, monomethyl fumarate, an active metabolite, is primarily used to treat multiple sclerosis diseases through activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) pathway. It has been reported to have an effect. (Brain, 2011, 678.; Human Molecular Genetics, 2017, 26(15), 2864.) Also, antioxidant Nrf2 activators such as monomethyl fumarate, including multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic It shows the therapeutic effect on various neurodegenerative diseases such as colorimetric sclerosis. (British Journal of Pharmacology, 2017, 174(12), 1750.) In addition to the above diseases, monomethyl fumarate or dimethyl fumarate is used for atopic, macular degeneration, sleep apnea (Sleep Apnea), multiple sclerosis-related image alone syndrome ( Radiologically Isolated Syndrome), Scleroderma, Systemic Sclerosis-Associated Pulmonary Arterial Hypertension, It is known to be useful in the treatment, improvement or prevention of cancer or tumors (https://clinicaltrials.gov/ct2/show/NCT02438137, https://clinicaltrials.gov/ct2/show/NCT02739542, https://clinicaltrials. gov/ct2/show/NCT02981082, J Neuroinflammation. 2015; 12: 239, Aging (Albany NY). 2016 Jul; 8(7): 1289-1290, J Invest Dermatol. 2018 Jan;138(1):78-88 , Nature Scientific Reports 7, Article number: 41605 (2017), Front Immunol. 2018; 9: 1896, J Investig Allergol Clin Immunol 2018; Vol. 28(3): 182-215).

Although all of the above mentioned psoriasis, multiple sclerosis, and inflammatory or neurodegenerative diseases are intractable diseases that are very difficult or impossible to treat, products containing dimethyl fumarate that have already been commercialized as an active ingredient are suitable for the treatment of some diseases such as psoriasis and multiple sclerosis. Therefore, it is recognized as having excellent clinical efficacy. However, due to the nature of the disease, dimethyl fumarate formulations are known to have severe side effects and inevitable long-term administration for at least 1 month.

For example, Tekpidera, which is used as a treatment for multiple sclerosis, was commercialized as a capsule formulation (120mg and 240mg), and the initial dose was administered twice a day, 120mg once for 7 days, and then the recommended dose for one day. It is used as a dosage increasing to 240mg twice, once. However, side effects from long-term use, such as gastrointestinal disorders (diarrhea, nausea, abdominal pain, epigastric pain), flushing, lymphopenia, progressive multifocal leukoencephalopathy, etc., are common, especially the gastrointestinal tract. Disability is known to be a very common side effect in 10 to 15% of the patient group and flushing in 40% of the patient group. In addition, since Tekpidera has a high risk of side effects, it is recommended to improve tolerability by taking it with food, and if flushing or gastrointestinal disorders are serious, the dose can be temporarily reduced to 120mg twice a day, once a time. However, even in this case, the dose must be increased to 240mg twice a day, which is the recommended dose within one month.

In addition to the existing dimethyl fumarate, the precursor drug compound of monomethyl fumarate has several new chemical structure candidates in the clinical trial stage.For example, ALKS8700 (Alkemes, USA) is a diroximel fumarate compound and is currently in phase 3 clinical trials. The test is in progress and the technology has been transferred to Biogen. (U.S. Patent 8,669,281) In addition, XP23829 (Xenoport, USA) has currently completed phase 2 clinical trials, and technology has been transferred to Dr. Reddy's Laboratories of India. (U.S. Patent 8,148,414) All of these candidates are precursor drugs of monomethyl fumarate to be developed as treatments for multiple sclerosis, and the focus was on improving the serious side effects of existing dimethyl fumarate, especially redness and gastrointestinal disorders. These two candidates are drugs whose stability is first proven in phase 1 clinical trials. In terms of efficacy for the treatment of multiple sclerosis, when using the conventional dimethyl fumarate formulation as a reference drug, the characteristics of bioequivalent therapy versus toxicity This is a situation that has not been sufficiently proven. In particular, in the case of the XP23829 candidate, the dosages administered in phase 2 clinical trials were 400 mg and 800 mg, respectively, once or twice a day in a capsule formulation, and the dosage was designed to be a higher dose compared to the existing dimethyl fumarate formulation.

US Patent Registration No. 8,669,281 US Patent Registration No. 8,148,414

Therefore, the problem to be solved by the present invention is a precursor drug of monomethyl fumarate that reduces side effects and exhibits excellent pharmacokinetics, pharmaceutical compositions containing these drugs, and various diseases such as abnormalities in the immune system, neurodegeneration, or inflammatory diseases of these drugs. It is to provide a therapeutic or improved pharmaceutical use.

In order to solve the above problems, the present invention provides a compound represented by the following formula (1).

[Formula 1]

In Formula 1,

R ₁ and R ₂ are each independently selected from hydrogen or Formula 2 below.

[Formula 2]

As a result of preparing and evaluating the precursor drugs of the above structure, the present inventors confirmed that the compound exhibited very excellent effects in terms of side effects improvement and pharmacokinetics, and in addition to these aspects, it was confirmed that it exhibits excellent physical properties or properties as a precursor drug. Completed.

In one embodiment of the present invention (Embodiment), preferably, the compounds are

(5-(((E)-4-methoxy-4-oxobut-2-enoyl)oxy)-4-oxo-4H-pyran-2-yl)methyl methyl fumarate;

6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl methyl fumarate;

or

(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl methyl fumarate.

The term "compound of the present invention" as used herein is meant to include not only the compounds of Formula 1, but also clathrates, hydrates, solvates, or (crystalline) polymorphs thereof.

As used herein, the term "polymorph" refers to a solid crystalline form of the compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in terms of physical properties include, but are limited to, stability (e.g., thermal or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rates (which may affect bioavailability). It doesn't work. Differences in stability may be due to changes in chemical reactivity (e.g., differential oxidation, which discolors more rapidly when composed of one polymorph than when composed of another polymorph) or mechanical characteristics (e.g., kinetic As the preferred polymorph, the stored tablet fragments thermodynamically convert to a more stable polymorph) or both (one polymorphic tablet is more susceptible to degradation at high humidity). Other physical properties of polymorphs can influence their processing. For example, one polymorph may be more likely to form a solvate than another polymorph, for example due to its shape or size distribution of the particles, or may be more difficult to filter or wash.

The term "solvent compound" as used herein refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by force between non-covalent molecules. Preferred solvents are volatile, non-toxic and can be administered in very small amounts to humans.

The term "Hydrate" as used herein refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by a force between non-covalent molecules. .

As used herein, the term "Clathrate" refers to a compound of the present invention in the form of a crystal lattice including a space (eg, a channel) confining a guest molecule (eg, solvent or water). Or its salt.

The compound represented by Chemical Formula 1 of the present invention can be synthesized, for example, by the following route.

In the above reaction scheme, R ₁ and R ₂ are as described above.

The compound represented by Formula 1 of the present invention can be obtained by an ester condensation reaction of monomethyl fumarate in the form of an active ester and Kojic acid. Several activators commonly used for the activation of monomethyl fumarate, such as N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiyi Mid (EDC) or its hydrochloride (EDC HCl), N,N'-diisopropylcarbodiimide (DIPC), oxalyl chloride, may be selected from thionyl chloride, the most preferred of which is oxalyl chloride. In addition, in order to increase the reaction rate, 4-dimethylaminopyridine (DMAP) may be added in a catalytic amount to 2 times equivalent. The reaction solvent was dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dichloromethane (MC), dichloroethane (DCE), N-methylpyrrolidine (NMP), acetonitrile (ACN) ) May be selected, and the most preferred among them is acetonitrile. The reaction temperature is at room temperature, and if necessary, purification may be performed by extraction, chromatography, or recrystallization. All of the derivatives obtained by the above method, that is, the compound represented by Formula 1, were all identified as white solids.

The present inventors have modified the chemical structure of the monomethyl fumarate compound to create and manufacture a novel compound having a new structure having sufficient oral absorption rate, desirable blood pharmacokinetics, desirable physicochemical properties, etc. I did. After oral administration of the novel compound thus prepared in vivo, the concentration of the monomethyl fumarate substance exposed in the blood is ultimately the efficacy of the drug for the treatment or improvement of various diseases such as various immune system abnormalities, neurodegeneration and/or inflammatory diseases. Is directly proportional to This is based on the concentration of the monomethyl fumarate substance exposed in blood after intravenous administration of monomethyl fumarate, and the concentration of the monomethyl fumarate substance exposed in the blood through a metabolic process after oral administration of the novel compound according to the present invention. It means that the doses of intravenous administration and oral administration can be proportionally applied by comparing them.

The present inventors prepared and evaluated compounds having various chemical structures in order to derive the novel compounds mentioned above. In addition, in terms of the physicochemical aspect of the compound, the absorption of the drug was evaluated by considering the degree of fat solubility, considering that the absorption of the drug is basically performed by passive diffusion. In order to prevent a decrease in absorption due to too low water solubility, It was also evaluated whether it could show solubility. In particular, by adopting kojic acid (Kojic acid; Biotechnology and Molecular Biology Reviews, Vol.5(2), pp.24-37, 2010), which has an antioxidant effect, as a substructure, it increases the safety after metabolism in the body, and is desirable. It not only plays an important role in securing pharmacokinetics, but also activates the pharmacological action of monomethyl fumarate, and can be expected to reduce side effects.

Specifically, the results of the akinetic evaluation of the compound of Example 1 below among the compounds of Formula 1 according to the present invention are, for example, when the oral absorption of the currently commercially available drug dimethyl fumarate control material is considered to be 100%, The relative absorption of the compound of Example 1 administered orally at the same molar ratio (mmol/kg) was 172.5%. In addition, another control substance, that is, the compound of Reference Example 1 (XP23829), which is currently in clinical trials, showed a relative absorption of 77.0% compared to dimethyl fumarate when administered orally at the same molar ratio. Therefore, the novel compound presented in the present invention has a very high concentration of monomethyl fumarate exposed in blood compared to the two control substances, which means that administration of a low dose can exhibit the same drug efficacy.

In another aspect, the present invention provides a pharmaceutical composition comprising the compound of formula 1 and a pharmaceutically acceptable carrier according to the present invention.

As used herein, an "effective amount or effective amount" slows or minimizes immune system abnormalities, neurodegeneration and/or inflammatory diseases; Or an amount of a compound of the present invention sufficient to provide a therapeutic benefit in the treatment or management of immune system abnormalities, neurodegeneration and/or inflammatory diseases.

As the pharmaceutically acceptable carrier, for example, a carrier for oral administration or a carrier for parenteral administration may be used. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. In addition, the carrier for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycol, and the like, and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives are benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Other pharmaceutically acceptable carriers may refer to documents well known in the field to which the present invention pertains.

The pharmaceutical composition of the present invention can be administered to mammals including humans by any route of administration, and can be administered orally or parenterally. However, the oral route of administration is more preferable in view of the excellent oral absorption of the compounds of the present invention.

Parenteral administration methods include, for example, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration. However, it is not limited thereto. For example, the pharmaceutical composition of the present invention may be prepared in an injectable formulation and administered by a method of lightly pricking the skin with a 30 gauge thin injection needle, or by applying it directly to the skin.

The pharmaceutical composition of the present invention may be formulated as a formulation for oral administration or parenteral administration according to the route of administration as described above.

In the case of a formulation for oral administration, the composition of the present invention may be formulated using a method known in the art as a powder, granule, tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension, etc. I can. For example, oral preparations can obtain tablets by blending the active ingredient with a solid excipient, pulverizing it, adding a suitable adjuvant, and processing it into a granule mixture. Examples of suitable excipients include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches, including corn starch, wheat starch, rice starch and potato starch, etc., cellulose, Fillers such as celluloses including methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose, gelatin, and polyvinylpyrrolidone may be included. In addition, in some cases, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant. Furthermore, the pharmaceutical composition of the present invention may further include an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and a preservative. In addition, in order to alleviate irritation of the gastrointestinal tract, an enteric coating or microencapsulation intended to be released when the drug passes through the intestine without being released in the stomach can be performed.

In the case of a formulation for parenteral administration, it can be formulated in the form of injections, creams, lotions, ointments for external use, oils, moisturizers, gels, aerosols, and nasal inhalants by methods known in the art.

The total dosage of the pharmaceutical composition of the present invention may be administered to a patient in a single dose, and may be administered by a fractionated treatment protocol that is administered for a long period of time in multiple doses. . The pharmaceutical composition of the present invention may vary the content of the active ingredient according to the symptoms of the disease. Preferably, the preferred total dose of the composition of the present invention may be about 0.01 μg to 1,000 mg, most preferably 1 mg to 100 mg per 1 kg of patient body weight per day. However, the dosage of the pharmaceutical composition of the present invention is not only the route of administration and the number of treatments, but also considers various factors such as the patient's age, weight, health status, sex, disease severity, diet, and excretion rate. The possessor will be able to determine the appropriate effective dosage. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, route of administration, and method of administration as long as it exhibits the effects of the present invention.

In addition, the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents. When administered in combination with another therapeutic agent, the composition of the present invention and the other therapeutic agent may be administered simultaneously, separately or sequentially. At this time, the other therapeutic agent may be a substance already known to have an effect of treating or improving various diseases such as immune system abnormalities, neurodegeneration and/or inflammatory diseases. When the pharmaceutical composition of the present invention is administered in combination with another therapeutic agent, the composition of the present invention and the other therapeutic agent may be separately formulated into separate containers, or may be formulated in combination in the same formulation.

In order to administer the compounds presented in the present invention to the human body, a representative pharmaceutical method is described in Table 1 below by using an enteric-coated tablet as an example. Compound A and Compound B presented below refer to substances presented as active ingredients for the treatment, improvement or prevention of immune system abnormalities, neurodegeneration, and inflammatory diseases in the present invention.

(Unit: weight %) Composition 1 Composition 2 Tablet before coating
(Najeong) Medicinal ingredients Compound A
10 Compound B
15 Mannitol 50 48 Hydroxypropyl cellulose 20 20 Sodium stearyl fumarate 2 One Separator Polyvinylpyrrolidone 4 2 Enteric coating Hypromellose phthalate 12 12 Dibutyl sebacate 1.5 1.5 Titanium dioxide 0.5 0.5

The present invention also includes the compound of formula 1 according to the present invention as an active ingredient, psoriasis, atopy, macular degeneration, multiple sclerosis, asthma, arthritis, inflammatory bowel disease, lupus, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, sleep apnea (Sleep Apnea), Radiologically Isolated Syndrome (Radiologically Isolated Syndrome), skin sclerosis (Scleroderma), it provides a pharmaceutical composition for the treatment or improvement of cancer or tumor. That is, the present invention provides a pharmaceutical use of the compound of Formula 1 according to the present invention for treating or improving the disease.

In another embodiment, the present invention provides psoriasis, atopy, macular degeneration, multiple sclerosis, asthma, arthritis, inflammatory bowel disease, lupus, comprising administering a therapeutically effective amount of a compound of formula 1 to an individual in need thereof. , Amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, sleep apnea (Sleep Apnea), Radiologically Isolated Syndrome, scleroderma (Scleroderma), cancer or tumors. In another aspect, the subject is a human. In one aspect, the treatment is a preventative treatment. In another embodiment, the treatment is a palliative treatment. In another embodiment, the treatment is a restorative treatment.

The present invention includes compounds effective in the treatment or improvement of various diseases such as immune system abnormalities, neurodegeneration or inflammatory diseases, pharmaceutical compositions containing them as active ingredients, their pharmaceutical uses, and administering them to individuals in need of treatment or prevention Provides a method of treatment. The compound according to the present invention is an active ingredient of a pharmaceutical product and has various advantages in various aspects such as solubility, and is particularly excellent in bioavailability and pharmacokinetics after oral administration.

Figure 1 is a blood concentration of monomethyl fumarate in rats over time after oral administration of dimethyl fumarate as a control substance and a single oral administration of Example 1 compound and dimethyl fumarate as a control substance according to the present invention. It is a graph. In Figure 1, ▲ is the result of the oral administration group of dimethyl fumarate, and △ is the result of the oral administration group of the compound of Example 1.

The present invention will be described in more detail based on the following examples, but this is not intended to limit the scope of the present invention. In addition, those of ordinary skill in the art will be able to make various modifications and modifications to the present invention within the scope not detrimental to the spirit of the present invention.

First, examples of the compound of Formula 1 according to the present invention are described below. Representative examples corresponding thereto along with specific preparation steps are described below, and compounds having different substituents may be prepared through similar steps. Those of ordinary skill in the art will be able to easily prepare compounds of Formula 1 with different substituents with reference to the following representative examples.

Reference Example 1: 2-(diethylamino)-2-oxoethyl methyl fumarate (XP23829)

1.0 g of monomethyl fumarate was dissolved in 5 ml of dimethylformamide, and 1.0 g of 2-bromo-N,N-diethylacetamide and 2.01 g of cesium carbonate were added. After stirring at room temperature for 1 hour, filtered through Celite, and then diluted with 80 ml of ethyl acetate. Washed three times with 80 ml of water, dried over anhydrous magnesium sulfate, concentrated and crystallized with normal hexane to obtain 0.5 g of a white solid. (Yield: 27%)

¹ H NMR (400MHz, CDCl ₃ ) δ 1.13 (t, 3H), 1.23 (t, 3H), 3.25 (q, 2H), 3.39 (q, 2H), 3.80 (s, 3H), 4.83 (s, 2H) ), 6.95 (s, 1H), 6.96 (s, 1H)

Example 1: (5-(((E)-4-methoxy-4-oxobut-2-enoyl)oxy)-4-oxo-4H-pyran-2-yl)methyl methyl fumarate

1.0 g of monomethyl fumarate was dissolved in 10 ml of dichloromethane, and a catalytic amount of dimethylformamide was added. 1 ml of oxalyl chloride was gradually added dropwise for 5 minutes at room temperature. The reaction was completed by stirring at room temperature for 1 hour and 30 minutes, and then concentrated under reduced pressure to obtain a yellow oily residue. (Activator of monomethyl fumarate) 0.91 g of kojic acid and 2.5 g of cesium carbonate were suspended in 10 ml of acetonitrile in a separate container, and the monomethyl fumarate activator was dissolved in 5 ml of acetonitrile and added dropwise for 5 minutes. After stirring at room temperature for 2 hours to complete the reaction, the filtrate was recovered by filtration through Celite. 30 ml of ethyl acetate was added thereto, diluted, and washed with 30 ml of deionized water. The separated organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was eluted and purified by a column packed with silica gel. (Dichloromethane: Methanol = 20: 1) When the eluted fraction was analyzed by thin layer chromatography (silica gel coating, dichloromethane: methanol = 9: 1), the fraction corresponding to R _f = 0.80 was concentrated under reduced pressure and a white solid 0.86 g of the title compound was obtained. (Yield: 30.5%)

¹ H NMR (400MHz, DMSO-d ₆ ) δ 3.76 (3H, s), 3.78 (3H, s), 5.19 (2H, s), 6.76 (1H, s), 6.89 (2H, s), 6.99 (2H , s), 8.67 (1H, s)

Mass (FAB): [M+1] ⁺ 367

Example 2: 6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl methyl fumarate

Prepared in the same manner as in Example 1, but the fraction corresponding to R _f = 0.55 was concentrated under reduced pressure when analyzed by thin film chromatography (silica gel coating, dichloromethane: methanol = 9: 1) at the time of purification in the final step, and a white solid 0.30 g of the phosphorus title compound was obtained. (Yield: 15.4%)

¹ H NMR (400MHz, DMSO-d ₆ ) δ 3.78 (3H, s), 4.37 (2H, d), 5.80 (1H, t), 6.47 (1H, s), 6.99 (2H, s), 8.60 (1H , s)

Mass (FAB): [M+1] ⁺ 255

Example 3: (5-hydroxy-4-oxo-4H-pyran-2-yl) methyl methyl fumarate

1.0 g of kojic acid was suspended in 20 ml of dichloromethane, and 1.78 ml of triethylamine was added. At room temperature, 1.17 g of t-butyldimethylsilyl chloride was temporarily added and stirred for 3 hours to complete the reaction, followed by washing with 20 ml of deionized water. The separated organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure and dried in vacuo to a yellow solid 5-((t-butyldimethylsilyl)oxy)-2-(hydroxymethyl)-4H-pyran-4- 1.35 g of whole was obtained. (Yield: 75%) 4.29 g of cesium carbonate was added thereto, and then suspended with 20 ml of acetonitrile, and then a diluent of 5 ml of acetonitrile of 0.78 g of the monomethyl fumarate activator of Example 1 was gradually added dropwise for 5 minutes. After stirring at room temperature for 2 hours to complete the reaction, it was filtered through Celite, and the filtrate was recovered and concentrated under reduced pressure. To the concentrated residue, 25 ml of dichloromethane and 25 ml of deionized water were added, stirred for 3 minutes, and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure, and then sufficiently dried under vacuum (5-((t-butyldimethylsilyl)oxy)-4-oxo-4H-pyran-2-yl)methyl methyl fumarate. 1.55 g was obtained as a yellow solid. (Yield: 79.9%) The compound was diluted in 15 ml of tetrahydrofuran, and 4.2 ml of 1N-tetrabutylammonium fluoride was added, followed by stirring at room temperature for 4 hours to complete the reaction. The reaction solvent was concentrated under reduced pressure, and the residue was diluted in 15 ml of ethyl acetate and washed with 15 ml of deionized water. The separated organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The concentrated residue was crystallized with methyl t-butyl ether and filtered to obtain 0.81 g of the title compound. (Yield: 75.8%)

¹ H NMR (400MHz, DMSO-d ₆ ) δ 3.79 (3H, s), 5.10 (2H, s), 6.51 (1H, s), 6.76 (2H, s), 8.84 (1H, s), 10.78 (1H , br s)

Mass (FAB): [M+1] ⁺ 255

Experimental Example 1: Pharmacokinetic evaluation

The pharmacokinetic test for the compounds of Examples and Reference Examples was carried out as follows. Test substances are each of the substances prepared in Examples 1 to 3, and the control substance is dimethyl fumarate (Sigma Aldrich, catalog number 50744), which is the main component of the Tekpidera product, and the substance prepared in Reference Example 1 (XP-23829). Used. After a single oral administration of the three test substances and two control substances to SD (Sprague-Dawley) rats, follow-up analysis of the concentration of monomethyl fumarate drug released into the blood by metabolic processes over time, the compound of the present invention Demonstrated the efficacy of.

The test substance and the control substance were prepared in the same manner and administered to rats at a dose of 0.139 mmol/kg, and blood was collected at a predetermined time and plasma was separated. Analysis of the drug was performed using HPLC (XBridge column C ₁₈ , Waters, mobile phase 0.1% formic acid:acetonitrile (30:70, %/%)) and MS/MS (ESI positive, MRM), and rat donor plasma And each of the commercial standard solutions were mixed in a ratio of 9:1 to prepare and weigh at concentrations of 5, 50, 100, 500, 100 and 5,000 ng/ml. In addition, the preparation of the QC sample was prepared by mixing the rat donor plasma and the standard solution for QC at a ratio of 9:1, and at concentrations of 100, 750 and 2,500 ng/ml. In the pretreatment method, 100 μl of a plasma sample was transferred to a tube for centrifugation, 10 μl of an internal standard solution and 300 μl of methanol were added, followed by mixing for about 30 seconds. The tube was centrifuged at 3,000 xg (4°C) for about 5 minutes, and the supernatant was taken and transferred to an LC vial, and then injected into the instrument. In addition, the concentration of an active ingredient, that is, monomethyl fumarate, in rat plasma was quantified by applying a previously verified analysis method. For pharmacokinetic parameters, WinNonlin 5.2 (Pharsight, USA) program was used, and AUC _0-t , AUC _0-∞ , C _max , T _max , and t _1/2 were calculated by Noncompartment modeling (best fit). The pharmacokinetic parameter results were expressed as mean (Mean) and standard deviation (SD), and statistically processed using the SPSS program (Statistical Package for the Social Sciences, 10.0K, USA).

The test results, bioavailability after oral administration of the control substance and the test substance are summarized in Table 2 below.

division AUC _0-24
(ng/ml) Standard Deviation
(SD) Relative absorption
(Compared to dimethyl fumarate, %) Route of administration Control substance Dimethyl fumarate 7,641 1,424 100.0 oral- Reference Example 1 (XP23829) 6,678 1,137 87.4 oral- Test substance Example 1 13,182 8,198 172.5 oral- Example 2 7,074 3,988 92.6 oral- Example 3 6,737 3,638 88.2 oral-

Representatively, for the compound of Example 1, the average AUC _0-24 is 13,182 hr*ng/ml, the average AUC _inf is 15,312 hr*ng/ml, the average C _max is 3,748 ng/ml, the average T _max is 0.25 hours, and the average t _1/2 was 8.95 hours and the relative absorption was 172.5% compared to dimethyl fumarate. Example 1 The trends in blood concentration of monomethyl fumarate by time after oral administration of the compound are shown in FIG. 1 in comparison with the control substance, dimethyl fumarate.

The compound of the present invention, particularly the compound of Example 1, has a relatively very high blood AUC for monomethyl fumarate as an active ingredient compared to dimethyl fumarate as a control substance in the in vivo pharmacokinetic results, and, on the contrary, has a low Cmax and a large half-life. It has an increased sustained-release characteristic profile. This suggests that dimethyl fumarate can maintain the blood concentration of the active ingredient by administering once a day, in contrast to the pharmacokinetic properties that must be administered twice a day.

On the other hand, the clinically most common side effects of dimethyl fumarate are gastrointestinal side effects and hot flashes, which are the two biggest reasons for discontinuing medication. In general, side effects of drugs often occur due to a rapid increase in blood concentration of the drug, so it can be expected that side effects will decrease if the drug has the same blood concentration pattern as the compound of the present invention.

In addition, facial flushing is due to the pharmacological action of the active ingredient, monomethyl fumarate, and is thought to be clinically overcome by having the characteristic of a sustained-release type that lowers Cmax and increases half-life. Facial flushing, which is clinically observed at a high rate when dimethyl fumarate is administered, occurs over several months from immediately after taking dimethyl fumarate, and sometimes adapts or disappears when administered for a long period of time, but the medication is discontinued depending on the patient. Facial flushing caused by dimethyl fumarate is very similar to that of niacin administration, and it has been reported that Prostaglandin D2 (PGD2) is involved. Indeed, according to the Journal of the International Journal (Clinical Therapeutics/Volume 35, Number 10, 2013), when dimethyl fumarate is administered, the blood levels of 9α,11β-PGF2 (9α,11β-prostaglandin F2), the major metabolite of PGD2 Increasing concentrations have been reported. In the literature, it is reported that the concentration of 9α,11β-PGF2 in the blood decreases to the placebo level when the 4th day is reached when the sustained-release formulation of dimethyl fumarate is administered. However, dimethyl fumarate is not effective in reducing hot flashes because it has the pharmacokinetic properties of reducing the dose of 3 times a day to 2 times a day in the case of commercially available Tekpidera, even if it is a sustained-release formulation. It is recommended to use it together. Unlike dimethyl fumarate, which is a fast-acting prodrug of monomethyl fumarate, the compound of the present invention has a sustained-release property of monomethyl fumarate, and has excellent efficacy and reduction of side effects when combined with sustained-release formulation technology in clinical practice. Is predicted.

The present inventors have maintained a high blood concentration of monomethyl fumarate while having a pharmacokinetic profile with sustained-release characteristics, and at the same time, in an autoimmune disease model, the efficacy of dimethyl fumarate administered twice a day with only one administration once a day. It shows an excellent effect that surpasses it.

Claims (5)

A compound represented by the following formula (1).
[Formula 1]

In Formula 1,
R ₁ and R ₂ are each independently selected from hydrogen or Formula 2.
[Formula 2]

The method of claim 1, wherein the compound is
(5-(((E)-4-methoxy-4-oxobut-2-enoyl)oxy)-4-oxo-4H-pyran-2-yl)methyl methyl fumarate;
6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl methyl fumarate;
or
(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl methyl fumarate, a compound. The method of claim 2, wherein the compound is (5-(((E)-4-methoxy-4-oxobut-2-enoyl)oxy)-4-oxo-4H-pyran-2-yl)methyl methyl Fumarate, the compound. A pharmaceutical composition comprising the compound of any one of claims 1 to 3, and a pharmaceutically acceptable carrier. Psoriasis, atopy, macular degeneration, multiple sclerosis, asthma, arthritis, inflammatory bowel disease, lupus, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, including the compound of any one of claims 1 to 3 as an active ingredient , Sleep apnea (Sleep Apnea), imaging alone syndrome (Radiologically Isolated Syndrome), skin sclerosis (Scleroderma), a pharmaceutical composition for the treatment or improvement of cancer or tumor.

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