Porphyria prevention or treatment agents

Abstract

1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl} piperidine-4-carboxylic acid or a pharmaceutically permissible salt or eutectic thereof for the manufacture of medicaments for the treatment or prevention of porphyria. The dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salt or eutectic is 50-500 mg / day.

Description

[0001] This application is a divisional application of the invention patent application filed on June 10, 2021, with application number 202180041935.2 (international application number: PCT / JP2021 / 022036) and entitled "Prevention or treatment agent for porphyria". Technical Field

[0002] This invention relates to pharmaceutical compositions for the treatment or prevention of porphyria using compounds having melanocortin receptor (MCR) agonist activity (agonist activity). Background Technology

[0003] Of the sunlight, wavelengths below 300nm are absorbed by the ozone layer in the stratosphere. Therefore, the sunlight reaching the Earth's surface consists of ultraviolet, visible, and infrared rays with wavelengths above 300nm. Physiological reactions to sunlight exposure include sunburn (photodermatitis) and photoaging (wrinkles, sagging, pigmentation) caused by prolonged exposure. On the other hand, diseases caused by light exposure at levels that do not elicit a reaction in healthy individuals are called photodermatitis. Porphyria is known to be a type of photodermatitis.

[0004] Porphyria is a disease caused by the accumulation of porphyrin bodies or their precursors due to decreased activity of heme-metabolizing enzymes. Symptoms include photosensitivity (sunburn or burn-like symptoms), sometimes accompanied by gastrointestinal and neurological symptoms. Once the disease develops, symptoms often persist for life, and there is no cure; symptomatic treatments such as sun protection are the primary approach.

[0005] For example, Patent Document 1 discloses the use of MCR agonist peptides such as afamelanotide for the treatment of photosensitive skin diseases such as erythropoietic protoporphyria. However, since afamelanotide is not a selective MC1R agonist, there are concerns about potential side effects. Furthermore, because it is a peptide, it cannot be administered orally, and its short half-life necessitates periodic subcutaneous implantation by medical professionals.

[0006] On the other hand, Patent Document 2 discloses that pyrrolidine compounds such as 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid, or their pharmaceutically permissible salts, solvates or hydrates, cocrystals, etc., possess excellent MCR, especially MC1R, activating activity. Furthermore, Patent Document 2 discloses that this compound is useful in the prevention or treatment of various diseases or symptoms related to MCR, especially MC1R, activation, and also describes protoporphyria as a target disease, but does not specify the specific dosage.

[0007] Furthermore, Patent Document 3 discloses a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid. However, it does not describe the specific dosage of the cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid for the treatment of porphyria.

[0008] Existing technical documents Patent documents Patent Document 1: WO2008 / 025094 Patent Document 2: WO2015 / 182723 Patent Document 3: WO2020 / 138481 Summary of the Invention

[0009] The problem that the invention aims to solve There are few fundamental treatments for porphyria, and avoiding sun exposure has become the mainstream approach to prevent or alleviate symptoms. Patients known to have photodermatitis induced by visible light often tend to avoid going out during the day, significantly impairing their quality of life (QOL).

[0010] As mentioned above, although an analogue of α-melanocyte-stimulating hormone (α-MSH), a ligand of MCR, has been developed as a therapeutic agent for photodermatitis such as erythropoietic protoporphyria (Patent Document 1), it is not a selective agonist of MC1R. In addition, it cannot be administered orally because it is a peptide. Furthermore, it requires periodic implantation because it disappears quickly in the human body.

[0011] Therefore, there is a search for pharmaceutical compositions for the treatment or prevention of porphyria that can be more safely and effectively treated without burdening patients.

[0012] Methods for solving problems The inventors of this application conducted in-depth research to solve the aforementioned problems. As a result, for 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salts or cocrystals, a dosage that is particularly effective in human clinical trials was discovered. It was found that at this dosage, excellent therapeutic or preventive effects can be achieved against porphyria, including erythropoietic protoporphyria (EPP) and X-linked porphyria. In particular, they successfully discovered a dosage that significantly outperforms placebo not only in seasons with strong sunlight and long daylight hours (such as spring and summer in the Northern Hemisphere) but also in seasons with weaker sunlight and shorter daylight hours (such as autumn and winter in the Northern Hemisphere), meaning that it can effectively treat or prevent porphyria throughout the year. Furthermore, while clinical trials have confirmed the therapeutic efficacy of afanotide, an existing drug, for symptoms caused by exposure to direct sunlight, it has been confirmed that, at the dosage of this invention, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidin-4-carboxylic acid or its pharmaceutically permissible salts or cocrystals are effective not only for direct sunlight but also for symptoms caused by indirect sunlight exposure, even when exposed indoors. This invention was completed based on these insights.

[0013] This invention provides a medicament for treating or preventing porphyria such as erythropoietic protoporphyria and X-linked porphyria, wherein the medicament comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt thereof. The cocrystal, as the active ingredient, is 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt thereof, or the cocrystal, administered at a dose of 50–500 mg / day, preferably 100–300 mg / day.

[0014] This invention provides a method for treating or preventing porphyria such as erythropoietic protoporphyria and X-linked porphyria, the method comprising administering an effective amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof to the subject requiring treatment or prevention, wherein the aforementioned effective amount is 50 to 500 mg / day, preferably 100 to 300 mg / day.

[0015] This invention provides 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof, which is used for the treatment or prevention of porphyria such as erythropoietic protoporphyria and X-linked porphyria. The dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salt or cocrystal is 50-500 mg / day, preferably 100-300 mg / day.

[0016] This invention provides 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidin-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof in a medicament for the treatment or prevention of porphyria such as erythropoietic protoporphyria and X-linked porphyria. For manufacturing purposes, the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salt or eutectic is 50 to 500 mg / day, preferably 100 to 300 mg / day.

[0017] The present invention provides the following solution.

[0018] 1. A medicine for the treatment or prevention of porphyria, said medicine comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof. The active ingredient, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salt or cocrystal, is administered at a dose of 50–500 mg / day.

[0019] 2. The drug as described in item 1, wherein the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof is 100-300 mg / day.

[0020] 3. The drug as described in any one of items 1 or 2, wherein the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof is 100 mg / day, 200 mg / day or 300 mg / day.

[0021] 4. The drug as described in any one of items 1 to 3, wherein the porphyria is erythropoietic protoporphyria, X-linked porphyria, congenital erythropoietic porphyria, variant porphyria, acute intermittent porphyria, delayed cutaneous porphyria, or hereditary coprophyria.

[0022] 5. The drug as described in item 4, wherein the porphyria is erythropoietic protoporphyria or X-linked porphyria.

[0023] 6. The drug as described in any one of items 1 to 5, wherein 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or eutectic thereof is a eutectic of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid.

[0024] Invention Effects According to the present invention, porphyria can be treated and prevented in any environment, whether indoors or outdoors, throughout the year. 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salts or cocrystals can be administered orally, and its in vivo dynamics are good. In addition, since it is an MC1R-selective compound, it has few side effects and can safely and effectively treat and prevent porphyria without burdening the patient. In particular, by administering 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidin-4-carboxylic acid or its pharmaceutically permissible salts or cocrystals, excellent therapeutic effects can be achieved throughout the year, both indoors and outdoors, for porphyria including erythropoietic protoporphyria and X-linked porphyria (including extended time to phototoxicity presentation (also known as the time to the appearance of phototoxicity-related signs or the time to prodromal symptoms), reduced pain events, and improved QOL). Detailed Implementation

[0025] The present invention will now be described.

[0026] <Active Ingredients> Regarding 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or eutectic thereof, which is the active ingredient of the drug of the present invention, Patent Document 2 describes that it can be manufactured using the methods described in Patent Document 2, etc. In addition, the cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid can be obtained by conventional methods, for example, by the method described in Patent Document 3.

[0027] It should be noted that in this specification, the dosage referred to as "1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salt or eutectic" or "Compound A" indicates the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid, i.e., the amount in free volume.

[0028] <Medical Uses> 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salts or cocrystals exhibit excellent MC1R agonist activity, thus providing excellent therapeutic and preventative effects against porphyria throughout the year in any environment, including prolonged phototoxicity presentation time, reduced pain events, and improved QOL.

[0029] In addition, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salts or cocrystals have shown particularly excellent effects in prolonging the time to phototoxicity in specific patient groups (patients with a baseline median level of erythrocyte protoporphyrin IX of ≥1980.50 mcg / dL), and have excellent therapeutic and preventive effects on porphyria.

[0030] Furthermore, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidin-4-carboxylic acid or its pharmaceutically permissible salts or cocrystals have shown excellent efficacy in prolonging the time to phototoxicity in specific patient groups (patients with a median melanin density of 3.0915 or higher) regardless of dosage. In addition, in specific patient groups (patients with a median melanin density of less than 3.0915), it has shown excellent efficacy in prolonging the time to phototoxicity at specific dosages (preferably a daily dose of 300 mg), thus exhibiting excellent therapeutic and preventive effects against porphyria.

[0031] Therefore, drugs containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salts or cocrystals as active ingredients are useful for the treatment or prevention of porphyria.

[0032] Examples of porphyria include erythropoietic proporphyria, X-linked porphyria, congenital erythropoietic porphyria, variant porphyria, acute intermittent porphyria, tarda cutaneous porphyria, and hereditary coprophyria.

[0033] It should be noted that the term "erythropoietic protoporphyria" here also includes congenital erythropoietic protoporphyria.

[0034] The time from the onset of phototoxicity refers to the period from the appearance of phototoxicity-related signs (or simply signs). It is also called the time from the appearance of prodromal symptoms. Examples of phototoxicity-related signs, symptoms, or prodromal symptoms include burning, tingling, itching, and stinging.

[0035] 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid can be supplied for pharmaceutical use in its free form or in the form of its pharmaceutically permissible salts or eutectic forms.

[0036] Here, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or any of its pharmaceutically permissible salts or eutectics, including intramolecular salts, adducts, and their solvates or hydrates, polymorphs, etc.

[0037] Examples of substances that are permissible in pharmaceutical applications, such as salts, eutectics, intramolecular salts, and adducts, include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid, and organic acids such as acetic acid, fumaric acid, oxalic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or maleic acid. Eutectics with phosphoric acid are particularly preferred.

[0038] One or more of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salts or cocrystals can be directly administered to the patient, but preferably 1-{2-[( 3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or eutectic thereof, mixed with pharmaceutically and pharmaceutically permissible additives, are provided in the form of a formulation known to those skilled in the art.

[0039] As pharmaceutically and pharmaceutically permissible additives, appropriate excipients, disintegrants, binders, lubricants, coating agents, pigments, diluents, matrices, and isotonic agents commonly used in the manufacture of pharmaceuticals can be used. For example, as excipients, glucose, lactose, D-mannitol, starch, or crystalline cellulose can be used; as disintegrants, carboxymethyl cellulose, starch, or calcium carboxymethyl cellulose can be used; as binders, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, or gelatin can be used; as lubricants, magnesium stearate or talc can be used; as coating agents, hydroxypropyl methyl cellulose, white sugar, polyethylene glycol, or titanium dioxide can be used; and as matrices, petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or stearin can be used. In addition, in formulations suitable for injection or infusion, the following additives may be used: aqueous solvents or solubilizers such as distilled water for injection, physiological saline, and propylene glycol, which can form a solution-soluble injection; osmotic agents such as glucose, sodium chloride, D-mannitol, and glycerin; and pH adjusters such as inorganic acids, organic acids, inorganic bases, or organic bases.

[0040] 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidin-4-carboxylic acid or a pharmaceutically permissible salt or eutectic thereof may be prepared together with the above-described additives into a suitable administration form (powder, injection, tablet, capsule, or topical preparation, etc.), and then administered to a patient (human or animal) using a suitable administration method corresponding to the administration form (e.g., intravenous administration, oral administration, transdermal administration, or topical administration, etc.). Oral administration is preferred.

[0041] The dosage of a drug containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidin-4-carboxylic acid or its pharmaceutically permissible salt or cocrystal is low in toxicity and safe to use, and is effective in treating or preventing porphyria both indoors and outdoors throughout the year. The dosage of R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or eutectic thereof is 50 to 500 mg / day, more preferably 80 to 400 mg / day, particularly preferably 100 to 300 mg / day. Examples of dosages include 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, or amounts between thereof.

[0042] Particularly preferred are oral administration of drugs comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof, administered orally, according to the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-( The dosage is 50–500 mg / day, preferably 80–400 mg / day, more preferably 100–300 mg / day, specifically 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, or between thereof, based on the amount of 4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salt or eutectic thereof. Particularly preferred dosages are 100 mg / day, 200 mg / day, or 300 mg / day.

[0043] Further preferred is to administer the eutectic of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid at an dosage of 100 mg / day or 300 mg / day, based on the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0044] In addition, it is preferred to administer the cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid at an dosage of 100 mg / day or 200 mg / day, based on the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0045] As another possible method, one could cite administering a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid at a dosage of 100 mg / day, based on the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0046] As another possible method, one could cite administering a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid with phosphoric acid at a dosage of 200 mg / day, based on the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0047] As another possible method, one could cite administering a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid with phosphoric acid at a dosage of 300 mg / day, based on the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0048] As described in the following examples, it has been demonstrated that, compared with placebo, a daily dose of 100 mg or 300 mg of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidin-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof has therapeutic effects such as prolonged time to phototoxicity, reduced pain events, and improved QOL in patients with erythropoietic protoporphyria and X-linked porphyria. Particularly in patients with a baseline median erythropoietic protoporphyrin IX level of ≥1980.50 mcg / dL, the effect of prolonged time to phototoxicity was statistically significant compared with placebo at any daily dose of 100 mg or 300 mg. Furthermore, when comparing patients with a median melanin density of 3.0915 or higher with those with a median melanin density of less than 3.0915, the former showed a similarly prolonged time to phototoxicity at any dose of 100 mg or 300 mg per day, while the latter showed a further prolonged time to phototoxicity at a dose of 300 mg per day.

[0049] In addition, therapeutic effects on patients with erythropoietic protoporphyria and X-linked porphyria have been confirmed at a daily dose of 100 mg or 200 mg of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidin-4-carboxylic acid or its pharmaceutically permissible salts or cocrystals.

[0050] Although erythropoietic protoporphyria is also described as a target disease in Patent Document 2 or Patent Document 3, no specific dosage is described, and there is no record of the present invention effectively treating erythropoietic protoporphyria throughout the year, whether indoors or outdoors, by administering the dosage determined in this clinical trial, such as 100 mg / day or 300 mg / day, for example 50 to 500 mg / day, preferably 80 to 400 mg / day, more preferably 100 to 300 mg / day.

[0051] That is, in one aspect of the invention, a medicament for treating or preventing porphyria can be provided, which is administered to a porphyria patient, said medicament comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof as an active ingredient, wherein for the porphyria patient, 1-{2-[(3S,4R)-1-{[( The dosage of piperidine-4-carboxylic acid or a pharmaceutically permissible salt or eutectic thereof is 50 to 500 mg / day, preferably 80 to 400 mg / day, more preferably 100 to 300 mg / day, specifically 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, or amounts between thereof.

[0052] As another aspect of the present invention, a medicament for treating or preventing erythropoietic protoporphyria and X-linked porphyria can be provided, which is administered to patients with erythropoietic protoporphyria and X-linked porphyria. The medicament comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof as the active ingredient, for patients with erythropoietic protoporphyria and X-linked porphyria. For the purposes of this study, the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or eutectic thereof is: 50 to 500 mg / day, preferably 80 to 400 mg / day, more preferably 100 to 300 mg / day, specifically 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, or dosages thereof.

[0053] As another aspect of the invention, a medicament is provided for prolonging the time of phototoxic presentation (or the time to prodromal symptoms) and / or reducing painful events in erythropoietic proporphyria and X-linked porphyria, administered to patients with erythropoietic proporphyria and X-linked porphyria, wherein the medicament comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof as the active ingredient, for erythropoiesis For patients with protoporphyria and X-linked porphyria, the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof is 50 to 500 mg / day, preferably 80 to 400 mg / day, more preferably 100 to 300 mg / day, specifically 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, or dosages between these.

[0054] As another aspect of the invention, a medicament for treating or preventing porphyria including erythropoietic protoporphyria, X-linked porphyria, etc., is provided, administered to patients with erythropoietic protoporphyria and X-linked porphyria, wherein the medicament comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof as the active ingredient, particularly for patients with a baseline median erythropoietic protoporphyria IX level of ≥1980.50 mcg / dL. For patients with erythropoietic proporphyria and X-linked porphyria, the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof is 50 to 500 mg / day, preferably 80 to 400 mg / day, more preferably 100 to 300 mg / day, specifically 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, or dosages between these.

[0055] As another aspect of the invention, a medicament for treating or preventing porphyria including erythropoietic protoporphyria, X-linked porphyria, etc., is provided, administered to patients with erythropoietic protoporphyria and X-linked porphyria, wherein the medicament comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof as an active ingredient, particularly for erythropoietic protoporphyria with a median melanin density of 3.0915 or higher. For patients with protoporphyria and X-linked porphyria, the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof is 50 to 500 mg / day, preferably 80 to 400 mg / day, more preferably 100 to 300 mg / day, specifically 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, or dosages between these.

[0056] As another aspect of the invention, a medicament for treating or preventing porphyria including erythropoietic protoporphyria, X-linked porphyria, etc., is provided, administered to patients with erythropoietic protoporphyria and X-linked porphyria, wherein the medicament comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof as an active ingredient, particularly for patients with erythropoietic protoporphyria and X-linked porphyria with a median melanin density of less than 3.0915, 1-{2-[(3S,4R)- The dosage of 1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or eutectic thereof is 50-500 mg / day, preferably 80-400 mg / day, more preferably 100-300 mg / day, further preferably 200-300 mg / day, specifically 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day or dosages thereof, more preferably 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day or dosages thereof.

[0057] Example The present invention will be specifically illustrated by the following embodiments, but the present invention is not limited to the embodiments described below.

[0058] Compound A used in the examples is one of the following compounds.

[0059] A cocrystal containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid is manufactured using the method described in Patent Document 2, and the eutectic with phosphoric acid is manufactured using the following method.

[0060] Specifically, to a suspension of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl} piperidine-4-carboxylic acid 1 / 2 ethane-1,2-disulfonic acid (19.3 kg) in ethyl acetate (86.6 kg), a solution of potassium carbonate (3.4 kg) in water (77.0 L) and water (19.3 L) were added sequentially at 20–30 °C, and the mixture was stirred for 10 minutes. After standing, the aqueous layer was removed, and the organic layer was washed twice with water (96.3 L). The organic layer was concentrated to 35 L, and then ethanol (75.9 kg) was added, concentrating the mixture to 35 L. After diluting with ethanol (30.3 kg), the insoluble matter was filtered off and washed with ethanol (75.6 kg). The filtrate was concentrated to 35 L and diluted with ethanol (17.9 kg). A 24% sodium hydroxide aqueous solution (6.1 kg) and water (15.6 kg) were added sequentially at 20–30 °C, and the mixture was stirred for 5 hours at 20–30 °C. A solution of phosphoric acid (8.5 kg) in water (28.9 L) and water (115.5 L) were added sequentially at 20–40 °C. Compound A (0.48 kg) was added as a seed crystal at 30–40 °C, and the mixture was stirred for 19.5 hours, then cooled to 20 °C. The solid was filtered off and washed with water (96.3 L). The solid was dried below 50 °C and then pulverized to obtain compound A (17.5 kg).

[0061] The obtained compound A was identified using IR.

[0062] Example 1 The time until phototoxicity-related signs appeared in clinical trials of compound A in patients with erythropoietic protoporphyria and X-linked porphyria. In a randomized, double-blind clinical trial involving adult men and women with erythropoietic protoporphyria and X-linked porphyria, compound A was administered for 16 weeks. As the primary measure of clinical efficacy, the time from one hour after sunrise to one hour before sunset until the initial appearance of symptoms induced by light exposure (including both direct and indirect sunlight) was evaluated.

[0063] To determine the baseline median level of protoporphyrin IX in erythrocytes, erythrocytes in the blood are separated, and the protoporphyrin IX level is measured.

[0064] The median melanin density is determined by measuring the skin density in six areas: the forehead, left cheek, right inner upper arm, left inner forearm, right abdomen, and left buttock using a spectrophotometer.

[0065] Table 1 shows the evaluation results at 16 weeks in 35 patients receiving placebo, 33 patients receiving 100 mg of compound A orally once daily, and 34 patients receiving 300 mg of compound A orally once daily. Significant time prolongations of 53.8 minutes and 62.5 minutes were observed in the 100 mg and 300 mg groups of compound A compared to the placebo group, respectively.

[0066] [Table 1] In patients with a baseline median erythrocyte protoporphyrin IX level of ≥1980.50 mcg / dL, analysis of the above parameters showed that the least-squares mean time to the onset of symptoms was 69.3 minutes with 100 mg of compound A (P = 0.020) and 82.6 minutes with 300 mg (P = 0.003), both statistically significant. A tendency to prolong the time to the onset of symptoms was also observed in patients with a baseline median erythrocyte protoporphyrin IX level less than 1980.50 mcg / dL.

[0067] Furthermore, when analyzing the above items by dividing patients into groups with a median melanin density of 3.0915 or higher and those with a median melanin density of less than 3.0915, it was found that in the former group, the least squares mean time (minutes) from the first appearance of symptoms during the day was 85.0 minutes when administered 100 mg (P < 0.001) and 80.3 minutes (P < 0.002) when administered 300 mg. In contrast, in the latter group, the least squares mean time (minutes) from the first appearance of symptoms during the day was 23.2 minutes (P < 0.499) when administered 100 mg and 63.7 minutes (P < 0.051) when administered 300 mg. This indicates that the effect of 300 mg in prolonging the time to the appearance of phototoxicity-related symptoms was greater.

[0068] Example 2 The time until the appearance of phototoxicity-related signs in patients with erythropoietic protoporphyria and X-linked porphyria in the subgroups that first took compound A in early spring / summer and the subgroups that first took compound A in early autumn / winter (primary clinical evaluation item). The following trial was conducted in the Northern Hemisphere. Table 2 shows the evaluation results at 16 weeks in the subgroups that first received compound A in spring / summer (n=20 receiving placebo, n=18 receiving 100 mg of compound A orally once daily, and n=18 receiving 300 mg of compound A orally once daily) and the subgroups that first received compound A in autumn / winter (n=15 receiving placebo, n=15 receiving 100 mg of compound A orally once daily, and n=16 receiving 300 mg of compound A orally once daily). In the spring / summer subgroups, compared to placebo, a time extension of 54.4 minutes and 42.2 minutes were observed in the 100 mg and 300 mg compound A administration groups, respectively. In the autumn / winter subgroups, compared to placebo, a significant time extension of 52.8 minutes and 95.8 minutes was observed in the 100 mg and 300 mg compound A administration groups, respectively. Regardless of the season, prolonged administration time was observed in both the 100 mg and 300 mg groups of compound A.

[0069] [Table 2] Example 3 The number of pain events recorded in electronic diaries by patients during the 16-week evaluation period in a clinical trial of compound A in patients with erythropoietic protoporphyria and X-linked porphyria. In a randomized, double-blind clinical trial, compound A was administered for 16 weeks to adult men and women with erythropoietic protoporphyria and X-linked porphyria. As part of the clinical efficacy assessment, patients recorded the number of pain events during the 16-week evaluation period in an electronic diary.

[0070] The evaluation results for 23 patients receiving placebo, 24 patients receiving 100 mg of compound A orally once daily, and 24 patients receiving 300 mg of compound A orally once daily are shown in Table 3. The pain attack rates during the evaluation period were 7.5, 3.3, and 3.5 in the placebo group, the 100 mg compound A group, and the 300 mg compound A group, respectively. This indicates that, compared with the placebo group, the 100 mg and 300 mg compound A groups showed a significant reduction of 60% and 50%, respectively, in the pain events (Table 3).

[0071] [Table 3] Example 4 Health-related QOL evaluation of compound A in clinical trials involving patients with erythropoietic protoporphyria and X-linked porphyria. In a randomized, double-blind clinical trial, compound A was administered to adult men and women with erythropoietic protoporphyria and X-linked porphyria for 16 weeks. As a secondary assessment of clinical efficacy, patients self-reported their health-related QOL, specifically the Patient Global Impression of Change (PGIC) score, at 16 weeks. A questionnaire was developed to assess the overall improvement in physical and mental health across seven stages. In this embodiment, a PGIC score of 1 indicates no change or worsening, while 7 indicates significant improvement.

[0072] The evaluation results of 30 patients receiving placebo, 25 patients receiving 100 mg of compound A orally once daily, and 24 patients receiving 300 mg of compound A orally once daily are shown in Table 4. The PGIC scores at the 16-week time point were 2.9, 6.4, and 6.6 in the placebo group, the 100 mg compound A group, and the 300 mg compound A group, respectively. Therefore, compared with the placebo group, the PGIC scores in the 100 mg and 300 mg compound A groups were significantly increased, indicating an improvement in the subjects' overall impression (Table 4).

[0073] [Table 4] Example 5: Phase III test using compound A as the test substance Subjects Patients with erythropoietic protoporphyria and X-linked porphyria aged 12 to 75 years (male and female) Experimental Overview Randomized double-blind clinical trials The study included 53 patients who received a placebo, 53 patients who received 100 mg of compound A orally once a day, and 53 patients who received 200 mg of compound A orally once a day.

[0074] Test Project (1) The time until the appearance of phototoxicity-related signs in clinical trials of compound A in patients with erythropoietic protoporphyria and X-linked porphyria. In a randomized, double-blind clinical trial, compound A was administered to subjects for 26 weeks, with additional administration for up to 58 weeks as needed. As the primary measure of clinical efficacy, the time from the initial appearance of light exposure-induced symptoms during the day was evaluated at week 26.

[0075] (2) The number of pain events recorded in electronic diaries by patients during the 26-week evaluation period in clinical trials of compound A in patients with erythropoietic protoporphyria and X-linked porphyria. In a randomized, double-blind clinical trial, compound A was administered to participants for 26 weeks, with an additional 26 weeks, up to a maximum of 58 weeks, as needed. As another assessment of clinical efficacy, patients recorded the number of pain events during the 26-week evaluation period in an electronic diary.

[0076] (3) Health-related QOL evaluation of patients in clinical trials of compound A in patients with erythropoietic protoporphyria and X-linked porphyria. In a randomized, double-blind clinical trial, compound A was administered to participants for 26 weeks, with an additional 26 weeks, up to a maximum of 58 weeks, depending on the circumstances. As a secondary assessment of clinical efficacy, patients self-reported their health-related QOL, specifically the Patient Global Impression of Change (PGIC) score, at 26-week intervals. This questionnaire assessed the overall improvement in physical and mental health across seven stages. In this embodiment, a PGIC score of 1 represents significant improvement, and 7 represents significant deterioration.

Claims

1. 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof for the manufacture of a medicament for the treatment or prevention of porphyria, wherein, The dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salt or eutectic is 50-500 mg / day.

2. The use as described in claim 1, wherein, The dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salt or eutectic is 100-300 mg / day.

3. The use as described in claim 1, wherein, The dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salt or cocrystal is 100 mg / day, 200 mg / day or 300 mg / day.

4. The use as described in any one of claims 1 to 3, wherein, Porphyria includes erythropoietic protoporphyria, X-linked porphyria, congenital erythropoietic porphyria, variant porphyria, acute intermittent porphyria, delayed cutaneous porphyria, or hereditary coprophyria.

5. The use as described in claim 4, wherein, Porphyria is also known as erythropoietic protoporphyria or X-linked porphyria.

6. The use as described in any one of claims 1 to 3, wherein, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl} piperidine-4-carboxylic acid or its pharmaceutically permissible salt or eutectic is a eutectic of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl} piperidine-4-carboxylic acid and phosphoric acid.

7. The use as described in claim 4, wherein, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl} piperidine-4-carboxylic acid or its pharmaceutically permissible salt or eutectic is a eutectic of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl} piperidine-4-carboxylic acid and phosphoric acid.

8. The use as described in claim 5, wherein, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl} piperidine-4-carboxylic acid or its pharmaceutically permissible salt or eutectic is a eutectic of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl} piperidine-4-carboxylic acid and phosphoric acid. 9.1-The use of {2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof in the manufacture of a medicament for prolonging the time of phototoxicity in porphyria, wherein, The dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salt or eutectic is 50-500 mg / day. 10.1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically permissible salt or cocrystal thereof for the manufacture of a medicament for reducing pain in porphyria, wherein, The dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically permissible salt or eutectic is 50-500 mg / day.

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