Preventive or therapeutic agent for porphyria

Abstract

To provide a pharmaceutical composition for treating or preventing porphyria, which can be more safely and effectively treated without imposing a burden on a patient.SOLUTION: A medicament for treating or preventing porphyria, comprising 1 - {2 - [(3S, 4R) - 1 - {[(3R, 4R) - 1-cyclopentyl-3-fluoro-4 - (4-methoxyphenyl) pyrrolidin-3-yl] carbonyl} - 4 - (methoxymethyl) pyrrolidin-3-yl] - 5 - (trifluoromethyl) phenyl} piperidine-4-carboxylic acid or pharmaceutically acceptable salts or cocrystals thereof as an active ingredient, A medicament for treating or preventing porphyria, wherein the dosage of 1 - {2 - [(3S, 4R) - 1 - {[(3R, 4R) - 1-cyclopentyl-3-fluoro-4 - (4-methoxyphenyl) pyrrolidin-3-yl] carbonyl} - 4 - (methoxymethyl) pyrrolidin-3-yl] - 5 - (trifluoromethyl) phenyl} piperidine-4-carboxylic acid or pharmaceutically acceptable salts or co-crystals thereof is 50 to 500mg / day.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition for treating or preventing porphyria using a compound having melanocortin receptor (MCR) agonistic activity. [Background technology]

[0002] Of the light emitted from the sun, rays with wavelengths of 300 nm or less are absorbed by the ozone layer in the stratosphere. Therefore, sunlight that reaches the earth consists of ultraviolet rays, visible light, and infrared rays over 300 nm. Physiological reactions that occur when exposed to sunlight include sunburn (photodermatitis) and skin changes (wrinkles, sagging, pigmented spots) called photoaging that occur with long-term exposure. On the other hand, diseases that cause pathological changes such as dermatitis due to light exposure at a level that does not cause a reaction in healthy people are called photodermatological diseases. Porphyria is known as one type of photodermatological disease.

[0003] Porphyria is a disease caused by the accumulation of porphyrins or their precursors due to a decrease in the activity of heme metabolic enzymes. Symptoms include photosensitivity (sunburn, burn-like symptoms), as well as gastrointestinal and neurological symptoms. Once the disease develops, symptoms often persist for life, but there is no cure, and symptomatic treatment such as light protection is the main treatment.

[0004] For example, Patent Document 1 discloses MCR agonists such as afamelanotide. Although afamelanotide has been reported as a peptide for the treatment of photocutaneous diseases such as erythropoietic protoporphyria, it is not a selective MC1R agonist, raising concerns about side effects. Furthermore, as a peptide, it cannot be administered orally, and its short half-life requires periodic subcutaneous implantation by medical professionals.

[0005] Meanwhile, Patent Document 2 discloses that pyrrolidine compounds such as 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or pharmaceutically acceptable salts thereof, solvates or hydrates, cocrystals, etc., have excellent MCR, particularly MC1R, activation activity. Patent Document 2 also discloses that the compounds are useful for the prevention or treatment of various diseases or symptoms associated with MCR, particularly MC1R activation, and mentions protoporphyria as a target disease, but does not disclose specific dosages. Furthermore, Patent Document 3 discloses a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid. However, it does not disclose a specific dosage for the use of the cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid in the treatment of porphyria. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO2008 / 025094 [Patent Document 2] WO2015 / 182723 [Patent Document 3] WO2020 / 138481 Summary of the Invention [Problem to be solved by the invention]

[0007] There are few fundamental treatments for porphyria, and the main method of avoiding or alleviating symptoms is to prevent the skin from being exposed to sunlight. In particular, patients with photodermatosis induced by visible light tend to avoid going outside during the day, which is known to significantly impair their quality of life (QOL). As mentioned above, analogs of α-melanocyte-stimulating hormone (α-MSH), a ligand for MCR, have been developed as therapeutic agents for photodermatological diseases such as erythropoietic protoporphyria (Patent Document 1). However, these analogs are not selective agonists of MC1R, and because they are peptides, they cannot be administered orally. Furthermore, they are rapidly eliminated in the human body, requiring periodic implantation. Therefore, there is a need for a pharmaceutical composition for treating or preventing porphyria that allows for safer and more effective treatment without burdening patients. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above-mentioned problems. As a result, they have found a particularly effective dose of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof in human clinical trials, and have found that this dose is effective in treating erythropoietic protoporphyria (EPP: also known as erythropoietic protoporphyria) and X-ray-related encephalopathy. In particular, we have found that a dose of this compound exhibits significant therapeutic effects compared to placebo not only in seasons when sunlight is strong and daylight hours are long (e.g., spring and summer in the Northern Hemisphere), but also in seasons when sunlight is weaker and daylight hours are shorter (e.g., autumn and winter in the Northern Hemisphere), i.e., a dose that can effectively treat or prevent porphyria throughout the year. Furthermore, the prior drug afamelanotide has been confirmed in clinical trials to be effective in treating symptoms caused by exposure to direct sunlight. However, at the doses of the present invention, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof is effective against symptoms caused by exposure to not only direct sunlight but also indirect sunlight, even when indoors. It was confirmed that the therapeutic effect was also exhibited. Based on these findings, the present invention was completed.

[0009] The present invention relates to a method for treating porphyrias such as erythropoietic protoporphyria and X-linked porphyria, comprising administering to a patient a therapeutically effective amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient. The present invention provides a pharmaceutical for treating or preventing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, administered in an amount of 50 to 500 mg / day, preferably 100 to 300 mg / day.

[0010] The present invention provides a method for treating or preventing porphyria, such as erythroblastic protoporphyria and X-linked porphyria, comprising the step of administering an effective amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or co-crystal thereof to a subject in need of such treatment or prevention, The method provides a method in which the effective amount is 50 to 500 mg / day, preferably 100 to 300 mg / day.

[0011] The present invention relates to porphyrin-related diseases such as erythropoietic protoporphyria and X-linked porphyria. 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or co-crystal thereof, wherein the salt is 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid for the treatment or prevention of rheumatoid arthritis. The dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or co-crystal thereof is 50 to 500 mg / day, preferably 100 to 300 mg / day.

[0012] The present invention relates to a method for treating or preventing porphyrias, such as erythropoietic protoporphyria and X-linked porphyria, using 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof. The present invention provides use of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof in the manufacture of a medicament for treating a patient with atopic dermatitis, wherein the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof is 50 to 500 mg / day, preferably 100 to 300 mg / day. [Effects of the Invention]

[0013] According to the present invention, porphyria can be treated or prevented throughout the year in any environment, whether indoors or outdoors. 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof can be orally administered and exhibits favorable pharmacokinetics in humans. Furthermore, because it is an MC1R-selective compound, it has few side effects, allowing for safe and effective treatment or prevention of porphyria without burdening patients. In particular, administration of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof at a specific dose has been shown to improve the time to onset of phototoxicity (phototoxicity-related symptoms) in porphyrias including erythropoietic protoporphyria and X-linked porphyria. This product provides excellent therapeutic effects, including extending the time to symptom onset (also known as the time to prodromal symptoms), reducing pain events, and improving quality of life, all year round, both indoors and outdoors. It is possible. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention will be described below.

[0015] <Active ingredient> The active ingredient of the pharmaceutical of the present invention, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, is described in Patent Document 2 and can be produced by, for example, the method described in Patent Document 2. Furthermore, a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid can be obtained by a conventional method, but can also be obtained, for example, by the method described in Patent Document 3. In this specification, the dose of "1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof" or the dose of "Compound A" refers to 1-{2-[(3S,4R) The amount is shown as -1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid, i.e., as a free form.

[0016] <Medicinal uses> 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof has excellent MC1R agonist activity, and thereby provides excellent treatment for porphyria, including extension of the time to onset of phototoxicity, reduction of pain events, and improvement of QOL, in any environment throughout the year. and exerts a preventive effect. In addition, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof may be effective in a specific patient population (those with a median baseline erythrocyte protoporphyrin IX level of 1980.50 mcg / dL or greater). It has been shown to have a particularly excellent effect in extending the time to onset of phototoxicity in certain patient groups, and has excellent therapeutic and preventive effects against porphyria. Furthermore, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof exhibits an excellent effect of extending the time to onset of phototoxicity regardless of dose in a specific patient group (a patient group with a median melanin density of 3.0915 or more), and also exhibits an excellent effect of extending the time to onset of phototoxicity at a specific dose (preferably a daily dose of 300 mg) in a specific patient group (a patient group with a median melanin density of less than 3.0915). It shows a prolonged effect and exerts excellent therapeutic and preventive effects against porphyria. Therefore, a medicine containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient is useful for treating or preventing porphyria.

[0017] Porphyrias include erythropoietic protoporphyria, X-linked porphyria, and erythropoietic porphyria. These include hereditary erythropoietic porphyria, variegate porphyria, acute intermittent porphyria, porphyria cutanea tarda, and hereditary coporphyria. The term "erythropoietic protoporphyria" as used herein also includes congenital erythropoietic protoporphyria.

[0018] The onset time of phototoxicity refers to the time until the onset of phototoxicity-related symptoms (or simply "signs"). It is also called the time until prodromal symptoms. Examples of phototoxicity-related signs, symptoms, or prodromal symptoms include burning, tingling, itching, and stinging.

[0019] 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid can be used for pharmaceutical purposes in the free form or in the form of a pharmaceutically acceptable salt or co-crystal thereof. Here, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof includes any of an internal salt, an adduct, a solvate or hydrate thereof, a crystalline polymorph, and the like. Pharmaceutically acceptable salts, co-crystals, intramolecular salts, adducts, etc. include those containing inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and organic acids such as acetic acid, fumaric acid, oxalic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, tosylic acid, and maleic acid. Co-crystals with phosphoric acid are particularly preferred.

[0020] One or more of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof may be administered to a patient as is, but preferably, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof may be mixed with pharmaceutically and pharmaceutically acceptable additives, and provided as a formulation in a form well known to those skilled in the art.

[0021] Examples of pharmaceutically and pharmaceutically acceptable additives that can be used include suitable excipients, disintegrants, binders, lubricants, coating agents, dyes, diluents, bases, and isotonicity agents that are commonly used in the manufacture of pharmaceuticals. For example, examples of excipients include glucose, lactose, D-mannitol, starch, and crystalline cellulose; examples of disintegrants include carboxymethylcellulose, starch, and carboxymethylcellulose calcium; and examples of binders include hydroxypropyl cellulose, cellulose acetate, cellulose acetate stearate, and cellulose acetate stearate. Examples of suitable lubricants include hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and gelatin; lubricants include magnesium stearate and talc; coating agents include hydroxypropylmethylcellulose, sucrose, polyethylene glycol, and titanium oxide; and bases include petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, and hard fat. Other additives that can be used in formulations suitable for injection or infusion include solubilizers or solubilizers that can constitute aqueous or ready-to-use injections, such as distilled water for injection, physiological saline, and propylene glycol; isotonic agents, such as glucose, sodium chloride, D-mannitol, and glycerin; and pH adjusters, such as inorganic acids, organic acids, inorganic bases, and organic bases.

[0022] 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof can be prepared together with the above-mentioned additives into an appropriate dosage form (such as a powder, injection, tablet, capsule, or topical preparation), and then administered to a patient (human or animal) by an administration method appropriate for the dosage form (for example, intravenous administration, oral administration, transdermal administration, or topical administration). Among these, oral administration is preferred.

[0023] The dosage of the medicine containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof is an amount that can be used safely with low toxicity and that can exert a therapeutic or preventive effect on porphyria both indoors and outdoors throughout the year, and 1-{2-[(3S,4R)-1-{[(3R, The amount of 4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof is 50 to 500 mg / day, more preferably 80 to 400 mg / day, and particularly preferably 100 to 300 mg / day, and examples thereof include 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, and doses therebetween.

[0024] Oral administration is particularly preferred, and a medicine containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof can be orally administered. The amount of {4-(methoxymethyl)pyrrolidin-3-yl)-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable 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 a dose between these. A dose of 100 mg / day, 200 mg / day, or 300 mg / day is particularly preferred.

[0025] More preferably, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl )phenyl}piperidine-4-carboxylic acid and phosphoric acid co-crystal is administered at a dose of 100 mg / day or 300 mg / day of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid. In another preferred embodiment, the co-crystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid is administered at a dosage of 100 mg / day or 200 mg / day of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0026] In another embodiment, a co-crystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid is administered at a dosage of 100 mg / day of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0027] In another embodiment, a co-crystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid is administered at a dosage of 200 mg / day of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0028] In another embodiment, a co-crystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid is administered at a dosage of 300 mg / day of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0029] As described in the Examples below, a daily dose of 100 mg or 300 mg of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof was shown to prolong the time to onset of phototoxicity, reduce pain, and improve overall well-being in patients with erythropoietic protoporphyria and X-linked porphyria compared to placebo. It has been shown to have therapeutic effects such as reducing events and improving quality of life. Patients with a median baseline toporphyrin IX level of 1980.50 mcg / dL or higher were phototoxic The effect on prolonging sexual onset was observed at both the 100 mg and 300 mg daily doses. The effect was statistically significant compared with placebo. Furthermore, when comparing patients with a median melanin density of 3.0915 or greater with those with a median melanin density of less than 3.0915, the former group showed a similar prolongation of the time to onset of phototoxicity at both the 100 mg and 300 mg daily doses, while the latter group showed a greater prolongation of the time to onset of phototoxicity in the 300 mg daily dose group. Furthermore, a daily dose of 100 mg or 200 mg of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or its pharmaceutically acceptable salt or cocrystal has not been shown to be effective in patients with erythroblastic protoporphyria and X-linked porphyria. The therapeutic effect on patients with leucoderma has been confirmed.

[0030] Patent Document 2 and Patent Document 3 also mention erythropoietic protoporphyria as a target disease, but do not mention a specific dosage. In the present invention, administration of the compound at a dose including 100 mg / day or 300 mg / day, which was identified in the clinical trial this time, for example, at a dose of 50 to 500 mg / day, preferably 80 to 400 mg / day, more preferably 100 to 300 mg / day, provides an excellent treatment for erythropoietic protoporphyria, including extension of the time during which phototoxicity occurs, reduction of pain events, and improvement of QOL, both indoors and outdoors throughout the year. There is no description of the effective exertion of therapeutic effects.

[0031] That is, in one aspect of the present invention, there is provided a pharmaceutical for treating or preventing porphyria, which comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient, and which is administered to a patient with porphyria. The dosage of 3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable 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 a dosage between these dosages.

[0032] Another aspect of the present invention is a method for treating erythropoietic protoporphyria and X-linked porphyria. a therapeutic agent for erythropoietic protoporphyria or X-linked porphyria, the active ingredient of which is 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, administered to patients with erythropoietic protoporphyria or X-linked porphyria; A pharmaceutical for treating or preventing erythropoietic protoporphyria and X-ray-related The present invention provides a pharmaceutical composition for treating bromo-amyloid porphyria, comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, administered at a dose of 50 to 500 mg / day, preferably 80 to 400 mg / day, more preferably 100 to 300 mg / day, and specifically 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, or any dose therebetween.

[0033] Another aspect of the present invention is a method for treating erythropoietic protoporphyria and X-linked porphyria. a therapeutic agent for erythropoietic protoporphyria or X-linked porphyria, the active ingredient of which is 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, administered to patients with erythropoietic protoporphyria or X-linked porphyria; A pharmaceutical agent for prolonging the time to onset of phototoxicity (or time to prodromal symptoms) and / or reducing pain events in patients with erythropoietic protoporphyria and X-linked polyposis The present invention provides a medicine for patients with leufilia, in which the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable 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 a dosage between these dosages.

[0034] Another aspect of the present invention is a method for treating erythropoietic protoporphyria and X-linked porphyria. a therapeutic agent for erythropoietic protoporphyria or X-linked porphyria, the active ingredient of which is 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, administered to patients with erythropoietic protoporphyria or X-linked porphyria; and the like, and particularly a pharmaceutical composition for treating or preventing erythropoietin IX (erythropoietin IX) in which the median baseline level of erythropoietin IX is 1980.50 mcg / dL or more. 1-{2-[(3S,4R)- The pharmaceutical composition provides 1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, in an amount of 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 any amount therebetween.

[0035] Another aspect of the present invention is a method for treating erythropoietic protoporphyria and X-linked porphyria. a therapeutic agent for erythropoietic protoporphyria or X-linked porphyria, the active ingredient of which is 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, administered to patients with erythropoietic protoporphyria or X-linked porphyria; and the like, and is particularly useful for treating or preventing porphyria in patients with erythropoietic protoporphyria and X-linked porphyria in which the median melanin density is 3.0915 or more. The present invention provides a pharmaceutical composition comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, administered at a dose of 50 to 500 mg / day, preferably 80 to 400 mg / day, more preferably 100 to 300 mg / day, and specifically 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, or a dose therebetween.

[0036] Another aspect of the present invention is a method for treating erythropoietic protoporphyria and X-linked porphyria. a therapeutic agent for erythropoietic protoporphyria or X-linked porphyria, the active ingredient of which is 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, administered to patients with erythropoietic protoporphyria or X-linked porphyria; and the like, and in particular, a pharmaceutical composition for treating or preventing porphyria, comprising the pharmaceutical composition for treating erythropoietic protoporphyria and X-linked porphyria, the median melanin density of which is less than 3.0915. The present invention provides a pharmaceutical composition comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, administered at a dose of 50 to 500 mg / day, preferably 80 to 400 mg / day, more preferably 100 to 300 mg / day, and even more preferably 200 to 300 mg / day, specifically 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, or a dose therebetween, more preferably 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, or a dose therebetween. [Example]

[0037] The present invention will be specifically described below with reference to examples, but the present invention is not limited to the examples below.

[0038] Compound A used in the examples is the following compound. Cocrystal containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid

[0039] 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid was produced by the method described in Patent Document 2, and a cocrystal with phosphoric acid was produced by the following method. Specifically, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid was prepared by adding a solution of potassium carbonate (3.4 kg) in water (77.0 L) and water (19.3 L) sequentially to a suspension of 1 / 2 ethane-1,2-disulfonic acid (19.3 kg) in ethyl acetate (86.6 kg) at 20-30°C, followed by stirring for 10 minutes. After allowing to stand, 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 and the mixture was concentrated to 35 L. After dilution with ethanol (30.3 kg), the insoluble matter was filtered and washed with ethanol (75.6 kg). The filtrate and washings were concentrated to 35 L and diluted with ethanol (17.9 kg). A 24% aqueous sodium hydroxide solution (6.1 kg) and water (15.6 kg) were added in sequence at 20-30°C, and the mixture was stirred at 20-30°C for 5 hours. A solution of phosphoric acid (8.5 kg) in water (28.9 L) and water (115.5 L) were added in sequence at 20-40°C. Compound A (0.48 kg) was added as seed crystals at 30-40°C, and the mixture was stirred for 19.5 hours and then cooled to 20°C. The solid was collected by filtration and washed with water (96.3 L). The solid was dried at 50°C or below and then pulverized to obtain compound A (17.5 kg). The obtained compound A was identified using IR.

[0040] Example 1 Compound A for patients with erythropoietic protoporphyria and X-linked porphyria Time to onset of phototoxicity-related signs in clinical trials Compound A was administered for 16 weeks to adult male and female patients with erythropoietic protoporphyria and X-linked porphyria in a randomized, double-blind clinical trial. Symptoms caused by exposure to light, including not only direct sunlight but also indirect sunlight, appear within one hour after sunrise. The time to first onset was assessed between 1 and 1 hour before sunset. The median baseline erythrocyte protoporphyrin IX level was determined by fractionating erythrocytes in the blood and measuring the protoporphyrin IX level. The median melanin density was determined by measuring the skin using a spectrophotometer at six locations: the forehead, left cheek, right inner upper arm, left inner forearm, right side of the abdomen, and left side of the buttocks.

[0041] The evaluation results at 16 weeks for 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 are shown in Table 1. In the 00mg and 300mg groups, significant extensions of time were observed, by 53.8 minutes and 62.5 minutes, respectively, compared to placebo.

[0042] [Table 1]

[0043] The above items were compared with a baseline median erythrocyte protoporphyrin IX level of 1980.50 mcg / dL. In the above patient group, the least squares mean time (minutes) to the first symptom onset in a day after administration of 100 mg of Compound A was 69.3 minutes (P value 0.020), and after administration of 300 mg The least squares mean time to first symptom onset in one day was 82.6 minutes (P = 0.003), both of which were statistically significant. Even in patients with a baseline median erythrocyte protoporphyrin IX level of 1980.50 mcg / dL or less, the mean time to first symptom onset in one day was 1.5 minutes (P = 0.003). There was a tendency for the time to onset of symptoms to be prolonged. Furthermore, when the above items were analyzed by dividing the patients into those with a median melanin density of 3.0915 or more and those with a median melanin density of less than 3.0915, the first symptoms appeared within one day of administration of 100 mg in the former group. The least squares mean time (minutes) to first trigeminal release was 85.0 minutes (P < 0.001) for the 300 mg dose and 80.3 minutes (P 0.002) for the 100 mg dose, whereas the latter was significantly shorter than the 100 mg dose. The least squares mean time to symptom onset (minutes) was 23.2 minutes (P value 0.499), and In the study, the time to onset of phototoxicity-related symptoms was 63.7 minutes (P value 0.051) at 300 mg. The effect was found to be greater.

[0044] Example 2 Erythroblasts in the subgroups that first took Compound A in spring / summer and in autumn / winter Time to onset of phototoxicity-related symptoms in patients with idiopathic protoporphyria and X-linked porphyria (primary clinical endpoint) The following study was conducted in the Northern Hemisphere. The subgroup ( 20 patients received placebo, 18 patients received 100 mg of compound A orally once daily, and 18 patients received 300 mg of compound A orally once daily), and a subgroup (placebo) who first took compound A in the fall and winter. 15 patients took Sebo, 15 patients took 100 mg of compound A orally once a day, and 15 patients took 300 mg of compound A orally once a day. The evaluation results at 16 weeks of oral administration of Compound A once daily (16 subjects) are shown in Table 2. In the spring / summer subgroup, the 100 mg and 300 mg groups of Compound A showed a significant improvement compared to placebo administration. In the autumn / winter subgroup, the time was extended by 54.4 minutes and 42.2 minutes, respectively, and in the 100 mg and 300 mg groups of Compound A compared to placebo, the time was extended by 52. The time was significantly prolonged at 100 mg of Compound A, 95.8 minutes and 95.8 minutes, respectively, regardless of the season. The time extension was observed in both the 300 mg and 300 mg groups.

[0045] [Table 2]

[0046] Example 3 Compound A for patients with erythropoietic protoporphyria and X-linked porphyria Number of pain events recorded by patients in electronic diaries during a 16-week evaluation period in a clinical trial Compound A was administered for 16 weeks to adult male and female patients with erythropoietic protoporphyria and X-linked porphyria in a randomized, double-blind clinical trial. The outcome measure was the number of pain events recorded by the patients themselves in an electronic diary during the 16-week evaluation period.

[0047] 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 incidence rates during the evaluation period were 7.5, 3.3, and 3.5 in the placebo group, the compound A 100 mg group, and the compound A 300 mg group, respectively. The 100 mg and 300 mg dose groups showed a significant reduction in pain events of 60% and 50%, respectively (Table 3).

[0048] [Table 3]

[0049] Example 4 Compound A for patients with erythropoietic protoporphyria and X-linked porphyria Assessment of health-related quality of life for patients in clinical trials Compound A was administered for 16 weeks to adult male and female patients with erythropoietic protoporphyria and X-linked porphyria in a randomized, double-blind clinical trial. As a first step, the PGIC (Patient Global Impression of Change) score, which is a measure of the patient's health-related quality of life, was recorded by the patient at 16 weeks. Specifically, a questionnaire was created to assess the overall improvement in physical and mental health on a 7-point scale. In this example, a PGIC score of 1 indicates no change or worsening, and a score of 7 indicates significant improvement.

[0050] The evaluation results for 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 16 weeks were 2.9, 6.4, and 6.6 in the placebo group, the compound A 100 mg group, and the compound A 300 mg group, respectively. Compared to the placebo group, the compound A 100 mg and 300 mg groups had significantly increased PGIC scores, and the subjects' Improvement in the general impression was demonstrated (Table 4).

[0051] [Table 4]

[0052] Example 5 Phase 3 study using Compound A as the test substance subject Male and female patients with erythropoietic protoporphyria and X-linked porphyria aged 12 to 75 years Test Overview Randomized double-blind clinical trial 53 patients received placebo, 53 patients received 100 mg of compound A orally once daily, and 53 patients received 200 mg of compound A orally once daily. Test items (1) Time to onset of phototoxicity-related symptoms in clinical trials of Compound A in patients with erythropoietic protoporphyria and X-linked porphyria Compound A was administered to subjects in a randomized, double-blind clinical trial for 26 weeks with optional follow-up. The study will be administered for 26 weeks at a time, up to a maximum of 58 weeks. The primary endpoint of clinical efficacy will be the time to the first daily occurrence of symptoms due to light exposure, evaluated at 26 weeks. (2) The number of pain events recorded by patients in their electronic diaries during the 26-week evaluation period in clinical trials of Compound A in patients with erythropoietic protoporphyria and X-linked porphyria. Compound A was administered to subjects in a randomized, double-blind clinical trial for 26 weeks with optional follow-up. The treatment will be administered for an additional 26 weeks, up to a maximum of 58 weeks. Other clinical efficacy evaluation measures will include the number of pain events recorded by patients themselves in an electronic diary during the 26-week evaluation period. (3) Evaluation of patients' health-related quality of life in clinical trials of Compound A in patients with erythropoietic protoporphyria and X-linked porphyria Compound A was administered to subjects in a randomized, double-blind clinical trial for 26 weeks with optional follow-up. The treatment will be administered for 26 weeks at a time, up to a maximum of 58 weeks. The secondary endpoint of clinical efficacy will be the Patient Global Impression (PGIC), which measures the patient's health-related quality of life at 26 weeks. The PGIC score is recorded by the patient. Specifically, a questionnaire is created to assess the overall improvement in physical and mental health on a 7-point scale. In this example, a PGIC score of 1 indicates significant improvement, and a score of 7 indicates significant deterioration.

Claims

1. A pharmaceutical for treating or preventing porphyria, comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient, wherein the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof is 50 to 500 mg / day.

2. The medicine according to claim 1, wherein the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof is 100 to 300 mg / day.

3. The medicament according to any one of claims 1 and 2, wherein the dosage of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof is 100 mg / day, 200 mg / day, or 300 mg / day.

4. Porphyrias include erythropoietic protoporphyria, X-linked porphyria, and congenital osteoporosis. The pharmaceutical agent according to any one of claims 1 to 3, which is medullogeneic porphyria, variegate porphyria, acute intermittent porphyria, porphyria cutanea tarda, or hereditary coporphyria.

5. The pharmaceutical composition according to claim 4, wherein the porphyria is erythropoietic protoporphyria or X-linked porphyria.

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