AU2024203992B2

AU2024203992B2 - Prophylactic or therapeutic agent for porphyria

Info

Publication number: AU2024203992B2
Application number: AU2024203992A
Authority: AU
Inventors: Kazumi HYOUDOU; Masahiro Kondo; Akihito Ogasawara; Tsuyoshi Suzuki; Fumihiro Takahashi
Original assignee: Mitsubishi Tanabe Pharma Corp
Current assignee: Tanabe Pharma Corp
Priority date: 2020-06-10
Filing date: 2024-06-12
Publication date: 2026-03-19
Anticipated expiration: 2041-06-10
Also published as: JPWO2021251450A1; US20230248713A1; AU2024203992A1; MY210457A; MX2022015804A; KR102952931B1; PH12022553388A1; IL298952A; EP4166140A4; BR112022025099A2; CA3186880A1; EP4166140A1; JP6959478B1; CN115942934A; AU2021289913A1; AU2021289913B2; EP4585214A1; KR20230016006A

Abstract

A medicine for treating or preventing porphyria, which contains, as an active ingredient, 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 medicine for treating or preventing porphyria, the 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 to be administered is 50 to 500 mg/day.

Description

PROPHYLACTICORORTHERAPEUTIC PROPHYLACTIC THERAPEUTIC AGENT AGENT FORFOR PORPHYRIA PORPHYRIA BACKGROUNDOFOFTHE BACKGROUND THEINVENTION INVENTION

Cross-ReferencetotoRelated Cross-Reference RelatedApplications Applications

5 5 [0001]

[0001] 2024203992

This application is a divisional of Australian Patent Application No. This application is a divisional of Australian Patent Application No.

2021289913,filed 2021289913, filedonon2222December December 2022, 2022, and and is related is related to to InternationalPatent International Patent

Application No. Application No.PCT/JP2021/022036, PCT/JP2021/022036, filed filed on June on 10 10 June 2021, 2021, and and claims claims priority priority to to

Japan Provisional Japan Provisional Patent Patent Application ApplicationNo. No.2020-100952, 2020-100952, filedonon2020 filed June June 2020, 2020, andand

10 10 Japan Provisional Japan Provisional Patent Patent Application ApplicationNo. No.2020-134451, 2020-134451, filedonon7 7August filed August 2020; 2020; each each

of which are incorporated herein by reference in their entirety. of which are incorporated herein by reference in their entirety.

Field of the Invention Field of the Invention

[0001a]

Thepresent The present invention invention relates relates to to aapharmaceutical pharmaceutical composition for treatment composition for treatment

15 15 or prevention or of porphyria, prevention of porphyria, comprising comprising aa compound compound having having melanocortin melanocortin receptor receptor

(MCR) agonistic activity (agonist activity). (MCR) agonistic activity (agonist activity).

Description of Description of the the Related Related Art Art

[0002]

Among Among thethe lightradiated light radiatedfrom fromthe thesun, sun,the the rays rays having havingwavelengths wavelengthsofofnot not

20 20 morethan more than300 300nmnm areabsorbed are absorbed in in theozone the ozone layerininthe layer thestratosphere. stratosphere. Thus, Thus, thethe

sunlight that sunlight that reaches reaches the theground ground is iscomposed of ultraviolet composed of ultraviolet light lighthaving havingwavelengths wavelengths

of not less than 300 nm, visible light, and infrared light. Physiological reactions of not less than 300 nm, visible light, and infrared light. Physiological reactions

caused by exposure to the sunlight include solar dermatitis (sunburn), and skin caused by exposure to the sunlight include solar dermatitis (sunburn), and skin

changes(wrinkling, changes (wrinkling, sagging, sagging,and anddevelopment developmentof of pigmented pigmented spots) spots) called called photoaging photoaging

25 25 that occur that occur due due to to long-term long-term exposure. exposure. OnOn thethe other other hand, hand, there there arediseases are diseasescalled called

photodermatoses,ininwhich photodermatoses, whichpathological pathologicalchanges changes such such as as dermatitisoccur dermatitis occur due due to to light light

irradiation even when the light irradiation is at a level at which healthy individuals irradiation even when the light irradiation is at a level at which healthy individuals

1a 1a 12 Jun 2024

do not do not respond. respond. Oneknown One known example example of photodermatoses of photodermatoses is porphyria. is porphyria.

[0003]

Porphyriais Porphyria is aa disease disease that thatdevelops develops due due to to accumulation of porphyrins accumulation of or porphyrins or

precursors thereof precursors thereof as as aa result resultofofdecreased decreasedactivity activityof of heme hememetabolic metabolicenzyme. enzyme.

5 5 Porphyriamay Porphyria mayexhibit exhibitsymptoms symptoms such such as photosensitivity as photosensitivity (sunburn, (sunburn, burn-like burn-like 2024203992

symptoms),and symptoms), andalso alsogastrointestinal gastrointestinal symptoms symptoms and and neurological neurological symptoms. symptoms. Once Once

porphyria develops, porphyria develops,its its symptoms oftencontinue symptoms often continuethroughout throughout life.Since life. Since there there is is nono

curative treatment therefor, symptomatic treatment such as light shielding is carried curative treatment therefor, symptomatic treatment such as light shielding is carried

2 12 Jun 2024

out as out as the the main main therapeutic therapeutic method. method.

[0004]

For example, For example,Patent PatentDocument Document 1 discloses 1 discloses useuse of of MCR MCR agonist agonist peptides peptides suchsuch

as afamelanotide as for the afamelanotide for the purpose of treatment purpose of of photodermatoses treatment of such as photodermatoses such as

5 5 erythropoietic protoporphyria. erythropoietic However, protoporphyria. However, since since afamelanotide afamelanotide is not is not an an MC1R- MC1R- 2024203992

selective agonist, there is a concern of the occurrence of side effects. Moreover, selective agonist, there is a concern of the occurrence of side effects. Moreover,

since afamelanotide is a peptide, it cannot be orally administered, and its half-life is since afamelanotide is a peptide, it cannot be orally administered, and its half-life is

short. Thus, short. Thus,there thereisis aa problem problemthat that periodic periodic subcutaneous subcutaneousimplanting implantingbybya amedical medical

professional is required. professional is required.

10 10 [0005]

[0005]

Onthe On the other other hand, hand, Patent Patent Document Document 2 disclosesthat 2 discloses thatpyrrolidine pyrrolidinecompounds compounds

such as such as 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- -{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

(trifluoromethyl)phenyl}piperidine-4-carboxylic acid,and (trifluoromethyl)phenyl}piperidine-4-carboxylicacid, andpharmaceutically pharmaceutically

15 15 acceptable salts, solvates, hydrates, cocrystals, and the like thereof have excellent acceptable salts, solvates, hydrates, cocrystals, and the like thereof have excellent

MCR-,especially MCR-, especiallyMCIR-, MC1R-, activating activating action. action. Patent Patent Document Document 2 discloses 2 discloses that that the the

compounds compounds areare usefulfor useful forprevention preventionorortreatment treatmentofofdiseases diseasesor or symptoms symptoms associated associated

with activation with activation of of MCR, especiallyMCIR, MCR, especially MC1R,andand that that such such diseases diseases include include

protoporphyria. However, protoporphyria. However, the the document document does does not specifically not specifically describe describe their their doses. doses.

20 20 Patent Document Patent Document 3 3 disclosesa acocrystal discloses cocrystalofof1-{2-[(3S,4R)-1-{[(3R,4R)-1- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-

cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4- cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-

(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic (methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxyl

acid. However, acid. However,thethe document document doesdoes not specifically not specifically describe describe thethe dose dose of of thethe

cocrystal of cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

25 25 methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

(trifluoromethyl)phenyl}piperidine-4-carboxylic acidfor (trifluoromethyl)phenyl}piperidine-4-carboxylic acid for use use in in treatment treatment of of

porphyria. porphyria.

[0005a]

Reference to any prior art in the specification is not an acknowledgement or

suggestion that this prior art forms part of the common general knowledge in any

jurisdiction or that this prior art could reasonably be expected to be combined with any 2024203992

other piece of prior art by a skilled person in the art.

Prior Art Documents

[Patent Documents]

[0006]

[Patent Document 1] WO 2008025094

[Patent Document 2] WO 2015182723

[Patent Document 3] WO2020/138481

SUMMARY OF THE INVENTION

Problems to be solved by the invention

[0006a]

In a first aspect of the invention, there is provided a medicament when used

for treating or preventing porphyria, the medicament 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 a cocrystal thereof as an active

3a 20 Feb 2026

ingredient, wherein the dose of the 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 the pharmaceutically

acceptable salt or cocrystal thereof is 100 to 300 mg/day. 2024203992

[0006b]

In a second aspect of the invention, there is provided a method for treating or

preventing porphyria in a subject in need thereof, the method comprising administering

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 to the subject, wherein the dose of the 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 the pharmaceutically

acceptable salt or cocrystal thereof is 100 to 300 mg/day.

[0006c]

In a third aspect of the invention, there is provided a use of 1-{2-[(3S,4R)-1-

acid or a pharmaceutically acceptable salt or cocrystal thereof in the manufacture of a

medicament for treating or preventing porphyria, wherein the dose of the 1-{2-[(3S,4R)-

1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-

acid or the pharmaceutically acceptable salt or cocrystal thereof is 100 to 300 mg/day.

3b 20 Feb 2026

[0007]

Methods of curative treatment of porphyria are limited, and the main method

for avoiding development of symptoms or for alleviation of symptoms has been

prevention of exposure of the skin to sunlight. In particular, it is known that 2024203992

patients with photodermatoses induced by visible light tend to avoid going out in the

daytime, so that the quality of life (QOL) of the patients may be remarkably

deteriorated.

As described above, an analog of α-melanocyte-stimulating hormone (α-

MSH), which is a ligand of MCR, has been developed as a therapeutic agent for

photodermatoses and the like such as erythropoietic protoporphyria (Patent

Document 1). However, it is not an MC1R-selective agonist, and cannot be orally

administered since it is a peptide. Moreover, since it disappears quickly in the

human body, periodic implanting is required.

Therefore, a pharmaceutical composition for treatment or prevention of

porphyria, which pharmaceutical composition is safer and not burdensome for

patients, and which enables effective treatment, is demanded.

Means to solve the problems

[0008]

In order to solve the above problems, the present inventors intensively studied.

[Text continues on page 4]

4 12 Jun 2024

As aa result, As result, the thepresent presentinventors inventorsdiscovered discoveredaadose doseof of1-{2-[(3S,4R)-1-{[(3R,4R)-1- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-

(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic (methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxy

acid or a pharmaceutically acceptable salt or cocrystal thereof, which dose is acid or a pharmaceutically acceptable salt or cocrystal thereof, which dose is

5 5 especially effective in a human clinical trial and exerts an excellent therapeutic or especially effective in a human clinical trial and exerts an excellent therapeutic or 2024203992

prophylactic effect prophylactic effect on on porphyria porphyria including including erythropoietic erythropoietic protoporphyria (EPP)and protoporphyria (EPP) and

X-linkedporphyria. X-linked porphyria. In In particular,aadose particular, doseatat which whichaasignificant significant pharmacological pharmacological

effect can be produced relative to placebo not only in seasons with strong sunlight for effect can be produced relative to placebo not only in seasons with strong sunlight for

long time long time such such as as spring spring and summer and summer inin theNorthern the NorthernHemisphere, Hemisphere, but but also also in in

10 10 seasons with weak sunlight for short time such as fall and winter in the Northern seasons with weak sunlight for short time such as fall and winter in the Northern

Hemisphere, that is, a dose at which effective treatment or prevention of porphyria is Hemisphere, that is, a dose at which effective treatment or prevention of porphyria is

possible throughout possible the year, throughout the year, could could be be discovered. The discovered. The preceding preceding agent agent

afamelanotidehas afamelanotide hasbeen beenconfirmed confirmedtoto have have a a therapeuticeffect therapeutic effecton onsymptoms symptoms that that

occur after exposure to direct sunlight in a clinical trial. In contrast, at the dose in occur after exposure to direct sunlight in a clinical trial. In contrast, at the dose in

15 15 the present the present invention, invention, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- -{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4

(trifluoromethyl)phenyl}piperidine-4-carboxylic acidor (trifluoromethyl)phenyl}piperidine-4-carboxylic acid or aa pharmaceutically pharmaceutically

acceptable salt or cocrystal thereof was confirmed to exert a therapeutic effect not acceptable salt or cocrystal thereof was confirmed to exert a therapeutic effect not

only on only on symptoms symptoms caused caused by by exposure exposure to direct to direct sunlight,but sunlight, butalso alsoononsymptoms symptoms

20 20 caused by exposure to indirect sunlight that may occur even in the inside of a caused by exposure to indirect sunlight that may occur even in the inside of a

building or building or the the like. Thepresent like. The presentinvention inventionwas wascompleted completed based based on on such such findings. findings.

[0009]

Thepresent The present invention invention provides providesaa medicament medicamentforfor treatment treatment oror prevention prevention ofof

porphyria such porphyria suchas as erythropoietic erythropoietic protoporphyria or X-linked protoporphyria or X-linkedporphyria, porphyria,the the

25 25 medicament medicament comprising comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- -2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4

(trifluoromethyl)phenyl}piperidine-4-carboxylic acidororaa pharmaceutically (trifluoromethyl)phenyl}piperidine-4-carboxylic acid pharmaceutically

5 12 Jun 2024

acceptable salt or cocrystal thereof as an active ingredient, wherein the dose of the 1- acceptable salt or cocrystal thereof as an active ingredient, wherein the dose of the 1 -

{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3- {2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-

yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- yl]carbony1}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

(trifluoromethyl)phenyl}piperidine-4-carboxylicacid (trifluoromethyl)phenyl}piperidine-4-carboxylic acidororthe the pharmaceutically pharmaceutically

5 5 acceptable saltororcocrystal acceptable salt cocrystal thereof thereof is 50 is 50 to 500 to 500 mg/day, mg/day, preferably preferably 100 to 300 100 to 300 2024203992

mg/day. mg/day.

[0010]

Thepresent The present invention invention provides providesaa method methodofoftreatment treatmentororprevention preventionofof

porphyria such porphyria suchas as erythropoietic erythropoietic protoporphyria or X-linked protoporphyria or X-linkedporphyria, porphyria,the the method method

10 10 comprisingthe comprising thestep step of of administering an effective administering an effective amount of 1-{2-[(3S,4R)-1- amount of 1-{2-[(3S,4R)-1-

{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4- {[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4

(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic (methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic

acid or a pharmaceutically acceptable salt or cocrystal thereof to a subject in need of acid or a pharmaceutically acceptable salt or cocrystal thereof to a subject in need of

treatment or treatment or prevention, prevention, wherein the effective wherein the effective amount is 50 amount is to 500 50 to 500 mg/day, mg/day,

15 15 preferably 100 preferably to 300 100 to mg/day. 300 mg/day.

[0011]

Thepresent The present invention inventionprovides provides1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-

fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin- fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrroliding

3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acidor 3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or aa pharmaceutically pharmaceutically

20 20 acceptable salt or cocrystal thereof, for treatment or prevention of porphyria such as acceptable salt or cocrystal thereof, for treatment or prevention of porphyria such as

erythropoietic protoporphyria erythropoietic or X-linked protoporphyria or porphyria, wherein X-linked porphyria, whereinthe thedose doseofofthe the 1-{2- 1-{2-

[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3- (3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-

yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- 1]carbony1}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

25 25 acceptable salt or cocrystal thereof is 50 to 500 mg/day, preferably 100 to 300 acceptable salt or cocrystal thereof is 50 to 500 mg/day, preferably 100 to 300

mg/day. mg/day.

[0012]

6 12 Jun 2024

Thepresent The present invention inventionprovides providesuse useof of 1-{2-[(3S,4R)-1-{[(3R,4R)-1- 1-{2-[(3S,4R)-1-{[(3R,4R)-1- -

acid or a pharmaceutically acceptable salt or cocrystal thereof, in manufacture of aa acid or a pharmaceutically acceptable salt or cocrystal thereof, in manufacture of

5 5 medicament medicament fortreatment for treatmentororprevention preventionofofporphyria porphyriasuch suchasaserythropoietic erythropoietic 2024203992

protoporphyriaor protoporphyria or X-linked X-linkedporphyria, porphyria,wherein whereinthe thedose doseofofthe the1-{2-[(3S,4R)-1- 1-{2-[(3S,4R)-1-

{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4- {[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-

acid or the pharmaceutically acceptable salt or cocrystal thereof is 50 to 500 mg/day, acid or the pharmaceutically acceptable salt or cocrystal thereof is 50 to 500 mg/day,

10 10 preferably 100 preferably to 300 100 to mg/day. 300 mg/day.

[0013]

According to the present invention, treatment or prevention of porphyria is According to the present invention, treatment or prevention of porphyria is

possible in possible in any any environment either indoors environment either indoors or or outdoors outdoors throughout throughoutthe theyear. year. 1-{2- 1-{2-

[(3S,4R)-1-{[(3R,4R)-1-Cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-

15 15 yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

acceptable salt or cocrystal thereof can be orally administered, and exhibits excellent acceptable salt or cocrystal thereof can be orally administered, and exhibits excellent

kinetics in kinetics inthe thehuman body. Moreover, human body. Moreover, since since it it isisan anMC1R-selective MC1R-selective compound, compound, it it

causes less side effects, and enables safe and effective treatment or prevention of causes less side effects, and enables safe and effective treatment or prevention of

20 20 porphyria without porphyria withoutimposing imposinga aburden burdenonon thepatient. the patient.In In particular,ininporphyria particular, porphyriasuch such

as erythropoietic as erythropoietic protoporphyria protoporphyria or or X-linked porphyria, administration X-linked porphyria, administration of of 1-{2- 1-{2-

[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3- (3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3

25 25 acceptable salt or cocrystal thereof at a particular dose enables excellent therapeutic acceptable salt or cocrystal thereof at a particular dose enables excellent therapeutic

effects such as prolongation of the time to the occurrence of phototoxicity (in other effects such as prolongation of the time to the occurrence of phototoxicity (in other

words, time words, time to to occurrence occurrenceof of phototoxicity-related phototoxicity-related symptom symptom oror timetotoprodromal time prodromal

7 12 Jun 2024

symptoms),reduction symptoms), reductionofofpain painevents, events,and andimprovement improvementof of QOL, QOL, either either indoors indoors or or

outdoors throughout outdoors throughoutthe theyear. year.

DETAILED DESCRIPTION DETAILED DESCRIPTIONOF OF THE THE INVENTION INVENTION

[0014]

5 5 Thepresent The present invention inventionis is described below. described below. 2024203992

[0015]

The active ingredient of the medicament of the present invention, that is, 1- The active ingredient of the medicament of the present invention, that is, 1- -

10 10 yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

(trifluoromethyl)phenyl}piperidine-4-carboxylicacid (trifluoromethyl)phenyl}piperidine-4-carboxylic acidororaapharmaceutically pharmaceutically

acceptable salt or cocrystal thereof, is described in Patent Document 2, and can be acceptable salt or cocrystal thereof, is described in Patent Document 2, and can be

producedby, produced by,for for example, example,the the method methoddescribed describedininPatent PatentDocument Document2. A2.cocrystal A cocrystal

of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4

15 15 methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

(trifluoromethyl)phenyl}piperidine-4-carboxylic acidand trifluoromethyl)phenyl}piperidine-4-carboxylic acid andphosphoric phosphoricacid acidcan canbebe

obtained by obtained by aa conventional conventionalmethod methodor,or,for forexample, example,the themethod method described described in in Patent Patent

Document3. Document 3.

In this specification, the “dose of the 1-{2-[(3S,4R)-1-{[(3R,4R)-1- In this specification, the "dose of the 1-{2-[(3S,4R)-1-{[(3R,4R)-1-

20 20 cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4- cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-

acid or the pharmaceutically acceptable salt or cocrystal thereof” or the dose or acid or the pharmaceutically acceptable salt or cocrystal thereof" or the dose or

amountofof"Compound amount “Compound A” refers A" refers to the to the dose dose or or amount amount in terms in terms of the of the amount amount of-1- of 1-

{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3- 2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3

25 25 yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- 1]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

(trifluoromethyl)phenyl}piperidine-4-carboxylic acidas (trifluoromethyl)phenyl}piperidine-4-carboxylic acid as free free form. form.

[0016]

Since 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- Since e1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- hethoxyphenyl)pyrrolidin-3-yl]carbony1}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

(trifluoromethyl)phenyl}piperidine-4-carboxylic (trifluoromethyl)phenyl}piperidine-4-carboxylica acid acid or or aa pharmaceutically pharmaceutically

5 5 acceptable salt or cocrystal thereof has excellent MC1R agonist activity, it exerts acceptable salt or cocrystal thereof has excellent MC1R agonist activity, it exerts 2024203992

excellent therapeutic and prophylactic effects on porphyria, such as prolongation of excellent therapeutic and prophylactic effects on porphyria, such as prolongation of

the time to the occurrence of phototoxicity, reduction of pain events, and the time to the occurrence of phototoxicity, reduction of pain events, and

improvement improvement ofof QOL, QOL, in any in any environment environment throughout throughout the year. the year.

Further, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- Further, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

10 10 methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- mnethoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

acceptable salt or cocrystal thereof exerts an especially excellent effect on acceptable salt or cocrystal thereof exerts an especially excellent effect on

prolongation of the time to the occurrence of phototoxicity in a particular patient prolongation of the time to the occurrence of phototoxicity in a particular patient

group (patient group group (patient whosebaseline group whose baselinemedian medianofof theerythrocyte the erythrocyteprotoporphyrin protoporphyrinIX IX

15 15 level is not less than 1980.50 mcg/dL), thereby exerting excellent therapeutic and level is not less than 1980.50 mcg/dL), thereby exerting excellent therapeutic and

prophylactic effects prophylactic effects on on porphyria porphyria

Furthermore,{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4 Furthermore, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

20 20 acceptable saltororcocrystal acceptable salt cocrystal thereof thereof exerts exerts an excellent an excellent effecteffect on prolongation on prolongation of the of the

time to the occurrence of phototoxicity in a particular patient group (patient group time to the occurrence of phototoxicity in a particular patient group (patient group

whosemedian whose medianofof themelanin the melanin density density isisnot notless less than than 3.0915) 3.0915)independent independentofofthe thedose, dose,

and exerts an excellent effect on prolongation of the time to the occurrence of and exerts an excellent effect on prolongation of the time to the occurrence of

phototoxicity in a particular patient group (patient group whose median of the phototoxicity in a particular patient group (patient group whose median of the

25 25 melanin density is less than 3.0915) at a particular dose (preferably at a daily dose of melanin density is less than 3.0915) at a particular dose (preferably at a daily dose of

300 mg), 300 mg),thereby therebyexerting exertingexcellent excellent therapeutic therapeutic and and prophylactic prophylactic effects effects on on porphyria. porphyria.

Thus, aa medicament Thus, medicament containing containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-

9 12 Jun 2024

fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin- fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-

3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylicacid 3-y1]-5-(trifluoromethy1)phenyl}piperidine-4-carboxylic acidoror aa pharmaceutically pharmaceutically

acceptable salt or cocrystal thereof as an active ingredient is useful for treatment or acceptable salt or cocrystal thereof as an active ingredient is useful for treatment or

prevention of prevention of porphyria. porphyria.

5 5 [0017]

[0017] 2024203992

Examplesofofthe Examples theporphyria porphyriainclude includeerythropoietic erythropoieticprotoporphyria, protoporphyria,X-linked X-linked

porphyria, congenital erythropoietic porphyria, variegate porphyria, acute porphyria, congenital erythropoietic porphyria, variegate porphyria, acute

intermittent porphyria, intermittent porphyria, porphyria porphyria cutanea cutanea tarda, tarda, and and hereditary hereditary coproporphyria. coproporphyria.

Theerythropoietic The erythropoietic protoporphyria protoporphyriaherein hereinincludes includescongenital congenitalerythropoietic erythropoietic

10 10 protoporphyria. protoporphyria.

[0018]

Thetime The timeto to the the occurrence of phototoxicity occurrence of phototoxicity has has the the same meaningofofthe same meaning thetime time

to occurrence to of phototoxicity-related occurrence of phototoxicity-related symptom, orsimply symptom, or simplya asymptom. symptom.It It alsomeans also means

the time the time to to prodromal symptom. prodromal symptom. Examples Examples of phototoxicity-related of phototoxicity-related symptom, symptom,

15 15 symptom symptom oror prodromal prodromal symptom symptom include include burning, burning, tingling, tingling, itching itching and and stinging. stinging.

[0019]

Thee1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- The 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

(trifluoromethyl)phenyl}piperidine-4-carboxylic acidmay (trifluoromethyl)phenyl}piperidine-4-carboxylic acid maybebesubjected subjectedtotothe the

20 20 pharmaceutical use either in the free form, or in the form of a pharmaceutically pharmaceutical use either in the free form, or in the form of a pharmaceutically

acceptable salt or cocrystal thereof. acceptable salt or cocrystal thereof.

Here, the1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- Here, the 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

(trifluoromethyl)phenyl}piperidine-4-carboxylic acidororthe (trifluoromethyl)phenyl}piperidine-4-carboxylic acid the pharmaceutically pharmaceutically

25 25 acceptable salt or cocrystal thereof includes any of intramolecular salts and adducts, acceptable salt or cocrystal thereof includes any of intramolecular salts and adducts,

and solvates, hydrates, crystalline polymorphs, and the like thereof. and solvates, hydrates, crystalline polymorphs, and the like thereof.

Examplesofofthe Examples thepharmaceutically pharmaceuticallyacceptable acceptable salts,cocrystals, salts, cocrystals, intramolecular intramolecular

10 12 Jun 2024

salts, and adducts include those containing: an inorganic acid such as hydrochloric salts, and adducts include those containing: an inorganic acid such as hydrochloric

acid, sulfuric acid, phosphoric acid, or hydrobromic acid; or an organic acid such as acid, sulfuric acid, phosphoric acid, or hydrobromic acid; or an organic acid such as

acetic acid, fumaric acid, oxalic acid, citric acid, methanesulfonic acid, acetic acid, fumaric acid, oxalic acid, citric acid, methanesulfonic acid,

benzenesulfonicacid, benzenesulfonic acid, p-toluenesulfonic p-toluenesulfonic acid, acid, or or maleic maleic acid. Cocrystalswith acid. Cocrystals with

5 5 phosphoric acid are especially preferred. phosphoric acid are especially preferred. 2024203992

[0020]

Oneof, One of, or or two or more two or of, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3- more of, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-

3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid, 3-y1]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylica acid, and and pharmaceutically pharmaceutically

10 10 acceptable salts and cocrystals thereof may be administered as they are to the patient. acceptable salts and cocrystals thereof may be administered as they are to the patient.

Preferably, however, Preferably, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- however, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

(trifluoromethyl)phenyl}piperidine-4-carboxylic acidororaapharmaceutically trifluoromethyl)phenyl}piperidine-4-carboxylic acid pharmaceutically

acceptable salt acceptable salt or orcocrystal cocrystalthereof thereofmay may be be mixed with aa pharmacologically mixed with and pharmacologically and

15 15 pharmaceuticallyacceptable pharmaceutically acceptableadditive(s) additive(s) to to be be provided as aa formulation provided as in aa form formulation in form

well known to those skilled in the art. well known to those skilled in the art.

[0021]

Examplesofofthe Examples thepharmacologically pharmacologically and and pharmaceutically pharmaceutically acceptable acceptable

additive(s) include appropriate excipients, disintegrants, binders, lubricants, coating additive(s) include appropriate excipients, disintegrants, binders, lubricants, coating

20 20 agents, colorants, diluents, bases, and isotonic agents usually used in the production agents, colorants, diluents, bases, and isotonic agents usually used in the production

of pharmaceuticals. of Examples pharmaceuticals. Examples of the of the excipients excipients include include glucose, glucose, lactose,D-D- lactose,

mannitol, starch, mannitol, starch, and and crystalline crystallinecellulose. cellulose. Examples Examples ofofthe thedisintegrants disintegrants include include

carboxymethylcellulose, carboxymethyl cellulose,starch, starch, and and calcium calciumcarboxymethyl carboxymethyl cellulose.Examples cellulose. Examples

of the of the binders binders include include hydroxypropyl cellulose, hydroxypropyl hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose,

25 25 polyvinyl pyrrolidone, polyvinyl pyrrolidone, and and gelatin. gelatin. Examples Examplesof of thethe lubricantsinclude lubricants includemagnesium magnesium

stearate and stearate and talc. Examplesofofthe talc. Examples thecoating coatingagents agentsinclude includehydroxypropyl hydroxypropyl

methylcellulose, sucrose, methylcellulose, sucrose, polyethylene glycol, and polyethylene glycol, titanium oxide. and titanium oxide. Examples Examples of the of the

11 12 Jun 2024

bases include vaseline, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, bases include vaseline, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin,

purified water, and hard fat. In addition, for formulations suitable for injection or purified water, and hard fat. In addition, for formulations suitable for injection or

infusion, the infusion, the following following may be used may be usedas as formulation formulationadditives: additives: solvents solvents and and

solubilizers that may constitute aqueous injection solutions, or may constitute solubilizers that may constitute aqueous injection solutions, or may constitute

5 5 injection solutions to be prepared before use, such as distilled water for injection, injection solutions to be prepared before use, such as distilled water for injection, 2024203992

physiological saline, physiological saline, and and propylene glycol; isotonic propylene glycol; isotonic agents agents such such as as glucose, glucose,sodium sodium

chloride, D-mannitol, and glycerin; pH regulators such as inorganic acids, organic chloride, D-mannitol, and glycerin; pH regulators such as inorganic acids, organic

acids, inorganic bases, and organic bases; and the like. acids, inorganic bases, and organic bases; and the like.

[0022]

10 10 The1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- The 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

acceptable salt or cocrystal thereof, together with the above-described additives, may acceptable salt or cocrystal thereof, together with the above-described additives, may

be prepared be prepared into into an an appropriate appropriate dosage form(such dosage form (suchasasaa powder, powder,ananinjection injection solution, solution,

15 15 a tablet, a capsule, or a topical preparation), and may then be administered to a a tablet, a capsule, or a topical preparation), and may then be administered to a

patient (human patient or animal) (human or animal)using usingananappropriate appropriateadministration administrationmethod methodinin accordance accordance

with the dosage form (such as intravenous administration, oral administration, with the dosage form (such as intravenous administration, oral administration,

percutaneousadministration, percutaneous administration,or or topical topical administration). Among administration). Among these, oral these, oral

administration is preferred. administration is preferred.

20 20 [0023]

[0023]

Thedose The doseofof the the medicament medicament comprising comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-

(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic (methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxy)

acid or a pharmaceutically acceptable salt or cocrystal thereof is an amount at which acid or a pharmaceutically acceptable salt or cocrystal thereof is an amount at which

25 25 the medicament the canbebesafely medicament can safelyused usedwith withlow low toxicityand toxicity andatatwhich whicha atherapeutic therapeuticeffect effect

or prophylactic effect can be exerted on porphyria either indoors or outdoors or prophylactic effect can be exerted on porphyria either indoors or outdoors

throughoutthe throughout the year. year. The The dose dose in in terms terms of of theamount the amountof of 1-{2-[(3S,4R)-1- 1-{2-[(3S,4R)-1 -

12 12 Jun 2024

morepreferably more preferably80 80toto 400 400mg/day, mg/day,especially especiallypreferably preferably100 100toto300 300mg/day. mg/day.

5 5 Examplesofofthe Examples thedose doseinclude include100 100mg/day, mg/day, 150 150 mg/day, mg/day, 200200 mg/day, mg/day, 250 250 mg/day, mg/day, 2024203992

300 mg/day, 300 mg/day,and anddoses dosesbetween between these. these.

[0024]

Oral administration Oral administration is is especially especially preferred. Thedose preferred. The doseofofthe the medicament medicament

comprising1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

10 10 methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or (trifluoromethyl)phenyl}piperidine-4-carboxylic acid or aa pharmaceutically pharmaceutically

acceptable saltororcocrystal acceptable salt cocrystal thereof thereof for for oraloral administration, administration, in terms in terms of the of the amount amount of of

1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-

3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- 3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-y1]-5-

15 15 (trifluoromethyl)phenyl}piperidine-4-carboxylic acid or (trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the the pharmaceutically pharmaceutically

acceptable saltororcocrystal acceptable salt cocrystal thereof thereof is 50 is 50 to 500 to 500 mg/day, mg/day, preferably preferably 80mg/day, 80 to 400 to 400 mg/day,

morepreferably more preferably100 100toto300 300mg/day, mg/day,more more specifically,100 specifically, 100mg/day, mg/day, 150 150 mg/day, mg/day, 200200

mg/day,250 mg/day, 250mg/day, mg/day,300 300 mg/day, mg/day, or or a dose a dose between between these. these. The medicament The medicament is is

especially preferably especially preferably administered at aa dose administered at dose of of 100 100 mg/day, 200 mg/day, mg/day, 200 mg/day,oror300 300

20 20 mg/day. mg/day.

[0025]

Still more preferably, a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1- Still more preferably, a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1- -

cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4- cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4

25 25 acid and acid phosphoricacid and phosphoric acidis is administered at aa dose administered at dose of of 100 100 mg/day or300 mg/day or 300mg/day mg/dayin in

terms of terms of the the amount of -{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- 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- methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5

13 12 Jun 2024

(trifluoromethyl)phenyl}piperidine-4-carboxylic acid. (trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

Otherwise, preferably, aa cocrystal Otherwise, preferably, cocrystal of of1-{2-[(3S,4R)-1-{[(3R,4R)-1- 1-{2-(3S,4R)-1-{[(3R,4R)-1-

5 5 acid and acid phosphoricacid and phosphoric acid is is administered at aa dose administered at dose of of 100 100 mg/day or200 mg/day or 200mg/day mg/dayin in 2024203992

terms of terms of the the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- 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- methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-:

[0026]

10 10 In another In another mode, mode, aa cocrystal cocrystal of of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-

fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin- fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin

3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and B-y1]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric phosphoricacid acidisis

administeredat administered at aa dose dose of of 100 mg/dayininterms 100 mg/day termsofofthe the amount amountofof1-{2-[(3S,4R)-1- 1-{2-[(3S,4R)-1-

15 15 (methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic (methoxymethyl)pyrrolidin-3-y1]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic

acid. acid.

[0027]

In another In another mode, mode, aa cocrystal cocrystal of of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-

20 20 3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and 3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid andphosphoric phosphoricacid acidisis

administeredat administered at aa dose dose of of 200 mg/dayininterms 200 mg/day termsofofthe the amount amountofof1-{2-[(3S,4R)-1- 1-{2-[(3S,4R)-1-

{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4- {[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbony1}-4

(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic (methoxymethyl)pyrrolidin-3-y1]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic

acid. acid.

25 25 [0028]

[0028]

fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin- luoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-

14 12 Jun 2024

3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic 3-y1]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid acid and and phosphoric phosphoric acid acid is is

administeredat administered at aa dose dose of of 300 mg/dayininterms 300 mg/day termsofofthe the amount amountofof1-{2-[(3S,4R)-1- 1-{2-[(3S,4R)-1-

{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4- (3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-

5 5 acid. acid. 2024203992

[0029]

As described As describedin in the the Examples below,ititwas Examples below, wasshown shown that,atataa daily that, daily dose dose of of 100 100

mgoror300 mg 300mg, mg,-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

10 10 (trifluoromethyl)phenyl}piperidine-4-carboxylic acidororaa pharmaceutically (trifluoromethyl)phenyl}piperidine-4-carboxylic acid pharmaceutically

acceptable salt or cocrystal thereof exerts therapeutic effects such as prolongation of acceptable salt or cocrystal thereof exerts therapeutic effects such as prolongation of

improvement improvement ofof QOL QOL relative relative to to placebo placebo in in patientswith patients witherythropoietic erythropoietic

protoporphyriaand protoporphyria andpatients patients with with X-linked X-linkedporphyria. porphyria.In In particular,ininaa patient particular, patient

15 15 group whosebaseline group whose baselinemedian medianof of theerythrocyte the erythrocyteprotoporphyrin protoporphyrin IX IX level level waswas notnot less less

than 1980.50 mcg/dL, a statistically significant effect on prolongation of the time to than 1980.50 mcg/dL, a statistically significant effect on prolongation of the time to

the occurrence of phototoxicity relative to placebo was found at a daily dose of either the occurrence of phototoxicity relative to placebo was found at a daily dose of either

100 mgoror300 100 mg 300mg. mg.According According to comparison to comparison between between a patient a patient group group whose whose

medianofofthe median the melanin melanindensity densitywas wasnot notless lessthan than3.0915 3.0915and anda apatient patient group groupwhose whose

20 20 medianofofthe median the melanin melanindensity densitywas wasless lessthan than3.0915, 3.0915,the theformer formergroup groupshowed showed similar similar

levels of prolongation of the time to the occurrence of phototoxicity at daily doses of levels of prolongation of the time to the occurrence of phototoxicity at daily doses of

both 100 mg and 300 mg, but, in the latter group, the patient group with a daily dose both 100 mg and 300 mg, but, in the latter group, the patient group with a daily dose

of 300 of mgshowed 300 mg showed betterprolongation better prolongation ofof thetime the timetotothe theoccurrence occurrenceofofphototoxicity. phototoxicity.

Also at Also at daily daily doses doses of of 100 100 mg and200 mg and 200mg, mg,a atest test which whichconfirms confirmsa a

25 25 therapeutic effect therapeutic effectof of1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

(trifluoromethyl)phenyl}piperidine-4-carboxylic acidoror aa pharmaceutically (trifluoromethyl)phenyl}piperidine-4-carboxylic acid pharmaceutically

15 12 Jun 2024

acceptable salt or cocrystal thereof on patients with erythropoietic protoporphyria acceptable salt or cocrystal thereof on patients with erythropoietic protoporphyria

and patients and patients with with X-linked porphyriais X-linked porphyria is conducted. conducted.

[0030]

AlthoughPatent Although PatentDocument Document 2 and 2 and Patent Patent Document Document 3 describe 3 describe erythropoietic erythropoietic

5 5 protoporphyria as a target disease, these documents do not specifically describe doses. protoporphyria as a target disease, these documents do not specifically describe doses. 2024203992

In the clinical trial shown in the present invention, it was found that administration at In the clinical trial shown in the present invention, it was found that administration at

a dose a dose including 100 mg/day including 100 mg/dayand and300300 mg/day, mg/day, forfor example, example, 50 50 to 500 to 500 mg/day, mg/day,

preferably 80 preferably to 400 80 to 400 mg/day, morepreferably mg/day, more preferably100 100toto300 300mg/day, mg/day, enables enables exertion exertion of of

excellent therapeutic effects on erythropoietic protoporphyria either indoors or excellent therapeutic effects on erythropoietic protoporphyria either indoors or

10 10 outdoors throughout the year, which therapeutic effects include prolongation of the outdoors throughout the year, which therapeutic effects include prolongation of the

time to time to the the occurrence occurrence of of phototoxicity, phototoxicity, reduction reduction of ofpain painevents, events,and andimprovement improvement

of QOL. of These QOL. These finding finding werewere not not described described or suggested or suggested in the in the above above documents documents at at

all. all.

[0031]

15 15 Thus, one Thus, onemode modeofofthe thepresent presentinvention inventionprovides providesa amedicament medicamentto to be be

administered to a patient with porphyria for treatment or prevention of porphyria, the administered to a patient with porphyria for treatment or prevention of porphyria, the

medicament medicament comprising comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

20 20 acceptable salt or cocrystal thereof as an active ingredient, wherein the dose of the 1-- acceptable salt or cocrystal thereof as an active ingredient, wherein the dose of the 1

{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3- 2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-

yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- y1]carbony1}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

acceptable salt or cocrystal thereof for the patient with porphyria is 50 to 500 mg/day, acceptable salt or cocrystal thereof for the patient with porphyria is 50 to 500 mg/day,

25 25 preferably 80 preferably to 400 80 to mg/day,more 400 mg/day, morepreferably preferably100 100toto300 300mg/day, mg/day, more more specifically, specifically,

100 mg/day,150 100 mg/day, 150mg/day, mg/day,200 200 mg/day, mg/day, 250250 mg/day, mg/day, 300 300 mg/day, mg/day, or a or a dose dose between between

these. these.

16 12 Jun 2024

[0032]

In another In another mode ofthe mode of the present present invention, invention, aa medicament medicament isisadministered administeredtotoaa

patient with erythropoietic protoporphyria or a patient with X-linked porphyria for patient with erythropoietic protoporphyria or a patient with X-linked porphyria for

treatment or treatment or prevention of erythropoietic prevention of erythropoietic protoporphyria or X-linked protoporphyria or porphyria, X-linked porphyria,

5 5 whereinthe wherein the medicament medicament comprises comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3- 2024203992

fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin- uoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-

3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or 3-y1]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or aa pharmaceutically pharmaceutically

acceptable saltororcocrystal acceptable salt cocrystal thereof thereof as active as an an active ingredient, ingredient, wherein wherein the dosethe of dose the 1 of - the 1-

{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3- {2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3- -

(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or (trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the the pharmaceutically pharmaceutically

acceptable salt or cocrystal thereof for the patient with erythropoietic protoporphyria acceptable salt or cocrystal thereof for the patient with erythropoietic protoporphyria

or the patient with X-linked porphyria is 50 to 500 mg/day, preferably 80 to 400 or the patient with X-linked porphyria is 50 to 500 mg/day, preferably 80 to 400

mg/day,more mg/day, morepreferably preferably100 100toto300 300mg/day, mg/day, more more specifically,100 specifically, 100 mg/day, mg/day, 150150

15 15 mg/day,200 mg/day, 200mg/day, mg/day,250 250 mg/day, mg/day, 300300 mg/day, mg/day, or aordose a dose between between these. these.

[0033]

prolongation of the time to the occurrence of phototoxicity and/or reduction of pain prolongation of the time to the occurrence of phototoxicity and/or reduction of pain

20 20 events, wherein events, the medicament wherein the medicament comprises comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-

(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic (methoxymethyl)pyrrolidin-3-y1]-5-(trifluoromethyl)phenyl}piperidine-4-carboxy

acid or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient, acid or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient,

whereinthe wherein the dose doseof of the the 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- -{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

(trifluoromethyl)phenyl}piperidine-4-carboxylic acidoror the (trifluoromethyl)phenyl}piperidine-4-carboxylic acid the pharmaceutically pharmaceutically

17 12 Jun 2024

or the or the patient patientwith withX-linked X-linked porphyria porphyria is is50 50 to to500 500 mg/day, mg/day, preferably preferably 80 80 to to 400 400

mg/day,200 mg/day, 200mg/day, mg/day,250 250 mg/day, mg/day, 300300 mg/day, mg/day, or aordose a dose between between these. these.

[0034]

5 5 In another In another mode ofthe mode of the present present invention, invention, aa medicament medicament isisadministered administeredtotoaa 2024203992

whereinaa patient wherein patient group is the group is the group group whose baselinemedian whose baseline medianofofthe theerythrocyte erythrocyte

protoporphyrinIXIXlevel protoporphyrin level is is not not less lessthan than1980.50 1980.50 mcg/dL, whereinthe mcg/dL, wherein themedicament medicament

10 10 comprises1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

15 15 yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- 1]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

or the or the patient patientwith withX-linked X-linked porphyria porphyria is is 50 50 to to500 500 mg/day, mg/day, preferably preferably 80 80 to to 400 400

20 20 mg/day,200 mg/day, 200mg/day, mg/day,250 250 mg/day, mg/day, 300300 mg/day, mg/day, or aordose a dose between between these. these.

[0035]

25 25 whereinaa patient wherein patient group is the group is the group group whose medianofofthe whose median themelanin melanindensity densityisisnot notless less

than 3.0915, than whereinthe 3.0915, wherein the medicament medicament comprises comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-

18 12 Jun 2024

(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic (methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxyli

whereinthe wherein the dose doseof of the the 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

5 5 (trifluoromethyl)phenyl}piperidine-4-carboxylic acidor (trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the the pharmaceutically pharmaceutically 2024203992

10 10 [0036]

[0036]

whereinaa patient wherein patient group is the group is the group group whose medianofofthe whose median themelanin melanindensity densityisisless less than than

15 15 3.0915, wherein 3.0915, whereinthe the medicament medicament comprises comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1- 1-{2-[(3S,4R)-1-{[(3R,4R)-1-

(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic (methoxymethyl)pyrrolidin-3-y1]-5-(trifluoromethyl)phenyl}piperidine-4-carboxyl

20 20 methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- methoxyphenyl)pyrrolidin-3-yl]carbony1}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

mg/day,more mg/day, morepreferably preferably100 100toto300 300mg/day, mg/day, more more preferably preferably 200200 to 300 to 300 mg/day, mg/day,

25 25 morespecifically, more specifically, 100 100 mg/day, 150mg/day, mg/day, 150 mg/day,200 200mg/day, mg/day, 250250 mg/day, mg/day, 300 300 mg/day, mg/day, or or

a dose a dose between these, more between these, morepreferably150 preferably150mg/day, mg/day, 200200 mg/day, mg/day, 250 250 mg/day, mg/day, 300 300

mg/day,or mg/day, or aa dose dose between betweenthese. these.

19 12 Jun 2024

EXAMPLES EXAMPLES

[0037]

Thepresent The present invention inventionis is described belowmore described below morespecifically specificallyby byshowing showing

Examples.However, Examples. However, the scope the scope of present of the the present invention invention is not is not limited limited to to the the

5 5 embodiments embodiments in in thefollowing the followingExamples. Examples. 2024203992

[0038]

Compound Compound A, A, which which was was usedused in the in the Examples, Examples, is the is the following following compound: compound:

cocrystal containing cocrystal containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- -{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5- methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-

10 10 (trifluoromethyl)phenyl}piperidine-4-carboxylic acidand (trifluoromethyl)phenyl}piperidine-4-carboxylicacid andphosphoric phosphoric acid. acid.

[0039]

The1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- The 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-

(trifluoromethyl)phenyl}piperidine-4-carboxylic acidwas (trifluoromethyl)phenyl}piperidine-4-carboxylicacid was produced produced by the by the method method

15 15 described in described in Patent Patent Document Document 2,2,and andthe thecocrystal cocrystalwith withphosphoric phosphoricacid acidwas was

producedbybythe produced thefollowing followingmethod. method.

More specifically, a solution of potassium carbonate (3.4 kg) in water (77.0 More specifically, a solution of potassium carbonate (3.4 kg) in water (77.0

L), and L), and water (19.3 L), water (19.3 L), were were sequentially sequentially added to aa suspension added to of 1-{2-[(3S,4R)-1- suspension of 1-{2-[(3S,4R)-1-

20 20 (methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic (methoxymethyl)pyrrolidin-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) at 20 to 30°C, acid 1/2 ethane-1,2-disulfonic acid (19.3 kg) in ethyl acetate (86.6 kg) at 20 to 30°C,

and the and the resulting resulting mixture mixture was stirred for was stirred for10 10minutes. Afterleaving minutes. After leavingthe themixture mixturetoto

stand, the stand, the aqueous layer was aqueous layer removed,and was removed, andthe theorganic organiclayer layerwas waswashed washed twice twice with with

water (96.3 water (96.3 L). L). After Afterconcentrating concentratingthe theorganic organiclayer layertoto35 35L, L, ethanol ethanol (75.9 (75.9 kg) kg) was was

25 25 addedthereto, added thereto, followed by concentrating followed by concentratingthe the resulting resulting mixture to 35 mixture to 35 L. The L. The

resulting concentrate was diluted with ethanol (30.3 kg), and the insoluble matter resulting concentrate was diluted with ethanol (30.31 kg), and the insoluble matter

wasfiltered was filtered off offand and washed with ethanol washed with ethanol (75.6kg) (75.6 kg).The The filtrate filtrate andand washings washings werewere

20 12 Jun 2024

combined,concentrated combined, concentratedtoto3535L,L,and andthen thendiluted dilutedwith withethanol ethanol(17.9 (17.9kg). kg). After After

sequential addition sequential addition of of 24% aqueoussodium 24% aqueous sodium hydroxide hydroxide solution solution (6.1 (6.1 kg)kg) andand water water

(15.6 kg) thereto at 20 to 30°C, the resulting mixture was stirred at 20 to 30°C for 5 (15.6kg) thereto at 20 to 30°C, the resulting mixture was stirred at 20 to 30°C for 5

hours. AtAt2020 hours. toto 40°C, 40°C, a a solutionofofphosphoric solution phosphoricacid acid(8.5 (8.5kg) kg)ininwater water(28.9 (28.9L), L), and and

5 5 water (115.5L), water (115.5 L),were weresequentially sequentiallyadded addedthereto. thereto.At At 30 30 to to 40°C, 40°C, compound compound A (0.48 (0.48 A 2024203992

kg) was kg) was added addedthereto theretoas as seed seed crystals. crystals. The Theresulting resultingmixture mixturewas was stirredfor stirred for19.5 19.5

hours, and hours, then cooled and then cooled to to 20°C. 20°C. TheThe solid solid waswas collected collected by by filtration, and filtration, andthen then

washedwith washed withwater water(96.3 (96.3L). L).TheThe solid solid waswas dried dried at not at not more more than than 50°C, 50°C, and and

pulverized to pulverized to obtain obtain compound compound A A (17.5 (17.5 kg). kg).

10 10 Thecompound The compound A obtained A obtained was was identified identified using using IR.IR.

[0040]

Example11 Example

Timetoto Occurrence Time OccurrenceofofPhototoxicity-Related Phototoxicity-Related Symptom Symptom in Clinical in Clinical Trial Trial of of

Compound Compound A for A for Patients Patients with with Erythropoietic Erythropoietic Protoporphyria Protoporphyria andand Patients Patients with with X- X-

15 15 LinkedPorphyria Linked Porphyria

Compound Compound A was A was administered administered to adult to adult malemale and and female female patients patients withwith

erythropoietic protoporphyria erythropoietic or X-linked protoporphyria or X-linkedporphyria porphyriafor for 16 16weeks weeksininaarandomized randomized

double-blind clinical trial. As a primary endpoint for the clinical effect, the time to double-blind clinical trial. As a primary endpoint for the clinical effect, the time to

the first symptom due to exposure to light, including indirect sunlight as well as the first symptom due to exposure to light, including indirect sunlight as well as

20 20 direct sunlight, during the period from 1 hour after sunrise to 1 hour before sunset direct sunlight, during the period from 1 hour after sunrise to 1 hour before sunset

wasevaluated. was evaluated.

Thebaseline The baseline median medianofofthe theerythrocyte erythrocyteprotoporphyrin protoporphyrinIXIXlevel levelwas was

determinedbybymeasuring determined measuring theprotoporphyrin the protoporphyrin IX IX level level in in thefraction the fractionofoferythrocytes erythrocytes

in blood. in blood.

25 25 Themedian The medianofofthe themelanin melanindensity densitywas was determined determined by by spectrophotometric spectrophotometric

measurement for the skin at the following six sites: the forehead, the left cheek, the measurement for the skin at the following six sites: the forehead, the left cheek, the

inner side of the right upper arm, the inner side of the left forearm, the right side of inner side of the right upper arm, the inner side of the left forearm, the right side of

21 12 Jun 2024

the abdomen, and the left side of the hip. the abdomen, and the left side of the hip.

[0041]

Table 11 shows Table showsthe theevaluation evaluationresults results at at week 16 obtained week 16 obtainedfor for 35 35 cases cases in in

whichplacebo which placebowas wasgiven, given,3333cases casesininwhich which100100 mg mg of compound of compound A wasAorally was orally takentaken

5 5 once daily, once daily, and and 34 34 cases cases in in which 300 mg which 300 mgofofcompound compound A was A was orally orally taken taken onceonce daily. daily. 2024203992

Thegroups The groupsininwhich which100 100mgmg or or 300300 mg mg of compound of compound A was A was administered administered showed showed

lengths of time of 53.8 minutes and 62.5 minutes, respectively, indicating significant lengths of time of 53.8 minutes and 62.5 minutes, respectively, indicating significant

prolongation of the length of time relative to the group in which placebo was prolongation of the length of time relative to the group in which placebo was

administered. administered.

10 10 [0042]

[0042]

[Table 1]

Compound A 100mg (N=33) vs Compound A 300mg (N=34) vs Item placebo (N=35) placebo (N=35)

Least squares mean of the 53. 8 62. 5 length of time (in minutes) before the first occurrence of a symptom in a day

P value 0. 008 0. 003

[0043]

Accordingtotoanalysis According analysis of of the the above item in above item in the the patient patient group group whose baseline whose baseline

15 15 medianofofthe median the erythrocyte erythrocyteprotoporphyrin protoporphyrinIXIXlevel levelwas wasnotnotless lessthan than1980.50 1980.50mcg/dL, mcg/dL,

when100 when 100mgmg of of compound compound A administered, A was was administered, the least the least squares squares meanmean oftime of the the time

(in minutes) (in minutes) to to the the first firstoccurrence occurrenceofof thethe symptom symptom in in aaday day was was 69.3 69.3 minutes (P minutes (P

value, 0.020), value, 0.020), and, and, when 300mg when 300 mgofofcompound compound A was A was administered, administered, the least the least squares squares

meanofofthe mean the time time (in (in minutes) to the minutes) to the first firstoccurrence occurrenceof ofthe thesymptom in aa day symptom in day was was

20 20 82.6 minutes 82.6 minutes(P (P value, value, 0.003). Thus,both 0.003). Thus, both casesshowed cases showed statisticalsignificance. statistical significance.

Also in Also in the the patient patient group group whose baseline median whose baseline medianofofthe theerythrocyte erythrocyteprotoporphyrin protoporphyrin

IX level was less than 1980.50 mcg/dL, the time to the first occurrence of the IX level was less than 1980.50 mcg/dL, the time to the first occurrence of the

symptom symptom inin a aday daytended tendedtotobebeprolonged. prolonged.

22 12 Jun 2024

In addition, analysis of the above item was carried out after dividing the In addition, analysis of the above item was carried out after dividing the

subjects into subjects into the thepatient patientgroup groupwhose whose median of the median of the melanin melanindensity densitywas wasnot notless less

than 3.0915 than 3.0915 and andthe the patient patient group whosemedian group whose medianof of themelanin the melanin density density waswas less less than than

3.0915. As As 3.0915. a result,ininthe a result, the former formergroup, group,when when100100 mg mg of the of the compound compound was was

5 5 administered, the least squares mean of the time (in minutes) to the first occurrence administered, the least squares mean of the time (in minutes) to the first occurrence 2024203992

of the of the symptom symptom ininaaday daywas was85.0 85.0minutes minutes(P(P value,< <0.001), value, 0.001),and, and,when when 300 300 mg mg of of

the compound the was compound was administered, administered, it it was was 80.3 80.3 minutes minutes (P (P value, value, 0.002).In the 0.002). In the latter latter

group, when group, when100 100mgmg of of thecompound the compound was was administered, administered, the least the least squares squares meanmean of of

the time (in minutes) to the first occurrence of the symptom in a day was 23.2 the time (in minutes) to the first occurrence of the symptom in a day was 23.2

10 10 minutes(P minutes (P value, value, 0.499), 0.499), and, and, when 300mgmgofofthe when 300 thecompound compoundwas was administered, administered, it it

was 63.7 minutes (P value, 0.051), indicating that the effect that prolongs the time to was 63.7 minutes (P value, 0.051), indicating that the effect that prolongs the time to

the occurrence the of the occurrence of the phototoxicity-related phototoxicity-related symptom symptom isis higher higherat at 300 mg. 300 mg.

[0044]

Example22 Example

15 15 Timetoto Occurrence Time OccurrenceofofPhototoxicity-Related Phototoxicity-Related Symptom Symptom (Clinical (Clinical Primary Primary Endpoint) Endpoint)

in Patients in Patients with with Erythropoietic Erythropoietic Protoporphyria and Patients Protoporphyria and Patients with with X-Linked Porphyria X-Linked Porphyria

Evaluatedfor Evaluated for Subgroup SubgroupininWhich Which InitialDosing Initial DosingofofCompound Compound A WasACarried Was Carried Out inOut in

Spring or Spring or Summer Summer andand Subgroup Subgroup in Which in Which Initial Initial Dosing Dosing of Compound of Compound A Was A Was

Carried Out Carried Out in in Fall Fall or or Winter Winter

20 20 Thetest The test in in Example Example 22was wasconducted conductedin in theNorthern the Northern Hemisphere. Hemisphere. Table Table 2 2

shows the evaluation results at week 16 obtained for a subgroup in which initial shows the evaluation results at week 16 obtained for a subgroup in which initial

dosing of dosing of compound compound A was A was carried carried outout in in springororsummer spring summer(20 (20 cases cases in in which which

placebo was placebo wasgiven, given,1818cases casesinin which which100 100mgmg of of compound compound A orally A was was orally takentaken once once

daily, and daily, and 18 18 cases cases in inwhich which 300 mgofofcompound 300 mg compound A was A was orally orally taken taken once once daily) daily) andand

25 25 a subgroup a in which subgroup in whichinitial initial dosing dosing of compound compound A A was was carried carried outininfall out fall or or winter winter

(15 cases (15 cases in in which placebowas which placebo wasgiven, given,1515cases casesinin which which100 100mgmg of of compound compound A wasA was

orally taken orally taken once once daily, daily,and and 16 16 cases cases in inwhich which 300 300 mg of compound mg of compound A was A was orally orally

23 12 Jun 2024

taken once taken once daily). daily). InInthe thespring-summer spring-summer subgroup, subgroup, the the groups groups in which in which 100 100 mg mg or or

300 mg 300 mgofofcompound compound A was A was administered administered showed showed lengths lengths of of of time time of 54.4 54.4 minutes minutes

and 42.2 minutes, respectively, indicating prolongation of the length of time relative and 42.2 minutes, respectively, indicating prolongation of the length of time relative

to the to the group group in in which placebo was which placebo wasadministered. administered.In the In the fall-wintersubgroup, fall-winter subgroup, the the

5 5 groups in groups in which which100 100mgmg oror 300 300 mgmg of of compound compound A wasAadministered was administered showedshowed lengths lengths 2024203992

of time of 52.8 minutes and 95.8 minutes, respectively, indicating significant of time of 52.8 minutes and 95.8 minutes, respectively, indicating significant

administered. Thus, administered. Thus, both both groups groups in in which which 100 100 mg300 mg or or 300 mg ofmg of compound compound A was A was

administered showed prolongation of the length of time irrespective of the season. administered showed prolongation of the length of time irrespective of the season.

10 10 [0045]

[0045]

[Table 2]

Subgroup in which initial dosing of compound A was carried out in spring or summer

Items Compound A 100mg (N=18) Compound A 300mg (N=18)

vs Placebo (N=20) vs Placebo (N=20)

Least squares mean of the 54.4 42. 2 length of time (in minutes) before the first occurrence

of a symptom in a day

P value 0. 073 0. 168

Subgroup in which initial dosing of compound A was carried out in fall or winter

Compound A 100mg (N=15) Compound A 300mg (N=16)

VS Placebo (N=15) VS Placebo (N=15)

Least squares mean of the 52. 8 95. 8 length of time (in minutes) before the first occurrence of a symptom in a day

P value 0. 029 <0. 001

[0046]

Example 33 Example

15 15 NumberofofPain Number PainEvents Events Recorded Recorded in Electronic in Electronic Diary Diary by Patients by Patients during during Evaluation Evaluation

Period of Period of 16 16 Weeks Weeks ininClinical Clinical Trial Trial of of Compound Compound A A forfor Patientswith Patients withErythropoietic Erythropoietic

Protoporphyriaand Protoporphyria andPatients Patientswith withX-Linked X-Linked Porphyria Porphyria

24 12 Jun 2024

double-blind clinical trial. As another endpoint for the clinical effect, the number of double-blind clinical trial. As another endpoint for the clinical effect, the number of

pain events pain events during during the the evaluation evaluation period period of of 16 16 weeks wasrecorded weeks was recordedininananelectronic electronic

5 5 diary by the patients themselves. diary by the patients themselves. 2024203992

[0047]

Table 33 shows Table showsthe theevaluation evaluationresults results obtained for 23 obtained for 23 cases cases in in which placebo which placebo

wasgiven, was given, 24 24 cases cases in in which 100mgmg which 100 ofof compound compound A was A was orally orally taken taken onceonce daily, daily,

and 24 and 24 cases cases in in which 300mgmgofofcompound which 300 compound A was A was orally orally taken taken onceonce daily. daily. The The

10 10 incidence rates of pain during the evaluation period in the placebo administration incidence rates of pain during the evaluation period in the placebo administration

group, the group, the 100-mg compound 100-mg compound A-administration A-administration group, group, and 300-mg and the the 300-mg compound compound A- A-

administration group administration groupwere were7.5, 7.5, 3.3, 3.3, and 3.5, respectively. and 3.5, Thus,the respectively. Thus, the 100-mg 100-mg

compound compound A-administration A-administration group group and and the the 300-mg 300-mg compound compound A-administration A-administration

group significantly group significantly showed reductionofofpain showed reduction pain events eventsby by60% 60% and and 50%, 50%, respectively, respectively,

15 15 relative to the placebo administration group (Table 3). relative to the placebo administration group (Table 3).

[0048]

[Table 3]

Item Placebo Compound A 100mg Compound A 300mg

N (number) 23 24 24 Incidence rate of pain 3.3 7.5 3.5 Ratio to placebo 0.4 0.5 P value - 0.027 0.028 -

[0049]

20 20 Example 44 Example

Evaluation of Evaluation of Health-Related Health-RelatedQOL QOLof of Patients Patients inin ClinicalTrial Clinical Trial of of Compound Compound A for A for

Patients with Patients with Erythropoietic Erythropoietic Protoporphyria andPatients Protoporphyria and Patients with with X-Linked X-LinkedPorphyria Porphyria

erythropoietic protoporphyria erythropoietic or X-linked protoporphyria or X-linked porphyria porphyriafor for 16 16weeks weeksininaarandomized randomized

25 12 Jun 2024

double-blind clinical double-blind clinical trial. trial. AsAs a secondary a secondary endpoint endpoint for thefor the clinical clinical effect,effect, the the PGIC PGIC

(Patient (Patient Global Global Impression of Change) Impression of Change)score, score,which whichisisaahealth-related health-related QOL, QOL,ofofeach each

patient at patient atweek week 16 16 was recordedbybythe was recorded thepatients patients themselves. themselves. More More specifically, specifically, each each

patient was patient was provided withaa questionnaire provided with questionnaire for for scoring scoring the the degree degree of of improvement improvement ofof

5 5 the overall physical and mental health conditions on a 7-point scale. the overall physical and mental health conditions on a 7-point scale. In this case,In this case, 2024203992

the score 1 of the PGIC score indicates that no change occurred or that exacerbation the score 1 of the PGIC score indicates that no change occurred or that exacerbation

occurred, and occurred, and wherein whereinthe thescore score 77 indicates indicates that that remarkable improvement remarkable improvement was was

achieved. achieved.

[0050]

10 10 Table 44 shows Table showsthe theevaluation evaluationresults results obtained for 30 obtained for 30 cases cases in in which which placebo placebo

wasgiven, was given, 25 25 cases cases in in which 100mgmg which 100 ofof compound compound A was A was orally orally taken taken onceonce daily, daily,

PGICscores PGIC scoresatatweek week1616ininthe theplacebo-administration placebo-administrationgroup, group,the the100-mg 100-mg compound compound

A-administrationgroup, A-administration group,and andthe the300-mg 300-mg compound compound A-administration A-administration groupgroup were were 2.9, 2.9,

15 15 6.4, and 6.4, and 6.6, 6.6,respectively. Thus, the respectively. Thus, the 100-mg 100-mgcompound compound A-administration A-administration groupgroup and and

the 300-mg the compound 300-mg compound A-administration A-administration group group showed showed significant significant increases increases in in the the

PGIC score relative to the placebo-administration group, indicating their global PGIC score relative to the placebo-administration group, indicating their global

impressionimprovement impression improvement (Table (Table 4).4).

[0051]

20 20 [Table 4]

[Table 4]

Item Placebo Compound A 100mg Compound A 300mg

N (number) 30 25 24

Least squares mean of the scores 2.9 6.4 6.6 P value <0.001 <0.001 -

[0052]

Example 55 Example Phase III Phase III Trial TrialUsing Using Compound A as Compound A as Test Test Substance Substance

Subjects: Male Subjects: andfemale Male and femalepatients patientswith witherythropoietic erythropoietic protoporphyria protoporphyriaororX-linked X-linked

25 25 porphyria, whose porphyria, whoseages agesrange rangefrom from1212 yearsoldoldtoto7575years years yearsold. old.

26 12 Jun 2024

Outline of Outline of Trial: Trial:Randomized Double-Blind Randomized Double-Blind Clinical Clinical Trial Trial

In 53 In 53 cases, cases, placebo placebo is is given. In 53 given. In 53cases, cases, 100 100 mg mgofofcompound compound A orally A is is orally

taken once taken once daily. daily. InIn5353cases, cases,200 200mgmg ofof compound compound A isAorally is orally taken taken once once daily. daily.

Test Items Test Items

5 5 (1) The (1) time to The time to the the occurrence occurrence of of aa phototoxicity-related phototoxicity-relatedsymptom in aa symptom in 2024203992

clinical trial of compound A for patients with erythropoietic protoporphyria and clinical trial of compound A for patients with erythropoietic protoporphyria and

patients with patients with X-linked porphyria X-linked porphyria

In aa randomized In double-blindclinical randomized double-blind clinical trial, trial, compound compound AAis is administered administeredtoto

the subjects for 26 weeks, and, depending on conditions, additional administration is the subjects for 26 weeks, and, depending on conditions, additional administration is

10 10 carried out carried out for for26 26 weeks or up weeks or up to to 58 58 weeks. weeks. AsAs a primary a primary endpoint endpoint forfor thethe clinical clinical

effect, the time to the first occurrence of a symptom due to exposure to light in a day effect, the time to the first occurrence of a symptom due to exposure to light in a day

is evaluated at week 26. is evaluated at week 26.

(2) The number of pain events recorded in an electronic diary by patients (2) The number of pain events recorded in an electronic diary by patients

during an evaluation period of 26 weeks in a clinical trial of compound A for patients during an evaluation period of 26 weeks in a clinical trial of compound A for patients

15 15 with erythropoietic with erythropoietic protoporphyria andpatients protoporphyria and patients with with X-linked X-linkedporphyria porphyria

carried out carried out for for26 26 weeks weeks or or up up to to 58 58 weeks. weeks. AsAs another another endpoint endpoint forfor thethe clinical clinical

effect, the number of pain events during the evaluation period of 26 weeks is effect, the number of pain events during the evaluation period of 26 weeks is

20 20 recorded in an electronic diary by the patients themselves. recorded in an electronic diary by the patients themselves.

(3) Evaluation of the health-related QOL of patients in a clinical trial of (3) Evaluation of the health-related QOL of patients in a clinical trial of

compound compound A for A for patientswith patients witherythropoietic erythropoieticprotoporphyria protoporphyriaand and patientswith patients withX-X-

linked porphyria linked porphyria

25 25 the subjects for 26 weeks, and, depending on conditions, additional administration is the subjects for 26 weeks, and, depending on conditions, additional administration is

carried out carried out for for26 26 weeks weeks or or up up to to 58 58 weeks. weeks. AsAs a secondary a secondary endpoint endpoint for for thethe

clinical effect, the PGIC (Patient Global Impression of Change) score, which is a clinical effect, the PGIC (Patient Global Impression of Change) score, which is a

27 12 Jun 2024

health-related QOL, health-related ofeach QOL, of eachpatient patient at at week 26is week 26 is recorded recorded by by the the patients patients themselves. themselves.

More specifically, each patient is provided with a questionnaire for scoring the More specifically, each patient is provided with a questionnaire for scoring the

degree of degree of improvement improvement ofof theoverall the overallphysical physicaland andmental mentalhealth healthconditions conditionsonona a7-7-

point scale. In this case, the lowest score of the PGIC score, 1 point, indicates point scale. In this case, the lowest score of the PGIC score, 1 point, indicates

5 5 “Very Much "Very Much Improved” Improved" and and wherein wherein the highest the highest score, score, 7 points, 7 points, indicates indicates “Very "Very 2024203992

MuchWorse". Much Worse”.

Claims

1. A medicament when used for treatment or prevention of porphyria, comprising

yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine- 2024203992

4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as an active

(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically

acceptable salt or cocrystal thereof is 100 to 300 mg/day.

2. The medicament according to claim 1, wherein the dose of the 1-{2-[(3S,4R)-

acid or the pharmaceutically acceptable salt or cocrystal thereof is 100 mg/day, 200

mg/day, or 300 mg/day.

3. The medicament according to claim 1 or claim 2, wherein the porphyria is

erythropoietic protoporphyria, X-linked porphyria, congenital erythropoietic porphyria,

variegate porphyria, acute intermittent porphyria, porphyria cutanea tarda, or hereditary

coproporphyria.

4. The medicament according to claim 3, wherein the porphyria is erythropoietic

protoporphyria or X-linked porphyria.

5. A method for treating or preventing porphyria in a subject in need thereof, the

method comprising administering 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-

(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-

{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 the pharmaceutically acceptable salt or cocrystal thereof is 100 to 2024203992

300 mg/day.

6. The method according to claim 5, wherein the dose of the 1-{2-[(3S,4R)-1-

mg/day, or 300 mg/day.

7. The method according to claim 5 or claim 6, wherein the porphyria is

coproporphyria.

8. The method according to claim 7, wherein the porphyria is erythropoietic

protoporphyria or X-linked porphyria.

9. 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-

salt or cocrystal thereof in the manufacture of a medicament for treating or preventing

porphyria, wherein the dose of the 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 the pharmaceutically

acceptable salt or cocrystal thereof is 100 to 300 mg/day.

10. The use according to claim 9, wherein the dose of the 1-{2-[(3S,4R)-1-

acid or the pharmaceutically acceptable salt or cocrystal thereof is 100 mg/day, 200 2024203992

mg/day, or 300 mg/day.

11. The use according to claim 9 or claim 10, wherein the porphyria is

coproporphyria.

12. The use according to claim 11, wherein the porphyria is erythropoietic

protoporphyria or X-linked porphyria.