EA043027B1 - METHOD FOR TREATMENT OF PULMONARY ARTERIAL HYPERTENSION - Google Patents

Description

Methods useful for the treatment of pulmonary arterial hypertension (PAH) are provided; idiopathic PAH; familial PAH; PAH associated with vascular collagenosis, congenital heart disease, portal hypertension, HIV infection, drug or toxin intake, hereditary hemorrhagic telangiectasia, splenectomy, pulmonary veno-occlusive disease (PVOD), or pulmonary capillary hemangiomatosis (PCH); and PAH with significant vein or capillary involvement.

Prostacyclin (PGI2) is a lipid molecule derived from arachidonic acid via the cyclooxygenase pathway. It is a potent vasodilator, antiproliferative, antithrombotic, and antiplatelet agent mediated by its G protein-coupled receptor (PGI2 receptor; e.g., human PGI2 receptor, GenBank® Accession No. NP 000951, and its alleles) activity. Binding of PGI2 (or another such agonist) to the PGI2 receptor is known to result in Gs-protein pairing and an increase in intracellular cAMP levels (see, for example, Zhang et al., Arch. Biochem. Biophys., 2006, 454:80- 88).

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary vasculopathy leading to right ventricular hypertrophy. Left untreated, right heart failure develops. It has been established that prostacyclin, which has a vasodilating and antiproliferative effect on the pulmonary vasculature, is at a low level in patients with PAH compared with normal control individuals. Exogenous administration of prostacyclin or a prostacyclin analog (i.e., a PGI2 receptor agonist) has become an important strategy in the treatment of PAH (see, for example, Tuder et al., Am. J. Respir. Crit. Care. Med., 1999, 159:1925 -1932; Humbert et al., J. Am. Coll. Cardiol., 2004, 43: 13S-24S; Rosenzweig, Expert Opin. Emerging Drugs, 2006, 11: 609-619; McLaughlin et al., Circulation, 2006, 114: 1417-1431; Rosenkranz, Clin. Res. Cardiol., 2007, 96: 527-541; Driscoll et al., Expert Opin. Pharmacother., 2008, 9: 65-81).

Trepostinil and iloprost are FDA-approved prostacyclin analogs that, like prostacyclin, are inactive when taken orally. Beraprost is an orally active prostacyclin analogue approved for the treatment of PAH in Japan, but has not been approved for the treatment of PAH in Europe and the United States. Of the three FDA-approved drugs, prostacyclin has been the most studied for the treatment of patients with PAH. The estimated annual cost of treating PAH with these drugs is $25,000-$200,000, depending on the dose. Currently, many experts consider intravenous prostacyclin to be the most reliable treatment for disease control in patients with the most severe form of PAH. Due to the short half-life of prostacyclin, treatment by intravenous administration is difficult due to the need for continuous infusion. Patients are at risk of potentially fatal recurrence of symptoms of pulmonary hypertension if the infusion is stopped abruptly, as well as a significant risk of catheter-related complications, including sepsis. (See, for example, Rosenzweig, Expert Opin. Emerging Drugs, 2006, 11: 609-619; Naeije et al., Expert Opin. Pharmacother., 2007, 8: 2247-2265; Strauss et al., Clin. Chest. Med., 2007, 28: 127-142; Driscoll et al., Expert Opin. Pharmacother., 2008, 9: 65-81).

2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (compound 1), also known as APD811, which is an orally administered prostacyclin receptor agonist ( IP) is described in US Patent Publication No. 2011/0053958, the entire contents of which are incorporated herein by reference. Compound 1 is an investigational potential drug for the treatment of vasospastic diseases such as pulmonary arterial hypertension.

There is a need to effectively treat patients who are in need of treatment with Compound 1. The present invention satisfies this need and also provides additional benefits.

The essence of the invention

What is proposed is a method for the treatment of pulmonary arterial hypertension, which includes administering to a patient in need of it, 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (compound 1) or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is orally administered; while compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is administered according to the titration scheme; where the titration scheme includes the introduction of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate at an initial dose equivalent to 0.05 mg of compound 1 once a day for about one week, and if the patient tolerates the initial dose, the introduction of an increased dose equivalent to 0 .1 mg compound 1 once a day; until an optimized dose for the treatment of pulmonary arterial hypertension is administered, wherein optimized dose means a therapeutic dose optimized for the needs of a particular patient, and means the highest dose of compound 1, or a dose of its pharmaceutically acceptable salt, solvate or hydrate, equivalent to the highest dose of compound 1, which elicits a biological or medical response in a patient, and which can be tolerated by the patient, as determined by the patient.

- 1 043027

In a preferred embodiment of the invention, provided that the patient tolerates the initial dose, an increased dose is administered that is equivalent to 0.1 mg of Compound 1 once a day for about one week.

In addition, provided that the patient tolerates the increased dose, additional administration of the increased dose is carried out, which is equivalent to 0.2 mg of Compound 1 once a day.

In a particular embodiment of the invention, the titration scheme comprises a cycle of administering an increased dose over a period of approximately one week, and then an additional administration of an increased dose, where the dose increment is equivalent to 0.1 mg of compound 1 once a day, while the cycle is repeated until as long as the patient tolerates the higher dose until the optimized dose is reached.

Preferably, dose escalation is performed over about 9 weeks.

An optimized daily dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof may be equivalent to 0.16, 0.2, 0.4, 0.6 or 1.2 mg of compound 1.

Also, in particular embodiments of the invention, Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, may be formulated as a capsule or tablet suitable for oral administration.

In this case, the capsule or tablet may contain an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate, equivalent to an amount from 0.01 to 0.6 mg of compound 1.

In accordance with the invention, pulmonary arterial hypertension (PAH) is selected from: idiopathic PAH;

familial PAH;

PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis;

PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient;

PAH associated with portal hypertension;

PAH associated with HIV infection;

PAH associated with taking a drug or toxin;

PAH associated with hereditary hemorrhagic telangiectasia;

PAH associated with splenectomy;

PAH associated with significant damage to the veins or capillaries;

PAH associated with pulmonary veno-occlusive disease (PVOD); And

PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient.

Detailed description of the invention

When used in the present description, the following words and phrases, as a rule, should have the meanings set forth below, unless the context in which they are used implies otherwise.

Compound 1: As used herein, the term compound 1 means 2-(((1r,4r)-4(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid, including its crystalline forms. As a non-limiting example, Compound 1 may be present in the crystalline form disclosed in WO 2009117095 (the entire content of which is incorporated herein by reference), which can be characterized by one or more of the following 20 values for the peaks in the XRD spectrum: 8 .9, 10.8, 11.9, 15.2, 16.4, 16.8, 18.9, 20.3, 20.7 and 21.5, while these peaks may differ by approximately ±0, 2° 2θ.

Administration: As used herein, the term administration means the provision of a compound, or other therapy, treatment, or treatment. For example, a healthcare professional may directly provide a patient with a compound in the form of a sample, or may indirectly provide a patient with a compound by providing an oral or written prescription for the compound. In addition, for example, the patient can receive the compound on their own, without the participation of a medical professional. Administration of a compound may or may not involve actual uptake by the patient of the compound. In the event that a patient ingests a compound, his body is altered in some way by the compound.

Prescribing: As used herein, the term prescribing means an indication, prescription, or recommendation for the use of a drug or other therapy, intervention, or treatment. In some embodiments, a healthcare professional may verbally advise, recommend, or prescribe the use of a compound, dosage regimen, or other treatment to a patient. In this case, the healthcare professional may or may not provide a prescription for the compound, dosage regimen, or treatment. In addition, the healthcare professional may or may not provide the recommended compound or treatment. For example, a medical professional may advise a patient where to purchase a compound without providing the compound. In some

- 2 043027 embodiments, a healthcare professional may provide a patient with an prescription for a compound, dosage regimen, or treatment. For example, a healthcare professional may issue a written or oral prescription to a patient. The assignment may be recorded on paper or on an electronic medium, such as in the form of a computer file, such as on a hand-held computer device. For example, a medical professional may change a written prescription for a compound, dosage regimen, or treatment recorded on paper or electronic media. In addition, the appointment can be given during a telephone conversation (oral) or sent by fax (in writing) to a pharmacy or outpatient clinic. In some embodiments, a sample of the compound or treatment may be provided to the patient. As used herein, issuing a compound sample means the implied purpose of the compound. Different health systems in the world use different ways of prescribing and/or administering compounds or treatment options, and these methods are covered by the present invention.

The assignment may include, for example, the patient's name and/or identification information such as date of birth. In addition, for example, the prescription may include the name of the drug, concentration, dose, frequency of administration, route of administration, number dispensed or number and number of refills of the drug, physician's name, and physician's signature. In addition, for example, the designation may contain a DEA number or a public registry number.

The healthcare professional may be, for example, a physician, nurse, nurse practitioner, or other healthcare professional who may prescribe or administer compounds (drugs) to optimize weight. In addition, the term healthcare professional may include anyone who may recommend, prescribe, administer, or caution a patient against the use of a compound or drug, including, for example, an employee of an insurance company.

Prevent, prevention, or prophylaxis: As used herein, the term prevent, prevention, or prophylaxis, such as the prevention of obesity, means preventing the occurrence or onset of one or more symptoms associated with a particular disease, and does not necessarily mean the complete prevention of the disease. For example, the term prevent, prevention, or prophylaxis means administering a therapeutic agent on a prophylactic or prophylactic basis to a patient who may eventually develop at least one symptom of a disease or condition, but who has not yet experienced the event. Such patients can be identified based on risk factors known to correlate with subsequent disease progression. Alternatively, preventive therapy can be carried out without prior identification of the risk factor, as a preventive measure. Delaying the onset of at least one symptom may also be considered prevention or prophylaxis.

Treat, treatment, or therapy: As used herein, the term treat, treatment, or therapy means administering a therapeutic agent to a patient who has already exhibited at least one symptom of a disease or condition, or who has previously exhibited at least one symptom of a disease or condition. For example, treatment may include alleviating, ameliorating, or alleviating symptoms of a disease or condition, preventing additional symptoms, addressing the underlying metabolic causes of symptoms, inhibiting a disease or condition, e.g., arresting the progress of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, a condition caused by a disease or condition, or the elimination of symptoms of a disease or condition. For example, the term treatment in relation to a disease means reducing the severity of one or more symptoms associated with a particular disease. Thus, treating a disease does not necessarily mean reducing the severity of all symptoms associated with the disease, and does not necessarily mean completely reducing the severity of one or more symptoms associated with the disease.

Tolerate: This document states that a patient will tolerate a dose of a compound if administration of that dose to that patient does not result in an unacceptable adverse event or an unacceptable combination of adverse events. One skilled in the art understands that tolerability is a subjective category, and that what may be tolerable for one patient may not be tolerable for another patient. For example, one patient may be unable to tolerate a headache, while a second patient may find the headache tolerable but unable to tolerate vomiting, while for a third patient either the headache or the vomiting alone is tolerable but the patient is unable to tolerate the headache combination. and vomiting, even if the severity of each of these events is less than in the case of each of them individually.

Adverse Event: As used herein, the term adverse event refers to an adverse medical event associated with treatment with Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, the adverse event is selected from headache, nausea, vomiting, and jaw pain. In one embodiment, the adverse event is selected from headache, nausea, vomiting, jaw pain, flushing, abnormal heart rate, abnormal QT interval, sitting systolic blood pressure

- 3 043027 position >160 mmHg Art., diastolic blood pressure in a sitting position> 100 mm Hg. Art., systolic blood pressure <90 mm Hg. Art., or a combination of two or more of the above. In one embodiment, the adverse event is selected from abdominal pain, nosebleeds, muscle pain, feeling hot, palpitations, dizziness, itching, diarrhea, chest pressure, joint pain, tingling or tingling sensation in the skin, and low blood pressure. . In one embodiment, the adverse event is selected from chest pain, chest discomfort, and erythema.

Optimized Dose: As used herein, the term optimized dose means a therapeutic dose optimized for the needs of a particular patient and means the highest dose of Compound 1, or a dose of a pharmaceutically acceptable salt, solvate or hydrate thereof, equivalent to the highest dose of Compound 1 that produces the desired biological or medical response in the patient, and which may be tolerated by the patient, as determined by the patient, optionally in consultation with the healthcare professional treating the patient. The amount of compound 1 in an optimized dose may be different for different patients. In addition, the amount of compound 1 may vary from time to time for a particular patient.

Dose escalation: As used herein, the term compound escalation means increasing the amount of the compound until the increased amount is no longer tolerated by the patient. Dose increases can be achieved by one or more dose increments, which may be the same or different. In some embodiments, the method comprises administering and/or administering Compound 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, in an amount equivalent to 0.01 mg of Compound 1 2 times daily for about one week, followed by an increase in dose as described herein until the optimized dose is reached. The administration of the optimized dose twice a day can then be continued for as long as necessary. In some embodiments, the method comprises administering and/or administering Compound 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, in an amount equivalent to 0.01 mg of Compound 1 once daily for about one week, followed by escalation to the amount equivalent to 0.01 mg Compound 1 twice daily for about one week, followed by dose escalation as described herein until the optimized dose is reached. The administration of the optimized dose twice a day can then be continued for as long as necessary.

It is understood that the expression pharmaceutically acceptable salts, solvates and hydrates or the expression pharmaceutically acceptable salt, solvate or hydrate as used in connection with Compound 1 includes pharmaceutically acceptable solvates and/or hydrates of Compound 1, pharmaceutically acceptable salts of Compound 1, as well as pharmaceutically acceptable solvates and /or hydrates of pharmaceutically acceptable salts of compound 1. It is also understood that the expression pharmaceutically acceptable salts, solvates and hydrates or the expression pharmaceutically acceptable salt, solvate or hydrate, as used in relation to compound 1, which is in the form of salts, encompasses pharmaceutically acceptable solvates and/or hydrates of these salts.

Those skilled in the art will appreciate that the dosage forms described herein may contain either Compound 1 or a pharmaceutically acceptable salt or solvate or hydrate thereof as the active ingredient. In addition, various hydrates and solvates of compound 1 and its salts will find use as intermediates in the manufacture of pharmaceutical compositions. Conventional methods for the manufacture and determination of suitable hydrates and solvates other than those mentioned herein are well known to those skilled in the art; see, for example, pages 202-209 of K.J. Guillory, Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids in Polymorphism in Pharmaceutical Solids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999. Accordingly, one aspect of the present invention relates to methods of prescribing and/or administering hydrates and solvates of compound 1 and/or pharmaceutically acceptable salts thereof, which can be isolated and characterized by methods known in the art. in the art, such as thermogravimetric analysis (TGA), TGA mass spectroscopy, TGA infrared spectroscopy, X-ray powder diffraction (XRD), Karl Fischer titration, high-resolution X-ray diffraction, and the like. There are several commercial organizations that provide fast and efficient services for the determination of solvates and hydrates on a regular basis. Examples of companies providing such services include Wilmington PharmaTech (Wilmington, DE), Avantium Technologies (Amsterdam), and Aptuit (Greenwich, CT).

The present invention covers all isotopes of atoms in the present compounds, salts, solvates and hydrates. Isotopes are atoms that have the same atomic number but different mass numbers. One aspect of the present invention includes each combination of one or more atoms in the present compounds, salts, solvates and hydrates, which is replaced by an atom having the same atomic number but a different mass number. One such example is the replacement of an atom that is the most abundant naturally occurring isotope, such as 1H or ^12C , which is present in the present compounds, salts, solvates, and hydrates, with another atom that is not the most abundant.

- 4 043027 with a naturally occurring isotope, for example ² H or ³ H (instead of 1 H), or ^PS , ¹³ C or ¹⁴ C (instead of ¹² C). A salt in which such a substitution takes place is commonly referred to as an isotopically labeled salt. Isotopic labeling of the present compounds, salts, solvates and hydrates can be carried out using any of a variety of synthetic methods known to the person skilled in the art, and it is believed that those skilled in the art are also aware of the synthetic methods and available reagents necessary to perform such isotopic labeling. As a general example, and without limitation, isotopes of hydrogen include ² H (deuterium) and ³ H (tritium). The isotopes of carbon include ^PS , ¹³ C and ¹⁴ C. The isotopes of nitrogen include ¹³ N and ¹⁵ N. The isotopes of oxygen include ¹⁵ O, ¹⁷ O and ¹⁸ C. The isotope of phosphorus is ¹⁸ F. The isotope of sulfur is ³⁵ S. The isotope of chlorine is ³⁶ Cl . Isotopes of bromine include ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. The isotopes of iodine include ¹²³ 1 , ¹²⁴ 1 , ¹²⁵ I and ¹³¹ I. Another aspect of the present invention includes compositions such as compositions obtained from synthesis, preformulation and the like, as well as pharmaceutical compositions such as compositions obtained for the purpose of using in a mammalian body for the treatment of one or more of the diseases described herein, containing one or more of the present compounds, salts, solvates and hydrates, while the natural distribution of isotopes in the composition is changed. Another aspect of the present invention includes compositions and pharmaceutical compositions containing the compounds, salts, solvates and hydrates described herein, wherein the salt is enriched at one or more positions in an isotope other than the most abundant isotope in nature. Methods for quantifying such changes or enrichments in isotopes are well known, such as mass spectrometry, and in the case of isotopes that are radioactive isotopes, additional methods are known, such as the use of radioactivity detectors in combination with HPLC or GC.

In this document, the term more than is used interchangeably with the symbol >, and the term less than is used interchangeably with the symbol <. Likewise, the term less than or equal to is used interchangeably with the symbol <.

When using an integer in the description of the method disclosed herein, the term approximately may be included before the integer.

Throughout this specification, unless the context dictates otherwise, the word include, or variations thereof, such as includes or including, shall mean the inclusion of a specified step or element, or an integer, or a group of steps or elements, or integers, but not exclusion of any other stage or element or integer or group of elements or integers.

Throughout this specification, unless specifically indicated otherwise or the context dictates otherwise, reference to one step, composition, group of steps, or group of compositions should be understood to encompass one and more (i.e., one or more) of these steps. , songs, step groups, or song groups.

Each embodiment described herein shall apply, mutatis mutandis, to any and every other embodiment unless specifically stated otherwise.

Those skilled in the art will appreciate that the invention(s) described herein may be subject to changes and modifications beyond those specifically described. It is to be understood that the invention(s) includes all such variations and modifications. The invention(s) also includes all of the steps, features, compositions and compounds described or referred to herein, alone or collectively, and any and all combinations, or any two or more of these steps or features, unless specifically stated otherwise.

The present invention(s) should not be limited in scope to the specific embodiments described herein, which are for illustrative purposes only. It is obvious that functionally equivalent products, compositions and methods are included in the scope of the invention(s) described in this document.

It is understood that certain features of the invention(s), which are described in the context of separate embodiments for clarity, may also be provided in combination in one embodiment. Conversely, various features of the invention(s), which for brevity are described in the context of one embodiment, may also be provided separately or in any suitable partial combination. For example, a method involving administration and/or administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof can be divided into two methods; one comprising administering Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, and another comprising administering Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. In addition, for example, a method comprising the administration of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and a separate method of the invention comprising the administration of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof may be combined into a single method comprising the administration of and/or administering compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

What is proposed is a method for the treatment of pulmonary arterial hypertension, which includes the administration and/or administration to a patient in need of it of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate, wherein compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is administered according to the titration scheme, including increasing the dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate, for a period of time not more than about nine weeks until the optimized dose is reached.

Also provided is a method for determining an optimized dose for a patient in need of treatment for pulmonary arterial hypertension, including prescribing and/or administering compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof to the patient and increasing the dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof. , for a period of time not exceeding about nine weeks until the optimized dose for the patient is reached.

Also provided is a method for determining an optimized dose for a patient in need of treatment with compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, comprising:

administering and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, to a patient at an initial dose equivalent to 0.01 mg of Compound 1 once daily for about one week; and determining whether the patient tolerates the initial dose;

however, if the patient tolerates the initial dose, the dose is increased to a dose equivalent to 0.01 mg of compound 1 twice a day;

however, if the patient does not tolerate the initial dose, then the optimized dose for the patient is less than the dose equivalent to 0.01 mg of compound 1 once a day.

In some embodiments, a method for determining an optimized dose for a patient in need further comprises:

determining whether the patient tolerates a dose equivalent to 0.01 mg of compound 1 twice a day;

however, if the patient tolerates a dose equivalent to 0.01 mg of compound 1 twice a day, the dose is increased by an amount equal to the first increment value;

however, if the patient does not tolerate a dose equivalent to 0.01 mg of compound 1 twice a day, then the optimized dose for the patient is less than the dose equivalent to 0.01 mg of compound 1 twice a day.

In some embodiments, a method for determining an optimized dose for a patient in need further comprises:

administering and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, to a patient at an increased dose for about one week; and determining if the patient is tolerating the increased dose;

wherein, if the patient tolerates the increased dose, the dose is further increased by an amount equal to the second increment, the second increment being the same as or different from the first increment;

however, if the patient does not tolerate the increased dose, then the optimized dose for the patient is equal to the difference between the increased dose and the first increment value.

Also provided is a method for determining an optimized dose for a patient in need thereof, comprising:

administration and/or administration of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof at an initial dose equivalent to 0.01 mg of compound 1 twice daily for about one week; and determining whether the patient tolerates the initial dose;

wherein, if the patient tolerates the initial dose, the dose is increased by an amount equal to the first increment value; and yet, if the patient does not tolerate the initial dose, then the optimized dose for the patient is less than the equivalent of 0.01 mg Compound 1 twice daily.

In some embodiments, the method for determining an optimized dose for a patient further comprises:

administering and/or administering compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof at an increased dose for about one week; and determining if the patient is tolerating the increased dose;

wherein, if the patient tolerates the increased dose, the dose is further increased by an amount equal to the second increment, the second increment being the same as or different from the first increment;

however, if the patient does not tolerate the increased dose, then the optimized dose for the patient is equal to the difference between the increased dose and the first increment value.

Also provided is a method for determining an optimized dose for a patient in need thereof, comprising a cycle of:

- 6 043027 prescribing and/or administering an increased dose for about one week;

an additional dose increase by an amount equal to the increment value; and determining whether the patient tolerates an additional increased dose;

wherein the cycle is repeated as long as the patient tolerates an additional increased dose, and the magnitude of the increment in each repetition of the cycle is the same or different; and wherein, if the patient does not tolerate the further increased dose, then the optimized dose for the patient is equal to the difference between the further increased dose and the increment value for the last iteration of the cycle.

In some embodiments, the method further comprises administering and/or administering to the patient an optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In some embodiments, the dose increase is performed over a period of about 9 weeks.

In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, administered to a patient is increased at approximately equal time intervals until an optimized dose is reached. In some embodiments, the amount is increased at about weekly intervals.

In some embodiments, the titration regimen comprises administering and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at an initial dose equivalent to 0.01 mg of Compound 1 twice daily for about one week and, if the patient tolerates the initial dose, dose increase.

In some embodiments, the titration schedule further comprises administering and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, at an increased dose for about one week and, if the patient is tolerant of the increased dose, further increasing the dose.

In some embodiments, the titration schedule includes a cycle of giving and/or administering an increased dose for about one week and then further increasing the dose, the cycle being repeated as long as the patient tolerates the additional increased dose until the optimized dose is reached.

In some embodiments, in which the titration scheme includes a cycle of prescribing and/or administering an increased dose, as described herein, the cycle is performed once. In some embodiments, the cycle is repeated twice. In some embodiments, the cycle is repeated three times. In some embodiments, the cycle is repeated four times. In some embodiments, the cycle is repeated five times. In some embodiments, the cycle is repeated six times. In some embodiments, the cycle is repeated seven times. In some embodiments, the cycle is repeated eight times. In some embodiments, the cycle is repeated nine times. In some embodiments, the cycle is not repeated.

In some embodiments, a method for treating pulmonary arterial hypertension comprises administering a titration scheme comprising a cycle

1) prescribing and/or administering, over about one week, a dose that is incrementally higher than the dose for the previous period, and

2) determining if the patient is tolerating the higher dose over such a period of approximately one week;

wherein steps 1) and 2) of the cycle are repeated as long as the patient tolerates a higher dose, with the increment value at each repetition of the cycle being the same or different from the previous increment value;

however, if the patient does not tolerate the higher dose, then the optimized dose for the patient is equal to the difference between the higher dose and the increment for the last iteration of the cycle.

In some embodiments, a method of determining an optimized dose for a patient in need thereof comprises administering and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for more than one period of about one week each, wherein the method includes cycle

1) prescribing and/or administering, over about one week, a dose that is incrementally higher than the dose for the previous period, and

2) determining if the patient is tolerating the higher dose over such a period of approximately one week;

wherein steps 1) and 2) of the cycle are repeated as long as the patient tolerates a higher dose, with the increment value at each repetition of the cycle being the same or different from the previous increment value;

however, if the patient does not tolerate the higher dose, then the optimized dose for the patient is equal to the difference between the higher dose and the increment for the last iteration of the cycle.

In some embodiments of the cycle

1) prescribing and/or administering, over a period of about one week, a dose that is higher by

- 7 043027 increments than the dose for the previous period, and

2) determining if the patient is tolerating the higher dose over such a period of about one week, the higher dose administered is equal to the twice daily amount that is higher than the twice daily amount in the previous period, and determining whether Whether the patient tolerates a higher dose includes:

a) determining if the patient tolerates the higher twice daily amount;

b) if the patient does not tolerate a higher amount administered twice a day, administering to the patient a higher amount once a day;

c) if the patient tolerates the higher once daily dose, re-administering the higher twice daily dose to the patient; And

d) determining if the patient tolerates the higher twice daily dose.

In some embodiments, determining if a patient is tolerating a higher dose includes:

a) determining if the patient tolerates the higher twice daily amount;

b) if the patient does not tolerate a higher amount administered twice a day, administering to the patient a higher amount once a day;

c) if the patient tolerates the higher once daily dose, re-administering the higher twice daily dose to the patient; And

d) determining if the patient tolerates the higher twice daily dose.

In some embodiments, the patient is intolerant of the initial dose and the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is less than the equivalent of 0.01 mg of Compound 1 once daily. In some embodiments, the optimized dose of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is equivalent to 0.01 mg of Compound 1 administered at a frequency of less than twice daily.

In some embodiments, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.01 mg of compound 1 once daily.

In some embodiments, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.01 mg of compound 1 twice daily.

In some embodiments, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.02 mg of compound 1 twice daily.

In some embodiments, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.03 mg of compound 1 twice daily.

In some embodiments, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.04 mg of compound 1 twice daily.

In some embodiments, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.06 mg of compound 1 twice daily.

In some embodiments, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.08 mg of compound 1 twice daily.

In some embodiments, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.1 mg of compound 1 twice daily.

In some embodiments, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.2 mg of compound 1 twice daily.

In some embodiments, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.3 mg of compound 1 twice daily.

In some embodiments, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.6 mg of compound 1 twice daily.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is administered orally.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a capsule or tablet suitable for oral administration.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a capsule.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is Compound 1, or a hydrate or solvate thereof.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is Compound 1.

In some embodiments, a pharmaceutical composition is provided comprising an amount of compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.01 mg of compound 1.

In some embodiments, a pharmaceutical composition is provided containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.02 mg of Compound 1.

In some embodiments, a pharmaceutical composition is provided containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.03 mg of Compound 1.

In some embodiments, a pharmaceutical composition is provided containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.04 mg of Compound 1.

In some embodiments, a pharmaceutical composition is provided containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.06 mg of Compound 1.

In some embodiments, a pharmaceutical composition is provided containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.08 mg of Compound 1.

In some embodiments, a pharmaceutical composition is provided containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.1 mg of Compound 1.

In some embodiments, a pharmaceutical composition is provided containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.2 mg of Compound 1.

In some embodiments, a pharmaceutical composition is provided containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.3 mg of Compound 1.

In some embodiments, a pharmaceutical composition is provided containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.6 mg of Compound 1.

In some embodiments, a pharmaceutical composition is provided comprising an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.01-0.6 mg of Compound 1, such as 0.01-0.3 mg of Compound 1, such as 0.01 -0.2 mg of compound 1, e.g. 0.01-0.1 mg of compound 1, e.g. 0.02-0.08 mg of compound 1, e.g. 0.03-0.06 mg of compound 1, e.g. 0.04 mg of compound 1.

In some embodiments of the pharmaceutical composition, the composition is in the form of a capsule or tablet. In some embodiments of the pharmaceutical composition, the composition is in the form of a capsule. In some embodiments of the pharmaceutical composition, the composition is in the form of a tablet.

Pulmonary arterial hypertension (PAH) has a multifactorial pathology. Vasoconstriction, remodeling of the walls of the pulmonary vessels and thrombosis contribute to the increase in pulmonary vascular resistance in PAH (Humbert et al., J. Am. Coll. Cardiol., 2004, 43: 13S-24S).

The compounds disclosed herein are useful in the treatment of pulmonary arterial hypertension (PAH) and its symptoms. It is known that PAH includes the following forms of pulmonary arterial hypertension, described in the clinical classification of pulmonary arterial hypertension according to the World Health Organization (WHO) in 2003: idiopathic PAH (IPAH); familial PAH (SLAH); PAH associated with other conditions (ALH), e.g., PAH associated with vascular collagenosis, PAH associated with congenital systemic lung shunts, PAH associated with portal hypertension, PAH associated with HIV infection, PAH associated with drug use agents or toxins, or PAH associated with other conditions; and PAH associated with significant damage to the veins or capillaries.

Idiopathic PAH means PAH for unknown reasons.

Familial PAH means PAH for which inheritance is suspected or documented.

PAH associated with vascular collagenosis includes PAH associated with scleroderma, PAH associated with CREST syndrome (skin calcification, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly and telangiectasia), PAH associated with systemic lupus erythematosus (SLE), PAH associated with rheumatoid arthritis, PAH associated with Takayasu's arteritis, PAH associated with polymyositis, and PAH associated with dermatomyositis.

PAH associated with congenital systemic lung shunts includes PAH associated with atrial septic defect (ASD), PAH associated with ventricular septic defect (VSD), and PAH associated with patent ductus arteriosus.

PAH associated with drugs or toxins includes PAH associated with taking aminorex, PAH associated with taking a fenfluramine compound (for example,

- 9 043027

PAH associated with fenfluramine or PAH associated with dexfenfluramine), PAH associated with certain toxic oils (eg, PAH associated with rapeseed oil), PAH associated with pyrrolizidine alkaloids (eg, PAH associated with rooibos) and PAH associated with monocrotaline.

PAH associated with other conditions includes PAH associated with thyroid disease, PAH associated with glycogenosis, PAH associated with Gaucher disease, PAH associated with hereditary hemorrhagic telangiectasia, PAH associated with hemoglobinopathy, PAH associated with myeloproliferative disease, and PAH associated with splenectomy.

PAH associated with significant venous or capillary involvement includes PAH associated with pulmonary veno-occlusive disease (PVOD) and PAH associated with pulmonary capillary hemangiomatosis (PCH). (See, for example, Simonneau et al., J. Am. Coll. Cardiol., 2004, 43: 5S-12S; McGoon et al., Chest, 2004, 126: 14S-34S; Rabinovitch, Annu. Rev. Pathol Mech Dis., 2007, 2: 369-399; McLaughlin et al., Circulation, 2006, 114: 1417-1431; Strauss et al., Clin. Chest. Med., 2007, 28: 127-142; Taichman et al., Clin. Chest. Med., 2007, 28: 1-22).

Evidence for the association of PAH with scleroderma and the positive effect of a PGI2 receptor agonist on PAH is described in Badesch et al. (Badesch et al., Ann. Intern. Med., 2000, 132: 425-434). Evidence for an association of PAH with collagenosis, mixed connective tissue disease (MCTD), systemic lupus erythematosus (SLE), Sjögren's syndrome, and CREST syndrome, and the positive effect of a PGI2 receptor agonist on PAH are described in Humbert et al. (Eur. Respir. J., 1999, 13: 1351-1356). Evidence for the association of PAH with CREST syndrome and the positive effect of a PGI2 receptor agonist on PAH is described in Miwa et al. (Int. Heart J., 2007, 48: 417-422). Evidence for the association of PAH with SLE and the positive effect of a PGI2 receptor agonist on PAH is described in Robbins et al. (Chest, 2000, 117:14-18). Evidence for the association of PAH with HIV infection and the positive effect of a PGI2 receptor agonist on PAH is described in Aguilar et al. (Am. J. Respir. Crit. Care Med., 2000, 162: 18461850). Evidence for an association of PAH with congenital heart disease (including ASD, VSD, and patent ductus arteriosus) and the positive effect of a PGI2 receptor agonist on PAH is described in Rosenzweig et al. (Circulation, 1999, 99: 1858-1865). Evidence for an association of PAH with fenfluramine and dexfenfluramine, both anorexigens, is described in Archer et al. (Am. J. Respir. Crit. Care Med., 1998, 158: 1061-1067). Evidence for an association of PAH with hereditary hemorrhagic telangiectasia is described in McGoon et al. (Chest, 2004, 126:14-34). Evidence for the association of PAH with splenectomy is described in Hoeper et al. (Ann. Intern. Med., 1999, 130: 506-509). Evidence for the association of PAH with portal hypertension and the positive effect of a PGI2 receptor agonist on PAH is described in Hoeper et al. (Eur. Respir. J., 2005, 25: 502-508).

Symptoms of PAH include dyspnea, angina pectoris, syncope and edema (McLaughlin et al., Circulation, 2006, 114: 1417-1431). The compounds disclosed herein are useful in the treatment of symptoms of PAH.

In some embodiments, pulmonary arterial hypertension (PAH) is selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient.

Also provided are methods of treating PAH in a patient in need thereof, comprising administering and/or administering to the patient compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. Also provided are methods for treating PAH in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

Also provided are methods of treating idiopathic PAH in a patient in need thereof, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to the titration scheme disclosed herein. Also provided are methods for treating idiopathic PAH in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

Also provided are methods for treating familial PAH in a patient in need thereof, including prescribing and/or administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient,

- 10 043027 hydrate or solvate, or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided are methods of treating familial PAH in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

Also provided are methods of treating PAH associated with vascular collagenosis in a patient in need thereof, comprising prescribing and/or administering to the patient Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. document. Also provided are methods for treating PAH associated with vascular collagenosis in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

Also provided are methods for treating PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis, in a patient in need thereof, comprising prescribing and/or administering compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, to a patient, according to the titration scheme disclosed herein. Also provided are methods of treating PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis in a patient in need thereof, comprising administering Compound 1 to the patient. according to the titration scheme disclosed in this document.

Also provided are methods for treating PAH associated with congenital heart disease in a patient in need thereof, comprising prescribing and/or administering to the patient Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, according to the titration scheme disclosed in this document. Also provided are methods for treating PAH associated with congenital heart disease in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

Also provided are methods of treating PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus, in a patient in need thereof, comprising prescribing and/or administering Compound 1 to the patient. or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. Also provided are methods of treating PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient in need thereof, comprising administering Compound 1 to the patient in a titration scheme, disclosed in this document.

Also provided are methods for treating PAH associated with portal hypertension in a patient in need thereof, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to the titration scheme disclosed herein. document. Also provided are methods of treating PAH associated with portal hypertension in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

Also provided are methods for treating PAH associated with HIV infection in a patient in need thereof, comprising prescribing and/or administering to the patient Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, according to the titration scheme disclosed in this document. Also provided are methods for treating PAH associated with HIV infection in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

Also provided are methods for treating PAH associated with taking a drug or toxin in a patient in need thereof, including prescribing and/or administering to the patient Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, according to a titration scheme, disclosed in this document. Also provided are methods for treating drug or toxin associated PAH in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

Also provided are methods of treating PAH associated with hereditary hemorrhagic telangiectasia in a patient in need thereof, comprising prescribing and/or administering to the patient Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, according to the titration scheme disclosed in this document. Also provided are methods of treating PAH associated with hereditary hemorrhagic telangiectasia in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

Also provided are methods of treating PAH associated with splenectomy in a patient in need thereof, comprising prescribing and/or administering to the patient compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, according to a titration scheme, disclosed in this document. Also provided are methods of treating PAH associated with splenectomy in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

Also provided are methods for treating PAH associated with significant venous or capillary damage in a patient in need thereof, comprising prescribing and/or administering to the patient Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, according to a titration scheme, disclosed in this document. Also provided are methods of treating PAH associated with significant venous or capillary disease in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

Also provided are methods for treating PAH associated with pulmonary veno-occlusive disease (PVOD) in a patient in need thereof, including prescribing and/or administering compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to a titration scheme. disclosed in this document. Also provided are methods of treating PAH associated with pulmonary veno-occlusive disease (PVOD) in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

Also provided are methods for treating PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient in need thereof, including prescribing and/or administering compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to a titration scheme. disclosed in this document. Also provided are methods of treating PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient in need thereof, comprising administering Compound 1 to the patient according to the titration scheme disclosed herein.

In some embodiments of the methods for treating PAH in a patient in need thereof, disclosed herein, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to the titration scheme disclosed in herein, an optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.01 mg of compound 1 once a day.

In some embodiments of the methods for treating PAH in a patient in need thereof, disclosed herein, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to the titration scheme disclosed in herein, an optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.01 mg of compound 1 twice daily.

In some embodiments of the methods for treating PAH in a patient in need thereof, disclosed herein, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to the titration scheme disclosed in herein, an optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.02 mg of compound 1 twice daily.

In some embodiments of the methods for treating PAH in a patient in need thereof, disclosed herein, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to the titration scheme disclosed in herein, an optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.03 mg of compound 1 twice daily.

In some embodiments of the methods for treating PAH in a patient in need thereof, disclosed herein, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to the titration scheme disclosed in herein, an optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.04 mg of compound 1 twice daily.

In some embodiments of the methods for treating PAH in a patient in need thereof, disclosed herein, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to the titration scheme disclosed in herein, an optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.06 mg of compound 1 twice daily.

In some embodiments of methods for treating PAH in a patient who is in need of

- 12 043027 disclosed herein, including the administration and / or administration to the patient of a compound or its pharmaceutically acceptable salt, hydrate or solvate, or its pharmaceutical composition, according to the titration scheme disclosed herein, an optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is equivalent to 0.08 mg of compound 1 twice a day.

In some embodiments of the methods for treating PAH in a patient in need thereof, disclosed herein, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to the titration scheme disclosed in herein, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.1 mg of compound 1 twice daily.

In some embodiments of the methods for treating PAH in a patient in need thereof, disclosed herein, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to the titration scheme disclosed in herein, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.2 mg of compound 1 twice daily.

In some embodiments of the methods for treating PAH in a patient in need thereof, disclosed herein, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to the titration scheme disclosed in herein, an optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.3 mg of compound 1 twice daily.

In some embodiments of the methods for treating PAH in a patient in need thereof, disclosed herein, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, to the patient, according to the titration scheme disclosed in herein, the optimized dose of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is equivalent to 0.6 mg of compound 1 twice daily.

In some embodiments, the present invention provides a method of treating PAH, comprising prescribing and/or administering to a patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.01 mg of compound 1, once a day.

In some embodiments, the present invention provides a method of treating PAH, comprising prescribing and/or administering to a patient a pharmaceutical composition containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.01 mg of Compound 1, twice daily.

In some embodiments, the present invention provides a method of treating PAH, comprising prescribing and/or administering to a patient a pharmaceutical composition containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.02 mg of Compound 1, twice daily.

In some embodiments, the present invention provides a method of treating PAH, comprising prescribing and/or administering to a patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.03 mg of compound 1, twice daily.

In some embodiments, the present invention provides a method of treating PAH, comprising prescribing and/or administering to a patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.04 mg of compound 1, twice daily.

In some embodiments, the present invention provides a method of treating PAH, comprising prescribing and/or administering to a patient a pharmaceutical composition containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.06 mg of Compound 1, twice daily.

In some embodiments, the present invention provides a method of treating PAH, comprising prescribing and/or administering to a patient a pharmaceutical composition containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.08 mg of Compound 1, twice daily.

In some embodiments, the present invention provides a method of treating PAH, comprising prescribing and/or administering to a patient a pharmaceutical composition containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.1 mg of Compound 1, twice daily.

In some embodiments, the present invention provides a method for treating PAH,

- 13 043027, which includes prescribing and/or administering to a patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.2 mg of compound 1, twice a day.

In some embodiments, the present invention provides a method of treating PAH, comprising prescribing and/or administering to a patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.3 mg of compound 1, twice daily.

In some embodiments, the present invention provides a method of treating PAH, comprising administering and/or administering to a patient a pharmaceutical composition containing an amount of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.6 mg of Compound 1 twice daily.

In some embodiments, the present invention provides a method for treating PAH, comprising administering and/or administering to a patient a pharmaceutical composition containing an amount of compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.01-0.6 mg of compound 1, twice a day. day, for example, 0.01-0.3 mg of compound 1, twice a day, for example, 0.01-0.2 mg of compound 1, twice a day, for example, 0.01-0.1 mg of compound 1 , twice a day, for example, 0.02-0.08 mg of compound 1, twice a day, for example, 0.03-0.06 mg of compound 1, twice a day, for example, 0.04 mg of compound 1 twice a day.

In some embodiments of methods for treating PAH, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a capsule or tablet suitable for oral administration. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a capsule. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a tablet.

In some embodiments, the present invention provides a method for treating PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient, including prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.01 mg of compound 1, once a day .

In some embodiments, the present invention provides a method for treating PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient, including prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.01 mg of compound 1, twice a day .

In some embodiments, the present invention provides a method for treating PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient, which includes prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.02 mg of compound 1, twice a day.

In some embodiments, the present invention provides a method for treating PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient, which includes prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.03 mg of compound 1, twice a day .

In some embodiments, the present invention provides a method for treating PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient, including prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.04 mg of compound 1, twice a day .

In some embodiments, the present invention provides a method for treating PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient, including prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.06 mg of compound 1, twice a day .

In some embodiments, the present invention provides a method for treating PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient, which includes prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.08 mg of compound 1, twice a day .

In some embodiments, the present invention provides a method for treating PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis,

- 15 043027 selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient, including prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.1 mg of compound 1, twice a day .

In some embodiments, the present invention provides a method for treating PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient, including prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.2 mg of compound 1, twice a day .

In some embodiments, the present invention provides a method for treating PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient, including prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.3 mg of compound 1, twice a day .

In some embodiments, the present invention provides a method for treating PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient, which includes prescribing and / or administering to the patient a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.6 mg of compound 1, twice a day .

In some embodiments, methods for treating PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with spleen

- 16 043027 nectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated as a capsule or tablet suitable for oral administration. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a capsule. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a tablet.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a medicinal product for the treatment of PAH, including the appointment and / or administration to the patient of a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.01 mg of compound 1, once a day.

Also provided is the use of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein in the manufacture of a medicament for the treatment of PAH, which involves prescribing and/or administering to a patient a pharmaceutical composition containing an amount of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.01 mg of compound 1, twice a day.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a medicinal product for the treatment of PAH, including the appointment and / or administration to the patient of a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.02 mg of compound 1, twice a day.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a medicinal product for the treatment of PAH, including the appointment and / or administration to the patient of a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.03 mg of compound 1, twice a day.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a medicinal product for the treatment of PAH, including the appointment and / or administration to the patient of a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.04 mg of compound 1, twice a day.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a medicinal product for the treatment of PAH, including the appointment and / or administration to the patient of a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.06 mg of compound 1, twice a day.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a medicinal product for the treatment of PAH, including the appointment and / or administration to the patient of a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.08 mg of compound 1, twice a day.

Also provided is the use of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein in the manufacture of a medicament for the treatment of PAH, which involves prescribing and/or administering to a patient a pharmaceutical composition containing an amount of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.1 mg of compound 1, twice a day.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a medicinal product for the treatment of PAH, including the appointment and / or administration to the patient of a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.2 mg of compound 1, twice a day.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a medicinal product for the treatment of PAH, including the appointment and / or administration to the patient of a pharmaceutical composition containing an amount of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.3 mg of compound 1, twice a day.

Also provided is the use of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein in the manufacture of a medicament for the treatment of PAH, which involves prescribing and/or administering to a patient a pharmaceutical composition containing an amount of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.6 mg of compound 1, twice a day.

- 17 043027

Also provided is the use of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein in the manufacture of a medicament for the treatment of PAH, which involves prescribing and/or administering to a patient a pharmaceutical composition containing an amount of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate equivalent to 0.01-0.6 mg of compound 1, twice a day, for example, 0.01-0.3 mg of compound 1, twice a day, for example, 0.01-0.2 mg of compound 1, twice a day, for example, 0.01-0.1 mg of compound 1, twice a day, for example, 0.02-0.08 mg of compound 1, twice a day, for example, 0.03-0.06 mg compound 1 twice daily, eg 0.04 mg compound 1 twice daily.

In some embodiments of methods for treating PAH, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a capsule or tablet suitable for oral administration. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a capsule. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a tablet.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), which includes prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.01 mg of compound 1, once a day.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), which includes prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.01 mg of compound 1, twice a day.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), which includes prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.02 mg of compound 1, twice a day.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH selected from: idiopathic PAH; familial PAH; PAH associated with collagenosis su

- 18,043,027 selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), which includes prescribing and/or administering to a patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.03 mg of compound 1, twice a day.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), which includes prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.04 mg of compound 1, twice a day.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), which includes prescribing and/or administering to the patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.06 mg of compound 1, twice a day.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), which includes prescribing and/or administering to a patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.08 mg of compound 1, twice a day.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital

- 19 043027 heart disease, selected from: atrial septic defect (ASD), ventricular septic defect (VSD) and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), which includes prescribing and/or administering to a patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.1 mg of compound 1, twice a day.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), which includes prescribing and/or administering to a patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.2 mg of compound 1, twice a day.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), which includes prescribing and/or administering to a patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.3 mg of compound 1, twice a day.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), which includes prescribing and/or administering to a patient a pharmaceutical composition containing an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to 0.6 mg of compound 1, twice a day.

In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; LAS, associations

- 20 043027 with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated as a capsule or tablet suitable for oral administration. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a capsule. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formulated as a tablet.

In some embodiments, a pharmaceutical composition or method for treating PAH is selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), a dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is effective to create a difference of at least about 40 meters in 6MWD relative to pre-dose 6MWD.

In some embodiments, a pharmaceutical composition or method for treating PAH is selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), a dose of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is effective to create a difference of at least about 45 meters in 6MCD relative to pre-dose 6MCD.

In some embodiments, a pharmaceutical composition or method for treating PAH is selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); and PAH associated with pulmonary capillary hemangiomatosis (PCH), a dose of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is effective to create a difference of at least about 50 meters in 6MCD relative to pre-dose 6MCD.

As used herein, the term 6MWD means a six-minute walking distance, i.e. the distance the patient walks in a six-minute period of time. In some embodiments, the implementation of the 6MHD is the distance that the patient walks for six minutes indoors. In some embodiments, 6MXD is the distance that the patient walks for six minutes on a flat indoor surface, i.e. from about 15 to about 50 meters in length, turning around each time it reaches a predetermined turning point on the surface.

In some embodiments, 6MWT is determined according to the American Society of Thoracic Medicine guidelines in the Six Minute Walk Test (6MWT) described in Am. J. Respir. Crit. Care Med. Vol. 166, p. 111-117, 2002; DOI: 10.1164/rccm.166/1/111, the entire content of which is incorporated herein by reference; also available at https://www.thoracic.org/statements/resources/pfet/sixminute.pdf.

In some embodiments, 6MXD equipment that can be used or

- 21 043027 nearby, may include _O2 blood saturation measurement equipment and headband sensors; countdown timer or stopwatch; mechanical lap counter; two small cones to indicate turning points; a chair that can be moved along the walking route; worksheet; source of oxygen; telephone and automated electronic defibrillator. The subject may prepare for 6MWT by wearing comfortable clothing and walking shoes; use any assistive devices for walking, such as a cane or walker; continue to use any treatment regimen, including taking compound 1 before starting 6MXT; eat a light meal before the early morning or early afternoon 6MW and avoid vigorous exercise 2 hours before the test. Prior to the test, the subject may sit and rest in a chair adjacent to the starting position for at least 10 minutes. The information that may be recorded includes one or more of the following: starting position, corridor length, direction of movement of the subject, time of the test, and general health of the subject.

The 6MXT test may be stopped immediately for the following reasons: (1) chest pain, (2) unbearable dyspnea, (3) leg cramps, (4) staggering, unsteady gait, (5) profuse sweating, and (6) pallor or deathly pale complexion. Subjects requiring supplemental oxygen should inhale a constant dose of oxygen for at least 15 minutes prior to measurement of blood O ₂ saturation and until completion of the 6MXT test. Absolute contraindications for the 6MXT test include the following: unstable angina within the previous month and myocardial infarction within the previous month. Relative contraindications include resting heart rate over 120, skp over 180 mmHg. Art. and dKD more than 100 mm Hg. Art.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof. , according to the titration scheme disclosed in this document. Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH, comprising administering Compound 1 according to the titration scheme disclosed herein.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a drug for the treatment of idiopathic PAH, including the appointment and/or administration of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate, or its pharmaceutical compositions according to the titration scheme disclosed in this document. Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of idiopathic PAH, comprising administering Compound 1 according to the titration scheme disclosed herein.

Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of familial PAH, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical formulation thereof. compositions according to the titration scheme disclosed herein. Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, described herein, in the manufacture of a medicament for the treatment of familial PAH, comprising administering Compound 1 according to the titration scheme disclosed herein.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a drug for the treatment of PAH associated with vascular collagenosis, including the appointment and/or administration of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate , or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein, in the manufacture of a medicament for the treatment of PAH associated with vascular collagenosis, comprising administering Compound 1 according to the titration scheme disclosed herein.

Also provided is the use of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein in the manufacture of a medicament for the treatment of PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. Also provided is the use of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein in the manufacture of a medicament for the treatment of PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, limyositis, and dermatomyositis, comprising the administration of Compound 1 according to the titration scheme disclosed herein.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a medicinal product for the treatment of PAH associated with congenital heart disease, including the appointment and/or administration of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate, or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein, in the manufacture of a medicament for the treatment of PAH associated with congenital heart disease, comprising administering Compound 1 according to the titration scheme disclosed herein.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a drug for the treatment of PAH associated with congenital heart disease, selected from: atrial septic defect (ASD), ventricular septic defect (VSD) and patent ductus arteriosus, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a drug for the treatment of PAH associated with congenital heart disease, selected from: atrial septic defect (ASD), ventricular septic defect (VSD) and patent ductus arteriosus, comprising the administration of Compound 1 according to the titration scheme disclosed herein.

Also provided is the use of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein in the manufacture of a medicament for the treatment of PAH associated with portal hypertension, comprising the administration and/or administration of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof. , or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH associated with portal hypertension, comprising administering Compound 1 according to the titration scheme disclosed herein.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a medicinal product for the treatment of PAH associated with HIV infection, including the appointment and/or administration of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate, or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH associated with HIV infection, comprising administering Compound 1 according to the titration scheme disclosed herein.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a drug for the treatment of PAH associated with taking a drug or toxin, including the administration and / or administration of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of drug- or toxin-associated PAH, comprising administering Compound 1 according to the titration scheme disclosed herein.

Also provided is the use of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein in the manufacture of a medicament for the treatment of PAH associated with hereditary hemorrhagic telangiectasia, comprising the administration and/or administration of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate, or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH associated with hereditary hemorrhagic telangiectasia, comprising administering Compound 1 according to the titration scheme disclosed herein.

Also provided is the use of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein in the manufacture of a medicament for the treatment of PAH associated with splenectomy, comprising the administration and/or administration of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also proposed is the use of compound 1

- 23 043027 or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein, in the manufacture of a medicament for the treatment of PAH associated with splenectomy, comprising the administration of Compound 1 according to the titration scheme disclosed herein.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a drug for the treatment of PAH associated with significant damage to the veins or capillaries, including the appointment and / or administration of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH associated with significant venous or capillary disease, comprising administering Compound 1 according to the titration scheme disclosed herein.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a drug for the treatment of PAH associated with pulmonary veno-occlusive disease (PVOD), including the appointment and/or administration of compound 1 or its pharmaceutically acceptable salt , hydrate or solvate, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a drug for the treatment of PAH associated with pulmonary veno-occlusive disease (PVOD), including the administration of compound 1 according to the titration scheme disclosed herein.

Also proposed is the use of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate described herein in the manufacture of a drug for the treatment of PAH associated with pulmonary capillary hemangiomatosis (PCH), including the appointment and/or administration of compound 1 or its pharmaceutically acceptable salt , hydrate or solvate, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. Also provided is the use of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH associated with pulmonary capillary hemangiomatosis (PCH), comprising administering Compound 1 according to the titration scheme disclosed herein.

In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or pharmaceutical composition, according to the titration scheme disclosed herein, the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is equivalent to 0.01 mg of compound 1 once a day.

In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or pharmaceutical composition, according to the titration scheme disclosed herein, the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is equivalent to 0.01 mg of compound 1 twice a day.

In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or pharmaceutical composition, according to the titration scheme disclosed herein, the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is equivalent to 0.02 mg of compound 1 twice a day.

In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or pharmaceutical composition, according to the titration scheme disclosed herein, the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is equivalent to 0.03 mg of compound 1 twice a day.

In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or pharmaceutical composition, according to the titration scheme disclosed herein, the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is equivalent to 0.04 mg of compound 1 twice a day.

In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, described herein, in the manufacture of a drug

- 24 043027 means for the treatment of PAH, including the appointment and / or administration of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate, or its pharmaceutical composition, according to the titration scheme disclosed herein, an optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is equivalent to 0.06 mg of compound 1 twice a day.

In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or pharmaceutical composition, according to the titration scheme disclosed herein, the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is equivalent to 0.08 mg of compound 1 twice a day.

In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or pharmaceutical composition, according to the titration scheme disclosed herein, the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is equivalent to 0.1 mg of compound 1 twice a day.

In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or pharmaceutical composition, according to the titration scheme disclosed herein, the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is equivalent to 0.2 mg of compound 1 twice a day.

In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or pharmaceutical composition, according to the titration scheme disclosed herein, the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is equivalent to 0.3 mg of compound 1 twice a day.

In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, in the manufacture of a medicament for the treatment of PAH, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or pharmaceutical composition, according to the titration scheme disclosed herein, the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is equivalent to 0.6 mg of compound 1 twice a day.

Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, is also provided for use in a method for the treatment of PAH, including administration and/or administration of compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating PAH, comprising administering Compound 1 according to the titration scheme disclosed herein.

Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, is also provided for use in a method for treating idiopathic PAH, including the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, according to the titration scheme disclosed in this document. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating idiopathic PAH, comprising administering Compound 1 according to the titration scheme disclosed herein.

Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, is also provided for use in a method for treating familial PAH, including the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, according to the titration scheme disclosed in this document. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating familial PAH, comprising administering Compound 1 according to the titration scheme disclosed herein.

Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof as described herein is also provided for use in a method for treating PAH associated with vascular collagenosis, comprising administering and/or administering compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating PAH associated with vascular collagenosis, comprising administering Compound 1 according to the titration scheme disclosed herein.

Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof as described herein is also provided for use in a method of treating PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis, comprising the administration and/or administration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof as described herein is also provided for use in a method of treating PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis, comprising administering Compound 1 according to the titration scheme disclosed herein.

Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, is also provided for use in a method for treating PAH associated with congenital heart disease, comprising the administration and/or administration of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating PAH associated with congenital heart disease, comprising administering Compound 1 according to the titration scheme disclosed herein.

Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, is also provided for use in a method of treating PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD) and non-closure arterial duct, including the appointment and / or administration of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate, or its pharmaceutical composition, according to the titration scheme disclosed herein. Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, is also provided for use in a method of treating PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD) and non-closure arterial duct, including the introduction of compound 1 according to the titration scheme disclosed in this document.

Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof as described herein is also provided for use in a method of treating PAH associated with portal hypertension, comprising administration and/or administration of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating PAH associated with portal hypertension, comprising administering Compound 1 according to the titration scheme disclosed herein.

Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, is also provided for use in a method for the treatment of PAH associated with HIV infection, comprising the administration and/or administration of compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating PAH associated with HIV infection, comprising administering Compound 1 according to the titration scheme disclosed herein.

Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof as described herein is also provided for use in a method of treating PAH associated with a drug or toxin intake, comprising administration and/or administration of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof. solvate, or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating drug or toxin associated PAH, comprising administering Compound 1 according to the titration scheme disclosed herein.

Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, is also provided for use in a method for the treatment of PAH associated with hereditary hemorrhagic telangiectasia, including the administration and/or administration of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for the treatment of PAH associated with hereditary hemorrhagic telangiectasia, comprising administering Compound 1 according to the titration scheme disclosed herein.

Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, is also provided for use in a method for the treatment of PAH associated with splenectomy, comprising administering and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating PAH associated with splenectomy, comprising administering Compound 1 according to the titration scheme disclosed herein.

Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating PAH associated with significant venous or capillary damage, comprising prescribing and/or administering Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate, or its pharmaceutical composition, according to the titration scheme disclosed in this document. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating PAH associated with significant vein or capillary disease, comprising administering Compound 1 according to the titration scheme disclosed herein.

Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, is also provided for use in a method for treating PAH associated with pulmonary veno-occlusive disease (PVOD), including the administration and/or administration of compound 1 or a pharmaceutically acceptable salt, hydrate thereof. or a solvate, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating PAH associated with pulmonary veno-occlusive disease (PVOD), comprising administering Compound 1 according to the titration scheme disclosed herein.

Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, is also provided for use in a method for treating PAH associated with pulmonary capillary hemangiomatosis (PCH), including the administration and/or administration of compound 1, or a pharmaceutically acceptable salt, hydrate thereof. or a solvate, or a pharmaceutical composition thereof, according to the titration scheme disclosed herein. Also provided is Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, for use in a method for treating PAH associated with pulmonary capillary hemangiomatosis (PCH), comprising administering Compound 1 according to the titration scheme disclosed herein.

In some embodiments, the present invention provides a method for treating pulmonary arterial hypertension, comprising administering and/or administering to a patient in need thereof, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at the starting dose disclosed herein;

administering compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the titration scheme disclosed herein until the optimized dose is reached; and administering or administering the optimized dose to the patient twice daily for about 13 weeks.

In some embodiments, the present invention provides a method for treating pulmonary arterial hypertension, comprising administering and/or administering to a patient in need thereof, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at the starting dose disclosed herein;

administering compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the titration scheme disclosed herein until the optimized dose is reached; and administering or administering to the patient an optimized dose twice daily for about 13 weeks to achieve a difference of at least about 40 meters in the patient's 6MCD relative to the 6MCD before the initial dose.

In some embodiments, the present invention provides a method for treating pulmonary arterial hypertension, comprising administering and/or administering to a patient in need thereof, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at the starting dose disclosed herein;

administering compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the titration scheme disclosed herein until the optimized dose is reached; and administering or administering to the patient an optimized dose twice daily for about 13 weeks to achieve a difference of at least about 45 meters in the patient's 6MCD relative to the 6MCD before the initial dose.

- 27 043027

In some embodiments, the present invention provides a method for treating pulmonary arterial hypertension, comprising administering and/or administering to a patient in need thereof, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at the starting dose disclosed herein;

administering compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the titration scheme disclosed herein until the optimized dose is reached; and administering or administering to the patient an optimized dose twice daily for about 13 weeks to achieve a difference of at least about 50 meters in the patient's 6MCD relative to the 6MCD before the initial dose.

In some embodiments, the present invention provides a method for treating pulmonary arterial hypertension, comprising administering and/or administering to a patient in need thereof, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at the starting dose disclosed herein;

administering compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the titration scheme disclosed herein until the optimized dose is reached; and administering or administering to the patient the optimized dose twice daily for a period of time sufficient to achieve a difference of at least about 40 meters in the patient's 6MCD relative to the 6MCD prior to the initial dose.

In some embodiments, the present invention provides a method for treating pulmonary arterial hypertension, comprising administering and/or administering to a patient in need thereof, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at the starting dose disclosed herein;

administering compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the titration scheme disclosed herein until the optimized dose is reached; and administering or administering to the patient the optimized dose twice daily for a period of time sufficient to achieve a difference of at least about 45 meters in the patient's 6MCD relative to the 6MCD prior to the initial dose.

In some embodiments, the present invention provides a method for treating pulmonary arterial hypertension, comprising administering and/or administering to a patient in need thereof, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at the starting dose disclosed herein;

administering compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the titration scheme disclosed herein until the optimized dose is reached; and administering or administering to the patient the optimized dose twice daily for a period of time sufficient to achieve a difference of at least about 50 meters in the patient's 6MCD relative to the 6MCD prior to the initial dose.

In some embodiments, the present invention provides a method for treating pulmonary arterial hypertension, comprising administering and/or administering to a patient in need thereof, Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at the starting dose disclosed herein; and administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the titration scheme disclosed herein, until an optimized dose is reached, wherein the titration scheme includes increasing the dose of Compound 1, or a pharmaceutically acceptable salt, hydrate thereof or solvate, for a period of time not exceeding about nine weeks until the optimized dose is reached.

Also proposed is a module for titration, which allows you to follow the regimen of changing the dosage of the drug over a certain period of time, while the drug is compound 1 or its pharmaceutically acceptable salt, hydrate or solvate, including:

a substrate with a set of receiving cells, and the specified set includes many columns and many rows;

a plurality of sets of solid dosage forms, with each solid dosage form in the set having the same dose of drug, which is different from the dose of the solid dosage form of another set, each set is placed in the receiving cells of one of the adjacent rows and one of the adjacent columns; other sets of solid dosage forms are placed in different rows, each row is marked as referring to a consecutive period of time, each column is marked as referring to a different day of the time period, sets of solid dosage forms with increased doses are placed in the receiving cells of rows marked as consecutive periods time;

- 28 043027 and the signs placed next to the columns and rows indicate common days and consecutive periods of time.

In some embodiments of the titration module, multiple doses of 0.01 mg each are placed in the first row receiving cells.

In some embodiments of the titration module, multiple doses of 0.02 mg each are placed in the second row receiving cells.

In some embodiments of the titration module, multiple doses of 0.03 mg each are placed in the receiving cells of the third row.

In some embodiments of the titration module, multiple doses of 0.04 mg each are placed in the fourth row receiving cells.

In some embodiments of the titration module, multiple doses of 0.06 mg each are placed in the fifth row receiving cells.

In some embodiments of the titration module, multiple doses of 0.08 mg each are placed in the sixth row receiving cells.

In some embodiments of the titration module, multiple doses of 0.1 mg each are placed in the seventh row receiving cells.

In some embodiments of the titration module, multiple doses of 0.2 mg each are placed in the eighth row receiving cells.

In some embodiments of the titration module, multiple doses of 0.3 mg each are placed in the ninth row receiving cells.

In some embodiments of the titration module, multiple doses of 0.6 mg each are placed in the tenth row receiving cells.

In some embodiments of the titration module, multiple doses of 0.01 mg each are placed in the first row receiving cells.

In some embodiments of the titration module, multiple doses of 0.01 mg each are placed in the second row receiving cells, with twice the number of doses placed in the second row receiving cells as the number of doses placed in the first row receiving cells.

In some embodiments of the titration module, multiple doses of 0.02 mg each are placed in the receiving cells of the third row.

In some embodiments of the titration module, multiple doses of 0.03 mg each are placed in the fourth row receiving cells.

In some embodiments of the titration module, multiple doses of 0.04 mg each are placed in the fifth row receiving cells.

In some embodiments of the titration module, multiple doses of 0.06 mg each are placed in the sixth row receiving cells.

In some embodiments of the titration module, multiple doses of 0.08 mg each are placed in the seventh row receiving cells.

In some embodiments of the titration module, multiple doses of 0.1 mg each are placed in the eighth row receiving cells.

In some embodiments of the titration module, multiple doses of 0.2 mg each are placed in the ninth row receiving cells.

In some embodiments of the titration module, multiple doses of 0.3 mg each are placed in the tenth row receiving cells.

In some embodiments of the titration module, multiple doses of 0.6 mg each are placed in the eleventh row receiving cells.

In some embodiments of the titration module, each time period is approximately one week.

Also proposed is a method of combination therapy, including the appointment and/or administration of compound 1 or its pharmaceutically acceptable salt, solvate or hydrate, in combination with at least one known pharmaceutical agent. Also provided is a combination therapy method comprising administration and/or administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, in combination with at least one known pharmaceutical agent described herein and a pharmaceutically acceptable carrier. As used herein, the term combination in relation to drug combinations and/or combinations of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, with at least one additional pharmaceutical agent means (1) a preparation consisting of two or more components, i.e. e. drug/device, biological product/device, drug/biological product, or drug/device/biological product that is physically, chemically or otherwise combined or mixed and produced as a whole; (2) two or more separate products packaged together in one package or as a module, and consisting of medicinal products and devices, devices and biological products, or biological products and medicinal products; (3) a separately packaged drug, device, or biological product that, in accordance with its research plan or proposed labeling, is intended to be used only in conjunction with an approved, specifically specified drug, device, or biological product, and both are necessary to achieve the intended use, purpose, or effect, and once the proposed product is approved, the labeling of the approved product must be changed, for example, to reflect changes in the intended use, dosage form, concentration, route of administration, or a significant change in dose; or (4) any individually packaged investigational medicinal product, device or biologic that, according to its proposed labeling, is intended for use only with another specifically identified investigational medicinal product, device or biologic, both of which are required for implementation of the intended use, purpose or effect. Combinations include, without limitation, a fixed dose combination preparation (FDC) in which two or more separate drug components are combined in a single dosage form; co-packaged products containing two or more separate medicinal products in their final dosage forms packaged together, with appropriate labeling indicating combined use; and an adjunctive therapy, in which case the patient is on a maintenance regimen of a second drug that they use in conjunction (i.e., additionally) with the first drug, although the relative doses are not fixed and drugs or biologics are not necessarily taken in the same time. Complementary therapies may be packaged together and may or may not be labeled for concurrent use.

In some embodiments, compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in combination with a thrombolytic therapeutic agent, e.g., tissue plasminogen activator (t-PA), to provide cardioprotection after MI or post-ischemic myocardial dysfunction, or protection against ischemic injury. in the process of percutaneous intervention on the coronary vessels, and the like, including complications of these conditions. PGI2 receptor agonists can also be used in antiplatelet therapy in combination with, for example, alpha-tocopherol (vitamin E), echistatin (disintegrin) or, in hypercoagulable states, heparin. (See, for example, Chan., J. Nutr., 1998, 128: 1593-1596; Mardla et al., Platelets, 2004, 15: 319324; Bernabei et al., Ann. Thorac. Surg., 1995, 59 : 149-153; Gainza et al., J. Nephrol., 2006, 19: 648-655).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is co-administered with at least one pharmaceutical agent known to prevent or treat one or more of the adverse events described herein.

In some embodiments, at least one pharmaceutical agent is a thrombolytic therapy agent. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and the thrombolytic agent are formulated as a fixed dose combination formulation. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and the thrombolytic agent are formulated as co-packaged preparations. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a thrombolytic agent are formulated for adjuvant therapy.

In some embodiments, at least one pharmaceutical agent is a tissue plasminogen activator. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and tissue plasminogen activator are formulated as a fixed dose combination formulation. In some embodiments, compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and tissue plasminogen activator are formulated as co-packaged preparations. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and tissue plasminogen activator are formulated for adjuvant therapy.

In some embodiments, the implementation of at least one pharmaceutical agent is an agent for antiplatelet therapy. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and the antiplatelet agent are formulated as a fixed dose combination formulation. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and an antiplatelet agent are formulated as co-packaged preparations. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and an antiplatelet agent are formulated for adjuvant therapy.

In some embodiments, the implementation of at least one pharmaceutical agent is an agent for antiplatelet therapy. In some embodiments, with

- 30 043027 Unit 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and an antiplatelet therapy agent are formulated as a fixed dose combination preparation. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and an antiplatelet agent are formulated as co-packaged preparations. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and an antiplatelet agent are formulated for adjuvant therapy.

In some embodiments, at least one pharmaceutical agent is alpha-tocopherol. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and alpha-tocopherol are formulated as a fixed dose combination formulation. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and alpha-tocopherol are formulated as co-packaged preparations. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and alpha-tocopherol are formulated for adjuvant therapy.

In some embodiments, at least one pharmaceutical agent is echistatin. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and echistatin are formulated as a fixed dose combination formulation. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and echistatin are formulated as co-packaged preparations. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and echistatin are formulated for adjuvant therapy.

In some embodiments, at least one pharmaceutical agent is heparin. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and heparin are formulated as a fixed dose combination formulation. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and heparin are formulated as co-packaged preparations. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and heparin are formulated for adjuvant therapy.

In some embodiments, the at least one pharmaceutical agent is at least one pharmaceutical agent known to prevent and/or treat one or more of the adverse events described herein. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and at least one pharmaceutical agent known to prevent and/or treat one or more of the adverse events described herein, are formulated as a combination fixed dose drug. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and at least one pharmaceutical agent known to prevent and/or treat one or more of the adverse events described herein, are formulated as packaged drugs. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and at least one pharmaceutical agent known to prevent and/or treat one or more of the adverse events described herein, are formulated for adjunctive therapy. .

Also provided is a kit comprising the titration module disclosed herein and instructions for administering a drug to a patient in need of treatment for pulmonary arterial hypertension.

Also provided is a method for treating pulmonary arterial hypertension, comprising providing the titration module disclosed herein to a patient in need thereof.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered as a tablet or capsule suitable for oral administration. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered as a capsule suitable for oral administration.

In tablets and capsules for oral administration, conventional excipients such as binders, fillers, acceptable wetting agents, lubricating agents and tableting disintegrants may be used. Liquid preparations for oral administration may take the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, oral preparations may be in the form of a dry powder which may be reconstituted in water or other suitable liquid vehicle prior to use. In liquid preparations, additives such as suspending agents or emulsifiers, non-aqueous vehicles (including edible oils), preservatives, and flavoring and coloring agents may be further included. Parenteral dosage forms can be prepared by dissolving the compound in an appropriate liquid medium and filter sterilizing the solution before filling it into an appropriate vial or ampoule, followed by sealing. These are just a few examples of many suitable methods well known in the art for preparing dosage forms. Suitable pharmaceutically acceptable carriers other than those mentioned herein are known in the art; for example, see Remington, The Science and Practice of Pharmacy, ^20th edition, 2000, Lippincott Williams & Wilkins, (edited by Gennaro et al.).

While it is possible that, in an alternative application for prophylactic or therapeutic use, the compound may be administered as the raw material or pure chemical, it is preferred, however, to provide the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.

Pharmaceutical preparations include preparations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration, or preparations in a form suitable for administration by inhalation, insufflation or transdermal patch . The transdermal patches release the drug at a controlled rate so that the drug is absorbed efficiently with minimal drug degradation. Typically, transdermal patches include an impervious backing layer, a single-pressure adhesive layer, and a removable backing layer with a release liner. Those skilled in the art are familiar and understand the methods suitable for making an effective transdermal patch that meets specific needs.

The compounds provided herein, together with a conventional adjuvant, carrier or diluent, can be formulated into pharmaceutical preparations and unit dosage forms, and can be used as solid forms such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or liquid-filled capsules, for oral administration, in the form of suppositories for rectal administration or in the form of sterile injectable preparations for parenteral (including subcutaneous) administration. Such pharmaceutical compositions and their unit dosage forms may contain conventional ingredients in conventional proportions, with or without the addition of additional active compounds or elements, and such unit dosage forms may contain any suitable effective amount of the active ingredient corresponding to the intended range of daily doses for administration.

The pharmaceutical composition for oral administration may take the form of, for example, tablets, capsules, suspensions or liquids. The pharmaceutical composition is preferably in unit dosage form containing a specific amount of the active ingredient. Examples of such unit dosage forms are capsules, tablets, powders, granules or suspensions with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatins; with disintegrants such as corn starch, potato starch or sodium carboxymethyl cellulose, and with lubricants such as talc or magnesium stearate. The active ingredient can also be administered by injection in the form of a composition in which, for example, saline, dextrose or water can be used as an appropriate pharmaceutically acceptable carrier.

The compounds provided herein can be administered in a wide variety of oral and parenteral dosage forms. Those skilled in the art will appreciate that the dosage forms may contain, as an active ingredient, either a compound as provided herein or a pharmaceutically acceptable salt, solvate, or hydrate of a compound as provided herein.

Some embodiments include a method for preparing a pharmaceutical composition for combination therapy, comprising mixing at least one compound of any of the embodiments disclosed herein with at least one known pharmaceutical agent described herein and a pharmaceutically acceptable carrier.

Additional embodiments include the embodiment described in the following example, which should not be construed as limiting the invention in any way.

Example 1 Study of the effect of single incremental doses in healthy subjects.

This study was a randomized, double-blind, placebo-controlled phase 1 study involving four groups, 8 subjects in each group (2 subjects received placebo administration and 6 subjects were to receive compound 1). Subjects in each arm were to receive a single dose of the masked study drug on an escalating dose schedule; dosing was started at 0.1 mg.

All subjects included in the study received a single oral dose of study drug (compound 1 or placebo). Dose escalation was slowed or stopped if the situation fell outside pre-established safety criteria based on peak plasma exposure levels, changes in blood pressure, or the occurrence of adverse events (AEs). Dose escalation was terminated when AEs occurred in the form of prolonged nausea and intense vomiting experienced by subjects in group 2 (0.2 mg Compound 1). Two lower dose groups were added, for which the doses of Compound 1 were 0.05 mg and 0.03, respectively.

After dosing, the following safety parameters were monitored in each group: key body parameters, clinical laboratory test results to determine serum biochemical parameters, blood and urine test results, 12-lead ECG, plasma concentration of Compound 1 and AE. For compound 1, pharmacokinetic parameters were monitored and calculated.

Undesirable phenomena.

Summary data on adverse events observed in this study are given in table. 1.

Table 1

a) Summary of adverse events

placebo 0.03 mg 0.05 mg 0.1 mg 0.2 mg Number of subjects 8 6 6 6 6 Number of entities reporting AEs 3 2 5 6 6 Photophobia 0 0 1 0 0 Nausea 0 0 1 2 3 Vomit 0 0 0 2 6 Abdominal pain 0 0 1 1 0 Diarrhea 0 0 0 0 1 Jaw pain 0 0 2 3 1 Pain in the neck 0 0 0 1 0 Muscle spasms 0 0 0 0 1 Pain in the limbs 0 0 0 0 1 Headache 3 2 5 5 5 Dizziness 0 0 0 1 0 Cough 1 0 0 0 0 Pain in the oropharynx 0 0 0 0 1 Hyperemia 0 0 1 1 2

At each level of generalization in table. 1a), subjects reporting more than one event were counted only once.

b) Number of subjects reporting AEs directly related to study drug

placebo 0.03 mg 0.05 mg 0.1 mg 0.2 mg Probably related 0 0 0 1 6 Possibly related 1 2 5 4 0 Probably not related 0 0 0 0 0 not exactly related 2 0 0 1 0

Example 2 Study of the effect of multiple incremental doses in healthy subjects.

This study was a randomized, double-blind, placebo-controlled, multiple-dose, phase 1 dose titration study. A 6-day titration interval was used, with each dose administered for at least 5 days. One of the objectives of the study was to determine the effect of dose titration on adverse events.

In each of the two groups of subjects, group 1 and group 2, subjects received each dose level for 5 days, except for the last dose level, which was administered for 7 days.

The study protocol was amended to include an additional group, group 3, in order to evaluate a different dose escalation regimen as described below.

Groups 1 and 2: Two groups of 15 subjects were formed and randomized to receive placebo (5 subjects per group) or an initial dose of 0.05 mg Compound 1 (10 subjects per group) on day 1. Dose once daily (q.d.) continued for 5 days. If subjects tolerated the dose, the next dose escalation (placebo or 0.1 mg Compound 1, q.d.) was given on day 6,

- 33 043027 and this dose was administered daily until day 10. Subsequent dose escalations were performed similarly on every 6th day, for a total of 3 additional dose escalations, if tolerated (placebo or 0.2, 0.3 and 0 .4 mg of compound 1), maintaining the final dose for 7 days. The dose may have been reduced (de-escalation) or increased (re-escalation) based on a safety and tolerability assessment.

Group 3: One group of 25 subjects (5 placebo and 20 active substance) was formed and randomized on day 1 to receive an initial dose of 0.01 mg Compound 1 or placebo twice daily. The twice-daily dosing was continued for 5 days. If subjects tolerated the dose, the next dose escalation (placebo or 0.02 mg Compound 1 twice daily) was administered on day 6, and this dose was administered daily until day 10. Subsequent dose escalations were administered in a similar manner on every 6th day, at up to a total of 4 additional dose escalations, if tolerated (placebo or 0.03, 0.04, 0.05 and 0.07 mg Compound 1 twice daily).

The dose may have been reduced (de-escalation) or increased (re-escalation) based on a safety and tolerability assessment. The doses tested in this group were doses of 0.01, 0.02, 0.03, 0.04, 0.05 and 0.07 mg administered twice daily, for a total daily dose of 0.02, 0.04 , 0.06, 0.08, 0.1 and 0.14 mg, respectively.

Compound 1 capsules were provided in doses of 0.01 mg (all groups) and 0.1 mg (groups 1 and 2 only).

In the single incremental dose study of Example 1 above, an initial dose of 0.1 mg was tolerated, however some subjects experienced nausea, vomiting, headache and jaw pain. In this study, intolerable AEs occurred at the next dose level of 0.2 mg. Accordingly, the starting dose in Groups 1 and 2 in Example 2 was 0.05 mg.

Undesirable phenomena.

In groups 1 and 2, three subjects (15%) were unable to tolerate the initial dose of 0.05 mg once daily. Of these, 2 subjects were de-escalated to a lower dose of 0.03 mg once daily for the remainder of the study; 1 of the subjects was able to subsequently escalate to 0.05 mg for the remainder of the study. One subject withdrew from the study on Day 1. For one subject, dose escalation to 0.2 mg once daily was possible, but dose was subsequently de-escalated to 0.03 mg once daily for the remainder of the study. One subject was able to tolerate the 0.2 mg once daily dose and the same subject reached the maximum dose administered during the study to subjects in Groups 1 and 2, 0.4 mg once daily. However, the 0.4 mg once daily dose was not tolerated and the subject received the 0.3 mg once daily dose for the remainder of the study.

In Group 3, all subjects were able to tolerate an initial dose of 0.01 mg twice daily and a first dose escalation to 0.02 mg Compound 1 twice daily. Five subjects completed the study with a dose of 0.03 mg twice daily. Dose escalation to 0.04 mg twice daily was possible for two subjects until completion of the study. For five subjects, dose escalation to 0.05 mg was possible before completion of the study. For two subjects, dose escalation to 0.07 mg twice daily, the maximum dose level administered in the study to subjects in group 3, was possible. This dose was tolerated by the subjects until study completion. One subject discontinued participation in the study on day 20 due to an adverse event.

For each group, the final daily doses of compound 1 taken by the subjects are given in table. 2 below.

table 2

Final total daily doses of Compound 1 (mg)

Groups 1 and 2 Group 3 0.03 mg - 3 subjects 0.04 mg - 4 subjects 0.05 mg - 9 subjects 0.06 mg - 6 subjects 0.10 mg - 7 subjects 0.08 mg - 2 subjects 0.30 mg - 1 subject 0.10 mg - 6 subjects 0.14 mg - 2 subjects

The maximum doses received by subjects for at least 3 days, either in groups 1 and 2, or in group 3, are given in table. 3 below.

- 34 043027

Table 3

Maximum doses received by subjects for at least 3 days

Groups 1 and 2 Group 3 0.03 mg - 17 subjects 0.04 mg - 20 subjects 0.1 mg - 8 subjects 0.04 mg - 20 subjects 0.2 mg - 1 subject 0.06 mg - 19 subjects 0.30 mg - 1 subject 0.08 mg - 11 subjects 0.10 mg - 8 subjects 0.14 mg - 3 subjects

Summary data on adverse events leading to a decrease in the dose of compound 1, which occurred in groups 1 and 2, are shown in table. 4.

Table 4

Adverse events (number of subjects) leading to dose reduction of _________________________compound 1 in groups 1 and 2 _______________________

placeb Total 0.03 mg 0.05 mg 0.1 mg 0.2 mg 0.3 mg 0.4 O (N=10) (all doses) (N=20) (N=4) (N=20) (N=16) (N=5) (N=l) mg (N=l) Vomit 0 8 0 4 2 2 0 0 head pain 0 8 0 2 5 1 0 0 Nausea 0 4 0 1 1 2 0 0 Diarrhea 0 1 0 1 0 0 0 0 Pain in chest 0 1 0 0 1 0 0 0 Pain in jaws 0 1 0 0 1 0 0 0 Erythema 0 1 0 0 0 0 0 1

At each level of generalization in table. The 4 subjects reporting more than one event were counted only once.

Summary data on adverse events leading to a decrease in the dose of compound 1, which occurred in group 3, are shown in table. 5.

- 35 043027

Table 5

Adverse Events (Number of Subjects) Leading to Compound 1 Dose Reduction in Group 3

Placebo (N=5) Total (all doses) (N=20) 0.01 mg (N=20) 0.02 mg (N=20) 0.03 mg (N=20) 0.04 mg (N=12) 0.05 mg (N=8) 0.07 mg (N=4) head pain 0 10 1 6 1 1 0 1 Nausea 0 5 0 3 1 0 0 1 Myalgia 0 4 1 2 1 0 0 0 Dizziness 0 3 0 0 0 2 1 0 Pain in stomach 0 2 0 0 1 0 1 0 Diarrhea 0 2 0 1 1 0 0 0 Arthralgia 1 2 0 1 0 0 0 1 Discomfort in the chest 0 1 0 0 1 0 0 0 Pain in chest 0 1 0 1 0 0 0 0 increased 0 1 0 1 0 0 0 0 heartbeat nie Vomit 0 1 0 1 0 0 0 0 Priapism 0 1 0 0 1 0 0 0 Pain in jaws 0 1 0 0 0 0 0 1

Most subjects, regardless of drug group, experienced one or more AEs. Most of the AEs reported in the study were considered moderate in intensity (88%). In the Compound 1 group, 95% of the AEs were considered moderate in severity and 90%, according to the investigator, were presumably related to the study drug.

Example 3 Administration of Compound 1 to Patients.

A capsule containing an initial dose of 0.01 mg of Compound 1 is administered to the patient twice a day for one week. The patient's health is then assessed by a physician to determine if the patient is tolerating the initial dose. If the patient does not tolerate the initial dose of 0.01 mg, compound 1 is no longer administered to the patient. If the patient tolerates the initial dose, the dose is increased to 0.02 mg. A capsule containing an increased dose of 0.02 mg of Compound 1 is administered to the patient twice a day for one week and the patient's health is re-evaluated to determine if the patient is tolerating the dose. The cycle is repeated with additional dose increases according to the following schedule, provided that the patient continues to tolerate the increased or further increased dose.

Table 6

The amount of compound 1 (in mg) administered to the patient during each of the nine weeks

A week 1 A week 2 A week 3 A week 4 A week 5 A week 6 A week 7 A week 8 A week 9 Doyoa 0.01 enlarged dose 0.02 Extra enlarged dose 0.03 0.04 0.06 0.08 0.1 0.2 0.3

-36043027

If a dose that is not tolerated by the patient is reached, Compound 1 is no longer administered to the patient. The optimized dose for this patient is the maximum dose tolerated by that patient. As an example, the patient is administered 0.01 mg of compound 1 twice a day in week 1, 0.02 mg of compound 1 twice a day in week 2, 0.03 mg of compound 1 twice a day in weeks 3 and 0, 04 mg Compound 1 twice a day at week 4, and each time the patient tolerates the dose. The patient is administered 0.06 mg of Compound 1 twice daily at week 5 and the patient does not tolerate the 0.06 mg twice daily dose. The optimized dose for the patient is 0.04 mg Compound 1 twice daily.

Example 4 Administration of Compound 1 to Patients.

This study is conducted as a 22-week randomized, double-blind, placebo-controlled study in which dose titration is performed over a period of time up to 9 weeks. Patients are randomized in a ratio of 2:1 (active substance:placebo).

For patients, right heart catheterization (RCH) measurements are performed prior to day 1 of the dose titration period and at week 22 of the study. The following indicators are measured and recorded: PAP (systolic, diastolic and mean), heart rate, right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), right ventricular pressure (RVP), as well as cardiac output (CO), pulmonary vascular resistance (VR), arterial and mixed venous oxygen saturation, FiO ₂ (if applicable). Systemic vascular resistance (SVR) is assessed based on blood pressure readings.

The main indicators of effectiveness are: a) change from baseline in PVR after 22 weeks of dosing and b) change from baseline in 6MCD after 22 weeks of dosing. Efficacy is assessed stepwise: the statistical significance of the results of compound 1 in comparison with placebo is determined for the change from the initial level of PVR at the end of 22 weeks of dosing. If the change from baseline in PVR is significant (p<0.05, two-tailed), then change from baseline to 6MCD is tested.

Compound 1 is administered in the form of hard gelatin capsules with the drug at a dose of 0.01, 0.02, 0.03, 0.04 and 0.10 mg.

The initial dose of Compound 1 is 0.01 mg twice daily. The dose of compound 1 is titrated depending on its tolerance for the patient. Available dosage forms contain 0.01, 0.02, 0.03, 0.04 mg and 0.10 mg.

If the patient tolerates the initial dose (0.01 mg twice a day), then the dose is increased once a week as follows: 0.02 mg twice a day, 0.03 mg twice a day, 0.04 mg twice a day per day, 0.06 mg twice a day, 0.08 mg, 0.1 mg twice a day, 0.2 mg twice a day and 0.3 mg twice a day. Dose escalation can be carried out up to a possible maximum total daily dose of 0.6 mg (0.3 mg twice a day), depending on its tolerability.

If the patient does not tolerate the dose, then the study drug dose may be reduced to the previous dose level. If the patient does not tolerate the initial dose of 0.01 mg twice daily, the dose may be reduced to 0.01 mg once daily.

In this example, 6MWT is determined using the following six-minute walk test (6MWT): 6MWT is performed indoors, in a long, straight corridor with a flat hard floor surface 15-50 meters long, which has a marked start line and turning points. If more than one test is performed, then retesting is performed at approximately the same time of day. Before the test, the lap counter is set to 0 and the timer is set to 6 minutes. The subject is instructed to walk back and forth along the corridor for the greatest possible distance for 6 minutes, without quickening the pace or running. The subject is warned to remain silent while walking. The subject is notified at one-minute intervals of the remaining time for 6MWT—thus, for example, after the first minute, the subject is notified that five minutes remain before the end of the test. 15 seconds before the end of 6MWT, the subject is notified that they will soon be ordered to stop. After six minutes, as signaled by (for example) a bell, the subject is asked to stop and the place where the subject stops is marked with tape. Record the number of laps completed and the number of meters in the last incomplete lap using a tape measure. Calculate the total distance traveled, rounded to the nearest whole metre, and record.

Other uses of the disclosed methods will become apparent to those skilled in the art, in particular upon examination of this patent document.

Claims (16)

1. A method for treating pulmonary arterial hypertension, comprising administering to a patient in need thereof 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid ( compound 1) or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered orally; while compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is administered according to the titration scheme; where the titration scheme includes the introduction of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate at an initial dose equivalent to 0.05 mg of compound 1 once a day for about one week, and if the patient tolerates the initial dose, the introduction of an increased dose equivalent to 0 .1 mg compound 1 once a day; until an optimized dose for the treatment of pulmonary arterial hypertension is administered, whereby optimized dose means a therapeutic dose optimized for the needs of a particular patient and means the highest dose of Compound 1, or a dose of a pharmaceutically acceptable salt, solvate or hydrate thereof, equivalent to the highest dose of Compound 1 that is causes a biological or medical response in the patient, and which can be tolerated by the patient, as determined by the patient. 2. The method according to claim 1, where, provided that the patient tolerates the initial dose, an increased dose is administered, which is equivalent to 0.1 mg of compound 1 once a day for about one week. 3. The method according to claim 2, where, provided that the patient tolerates an increased dose, additional administration of an increased dose is carried out, which is equivalent to 0.2 mg of compound 1 once a day. 4. The method according to claim 3, where the titration scheme includes a cycle of administering an increased dose over a period of approximately one week, and then an additional administration of an increased dose, where the dose increment is equivalent to 0.1 mg of compound 1 once a day, while the cycle repeat as long as the patient tolerates the higher dose until the optimized dose is reached. 5. The method of any one of claims 1 to 4, wherein the dose escalation is performed over a period of about 9 weeks. 6. The method according to claim 1, where the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate administered per day is equivalent to 0.16 mg of compound 1. 7. The method according to claim 1, where the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate administered per day is equivalent to 0.2 mg of compound 1. 8. The method according to claim 1, where the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate administered per day is equivalent to 0.4 mg of compound 1. 9. The method according to claim 1, where the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate administered per day is equivalent to 0.6 mg of compound 1. 10. The method according to claim 1, where the optimized dose of compound 1 or its pharmaceutically acceptable salt, hydrate or solvate administered per day is equivalent to 1.2 mg of compound 1. 11. The method according to any one of claims 1 to 10, wherein compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is compound 1 or a hydrate or solvate thereof. 12. The method according to any one of claims 1 to 10, wherein compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is compound 1. 13. The method according to any one of claims 1 to 12, wherein compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered orally. 14. The method according to any one of claims 1 to 13, wherein compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated as a capsule or tablet suitable for oral administration. 15. The method of claim 14, wherein the capsule or tablet contains an amount of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, equivalent to an amount of 0.01 to 0.6 mg of compound 1. 16. The method according to any one of claims 1 to 15, wherein pulmonary arterial hypertension (PAH) is selected from: idiopathic PAH; familial PAH; PAH associated with vascular collagenosis selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis and dermatomyositis; PAH associated with congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD), and patent ductus arteriosus in a patient; - 38 043027 PAH associated with portal hypertension; PAH associated with HIV infection; PAH associated with taking a drug or toxin; PAH associated with hereditary hemorrhagic telangiectasia; PAH associated with splenectomy; PAH associated with significant damage to the veins or capillaries; PAH associated with pulmonary veno-occlusive disease (PVOD); And PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient.