Methods of treatment

Abstract

To provide new compounds for treating Raynaud's.SOLUTION: Provided are methods of treating or preventing Raynaud's, comprising prescribing and / or administering to an individual in need thereof 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharmaceutically acceptable salt, hydrate or solvate thereof.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Methods useful in the treatment of Raynaud's are provided.

Background Art

[0002] Raynaud's (also called Raynaud / Raynaud’s syndrome, Raynaud / Raynaud’s disease, and / or Raynaud / Raynaud’s phenomenon) is a condition in which blood flow is reduced due to arterial vasospasm. During an "attack," the blood vessels constrict, usually restricting blood circulation to the affected areas involving the fingers, and in some cases the toes, nose, or ears. Raynaud's is induced by the sympathetic nervous system, cold exposure, and / or emotional stress. The most serious complication is severe digital ischemia, which can lead to finger ulceration and in some cases gangrene.

[0003] Raynaud's exists in primary and secondary forms. The cause of primary Raynaud's is unknown. The vascular abnormalities in this form are purely functional and are thought not to progress to reversible or irreversible damage. However, some cases of primary Raynaud's progress to secondary Raynaud's.

[0004] Secondary Raynaud's results from another condition such as systemic sclerosis (also called scleroderma or systemic scleroderma), rheumatoid arthritis, lupus, vasculitis, atherosclerosis, cryoglobulinemia, hypothyroidism, injury, and / or drug reaction. For example, more than 95% of individuals with systemic sclerosis also present for examination with Raynaud's. The severity of secondary Raynaud's is related to the occurrence of structural and functional abnormalities of the blood vessels.

[0005] Raynaud's phenomenon is complex and appears to involve interactions between vascular, neural control mechanisms, and intravascular elements. Treatment approaches for Raynaud's are consistent in mild cases but vary in cases with moderate to severe finger ulceration or underlying systemic sclerosis. Intravenous prostanoids (prostacyclin and analogues) are used in individuals developing ischemic finger complications. Intravenous iloprost has been shown to reduce weekly Raynaud's phenomenon attacks (22.2% vs. 39.1%) and improve severity scores (19.7% vs. 34.8%) over 9 weeks. Wigley 1994 Ann Intern Med. 1994 Feb 1;120(3):199~206. Intravenous epoprostenol has been associated with a reduction in the frequency and duration of Raynaud's phenomenon attacks, but the clinical response was lost 8–10 weeks after the last infusion. Belch 1983 Lancet.1(8320):313e5.

[0006] Intravenous administration, even if effective, is inconvenient and unsuitable for long-term treatment. Furthermore, oral prostanoids are often poorly tolerated and provide little to no meaningful benefit. A recent study found that only 16% of individuals with Raynaud's disease felt that their current drug therapy was effective. (Hughes et al., Rheum 2015.54(8):1443~1447.)

[0007] While the 5-HT2A antagonistic effect on Raynaud's disease has been evaluated, clinical results are mixed. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] U.S. Patent No. 8,980,891 [Non-patent literature]

[0009] [Non-Patent Document 1] Wigley 1994 Ann Intern Med.1994 Feb 1;120(3):199~206 [Non-Patent Document 2] Belch 1983 Lancet.1(8320):313e5 [Non-Patent Document 3] Hughes et al., Rheum 2015.54(8):1443~1447 [Non-Patent Document 4] KJ Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," pp. 202-209. Source: Polymorphism in Pharmaceutical Solids, edited by Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999. [Non-Patent Document 5] Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations. Center for Drug Evaluation and Research (CDER), U.S. Department of Health and Human Services, March 2003, first revised edition, www.fda.gov / cder / guidance / index.htm) [Non-Patent Document 6] Mehran et al. (2011) Circulation 123(23)2736~2747 [Non-Patent Document 7] Remington, The Science and Practice of Pharmacy, 20th edition, 2000, Lippincott Williams & Wilkins (Gennaro et al., co-editors) [Non-Patent Document 8] LeRoy et al. (2001) J.Rheumatol. 28:1573~1576 [Non-Patent Document 9] van den Hoogen et al. (2013) Arthritis Rheum 65:2737~2747 [Non-Patent Document 10] Avouac et al. (2011) Ann.Rheum.Dis.70(3):476~481 [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] Currently, there are no approved drugs for treating Raynaud's disease. New compounds are needed for the treatment of Raynaud's disease. [Means for solving the problem]

[0011] This specification describes methods for treating or preventing Raynaud's disease, A method is provided which involves formulating and / or administering to an individual in need of it 3-methoxy-N-[3-(2-methylpyrazole-3-yl)-4-(2-morpholine-4-ylethoxy)phenyl]benzamide (compound 1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0012] The Specified Use of 3-methoxy-N-[3-(2-methylpyrazole-3-yl)-4-(2-morpholine-4-ylethoxy)phenyl]benzamide (Compound 1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof in the manufacture of a pharmaceutical for treating Raynaud's disease in individuals requiring it.

[0013] This specification also provides 3-methoxy-N-[3-(2-methylpyrazole-3-yl)-4-(2-morpholine-4-ylethoxy)phenyl]benzamide (compound 1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof for use in methods of treating Raynaud's disease in individuals requiring it.

[0014] This specification also provides 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-yl ethoxy)phenyl]benzamide (Compound 1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof in the treatment of Raynaud's in an individual who requires it.

[0015] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a pharmaceutically acceptable salt of Compound 1.

[0016] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is the HCl salt of Compound 1.

[0017] These and other aspects of the invention will become apparent upon reference to the following detailed description. For this purpose, various references with more detailed descriptions of certain background information, procedures, compounds, and / or compositions are specified herein, each of which is hereby incorporated by reference in its entirety.

Brief Description of the Drawings

[0018] [Figure 1] Figure 1 shows the left hind paw temperature upon introduction into a water bath at 40°C, 15°C, and room temperature in Groups 4 - 6. [Figure 2] Figure 2 shows the right hind paw temperature upon introduction into water at room temperature in Groups 4 - 6. [Figure 3] Figure 3 shows the change from the baseline of the left hind paw temperature upon introduction into a water bath at 40°C, 15°C, and room temperature in Groups 4 - 6. [Figure 4] Figure 4 shows the change from the baseline of the left hind paw temperature at the time of cooling for 30 minutes and at the time of recovery for 15 minutes in Groups 4 - 6.

Modes for Carrying Out the Invention

[0019] When used herein, the following words and phrases are generally intended to have the meanings set forth below, unless otherwise indicated by the context in which they are used.

[0020] Compound 1: As used herein, "Compound 1" means 3-methoxy-N-[3-(2-methylpyrazole-3-yl)-4-(2-morpholine-4-ylethoxy)phenyl]benzamide, including its crystalline form. As a non-limiting example, Compound 1 may exist as a crystalline form disclosed in U.S. Patent No. 8,980,891 (which is incorporated herein by reference in its entirety), characterized by one or more of the following °2θ values ​​for peaks in a PXRD spectrum using CuKα irradiation: 5.0998, 18.7064, 19.1157, 19.3029, and 23.6567 (the reported peaks may vary by approximately ±0.2°2θ).

[0021] Compound 1 or its pharmaceutically acceptable salt, hydrate, or solvate, and its active metabolites (M1 and M2) have high affinity for human 5-HT2A, and 5-HT 2B and 5-HT 2C The affinity for the receptor is not significant enough to be observed. M1 refers to N-(4-(2-(2-hydroxyethylamino)ethoxy)-3-(1-methyl-1H-pyrazole-5-yl)phenyl)-3-methoxybenzamide. M2 refers to N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazole-5-yl)phenyl)-3-methoxybenzamide.

[0022] To treat, to treat, or to treat: As used herein, the terms “to treat,” “to treat,” or “treatment” mean the administration of treatment to an individual (i.e., a human) who is already exhibiting or has previously exhibited at least one symptom of a disease or condition. For example, “to treat” may include alleviating, mitigating, or improving a disease, condition or symptom; preventing additional symptoms; improving the underlying cause of the symptoms; suppressing the disease or condition, for example, preventing the progression of the disease or condition; eliminating the disease or condition; reversing the disease or condition; resolving a condition caused by the disease or condition; or stopping the symptoms of the disease or condition. For example, with respect to a disability, the term “to treat” means reducing the severity of one or more symptoms associated with a particular disability. Thus, treating a disability does not necessarily mean reducing the severity of all symptoms associated with the disability, nor does it necessarily mean the complete elimination of the severity of one or more symptoms associated with the disability.

[0023] To prevent, to prevent, or prevention: As used herein, the terms “to prevent,” “to prevent,” or “prevention” mean the prevention of the onset or occurrence of one or more symptoms associated with a particular disorder, and not necessarily the complete prevention of the disorder. For example, the terms “to prevent,” “to prevent,” and “prevention” refer to the administration of preventive measures or preventive treatment to an individual who may eventually develop at least one symptom of a disease or condition, but who has not yet developed it. Such individuals can be identified from risk factors known to be interrelated with the subsequent development of the disease. Alternatively, preventive treatment may be administered as a preventive measure even if risk factors have not been identified beforehand. Delaying the onset of at least one symptom may also be considered prevention or preventive measures.

[0024] Dosage: As used herein, “dose” means the measured amount of the active agent that an individual receives in a single dose. In certain embodiments where the active agent is not the free base of compound 1, the amount is the molar equivalent of the amount of the free base of compound 1. For example, often the drug is packaged as a pharmaceutically acceptable salt form of compound 1, e.g., an HCl salt, and the dose for potency refers to the mass of the molar equivalent of the corresponding free base of compound 1.

[0025] Tolerable: As used herein, an individual is said to "tolerate" a dose of a compound if, as a result of being administered a certain dose, no unacceptable adverse event or combination of unacceptable adverse events occurs. Those skilled in the art will understand that tolerability is a subjective measure, and that what is tolerable to one individual may not be tolerable to another. For example, one individual may not be able to tolerate a headache; a second individual may find a headache tolerable but not vomiting; and a third individual may be able to tolerate either a headache or vomiting alone, but not a combination of headache and vomiting (even if the severity of each is lower than when experienced individually).

[0026] Adverse Events: As used herein, “adverse event” means an undesirable medical occurrence associated with treatment with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, the adverse event is selected from dizziness, headache, and nausea.

[0027] The phrase "pharmaceutically acceptable salts, solvates, and hydrates" or "pharmaceutically acceptable salts, solvates, or hydrates," when used in reference to compound 1, is understood to include pharmaceutically acceptable solvates and / or hydrates of compound 1, pharmaceutically acceptable salts of compound 1, and pharmaceutically acceptable solvates and / or hydrates of pharmaceutically acceptable salts of compound 1. Furthermore, the phrase "pharmaceutically acceptable solvates, and hydrates" or "pharmaceutically acceptable solvates, or hydrates," when used in reference to a salt of compound 1, is understood to include pharmaceutically acceptable solvates and / or hydrates of such salts.

[0028] It will be apparent to those skilled in the art that the dosage forms described herein may contain, as the active ingredient, either Compound 1 or a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof. Furthermore, various hydrates and solvates of Compound 1 and its salts are also used as intermediates in the manufacture of pharmaceutical compositions. Beyond those mentioned herein, typical procedures for the manufacture and identification of suitable hydrates and solvates are well known to those skilled in the art. See, for example, K.J. Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," pp. 202–209, and source: Polymorphism in Pharmaceutical Solids, edited by Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999. Accordingly, one aspect of the present disclosure relates to a method for formulating 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, such as thermogravimetric analysis (TGA), TGA-mass spectrometry, TGA-infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, and high-resolution X-ray diffraction.

[0029] As used herein, the term "greater than" is used interchangeably with the symbol >, and the term "less than" is used interchangeably with the symbol <. Similarly, the term "greater than or equal to" is used interchangeably with the symbol ≧, and the term "less than or equal to" is used interchangeably with the symbol ≦.

[0030] When integers are used in the methods disclosed herein, the term “about” may be inserted before the integer.

[0031] Throughout this specification, unless otherwise specified in the context, the word “comprise” or variations such as “comprises” or “comprising” are understood to mean including the specified step, element, integer, or group of steps, elements, or integers, but not to mean excluding any other step, element, integer, or group of elements or integers.

[0032] Throughout this specification, unless otherwise specified in detail or provided for in the context, any reference to a single step, material composition, group of steps, or group of material compositions shall be interpreted as encompassing one or more such steps, material compositions, groups of steps, or groups of material compositions.

[0033] Each embodiment described herein shall apply mutatis mutandis to all other embodiments unless otherwise specified in detail.

[0034] Those skilled in the art will recognize that the invention described herein is subject to modifications and improvements other than those described in detail. The invention is understood to encompass all such modifications and improvements. The invention also encompasses all steps, features, compositions, and compounds mentioned or pointed out herein, individually or comprehensively, as well as any combination of any two or more of the aforementioned steps or features, unless otherwise specified in detail.

[0035] The present invention is not limited in scope by the detailed embodiments described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention as described herein. For example, the dosage of Compound 1 disclosed herein or a pharmaceutically acceptable salt, solvate, or hydrate thereof, when measured by the method disclosed in the FDA's Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations (Center for Drug Evaluation and Research (CDER), March 2003, first revised, www.fda.gov / cder / guidance / index.htm), yields AUC and / or C max The specified amount of compound 1 or other salts or crystalline forms, formulations, and dosages in the administration plan that exhibit bioequivalence to a pharmaceutically acceptable salt, solvate, or hydrate thereof, including forms having 80-125% of the compound 1, may be substituted. For example, the dosage of compound 1 disclosed herein may be substituted with other salts or crystalline forms, formulations, or dosages in the administration plan that exhibit bioequivalence to the dosage of compound 1.

[0036] For clarity, certain features of the present invention described in the context of separate embodiments may be provided in combination as a single embodiment. For example, a method claiming to formulate Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof may be combined with another method of the present invention claiming to administer Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to form a single method claiming to formulate and administer Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0037] What is provided is a method for treating or preventing Raynaud's disease, The method involves formulating and / or administering to an individual in need of it 3-methoxy-N-[3-(2-methylpyrazole-3-yl)-4-(2-morpholine-4-ylethoxy)phenyl]benzamide (compound 1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0038] What is provided is a method for treating or preventing SSc-RP, The method involves formulating and / or administering to an individual in need of it 3-methoxy-N-[3-(2-methylpyrazole-3-yl)-4-(2-morpholine-4-ylethoxy)phenyl]benzamide (compound 1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0039] In some embodiments, Raynaud is Raynaud's syndrome. In some embodiments, Raynaud is Raynaud's disease. In some embodiments, Raynaud is Raynaud's phenomenon. In some embodiments, Raynaud is primary Raynaud's syndrome. In some embodiments, Raynaud is secondary Raynaud's syndrome. In some embodiments, Raynaud is primary Raynaud's disease. In some embodiments, Raynaud is secondary Raynaud's disease. In some embodiments, Raynaud is primary Raynaud's phenomenon. In some embodiments, Raynaud is secondary Raynaud's phenomenon. In some embodiments, Raynaud is Raynaud's disease secondary to systemic sclerosis. In some embodiments, Raynaud is Raynaud's disease secondary to another autoimmune disease. In some embodiments, Raynaud is Raynaud's syndrome secondary to systemic sclerosis. In some embodiments, Raynaud is Raynaud's syndrome secondary to another autoimmune disease. In some embodiments, Raynaud is Raynaud's phenomenon secondary to an autoimmune disease. In some embodiments, Raynaud is progressive systemic sclerosis (PSS).

[0040] In some embodiments, the individual has at least one finger ulcer.

[0041] In some embodiments, the individual has finger gangrene.

[0042] In some embodiments, the individual has systemic sclerosis.

[0043] In some embodiments, individuals have Raynaud's disease secondary to a condition selected from systemic sclerosis, rheumatoid arthritis, lupus, vasculitis, atherosclerosis, cryoglobulinemia, hypothyroidism, injury, and drug reactions.

[0044] In some embodiments, the individual has Raynaud's disease secondary to systemic sclerosis.

[0045] In some embodiments, the individual has systemic sclerosis and at least one finger ulcer.

[0046] In some embodiments, the treatment includes at least one of reducing the frequency of seizures, shortening the duration of seizures, reducing the severity of seizures, reducing ischemic tissue injury, and reducing finger ulceration.

[0047] In some embodiments, the treatment includes reducing the frequency, duration, and / or severity of seizures.

[0048] In some embodiments, prevention includes at least one of preventing seizures, preventing ischemic tissue injury, and preventing finger ulceration.

[0049] In some embodiments, approximately 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, or 160 mg of compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered per day.

[0050] In some embodiments, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered.

[0051] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered three times daily (TID).

[0052] In some embodiments, Raynaud's disease is determined using patient-reported outcomes (PROs).

[0053] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered during the winter.

[0054] In some embodiments, the method further includes instructing the individual to minimize exposure to ultraviolet light. In some embodiments, the method further includes instructing the individual to wear protective clothing, protective eyewear, and to apply sunscreen to exposed areas of the body.

[0055] In some embodiments, the treatment methods provided herein are maintenance treatments for individuals who have previously received or are currently receiving other treatments for Raynaud's disease. In some embodiments, individuals with Raynaud's disease have become resistant to previous Raynaud's treatments. For example, in some embodiments, individuals with Raynaud's disease are resistant to Ca2+ blockers, antiplatelet agents, topical nitroglycerin, ACE inhibitors or ARBs, alpha-blockers, SSRIs or other anxiolytics, PDE5, ETRA, or IV prostacyclin analogs. In some embodiments, individuals with Raynaud's disease are resistant to vasodilatory treatments. In some embodiments, individuals with Raynaud's disease are resistant to intravenous prostanoid treatments. In some embodiments, individuals with Raynaud's disease are resistant to epoprostenol, iloprost, bosentan, tadalafil, nifedipine, nicardipine, or quinapril treatments.

[0056] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 10 mg to about 250 mg of free base of compound 1.

[0057] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 20 mg to about 250 mg of free base of compound 1.

[0058] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 10 mg to about 200 mg of free base of compound 1.

[0059] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 10 mg to about 80 mg of free base of compound 1.

[0060] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 10 mg to about 60 mg of free base of compound 1.

[0061] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 10 mg of compound 1 free base. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 15 mg of compound 1 free base. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 20 mg of compound 1 free base. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 25 mg of compound 1 free base. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 30 mg of compound 1 free base. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 40 mg of compound 1 free base. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 50 mg of compound 1 free base. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 60 mg of compound 1 free base. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 70 mg of compound 1 free base. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 75 mg of compound 1 free base. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 80 mg of compound 1 free base. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 90 mg of compound 1 free base. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 100 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 110 mg of free base compound 1.In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 120 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 130 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 140 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 150 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 160 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 170 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 180 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 190 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 200 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 210 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 220 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 230 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 240 mg of free base compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered in an amount equivalent to about 250 mg of free base compound 1.

[0062] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered once daily (QD).

[0063] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered twice daily (BID).

[0064] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered three times daily (TID).

[0065] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered as a TID in an amount equivalent to about 10 mg to about 80 mg of free compound 1 base (equivalent to about 30 mg to about 240 mg of free compound 1 base daily).

[0066] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered as a TID in an amount equivalent to about 10 mg to about 60 mg of free compound 1 base (equivalent to about 30 mg to about 180 mg of free compound 1 base daily).

[0067] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered orally.

[0068] In some embodiments, the oral formulation is administered for at least, or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0069] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is formulated as a capsule suitable for oral administration. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is formulated as a tablet suitable for oral administration.

[0070] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a pharmaceutically acceptable salt of compound 1 or a hydrate or solvate thereof.

[0071] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a pharmaceutically acceptable salt of compound 1.

[0072] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is the HCl salt of compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is the hydrate of compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is the solvate of compound 1.

[0073] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is useful in inhibiting platelet aggregation in Raynaud's phenomenon. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is useful in inhibiting vasoconstriction in Raynaud's phenomenon. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is useful in inhibiting both platelet aggregation and vasoconstriction in Raynaud's phenomenon.

[0074] The compounds disclosed herein are useful in the treatment of systemic sclerosis and its symptoms. Systemic sclerosis may include, for example, CREST syndrome (calcification, Raynaud's, hypoesophageal motility, scleroderm, and telangiectasia). Symptoms of systemic sclerosis include, for example, Raynaud's.

[0075] The compounds disclosed herein are useful in the treatment of Raynaud's syndrome and its symptoms. Symptoms of Raynaud's syndrome include, for example, finger ulceration and gangrene. The compounds disclosed herein are useful in the treatment of symptoms of Raynaud's syndrome.

[0076] In some embodiments, treatment or prevention of Raynaud's disease is determined by the nature of Raynaud's seizures. In some embodiments, treatment or prevention of Raynaud's disease is determined by the frequency of Raynaud's seizures. In some embodiments, treatment or prevention of Raynaud's disease is determined by the duration of Raynaud's seizures. In some embodiments, treatment or prevention of Raynaud's disease is determined by the severity of Raynaud's seizures. In some embodiments, treatment or prevention of Raynaud's disease is determined by the impact of Raynaud's seizures.

[0077] In some embodiments, the frequency of Raynaud's seizures is measured on a daily basis. In some embodiments, the frequency of Raynaud's seizures is measured on a weekly basis. In some embodiments, the frequency of Raynaud's seizures is measured on a monthly basis. In some embodiments, the frequency of Raynaud's seizures is measured on a yearly basis. In some embodiments, the frequency of Raynaud's seizures is measured as the time between seizures.

[0078] In some embodiments, the duration of a Raynaud's seizure is measured in minutes. In some embodiments, the duration of a Raynaud's seizure is measured in hours. In some embodiments, the duration of a Raynaud's seizure is measured in days.

[0079] In some embodiments, changes in the frequency, duration, and / or severity of Raynaud's seizures are determined compared to baseline. In some embodiments, changes from baseline are determined at weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 20, 44, 48, or 52.

[0080] In some embodiments, treatment or prevention of Raynaud's disease is determined by the reduction of the ulcer load of secondary Raynaud's disease. In some embodiments, treatment or prevention of Raynaud's disease is determined by the healing of finger ulcers. In some embodiments, treatment or prevention of Raynaud's disease is determined by the healing of one or more finger ulcers. In some embodiments, treatment or prevention of Raynaud's disease is determined by the healing of all finger ulcers. In some embodiments, treatment or prevention of Raynaud's disease is determined by the prevention of new active finger ulcers. In some embodiments, treatment or prevention of Raynaud's disease is determined by the time it takes to heal one or more finger ulcers.

[0081] In some embodiments, Raynaud's treatment or prevention is determined by a visual analog scale (VAS). In some embodiments, Raynaud's treatment or prevention is determined by a Raynaud's severity visual analog score. In some embodiments, Raynaud's treatment or prevention is determined by a Raynaud's state score visual analog score. In some embodiments, Raynaud's treatment or prevention is determined by finger blood pressure. In some embodiments, Raynaud's treatment or prevention is determined by capillary diameter. In some embodiments, Raynaud's treatment or prevention is determined by a decrease in the hand disability score.

[0082] In some embodiments, the treatment or prevention of Raynaud's disease is determined by the patient's assessment. In some embodiments, the treatment or prevention of Raynaud's disease is determined by the physician's assessment.

[0083] In some embodiments, the treatment or prevention of Raynaud's is determined by patient-reported outcomes (PROs). In some embodiments, the PRO is a Raynaud's Status Score (RCS). In some embodiments, the PRO is a Likert scale. In some embodiments, the PRO is a 10-point Likert scale. In some embodiments, the PRO is an 11-point Likert scale. In some embodiments, the PRO is a daily patient scale. In some embodiments, the PRO is an individual's assessment of pain during a Raynaud's attack. In some embodiments, the PRO is an individual's assessment of numbness during a Raynaud's attack. In some embodiments, the PRO is an individual's assessment of stabbing pain during a Raynaud's attack. In some embodiments, the PRO is an individual's comprehensive assessment of the severity of Raynaud's. In some embodiments, the PRO is an individual's assessment of quality of life (QOL) with Raynaud's.

[0084] In some embodiments, Raynaud's treatment or prevention is the treatment or prevention of the measurement described herein. For example, in some embodiments, Raynaud's treatment or prevention is the improvement of PRO.

[0085] In some embodiments, the methods described herein are useful for the prevention or treatment of critical ischemia in SSc-RP. In some embodiments, critical ischemia is defined as the presence of ischemic symptoms at rest. In some embodiments, the methods described herein are useful for the prevention or treatment of severe ischemia in SSc-RP. In some embodiments, severe ischemia is defined as requiring intravenous vasodilator therapy, surgical resection of necrotic tissue, and / or amputation.

[0086] In some embodiments, the method described herein is useful for preventing or treating discoloration of the fingers. In some embodiments, the method described herein is useful for preventing or treating one or more finger ulcers. In some embodiments, the method described herein is useful for preventing or treating gangrene in SSc-RP. In some embodiments, the method described herein is useful for preventing amputation. In some embodiments, the method described herein is useful for preventing amputation of one or more fingers.

[0087] In some embodiments, the methods described herein are useful for preventing or treating vascular damage in SSc-RP. In some embodiments, the methods described herein are useful for preventing or treating endothelial damage in SSc-RP. In some embodiments, the methods described herein are useful for preventing or treating tissue fibrosis in SSc-RP.

[0088] In some embodiments, the method described herein is useful for improving blood flow to the fingers. In some embodiments, the method described herein is useful for improving blood pressure to the fingers. In some embodiments, the method described herein is useful for reducing capillary damage to the fingers. In some embodiments, the method described herein is useful for reducing endothelial damage. In some embodiments, the method described herein is useful for preventing or treating decreased blood flow after cold exposure. In some embodiments, the method described herein is useful for improving the recovery of blood flow after cold exposure.

[0089] In some embodiments, the compounds described herein are administered seasonally. In some embodiments, the compounds described herein are administered during the winter. In some embodiments, the compounds described herein are administered when an individual is exposed to temperatures of 60°F, 55°F, 50°F, 45°F, 40°F, 35°F, or less than 32°F or about these temperatures. In some embodiments, the compounds described herein are administered after the symptoms described herein are detected. In some embodiments, secondary Raynaud's phenomenon is diagnosed using blood tests.

[0090] In some embodiments, the method further includes monitoring for bleeding-related adverse events. In some embodiments, the evaluation is categorized using the BARC definition of bleeding as described in Mehran et al. (2011) Circulation 123(23)2736-2747, which is as follows: ●Type 0 is defined as no bleeding. ●Type 1 is defined as bleeding that is not complainable and does not cause the patient to request unplanned research, hospitalization, or medical treatment, and may include episodes that lead to the patient's self-discontinuation of medical therapy without consultation with a medical professional. ●Type 2 does not meet the criteria for Type 3, 4, or 5, but the following criteria apply: ○ Non-surgical medical intervention by medical professionals is necessary. ○ Leads to hospitalization or an increase in nursing care levels. ○ Encourage a medical examination It is defined as any obvious symptomatic hemorrhage sign (i.e., bleeding greater than expected given the clinical circumstances, including bleeding only detected by imaging) that satisfies at least one of the following conditions. ●Type 3 is, ○In addition to obvious bleeding, a decrease in hemoglobin between 3g / dLa and less than 5g / dLa (however, the decrease in hemoglobin is related to bleeding). Blood transfusion due to obvious bleeding. ○ Obvious bleeding in addition to a decrease in hemoglobin of 5 g / dLa or more (however, the decrease in hemoglobin is related to bleeding). Cardiac tamponade bleeding requiring surgical intervention for control (excluding dental / nasal / cutaneous / hemorrhoidal bleeding). Bleeding requiring intravenous vasoactive drugs, or ○ Massive intracranial hemorrhage (excluding microhemorrhages or hemorrhagic deformities, including intraspinal cord hemorrhage). Sub-categories confirmed by autopsy, imaging, or lumbar puncture. Intraocular hemorrhage affecting vision. It is stipulated that ●Type 4 is defined as CABG-related bleeding. Intracranial hemorrhage within 48 hours of surgery. Reoperation after sternotomy and suturing for bleeding control purposes. Transfusion of 5 U or more of whole blood or packed red blood cells within the 48-hour period. Discharge of 2 L or more of the pleural tube within the 24-hour period. ●Type 5 is defined as lethal bleeding.

[0091] Furthermore, a method for identifying subjects likely to respond to treatment with compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, Administer compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof to the target. To obtain a sample from the target, To determine the levels of biomarkers in the sample, and If the level of a biomarker in a sample differs from the reference level of the biomarker, the subject is diagnosed as likely to respond to the treatment compound. Methods including this are also provided.

[0092] In some embodiments, the sample is a blood sample. In some embodiments, the sample is a tissue sample.

[0093] In some embodiments, biomarkers include plasma serotonin concentration, markers of vascular damage and endothelial dysfunction (endothelin 1, factor VIII activity, intracellular adhesion molecule 1 [ICAM-1], thromboxane B2, tissue-type plasminogen activator antigen [t-PA], plasminogen activator inhibitor 1 [PAI-1] activity, PAI-1 antigen, vascular adhesion molecule 1 (VCAM-1), vascular endothelial growth factor (VEGF), and von Willebrand factor [VWF]).

[0094] In some embodiments, the level of the biomarker in the sample is higher than the reference level of the biomarker. In some embodiments, the level of the biomarker in the sample is lower than the reference level of the biomarker.

[0095] In some embodiments, the level of the biomarker is measured by determining the protein level of the biomarker. In some embodiments, the level of the biomarker is measured by determining the mRNA level of the biomarker. In some embodiments, the level of the biomarker is measured by determining the cDNA level of the biomarker. In some embodiments, the biomarker is identified by DNA sequencing. In some embodiments, the biomarker is identified by RNA sequencing (RNA-seq).

[0096] Furthermore, the use of Compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof as described herein in the manufacture of a pharmaceutical product for treating Raynaud's disease as described herein is also provided herein.

[0097] Furthermore, Compound 1 as described herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in the method of treating Raynaud's disease as described herein, is also provided herein.

[0098] Compound 1 as described herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for treating Raynaud's disease as described herein, is also provided herein.

[0099] Furthermore, a kit is also provided herein, which includes a dosage setting package as disclosed herein and instructions indicating that the drug therapy is to be administered to individuals requiring treatment for Raynaud's disease.

[0100] Tablets and capsules for oral administration may contain conventional excipients, such as binders, fillers, acceptable wetting agents, tableting lubricants, and disintegrants. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, oral preparations may be in the form of a dry powder that can be reconstituted with water or another suitable liquid medium before use. Additional additives, such as suspending agents, emulsifiers, non-aqueous media (including edible oils), preservatives, flavoring agents, and coloring agents, may be added to liquid preparations.

[0101] Parenteral dosage forms can be prepared by dissolving the compound in a suitable liquid medium, sterilizing the solution by filtration, and then filling and sealing it into appropriate vials or ampoules. These are just a few examples of the many suitable methods well known in the art for preparing dosage forms. In addition to those mentioned herein, suitable pharmaceutically acceptable carriers are known in the art. See, for example, Remington, The Science and Practice of Pharmacy, 20th edition, 2000, Lippincott Williams & Wilkins (Gennaro et al., eds.).

[0102] The compounds provided herein can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the dosage form may contain, as the active ingredient, the compounds provided herein, or any pharmaceutically acceptable salts, solvates, or hydrates of the compounds provided herein.

[0103] In some embodiments, compound 1 further comprises a pharmaceutical formulation or a pharmaceutically acceptable carrier. Pharmaceutical formulations may include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal, or parenteral (including intramuscular, subcutaneous, and intravenous) administration, or those suitable for inhalation, gas injection, or transdermal patch administration. Accordingly, the compounds provided herein may be incorporated into pharmaceutical formulations and their unit dosage forms together with conventional adjuvants, carriers, or diluents, in which case they may be used as solids such as tablets or filled capsules for oral use, or as liquids such as solutions, suspensions, emulsions, elixirs, gels, or gel-filled capsules, in the form of suppositories for rectal administration, or as sterile solutions for injection for parenteral (including subcutaneous) use. The active ingredient may also be administered by injection as a composition in which, for example, saline, dextrose, or water may be used as a suitable pharmaceutically acceptable carrier. Such pharmaceutical compositions and their unit dosage forms may contain conventional components in conventional proportions, with or without additional active compounds or active pharmaceutical ingredients (principle), and such unit dosage forms may contain an appropriate effective amount of the active ingredient corresponding to the intended daily dose range. In some embodiments, the capsules are gelatin capsules. In some embodiments, the capsules are hard gelatin capsules.

[0104] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, suspensions, or liquids. The pharmaceutical composition is preferably manufactured in the form of dosage units containing a specific amount of the active ingredient. Examples of such dosage units include capsules, tablets, powders, granules, or suspensions using conventional additives such as lactose, mannitol, corn starch, potato starch; binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch, gelatin; disintegrants such as corn starch, potato starch, sodium carboxymethylcellulose; and lubricants such as talc or magnesium stearate.

[0105] In some embodiments, the oral formulation of compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is an immediate-release dosage form comprising compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0106] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is formulated as a capsule suitable for oral administration. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is formulated as a tablet suitable for oral administration.

[0107] In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is co-administered with at least one antiplatelet agent. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is co-administered with dual antiplatelet therapy (DAPT). In some embodiments, the individual has already been administered at least one antiplatelet agent prior to the administration of compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof as described herein. In some embodiments, the individual receives an initial dose of at least one antiplatelet agent prior to PCI. In some embodiments, the individual receives a loading dose of at least one antiplatelet agent prior to PCI. In some embodiments, the antiplatelet agent is aspirin. In some embodiments, the antiplatelet agent is a P2Y12 inhibitor. In some embodiments, the P2Y12 inhibitor is an oral P2Y12 inhibitor. In some embodiments, the P2Y12 inhibitor is selected from clopidogrel, ticlopidine, ticagrelor, prasugrel, and cangrelor. In some embodiments, the DAPT is aspirin and clopidogrel. In some embodiments, compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is co-administered with clopidogrel but not with prasugrel or ticagrelor.

[0108] In some embodiments, vasodilators are co-administered to the individual. In some embodiments, calcium channel blockers (CCBs), phosphodiesterase (PDE) 5 inhibitors, angiotensin II receptor blockers (ARBs), topical nitrates, intravenous (IV) prostanoids, and / or endothelin 1 receptor antagonists are co-administered to the individual.

[0109] In some embodiments, the CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer is not co-administered to the individual with compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the individual has already been administered at least one CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer prior to the administration of compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof as described herein. In some embodiments, the administration of the CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer is interrupted when the individual is administered compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, a lower dose of an inhibitor or inducer of CYP3A4, CYP3A5, and / or P-glycoprotein is co-administered to the individual when co-administered with compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, a lower dose of compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered to the individual when co-administered with an inhibitor or inducer of CYP3A4, CYP3A5, and / or P-glycoprotein. In some embodiments, a lower dose of an inhibitor or inducer of CYP3A4, CYP3A5, and / or P-glycoprotein is co-administered to the individual with a lower dose of compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the inhibitor or inducer of CYP3A4, CYP3A5, and / or P-glycoprotein is a strong inhibitor or inducer of CYP3A4, CYP3A5, and / or P-glycoprotein. In some embodiments, the inhibitor or inducer of CYP3A4, CYP3A5, and / or P-glycoprotein is selected from ketoconazole, itraconazole, clarithromycin, erythromycin, rifampicin, and verapamil. In some embodiments, the inhibitor or inducer of CYP3A4, CYP3A5, and / or P-glycoprotein is a CYP3A4 inhibitor or inducer.In some embodiments, the inhibitor or inducer of CYP3A4, CYP3A5, and / or P-glycoprotein is a CYP3A5 inhibitor or inducer. In some embodiments, the individual is co-administered intra-arterial verapamil for radial artery PCI.

[0110] Some embodiments include a method for producing a pharmaceutical composition for a fixed-dose combination therapy, comprising mixing at least one compound according to any of the compound embodiments disclosed herein with at least one known pharmaceutically and pharmaceutically acceptable carrier as described herein.

[0111] Further embodiments include those disclosed in the following embodiments, and these embodiments shall not be construed as limiting in any respect. [Examples]

[0112] (Example 1) We conducted a study to evaluate the effects of intra-arterial administration of compound 1 and ketanserin on body temperature, peripheral cooling, and peripheral blood flow in anesthetized, untreated male New Zealand white rabbits.

[0113] [Table 1]

[0114] Formulations of each test compound were prepared by adding saline solution, vortex stirring, and sonication until a clear solution was obtained.

[0115] The rabbits were sedated with ketamine / xylazine (25 / 5 mg / kg subcutaneously), then intubated and anesthetized with 1-2% isoflurane (1-2 L / min) delivered with 100% oxygen. The animals were placed under mechanical ventilation and normal body temperature (38-40°C) was maintained using an external heat source (e.g., circulating water blanket, heated operating table). 1 mg / kg of intradermal bupivacaine was infiltrated into the incision site in the thigh. A catheter for administration was inserted into the left femoral artery by cutdown.

[0116] Peripheral temperature was assessed by placing a thermal thermistor on the skin of the dorsal surface of the left hind leg (LHFT) and right hind leg (RHFT), and core body temperature was assessed by inserting it rectally. Temperature values ​​were reported as a 1-minute average from 5 minutes before the start of dose 1 administration (the values ​​were averaged and used as the baseline) until the completion of dose 2 administration.

[0117] Transonics Systems, Inc. (Ithaca, New York) evaluated peripheral blood flow by attaching a Doppler flow probe to the dorsal surface of the left hind leg. Peripheral blood flow (PBF) was reported as a 1-minute average from 5 minutes before the start of dose 1 administration (the average value was used as the baseline) until the completion of dose 2 administration.

[0118] An electrocardiogram (ECG) was recorded via surface leads.

[0119] At the start of dose 1 administration, each rabbit's left hind leg was immersed in a water bath set to maintain a temperature of approximately 40°C. Immediately after dose 1 administration, dose 2 administration was started. At the start of dose 2 administration, each rabbit's left hind leg was immersed in a water bath set to maintain a temperature of approximately 15°C. Thirty minutes after the start of dose 2 administration, only in groups 4-6, each rabbit's left hind leg was removed, allowed to return to room temperature, monitored, and administered for another 15 minutes.

[0120] At the end of dose 2 administration, blood samples were collected from the right and left femoral veins. The blood samples were collected in collection tubes containing K2EDTA anticoagulant and 0.5 mM PGE1 (0.17725 mg / mL in ethanol) and 0.5 mM citalopram (0.20265 mg / mL in water) in a ratio of 1:500 relative to the blood volume (for example, 0.5 mL of blood contains 0.001 mL of PGE1 and 0.001 mL of citalopram). The samples were stored at room temperature for at least 30 minutes, and then centrifuged at approximately 850 g for 10 minutes at ambient temperature. Approximately 2 / 3 volume of plasma was transferred. This was then centrifuged at approximately 4500–5000 g for 5–10 minutes.

[0121] At the end of dose 2 administration, an additional 0.5 mL of sample was collected from systemic blood vessels into a collection tube containing K2EDTA anticoagulant. The sample was centrifuged at ambient temperature for approximately 10 minutes.

[0122] Using time-matched media-controlled data as a baseline, we determined the mean percentage changes in temperature and blood flow between baseline and each dose-dosing fraction.

[0123] Compound 1 and ketanserin partially reduced cold-induced vasoconstriction in rabbit feet (Figures 1-4). Figure 1 shows the left hind foot temperature in groups 4-6 upon introduction to 40°C, 15°C, and room temperature water baths. Figure 2 shows the right hind foot temperature in groups 4-6 upon introduction to room temperature water. Figure 3 shows the change from baseline in left hind foot temperature in groups 4-6 upon introduction to 40°C, 15°C, and room temperature water baths. Figure 4 shows the change from baseline in left hind foot temperature in groups 4-6 after 30 minutes of cooling and 15 minutes of recovery.

[0124] (Example 2) Oral preparations Table 1 shows an example of an oral formulation of compound 1.

[0125] [Table 2]

[0126] (Example 3) Clinical Trial 1 A phase 1 randomized, double-blind, placebo-controlled single-dose escalation study was conducted to evaluate the tolerability, pharmacokinetic (PK), and disease progression (PD) of a single dose of the compound, ranging from 1 to 320 mg, administered orally to a total of 91 healthy subjects.

[0127] Compound 1 was rapidly absorbed at all doses, and plasma exposure levels increased in a manner that was more than dose-proportional. Active metabolites M1 and M2 had longer half-lives than the parent compound, and as the dose of compound 1 gradually increased, the half-life of compound 1 lengthened, exposure increased, and the metabolite-to-parent ratio decreased.

[0128] PD assessment consisted of measuring pre- and post-administration platelet aggregation using in vitro assays with or without 5-HT in combination with ADP. The degree of platelet aggregation inhibition induced by thrombin receptor-activated peptide (TRAP) was similar across groups. However, at doses above 1 mg, compound 1 inhibited 5-HT-mediated platelet aggregation amplification.

[0129] Data on 5-HT-mediated platelet aggregation from a single dose of compound ranging from 5 to 320 mg showed maximum inhibition at 1 to 2 hours. Although interpretation was complex due to high variability, the data suggests a tendency for longer duration of inhibition at higher doses.

[0130] (Example 4) Clinical Trial 2 A phase 1 randomized, double-blind, placebo-controlled, multiple dose-escalation study was conducted to evaluate the safety, tolerability, disease progression (PD), and steady-state drug transport (PK) of compound 1 administered orally in doses ranging from 5 to 80 mg over 7 days in a total of 50 healthy subjects.

[0131] Compound 1 was rapidly absorbed at all doses, and the day 1 AUC and Cmax values ​​at equivalent doses were similar to those for the study in Example 3. Exposure, as measured by AUC, was dose-proportional at 5 and 10 mg on days 1 and 7, but more dose-proportional at 40, 60, and 80 mg. The Cmax and AUC accumulation ratios were less than 2 for all doses when comparing day 1 and day 7, indicating no accumulation after 7 days of TID administration. The half-lives were similar for all doses and days.

[0132] As exposure to active metabolites M1 and M2 increased and the compound dose increased, the metabolite-to-parent ratio decreased. For M1 and M2, the accumulation ratio, as measured by AUCtau values, was approximately 2 at 60 and 80 mg, respectively, suggesting a twofold accumulation of these metabolites after 7 days of TID administration.

[0133] Administration of compound 1 inhibited 5-HT-mediated platelet aggregation amplification ex vivo. The inhibition was substantially maximal at doses of 60 mg and 80 mg after administration on days 1, 4, and 7.

[0134] (Example 5) Clinical Trial 3 To evaluate the effect of oral compound 1 on finger blood flow in subjects with Raynaud's phenomenon secondary to systemic sclerosis (SSc-RP), a phase 2 randomized, double-blind, placebo-controlled crossover study will be conducted. Raynaud's phenomenon is defined as a history of cold sensitivity of the fingers with cyanosis and pallor, occurring during the winter months, with an average of five attacks per week or two attacks per day, secondary to systemic sclerosis, based on either (1) a diagnosis of SSc using the LeRoy and Medsger classification as described by the American College of Rheumatology / European League Against Rheumatism and / or LeRoy et al. (2001) J.Rheumatol.28:1573~1576 or van den Hoogen et al. (2013) Arthritis Rheum 65:2737~2747, or (2) a diagnosis of very early SSc using the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) criteria as described by Avouac et al. (2011) Ann.Rheum.Dis.70(3):476~481.

[0135] In a randomized, three-period crossover design, subjects will receive a single oral dose of the study treatment on days 1, 8, and 15. The oral formulation of compound 1 contains the active pharmaceutical ingredient as an HCl salt. In Part A of the study, each subject will receive a single dose of each dose intensity. Dose selection for Part B of the study will be based on the efficacy and safety results from Part A.

[0136] In Part A, participants are equally and double-blindly randomized to one of three crossover consecutive treatments. Each participant participates in three treatment visits, separated by a drug-free period of at least 72 hours and up to 7 days. Between each treatment visit, participants receive a single dose of the study treatment (placebo, 60 mg of compound 1 free base, or 120 mg of compound 1 free base) according to their crossover consecutive treatment assignment. On Day 1, participants enter the clinic for Treatment Visit 1. Participants are instructed to eat a breakfast of approximately 400-500 calories with a fat content of less than 25% (11-14 g) at least 2 hours before the treatment.

[0137] After acclimatization, subjects undergo pre-administration blood sampling and evaluation of finger blood flow using infrared (IR) thermography or laser speckle contrast imaging (LSCI). IR thermography is an indirect method for evaluating blood flow based on imaged skin temperature, while LSCI is based on differences in speckle patterns (generated when laser light illuminates tissue) due to the movement of blood cells. Image processing software for IR thermography and LSCI allows for quantitative measures of blood flow within a given region of interest (ROI) to be obtained as mean temperature (°C) and arbitrary perfusion units (pu), respectively.

[0138] After administration of the study treatment, subjects will undergo at least 20 minutes of re-acclimatization. 45 minutes (±5 minutes) after administration, blood samples will be collected for pharmacokinetics (PK) and plasma serotonin concentration. After reassessing finger blood flow, subjects will be subjected to a 5-minute cold load at room temperature. The cold load will be administered by immersing the hands in a temperature-controlled water bath (15°C) for 1 minute. After reassessing blood samples for PK and plasma serotonin concentration, finger blood flow will be assessed for 30 minutes. After the post-cold load finger blood flow assessment is complete, blood samples for PK and biomarkers will be collected again.

[0139] The mechanism of action of compound 1 (plasma serotonin concentration) and biomarkers related to vascular damage and endothelial dysfunction will be evaluated. Such biomarkers may include plasma serotonin concentration and markers of vascular damage and endothelial dysfunction (endothelin 1, factor VIII activity, intracellular adhesion molecule 1 [ICAM-1], thromboxane B2, tissue-type plasminogen activator antigen [t-PA], plasminogen activator inhibitor 1 [PAI-1] activity, PAI-1 antigen, vascular adhesion molecule 1 (VCAM-1), vascular endothelial growth factor (VEGF), and von Willebrand factor [VWF]).

[0140] For treatment visits 2 and 3, subjects will undergo the same evaluation as on day 1. After the pre-administration evaluation is complete, subjects will undergo post-administration evaluation following the study treatment as defined by their randomized sequence of treatments.

[0141] After Part A is conducted in a double-blind manner, an open-label evaluation of efficacy and safety results will be performed before proceeding to Part B. In Part B, two additional single doses of compound 1 and placebo may be evaluated using the same study design as in Part A, in order to describe the dose-response in more detail. The sample size may be adjusted based on the results of Part A.

[0142] The primary outcome measures were (i) changes in finger blood flow based on reheat AUC (°C, assessed by IR thermography) up to 30 minutes after cold exposure, and (ii) changes in reperfusion AUC (perfusion units (pu) assessed by LSCI) up to 30 minutes after cold exposure.

[0143] Other outcome measures include the following: ●The following temperature (°C, assessed by IR thermography) and perfusion (pu, assessed by LSCI) parameters were used with Compound 1 and placebo, i.e. ○Maximum reduction after cold load ○Maximum recovery within 30 minutes after cold load. ○ AUC during the first 2 minutes after cold load is applied ○Slope during the first 2 minutes after cold load ○Time to recover 50% from the reduction induced by cold load ○Time to recover 70% from the reduction induced by cold load Change ●The following temperature (°C, evaluated by IR thermography) and perfusion (pu, evaluated by LSCI) parameters were measured using compound 1 and placebo, i.e., ○ Room temperature ○Dorsal finger difference (DDD) at room temperature (defined as the difference between dorsal and finger measurements) Changes from before administration to after administration ● Safety and tolerability of Compound 1 ● Plasma serotonin concentration ● Relationship between selected PD endpoints and plasma serotonin ● Relationship between selected PD endpoints and the concentrations of compound 1 and / or active metabolites ● VAS for pain

[0144] The hiring criteria include the following: ● Raynaud's phenomenon secondary to systemic sclerosis (SSc) (defined as a history of cold sensitivity of the fingers, accompanied by cyanosis and pallor, occurring at least five times a week on average during the winter months). ● If there is a possibility of conception, consent to use highly effective birth control methods. ●Body type index: 18.0-40.0 kilograms per square meter (kg / m²) 2 (Including the numbers at both ends)

[0145] The criteria for rejecting a candidate include the following: ● Active finger ulcers, recent history of finger ulcers (within 3 months of screening), history of recurrent finger ulceration that increases the risk of developing finger ulcers during the study in the investigator's opinion, or history of gangrene, amputation, or any other severe finger ischemic event. ● Raynaud's phenomenon caused by any other reason besides SSc ●Serious gastrointestinal complications associated with SSc that could significantly affect the absorption of compound 1. ● History of gastrointestinal bleeding or active stomach or duodenal ulcers

[0146] Plasma serotonin levels are assessed before the start of post-administration finger blood flow assessment and immediately after its completion. This allows for exploration of the relationship between plasma serotonin levels and the selected PD scale.

[0147] Blood samples for plasma PK analysis of compound 1 and its metabolites are collected before administration, after administration of the study procedure (before the start of post-administration finger blood flow assessment), after cold loading, and again after the completion of post-administration finger blood flow assessment. The relationship between the plasma concentration of the selected analytes (compound 1, its active metabolites, and / or all combined analytes) and the selected PD scale can be explored.

[0148] Safety assessments include evaluation of adverse events, ECG, vital signs, clinical chemistry and hematology, physical examination, and concomitant drug therapy.

[0149] Treatment with compound 1 is expected to result in a reduction in the frequency, duration, and / or severity of Raynaud's seizures; improvement in finger blood flow and / or finger pressure; and / or reduction in finger capillary dysfunction.

Claims

1. A pharmaceutical composition comprising 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1) or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for the treatment or prevention of Raynaud's in an individual.

2. The pharmaceutical composition of claim 1 , wherein the individual has primary Raynaud's.

3. The pharmaceutical composition of claim 1 , wherein the individual has secondary Raynaud's.

4. The pharmaceutical composition of claim 1 , wherein the individual has at least one digital ulcer.

5. The pharmaceutical composition of claim 1 , wherein the individual has digital gangrene.

6. The pharmaceutical composition of claim 1 , wherein the individual has systemic sclerosis.

7. 10. The pharmaceutical composition of claim 1, wherein the individual has Raynaud's disease secondary to a condition selected from systemic sclerosis, rheumatoid arthritis, lupus, vasculitis, atherosclerosis, cryoglobulinemia, hypothyroidism, injury, and drug reactions.

8. 2. The pharmaceutical composition of claim 1, wherein the individual has Raynaud's disease secondary to systemic sclerosis.

9. 2. The pharmaceutical composition of claim 1, wherein the individual has systemic sclerosis and at least one digital ulcer.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the pharmaceutical composition is administered orally.

11. 10. The pharmaceutical composition of claim 1 in the form of a tablet.

12. 10. The pharmaceutical composition of claim 1 in the form of a capsule.

13. The pharmaceutical composition of claim 1 , wherein the compound is Compound 1 or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

14. The pharmaceutical composition of claim 1 , wherein Compound 1 or a pharma- ceutically acceptable salt, hydrate, or solvate thereof is a pharma- ceutically acceptable salt of Compound 1.

15. 2. The pharmaceutical composition of claim 1, wherein compound 1 or a pharma- ceutically acceptable salt, hydrate, or solvate thereof is an HCl salt of compound 1.

16. 2. The pharmaceutical composition of claim 1, wherein the treatment comprises at least one of reducing the frequency of attacks, shortening the duration of attacks, reducing the severity of attacks, reducing ischemic tissue damage, and reducing digital ulceration.

17. 2. The pharmaceutical composition of claim 1, wherein treatment comprises reducing the frequency, duration, and / or severity of attacks.

18. 2. The pharmaceutical composition of claim 1, wherein the prevention comprises at least one of preventing stroke, preventing ischemic tissue injury, and preventing digital ulceration.

19. 2. The pharmaceutical composition of claim 1, wherein about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, or 180 mg of Compound 1 or a pharma- ceutically acceptable salt, hydrate, or solvate thereof is administered per day.

20. 2. The pharmaceutical composition of claim 1, wherein about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of Compound 1 or a pharma- ceutically acceptable salt, hydrate, or solvate thereof is administered.

21. 21. The pharmaceutical composition of claim 20, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered three times daily (TID).

22. The pharmaceutical composition of claim 1 , wherein Raynaud's is assessed using Patient Reported Outcomes (PRO).

23. 10. The pharmaceutical composition of claim 1, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered during the winter months.

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