Synthesis of Tetrahydronaphthalenols and Their Uses

Abstract

Provided herein are compounds and synthetic methods useful for preparing tetrahydronaphthalenol derivatives, and uses of said compounds.

Description

Technical Field

[0001] (Related Application) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 355,880, filed Jun. 27, 2022, and the entire disclosure of U.S. Provisional Patent Application No. 63 / 355,880 is incorporated herein by reference in its entirety.

Background Art

[0002] Compound 6, sometimes referred to as AGN-195183 in the literature, has been prepared by a multi-step method requiring at least seven synthetic procedures, as described in Non-Patent Document 1 by Richard L. Beard et al. However, there is a need for a synthetic method that reduces the synthetic burden, improves the overall yield efficiency, and ensures scalability on a commercial scale. Compound 6 is useful as a modulator of retinoic acid receptor α (RARα), including activation of RARα, and is thereby useful for the treatment of diseases including RARα-related diseases.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] Accordingly, provided herein are improved compounds and synthetic methods useful for the preparation of tetrahydronaphthalenols, as well as methods of using compound 6 or a salt thereof.

Means for Solving the Problems

[0005] Provided herein is a compound of formula [ka] or a salt thereof.

[0006] chemical formula [ka] Also provided herein are compounds having the formula: or a salt thereof.

[0007] In addition, the present specification [ka] , [ka] ,or [ka] Also provided are methods for preparing the compounds or salts thereof. [Brief description of the drawings]

[0008]

Figure 1

Figure 2

[0009] Certain tetrahydronaphthalenols are prepared as described, for example, in U.S. Patent Nos. 6,387,950, 5,965,606, and 5,856,490, the contents of each of which are incorporated herein by reference. However, an improved method for preparing tetrahydronaphthalenols is needed to provide the compounds described herein on a commercial scale.

[0010] (Definition) The articles “a” and “an” refer to one or more of the grammatical objects of the article.

[0011] Numerical values regarding measurements are subject to measurement error and are limited in their accuracy. For this reason, unless otherwise specified, all numerical values provided herein should be understood to be modified by the term “about”. Accordingly, the last digit after the decimal point of the numerical values provided herein indicates the accuracy of the numerical value. When no other error range is indicated, the maximum error range is determined by applying the rounding convention to the last digit after the decimal point or, when there is no decimal point in the numerical value, the last significant digit.

[0012] The term “amelioration” means a reduction in the severity of at least one indicator of a symptom or disease, such as a delay or deceleration in the progression of one or more indicators of the symptom or disease. The severity of the indicator may be determined by subjective or objective measurements known in the art.

[0013] The terms “composition” and “pharmaceutical composition” refer to a mixture of at least one compound described herein and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates the administration of the compound to a patient or subject. There are multiple techniques for administering the compound, including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, nasal, pulmonary, and topical administration.

[0014] The terms "effective amount" and "therapeutically effective amount" refer to the amount of a therapeutic compound administered to a subject as a single dose or as part of a series of doses as described herein and which is effective to produce the desired therapeutic effect. Generally, a therapeutically effective amount can first be estimated in cell culture assays or in mammalian models, such as animal models of non-human primates, mice, rabbits, dogs, pigs, etc. The animal models may be used to determine the appropriate concentration range and route of administration. Thereafter, such information can be used to determine useful dosages and routes of administration in non-human and human subjects.

[0015] The term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier, such as a liquid filler, solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, used to carry or transport at least one compound described herein into the body of a patient or to the patient, whereby the compound may perform its intended function. A particular carrier is "acceptable" in that it is compatible with the other ingredients of a particular formulation containing a compound described herein and must not be harmful to the patient. Other ingredients that may be included in the pharmaceutical compositions described herein are known in the art and are described, for example, in "Remington’s Pharmaceutical Sciences" (Genaro (ed.), Mack Publishing Co., 1985), the contents of which are hereby incorporated by reference in their entirety.

[0016] The term "refractory disease" refers to a disease that continues to progress during treatment with pharmaceutical ingredients other than the compounds provided herein, a disease that responds partially to other treatments, or a disease that responds temporarily to other treatments. This term may apply to each disease referenced herein.

[0017] The term "salt" or "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Salts, including pharmaceutically acceptable salts, can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or free base forms of these compounds with an appropriate amount of base or acid in water or an organic solvent, or a mixture of these solvents. A list of suitable salts is described in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (P. Henrich Stahl and Camille G. Wermuth (eds.), VHCA and Wiley-VCH, 2002), the contents of which are hereby incorporated by reference in their entirety.

[0018] The term "treatment" or "treating" refers to the application of one or more specific procedures used for the improvement of a disease. "Preventive" treatment refers to reducing the rate of progression of a disease or condition being treated, delaying the onset of that disease or condition, or reducing the severity of its onset.

[0019] The recitation of a range of values herein is merely intended to be a shorthand method of referring individually to each value falling within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any example, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the subject matter and does not limit the scope of the claimed subject matter. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the subject matter described herein.

[0020] The grouping of alternative components or embodiments in this disclosure should not be construed as limiting. Members of each group may be claimed individually by reference, or in any combination with other members of the group or other components used herein. Further, members described in a group may, for convenience or for reasons of securing patentability, be included in or excluded from another group. In the event of such inclusion or exclusion, the specification is deemed to include the group as modified so as to meet the requirements for the description of all Markush groups used in the appended claims.

[0021] Throughout this specification, references to patents and publications are made, and each of them is hereby incorporated by reference in its entirety.

[0022] It should be understood that the embodiments of this disclosure are illustrative. Accordingly, this disclosure is not limited to exactly what is illustrated and described.

[0023] (Compounds and Synthetic Methods) Provided herein are methods for preparing tetrahydronaphthalenols and intermediate compounds useful in such methods.

[0024] Thus, in some embodiments, provided herein are intermediate compounds that may be useful in preparing tetrahydronaphthalenols comprising Compound 6. The intermediate compounds comprise Compound 4 and Compound 5, or salts thereof. The intermediate compounds may be prepared as described herein, for example, as shown in FIG. 1.

[0025] In some embodiments, the chemical formula

Chemical formula

[0026] In some embodiments, a compound having the chemical formula

Chemical formula

[0027] In some embodiments, a compound having the chemical formula

Chemical formula

[0028] In some embodiments,

Chemical formula

[0029] In some embodiments, [Chemical formula] or [Chemical formula] A method for preparing R 1 is H, F, Cl or Br, R 2 is H, F, Cl or Br, R 1 or R 2 at least one of them is F, Cl or Br, R 3 each is independently F, Cl or Br, n is 0, 1 or 2.

[0030] In some embodiments of the chemical formulas provided herein, R 1 is H, and R 2 is F, Cl, or Br. In some embodiments, R 1is H, and R 2 is F. In some embodiments, n is 2. In some embodiments, n is 0. In some embodiments, each R 3 is F and n is 2. In some embodiments, R 1 is H, and R 2 is F, Cl, or Br, and n is 2. In some embodiments, R 1 , R 2 , or R 3 has at least one occurrence that is F. In some embodiments, R 1 , R 2 , and R 3 each is H or F, where at least one of R 1 , R 2 , or R 3 is F. In some embodiments, n is 2, 3, or 4, and each R 3 independently contains F at each meta position (i.e., the 3 - and 5 - positions).

[0031] In some embodiments, a compound having the chemical formula

Chem.

[0032] In some embodiments, a compound having the chemical formula

Chem.

[0033] In some embodiments, a compound having the chemical formula

Chem.

[0034] In some embodiments,[[]]

Chem.

[0035] The synthetic steps described herein may be carried out independently in the presence of one or more solvents suitable for the particular chemical reactions required for the synthesis. In some embodiments, the solvent is an anhydrous solvent or the reaction is carried out under anhydrous conditions.

[0036] The compounds described herein are synthesized using the techniques and materials described herein, such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of these references are incorporated by reference for such disclosures). As described herein, general methods for the preparation of the compounds are modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the chemical formulas provided herein. The compounds described herein are synthesized using any suitable procedure starting from commercially available compounds or are prepared using the procedures described herein.

[0037] The compounds described herein include isotopically labeled compounds in which one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than the atomic mass or mass number predominately found in nature. Examples of isotopes suitable for inclusion in the compounds described herein are 2 H,3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S, including but not limited to. In some embodiments, the isotope-labeled compounds are useful in drug or substrate tissue distribution studies. In another embodiment, substitution with heavy isotopes such as deuterium improves metabolic stability (e.g., increases in vivo half-life or reduces dosing requirements). In yet another embodiment, 11 C, 18 F, 15 O, and 13 substitution with positron-emitting isotopes such as N is useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotope-labeled compounds are prepared by using an appropriate isotope-labeled reagent in place thereof in any suitable method or manufacturing process in which an unlabeled reagent would normally be used.

[0038] In some embodiments, the compounds described herein are labeled by other means including, but not limited to, the use of a chromophore or fluorophore, a bioluminescent label, or a chemiluminescent label.

[0039] In some embodiments, the solid forms (e.g., precipitated or crystalline forms) provided herein are prepared as particles or compressed solids. In some embodiments, these solid forms are coated. In some embodiments, the particles include an average particle diameter of about 10 microns or less. In some embodiments, the particles include an average particle diameter of about 2 microns or less. In some embodiments, the particles include an average particle diameter of about 10 to 20 microns or more. In some embodiments, the solid forms or particles provided herein are formulated as a suspension in a liquid or as a dry powder for aerosol administration.

[0040] In some embodiments, the solid form is about 75, 80, 85, 90, 95, or 100% based on the mass of the particles.

[0041] In some embodiments, the particles include a particle surface. The particle surface includes a coating on at least a portion of the particle surface. In some embodiments, the coating includes a film coating. In some embodiments, the particles include a film coating with a polymer or copolymer to form microcapsules, which may be used to form chewable taste-masking granules. In some embodiments, the coating includes a polymer or copolymer. In some embodiments, the coating includes one or more materials including cellulose acetate phthalate, cellulose acetate trimellate, ethyl cellulose, glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, high molecular weight polyethylene, polyvinyl alcohol, polyvinyl pyrrolidone, starch, or shellac. In some embodiments, the coating includes sugar. In some embodiments, the coating includes a sugar coating. In some embodiments, the particles described herein are sugar-coated. In some embodiments, the particles described herein are not sugar-coated. In some embodiments, the coating includes an enteric coating. In some embodiments, the coating is a sustained-release coating. In some embodiments, the coating is a controlled-release coating. In some embodiments, the coating includes a delayed-release coating. In some embodiments, the particles described herein may include a second coating disposed layerwise over the first coating. In some embodiments, the coating is stable at a pH of less than about 7. In some embodiments, the coating is stable at a pH of less than about 5.5. In some embodiments, the coating is stable in an acidic environment. In some embodiments, the coating is stable in gastric juice and unstable in intestinal juice.

[0042] In some embodiments, a dosage form comprising a plurality of particles comprises particles coated with a coating selected, independently for each particle, from the coatings described herein. Thus, in some embodiments, the plurality of particles may comprise a mixture of enteric-coated particles and sustained-release-coated particles.

[0043] In some embodiments, the particles described herein are encapsulated within a coating.

[0044] In some embodiments of the particles described herein, the coating is 25% by mass or less of the coated particles.

[0045] In some embodiments, the particles described herein are provided as a composition comprising a plurality of particles that may include one or more carriers. In some embodiments, the plurality of particles are encapsulated within a capsule, a compression coating, a film coating, or a powder coating. In some embodiments, the particle or plurality of particles are spray-coated, whether as a powder, a compressed powder, or a tablet. In some embodiments, the plurality of particles are a loose powder within an ingestible capsule. In some embodiments, the plurality of particles are compressed into a friable solid.

[0046] In some embodiments, a dosage form is provided that comprises a particle, composition, or pharmaceutical composition described herein. In some embodiments, the dosage form comprises the plurality of particles as a powder or as a compressed powder. In some embodiments, the dosage form comprises the plurality of particles in a suspension. As described above, the particles may be coated.

[0047] In some embodiments, the solid forms, particles, compositions, or pharmaceutical compositions described herein are contained in at least one container.

[0048] The compounds described in this specification are synthesized using any suitable procedure starting from compounds available from commercial sources or are prepared using the procedures described herein.

[0049] In some embodiments, the compounds described herein may be prepared by a synthetic method that includes any one or more of the synthetic schemes shown in the Examples, Figure 1, or Figure 2.

[0050] In some embodiments, reactive functional groups such as hydroxyl are protected to avoid unwanted participation in the reaction. Protecting groups are used to block some or all of the reactive moiety and prevent such groups from participating in chemical reactions until the protecting group is removed. In another embodiment, each protecting group is removable by different means. Protecting groups that are cleaved under entirely different reaction conditions meet the requirements for specific removal. In some embodiments, the protecting group is removed by acid, base, reducing conditions (e.g., by hydrogenolysis), or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are acid-labile.

[0051] In some embodiments, the compounds provided herein are provided as salts. In some embodiments, the salt form is a pharmaceutically acceptable salt of the compound.

[0052] (Composition) In some embodiments, compositions are provided that include the compounds described herein.

[0053] In some embodiments, pharmaceutical compositions are provided that include the compounds described herein and a pharmaceutically acceptable carrier.

[0054] (Method of Treatment) Compound 6 is a selective retinoic acid receptor α (RARα) agonist, has oral bioavailability, and is expected to have antitumor activity. Compound 6 has no observable activity against RARβ / γ. Without wishing to be bound by theory, when administered, Compound 6, which is an RARα agonist, binds to and activates RARα, promoting RARα-mediated signal transduction. As a result, RARα-responsive genes involved in cell differentiation and proliferation are transcribed. As a result, cell differentiation and apoptosis are induced, and cell proliferation and tumor formation are suppressed. RARα is a nuclear receptor and a member of the steroid receptor superfamily. Modulated RARα signal transduction correlates with the development of cancer in a variety of cancer cell types, including lymphoma, multiple myeloma, or blood cancers such as leukemia.

[0055] In some embodiments, provided is a method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., Compound 6, or a salt form thereof). In some embodiments, provided is a method of modulating RARα in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., Compound 6, or a salt form thereof). In some embodiments, the modulation is activation of RARα. In some embodiments, provided is a method of modulating gene expression, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., Compound 6, or a salt form thereof).

[0056] In some embodiments, the disease is related to one or more cell processes including cell proliferation or immune response. In some embodiments of the methods provided herein, the disease is selected from a cellular proliferation disorder (e.g., cancer or tumor), or an autoimmune disorder. In some embodiments, the cancer is a non-solid cancer (e.g., a liquid cancer, e.g., a blood cancer). In some embodiments, the cancer or tumor is a solid cancer or tumor.

[0057] In some embodiments, the subject includes a refractory disease. In some embodiments, the refractory disease includes a refractory cell proliferation disorder, such as cancer or tumor, or a refractory autoimmune disorder.

[0058] In certain embodiments of a method for treating an autoimmune disorder, the method treats an autoimmune disease selected from the group consisting of acute disseminated encephalomyelitis (ADEM), Addison's disease, allergy, allergic rhinitis, antiphospholipid antibody syndrome (APS), arthritis, asthma, acquired immunodeficiency syndrome (AIDS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, celiac disease, Chagas disease, chronic obstructive pulmonary disease (COPD), type 1 diabetes mellitus (IDDM), endometriosis, gastrointestinal disorder, glomerulonephritis, Goodpasture syndrome, Graves' disease, Guillain - Barré syndrome (GBS), Hashimoto's thyroiditis, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial nephritis, interstitial cystitis, lupus, morphea, multiple sclerosis (MS), myasthenia gravis, myopathy, myositis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, pulmonary fibrosis, recurrent disseminated encephalomyelitis, rheumatic fever, schizophrenia, scleroderma, Sjögren's syndrome, skin disorder, tenosynovitis, uveitis, vasculitis, or vitiligo.

[0059] In certain embodiments, the disease does not include multiple sclerosis, i.e., the subject being treated does not have multiple sclerosis or is not diagnosed with multiple sclerosis.

[0060] In certain embodiments, arthritis is monoarthritis, oligoarthritis, polyarthritis, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, septic arthritis, spondyloarthritis, gout, pseudogout, or Still's disease.

[0061] In some embodiments, the gastrointestinal disorder is an irritable bowel disease or an inflammatory bowel disease. In other embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

[0062] In some embodiments, the lupus is discoid lupus erythematosus, drug-induced lupus erythematosus, lupus nephritis, neonatal lupus, subacute cutaneous lupus erythematosus, or systemic lupus erythematosus.

[0063] In some embodiments, the autoimmune disorder is a myopathy having an autoimmune component such as dermatomyositis, inclusion body myositis, or polymyositis.

[0064] In some embodiments, the skin disorder is dermatitis, eczema, stasis dermatitis, hidradenitis suppurativa, psoriasis, rosacea, or scleroderma.

[0065] In some embodiments, the vasculitis is Burger's disease, cerebral vasculitis, Churg-Strauss arteritis, cryoglobulinemia, essential cryoglobulinemic vasculitis, giant cell arteritis, golfer's vasculitis, Henoch-Schönlein purpura, hypersensitivity vasculitis, Kawasaki disease, microscopic polyarteritis / polyangiitis, polyarteritis nodosa, polymyalgia rheumatica (PMR), rheumatoid-like vasculitis, Takayasu arteritis, or Wegener's granulomatosis.

[0066] In some embodiments, the autoimmune disease is multiple sclerosis, psoriasis, rheumatoid arthritis, glomerulonephritis, pulmonary fibrosis, interstitial nephritis, or inflammatory bowel disease.

[0067] The methods as described herein refer to the compounds described herein, but it should be understood that the compounds may also be used in the form of a composition or a pharmaceutical composition together with these methods.

[0068] The actual dosage of the active ingredient (e.g., the compound of the chemical formula provided herein), the composition provided herein, or the pharmaceutical composition may be varied to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration and that is not toxic to the patient.

[0069] In particular, the dosage levels selected will depend on a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, medical condition, general health, and prior medical history of the patient being treated, as well as similar factors well known in the medical arts. A physician having ordinary skill in the art, e.g., a medical doctor or veterinarian, may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a medical doctor or veterinarian may initiate the dosage of the compound employed in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0070] Administration of the compounds, compositions, or combinations disclosed herein may be by any of a variety of enteral or parenteral approaches selected from, but not limited to, oral administration in any acceptable form, e.g., tablets, liquids, capsules, powders, etc.; topical administration in any acceptable form, e.g., drip medications, sprays, creams, gels or ointments; buccal, intranasal and / or inhalation administration in any acceptable form; rectal administration in any acceptable form; vaginal administration in any acceptable form; intravascular administration in any acceptable form, e.g., intravenous bolus injection, intravenous infusion, intra-arterial bolus injection, intra-arterial infusion, catheter infusion into a blood vessel; peri-tissue and intra-tissue administration in any acceptable form, e.g., intraperitoneal injection, intramuscular injection, subcutaneous injection, subcutaneous infusion, intraocular injection, retinal injection, or subretinal injection, epidural injection; intravesical administration in any acceptable form, e.g., catheter infusion; and administration by implantable devices such as, for example, implants, stents, patches, pellets, catheters, osmotic pumps, suppositories, bioerodible delivery systems, non-bioerodible delivery systems and other implantable extended release or slow release systems.

[0071] The compounds, compositions, or combinations disclosed herein can be administered to mammals using various routes. Routes of administration include, but are not limited to, oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. In some embodiments, the oral or nasal route of administration is the route of oral inhalation or nasal inhalation. The compounds for the uses as described herein may be formulated to be administered by any suitable route in order to achieve the particular method of application. In some embodiments, the routes of administration suitable for the treatment of RARα-related diseases disclosed herein include both topical and systemic administration. Topical administration leads to much more delivery of the compound, composition, or combination to a specific location as compared to systemic administration in mammals, while systemic administration leads to delivery of the compound, composition, or combination to substantially the whole body of an individual. The routes of administration suitable for the treatment of RARα-related diseases disclosed herein also include both central and peripheral administration. Central administration means delivering the compound, composition, or combination essentially to the central nervous system of an individual and includes, for example, nasal administration, intrathecal administration, epidural administration, and intracranial injection or implantation. In some embodiments, central administration is used to administer the compounds, compositions, or combinations described herein.

[0072] Central administration via the nasal route for the purpose of drug absorption via the nasal vasculature is different from administration by nasal inhalation that delivers the drug via the pulmonary system. The latter typically uses a liquid or dry powder aerosol with an average particle size of less than 10 microns, and in some embodiments less than 2 microns, whereas central administration is typically performed using particles with an average particle size of 10 to 20 microns or more. Mists and aerosols can be generated using nebulizers, dry powder inhalers, pressurized aerosols, and spray pumps (the latter being preferred). It is also possible to use nasal drops for central administration via the nasal route.

[0073] Peripheral administration results in the administration of a compound, composition, or combination to any area of an individual outside the central nervous system and includes any route of administration other than direct administration to the spine or brain. The actual route of administration of the compounds, compositions, or combinations disclosed for use herein will depend on factors including, but not limited to, the type of RARα-related disease, the site of the RARα-related disease, the cause of the RARα-related disease, the severity of the RARα-related disease, the desired treatment period, the desired degree of alleviation, the desired alleviation period, the particular compound, composition, or combination, the excretion rate of the compound, composition, or combination being used, the pharmacodynamics of the compound, composition, or combination being used, the properties of other compounds included in the compound, composition, or combination being used, the particular route of administration, the specific characteristics of the individual such as age, weight, general health, etc., medical history and risk factors, the individual's response to treatment, or any combination of these, and can be determined by one of ordinary skill in the art by considering these factors. The effective dosage of the compounds, compositions, or combinations disclosed herein can be readily determined by one of ordinary skill in the art by considering all criteria and making the best judgment on behalf of the individual.

[0074] In some embodiments, a compound prepared as described herein having the chemical formula

Chemical formula

Chemical formula

[0075] It should be understood that the methods described as such refer to the compounds described herein, but that the compounds may be used in combination with these methods in the form of a composition or pharmaceutical composition.

[0076] The actual dosage levels of the active ingredient (e.g., a compound of the formula provided herein), composition, or pharmaceutical composition effective to achieve a desired therapeutic response for a particular patient provided herein may be varied to obtain an amount of the active ingredient, composition, or pharmaceutical composition effective to achieve the desired therapeutic response for a particular patient, while being non-toxic to the patient.

[0077] In particular, the dosage level selected will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A physician or veterinarian of ordinary skill will readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian may start the dosage of the compound employed in the pharmaceutical composition at a level lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0078] (Kit) In some embodiments, provided herein is a packaged compound, packaged composition, or packaged pharmaceutical composition comprising a container containing a therapeutically effective amount of a compound described herein and instructions for using the compound according to one or more methods provided herein.

[0079] The compounds and related materials of the present invention can be made into commercial products by ordinary processes practiced in the art, such as appropriate sterilization and packaging processes. For example, the materials can be treated by UV / visible light irradiation (200 to 500 nm) using, for example, photoinitiators having different absorption wavelengths (such as Irgacure 184, 2959), preferably water-soluble initiators (such as Irgacure 2959). These irradiations are usually carried out with an irradiation time of 1 to 60 minutes, but longer irradiation times may be applied depending on the specific method. The materials according to the present disclosure can be finally aseptically packaged and packaged in suitable containers (such as boxes) (for example, by adding specific product information leaflets) so as to maintain sterility until use.

[0080] According to a further embodiment, the compounds of the present invention can also be provided in the form of a kit combined with other components necessary for the administration of the material to a patient. For example, the disclosed kits for use in the treatment of autoimmune or cell proliferation disorders can further include, for example, the administration material.

[0081] The kits are designed in various forms based on the specific deficiencies designed for treatment.

[0082] The compounds or compositions provided herein may be prepared and housed in a container for storage at room temperature or elevated temperatures. When the compound or composition is stored in a plastic container made of polyolefin as compared to a plastic container made of polyvinyl chloride, the discoloration of the compound or composition may be reduced whether dissolved or suspended in a liquid composition (e.g., an aqueous solution or an organic liquid solution) or as a solid. Without wishing to be bound by theory, the container may reduce the exposure of the contents of the container to electromagnetic radiation, whether visible light (e.g., having a wavelength of about 380 to 780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190 to 320 nm (UV B light) or about 320 to 380 nm (UV A light)). Some containers include the ability to reduce the exposure of the contents of the container to infrared radiation or a second component having such ability. Containers that may be used include those made of polyolefins such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, particularly polyethylene, polypropylene, or combinations thereof. In some embodiments, the container is a glass container. The container may be further disposed within a second container that is, for example, paper, cardboard, paperboard, a metal film, or foil, or combinations thereof, that reduces further exposure of the contents of the container to ultraviolet, visible, or infrared light. Compounds and compositions that benefit from reduced discoloration, degradation, or both during storage include ophthalmic drops or grafts that include the compounds or compositions provided herein. The compounds or compositions provided herein may need to be stored for up to 3 months, or longer periods, and in some cases up to 1 year, or longer periods. The container can be any form suitable for containing the contents, such as a bag, bottle, or box. In some embodiments, the container includes a reduced ability to adsorb the compounds or compositions provided herein to the surface of the container, thereby preventing an apparent decrease in the concentration of the compound or composition disposed within the container.

[0083] The following examples further illustrate aspects of the present disclosure. However, these are not intended in any way to limit the teachings or disclosures as described herein.

[0084] (Example) Example 1 Preparation of Compound 6: 4-(4-chloro-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide)-2,6-difluorobenzoic acid Compound 6 may be prepared as shown in FIG. 1 starting from commercially available Compound 1 (2,5-dichloro-2,5-dimethylhexane), or generally starting from commercially available Compound 2 (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ol) and prepared as described in Steps 2 to 5 below.

[0085] Step 2 - Synthesis of Compound 3: 3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid. 100 g of sodium 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-olate (Na·Compound 2) and 40 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-β-naphthol are added to a pressure reaction vessel and stirred in a high-boiling solvent at 170 °C under a carbon dioxide pressure of 10 kg / cm 2 (G) for 2 hours. The reaction mixture is cooled, 500 mL of water is added, and it is separated into a reaction medium layer and an aqueous layer at 90 °C. The aqueous layer is extracted with 50 mL of xylene. The aqueous layer is acidified with dilute sulfuric acid to isolate Compound 3.

[0086] Step 3 - Synthesis of Compound 4: 4-chloro-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid. Sulfuryl chloride (12.7 kg, 1 equivalent) is added portion-wise to a solution of Compound 3 (23.0 kg, 1 equivalent) in tetrahydrofuran, and then the mixture is heated and stirred until the reaction is complete. The mixture is cooled, and ethyl acetate is added. The mixture is washed with brine, the organics are concentrated, and co-evaporated with heptane. Heptane is added, the slurry is cooled, and the product is collected by filtration and washed with heptane. The product, Compound 4, is dried (17.7 to 23.8 kg, yield 67 to 91%).

[0087] Step 4 - Synthesis of Compound 5. Phosphorus trichloride (4.2 kg, 1.44 equivalents) is added to a toluene suspension of Compound 4 (18 kg, 1.0 equivalent), and the mixture is heated and stirred until a solution is obtained. Next, a toluene solution of 3,5-difluoroaniline (9 kg, 1.09 equivalents) is added, and heating is continued until the reaction is complete. The mixture is cooled slightly, partially concentrated, and co-evaporated with isopropanol. More isopropanol is added, the slurry is heated to dissolve the product, and then partially concentrated again. The resulting slurry is cooled, and then the product is collected by filtration. The filtrate is partially concentrated, then cooled to precipitate a second crop, which is collected by filtration. Next, both crops are dried under vacuum at less than 60 °C to obtain Compound 5 (18.1 to 20.1 kg, yield 72 to 80%).

[0088] Step 5 - Synthesis of Compound 6. A mixture of Compound 5 (15 kg, 1 equivalent) and 2,2,6,6 - tetramethylpiperidine (10.7 kg, 2 equivalents) in tetrahydrofuran is cooled. n - Hexyllithium (43.1 kg, 2.5 M in hexane, 4 eq) is slowly added to the mixture while maintaining the temperature, and then the mixture is stirred for a predetermined time. The mixture is quenched on dry ice (about 186 kg), and then heated and stirred until all the solid dry ice has disappeared. Water is added, the layers are separated, and the organic matter is extracted a second time with water. The aqueous layers are combined, acidified with hydrochloric acid (15.01 kg, 4 equivalents), and extracted twice with ethyl acetate. The combined organic matter is concentrated and co - evaporated with toluene. Further toluene is added, and the mixture is cooled. The resulting slurry is filtered and washed with cold toluene. The product, Compound 6, is dried (40 to 50 °C), stored in the dark, and refrigerated (11.7 to 15.9 kg, yield 70 to 95%). 1 HNMR (CD3OD): δ 1.34 (s, 6H), 1.54 (s, 6H), 1.68 (m, 2H), 1.75 (m, 2H), 7.53 (d,J HF = 10.2 Hz, 2H).

[0089] Unless otherwise specified, all numerical values representing characteristics such as amounts of ingredients, molecular weights, reaction conditions, etc. used in this specification and the claims are to be understood as being modified in all instances by the term "about". As used herein, the terms "about" and "approximately" mean within 10 to 15%, preferably within 5 to 10%. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At a minimum, and not as an attempt to limit the application of the doctrine of equivalents to the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Although the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors resulting from the standard deviation found in the respective test measurements.

[0090] The terms "a", "an", "the" and similar reference terms used in the context of describing the present invention (particularly in the context of the following claims) are to be construed to cover both the singular and the plural forms unless otherwise specified herein or clearly contradicted by the context. The recitation of numerical ranges herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise specified herein, each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise specified herein or clearly contradicted by the context. The use of any example, or exemplary language (e.g., "such as") provided herein is merely intended to better illustrate the invention and is not intended to limit the scope of the invention claimed otherwise. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0091] The grouping of alternative elements or embodiments of the invention disclosed herein should not be construed as limiting. Members of each group may be referred to individually, or in any combination with other members of the group or other elements found herein, and may be claimed. For reasons of convenience and / or patentability, it is expected that one or more members of a group may be included in or deleted from the group. When such inclusion or deletion occurs, this specification is considered to include the modified group and meets the written description requirements of all Markush groups used in the appended claims.

[0092] Some embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations of these described embodiments will be apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to adopt such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, the invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Further, any combination of the above-described elements in all possible variations thereof is included in the invention unless otherwise specifically stated herein or clearly precluded by context.

[0093] Certain embodiments disclosed herein may be further limited in the claims by the recitation of "consisting of" or "consisting essentially of." Whether initially claimed or added by amendment, when used in the claims, the transitional term "consisting of" excludes components, steps, or ingredients not specified in the claims. The transitional term "consisting essentially of" limits the claim to the specified materials or steps and those that do not materially affect the basic and novel one or more features. Thus, the embodiments of the invention described in the claims are those inherent or explicitly described herein and are practicable.

[0094] Further, throughout this specification, numerous patents and printed publications have been referenced. Each of the cited references and printed publications are hereby incorporated by reference in their entirety individually into this specification.

[0095] Finally, it should be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications which may be employed are within the scope of the invention. Accordingly, alternative configurations of the invention may be utilized in accordance with the teachings of this specification by way of example and not of limitation. Thus, the invention is not limited to what has been precisely shown and described.

[0096] (Appendix) (Appendix 1) Chemical formula [Chemical formula] A compound having the formula or a salt thereof.

[0097] (Appendix 2) [Chemical formula] A method for preparing the compound according to Appendix 1, comprising contacting with sulfuryl chloride to form the compound according to Appendix 1.

[0098] (Appendix 3) Chemical formula [Chemical formula] A compound having the formula or a salt thereof.

[0099] (Appendix 4) A) [Chemical formula] Contacting with phosphorus trichloride to form an intermediate, and B) Contacting the intermediate with 3,5-difluoroaniline to form the compound according to Appendix 3, A method for preparing the compound according to Appendix 3, comprising the above steps.

[0100] (Appendix 5) Chemical formula [Chemical formula] A compound having the formula or a salt thereof.

[0101] (Appendix 6) A) [Chemical formula] Contacting with phosphorus trichloride to form an intermediate, and B) Contacting the intermediate with 3,5-difluoroaniline to form the compound according to Appendix 5, A method for preparing the compound according to Appendix 5, comprising the above steps.

[0102] (Appendix 7) [Chemical formula] A method for preparing the compound according to Appendix 5, comprising contacting with sulfuryl chloride to form the compound according to Appendix 5.

[0103] (Supplementary Note 8) Chemical formula [Chem.] A method for preparing a compound having the following or a salt thereof, A) contacting the compound described in Supplementary Note 5 with lithium tetramethylpiperidine to form an intermediate; and, B) contacting the intermediate with CO2 to form the compound, The method comprising.

[0104] (Supplementary Note 9) The method according to any one of Supplementary Notes 2, 4, 6, 7 or 8, wherein the contacting is each independently carried out in the presence of a solvent.

[0105] (Supplementary Note 10) [Chem.] The compound described in Supplementary Note 5 in solid form of the following.

[0106] (Supplementary Note 11) The compound described in Supplementary Note 10 prepared by precipitation from a solvent containing isopropanol.

[0107] (Supplementary Note 12) [Chem.] The compound described in Supplementary Note 5 in crystalline form of the following.

[0108] (Supplementary Note 13) The compound described in Supplementary Note 12 prepared by crystallization from a solvent containing isopropanol.

[0109] (Supplementary Note 14) Prepared by precipitation from toluene, [Chem.] Solid form.

[0110] (Appendix 15) Prepared by crystallization from toluene, [Chemical formula] Crystal form.

[0111] (Appendix 16) [Chemical formula] The compound described in Appendix 3, which is in solid form.

[0112] (Appendix 17) A composition comprising a compound, solid form or crystal form described in any one of Appendices 1, 3, 5 or 10 to 16.

[0113] (Appendix 18) Particles comprising the solid form described in Appendix 14 or the crystal form described in Appendix 15 and a pharmaceutically acceptable carrier.

[0114] (Appendix 19) A pharmaceutical composition comprising the solid form described in Appendix 14, the crystal form described in Appendix 15 or the particles described in Appendix 18 and a pharmaceutically acceptable carrier.

[0115] (Appendix 20) The pharmaceutical composition described in Appendix 19, wherein the compound is present in the pharmaceutical composition in an amount of at least about 80% by weight.

[0116] (Appendix 21) The pharmaceutical composition described in Appendix 19 or 20, formulated as an oral, parenteral, topical or inhalation dosage form or formulated for administration by oral, parenteral, topical or inhalation.

[0117] (Appendix 22) A method of treating a disease in a subject in need of treatment for the disease, comprising the solid form described in Appendix 14, The crystalline form described in Supplementary Note 15, the particles described in Supplementary Note 18, or the pharmaceutical composition described in one of Supplementary Notes 19 to 21 administering an effective amount of to the subject, Method.

[0118] (Supplementary Note 23) The method according to Supplementary Note 22, wherein the disease is a retinoic acid receptor α-related disease.

[0119] (Supplementary Note 24) The method according to Supplementary Note 22, wherein the disease is an autoimmune disorder.

[0120] (Supplementary Note 25) The method according to Supplementary Note 22, wherein the disease is selected from cell proliferation disorders.

[0121] (Supplementary Note 26) The method according to Supplementary Note 22, wherein the disease is selected from cancer or tumor.

[0122] (Supplementary Note 27) A method for regulating retinoic acid receptor α in a subject in need of regulating retinoic acid receptor α, comprising the solid form described in Supplementary Note 14, the crystalline form described in Supplementary Note 15, the particles described in Supplementary Note 18, or the pharmaceutical composition described in one of Supplementary Notes 19 to 21, administering an effective amount of to the subject, Method.

Claims

1. Chemical formula 【Chemical 1】 A compound having the same or a salt thereof.

2. 【Fig. 2】 A method for preparing the compound according to claim 1, comprising contacting the same with sulfuryl chloride to form the compound according to claim 1.

3. Chemical formula 【Chemical Formula 3】 A compound having the same or a salt thereof.

4. A) 【Chemical Formula 4】 Contacting the same with phosphorus trichloride to form an intermediate, and B) Contacting the intermediate with 3,5-difluoroaniline to form the compound according to claim 3, A method for preparing the compound according to claim 3, comprising the same.

5. Chemical formula ​ A compound having the same or a salt thereof.

6. A) 【Chemical Formula 6】 Contacting the same with phosphorus trichloride to form an intermediate, and B) Contacting the intermediate with 3,5-difluoroaniline to form the compound according to claim 5, A method for preparing the compound according to claim 5, comprising the same.

7. 【Fig. 7】 A method for preparing the compound according to claim 5, comprising contacting the same with sulfuryl chloride to form the compound according to claim 5.

8. Chemical formula 【Chemical 8】 A method for preparing a compound having the same or a salt thereof, comprising A) Contacting the compound according to claim 5 with lithium tetramethylpiperidine to form an intermediate, and B) contacting the intermediate with CO ２ to form the compound Comprising the same.

9. The method according to any one of claims 2, 4, 6, 7 or 8, wherein the contacting is each independently carried out in the presence of a solvent.

10. 【Fig. 9】 The compound according to claim 5, which is in a solid form of

11. The compound according to claim 10, which is prepared by precipitation from a solvent containing isopropanol.

12. 【Fig. 10】 The compound according to claim 5, which is in a crystalline form of

13. The compound according to claim 12, which is prepared by crystallization from a solvent containing isopropanol.

14. Prepared by precipitation from toluene, 【Chemical 11】 In a solid form of

15. Prepared by crystallization from toluene, 【Chemical 12】 In a crystalline form of

16. 【Fig. 13】 The compound according to claim 3, which is in a solid form of

17. A composition comprising the compound, solid form or crystalline form according to any one of claims 1, 3, 5 or 10 to 16.

18. Particles comprising the solid form according to claim 14 or the crystalline form according to claim 15 and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising the solid form according to claim 14, the crystalline form according to claim 15 or the particles according to claim 18 and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 19, wherein the compound is present in the pharmaceutical composition in an amount of at least about 80% by weight.

21. The pharmaceutical composition according to claim 19 or 20, formulated as an oral, parenteral, topical, or inhalation dosage form, or formulated for administration by oral, parenteral, topical, or inhalation.

22. A method of treating a disease in a subject in need of treatment for the disease, comprising: the solid form according to claim 14, the crystalline form according to claim 15, the particles according to claim 18, or the pharmaceutical composition according to any one of claims 19 to 21, administering an effective amount of the above to the subject. Method.

23. The method according to claim 22, wherein the disease is a retinoic acid receptor alpha-related disease.

24. The method according to claim 22, wherein the disease is an autoimmune disorder.

25. The method according to claim 22, wherein the disease is selected from cell proliferation disorders.

26. The method according to claim 22, wherein the disease is selected from cancer or tumors.

27. A method of regulating retinoic acid receptor alpha in a subject in need of regulation of retinoic acid receptor alpha, comprising: the solid form according to claim 14, the crystalline form according to claim 15, the particles according to claim 18, or the pharmaceutical composition according to any one of claims 19 to 21, administering an effective amount of the above to the subject. Method.

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