Synthesis and application of tetrahydronaphthol

Abstract

Provided herein are selective tetrahydronaphthol retinoic acid receptor alpha (RAalpha) agonist compounds, synthetic processes for preparing such compounds, starting from commercially available 5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalene-2-phenols, the production of novel tetrahydronaphthol derivatives, and the use of such compounds for the treatment of RARalpha-mediated diseases, including, for example, RARalpha-mediated diseases. The diseases include cancer and autoimmune diseases such as arthritis, multiple sclerosis and inflammatory bowel disease.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 355,880, filed on June 27, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] Compound 6, which may be referred to as AGN-195183 in the literature, has been prepared in a multi-step process requiring at least 7 synthetic sequences, as described by Richard L. Beard, et al. in Synthesis and Biological Activity of Retinoic Acid Receptor-Specific Amides, Bioorganic & Medicinal Chemistry Letters, 12, 3145–3148 (2002). However, the synthetic method needs to shorten the synthetic burden, improve the overall yield efficiency, and have commercial scalability. Compound 6 can be used as a modulator of retinoic acid receptor alpha (RARα), including by activating RARα, and thereby used in the treatment of diseases, including RARα-related diseases.

[0004] Therefore, provided herein are improved compounds and synthetic methods for preparing tetrahydronaphthol, as well as methods of using compound 6 or a salt thereof. Summary of the invention

[0005] Provided herein are compounds having the formula:

[0006]

[0007] or a salt thereof.

[0008] Also provided herein are compounds having the formula:

[0009]

[0010] or a salt thereof.

[0011] Also provided herein is a method for preparing the following compound or a salt thereof:

[0012]

[0013] BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 An example of a synthetic scheme for preparing the tetrahydronaphthols described herein is shown.

[0015] Figure 2 Another example of a synthetic scheme useful in preparing tetrahydronaphthol described herein is shown. DETAILED DESCRIPTION

[0016] Certain tetrahydronaphthols have been prepared, for example as described in US 6,387,950, US 5,965,606 and US 5,856,490, the contents of each of which are incorporated herein by reference. However, there is a need for improved methods of preparing tetrahydronaphthols in order to provide the compounds described herein on a commercial scale.

[0017] The articles "a" and "an" refer to one or more than one of the grammatical object of the article.

[0018] The numerical value related to measurement is susceptible to measurement error, which can limit the accuracy of the numerical value. For this reason, unless otherwise stated, all numerical values ​​provided herein are understood to be modified by the term "about". Therefore, the last decimal place of the numerical value provided herein indicates its accuracy. In the absence of other error tolerances, the maximum error tolerance is determined by applying rounding conventions to the last decimal place or the last significant figure (when there is no decimal place in the given numerical value).

[0019] The term "improvement" means to reduce the severity of at least one indication of a condition or disease, such as to delay or slow the progression of one or more indications of a condition or disease. The severity of an indication can be determined by subjective or objective metrics known to those skilled in the art.

[0020] 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 administration of the compound to a patient or subject. There are a variety of techniques for administering the compound, including but not limited to intravenous, oral, aerosol, parenteral, ocular, nasal, pulmonary, and topical administration.

[0021] The terms "effective amount" and "therapeutically effective amount" refer to the amount of a therapeutic compound (e.g., a compound described herein) administered to a subject as a single dose or as part of a series of doses, which is effective to produce the desired therapeutic effect. In general, a therapeutically effective amount can be initially estimated in a cell culture assay or in a mammalian model (e.g., in a non-human primate, mouse, rabbit, dog, or pig). Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration for non-human subjects and human subjects.

[0022] The term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or carrier that is involved in carrying or transporting at least one compound described herein in or to a patient so that the compound can perform its intended function, such as a liquid filler, solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material. A given carrier must be "acceptable" in the sense of being compatible with the other ingredients of a particular formulation (including the compounds described herein) and not causing harm 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 entire contents of which are incorporated herein by reference.

[0023] The term "refractory disease" refers to a disease that continues to progress during treatment with a pharmaceutical ingredient other than the compounds provided herein, has a partial response to other treatments, or has a transient response to other treatments. The term can be applied to each of the diseases mentioned herein.

[0024] The term "salt" or "pharmaceutically acceptable salt" refers to a derivative of a disclosed compound in which the parent compound is modified by converting an existing acid or base fragment into its salt form. Salts, including pharmaceutically acceptable salts, can be synthesized from parent compounds containing basic or acidic fragments by conventional chemical methods. In general, these salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or in a mixture of these two solvents. A list of suitable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (P. Henrich Stahl & Camille G. Wermuth (Eds.), VHCA & Wiley-VCH, 2002), which is incorporated herein by reference in its entirety.

[0025] The terms "treatment" and "treating" refer to the application of one or more specific procedures for the improvement of a disease. "Preventative" treatment refers to reducing the rate of progression of the disease or condition being treated, delaying the onset of the disease or condition, or lessening the severity of the onset of the disease or condition.

[0026] The description of the value range herein is intended only to be used as a shorthand method for quoting each individual value falling into the range. Unless otherwise specified herein, each individual value is incorporated into the specification as if it were individually narrated herein. Unless otherwise specified herein or obviously contradictory to the context, all methods described herein may be performed in any suitable order. The use of any and all examples or illustrative language (such as "for example") provided herein is intended only to better illustrate the described subject matter, rather than to limit the scope of the claimed subject matter. Any language in the specification should not be interpreted as indicating that any unclaimed element is essential for practicing the described subject matter.

[0027] The grouping of alternative elements or embodiments of the present disclosure should not be construed as limiting. Each group member may be mentioned and claimed individually or in any combination with other members in the group or other elements found herein. In addition, for convenience or patentability reasons, a member described in one group may be included in another described group, or excluded from another described group. When any such inclusion or exclusion occurs, this specification is deemed to include the modified group, thereby satisfying the written description of all Markush groups used in the appended claims.

[0028] Patents and printed publications have been cited throughout this specification, each of which is individually incorporated herein by reference in its entirety.

[0029] It should be understood that the embodiments of the present disclosure are illustrative and, therefore, the present disclosure is not to be limited to what has been precisely shown and described.

[0030] Compounds and Synthesis Methods

[0031] Provided herein are methods for preparing tetrahydronaphthol and useful intermediate compounds for use in such methods.

[0032] Therefore, in some embodiments, provided herein are intermediate compounds that can be used in the preparation of tetrahydronaphthol (including compound 6). The intermediate compounds include compound 4 and compound 5 or salts thereof. The intermediate compounds can be prepared according to the methods described herein, for example, Figure 1 shown.

[0033] In some embodiments, provided herein are compounds having the formula:

[0034]

[0035] or a salt thereof,

[0036] in

[0037] R 1is H, F, Cl or Br;

[0038] R 2 is H, F, Cl or Br; and

[0039] R 1 or R 2 At least one of them is F, Cl or Br.

[0040] In some embodiments, provided herein are compounds having the formula:

[0041]

[0042] or a salt thereof,

[0043] in,

[0044] R 1 is H, F, Cl or Br;

[0045] R 2 is H, F, Cl or Br;

[0046] R 1 or R 2 At least one of them is F, Cl or Br;

[0047] Each R 3 are independently F, Cl or Br; and

[0048] n is 0, 1, 2, 3 or 4.

[0049] In some embodiments, provided herein are compounds having the formula:

[0050]

[0051] or a salt thereof,

[0052] in

[0053] R 1 is H, F, Cl or Br;

[0054] R 2 is H, F, Cl or Br;

[0055] R 1 or R 2 At least one of them is F, Cl or Br;

[0056] Each R3 is independently F, Cl or Br; and

[0057] n is 0, 1 or 2.

[0058] In some embodiments, provided herein are methods for preparing the following compounds or salts thereof:

[0059]

[0060] in

[0061] R 1 is H, F, Cl or Br;

[0062] R 2 is H, F, Cl or Br;

[0063] R 1 or R 2 At least one of them is F, Cl or Br

[0064] Each R 3 are independently F, Cl or Br; and

[0065] n is 0, 1, 2, 3 or 4.

[0066] In some embodiments, provided herein is a method for preparing the following compound or a salt thereof:

[0067] in

[0068] R 1 is H, F, Cl or Br;

[0069] R 2 is H, F, Cl or Br;

[0070] R 1 or R 2 At least one of them is F, Cl or Br

[0071] Each R 3 are independently F, Cl or Br; and

[0072] n is 0, 1 or 2.

[0073] In some embodiments of the formulae provided herein, R 1 is H, and R 2 is F, Cl or Br. In some embodiments, R 1 is H, and R 2 is F. In some embodiments, n is 2. In some embodiments, n is 0. In some embodiments, each R 3 are independently F, and n is 2. In some embodiments, R 1 Yes H, R 2 is F, Cl or Br, and n is 2. In some embodiments, R 1 , R 2 or R 3 In some embodiments, at least one position in R1 , R 2 and R 3 Each of them is H or F, where R 1 , R 2 or R 3 In some embodiments, n is 2, 3 or 4, and each R 3 Independently, F is included at each meta position (ie, position 3 and position 5).

[0074] In some embodiments, provided herein are compounds having the formula:

[0075] or a salt thereof.

[0076] In some embodiments, provided herein are compounds having the formula:

[0077] or a salt thereof.

[0078] In some embodiments, provided herein are compounds having the formula:

[0079] or a salt thereof.

[0080] In some embodiments, provided herein are methods for preparing the following compounds:

[0081]

[0082] The synthetic steps described herein can be independently carried out in the presence of one or more solvents suitable for the specific chemical reaction desired for the synthesis. In some embodiments, the solvent is an anhydrous solvent, or the reaction is carried out under anhydrous conditions.

[0083] The compounds described herein were synthesized using the techniques and materials described herein, as well as using techniques and materials described in, for example, 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 4 th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry4 th Ed.,Vols.A and B(Plenum 2000,2001),and Green and Wuts,Protective Groups inOrganic Synthesis 3 rd Ed., (Wiley 1999) (all of which are incorporated herein by reference). The general methods for preparing the compounds described herein can be modified by using appropriate reagents and conditions to introduce different fragments in the formulas provided herein. The compounds described herein are synthesized using any suitable procedure starting from compounds available from commercial sources, or prepared using the procedures described herein.

[0084] The compounds described herein include isotopically labeled compounds in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. Examples of suitable isotopes for inclusion in the compounds described herein include, but are not limited to 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. In some embodiments, isotope-labeled compounds can be used for drug or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes (e.g., deuterium) provides greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In yet another embodiment, substitution with positron-emitting isotopes (e.g., 11 C. 18 F. 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process using a suitable isotopically labeled reagent in place of an otherwise non-labeled reagent.

[0085] In some embodiments, the compounds described herein are labeled by other methods, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0086] In some embodiments, the solid form (e.g., precipitated form or crystalline form) provided herein is prepared as a granule or compressed solid. In some embodiments, these solid forms are coated. In some embodiments, the granule comprises an average particle size of about 10 microns or less. In some embodiments, the granule comprises an average particle size of about 2 microns or less. In some embodiments, the granule comprises an average particle size of about 10-20 microns or more. In some embodiments, the solid form or granule provided herein is formulated into a suspension in a liquid or a dry powder for aerosol administration.

[0087] In some embodiments, the solid form is about at least about 75%, 80%, 85%, 90%, 95%, or 100% by mass of the particles.

[0088] In some embodiments, the particle includes a particle surface, wherein 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 particle includes a film coating with a polymer or copolymer to form a microcapsule, which can be used to form a chewable taste-masking granular object. In some embodiments, the coating includes a polymer or copolymer. In some embodiments, the coating includes cellulose acetate phthalate, cellulose acetate trimellitate, ethyl cellulose, ethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, high molecular weight polyethylene, polyvinyl alcohol, polyvinyl pyrrolidone, starch, or one or more of 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 coated with sugar. In some embodiments, the particles described herein are not coated with sugar. In some embodiments, the coating includes an enteric coating. In some embodiments, the coating is a delayed release coating. In some embodiments, the coating is a sustained release coating. In some embodiments, the coating comprises a controlled release coating. In some embodiments, the coating is a delayed release coating. In some embodiments, the particles described herein may include a second coating on top of a first coating. In some embodiments, the coating is stable below about pH 7. In some embodiments, the coating is stable below about pH 5.5. In some embodiments, the coating is stable in an acidic environment. In some embodiments, the coating is stable in gastric fluid and unstable in intestinal fluid.

[0089] In some embodiments, the dosage form comprising a plurality of particles comprises coated particles, wherein the coating is 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 delayed release coated particles.

[0090] In some embodiments, the particles described herein are encapsulated within a coating.

[0091] In some embodiments of the particles described herein, the coating is 25% or less of the coated particle by mass.

[0092] In some embodiments, the particles described herein are provided as a composition comprising a plurality of particles which may include one or more carriers. In some embodiments, the plurality of particles are encapsulated in a capsule, a compression coating, a film coating, or a powder coating. In some embodiments, the particle or particles, whether as a powder, a compressed powder, or a tablet, are spray-coated. In some embodiments, the plurality of particles are loose powders in an ingestible capsule. In some embodiments, the plurality of particles are compressed into a fragile solid.

[0093] In some embodiments, provided herein is a dosage form comprising a particle, composition, or pharmaceutical composition as described herein. In some embodiments, the dosage form comprises a plurality of particles as a powder or as a compressed powder. In some embodiments, the dosage form comprises a plurality of particles in a liquid suspension. As described above, the particles can be coated.

[0094] In some embodiments, a solid form, particle, composition, or pharmaceutical composition described herein is contained in at least one container.

[0095] The syntheses of the compounds described herein are prepared using any suitable procedure starting from compounds obtained from commercial sources, or using the procedures described herein.

[0096] In some embodiments, the compounds described herein may be prepared by including Examples, Figure 1 or Figure 2 The compositions may be prepared by any one or more of the synthetic schemes shown in .

[0097] In some embodiments, in order to avoid unwanted reactions in the reaction, reactive functional groups (such as hydroxyl) are protected. Protective groups are used to block some or all of the reactive fragments and prevent these groups from participating in chemical reactions until the protective groups are removed. In another embodiment, each protective group can be removed in different ways. Protective groups that break under completely different reaction conditions meet different removal requirements. In some embodiments, protective groups can be removed by acid, base, reducing conditions (such as hydrogenolysis) or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid unstable.

[0098] In some embodiments, the compounds provided herein are provided in the form of a salt. In some embodiments, the salt form is a pharmaceutically acceptable salt of the compound.

[0099] Composition

[0100] In some embodiments, provided herein are compositions comprising a compound described herein.

[0101] In some embodiments, provided herein are pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable carrier.

[0102] Treatment

[0103] Compound 6 is a selective retinoic acid receptor alpha (RARα) agonist with high oral bioavailability and potential anti-tumor activity. Compound 6 has no significant activity against RARβ / γ. Without being bound by theory, the RARα agonist compound 6 binds to and activates RARα upon administration, thereby promoting RARα-mediated signaling. This leads to the transcription of RARα-responsive genes, which are responsible for cell differentiation and proliferation. This leads to the induction of cell differentiation and apoptosis, and the inhibition of cell proliferation and tumorigenesis. RARα is a nuclear receptor that belongs to the steroid receptor superfamily. Regulation of RARα signaling is associated with cancer development in a variety of cancer cell types, including lymphomas or blood cancers such as multiple myeloma or leukemia.

[0104] In some embodiments, provided herein is a method for 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., a form of compound 6 or a salt thereof). In some embodiments, provided herein is a method for regulating RARα in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a form of compound 6 or a salt thereof). In some embodiments, regulation is activation of RARα. In some embodiments, provided herein is a method for regulating gene expression, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a form of compound 6 or a salt thereof).

[0105] In some embodiments, the disease is associated with one or more cellular processes, including cell proliferation or immune response. In some embodiments of the methods provided herein, the disease is selected from a cell proliferation disorder (such as a cancer or tumor) or an autoimmune disorder. In some embodiments, the cancer is a non-solid cancer (such as a liquid cancer, such as a blood cancer). In some embodiments, the cancer or tumor is a solid cancer or tumor.

[0106] In some embodiments, the subject comprises a refractory disease. In some embodiments, the refractory disease comprises a refractory cell proliferative disorder, such as a cancer or a tumor, or a refractory autoimmune disorder.

[0107] In certain embodiments of the 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, allergies, 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), diabetes mellitus type 1 (DM1), and leukemia. 1, IDDM), endometriosis, gastrointestinal disorders, glomerulonephritis, Goodpasture's 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, relapsing disseminated encephalomyelitis, rheumatic fever, schizophrenia, scleroderma, Sjögren's syndrome, skin disorders, tenosynovitis, uveitis, vasculitis, or vitiligo.

[0108] In certain embodiments, the disease does not include multiple sclerosis, ie, the subject being treated does not suffer from or has not been diagnosed as having multiple sclerosis.

[0109] In certain embodiments, the arthritis is monoarthritis, oligoarthritis, polyarthritis, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, septic arthritis, spondyloarthropathy, gout, pseudogout, or Still's disease.

[0110] In some embodiments, the gastrointestinal disorder is irritable bowel disease or inflammatory bowel disease. In other embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

[0111] 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.

[0112] In some embodiments, the autoimmune disorder is a myopathy with an autoimmune component, such as dermatomyositis, inclusion body myositis, or polymyositis.

[0113] In some embodiments, the skin disorder is dermatitis, eczema, stasis dermatitis, hidradenitis suppurativa, psoriasis, rosacea, or scleroderma.

[0114] 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, allergic vasculitis, Kawasaki disease, microscopic polyarteritis / polyangiitis, polyarteritis nodosa, polymyalgia rheumatica (PMR), rheumatoid vasculitis, Takayasu's arteritis, or Wegener's granulomatosis.

[0115] In some embodiments, the autoimmune disease is multiple sclerosis, psoriasis, rheumatoid arthritis, glomerulonephritis, pulmonary fibrosis, interstitial nephritis, or inflammatory bowel disease.

[0116] Although the methods described refer to the compounds described herein, it should be understood that the compounds can also be used in conjunction with these methods in the form of compositions or pharmaceutical compositions.

[0117] Actual dosage levels of the active ingredients provided herein (e.g., compounds represented by the formulae provided herein), compositions, or pharmaceutical compositions may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0118] Specifically, the selected dosage level will depend on a variety of factors, including the activity of the specific compound employed, the time of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical field. A physician (e.g., a physician or veterinarian) with ordinary skills in the art can easily determine the effective amount of the desired pharmaceutical composition and prescribe it. For example, a physician or veterinarian can start the dosage of the compound used in the pharmaceutical composition at a lower level than the level required to achieve the desired therapeutic effect, and then gradually increase the dosage until the desired effect is achieved.

[0119] Administration of the compounds, compositions or combinations disclosed herein includes a variety of enteral or parenteral methods selected from, but not limited to, the following: oral administration in any acceptable form (e.g., tablets, liquids, capsules, powders, etc.); topical administration in any acceptable form (e.g., drops, sprays, creams, gels or ointments); buccal, nasal 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, such as intravenous bolus injection, intravenous infusion , intra-arterial bolus, intra-arterial infusion, and catheter instillation into the vasculature; administration around and within tissues in any acceptable form, such as intraperitoneal injection, intramuscular injection, subcutaneous injection, subcutaneous infusion, intraocular injection, retinal injection, or subretinal or epidural injection; intravesical administration in any acceptable form, such as catheter instillation; and through placement of devices, such as implants, stents, patches, pellets, catheters, osmotic pumps, suppositories, bioerodible delivery systems, non-bioerodible delivery systems, or another implanted delayed or sustained release system.

[0120] Compounds, compositions or combinations disclosed herein can be administered to mammals using a variety of 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 an oral inhalation or nasal inhalation route of administration. The compound for use as described herein can be formulated for administration by any suitable route to achieve the specific method being applied. In some embodiments, routes of administration suitable for treating RARα-related diseases as disclosed herein include both local administration and systemic administration. Compared to the entire body of a mammal, local administration results in significantly more delivery of compounds, compositions or combinations to a specific location, while systemic administration results in delivery of compounds, compositions or combinations to substantially the entire body of an individual. Routes of administration suitable for treating RARα-related diseases as disclosed herein also include central and peripheral administration. Central administration results in delivery of compounds, compositions or combinations to substantially 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.

[0121] The central administration through the nasal route that targets the vascular plexus for drug absorption via the nasal cavity is different from the administration through nasal inhalation via the pulmonary system for drug delivery. Although the latter usually uses a mean particle size less than 10 microns, and in some embodiments about 2 microns or less liquid or dry powder aerosol, central administration is usually completed using a mean particle size of 10-20 microns or more. Sprayers, dry powder inhalers, pressurized aerosols, and atomizing pumps can be used to generate mist and aerosols, wherein aerosols are preferred. It is also feasible to use nasal drops to carry out central administration through the nasal route.

[0122] Peripheral administration results in the delivery of compounds, compositions or combinations to substantially any area outside the central nervous system of an individual, and encompasses any route of administration other than direct administration to the spine or brain. A person of ordinary skill in the art can determine the actual route of administration of the compounds, compositions or combinations disclosed herein by considering a variety of factors, including but not limited to the type of RARα-related disease, the location of the RARα-related disease, the cause of the RARα-related disease, the severity of the RARα-related disease, the duration of treatment required, the degree of relief required, the duration of relief required, the specific compound, composition or combination, the excretion rate of the compound, composition or combination used, the pharmacodynamics of the compound, composition or combination used, the properties of other compounds to be included in the composition or combination, the specific route of administration, the specific characteristics, medical history and risk factors (e.g., age, weight, overall health, etc.) of the individual, the individual's response to treatment, or any combination thereof. Therefore, a person of ordinary skill in the art can easily determine the amount of the effective dose of the compounds, compositions or combinations disclosed herein by considering all criteria and according to the best judgment of the individual.

[0123] In some embodiments, the compound prepared by the methods described herein has the formula:

[0124] or a salt thereof,

[0125] For example, or a salt thereof,

[0126] The compounds are used in methods of treating RARα-associated diseases, including those that would benefit from therapeutic RARα modulation (eg, RARα activation) or anti-tumor activity.

[0127] Although the methods are described with respect to the compounds described herein, it should be understood that these compounds can also be used in conjunction with these methods in the form of compositions or pharmaceutical compositions.

[0128] Actual dosage levels of the active ingredients provided herein (e.g., compounds represented by the formulae provided herein), compositions, or pharmaceutical compositions may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0129] Specifically, the selected dosage level will depend on a variety of factors, including the activity of the specific compound employed, the time of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical field. A physician (e.g., a physician or veterinarian) with ordinary skills in the art can easily determine the effective amount of the desired pharmaceutical composition and prescribe it. For example, a physician or veterinarian can start the dosage of the compound used in the pharmaceutical composition at a lower level than the level required to achieve the desired therapeutic effect, and then gradually increase the dosage until the desired effect is achieved.

[0130] Reagent test kit

[0131] In some embodiments, provided herein are packaged compounds, packaged compositions, or packaged pharmaceutical compositions comprising a container holding a therapeutically effective amount of a compound described herein, and instructions for using the compound according to one or more of the methods provided herein.

[0132] The compounds of the invention and associated materials can be finally used as commercial products by conventional steps performed in the art, such as by appropriate sterilization and packaging steps. For example, the materials can be treated by ultraviolet / visible light irradiation (200-500nm), such as using photoinitiators with different absorption wavelengths (e.g., Irgacure 184, 2959), preferably water-soluble initiators (e.g., Irgacure 2959). Such irradiation is usually performed for 1-60min irradiation time, but longer irradiation times can also be applied depending on the specific method. The materials according to the present disclosure can finally be aseptically packaged so as to maintain a sterile state before use, and packaged (e.g., by adding a specific product information leaflet) into a suitable container (box, etc.).

[0133] According to another embodiment, the compounds of the present invention may also be provided in the form of a kit in combination with other components required for administering the materials to a patient. For example, the disclosed kits, such as kits for the treatment of autoimmune or cell proliferation disorders, may further comprise, for example, administration materials.

[0134] The kits are designed in a variety of formats depending on the specific defect they are designed to treat.

[0135] Compound or composition provided herein can be prepared and placed in container so that store at ambient temperature or elevated temperature.Compared with polyvinyl chloride plastic container, when compound or composition is stored in polyolefin plastic container, no matter it is dissolved or suspended in liquid composition (for example, aqueous or organic liquid solution), or as solid, the discoloration of described compound or composition can be reduced.Not wishing to be bound by theory, container can reduce the exposure of container contents to electromagnetic radiation, and no matter it is visible light (for example, wavelength is about 380-780nm) or ultraviolet (UV) light (for example, wavelength is about 190-320nm (UV B light) or about 320-380nm (UVA light)).Some containers also include the ability to reduce the exposure of container contents to infrared light, or have the second component of this ability.Operable container includes by polyolefin, for example polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutylene or their combination, especially polyethylene, polypropylene or their combination made of container.In some embodiments, described container is glass container. The container can be further arranged in a second container, such as a paper container, a cardboard container, a cardboard container, a metal film container, or a foil container or a combination thereof, to further reduce the exposure of the container contents to UV, visible light, or infrared light. Compounds and compositions that benefit from discoloration, decomposition, or both reduction during storage include eye drop solutions or implants comprising compounds provided herein or compositions thereof. Compounds or compositions provided herein may need to be stored for up to three months or longer than three months; up to one year or longer than one year in some cases. The container can be any form suitable for holding contents—such as a bag, a bottle, or a box. In some embodiments, the container is a container that includes reducing the ability of compounds or compositions provided herein to be adsorbed to its surface, thereby preventing the concentration of compounds or compositions placed in the container from being significantly reduced.

[0136] The following examples further illustrate various aspects of the present disclosure. However, they are in no way limiting to the teachings or disclosure as described herein.

[0137] Example

[0138] Example 1—Preparation of Compound 6: 4-(4-chloro-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamido)-2,6-difluorobenzoic acid

[0139] The preparation method of compound 6 is as follows Figure 1 As shown, starting from commercially available compound 1 (2,5-dichloro-2,5-dimethylhexane), it can also be generally prepared as described in steps 2-5 below, starting from commercially available compound 2 (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-ol).

[0140] Step 2—Synthesis of Compound 3: 3-Hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid. In a pressure reactor, 100 g of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-acid sodium (Na salt of Compound 2) and 40 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-β-naphthol were injected in a high boiling point solvent at a temperature of 170°C and a carbon dioxide pressure of 10 kg / cm 2 (G) and stirred for 2 hours. The reaction mixture was cooled and injected with 500 ml of water, and then separated into a reaction medium layer and an aqueous layer at 90°C. The aqueous layer was extracted with 50 ml of xylene. The aqueous layer was made acidic with dilute sulfuric acid, and compound 3 was isolated.

[0141] 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) was added in portions to a solution of Compound 3 (23.0 kg, 1 equivalent) in tetrahydrofuran, and the mixture was heated and stirred until the reaction was complete. The mixture was cooled, and ethyl acetate was added. The mixture was washed with brine, and the organics were then concentrated and evaporated with heptane. Heptane was added and the slurry was cooled, and the product was collected by filtration and rinsed with heptane. The product Compound 4 was dried (17.7-23.8 kg, yield 67-91%).

[0142] Step 4 - Synthesis of Compound 5. Phosphorus trichloride (4.2 kg, 1.44 equivalents) was added to a suspension of Compound 4 (18 kg, 1.0 equivalents) in toluene, and the mixture was heated and stirred until a solution was formed. A solution of 3,5-difluoroaniline (9 kg, 1.09 equivalents) in toluene was then added, and heating was continued until the reaction was complete. The mixture was cooled slightly, then partially concentrated and co-evaporated with isopropanol. Isopropanol was added, and the slurry was then heated to dissolve the product and partially concentrated again. The resulting slurry was cooled and the product was collected by filtration. The filtrate was partially concentrated and then cooled to precipitate a second fraction, which was collected by filtration. It was then dried in vacuo at a temperature less than 60°C to obtain Compound 5 (18.1-20.1 kg, 72-80% yield).

[0143] Step 5 - Synthesis of Compound 6. A mixture of Compound 5 (15 kg, 1 eq.) and 2,2,6,6-tetramethylpiperidine (10.7 kg, 2 eq.) in tetrahydrofuran was cooled. While maintaining the temperature, n-hexyllithium (43.1 kg, 2.5 M, in hexane, 4 eq.) was slowly added to the mixture, and the mixture was stirred for a certain time. The mixture was quenched on dry ice (about 186 kg), and then heated and stirred until all solid dry ice disappeared. Water was added, and the layers were separated, and the organic matter was extracted a second time with water. The aqueous layers were combined, acidified with hydrochloric acid (15.01 kg, 4 eq.), and then extracted twice with ethyl acetate. The combined organic matter was concentrated and co-evaporated with toluene. Toluene was added, and the mixture was cooled. The resulting slurry was filtered and rinsed with cold toluene. The product compound 6 was dried (40-50°C) and then refrigerated in the dark (11.7-15.9 kg, yield 70-95%). 1 HNMR(CD3OD): d1.34(s,6H), 1.54(s,6H), 1.68(m,2H), 1.75(m,2H), 7.53(d,J HF =10.2Hz,2H).

[0144] Unless otherwise indicated, all numbers used in the specification and claims to represent the amount of ingredients, properties (e.g., molecular weight), reaction conditions, etc. should be understood to be modified by the term "about" in all cases. As used herein, the terms "about" and "roughly" refer to within 10% to 15%, preferably within 5% to 10%. Therefore, unless otherwise indicated, the numerical parameters listed in the specification and the appended claims are approximate values, which can vary according to the desired properties sought to be obtained by the present invention. At the very least, in any case, it is not intended to limit the application of the principle of equivalents of the scope of the claims, and each numerical parameter should be interpreted at least according to the number of reported significant digits and by applying ordinary rounding techniques. Although the numerical ranges and parameters describing the wide range of the present invention are approximate values, the numerical values ​​listed in the specific examples are reported as accurately as possible. However, any numerical value inherently contains certain errors caused by the standard deviations present in its respective corresponding test measurements.

[0145] Unless otherwise specified herein or obviously contradictory to the context, the terms "one", "a (kind)", "the / said" and similar indicators used in the context of describing the present invention (especially in the context of the following claims) and the situation of not using quantifiers should be interpreted as covering both the singular and the plural. The description of the value range herein is intended only to be used as a shorthand method for quoting each individual value falling into the range. Unless otherwise specified herein, each individual value is incorporated into the specification as if it is quoted separately in this article. Unless otherwise specified herein or obviously contradictory to the context, all methods described herein can be carried out in any suitable order. The use of any and all examples or illustrative language (such as "for example") provided herein is only intended to better illustrate the present invention, rather than to limit the scope of the claimed invention. Any language in the specification should not be interpreted as indicating that any unclaimed element is essential for the practice of the present invention.

[0146] The grouping of the alternative elements or embodiments of the present invention disclosed herein should not be construed as limiting. Each group member can be mentioned and claimed individually or in any combination with other members in the group or other elements found herein. It is expected that one or more members in the group may be included in the group or deleted from the group for convenience and / or patentability reasons. When any such inclusion or deletion occurs, this specification is deemed to include the modified group, thereby satisfying the written description of all Markush groups used in the appended claims.

[0147] Certain embodiments of the present invention are described herein, including the best mode known to the inventor for implementing the present invention. Of course, variations of the embodiments described will become apparent to those of ordinary skill in the art after reading the foregoing description. The inventors hope that the skilled person will appropriately adopt such variations, and the inventors hope to practice the present invention in a manner different from that specifically described herein. Therefore, the present invention includes all modifications and equivalents of the subject matter described in the claims appended hereto as permitted by applicable law. In addition, unless otherwise specified herein or clearly contradictory to the context, the present invention encompasses any combination of all possible variations of the above elements.

[0148] Specific embodiments disclosed herein may be further limited in the claims using language consisting of or consisting essentially of. When used in a claim, whether as originally filed or added by amendment, the transitional term "consisting of" excludes any elements, steps, or ingredients not specified in the claim. The transitional term "consisting essentially of" limits the scope of the claim to the specified materials or steps, and those materials or steps that do not materially affect the basic and novel characteristics. Embodiments of the invention so claimed are inherently or expressly described and enabled herein.

[0149] In addition, throughout the specification, numerous references have been made to patents and printed publications. The entire contents of each of the above-cited references and printed publications are individually incorporated herein by reference.

[0150] Finally, it should be understood that the embodiments of the present invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the present invention. Therefore, by way of example and not limitation, alternative configurations of the present invention may be used in accordance with the teachings herein. Therefore, the present invention is not limited to those precisely as shown and described.

Claims

1. A compound having the formula: or a salt thereof.

2. A method for preparing the compound according to claim 1, comprising: Contact with sulfuryl chloride to form the compound.

3. A compound having the formula: or a salt thereof.

4. A method for preparing the compound according to claim 3, comprising A) Make contacting with phosphorus trichloride to form an intermediate; and B) contacting the intermediate with 3,5-difluoroaniline to form the compound.

5. A compound having the formula: or a salt thereof.

6. A method for preparing the compound according to claim 5, comprising A) Make contacting with phosphorus trichloride to form an intermediate; and B) contacting the intermediate with 3,5-difluoroaniline to form the compound.

7. A method for preparing the compound according to claim 5, comprising: Contact with sulfuryl chloride to form the compound.

8. A method for preparing a compound having the following formula or a salt thereof: The method comprises: A) contacting the compound of claim 5 with lithium tetramethylpiperidin to form an intermediate; and B) contacting said intermediate with CO2 to form said compound.

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

10. The compound according to claim 5, which is in the solid form of the following compound:

11. The compound of claim 10, prepared by precipitation from a solvent comprising isopropanol.

12. The compound according to claim 5, which is a crystalline form of:

13. The compound of claim 12, prepared by crystallization from a solvent comprising isopropanol.

14. A solid form of the following compound: It is prepared by precipitation from toluene.

15. A crystalline form of the following compound: It is prepared by crystallization from toluene.

16. The compound according to claim 3, which is in the solid form of:

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

18. A particle 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, the particles according to claim 18 and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of 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, which is formulated for oral, parenteral, topical or inhalation dosage form, or is formulated for oral, parenteral, topical or inhalation administration.

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

23. The method of claim 22, wherein the disease is a retinoic acid receptor alpha-associated disease.

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

25. The method of claim 22, wherein the disease is selected from a cell proliferative disorder.

26. The method of claim 22, wherein the disease is selected from cancer or a tumor.

27. A method of modulating retinoic acid receptor alpha in a subject in need thereof, comprising administering to the subject an effective amount of: The solid form according to claim 14; The crystalline form according to claim 15; The particle according to claim 18; or A pharmaceutical composition according to any one of claims 19 to 21.

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