US20220112190A1 - Inhibitors of ror gamma - Google Patents
Inhibitors of ror gamma Download PDFInfo
- Publication number
- US20220112190A1 US20220112190A1 US17/509,630 US202117509630A US2022112190A1 US 20220112190 A1 US20220112190 A1 US 20220112190A1 US 202117509630 A US202117509630 A US 202117509630A US 2022112190 A1 US2022112190 A1 US 2022112190A1
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- Prior art keywords
- crystalline form
- compound
- hydrogen bromide
- bromide salt
- ray powder
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- RORs Retinoic acid receptor-related orphan receptors
- the ROR family consists of ROR alpha (ROR ⁇ ), ROR beta (ROR ⁇ ) and ROR gamma (ROR ⁇ ), each encoded by a separate gene (in human: RORA, RORB and RORC, respectively; in mouse: rora, rorb and rorc, respectively).
- RORs contain four principal domains shared by the majority of nuclear receptors: an N-terminal domain, a highly conserved DNA-binding domain (DBD) consisting of two zinc finger motifs, a hinge domain, and a ligand binding domain (LBD).
- ROR ⁇ has two isoforms: ROR ⁇ 1 and ROR ⁇ 2 (also known as ROR ⁇ t).
- ROR ⁇ 1 is expressed in a variety of tissues including thymus, muscle, kidney and liver, while ROR ⁇ t is exclusively expressed in the cells of the immune system.
- ROR ⁇ t has a critical role in thymopoiesis and the development of several secondary lymphoid tissues, and is a key regulator of Th17 cell differentiation (Jetten, 2009, Nucl. Recept. Signal., 7:e003, doi:10.1621/nrs.07003, Epub 2009 Apr. 3).
- Th17 cells are a subset of T helper cells which preferentially produce the pro-inflammatory cytokines IL-17A, IL-17F, IL-21 and IL-22.
- Th17 cells and their effector molecules such as IL-17, IL-21, IL-22, GM-CSF and CCL20, are associated with the pathogenesis of several autoimmune and inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease, allergy and asthma (Maddur et al., 2012, Am. J. Pathol., 181:8-18).
- Compound 1 is an inhibitor of ROR ⁇ and has therapeutic properties against a number of ROR ⁇ mediated diseases.
- Compound 1 is exemplified in U.S. Pat. No. 9,266,886 and has the formula:
- HBr salts can be prepared with minimal concern for degradation or minimal need for special precautions such as working in oxygen free atmospheres. See e.g., the Exemplification section below.
- initial attempts employed a two-step process started from Compound 1.
- This process involved the formation and isolation of a mono-hydrogen bromide salt by treatment with hydrobromic acid followed by a second independent treatment step with hydrobromic acid to form a bis-hydrogen bromide salt of Compound 1.
- This two-step method was utilized because initial attempts to produce a purified version of the bis-hydrogen bromide salt directly (i.e., without first isolating the mono-bromide salt) did not afford the desired level of purity required for large batch processing.
- the disclosed two-step method required the use of HBr and MeOH during the final steps of the synthesis. This transformation led to contamination of the product from production of MeBr.
- a one step process of forming the disclosed bis-hydrogen bromide salt directly from Compound 1 was also found.
- neutralizing the reductive amination reaction mixture, thereby resulting in precipitation provided Compound 1 as a free base in high purity and good yield, particularly on a larger scale.
- reactions were effective at >3 kg scale with 98% yield and in >99 area % purity. See e.g., the Exemplification section.
- treatment with a sufficient amount of hydrobromic acid afforded the desired bis-hydrogen bromide salt without the need to use MeOH. While no detectable contamination from MeBr was observed, this process led to the formation of a mixture of crystalline forms: Form E, Form F, and Form G.
- FIG. 1 depicts an X-ray powder diffraction pattern (XRPD) for Form A of Compound 1.
- FIG. 2 depicts a Differential Scanning calorimetry (DSC) spectrum for Form A of Compound 1.
- FIG. 3 depicts a thermal gravimetric analysis (TGA) pattern for Form A of Compound 1.
- FIG. 4 depicts a Dynamic Vapor Sorption (DVS) isotherm plot for Form A of Compound 1.
- FIG. 5 depicts an X-ray powder diffraction pattern (XRPD) for Form B of Compound 1.
- FIG. 6 depicts a Differential Scanning calorimetry (DSC) spectrum for Form B of Compound 1.
- FIG. 7 depicts a thermal gravimetric analysis (TGA) pattern for Form B of Compound 1.
- FIG. 8 depicts a Dynamic Vapor Sorption (DVS) isotherm plot for Form B of Compound 1.
- FIG. 9 depicts an X-ray powder diffraction pattern (XRPD) for Form C of Compound 1.
- FIG. 10 depicts a Differential Scanning calorimetry (DSC) spectrum for Form C of Compound 1.
- FIG. 11 depicts a thermal gravimetric analysis (TGA) pattern for Form C of Compound 1.
- FIG. 12 depicts a Dynamic Vapor Sorption (DVS) isotherm plot for Form C of Compound 1
- FIG. 13 depicts an X-ray powder diffraction pattern (XRPD) for Form D of Compound 1.
- FIG. 14 depicts a Differential Scanning calorimetry (DSC) spectrum for Form D of Compound 1.
- FIG. 15 depicts a thermal gravimetric analysis (TGA) pattern for Form D of Compound 1.
- FIG. 16 depicts a Dynamic Vapor Sorption (DVS) isotherm plot for Form D of Compound 1.
- FIG. 17 depicts an X-ray powder diffraction pattern (XRPD) for Form E of Compound 1.
- FIG. 18 depicts a Differential Scanning calorimetry (DSC) spectrum for Form E of Compound 1.
- FIG. 19 depicts a thermal gravimetric analysis (TGA) pattern for Form E of Compound 1.
- FIG. 20 depicts an X-ray powder diffraction pattern (XRPD) overlay of Form A, Form B, Form C, Form D, and Form E of Compound 1.
- XRPD X-ray powder diffraction pattern
- FIG. 21 depicts a Differential Scanning calorimetry (DSC) spectrum overlay of Form A, Form B, Form C, Form D, and Form E of Compound 1.
- DSC Differential Scanning calorimetry
- FIG. 22 depicts a thermal gravimetric analysis (TGA) pattern overlay of Form A, Form B, Form C, Form D, and Form E of Compound 1.
- TGA thermal gravimetric analysis
- FIG. 23 depicts an 1H-NMR spectrum for Compound 1 made by conditions described herein.
- FIG. 24 depicts an 1H-NMR spectrum for a mono-hydrogen bromide salt Form B of Compound 1 made by conditions described herein.
- FIG. 25 depicts an XRPD spectrum for a mono-hydrogen bromide salt Form B of Compound 1 made by conditions described herein.
- a mono-hydrogen bromide salt having the formula:
- the mono-hydrogen bromide salt has a purity of >95% such as, e.g., >96%, >97%, >98%, or >99%, or 99.5% or greater.
- the bis-hydrogen bromide salt has a purity of >95% such as, e.g., >96%, >97%, >98%, >99%, or 99.5% or greater.
- provided herein are methods of manufacturing one or more of the salt and crystalline forms described herein.
- Form A refers to the crystalline polymorph Form A of Compound 1.
- Form B refers to the crystalline polymorph Form B of Compound 1.
- Form B refers to the crystalline polymorph Form B of Compound 1.
- Form B refers to the crystalline polymorph Form B of Compound 1
- crystalline Form B of Compound 1 refers to the crystalline polymorph Form C of Compound 1.
- Form C refers to the crystalline polymorph Form C of Compound 1.
- Form D refers to the crystalline polymorph Form D of Compound 1.
- Form D refers to the crystalline polymorph Form D of Compound 1.
- Form D refers to the crystalline polymorph Form D of Compound 1
- crystalline Form D of Compound 1 refers to the crystalline polymorph Form E of Compound 1.
- Form E refers to the crystalline polymorph Form E of Compound 1.
- Form E refers to the crystalline polymorph Form E of Compound 1
- crystalline Form E of Compound 1 are used interchangeably.
- amorphous means a solid that is present in a non-crystalline state or form.
- Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering.
- Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).
- XRPD X-ray powder diffraction
- DSC differential scanning calorimetry
- Amorphous solids can also be differentiated from crystalline solids e.g., by birefringence using polarized light microscopy.
- purity is expressed in terms of percentage and can be calculated by dividing the mass of the mono- and bis-hydrogen bromide salt forms of Compound 1 by the total mass of the sample, and then multiplying this number by 100.
- 90% pure or has a purity of 90% means that the designated mono- or bis-hydrogen bromide salt form of Compound 1, or designated polymorphic form makes up 90% by weight of the sample.
- the purity of the salt and crystalline forms described herein are >90%, >95%, >97%, and >99% pure (e.g., >99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, and 99.9%) by weight. In one aspect, the purity of the salt and crystalline forms described herein are >90%, >95%, >97%, and >99% pure (e.g., >99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, and 99.9%) by weight and free from other salt or polymorphic forms.
- pharmaceutically acceptable carrier refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound with which it is formulated, and which is also safe for human use.
- Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lac
- treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
- treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment.
- treatment may be administered in the absence of symptoms.
- treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to reduce the likelihood of obtaining or to delay recurrence.
- the 2-theta values of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation. Therefore, the MOD patterns/assignments recited herein are not to be construed as absolute and can vary ⁇ 0.2 degrees.
- substantially the same XRPD pattern means that for comparison purposes, at least 90% of the peaks shown are present. It is to be further understood that for comparison purposes some variability in peak intensities from those shown are allowed, such as ⁇ 0.2 degrees.
- the present disclosure provides crystalline Form A, crystalline Form B, crystalline Form C, crystalline Form D, and crystalline Form E of Compound 1.
- crystalline Form A of Compound 1 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2 ⁇ angles selected from 14.90°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46°.
- crystalline Form A of Compound 1 is characterized by x-ray powder diffraction peaks at 2 ⁇ angles 14.90°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46.
- crystalline Form A of Compound 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty seven or at least thirty-eight x-ray powder diffraction peaks at 2 ⁇ angles selected from Table 4.
- crystalline Form A of compound 1 is characterized by x-ray powder diffraction peaks at 7.54°, 8.04°, 14.24°, 14.90°, 16.32°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46°.
- crystalline Form A of Compound 1 is characterized by x-ray powder diffraction peaks in Table 4.
- crystalline Form A of Compound 1 has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 1 .
- crystalline Form A of Compound 1 has a DSC pattern that is substantially the same DSC pattern shown in FIG. 2 .
- crystalline Form A of Compound 1 has a TGA pattern that is substantially the same TGA pattern shown in FIG. 3 .
- the crystalline Form A of Compound 1 is a bis-hydrogen bromide salt having one or more of the XRPD peaks defined above.
- crystalline Form B of Compound 1 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2 ⁇ angles selected from 5.24°, 7.98°, 12.12°, 19.42°, 21.18°, and 21.52°.
- crystalline Form B of Compound 1 is characterized by x-ray powder diffraction peaks at 2 ⁇ angles 5.24°, 7.98°, 12.12°, 19.42°, 21.18°, and 21.52°.
- crystalline Form B of Compound 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty seven, at least thirty-eight, at least thirty-nine, at least forty, or at least forty-one x-ray powder diffraction peaks at 2 ⁇ angles selected from Table 5.
- crystalline Form B of compound 1 is characterized by x-ray powder diffraction peaks at 3.94°, 5.24°, 7.98°, 12.12°, 16.64°, 19.42°, 21.18°, and 21.52°, 26.18°, and 27.80°.
- crystalline Form B of Compound 1 is characterized by x-ray powder diffraction peaks in Table 5.
- crystalline Form B of Compound 1 has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 5 .
- crystalline Form B of Compound 1 has a DSC pattern that is substantially the same DSC pattern shown in FIG. 6 .
- crystalline Form B of Compound 1 has a TGA pattern that is substantially the same TGA pattern shown in FIG. 7 .
- the crystalline Form B of Compound 1 is a mono-hydrogen bromide salt having one or more of the XRPD peaks defined above.
- the crystalline Form B of Compound 1 is a solvate having one or more of the XRPD peaks defined above.
- the crystalline Form B of Compound 1 is an isopropanol solvate having one or more of the XRPD peaks defined above.
- the crystalline Form B of Compound 1 is a mono-hydrogen bromide salt isopropanol solvate having one or more of the XRPD peaks defined above.
- crystalline Form C of Compound 1 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2 ⁇ angles selected from 20.28°, 20.70°, 23.18°, 23.34°, 25.24°, and 26.46.
- crystalline Form C of Compound 1 is characterized by x-ray powder diffraction peaks at 2 ⁇ angles 20.28°, 20.70°, 23.18°, 23.34°, 25.24°, and 26.46.
- crystalline Form C of Compound 1 has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 9 .
- crystalline Form C of Compound 1 has a DSC pattern that is substantially the same DSC pattern shown in FIG. 10 .
- crystalline Form C of Compound 1 has a TGA pattern that is substantially the same TGA pattern shown in FIG. 11 .
- the crystalline Form C of Compound 1 is a bis-hydrogen bromide salt having one or more of the XRPD peaks defined above.
- crystalline Form D of Compound 1 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2 ⁇ angles selected from 14.24°, 15.24°, 15.90°, 18.54°, 18.82°, and 22.46°.
- crystalline Form D of Compound 1 is characterized by x-ray powder diffraction peaks at 2 ⁇ angles 14.24°, 15.24°, 15.90°, 18.54°, 18.82°, and 22.46°.
- crystalline Form D of Compound 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, or at least thirty-six, x-ray powder diffraction peaks at 2 ⁇ angles selected from Table 12.
- crystalline Form D of compound 1 is characterized by x-ray powder diffraction peaks at 7.58°, 9.02°, 14.56°, 14.24°, 15.24°, 15.90°, 17.16°, 18.54°, 18.82°, 20.14°, and 22.46°.
- crystalline Form D of compound 1 is characterized by x-ray powder diffraction peaks at 7.58°, 9.02°, 14.56°, 14.24°, 15.24°, 15.90°, 17.16°, 18.54°, 18.82°, 20.14°, 22.46°, 20.70°, 21.02°, 21.70°, 24.36°, and 24.58°.
- crystalline Form D of compound 1 is characterized by x-ray powder diffraction peaks at 7.58°, 9.02°, 14.56°, 14.24°, 15.24°, 15.90°, 17.16°, 18.54°, 18.82°, 20.14°, 22.46°, 20.70°, 21.02°, 21.70°, 24.36°, 24.58°, 25.66°, 25.82°, 26.51°, 26.82°, 29.68°, and 33.70°.
- crystalline Form D of Compound 1 is characterized by x-ray powder diffraction peaks in Table 12.
- crystalline Form D of Compound 1 has an XRPD pattern that is substantially the same XRPD pattern shown in FIG.
- crystalline Form D of Compound 1 has a DSC pattern that is substantially the same DSC pattern shown in FIG. 14 .
- crystalline Form D of Compound 1 has a TGA pattern that is substantially the same TGA pattern shown in FIG. 15 .
- the crystalline Form D of Compound 1 is a bis-hydrogen bromide salt having one or more of the XRPD peaks defined above.
- Form D of Compound 1 is a hydrate (e.g., a dihydrate) having one or more of the XRPD peaks defined above.
- Form D of Compound 1 is a bis-hydrogen bromide salt that is a dihydrate and has one or more of the XRPD peaks defined above.
- crystalline Form E of Compound 1 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2 ⁇ angles selected from 4.1°, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°.
- crystalline Form E of Compound 1 is characterized by x-ray powder diffraction peaks at 2 ⁇ angles 4.1°, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°.
- crystalline Form E of Compound 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, or at least thirty-six x-ray powder diffraction peaks at 2 ⁇ angles selected from Table 10.
- crystalline Form E of Compound 1 is characterized by x-ray powder diffraction peaks in Table 10.
- crystalline Form E of Compound 1 has an XRPD pattern that is substantially the same XRPD pattern shown in FIG. 17 .
- crystalline Form E of Compound 1 has a DSC pattern that is substantially the same DSC pattern shown in FIG. 18 .
- crystalline Form E of Compound 1 has a TGA pattern that is substantially the same TGA pattern shown in FIG. 19 .
- the crystalline Form E of Compound 1 is a bis-hydrogen bromide salt having one or more of the XRPD peaks defined above.
- FIGS. 20-22 For ease of comparison, XRPD, DSC, and TGA overlays of the polymorphic forms are shown in FIGS. 20-22 .
- crystalline Form A, C, D, or E may each independently be a solvate such as e.g., solvated with water (i.e., a hydrate).
- the amount of a disclosed form is such that it is effective as an inverse agonist or antagonist to ROR ⁇ in a biological sample or in a subject.
- a provided composition is formulated for administration to a subject in need of such composition.
- a provided composition is formulated for oral administration to a subject.
- compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
- the amount of a provided compound in the composition will also depend upon the particular compound in the composition.
- Diseases and disorders treatable using one of more of the disclosed forms of Compound 1 include, but are not limited to, inflammatory, metabolic and autoimmune conditions mediated by ROR ⁇ . These conditions include, for example, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic rhinitis, atopic dermatitis, contact dermatitis, acne, cystic fibrosis, allograft rejection, multiple sclerosis, scleroderma, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE), psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, type I diabetes, autoimmune ocular disease, ulcerative colitis, Crohn's disease, regional enteritis, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjögren's syndrome, optic neuritis
- rhythms which are implicated by the regulation of the circadian rhythm of individuals and include, e.g., major depression, seasonal affective disorder, post-traumatic stress disorder (PTSD), bipolar disorder, autism, epilepsy, Alzheimer's disease and other central nervous system (CNS) disorders associated with altered sleep and/or circadian rhythms.
- PTSD post-traumatic stress disorder
- CNS central nervous system
- the diseases and disorders treated by a disclosed form of Compound 1 include, e.g., asthma, atopic dermatitis, acne, Crohn's disease, regional enteritis, ulcerative colitis, Sjögren's syndrome, uveitis, Behçet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, systemic lupus erythematosus (SLE), scleroderma, psoriasis, psoriatic arthritis (PsA), steroid resistant asthma and rheumatoid arthritis in the patient.
- asthma e.g., asthma, atopic dermatitis, acne, Crohn's disease, regional enteritis, ulcerative colitis, Sjögren's syndrome, uveitis, Behçet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, systemic lupus erythemato
- a human subject is treated with a disclosed form of Compound 1, wherein said form is present in an amount to treat one or more of the diseases and disorders recited above.
- a human subject is treated with a composition comprising a disclosed form of Compound 1, wherein said form is present in an amount to treat one or more of the diseases and disorders recited above.
- a disclosed form of Compound 1 for use in treating one or more of the diseases and disorders recited above is provided.
- compositions may be formulated such that a dosage of between 0.001-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
- a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
- a two-step process was initially developed to form the bis-hydrogen bromide salt of Compound 1. See e.g., Scheme 5 in the Exemplification section, a portion of which is depicted here as Scheme 1.
- This process comprised first forming and isolating a mono-hydrogen bromide salt of Compound 1 followed by conversion of the mono-hydrogen bromide salt to the bis-hydrogen bromide salt of Compound 1.
- step ii) Compound 1 is dissolved in a mixture of isopropanol and acetic acid prior to the addition of hydrobromic acid.
- step ii) the mono-hydrogen bromide salt of Compound 1 is precipitated via the addition of hydrobromic acid.
- the amine compound is formed in situ from treating an acid salt form (e.g., a hydrochloric acid salt such as a di-hydrochloric acid salt) of the amine with a tertiary amine base (e.g., trimethylamine or diisopropylethylamine).
- an acid salt form e.g., a hydrochloric acid salt such as a di-hydrochloric acid salt
- a tertiary amine base e.g., trimethylamine or diisopropylethylamine.
- the above method further comprises the step of iv) dissolving the isolated mono-hydrogen bromide salt of Compound 1 in solvent (e.g., in MeOH) and adding to the solution MTBE and a sufficient amount of hydrobromic acid to form crystalline Form D bis-hydrogen bromide salt of Compound 1 having the formula:
- the solution is step iv) is seeded.
- crystalline Form D bis-hydrogen bromide salt of Compound 1 precipitates from the solution is step iv) upon cooling (e.g., to 5° C. in 30 min/5 to 6 hrs) and is filtered.
- Reducing agents for performing reductive aminations include, but are not limited to, sodium triacetoxyborohydride (NaBH(OAc) 3 ), sodium borohydride (NaBH 4 ), palladium on carbon with H 2 , and platinum on carbon with H 2 . See e.g., March's Advanced Organic Chemistry, fifth edition, John Wiley & Sons 2001.
- the reducing agent is NaBH(OAc) 3 .
- the amount and concentration of hydrobromic acid that is sufficient to form the mono- or bis-hydrogen bromide salt can vary. For example, 35% to 55% hydrobromic acid can be used, 37% to 53% hydrobromic acid can be used, or 40% to 48% hydrobromic acid can be used. In one aspect, 40% or 48% hydrobromic acid is used. Amounts of hydrobromic acid can range from 0.8 equivalents to 1.4 equivalents. For example, 0.9 to 1.3 equivalents, 1.0 to 1.3 equivalents, or 1.0 to 1.2 equivalents can be used. In one aspect, 1.0 or 1.2 equivalents of hydrobromic acid is used. In one aspect, 1.2 equivalents of 40% hydrobromic acid is used. In another aspect, 1.0 equivalents of 48% hydrobromic acid is used.
- the concentration and amount of hydrobromic acid that is sufficient to form both the mono- and bis-hydrogen bromide salts of Compound 1 are the same and include e.g., 1.2 equivalents of 40% hydrobromic acid or 1.0 equivalents of 48% hydrobromic acid is use for both steps.
- the hydrobromic acid is a mixture of hydrogen bromide in acetic acid or aqueous hydrobromic acid.
- a method of removing methyl bromide from a composition comprising methyl bromide and a bis-hydrogen bromide salt of Compound 1 comprising i) slurrying the composition in a mixture of isopropyl acetate/water or a mixture of heptane/water; and ii) separating the bis-hydrogen bromide salt of the compound from the mixture of isopropyl acetate/water or the mixture of heptane/water.
- removing methyl bromide from a composition comprising methyl bromide and a bis-hydrogen bromide salt of Compound 1 comprises slurrying the composition in a mixture of isopropyl acetate comprising 0.25% to 2.5% v/v of water; and ii) separating the bis-hydrogen bromide salt of the compound from the mixture of isopropyl acetate/water.
- the mixture comprises isopropyl acetate comprising 0.5% to 2.0% v/v of water, 0.7% to 1.7% v/v of water, 0.8% to 1.5% v/v of water, 0.9% to 1.3% v/v of water, 0.9% to 1.1% v/v of water, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%.
- the methyl bromide present in the composition prior to slurrying the composition, is greater than 45 ppm, greater than 50 ppm, greater than 55 ppm, or greater than 60 ppm.
- the amount of methyl bromide present in the composition may be from 50 ppm to 1000 ppm.
- the amounts of methyl bromide present in the composition prior to slurrying refers to the amount present in a dried composition, e.g., prior to slurrying the composition is dried (e.g., at approximately 15 to 50° C. such as 20 to 25° C.) under approximately ⁇ 0.096 MPa vacuum for 20 hours or more.
- the methyl bromide present in the composition is greater than 45 ppm, greater than 50 ppm, greater than 55 ppm, greater than 60 ppm, or from 50 ppm to 1000 ppm; and the mixture comprises isopropyl acetate comprising 0.5% to 2.0% v/v of water, 0.7% to 1.7% v/v of water, 0.8% to 1.5% v/v of water, 0.9% to 1.3% v/v of water, 0.9% to 1.1% v/v of water, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%.
- separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having less than 45 ppm of methyl bromide present.
- separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having is less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm of methyl bromide present.
- separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having an amount of methyl bromide present that is below the level of detection.
- separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having less than 45 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm of methyl bromide present, or an amount of methyl bromide that is below the level of detection; and wherein prior to slurrying the composition, the methyl bromide present in the composition is greater than 45 ppm, greater than 50 ppm, greater than 55 ppm, greater than 60 ppm, or from 50 ppm to 1000 ppm.
- separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having less than 45 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm of methyl bromide present, or an amount of methyl bromide that is below the level of detection; wherein prior to slurrying the composition, the methyl bromide present in the composition is greater than 45 ppm, greater than 50 ppm, greater than 55 ppm, greater than 60 ppm, or from 50 ppm to 1000 ppm; and wherein the mixture comprises isopropyl acetate comprising 0.5% to 2.0% v/v of water, 0.7% to 1.7% v/v of water, 0.8% to 1.5% v/v of water, 0.9% to 1.3% v/v of water, 0.9% to 1.1% v/v of water, 0.5%, 0.
- the reductive amination is carried out in the presence of ethanol, and in the presence of an imine reducing agent; ii) quenching the reductive amination mixture with acid; iii) neutralizing the resulting solution with base, thereby precipitating the free base form of the compound; and iv) isolating the precipitated free-based form of the compound from the solution.
- a solution of the aldehyde compound in isopropyl acetate is added to a slurry of the imine reducing agent in a solution of the trialkyl amine and the amine compound in ethanol.
- the acid used for quenching is hydrochloric acid.
- the base used is an aqueous base such as a solution of aqueous sodium hydroxide.
- the solution is neutralized in step iii) to pH 5 to 7.
- the amine compound is formed in situ from treating an acid salt form (e.g., a hydrochloric acid salt such as a di-hydrochloric acid salt) of the amine with a tertiary amine base.
- tertiary amines for performing reductive aminations include, but are not limited to, trialkylamines such as diisopropylethylamine (DIPEA or iPr 2 NEt) and trimethylamine (TEA). See e.g., March's Advanced Organic Chemistry, fifth edition, John Wiley & Sons 2001. In one instance, the amine used is DIPEA.
- DIPEA diisopropylethylamine
- TEA trimethylamine
- reducing agents for performing reductive aminations include, but are not limited to, sodium triacetoxyborohydride (NaBH(OAc) 3 ), sodium borohydride (NaBH 4 ), palladium on carbon with H 2 , and platinum on carbon with H 2 . See e.g., March's Advanced Organic Chemistry, fifth edition, John Wiley & Sons 2001.
- the reducing agent is NaBH(OAc) 3 .
- the bis-hydrogen bromide salt can then be prepared directly (i.e., without first isolating the mono-hydrogen bromide salt) by adding sufficient hydrobromic acid to the free-base to form the bis-hydrogen bromide salt.
- formation of the bis-hydrogen bromide salt from the free-based further comprises the addition of a mixture of isopropanol, MTBE, and acetic acid.
- formation of the bis-hydrogen bromide salt from the free-based further comprises the addition of a mixture of acetic acid and MEK.
- the amount and concentration of hydrobromic acid that is sufficient to form the bis-hydrogen bromide salt can vary, but is typically from 2 to 5 equivalents of, for example, 35% to 55% hydrobromic acid, 37% to 53% hydrobromic acid, or 40% to 48% hydrobromic acid. In one aspect, 40% or 48% hydrobromic acid is used. In one aspect, 2 to 4 equivalents, 2 to 3 equivalents, 2 to 2.5 equivalents or 2.1 equivalents of 40% or 48% hydrobromic acid is used.
- a method of converting crystalline Forms E, F and G of the bis-hydrogen bromide salt of Compound 1 to crystalline Form D bis-hydrogen bromide salt comprising i) slurrying a composition comprising one or more of crystalline forms E, F and G in a mixture of isopropyl acetate/water containing between 0.25%-2.5% v/v; and ii) separating (e.g., via filtration) the crystalline form D of the bis-hydrogen bromide salt of the compound from the mixture of isopropyl acetate/water.
- the mixture comprises isopropyl acetate comprising 0.5% to 2.0% v/v of water, 0.7% to 1.7% v/v of water, 0.8% to 1.5% v/v of water, 0.9% to 1.3% v/v of water, 0.9% to 1.1% v/v of water, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%.
- the amount of Form E, F, and G present in the composition is greater than 90% by weight, such as greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, or greater than 98%, greater than 99%.
- the product formed is crystalline Form D bis-hydrogen bromide salt
- that product may be further characterized by the XRPD peaks and data described herein e.g., by at least three, at least four, or at least five x-ray powder diffraction peaks at 2 ⁇ angles selected from 14.24°, 15.24°, 15.90°, 18.54°, 18.82°, and 22.46°; or by x-ray powder diffraction peaks at 2 ⁇ angles 14.24°, 15.24°, 15.90°, 18.54°, 18.82°, and 22.46°; or by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four
- crystalline Forms E, F and G referred to in the methods described herein may be further characterized by the XRPD peaks and data described herein for each of these forms.
- thermogram was performed using a TA Instruments 2920 differential scanning calorimeter. Temperature calibration was performed using NIST-traceable indium metal. The sample was placed into an aluminum Tzero crimped pan (TOC) and the weight was accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The data acquisition parameters and pan configuration for each thermogram are displayed in the image in the figure.
- the method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate; e.g., ( ⁇ 30)-250-10 means “from ⁇ 30° C. to 250° C., at 10° C./min”.
- thermogravimetric analyzer a thermogravimetric analyzer
- Temperature calibration was performed using nickel and AlumelTM.
- Each sample was placed in a platinum pan. The sample was hermetically sealed, the lid pierced, then inserted into the TG furnace. The furnace was heated under nitrogen.
- the data acquisition parameters for each thermogram are displayed in the in the figure.
- the method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate; e.g., 00-350-10 means “from ambient ° C. to 350° C., at 10° C./min”.
- XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source.
- An elliptically graded multilayer mirror was used to focus Cu K ⁇ X-rays through the specimen and onto the detector.
- a silicon specimen NIST SRM 640e was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position.
- a specimen of the sample was sandwiched between 3- ⁇ m-thick films and analyzed in transmission geometry.
- a beam-stop, short antiscatter extension, antiscatter knife edge were used to minimize the background generated by air.
- Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b. The data acquisition parameters for each pattern are displayed above the image in the Data section of this report including the divergence slit (DS) before the mirror.
- X'Celerator scanning position-sensitive detector located 240 mm from the specimen
- Data Collector software v. 2.2b.
- the data acquisition parameters for each pattern are displayed above the image in the Data section of this report including the divergence slit (DS) before the mirror.
- a salt/co-crystal screening was conducted under 127 conditions with 20 salt/co-crystal co-formers and seven solvent systems. For each condition, approximately 20 mg of Compound 1 was dispersed in the selected solvent in a glass vial and then salt/co-crystal co-former was added. Observation of slurries were followed by isolation and analysis of the resulting solids. Even though some crystalline solids were isolated and analyzed by)(RFD, discoloration, possibly associated with decomposition was also observed (Table 1). Salt-screening experiments yielding a unique XRPD pattern were analyzed by HPLC-UV and were all determined to be primarily composed of degradants. A re-preparation and scale up of the adipic acid prepared under strictly nitrogen atmosphere still yielded primarily degradants and was not pursued further.
- HBr salt screening was unsuccessful in identifying further options for new forms of Compound 1 because of degradation. While the HCl and sulfate salts, having less degradation than others, did initially prove promising, additional techniques were required to reduce oxidation during their production. For example, solvent systems in which Compound 1 has limited solubility were chosen for formation of the HCl and sulfates salts to limit oxidation, while providing enough solubility to promote conversion to crystalline salts. However, this approach is time consuming and not favorable for large scale manufacturing methods. Also, the counterpart HBr salt was found to not require such approaches as it was stable under oxygen atmosphere and did not degrade during preparation or after air-drying.
- both a mono- and bis-hydrogen bromide salt of Compound 1 were prepared. Although both of these forms did not degrade during preparation, the mono-hydrogen bromide salt absorbs about twice the amount of water than the corresponding bis-hydrogen bromide form. See e.g., FIGS. 8 and 16 . Indeed, the bis-hydrogen bromide salt exhibits no more than a 5% weight change. This is a significant advantage because higher moisture uptake can lead to diminished shelf life and unwanted conversion to other forms and/or degradation.
- Amorphous hydrogen bromide salt of Compound 1 was prepared according to General Procedure B as described for Compound 2 in U.S. Pat. No. 9,266,886, the contents of which are incorporated herein by reference.
- the bis-hydrogen salt crystalline Form D of Compound 1 proved to be the most useful, particularly in view of its advantages over the other four forms.
- the moisture uptake of Form D is significantly less than the other forms. Compare e.g., the DVS isotherm plot of Form D ( FIG. 16 ) with Form A ( FIG. 4 ), Form B ( FIG. 8 ), and Form C ( FIG. 12 ).
- Form D was found to be reproducible at large scale.
- the initial material produced was an oil. While this eventually converted to a solid, passing through an oil stage during plant operations could lead to problems with product formation on large scale.
- these forms contained residual acetone which is not acceptable for plant API production.
- Last, Form D has a high melting point. This allows for added stability during manufacturing, transport, and storage. More specific details for each of the five hydrogen bromide salt forms are as follows.
- Amorphous HBr salt of Compound 1 was slurried in various solvents. 50 mg of the amorphous HBr salts were suspended in ethyl acetate (EA), ethanol (EtOH), methyl-tert-butyl-ether (MtBE or MTBE), isopropyl acetate (IPAc), methyl ethyl ketone (MEK), and methyl isobutyl ketone (MIBK) solvents (about 10 vol) at 10° C. for 20 hours. Samples were taken from the suspensions under nitrogen protection and dried at 50° C. for 10 minutes. All residual solids were still amorphous.
- EA ethyl acetate
- EtOH ethanol
- MtBE or MTBE methyl-tert-butyl-ether
- IPAc isopropyl acetate
- MEK methyl ethyl ketone
- MIBK methyl isobutyl ketone
- Form A and Form B can also be prepared starting from amorphous Compound 1, i.e., the free-based form instead of an HBr salt form.
- Form A was determined to be a bis-hydrogen bromide salt
- Form B was determined to be a mono-hydrogen bromide salt. Procedures for their formation as follows.
- Form A identified as a bis-hydrogen bromide salt
- 1 g of amorphous free base i.e., Compound 1
- 40% HBr/water solution (0.66 ⁇ ; 2.00 e.q.) was then added dropwise at RT. Seeds of Form A were added and the mixture was cooled to 10° C. and slurried overnight. The mixture was then filtered and dried at RT overnight.
- Form A bis salt
- Form B mono-hydrogen bromide salt
- DVS scan showed Form A absorbs around 20% water at 90% RH.
- Form A is chemically stable at RT and 50° C. under vacuum. However, some crystallinity was lost at 50° C. (XRPD pattern changed slightly). Also, during the salt formation procedure, the material transforms to an oil and then converts to solid (Form A).
- Form B identified as a mono-hydrogen bromide salt
- 1 g of amorphous free base i.e., Compound 1
- 35% HBr/AcOH 0.48 ⁇ , 1.15 eq
- Seeds of Form B were added and the mixture was cooled to 10° C. and slurried overnight. The mixture was then filtered and dried at RT overnight.
- Form B After drying the solid at 50° C., the solid converted to amorphous, and IPA content was reduced to 3800 pm. Form B is therefore a potential IPA solvate.
- the bromine content of Form B (or amorphous from conversion) solid is 12%. This confirms that Form B (or amorphous) solid is a mono salt and is not a stable structure (due to conversion). DVS scan showed Form B absorbs around 10% water at 90% RH.
- Form E 1 g of amorphous mono-hydrogen bromide salt Form B is charged to a reactor. 10 vol acetone is added to the reactor at RT followed by 40% HBr/water solution (to make the total HBr amount as 2.0 e.q. mole) dropwise at RT. Seeds of Form E are added, the mixture is cooled to 5° C., slurried overnight, and then dried at 50° C. overnight.
- Form D 1 g of amorphous mono-hydrogen bromide salt Form B is charged to a reactor. 5 vol of MeOH at RT is added until the solid is fully dissolved. 40% HBr/Water solution (1.2 e.q.) at RT followed by 8-9 vol of MtBE, and seeded. The mixture is held for 30 min to 1 hr, cooled to 5° C. in 30 min/5 to 6 hrs (two separated experiments; fast/slow cooling rate), and slurried overnight. 14-15 vol of MtBE in 2 to 3 hrs is added, the mixture is slurried for 2 to 3 hours, filtered, and then dried at 45° C.
- Scale up of Form D was performed as follows. 2 g amorphous mono salt Form B is charged to a reactor at RT. 5 vol MeOH was added and the solid was made sure to fully dissolve. 40% HBr/water solution (1.2 e.q.) was added dropwise at RT followed by 13 vol MtBE with seeding (first add 4 vol and seed, followed by 2 vol and seed, followed by 2 vol and seed, and so on). The mixture was slurried for half an hour, cooled to 5° C. in 2 hrs, slurried overnight, 10 vol MtBE was added in 2 to 3 hrs and the mixture was slurried over the weekend. The mixture was then filtered and dried at 60° C. and RT for 5 hrs. Results are shown in Table 11.
- Form D can also isolated from the amorphous bis-hydrogen bromide salt form of Compound 1 in a slurry experiment comprising acetone/water (1:1 v/v).
- a saturated solution the amorphous bis-hydrogen bromide salt form om acetone/water (1:1 v/v) was slurried for one week at ambient and the solid was harvested to obtain Form D.
- the water activity (a w ) of an equal volume mixture of acetone and water is 0.91. See SSCI internal report, Water Activity Calculations using UNIFAC Calculator, SR-20150515.01, dated Jul. 23, 2015.
- the mono-HBr salt is then converted to the bis-HBr salt by dissolving the mono salt in methanol, adding 1.1 equiv of 40% aqueous HBr, then seeding, followed by additions of MTBE and water.
- the bis-HBr salt is isolated by filtration and drying at 30-45° C. in vacuum.
- the final product is isolated as the bis-hydrogen bromide salt Form D with contamination from MeBr (approximately 40 ppm or more at laboratory scale and approximately 227 ppm or greater on plant production of 100 grams or greater).
- a typical reaction can proceed as follows. To the 30-gal reactor was added 2 (5.12 kg, 9.2 mol, 1.0 equiv). In a carboy was charged ethanol (27.3 L, 7 vol relative to sodium triacetoxyborohydride (STAB)) and DIPEA (3.57 kg, 27.6 mol, 3 equiv relative to 2). The solution of DIPEA/EtOH was added to the reactor with the 2 with no stirring. A cloud of amine hydrochloride formed in the reactor making it difficult to see the slurry, so the batch was allowed to sit without stirring until this cloud dissipated. After 35 min, the cloud dissipated and the mixture was gently stirred. In an hour, the solids had dissolved. The batch was stirred gently overnight at 10° C. and then the 2 was drained from the reactor into a carboy.
- STAB sodium triacetoxyborohydride
- the reactor was charged with STAB (3.91 kg, 18.4 mol, 2 equiv) and pre-made solution of DIPEA (2.383 kg, 18.4 mol, 2 equiv) and ethanol (27.2 L, 7 vol relative to STAB) with the jacket at ⁇ 5° C.
- the mixture was allowed to cool to 0° C. over 20 min.
- the solution of 2 in DIPEA/EtOH was added over 27 min followed by the free aldehyde solution in IPAc over 45 min.
- the maximum temperature during the aldehyde addition was 3.7° C.
- the mixture was stirred for 1 h and was sampled for reaction completion.
- the reaction was quenched by the addition of 1 N HCl (31.2 L, 8 vol relative to STAB) over 33 min. The temperature rose to 11° C. during this addition. The solids dissolved during this quench and the solution was stirred 1 h. The quenched reaction was transferred to a 100-gal. Pfaudler, glass-lined reactor with the jacket set to 10° C. To the 100-gal reactor was charged 1 N NaOH solution (31.2 L, 8 vol relative to STAB). After this addition, the pH rose from approximately 5 to approximately 6 and solids precipitated. The free base slurry was allowed to stir overnight at approximately 10° C. for convenience. The batch was then transferred to a pressure filter equipped with a tight weave cloth.
- the initial filtration was performed with occasional stirring and the batch de-liquored in about 4 h.
- the reactor and filter cake were washed with DI water (2 ⁇ 16 L) and 1:1 ethanol/DI water (16 L). The washes took approximately 30 min each.
- the wet cake was conditioned for 2 h under 8 psig of nitrogen and then was dried at a jacket temperature 35° C. The drying was monitored by KF analysis.
- the wet cake contained 21% water and the dried cake before off-loading was 5.4% water.
- the yield was 4.97 kg (98%).
- the HPLC analysis of the product was 99.7 area %.
- the NMR weight assay was 90.8 wt % ( FIG. 23 ) and the final KF analysis was 4.7% water.
- Residue-on-ignition (ROI) analysis of the free base indicated it had 0.2% residual inorganic material.
- the material can then be converted to the bis-hydrogen bromide salt by e.g., contacting the free base (0.8026 g) with acetic acid (2 vol, 1.6052 ml) and stirring the mixture at 250 RPM, heated 30° C. A 48% HBr solution is then added (0.3438 ml, 2.1 equiv) drop wise over 9 min.
- MEK (4.816 ml, 6 vol) is then added over 50 minutes and the reaction is seeded with bis-hydrogen bromide salt Form D.
- MEK (8.000 ml, 10 vol) is added at 2 ml slowly added every 5 min. The mixture is then chilled to 5° C.
- parts from the one-step and two-step methods can also be combined.
- the IPAc/water reslurry procedure to remove the residual methyl bromide can be used in the product formation of both the mono- and bis-hydrogen bromide salt forms from the two-step process.
- the solvent for the reductive amination may also be EtOH instead of methylene chloride and the base may be iPr 2 Net.
- a representative approach is shown below in Scheme 3.
- a large scale process to form the mono-hydrogen bromide product using the EtOH/DIPEA conditions was as follows.
- Compound 3 can be made according to the procedure set forth above. From there, a 30-gal, Pfaudler, glass-lined reactor was charged with 3 free base (4.959 kg, 8.97 mol, 1.0 equiv) and isopropanol (49.5 L, 10 vol). Acetic acid (1.49 L, 0.3 vol) was charged to the stirred mixture. Aqueous hydrobromic acid (48%, 1.664 kg, 9.87 mol, 1.1 equiv) was added to mixture over 16 min and the mixture was stirred at room temperature for 32 min. The batch was then warmed to 40° C. over 48 min. No solids were observed at this point.
- the batch was cooled to 6.7° C. over 5 h. Crystallization was noted at after 1.5 h of cooling (10.6° C.). The batch was stirred overnight at 5° C. for convenience. The thick slurry was transferred to a pressure filter equipped with regular weave cloth. The batch de-liquored in 1 h. The reactor and filter cake was washed with IPA (2 ⁇ 17.5 L). Stirring the wet cake caused it to ball up, so it was conditioned under nitrogen pressure overnight with the jacket at 30° C. Overnight some of the batch melted and passed the cloth. The filter was opened and the residue was scraped out of filter with some difficulty. The residue was tray dried in a vacuum oven at 35° C.
Abstract
The present disclosure relates to salts and crystalline forms of a compound having the formula:Also described are processes for the production of the salts and crystalline forms described herein.
Description
- This application is a divisional application of U.S. Ser. No. 16/633,334, filed on Jan. 23, 2020, which is a 35 U.S.C. § 371 national stage filing of international application No. PCT/US2018/043463, filed Jul. 24, 2018, which claims the benefit of priority to international application No. PCT/CN2017/094043, filed Jul. 24, 2017, the entire contents of each of which are incorporated herein by reference.
- Retinoic acid receptor-related orphan receptors (RORs) are a subfamily of transcription factors in the steroid hormone nuclear receptor superfamily (Jetten & Joo (2006) Adv. Dev. Biol. 2006, 16, 313-355). The ROR family consists of ROR alpha (RORα), ROR beta (RORβ) and ROR gamma (RORγ), each encoded by a separate gene (in human: RORA, RORB and RORC, respectively; in mouse: rora, rorb and rorc, respectively). RORs contain four principal domains shared by the majority of nuclear receptors: an N-terminal domain, a highly conserved DNA-binding domain (DBD) consisting of two zinc finger motifs, a hinge domain, and a ligand binding domain (LBD). RORγ has two isoforms: RORγ1 and RORγ2 (also known as RORγt). RORγ1 is expressed in a variety of tissues including thymus, muscle, kidney and liver, while RORγt is exclusively expressed in the cells of the immune system. RORγt has a critical role in thymopoiesis and the development of several secondary lymphoid tissues, and is a key regulator of Th17 cell differentiation (Jetten, 2009, Nucl. Recept. Signal., 7:e003, doi:10.1621/nrs.07003, Epub 2009 Apr. 3).
- Th17 cells are a subset of T helper cells which preferentially produce the pro-inflammatory cytokines IL-17A, IL-17F, IL-21 and IL-22. Th17 cells and their effector molecules, such as IL-17, IL-21, IL-22, GM-CSF and CCL20, are associated with the pathogenesis of several autoimmune and inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease, allergy and asthma (Maddur et al., 2012, Am. J. Pathol., 181:8-18). They are also important in the pathogenesis of acne (Thiboutot et al., 2014, J. Invest. Dermatol., 134(2):307-10, doi: 10.1038/jid.2013.400; Agak et al., 2014, J. Invest. Dermatol., 134(2):366-73, doi: 10.1038/jid.2013.334, Epub 2013 Aug. 7), inflammation associated with endometriosis (Hirata et al., 2010, Endocrinol., 151:5468-5476; Hirata et al., 2011, Fertil Steril., July; 96(1):113-7, doi: 10.1016/j.fertnstert.2011.04.060, Epub 2011 May 20), and many other conditions such as multiple sclerosis, rheumatoid arthritis, cancer, metabolic syndrome, obesity hepatosteatosis, insulin resistance, and diabetes (Meissburger et al., 2011, EMBO Mol. Med., 3:637-651; Tosolini et al., 2011, Cancer Res., 71:1263-1271, doi: 10.1158/0008-5472.CAN-10-2907, Epub 2011 Feb. 8; Su et al., 2014, Immunol. Res., 58:118-124, doi: 10.1007/s12026-013-8483-y, Epub 2014 Jan. 9; Carmi et al., 2011, J. Immunol., 186:3462-3471, doi: 10.4049/jimmunol.1002901, Epub 2011 Feb. 7; Chen et al., 2013, Histopathology, 63:225-233, doi: 10.1111/his.12156, Epub 2013 Jun. 6).
-
Compound 1 is an inhibitor of RORγ and has therapeutic properties against a number of RORγ mediated diseases.Compound 1 is exemplified in U.S. Pat. No. 9,266,886 and has the formula: - Despite its potential for commercialization, Compound 1 is susceptible to oxidation, particularly in solution. This makes it difficult to formulate pharmaceutically acceptable salts and polymorphs which are amendable to large scale manufacturing and formulating. Thus, the need to generate alternative forms for this potent inhibitor remains.
- In one aspect, provided herein are stable hydrogen bromide salt forms of
Compound 1. Unlike other salt forms, the disclosed HBr salts can be prepared with minimal concern for degradation or minimal need for special precautions such as working in oxygen free atmospheres. See e.g., the Exemplification section below. - In another aspect, specific mono- and bis-hydrogen bromide crystalline salts of
Compound 1 are disclosed, as well as methods for their preparation. Of the five characterized crystalline salt forms, Form D was found to have significantly less moisture update than other solid forms and to be more reproducible at large scale syntheses, thus making this form an attractive option for commercial processing. - During production of the bis-hydrogen bromide salt, initial attempts employed a two-step process started from Compound 1. This process involved the formation and isolation of a mono-hydrogen bromide salt by treatment with hydrobromic acid followed by a second independent treatment step with hydrobromic acid to form a bis-hydrogen bromide salt of
Compound 1. This two-step method was utilized because initial attempts to produce a purified version of the bis-hydrogen bromide salt directly (i.e., without first isolating the mono-bromide salt) did not afford the desired level of purity required for large batch processing. The disclosed two-step method required the use of HBr and MeOH during the final steps of the synthesis. This transformation led to contamination of the product from production of MeBr. This problem was subsequently solved by slurrying the product in a mixture of isopropyl acetate and water. Thus, in addition to the two step method and the formation of the mono- and bis-hydrogen bromide salt, disclosed herein are methods of removing methyl bromide from a composition comprising methyl bromide and crystalline form D bis-hydrogen bromide salt ofCompound 1. - A one step process of forming the disclosed bis-hydrogen bromide salt directly from
Compound 1 was also found. In this aspect, neutralizing the reductive amination reaction mixture, thereby resulting in precipitation, providedCompound 1 as a free base in high purity and good yield, particularly on a larger scale. For example, reactions were effective at >3 kg scale with 98% yield and in >99 area % purity. See e.g., the Exemplification section. From this, treatment with a sufficient amount of hydrobromic acid afforded the desired bis-hydrogen bromide salt without the need to use MeOH. While no detectable contamination from MeBr was observed, this process led to the formation of a mixture of crystalline forms: Form E, Form F, and Form G. This problem, however, was solved by slurrying the product in a mixture of isopropyl acetate and water to afford a single bis-hydrogen bromide crystal form ofCompound 1, i.e., Form D. Thus, in addition to the one-step process, provided herein are methods of converting crystalline Forms E, F and G of a bis-hydrogen bromide salt ofCompound 1 to Form D crystalline bis-hydrogen bromide salt ofCompound 1. - Also provided herein are methods of using the disclosed forms such treat a disease or disorder mediated by RORγ.
-
FIG. 1 . depicts an X-ray powder diffraction pattern (XRPD) for Form A ofCompound 1. -
FIG. 2 . depicts a Differential Scanning calorimetry (DSC) spectrum for Form A ofCompound 1. -
FIG. 3 . depicts a thermal gravimetric analysis (TGA) pattern for Form A ofCompound 1. -
FIG. 4 . depicts a Dynamic Vapor Sorption (DVS) isotherm plot for Form A ofCompound 1. -
FIG. 5 . depicts an X-ray powder diffraction pattern (XRPD) for Form B ofCompound 1. -
FIG. 6 . depicts a Differential Scanning calorimetry (DSC) spectrum for Form B ofCompound 1. -
FIG. 7 . depicts a thermal gravimetric analysis (TGA) pattern for Form B ofCompound 1. -
FIG. 8 . depicts a Dynamic Vapor Sorption (DVS) isotherm plot for Form B ofCompound 1. -
FIG. 9 . depicts an X-ray powder diffraction pattern (XRPD) for Form C ofCompound 1. -
FIG. 10 . depicts a Differential Scanning calorimetry (DSC) spectrum for Form C ofCompound 1. -
FIG. 11 . depicts a thermal gravimetric analysis (TGA) pattern for Form C ofCompound 1. -
FIG. 12 . depicts a Dynamic Vapor Sorption (DVS) isotherm plot for Form C ofCompound 1 -
FIG. 13 . depicts an X-ray powder diffraction pattern (XRPD) for Form D ofCompound 1. -
FIG. 14 . depicts a Differential Scanning calorimetry (DSC) spectrum for Form D ofCompound 1. -
FIG. 15 . depicts a thermal gravimetric analysis (TGA) pattern for Form D ofCompound 1. -
FIG. 16 . depicts a Dynamic Vapor Sorption (DVS) isotherm plot for Form D ofCompound 1. -
FIG. 17 . depicts an X-ray powder diffraction pattern (XRPD) for Form E ofCompound 1. -
FIG. 18 . depicts a Differential Scanning calorimetry (DSC) spectrum for Form E ofCompound 1. -
FIG. 19 . depicts a thermal gravimetric analysis (TGA) pattern for Form E ofCompound 1. -
FIG. 20 . depicts an X-ray powder diffraction pattern (XRPD) overlay of Form A, Form B, Form C, Form D, and Form E ofCompound 1. -
FIG. 21 . depicts a Differential Scanning calorimetry (DSC) spectrum overlay of Form A, Form B, Form C, Form D, and Form E ofCompound 1. -
FIG. 22 . depicts a thermal gravimetric analysis (TGA) pattern overlay of Form A, Form B, Form C, Form D, and Form E ofCompound 1. -
FIG. 23 . depicts an 1H-NMR spectrum forCompound 1 made by conditions described herein. -
FIG. 24 . depicts an 1H-NMR spectrum for a mono-hydrogen bromide salt Form B ofCompound 1 made by conditions described herein. -
FIG. 25 . depicts an XRPD spectrum for a mono-hydrogen bromide salt Form B ofCompound 1 made by conditions described herein. - In one aspect, provided herein is a mono-hydrogen bromide salt having the formula:
- wherein the mono-hydrogen bromide salt has a purity of >95% such as, e.g., >96%, >97%, >98%, or >99%, or 99.5% or greater.
- In another aspect, provided herein is a bis-hydrogen bromide salt having the formula:
- wherein the bis-hydrogen bromide salt has a purity of >95% such as, e.g., >96%, >97%, >98%, >99%, or 99.5% or greater.
- In other aspects, provided herein are crystalline Forms A, B, C, D, and E of
Compound 1. - In yet other aspects, provided herein are methods of manufacturing one or more of the salt and crystalline forms described herein.
- When used alone, the term “Form A” refers to the crystalline polymorph Form A of
Compound 1. The terms “Form A”, “Form A ofCompound 1”, and “crystalline Form A ofCompound 1” are used interchangeably. Similarly, when used alone, the term “Form B” refers to the crystalline polymorph Form B ofCompound 1. The terms “Form B”, “Form B ofCompound 1”, and “crystalline Form B ofCompound 1” are used interchangeably. Similarly, when used alone, the term “Form C” refers to the crystalline polymorph Form C ofCompound 1. The terms “Form C”, “Form C ofCompound 1”, and “crystalline Form C ofCompound 1” are used interchangeably. Similarly, when used alone, the term “Form D” refers to the crystalline polymorph Form D ofCompound 1. The terms “Form D”, “Form D ofCompound 1”, and “crystalline Form D ofCompound 1” are used interchangeably. Similarly, when used alone, the term “Form E” refers to the crystalline polymorph Form E ofCompound 1. The terms “Form E”, “Form E ofCompound 1”, and “crystalline Form E ofCompound 1” are used interchangeably. - The term “amorphous” means a solid that is present in a non-crystalline state or form. Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering. Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). Amorphous solids can also be differentiated from crystalline solids e.g., by birefringence using polarized light microscopy.
- When used in reference to the mono- and bis-hydrogen bromide salt forms of
Compound 1, as well as the polymorphic forms described herein, but not including solvated forms of these compounds, “purity” is expressed in terms of percentage and can be calculated by dividing the mass of the mono- and bis-hydrogen bromide salt forms ofCompound 1 by the total mass of the sample, and then multiplying this number by 100. Thus, 90% pure or has a purity of 90% means that the designated mono- or bis-hydrogen bromide salt form ofCompound 1, or designated polymorphic form makes up 90% by weight of the sample. In one aspect, the purity of the salt and crystalline forms described herein are >90%, >95%, >97%, and >99% pure (e.g., >99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, and 99.9%) by weight. In one aspect, the purity of the salt and crystalline forms described herein are >90%, >95%, >97%, and >99% pure (e.g., >99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, and 99.9%) by weight and free from other salt or polymorphic forms. - When purity is defined in terms of area such as >99% area, it will be understood that this refers to the purity of the identified compound as determined by the HPLC peak area percentage.
- The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound with which it is formulated, and which is also safe for human use. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate, and crosscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
- The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In one embodiment, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to reduce the likelihood of obtaining or to delay recurrence.
- The 2-theta values of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation. Therefore, the MOD patterns/assignments recited herein are not to be construed as absolute and can vary ±0.2 degrees.
- “Substantially the same XRPD pattern” means that for comparison purposes, at least 90% of the peaks shown are present. It is to be further understood that for comparison purposes some variability in peak intensities from those shown are allowed, such as ±0.2 degrees.
- In one aspect, the present disclosure provides crystalline Form A, crystalline Form B, crystalline Form C, crystalline Form D, and crystalline Form E of
Compound 1. - In one aspect, crystalline Form A of
Compound 1 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Θ angles selected from 14.90°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46°. Alternatively, crystalline Form A ofCompound 1 is characterized by x-ray powder diffraction peaks at 2Θ angles 14.90°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46. In another alternative, crystalline Form A ofCompound 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty seven or at least thirty-eight x-ray powder diffraction peaks at 2Θ angles selected from Table 4. In another alternative, crystalline Form A ofcompound 1 is characterized by x-ray powder diffraction peaks at 7.54°, 8.04°, 14.24°, 14.90°, 16.32°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46°. In another alternative, crystalline Form A ofCompound 1 is characterized by x-ray powder diffraction peaks in Table 4. In another aspect, crystalline Form A ofCompound 1 has an XRPD pattern that is substantially the same XRPD pattern shown inFIG. 1 . In another aspect, crystalline Form A ofCompound 1 has a DSC pattern that is substantially the same DSC pattern shown inFIG. 2 . In another aspect, crystalline Form A ofCompound 1 has a TGA pattern that is substantially the same TGA pattern shown inFIG. 3 . In one aspect, the crystalline Form A ofCompound 1 is a bis-hydrogen bromide salt having one or more of the XRPD peaks defined above. - In one aspect, crystalline Form B of
Compound 1 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Θ angles selected from 5.24°, 7.98°, 12.12°, 19.42°, 21.18°, and 21.52°. Alternatively, crystalline Form B ofCompound 1 is characterized by x-ray powder diffraction peaks at 2Θ angles 5.24°, 7.98°, 12.12°, 19.42°, 21.18°, and 21.52°. In another alternative, crystalline Form B ofCompound 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty seven, at least thirty-eight, at least thirty-nine, at least forty, or at least forty-one x-ray powder diffraction peaks at 2Θ angles selected from Table 5. In another alternative, crystalline Form B ofcompound 1 is characterized by x-ray powder diffraction peaks at 3.94°, 5.24°, 7.98°, 12.12°, 16.64°, 19.42°, 21.18°, and 21.52°, 26.18°, and 27.80°. In another alternative, crystalline Form B ofCompound 1 is characterized by x-ray powder diffraction peaks in Table 5. In another aspect, crystalline Form B ofCompound 1 has an XRPD pattern that is substantially the same XRPD pattern shown inFIG. 5 . In another aspect, crystalline Form B ofCompound 1 has a DSC pattern that is substantially the same DSC pattern shown inFIG. 6 . In another aspect, crystalline Form B ofCompound 1 has a TGA pattern that is substantially the same TGA pattern shown inFIG. 7 . In one aspect, the crystalline Form B ofCompound 1 is a mono-hydrogen bromide salt having one or more of the XRPD peaks defined above. In one aspect, the crystalline Form B ofCompound 1 is a solvate having one or more of the XRPD peaks defined above. In another aspect, the crystalline Form B ofCompound 1 is an isopropanol solvate having one or more of the XRPD peaks defined above. In yet another aspect, the crystalline Form B ofCompound 1 is a mono-hydrogen bromide salt isopropanol solvate having one or more of the XRPD peaks defined above. - In one aspect, crystalline Form C of
Compound 1 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Θ angles selected from 20.28°, 20.70°, 23.18°, 23.34°, 25.24°, and 26.46. Alternatively, crystalline Form C ofCompound 1 is characterized by x-ray powder diffraction peaks at 2Θ angles 20.28°, 20.70°, 23.18°, 23.34°, 25.24°, and 26.46. In another aspect, crystalline Form C ofCompound 1 has an XRPD pattern that is substantially the same XRPD pattern shown inFIG. 9 . In another aspect, crystalline Form C ofCompound 1 has a DSC pattern that is substantially the same DSC pattern shown inFIG. 10 . In another aspect, crystalline Form C ofCompound 1 has a TGA pattern that is substantially the same TGA pattern shown inFIG. 11 . In one aspect, the crystalline Form C ofCompound 1 is a bis-hydrogen bromide salt having one or more of the XRPD peaks defined above. - In one aspect, crystalline Form D of
Compound 1 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Θ angles selected from 14.24°, 15.24°, 15.90°, 18.54°, 18.82°, and 22.46°. Alternatively, crystalline Form D ofCompound 1 is characterized by x-ray powder diffraction peaks at 2Θ angles 14.24°, 15.24°, 15.90°, 18.54°, 18.82°, and 22.46°. In another alternative, crystalline Form D ofCompound 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, or at least thirty-six, x-ray powder diffraction peaks at 2Θ angles selected from Table 12. In another alternative, crystalline Form D ofcompound 1 is characterized by x-ray powder diffraction peaks at 7.58°, 9.02°, 14.56°, 14.24°, 15.24°, 15.90°, 17.16°, 18.54°, 18.82°, 20.14°, and 22.46°. In another alternative, crystalline Form D ofcompound 1 is characterized by x-ray powder diffraction peaks at 7.58°, 9.02°, 14.56°, 14.24°, 15.24°, 15.90°, 17.16°, 18.54°, 18.82°, 20.14°, 22.46°, 20.70°, 21.02°, 21.70°, 24.36°, and 24.58°. In another alternative, crystalline Form D ofcompound 1 is characterized by x-ray powder diffraction peaks at 7.58°, 9.02°, 14.56°, 14.24°, 15.24°, 15.90°, 17.16°, 18.54°, 18.82°, 20.14°, 22.46°, 20.70°, 21.02°, 21.70°, 24.36°, 24.58°, 25.66°, 25.82°, 26.51°, 26.82°, 29.68°, and 33.70°. In another alternative, crystalline Form D ofCompound 1 is characterized by x-ray powder diffraction peaks in Table 12. In another aspect, crystalline Form D ofCompound 1 has an XRPD pattern that is substantially the same XRPD pattern shown inFIG. 13 . In another aspect, crystalline Form D ofCompound 1 has a DSC pattern that is substantially the same DSC pattern shown inFIG. 14 . In another aspect, crystalline Form D ofCompound 1 has a TGA pattern that is substantially the same TGA pattern shown inFIG. 15 . In one aspect, the crystalline Form D ofCompound 1 is a bis-hydrogen bromide salt having one or more of the XRPD peaks defined above. In one aspect, Form D ofCompound 1 is a hydrate (e.g., a dihydrate) having one or more of the XRPD peaks defined above. In another aspect, Form D ofCompound 1 is a bis-hydrogen bromide salt that is a dihydrate and has one or more of the XRPD peaks defined above. - In one aspect, crystalline Form E of
Compound 1 is characterized by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Θ angles selected from 4.1°, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°. Alternatively, crystalline Form E ofCompound 1 is characterized by x-ray powder diffraction peaks at 2Θ angles 4.1°, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°. In another alternative, crystalline Form E ofCompound 1 is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, or at least thirty-six x-ray powder diffraction peaks at 2Θ angles selected from Table 10. In another alternative, crystalline Form E ofCompound 1 is characterized by x-ray powder diffraction peaks in Table 10. In another aspect, crystalline Form E ofCompound 1 has an XRPD pattern that is substantially the same XRPD pattern shown inFIG. 17 . In another aspect, crystalline Form E ofCompound 1 has a DSC pattern that is substantially the same DSC pattern shown inFIG. 18 . In another aspect, crystalline Form E ofCompound 1 has a TGA pattern that is substantially the same TGA pattern shown inFIG. 19 . In one aspect, the crystalline Form E ofCompound 1 is a bis-hydrogen bromide salt having one or more of the XRPD peaks defined above. - For ease of comparison, XRPD, DSC, and TGA overlays of the polymorphic forms are shown in
FIGS. 20-22 . - In one aspect, crystalline Form A, C, D, or E may each independently be a solvate such as e.g., solvated with water (i.e., a hydrate).
- In one aspect, provided are methods of treating a subject (e.g., a human) with a disease or disorder mediated by RORγ using one of more of the disclosed forms of
Compound 1; or a composition comprising one of more of the disclosed forms ofCompound 1 and a pharmaceutically acceptable carrier. In one aspect, the amount of a disclosed form is such that it is effective as an inverse agonist or antagonist to RORγ in a biological sample or in a subject. In certain aspects, a provided composition is formulated for administration to a subject in need of such composition. In some aspects, a provided composition is formulated for oral administration to a subject. - Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- A specific dosage and treatment regimen for any particular subject will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a provided compound in the composition will also depend upon the particular compound in the composition.
- Diseases and disorders treatable using one of more of the disclosed forms of
Compound 1 include, but are not limited to, inflammatory, metabolic and autoimmune conditions mediated by RORγ. These conditions include, for example, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic rhinitis, atopic dermatitis, contact dermatitis, acne, cystic fibrosis, allograft rejection, multiple sclerosis, scleroderma, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE), psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, type I diabetes, autoimmune ocular disease, ulcerative colitis, Crohn's disease, regional enteritis, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjögren's syndrome, optic neuritis, obesity, hepatosteatosis, adipose tissue-associated inflammation, insulin resistance, type II diabetes, neuromyelitis optica, myasthenia gravis, age related macular degeneration, dry eye, uveitis, Guillain-Barré syndrome, psoriasis, psoriatic arthritis (PsA), steroid resistant asthma, Graves' disease, scleritis, endometriosis, obstructive sleep apnea syndrome (OSAS), Behcet's disease, dermatomyositis, polymyocitis, graft versus host disease, primary biliary cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), sarcoidosis, primary sclerosing cholangitis, autoimmune thyroid disease, autoimmune polyendocrine syndrome type I, autoimmune polyendocrine syndrome type II, celiac disease, neuromyelitis, juvenile idiopathic arthritis, systemic sclerosis, myocardial infarction, pulmonary hypertension, osteoarthritis, cutaneous leishmaniasis, sinonasal polyposis, and cancer, including but not limited to lung cancer, gastric cancer, breast cancer and colon cancer. - Also included are conditions which are implicated by the regulation of the circadian rhythm of individuals and include, e.g., major depression, seasonal affective disorder, post-traumatic stress disorder (PTSD), bipolar disorder, autism, epilepsy, Alzheimer's disease and other central nervous system (CNS) disorders associated with altered sleep and/or circadian rhythms.
- In one aspect, the diseases and disorders treated by a disclosed form of
Compound 1 include, e.g., asthma, atopic dermatitis, acne, Crohn's disease, regional enteritis, ulcerative colitis, Sjögren's syndrome, uveitis, Behçet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, systemic lupus erythematosus (SLE), scleroderma, psoriasis, psoriatic arthritis (PsA), steroid resistant asthma and rheumatoid arthritis in the patient. - In one aspect, a human subject is treated with a disclosed form of
Compound 1, wherein said form is present in an amount to treat one or more of the diseases and disorders recited above. - In one aspect, a human subject is treated with a composition comprising a disclosed form of
Compound 1, wherein said form is present in an amount to treat one or more of the diseases and disorders recited above. - In one aspect, the use of a disclosed form of
Compound 1 for the manufacture of a medicament for treating one or more of the diseases and disorders recited above is provided. - In one aspect, a disclosed form of
Compound 1 for use in treating one or more of the diseases and disorders recited above is provided. - The amount of provided form of
Compound 1 form that may be combined with carrier materials to produce dosage form will vary depending upon the patient to be treated and the particular mode of administration. Provided compositions may be formulated such that a dosage of between 0.001-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions. - A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
- Provided herein are processes for preparing mono- and bis-hydrogen bromide salts of
Compound 1. Starting materials and synthetic methods for preparingCompound 1 and precursor materials can be found in e.g., General Procedure B of U.S. Pat. No. 9,266,886, the contents of which are incorporated herein by reference. - A. Two Step Method
- A two-step process was initially developed to form the bis-hydrogen bromide salt of
Compound 1. See e.g.,Scheme 5 in the Exemplification section, a portion of which is depicted here asScheme 1. This process comprised first forming and isolating a mono-hydrogen bromide salt ofCompound 1 followed by conversion of the mono-hydrogen bromide salt to the bis-hydrogen bromide salt ofCompound 1. - Provided herein, therefore are methods of forming a mono-hydrogen bromide salt of Compound 1, comprising the steps of i) reductively aminating an aldehyde compound represented by the following structural formula:
- with an amine compound represented by the following structural formula:
- wherein the reductive amination is carried out in the presence of an imine reducing agent to form Compound 1; ii) adding after the formation of Compound 1, sufficient hydrobromic acid to form the mono-hydrogen bromide salt of Compound 1 having the formula:
- and
iii) isolating the mono-hydrogen bromide salt of Compound 1. In some instances, the mono-hydrogen bromide salt of Compound 1 is amorphous. In one aspect, in step ii) Compound 1 is dissolved in a mixture of isopropanol and acetic acid prior to the addition of hydrobromic acid. In another aspect, in step ii) the mono-hydrogen bromide salt of Compound 1 is precipitated via the addition of hydrobromic acid. In one aspect, the amine compound is formed in situ from treating an acid salt form (e.g., a hydrochloric acid salt such as a di-hydrochloric acid salt) of the amine with a tertiary amine base (e.g., trimethylamine or diisopropylethylamine). In one aspect, the above method further comprises the step of iv) dissolving the isolated mono-hydrogen bromide salt of Compound 1 in solvent (e.g., in MeOH) and adding to the solution MTBE and a sufficient amount of hydrobromic acid to form crystalline Form D bis-hydrogen bromide salt of Compound 1 having the formula: - In one aspect, the solution is step iv) is seeded. In one aspect, crystalline Form D bis-hydrogen bromide salt of
Compound 1 precipitates from the solution is step iv) upon cooling (e.g., to 5° C. in 30 min/5 to 6 hrs) and is filtered. - Reducing agents for performing reductive aminations are known and include, but are not limited to, sodium triacetoxyborohydride (NaBH(OAc)3), sodium borohydride (NaBH4), palladium on carbon with H2, and platinum on carbon with H2. See e.g., March's Advanced Organic Chemistry, fifth edition, John Wiley &
Sons 2001. In one instance, the reducing agent is NaBH(OAc)3. - The amount and concentration of hydrobromic acid that is sufficient to form the mono- or bis-hydrogen bromide salt can vary. For example, 35% to 55% hydrobromic acid can be used, 37% to 53% hydrobromic acid can be used, or 40% to 48% hydrobromic acid can be used. In one aspect, 40% or 48% hydrobromic acid is used. Amounts of hydrobromic acid can range from 0.8 equivalents to 1.4 equivalents. For example, 0.9 to 1.3 equivalents, 1.0 to 1.3 equivalents, or 1.0 to 1.2 equivalents can be used. In one aspect, 1.0 or 1.2 equivalents of hydrobromic acid is used. In one aspect, 1.2 equivalents of 40% hydrobromic acid is used. In another aspect, 1.0 equivalents of 48% hydrobromic acid is used. These amounts and concentrations apply independently for both the mono- and bis-hydrogen bromide salt formation steps. In one aspect, the concentration and amount of hydrobromic acid that is sufficient to form both the mono- and bis-hydrogen bromide salts of
Compound 1 are the same and include e.g., 1.2 equivalents of 40% hydrobromic acid or 1.0 equivalents of 48% hydrobromic acid is use for both steps. In one aspect, the hydrobromic acid is a mixture of hydrogen bromide in acetic acid or aqueous hydrobromic acid. - While this process initially proved useful in forming the desired product, the combination of HBr and MeOH resulted in product contamination, i.e., excess methyl bromide was present in the initially isolated product. It was not until after significant efforts, that slurrying the product in a mixture of isopropyl acetate and water was found to effectively remove the excess methyl bromide. Although a mixture of heptane and water was also found to be effective, the solubility of the bis-hydrogen bromide crystalline Form D salt was greater in the isopropyl acetate/water mixture, and therefore this mixture was chosen for scale up purposes. A schematic representation of this process is shown below as
Scheme 2. - Provided herein, therefore is a method of removing methyl bromide from a composition comprising methyl bromide and a bis-hydrogen bromide salt of Compound 1 (e.g., crystalline Form D of the bis-hydrogen bromide salt of Compound 1) comprising i) slurrying the composition in a mixture of isopropyl acetate/water or a mixture of heptane/water; and ii) separating the bis-hydrogen bromide salt of the compound from the mixture of isopropyl acetate/water or the mixture of heptane/water.
- In one aspect, removing methyl bromide from a composition comprising methyl bromide and a bis-hydrogen bromide salt of
Compound 1 comprises slurrying the composition in a mixture of isopropyl acetate comprising 0.25% to 2.5% v/v of water; and ii) separating the bis-hydrogen bromide salt of the compound from the mixture of isopropyl acetate/water. In one aspect, the mixture comprises isopropyl acetate comprising 0.5% to 2.0% v/v of water, 0.7% to 1.7% v/v of water, 0.8% to 1.5% v/v of water, 0.9% to 1.3% v/v of water, 0.9% to 1.1% v/v of water, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%. - In some aspects, prior to slurrying the composition, the methyl bromide present in the composition is greater than 45 ppm, greater than 50 ppm, greater than 55 ppm, or greater than 60 ppm. For example, the amount of methyl bromide present in the composition may be from 50 ppm to 1000 ppm. The amounts of methyl bromide present in the composition prior to slurrying refers to the amount present in a dried composition, e.g., prior to slurrying the composition is dried (e.g., at approximately 15 to 50° C. such as 20 to 25° C.) under approximately −0.096 MPa vacuum for 20 hours or more. In a further aspect, prior to slurrying the composition, the methyl bromide present in the composition is greater than 45 ppm, greater than 50 ppm, greater than 55 ppm, greater than 60 ppm, or from 50 ppm to 1000 ppm; and the mixture comprises isopropyl acetate comprising 0.5% to 2.0% v/v of water, 0.7% to 1.7% v/v of water, 0.8% to 1.5% v/v of water, 0.9% to 1.3% v/v of water, 0.9% to 1.1% v/v of water, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%.
- In some aspects, separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having less than 45 ppm of methyl bromide present. For example, in certain instances, separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having is less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm of methyl bromide present. In one aspect, separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having an amount of methyl bromide present that is below the level of detection.
- In some aspects, separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having less than 45 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm of methyl bromide present, or an amount of methyl bromide that is below the level of detection; and wherein prior to slurrying the composition, the methyl bromide present in the composition is greater than 45 ppm, greater than 50 ppm, greater than 55 ppm, greater than 60 ppm, or from 50 ppm to 1000 ppm. In some aspects, separating the crystalline form D bis-hydrogen bromide salt from the mixture results in a crystalline form D bis-hydrogen bromide salt having less than 45 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm of methyl bromide present, or an amount of methyl bromide that is below the level of detection; wherein prior to slurrying the composition, the methyl bromide present in the composition is greater than 45 ppm, greater than 50 ppm, greater than 55 ppm, greater than 60 ppm, or from 50 ppm to 1000 ppm; and wherein the mixture comprises isopropyl acetate comprising 0.5% to 2.0% v/v of water, 0.7% to 1.7% v/v of water, 0.8% to 1.5% v/v of water, 0.9% to 1.3% v/v of water, 0.9% to 1.1% v/v of water, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%.
- Further detailed procedures on this two-step method are provided in the Exemplification section below.
- B. One Step Method
- A one-step method for preparing bis-hydrogen bromide salt of
Compound 1 was also identified. In this instance, it was found that switching the solvent from CH2Cl2 to EtOH in the reductive amination reaction followed by neutralizing the reductive amination mixture, and precipitating the resulting free base afforded a highly purified free-base product, or at least in pure enough form such that it could be directly converted to the bis-hydrogen bromide salt without the separate step of isolating the mono-hydrogen bromide salt. This method is depicted inScheme 6 below, a portion of which is represented here asScheme 3. - Thus, in one aspect, provided herein are alternative methods for preparing a free base form of Compound 1, the method comprising i) reductively aminating an aldehyde compound represented by the following structural formula:
- with an amine compound represented by the following structural formula:
- wherein the reductive amination is carried out in the presence of ethanol, and in the presence of an imine reducing agent; ii) quenching the reductive amination mixture with acid; iii) neutralizing the resulting solution with base, thereby precipitating the free base form of the compound; and iv) isolating the precipitated free-based form of the compound from the solution. In one aspect, a solution of the aldehyde compound in isopropyl acetate is added to a slurry of the imine reducing agent in a solution of the trialkyl amine and the amine compound in ethanol. In one aspect, the acid used for quenching is hydrochloric acid. In one aspect, the base used is an aqueous base such as a solution of aqueous sodium hydroxide. In one aspect, the solution is neutralized in step iii) to
pH 5 to 7. In one aspect, the amine compound is formed in situ from treating an acid salt form (e.g., a hydrochloric acid salt such as a di-hydrochloric acid salt) of the amine with a tertiary amine base. - Again, tertiary amines for performing reductive aminations are known and include, but are not limited to, trialkylamines such as diisopropylethylamine (DIPEA or iPr2NEt) and trimethylamine (TEA). See e.g., March's Advanced Organic Chemistry, fifth edition, John Wiley &
Sons 2001. In one instance, the amine used is DIPEA. - Again, reducing agents for performing reductive aminations are known and include, but are not limited to, sodium triacetoxyborohydride (NaBH(OAc)3), sodium borohydride (NaBH4), palladium on carbon with H2, and platinum on carbon with H2. See e.g., March's Advanced Organic Chemistry, fifth edition, John Wiley &
Sons 2001. In one instance, the reducing agent is NaBH(OAc)3. - From the free-base, the bis-hydrogen bromide salt can then be prepared directly (i.e., without first isolating the mono-hydrogen bromide salt) by adding sufficient hydrobromic acid to the free-base to form the bis-hydrogen bromide salt. In one aspect, formation of the bis-hydrogen bromide salt from the free-based further comprises the addition of a mixture of isopropanol, MTBE, and acetic acid. In another aspect, formation of the bis-hydrogen bromide salt from the free-based further comprises the addition of a mixture of acetic acid and MEK.
- Here, the amount and concentration of hydrobromic acid that is sufficient to form the bis-hydrogen bromide salt can vary, but is typically from 2 to 5 equivalents of, for example, 35% to 55% hydrobromic acid, 37% to 53% hydrobromic acid, or 40% to 48% hydrobromic acid. In one aspect, 40% or 48% hydrobromic acid is used. In one aspect, 2 to 4 equivalents, 2 to 3 equivalents, 2 to 2.5 equivalents or 2.1 equivalents of 40% or 48% hydrobromic acid is used.
- Although the need to isolate the mono-hydrogen bromide salt first prior to forming the bis-hydrogen bromide salt was eliminated with this one-step method, and contamination of product from methyl bromide was absent because of the avoidance of MeOH, the initial bis-hydrogen bromide salt formed was determined to be existed as a mixture of crystalline Forms E, F, and G. Forms F and G were not characterized further. To overcome this problem, it was found that slurrying the mixture of crystalline forms in isopropyl acetate/water resulted in the formation of single crystalline Form D bis-hydrogen bromide salt. See e.g.,
Scheme 4 below. - Thus, in one aspect, provided herein is a method of converting crystalline Forms E, F and G of the bis-hydrogen bromide salt of
Compound 1 to crystalline Form D bis-hydrogen bromide salt, comprising i) slurrying a composition comprising one or more of crystalline forms E, F and G in a mixture of isopropyl acetate/water containing between 0.25%-2.5% v/v; and ii) separating (e.g., via filtration) the crystalline form D of the bis-hydrogen bromide salt of the compound from the mixture of isopropyl acetate/water. - In one aspect, the mixture comprises isopropyl acetate comprising 0.5% to 2.0% v/v of water, 0.7% to 1.7% v/v of water, 0.8% to 1.5% v/v of water, 0.9% to 1.3% v/v of water, 0.9% to 1.1% v/v of water, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%.
- In one aspect, the amount of Form E, F, and G present in the composition is greater than 90% by weight, such as greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, or greater than 98%, greater than 99%.
- In one aspect, in the methods described herein, when the product formed is crystalline Form D bis-hydrogen bromide salt, that product may be further characterized by the XRPD peaks and data described herein e.g., by at least three, at least four, or at least five x-ray powder diffraction peaks at 2Θ angles selected from 14.24°, 15.24°, 15.90°, 18.54°, 18.82°, and 22.46°; or by x-ray powder diffraction peaks at 2Θ angles 14.24°, 15.24°, 15.90°, 18.54°, 18.82°, and 22.46°; or by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, or at least thirty-six, x-ray powder diffraction peaks at 2Θ angles selected from Table 12; or by x-ray powder diffraction peaks in Table 12.
- Similarly, crystalline Forms E, F and G referred to in the methods described herein may be further characterized by the XRPD peaks and data described herein for each of these forms.
- Other processes, compounds, and compositions are described below in the Exemplification section and are included herein.
- The following non-limiting examples are provided to further illustrate the present disclosure.
- DSC was performed using a TA Instruments 2920 differential scanning calorimeter. Temperature calibration was performed using NIST-traceable indium metal. The sample was placed into an aluminum Tzero crimped pan (TOC) and the weight was accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The data acquisition parameters and pan configuration for each thermogram are displayed in the image in the figure. The method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate; e.g., (−30)-250-10 means “from −30° C. to 250° C., at 10° C./min”.
- TG analyses were performed using a TA Instruments Q5000 IR thermogravimetric analyzer. Temperature calibration was performed using nickel and Alumel™. Each sample was placed in a platinum pan. The sample was hermetically sealed, the lid pierced, then inserted into the TG furnace. The furnace was heated under nitrogen. The data acquisition parameters for each thermogram are displayed in the in the figure. The method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate; e.g., 00-350-10 means “from ambient ° C. to 350° C., at 10° C./min”.
- XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Kα X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample was sandwiched between 3-μm-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, antiscatter knife edge were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b. The data acquisition parameters for each pattern are displayed above the image in the Data section of this report including the divergence slit (DS) before the mirror.
- Because
Compound 1 is highly susceptible to oxidation, particularly in solution, it was significantly difficult to produce a stable salt form of this compound. - A salt/co-crystal screening was conducted under 127 conditions with 20 salt/co-crystal co-formers and seven solvent systems. For each condition, approximately 20 mg of
Compound 1 was dispersed in the selected solvent in a glass vial and then salt/co-crystal co-former was added. Observation of slurries were followed by isolation and analysis of the resulting solids. Even though some crystalline solids were isolated and analyzed by)(RFD, discoloration, possibly associated with decomposition was also observed (Table 1). Salt-screening experiments yielding a unique XRPD pattern were analyzed by HPLC-UV and were all determined to be primarily composed of degradants. A re-preparation and scale up of the adipic acid prepared under strictly nitrogen atmosphere still yielded primarily degradants and was not pursued further. -
TABLE 1 Acids, molar E F G ratio A B C D THF/water THF/water EtOH/Water Exp # (API/acid) EtOH ACN Acetone THF 3:1 1:1 9:1 0 control YS WS OS YS OS YD WS 1 hydrochloric YS RD RS RG OS YE YD acid (1:1) 2 hydrochloric OS BS OS BG RG YE YD acid (2:1) 3 sulfuric acid YS YD RG OG OG YE YD (1:1) 4 sulfuric acid YD YG RG OG OG YE YD (2:1) 5 phosphoric YS YG RD BG BG YE WS acid (1:1) 6 phosphoric YS OG RD OG BD YE YD acid (2:1) 7 CH3SO3H YS YD YD YG YG NT YD (1:1) toluene 8 sulfonic YS YD YD YG YG NT OD acid*H2O (1:1) 9 fumaric acid YS YS OS YS BG NT OD (1:1) 10 L-tartaric YS BD RD YS WS NT OD acid (1:1) 11 maleic acid RS RD BD BG BG NT OD (1:1) 12 adipic acid YS YS YS OS OD NT OD (1:1) 13 gentisic acid YD RD BD BG RD NT OD (1:1) 14 Glutamic YS YS OS OS BS NT WS acid 15 citric acid YS OD OD OG BD NT OD (1:1) 16 L-malic acid YS YD YS YS OS NT OD (1:1) 17 DL-lactic OS RD OD OS WS NT OD acid (1:1) 18 succinic acid YS YS WS YS OG NT OD (1:1) 19 benzoic acid YS YD OD OS OG NT OD (1:1) 20 L-ascorbic YS OD BS OS BG NT OD acid (1:1) Key Colors: (W)hite, (Y)ellow, (O)range, (R)ed, B(rown) Physical Form: (S)olid, (G)el, (D)issolved, (E)mulsion; NT = not tested - With the exception of the HBr salt, salt screening was unsuccessful in identifying further options for new forms of
Compound 1 because of degradation. While the HCl and sulfate salts, having less degradation than others, did initially prove promising, additional techniques were required to reduce oxidation during their production. For example, solvent systems in whichCompound 1 has limited solubility were chosen for formation of the HCl and sulfates salts to limit oxidation, while providing enough solubility to promote conversion to crystalline salts. However, this approach is time consuming and not favorable for large scale manufacturing methods. Also, the counterpart HBr salt was found to not require such approaches as it was stable under oxygen atmosphere and did not degrade during preparation or after air-drying. - During process, and as described in further detail below, both a mono- and bis-hydrogen bromide salt of
Compound 1 were prepared. Although both of these forms did not degrade during preparation, the mono-hydrogen bromide salt absorbs about twice the amount of water than the corresponding bis-hydrogen bromide form. See e.g.,FIGS. 8 and 16 . Indeed, the bis-hydrogen bromide salt exhibits no more than a 5% weight change. This is a significant advantage because higher moisture uptake can lead to diminished shelf life and unwanted conversion to other forms and/or degradation. - Slurry experiments starting with amorphous hydrogen bromide salt of
Compound 1 in various solvents with different water activities were conducted. A total of five crystalline hydrogen bromide salt forms (both mono and bis-HBr salts) were found and classified as Form A, Form B, Form C, Form D, and Form E. The summary of each of these five forms is discussed below. Amorphous hydrogen bromide salt ofCompound 1 was prepared according to General Procedure B as described forCompound 2 in U.S. Pat. No. 9,266,886, the contents of which are incorporated herein by reference. - Out of these forms, the bis-hydrogen salt crystalline Form D of
Compound 1 proved to be the most useful, particularly in view of its advantages over the other four forms. First, the moisture uptake of Form D is significantly less than the other forms. Compare e.g., the DVS isotherm plot of Form D (FIG. 16 ) with Form A (FIG. 4 ), Form B (FIG. 8 ), and Form C (FIG. 12 ). - Next, from a manufacturing perspective, Form D was found to be reproducible at large scale. For example, during preparation of Form A, the initial material produced was an oil. While this eventually converted to a solid, passing through an oil stage during plant operations could lead to problems with product formation on large scale. In addition, with respect to Forms C and E, these forms contained residual acetone which is not acceptable for plant API production.
- Last, Form D has a high melting point. This allows for added stability during manufacturing, transport, and storage. More specific details for each of the five hydrogen bromide salt forms are as follows.
- Amorphous HBr salt of
Compound 1 was slurried in various solvents. 50 mg of the amorphous HBr salts were suspended in ethyl acetate (EA), ethanol (EtOH), methyl-tert-butyl-ether (MtBE or MTBE), isopropyl acetate (IPAc), methyl ethyl ketone (MEK), and methyl isobutyl ketone (MIBK) solvents (about 10 vol) at 10° C. for 20 hours. Samples were taken from the suspensions under nitrogen protection and dried at 50° C. for 10 minutes. All residual solids were still amorphous. - Mixed solvents of different water quantities were examined. 50 mg amorphous HBr salt was placed in the solvent/water systems and the suspensions were re-slurried at 10° C. for 2 days. The material was filtered and XRPD was run as wet. The material was then dried in an oven at 50° C. for 10 minutes the dry solid was analyzed via XRPD. Table 1a below shows the results of these studies. Isopropanol is IPA.
-
TABLE 1a Solvent Form before drying Form after drying MtBE/water = 97/3 Form A Form A MtBE/water = 94/6 Form A Form A MtBE/water = 90/10 Form A Form A EA/water = 97/3 Form A Form A EA/water = 94/6 Form A Form A EA/water = 90/10 Form A Form A EtOH/water = 97/3 Clear solution Clear solution EtOH/water = 94/6 Clear solution Clear solution EtOH/water = 90/10 Clear solution Clear solution IPA/water = 97/3 Form B Form B IPA/water = 94/6 Form B Form B IPA/water = 90/10 Form B Form B IPAc/water = 97/3 Form A Form A IPAc/water = 94/6 Form A Form A IPAc/water = 90/10 Form A Form A - Form A and Form B can also be prepared starting from
amorphous Compound 1, i.e., the free-based form instead of an HBr salt form. In this instance, Form A was determined to be a bis-hydrogen bromide salt, and Form B was determined to be a mono-hydrogen bromide salt. Procedures for their formation as follows. - For Form A, identified as a bis-hydrogen bromide salt, 1 g of amorphous free base (i.e., Compound 1) was dissolved/suspended in 10 vol of ethyl acetate at RT. 40% HBr/water solution (0.66×; 2.00 e.q.) was then added dropwise at RT. Seeds of Form A were added and the mixture was cooled to 10° C. and slurried overnight. The mixture was then filtered and dried at RT overnight.
- In order to confirm the formation of Form A at larger scale, a 5 g scale up experiment was carried out. 5 g of Form B was charged to the reactor at RT. 10 vol of EA/water=97/3 was added at RT followed by 40% HBr/water solution (0.2×; 0.7e.q.) dropwise at RT. Seeds of Form A were added and cooled to 10° C. The system was protected with N2 and the mixture was stirred overnight. The mixture was filtered and dried at 40° C. with water in oven. Table 2 shows the analytical data of a typical sample of Form A. The bromine (Br) content is 21.1%, therefore indicating a bis-hydrogen bromide salt. The IPA and EA content confirms that Form A is not an IPA or EA solvate.
-
TABLE 2 Residual IPA Residual EA Residual Br-(%) solvent solvent by IC Purity 13 ppm N.D. 21.1% 96.3% - When Form A (bis salt) is obtained directly from the amorphous free base,
Compound 1, directly, purification was not satisfactory. Form A was therefore primarily produced from the mono-hydrogen bromide salt, Form B. DVS scan showed Form A absorbs around 20% water at 90% RH. Form A is chemically stable at RT and 50° C. under vacuum. However, some crystallinity was lost at 50° C. (XRPD pattern changed slightly). Also, during the salt formation procedure, the material transforms to an oil and then converts to solid (Form A). - For Form B, identified as a mono-hydrogen bromide salt, 1 g of amorphous free base (i.e., Compound 1) was dissolved/suspended in 10 vol of isopropanol at RT. 35% HBr/AcOH (0.48×, 1.15 eq) was added dropwise into the reactor at RT. Seeds of Form B were added and the mixture was cooled to 10° C. and slurried overnight. The mixture was then filtered and dried at RT overnight.
- In order to confirm that the mono-hydrogen bromide salt Form B can be generated from
free base Compound 1, a scale up experiment was carried out. 5 g of free base was dissolved/suspended in 10 vol of IPA/3% water at RT. 35% HBr/AcOH (0.48×, 1.15 eq) was added dropwise into the reactor at RT. Seeds of Form B were added and the mixture was cooled to 10° C. The mixture was protected with N2 and slurried overnight. The mixture was filtered and dried at 50° C. for 5 hrs. Table 3 shows the analytical data of a typical sample of Form B. As shown in Table 3, the IPA content is around 4%. After drying the solid at 50° C., the solid converted to amorphous, and IPA content was reduced to 3800 pm. Form B is therefore a potential IPA solvate. The bromine content of Form B (or amorphous from conversion) solid is 12%. This confirms that Form B (or amorphous) solid is a mono salt and is not a stable structure (due to conversion). DVS scan showed Form B absorbs around 10% water at 90% RH. -
TABLE 3 Residual IPA Residual Br-(%) solvent by IC Purity XRPD form ~4% 12.0% 97.6% Form B (wet) (as Form B) Amorphous (dry) 3800 ppm (as amorphous) - Representative XRPD peaks for Form A and Form B are provided in Tables 4 and 5 below.
-
TABLE 4 Form A 2-Theta d(A) Height I % 7.541 11.714 26 25.2 8.04 10.9878 27 26.2 10.495 8.4226 20 19.4 13.061 6.773 22 21.4 14.242 6.2136 26 25.2 14.899 5.9413 55 53.4 16.317 5.428 32 31.1 17.72 5.001 11 10.7 17.94 4.9403 15 14.6 18.648 4.7543 9 8.7 19.405 4.5705 13 12.6 19.542 4.5387 13 12.6 20.28 4.3752 103 100 20.699 4.2876 61 59.2 22 4.037 69 67 22.8 3.897 7 6.8 23.182 3.8337 46 44.7 23.341 3.808 73 70.9 23.745 3.744 13 12.6 25.084 3.5472 21 20.4 25.242 3.5253 26 25.2 26.02 3.4216 9 8.7 26.459 3.3658 55 53.4 27.121 3.2852 26 25.2 27.5 3.2407 2 1.9 28.981 3.0785 27 26.2 29.161 3.0599 27 26.2 29.381 3.0374 29 28.2 30.52 2.9266 6 5.8 30.82 2.8988 8 7.8 31.444 2.8427 12 11.7 32.322 2.7675 16 15.5 32.501 2.7526 17 16.5 32.784 2.7295 16 15.5 33.823 2.648 14 13.6 34.203 2.6194 13 12.6 34.799 2.5759 17 16.5 35.23 2.5454 8 7.8 35.457 2.5296 12 11.7 -
TABLE 5 Form B 2-Theta d(A) Height I % 3.94 22.4078 151 74 5.24 16.8507 117 57.4 6.897 12.8053 20 9.8 7.98 11.0698 204 100 10.622 8.3222 46 22.5 11.182 7.9062 15 7.4 12.119 7.2968 130 63.7 13.462 6.5718 11 5.4 14.02 6.3114 52 25.5 14.42 6.1374 8 3.9 14.861 5.9564 41 20.1 15.24 5.8089 5 2.5 15.58 5.6831 47 23 16.1 5.5004 79 38.7 16.641 5.3229 132 64.7 17.62 5.0294 65 31.9 18.56 4.7767 9 4.4 19.04 4.6573 51 25 19.42 4.567 143 70.1 20.48 4.333 75 36.8 21.18 4.1914 111 54.4 21.518 4.1262 113 55.4 22.681 3.9172 46 22.5 23.159 3.8374 80 39.2 23.74 3.7448 8 3.9 24.101 3.6896 65 31.9 24.58 3.6187 68 33.3 24.938 3.5676 68 33.3 25.34 3.5119 21 10.3 25.641 3.4713 58 28.4 26.181 3.401 87 42.6 26.9 3.3117 46 22.5 27.8 3.2065 88 43.1 28.36 3.1444 28 13.7 28.782 3.0993 75 36.8 29.678 3.0077 50 24.5 30.602 2.919 27 13.2 30.824 2.8984 32 15.7 31.138 2.8699 36 17.6 32.295 2.7697 29 14.2 33.118 2.7027 52 25.5 34.122 2.6254 15 7.4 - As explained above, during the crystallization experiments for Form A, the material initially converted to oil. After slurring the oil for several hours, the oil gradually converted to solid. Although it was not determined to be an issue here, passing through an oil stage for in plant operations could lead to problems in product formation on large scale. To overcome this potential problem, other solvent system were investigated which ultimately lead to the finding of a new form, Form C.
- In these experiments, 100 mg of the mono-hydrogen bromide salt Form B was charged to a reactor at RT. 10 vol of acetone/water=97/3; DCM/water=97/3; EtOH/water=97/3; or ACN/water=97/3 was added to the reactor at RT. 40% HBr/water solution was added dropwise at RT (to make the total HBr amount as 2.0 e.q. mole). Seeds of the bis-hydrogen bromide salt Form A was added and the mixture was cooled to 5° C. and slurried overnight. The results are shown below in Table 6.
-
TABLE 6 Solvent system Form Acetone/water Form C DCM/water Form A EtOH/water Clear solution Acetonitrile/water Clear solution - As shown above, no solid was generated from EtOH/water or acetonitrile/water system. DCM/water system produced bis salt (Form A), however, this experiment also passed through oil. Acetone/water system crystallized without oil out issue while produced a new form (called Form C). Once identified, formation of Form C was optimized as follows. For Form C, 1 g of amorphous mono-hydrogen bromide salt Form B is charged to a reactor a RT. 10 vol acetone/water=97/3 is added followed by 40% HBr/water solution (to make the total HBr amount as 2.0 e.q. mole) dropwise at RT. Seeds of Form C are added, the mixture is cooled to 5° C., and slurried for 2-3 hours. The mixture is dried at 50° C. overnight.
- For Form E, 1 g of amorphous mono-hydrogen bromide salt Form B is charged to a reactor. 10 vol acetone is added to the reactor at RT followed by 40% HBr/water solution (to make the total HBr amount as 2.0 e.q. mole) dropwise at RT. Seeds of Form E are added, the mixture is cooled to 5° C., slurried overnight, and then dried at 50° C. overnight.
- DVS scan of Form C showed the solid absorbs 9% water at 90% RH. After drying the wet cake of Forms C and E at 50° C., some brown/black particles were found on the surface of the dry cake. Although the brown/black particles can be avoided by optimization of drying procedure (lower drying temperature and protection of N2), this drying procedure did not completely remove residual acetone (residual acetone in the solid >2.4%). See e.g., Table 7 below. Because of the brown/black particles and the residual acetone issue, Forms C or E (acetone/water system) were not selected as the final form for API production.
-
TABLE 7 Observation of the dry cake Br— content Residual solvent White solid 20.8% Acetone: 2.4% White solid 22.4% Acetone: 2.7% - Analytical data of a typical Form C sample is shown in Table 8. The bromine content of the solid is generally 17.8%-22.4%. Form C has a wide endotherm between 50-100° C. on DSC scan, and TGA scan shows 2.3% weight loss in this temperature range. DVS scan also showed the solid absorbs 9% water at 90% RH.
-
TABLE 8 Residual solvent Form Br— content Purity Acetone: 1000 ppm Form C 17.8% 99.2% IPA: N.D. KF: 2.8% - Analytical data of a typical Form E sample is shown in Table 9.
-
TABLE 9 Recovery(by Residual solvent Form Br— content ML) Purity Acetone: 5800 ppm Form E n/a 97% 98.4% IPA: N.D. KF: 2.5% - Representative XRPD peaks for Form E are provided in Table 10 below.
-
TABLE 10 Form E 2-Theta d(A) Height I % 4.1 21.5348 75 41 5.662 15.5969 17 9.3 5.801 15.2235 16 8.7 8.3 10.6434 157 85.8 11.781 7.5054 15 8.2 12.659 6.9866 183 100 14.008 6.3168 13 7.1 14.241 6.214 12 6.6 14.403 6.1446 13 7.1 14.677 6.0305 11 6 15.7 5.6398 16 8.7 16.34 5.4203 5 2.7 16.644 5.3219 26 14.2 16.98 5.2174 84 45.9 17.523 5.0569 12 6.6 18.388 4.8209 10 5.5 19.015 4.6635 9 4.9 19.16 4.6284 6 3.3 19.44 4.5624 5 2.7 20.02 4.4315 7 3.8 20.579 4.3123 17 9.3 21.323 4.1636 40 21.9 21.68 4.0957 30 16.4 21.9 4.0551 16 8.7 22.487 3.9506 10 5.5 22.914 3.8779 10 5.5 23.685 3.7535 11 6 24.18 3.6777 8 4.4 24.419 3.6422 22 12 24.779 3.5901 31 16.9 24.779 3.5901 31 16.9 25.72 3.4609 20 10.9 26.499 3.3608 10 5.5 27.041 3.2947 14 7.7 27.204 3.2753 17 9.3 28.14 3.1685 6 3.3 28.604 3.1181 13 7.1 - To prepare Form D, 1 g of amorphous mono-hydrogen bromide salt Form B is charged to a reactor. 5 vol of MeOH at RT is added until the solid is fully dissolved. 40% HBr/Water solution (1.2 e.q.) at RT followed by 8-9 vol of MtBE, and seeded. The mixture is held for 30 min to 1 hr, cooled to 5° C. in 30 min/5 to 6 hrs (two separated experiments; fast/slow cooling rate), and slurried overnight. 14-15 vol of MtBE in 2 to 3 hrs is added, the mixture is slurried for 2 to 3 hours, filtered, and then dried at 45° C.
- Scale up of Form D was performed as follows. 2 g amorphous mono salt Form B is charged to a reactor at RT. 5 vol MeOH was added and the solid was made sure to fully dissolve. 40% HBr/water solution (1.2 e.q.) was added dropwise at RT followed by 13 vol MtBE with seeding (first add 4 vol and seed, followed by 2 vol and seed, followed by 2 vol and seed, and so on). The mixture was slurried for half an hour, cooled to 5° C. in 2 hrs, slurried overnight, 10 vol MtBE was added in 2 to 3 hrs and the mixture was slurried over the weekend. The mixture was then filtered and dried at 60° C. and RT for 5 hrs. Results are shown in Table 11.
-
TABLE 11 Batch Form purity 1 Form D 99.5% 2 Form D 99.5% - Form D can also isolated from the amorphous bis-hydrogen bromide salt form of
Compound 1 in a slurry experiment comprising acetone/water (1:1 v/v). For example, a saturated solution the amorphous bis-hydrogen bromide salt form om acetone/water (1:1 v/v) was slurried for one week at ambient and the solid was harvested to obtain Form D. The water activity (aw) of an equal volume mixture of acetone and water is 0.91. See SSCI internal report, Water Activity Calculations using UNIFAC Calculator, SR-20150515.01, dated Jul. 23, 2015. When solvent-free polymorphs are considered, the relative thermodynamic stability of two polymorphs is determined by the Gibbs free energy difference at a given temperature and pressure. However, when hydrate forms are considered, the water activity in the solvent contributes to the relative physical stability and thus, the resulting form. See Qu H, Louhi-Kultanen M, Kallas J. Solubility and stability of anhydrate/hydrate in solvent mixtures. Int J Pharm. 2006; 321:101-107 and Zhu H, Grant D J W. Influence of water activity in organic solvent+water mixtures on the nature of the crystallizing drug phase. 2. Ampicillin. Int J Pharm. 1996; 139:33-43. This outcome is consistent with Form D as a hydrate and indicates that the hydrate is stable at aw=0.91. - Representative XRPD peaks for Form D are provided in Table 12 below.
-
TABLE 12 Form D 2-Theta d(A) Height I % 7.579 11.655 45 36 9.02 9.7963 64 51.2 13.403 6.6006 15 12 14.24 6.2147 85 68 14.562 6.0778 31 24.8 15.241 5.8087 125 100 15.9 5.5692 103 82.4 16.8 5.2729 22 17.6 17.162 5.1624 44 35.2 17.342 5.1092 26 20.8 18.54 4.7817 55 44 18.818 4.7117 53 42.4 19.279 4.6001 13 10.4 19.643 4.5157 20 16 20.14 4.4054 48 38.4 20.7 4.2873 49 39.2 21.02 4.2229 42 33.6 21.699 4.0921 49 39.2 22.46 3.9553 88 70.4 23.362 3.8045 24 19.2 23.698 3.7513 17 13.6 24.362 3.6505 41 32.8 24.578 3.619 29 23.2 24.799 3.5873 11 8.8 25.237 3.526 35 28 25.406 3.503 18 14.4 25.659 3.4689 42 33.6 25.822 3.4474 59 47.2 26.102 3.411 25 20 26.506 3.36 27 21.6 26.82 3.3213 67 53.6 27.122 3.285 19 15.2 27.562 3.2336 10 8 28.004 3.1835 19 15.2 28.604 3.1182 20 16 29.679 3.0076 35 28 33.701 2.6573 48 38.4 - The two-step formation to arrive at Form D is shown below in
Scheme 5. Intermediate 2 was prepared according to general procedure B in U.S. Pat. No. 9,266,886, the contents of which are incorporated herein by reference. - Intermediate 2 is suspended in dichloromethane and the amine liberated by treatment with diisopropylethylamine. The solution is cooled to −50° C. and subsequently treated with NaBH(OAc)3 and the aldehyde. After the reductive amination reaction is complete, the bis-hydrogen bromide is isolated by the following sequence of operations. The dichloromethane solution of 3 is acidified with acetic acid, treated with active carbon and filtered. The solvent is switched to isopropanol. Addition of 40% aqueous HBr (1.4 equivalents), cooling to 10-15° C., seeding and continued aging affords the mono-HBr salt. This material was isolated by centrifugation and dried at 30-45° C. in vacuum. The mono-HBr salt is then converted to the bis-HBr salt by dissolving the mono salt in methanol, adding 1.1 equiv of 40% aqueous HBr, then seeding, followed by additions of MTBE and water. The bis-HBr salt is isolated by filtration and drying at 30-45° C. in vacuum. The final product is isolated as the bis-hydrogen bromide salt Form D with contamination from MeBr (approximately 40 ppm or more at laboratory scale and approximately 227 ppm or greater on plant production of 100 grams or greater).
- After numerous attempts and various conditions, it was found that slurrying the bis-hydrogen bromide salt Form D from isopropyl acetate containing 1% water at room temperature effectively produced the bis-hydrogen bromide salt Form D free from detectable amounts of methyl bromide. A combination of heptane and water also removed the methyl bromide, but this combination was not pursued further. A summary of the experiments leading up to these conclusions is provided below.
- Based on previous research, residual MeBr could be removed effectively by re-crystallizing from MeOH/MTBE/H2O=1.75 V/12 V/0.15 V. However, considering the potential risk which MeOH may react with HBr contained in
Compound 1, MTBE was tried as only re-slurry solvent. Two reactions were carried out under different N2 atmosphere: Stirring at approximately 30 to 35° C. for 96 h, residual MeBr was 65 ppm and 40 ppm respectively. See Table 13. After re-slurry with 20 V of MTBE at approximately 30 to 35° C. for 116 h, residual MeBr in both reactions was decreased to less than 50 ppm. -
TABLE 13 Residual MeBr Scale Conditions (ppm) Br content Yield Note 40 g Re-slurry with 164 (48 h) 21.1% 94.1% Residual 20 V MTBE at 65 (96 h) (Corrected MeOH: 30~35° C. and 34 (114 h) by KF) 0.07% stir with 180 17 (140 h) MTBE: rpm. 0.23% Adjust to 20~25° C. Filter, and dry N2 balloon always 40 g Re-slurry with 180 (48 h) 21.4% 93.8% Residual 20 V MTBE at 40 (96 h) (Corrected MeOH: 30~35° C. and 20 (116 h) by KF) 0.12% stir with 180 N.D (140 h) MTBE: rpm. 0.11% Adjust to 20-25° C. Filter, and dry. N2 flow after 48 h - The developed purification process was then executed in pilot plant study but failed as the residual MeBr was 227 ppm (limitation: Residual MeBr ≤40 ppm). Because of this, other solvents (DCM, IPAc, and n-heptane) were tried. After investigation, it was found that DCM was not a good choice because the crystal form changed, whereas the crystal form remained consistent with Form D after stirring at approximately 20 to 30° C. for 3 days IPAc or n-heptane So studies about how to remove residual MeBr were carried out in IPAc and n-heptane. See Table 14. The effect of removing MeBr was no different after stirring for 23 h (n-heptane: 148 ppm; IPAc: 153 ppm). However, since the solubility of the bis-hydrogen bromide salt Form D was slightly higher than that in n-heptane, IPAc was chosen as re-slurry solvent. NMR data for bis-hydrogen bromide crystalline Form D of
Compound 1 is as follows: 1H NMR (500 MHz, CD3OD): δ 9.12 (s, 1H), 9.11 (s, 1H), 8.57 (d, J=8.5 Hz, 1H), 8.37 (s, 1H), 7.97 (d, J=8.5 Hz, 1H), 5.22 (d, J=16 Hz, 1H), 4.89 (d, J=4.0 Hz, 1H), 4.85 (s, 2H), 4.77 (d, J=17.5 Hz, 1H), 3.42 (m, 2H), 3.37 (q, J=7.5 Hz, 2H), 2.54 (m, 1H), 2.17 (m, 1H), 2.04 (m, 5H), 1.45 (m, 2H), 1.33 (d, J=7.0 Hz, 3H), 1.28 (t, J=7.5 Hz, 3H), 1.23 (m, 2H), 1.11 (d, J=6.5 Hz, 3H). -
TABLE 14 Residual MeBr Scale Conditions Time Wet cake Dried cake 7 g Re-slurry 7 g with 10 V 3 h 117 201 IPAc at 20~25° C. under 6 h 140 216 nitrogen balloon 23 h 121 153 7 g Re-slurry 7 g with 10 V 3 h 120 201 n-heptane at 20~25° C. 6 h 115 227 under nitrogen balloon 23 h 110 148 - To study the influence on the amount of water for the IPAc/water mixture, reactions with different content of water in IPAc were carried out (0.25%, 0.5%, 1.0%, 2.0%). It was found water could improve the efficiency of removing MeBr and that best results were obtained when 1.0% water was used (Table 15,
Entry 3; residual MeBr was less than 40 ppm after stirred for 6 h). XRPD was consistent. -
TABLE 15 Residual MeBr Br (ppm) content Wet Dried corrected Entry Scale Conditions Time cake cake by KF Note 1 10 g Re-slurry 10 g 3 h 102 91 20.95% Residual with 5 V 6 h 44 66 KF: 5.5% MeOH: N.D IPAc containing 23 h <40 <40 0.25% water IPAc: 0.025% at 20~25° C. with 150 rpm 2 10 g Re-slurry 10 g 3 h 87 66 21.88% Residual of S with 6 h <40 51 KF: 5.85% MeOH: N.D 5 V IPAc 23 h ND ND IPAc: 0.029% containing 0.5% water at 20-25° C. with 150 rpm 3 10 g Re-slurry 10 g 3 h <40 42 21.88% Residual of S with 6 h <40 <40 KF: 5.86% MeOH: N.D 5 V IPAc 23 h ND ND IPAc: 0.045% containing 1% water at 20~25° C. with 150 rpm 4 10 g Re-slurry 10 g 3 h 42 64 22.34% Residual of S with 6 h <40 <40 KF: 5.99% MeOH: N.D 5 V IPAc 23 h 67 ND IPAc: 0.016% containing 2% water at 20~25° C. with 150 rpm - With the excess methyl bromide problem solved, another drawback to the two-step process was solved. That is, the two-step process also employed methylene chloride as the solvent for the reductive amination procedure. On large manufacturing scale, this would require strict controls due to air and water quality regulations. To overcome these obstacles, a one-step approach to obtain the bis-hydrogen bromide salt Form D directly from the free base of
Compound 1 was realized. - The one-step approach employing is shown below in
Scheme 6. Intermediate 2 was again prepared according to general procedure B in U.S. Pat. No. 9,266,886. - A typical reaction can proceed as follows. To the 30-gal reactor was added 2 (5.12 kg, 9.2 mol, 1.0 equiv). In a carboy was charged ethanol (27.3 L, 7 vol relative to sodium triacetoxyborohydride (STAB)) and DIPEA (3.57 kg, 27.6 mol, 3 equiv relative to 2). The solution of DIPEA/EtOH was added to the reactor with the 2 with no stirring. A cloud of amine hydrochloride formed in the reactor making it difficult to see the slurry, so the batch was allowed to sit without stirring until this cloud dissipated. After 35 min, the cloud dissipated and the mixture was gently stirred. In an hour, the solids had dissolved. The batch was stirred gently overnight at 10° C. and then the 2 was drained from the reactor into a carboy.
- The reactor was charged with STAB (3.91 kg, 18.4 mol, 2 equiv) and pre-made solution of DIPEA (2.383 kg, 18.4 mol, 2 equiv) and ethanol (27.2 L, 7 vol relative to STAB) with the jacket at −5° C. The mixture was allowed to cool to 0° C. over 20 min. The solution of 2 in DIPEA/EtOH was added over 27 min followed by the free aldehyde solution in IPAc over 45 min. The maximum temperature during the aldehyde addition was 3.7° C. The mixture was stirred for 1 h and was sampled for reaction completion.
- The reaction was quenched by the addition of 1 N HCl (31.2 L, 8 vol relative to STAB) over 33 min. The temperature rose to 11° C. during this addition. The solids dissolved during this quench and the solution was stirred 1 h. The quenched reaction was transferred to a 100-gal. Pfaudler, glass-lined reactor with the jacket set to 10° C. To the 100-gal reactor was charged 1 N NaOH solution (31.2 L, 8 vol relative to STAB). After this addition, the pH rose from approximately 5 to approximately 6 and solids precipitated. The free base slurry was allowed to stir overnight at approximately 10° C. for convenience. The batch was then transferred to a pressure filter equipped with a tight weave cloth. The initial filtration was performed with occasional stirring and the batch de-liquored in about 4 h. The reactor and filter cake were washed with DI water (2×16 L) and 1:1 ethanol/DI water (16 L). The washes took approximately 30 min each. The wet cake was conditioned for 2 h under 8 psig of nitrogen and then was dried at a
jacket temperature 35° C. The drying was monitored by KF analysis. The wet cake contained 21% water and the dried cake before off-loading was 5.4% water. The yield was 4.97 kg (98%). The HPLC analysis of the product was 99.7 area %. The NMR weight assay was 90.8 wt % (FIG. 23 ) and the final KF analysis was 4.7% water. Residue-on-ignition (ROI) analysis of the free base indicated it had 0.2% residual inorganic material. - The material can then be converted to the bis-hydrogen bromide salt by e.g., contacting the free base (0.8026 g) with acetic acid (2 vol, 1.6052 ml) and stirring the mixture at 250 RPM, heated 30° C. A 48% HBr solution is then added (0.3438 ml, 2.1 equiv) drop wise over 9 min. MEK (4.816 ml, 6 vol) is then added over 50 minutes and the reaction is seeded with bis-hydrogen bromide salt Form D. MEK (8.000 ml, 10 vol) is added at 2 ml slowly added every 5 min. The mixture is then chilled to 5° C. over 1 hour, filtered, rinsed w/MEK (2×3.21 ml), and dried in 40° C. vacuum oven/21 hrs to afford a mixture of bis-hydrogen bromide crystalline salt Forms E, D, and F. This procedure was also completed on a 2.5 kg scale. These forms were not characterized further. It should be noted that a mixture of acetic acid/MEK (or acetic acid/acetone) prevents the product from oiling out as well as the production of MeBr. To obtain a single crystalline form, the mixture of forms were slurried in isopropyl acetate with 1% water which gave the bis-hydrogen bromide salt Form D with 98% yield and in >99 area % purity.
- As an alternative, parts from the one-step and two-step methods can also be combined. For example, the IPAc/water reslurry procedure to remove the residual methyl bromide can be used in the product formation of both the mono- and bis-hydrogen bromide salt forms from the two-step process. The solvent for the reductive amination may also be EtOH instead of methylene chloride and the base may be iPr2Net. A representative approach is shown below in
Scheme 3. - For example a large scale process to form the mono-hydrogen bromide product using the EtOH/DIPEA conditions was as follows.
Compound 3 can be made according to the procedure set forth above. From there, a 30-gal, Pfaudler, glass-lined reactor was charged with 3 free base (4.959 kg, 8.97 mol, 1.0 equiv) and isopropanol (49.5 L, 10 vol). Acetic acid (1.49 L, 0.3 vol) was charged to the stirred mixture. Aqueous hydrobromic acid (48%, 1.664 kg, 9.87 mol, 1.1 equiv) was added to mixture over 16 min and the mixture was stirred at room temperature for 32 min. The batch was then warmed to 40° C. over 48 min. No solids were observed at this point. The batch was cooled to 6.7° C. over 5 h. Crystallization was noted at after 1.5 h of cooling (10.6° C.). The batch was stirred overnight at 5° C. for convenience. The thick slurry was transferred to a pressure filter equipped with regular weave cloth. The batch de-liquored in 1 h. The reactor and filter cake was washed with IPA (2×17.5 L). Stirring the wet cake caused it to ball up, so it was conditioned under nitrogen pressure overnight with the jacket at 30° C. Overnight some of the batch melted and passed the cloth. The filter was opened and the residue was scraped out of filter with some difficulty. The residue was tray dried in a vacuum oven at 35° C. The batch was completely dried in 22 h, but the material needed to be crushed with a pestle. The yield was 4.556 kg (80%). KF analysis showed the material had 2.97% water. Titration of the material showed that the HBr content was 11.4%. The HPLC analysis was 99.8 area % and the NMR weight assay was 91.7 wt % (FIG. 24 ). XRPD analysis was consistent with Form B observed in earlier batches. SeeFIG. 25 . Conversion to the bis-hydrogen bromide salt can then occur following the procedures described above. - While have described a number of embodiments of this, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this disclosure. Therefore, it will be appreciated that the scope of this disclosure is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.
- The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.
Claims (39)
3. The bis-hydrogen bromide salt of claim 2 , wherein the bis-hydrogen bromide salt is crystalline and the crystalline form is crystalline Form A, C, or E.
4. The crystalline Form A of claim 3 , wherein the crystalline form is characterized by at least three x-ray powder diffraction peaks at 2Θ angles selected from 14.90°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46°.
5. The crystalline Form A of claim 3 , wherein the crystalline form is characterized by at least four x-ray powder diffraction peaks at 2Θ angles selected from 14.90°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46°.
6. The crystalline Form A of claim 3 , wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2Θ angles selected from 14.90°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46°.
7. The crystalline Form A of claim 3 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2Θ angles at 14.90°, 20.28°, 20.70°, 22.00°, 23.34°, and 26.46°.
8. The crystalline Form C of claim 3 , wherein the crystalline form is characterized by at least three x-ray powder diffraction peaks at 2Θ angles selected from 20.28°, 20.70°, 23.18°, 23.34°, 25.24°, and 26.46°.
9. The crystalline Form C of claim 3 , wherein the crystalline form is characterized by at least four x-ray powder diffraction peaks at 2Θ angles selected from 20.28°, 20.70°, 23.18°, 23.34°, 25.24°, and 26.46.
10. The crystalline Form C of claim 3 , wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2Θ angles selected from 20.28°, 20.70°, 23.18°, 23.34°, 25.24°, and 26.46.
11. The crystalline Form C of claim 3 , wherein the crystalline form is characterized by at x-ray powder diffraction peaks at 2Θ angles at 20.28°, 20.70°, 23.18°, 23.34°, 25.24°, and 26.46.
12.-15. (canceled)
16. The crystalline Form E of claim 3 , wherein the crystalline form is characterized by at least three x-ray powder diffraction peaks at 2Θ angles selected from 4.1°, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°.
17. The crystalline Form E of claim 3 , wherein the crystalline form is characterized by at least four x-ray powder diffraction peaks at 2Θ angles selected from 4.1°, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°.
18. The crystalline Form E of claim 3 , wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2Θ angles selected from 4.1°, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°.
19. The crystalline Form E of claim 3 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2Θ angles at 4.1°, 8.3°, 12.70°, 16.64°, 16.98°, and 21.32°.
20. The crystalline Form A, C, or E of claim 3 , wherein the crystalline form is a solvate.
21. The crystalline Form A, C, or E of claim 3 , wherein the crystalline form is a hydrate.
22. The mono-hydrogen bromide salt of claim 1 , wherein the mono-hydrogen bromide salt is crystalline and the crystalline form is crystalline Form B.
23. The crystalline Form B of claim 22 , wherein the crystalline form is characterized by at least three x-ray powder diffraction peaks at 2Θ angles selected from 5.24°, 7.98°, 12.12°, 19.42°, 21.18°, and 21.52°.
24. The crystalline Form B of claim 22 , wherein the crystalline form is characterized by at least four x-ray powder diffraction peaks at 2Θ angles selected from 5.24°, 7.98°, 12.12°, 19.42°, 21.18°, and 21.52°.
25. The crystalline Form B of claim 22 , wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2Θ angles selected from 5.24°, 7.98°, 12.12°, 19.42°, 21.18°, and 21.52°.
26. The crystalline Form B of claim 22 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2Θ angles at 5.24°, 7.98°, 12.12°, 19.42°, 21.18°, and 21.52°.
27. The crystalline Form B of claim 22 , wherein the crystalline form is an isopropanol solvate.
28. A pharmaceutical composition comprising the hydrogen bromide salt of claim 2 ; and a pharmaceutically acceptable carrier.
29. A method of treating a disease or disorder associated with the expression of RORγ in a subject, comprising administering to the subject the hydrogen bromide salt of claim 2 .
30. The method of claim 29 , wherein the disease or disorder is selected from asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic rhinitis, atopic dermatitis, contact dermatitis, acne, cystic fibrosis, allograft rejection, multiple sclerosis, scleroderma, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE), psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, type I diabetes, autoimmune ocular disease, ulcerative colitis, Crohn's disease, regional enteritis, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjögren's syndrome, optic neuritis, obesity, hepatosteatosis, adipose tissue-associated inflammation, insulin resistance, type II diabetes, neuromyelitis optica, myasthenia gravis, age related macular degeneration, dry eye, uveitis, Guillain-Barré syndrome, psoriasis, psoriatic arthritis (PsA), steroid resistant asthma, Graves' disease, scleritis, major depression, seasonal affective disorder, PTSD, bipolar disorder, autism, epilepsy, Alzheimer's, CNS disorders associated with altered sleep and/or circadian rhythms, endometriosis, obstructive sleep apnea syndrome (OSAS), Behcet's disease, dermatomyositis, polymyocitis, graft versus host disease, primary biliary cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), sarcoidosis, primary sclerosing cholangitis, autoimmune thyroid disease, autoimmune polyendocrine syndrome type I, autoimmune polyendocrine syndrome type II, celiac disease, neuromyelitis, juvenile idiopathic arthritis, systemic sclerosis, myocardial infarction, pulmonary hypertension, osteoarthritis, cutaneous leishmaniasis, sinonasal polyposis, and cancer.
31. The method of claim 30 , wherein the disease or disorder is selected from asthma, atopic dermatitis, acne, Crohn's disease, regional enteritis, ulcerative colitis, Sjögren's syndrome, uveitis, Behçet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, systemic lupus erythematosus (SLE), scleroderma, psoriasis, psoriatic arthritis (PsA), steroid resistant asthma, and rheumatoid arthritis.
32. A method of forming a mono-hydrogen bromide salt of Compound 1, comprising the steps of
i) reductively aminating an aldehyde compound represented by the following structural formula:
with an amine compound represented by the following structural formula:
wherein the reductive amination is carried out in the presence of an imine reducing agent to form Compound 1:
ii) adding after the formation of Compound 1, sufficient hydrobromic acid to form the mono-hydrogen bromide salt of Compound 1 having the formula:
and
iii) isolating the mono-hydrogen bromide salt of Compound 1.
33. The method of claim 32 , wherein in step ii) Compound 1 is dissolved in a mixture of isopropanol and acetic acid prior to the addition of hydrobromic acid.
34. The method of claim 32 , wherein in step ii) the mono-hydrogen bromide salt of Compound 1 is precipitated via the addition of the hydrobromic acid.
35. The method of claim 32 , wherein the amine compound is formed in situ from treating an acid salt form of the amine with a tertiary amine base.
36. The method of claim 32 , wherein the amine is formed in situ from treating a di-hydrochloric acid salt form of the amine with diisopropylethylamine.
37.-38. (canceled)
39. The method of claim 32 , wherein said sufficient amount of hydrobromic acid comprises 1 to 2 weight equivalents of 35% to 55% hydrobromic acid or 35% to 55% hydrogen bromide in acetic acid.
40. The method of claim 32 , wherein the imine reducing agent is sodium triacetoxyborohydride.
41. (canceled)
42. A pharmaceutical composition comprising the hydrogen bromide salt of claim 1 ; and a pharmaceutically acceptable carrier.
43. A method of treating a disease or disorder associated with the expression of RORγ in a subject, comprising administering to the subject the hydrogen bromide salt of claim 1 .
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015116904A1 (en) | 2014-02-03 | 2015-08-06 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ror-gamma |
MA53943A (en) | 2015-11-20 | 2021-08-25 | Vitae Pharmaceuticals Llc | ROR-GAMMA MODULATORS |
CN111225914B (en) | 2017-07-24 | 2022-10-11 | 生命医药有限责任公司 | Inhibitors of ROR gamma |
WO2019018975A1 (en) | 2017-07-24 | 2019-01-31 | Vitae Pharmaceuticals, Inc. | Inhibitors of ror gamma |
WO2023232870A1 (en) | 2022-05-31 | 2023-12-07 | Immunic Ag | Rorg/rorgt modulators for the treatment of virus infections like covid-19 |
Family Cites Families (259)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3751524T2 (en) | 1986-07-28 | 1996-06-13 | American Cyanamid Co | 5 (and / or 6) substituted 2- (2-imidazolin-2-yl) nicotinic acids, esters and salts, usable as herbicidal agents and intermediates for the preparation of these nicotinic acids, esters and salts. |
FR2624698A1 (en) | 1987-12-18 | 1989-06-23 | Bernard Lyon I Universite Clau | HETEROCYCLIC DERIVATIVES OF N-CARBAMOYL-, N-THIOCARBAMOYL- OR N-AMIDINO-AMINOMALONYL OR AMINOSUCCINYL AMIDES USEFUL AS SULFURING AGENTS |
EP0462179A4 (en) | 1989-02-27 | 1992-03-18 | The Du Pont Merck Pharmaceutical Company | Novel sulfonamides as radiosensitizers |
US5776963A (en) | 1989-05-19 | 1998-07-07 | Hoechst Marion Roussel, Inc. | 3-(heteroaryl)-1- (2,3-dihydro-1h-isoindol-2-yl)alkyl!pyrrolidines and 3-(heteroaryl)-1- (2,3-dihydro-1h-indol-1-yl)alkyl!pyrrolidines and related compounds and their therapeutic untility |
GB8927872D0 (en) | 1989-12-08 | 1990-02-14 | Beecham Group Plc | Pharmaceuticals |
JP2807577B2 (en) | 1990-06-15 | 1998-10-08 | エーザイ株式会社 | Cyclic amide derivative |
EP0520573A1 (en) | 1991-06-27 | 1992-12-30 | Glaxo Inc. | Cyclic imide derivatives |
DE4121214A1 (en) | 1991-06-27 | 1993-01-14 | Bayer Ag | 7-AZAISOINDOLINYL CHINOLONE AND NAPHTHYRIDONE CARBONIC ACID DERIVATIVES |
US5272158A (en) | 1991-10-29 | 1993-12-21 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
US5416099A (en) | 1991-10-29 | 1995-05-16 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
US5389631A (en) | 1991-10-29 | 1995-02-14 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
US5238950A (en) | 1991-12-17 | 1993-08-24 | Schering Corporation | Inhibitors of platelet-derived growth factor |
US5364869A (en) | 1992-03-09 | 1994-11-15 | Abbott Laboratories | Heterocycle-substituted benzyaminopyridine angiotensin II receptor antagonists |
US5326760A (en) | 1992-06-29 | 1994-07-05 | Glaxo, Inc. | Aminobutanoic acid compounds having metalloprotease inhibiting properties |
JPH06236056A (en) | 1993-02-10 | 1994-08-23 | Fuji Xerox Co Ltd | Electrophotographic sensitive body |
JP3760474B2 (en) | 1993-04-22 | 2006-03-29 | ダイキン工業株式会社 | Method and apparatus for generating electric energy, and compound having NF bond used therefor |
CA2134192A1 (en) | 1993-11-12 | 1995-05-13 | Michael L. Denney | 5, 6-bicyclic glycoprotein iib/iiia antagonists |
DE4343922A1 (en) | 1993-12-22 | 1995-06-29 | Basf Ag | Pyridine-2,3-dicarboximides, process for their preparation and their use in combating undesirable plant growth |
KR970007419B1 (en) | 1993-12-30 | 1997-05-08 | 한솔제지 주식회사 | Subliming type dye for thermal transfer printing |
FR2725946A1 (en) | 1994-10-24 | 1996-04-26 | Lohr Ind | Vehicle chock, for use on transporters with perforated carrying surfaces, |
US5719144A (en) | 1995-02-22 | 1998-02-17 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
EP0733632B1 (en) | 1995-03-24 | 2003-06-04 | Takeda Chemical Industries, Ltd. | Cyclic compounds, their production and use as tachykinin receptor antagonists |
US5770590A (en) | 1995-03-24 | 1998-06-23 | Takeda Chemical Industries, Ltd. | Cyclic compounds, their prudiction and use |
DK0882718T3 (en) | 1995-12-28 | 2005-12-12 | Astellas Pharma Inc | benzimidazole |
DE19608791A1 (en) | 1996-03-07 | 1997-09-11 | Hoechst Ag | Process for the preparation of fluorinated aromatics and fluorinated nitrogen-containing heteroaromatics |
DE19702282C2 (en) | 1997-01-23 | 1998-11-19 | Hoechst Ag | Catalyst for Halex reactions |
US6177443B1 (en) | 1997-03-07 | 2001-01-23 | Novo Nordisk A/S | 4,5,6,7-tetrahydro-thieno[3, 2-C]pyridine derivatives, their preparation and use |
JP2001514631A (en) | 1997-03-07 | 2001-09-11 | ノボ ノルディスク アクティーゼルスカブ | 4,5,6,7-tetrahydro-thieno [3,2-c] pyridine derivatives, their production and use |
KR19980074060A (en) | 1997-03-21 | 1998-11-05 | 김윤배 | Novel substituted 3,4-dialkoxyphenyl derivatives |
JPH1143489A (en) | 1997-05-30 | 1999-02-16 | Takeda Chem Ind Ltd | Heterocyclic compound, its production and agent |
KR20010041991A (en) | 1998-03-19 | 2001-05-25 | 다케다 야쿠힌 고교 가부시키가이샤 | Heterocyclic compounds, their production and use as tachykinin receptor antagonists |
US20020132817A1 (en) | 1998-03-19 | 2002-09-19 | Hideaki Natsugari | Heterocyclic compounds, their production and use |
FR2778662B1 (en) | 1998-05-12 | 2000-06-16 | Adir | NOVEL SUBSTITUTED CYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
JP2000007661A (en) | 1998-06-23 | 2000-01-11 | Nippon Nohyaku Co Ltd | Heterocyclic diamide dicarboxylate derivative, its intermediate and herbicide |
WO2000006549A1 (en) | 1998-07-28 | 2000-02-10 | Nihon Nohyaku Co., Ltd. | Fused-heterocycle dicarboxylic diamide derivatives or salts thereof, herbicides and usage thereof |
US6348032B1 (en) | 1998-11-23 | 2002-02-19 | Cell Pathways, Inc. | Method of inhibiting neoplastic cells with benzimidazole derivatives |
AU1409100A (en) | 1998-11-27 | 2000-06-19 | Takeda Chemical Industries Ltd. | Drugs |
WO2000067754A1 (en) | 1999-05-12 | 2000-11-16 | Nitromed, Inc. | Nitrosated and nitrosylated potassium channel activators, compositions and methods of use |
EP1194425B1 (en) | 1999-06-23 | 2005-08-10 | Aventis Pharma Deutschland GmbH | Substituted benzimidazole |
US6774132B1 (en) | 1999-07-21 | 2004-08-10 | Astrazeneca Ab | Spirooxindole derivatives that act as analgesics |
CN1166618C (en) | 1999-08-02 | 2004-09-15 | 霍夫曼-拉罗奇有限公司 | New selective retinoid agonists |
ES2309001T5 (en) | 1999-11-09 | 2011-12-28 | Abbott Laboratories | COMPOSITIONS OF HYDROMORFINONE AND HYDROCODEINONE, SYNTHESIS PROCEDURES OF THESE LAST. |
CA2363274A1 (en) | 1999-12-27 | 2001-07-05 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs for hepatitis c |
US6770666B2 (en) | 1999-12-27 | 2004-08-03 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
AU2001227757A1 (en) | 2000-01-12 | 2001-07-24 | Merck And Co., Inc. | Inhibitors of prenyl-protein transferase |
EP1189882A1 (en) | 2000-04-25 | 2002-03-27 | SAMSUNG ELECTRONICS Co. Ltd. | Biphenyl butyric acid derivative as a matrix metalloproteinase inhibitor |
DK1280757T3 (en) | 2000-05-02 | 2005-12-12 | Hoffmann La Roche | Gamma-selective retinoids |
EP1278744A1 (en) | 2000-05-05 | 2003-01-29 | Millenium Pharmaceuticals, Inc. | Heterobicyclic sulfonamides and their use as platelet adp receptor inhibitors |
CA2354606C (en) | 2000-08-03 | 2005-12-06 | Pfizer Products Inc. | Azabicycloalkane derivatives and therapeutic uses thereof |
AU2002212598A1 (en) | 2000-09-19 | 2002-04-02 | Centre National De La Recherche Scientifique (Cnrs) | Pyridinone and pyridinethione derivatives having hiv inhibiting properties |
US6884782B2 (en) | 2000-11-08 | 2005-04-26 | Amgen Inc. | STAT modulators |
TWI236474B (en) | 2001-04-03 | 2005-07-21 | Telik Inc | Antagonists of MCP-1 function and methods of use thereof |
WO2002081447A1 (en) | 2001-04-06 | 2002-10-17 | Daewoong Pharmaceutical Co., Ltd. | 3-cyclopentyloxy-4-methoxyphenyl-isothiazolinone derivatives and the use thereof |
ES2278016T3 (en) | 2001-04-09 | 2007-08-01 | Novartis Vaccines And Diagnostics, Inc. | GUANIDINE COMPOUNDS AS AGONISTS OF THE RECEIVER OF MELANOCORTINA 4 (MC4-R). |
WO2002088092A1 (en) | 2001-04-19 | 2002-11-07 | Eisai Co., Ltd. | 2-iminoimidazole derivative (2) |
DK1397364T3 (en) | 2001-05-24 | 2007-11-26 | Lilly Co Eli | Newly disclosed pyrrole derivatives as pharmaceutical agents |
MXPA04000449A (en) | 2001-07-16 | 2004-03-18 | Shionogi & Co | Process for preparation of amidine derivatives. |
US6627646B2 (en) * | 2001-07-17 | 2003-09-30 | Sepracor Inc. | Norastemizole polymorphs |
JP2003171380A (en) | 2001-09-28 | 2003-06-20 | Takeda Chem Ind Ltd | Method for producing tricyclic compound |
WO2003029254A1 (en) | 2001-09-28 | 2003-04-10 | Takeda Chemical Industries, Ltd. | Process for preparation of tricyclic compounds |
NZ531786A (en) | 2001-10-02 | 2006-10-27 | Upjohn Co | Azabicyclic-substituted fused-heteroaryl compounds for the treatment of disease |
DE10156719A1 (en) | 2001-11-19 | 2003-05-28 | Bayer Ag | New N-(aza-bicycloalkyl)-benzo-heterocyclic carboxamides, useful as Alpha-7-nicotinic acetylcholine receptor ligands for e.g. improving attention, concentration, learning and/or memory performance |
TWI263640B (en) | 2001-12-19 | 2006-10-11 | Bristol Myers Squibb Co | Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function |
CN100383124C (en) | 2002-02-04 | 2008-04-23 | 霍夫曼-拉罗奇有限公司 | Quinoline derivatives as NPY antagonists |
DE10207037A1 (en) | 2002-02-20 | 2003-08-28 | Bayer Cropscience Gmbh | New 2-amino-4-(bicyclic substituted amino)-1,3,5-triazine derivatives, useful as pre- or post-emergence, total or selective herbicides or as plant growth regulators |
WO2003076440A1 (en) | 2002-03-06 | 2003-09-18 | Smithkline Beecham Corporation | Condensed heterocyclic compounds as calcitonin agonists |
AU2003237492A1 (en) | 2002-06-10 | 2003-12-22 | Acadia Pharmaceuticals Inc. | Urotensin ii receptor modulators |
AU2003250482A1 (en) | 2002-08-13 | 2004-02-25 | Warner-Lambert Company Llc | Phthalimide derivatives as matrix metalloproteinase inhibitors |
US7365066B2 (en) | 2002-09-17 | 2008-04-29 | Eli Lilly And Company | Pyrazolopyridine derivatives as pharmaceutical agents |
US8604183B2 (en) | 2002-11-05 | 2013-12-10 | Isis Pharmaceuticals, Inc. | Compositions comprising alternating 2′-modified nucleosides for use in gene modulation |
JP2004203791A (en) | 2002-12-25 | 2004-07-22 | Dai Ichi Seiyaku Co Ltd | Aromatic compound |
CN1212674C (en) | 2003-01-08 | 2005-07-27 | 东南大学 | Transverse buffer P-type MOS transistors |
TW200503994A (en) | 2003-01-24 | 2005-02-01 | Novartis Ag | Organic compounds |
GB0308025D0 (en) | 2003-04-07 | 2003-05-14 | Glaxo Group Ltd | Compounds |
PL1638551T3 (en) | 2003-05-19 | 2012-05-31 | Irm Llc | Immunosuppressant compounds and compositions |
EP1644367B1 (en) | 2003-05-19 | 2015-10-14 | Novartis AG | Immunosuppressant compounds and compositions |
MY150088A (en) | 2003-05-19 | 2013-11-29 | Irm Llc | Immunosuppressant compounds and compositions |
JP4944613B2 (en) | 2003-05-19 | 2012-06-06 | アイアールエム・リミテッド・ライアビリティ・カンパニー | Immunosuppressive compounds and compositions |
WO2004108133A2 (en) | 2003-06-05 | 2004-12-16 | Vertex Pharmaceuticals Incorporated | Modulators of vr1 receptor |
CN1566099A (en) | 2003-06-13 | 2005-01-19 | 中国科学院上海药物研究所 | Isoquinoline-1,3,4-trione compounds, preparation method and uses thereof |
WO2005005392A1 (en) | 2003-07-07 | 2005-01-20 | Ionix Pharmaceuticals Limited | Azacyclic compounds as inhibitors of sensory neurone specific channels |
FR2857966A1 (en) | 2003-07-24 | 2005-01-28 | Aventis Pharma Sa | New piperazine and tetrahydropyridine derivatives are tubulin polymerization inhibitors used for treating cancer and disaggregating cell masses derived from vascular tissue |
JP2007501242A (en) | 2003-08-01 | 2007-01-25 | ファイザー・プロダクツ・インク | 6-membered heteroaryl compounds for the treatment of neurodegenerative diseases |
CA2537916A1 (en) | 2003-09-03 | 2005-03-31 | Neurogen Corporation | 5-aryl-pyrazolo[4,3-d]pyrimidines, pyridines, and pyrazines and related compounds |
CN1878773A (en) | 2003-09-05 | 2006-12-13 | 神经能质公司 | Heteroaryl fused pyridines, pyrazines and pyrimidines as CRF1 receptor ligands |
WO2005025504A2 (en) | 2003-09-12 | 2005-03-24 | Kemia, Inc. | Modulators of calcitonin and amylin activity |
US20050182061A1 (en) | 2003-10-02 | 2005-08-18 | Jeremy Green | Phthalimide compounds useful as protein kinase inhibitors |
US7732616B2 (en) | 2003-11-19 | 2010-06-08 | Array Biopharma Inc. | Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof |
AU2004293436B2 (en) | 2003-11-19 | 2010-12-09 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
US20050203151A1 (en) | 2003-12-19 | 2005-09-15 | Kalypsys, Inc. | Novel compounds, compositions and uses thereof for treatment of metabolic disorders and related conditions |
CA2549638A1 (en) | 2003-12-23 | 2005-07-14 | Pfizer Products Inc. | Therapeutic combination for cognition enhancement and psychotic disorders |
EP1732566A4 (en) | 2004-04-05 | 2010-01-13 | Takeda Pharmaceutical | 6-azaindole compound |
WO2005100334A1 (en) | 2004-04-14 | 2005-10-27 | Pfizer Products Inc. | Dipeptidyl peptidase-iv inhibitors |
GB0412467D0 (en) | 2004-06-04 | 2004-07-07 | Astrazeneca Ab | Chemical compounds |
WO2006032631A1 (en) | 2004-09-22 | 2006-03-30 | Janssen Pharmaceutica N.V. | Inhibitors of the interaction between mdm2 and p53 |
US20060128710A1 (en) | 2004-12-09 | 2006-06-15 | Chih-Hung Lee | Antagonists to the vanilloid receptor subtype 1 (VR1) and uses thereof |
WO2006065842A2 (en) | 2004-12-13 | 2006-06-22 | Synta Pharmaceuticals Corp. | 5,6,7,8-tetrahydroquinolines and related compounds and uses thereof |
JP5038905B2 (en) | 2005-01-07 | 2012-10-03 | エモリー・ユニバーシテイ | CXCR4 antagonist for the treatment of medical disorders |
BRPI0607311A2 (en) | 2005-02-07 | 2009-08-25 | Hoffmann La Roche | heterocyclyl-substituted phenyl methanones as glycine transporter inhibitors 1 |
GB0504556D0 (en) | 2005-03-04 | 2005-04-13 | Pfizer Ltd | Novel pharmaceuticals |
EP2332909B1 (en) | 2005-04-13 | 2014-10-15 | Astex Therapeutics Limited | Hydroxybenzamide derivatives and their use as inhibitors of hsp90 |
WO2007050124A1 (en) | 2005-05-19 | 2007-05-03 | Xenon Pharmaceuticals Inc. | Fused piperidine derivatives and their uses as therapeutic agents |
WO2007007054A1 (en) | 2005-07-08 | 2007-01-18 | Cancer Research Technology Limited | Phthalamides, succinimides and related compounds and their use as pharmaceuticals |
US20070093515A1 (en) | 2005-08-16 | 2007-04-26 | Arrington Mark P | Phosphodiesterase 10 inhibitors |
DE602006021044D1 (en) | 2005-09-29 | 2011-05-12 | Glaxo Group Ltd | PYRAZOLOÄ3,4-BÜPYRIDIN COMPOUNDS AND THEIR USE AS PDE4 INHIBITORS |
BRPI0618354B8 (en) | 2005-11-10 | 2021-05-25 | Banyu Pharma Co Ltd | compound and its use, pharmaceutical composition, preventive or medicine |
PE20071240A1 (en) | 2006-01-17 | 2008-01-14 | Schering Corp | HYDANTOIN-DERIVED COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS |
US20080108611A1 (en) | 2006-01-19 | 2008-05-08 | Battista Kathleen A | Substituted thienopyrimidine kinase inhibitors |
WO2007087231A2 (en) | 2006-01-25 | 2007-08-02 | Merck & Co., Inc. | Aminocyclohexanes as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
US7910596B2 (en) | 2006-02-15 | 2011-03-22 | Merck Sharp & Dohme Corp. | Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
AU2007220040A1 (en) | 2006-02-27 | 2007-09-07 | The Board Of Trustees Of The Leland Stanford Junior University | Methods to identify inhibitors of the unfolded protein response |
CA2644649C (en) | 2006-03-22 | 2014-06-17 | Janssen Pharmaceutica N.V. | Cyclic-alkylaminederivatives as inhibitors of the interaction between mdm2 and p53 |
US7977351B2 (en) | 2006-03-22 | 2011-07-12 | Allergan, Inc. | Heteroaryl dihydroindolones as kinase inhibitors |
EP2023919A4 (en) | 2006-05-08 | 2010-12-22 | Molecular Neuroimaging Llc | Compounds and amyloid probes thereof for therapeutic and imaging uses |
EA200802210A1 (en) | 2006-05-16 | 2009-06-30 | Бёрингер Ингельхайм Интернациональ Гмбх | SUBSTITUTED PROLINAMIDES, THEIR RECEIVING AND THEIR USE AS MEDICINES |
CN1869036A (en) | 2006-06-30 | 2006-11-29 | 中国药科大学 | 7-substituted-3-chloro pyrrolo [3,4-b] pyridine compound |
DE102006032824A1 (en) | 2006-07-14 | 2008-01-17 | Bayer Healthcare Ag | Substituted indazoles |
AU2007275816A1 (en) | 2006-07-17 | 2008-01-24 | Merck Sharp & Dohme Corp. | 1-hydroxy naphthyridine compounds as anti-HIV agents |
WO2008013963A2 (en) | 2006-07-28 | 2008-01-31 | University Of Connecticut | Fatty acid amide hydrolase inhibitors |
US8389739B1 (en) | 2006-10-05 | 2013-03-05 | Orphagen Pharmaceuticals | Modulators of retinoid-related orphan receptor gamma |
US8916552B2 (en) | 2006-10-12 | 2014-12-23 | Astex Therapeutics Limited | Pharmaceutical combinations |
EP2081891A2 (en) | 2006-10-12 | 2009-07-29 | Astex Therapeutics Limited | Pharmaceutical compounds having hsp90 inhibitory or modulating activity |
US8883790B2 (en) | 2006-10-12 | 2014-11-11 | Astex Therapeutics Limited | Pharmaceutical combinations |
WO2008044054A2 (en) | 2006-10-12 | 2008-04-17 | Astex Therapeutics Limited | Hydroxy-substituted benzoic acid amide compounds for use in therapy |
WO2008044029A1 (en) | 2006-10-12 | 2008-04-17 | Astex Therapeutics Limited | Pharmaceutical combinations |
PE20080888A1 (en) | 2006-10-18 | 2008-08-26 | Novartis Ag | HETEROCYCLIC COMPOUNDS AS ACIL-TRANSFERASE INHIBITORS OF ACIL-CoA-DIACIL-GLYCEROL 1 (DGAT1) |
KR20090098877A (en) | 2006-12-11 | 2009-09-17 | 노파르티스 아게 | Method of preventing or treating myocardial ischemia |
WO2008083070A1 (en) | 2006-12-29 | 2008-07-10 | Neurogen Corporation | Crf1 receptor ligands comprising fused bicyclic heteroaryl moieties |
EA200900969A1 (en) | 2007-01-08 | 2010-02-26 | Феномикс Корпорейшн | MACROCYCLIC INHIBITORS OF HEPATITIS C PROTEASE |
WO2009004496A2 (en) | 2007-04-13 | 2009-01-08 | University Of Manitoba | Bisanthrapyrazoles as anti-cancer agents |
US20110189167A1 (en) | 2007-04-20 | 2011-08-04 | Flynn Daniel L | Methods and Compositions for the Treatment of Myeloproliferative Diseases and other Proliferative Diseases |
US20100129933A1 (en) | 2007-04-26 | 2010-05-27 | Forschungszentrum Karlsruhe Gmbh | Method for detecting the binding between mdm2 and the proteasome |
TW200902533A (en) | 2007-05-02 | 2009-01-16 | Boehringer Ingelheim Int | Carboxylic acid amides, manufacturing and use thereof as medicaments |
WO2008135524A2 (en) | 2007-05-02 | 2008-11-13 | Boehringer Ingelheim International Gmbh | Substituted anthranilamides and analogues, manufacturing and use thereof as medicaments |
EP2754690B1 (en) | 2007-05-10 | 2017-12-13 | Plastipak Packaging, Inc. | Oxygen scavenging molecules, articles containing same, and methods of their use |
TW200902499A (en) | 2007-05-15 | 2009-01-16 | Astrazeneca Ab | New compounds |
GB0710844D0 (en) | 2007-06-06 | 2007-07-18 | Lectus Therapeutics Ltd | Potassium ion channel modulators & uses thereof |
DE102007034620A1 (en) | 2007-07-25 | 2009-01-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New B1 antagonists |
WO2009026248A2 (en) | 2007-08-17 | 2009-02-26 | The Government Of The United States, As Represented By The Secretary Of Health And Human Services, National Institutes Of Health, Office Of Technology Transfer | Hydrazide, amide, phthalimide and phthalhydrazide analogs as inhibitors of retroviral integrase |
NZ600371A (en) | 2007-09-17 | 2014-07-25 | Abbvie Bahamas Ltd | Uracil or thymine derivative for treating hepatitis c |
US20090076275A1 (en) | 2007-09-19 | 2009-03-19 | David Robert Bolin | Diacylglycerol acyltransferase inhibitors |
EP2217068A4 (en) | 2007-10-11 | 2011-09-14 | Glaxosmithkline Llc | NOVEL sEH INHIBITORS AND THEIR USE |
CA2702946A1 (en) | 2007-10-16 | 2009-04-23 | Northeastern University | Monoacylglycerol lipase inhibitors for modulation of cannabinoid activity |
WO2009050228A2 (en) | 2007-10-18 | 2009-04-23 | Novartis Ag | Csf-1r inhibitors for treatment of cancer and bone diseases |
KR101196543B1 (en) | 2007-11-29 | 2012-11-01 | 에프. 호프만-라 로슈 아게 | Process for the preparation of isoindole derivatives as well as a process for the preparation of their intermediates |
WO2009073788A1 (en) | 2007-12-07 | 2009-06-11 | Firestone Leigh H | Compositions and methods for treating menopausal females |
EP2078711A1 (en) | 2007-12-28 | 2009-07-15 | AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO A.C.R.A.F. S.p.A. | (Aza)indole derivative substituted in position 5, pharmaceutical composition comprising it, intermediate compounds and preparation process therefor |
GB0800035D0 (en) | 2008-01-02 | 2008-02-13 | Glaxo Group Ltd | Compounds |
FR2926554B1 (en) | 2008-01-22 | 2010-03-12 | Sanofi Aventis | AZABICYCLIC CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF |
CN101225070B (en) | 2008-01-31 | 2010-04-14 | 上海交通大学 | Antineoplastic medicament |
EP2242740B1 (en) | 2008-02-05 | 2012-12-12 | Sanofi | Sf5 derivatives as par1 inhibitors, production thereof, and use as medicaments |
WO2009112445A1 (en) | 2008-03-10 | 2009-09-17 | Novartis Ag | Method of increasing cellular phosphatidyl choline by dgat1 inhibition |
GB0804702D0 (en) | 2008-03-13 | 2008-04-16 | Amura Therapeutics Ltd | Compounds |
GB0804701D0 (en) | 2008-03-13 | 2008-04-16 | Amura Therapeutics Ltd | Compounds |
WO2009124755A1 (en) | 2008-04-08 | 2009-10-15 | European Molecular Biology Laboratory (Embl) | Compounds with novel medical uses and method of identifying such compounds |
US7863291B2 (en) | 2008-04-23 | 2011-01-04 | Bristol-Myers Squibb Company | Quinuclidine compounds as alpha-7 nicotinic acetylcholine receptor ligands |
US8309577B2 (en) | 2008-04-23 | 2012-11-13 | Bristol-Myers Squibb Company | Quinuclidine compounds as α-7 nicotinic acetylcholine receptor ligands |
GB0809776D0 (en) | 2008-05-29 | 2008-07-09 | Amura Therapeutics Ltd | Compounds |
MX2010014565A (en) | 2008-07-01 | 2011-03-04 | Genentech Inc | Isoindolone derivatives as mek kinase inhibitors and methods of use. |
US8143259B2 (en) | 2008-08-19 | 2012-03-27 | Janssen Pharmaceutica, Nv | Cold menthol receptor antagonists |
JPWO2010024258A1 (en) | 2008-08-29 | 2012-01-26 | 塩野義製薬株式会社 | Fused azole derivative having PI3K inhibitory activity |
EP2334183A4 (en) | 2008-09-16 | 2012-06-06 | Merck Sharp & Dohme | Sulfonamide derivative metabotropic glutamate r4 ligands |
US20100125081A1 (en) | 2008-11-14 | 2010-05-20 | Astrazeneca Ab | New compounds 574 |
US20100125087A1 (en) | 2008-11-14 | 2010-05-20 | Astrazeneca Ab | New compounds 575 |
CN101455661B (en) | 2008-11-19 | 2012-10-10 | 中国科学院上海有机化学研究所 | Use of 3-substituted phthalide and the analogue |
US9040508B2 (en) | 2008-12-08 | 2015-05-26 | Vm Pharma Llc | Compositions of protein receptor tyrosine kinase inhibitors |
JP5592398B2 (en) | 2009-01-28 | 2014-09-17 | バイエル・クロップサイエンス・アーゲー | Disinfectant N-cycloalkyl-N-bicyclic methylene-carboxamide derivatives |
WO2011078143A1 (en) | 2009-12-22 | 2011-06-30 | 塩野義製薬株式会社 | Pyrimidine derivatives and pharmaceutical composition containing same |
WO2011090473A1 (en) | 2010-01-19 | 2011-07-28 | Frank Ivy Carroll | Kappa opioid receptor binding ligands |
CN102844313B (en) | 2010-01-28 | 2016-10-05 | 哈佛大学校长及研究员协会 | Improve compositions and the method for proteasome activity |
EP2368886A1 (en) | 2010-03-01 | 2011-09-28 | Phenex Pharmaceuticals AG | Novel compounds for modulation of orphan nuclear receptor RAR-related orphan receptor-gamma (ROR gamma, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune desease |
CN102241621A (en) | 2010-05-11 | 2011-11-16 | 江苏恒瑞医药股份有限公司 | 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof |
EP2571876B1 (en) | 2010-05-21 | 2016-09-07 | Merck Sharp & Dohme Corp. | Substituted seven-membered heterocyclic compounds as dipeptidyl peptidase-iv inhibitors for the treatment of diabetes |
US8299117B2 (en) | 2010-06-16 | 2012-10-30 | Metabolex Inc. | GPR120 receptor agonists and uses thereof |
WO2011159297A1 (en) | 2010-06-16 | 2011-12-22 | Metabolex, Inc. | Gpr120 receptor agonists and uses thereof |
WO2012027965A1 (en) | 2010-09-01 | 2012-03-08 | Glaxo Group Limited | Novel compounds |
WO2012028100A1 (en) | 2010-09-01 | 2012-03-08 | Glaxo Group Limited | Novel compounds |
EP2611804A1 (en) | 2010-09-03 | 2013-07-10 | Forma TM, LLC. | Novel compounds and compositions for the inhibition of nampt |
US9266855B2 (en) | 2010-09-27 | 2016-02-23 | AbbVie Deutschland GmbH & Co. KG | Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors |
JP2013253019A (en) | 2010-09-28 | 2013-12-19 | Kowa Co | New piperidine derivative and pharmaceutical containing the same |
WO2012064744A2 (en) | 2010-11-08 | 2012-05-18 | Lycera Corporation | Tetrahydroquinoline and related bicyclic compounds for inhibition of rorϒ activity and the treatment of disease |
MX2013005008A (en) | 2010-11-10 | 2013-08-01 | Gruenenthal Gmbh | Substituted heteroaromatic carboxamide and urea derivatives as vanilloid receptor ligands. |
WO2012100732A1 (en) | 2011-01-24 | 2012-08-02 | Glaxo Group Limited | Retinoid-related orphan receptor gamma modulators, composition containing them and uses thereof |
WO2012100734A1 (en) | 2011-01-24 | 2012-08-02 | Glaxo Group Limited | Compounds useful as retinoid-related orphan receptor gamma modulators |
EP2487159A1 (en) | 2011-02-11 | 2012-08-15 | MSD Oss B.V. | RorgammaT inhibitors |
CN102180780A (en) | 2011-03-07 | 2011-09-14 | 中国科学技术大学 | Indenone derivative and applications thereof as developing agent and aggregation inhibitor of amyloid protein deposit and neurofibrillary tangle |
WO2012125521A1 (en) | 2011-03-14 | 2012-09-20 | Eternity Bioscience Inc. | Quinazolinediones and their use |
CN103635458B (en) | 2011-03-25 | 2016-10-19 | 艾伯维公司 | TRPV1 antagonist |
CN103459403B (en) | 2011-04-04 | 2016-08-17 | 默克专利有限公司 | Metal complex |
EP2511263A1 (en) | 2011-04-14 | 2012-10-17 | Phenex Pharmaceuticals AG | Pyrrolo sulfonamide compounds for modulation of orphan nuclear receptor RAR-related orphan receptor-gamma (RORgamma, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
TWI532728B (en) | 2011-04-28 | 2016-05-11 | 日本煙草產業股份有限公司 | Amide compounds and pharmaceutical uses thereof |
US9938269B2 (en) | 2011-06-30 | 2018-04-10 | Abbvie Inc. | Inhibitor compounds of phosphodiesterase type 10A |
EP2747560A4 (en) | 2011-07-29 | 2015-02-25 | Tempero Pharmaceuticals Inc | Compounds and methods |
WO2013018695A1 (en) | 2011-07-29 | 2013-02-07 | 武田薬品工業株式会社 | Heterocyclic compound |
WO2013019653A1 (en) | 2011-07-29 | 2013-02-07 | Tempero Pharmaceuticals, Inc. | Compounds and methods |
WO2013019621A1 (en) | 2011-07-29 | 2013-02-07 | Tempero Pharmaceuticals, Inc. | Compounds and methods |
WO2013019682A1 (en) | 2011-07-29 | 2013-02-07 | Tempero Pharmaceuticals, Inc. | Compounds and methods |
WO2013029338A1 (en) | 2011-09-01 | 2013-03-07 | Glaxo Group Limited | Novel compounds |
JP6043290B2 (en) | 2011-09-22 | 2016-12-14 | 武田薬品工業株式会社 | Fused heterocyclic compounds |
GB201116641D0 (en) | 2011-09-27 | 2011-11-09 | Glaxo Group Ltd | Novel compounds |
WO2013064231A1 (en) | 2011-10-31 | 2013-05-10 | Phenex Pharmaceuticals Ag | SEVEN-MEMBERED SULFONAMIDES AS MODULATORS OF RAR-RELATED ORPHAN RECEPTOR-GAMMA (RORγ, NR1F3) |
US20140256767A1 (en) | 2011-10-31 | 2014-09-11 | The Broad Institute, Inc. | Direct inhibitors of keap1-nrf2 interaction as antioxidant inflammation modulators |
US9309227B2 (en) | 2011-11-22 | 2016-04-12 | The Scripps Research Institute | N-biphenylmethylbenzimidazole modulators of PPARG |
US20140249196A1 (en) | 2011-11-22 | 2014-09-04 | Theodore Mark Kamenecka | N-benzylbenzimidazole modulators of pparg |
WO2013079223A1 (en) | 2011-12-02 | 2013-06-06 | Phenex Pharmaceuticals Ag | Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
US8741892B2 (en) | 2011-12-05 | 2014-06-03 | Boehringer Ingelheim International Gmbh | Compounds |
US8642774B2 (en) | 2011-12-08 | 2014-02-04 | Boehringer Ingelheim International Gmbh | Compounds |
US8796467B2 (en) | 2011-12-13 | 2014-08-05 | Boehringer Ingelheim International Gmbh | Compounds |
WO2013092460A1 (en) | 2011-12-20 | 2013-06-27 | Syngenta Participations Ag | Cyclic bisoxime microbicides |
WO2013096496A2 (en) | 2011-12-21 | 2013-06-27 | Allergan, Inc. | Compounds acting at multiple prostaglandin receptors giving a general anti-inflammatory response |
US20130190356A1 (en) | 2011-12-22 | 2013-07-25 | Genentech, Inc. | Benzyl sulfonamide derivatives as rorc modulators |
US9216988B2 (en) | 2011-12-22 | 2015-12-22 | Genentech, Inc. | Benzyl sulfonamide derivatives as RORc modulators |
WO2013100027A1 (en) | 2011-12-28 | 2013-07-04 | 武田薬品工業株式会社 | Heterocyclic compound |
WO2013159095A1 (en) | 2012-04-20 | 2013-10-24 | Anderson Gaweco | Ror modulators and their uses |
GB201207406D0 (en) | 2012-04-27 | 2012-06-13 | Glaxo Group Ltd | Novel compounds |
WO2013160418A1 (en) | 2012-04-27 | 2013-10-31 | Glaxo Group Limited | Novel compounds |
EP2844259A4 (en) | 2012-04-30 | 2015-11-11 | Anderson Gaweco | Ror modulators and their uses |
CA2872014A1 (en) | 2012-05-08 | 2013-11-14 | Lycera Corporation | Tetrahydro[1,8]naphthyridine sulfonamide and related compounds for use as agonists of ror.gamma. and the treatment of disease |
AU2013259904A1 (en) | 2012-05-08 | 2014-10-02 | Lycera Corporation | Bicyclic sulfone compounds for inhibition of RORy activity and the treatment of disease |
MX367341B (en) | 2012-05-08 | 2019-08-14 | Merck Sharp & Dohme | TETRAHYDRONAPHTHYRIDINE AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE. |
AR091194A1 (en) | 2012-05-31 | 2015-01-21 | Phenex Pharmaceuticals Ag | TIAZOLS REPLACED BY CARBOXAMIDE AND RELATED DERIVATIVES AS MODULATORS FOR THE HUERFANO RORg NUCLEAR RECEIVER |
WO2014008214A1 (en) | 2012-07-02 | 2014-01-09 | Biogen Idec Ma Inc. | Biaryl-containing compounds as inverse agonists of ror-gamma receptors |
TW201408652A (en) | 2012-07-11 | 2014-03-01 | Hoffmann La Roche | Aryl sultam derivatives as RORc modulators |
WO2014026329A1 (en) | 2012-08-15 | 2014-02-20 | Merck Sharp & Dohme Corp. | N-alkylated indole and indazole compounds as rorgammat inhibitors and uses thereof |
WO2014026330A1 (en) | 2012-08-15 | 2014-02-20 | Merck Sharp & Dohme Corp. | 3-AMINOCYCLOALKYL COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF |
WO2014026328A1 (en) | 2012-08-15 | 2014-02-20 | Merck Sharp & Dohme Corp. | 3-cyclohexenyl substituted indole and indazole compounds as rorgammat inhibitors and uses thereof |
WO2014028669A1 (en) | 2012-08-15 | 2014-02-20 | Biogen Idec Ma Inc. | Novel compounds for modulation of ror-gamma activity |
WO2014026327A1 (en) | 2012-08-15 | 2014-02-20 | Merck Sharp & Dohme Corp. | 4-heteroaryl substituted benzoic acid compounds as rorgammat inhibitors and uses thereof |
ES2623528T3 (en) | 2012-09-21 | 2017-07-11 | Sanofi | Benzoimidazolecarboxylic acid amide derivatives to treat metabolic or cardiovascular diseases |
WO2014062938A1 (en) | 2012-10-19 | 2014-04-24 | Bristol-Myers Squibb Company | Rory modulators |
BR112015013137B1 (en) | 2012-12-06 | 2022-05-10 | Glaxo Group Limited | Orphan receptor modulators for retinoid of the gamma subtype (ror-gamma) and pharmaceutical composition comprising said modulators in the treatment of autoimmune and inflammatory diseases |
WO2013171729A2 (en) | 2013-01-08 | 2013-11-21 | Glenmark Pharmaceuticals S.A. | Aryl and heteroaryl amide compounds as rorgamat modulator |
JP6346904B2 (en) | 2013-01-10 | 2018-06-20 | ベナトルクス ファーマシューティカルズ,インク. | Beta-lactamase inhibitor |
US9868748B2 (en) | 2013-05-01 | 2018-01-16 | Vitae Pharmaceuticals, Inc. | Thiazolopyrrolidine inhibitors of ROR- γ |
WO2015017335A1 (en) | 2013-07-30 | 2015-02-05 | Boehringer Ingelheim International Gmbh | Azaindole compounds as modulators of rorc |
US9745267B2 (en) | 2013-09-05 | 2017-08-29 | Boehringer Ingelheim International Gmbh | Compounds as modulators of RORC |
TWI652014B (en) | 2013-09-13 | 2019-03-01 | 美商艾佛艾姆希公司 | Heterocyclic substituted bicycloazole insecticide |
TW201609665A (en) | 2013-11-05 | 2016-03-16 | 赫孚孟拉羅股份公司 | Pyridazine derivatives as RORc modulators |
WO2015083130A1 (en) | 2013-12-06 | 2015-06-11 | Aurigene Discovery Technologies Limited | Fused pyridine and pyrimidine derivatives as ror gamma modulators |
TN2016000240A1 (en) | 2013-12-24 | 2017-10-06 | Harvard College | Cortistatin analogues and syntheses and uses thereof. |
JP2015124178A (en) | 2013-12-26 | 2015-07-06 | 東レ株式会社 | Cyclic amine derivative and medicinal use thereof |
WO2015101928A1 (en) | 2013-12-31 | 2015-07-09 | Aurigene Discovery Technologies Limited | Fused thiophene and thiazole derivatives as ror gamma modulators |
CR20160402A (en) | 2014-02-03 | 2017-02-07 | Basf Se | Compound of cyclopentene and cyclopentadiene to control invertebrate pests |
WO2015116904A1 (en) | 2014-02-03 | 2015-08-06 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ror-gamma |
EP3590939A1 (en) | 2014-03-26 | 2020-01-08 | F. Hoffmann-La Roche AG | Bicyclic compounds as autotaxin (atx) and lysophosphatidic acid (lpa) production inhibitors |
US9815798B2 (en) | 2014-03-26 | 2017-11-14 | Basf Se | Substituted [1,2,4]triazole and imidazole compounds as fungicides |
JO3512B1 (en) | 2014-03-26 | 2020-07-05 | Astex Therapeutics Ltd | Quinoxaline derivatives useful as fgfr kinase modulators |
SG11201607845RA (en) | 2014-03-26 | 2016-10-28 | Hoffmann La Roche | Condensed [1,4]diazepine compounds as autotaxin (atx) and lysophosphatidic acid (lpa) production inhibitors |
PE20161399A1 (en) | 2014-04-16 | 2017-01-14 | Glenmark Phamaceuticals S A | ARIL AND HETEROARYL ETHER COMPOUNDS AS ROR GAMMA MODULATORS |
SI3207043T1 (en) | 2014-10-14 | 2019-04-30 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ror-gamma |
CN107206004A (en) | 2014-10-22 | 2017-09-26 | 德克萨斯大学系统董事会 | Target micromolecular inhibitor of discoidin domain receptor 1 and application thereof |
US9663515B2 (en) | 2014-11-05 | 2017-05-30 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
CN107635984B (en) | 2015-03-11 | 2021-04-13 | Fmc公司 | Heterocyclic substituted bicyclic azoles as pesticidal agents |
EP3331876B1 (en) | 2015-08-05 | 2020-10-07 | Vitae Pharmaceuticals, LLC | Modulators of ror-gamma |
MA53943A (en) | 2015-11-20 | 2021-08-25 | Vitae Pharmaceuticals Llc | ROR-GAMMA MODULATORS |
TWI757266B (en) | 2016-01-29 | 2022-03-11 | 美商維它藥物有限責任公司 | Modulators of ror-gamma |
US9481674B1 (en) * | 2016-06-10 | 2016-11-01 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
WO2019018975A1 (en) | 2017-07-24 | 2019-01-31 | Vitae Pharmaceuticals, Inc. | Inhibitors of ror gamma |
CN111225914B (en) | 2017-07-24 | 2022-10-11 | 生命医药有限责任公司 | Inhibitors of ROR gamma |
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