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WO2023161327A1 - Compound for use in and methods of treatment of inflammatory diseases - Google Patents

Compound for use in and methods of treatment of inflammatory diseases Download PDF

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Publication number
WO2023161327A1
WO2023161327A1 PCT/EP2023/054526 EP2023054526W WO2023161327A1 WO 2023161327 A1 WO2023161327 A1 WO 2023161327A1 EP 2023054526 W EP2023054526 W EP 2023054526W WO 2023161327 A1 WO2023161327 A1 WO 2023161327A1
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WO
WIPO (PCT)
Prior art keywords
inducers
compound
cyp
cyp3a4
compounds
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PCT/EP2023/054526
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French (fr)
Inventor
Edouard HELLOT
Justine DAO
Natalia RUEDA RINCON
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Galapagos Nv
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Publication of WO2023161327A1 publication Critical patent/WO2023161327A1/en

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to improved methods for the use of the compound of the invention in the treatment of inflammatory diseases, and/or diseases associated with hypersecretion of IFNa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL- 12 and/or IL-23, by avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are cytochrome P450 (CYP) inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
  • CYP cytochrome P450
  • Janus kinases are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to STAT transcription factors.
  • JAK family members Four JAK family members are described, JAK1, JAK2, JAK3 and TYK2.
  • JAK family members Upon binding of the cytokine to its receptor, JAK family members auto- and/or transphosphorylate each other, followed by phosphorylation of STATs that then migrate to the nucleus to modulate transcription.
  • JAK-STAT intracellular signal transduction serves the interferons, most interleukins, as well as a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL (Vainchenker, Dusa, and Constantine scu 2008).
  • JAKinibs JAK inhibitors
  • JAKinibs JAK inhibitors with various degrees of selectivity profdes versus the JAK family members.
  • JAK inhibitors with various degrees of selectivity profdes versus the JAK family members.
  • targeting multiple JAK may not be detrimental (Brockman, Giovannetti, and Peters 2011)
  • developing selective JAK inhibitors would be very desirable to develop treatment course tailored to the needs of the patient despite the challenge it represents (Fabian et al. 2005).
  • JAK2 inhibition has proven useful in the treatment of polycythemia and myelofibrosis
  • undesirable effect associated with JAK2 inhibition were observed (O’Shea and Plenge 2012) thus rendering compounds with JAK2 inhibition components unsuitable for the treatment of non-JAK2 mediated diseases.
  • IL-6, IL-10, IL-11, IL-12, IL-13, IL-19, IL- 20, IL-22, IL-23, IL-27, IL-28, IL-29, IL-31, IL-35 and/or type 1 interferons signaling are dependent on TYK2 (Schwartz et al. 2016).
  • TYK2 is involved in type I interferons (including IFNa, INF[3), IL- 23 and IL- 12 signaling (Gillooly, Zhang, and Yang 2016). Since the activity of IL- 12 and IL-23 is particularly increased in patients with auto-immune diseases such as psoriasis and/or inflammatory bowel disorders, selective TYK2 inhibition may be particularly advantageous in the treatment of these diseases while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer et al. 1998). [0005] Furthermore, TYK2 has been reported as a target for multiple autoimmune disorders, providing protection against inflammatory diseases as well as type 2 diabetes with a limited impact on the immune system (Dendrou et al. 2016).
  • Compound 1 is a small molecule inhibitor of JAK, a family of tyrosine kinases, more particularly TYK2, and is currently under investigation as a drug for the treatment of inflammatory diseases and/or diseases associated with hypersecretion of IFNa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL- 12 and/or IL-23.
  • interferonopathies especially type I interferonopathies
  • IL- 12 and/or IL-23 The identification and synthesis of Compound 1 have previously been described in WO2019/076716.
  • interferonopathies especially type I interferonopathies
  • IL-12 and/or IL-23 in particular diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis and/or Crohn’s disease.
  • Cytochrome P450 (CYP) enzymes are essential for the metabolism of many medicines and endogenous compounds (Danielson 2002).
  • the cytochrome P450 3 A family is the most abundant subfamily of the CYP isoforms in the liver. There are at least three isoforms: 3A4, 3A5 and 3A7 in adults, of which 3A4 is considered the most important of all CYP enzymes in the liver (Ince et al. 2013).
  • CYP enzymes can be inhibited or induced by drugs, which may result in clinically significant drugdrug interactions that may cause unanticipated adverse reactions or therapeutic failures (Lynch and Price 2007). It is therefore crucial to understand which combinations of drugs should be contraindicated or their co-administration avoided.
  • cytochrome P450 3A4 (CYP3A4) inhibitors are known (https://www.fda.gov/drugs/drug- interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers) and Itraconazole, given its strong CYP3A inhibition, has emerged as probe to evaluate clinical drug-drug interaction (DDI) studies (Liu et al. 2016).
  • Exposure of a drug may be influenced by the co-administration of a CYP3A4 inhibitor (Teo, Ho, and Chan 2015), leading to under or overdosing of said drug; therefore it is essential to ensure stable dose and exposure to avoid undesirable side effects or toxicity.
  • a CYP3A4 inhibitor Teo, Ho, and Chan 2015
  • P-glycoprotein also referred to as “Multidrug Resistance Protein (MDR1)” and by its gene name “ABCB1”
  • MDR1 Multidrug Resistance Protein
  • ABSCB1 ATP Binding Cassette transporters
  • P-glycoprotein plays an important role transporting drug substances outside the cell (efflux) influencing their elimination from the body.
  • P-glycoprotein is an important mediator of drug -drug interactions.
  • the pharmacokinetics of a drug may be altered when co-administered with compounds which inhibit or induce P-glycoprotein (Konig, Muller, and Fromm 2013). It is therefore crucial to understand which combinations of drugs should be contraindicated or their co-administration avoided.
  • a substance acting as P-gp inhibitor which can also act as CYP inhibitor
  • a substance acting as P-gp inhibitor may result in a reduced therapeutic effect due to a doble effect.
  • a P-gp inhibition-mediated enhanced the intracellular accumulation of the parent drug
  • a CYP inhibition-mediated may cause excessive drug accumulation of the parent drug and increased its toxicity, resulting in the need to reduce the dose of the therapeutic agent. Therefore, it is crucial to understand which combinations of drugs should be contraindicated or their co-administration avoided (Wandel et al. 1999).
  • the invention described herein is based upon the observation that the compound of the invention is metabolized by CYP3A4 and/or transported by P-gp, which could result in undesired drug-drug interactions when administered in combination with one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
  • the present invention provides the compound of the invention for use in treating a patient in need of the compound of the invention therapy, characterized in that the treating comprises avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
  • the present invention also provides the use of the compound of the invention in the manufacture of a medicament for treating a patient in need of therapy using the compound of the invention, characterized in that the treating comprises avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
  • the present invention provides a method of administering treatment using the compound of the invention to a patient in need of therapy using the compound of the invention comprising administering the patient a therapeutically effective amount of the compound of the invention, and, avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
  • the patient in need of therapy is a patient suffering from inflammatory diseases, and/or diseases associated with hypersecretion of IFNa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL- 12 and/or IL-23.
  • interferonopathies especially type I interferonopathies
  • diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis and/or Crohn’s disease.
  • the one or more compounds that may produce potentially serious side effects or toxicity or exhibit adverse drug interactions when co-administered with the compound of the invention are CYP inducers and/or P-gp inducers, more particularly CYP3A4 inducers and/or P-gp inducers, even more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
  • the compound of the invention is according to Formula I below:
  • the chemical name of the compound of the invention is 4-methyl-5-[3-methyl-7-[(6-morpholin-4- ylpyridazin-3 -yl)amino]imidazo [4,5 -b]pyridin-5 -yl]oxypyridine-2 -carbonitrile (Compound 1 ) .
  • the compound of the invention useful in the pharmaceutical compositions and treatment methods disclosed herein is pharmaceutically acceptable as prepared and used.
  • the compound of the invention may be metabolized to yield biologically active metabolites.
  • analogue means one analogue or more than one analogue.
  • the Compound of the Invention means the compound of Formula I or Compound 1, which expression includes the pharmaceutically acceptable salts/cocrystals, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts/cocrystals, where the context so permits.
  • reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts/cocrystals, and solvates, where the context so permits.
  • ‘Pharmaceutically acceptable salt/cocrystal’ refers to a salt and/or cocrystal of Compound 1 that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts or cocrystals are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • Cocrystal refers to a crystalline material composed of Compound 1 and a cocrystal former ('coformer') in the same crystal lattice.
  • cocrystal and “co-crystal” are used interchangeably herein.
  • Reference to a certain ‘dose’ or ‘dosage’ of the Compound of the Invention refers to the equivalent weight of free base compound being administered, i.e. not including the weight of any salt, solvate or cocrystal counterpart or component.
  • ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which the compound of the invention is administered.
  • Solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • Conventional solvents include water, EtOH, acetic acid and the like.
  • the compound of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • Subject includes humans.
  • the terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.
  • Effective amount means the amount of the compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “effective amount” can vary depending on the disease and its severity, and the age, weight, etc, of the subject to be treated.
  • Preventing refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • prophylaxis is related to ‘prevention’ and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti- malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both.
  • “treating” or “treatment” relates to slowing the progression of the disease.
  • inflammatory disease(s) refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis), endotoxin-driven disease states (e.g. complications after bypass surgery, acute kidney injury (AKI), Alport syndrome or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints.
  • allergic airway disease e.g. asthma, rhinitis
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • endotoxin-driven disease states e.g. complications after bypass surgery, acute kidney injury (AKI), Alport syndrome or chronic
  • the term refers to rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and inflammatory bowel diseases. More particularly the term refers to psoriasis, rheumatoid arthritis and inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease.
  • IL-12 and/or IL-23 includes conditions such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis and/or Crohn’s disease.
  • Adverse Event refers to any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
  • An Adverse Event can therefore be any unfavorable and/or unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
  • AEs may also include pre- or post-treatment complications that occur as a result of protocol mandated procedures, lack of efficacy, overdose or drug abuse/misuse reports. Pre-existing events that increase in severity or change in nature during or as a consequence of participation in the clinical study will also be considered AEs.
  • Treatment Emergent Adverse Event refers to any Adverse Event (AE) (or worsening of any Adverse Event (AE)) with an onset date on or after the start date of the respective treatment and no later than 30 days after the last dose of the respective treatment.
  • SESs Serious Adverse Event
  • AE Adverse Event
  • death a life-threatening event (an event in which the subject was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe.)
  • in-subject hospitalization or prolongation of existing hospitalization persistent or significant disability/incapacity
  • a congenital anomaly/birth defect or a medically significant event (medical and scientific judgment should be exercised in deciding whether other situations should be considered serious such as important medical events that might not be immediately life-threatening or result in death or hospitalization but might jeopardize the subject or might require intervention to prevent one of the other outcomes listed in the definition above).
  • the term “respective medicament” “said medicament” or “contraindicated medicament” refers to the medicament or the one or more compounds that may produce potentially serious side effects or toxicity or exhibit adverse drug interactions when co-administered with the compound of the invention.
  • the term “avoiding the concomitant use or co-administration of’ comprises or relates to avoidance of the use of the contraindicated medicament by looking into alternatives to the respective medicament in a patient in need of therapy with the respective medicament.
  • discontinue and forms thereof, are contemplated to have as alternatives the terms cease, stop, suspend, and quit, and forms thereof.
  • the term “contraindicating” and forms thereof such as “contraindication” are contemplated to contain the instruction to not enter in the contraindicated activity.
  • CYP inducers refers to one or more compounds that decrease the AUC of substrates of a given CYP.
  • CYP inducers may be either weak, moderate or strong inducers.
  • the term refers to CYP3A4 inducers.
  • Examples of CYP3A4 inducers include Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Dexamethasone, Pioglitazone, Rifabutin, Rifampicin, St. John’s wort, Phenobarbital and Troglitazone.
  • the term refers to Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, and St. John’s wort.
  • strong CYP3A4 inducers refers to one or more compounds that decrease the AUC of oral Midazolam or other specific 3A4 substrate by >5-fold or results in a >80% increase in its clearance.
  • strong CYP3A4 inducers include Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, and St. John’s wort (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table- substrates-inhibitors-and-inducers).
  • P-gp inducers refers to one or more compounds that decrease the AUC of substrates of P-gp.
  • substrates of p-gp include Dabigatran etexilate, digoxin, fexofenadine, Midazolam and Prazosin.
  • P-pg inducers include Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Apalutamide, Carbamazepine, Fosphenytoin, Lorlatinib, Phenytoin, Dexamethasone, Rifabutin, Rifampicin and St.
  • strong P-gp inducer refers to one or more compounds that decrease the AUC of oral P- gp substrate by >5-fold, for example Midazolam and Prazosin.
  • strong P-gp inducers include Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Carbamazepine, Phenytoin, Rifabutin, Rifampicin and St. John's Wort (https://www.fda.gov/drugs/drug-interactions- labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers).
  • a combined CYP3A4/P-gp inducer is a substance that upon administration to a subject increases CYP3A4 and P-gp mediated activity.
  • Examples of combined CYP3A4/P-gp inducers include phenytoin, carbamazepine, rifampicin, dexamethasone and St. John’s wort.
  • the term “rendered therapeutically ineffective” refers to a loss of efficacy of a medicament in a given patient or patient population by virtue of reduced exposure.
  • the present disclosure includes all isotopic forms of the compound of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers.
  • unnatural variant isotopic form also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form").
  • the term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring.
  • Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
  • An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium ( 2 H or D), carbon-11 ( n C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), phosphorus-32 ( 32 P), sulphur-35 ( 35 S), chlorine-36 ( 36 C1), chlorine-37 ( 37 C1), fluorine-18 ( 18 F) iodine-123 ( 123 I), iodine-125 ( 125 I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
  • an artificial or uncommon isotopes such as deuterium ( 2 H or D), carbon-11 ( n C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen
  • Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Unnatural variant isotopic forms which incorporate deuterium i.e. 2 H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as n C, 18 F, 15 0 and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 7i electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compound of the invention may be metabolized to yield biologically active metabolites.
  • the compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • a compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
  • the reaction mixture was stirred during one hour after the last addition.
  • the suspension was filtered on Dicalite 4158 (Carlo Erba, ref P8880014), washed with THF (IL) and the combined organic layers were concentrated.
  • the residue was slowly poured into a cold mixture of 20% ammoniac solution (100 mb) and water (2 L). The resulting solid was filtered, washed with water (2 L) and dried to afford the desired product.
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention, for use in the treatment of a patient in need of therapy using the compound of the invention, characterized in that the treating comprises avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/ or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
  • the patient in need of therapy is suffering from one or more inflammatory diseases, and/or diseases associated with hypersecretion of INFa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL- 12 and/or IL-23.
  • interferonopathies especially type I interferonopathies
  • the disease is systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis or Crohn’s disease.
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for use in the treatment of a patient in need of therapy using the compound of the invention, characterized in that the treatment comprises avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P- gp inducers.
  • the patient in need of therapy is suffering from one or more inflammatory diseases, and/or diseases associated with hypersecretion of INFa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL-12 and/or IL-23.
  • interferonopathies especially type I interferonopathies
  • the disease is systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis or Crohn’s disease.
  • this invention provides methods of treatment of a patient in need of therapy thereof, which methods comprise the administration of an effective amount of the compound of the invention or one or more of the pharmaceutical compositions herein described wherein the treatment additionally comprises avoiding, contraindicating or discontinuing concomitant use or co- administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P- gp inducers.
  • the patient in need of therapy is suffering from one or more inflammatory diseases, and/or diseases associated with hypersecretion of INFa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL-12 and/or IL-23.
  • interferonopathies especially type I interferonopathies
  • the disease is systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis or Crohn’s disease.
  • the invention provides a method of administering the compound of the invention to a patient in need of therapy thereof, comprising administering to the patient a therapeutically effective amount of the compound of the invention, and avoiding (concomitant) use or (co-)administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
  • the invention provides a method of administering the compound of the invention to a patient in need of therapy thereof, comprising discontinuing administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, and then administering a therapeutically effective amount of the compound of the invention.
  • the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, is discontinued concurrently with starting administration of the compound of the invention.
  • the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers is discontinued at least 12 hours to 1 week prior to or after starting the compound of the invention therapy. This time period, for example, can permit adequate time for tapering and withdrawal without adverse effects.
  • the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers is discontinued to avoid an adverse drug interaction or to avoid an adverse event; in particular, a treatment-emergent adverse event (TEAE), the contraindicated medicament is preferably discontinued within at least 3 days prior to starting the compound of the invention therapy.
  • TEAE treatment-emergent adverse event
  • the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers is discontinued within at least 4 days, or at least 5 days, or at least 6 days, or at least 7 days (or one week), or at least 8 days, or at least 9 days, or at least 10 days, or at least 11 days, or at least 12 days, or at least 13 days, or at least 14 days (or two weeks), or at least 15 days, or at least 16 days, or at least 17 days, or at least 18 days, or at least 19 days, or at least 20 days, or at least 21 days (or three weeks), or at least 22 days, or at least 23 days, or at least 24 days, or at least 25 days, or at least 26 days, or at least 27 days, or at least 28 days (or four weeks), or at least 29 days
  • the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers is discontinued within at least 2 half-lives, or at least 3 half-lives, or at least 4 half-lives, or at least 5 half-lives, or at least 6 half-lives, or at least 7 half-lives, or at least 8 half-lives, or at least 9 half-lives, or at least 10 half-lives, prior to starting the compound of the invention therapy.
  • the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers is discontinued no earlier than one month, 3 weeks, 2 weeks or 1 week before starting the compound of the invention therapy. Preferably, sufficient time is allowed for tapering and/or withdrawal of the contraindicated medicament.
  • the contraindicated medicament is preferably discontinued within at least 3 days after starting Compound 1 therapy.
  • the patient preferably avoids the use of the medicament or the one or more of compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers to allow sufficient time to avoid adverse drug interactions or adverse events following starting the compound of the invention therapy.
  • the invention provides a method of administering the compound of the invention therapy to a patient in need of thereof and in need of therapy with another medicament that may produce serious side effects or toxicity or may exhibit adverse drug interactions when administered with or alongside CYP3A4 inducers and/or P-gp inducers, comprising administering a therapeutically effective amount of the compound of the invention to the patient, and administering an alternative therapy with a medicament of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
  • the method comprises concomitant use or co-administration of a medicament from the same class or mechanism of action or known to be a suitable alternative medicament for the respective therapy and that are not CYP inducers and/or not P-gp inducers, particularly not CYP3 A4 inducers and/or not P-gp inducers, and more particularly not strong CYP3A4 inducers and/or not strong P- gp inducers.
  • the method comprises discontinuing treatment with the medicament that may produce serious side effects or toxicity or may exhibit adverse drug interactions when administered with or alongside CYP3A4 inducers and/or P-gp inducers and commencing treatment with a medicament from the same class or mechanism of action or known to be a suitable alternative medicament for the respective therapy and the medicament or the one or more compounds that are not CYP inducers and/or P-gp inducers, particularly not CYP3A4 inducers and/or not P-gp inducers, and more particularly not strong CYP3A4 inducers and/or not strong P-gp inducers.
  • the administration of a therapeutically effective amount of the compound of the invention to a patient in need of therapy thereof can be improved.
  • the patient is advised that coadministration of the compound of the invention with a medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, can alter the therapeutic effect or adverse reaction profile of the compound of the invention and/or the respective medicament.
  • the patient if receiving therapy with a medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, is advised that coadministration of the compound of the invention with the respective medicament can alter the therapeutic effect or adverse reaction profile of the compound of the invention and/or the respective medicament and that therapy with the respective medicament should be discontinued prior to commencing the compound of the invention therapy.
  • Injection dose levels range from about 0.01 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h.
  • a preloading bolus may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 1 g/day for a 40 to 80 kg human patient.
  • the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance.
  • one to four (1-4) regular doses daily especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens.
  • dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.
  • each dose provides from about 1 mg to about 1000 mg daily dose of the compound of the invention, with particular doses each providing from about 10 mg to about 600 mg daily dose.
  • the compound of the invention is administered from about 60 mg to 200 mg daily dose.
  • the compound of the invention is administered at about 80 mg, 90 mg, 100 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, or 200 mg daily dose for the treatment and/or prevention of inflammatory diseases, diseases associated with hypersecretion of IFNa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL- 12 and/or IL-23.
  • interferonopathies especially type I interferonopathies
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, provided that concomitant use or co-administration treatment with a medicament or one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, is avoided, contraindicated or discontinued, said other therapeutic agents may demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration.
  • co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
  • the compound of the invention or a pharmaceutical composition comprising the compound of the invention is administered as a medicament.
  • said pharmaceutical composition additionally comprises a further active ingredient, provided said further active ingredient is not selected from one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
  • the compound of the invention is not an isotopic variant.
  • the compound of the invention according to any one of the embodiments herein described is present as the free base.
  • the compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt or cocrystal.
  • the compound of the invention according to any one of the embodiments herein described is a solvate of the compound.
  • the compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt or cocrystal of the compound of the invention.
  • the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.
  • the compound of the invention When employed as a pharmaceutical, the compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, the compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
  • compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • the compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • the compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier.
  • Typical unit dosage forms include prefdled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound of the invention according to Formula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, citric acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, citric acid, Primogel, or com
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington’s Pharmaceutical Sciences.
  • the compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 210-270 mg tablets (70-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.
  • the compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio.
  • the mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).
  • the compound of the invention according to Formula I may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.
  • the compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.
  • the compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of the compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
  • Compound 1 was incubated at 3 concentrations (0.1, 0.5 and 1 pM) at 37 °C with HLM (with NADPH) at 0.5 and 2 mg/mL for up to 45 minutes to determine whether sufficient metabolism was observed to warrant further investigation.
  • Compoundl (0.1 pM) was also incubated with human recombinant CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and NADPH at 37 °C for up to 45 min to identify potential enzymes involved in the metabolism of Compound 1 and to determine conditions for further enzyme kinetics investigations.
  • Compound 1 was incubated with human CYP3A4 recombinant enzyme at 11 substrate concentrations (0.08 - 200 pM) in triplicate at 37 °C with NADPH in order to determine the depletion rate constant at each concentration and thus calculate the Km and Vmax values.
  • Compound 1 showed low metabolism in HLM resulting in an intrinsic clearance up to 8.72 pL/min/mg protein.
  • Compound 1 is an in vitro substrate of the human CYP3A4 isoform.
  • Compound 1 was incubated at 3 concentrations (0.625, 2.00 and 6.25 pM; triplicates) in bidirectional permeability assay (monolayer substrate assay) with Madin-Darby canine kidney multidrug resistance 1 (MDCKII-MDR1) transfected cells for 0, 60 and 120 minutes to determine whether there was active transport (direction apical to basolateral [A-B] and basolateral to apical [B-A]). As an active transport was identified, Compound 1 (2 pM; triplicates) was incubated for 120 minutes with MDCKII-MDR1 cells in the presence of a strong MDR1 inhibitor (10 pM valspodar) to confirm the specificity of the MDR1 transporter.
  • a strong MDR1 inhibitor (10 pM valspodar
  • Compound 1 was incubated with MDCKII-MDR1 cells at 8 concentrations (0.50 - 6.0 pM) in triplicate for 15, 30, 60 and 120 minutes in order to determine the Km and Vmax values to test the unidirectional permeability B-A.
  • Bidirectional transport of Compound 1 was determined by quantification of Compound 1 in the samples using a LC-MS/MS analytical method.
  • Compound 1 is an in vitro substrate of the human MDR1 ABC efflux transporters.
  • the study of the current example is a non-randomized, fixed-sequence, open-label, drug-drug interaction study to evaluate the effect of multiple doses of Itraconazole on the single dose pharmacokinetics of Compound 1 in adult, healthy subjects.
  • the primary objective of this study is to evaluate the effect of Itraconazole on the PK of Compound 1.
  • the secondary objective of this study is to evaluate the safety and tolerability of Compound 1 when administered alone or in combination with Itraconazole and to evaluate the PK of Itraconazole, to confirm relevant exposure for CYP3A4 and P-gp inhibition.
  • the primary outcome measure is C max and AUCo- «> of Compound 1.
  • the secondary outcome measures are:
  • Safety and tolerability of Compound 1 when administered alone or in combination with Itraconazole safety and tolerability, assessed by the incidence and severity of TEAEs, treatment- emergent SAEs, and TEAEs leading to treatment discontinuation;
  • the study is divided in three different periods: a. Screening period: Day-21 to Day -1 b. Open-label study period: Day 1 to Day 11, comprising the periods: i. Open-label study period 1: Day 1 to Day 4 ii. Open-label study period 2: Day 5 to Day 11 c.
  • Subjects receive oral q.d. doses of 200 mg Itraconazole as a solution (10 mg/mL).
  • the study drugs are administered under fasting conditions on Day 1 (Compound 1 alone) and Day 8 (Compound 1 + Itraconazole).
  • Compound 1 is provided as a 25 mg capsule for oral administration.
  • Itraconazole is administered as a 10 mg/mL oral solution (commercially available as Sponarox). Composition of the solution: each milliliter of Sponarox oral solution contains 10 mg of Itraconazole as well as hydroxypropyl-P-cyclodextrin, sorbitol, propylene glycol, hydrochloric acid, flavouring, sodium saccharin, sodium hydroxide and purified water.
  • Subject must be able and willing to comply with restrictions on prior medication: all medication (including OTC and/or prescription medication, dietary supplements, nutraceuticals, vitamins and/or herbal supplements [e.g. St. John’s wort], oral hormonal contraceptives for WOCBP, and hormonal replacement therapy for postmenopausal subjects) except occasional paracetamol (maximum dose 2 g/day and a maximum of 10 g/2 weeks) should be discontinued at least 2 weeks or 5 half-lives of the drug, whichever is longer, prior to the first dose of Compound 1 administration and throughout the study.
  • all medication including OTC and/or prescription medication, dietary supplements, nutraceuticals, vitamins and/or herbal supplements [e.g. St. John’s wort], oral hormonal contraceptives for WOCBP, and hormonal replacement therapy for postmenopausal subjects
  • occasional paracetamol maximum dose 2 g/day and a maximum of 10 g/2 weeks
  • Negative screen for drugs (amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, opiates, methadone, tricyclic antidepressants) and alcohol.
  • Female subjects should be of non-childbearing potential, defined as permanently surgically sterile (bilateral oophorectomy, i.e. surgical removal of ovaries, bilateral salpingectomy or hysterectomy, i.e. surgical removal ofuterus), orwithno menses for 12 ormore months without an alternative medical cause AND a follicle-stimulating hormone (FSH) level in the postmenopausal range.
  • FSH follicle-stimulating hormone
  • Female Subjects o In line with the HMA’s Clinical Trial Facilitation Group recommendation, female subjects are considered of non-childbearing potential if they meet one of the following criteria: o No menses for 12 or more months without an alternative medical cause. A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. o Permanently surgically sterile (bilateral oophorectomy, i.e. surgical removal of ovaries, bilateral salpingectomy or hysterectomy, i.e. surgical removal of uterus). o All other female subjects are considered to be WOCBP and must use one of the following highly effective methods of birth control prior to the first dose of Compound 1, during the clinical study and for at least 35 days after the last dose of Compound 1:
  • Sexual abstinence defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the subject. o A female subject is not allowed to use any of the following contraception methods in this study:
  • Intrauterine hormone-re leasing system ⁇ Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a clinical study, withdrawal, spermicides only, and lactational amenorrhea method. Hormonal contraceptives are not allowed due to the potential interference with the drug-drug interaction evaluation. In case a WOCBP has a vasectomized partner, provided that partner is the sole sexual partner of the WOCBP clinical study participant and that the vasectomized partner has received medical assessment of the surgical success, then she is not required to use an additional form of contraception. Within these limits, the specific forms of contraception employed are left to the discretion of the subject, the investigator, and/or the subject’s physician. The safety of Compound 1 during breastfeeding is unknown. Nursing women are not allowed to take part in this clinical study.
  • Non-vasectomized male subjects with female partners of childbearing potential must be willing to use a condom from the time of the first dose of IP, during the clinical study, and until FU, in addition to having their female partner use one of the following forms of contraception:
  • Progesterone-only hormonal contraception associated with inhibition of ovulation oral, injectable, implantable.
  • Sexual abstinence defined as refraining from heterosexual intercourse is considered a highly effective contraceptive measure only if it is the preferred and usual lifestyle of the subject.
  • the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study.
  • Periodic abstinence e.g. calendar, symptothermal, post-ovulation methods
  • declaration of abstinence for the duration of a clinical study withdrawal, spermicides only, and lactational amenorrhea method are not acceptable methods of contraception.
  • hepatitis B virus surface antigen HBsAg
  • HCV hepatitis C virus
  • Baseline is defined as the last available assessment prior to the first intake of Compound 1.
  • a package or kit comprising the compound of the invention, optionally in a container, and, a package insert, package label, instructions or other labelling including information, recommendation or instruction regarding avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, in general, as described in different aspects and embodiments herein.
  • a package insert, package label, instructions or other labelling may include any one or more of the following information, recommendation, or instruction:
  • Informing or advising the patient that concurrent use of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, should be discontinued, e.g. for at least 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, at least two weeks, at least 3 weeks or at least 4 weeks prior to compound 1 therapy;
  • Informing or advising the patient that concurrent use of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3 A4 inducers and/or strong P-gp inducers, can alter the therapeutic effect of the respective medicament or of the compound of the invention, e.g. decreases the therapeutic effect of Compound 1 or the respective medicament, and/or leads to adverse drug interactions or adverse events, in which case the instruction may further state that therefore concurrent use is contraindicated;
  • CYP inducers and/or P-gp inducers particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers;
  • the CYP3A4 inducer is selected from: Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Dexamethasone, Pioglitazone, Rifabutin, Rifampicin, St. John’s wort, Phenobarbital and Troglitazone.
  • the term refers to Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, and St. John’s wort.
  • the strong CYP3A4 inducer is selected from: Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, and St. John’s wort.
  • the P-gp inducers is selected from: Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Apalutamide, Carbamazepine, Fosphenytoin, Lorlatinib, Phenytoin, Dexamethasone, Rifabutin, Rifampicin and St. John's wort.
  • the strong P-gp inducer is selected from: Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Carbamazepine, Phenytoin, Rifabutin, Rifampicin and St. John's wort.
  • the CYP3A4 inducer and/or P- gp inducer is a combined CYP3A4/P-gp inducer, which is a substance that upon administration to a subject increases CYP3A4 and P-gp mediated activity, and is in particular phenytoin, carbamazepine, rifampicin, dexamethasone and St. John’s wort, especially rifampicin.
  • a method of administering treatment using the compound according to Formula I or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof, to a patient in need of therapy thereof comprising administering the patient a therapeutically effective amount of compound 1, and avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
  • interferonopathies especially type I interferonopathies
  • IL- 12 and/or IL-23 IL- 12 and/or IL-23.
  • the compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has polymyositis.
  • the compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has trisomy 21.
  • cytochrome P450 (CYP) inducer is a CYP3A4 inducer and is one or more medicaments selected from: Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Dexamethasone, Pioglitazone, Rifabutin, Rifampicin, St. John’s wort, Phenobarbital and Troglitazone.
  • the P-gp inducer is one or more medicaments selected from: Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Apalutamide, Carbamazepine, Fosphenytoin, Lorlatinib, Phenytoin, Dexamethasone, Rifabutin, Rifampicin and St. John's wort.
  • a package or kit comprising: i. the compound according to Formula I or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof, and ii. a package insert, package label, instructions or other labelling comprising instructions to avoid or discontinue or contraindication of concomitant use or co-administration of one or more compounds that are CYP inducers.
  • a package or kit according to embodiment 27 further comprising one or more of the features according to embodiments 1 to 26.
  • CYP inducer is a strong CYP3A4 inducer.
  • cytochrome P450 (CYP) inducer is a CYP3A4 inducer and is one or more medicaments selected from Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Dexamethasone, Pioglitazone, Rifabutin, Rifampicin, St.
  • cytochrome P450 (CYP) inducer is a CYP3A4 inducer and is one or more medicaments selected from Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, St. John’s wort, Phenobarbital and Troglitazone.
  • CYP cytochrome P450
  • cytochrome P450 (CYP) inducer is a strong CYP3A4 inducer and is one or more medicaments selected from Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, and St. John’s wort.
  • the P-gp inducer is one or more medicaments selected from Barbiturates,
  • John's wort John's wort.

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Abstract

The present invention relates to improved methods for the use of the compound according to Formula (I) in the treatment of inflammatory diseases, and/or diseases associated with hypersecretion of INFα and/or interferons ("interferonopathies", especially type I interferonopathies), IL-12 and/or IL-23, avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are cytochrome P450 (CYP) inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.

Description

COMPOUND FOR USE IN AND METHODS OF TREATMENT OF INFEAMMATORY
DISEASES
FIELD OF THE INVENTION
[0001] The present invention relates to improved methods for the use of the compound of the invention in the treatment of inflammatory diseases, and/or diseases associated with hypersecretion of IFNa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL- 12 and/or IL-23, by avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are cytochrome P450 (CYP) inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
BACKGROUND OF THE INVENTION
[0002] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to STAT transcription factors. Four JAK family members are described, JAK1, JAK2, JAK3 and TYK2. Upon binding of the cytokine to its receptor, JAK family members auto- and/or transphosphorylate each other, followed by phosphorylation of STATs that then migrate to the nucleus to modulate transcription. JAK-STAT intracellular signal transduction serves the interferons, most interleukins, as well as a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL (Vainchenker, Dusa, and Constantine scu 2008).
[0003] The combination of genetic models and small molecule JAK inhibitor research revealed the therapeutic potential of JAK inhibitors (JAKinibs) (Babon et al. 2014). The last decade has seen the development of JAK inhibitors with various degrees of selectivity profdes versus the JAK family members. In particular, whereas targeting multiple JAK may not be detrimental (Brockman, Giovannetti, and Peters 2011), developing selective JAK inhibitors would be very desirable to develop treatment course tailored to the needs of the patient despite the challenge it represents (Fabian et al. 2005). For example, whereas JAK2 inhibition has proven useful in the treatment of polycythemia and myelofibrosis, undesirable effect associated with JAK2 inhibition were observed (O’Shea and Plenge 2012) thus rendering compounds with JAK2 inhibition components unsuitable for the treatment of non-JAK2 mediated diseases.
[0004] Using TYK2 knock out mice, it has been shown that IL-6, IL-10, IL-11, IL-12, IL-13, IL-19, IL- 20, IL-22, IL-23, IL-27, IL-28, IL-29, IL-31, IL-35 and/or type 1 interferons signaling are dependent on TYK2 (Schwartz et al. 2016). However, it has recently been shown that whereas JAK1 is a key driver in IFNa, IL-6, IL- 10 and IL-22 signaling, TYK2 is involved in type I interferons (including IFNa, INF[3), IL- 23 and IL- 12 signaling (Gillooly, Zhang, and Yang 2016). Since the activity of IL- 12 and IL-23 is particularly increased in patients with auto-immune diseases such as psoriasis and/or inflammatory bowel disorders, selective TYK2 inhibition may be particularly advantageous in the treatment of these diseases while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer et al. 1998). [0005] Furthermore, TYK2 has been reported as a target for multiple autoimmune disorders, providing protection against inflammatory diseases as well as type 2 diabetes with a limited impact on the immune system (Dendrou et al. 2016).
[0006] Compound 1 is a small molecule inhibitor of JAK, a family of tyrosine kinases, more particularly TYK2, and is currently under investigation as a drug for the treatment of inflammatory diseases and/or diseases associated with hypersecretion of IFNa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL- 12 and/or IL-23. The identification and synthesis of Compound 1 have previously been described in WO2019/076716.
[0007] There is an ongoing unmet medical need for the development of new and improved therapies in the treatment of inflammatory diseases and/or diseases associated with hypersecretion of IFNa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL-12 and/or IL-23, in particular diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis and/or Crohn’s disease.
[0008] Cytochrome P450 (CYP) enzymes are essential for the metabolism of many medicines and endogenous compounds (Danielson 2002). The cytochrome P450 3 A family is the most abundant subfamily of the CYP isoforms in the liver. There are at least three isoforms: 3A4, 3A5 and 3A7 in adults, of which 3A4 is considered the most important of all CYP enzymes in the liver (Ince et al. 2013).
[0009] CYP enzymes can be inhibited or induced by drugs, which may result in clinically significant drugdrug interactions that may cause unanticipated adverse reactions or therapeutic failures (Lynch and Price 2007). It is therefore crucial to understand which combinations of drugs should be contraindicated or their co-administration avoided.
[0010] Various cytochrome P450 3A4 (CYP3A4) inhibitors are known (https://www.fda.gov/drugs/drug- interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers) and Itraconazole, given its strong CYP3A inhibition, has emerged as probe to evaluate clinical drug-drug interaction (DDI) studies (Liu et al. 2016).
[0011] In a study by (Hu et al. 2020) it has been shown that 64% from the FDA-approved small molecule drugs (2005-2016) is metabolized by CYP3A4, so therefore it is important to mitigate the CYP3 Ad- mediated victim -drug -drug interactions risk, if warranted by the desired clinical profile of the drug.
[0012] Exposure of a drug may be influenced by the co-administration of a CYP3A4 inhibitor (Teo, Ho, and Chan 2015), leading to under or overdosing of said drug; therefore it is essential to ensure stable dose and exposure to avoid undesirable side effects or toxicity.
[0013] P-glycoprotein (P-gp), also referred to as "Multidrug Resistance Protein (MDR1)" and by its gene name "ABCB1", is a member of a class of transport molecules called "ATP Binding Cassette" transporters or "ABC" transporters, which are located in the cell membrane of various tissues of the human body, such as intestines, kidney, liver and at the blood-brain barrier. P-glycoprotein plays an important role transporting drug substances outside the cell (efflux) influencing their elimination from the body. Along with the CYP enzymes, P-glycoprotein is an important mediator of drug -drug interactions. The pharmacokinetics of a drug may be altered when co-administered with compounds which inhibit or induce P-glycoprotein (Konig, Muller, and Fromm 2013). It is therefore crucial to understand which combinations of drugs should be contraindicated or their co-administration avoided.
[0014] The FDA has recognized and listed various drugs as potential P-gp inducers (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table- substrates-inhibitors-and-inducers).
[0015] In addition, the co-administration of a substance acting as P-gp inhibitor, which can also act as CYP inhibitor, may result in a reduced therapeutic effect due to a doble effect. On one side, a P-gp inhibition-mediated, enhanced the intracellular accumulation of the parent drug; and on another side, a CYP inhibition-mediated, may cause excessive drug accumulation of the parent drug and increased its toxicity, resulting in the need to reduce the dose of the therapeutic agent. Therefore, it is crucial to understand which combinations of drugs should be contraindicated or their co-administration avoided (Wandel et al. 1999).
SUMMARY OF THE INVENTION
[0016] The invention described herein is based upon the observation that the compound of the invention is metabolized by CYP3A4 and/or transported by P-gp, which could result in undesired drug-drug interactions when administered in combination with one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
[0017] Accordingly, in a first aspect the present invention provides the compound of the invention for use in treating a patient in need of the compound of the invention therapy, characterized in that the treating comprises avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
[0018] In a further aspect, the present invention also provides the use of the compound of the invention in the manufacture of a medicament for treating a patient in need of therapy using the compound of the invention, characterized in that the treating comprises avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
[0019] In a another aspect, the present invention provides a method of administering treatment using the compound of the invention to a patient in need of therapy using the compound of the invention comprising administering the patient a therapeutically effective amount of the compound of the invention, and, avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
[0020] In specific embodiments the patient in need of therapy is a patient suffering from inflammatory diseases, and/or diseases associated with hypersecretion of IFNa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL- 12 and/or IL-23. In particular, diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis and/or Crohn’s disease.
[0021] In specific embodiments, the one or more compounds that may produce potentially serious side effects or toxicity or exhibit adverse drug interactions when co-administered with the compound of the invention are CYP inducers and/or P-gp inducers, more particularly CYP3A4 inducers and/or P-gp inducers, even more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
[0022] In one embodiment, the compound of the invention is according to Formula I below:
Figure imgf000005_0001
[0023] The chemical name of the compound of the invention is 4-methyl-5-[3-methyl-7-[(6-morpholin-4- ylpyridazin-3 -yl)amino]imidazo [4,5 -b]pyridin-5 -yl]oxypyridine-2 -carbonitrile (Compound 1 ) .
[0024] Moreover, the compound of the invention useful in the pharmaceutical compositions and treatment methods disclosed herein, is pharmaceutically acceptable as prepared and used.
[0025] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.
[0026] It will be appreciated that the compound of the invention may be metabolized to yield biologically active metabolites.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
[0028] When describing the invention, which may include the compound of the invention, pharmaceutical compositions containing said compound and methods of using said compound and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. [0029] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue.
[0030] ‘ ‘The Compound of the Invention” means the compound of Formula I or Compound 1, which expression includes the pharmaceutically acceptable salts/cocrystals, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts/cocrystals, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts/cocrystals, and solvates, where the context so permits.
[0031] ‘Pharmaceutically acceptable salt/cocrystal’ refers to a salt and/or cocrystal of Compound 1 that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts or cocrystals are non-toxic may be inorganic or organic acid addition salts and base addition salts.
[0032] “Cocrystal” refers to a crystalline material composed of Compound 1 and a cocrystal former ('coformer') in the same crystal lattice. The terms “cocrystal” and “co-crystal” are used interchangeably herein.
[0033] Reference to a certain ‘dose’ or ‘dosage’ of the Compound of the Invention refers to the equivalent weight of free base compound being administered, i.e. not including the weight of any salt, solvate or cocrystal counterpart or component.
[0034] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which the compound of the invention is administered.
[0035] ‘ Solvate’ refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid and the like. The compound of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
[0036] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.
[0037] ‘ Effective amount’ means the amount of the compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “effective amount” can vary depending on the disease and its severity, and the age, weight, etc, of the subject to be treated.
[0038] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
[0039] The term ‘prophylaxis’ is related to ‘prevention’ and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti- malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
[0040] ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.
[0041] As used herein the term ‘inflammatory disease(s)’ refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis), endotoxin-driven disease states (e.g. complications after bypass surgery, acute kidney injury (AKI), Alport syndrome or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints. Particularly the term refers to rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and inflammatory bowel diseases. More particularly the term refers to psoriasis, rheumatoid arthritis and inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease.
[0042] As used herein the term ‘disease(s) associated with hypersecretion of IFNa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL-12 and/or IL-23 includes conditions such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis and/or Crohn’s disease.
[0043] As used herein the term “Adverse Event (AE)” refers to any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An Adverse Event (AE) can therefore be any unfavorable and/or unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs may also include pre- or post-treatment complications that occur as a result of protocol mandated procedures, lack of efficacy, overdose or drug abuse/misuse reports. Pre-existing events that increase in severity or change in nature during or as a consequence of participation in the clinical study will also be considered AEs.
[0044] As used herein the term “Treatment Emergent Adverse Event (TEAE)” refers to any Adverse Event (AE) (or worsening of any Adverse Event (AE)) with an onset date on or after the start date of the respective treatment and no later than 30 days after the last dose of the respective treatment. [0045] As used herein the term “Serious Adverse Event (SAEs)” refers to an Adverse Event (AE) that results in one of the following: death, a life-threatening event (an event in which the subject was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe.), in-subject hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect, or a medically significant event (medical and scientific judgment should be exercised in deciding whether other situations should be considered serious such as important medical events that might not be immediately life-threatening or result in death or hospitalization but might jeopardize the subject or might require intervention to prevent one of the other outcomes listed in the definition above).
[0046] As used herein, the term “avoid” and forms thereof are contemplated to have as alternatives the terms abstain, desist, forbear, and refrain, and forms thereof.
[0047] As used herein, the term “respective medicament” “said medicament” or “contraindicated medicament” refers to the medicament or the one or more compounds that may produce potentially serious side effects or toxicity or exhibit adverse drug interactions when co-administered with the compound of the invention.
[0048] As used herein, the term “avoiding the concomitant use or co-administration of’ comprises or relates to avoidance of the use of the contraindicated medicament by looking into alternatives to the respective medicament in a patient in need of therapy with the respective medicament.
[0049] As used herein, the term “discontinue” and forms thereof, are contemplated to have as alternatives the terms cease, stop, suspend, and quit, and forms thereof.
[0050] As used herein, the term “contraindicating” and forms thereof such as “contraindication” are contemplated to contain the instruction to not enter in the contraindicated activity.
[0051] As used herein, the term “CYP inducers” refers to one or more compounds that decrease the AUC of substrates of a given CYP. CYP inducers may be either weak, moderate or strong inducers. In particular, the term refers to CYP3A4 inducers. Examples of CYP3A4 inducers include Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Dexamethasone, Pioglitazone, Rifabutin, Rifampicin, St. John’s wort, Phenobarbital and Troglitazone. In particular, the term refers to Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, and St. John’s wort.
[0052] As used herein the term “strong CYP3A4 inducers” refers to one or more compounds that decrease the AUC of oral Midazolam or other specific 3A4 substrate by >5-fold or results in a >80% increase in its clearance. Examples of strong CYP3A4 inducers include Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, and St. John’s wort (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table- substrates-inhibitors-and-inducers).
[0053] As used herein, the term “P-gp inducers” refers to one or more compounds that decrease the AUC of substrates of P-gp. Examples of substrates of p-gp include Dabigatran etexilate, digoxin, fexofenadine, Midazolam and Prazosin. In addition, examples of P-pg inducers include Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Apalutamide, Carbamazepine, Fosphenytoin, Lorlatinib, Phenytoin, Dexamethasone, Rifabutin, Rifampicin and St. John's Wort (https://www.fda.gov/drugs/drug- interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers). [0054] The term “strong P-gp inducer” refers to one or more compounds that decrease the AUC of oral P- gp substrate by >5-fold, for example Midazolam and Prazosin. In addition, examples of strong P-gp inducers include Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Carbamazepine, Phenytoin, Rifabutin, Rifampicin and St. John's Wort (https://www.fda.gov/drugs/drug-interactions- labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers).
[0055] A combined CYP3A4/P-gp inducer is a substance that upon administration to a subject increases CYP3A4 and P-gp mediated activity. Examples of combined CYP3A4/P-gp inducers include phenytoin, carbamazepine, rifampicin, dexamethasone and St. John’s wort.
[0056] As used herein the term “rendered therapeutically ineffective” refers to a loss of efficacy of a medicament in a given patient or patient population by virtue of reduced exposure.
[0057] Coadministration of medicaments that are known to be substrates of CYP3A4 and/or P-gp and/or known to be metabolized by cytochrome P450 3A4 (CYP3A4) with substances that are inducers, in particular moderate or strong inducers, of CYP3A4 and/or P-g can be problematic as they can produces serious side effects or toxicity or exhibit adverse drug interactions or the patient’s exposure to said medicament can be reduced to point that the medicament is rendered therapeutically ineffective.
[0058] When ranges are referred to herein, for example but without limitation, Ci-s alkyl, the citation of a range should be considered a representation of each member of said range.
[0059] The present disclosure includes all isotopic forms of the compound of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
[0060] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (nC), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36C1), chlorine-37 (37C1), fluorine-18 (18F) iodine-123 (123I), iodine-125 (125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
[0061] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e. 2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as nC, 18F, 150 and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
[0062] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.
[0063] ‘ Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 7i electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
[0064] It will be appreciated that the compound of the invention may be metabolized to yield biologically active metabolites.
SYNTHETIC PREPARATION OF THE COMPOUND OF THE INVENTION
[0065] The methods for the preparation of Compound 1 have been described in WO2019/076716 (the Compound of the Invention is referred to as “compound 38” in WO2019/076716) and a summary is provided below.
General synthetic methods
[0066] The compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[0067] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (“Greene’s Protective Groups in Organic Synthesis, 4th Edition | Wiley” 2006)
[0068] The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
[0069] All reagents were of commercial grade and were used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Column chromatography is performed on silica gel 60 (35-70 pm). Thin layer chromatography is carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). ’H NMR spectra were recorded on a Bruker Advance 300 NMR spectrometer (300 MHz). Chemical shifts (5) for 'H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (5 0.00) or the appropriate residual solvent peak, i.e. CHCls (5 7.27), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), quintuplet (quin), multiplet (m) and broad (br). Electrospray MS spectra were obtained on a Waters platform LC/MS spectrometer or with Waters Acquity H-Class UPLC coupled to a Waters Mass detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 pm, 2.1 mm ID x 50 mm L, Waters Acquity UPLC BEH C18 1.7 pm, 2.1 mm ID x 30 mm L, or Waters Xterra MS 5pm C18, 100 x 4.6 mm. The methods are using either MeCN/H2O gradients (H2O contains either 0.1% TFA or 0.1% NH3) or MeOH /H2O gradients (H2O contains 0.05% TFA). Microwave heating is performed with a Biotage Initiator.
Table A. List of abbreviations used in the chemical synthesis experimental section:
Figure imgf000011_0001
Figure imgf000012_0002
Example 1. Synthesis of intermediates
1.1. Intermediate 1: 7-Chloro-5-iodo-3-methyl-3H-imidazo[4,5-b]pyridine
Figure imgf000012_0001
1.1.1. Step 1: 2,4-Dichloro-6-iodo-pyridin-3-ylamine:
[0070] To a solution of 2, 4-dichloro-3 -aminopyridine (250 g, 1.54 mmol, 1 eq.) in dry MeCN (1.2 L) under N2 atmosphere at room temperature was added NIS (382 g, 1.70 mmol, 1.1 eq.) and TFA (35.45 mL, 0.46 mmol, 0.3 eq.). The mixture was stirred at 40 °C for 18 hours in 3 L round-bottom flask. Reaction mixture was then quenched with saturated Na2S20s (500 mL) and NaHCCL (700 mL). Organic layer was washed with saturated NaHCCL and aqueous layers were washed twice with EtOAc (2 x 700 mL). Combined organic layers were dried over MgSO4, fdtered and concentrated to dryness to obtain crude product. It was purified by column chromatography using cyclohexane and EtOAc (10 %) to give the desired product LCMS: m/z = 289 [M+H],
1.1.2. Step 2: 4-Chloro-6-iodo-N2-methyl-pyridine-2,3-diamine
[0071] 2,4 -dichloro-6-iodo-pyridin-3-amine (20 g, 0.07 mmol, 1 eq.) was dissolved in n-butanol (300 mL) at autoclave (600 mL). Methylamine (33 % in EtOH, 28.72 mL, 0.28 mmol, 4 eq.) was added under N2 at room temperature. The mixture was stirred at 180 °C for 18 hours and then cooled to room temperature. This step was repeated twice and, in the end, all the reaction mixtures were combined and concentrated to give 60 g of title compound that was used in next step as such. LCMS: m/z = 284 [M+H],
1.1.3. Step 3: 7-Chloro-5-iodo-3-methyl-3H-imidazo[4,5-b]pyridine
[0072] To a solution of 4-chloro-6-iodo-N-2-methyl-pyridine-2,3-diamine (60 g, 021 mmol, 1.0 eq.) in formic acid (30 mL) was added trimethyl orthoformate (69.5 mL, 0.64 mmol, 3.0 eq.). The mixture was stirred at 60 °C for 1 hour. Reaction was concentrated to dryness after which the residue was diluted with DCM and quenched with saturated aqueous NaHCOs solution. After extraction with DCM, organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford crude material. It was purified by column chromatography using eluent cyclohexane/EtOAc from 10 to 60 % of EtOAc to give the desired product. LCMS: m/z = 294 [M+H], 1H NMR (300 MHz, DMSO-de) 5 ppm: 8.46 (s, 1H), 7.83 (s, 1H), 3.81 (s, 3H).
1 .2. Intermediate 2: 5-(7-Chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridine-2- carbonitrile
Figure imgf000013_0001
[0073] Intermediate 1 (68.51 g, 233.83 mmol, 1.0 eq), 5-Hydroxy-4-methyl-2 -pyridinecarbonitrile (CAS# 1256792-51-4, 47.00 g, 350.75 mmol, 1.5 eq.), Cui (8.89 g, 46.77 mmol, 0.2 eq.), TMHD (97.45 mL, 467.66 mmol, 2.0 eq.) and CS2CO3 (152 g, 467.66 mmol, 2.0 eq.) were mixed together under air, DML (234 mL) was added, and the mixture was stirred at 85 °C for 2 nights. If full conversion was not reached, additional Cui (0. 1 eq.) and TMHD (1.0 eq.) were added after which the mixture was stirred further at 85 °C for another night. Next, the mixture was cooled to 0 °C. The resulting thick paste was then filtered, and the cake was washed with ice cooled DML (2 x 20 mL). It was then washed with ice cooled MTBE (3 x 150 mL). After drying the cake, it was suspended in 500 mL of 10 % aqueous TMEDA solution. It was stirred for 2 hours, filtered and the cake was washed with H2O to afford the desired product. LCMS: m/z = 300 [M+H]+.
1.3. Intermediate 3: 5-(7-Amino-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridine-2- carbonitrile
Figure imgf000013_0002
[0074] To a mixture of Intermediate 2 (5.0 g, 16.72 mmol, 1.0 eq.), benzophenone imine (CAS# 1013-88- 3), 2.81 mL, 16.72 mmol, 1.0 eq.), Pd2CL2(allyl)2 (122 mg, 0.33 mmol, 0.02 eq.), XantPhos (387 mg, 0.67 mmol, 0.04 eq.) and CS2CO3 (6.54 g, 20.07 mmol, 1.2 eq.) under N2 atmosphere, 1,4-dioxane (100 mL) was added and the mixture was stirred at 110 °C for 24 hours. After letting it cool down till room temperature, the mixture was diluted with EtOAc and fdtered over celite. The cake was washed with EtOAc (100 mL) and the fdtrate was poured in 2 N aqueous HC1 solution (200 mL), stirring it for 10 min. After extraction with EtOAc, the aqueous phase was neutralized to pH = 7 using NaHCOs. This was followed by an extraction with EtOAc (5 x 100 mL) after which the combined organic layers were dried over MgSO4, filtered and concentrated to dryness to afford the crude material which was triturated with DCM to afford the desired product. LCMS: m/z = 281 [M+H]+.
1.4. Alternative synthesis of Intermediate 3: 5-(7-Amino-3-methyl-3H-imidazo[4,5-b]pyridin-5- yloxy)-4-methyl-pyridin e-2-carbon itrile
Figure imgf000014_0001
1.4.1. Step 1:
[0075] 2,6 -Dichloro-4-amino-5-nitropyridine (520 g, 2.5 mol, 1.0 eq.), was added to acetonitrile (5.2 L) at room temperature. To the mixture were added, under stirring at room temperature, BOC2O (710 g, 3.25 mol, 1.3 eq.) and K3PO4 (1000 g, 4.71 mol, 1.9 eq.). The reaction mixture was heated at reflux for 1-2 hours. Then a solution of BOC2O (110 g, 0.5 mol, 0.2 eq.) in acetonitrile (100 mL) was added and the reaction mixture was heated at reflux for one additional hour. The reaction mixture was cooled down to room temperature and filtered on a pad Na2SC>4. The Na2SC>4 was washed with acetonitrile (2 L). The filtrate was evaporated under reduced pressure and redissolved in DCM (5 L). The DCM layer was washed with water. The organic layer was extracted with DCM (5 L) and the combined organic layers were dried over Na2SC>4, filtered and evaporated to afford the desired product. LCMS: m/z = 306/308 [M+H],
1.4.2. Step 2:
[0076] 2,6 -Dichloro-4 Boc-amino-5-nitropyridine (770 g, 2.5 mol, 1.0 eq.) was added to isopropanol (11 L) at room temperature. To the mixture were added, under stirring at room temperature, methylamine 33 % in EtOH (800 mL, 3.0 eq.) over 1 hour and 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and 30 minutes. The suspension was fdtered, washed with isopropanol (1 L) then water (4 L). Following drying the desired product was obtained. LCMS: m/z = 302.9/304.8 [M+H],
1.4.3. Step 3:
[0077] Tert-butyl N-[6-chloro-2-(methylamino)-3-nitro-4-pyridyl]carbamate (788 g, 2.6 mol, 1.0 eq.), was added to acetonitrile (5.5 L) at room temperature. To the mixture were added, under stirring at room temperature, 5-hydroxy-4-methyl-pyridine-2-carbonitrile (384 g, 2.86 mol 1.1 eq.) and Na2CO3 (414 g, 3.9 mol, 1.5 eq.). The reaction mixture was heated at reflux for 48 hours. The reaction mixture was cooled down to room temperature and the insoluble were filtered and washed with acetonitrile (2 L). The combined organic layers were evaporated. The crude was washed with water (5 L), collected and dried to afford the desired product. LCMS: m/z = 401.1 [M+H]; m/z = 399.2 [M-H], 'HNMR (400 MHz, DMSO- 6) 5 10.70 (s, 1H), 9.05 (q, 1H), 8.62 (s, 1H), 8.13 (s, 1H), 7.23 (s, 1H), 2.59 (d, 3H), 2.24 (s, 3H), 1.50 (s, 9H).
1.4.4. Step 4:
[0078] Tert-butyl N-[6-[(6-cyano-4-methyl-3-pyridyl)oxy]-2-(methylamino)-3-nitro-4-pyridyl]carbamate (150 g, 375mmol, 1.0 eq.) was added to a mixture of acetic acid (750 mL, 35 eq.) and trimethyl orthoformate (750 mb, 18 eq.) at room temperature. To the mixture were added by portions, under vigorous stirring at 20-21°C, Zn dust < 10pm (total of 120g, 4.9 eq. added by portions of 15 g). Each addition was performed after the reaction mixture had cooled down to 20 - 21 °C. The reaction mixture was stirred during one hour after the last addition. The suspension was filtered on Dicalite 4158 (Carlo Erba, ref P8880014), washed with THF (IL) and the combined organic layers were concentrated. The residue was slowly poured into a cold mixture of 20% ammoniac solution (100 mb) and water (2 L). The resulting solid was filtered, washed with water (2 L) and dried to afford the desired product. LCMS: m/z = 381.0 [M+H] ; m/z = 379.2 [M-H], ’H NMR (400 MHz, DMSO- 6) 5 9.32 (bs, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.54 (s, 1H), 3.60 (s, 3H), 2.27 (s, 3H), 1.49 (s, 9H).
1.4.5. Step 5:
[0079] Tert-butyl N-[6-[(6-cyano-4-methyl-3-pyridyl)oxy]-2-(methylamino)-3-nitro-4-pyridyl]carbamate (197 g, 0.518 mol, 1.0 eq.) was suspended in a mixture of Hydrochloric acid, 4N solution in water (1 L) and THF (I L). The reaction mixture was heated at 60 °C for 5 hours. The reaction mixture was cooled down to room temperature and the solid was filtered, washed with THF (I L) and dried to afford the desired product as hydrochloric salt. LCMS: m/z = 281.4 [M+H], ’H NMR (400MHz, DMSO-de) 5 ppm: 9.28 (s, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 7.57 (bs, 2-3H), 6.33 (s, 1H), 3.67 (s, 3H), 2.25 (s, 3H).
Example 2. Synthesis of Compound 1
2.1. Compound 1: 4-Methyl-5-[3-methyl-7-(6-morpholin-4-yl-pyridazin-3-ylamino)-3H-imidazo[4,5- b]pyridin-5-yloxy]-pyridine-2-carbonitrile
Figure imgf000016_0001
2.2. Route 1
[0080] Intermediate 3 (1.0 eq., 409 g, 1.459 moles) and 4-(6-bromopyridazin-3-yl)morpholine (CAS# 66346-91-6, 1.1 eq., 392 g) were added to xylene mix of isomers (8 L) at room temperature. To the mixture was added, under stirring at room temperature, potassium phosphate tribasic (3.0 eq, 929 g). The reaction mixture was heated from room temperature to 135 °C in 2 hours and 30 minutes. Then a suspension of Pd(OAc)2 (2 mol%, 6.6 g) and Xantphos (4 mol%, 33.8 g) in xylene (50 mL) was added to the hot mixture. The reaction was heated at reflux for 1 hour and 30 minutes. Then a suspension of Pd(OAc)2 (2 mol%, 6.6 g) and Xantphos (4 mol%, 33.8 g) in xylenes (50 mL) was added and the reaction was heated at reflux for an additional 1 hour and 30 minutes. Then a suspension of Pd(OAc)2 (2 mol%, 6.6 g) and Xantphos (4 mol%, 33.8 g) in xylenes (50 mL) was added one last time. The reaction was refluxed for an additional lh30. The reaction mixture was cooled down to room temperature and stirred overnight. The suspension was fdtered, washed with acetonitrile (5 L). The solid was washed with water (15 L) until obtaining a neutral pH, dried under suction, then suspended in acetonitrile (6.5 L) and stirred at room temperature for 1 hour. The suspension was fdtered, washed with acetonitrile (2 L) and dried. Chromatography on SiCL (1 g of SiC>2 for 1 g of crude) using eluent CHCL/acetone (70/30) and then CHCL/MeOH (96/4) afforded the desired product (Compound 1).
2.3. Route 2
[0081] Intermediate 3 (280 mg, 1 mmol, 1.0 eq.), 4-(6-bromopyridazin-3-yl)morpholine (268 mg, 1.1 mmol, 1.1 eq.) and CsCOs (977 mg, 3 mmol, 3 eq.) are mixed under argon at room temperature and degassed tert-amyl alcohol or DMF (5 mL) is added. [Pd(cinnamyl)Cl]2 (5.18 mg, 0.010 mmol, 0.01 eq.) and JosiPhos (CAS# 1702311-34-9, 13 mg, 0.024 mmol, 0.024 eq.) are added under argon either as solid or as pre-mixed solution in 1 mL degassed tert-amyl alcohol or DMF. The mixture is heated to 100°C for at least 2 hours.
[0082] The reaction mixture is then cooled to room temperature and acetonitrile is added. The suspension is fdtered, the solid is triturated first with water then acetonitrile, and dried to afford the desired product (Compound 1). METHODS OF TREATMENT
[0083] In one embodiment, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention, for use in the treatment of a patient in need of therapy using the compound of the invention, characterized in that the treating comprises avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/ or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers. In a particular embodiment, the patient in need of therapy is suffering from one or more inflammatory diseases, and/or diseases associated with hypersecretion of INFa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL- 12 and/or IL-23. In a more particular embodiment, the disease is systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis or Crohn’s disease.
[0084] In another embodiment, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for use in the treatment of a patient in need of therapy using the compound of the invention, characterized in that the treatment comprises avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P- gp inducers. In a more particular embodiment, the patient in need of therapy is suffering from one or more inflammatory diseases, and/or diseases associated with hypersecretion of INFa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL-12 and/or IL-23. In a more particular embodiment, the disease is systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis or Crohn’s disease.
[0085] In additional method of treatment aspects, this invention provides methods of treatment of a patient in need of therapy thereof, which methods comprise the administration of an effective amount of the compound of the invention or one or more of the pharmaceutical compositions herein described wherein the treatment additionally comprises avoiding, contraindicating or discontinuing concomitant use or co- administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P- gp inducers. In a particular embodiment, the patient in need of therapy is suffering from one or more inflammatory diseases, and/or diseases associated with hypersecretion of INFa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL-12 and/or IL-23. In more a particular embodiment, the disease is systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis or Crohn’s disease. [0086] In one embodiment, the invention provides a method of administering the compound of the invention to a patient in need of therapy thereof, comprising administering to the patient a therapeutically effective amount of the compound of the invention, and avoiding (concomitant) use or (co-)administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
[0087] In another embodiment, the invention provides a method of administering the compound of the invention to a patient in need of therapy thereof, comprising discontinuing administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, and then administering a therapeutically effective amount of the compound of the invention.
[0088] In one embodiment, the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, is discontinued concurrently with starting administration of the compound of the invention.
[0089] In another embodiment, the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, is discontinued at least 12 hours to 1 week prior to or after starting the compound of the invention therapy. This time period, for example, can permit adequate time for tapering and withdrawal without adverse effects.
[0090] In another embodiment, the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, is discontinued to avoid an adverse drug interaction or to avoid an adverse event; in particular, a treatment-emergent adverse event (TEAE), the contraindicated medicament is preferably discontinued within at least 3 days prior to starting the compound of the invention therapy.
[0091] In various embodiments, the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, is discontinued within at least 4 days, or at least 5 days, or at least 6 days, or at least 7 days (or one week), or at least 8 days, or at least 9 days, or at least 10 days, or at least 11 days, or at least 12 days, or at least 13 days, or at least 14 days (or two weeks), or at least 15 days, or at least 16 days, or at least 17 days, or at least 18 days, or at least 19 days, or at least 20 days, or at least 21 days (or three weeks), or at least 22 days, or at least 23 days, or at least 24 days, or at least 25 days, or at least 26 days, or at least 27 days, or at least 28 days (or four weeks), or at least 29 days, or at least 30 days, or at least one month, prior to starting the compound of the invention therapy.
[0092] In another various embodiments, the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, is discontinued within at least 2 half-lives, or at least 3 half-lives, or at least 4 half-lives, or at least 5 half-lives, or at least 6 half-lives, or at least 7 half-lives, or at least 8 half-lives, or at least 9 half-lives, or at least 10 half-lives, prior to starting the compound of the invention therapy.
[0093] In one embodiment, the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, is discontinued no earlier than one month, 3 weeks, 2 weeks or 1 week before starting the compound of the invention therapy. Preferably, sufficient time is allowed for tapering and/or withdrawal of the contraindicated medicament.
[0094] In embodiments where the medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, cannot be or is not discontinued prior to the compound of the invention therapy, the contraindicated medicament is preferably discontinued within at least 3 days after starting Compound 1 therapy.
[0095] The patient preferably avoids the use of the medicament or the one or more of compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers to allow sufficient time to avoid adverse drug interactions or adverse events following starting the compound of the invention therapy.
[0096] In some aspects, the invention provides a method of administering the compound of the invention therapy to a patient in need of thereof and in need of therapy with another medicament that may produce serious side effects or toxicity or may exhibit adverse drug interactions when administered with or alongside CYP3A4 inducers and/or P-gp inducers, comprising administering a therapeutically effective amount of the compound of the invention to the patient, and administering an alternative therapy with a medicament of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers. In one embodiment according to these aspects, the method comprises concomitant use or co-administration of a medicament from the same class or mechanism of action or known to be a suitable alternative medicament for the respective therapy and that are not CYP inducers and/or not P-gp inducers, particularly not CYP3 A4 inducers and/or not P-gp inducers, and more particularly not strong CYP3A4 inducers and/or not strong P- gp inducers. In another embodiment according to these aspects, the method comprises discontinuing treatment with the medicament that may produce serious side effects or toxicity or may exhibit adverse drug interactions when administered with or alongside CYP3A4 inducers and/or P-gp inducers and commencing treatment with a medicament from the same class or mechanism of action or known to be a suitable alternative medicament for the respective therapy and the medicament or the one or more compounds that are not CYP inducers and/or P-gp inducers, particularly not CYP3A4 inducers and/or not P-gp inducers, and more particularly not strong CYP3A4 inducers and/or not strong P-gp inducers.
[0097] The administration of a therapeutically effective amount of the compound of the invention to a patient in need of therapy thereof can be improved. In some embodiments, the patient is advised that coadministration of the compound of the invention with a medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, can alter the therapeutic effect or adverse reaction profile of the compound of the invention and/or the respective medicament.
[0098] In some embodiments, the patient, if receiving therapy with a medicament or the one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, is advised that coadministration of the compound of the invention with the respective medicament can alter the therapeutic effect or adverse reaction profile of the compound of the invention and/or the respective medicament and that therapy with the respective medicament should be discontinued prior to commencing the compound of the invention therapy.
[0099] Injection dose levels range from about 0.01 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 1 g/day for a 40 to 80 kg human patient.
[0100] For the prophylaxis and/or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four (1-4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens. Alternatively, for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.
[0101] Using these dosing patterns, each dose provides from about 1 mg to about 1000 mg daily dose of the compound of the invention, with particular doses each providing from about 10 mg to about 600 mg daily dose. In a particular embodiment, the compound of the invention is administered from about 60 mg to 200 mg daily dose. In a more particular embodiment, the compound of the invention is administered at about 80 mg, 90 mg, 100 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, or 200 mg daily dose for the treatment and/or prevention of inflammatory diseases, diseases associated with hypersecretion of IFNa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL- 12 and/or IL-23.
[0102] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
[0103] According to the methods of the present invention, the compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, provided that concomitant use or co-administration treatment with a medicament or one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, is avoided, contraindicated or discontinued, said other therapeutic agents may demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
[0104] In one embodiment, the compound of the invention or a pharmaceutical composition comprising the compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient, provided said further active ingredient is not selected from one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
[0105] In one embodiment the compound of the invention is not an isotopic variant.
[0106] In one aspect the compound of the invention according to any one of the embodiments herein described is present as the free base.
[0107] In one aspect the compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt or cocrystal.
[0108] In one aspect the compound of the invention according to any one of the embodiments herein described is a solvate of the compound.
[0109] In one aspect the compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt or cocrystal of the compound of the invention. [0110] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.
PHARMACEUTICAL COMPOSITIONS
[oni] When employed as a pharmaceutical, the compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, the compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
[0112] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration. [0113] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term ‘unit dosage forms’ refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefdled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound of the invention according to Formula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
[0114] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, citric acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.
[0115] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
[0116] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
[0117] The compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
[0118] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
[0119] The compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.
[0120] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions. Formulation 1 - Tablets
[0121] The compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 210-270 mg tablets (70-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.
Formulation 2 - Capsules
[0122] The compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).
Formulation 3 - Liquid
[0123] The compound of the invention according to Formula I (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.
Formulation 4 - Tablets
[0124] The compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.
Formulation 5 - Injection
[0125] The compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
Formulation 6 - Topical
[0126] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of the compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
BIOLOGICAL EXAMPLES
[0127] The methods for the preparation of the compound of the invention and certain biological examples have been described in WO2019/076716.
CLINICAL EXAMPLES
Table I. List of abbreviations as used herein above and below:
Figure imgf000024_0001
Figure imgf000025_0001
Example 3. In vitro stability study of Compound 1 in human liver microsomes
3.1. Study objective
[0128] The objective of this in vitro study was to determine the stability of Compound 1 in human liver microsomes (HLM) and in human recombinant cytochrome P450 (CYP) enzymes. Following identification of CYP3A4 as the only CYP metabolising enzyme, the kinetic parameters Km (concentration of substrate at which half maximal rate of reaction is reached) and Vmax (maximum rate of reaction) parameters were determined using recombinant enzymes. 3.2. Materials and methods
[0129] Compound 1 was incubated at 3 concentrations (0.1, 0.5 and 1 pM) at 37 °C with HLM (with NADPH) at 0.5 and 2 mg/mL for up to 45 minutes to determine whether sufficient metabolism was observed to warrant further investigation.
[0130] Compoundl (0.1 pM) was also incubated with human recombinant CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and NADPH at 37 °C for up to 45 min to identify potential enzymes involved in the metabolism of Compound 1 and to determine conditions for further enzyme kinetics investigations. [0131] Subsequently, Compound 1 was incubated with human CYP3A4 recombinant enzyme at 11 substrate concentrations (0.08 - 200 pM) in triplicate at 37 °C with NADPH in order to determine the depletion rate constant at each concentration and thus calculate the Km and Vmax values.
[0132] The stability of Compound 1 was assessed by the quantification of the concentration of Compound 1 in the samples using LC-MS/MS analytical method.
3.3. Results of the study
[0133] Compound 1 showed low metabolism in HLM resulting in an intrinsic clearance up to 8.72 pL/min/mg protein.
[0134] No measurable metabolism of Compound 1 was observed following incubation with recombinant CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6. Metabolism of Compound 1 was observed following incubation with CYP3A4.
[0135] In the presence of CYP3A4 recombinant enzymes using the substrate depletion approach, the Km for Compound 1 was 4.19±0.414 pM and the calculated Vmax was 1.78 pmol/min/pmol P450 (577 pmol/min/mg microsomal protein).
[0136] In conclusion, Compound 1 is an in vitro substrate of the human CYP3A4 isoform.
Example 4. In vitro stability study of Compound 1 as P-gp substrate
4.1. Study objective
[0137] The objective of these in vitro studies was to inform whether Compound 1 was a potential substrate of the human ABC (efflux) transporter MDR1 (P-gp) and then to determine the kinetic parameters Km and Vmax parameters of Compound 1 with human MDR1 transporter.
4.2. Materials and methods
[0138] Compound 1 was incubated at 3 concentrations (0.625, 2.00 and 6.25 pM; triplicates) in bidirectional permeability assay (monolayer substrate assay) with Madin-Darby canine kidney multidrug resistance 1 (MDCKII-MDR1) transfected cells for 0, 60 and 120 minutes to determine whether there was active transport (direction apical to basolateral [A-B] and basolateral to apical [B-A]). As an active transport was identified, Compound 1 (2 pM; triplicates) was incubated for 120 minutes with MDCKII-MDR1 cells in the presence of a strong MDR1 inhibitor (10 pM valspodar) to confirm the specificity of the MDR1 transporter. [0139] Subsequently, Compound 1 was incubated with MDCKII-MDR1 cells at 8 concentrations (0.50 - 6.0 pM) in triplicate for 15, 30, 60 and 120 minutes in order to determine the Km and Vmax values to test the unidirectional permeability B-A.
[0140] Bidirectional transport of Compound 1 was determined by quantification of Compound 1 in the samples using a LC-MS/MS analytical method.
4.3. Results of the study
[0141] Compound 1 showed higher permeability in the B-A direction than in the A-B direction, indicating that there was active transport of this compound in the MDCKII-MDR1 cells. Considering the best recovery values (>60%) of Compound 1 at 6.25 pM, the observed net efflux ratio (net ER) was 34.6 after 60 minutes incubation. In the follow-up assay, the net ER decreased from 37.1 to 0.5 in the presence of valspodar, confirming the contribution of MDR1 to the transport of Compound 1 across MDCKII-MDR1 monolayers. [0142] In the unidirectional permeability B-A, the net ER was consistent with the previous results. The kinetic parameters Km was 15.06 pM and Vmax was 8.79 pmol/min.
[0143] In conclusion, Compound 1 is an in vitro substrate of the human MDR1 ABC efflux transporters.
Example 5. Drug-Drug interaction clinical study
5.1. Title of study
[0144] The study of the current example is a non-randomized, fixed-sequence, open-label, drug-drug interaction study to evaluate the effect of multiple doses of Itraconazole on the single dose pharmacokinetics of Compound 1 in adult, healthy subjects.
5.2. Study objective
[0145] The primary objective of this study is to evaluate the effect of Itraconazole on the PK of Compound 1.
[0146] The secondary objective of this study is to evaluate the safety and tolerability of Compound 1 when administered alone or in combination with Itraconazole and to evaluate the PK of Itraconazole, to confirm relevant exposure for CYP3A4 and P-gp inhibition.
5.3. Study endpoints
[0147] The primary outcome measure is Cmax and AUCo-«> of Compound 1.
[0148] The secondary outcome measures are:
• Safety and tolerability of Compound 1 when administered alone or in combination with Itraconazole: safety and tolerability, assessed by the incidence and severity of TEAEs, treatment- emergent SAEs, and TEAEs leading to treatment discontinuation;
• Effect of PK parameters of Itraconazole, to confirm relevant exposure for CYP3 A4 and P-gp: Cmax ss, AUC\. and CT of Itraconazole. 5.4. Study Design
[0149] This is an open-label, single fixed-sequence study comprising one cohort of 14 healthy male and female adult subjects to assess the impact of Itraconazole, a strong CYP3A4 inhibitor and strong P-gp inhibitor on the PK of Compound 1.
[0150] The study is divided in three different periods: a. Screening period: Day-21 to Day -1 b. Open-label study period: Day 1 to Day 11, comprising the periods: i. Open-label study period 1: Day 1 to Day 4 ii. Open-label study period 2: Day 5 to Day 11 c. Follow-up Period: 14 (± 3) days after last administration of Compound 1 or Itraconazole
5.4.1. Study Design - Open-label study period 1: Day 1 to Day 4
[0151] On Day 1 subjects receive a single oral dose of 25 mg of Compound 1, follow by a 72-hour PK blood sampling period.
5.4.2. Study Design - Open-label study period 2: Day 5 to Day 11
[0152] Subjects receive oral q.d. doses of 200 mg Itraconazole as a solution (10 mg/mL).
[0153] On Day 8 subjects receive a single oral dose of 25 mg of Compound 1, co-administered with Itraconazole, follow by a 96-hour PK blood sampling period.
[0154] The study drugs are administered under fasting conditions on Day 1 (Compound 1 alone) and Day 8 (Compound 1 + Itraconazole).
[0155] Subjects discharge from the clinical center on Day 11 , on the condition that all required assessments are performed. Each subject is in the study for approximately 7 weeks (screening visit to follow-up visit). A follow-up visit is conducted 14 ± 3 days after the last study drug administration.
5.4.3. Formulation Compound 1
[0156] Compound 1 is provided as a 25 mg capsule for oral administration.
5.4.4. Formulation Itraconazole
[0157] Itraconazole is administered as a 10 mg/mL oral solution (commercially available as Sponarox). Composition of the solution: each milliliter of Sponarox oral solution contains 10 mg of Itraconazole as well as hydroxypropyl-P-cyclodextrin, sorbitol, propylene glycol, hydrochloric acid, flavouring, sodium saccharin, sodium hydroxide and purified water.
5.4.5. Dosage administration - Open-label study period 1: Day 1 to Day 4
[0158] Subjects are instructed to not chew Compound 1 prior to swallowing, and to swallow the study drug as a whole.
[0159] On Day 1, subjects receive a single oral dose of 25 mg of Compound 1 together with 240 m of water in the morning, after an overnight fast of at least 10 hours and remain fast up to 4 hours postdose. [0160] On Day 1 to 4, fluid intake (including water) is prohibited from 1 hour prior to dose administration, except for water intake at dosing. Fluid intake is allowed ad libitum from 1 hour after dosing. No fluid restrictions apply on all other days. Subjects are encouraged to drink at least 1 liter of fluid per day throughout the study.
5.4.6. Dosage administration - Open-label study period 2: Day 5 to Day 11
[0161] Subjects is instructed to not chew Compound 1 prior to swallowing, and to swallow the study drug as a whole.
[0162] On Day 5 through Day 11 subjects receive doses of 200 mg q.d. of Itraconazole as an oral solution (10 mg/mL).
[0163] On Day 8, fluid intake (including water) is prohibited from 1 hour prior to dose administration. Then, a single oral dose of 25 mg Compound 1 is co-administered with Itraconazole in the morning, after an overnight fast of at least 10 hours and subjects remain fast up to 4 hours postdose.
[0164] On Days 5 to 7 and 9 to 10, a snack is served 30 minutes prior to Itraconazole dosing and breakfast is served 1 hour after Itraconazole intake.
[0165] All dose administrations are carried out by the investigator or by a member of the clinical center designated by the investigator.
[0166] On dosing days with Compound 1 (Days 1 and 8), fluid intake is prohibited from 1 hour prior to dose administration until 1 hour after dose administration, except for 240 mb water intake with dose administration. Fluid intake is allowed ad libitum from 1 hour after dosing. Subjects are advised to maintain a fluid intake of at least 1 liter per 24 hours. Fluid intake restrictions do not apply to other days.
5.5. Inclusion criteria
[0167] To be eligible, the subjects must meet all of the following inclusion criteria:
• Male or female subject between 18-55 years of age (extremes included), on the date of signing the ICF.
• BMI between 18-30 kg/m2, extremes included.
• Judged to be in good health by the investigator based upon the results of a medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and fasting clinical laboratory safety tests. Neutrophil, lymphocyte, and platelet counts must be above the lower limit of normal range. Total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) must be within normal ranges. Other clinical laboratory safety test results must be within the normal ranges or test results that are outside the normal ranges need to be considered not clinically significant in the opinion of the investigator.
• Subject must be able and willing to comply with restrictions on prior medication: all medication (including OTC and/or prescription medication, dietary supplements, nutraceuticals, vitamins and/or herbal supplements [e.g. St. John’s wort], oral hormonal contraceptives for WOCBP, and hormonal replacement therapy for postmenopausal subjects) except occasional paracetamol (maximum dose 2 g/day and a maximum of 10 g/2 weeks) should be discontinued at least 2 weeks or 5 half-lives of the drug, whichever is longer, prior to the first dose of Compound 1 administration and throughout the study.
• Negative screen for drugs (amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, opiates, methadone, tricyclic antidepressants) and alcohol.
• Able and willing to comply with the CSP requirements and signing the ICF as approved by the IEC/IRB, prior to any screening evaluations.
• Female subjects should be of non-childbearing potential, defined as permanently surgically sterile (bilateral oophorectomy, i.e. surgical removal of ovaries, bilateral salpingectomy or hysterectomy, i.e. surgical removal ofuterus), orwithno menses for 12 ormore months without an alternative medical cause AND a follicle-stimulating hormone (FSH) level in the postmenopausal range. For surgical sterilization, documented confirmation will be requested.
Female Subjects o In line with the HMA’s Clinical Trial Facilitation Group recommendation, female subjects are considered of non-childbearing potential if they meet one of the following criteria: o No menses for 12 or more months without an alternative medical cause. A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. o Permanently surgically sterile (bilateral oophorectomy, i.e. surgical removal of ovaries, bilateral salpingectomy or hysterectomy, i.e. surgical removal of uterus). o All other female subjects are considered to be WOCBP and must use one of the following highly effective methods of birth control prior to the first dose of Compound 1, during the clinical study and for at least 35 days after the last dose of Compound 1:
■ Intrauterine device (non-hormonal).
■ Bilateral tubal occlusion.
■ Sexual abstinence defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the subject. o A female subject is not allowed to use any of the following contraception methods in this study:
■ Combined (estrogen and progesterone containing) (oral, intravaginal, transdermal) hormonal contraception associated with inhibition of ovulation.
■ Progesterone-only hormonal (oral, injectable, implantable) contraception associated with inhibition of ovulation.
■ Intrauterine hormone-re leasing system. ■ Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a clinical study, withdrawal, spermicides only, and lactational amenorrhea method. Hormonal contraceptives are not allowed due to the potential interference with the drug-drug interaction evaluation. In case a WOCBP has a vasectomized partner, provided that partner is the sole sexual partner of the WOCBP clinical study participant and that the vasectomized partner has received medical assessment of the surgical success, then she is not required to use an additional form of contraception. Within these limits, the specific forms of contraception employed are left to the discretion of the subject, the investigator, and/or the subject’s physician. The safety of Compound 1 during breastfeeding is unknown. Nursing women are not allowed to take part in this clinical study.
Male Subjects Non-vasectomized male subjects with female partners of childbearing potential must be willing to use a condom from the time of the first dose of IP, during the clinical study, and until FU, in addition to having their female partner use one of the following forms of contraception:
■ Intrauterine device.
■ Intrauterine hormone-re leasing system.
■ Combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal).
■ Progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable). Sexual abstinence defined as refraining from heterosexual intercourse is considered a highly effective contraceptive measure only if it is the preferred and usual lifestyle of the subject. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study. Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a clinical study, withdrawal, spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. In a case where the female partner of a male subject has undergone documented surgical sterilization that was performed more than 1 year before screening, the subject is not required to use an additional form of contraception. Vasectomized male subjects with female partners of childbearing potential are not required to use an additional form of contraception providing that surgical sterilization has been successful (documented azoospermia by semen analysis). o No sperm donation is allowed from first dose of Compound 1 during the clinical study until FU.
5.6. Exclusion criteria
[0168] Key exclusion criteria: subjects meeting one or more of the following criteria cannot be enrolled in this study:
• History of serious allergic reaction to any drug as determined by the investigator (e.g. anaphylaxis requiring hospitalization) and/or known sensitivity to Compound 1 and/or Itraconazole or other antifimgals or their excipients as determined by the investigator.
• Positive serology for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus (HCV), or history of hepatitis from any cause with the exception of hepatitis A that was resolved at least 3 months prior to first dosing.
• Subject testing positive for SARS-CoV-2 infection as detected by real-time polymerase chain reaction (RT-PCR) or subjects who have been in contact with SARS CoV 2 infected individuals in the 2 weeks priorto first dosing. A subject presenting any signs or symptoms of SARS-CoV- 2 infection, as detected at screening or baseline (e.g. cough, fever, headaches, fatigue, dyspnea, myalgia, anosmia, dysgeusia, anorexia, sore throat, etc.) (BMJ, 2020a; BMJ, 2020b), should undergo a rapid antigen test (and confirmatory RT-PCR test in case the antigen test is negative) and excluded if positive. Any other locally applicable standard diagnostic criteria may also apply to diagnose SARS-CoV-2 infection.
• History of or a current immunosuppressive condition (e.g. HIV infection).
• Having any illness, judged by the investigator as clinically significant for participation in the study, in the 3 months prior to dosing.
• Presence or sequelae of gastrointestinal, liver, kidney (estimated glomerular filtration rate [eGFR] <90 mL/min/1.73 m2, using the CKD-EPI formula) or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
• History of malignancy within the past 5 years prior to screening, with the exception of excised and curatively treated non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of cervix which is considered cured with minimal risk of recurrence.
• History or presence of clinically significant abnormalities detected on 12-lead ECG of either rhythm or conduction e.g. known long QT syndrome or a QTcF >450 ms detected on the 12-lead ECG. A first-degree atrioventricular block will not be considered as a significant abnormality.
• Male subjects not willing to comply with the contraceptive methods described in the Inclusion criteria, section 1.5.
• Female subject is pregnant or breast feeding or intending to become pregnant or breastfeed during the study. • Significant blood loss (including blood donation [>450 mb]), or transfusion of any blood product within 12 weeks prior to screening.
• Treatment with any drug known to have a potential for major organ toxicity in the last 3 months prior to dosing.
• Treatment with any medication (including over-the-counter [OTC] and/or prescription medication, dietary supplements, nutraceuticals, vitamins and/or herbal supplements, and hormonal replacement therapy) except occasional paracetamol (maximum dose of 2 g/day and maximum of 10 g/2 weeks) in the last 2 weeks or 5 half-lives of the drug, whichever is longer, prior to the first dosing.
• Active drug abuse or alcohol abuse (alcohol abuse defined as regular weekly intake of more than 14 units in which 1 unit = 25 mb spirits, 125 mb wine, 250 mb beer or lager) within 2 years prior to dosing.
• Active smoker and/or has used nicotine or nicotine-containing products within the past 6 months prior to dosing.
• Regular consumption of a large quantity of caffeinated coffee, tea (>6 cups per day) or equivalent.
• Concurrent participation or participation in a drug, drug/device, or biologic investigational research study within 12 weeks or 5 half-lives of the investigational product, whichever is longer, prior to first dosing.
• Any condition or circumstances that in the opinion of the investigator may make a subject unlikely or unable to complete the study or comply with study procedures and requirements.
5.7. Ph armacokin etic assessment
5.7.1. Blood Samples for Determination of Compound 1 in Plasma
[0169] Samples are collected by venipuncture (or indwelling cannula) preferably in the forearm into tubes containing K2EDTA and are immediately chilled (ice bath). Within 30 min after blood collection, the plasma is separated in a refrigerated centrifuge at 4°C for 10 min at circa 1500 g’ and transferred into tubes as described in the laboratory manual. The plasma samples are stored at <=-65 °C at the clinical center until shipment to the bioanalytical laboratory.
5.7.2. Blood Samples for Determination of Itraconazole in Plasma
[0170] Blood samples are collected by venipuncture (or indwelling cannula) preferably in the forearm into tubes containing K2EDTA and are immediately chilled (ice bath). Within 30 min after blood collection, the plasma is separated in a refrigerated centrifuge at 4°C for 10 min at circa 1500 g’ and transferred into tubes as described in the lab manual. The plasma samples are stored at <=-20°C at the clinical center until shipment to the bioanalytical laboratory.
[0171] The following parameters, where appropriate, are determined for Compound 1 and Itraconazole by non-compartmental analysis using individual concentration-time profiles in plasma: [0172] For Compound 1 (Days 1 and 8): a. C max b . tmax c. AUCo-t d. AUG, e. ti/2,x,z f. Xz g. CL/F h. Vd/F
[0173] For Itraconazole (Day 8): a. CT b. C max ss C . tmax d. AUG
5.8. Pharmacokinetic analysis and assessment of drug interaction
[0174] All pharmacokinetic analyses are performed for subjects who have available and evaluable data (e.g. excluding all protocol deviations or AEs that may have an impact on the PK analysis).
[0175] Descriptive statistics are calculated by treatment for the plasma concentrations and the listed PK parameters. Mean ± SD plasma concentrations of Compound 1 and Itraconazole versus time are plotted per treatment.
[0176] Baseline is defined as the last available assessment prior to the first intake of Compound 1.
[0177] The effect of the Itraconazole on the PK of Compound 1 is assessed on log-transformed Compound 1 PK parameters Cmax and AUCo-«> by means of a mixed-effect model with treatment days as fixed effect and subject as random effect. Point estimate is calculated as the geometric mean of the individual ratios of each parameter for the test/reference treatments and expressed as a percentage. The 90% CI of the point estimates is calculated using the mean square error of the analysis of variance. Point estimate and 90% CI is calculated using Day 8 (Compound 1 + Itraconazole) as test treatment versus Day 1 (Compound 1 alone) as reference treatment.
5.9. Study results
[0178] The results of this clinical study can be found in Table II: compound 1 results in a AUCo-t of 3120 and concomitant use of compound 1 with Itraconazole results in a AUCo-t of 5750, which corresponds to a 1.8 fold increase in the AUCo-t. Table II: Clinical results:
Figure imgf000035_0001
PACKAGES, KITS, METHODS OF PACKAGING, AND METHODS OF DELIVERING
[0179] In another aspect, a package or kit is provided comprising the compound of the invention, optionally in a container, and, a package insert, package label, instructions or other labelling including information, recommendation or instruction regarding avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, in general, as described in different aspects and embodiments herein. Such as a package insert, package label, instructions or other labelling may include any one or more of the following information, recommendation, or instruction:
Informing or advising the patient that concurrent use of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, should be avoided;
Informing or advising the patient that concurrent use of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, is contraindicated;
Informing or advising the patient that concurrent use of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers, should be discontinued, e.g. for at least 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, at least two weeks, at least 3 weeks or at least 4 weeks prior to compound 1 therapy;
Informing or advising the patient that concurrent use of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3 A4 inducers and/or strong P-gp inducers, can alter the therapeutic effect of the respective medicament or of the compound of the invention, e.g. decreases the therapeutic effect of Compound 1 or the respective medicament, and/or leads to adverse drug interactions or adverse events, in which case the instruction may further state that therefore concurrent use is contraindicated;
Instructing the patient to discontinue concurrent use of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers;
Instructing the patient in need of Compound 1 therapy to not use or administer concurrently one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers; Contra-indicating the concurrent use or administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers.
[0180] In the above-referenced embodiments and aspects of the invention the CYP3A4 inducer is selected from: Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Dexamethasone, Pioglitazone, Rifabutin, Rifampicin, St. John’s wort, Phenobarbital and Troglitazone. In particular, the term refers to Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, and St. John’s wort.
[0181] In a more particular embodiment, the strong CYP3A4 inducer is selected from: Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, and St. John’s wort.
[0182] In the above-referenced embodiments and aspects of the invention the P-gp inducers is selected from: Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Apalutamide, Carbamazepine, Fosphenytoin, Lorlatinib, Phenytoin, Dexamethasone, Rifabutin, Rifampicin and St. John's wort.
[0183] In a more particular embodiment, the strong P-gp inducer is selected from: Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Carbamazepine, Phenytoin, Rifabutin, Rifampicin and St. John's wort.
[0184] In the above-referenced embodiments and aspects of the invention the CYP3A4 inducer and/or P- gp inducer is a combined CYP3A4/P-gp inducer, which is a substance that upon administration to a subject increases CYP3A4 and P-gp mediated activity, and is in particular phenytoin, carbamazepine, rifampicin, dexamethasone and St. John’s wort, especially rifampicin.
EMBODIMENTS
[0185] Further examples of embodiments of the invention include those given directly below:
1. The compound of the invention according to Formula I
Figure imgf000037_0001
or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof, for use in treating a patient in need of therapy thereof, characterized in that the treating comprises avoiding or contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3 A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers. The use of the compound according to Formula I or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof, in the manufacture of a medicament for treating a patient in need of therapy thereof, characterized in that the treating comprises avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers. A method of administering treatment using the compound according to Formula I or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof, to a patient in need of therapy thereof comprising administering the patient a therapeutically effective amount of compound 1, and avoiding, contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers. The compound for use according to embodiment 1, the use of the compound according to embodiment 2 or the method according to embodiment 3, wherein the patient in need of therapy thereof is currently undergoing treatment with one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers. The compound for use according to embodiment 1 or 4, the use of the compound according to embodiment 2 or 4, or the method according to embodiment 3 or 4, wherein the use or method comprises the step of discontinuing the use of or treatment of one or more compounds that are CYP inducers and/or P-gp inducers, prior to or at the same time as the step of starting the therapy thereof, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers. The compound for use according to embodiment 1, 4 or 5, the use of the compound according to embodiment 2, 4 or 5, or the method according to embodiment 3, 4 or 5, wherein the use or method comprises the step of discontinuing the use of or treatment of one or more compounds that are CYP inducers and/or P-gp inducers, particularly CYP3A4 inducers and/or P-gp inducers, and more particularly strong CYP3A4 inducers and/or strong P-gp inducers; at least 12 hours, or at least 24 hours, prior to commencing the therapy thereof. The compound for use according to embodiment 1, 4, 5 or 6, the use of the compound according to embodiment 2, 4 , 5 or 6, or the method according to embodiment 3, 4, 5 or 6, wherein the use or method further comprises concomitant use or co-administration of a medicament from the same class or mechanism of action or known to be a suitable alternative medicament for the respective therapy thereof and that is a medicament or one or more compounds that are not CYP inducers and/or P-gp inducers, particularly not CYP3A4 inducers and/or not P-gp inducers, and more particularly not strong CYP3A4 inducers and/or strong not P-gp inducers. The compound for use according to embodiment 1, 4, 5, 6 or 7, the use of the compound according to embodiment 2, 4, 5, 6 or 7, or the method according to embodiment 3, 4, 5, 6 or 7, wherein the use or method comprises discontinuing treatment with one or more compounds that are CYP inducers and/or P-gp inducers and commencing treatment with a medicament from the same class or mechanism of action or known to be a suitable alternative medicament for the respective therapy thereof and that is a medicament or one or more compounds that are not CYP inducers and/or P-gp inducers, particularly not CYP3A4 inducers and/or not P-gp inducers, and more particularly not strong CYP3A4 inducers and/or strong not P-gp inducers. The compound for use according to embodiment 1, 4, 5, 6, 7 or 8, the use of the compound according to embodiment 2, 4, 5, 6, 7 or 8, or the method according to embodiment 3, 4, 5, 6, 7 or 8, wherein the patient in need of therapy thereof has one or more inflammatory diseases, diseases associated with hypersecretion of IFNa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL- 12 and/or IL-23. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has systemic lupus erythematosus. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has cutaneous lupus erythematosus. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has lupus nephritis. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has dermatomyositis. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has polymyositis. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has Sjogren’s syndrome. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has psoriasis. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has rheumatoid arthritis. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has psoriatic arthritis. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has multiple sclerosis. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has trisomy 21. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has ulcerative colitis. The compound for use according to embodiment 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8 or 9, or the method according to embodiment 3, 4, 5, 6, 7, 8 or 9, wherein the patient in need of therapy thereof has Crohn’s disease. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22, or the method according to embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22, wherein the cytochrome P450 (CYP) inducer is a CYP3A4 inducer and is one or more medicaments selected from: Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Dexamethasone, Pioglitazone, Rifabutin, Rifampicin, St. John’s wort, Phenobarbital and Troglitazone. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, or the method according to embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, wherein the P-gp inducer is one or more medicaments selected from: Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Apalutamide, Carbamazepine, Fosphenytoin, Lorlatinib, Phenytoin, Dexamethasone, Rifabutin, Rifampicin and St. John's wort. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24, the use of the compound according to embodiment 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24, or the method according to embodiment 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24, wherein the compound according to Formula I or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof is administered from about 80 mg to about 200 mg daily dose. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25, the use of compound 1 according to embodiment 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25, or the method according to embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25, wherein the compound according to Formula I or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof, is administered from about 80 mg, 90 mg, 100 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg daily dose. A package or kit comprising: i. the compound according to Formula I or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof, and ii. a package insert, package label, instructions or other labelling comprising instructions to avoid or discontinue or contraindication of concomitant use or co-administration of one or more compounds that are CYP inducers. A package or kit according to embodiment 27 further comprising one or more of the features according to embodiments 1 to 26. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, or the use of the compound according to embodiment 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, or the method according to embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, or a package or kit according to embodiment 27 or 28, wherein the CYP inducer is a CYP3A4 inducer. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 29, or the use of the compound according to embodiment 2, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 29, or the method according to embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 29, or a package or kit according to embodiment 27, 28 or 29, wherein the CYP inducer is a strong CYP3A4 inducer. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29 or 30, or the use of the compound according to embodiment 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29 or 30, or the method according to embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29 or 30, or a package or kit according to embodiment 27, 28, 29 or 30 wherein the cytochrome P450 (CYP) inducer is a CYP3A4 inducer and is one or more medicaments selected from Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Dexamethasone, Pioglitazone, Rifabutin, Rifampicin, St. John’s wort, Phenobarbital and Troglitazone. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30 or 31, or the use of the compound according to embodiment 2, 4,
5. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30 or 31, or the method according to embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30 or 31, or a package or kit according to embodiment 27, 28, 29, 30 or 31, wherein the cytochrome P450 (CYP) inducer is a CYP3A4 inducer and is one or more medicaments selected from Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, St. John’s wort, Phenobarbital and Troglitazone. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 or 32, orthe use of the compound according to embodiment 2,
4. 5. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 or 32, or the method according to embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 or 32, or a package or kit according to embodiment 27, 28, 29, 30, 31 or 32, wherein the cytochrome P450 (CYP) inducer is a strong CYP3A4 inducer and is one or more medicaments selected from Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, and St. John’s wort. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 32 or 33, orthe use of the compound according to embodiment 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 32 or 33, or the method according to embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 32 or 33, or a package or kit according to embodiment 27, 28, 29, 30, 31, 32 or 33, wherein the P-gp inducer is one or more medicaments selected from Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Apalutamide, Carbamazepine, Fosphenytoin, Lorlatinib, Phenytoin, Dexamethasone, Rifabutin, Rifampicin and St. John's wort. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 32, 33 or 34, or the use of the compound according to embodiment 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 32, 33 or 34, or the method according to embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 32, 33 or 34, or a package or kit according to embodiment 27, 28, 29, 30, 31, 32, 33 or 34, wherein the P-gp inducer is a strong P-gp inducer. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 32, 33, 34 or 35, or the use of the compound according to embodiment 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 32, 33, 34 or 35, or the method according to embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 32, 33, 34 or 35, or a package or kit according to embodiment 27, 28, 29, 30, 31, 32, 33, 34 or 35, wherein the strong P-gp inducer and is one or more medicaments selected from Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Carbamazepine, Phenytoin, Rifabutin, Rifampicin and St. John's wort.
37. The compound for use according to embodiment 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 32, 33, 34, 35 or 36, or the use of the compound according to embodiment 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 32, 33, 34, 35 or 36, or the method according to embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31 32, 33, 34, 35 or 36, or a package or kit according to embodiment 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36, wherein the CYP3A4 inducer and/or P-gp inducer is a combined CYP3A4/P-gp inducer, in particular one or more of phenytoin, carbamazepine, rifampicin, dexamethasone and/or St. John’s wort, especially rifampicin.
FINAL REMARKS
[0186] It will be appreciated by those skilled in the art that the foregoing descriptions are exemplary and explanatory in nature and intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognize apparent modifications and variations that may be made without departing from the spirit of the invention. All such modifications coming within the scope of the appended claims are intended to be included therein. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents.
[0187] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication are specifically and individually indicated to be incorporated by reference herein as though fully set forth.
[0188] It should be understood that factors such as the differential cell penetration capacity of the compound can contribute to discrepancies between the activity of the compound in the in vitro biochemical and cellular assays.
[0189] At least some of the chemical names of compound of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control.
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Claims

CLAIMS The compound according to Formula I:
Figure imgf000044_0001
i or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof, for use in treating a patient in need of therapy thereof, characterized in that the treating comprises avoiding or contraindicating or discontinuing concomitant use or co-administration one or more compounds that are CYP inducers and/or P-gp inducers. The use of the compound according to Formula I or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof, in the manufacture of a medicament for treating a patient in need of therapy thereof, characterized in that the treating comprises avoiding or contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers. A method of administering treatment using the compound according to Formula I or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof, to a patient in need of therapy thereof comprising administering the patient a therapeutically effective amount of the compound according to Formula I or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof, and, avoiding or contraindicating or discontinuing concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers. The compound for use according to claim 1, the use of the compound according to claim 2 or method according to claim 3, wherein the patient in need of therapy thereof is currently undergoing treatment with one or more compounds that are CYP inducers and/or P-gp inducers. The compound for use according to claim 1 or 4, the use of the compound according to claim 2 or 4, or method according to claim 3 or 4, wherein the use or method comprises the step of discontinuing the use of or treatment of one or more compounds that are CYP inducers and/or P- gp inducers prior to or at the same time as the step of starting the therapy. The compound for use according to claim 1, 4 or 5, the use of the compound according to claim 2, 4 or 5, or the method according to claim 3, 4 or 5, wherein the use or method comprises the step of discontinuing the use of or treatment of one or more compounds that are CYP inducers and/or P- gp inducers, at least 12 hours, at least 24 hours, prior to commencing therapy thereof. The compound for use according to claim 1, 4, 5 or 6, the use of the compound according to claim 2, 4 , 5 or 6, or the method according to claim 3, 4, 5 or 6, wherein the use or method further comprises concomitant use or co-administration of a medicament from the same class or mechanism of action or known to be a suitable alternative medicament for the respective therapy thereof and that is a medicament or one or more compounds that are not CYP inducers and/or P-gp inducers, particularly not CYP3A4 inducers and/or not P-gp inducers, and more particularly not strong CYP3A4 inducers and/or strong not P-gp inducers. The compound for use according to claim 1, 4, 5, 6 or 7, the use of the compound according to claim 2, 4, 5, 6 or 7, or the method according to claim 3, 4, 5, 6 or 7, wherein the use or method comprises discontinuing treatment with one or more compounds that are CYP inducers and/or P- gp inducers and commencing treatment with a medicament from the same class or mechanism of action or known to be a suitable alternative medicament for the respective therapy thereof and that is a medicament or one or more compounds that are not CYP inducers and/or P-gp inducers, particularly not CYP3A4 inducers and/or not P-gp inducers, and more particularly not strong CYP3A4 inducers and/or strong not P-gp inducers. The compound for use according to claim 1, 4, 5, 6, 7 or 8, the use of the compound according to claim 2, 4, 5, 6, 7 or 8, or the method according to claim 3, 4, 5, 6, 7 or 8, wherein the patient in need of therapy thereof has one or more inflammatory diseases, diseases associated with hypersecretion of IFNa and/or interferons (“interferonopathies”, especially type I interferonopathies), IL- 12 and/or IL-23, in particular diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis and/or Crohn’s disease. A package or kit comprising: i. the compound according to Formula I or a pharmaceutically acceptable salt/cocrystal thereof, or a solvate or the solvate of a salt/cocrystal thereof, and ii. a package insert, package label, instructions or other labelling comprising instructions to avoid or discontinue or contraindication of concomitant use or co-administration of one or more compounds that are CYP inducers and/or P-gp inducers. A package or kit according to claim 10 further comprising one or more of the features according to any of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9. The compound for use according to claim 1, 4, 5, 6, 7, 8 or 9, the use of the compound according to claim 2, 4, 5, 6, 7, 8 or 9, or the method according to claim 3, 4, 5, 6, 7, 8 or 9, or the kit according to claim 10 or 11, wherein the CYP inducer is a CYP3A4 inducer. The compound for use according to claim 1, 4, 5, 6, 7, 8, 9 or 12, the use of the compound according to claim 2, 4, 5, 6, 7, 8, 9 or 12, or the method according to claim 3, 4, 5, 6, 7, 8, 9 or 12, or the kit according to claim 10, 11 or 12, wherein the CYP inducer is a CYP3A4 inducer and is one or more medicaments selected from Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Dexamethasone, Pioglitazone, Rifabutin, Rifampicin, St. John’s wort, Phenobarbital and Troglitazone. The compound for use according to claim 1, 4, 5, 6, 7, 8, 9, 12 or 13, the use of the compound according to claim 2, 4, 5, 6, 7, 8, 9, 12 or 13, or the method according to claim 3, 4, 5, 6, 7, 8, 9, 12 or 13, or the kit according to claim 10, 11, 12 or 13, wherein the CYP inducer is a strong CYP3A4 inducer and is one or more medicaments selected from Barbiturates, Carbamazepine, Glucocorticoids, Modafinil, Oxcarbazepine, Phenytoin, Pioglitazone, Rifabutin, Rifampicin, and St. John’s wort. The compound for use according to claim 1, 4, 5, 6, 7, 8, 9, 12, 13 or 14, the use of the compound according to claim 2, 4, 5, 6, 7, 8, 9, 12, 13 or 14, or the method according to claim 3, 4, 5, 6, 7, 8, 9, 12, 13 or 14, or the kit according to claim 10, 11, 12, 13 or 14, wherein the P-gp inducer is one or more medicaments selected from Barbiturates, Glucocorticoids, Modafinil, Oxcarbazepine, Pioglitazone, Apalutamide, Carbamazepine, Fosphenytoin, Lorlatinib, Phenytoin, Dexamethasone, Rifabutin, Rifampicin and St. John's wort. The compound for use according to claim 1, 4, 5, 6, 7, 8, 9, 12, 13, 14 or 15, the use ofthe compound according to claim 2, 4, 5, 6, 7, 8, 9, 12, 13, 14 or 15, or the method according to claim 3, 4, 5, 6, 7, 8, 9, 12, 13, 14 or 15, or the kit according to claim 10, 11, 12, 13, 14 or 15, wherein the P-gp inducer is a strong P-gp inducer and is one or more medicaments selected from Amiodarone, Azithromycin, Clarithromycin, Erythromycin, Roxithromycin, Telithromycin, Cyclosporine, Itraconazole, Ketoconazole, Tamoxifen, and Verapamil. The compound for use according to claim 1, 4, 5, 6, 7, 8, 9, 12, 13, 14, 15 or 16, the use of the compound according to claim 2, 4, 5, 6, 7, 8, 9, 12, 13, 14, 15 or 16, or the method according to claim 3, 4, 5, 6, 7, 8, 9, 12, 13, 14, 15 or 16, or the kit according to claim 10, 11, 12, 13, 14, 15 or 16, wherein the one or more compounds that are CYP inducers and/or P-gp inducers are combined CYP3A4/P-gp inducer, in particular one or more of phenytoin, carbamazepine, rifampicin, dexamethasone and/or St. John’s wort, especially rifampicin.
PCT/EP2023/054526 2022-02-24 2023-02-23 Compound for use in and methods of treatment of inflammatory diseases WO2023161327A1 (en)

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