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WO2025068448A1 - Inhibiteurs de l'atp synthase destinés à être utilisés dans le traitement de mycobactéries non tuberculeuses - Google Patents

Inhibiteurs de l'atp synthase destinés à être utilisés dans le traitement de mycobactéries non tuberculeuses Download PDF

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Publication number
WO2025068448A1
WO2025068448A1 PCT/EP2024/077192 EP2024077192W WO2025068448A1 WO 2025068448 A1 WO2025068448 A1 WO 2025068448A1 EP 2024077192 W EP2024077192 W EP 2024077192W WO 2025068448 A1 WO2025068448 A1 WO 2025068448A1
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Prior art keywords
compound
infection
mac
tbaj
enantiomer
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Inventor
Sushmita Dipak LAHIRI
Cuong Vuong
Ellen Anita LANCKACKER
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • Nontuberculous mycobacterial (NTM) lung disease is a significant cause of morbidity and mortality among individuals with preexisting lung conditions such as bronchiectasis and chronic obstructive pulmonary disease (COPD).
  • NTM non- tuberculosis mycobacteria
  • COPD chronic obstructive pulmonary disease
  • Mycobacterium avium complex (MAC), Mycobacterium abscessus group (MAB) and Mycobacterium kansasii are the mycobacterium species that result in NTM pulmonary disease (NTM-PD).
  • NTM-PD is distinct from the pulmonary infection caused by Mycobacterium tuberculosis.
  • Mycobacterium avium is one of several individual species within the MAC and it accounts for up to 70% of NTM-positive sputum cultures (although there are regional differences).
  • MAC species are naturally-occurring organisms common in water and soil that often colonize in natural water sources such as indoor water systems, hot tubs and pools.
  • MAC-pulmonary disease is most often seen in post-menopausal women and patients with underlying lung disease (such as cystic fibrosis or bronchiectasis) or immune deficiencies.
  • Clinical symptoms vary in scope and intensity but commonly include chronic cough, often with purulent sputum, while hemoptysis may also be present.
  • Systemic symptoms include malaise, fatigue, and weight loss in advanced disease.
  • MAC-PD Current treatment of MAC-PD involves prolonged antibiotic therapy (frequently more than 18 months), with a combination of at least three antibiotics, including a rifamycin (rifampin or rifabutin), a macrolide (azithromycin or clarithromycin), ethambutol and/or aminoglycosides, including injectable or inhalable (amongst others), which are associated with side-effects and a high failure rate.
  • This treatment regimen is currently recommended by the American Thoracic Society (see Griffith et al., Am. J. Respir. Crit. Care Med., 2007, 175, p367) and International Guidelines given the in vitro and clinical activity displayed by the combination against MAC.
  • amikacin liposome inhalation suspension (ALIS, Arikayce®) was approved by the US FDA for the treatment of MAC-PD in adults but otherwise this disease/condition has limited or no alternative treatment options. There are no other antibiotics approved for the treatment of MAC-PD and recommended use of the above agents is merely empirical.
  • Bedaquiline, or (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2- naphthalen-1-yl-1-phenylbutan-2-ol is a mycobacterium adenosine 5’-triphosphate (ATP) synthase inhibitor that has been developed as a part of a combination therapy for the treatment of pulmonary multidrug-resistant tuberculosis (MDR-TB) in adult patients.
  • Bedaquiline has been approved for that indication under certain conditions under the tradename Sirturo® in territories including the US, Japan, China, Russia, the EU, South Africa and the Republic of Korea.
  • Bedaquiline is known to show activity against Mycobacteria including drug resistant strains, in particular M. tuberculosis, M. bovis, M. avium, M. leprae, M. marinum, M. leprae, M. kansasii, and M. abscessus.
  • the active ingredient, including salt thereof shows activity against active, sensitive, susceptible Mycobacteria strains and latent, dormant, persistent Mycobacteria strains.
  • International Patent Application Publication No. WO 2004/011436 disclosed the activity of the free base of bedaquiline against Mycobacteria. Later documents such as International Patent Application Publication Nos.
  • WO 2005/117875 and WO 2006/067048 disclosed the use of bedaquiline in the treatment of inter alia drug resistant tuberculosis and latent tuberculosis.
  • Bedaquiline is currently being tested in the clinic in a Phase 2/3 trial in Japan to “Evaluate the Efficacy and Safety of Bedaquiline Administered as Part of a Treatment Regimen with Clarithromycin and Ethambutol in Adult Patients With Treatment- refractory Mycobacterium Avium Complex-lung disease (MAC-LD)”.
  • MAC-LD Mycobacterium Avium Complex-lung disease
  • TBAJ-876 a 3,5-Dialkoxypyridine Analogue of Bedaquiline, Is Active against Mycobacterium abscessus”, displays data in a certain model indicating as one of its conclusions “...we demonstrate that TBAJ-876 shows attractive in vitro and in vivo activities against M. abscessus, similar to its BDQ parent”. Because of the emerging resistance to multiple antibiotics, physicians are confronted with infections for which there is no effective therapy. The morbidity, mortality, and financial costs of such infections impose an increasing burden for health care systems worldwide.
  • the invention relates to the following compounds of formula (I) and (II):
  • the compounds of formula (I) and (II) are each racemix mixtures or racemates; each of them having four isomers/enantiomers.
  • the separation of these racemates may be performed by using a number of techniques, for instance by chiral chromatography, and their separation has been achieved, for instance as described in the experimental section using supercritical fluid chromatodgraphy (SFC).
  • One of the possible four enantiomers of the compound of formula (I) and one of the four possible enantiomers of the compound of formula (II) show particularly good activity in vitro, for instance as described herein in Test 1 in the pharmacological examples section (also referred to as the NTM Test 1 in M. avium (MAC) or M. abscessus (MAB)).
  • Test 1 in the pharmacological examples section
  • MAB M. abscessus
  • the other less active enantiomers/isomers are arbitrarily referred to as XX2, XX3 and XX4 - the specific enantiomer/isomer of the compound of formula (II) that displays the best potency (e.g. lowest IC90 values, or highest pIC90 values) in the NTM Test 1 (MAC and/or MAB) is referred to herein as Compound YY1.
  • the other less active enantiomers/isomers are arbitrarily referred to as YY2, YY3 and YY4.
  • XX1 is therefore the enantiomer/isomer that exhibits the lowest numerical IC90 value in the NTM Test 1 assay conditions (MAC or MAB), relative to the other enantiomeric/isomeric forms XX2, XX3 and XX4.
  • YY1 is therefore the enantiomer/isomer that exhibits the lowest numerical IC90 value in the NTM Test 1 assay conditions (MAC or MAB), relative to the other enantiomeric/isomeric forms YY2, YY3 and YY4.
  • XX1 and YY1 may also be characterised by how they are eluted using chiral chromatography separation tehniques, for instance SFC as described in the experimental hereinafter, Without being bound to any theory, it is understood that XX1 and YY1 respectively correspond to the following two compounds, where assignments are considered:
  • a compound of formula (I) or (II) that is, in each case, one of the four possible isomers/enantiomers (the most active one, as described herein), or a pharmaceutically acceptable salt thereof, for use in the treatment of Mycobacterium avium complex (MAC).
  • the treatment of MAC is in vivo treatment.
  • the compound is YY1, or a pharmaceutically acceptable salt thereof.
  • a compound XX1 or YY1, or a pharmaceutically acceptable salt thereof for use in the treatment of Mycobacterium avium complex (MAC).
  • the treatment of MAC is in vivo treatment.
  • the compound is YY1, or a pharmaceutically acceptable salt thereof.
  • a method of treating Mycobacterium avium complex (MAC) in a patient in need, e.g.
  • the method of treating MAC is a method of treating in vivo MAC.
  • the compound being administered to the patient is YY1, or a pharmaceutically acceptable salt thereof.
  • MAC Mycobacterium avium complex
  • diagnosed with MAC comprising administering to a patient a therapeutically effective amount of a compound of XX1 or YY1, or a pharmaceutically acceptable salt thereof.
  • the method of treating MAC is a method of treating in vivo MAC.
  • the compound being administered to the patient is YY1, or a pharmaceutically acceptable salt thereof.
  • BDQ bedaquiline
  • PK at a PK match
  • the dose is measured on the basis of the active ingredient itself (not considering the salt portion).
  • the dose match could be within a range of ⁇ 10% (by weight), for instance ⁇ 5%, but is preferably equal (within less than ⁇ 1%).
  • an equivalent dose or “at a dose match”
  • such administration still has to occur at a particular frequency, for instance daily – in which case the administration frequency should also be approximately equal – and so for the avoidance of doubt in the case when the administration is daily, then the dose is given at approximately the same time, for the purpose of the comparison / comparative test (for instance within one hour of each other, e.g. within 30 mins of each other).
  • PK active pharmaceutical ingredient
  • API active pharmaceutical ingredient
  • PK match is based on calculation of the exposure of the respective active pharmaceutical ingredient (API, plus associated metabolite).
  • API active pharmaceutical ingredient
  • single dose PK data in a mammal may be generated for each of the APIs (and their metabolites), and that data could be simulated for repeated dosing based on that single dose data in the mammal. And hence, for a planned daily dosing schedule, the simulation would be adapted to such repeated dosing.
  • the corresponding N- desmethyl metabolite is also subjected to the same criteria.
  • an approximate AUC for BDQ is calculated based on a specific repeated dose regime (e.g. a daily dose regime, such as 25 mg/kg daily for a specific period of time), and the approximate AUC is calculated for the comparators (i.e. XX1 and YY1, and their corresponding metabolites), then “at an equivalent PK” or “at a PK match” can be determined.
  • a specific repeated dose regime e.g. a daily dose regime, such as 25 mg/kg daily for a specific period of time
  • the approximate AUC is calculated for the comparators (i.e. XX1 and YY1, and their corresponding metabolites)
  • the equivalent PK or PK match will be approximate (and it is understood that it is calculated based on simulations as explained herein) and once the AUC of the API plus its metabolite is calculated, then corresponding daily doses can be adjusted accordingly by a certain fold.
  • the AUC for BDQ (plus its metabolite) is double that of the API to which it is being compared (e.g. XX1 or YY1 plus its corresponding metabolite), then the latter should also be doubled to achieve “an equivalent PK” or “a PK match”. It is understood that this is approximate for a number of reasons, not least due to the comparison being based on a a single PK data point and then simulation of repeated dose, and further due to the relative ratios of the AUCs being approximate.
  • the ratios of the AUCs when they are extrapolated to relate to the doses considered “an equivalent PK” or “a PK match” may be within a ⁇ 25% range in order for it to be considered an equivalent PK or a PK match, for instance within ⁇ 10%.
  • the resultant doses should be (roughly) equal to the exact ratio (of respective AUCs).
  • an AUC for one API is 10000, and the second API is 2500, and the daily dose of the first API is 100 mg/kg, then to be a PK match (or equivalent PK), the daily dose of the second API should be 25 mg/kg (and based on the foregoing approximate range, a PK equivalent dose may be considered to be within 31.25 mg/kg to 18.75 mg/kg daily dose, for instance).
  • compound XX1 and YY1 display improved in vivo efficacy (as demonstrated for example, in a mouse model), for instance when compared to bedaquiline (BDQ) at an equivalent dose (at a dose match) and/or at an equivalent PK (at a PK match), for instance as described in the experimental/examples.
  • BDQ bedaquiline
  • Such improvement may have a number of advantages, for instance, when only a comparatively lower dose (or lower PK equivalent dose) is required to achieve the same efficacy, then there may be advantages linked to fewer side effects (as only a lower relative dose or a lower relative PK matched dose is required), for instance there may be less toxicity / less toxic side effects.
  • the compounds XX1 and/or YY1 may display better efficacy.
  • Such compounds (and the one of four possible isomers/enatniomers described herein), including XX1 and/or YY1 may therefore in general have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g.
  • MAC Mycobacterial avium complex
  • the compound is one of four possible enantiomers/isomers of the respective compound (I) or (II) (for instance the most active enantiomer/isomer, e.g. which could be defined as compounds XX1 and YY1).
  • the compound is enantiomerically and/or isomerically pure.
  • the enantiomer/isomer of compound (I) and (II), respectively is: or a pharmaceutically acceptable salt thereof.
  • the higher in vivo potency compared to bedaquiline is measured in accordance with Test 3 (M.
  • avium non-established murine infection infection model to determine described herein, and for instance may be demonstrated: - via superior response at specific timepoints of lung weight, lung lesion count and/or colony forming units (CFUs) - by measuring at specific timepoints at 28 days and/or 56 days post-infection - by measurement of improvement in colony forming units (CFUs) at 56 days post infection
  • a compound of formula (I) or (II) that is, in each case, one of the four possible isomers/enantiomers (the most active one, as described herein, e.g.
  • MAC Mycobacterium avium complex
  • a method of improving patient response relative to bedaquiline in a patient suffering from a Mycobacterial avium complex (MAC) infection comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or (II): or a pharmaceutically acceptable salt thereof, wherein the compound is one of four possible enantiomers/isomers of the respective compound (I) or (II) (for instance the most active enantiomer/isomer, e.g.
  • the compound is enantiomerically and/or isomerically pure.
  • the enantiomer/isomer of compound (I) and (II), respectively is: or a pharmaceutically acceptable salt thereof.
  • the improved patient response may be demonstrated: - via superior response at specific timepoints of lung weight, lung lesion count and/or colony forming units (CFUs) - by measuring at specific timepoints at 28 days and/or 56 days post-infection - by measurement of improvement in colony forming units (CFUs) at 56 days post infection
  • a compound of formula (I) or (II) that is, in each case, one of the four possible isomers/enantiomers (the most active one, as described herein, e.g.
  • MAC Mycobacterial avium complex
  • a method of treating Mycobacterium avium complex (MAC) in vivo comprising administering to a patient in need thereof a therapeutically effective amount (for instance, in an embodiment that provides a more potent response in the patient compared to a bedaquiline at an approximate dose match and/or PK match) of a compound of formula (I) or (II): a pharmaceutically acceptable salt thereof, wherein the compound is one of four possible enantiomers/isomers of the respective compound (I) or (II) (for instance the most active enantiomer/isomer, e.g.
  • the compound is enantiomerically and/or isomerically pure.
  • the enantiomer/isomer of compound (I) and (II), respectively is:
  • a compound of formula (I) or (II) that is, in each case, one of the four possible isomers/enantiomers (the most active one, as described herein, e.g. XX1 or, in particular, YY1), or a pharmaceutically acceptable salt thereof, for use in the treatment of Mycobacterial avium complex (MAC) infection, wherein the compound provides a more potent response compared to a bedaquiline at an approximate dose match and/or PK match.
  • the pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the relevant active ingredient (e.g.
  • TBAJ-587, TBAJ-876) are able to form.
  • These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • butanedioic acid maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicyclic, pamoic and the like acids.
  • solvates, prodrugs, N-oxides and stereoisomers of the relevant active ingredient e.g. TBAJ-587, TBAJ-876) are also included within the scope of compound of formula (I) or (II).
  • prodrug of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
  • parenteral administration includes all forms of administration other than oral administration.
  • Prodrugs of compounds mentioned herein e.g. of formula (I) or (II), e.g.
  • TBAJ-8766 may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject.
  • the modifications typically are achieved by synthesising the parent compound with a prodrug substituent.
  • Prodrugs include compounds mentioned herein (e.g. of formula (I)) wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in that compound is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. “Design of Prodrugs” p. l-92, Elesevier, New York-Oxford (1985).
  • the methods of treatment, uses of the invention or compounds of the invention for use (in the treatment of MAC) may also be such that there is combination with other antibacterial drugs that are useful in the treatment of MAC.
  • the combinations of the invention may be useful as they have a bacteriostatic effect, but may also have a bacteriocidal effect against MAC.
  • drugs that may be used in combination include a macrolide (clarithromycin, azithromycin), ethambutol and rifampicin. Numerous other drugs may be combined, for instance those outlined in any official guidelines for the treatment of non-tuberculosis mycobacteria (especially MAC) or drug that may have been approved by a regulatory authority (but which is not another ATP synthase inhibitor).
  • the quantity of each drug should be an effective amount to elicit a biological or medicinal response.
  • the daily dose of the drug may of course vary depending on factors such as: - already approved (e.g.
  • Optional further antibacterial drugs that may be included in the combinations of the invention may be administered at daily doses recommended by a regulatory body (when e.g. approved in combination with other antibacterial agents), and are preferably administered at a daily dosage not exceeding 1 or 2 grams, e.g. in the range from 1 to 50 mg/kg body weight (for instance, in the range from 1 to 25 mg/kg, from 1.5 to 25 mg/kg, or from 2 to 15 mg/kg body weight). All amounts mentioned in this disclosure refer to the free form (i.e. non-salt form). The values given below represent free-form equivalents, i.e., quantities as if the free form would be administered. If salts are administered the amounts need to be calculated in function of the molecular weight ratio between the salt and the free form.
  • the doses (e.g. daily doses) described herein are calculated for an average body weight specified, and should be recalculated in case of paediatric applications, or when used with patients with a substantially diverging body weight.
  • the treatment duration for tuberculosis can be more than a year. However, it is envisioned that treatment duration may be reduced using the combinations of the invention. For instance, treatment duration may be 36 weeks or less, for instance 24 weeks or less. In certain embodiments, the treatment duration may be less than 20 weeks, for instance 16 weeks or less, or, 12 weeks or less.
  • Such combinations may be useful in the treatment of a disease caused by Mycobacterial tuberculosis (e.g. in the treatment of tuberculosis).
  • a pharmaceutical composition or formulation
  • Such combinations may be formulated into pharmaceutical compositions as described hereinafter.
  • a method of treating a patient suffering from, or at risk of, a disease caused by Mycobacterial tuberculosis (tuberculosis) comprises administering a therapeutically effective amount of a combination of the invention or a pharmaceutical composition of the invention.
  • the patient is human.
  • a method of treatment as defined herein wherein the method further comprises a treatment duration period as defined herein (e.g. a treatment duration of 36 weeks or less, 24 weeks or less or, in a particular embodiment, a treatement period of 16 weeks or less or 12 weeks or less).
  • a combination for use as described herein wherein the use is for a certain duration period (e.g. a treatment duration of 36 weeks or less, 24 weeks or less or, in a particular embodiment, a treatement period of 16 weeks or less or 12 weeks or less).
  • the components or antibacterial drugs of the combinations of the invention may be formulated separately (e.g.
  • the two (or optionally more) antibacterial drugs of the combinations of the invention can be co-administered, in other embodiments the antibacterial drugs (of the combinations) may be sequentially administered, while in still other embodiments they can be administered substantially simultaneously. In some of the latter embodiments, administration entails taking such antibacterial drugs within 30 minutes or less of each other, in some embodiments 15 minutes or less of each other. In some embodiments, the antibacterial drugs are administered once per day, at approximately the same time each day.
  • the antibacterial drugs are administered within a time range of 4 hours of the original time of administration on the first day, that is, ⁇ 2 hours, or ⁇ 1 hour, or in still other embodiments ⁇ 30 minutes of the time on the original administration day.
  • the antibacterial drugs of the invention are administered as separate oral capsules or oral tablets.
  • Other formulations may include solid dispersions.
  • a combination when referred to herein, such a combination may be a single formulation comprising all antibacterial drugs of the combinations of the invention (i.e.
  • each of the antibacterial drugs of the combinations of the invention may be packaged together either as separate forms (each comprising one of the antibacterial drugs) or as two or more forms (depending on the total number of antibacterial drugs in the combination of the invention).
  • each antibacterial drug of the combination of the invention is formulated separately and/or is also packaged separately but may be labelled for use in combination with one or more of the other antibacterial drugs of the combinations of the invention.
  • the antibacterial drugs of the combination may be co-administered, sequentially administered, or administered substantially simultaneously.
  • each of the antibacterial drugs can be administered as separate forms (e.g., as separate tablets or capsules) as described herein or, in other embodiments, may be administered as a single form containing all three active substances or as two forms (one containing any two of the active substances and the other containing the remaining active substance).
  • the antibacterial drugs of the combinations of the invention may be formulated into various pharmaceutical forms for administration purposes. As mentioned herein, this formulating may be done on an individual antibacterial drug or a combination of antibacterial drugs that form part of the combinations of the invention. As appropriate, compositions may include those usually employed for systemically administering drugs.
  • the relevant antibacterial drug (or combination of relevant antibacterial drugs) is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally or by parenteral injection.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the active ingredient(s), and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
  • Any pharmaceutical composition mentioned herein e.g.
  • a pharmaceutical composition comprising one antibacterial drug or a combination of antibacterial drugs of the combination of the invention
  • a lubricant for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • the combination of antibacterial drugs as described herein may be co-administered, sequentially administered, or administered substantially simultaneously (as described herein).
  • the individual dosage forms of each of the antibacterial drugs can be administered as separate forms (e.g. as separate tablets or capsules) as described herein or, in an alternative embodiment, may be administered as a single form containing all actives or as two or more forms (e.g. where there are three antibacterial drugs, one containing any two and the other containing the remaining one).
  • a process for preparing a pharmaceutical formulation as defined herein comprising bringing into association any one (or more, e.g. the two essential active ingredients and, optionally, further antibacterials as defined herein) of the active ingredients of the combination of the invention, with one (or more) pharmaceutically acceptable excipient or carrier.
  • a process for preparing a combination product as defined herein comprising: - bringing into association each of the components (e.g. as separate pharmaceutical formulations) of the combination product and co-packaging (e.g. as a kit of parts) or indicated that the intended use is in combination (with the other components); and/or - bringing into association each of the components in the preparation of a pharmaceutical formulation comprising such components.
  • Figure 1 Represents Lung Weight – following Test 3 described below
  • Figure 2 Represents Macroscopic lung lesions – scoring system – all following Test 3 described below
  • Figure 3 Represents Lung lesions –following Test 3 described below
  • Figure 4 Represents Lung CFUs – Results after 28 days of treatment – all following Test 3 desrcibed below
  • Figure 5 Represents Lung CFUs – Results after 56 days of treatment – all following Test 3 desrcibed below GENERAL PREPARATION
  • the compounds according to the invention can generally be prepared by a succession of steps, each of which may be known to the skilled person or described herein.
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • the reported molecular ion corresponds to the [M+H]+ (protonated molecule) and/or [M-H]- (deprotonated molecule).
  • the type of adduct is specified (i.e. [M+NH + 4] , [M+HCOO]-, etc).
  • the reported value is the one obtained for the lowst isotope mass. All results were obtainedwith experimental uncertainties that are commonly associated with the method used.
  • SQL Single Quadrupole Detector
  • MSD Mass Selective Detector
  • RT room temperature
  • BEH bridged ethylsiloxane/silica hybrid
  • DAD Diode Array Detector
  • HSS High Strength silica
  • MS Mass Spectrometer
  • iPrNH 2 means isopropylamine
  • iPrOH means 2- propanol
  • EtOH means ethanol
  • min mean minutes
  • DEA diethylamine
  • Hex means hexanes
  • IPA means isopropylamine.
  • Compounds of formula (I) and (II) may be prepared by reaction of compounds of formula (IA) and (IIA), respectively, with a compound of formula (III), under reaction conditions that couple the respective moieites, for instance using an appropriate base to deprotonate ⁇ to the quinolinyl ring (in compound (IA) or (IIA), for instance in the presence of a polar aprotic solvent, followed by a nucleophilic addition reaction with the ketone moiety of the compound of formula (III) and quench with a proton source H+.
  • n-BuLi e.g.
  • a compound of compound of formula (IV) that is coupled with either a compound of formula (IB) or of formula (IIB), to provide a compound of formula (IA) or (IIA) respectively.
  • a suitable catalyst system e.g. a metal (or a salt or complex thereof) such as Pd, CuI, Pd/C, PdCl 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 Cl 2 , Pd(Ph 3 P) 4 (i.e.
  • palladium tetrakistriphenylphosphine Pd 2 (dba) 3 and/or NiCl 2
  • preferred cataysts include RuPhos Pd G3, XPhos Pd and bis(tri-tert-butylphosphine)palladium(0)) and optionally a ligand such as PdCl 2 (dppf).DCM, t-Bu 3 P, (C 6 H 11 ) 3 P, Ph 3 P, AsPh 3 , P(o- Tol) 3 , 1,2-bis(diphenylphosphino)ethane, 2,2'-bis(di-tert-butylphosphino)-1,1'- biphenyl, 2,2'-bis(diphenylphosphino)-1,1'-bi-naphthyl, 1,1’-bis(diphenyl-phosphino- ferrocene), 1,3-bis(diphenylphosphino)propane
  • the compound of formula (III) may be prepared per the reaction scheme below where first oxalyl chloride (e.g.1.2 equiv.) is added to a suspension of 2,6- dimethoxyisonicotinic acid (e.g. I equiv.) in DCM (suitable quantity of solvent) and DMF (e.g.0.2 equiv.) at room temperature. Then, after 1 hour of stirring, the resultant colourless solution was cooled (e.g. to 0 ⁇ C).
  • first oxalyl chloride e.g.1.2 equiv.
  • DCM suitable quantity of solvent
  • DMF e.g.0.2 equiv.
  • N,O-dimethylhydroxylamine hydrochloride e.g.1.1 equiv.
  • pyridine suitable quantity of solvent
  • Vinvylmagnesium bromide e.g.3 equiv; in a THF solution
  • solvent e.g. THF
  • dimethylamine approximatelyx.6 equiv
  • water was added.
  • the desired of formula (III) can then be extracted and isolated.
  • the compound of formula (IV) was prepared by reaction of 6-bromo-2- methoxyquinoline (e.g.1 equiv) and triisopropylborate (e.g. approx.2 equiv), which was added dropwise to a solution of an appropriate lithiated base – thereby forming the compound of formula (IV).
  • the compounds of formulae (IB) and (IIB) may be known or prepared by methods in the literature, for instance compound of formula (IIB) may be prepared in accordance with the following scheme, under reaction conditions for instance those described in WO 2017/155909 or those in a literature article (e.g. mentioned herein).
  • XX1 RT 2.01 min, Area %: 100, Method: ChiralPak IG-3 (4.6x100 mm) 15:85 MeOH:CO2 (0.3% v/v iPrNH2) XX4 RT: 2.59, Area %: 100, Method: ChiralPak IG-3 (4.6x100 mm) 15:85 MeOH:CO2 (0.3% v/v iPrNH2) XX3 RT: 1.05, Area %: 100, Method: ChiralPak IG-3 (4.6x100 mm) 20:80 MeOH:CO2 (0.3% v/v iPrNH2) XX2 ee: 97.2 (RT: 1.68, Area %: 98.6, Method: ChiralPak IG-3 (4.6x100 mm) 20:80 MeOH:CO2 (0.
  • MIC Minimum Inhibitory Concentration
  • NTM Non-tuberculous mycobacteria
  • CLSI Clinical & Laboratory Standards Institute
  • MIC of avium ATCC700898 (MAC101) and M. abscessus ATCC19977 were determined with a start inoculum of 5x105 cells in Middlebrook 7H9 broth supplemented with 10% OADC, 0.5% glycerol, and 0.02% Tween 80.
  • Compounds were prepared in 384 well plates and were serially diluted (3-fold dilutions). Plates with compounds and with either M. avium ATCC700898 or M. abscessus ATCC19977 cells were inoculated with a final volume of 30 ⁇ L per well. Plates with M. avium ATCC700898 isolate were incubated at 37°C for 5 days whereas plates with M. abscessus ATCC19977 isolate were incubated at 37°C for 3 days, respectively.
  • CFU Colony forming units
  • avium ATCC700898 Infection was established within day 1 (D1). Test compounds or vehicle control were orally administrated QD 7 days/ week starting from day 1 post- infection.200 mg/kg Clarithromycin (CLA), 100 mg/kg Ethanbutol (EMD), and 10 mg/kg Rifampin (RIF) were used as standard of care (SOC) reference control. CLA and EMD were co-formulated in 0.5% methocel F4M suspension pH 7.2. Rif was formulated in 20% HPbCD. Investigational compounds bedaquiline (BDQ), TBAJ-876 and TBAJ-578 were solubilized in 20% HPpbCD HC pH2.5.
  • CLA Clarithromycin
  • EMD 100 mg/kg Ethanbutol
  • Rifampin Rifampin
  • BDQ dose 25 mg/kg was used to ensure maximum efficacious exposure based on PK profile.
  • TBAJ- 876 and TABJ-578 were dose matched at 25 mg/kg and PK matched (15 mg/kg for TBAJ-876 and 40 mg/kg for TABJ-578, respectively) with BDQ 25/mg/kg based on pharmacokinetic investigations.
  • Mice were euthanized at different time points (Day 1, Day 28, and Day 56) but 24 h after the last dose. Lungs and spleen samples were aseptically removed prior to homogenization with a gentleMACSTM Dissociator (Miltenyi Biotec). The weights of both organs were determined, and macroscopic lung lesion were scored.
  • the bacterial load in these organs was determined by plating serial dilutions of the organ homogenates onto Middlebrook 7H10 agar (BD Difco) supplemented with 0.5% (vol/vol) glycerol, 10% (vol/vol) OADC, and 0.4% charcoal.
  • Amphotericin B 100 ⁇ g/ml
  • polymycin B 25 ⁇ g/ml
  • carbenicillin 50 ⁇ g/ml
  • trimethoprim (20 ⁇ g/ml) were used in each agar plates to prevent growth by other organism.
  • the used drug was inactive against M. avium.
  • CFU on agar plates were counted after an incubation period of up to 8 weeks weeks at 37°C.
  • XX1 also referred to as TBAJ-587, which it is understood to correspond to
  • XX2, XX3 and XX4 The four possible stereoisomers of compound YY are assigned herein as YY1 (also referred to as TBAJ-876, which it is understood to correspond to), YY2, YY3 and YY4.
  • PK STUDIES IN ADVANCE OF TEST 3 Studies / modelling studies were performed in order to assess the PK of various doses of bedaquiline (BDQ), XX1 (TBAJ-587) and YY1 (TBAJ-876), as well as all of their corresponding M2 metabolites in order to make relative comparisons: - Single dose PK data was generated of the parent (XX1/YY1) and the corresponding N-desmethyl metabolite (referred to as the “M2 metabolite) - Exposure data of parent (XX1/YY1) and the M2 metabolite was simulated following repeated dosing starting from single dose data in mouse - Doses of XX1/YY1 (TBAJ-587 and TBAJ-876) were determined that would provide roughly equal exposure to Bedaquiline (BDQ) and its M2 metabolite (BDQ-M2) Bedaquiline (BDQ) - The total exposure of BDQ (+ BDQ-M2) at 25 mg/kg (repeated daily dos

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Abstract

La présente invention concerne une nouvelle utilisation in vivo dans le traitement de mycobactéries non tuberculeuses (notamment le complexe Mycobacterium avium).
PCT/EP2024/077192 2023-09-28 2024-09-27 Inhibiteurs de l'atp synthase destinés à être utilisés dans le traitement de mycobactéries non tuberculeuses Pending WO2025068448A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011436A1 (fr) 2002-07-25 2004-02-05 Janssen Pharmaceutica N.V. Derives de quinoleine et leur utilisation en tant qu'inhibiteurs mycobacteriens
WO2005117875A1 (fr) 2004-05-28 2005-12-15 Janssen Pharmaceutica N.V. Utilisation de derives quinoline substitues destines aux traitements de maladies mycobacteriennes resistant aux medicaments
WO2006067048A1 (fr) 2004-12-24 2006-06-29 Janssen Pharmaceutica N.V. Derives de quinoline destines au traitement de la tuberculose latente
WO2017155909A1 (fr) 2016-03-07 2017-09-14 The Global Alliance For Tb Drug Development, Inc. Composés antibactériens et utilisations de ceux-ci
WO2019034700A1 (fr) * 2017-08-16 2019-02-21 Glaxosmithkline Intellectual Property Development Limited Nouveaux composés

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011436A1 (fr) 2002-07-25 2004-02-05 Janssen Pharmaceutica N.V. Derives de quinoleine et leur utilisation en tant qu'inhibiteurs mycobacteriens
WO2005117875A1 (fr) 2004-05-28 2005-12-15 Janssen Pharmaceutica N.V. Utilisation de derives quinoline substitues destines aux traitements de maladies mycobacteriennes resistant aux medicaments
WO2006067048A1 (fr) 2004-12-24 2006-06-29 Janssen Pharmaceutica N.V. Derives de quinoline destines au traitement de la tuberculose latente
WO2017155909A1 (fr) 2016-03-07 2017-09-14 The Global Alliance For Tb Drug Development, Inc. Composés antibactériens et utilisations de ceux-ci
WO2019034700A1 (fr) * 2017-08-16 2019-02-21 Glaxosmithkline Intellectual Property Development Limited Nouveaux composés

Non-Patent Citations (6)

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Title
BUNDEGAARD, H: "Design of Prodrugs", 1985, ELESEVIER, pages: 1 - 92
FOO CAROLINE SHI-YAN ET AL: "Oxidative Phosphorylation-an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis", APPLIED SCIENCES, vol. 10, no. 7, 29 March 2020 (2020-03-29), pages 2339, XP093114837, ISSN: 2076-3417, Retrieved from the Internet <URL:https://www.mdpi.com/2076-3417/10/7/2339> DOI: 10.3390/app10072339 *
GRIFFITH ET AL., AM. J. RESPIR. CRIT. CARE MED, vol. 175, 2007, pages 367
KUMAR KARTIK ET AL: "Management of Mycobacterium avium complex and Mycobacterium abscessus pulmonary disease: therapeutic advances and emerging treatments", EUROPEAN RESPIRATORY REVIEW, 1 March 2022 (2022-03-01), pages 1 - 17, XP093233437, Retrieved from the Internet <URL:https://publications.ersnet.org/content/errev/31/163/210212.full.pdf> DOI: 10.1183/16000617.0212-2021 *
SARATHY ET AL.: "American Society for Microbiology", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 64, April 2020 (2020-04-01)
SARATHY JICKKY PALMAE ET AL: "TBAJ-876, a 3,5-Dialkoxypyridine Analogue of Bedaquiline, Is Active against Mycobacterium abscessus", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 64, no. 4, 24 March 2020 (2020-03-24), US, XP093066616, ISSN: 0066-4804, DOI: 10.1128/AAC.02404-19 *

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