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WO2025191054A1 - (s,e)-n-(1-cyclopropyl-3-(méthylsulfonyl)allyl)-2-(1,1-difluoroéthyl)-4-phénoxypyrimidine-5-carboxamide pour le traitement du cancer - Google Patents

(s,e)-n-(1-cyclopropyl-3-(méthylsulfonyl)allyl)-2-(1,1-difluoroéthyl)-4-phénoxypyrimidine-5-carboxamide pour le traitement du cancer

Info

Publication number
WO2025191054A1
WO2025191054A1 PCT/EP2025/056840 EP2025056840W WO2025191054A1 WO 2025191054 A1 WO2025191054 A1 WO 2025191054A1 EP 2025056840 W EP2025056840 W EP 2025056840W WO 2025191054 A1 WO2025191054 A1 WO 2025191054A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
inhibitor
cancer
patient
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/056840
Other languages
English (en)
Inventor
Sophia Maria BLAKE
Maria Isabel CUARTAS MAZA
Jan ECKMANN
Piergiorgio Francesco Tommaso PETTAZZONI
Juan SEOANE SUÁREZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Hoffmann La Roche Inc filed Critical F Hoffmann La Roche AG
Publication of WO2025191054A1 publication Critical patent/WO2025191054A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • FIGURE 1 shows (1) tumor volume and (2) Kaplan-Meyer curves of mice implanted with PDX2 and treated daily with the compound of formula (I) at the indicated doses.
  • FIGURE 2 shows (1) tumor volume and (2) Kaplan-Meyer curves of mice implanted with PDX3 and treated daily with the compound of formula (I) at the indicated doses.
  • an WRN inhibitor for the treatment of cancer, e.g., microsatellite instability (MSI-H) tumors, and/or in patients after relapse from a prior therapy such as an immunotherapy, wherein the WRN inhibitor is a compound having a structure of Formula (I): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) has an IIIPAC name of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4- phenoxypyrimidine-5-carboxamide.
  • the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof comprises at least one radioisotope.
  • radioisotopes are 2 H, 3 H, 13 C, 14 C and 18 F.
  • a WRN inhibitor may be useful in treating certain types of cancers, and more specifically tumors.
  • the tumor is an MSI-H tumor.
  • PDX Patient Derived Xenografts
  • CRC Colorectal cancer
  • the aim of this study is to investigate whether a novel WRN inhibitor would present antitumor activity in both patient immunotherapy naive and immunotherapy experienced.
  • the WRN inhibitor would have utility in both patients progressing after immunotherapy and as a first line treatment (i.e. , treatment naive patients), in combination with immune checkpoint inhibitors, in the latter case to delay or reduce the onset of resistance acquisition.
  • the agent investigated (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, is a novel covalent, irreversible inhibitor of WRN helicase that causes DNA damage accumulation and has selective antitumor activity in MSI cell lines and in vivo mouse models, including patient-derived models. Compound and synthesis are detailed in W02024/010782. [0016] The following definitions of the general terms used in the present description apply irrespectively of whether the terms in question appear alone or in combination with other groups.
  • inhibitor denotes a compound which competes with, reduces, or prevents the binding of a particular ligand to particular receptor, or which reduces or prevents the function of a particular protein.
  • pharmaceutically acceptable carrier and “pharmaceutically acceptable auxiliary substance” refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.
  • auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.
  • Such a formulation is a formulation in pharmaceutically acceptable form.
  • composition encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts.
  • a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state.
  • the “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
  • variable incorporates by reference the broad definition of the variable as well as in particular, more particularly and most particular definitions, if any.
  • the terms “treating,” “contacting” and “reacting” when referring to a chemical reaction mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e. , there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. Treatments include prophylactic treatment as well as the acute alleviation of symptoms.
  • pharmaceutically acceptable excipient denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, or lubricants used in formulating pharmaceutical products.
  • a "pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • the corresponding pharmaceutically acceptable salts with acids can be obtained by standard methods known to the person skilled in the art, e.g., by dissolving the compound of Formula (I) in a suitable solvent such as e.g., dioxan or THF and adding an appropriate amount of the corresponding acid.
  • a suitable solvent such as e.g., dioxan or THF
  • the products can usually be isolated by filtration or by chromatography.
  • the conversion of a compound of Formula (I) into a pharmaceutically acceptable salt with a base can be carried out by treatment of such a compound with such a base.
  • One possible method to form such a salt is e.g. by addition of 1/n equivalents of a basic salt such as e.g.
  • a suitable solvent e.g. ethanol, ethanol- water mixture, tetrahydrofuran-water mixture
  • the PD-1 inhibitor is selected from pembrolizumab (Keytruda®), nivolumab (Opdivo®) and RN888.
  • the PD-L1 inhibitor is selected from atezolizumab (Tecentriq®), avelumab (Bavencio®) and durvalumab (ImfinziTM).
  • the PD-L1 inhibitor is atezolizumab (Tecentriq®).
  • the patient suffers from brain metastases.
  • optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer of the compound.
  • a chirally pure or chirally enriched compound may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate.
  • Another embodiment provides a pharmaceutical composition containing the compound of Formula (I), or pharmaceutically acceptable salt thereof, for use according to the disclosure and one or more therapeutically inert carriers, diluents, or excipients, as well as a method to prepare such a pharmaceutical compositions.
  • the compound of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • compositions of the compound of Formula (I), alone or in combination with a second anticancer agent can be prepared for storage by mixing the active ingredients having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. (ed.) (1980)), in the form of lyophilized formulations or aqueous solutions.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine,
  • compositions of the compound of Formula (I) include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, as well as the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound of Formula (I) which produces a therapeutic effect.
  • compositions include the step of bringing into association the compound of Formula (I) with the carrier and, optionally, one or more accessory ingredients.
  • the pharmaceutical compositions can be prepared by uniformly and intimately bringing into association the compound of formula (I) with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of the compound of Formula (I) as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • the active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interracial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules
  • the formulations to be used for in vivo administration must be sterile. This can be readily accomplished by filtration through sterile filtration membranes.
  • the dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
  • the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general Formula (I) or of the corresponding amount of a pharmaceutically acceptable solvate thereof.
  • the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
  • the administration can be after a high-fat meal or following a 10-hour fast.
  • the checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor, optionally wherein the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (GP-675,206), or optionally wherein the PD-1 inhibitor is selected from pembrolizumab (Keytruda®), nivolumab (Opdivo®) and RN888, or optionally wherein the PD-L1 inhibitor is selected from atezolizumab (Tecentriq®), avelumab (Bavencio®) and durvalumab (ImfinziTM), or optionally wherein the PD-L1 inhibitor is atezolizumab (Tecentriq®).
  • the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (GP-675,206)
  • the PD-1 inhibitor is selected from pembrolizumab (Keytruda®
  • checkpoint inhibitor is atezolizumab (Tecentriq®).
  • a method of treating a patient suffering from a microsatellite instability (MSI-H) cancer comprising administering to the patient a therapeutically effective amount of a compound of Formula (I): or pharmaceutically acceptable salt thereof.
  • a method of treating a cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I): or pharmaceutically acceptable salt thereof, wherein the patient was previously administered an immunotherapy prior to start of the administration of the compound of Formula (I).
  • CTLA-4 inhibitor was ipilimumab (Yervoy®) or tremelimumab (GP-675,206).
  • checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.
  • CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (GP-675,206).
  • PD-1 inhibitor is pembrolizumab (Keytruda®), nivolumab (Opdivo®) or RN888.
  • PD-L1 inhibitor is atezolizumab (Tecentriq®), avelumab (Bavencio®) or durvalumab (ImfinziTM).
  • WRN inhibitor would have utility in both patients progressing immunotherapy and in first line, in combination with immune checkpoint inhibitors.
  • mice 2 mm x 2 mm tumor fragments of PDX2 and PDX3 were implanted subcutaneously in the right flank of NSG mice (NSG mouse (NOD scid gamma mouse) is a brand of immunodeficient laboratory mice). When tumor had grown to 100-300 mm 3 , mice were randomized according to their tumor volume (mm 3 ). Four groups were established as described below:
  • mice were distributed in four groups of 13 animals/group.
  • the treatments administered orally to each group are:
  • the Compound of formula (I) was administered daily through oral gavage at the doses of 5, 20 and 75 mg/kg to mice in groups 2, 3, and 4, respectively.
  • the animals were operated on and subcutaneously inoculating 100,000 cells/mouse. Once tumor growth started, measurements were taken. Tumor volume was measured twice weekly via caliper and mice euthanized when tumor reached a maximum of 1500 mm in diameter.
  • HPMC 1.25% (w/v) 6.25g in 500mL water
  • Figure 1 top graph shows tumor volume and lower graph shows Kaplan-Meyer curves of mice implanted with PDX2 and treated daily with the compound of formula (I) at the indicated doses.
  • Figure 2 top graph shows tumor volume and lower graph shows Kaplan-Meyer curves of mice implanted with PDX3 and treated daily with the compound of formula (I) at the indicated doses.
  • the pharmaceutical compositions conveniently contain about 1-500 mg, particularly 5-250 mg, of a compound of Formula (I), e.g., 5, 25, 100, or 500 mg of the compound of Formula (I).
  • the pharmaceutical compositions containing a compound of Formula (I) contains in addition about 1-500 mg, particularly 5-80 mg, of a MEK inhibitor in a fixed-dose combination.
  • compositions according to the disclosure are:
  • a film-coated tablet for oral administration may comprise the compound of formula (I) and the inactive ingredients sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, magnesium oxide, colloidal silicon dioxide, sodium croscarmellose and magnesium stearate.
  • the coating mixture may comprise polyvinyl alcohol, macrogol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.
  • the compound of Formula (I), lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine.
  • the mixture is returned to the mixer; the talc is added thereto and mixed thoroughly.
  • the mixture is filled by machine into suitable capsules, e.g., hard gelatin capsules.
  • Soft Gelatin Capsules of the following composition are manufactured with the components as listed in T able 3 or T able 4:
  • the compound of Formula (I) is dissolved in a warm melting of the other ingredients as listed in Table 3 or 4, and the mixture is filled into soft gelatin capsules of appropriate size.
  • the filled soft gelatin capsules are treated according to the usual procedures.
  • the suppository mass is melted in a glass or steel vessel, mixed thoroughly, and cooled to 45°C. Thereupon, the finely powdered compound of Formula (I) is added thereto and stirred until it has dispersed completely.
  • the mixture is poured into suppository molds of suitable size, left to cool; the suppositories are then removed from the molds and packed individually in wax paper or metal foil.
  • the compound of Formula (I) is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part).
  • the pH is adjusted to 5.0 by acetic acid.
  • the volume is adjusted to 1.0 ml by addition of the residual amount of water.
  • the solution is filtered, filled into vials using an appropriate overage and sterilized.
  • the compound of Formula (I) is mixed with lactose, microcrystalline cellulose, and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water.
  • the granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des méthodes d'utilisation d'un inhibiteur de l'hélicase WRN dépendant de l'ATP (WRNi) pour traiter des maladies associées à l'instabilité des microsatellites (MSI-H) et/ou pour traiter un patient atteint d'un cancer ayant fait une récidive lors d'une précédente immunothérapie (par exemple, une thérapie par inhibiteur de point de contrôle).
PCT/EP2025/056840 2024-03-15 2025-03-13 (s,e)-n-(1-cyclopropyl-3-(méthylsulfonyl)allyl)-2-(1,1-difluoroéthyl)-4-phénoxypyrimidine-5-carboxamide pour le traitement du cancer Pending WO2025191054A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP24163724.8 2024-03-15
EP24163724 2024-03-15
EP24172372 2024-04-25
EP24172372.5 2024-04-25

Publications (1)

Publication Number Publication Date
WO2025191054A1 true WO2025191054A1 (fr) 2025-09-18

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2025/056840 Pending WO2025191054A1 (fr) 2024-03-15 2025-03-13 (s,e)-n-(1-cyclopropyl-3-(méthylsulfonyl)allyl)-2-(1,1-difluoroéthyl)-4-phénoxypyrimidine-5-carboxamide pour le traitement du cancer

Country Status (1)

Country Link
WO (1) WO2025191054A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024010782A1 (fr) 2022-07-06 2024-01-11 Vividion Therapeutics, Inc. Compositions pharmaceutiques comprenant des inhibiteurs de l'hélicase wrn

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024010782A1 (fr) 2022-07-06 2024-01-11 Vividion Therapeutics, Inc. Compositions pharmaceutiques comprenant des inhibiteurs de l'hélicase wrn

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1980
SCHOENFELD, AJHELLMANN, MD: "Acquired Resistance to Immune Checkpoint Inhibitors", CANCER CELL, vol. 37, 2020, pages 443 - 455, XP086132195, DOI: 10.1016/j.ccell.2020.03.017

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