WO2023242103A1 - Nouveaux inhibiteurs de ras - Google Patents

Nouveaux inhibiteurs de ras Download PDF

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Publication number
WO2023242103A1
WO2023242103A1 PCT/EP2023/065616 EP2023065616W WO2023242103A1 WO 2023242103 A1 WO2023242103 A1 WO 2023242103A1 EP 2023065616 W EP2023065616 W EP 2023065616W WO 2023242103 A1 WO2023242103 A1 WO 2023242103A1
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kras
compound
ras
formula
pharmaceutically acceptable
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PCT/EP2023/065616
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English (en)
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Krishnaraj Rajalingam
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KHR Biotec GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring

Definitions

  • the present invention relates to the use of compounds of formula (I) as RAS inhibitors and as a medicament, in particular for use in treating proliferative disorders, inflammatory diseases and/or genetic disorders.
  • the present invention relates further to a pharmaceutical composition comprising the compounds of formula (I).
  • the present invention relates to a method of inhibiting growth, proliferation or metastasis of cancer cells in a subject in need thereof, in particular which may encompass subsets of patients defined by their mutational status of the RAS oncogene or patients who might have developed resistance to the standard of care or treatment with RAS mutation specific inhibitors.
  • the present invention also relates to a method of inhibiting RAS molecules in treating genetic disorders like RASopathies or inflammatory disorders like Adenomyosis where KRAS gene is mutationally activated.
  • the present invention relates to a method of inhibiting proliferation and or secretion of factors from a cell population sensitive towards inhibiting RAS activation in vitro, in particular sensitive towards inhibiting KRAS, HRAS and NRAS activation in vitro.
  • the present invention relates to a kit containing a formulation comprising a pharmaceutical composition comprising a compound of formula (I).
  • RAS proteins represent a group of closely related monomeric globular proteins which are associated with the plasma membrane and are able to bind either GDP or GTP.
  • RAS that contains bound GDP represents the "inactive" state
  • the binding of GTP to RAS in exchange to a GDP represents the "active” state, such that the protein is able to interact with other “effector” proteins of downstream targets.
  • RAS proteins can be regarded as small GTPases that function as molecular switches controlling the transmission of extracellular signals from outside of the cell to the nucleus by various effector proteins.
  • RAS mutations of RAS lead to defects in GAP-mediated GTP hydrolysis and thus result in the accumulation of RAS in the GTP-bound active state. This leads to uncontrollable proliferation, which is a hall mark of cancer cells. Uncontrolled activation of RAS is also detected in genetic disorders like RASOpathies. Activating RAS mutations are detected in inflammatory disorders like Adenomyosis/endometriosis which contributes to proliferation and invasions of endometrial cells and resistance to Progesterone (S. Inoue, Nature Comm. 2019, 10, 5785; PMID: 31857578).
  • KRAS oncogene inhibitors e.g. to KRAS G12 C inhibitors
  • KRAS G12 C inhibitors Tanaka et al., Cancer Discov, 2021 , PMID 33824136
  • the patients treated with KRAS G12 C inhibitors often develop secondary mutations in other RAS isoforms (Awad MM et al. New England J. Med., 2021 PMID34161704).
  • Bithionol is bis-dichlorophenol, and it is structurally similar to hexachlorophene. It is the antihelmintic drug of choice for treating humans infected with Fasciola hepatica. It is an alternative drug to praziquantel that is used for treating pulmonary and cerebral paragonimiasis.
  • WO2020/252131 relates to a method for treatment of bacterial infections caused by MRSA.
  • Bithionol shows bacterial activity against bacterial persister cells.
  • US3152041 refers to the preparation of bithionol and its use as and anthelmintic.
  • W02009/151644 refers to compounds, inter alia to bithionol, which inhibit growth and metastasis of cancer cells.
  • EP3578981 relates anti-proliferative compound or a pharmaceutical composition comprising said anti proliferative compound for use in the prevention or treatment of cancer.
  • RAS RAS isoforms like HRAS and NRAS
  • targeting of other RAS isoforms like HRAS and NRAS is required to combat secondary, acquired resistance to the standard of care including several cancer therapeutics.
  • R 3 is halogen
  • the invention further relates to the compound of the formula (I) wherein
  • R 1 is halogen
  • the invention further relates to the compound of the formula (I) wherein
  • R 3 is halogen
  • R 1 is halogen
  • R 2 is halogen
  • the invention further relates to the compound of the formula (I) wherein
  • R 3 is halogen
  • the invention further relates to the compound of the formula (I) wherein
  • R 4 is halogen; or a pharmaceutically acceptable salt thereof, as defined above and below, for use as inhibitor of RAS protein activation for treatment and/or prophylaxis of proliferative disorders and/or inflammatory diseases, which are resistant to treatment with RAS mutation specific inhibitors different from compounds of formula (I), preferably, wherein the resistance results from a secondary mutation, in particular results from a secondary mutation, wherein KRAS G12C/Y96D, KRAS G12C/Y96C and/or KRASG12C/Y96S is involved.
  • R 1 is halogen
  • R 2 is halogen
  • R 3 is halogen
  • the invention further relates to a composition (1) comprising at least one compound of formula (I) as defined above and below, in particular to compounds of formula (A) as defined above and below, or a pharmaceutically acceptable salt, and RAS mutation specific inhibitors.
  • the RAS mutation specific inhibitors are different from compounds of formula (I).
  • the invention further relates to compounds (I), in particular to compounds of formula (A) as defined above and below, or a pharmaceutically acceptable salt thereof, or a composition (1 ) as defined above and below, or pharmaceutical compositions comprising at least one compound of formula (I), in particular selected from compound (A) as defined above and below, or a composition (1) as defined above and below, for use as a RAS- RAF disruptor.
  • the invention further relates to compounds (I), in particular to compounds of formula (A) as defined above and below, or a pharmaceutically acceptable salt thereof, or a composition (1 ) as defined above and below, or pharmaceutical compositions comprising at least one compound of formula (I), in particular selected from compound (A) as defined above and below, or a composition (1) as defined above and below, for use as a medicament.
  • the invention further relates to compounds (I) according to the invention, in particular to compounds of formula (A) as defined above and below, or a pharmaceutically acceptable salt thereof, or a composition (1 ) as defined above and below, or pharmaceutical compositions comprising at least one compound of formula (I), in particular selected from compound (A) as defined above and below, or a composition (1) as defined above and below, for the treatment and/or prophylaxis of diseases.
  • the invention further relates to compounds (I) according to the invention, in particular to compound of formula (A) as defined above and below, or a pharmaceutically acceptable salt thereof, or a composition (1 ) as defined above and below, or pharmaceutical compositions comprising at least one compound of formula (I), in particular selected from compound (A) as defined above and below, or a composition (1) as defined above and below, for use in treating proliferative disorders.
  • the invention further relates to compounds (I) according to the invention, in particular to compounds of formulae (A) as defined above and below, or a pharmaceutically acceptable salt thereof, or a composition (1) as defined above and below, or a pharmaceutical compositions comprising at least one compound of formula (I), in particular selected from compounds (A) as defined above and below, or a composition (1) as defined above and below, for use in treating genetic disorders.
  • the invention further relates to compounds (I) according to the invention, in particular to compounds of formula (A) as defined above and below, or a pharmaceutically acceptable salt thereof, or a composition (1 ) as defined above and below, or a pharmaceutical compositions comprising at least one compound of formula (I), in particular selected from compound (A) as defined above and below, or a composition (1) as defined above and below, for use in treating endometriosis and/or adenomyosis, more especially, where KRAS is mutated.
  • the invention further relates to compounds (I) according to the invention, in particular to compound of formula (A) as defined above and below or a pharmaceutically acceptable salt thereof, or a composition (1 ) as defined above and below, or pharmaceutical compositions comprising at least one compound of formula (I), in particular selected from compound (A) as defined above and below, or a composition (1) as defined above and below, for use in treating cancer.
  • the invention further relates to compounds (I) according to the invention, in particular to compound of formula (A) as defined above and below or a pharmaceutically acceptable salt thereof, or a composition (1 ) as defined above and below, or pharmaceutical compositions comprising at least one compound of formula (I), in particular selected from compound (A) as defined above or below, or a composition (1) as defined above and below, for use as inhibitor of RAS protein (KRAS, HRAS or NRAS oncogenes) activation.
  • KRAS RAS protein
  • the invention further relates to compounds (I) according to the invention, in particular to compound of formula (A) as defined above and below or a pharmaceutically acceptable salt thereof, or a composition (1 ) as defined above and below, or pharmaceutical compositions comprising at least one compound of formula (I), in particular selected from compound (A) as defined above or below, or a composition (1) as defined above and below, for treating or preventing any diseases or conditions that are associated with the activity of RAS protein (RAS oncogene).
  • RAS oncogene RAS protein
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound (I) according to the invention, in particular compound of formula (A) as defined above and below, or a composition (1) as defined above and below, or a pharmaceutically acceptable salt thereof, or a composition (1) as defined above and below, and a pharmaceutically acceptable carrier.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound (I) according to the invention, in particular compound of formula (A) as defined above and below, or a pharmaceutically acceptable salt thereof, or a composition (1) as defined above and below, wherein the pharmaceutical composition additionally comprises a further active substance, preferably selected from chemotherapeutic agents, radiotherapeutic agents, immuno-oncology agents and combinations thereof.
  • the invention further relates to a method of inhibiting proliferation of a cell population sensitive towards inhibiting RAS activation in vitro or ex vivo, the method comprising contacting the cell population with a compound (I) according to the invention, in particular a compound of formula (A) as defined above and below, or a therapeutically acceptable salt thereof, or a composition (1 ) as defined above and below, or a pharmaceutical compositions comprising at least one compound of formulae (I), in particular selected from compound (A) as defined above or below, or a composition (1) as defined above and below.
  • a compound (I) according to the invention in particular a compound of formula (A) as defined above and below, or a therapeutically acceptable salt thereof, or a composition (1 ) as defined above and below, or a pharmaceutical compositions comprising at least one compound of formulae (I), in particular selected from compound (A) as defined above or below, or a composition (1) as defined above and below.
  • the compounds according to the invention exhibit advantageous RAS inhibition properties.
  • the compounds according to the invention qualify as inhibitors of RAS oncogene activation. It is assumed that RAS-effector interaction especially when RAS is activated by oncogenic somatic mutations is disrupted.
  • the compounds inhibit NRAS and HRAS by functionally uncoupling their binding to their effectors in the cells.
  • activations mean the ability of RAS to bind to its effector molecules like RAF kinases, PI3K kinases through the RAS binding domain (RBD) or RAS -Associated domain (RA domain) present in the effector proteins (Like RASSF) in a GTP dependent manner.
  • RAS RAS binding domain
  • RA domain RAS -Associated domain
  • proliferative disorders refer to disorders that are associated with some degree of abnormal cell proliferation.
  • proliferative disorder is cancer.
  • the cancer is selected from prostate, colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma), mesothelial lining, white blood cell (including lymphoma and leukemia), esophagus, breast, muscle, connective tissue, lung (including small cell lung carcinoma and non-small-cell carcinoma), adrenal gland, thyroid, kidney, or bone; or glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, cutaneous basocellular carcinoma, haematological malignancies (inclooding blood, bone marrow and lymph nodes) or testicular seminoma.
  • R 2 is selected from F and Cl
  • the invention relates to compound A or a pharmaceutically acceptable salt thereof, for use as inhibitor of RAS protein activation, for treatment and/or prophylaxis of diseases, wherein RAS-signaling is involved.
  • the invention relates to compound A or a pharmaceutically acceptable salt thereof, for use as inhibitor of RAS protein activation for treatment and/or prophylaxis of proliferative disorders and/or inflammatory diseases, which are resistant to treatment with RAS mutation specific inhibitors different from compounds of formula (I), preferably wherein the resistance results from a secondary mutation, in particular results from a secondary mutation, wherein KRAS G12C/Y96D, KRAS G12C/Y96C and/or KRAS G12C/Y96S is involved.
  • composition (1 ) comprising compound (A) or a pharmaceutically acceptable salt thereof, and at least one RAS mutation specific inhibitor, in particular KRAS mutation specific inhibitors, especially sotorasib (also known as AMG510 or (1 M)-6- Fluor-7-(2-fluor-6-hydroxyphenyl)-1 -[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2- methyl-4-(prop-2-enoyl)piperazin-1 -yl]pyrido[2,3-d]pyrim idin-2( 1 H)-on) and/or adagrasib (also known as MRTX848, or (2S)-4-[7-(8-Chlor-1 -naphthyl)-5,6,7,8-tetrahydro-2-[[(2"S")- 1 -methyl-2-pyrrolidinyl]methoxy]pyrido[3,4-"d”]pyrimidin-4-y
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benef it/risk ratio.
  • terapéuticaally effective is intended to qualify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence, while avoiding adverse side-effects typically associated with alternative therapies.
  • effective anticancer agents prolong the survivability of the patient or his/her life quality, inhibit the rapidly proliferating cell growth associated with the formation of neoplasms, or effect a regression of the neoplasms.
  • treat refers to any type of intervention or process performed on, or administering an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease.
  • prophylaxis or “prevention” refers to administration to a subject who does not have a disease to prevent the disease from occurring.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • subject includes any human or animal.
  • methods and compositions herein disclosed can be used to treat a subject having cancer.
  • a (non-human) animal includes all vertebrates, e.g. mammals and non-mammals, including cows, sheep, pigs, goats, horses, poultry, dogs, cats, non-human primates, rodents etc.
  • the subject is a human subject.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid diluent, solvent, excipient, manufacturing aid (e.g. lubricant) or encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable other ingredients are the afore-mentioned carrier and further additives, including adjuvants, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, bittering agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, dispensing agents, etc..
  • Suitable additives are selected depending on the nature of the mode of administration and dosage forms; and not injurious to the patient.
  • composition means a composition comprising a compound of the invention in combination with at least one further compound selected from a) at least one further pharmaceutically active substance and b) at least one additional pharmaceutically acceptable carrier and or additive.
  • RAS inhibitor refers to an agent capable of decreasing RAS protein levels, decreasing RAS activity levels and/or inhibiting RAS expression levels in the cells.
  • the RAS inhibitor may be a reversible or irreversible inhibitor.
  • RAS protein refers to a protein that is a member of a family of related proteins that are expressed in all human and animal cell lineages and organs. All RAS protein family members belong to a class of proteins called small GTPase (also known as small G proteins, a family of hydrolase enzymes that can bind and hydrolyse GTP), and are involved in transmitting signals within cells (cellular signal transduction).
  • RAS is the prototypical member of the RAS superfamily of proteins, which are all related in three-dimensional structure and regulate diverse cell behaviours. When RAS is 'switched on' by incoming signals, it subsequently switches on other proteins, which ultimately turn on genes involved in cell growth, differentiation, and survival. Mutations in RAS genes can lead to the production of permanently activated RAS proteins, which can cause unintended and overactive signaling inside the cell, even in the absence of incoming signals. Because these signals result in cell growth and division, overactive RAS signaling can ultimately lead to cancer.
  • the three RAS genes in humans (HRAS, KRAS, and NRAS) are the most common oncogenes in human cancer.
  • the clinically most notable members of the RAS subfamily are HRAS, KRAS and NRAS.
  • members of this subfamily which are e.g. selected from DIRAS1 , DIRAS2, DIRAS3, ERAS, GEM, MRAS, NKIRAS1 , NKIRAS2, NRAS, RALA, RALB, RAP1A, RAP1 B, RAP2A, RAP2B, RAP2C, RASD1 , RASD2, RASL10A, RASL10B, RASL11A, RASL11 B, RASL12, REM1 , REM2, RERG, RERGL, RRAD, RRAS, RRAS2.
  • the most common alterations in NRAS are NRAS Mutation (2.87%), NRAS Exon 3 Mutation (1.90%), NRAS Exon 3 Missense (1.88%), NRAS Codon 61 Missense (1.72%), and NRAS Exon 2 Mutation (0.95%)
  • the most common alterations in HRAS are HRAS Mutation (0.77%), HRAS Missense (0.75%), HRAS Exon 2 Mutation (0.30%), HRAS Codon 61 Missense (0.26%), and HRAS Q61 R (0.14%)
  • the most common alterations in HRAS are HRAS Mutation (0.77%), HRAS Missense (0.75%), HRAS Exon 2 Mutation (0.30%), HRAS Codon 61 Missense (0.26%), and HRAS Q61 R (0.14%) (Source Mycancer genome portal).
  • the compound(s) of formulae (I) and (A) as defined above and the composition (1) as defined above and a pharmaceutical composition comprising at least one compound of formulae (I) and (A) as defined above or the composition (1) as defined above may be administered to humans and animals, preferably humans.
  • any method of administration may be used to deliver the compound or pharmaceutical composition according to the invention to a subject.
  • Suitable methods of administration are orally, enterally, parenterally, intravenously, topically, intramuscular, subcutaneous routes.
  • the compound(s) of formulae (I) and (A) as defined above can selectively decrease RAS protein levels, decrease RAS activity levels, in particular decrease the activity levels of HRAS and NRAS, especially KRAS4A,and KRAS4B) in the cells.
  • the compound(s) of formulae (I) and (A) as defined above can be used to selectively decrease RAS activity levels in cells or in an individual in need of a decrease in RAS protein levels, decrease in RAS activity levels by administering an inhibiting amount of compound(s) of formulae (I) and (A) as defined above or a salt thereof.
  • the present invention provides a combined preparation of a compound or compounds of formulae (I) and (A) as defined above, and/or a pharmaceutically acceptable salt thereof, and (an) additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment and/or prophylaxis of (multiple) diseases, preferably of proliferative disorders (e.g. cancer), in particular disorders associated with the activity of RAS protein.
  • Additional therapeutic agent(s) are selected from chemotherapeutic agents, radiotherapeutic agents, immuno-oncology agents, and combinations thereof.
  • the compound(s) of formulae (I) and (A) as defined above are sequentially administered prior to administration of the immuno-oncology agent.
  • compound(s) of formulae (I) and (A) as defined above are administered concurrently with the immuno-oncology agent.
  • compound(s) of formulae (I) and (A) as defined above are sequentially administered after administration of the immuno- oncology agent.
  • compound(s) of formulae (I) and (A) as defined above may be coformulated with an immuno-oncology agent.
  • Immuno-oncology agents include, for example, a small molecule drug, antibody or other biologic or small molecule.
  • biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines.
  • the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human.
  • the immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators).
  • Suitable of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF).
  • IgSF immunoglobulin super family
  • B7 family which includes B7-1 , B7-2, B7-H1 (PD-L1 ), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • an antagonist of a protein that inhibits T cell activation e.g., immune checkpoint inhibitors
  • a protein that inhibits T cell activation e.g., immune checkpoint inhibitors
  • an agonist of a protein that stimulates T cell activation such as B7-1 , B7-2, CD28, 4- 1 BB (CD 137), 4-1 BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.
  • agents for combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1 R antagonists such as CSF-1 R antagonist antibodies including RG7155.
  • the combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • Combination therapy can also embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g surgery or radiation treatment).
  • the combination therapy further comprises a non-drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved.
  • the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • Types of cancers that may be treated with the compounds of formulae (I) and (A) as defined above include, but are not limited to, prostate, colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma), mesothelial lining, white blood cell (including lymphoma and leukemia), esophagus, breast, muscle, connective tissue, lung (including small cell lung carcinoma and non-small-cell carcinoma), adrenal gland, thyroid, kidney, or bone; or glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, cutaneous basocellular carcinoma, haematological malignancies (including blood, bone marrow and lymph nodes) or testicular seminoma.
  • prostate colon, rectum, pancreas, cer
  • the invention relats to the inhibition of HRAS mutations, which are detected in bladder urothelial carcinoma, breast invasive ductal carcinoma, lung adenocarcinoma, prostatecarcinoma and colon adenocarcinoma. This accounts to nearly 0.94% of all human cancers and nearly 1 .02% of solid tumours.
  • One or more additional pharmaceutical agents or treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g ., IL2 and GM-CSF), and/or tyrosine kinase inhibitors can be optionally used in combination with the compound(s) of formulae (I) and (A), as defined above, for treatment of RAS protein associated diseases, disorders or conditions.
  • the agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • Melanomas that are confined to the arms or legs may also be treated with a combination of agents including one or more compound(s) of formulae (I) and (A) as defined, using a hyperthermic isolated limb perfusion technique.
  • This treatment protocol temporarily separates the circulation of the involved limb from the rest of the body and injects high doses of chemotherapy into the artery feeding the limb, thus providing high doses to the area of the tumor without exposing internal organs to these doses that might otherwise cause severe side effects.
  • the fluid is warmed to 38.9 °C to 40 °C.
  • Melphalan is the drug most often used in this chemotherapy procedure. This can be given with another agent called tumor necrosis factor (TNF).
  • TNF tumor necrosis factor
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), mithramycin, deoxyco-formycin, mitomycin-C, L- asparaginase, interferons (especially IFN-a), etoposide, and teniposide.
  • certain natural products and their derivatives for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins
  • vinblastine vincristine, vindesine
  • bleomycin dactinomycin, daunorubicin, dox
  • cytotoxic agents include navelbene, CPT-11 , anastrazole, letrazole, capecitabine, reloxafme, and droloxafme.
  • anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4.
  • anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.
  • Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • at least one compound of formulae (I) and (A) as defined above and at least one chemotherapeutic agent are administered to the patient concurrently or sequentially.
  • at least one compound of formulae (I) and (A) as defined above may be administered first, at least one chemotherapeutic agent may be administered first, or at least one compound of formulae (I) and (A) as defined above may be administered at the same time.
  • the compounds may be administered in any order.
  • the invention also provides pharmaceutically compositions which comprise a therapeutically effective amount of one or more of the compound(s) of formulae (I) and (A), as defined above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally one or more additional therapeutic agents as described above.
  • the compound(s) of formulae (I) and (A), as defined above, may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the compound(s) and compositions of the compound(s) of formulae (I) and (A) as defined above, can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g.
  • aqueous or nonaqueous solutions or suspensions nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of suppositories.
  • nasally including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of suppositories.
  • nasally including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of suppositories.
  • nasally including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of suppositories.
  • nasally including administration to the nasal membranes, such as
  • any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparation.
  • exemplary oral preparations include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs.
  • Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration.
  • a pharmaceutical composition in accordance with the invention can contain at least one agent selected from sweetening agents, flavoring agents, bittering agents, coloring agents, demulcents, antioxidants, and preserving agents.
  • a tablet can either be uncoated, or coated by known techniques to either mask the bad taste of an unpleasantly tasting drug, or delay disintegration and absorption of the active ingredient in the gastrointestinal tract thereby sustaining the effects of the active ingredient for a longer period.
  • exemplary water soluble taste masking materials include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl- cellulose.
  • Exemplary time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.
  • Hard gelatin capsules can, for example, be prepared by mixing at least one compound of formulae (I) and (A) as defined above, and/or at least one salt thereof with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.
  • Soft gelatin capsules can, for example, be prepared by mixing at least one compound of formulae (I) and (A) as defined above, and/or at least one pharmaceutically acceptable salt thereof with at least one water soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.
  • An aqueous suspension can be prepared, for example, by admixing at least one compound of formulae (I) and (A) as defined above and/or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of an aqueous suspension.
  • An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and/or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.
  • Oily suspensions can, for example, be prepared by suspending at least one compound of formulae (I) and (A) as defined above and/or at least one pharmaceutically acceptable salt thereof in either a vegetable oil, such as, for example, arachis oil, olive oil, sesame oil and coconut oil or in mineral oil, such as, for example, liquid paraffin.
  • An oily suspension can also contain at least one thickening agent, such as, for example, beeswax, hard paraffin and cetyl alcohol.
  • at least one of the sweetening agents already described hereinabove, and/or at least one flavoring agent can be added to the oily suspension.
  • An oily suspension can further contain at least one preservative, including, but not limited to, for example, an anti-oxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol.
  • Dispersible powders and granules can, for example, be prepared by admixing at least one compound of formulae (I) and (A) as defined above and/or at least one pharmaceutically acceptable salt thereof with at least one dispersing and/or wetting agent; at least one suspending agent; and/or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents are as already described above.
  • Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid.
  • dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents.
  • the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • Suitable emulsifying agents include, but are not limited to, for example, naturally-occurring phosphatides, e.g., soy bean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the compound(s) of formulae (I) and (A) as defined above and/or at least one pharmaceutically acceptable salt thereof can, for example, also be delivered intravenously, subcutaneously, and/or intramuscularly via any pharmaceutically acceptable and suitable injectable form.
  • injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer’s solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions and aqueous or oleaginous suspensions.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • the active ingredient may also be administered by injection as a composition with suitable carriers, including saline, dextrose, water or with cyclodextrin solubilization (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or micellar solubilization (i.e. Tween 80).
  • suitable carriers including saline, dextrose, water or with cyclodextrin solubilization (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or micellar solubilization (i.e. Tween 80).
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3- butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1 ,3- butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • a sterile injectable oil-in-water microemulsion can, for example, be prepared by 1) dissolving at least one compound of formulae (I) and (A) as defined above in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the compound(s) of formulae (I) and (A) as defined above containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.
  • an oily phase such as, for example, a mixture of soybean oil and lecithin
  • a sterile aqueous or oleaginous suspension can be prepared in accordance with methods already known in the art.
  • a sterile aqueous solution or suspension can be prepared with a non-toxic parenterally-acceptable diluent or solvent, such as, for example, 1 ,3-butane diol; and a sterile oleaginous suspension can be prepared with a sterile non- toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.
  • Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art.
  • Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, L. V. Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.
  • the amounts of compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depend on a variety of factors, including the age, weight, sex, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods.
  • the daily dose can be administered in one to four doses per day. Other dosing schedules include one dose per week and one dose per two day cycle.
  • kits useful useful, for example, in the treatment or prevention of RAS protein-associated diseases.
  • the present invention also relates to a kit containing a formulation comprising: a) a pharmaceutical composition comprising a compound of formulae (I) and (A) as defined above, or a therapeutically acceptable salt thereof, or the composition (1) as defined above and a pharmaceutically acceptable carrier; and b) instructions for dosing of the pharmaceutical composition for the treatment of a disorder in which inhibition of RAS activation is effective in treating the disorder.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art.
  • kit components such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
  • Compound(s) of the formulae (I) and (A) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • a typical injectable preparation is produced by aseptically placing at least one of the compound of the formulae (I) and (A) (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions or the composition (1 ) as defined above of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound(s) of formulae (I) and (A) as defined above employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a suitable daily dose of compound(s) of formulae (I) and (A) as defined above will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compound(s) of formulae (I) and (A) as defined above for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain aspects of the invention, dosing is one administration per day.
  • Bithionol inhibits K-RAS, N-RAS and H-RAS.
  • Metabolic activity was quantified using Cell Proliferation Kit I (Roche, Basel, Switzerland). Cells were seeded in 96-well cell culture plates, using 5000 cells per well for NCI-H358 cells. After treatment, 10 pl of MTT solution was added and incubated for 2 h in CO2 incubator. Then 100 pl of solubilization buffer was added to each well and incubated overnight in CO2 incubator. Cell viability, assessed by the amount of metabolized MTT, was quantified by measuring absorbance at 570 nm.
  • MTT assay for the growth of different tumor cell lines with RAS mutations in soft agar with Bithionol Shown are data from three independent experiments.
  • NCI-H358, H358, H2122, ASPC-1 , HCT-116, T24 and HT1080 cells were used for the soft agar colony formation assay. After the treatment with Bithionol, the colonies were stained with MTT and the value was quantified by measuring absorbance at 570 nm after solubilization. The results represent mean ⁇ SEM from 3 independent experiments. growth of cancer.
  • Figure 3 RASOpathie-Model of Bithionol; MTT assay for cell viability in 96 well cell culture plate
  • Bithionol inhibits RAS protein of RASOpathie.
  • HeLa S3 (DSMZ) were authenticated by Eurofin genomics and cultured in DMEM (10 % heat inactivated FBS). NCI-H358 cells were cultured in RPMI-1640 (10% heat inactivated FBS).
  • Bithionol (2,2'-sulfanediylbis(4,6-dichlorophenol)), CAS. Nr.: 97-18-7 commercial available by Sigma Aldrich.

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Abstract

La présente invention concerne l'utilisation de composés de formule (I) en tant qu'inhibiteurs de RAS et en tant que médicament, en particulier pour une utilisation dans le traitement de troubles prolifératifs, de maladies inflammatoires et/ou de troubles génétiques. La présente invention concerne en outre une composition pharmaceutique comprenant les composés de formule (I). De plus, la présente invention concerne un procédé d'inhibition de la croissance, de la prolifération ou de la métastase de cellules cancéreuses chez un sujet en ayant besoin, comprenant en particulier des sous-ensembles de patients définis par leur état mutationnel de l'oncogène RAS ou des patients qui pourraient avoir développé une résistance à la norme de soins ou de traitement avec des inhibiteurs spécifiques de la mutation RAS. La présente invention concerne également un procédé d'inhibition de molécules RAS dans le traitement de troubles génétiques tels que les RASopathies ou les troubles inflammatoires tels que l'adénomyose où le gène KRAS est activé par mutation. De plus, la présente invention concerne un procédé d'inhibition de la prolifération et/ou de la sécrétion de facteurs à partir d'une population cellulaire sensible à l'inhibition de l'activation de RAS in vitro, en particulier sensible à l'inhibition de l'activation de KRAS, HRAS et NRAS in vitro. En outre, la présente invention concerne un kit contenant une formulation comprenant une composition pharmaceutique comprenant un composé de formule (I).
PCT/EP2023/065616 2022-06-13 2023-06-12 Nouveaux inhibiteurs de ras WO2023242103A1 (fr)

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Citations (4)

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WO2009151644A2 (fr) 2008-06-13 2009-12-17 Yale University Inhibiteurs à petites molécules d'autotaxine et procédés d'utilisation
EP3578981A1 (fr) 2018-06-06 2019-12-11 Technische Universität Dresden Traitement anticancéreux de sujets présélectionnée et procédés de criblage permettant d'identifier des sujets prédisposés
WO2020252131A1 (fr) 2019-06-12 2020-12-17 Ausubel Frederick M Composés antibiotiques

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US3152041A (en) 1961-05-25 1964-10-06 Diamond Lab Inc Piperazine-bithionol anthelmintic
WO2009151644A2 (fr) 2008-06-13 2009-12-17 Yale University Inhibiteurs à petites molécules d'autotaxine et procédés d'utilisation
EP3578981A1 (fr) 2018-06-06 2019-12-11 Technische Universität Dresden Traitement anticancéreux de sujets présélectionnée et procédés de criblage permettant d'identifier des sujets prédisposés
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