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EP4536630A1 - Nouveaux inhibiteurs de ras - Google Patents

Nouveaux inhibiteurs de ras

Info

Publication number
EP4536630A1
EP4536630A1 EP23728834.5A EP23728834A EP4536630A1 EP 4536630 A1 EP4536630 A1 EP 4536630A1 EP 23728834 A EP23728834 A EP 23728834A EP 4536630 A1 EP4536630 A1 EP 4536630A1
Authority
EP
European Patent Office
Prior art keywords
kras
compound
ras
formula
pharmaceutically acceptable
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
EP23728834.5A
Other languages
German (de)
English (en)
Inventor
Krishnaraj Rajalingam
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.)
KHR Biotec GmbH
Original Assignee
KHR Biotec GmbH
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 KHR Biotec GmbH filed Critical KHR Biotec GmbH
Publication of EP4536630A1 publication Critical patent/EP4536630A1/fr
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

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 froma 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
  • 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.
  • 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).
  • RAS Rasbet al.
  • GTP GTP-bound form
  • NRAS NRAS
  • their activation cycle is regulated by the binding of GDP or GTP which in turn is controlled by GAPs or GEFs.
  • GAPs or GEFs GAPs or GEFs.
  • GTP-bound form they bind to their effector proteins and trigger multiple signalling pathways that control various fundamental cellular processes.
  • 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.
  • 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).
  • Alexidine dihydrochloride is an antibacterial and antiplaque agent against Streptococcus mutans, Actinomyces viscosus, and Actinomyces naesludii.
  • alexidine dihydrochloride inhibits the activity of GtfB in solution and on the surface of SHA beads.
  • W02020/176825 discloses bis-biguanide derivatives, such as alexidine, for the use as medicament for treating cancer, in particular small cell lung cancer.
  • alexidine dihydrochloride is suitable for use as an inhibitor of RAS protein activation, in particular, wherein KRAS G12V, NRAS G12V, HRAS G12V, KRAS G12C, KRAS G12D, KRAS G12C/Y96C, KRAS G12C/Y96DS, KRAS G13C, KRAS G13D, KRASG13S, KRAS Q61 H, KRAS Q61 R or KRAS Q61 K is involved.
  • alexidine dihydrochloride inhibits the expression and/or the activation of RAS.
  • Activation is defined as 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.
  • RBD RAS binding domain
  • RA domain RAS -Associated domain
  • 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.
  • the invention relates to compounds of formula (I) wherein
  • R 1 is H or Ci-C 8 alkyl
  • the invention further relates to the compound of the formula (I) wherein
  • R 1 is H or Ci-C 8 alkyl
  • the invention further relates to the compound of the formula (I) wherein
  • the invention further relates to the compound of the formula (I) wherein
  • the invention in particular relates to compounds of formula (I) wherein
  • R 1 is H or Ci-C 8 alkyl
  • R 2 is H or Ci-C 8 alkyl; n is 2, 3, 4, 5, 6 or 7; or a pharmaceutically acceptable salt thereof, for use as inhibitor of RAS protein activation.
  • 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 formulae (A) and (B) 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 formulae (A) and (B) 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 compounds (A) and (B) 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 formulae (A) and (B) 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) and (B) as defined above and below, or a composition (1 ) as defined above and below, for use as a medicament.
  • compounds (I) in particular to compounds of formulae (A) and (B) 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) and (B) 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 formulae (A) and/or (B) 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) and (B) 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 compounds of formulae (A) and/or (B) 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) and (B) 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) and/or (B) 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) and (B) 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 formulae (A) and/or (B) 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) and (B) as defined above and below, or a composition (1 ) as defined above and below, for use in treating RASophatie.
  • the invention further relates to compounds (I) according to the invention, in particular to compounds of formulae (A) and/or (B) 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) and (B) as defined above and below, or a composition (1 ) as defined above and below, for use in treating inflammatory diseases.
  • the invention further relates to compounds (I) according to the invention, in particular to compounds of formulae (A) and/or (B) 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) and (B) 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 compounds of formulae (A) and/or (B) 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) and (B) 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 compounds of formulae (A) and/or (B) 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) and (B) as defined above and below, or a composition (1 ) as defined above and below, for use in treating proliferative disorders, inflammatory diseases and/or genetic disorders, wherein RAS-signalling is involved, preferably wherein KRAS G12V, KRAS G12A, NRAS G12V, HRAS G12V, KRAS G12C, KRAS G12D, KRAS G12C/Y96D, KRAS G12C/Y96C, KRAS G12C/Y96S, KRAS G13C, KRAS G13D, KRASG13S, KRAS Q61 H, KRAS Q61 R or KRAS Q61 K is involved
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound (I) according to the invention, in particular compounds of formulae (A) and/or (B) as defined above and below, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention further relates to a pharmaceutical composition 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 KRAS G12C/Y96S is involved.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one composition (1 ) as defined above and below, and a pharmaceutically acceptable carrier.
  • 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 formulae (A) and/or (B) 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 compounds (A) and (B) as defined above and below, or a composition (1 ) as defined above and below.
  • a compound (I) according to the invention in particular a compound of formulae (A) and/or (B) 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 compounds (A) and (B) as defined above and below, or a composition (1 ) as defined above and below.
  • the invention further relates to a kit containing a formulation comprising: a) a compound (I) according to the invention, in particular a compound of formulae (A) and/or (B) as defined above and below, or a composition (1) as defined above and below, or a pharmaceutical composition comprising a compound (I) according to the invention, in particular a compound of formulae (A) and/or (B) as defined above or below, or a therapeutically acceptable salt thereof, or a composition (1 ) as defined above and below, 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.
  • 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 KRAS irrespective of the mutations at concentrations which are pharmacologically achievable in human subjects.
  • the tolerability of these molecules is well studied in the context of other disease entities like rheumatid arthritis
  • the compounds inhibit NRAS and HRAS by functionally uncoupling their binding to their effectors in the cells.
  • Inactivation in the sense of the invention means inhibiting the activity of a protein, in particular RAS protein, especially NRAS, KRAS or HRAS protein, based on direct or indirect interaction of at least one of the compounds of formula (I) and the proteins including prohibitions involved in complex with RAS proteins. This interaction is not a translation process or part of a translation process.
  • 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
  • the value E corresponds to the effect (inhibition) which is to be expected if the activity of the individual compounds is additive. If the observed effect is higher than the value E calculated according to the equation, a synergistic effect is present.
  • 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 (including blood, bone marrow and lymph nodes) or testicular seminoma.
  • references made in the singular may also include the plural.
  • references made in the singular may also include the plural.
  • “a” and “an” may refer to either one, or one or more.
  • C n -C m indicates the number of carbon atoms that a molecule or residue designated thereby may contain.
  • Ci-C4-alkyl refers to unbranched or branched saturated hydrocarbon groups having 1 to 4 carbon atoms. Ci-C4-alkyl are e.g. methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1 ,1 - dimethylethyl.
  • the compounds of formulae (I), (A) and (B) form salts which are also within the scope of this invention.
  • Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the compounds of formulae (I),
  • (A) and (B) may be formed, for example, by reacting a compound of formulae (I), (A) and
  • 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.
  • patient includes humans and animals that receive either therapeutic or prophylactic treatment.
  • 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.
  • a pharmaceutically acceptable material 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.
  • manufacturing aid e.g. lubricant
  • 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), (A) and (B) as defined above and the composition (1) as defined above and a pharmaceutical composition comprising at least one compound of formulae (I), (A) and (B) 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), (A) and (B) 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), (A) and (B) 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), (A) and (B) as defined above or a salt thereof.
  • the present invention provides a combined preparation of a compound or compounds of formulae (I), (A) and (B) 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.
  • a compound or compounds of formulae (I), (A) and (B) as defined above and/or a pharmaceutically acceptable salt thereof
  • 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), (A) and (B) as defined above are sequentially administered prior to administration of the immuno-oncology agent.
  • compound(s) of formulae (I), (A) and (B) as defined above are administered concurrently with the immuno-oncology agent.
  • compound(s) of formulae (I), (A) and (B) as defined above are sequentially administered after administration of the immuno-oncology agent.
  • compound(s) of formulae (I), (A) and (B) 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.
  • 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.
  • TNF family of molecules that bind to cognate TNF receptor family members which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1 BBL, CD137 (4-1 BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGETL1A, TRAMP/DR3, EDAR, EDA1 , XEDAR, EDA2, TNFR1 , Lymphotoxin a/TNFp, TNFR2, TNFa, LTpR, Lymphotoxin a
  • T cell responses can be stimulated by a combination of compound(s) of formulae (I), (A) and (B) as defined above and one or more of:
  • 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 that can be combined with compound(s) of formulae (I), (A) and (B) as defined above for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells.
  • compound(s) of formulae (I), (A) and (B) as defined above can be combined with antagonists of KIR, such as Lirilumab.
  • 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.
  • the invention relates 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 tumors.
  • the invention relates to the inhibition of HRAS mutations, which are also detected in other cancers selected from chronic myelomonocytic leukemia, non-nodgkin lymphoma, thyroid gland carcinoma, head and neck squamous cell carcinoma, squamous cell lung carcinoma, ovarian carcinoma, poorly differentiated thyroid gland carcinoma, squamous cell carcinoma, small cell lung carcinoma, glioma, low grade glioma, pancreatic carcinoma, acute lymphoblastic leukemia, histiocytic and dendritic cell neoplasm, multiple myeloma, neurofibromatosis type, pancreatic ductal adenocarcinoma, thyroid gland follicular carcinoma, embryonal rhabdomyosarcoma, malignant thyroid gland neoplasm, thyroid gland undifferentiated (anaplastic) carcinoma, thymic carcinoma, urothelial carcinoma, thyroid gland papillary carcinoma cutaneous melanoma, mucosal
  • the invention also provides pharmaceutically compositions which comprise a therapeutically effective amount of one or more of the compound(s) of formulae(l), (A) and (B), 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.
  • 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.
  • excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc.
  • inert diluents such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate
  • granulating and disintegrating agents such as, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, and alginic acid
  • binding agents such as, for example, starch, gelatin, polyvinyl-pyrrol
  • 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), (A) and (B) 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.
  • at least one compound of formulae (I), (A) and (B) 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), (A) and (B) 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.
  • water soluble carrier such as, for example, polyethylene glycol
  • 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), (A) and (B) 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.
  • Oily suspensions can, for example, be prepared by suspending at least one compound of formulae (I), (A) and (B) 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), (A) and (B) 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.
  • An emulsion of at least one compound of formulae (I), (A) and (B) as defined above and/or at least one pharmaceutically acceptable salt thereof can, for example, be prepared as an oil-in-water emulsion.
  • the oily phase of the emulsions comprising compound(s) of formulae (I), (A) and (B) as defined above may be constituted from known ingredients in a known manner.
  • the oil phase can be provided by, but is not limited to, for example, a vegetable oil, such as, for example, olive oil and arachis oil; a mineral oil, such as, for example, liquid paraffin; and mixtures thereof.
  • 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 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 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. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agentcontaining composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. 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.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol poly ethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose
  • the pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.
  • the pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings.
  • Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
  • the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • 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.
  • compositions of this invention comprise at least one compound of formulae (I), (A) and (B) as defined above and/or at least one pharmaceutically acceptable salt thereof, or at least one composition (1) as defined above, and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle.
  • Alternate compositions of this invention comprise a compound of the formulae (I), (A) and (B) as defined above, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • 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), (A) and (B) as defined above, or a therapeutically acceptable salt thereof or at least one 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), (A) and (B) 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.
  • Dosage forms suitable for administration may contain from about 1 milligram to about 200 milligrams of active ingredient per dosage unit.
  • the active ingredient will ordinarily be present in an amount of about 0.1 -95 % by weight based on the total weight of the composition.
  • a typical capsule for oral administration contains at least one of the compound of the formulae (I), (A) and (B) (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a no. 1 gelatin capsule.
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compound of formulae (I), (A) and (B) as defined above, alone or in combination with a pharmaceutical carrier.
  • a pharmaceutical carrier e.g., a pharmaceutically acceptable carrier for a pharmaceutically acceptable carrier.
  • compound(s) of formulae (I), (A) and (B) as defined above can be used alone, in combination with other compound(s) of formulae (I), (A) and (B) as defined above, or in combination with one or more other therapeutic agent(s), e.g. an anticancer agent or other pharmaceutically active material.
  • the compound(s) of formulae (I), (A) and (B) as defined above which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • a suitable daily dose of compound(s) of formulae (I), (A) and (B) 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.
  • oral, intravenous, intracerebroventricular and subcutaneous doses of the compound(s) of formulae (I), (A) and (B) as defined above for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.
  • therapeutic agents when employed in combination with the compound(s) of formulae (I), (A) and (B) as defined above, may be used, for example, in those amounts indicated in the Physicians’ Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
  • PDR Physicians’ Desk Reference
  • such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds.
  • NCI-H358, H358, H2122, ASPC-1 , HCT-116, T24 and HT 1080 cells were used for the soft agar colony formation assay. After the treatment with Alexandrine dihydrochloride, the colonies were stained with MTT and the value was quantified by measuring absorbance at 570 nm after solubilization. The results represent mean ⁇ SSEM from 3 independent experiments.
  • Alexandrine dihydrochloride blocks the growth of different RAS-isoform addicted cell-lines and stops the growth of cancer.
  • FIG. 3 NanoBit assay for RAS activation (G12V, G12C, G12D, G12C/Y96D,)
  • NanoBiT assay for the RAS GTP-loading was performed in HeLa cells transfected with LgBit-KRAS mutants and SmBit-CRAF-RBD.
  • Cells were treated with Alexandrine dihydrochloride for 2 h in serum-free DMEM. After incubation, the substrate for NanoLuc was added, and the luminescence was measured in a multiplate reader. Data were normalized to cells transfected with the indicated mutant and exposed to DMSO for 2 h. DMSO-treated cells were set as 1 . The bars represent mean ⁇ SEM from 3 independent experiments. Alexandrine dihydrochloride inhibits different RAS-isoforms.
  • FIG. 4a Alexandrine dihydrochloride inhibits KRAS dependent cells irrespective of the presence of mutation. G12C/Y96D mutation is normally seen in patients, who develop resistance to G12C inhibitor. Thus, patients, who are resistant to G12C inhibitors can still be treated with Alexandrine dihydrochloride.
  • Figure 4b Comparison of the single compounds Alexandrine dihydrochloride and MRTX849 (Adagrasib) and the mixture of Alexandrine dihydrochloride (A) MRTX849 (M) in MTT assay in RAS mutated cells. Further, the calculated/expected values of the mixture and the actual/real values of the mixture is shown. Expected values were obtained using the equation:
  • Figure 5 RASOpathie-Model of Alexandrine dihydrochloride; MTT assay for cell viability in 96 well cell culture plate
  • Alexandrine dihydrochloride inhibits RAS protein of RASOpathie.

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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).
EP23728834.5A 2022-06-13 2023-06-12 Nouveaux inhibiteurs de ras Pending EP4536630A1 (fr)

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