US20190343836A1 - Pharmaceutical combination comprising an alk inhibitor and a shp2 inhibitor - Google Patents

Pharmaceutical combination comprising an alk inhibitor and a shp2 inhibitor Download PDF

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US20190343836A1
US20190343836A1 US16/475,982 US201816475982A US2019343836A1 US 20190343836 A1 US20190343836 A1 US 20190343836A1 US 201816475982 A US201816475982 A US 201816475982A US 2019343836 A1 US2019343836 A1 US 2019343836A1
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Prior art keywords
amino
methyl
decan
azaspiro
thio
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Leila DARDAEI ALGHALANDIS
Jeffrey Adam ENGELMAN
Huaixiang Hao
Matthew J. LaMarche
Fang Li
Hui-Qin Wang
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Novartis AG
General Hospital Corp
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Novartis AG
General Hospital Corp
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Assigned to NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC. reassignment NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LI, FANG
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
Assigned to THE GENERAL HOSPITAL CORPORATION reassignment THE GENERAL HOSPITAL CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ALGHALANDIS, LEILA DARDAEI
Assigned to THE GENERAL HOSPITAL CORPORATION reassignment THE GENERAL HOSPITAL CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ENGELMAN, Jeffrey Adam
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • FIG. 2 Plot of the growth inhibition of MGH049 tumor model with ceritinb, Compound No. 1, or the combination of ceritinib and Compound No. 1.
  • the MGH049 cell line was implanted into the flanks of nude mice. Animals were randomized into 4 groups when the average tumor volume was 200-300 mm 3 and received vehicle, ceritinib (20 mg/kg), Compound No. 1 (75 mg/kg) or both inhibitors in combination. Tumor dimensions and body weights were measured at the time of randomization and twice weekly thereafter for the study duration. Average tumor volume and SEM are shown as a function of time. Data shows the combination of ceritinib and Compound No. 1 is more effective in the inhibition of tumor growth than either compound alone in vivo.
  • the ALK inhibitor can be for example a compound selected from the group consisting of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine (ceritinib), (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (lorlatinib; PF-06463922),
  • drug active substance
  • active ingredient active ingredient
  • active agent active agent
  • agent agents that are to be understood as meaning a compound in free form or in the form of a pharmaceutically acceptable salt, in particular compounds specified herein.
  • an ALK inhibitor is also referred to as “combination partner (i)”.
  • SHP2 inhibitor is also referred to as “combination partner (ii)
  • joint therapeutically effective amount means the amount at which the therapeutic agents, when given separately (in a chronologically staggered manner, especially a sequence-specific manner) to a warm-blooded animal, especially to a human to be treated, show a (additive, but preferably synergistic) interaction (joint therapeutic effect). Whether this is the case can be determined inter alia by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals.
  • a pharmaceutical combination comprising:
  • SHP2 inhibitor is (S)-N-(3-((3-amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide.
  • a pharmaceutical composition comprising a pharmaceutical combination of any one of Embodiments 1 to 60 and at least one pharmaceutically acceptable carrier.
  • salt or “salts” is understood to be a salt of an ALK inhibitor and are preferably pharmaceutically acceptable salts.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Since a SHP2 inhibitor may include more than one acidic or basic moieties, the SHP2 inhibitor may include mono, di or tri-salts in a single active ingredient.
  • Suitable pharmaceutical compositions for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units, or the therapeutic effect may be achieved only after both combination partners are administered to the subject.
  • a therapeutically effective amount of a SHP2 inhibitor in vivo may range depending on the route of administration, between about 0.05 to about 15 mg per kg body weight per day, preferably about 0.1-5 mg/kg/day, more preferably from about 0.25-3 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to a preferable dosage range of about 17.5-210 mg per day.
  • each of the combination partners employed in the COMBINATION OF THE INVENTION may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, and the severity of the condition being treated.
  • the dosage regimen of the COMBINATION OF THE INVENTION is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient.
  • a clinician or physician of ordinary skill can readily determine and prescribe the effective amount of the single therapeutic agents required to alleviate, counter or arrest the progress of the condition.
  • each combination partner for treatment of a proliferative disease can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking.
  • Frequency of dosage may vary depending on the compound used and the particular condition to be treated or prevented. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art.
  • a pharmaceutical preparation comprising:
  • the combination of the invention may provide a synergistic therapeutic effect, e.g. with regard to alleviating, delaying progression of or inhibiting the symptoms of proliferative diseases, such as cancer, particularly lung cancer.
  • Certain combinations of the invention may provide an additive effect, e.g. with regard to alleviating, delaying progression of or inhibiting the symptoms of proliferative diseases, such as cancer, particularly lung cancer.
  • Another aspect of the present invention particularly pertains to a pharmaceutical combination
  • a pharmaceutical combination comprising:
  • ALK-positive cancer selected from anaplastic large-cell lymphoma, gastric cancer, breast cancers, oesophageal cancer, colorectal cancer, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer, pancreatic cancer and lung cancer.
  • a method for treating cancer, in a subject in need thereof, comprising the simultaneous or sequential administration to said subject a therapeutically effective amount of:
  • An aspect of the present invention relates to pharmaceutical combinations or pharmaceutical compositions comprising:
  • Embodiment 92 wherein the cancer is an ALK-positive cancer.
  • Embodiment 92 wherein the cancer is an ALK-positive cancer selected from anaplastic large-cell lymphoma, gastric cancer, breast cancers, oesophageal cancer, colorectal cancer, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer, pancreatic cancer and lung cancer.
  • ALK-positive cancer selected from anaplastic large-cell lymphoma, gastric cancer, breast cancers, oesophageal cancer, colorectal cancer, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer, pancreatic cancer and lung cancer.
  • Embodiment 92 wherein the cancer is an ALK-positive cancer resistant to the ALK inhibitor of the pharmaceutical combination.
  • a commercial package comprising the pharmaceutical combination of any one of Embodiments 1 to 60, together with instructions for simultaneous or sequential administration thereof for use in the treatment of cancer.
  • Embodiment 100 wherein the cancer is an ALK-positive cancer resistant to the ALK inhibitor of the pharmaceutical combination.
  • Cell colony formation assays were used to assess cell viability and proliferation after compound treatments.
  • Cells were plated into 6-well tissue culture plates (6 ⁇ 10 5 cells/well) in a total volume of 2 mL. After 24 hours, compounds were added to the plates. At the end points of the assays, cells were fixed, stained with crystal violet and photographed.
  • FIG. 1 shows the photographs obtained from cell colony formation assays with MGH049, MGH045-2A and MGH073-2B cells used to assess the anti-proliferative effect of ceritinib in combination with a SHP2 inhibitor (Compound No. 1).
  • Cells were exposed to ceritinib, Compound No. 1 or the combination for 14 days, and stained with crystal violet.
  • the combination of ALK and SHP2 inhibition led to significant inhibition of cell survival compared with ceritinib alone.
  • Compound No. 1 had no effect on cell growth as a single agent, suggesting that these cell lines are ALK-dependent and signaling via SHP2 functions as a survival pathway or confers resistance to ceritinib.
  • combination of ALK and SHP2 inhibition may either enhance the anti-tumor activity of an ALK inhibitor, particularly ceritinib, and/or overcome ALK inhibitor resistance, particularly ceritinib resistance in ALK-positive cancer, such as NSCLC.
  • MGH049 and MGH045-2A tumor xenograft models were used to evaluate the efficacy of the combination of an ALK inhibitor with a SHP2 inhibitor in vivo. All animal studies were conducted in accordance with the guidelines as published in the Guide for the Care and Use of Laboratory Animals and Novartis International Animal Care and Use Committee (IACUC) regulations and guidelines.
  • the MGH045-2A cells were harvested during exponential growth. Each athymic female nude mouse (Harlan Laboratories, Indianapolis, Ind.) was inoculated subcutaneously in the upper right flank with 5 ⁇ 10 6 NB-1 cells suspended in 0.2 mL cold PBS. The development of MGH049 xenograft tumors comprised 2 steps.
  • FIG. 2 demonstrates that in the MGH049 tumor xenograft model the combination of ceritinib and a SHP2 inhibitor (Compound No. 1) was more effective in the inhibition of tumor growth than either compound alone.
  • FIG. 3 demonstrates that in the MGH045-2A tumor xenograft model the combination of ceritinib and a SHP2 inhibitor (Compound No. 1) was more effective in the inhibition of tumor growth than either compound alone.
  • FIG. 4 demonstrates that in the MGH073-B tumor xenograft model the combination of ceritinib and a SHP2 inhibitor (Compound No. 1) was more effective in the inhibition of tumor growth than either compound alone.

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10894797B2 (en) 2018-09-18 2021-01-19 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors
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