WO2021205367A1 - Use of ep4 receptor antagonists for the treatment of liver cancer, melanoma, lymphoma and leukemia - Google Patents

Use of ep4 receptor antagonists for the treatment of liver cancer, melanoma, lymphoma and leukemia Download PDF

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Publication number
WO2021205367A1
WO2021205367A1 PCT/IB2021/052904 IB2021052904W WO2021205367A1 WO 2021205367 A1 WO2021205367 A1 WO 2021205367A1 IB 2021052904 W IB2021052904 W IB 2021052904W WO 2021205367 A1 WO2021205367 A1 WO 2021205367A1
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compound
ethyl
cancer
effective amount
compounds
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PCT/IB2021/052904
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French (fr)
Inventor
Yukinori Take
Shinichi Koizumi
Takako Okumura
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Askat Inc.
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Priority to CN202180033910.8A priority Critical patent/CN115697317A/en
Publication of WO2021205367A1 publication Critical patent/WO2021205367A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • EP4 receptor antagonists for the treatment of liver cancer, melanoma, lymphoma and leukemia
  • This invention relates to a prostaglandin E2 (PGE2) receptor 4 (EP4) antagonist for use in the treatment of liver cancer, melanoma, lymphoma and leukemia (hereinafter, “the cancers of the invention”).
  • the method for the treatment of the cancers of the invention comprises administering any one of Compound A, Compound B or Compound C, or a pharmaceutically acceptable salt thereof, as the EP4 antagonist (hereinafter, “the compounds of the invention”), or a pharmaceutical composition comprising the compounds of the invention to a human or animal.
  • the method of the treatment includes administering the compounds of the invention alone or in combination with one or more other active agents and/or therapies to the human or animal having the cancers of the invention.
  • Compounds A, B and C are:
  • the prostaglandins are mediators of pain, fever and other symptoms associated with inflammation.
  • PGE2 is the predominant eicosanoid expressed in inflammation conditions.
  • PGE2 is also involved in various physiological and/or pathological conditions, such as hyperalgesia, uterine contraction, digestive peristalsis, awakeness, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis, and cancer cell growth, invasion and metastasis, or the like.
  • Non-patent references disclose the characters of the prostanoid receptors, relationship with therapy, and selective agonists and antagonists most generally used (see, for example, Konya et al., Pharmacology & Therapeutics, 2013, 138:485-502; and Yokoyama et al., Pharmacol. Rev., 2013, 65:1010-1052).
  • PGE2 has been reported to be highly expressed in tumor tissues of various types of cancer, and it has also been demonstrated that PGE2 correlates to the initiation, growth and development of cancer and disease conditions of patients. It is generally accepted that PGE2 relates to activation of cancer cell proliferation and cell death and plays an important role in the processes of cancer initiation and proliferation, disease progression and cancer metastasis (see, for example, Konya et al., Pharmacology & Therapeutics, 2013, 138:485-502; and Yokoyama et al., Pharmacol. Rev., 2013, 65:1010-1052).
  • EP4 receptor subtypes There are four PGE2 receptor subtypes, EP1 , EP2, EP3 and EP4, which display different pharmacological properties.
  • the EP4 receptor subtype belongs to the Gs protein-coupled receptor subfamily, known as a receptor with seven transmemblene domains. Accordingly, EP4 plays a significant role in biological events by stimulating cAMP signal-mediated functions. From the aspect of pharmacological studies, lots of tests of compounds with EP4 receptor antagonistic activities have been conducted and several EP4 receptor-selective antagonists are known (Konya et al. , Pharmacology & Therapeutics, 2013, 138:485-502).
  • patent references e.g., US 8,921 ,391 B2 and US 9,688,674 B2 describe the use of EP4 antagonists, including the compounds of the invention, for the treatment of “cancer which PGE2 relates to”, and the “cancer which PGE2 relates to” includes brain tumor, bone cancer, and neoplasm derived from epithelial cells (epithelial cancer).
  • Some patent references e.g., WO 2015/179615 A1 , US 2015/0004175 A1 ) suggest therapeutic efficacy of EP4 receptor antagonists or inhibition of EP4 signaling results in the suppression of tumor growth.
  • the mesenchymal stem cells, major compartment of tumor microenvironment, are shown to promote HCC progression and metastasis and PGE2/EP4 axis support the HCC progression (Liu et al., J. Experimental & Clinical Cancer Research 201938:228).
  • PGE2/EP4 signaling may have roles in liver cancer initiation, promotion, and progression.
  • these references do not directly demonstrate the therapeutic efficacy of an EP4 antagonist in a malignant HCC/liver cancer animal model.
  • Skin cancers are malignancies that arise from the skin and include some types of tumors.
  • Epithelial skin cancer is the major skin cancer and it includes, e.g., basal cell carcinoma, squamous cell carcinoma, extramammary Paget’s disease, Merkel cell carcinoma, sweat gland carcinoma, sebaceous carcinoma, and hair follicle carcinoma. These tumors originate from the malignancy of epithelial cells.
  • Melanoma is a skin cancer, but it is categorized as a non-epithelial skin cancer, because it arises from the malignancy of melanocyte, a neural crest cell-origin.
  • EP4 receptor is a principal molecule conveying the growth-suppressive effect of PGE2 using mouse stable A20 lymphoma cell lines in which the EP4 receptor gene expressions are up-regulated or down-regulated by transfecting EP4 receptor genes or miRNAs against EP4 gene-containing expression vectors. Plantation of A20 cell line in which the EP4 gene expression is stably suppressed by miRNA to mice markedly accelerated tumor spread, whereas A20 cell line stably overexpressing the EP4 gene showed significant tumor growth suppression.
  • the present application provides a method for the treatment of liver cancer, melanoma, lymphoma, and leukemia using EP4 receptor antagonists.
  • the inventors have discovered that each of the following three compounds of the invention (i.e., Compounds A, B and C and pharmaceutically acceptable salts thereof) dramatically decrease the growth of these cancers by using validated mouse tumor models: 4-((1S)-1- ⁇ [5-chloro-2-(4-fluorophenoxy)benzoyl]amino ⁇ ethyl)benzoic acid (Compound A),
  • Compound B has extremely potent anti-tumor efficacy in a mouse H22 hepatocellular carcinoma cell-bearing tumor model, which is a popular model for liver cancer.
  • the inhibition of the tumor volume in Compound B-treated mice was 78.1 % compared to that of vehicle-treated mice.
  • sorafenib one of the current standard therapeutics to treat liver cancer, is reported to inhibit tumor volume by only 54.7% compared to a vehicle in the same H22 mouse model (Acta Biomaterialia 2019, 92:229-240).
  • Compound B has unexpected higher potency in terms of anti-tumor efficacy in a liver cancer model compared to sorafenib.
  • the Examples below also demonstrate that the therapy of H22 tumor-bearing mice with Compound B in combination with an anti-PD-1 antibody showed higher tumor growth suppression as compared to Compound B (alone) and the anti-PD-1 antibody (alone).
  • Compound A is an analog of Compound B with a very similar chemical structure. Their pharmacological activities, such as an inhibitory potency against EP4 receptor signaling, are almost the same in cAMP inhibition. Therefore, Compound A is expected to produce similar anti-tumor efficacy as that of Compound B demonstrated in the Examples below.
  • Compound C showed inhibition of H22 tumor growth in the same mouse model as Compound B of 61.2%, which is also more potent than sorafenib. Compound C also showed similar efficacy as Compound B when combined with an anti-PD-1 antibody.
  • Compound B or Compound C inhibits tumor growth in A20 B-cell lymphoma cell-bearing and WEFI 1-231 leukemia cell-bearing mice syngeneic models and clearly showed that EP4 antagonist systemic therapy has anti-tumorigenic mechanism of lymphoma and leukemia cells.
  • Compound A having a similar chemical structure to Compound B, is expected to also inhibit tumor growth in lymphoma cell-bearing mice and leukemia cell-bearing mice.
  • Figure 1 A depicts antitumor efficacy of Compound B tested in a H22 hepatocellular carcinoma (HCC)-bearing mouse model according to Example 1 as an example of treating liver cancer.
  • Figure 1A shows the change of tumor volume by the treatment of Compound B or a vehicle control group.
  • Figure 1 B depicts antitumor efficacy of the combined therapy of Compound B and an anti-PD-1 antibody tested in the mouse H22 model according to Example 2.
  • Figure 1 B shows the change of tumor volume by the treatment with Compound B alone, the combination of Compound B and an anti-PD-1 antibody, an anti-PD-1 antibody alone, or a vehicle control group.
  • Figures 2A and 2B depict antitumor efficacy of Compound C in the same manner as Figures 1 A and 1 B, respectively, except for using Compound C rather than Compound B, according to Examples 3 and 4.
  • Figure 2A shows the change of tumor volume by the treatment with Compound C or a vehicle control group according to Example 3.
  • Figure 2B shows the change of tumor volume by the treatment with Compound C alone, the combination of Compound C and anti-PD-1 antibody, an anti-PD-1 antibody alone, or a vehicle control group according to Example 4.
  • Figure 3A and Figure 3B depict antitumor efficacy of Compound B and Compound C, respectively, in a mouse B16F10 melanoma-bearing mice model according to Examples 5 and 6, respectively.
  • Figures 3A and 3B show the change of tumor volume by the treatment with Compound B, Compound C, or vehicle-treated control groups.
  • Figure 4A and Figure 4B depict antitumor efficacy of Compound B and Compound C, respectively, in a mouse A20 B-cell lymphoma mice model as an example of lymphoma, according to Examples 7 and 8, respectively.
  • Figures 4A and 4B show the change of tumor volume by the treatment with Compound B, Compound C or vehicle-treated control groups.
  • Figure 5A and Figure 5B depict antitumor efficacy of Compound B and Compound C, respectively, in a mouse WEFII-3 leukemia mice model, according to Examples 9 and 10, respectively.
  • Figures 5A and 5B show the change of tumor volume by the treatment with Compound B, Compound C or vehicle-treated control groups.
  • the compounds of the invention which are useful for the treatment of the cancer of the invention are:
  • the compounds of the invention also include the solvates, complexes, polymorphs, prodrugs, isomers, and isotope-labeled compounds thereof.
  • the compounds of the invention can be used either alone or in combination in any treatment of liver cancer, melanoma, lymphoma and leukemia.
  • Pharmaceutically acceptable salts include, but are not limited to, the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • a pharmaceutically acceptable salt of the compounds of the invention may be readily prepared by mixing solutions of the compound of the present invention and the desired acid or base as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the compounds containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionized, partially ionized, or non-ionized.
  • references to the compounds of the invention include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the invention include the compounds of the invention as herein before defined, polymorphs, prodrugs, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of the invention.
  • the invention includes all polymorphs of the compounds of the invention as defined herein.
  • prodrugs of the compounds of the invention.
  • certain derivatives of the compounds of the invention which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into the compounds having the formula of any one of the compounds of the invention having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as “prodrugs”.
  • Further information on the use of prodrugs may be found in “Pro-drugs as Novel Delivery Systems”, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the invention with certain moieties known to those skilled in the art as “pro-moieties” as described, for example, in “Design of Prodrugs” by H Bundgaard (Elsevier, 1985).
  • prodrugs in accordance with the invention include:
  • the compounds of the invention may themselves also act as prodrugs of other compounds of the invention.
  • tautomeric isomerism (“tautomerism”) can occur. It follows that a single compound may exhibit more than one type of isomerism.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
  • racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50 (w/w) % isopropanol, typically from 2 to 20(w/w) %, and from 0 to 5 (w/w) % of an alkylamine, typically 0.1 (w/w) % diethylamine. Concentration of the eluate affords the enriched mixture.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50 (w/w) % isopropanol, typically from 2 to 20(w/w) %, and from 0 to 5 (w/w) % of an alkylamine, typically 0.1 (w/w) % diethylamine.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art (see, for example, Stereochemistry of Organic Compounds by E L Eliel (Wiley, New York, 1994)).
  • the invention includes all pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Certain isotopically-labelled compounds of the invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies associated with cancer therapy which includes diagnosis, alleviation of symptoms, improvement of QOL, and prophylaxis.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labelled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • Each one of the compounds of the invention may be administered alone or in combination with each other or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable additives.
  • additive is used herein to describe any ingredient other than the compounds of the invention. The choice of additive will to a large extent depend on various factors, such as, the particular mode of administration, the effect of the additive on solubility and stability, and the nature of the dosage form.
  • the compounds of the invention may be administered alone or in combination with a pharmaceutically acceptable carrier or diluent by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses.
  • the compounds of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the compounds of the invention are present in such dosage forms at concentration levels ranging from 5% to 95% by weight.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • the invention provides the compounds of the invention, a solvate thereof, a prodrug thereof, a combination thereof, and a combination with one or more other pharmacologically active agents.
  • the invention provides a pharmaceutical composition comprising the compounds of the invention and a pharmaceutically acceptable additive, a diluent, or a carrier, particularly for the treatment of the cancers of the invention.
  • the invention provides a kit comprising: a first pharmaceutical composition comprising the compounds of the invention, or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition; and a container.
  • a kit for the treatment of the cancers of the invention which includes the compounds of the invention, or the pharmaceutically acceptable salts thereof, is also one of the inventions.
  • a commercial package comprising the pharmaceutical composition comprising the compounds of the invention, or the pharmaceutically acceptable salts thereof and a written matter associated therewith, wherein the written matter states that the compounds can or should be used for treating the cancers of the invention is also one of the inventions.
  • the compounds of the invention are administered in an amount effective to shrink cancer, reduce cancer tumor size, reduce cancer metastasis, regulate immune cell functions, and/or enhance effectiveness of cancer therapy.
  • Such therapeutic effective amount varies in accordance with the specific compound of the invention, the specific condition to be treated, the patient's condition, the route of administration, the formulation, the field decision, and other factors. In the light of the disclosure, depending on the things known to those skilled in the art, it is decided by routine optimization techniques.
  • the compounds of the invention can be administered via either the oral, parenteral or topical routes to mammals.
  • these compounds are most desirably administered to humans in doses ranging from 1 mg to 1000 mg, preferably from 10 mg to 600 mg, which may be administered in a single dose or in divided doses throughout the day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen.
  • a pharmaceutical composition can include the compounds of the invention or a pharmaceutical salt thereof combined with a pharmaceutically acceptable transport medium or carrier.
  • pharmaceutically acceptable transport medium includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the above medium also includes other active or inactive ingredients and is targeted to cancer tissues based on the composition.
  • Therapeutic efficacy of the compounds of the invention can be determined in light of this disclosure by standard therapeutic procedures in cell cultures or experimental animals, e.g., for determining the EDso (the dose therapeutically effective in 50% of the population).
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage may vary depending upon the formulation and the route of administration.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture. Such information can be used to more accurately determine useful doses in humans or animals. Levels in plasma may be measured, for example, by high performance liquid chromatography.
  • treatment of a mammal with a therapeutically effective amount of the compounds of the invention may include, but are not limited to, a single treatment, alternate-day treatment, or a series of treatments.
  • the compounds of the invention can be administered via either the oral, parenteral or topical routes to mammals. In general, these compounds are most desirably administered to humans, for example, once a day, or in two to four divided portions a day.
  • a daily dosage in terms of the compounds of the invention is usually in the order of about 0.02 to 200 mg, and preferably about 0.1 to 100 mg, per 1 kg body weight of a mammal (including a human), which may be administered once a day or in two to four divided portions a day. More particularly, for example, administration to humans, is about 0.02 to 20 mg, per kg body weight, per day, more particularly, about 0.2 to 12 mg, per kg body weight, per day.
  • Administration to dogs for example, is about 0.5 to 25 mg, per kg body weight, per day, more particularly, about 1 to 10 mg, per kg body weight, per day.
  • Administration to mice for example, is about 1 to 100 mg, per kg body weight, per day, more particularly, about 3 to 30 mg, per kg body weight, per day.
  • the compounds of the invention are conveniently administered in the form of a pharmaceutical composition for treatment of the cancers of the invention.
  • a pharmaceutical composition for treatment of the cancers of the invention.
  • Such composition may conveniently be presented for use in conventional manner in admixture with one or more pharmaceutically acceptable carriers or excipients.
  • the compounds of the invention While it is possible for the compounds of the invention to be administered as the raw chemical, it is preferable to present it as a pharmaceutical composition in the form of a pharmaceutical formulation.
  • the formulations comprise the compounds together with one or more acceptable carriers or diluents, and optionally other therapeutic ingredients.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a pharmaceutical composition is formulated to meet the desirable route of administration.
  • the administration route is, for example, parenteral (e.g., intravenous, in the skin, subcutaneous), oral (e.g., ingestion or inhalation), percutaneous (local), mucosal, and rectum, and local (including percutaneous, oral, and sublingual) administration.
  • a pharmaceutical composition formulated in the form of a solution or suspension can be prepared by the method described in, for example, Remington’s Pharmaceutical Sciences, 18 th ed., Gennaro, ed., Mack Publishing Co., Easton, PA, (1990).
  • the most suitable route of administration may be different depending upon, for example, the condition and disorder of the patient receiving the treatment.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compound (i.e. , the “active ingredient”) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units, such as capsules, cachets or tablets (e.g., chewable tablets in particular for pediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granule; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granule, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • the compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
  • Second active agents that are small molecules can also be used to alleviate adverse effects associated with the administration of the compounds of the invention. However, like some large molecules, many are believed to be capable of providing a synergistic effect when administered with (e.g., before, after or simultaneously) the compounds of the invention.
  • small molecule second active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids.
  • the invention also includes combining separate pharmaceutical compositions in kit form.
  • the kit comprises two separate pharmaceutical compositions; a compound of the invention; and a second therapeutic agent as described herein.
  • the kit comprises a container for containing the separate compositions, such as, a divided bottle or a divided foil packet, however, the separate compositions may also be contained within a single, undivided container.
  • the kit comprises directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally contain a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • the methods provided herein comprise administering the compounds of the invention in combination with one or more second active agents, and/or in combination with radiation therapy or surgery.
  • the second active agent include, for example, additional EP4 antagonists, immune checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, adoptive immune cell therapies, cancer vaccines, and other immuno-oncological drugs targeting, for example, colony-stimulating factor 1 receptor (CSF1 R), indoleamine 2,3-dioxytenase (IDO), or carcinoembryonic antigen (CEA).
  • CSF1 R colony-stimulating factor 1 receptor
  • IDO indoleamine 2,3-dioxytenase
  • CEA carcinoembryonic antigen
  • molecular-targeted anti-cancer drugs, and cancer chemotherapeutics are also included as the second active agent.
  • the second active agents include, for example, PD-1 antibodies such as nivolumab, labrolizumab/pembrolizumab, REGE2810, PD-L1 antibodies such as abelumab, atezolizumab, durvalumab, pembrolizumab, CTLA-4 antibodies such as ipilimumab and tremelimumab, molecular-targeted drugs such as anti-HER2 antibody, anti-VEGF antibody, anti-EGFR antibody, tyrosine kinase inhibitors against EGFR receptor, PDGFR receptor, VEGFR receptor kinases, c-kit, and Bcr-Abl, and anti-tumor chemotherapeutics such as alkylating agents, antimetabolites, anti-tumor antibiotics, anti-infective drugs, microtubule inhibitors, hormonal therapeutics, platinum drugs, topoisomerase inhibitors, humor therapeutics such as aromatase inhibitors, anti-estrogen drugs
  • the administration of the compounds of the invention and the second active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration.
  • the suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated.
  • Recommended routes of administration for the second active agents are known to those of ordinary skill in the art. See, e.g., Physicians’ Desk Reference.
  • ⁇ R4 antagonist refers to a compound which inhibits or blocks the cellular signaling triggered by the interaction of PGE2 with the EP4 receptor.
  • EP4 antagonists include, but are not limited to, ER-819762, MK-2894, MF 498, ONO-AE3-208, evatanepag, ONO-AE2-227, BGC201531 , ONO-AE3-240, GW 627368, TPST-1495 and AH23848.
  • Compounds A, B and C, and pharmaceutically acceptable salts thereof are also examples of EP4 antagonists.
  • Anti-PD-1 antibody refers to an antibody which targets programmed cell death 1 receptor (PD-1 ) and inhibits or blocks the cellular signaling of PD-1.
  • Examples of an anti-PD-1 antibody include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, and toripalimab.
  • immune checkpoint inhibitor refers to a type of drug that blocks certain proteins made by some types of immune cells, such as T cells, and some cancer cells. These proteins help keep immune responses in check and can keep T cells from killing cancer cells. When these proteins are blocked, the brakes on the immune system are released and T cells are able to kill cancer cells better.
  • immune checkpoint inhibitors include, but are not limited to, PD-1 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, BTLA inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, B7-1 inhibitors, B7-2 inhibitors, galectin-9 inhibitors, and HVEM inhibitors.
  • the immune checkpoint inhibitors may be small molecules, peptides, proteins such as antibody, nucleic acids or the like.
  • PD-1 inhibitor refers to an antibody or other molecule which inhibits programmed death protein 1 (PD1) function.
  • Exemplary inhibitors/antibodies include, but are not limited to, the antibodies set forth in U.S. Patent Nos. 7,029,674, 7,488,802, 7,521 ,051 , 8,008,449, 8,354,509, 8,617,546 and 8,709,417.
  • Particular embodiments of the antibody include MDX-1106/nivolumab, BMS-936558, (Bristol- Myers Squibb), labrolizumab (Merck), MK-3475/pembrolizumab (KEYTRUDA®, Merck), AMP-224 (GSK), and CT-011 (Cure Tech).
  • PDL1 inhibitor refers to an antibody or other molecule which inhibits programmed death ligand 1 (PDL1) function.
  • exemplary antibodies include, but are not limited to, the antibodies set forth in U.S. Patent Nos. 8,217,149, 8,383,796, 8,552,154 and 8,617,546.
  • the antibody is MPDL3280A/RG7446 (Roche), BMS-936559 (BMS), MEDI4736 (AstraZeneca), and MSB0010718C (MerckSerono).
  • CTLA4 inhibitor refers to an antibody or other molecule which inhibits cytotoxic t-lymphocyte antigen 4 (CTLA4) function.
  • Exemplary inhibitors/antibodies include, but are not limited to, antibodies that are CTLA4 antagonists or the CTLA4 antibodies set forth in U.S. Patent Nos. 8,685,394 and 8,709,417.
  • Some embodiments of the antibody include MDX-010 (ipilimumab, Bristol-Myers Squibb) and CP-675,206 (tremelimumab, AstraZeneca).
  • the antibody is ipilimumab and tremelimumab.
  • an “adoptive immune cell therapeutic” refers to a therapeutic that uses the cells of the immune system for cancer therapy and also known as a cellular immunotherapy.
  • adoptive immune cell therapeutics include, but are not limited to, tumor-infiltrating lymphocyte therapy, engineered T cell receptor therapy, chimeric antigen receptor T cell therapy, natural killer cell therapy, dendritic cell therapy, and stem cell therapy.
  • cancer vaccine refers to a cancer immunotherapeutic that uses vaccine technology for cancer treatment.
  • cancer vaccines include, but are not limited to, sipuleucel-T, DCVAC/PCa, OncoVAX, and gemogenovatucel-T.
  • immuno-oncological therapeutic refers to an anti-tumor drug that regulates the immune system to stimulate cancer therapy.
  • immuno-oncological therapeutics include, but are not limited to, T cell stimulant (stimulator of effector T cell development and function) that includes activators of cancer antigen presentation, priming and activation of T cells, T cell trafficking to tumors, recognition of cancer cells, and cancer cell killing such as activators of TNF-a, IL-1 , IFN-a, CD40L/CD40, CD28/B7.1 , CD137/CD137L, OX40/OX40L, CD27/CD70, HVEM, GITR, IL-2, IL-12, CX3CL1 , CXCL9, CXCL10, CCL5, LFA1/CAM1 , selectins, T cell receptor, IFN- , and inhibitors of IL-10, IL-4, IL-13, CTLA4/B7.1 , PD-L1/PD-1 , prostaglandins,
  • a “cancer chemotherapeutic” refers to a drug that inhibits cancer cell growth and metastasis that mainly comprises alkylating agents such as mustard gas derivatives, ethylenimines, alkylsulfonates, hydrazines and triazines, nitrosureas, metal salts; plant alkaloids such as vinca alkaloids, taxanes, podophyllotoxins, campthothecan analogs; antitumor antibotics such as anthracyclines, chromomycins, mitomycin and bleomycin; antimetabolites such as folic acid antagonist, pyrimidine analog, purine analog, adenosine deaminase inhibitor; topoisomerase inhibitors such as topoisomerase I inhibitor and topoisoerase II inhibitor; miscellaneous antineoplastics such as ribonucleotide reductase inhibitor, adrenocortical steroid inhibitor, enzyme inhibitors, antimicrotuble agent
  • cancer chemotherapeutics include, but are not limited to, Mechlorethamine, Cyclophosphamide, Chlorambucil, Melphalan, Ifosfamide, Thiotepa, Hexamethylmelamine, Busulfan, Altretamine, Procarbazine, dacarbazine, Temozolomide, Carmustine, Lomustine, Streptozocin, Carboplatin, Cisplatin, Oxaliplatin, Vincristine, Vinblastine, Vinorelbine, Paclitaxel, Docetaxel, Etoposide, Tenisopide, Irinotecan, Topotecan, Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, Idarubicin, Dactinomycin, Plicamycin, Mitomycin, Bleomycin, Methotrexate, 5-Fluorouracil, Foxuridine, Cytarabine, Capecitabine, Gemcitabine, 6-Mercaptopurine
  • Treatment refers to alleviating, inhibiting and/or reversing the progress of a cancer in a subject in need thereof.
  • the term “treating” is inclusive of any indicia of success in the treatment or amelioration of the cancer, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; delaying or slowing in the rate of progression, etc.
  • Measurement of the treatment or amelioration may be based on, e.g., the results of a physical examination, a pathological test and/or a diagnostic test as known in the art.
  • Treating may also refer to reducing the incidence or onset of a cancer, or a recurrence thereof (such as a lengthening in time of remission), as compared to that which would occur in the absence of the measure taken.
  • treatment includes not only shrinking the tumor tissue but also alleviation of symptoms, improvement of quality of life (QOL), and prophylaxis (radiotherapy, postoperative prevention of recurrence, adjuvant chemotherapy and the like).
  • a “pharmaceutically effective amount” refers to an amount that is effective for treating a cancer as noted through clinical testing and evaluation, patient observation, and/or the like.
  • An “effective amount” can further designate an amount that causes a detectable change in biological or chemical activity. The detectable changes may be detected and/or further quantified by one skilled in the art for the relevant mechanism or process.
  • an “effective amount” can designate an amount that maintains a desired physiological state, i.e., reduces or prevents significant decline and/or promotes improvement in the condition.
  • An “effective amount” can further refer to a therapeutically effective amount.
  • a pharmaceutically acceptable salt is consistent with the examples provided above and refers to a relatively nontoxic, inorganic or organic acid salt of a compound of the invention. These salts may be prepared in situ during the final isolation and purification of the compounds or by reacting the purified compound in its free form separately with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative acid salts include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tanna
  • “Second active agent” is a low molecular weight drug or biologic which has pharmacologically effective activity, and it includes, but is not limited to, PGE2 signal inhibitors such as additional EP4 antagonists, microsomal prostaglandin E synthase (mPGES)-1 inhibitor, COX-2 inhibitors, NSAIDs, and immune checkpoint inhibitors, cancer immunotherapeutics, immune cell therapeutics, molecular-targeted antitumor drugs, alkylating agents, antimetabolites, anti-tumor antibiotics, anti-infective drugs, microtubule inhibitors, hormonal therapeutics, platinum drugs, topoisomerase inhibitors, molecular-targeted cancer therapeutics, vaccine therapeutics and so on.
  • PGE2 signal inhibitors such as additional EP4 antagonists, microsomal prostaglandin E synthase (mPGES)-1 inhibitor, COX-2 inhibitors, NSAIDs, and immune checkpoint inhibitors, cancer immunotherapeutics, immune cell therapeutics, molecular-targeted antit
  • Immunocell therapeutics includes, but is not limited to, drugs or biologies for anti-tumor vaccine therapy, and adoptive immune cell therapy such as adoptive T-cell therapy, adoptive dendritic cell therapy, adoptive NK cell therapy, and CAR-T therapy.
  • Immune cells include, but is not limited to, B cells, T cells, regulatory T cells, natural killer cells, natural killer T cells, dendritic cells, myeloid-derived suppressor cells, monocytes and macrophages.
  • Molecules related to immune cells and cancer-immune cell interactions include, but is not limited to, PD-1 , PD-L1 , CTLA4, TIM3, LAG3, TIGIT, BTLA, OX-40, ICOS, CD137, GITR, CD40, CD28, CD27, IL-2, IL-7, IL-15, IL-21 , GM-CSF, IL-12, IFNa, ICAM1 , VCAM1 , CD103, IDO, TDO, NOS1 , Arginase, CSF1 , FOXP3, TGFp, IL-10, BATF3, XCR1/XCL1 , STING, IFNy, CXCL9/10/11 , CXCL1/13, CCL2/5.
  • Molecular-targeted antitumor drugs include, but are not limited to, small molecules and biologies which target specific molecules such as protein kinases, apoptosis regulators, growth factors, angiogenesis regulators, humoral receptors, transcription factors, cytokines, chemokines, receptors, enzymes, ion channels, etc. that related to the growth of cancer cells.
  • Molecular-targeted antitumor drugs include, but are not limited to, Imatinib, Gefitinib, Erlotinib, Sorafenib, Sunitib, Dasatinib, Lapatinib, Nilotinib, Bortezomib, Tamoxifen, tofacitinib, crizotinib, obatoclax, navitoclax, gossypol, iniparib, Olaparib, perifosine, Apatinib, vemurafenib, dabrafenib, trametinib, PD-0332991 , LEE011 , Vintafolide, Temsirolimus, Everolimus, Vemurafenib, Trametinib, Dabrafenib, Pembrolizumab, Rituximab, Trastuzumab, Alemtuzumab, Cetuximab, Panitumum
  • Liver cancer includes, but is not limited to, hepatocellular carcinoma, cholangiocarcinoma, mucinous cystic neoplasm and intraductal papillary biliary neoplasm. “Liver cancer” also includes, but is not limited to, cancers in liver associated with cirrhosis, hepatitis B, hepatitis C virus infections, and alcohol consumption.
  • Melanoma includes, but is not limited to, melanomas occurring in the skin, mouth, eye, gastrointestinal organs, liver, bone, and other organs, and includes primary melanoma and metastatic melanoma.
  • Lymphoma includes, but is not limited to, Hodgkin’s lymphomas, non-Hodgkin lymphomas and Epstein-barr virus-associated lymphoproliferative diseases. “Lymphoma” also includes, but is not limited to, mature B cell neoplasms, mature T cell and natural killer cell neoplasms, precursor lymphoid neoplasms, and immunodeficiency-associated lymphoproliferative disorders. In particular, lymphoma includes B-cell lymphoma.
  • Leukemia includes, but is not limited to, lymphocytic leukemia and myelogenous leukemia with acute or chronic properties. “Leukemia” also includes, but is not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, hairy cell leukemia, T-cell prolymphocytic leukemia, large granular lymphocytic leukemia, adult T-cell leukemia, and clonal eosinophilia. [0103]
  • ⁇ R4 signal or ⁇ R4 signaling
  • EP4 receptor-mediated cellular signal transductions such as the cyclic AMP and phosphoinositide 3-kinase (PI3K) signals and following signal transductions in association with agonistic stimulation of EP4 receptor.
  • PI3K phosphoinositide 3-kinase
  • mice tumor models were employed, and tested the tumor growth inhibition and the changes of body weight of mice during the experimental periods. No drug-related abnormal body weight changes or abnormal behaviors were observed in the experiments described in these Examples.
  • mice were divided into the group (ISM 3) and the drug therapy was started from Day 5 for 12 days.
  • Compound B was treated at 15 mg/kg/day, bid, p.o.
  • Anti-PD-1 antibody (Kang Long Chemicals, 695318J3) was treated at 2.5 mg/kg/day, i.p., twice a week. Tumor volume, body weight, and behavior were evaluated, and the statistical analysis of tumor volume was performed the same as Example 1.
  • Compound B therapy at 15 mg/kg/day inhibited tumor growth with 34.5% inhibition.
  • Anti-PD-1 antibody therapy at 2.5 mg/kg twice a week inhibited tumor growth with 33.8% inhibition on Day 17.
  • Combination therapy of Compound B and anti-PD-1 antibody showed higher tumor growth inhibition of 58.2% inhibition.
  • the experiment suggests the benefit of the combination therapy of Compound B with anti-PD-1 therapy or the combination of EP4 inhibitory mechanism with anti-PD-1 therapy. No drug-mediated abnormal behaviors or mean body weight change was observed throughout the experimental period.
  • Compound C therapy at 200 mg/kg/day inhibited 61.2% inhibition of H22 tumor growth compared to vehicle treated on Day 19 ( Figure 2A). This inhibition was statistically significant. No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.
  • Example 4 Compound C in combination with an anti-PD-1 antibody demonstrated combinational anti-tumor effects in the growth of H22 hepatocellular carcinoma in a mouse cancer model. ( Figure 2B)
  • mice were divided into the group (ISM 3) and the drug therapy was started from Day 5 for 12 days.
  • Compound C was treated at 50 mg/kg/day, bid, p.o.
  • Anti-PD-1 antibody (Kang Long Chemicals, 695318J3) was treated at 2.5 mg/kg/day, i.p., twice a week. Tumor volume, body weight, and behavior were evaluated, and the statistical analysis of tumor volume was performed the same as Example 1.
  • Compound C therapy at 50 mg/kg/day inhibited tumor growth with 54.2% inhibition.
  • Anti-PD-1 antibody therapy at 2.5 mg/kg twice a week (Kang Long Chemicals, 695318J3) inhibited tumor growth with 26.6% inhibition on Day 17.
  • Combination therapy of Compound C and anti-PD-1 antibody showed additive tumor growth inhibition with 67.3% inhibition.
  • the experiment suggests the benefit of the combination therapy of Compound C with anti-PD-1 therapy or EP4 inhibitory mechanism with anti-PD-1 therapy. No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.
  • Oral dosing of Compound B at 45 mg/kg/day demonstrated 20.6% inhibition of B16F10 melanoma growth compared to a vehicle treated group (P>0.05) on Day 24. No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.
  • Compound C was treated at 200 mg/kg/day, tid, p.o. Tumor volume, body weight, behavior evaluation and the statistical analysis of tumor volume were performed the same way as Example 1.
  • Oral dosing of Compound B at 45 mg/kg/day demonstrated 52.1% inhibition of A20 lymphoma cell growth compared to a vehicle treated group, which was statistically significant inhibition (P ⁇ 0.001) on Day 22. No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.
  • Compound C was treated at 200 mg/kg/day, tid, p.o. Tumor volume, body weight, behavior evaluation and the statistical analysis of tumor volume were performed the same way as in Example 1.

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Abstract

This invention is directed to prostaglandin E2 receptor 4 (EP4) antagonists useful in the treatment of liver cancer, melanoma, lymphoma and leukemia in a human or animal. The method comprises administering one or more of Compound A, Compound B or Compound C, or pharmaceutically acceptable salts thereof, as the EP4 antagonist(s). The method may include a pharmaceutical composition comprising the EP4 antagonist and may include one or more other active agents and/or therapies for liver cancer therapy, such as an anti-PD-1 antibody.

Description

Use of EP4 receptor antagonists for the treatment of liver cancer, melanoma, lymphoma and leukemia
Technical Field
[0001]
This invention relates to a prostaglandin E2 (PGE2) receptor 4 (EP4) antagonist for use in the treatment of liver cancer, melanoma, lymphoma and leukemia (hereinafter, “the cancers of the invention”). The method for the treatment of the cancers of the invention comprises administering any one of Compound A, Compound B or Compound C, or a pharmaceutically acceptable salt thereof, as the EP4 antagonist (hereinafter, “the compounds of the invention”), or a pharmaceutical composition comprising the compounds of the invention to a human or animal. The method of the treatment includes administering the compounds of the invention alone or in combination with one or more other active agents and/or therapies to the human or animal having the cancers of the invention. Compounds A, B and C are:
Compound A:
4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid, or a pharmaceutically acceptable salt thereof;
Compound B:
4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]-benzoi c acid, or a pharmaceutically acceptable salt thereof; and Compound C:
3-[2-(4-{2-ethyl-4,6-dimethyl-1 H-imidazo[4,5-c]pyridin-1 -yl}phenyl)ethyl]-1 -[(4-met hylbenzene)sulfonyl]urea, or a pharmaceutically acceptable salt thereof. Background Art
[0002]
The prostaglandins are mediators of pain, fever and other symptoms associated with inflammation. PGE2 is the predominant eicosanoid expressed in inflammation conditions. PGE2 is also involved in various physiological and/or pathological conditions, such as hyperalgesia, uterine contraction, digestive peristalsis, awakeness, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis, and cancer cell growth, invasion and metastasis, or the like. Non-patent references disclose the characters of the prostanoid receptors, relationship with therapy, and selective agonists and antagonists most generally used (see, for example, Konya et al., Pharmacology & Therapeutics, 2013, 138:485-502; and Yokoyama et al., Pharmacol. Rev., 2013, 65:1010-1052).
[0003]
PGE2 has been reported to be highly expressed in tumor tissues of various types of cancer, and it has also been demonstrated that PGE2 correlates to the initiation, growth and development of cancer and disease conditions of patients. It is generally accepted that PGE2 relates to activation of cancer cell proliferation and cell death and plays an important role in the processes of cancer initiation and proliferation, disease progression and cancer metastasis (see, for example, Konya et al., Pharmacology & Therapeutics, 2013, 138:485-502; and Yokoyama et al., Pharmacol. Rev., 2013, 65:1010-1052).
[0004]
There are four PGE2 receptor subtypes, EP1 , EP2, EP3 and EP4, which display different pharmacological properties. The EP4 receptor subtype belongs to the Gs protein-coupled receptor subfamily, known as a receptor with seven transmemblene domains. Accordingly, EP4 plays a significant role in biological events by stimulating cAMP signal-mediated functions. From the aspect of pharmacological studies, lots of tests of compounds with EP4 receptor antagonistic activities have been conducted and several EP4 receptor-selective antagonists are known (Konya et al. , Pharmacology & Therapeutics, 2013, 138:485-502).
[0005]
Regarding the roles of the EP4 receptor in cancer, several non-patent references (e.g., Yokoyama et al., Pharmacol. Rev., 2013, 65:1010-1052; Ma et al., Oncolmmunology, 2013, 2(1):e22647) and patent references (e.g., US 8,921 ,391 B2 and US 9,688,674 B2) demonstrate the tumor growth inhibitions and/or metastasis of the colon, breast, gastric, lung, prostate, and other cancer types in animal tumor models using EP4 receptor antagonists or genetical EP4 deletion techniques. The patent references (e.g., US 8,921 ,391 B2 and US 9,688,674 B2) describe the use of EP4 antagonists, including the compounds of the invention, for the treatment of “cancer which PGE2 relates to”, and the “cancer which PGE2 relates to” includes brain tumor, bone cancer, and neoplasm derived from epithelial cells (epithelial cancer). Some patent references (e.g., WO 2015/179615 A1 , US 2015/0004175 A1 ) suggest therapeutic efficacy of EP4 receptor antagonists or inhibition of EP4 signaling results in the suppression of tumor growth.
Liver Cancer
[0006]
The role of the EP4 receptor in liver cancer is reported in non-patent references. PGE2/EP4 receptor signaling through PKA/CREB activation upregulated c-Myc expression and resulted in promoting cell growth in hepatocellular carcinoma (HCC) cells in vitro (Xia et al., Oncology Reports, 2014, 32:1521-1530). Xu et al. reported PGE2 through EP4 receptor promote a hepatic stellate cell-induced myeloid-derived suppressor cell (MDSC) accumulation which promote liver cancer (Xu et al., Oncotarget, 2016, 7(8):8866-8878). The mesenchymal stem cells, major compartment of tumor microenvironment, are shown to promote HCC progression and metastasis and PGE2/EP4 axis support the HCC progression (Liu et al., J. Experimental & Clinical Cancer Research 201938:228). These references indicate that the PGE2/EP4 signaling may have roles in liver cancer initiation, promotion, and progression. However, these references do not directly demonstrate the therapeutic efficacy of an EP4 antagonist in a malignant HCC/liver cancer animal model.
Melanoma
[0007]
Skin cancers are malignancies that arise from the skin and include some types of tumors. Epithelial skin cancer is the major skin cancer and it includes, e.g., basal cell carcinoma, squamous cell carcinoma, extramammary Paget’s disease, Merkel cell carcinoma, sweat gland carcinoma, sebaceous carcinoma, and hair follicle carcinoma. These tumors originate from the malignancy of epithelial cells. Melanoma is a skin cancer, but it is categorized as a non-epithelial skin cancer, because it arises from the malignancy of melanocyte, a neural crest cell-origin.
[0008]
Inada et al. (J. Biological Chemistry 2015290:29781-93) indicate a therapeutic opportunity of EP4 signal inhibition in melanoma based on an evidence that a growth of B16 melanoma tumor is significantly reduced in EP4-null PtgerA-1- mice compared to that in wild-type mice. However, EP4 gene knock out mice lack EP4 receptors in advance of tumor inoculation, and this reference does not clearly suggest the therapeutic efficacy of EP4 signal inhibition after the formation of malignant melanoma. The reference merely suggests a suppression of the tumor initiation/promotion stage and/or growth of the melanoma and there is no direct and clear demonstration in the reference that EP4 signal inhibition is responsible for therapeutic antitumor efficacy against malignant tumors. Some patent references (e.g., WO 2015/179615 A1 , US 2015/0004175 A1 , and US 8,921 ,391 B2) describe a therapeutic opportunity of EP4 receptor antagonists or the inhibition of EP4 signaling for melanoma, but the references do not disclose experimental evidence of anti-melanoma tumor efficacy of the compounds of the invention in an animal model. In summary, prior art does not describe the therapeutic anti-tumor efficacy of the compounds of the invention in melanoma based on a validated animal tumor model.
Lymphoma and Leukemia
[0009]
Several non-patent references describe the role of EP4 receptor signaling in blood cancers, such as lymphoma and leukemia. Blood cancers are non-epithelial cancers, which originate from the malignancy of blood cells. Paul AG et al. (Translational Research 2013, 161 :447-468) demonstrate that EP4 signal inhibition with the EP4 antagonist GW627368X has anti-proliferative and cell death-inducing effects on Kaposi’s sarcoma-associated herpesvirus and Epstein-Barr virus related B-cell lymphoma cell lines using a cell culture experiment. Similarly, Kopp KL et al. (Leukemia 201024:1179-1185) report that PGE2 signal activation dose-dependently increased a proliferation of malignant T-cell lymphoma MyLa2000 cells and the EP4-selective antagonist L-161,982 reduced the PGE2-mediated cell growth using cell culture experiment.
[0010]
On the other hand, some references suggest that activation of PGE2/EP4 receptor signaling inhibit B-cell proliferations. Prijatelj et al. (J Pharmacy and Pharmacology 2012 64:1090-1098) report that the PGE2 activation through EP4 receptor mediates the cell growth-suppressive effects in WEHI231 B cells using in vitro cell culture system. In the WEHI231 cell culture, PGE2 suppressed cell growth and this was recovered by the addition of EP4 receptor-specific antagonist ONO-AE3-208 before the PGE2 treatment. Murn et al. (J. Exp Med 2008205:3091-3103) suggest that the EP4 receptor is a principal molecule conveying the growth-suppressive effect of PGE2 using mouse stable A20 lymphoma cell lines in which the EP4 receptor gene expressions are up-regulated or down-regulated by transfecting EP4 receptor genes or miRNAs against EP4 gene-containing expression vectors. Plantation of A20 cell line in which the EP4 gene expression is stably suppressed by miRNA to mice markedly accelerated tumor spread, whereas A20 cell line stably overexpressing the EP4 gene showed significant tumor growth suppression.
[0011]
In addition, there has been no direct evidence of malignant tumor growth inhibition by an EP4 antagonist in an animal tumor model before the invention of the present application, as shown in the Examples below.
Summary of Invention
[0012]
The present application provides a method for the treatment of liver cancer, melanoma, lymphoma, and leukemia using EP4 receptor antagonists. The inventors have discovered that each of the following three compounds of the invention (i.e., Compounds A, B and C and pharmaceutically acceptable salts thereof) dramatically decrease the growth of these cancers by using validated mouse tumor models: 4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid (Compound A),
4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]-benzoic acid (Compound B), and
3-[2-(4-{2-ethyl-4,6-dimethyl-1 H-imidazo[4,5-c]pyhdin-1 -yl}phenyl)ethyl]-1 -[(4-meth ylbenzene)sulfonyl]urea (Compound C).
[0013]
The major mechanism of action of PGE2 and EP4 signaling on the antitumor therapeutic efficacy is described to be the effects on the host’s immune system. Based on this theory, none of an in vitro cancer cell proliferation experiment, an in vivo antitumor efficacy experiment in an immune-deficient mice model, or an in vivo mouse model bearing cancer cells in which EP4 receptor expression is genetically controlled can detect the intrinsic efficacy of the EP4 antagonist, because these three experiments do not evaluate effects of the EP4 antagonist or EP4 signal inhibition on the host immune functions. The present inventors used syngeneic mouse tumor models and tested the tumor growth inhibition in mice with competent immune functions to evaluate the antitumor efficacy of the EP4 antagonist and the effects on immune cells.
[0014]
The Examples below show that Compound B has extremely potent anti-tumor efficacy in a mouse H22 hepatocellular carcinoma cell-bearing tumor model, which is a popular model for liver cancer. The inhibition of the tumor volume in Compound B-treated mice was 78.1 % compared to that of vehicle-treated mice. On the other hand, sorafenib, one of the current standard therapeutics to treat liver cancer, is reported to inhibit tumor volume by only 54.7% compared to a vehicle in the same H22 mouse model (Acta Biomaterialia 2019, 92:229-240). Compound B has unexpected higher potency in terms of anti-tumor efficacy in a liver cancer model compared to sorafenib. Moreover, the Examples below also demonstrate that the therapy of H22 tumor-bearing mice with Compound B in combination with an anti-PD-1 antibody showed higher tumor growth suppression as compared to Compound B (alone) and the anti-PD-1 antibody (alone).
[0015]
Compound A is an analog of Compound B with a very similar chemical structure. Their pharmacological activities, such as an inhibitory potency against EP4 receptor signaling, are almost the same in cAMP inhibition. Therefore, Compound A is expected to produce similar anti-tumor efficacy as that of Compound B demonstrated in the Examples below.
[0016]
Similarly, as shown in the Examples, Compound C showed inhibition of H22 tumor growth in the same mouse model as Compound B of 61.2%, which is also more potent than sorafenib. Compound C also showed similar efficacy as Compound B when combined with an anti-PD-1 antibody. These results clearly and strongly demonstrate the potential use of the compounds of the invention in the treatment of liver cancer, and superior efficacy of the compounds of the invention in the treatment of liver cancer compared to current standard drugs.
[0017]
As shown in the Examples, the inventors further demonstrated that Compound C inhibited growth of melanoma cells in a mouse B16F10 melanoma-bearing mouse model with 36.4% inhibition, and this inhibition was significant compared to the vehicle treated controls (P=0.049). Inhibition of B16F10 melanoma by Compound B was 20.6% in the same mouse model. Accordingly, the inventors demonstrated that EP4 antagonists, Compound B and Compound C, inhibit the growth of melanoma cells in mice bearing B16F10, strongly demonstrating the potential use of the compounds of the invention in a clinical environment. Compound A, having a similar chemical structure to Compound B, is expected to also inhibit the growth of melanoma cells.
[0018]
The effects of EP4 signaling on the growth of lymphoma and leukemia are completely controversial, whether growth promotive or growth suppressive, as noted above. The present inventors presumed that the controversial condition is attributed to a lack of anti-tumor evidence in a syngeneic mice model in which the roles of EP4 antagonist to the host immune cells are included. There was no clear evidence showing EP4 antagonist therapy in the treatment of lymphoma or leukemia in any mouse syngeneic cancer model before the Examples herein. The present inventors have demonstrated that oral systemic treatment of Compound B or Compound C inhibits tumor growth in A20 B-cell lymphoma cell-bearing and WEFI 1-231 leukemia cell-bearing mice syngeneic models and clearly showed that EP4 antagonist systemic therapy has anti-tumorigenic mechanism of lymphoma and leukemia cells. Compound A, having a similar chemical structure to Compound B, is expected to also inhibit tumor growth in lymphoma cell-bearing mice and leukemia cell-bearing mice.
Brief Explanation of the Drawings
[0019]
Figure 1 A depicts antitumor efficacy of Compound B tested in a H22 hepatocellular carcinoma (HCC)-bearing mouse model according to Example 1 as an example of treating liver cancer. Figure 1A shows the change of tumor volume by the treatment of Compound B or a vehicle control group.
[0020]
Figure 1 B depicts antitumor efficacy of the combined therapy of Compound B and an anti-PD-1 antibody tested in the mouse H22 model according to Example 2. Figure 1 B shows the change of tumor volume by the treatment with Compound B alone, the combination of Compound B and an anti-PD-1 antibody, an anti-PD-1 antibody alone, or a vehicle control group.
[0021]
Figures 2A and 2B depict antitumor efficacy of Compound C in the same manner as Figures 1 A and 1 B, respectively, except for using Compound C rather than Compound B, according to Examples 3 and 4. Figure 2A shows the change of tumor volume by the treatment with Compound C or a vehicle control group according to Example 3. Figure 2B shows the change of tumor volume by the treatment with Compound C alone, the combination of Compound C and anti-PD-1 antibody, an anti-PD-1 antibody alone, or a vehicle control group according to Example 4.
[0022]
Figure 3A and Figure 3B depict antitumor efficacy of Compound B and Compound C, respectively, in a mouse B16F10 melanoma-bearing mice model according to Examples 5 and 6, respectively. Figures 3A and 3B show the change of tumor volume by the treatment with Compound B, Compound C, or vehicle-treated control groups.
[0023]
Figure 4A and Figure 4B depict antitumor efficacy of Compound B and Compound C, respectively, in a mouse A20 B-cell lymphoma mice model as an example of lymphoma, according to Examples 7 and 8, respectively. Figures 4A and 4B show the change of tumor volume by the treatment with Compound B, Compound C or vehicle-treated control groups.
[0024]
Figure 5A and Figure 5B depict antitumor efficacy of Compound B and Compound C, respectively, in a mouse WEFII-3 leukemia mice model, according to Examples 9 and 10, respectively. Figures 5A and 5B show the change of tumor volume by the treatment with Compound B, Compound C or vehicle-treated control groups.
Detailed Description of the Invention
[0025]
The compounds of the invention which are useful for the treatment of the cancer of the invention are:
4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid (Compound A),
4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]-benzoic acid (Compound B), and
3-[2-(4-{2-ethyl-4,6-dimethyl-1 FI-imidazo[4,5-c]pyridin-1 -yl}phenyl)ethyl]-1 -[(4-meth ylbenzene)sulfonyl]urea (Compound C), or a pharmaceutically acceptable salt thereof.
The compounds of the invention also include the solvates, complexes, polymorphs, prodrugs, isomers, and isotope-labeled compounds thereof. The compounds of the invention can be used either alone or in combination in any treatment of liver cancer, melanoma, lymphoma and leukemia.
[0026] The compounds of the invention are disclosed in WO 2005/021508, US 8,921 ,391 B2 and US 10,342,785B2.
[0027]
Pharmaceutically acceptable salts include, but are not limited to, the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
[0028]
Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
[0029]
For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
[0030]
A pharmaceutically acceptable salt of the compounds of the invention may be readily prepared by mixing solutions of the compound of the present invention and the desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
[0031]
The compounds of the invention may exist in both unsolvated and solvated forms. The term “solvate” is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
[0032]
Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the compounds containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J. Pharm. Sci. , 64(8): 1269-1288 by Haleblian (August 1975).
[0033]
Hereinafter, all references to the compounds of the invention include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
[0034] The compounds of the invention include the compounds of the invention as herein before defined, polymorphs, prodrugs, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of the invention.
[0035]
As stated above, the invention includes all polymorphs of the compounds of the invention as defined herein.
[0036]
Also within the scope of the invention includes so-called “prodrugs” of the compounds of the invention. Thus, certain derivatives of the compounds of the invention which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into the compounds having the formula of any one of the compounds of the invention having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as “prodrugs”. Further information on the use of prodrugs may be found in “Pro-drugs as Novel Delivery Systems”, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
[0037]
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the invention with certain moieties known to those skilled in the art as “pro-moieties” as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).
[0038] Some examples of prodrugs in accordance with the invention include:
(i) where the compound of the invention contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (Ci-Ce)alkyl;
(ii) where the compound of the invention contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (Ci-C6)alkanoyloxymethyl; and
(iii) where the compound of the invention contains a primary or secondary amino functionality (-NH2 or -NHR where R ¹ H), an amide thereof, for example, replacement of one or both hydrogens with (Ci-Cio)alkanoyl.
[0039]
Further examples of substituent groups other than the foregoing examples are known to those skilled in the art and can be found in the aforementioned references, but not limited to them.
[0040]
Finally, the compounds of the invention may themselves also act as prodrugs of other compounds of the invention.
[0041]
Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism (“tautomerism”) can occur. It follows that a single compound may exhibit more than one type of isomerism. [0042]
Included within the scope of the invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than two types of equal isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counter ion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
[0043]
Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
[0044]
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC).
[0045]
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
[0046] Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50 (w/w) % isopropanol, typically from 2 to 20(w/w) %, and from 0 to 5 (w/w) % of an alkylamine, typically 0.1 (w/w) % diethylamine. Concentration of the eluate affords the enriched mixture.
[0047]
Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art (see, for example, Stereochemistry of Organic Compounds by E L Eliel (Wiley, New York, 1994)).
[0048]
The invention includes all pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
[0049]
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulfur, such as 35S.
[0050]
Certain isotopically-labelled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies associated with cancer therapy which includes diagnosis, alleviation of symptoms, improvement of QOL, and prophylaxis. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
[0051]
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
[0052]
Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
[0053]
Isotopically-labelled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
[0054]
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO. [0055]
Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
[0056]
Each one of the compounds of the invention (i.e., Compound A, B or C) may be administered alone or in combination with each other or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable additives. The term “additive” is used herein to describe any ingredient other than the compounds of the invention. The choice of additive will to a large extent depend on various factors, such as, the particular mode of administration, the effect of the additive on solubility and stability, and the nature of the dosage form. The compounds of the invention may be administered alone or in combination with a pharmaceutically acceptable carrier or diluent by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the compounds of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the compounds of the invention are present in such dosage forms at concentration levels ranging from 5% to 95% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
[0057]
Thus, the invention provides the compounds of the invention, a solvate thereof, a prodrug thereof, a combination thereof, and a combination with one or more other pharmacologically active agents. In addition, the invention provides a pharmaceutical composition comprising the compounds of the invention and a pharmaceutically acceptable additive, a diluent, or a carrier, particularly for the treatment of the cancers of the invention. Also, the invention provides a kit comprising: a first pharmaceutical composition comprising the compounds of the invention, or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition; and a container.
[0058] A kit for the treatment of the cancers of the invention, which includes the compounds of the invention, or the pharmaceutically acceptable salts thereof, is also one of the inventions. A commercial package comprising the pharmaceutical composition comprising the compounds of the invention, or the pharmaceutically acceptable salts thereof and a written matter associated therewith, wherein the written matter states that the compounds can or should be used for treating the cancers of the invention is also one of the inventions.
[0059]
Other features and advantages of the invention may be apparent from the following detailed description and the claims. Although particular embodiments of the invention have been described, various other known or usual changes and modifications in this field fall into the invention and are within the claims. The invention also includes the equivalents, changes, uses, or variations, which are within the spirit of the invention.
[0060]
The compounds of the invention are administered in an amount effective to shrink cancer, reduce cancer tumor size, reduce cancer metastasis, regulate immune cell functions, and/or enhance effectiveness of cancer therapy. Such therapeutic effective amount varies in accordance with the specific compound of the invention, the specific condition to be treated, the patient's condition, the route of administration, the formulation, the field decision, and other factors. In the light of the disclosure, depending on the things known to those skilled in the art, it is decided by routine optimization techniques. The compounds of the invention can be administered via either the oral, parenteral or topical routes to mammals. In general, these compounds are most desirably administered to humans in doses ranging from 1 mg to 1000 mg, preferably from 10 mg to 600 mg, which may be administered in a single dose or in divided doses throughout the day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen.
[0061]
A pharmaceutical composition can include the compounds of the invention or a pharmaceutical salt thereof combined with a pharmaceutically acceptable transport medium or carrier.
[0062]
As used herein the term “pharmaceutically acceptable transport medium” includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The above medium also includes other active or inactive ingredients and is targeted to cancer tissues based on the composition.
[0063]
Therapeutic efficacy of the compounds of the invention can be determined in light of this disclosure by standard therapeutic procedures in cell cultures or experimental animals, e.g., for determining the EDso (the dose therapeutically effective in 50% of the population).
[0064]
The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage may vary depending upon the formulation and the route of administration. For any EP4 receptor antagonist used in the method of the invention (i.e. , Compound A, B or C), the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture. Such information can be used to more accurately determine useful doses in humans or animals. Levels in plasma may be measured, for example, by high performance liquid chromatography.
[0065]
It is well known to those skilled in the art that certain factors may influence the dosage and timing required to effectively treat a mammal including, but not limited to, the severity of the disease or disorder, previous treatments, the general health and/or age of the mammal, and other diseases present. Further, treatment of a mammal with a therapeutically effective amount of the compounds of the invention may include, but are not limited to, a single treatment, alternate-day treatment, or a series of treatments. The compounds of the invention can be administered via either the oral, parenteral or topical routes to mammals. In general, these compounds are most desirably administered to humans, for example, once a day, or in two to four divided portions a day.
[0066]
The precise amount of the compounds administered to a human patient, will be particularly the responsibility of the attendant physician. However, the dose employed will depend upon a number of factors including the age and sex of the patient, the precise condition being treated and its severity, and the route of administration. In the case of oral administration, for example, a daily dosage in terms of the compounds of the invention is usually in the order of about 0.02 to 200 mg, and preferably about 0.1 to 100 mg, per 1 kg body weight of a mammal (including a human), which may be administered once a day or in two to four divided portions a day. More particularly, for example, administration to humans, is about 0.02 to 20 mg, per kg body weight, per day, more particularly, about 0.2 to 12 mg, per kg body weight, per day. Administration to dogs, for example, is about 0.5 to 25 mg, per kg body weight, per day, more particularly, about 1 to 10 mg, per kg body weight, per day. Administration to mice, for example, is about 1 to 100 mg, per kg body weight, per day, more particularly, about 3 to 30 mg, per kg body weight, per day.
[0067]
The compounds of the invention are conveniently administered in the form of a pharmaceutical composition for treatment of the cancers of the invention. Such composition may conveniently be presented for use in conventional manner in admixture with one or more pharmaceutically acceptable carriers or excipients.
[0068]
While it is possible for the compounds of the invention to be administered as the raw chemical, it is preferable to present it as a pharmaceutical composition in the form of a pharmaceutical formulation. The formulations comprise the compounds together with one or more acceptable carriers or diluents, and optionally other therapeutic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
[0069]
A pharmaceutical composition is formulated to meet the desirable route of administration. The administration route is, for example, parenteral (e.g., intravenous, in the skin, subcutaneous), oral (e.g., ingestion or inhalation), percutaneous (local), mucosal, and rectum, and local (including percutaneous, oral, and sublingual) administration. A pharmaceutical composition formulated in the form of a solution or suspension can be prepared by the method described in, for example, Remington’s Pharmaceutical Sciences, 18th ed., Gennaro, ed., Mack Publishing Co., Easton, PA, (1990).
[0070]
The most suitable route of administration may be different depending upon, for example, the condition and disorder of the patient receiving the treatment. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compound (i.e. , the “active ingredient”) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into the desired formulation.
[0071]
Formulations of the present invention suitable for oral administration may be presented as discrete units, such as capsules, cachets or tablets (e.g., chewable tablets in particular for pediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granule; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
[0072]
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granule, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
[0073]
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[0074]
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
[0075]
Formulations for topical administration in the mouth, for example, buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia. [0076]
The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0077]
In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
[0078]
Second active agents that are small molecules can also be used to alleviate adverse effects associated with the administration of the compounds of the invention. However, like some large molecules, many are believed to be capable of providing a synergistic effect when administered with (e.g., before, after or simultaneously) the compounds of the invention. Examples of small molecule second active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids.
[0079]
The invention also includes combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions; a compound of the invention; and a second therapeutic agent as described herein. The kit comprises a container for containing the separate compositions, such as, a divided bottle or a divided foil packet, however, the separate compositions may also be contained within a single, undivided container. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
[0080]
An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally contain a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
[0081]
In certain embodiments, the methods provided herein comprise administering the compounds of the invention in combination with one or more second active agents, and/or in combination with radiation therapy or surgery. Examples of the second active agent include, for example, additional EP4 antagonists, immune checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, adoptive immune cell therapies, cancer vaccines, and other immuno-oncological drugs targeting, for example, colony-stimulating factor 1 receptor (CSF1 R), indoleamine 2,3-dioxytenase (IDO), or carcinoembryonic antigen (CEA). Moreover, molecular-targeted anti-cancer drugs, and cancer chemotherapeutics are also included as the second active agent. More particularly, the second active agents include, for example, PD-1 antibodies such as nivolumab, labrolizumab/pembrolizumab, REGE2810, PD-L1 antibodies such as abelumab, atezolizumab, durvalumab, pembrolizumab, CTLA-4 antibodies such as ipilimumab and tremelimumab, molecular-targeted drugs such as anti-HER2 antibody, anti-VEGF antibody, anti-EGFR antibody, tyrosine kinase inhibitors against EGFR receptor, PDGFR receptor, VEGFR receptor kinases, c-kit, and Bcr-Abl, and anti-tumor chemotherapeutics such as alkylating agents, antimetabolites, anti-tumor antibiotics, anti-infective drugs, microtubule inhibitors, hormonal therapeutics, platinum drugs, topoisomerase inhibitors, humor therapeutics such as aromatase inhibitors, anti-estrogen drugs, anti-androgen drugs, progesterone, estradiol, LH-RH agonists, and immune therapies such as adoptive T-cell therapy, adoptive dendritic cell therapy, adoptive NK cell therapy and cancer vaccine therapy. The administration of the compounds of the invention and the second active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated. Recommended routes of administration for the second active agents are known to those of ordinary skill in the art. See, e.g., Physicians’ Desk Reference.
Definitions of Terms
[0082]
ΈR4 antagonist” refers to a compound which inhibits or blocks the cellular signaling triggered by the interaction of PGE2 with the EP4 receptor. Examples of EP4 antagonists include, but are not limited to, ER-819762, MK-2894, MF 498, ONO-AE3-208, evatanepag, ONO-AE2-227, BGC201531 , ONO-AE3-240, GW 627368, TPST-1495 and AH23848. Compounds A, B and C, and pharmaceutically acceptable salts thereof (the compounds of the invention), are also examples of EP4 antagonists.
[0083]
“Anti-PD-1 antibody” refers to an antibody which targets programmed cell death 1 receptor (PD-1 ) and inhibits or blocks the cellular signaling of PD-1. Examples of an anti-PD-1 antibody include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, and toripalimab.
[0084]
An “immune checkpoint inhibitor” refers to a type of drug that blocks certain proteins made by some types of immune cells, such as T cells, and some cancer cells. These proteins help keep immune responses in check and can keep T cells from killing cancer cells. When these proteins are blocked, the brakes on the immune system are released and T cells are able to kill cancer cells better. Examples of immune checkpoint inhibitors include, but are not limited to, PD-1 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, BTLA inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, B7-1 inhibitors, B7-2 inhibitors, galectin-9 inhibitors, and HVEM inhibitors. The immune checkpoint inhibitors may be small molecules, peptides, proteins such as antibody, nucleic acids or the like.
[0085]
“PD-1 inhibitor” refers to an antibody or other molecule which inhibits programmed death protein 1 (PD1) function. Exemplary inhibitors/antibodies include, but are not limited to, the antibodies set forth in U.S. Patent Nos. 7,029,674, 7,488,802, 7,521 ,051 , 8,008,449, 8,354,509, 8,617,546 and 8,709,417. Particular embodiments of the antibody include MDX-1106/nivolumab, BMS-936558, (Bristol- Myers Squibb), labrolizumab (Merck), MK-3475/pembrolizumab (KEYTRUDA®, Merck), AMP-224 (GSK), and CT-011 (Cure Tech).
[0086]
“PD-L1 inhibitor” refers to an antibody or other molecule which inhibits programmed death ligand 1 (PDL1) function. Exemplary antibodies include, but are not limited to, the antibodies set forth in U.S. Patent Nos. 8,217,149, 8,383,796, 8,552,154 and 8,617,546. In a particular embodiment, the antibody is MPDL3280A/RG7446 (Roche), BMS-936559 (BMS), MEDI4736 (AstraZeneca), and MSB0010718C (MerckSerono).
[0087]
“CTLA4 inhibitor” refers to an antibody or other molecule which inhibits cytotoxic t-lymphocyte antigen 4 (CTLA4) function. Exemplary inhibitors/antibodies include, but are not limited to, antibodies that are CTLA4 antagonists or the CTLA4 antibodies set forth in U.S. Patent Nos. 8,685,394 and 8,709,417. Some embodiments of the antibody include MDX-010 (ipilimumab, Bristol-Myers Squibb) and CP-675,206 (tremelimumab, AstraZeneca). In a particular embodiment, the antibody is ipilimumab and tremelimumab. [0088]
An “adoptive immune cell therapeutic” refers to a therapeutic that uses the cells of the immune system for cancer therapy and also known as a cellular immunotherapy. Examples of adoptive immune cell therapeutics include, but are not limited to, tumor-infiltrating lymphocyte therapy, engineered T cell receptor therapy, chimeric antigen receptor T cell therapy, natural killer cell therapy, dendritic cell therapy, and stem cell therapy.
[0089]
A “cancer vaccine” refers to a cancer immunotherapeutic that uses vaccine technology for cancer treatment. Examples of cancer vaccines include, but are not limited to, sipuleucel-T, DCVAC/PCa, OncoVAX, and gemogenovatucel-T.
[0090]
An “immuno-oncological therapeutic” refers to an anti-tumor drug that regulates the immune system to stimulate cancer therapy. Examples of immuno-oncological therapeutics include, but are not limited to, T cell stimulant (stimulator of effector T cell development and function) that includes activators of cancer antigen presentation, priming and activation of T cells, T cell trafficking to tumors, recognition of cancer cells, and cancer cell killing such as activators of TNF-a, IL-1 , IFN-a, CD40L/CD40, CD28/B7.1 , CD137/CD137L, OX40/OX40L, CD27/CD70, HVEM, GITR, IL-2, IL-12, CX3CL1 , CXCL9, CXCL10, CCL5, LFA1/CAM1 , selectins, T cell receptor, IFN- , and inhibitors of IL-10, IL-4, IL-13, CTLA4/B7.1 , PD-L1/PD-1 , prostaglandins, VEGF, endothelin B receptor, reduced pMFIC, IDO, TGF- S , BTLA, VIATA, LAG-3, arginase, MICA/MICB, B7-H4, TIM-3/phospholipids. Immuno-oncological therapeutics also include adoptive immune cell therapeutics and cancer vaccines. [0091]
A “cancer chemotherapeutic” refers to a drug that inhibits cancer cell growth and metastasis that mainly comprises alkylating agents such as mustard gas derivatives, ethylenimines, alkylsulfonates, hydrazines and triazines, nitrosureas, metal salts; plant alkaloids such as vinca alkaloids, taxanes, podophyllotoxins, campthothecan analogs; antitumor antibotics such as anthracyclines, chromomycins, mitomycin and bleomycin; antimetabolites such as folic acid antagonist, pyrimidine analog, purine analog, adenosine deaminase inhibitor; topoisomerase inhibitors such as topoisomerase I inhibitor and topoisoerase II inhibitor; miscellaneous antineoplastics such as ribonucleotide reductase inhibitor, adrenocortical steroid inhibitor, enzyme inhibitors, antimicrotuble agent, retinoids, and molecular-targeted antitumor drugs. Examples of cancer chemotherapeutics include, but are not limited to, Mechlorethamine, Cyclophosphamide, Chlorambucil, Melphalan, Ifosfamide, Thiotepa, Hexamethylmelamine, Busulfan, Altretamine, Procarbazine, Dacarbazine, Temozolomide, Carmustine, Lomustine, Streptozocin, Carboplatin, Cisplatin, Oxaliplatin, Vincristine, Vinblastine, Vinorelbine, Paclitaxel, Docetaxel, Etoposide, Tenisopide, Irinotecan, Topotecan, Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, Idarubicin, Dactinomycin, Plicamycin, Mitomycin, Bleomycin, Methotrexate, 5-Fluorouracil, Foxuridine, Cytarabine, Capecitabine, Gemcitabine, 6-Mercaptopurine, 6-Thioguanine, Cladribine, Fludarabine, Nelarabine, Pentostatin, Amsacrine, Etoposide, Etoposide phosphate, Teniposide, Flydroxyurea, Mitotane, Asparaginase, Pegaspargase, Estramustine, Bexarotene, Isotretinoin, and Tretinoin (ATRA).
[0092]
“Treatment,” “treat,” and “treating” refer to alleviating, inhibiting and/or reversing the progress of a cancer in a subject in need thereof. The term “treating” is inclusive of any indicia of success in the treatment or amelioration of the cancer, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; delaying or slowing in the rate of progression, etc. Measurement of the treatment or amelioration may be based on, e.g., the results of a physical examination, a pathological test and/or a diagnostic test as known in the art. Treating may also refer to reducing the incidence or onset of a cancer, or a recurrence thereof (such as a lengthening in time of remission), as compared to that which would occur in the absence of the measure taken. The term “treatment”, as used herein, includes not only shrinking the tumor tissue but also alleviation of symptoms, improvement of quality of life (QOL), and prophylaxis (radiotherapy, postoperative prevention of recurrence, adjuvant chemotherapy and the like).
[0093]
A “pharmaceutically effective amount” refers to an amount that is effective for treating a cancer as noted through clinical testing and evaluation, patient observation, and/or the like. An “effective amount” can further designate an amount that causes a detectable change in biological or chemical activity. The detectable changes may be detected and/or further quantified by one skilled in the art for the relevant mechanism or process. Moreover, an “effective amount” can designate an amount that maintains a desired physiological state, i.e., reduces or prevents significant decline and/or promotes improvement in the condition. An “effective amount” can further refer to a therapeutically effective amount.
[0094]
As used herein, the term “a pharmaceutically acceptable salt” is consistent with the examples provided above and refers to a relatively nontoxic, inorganic or organic acid salt of a compound of the invention. These salts may be prepared in situ during the final isolation and purification of the compounds or by reacting the purified compound in its free form separately with a suitable organic or inorganic acid and isolating the salt thus formed. Representative acid salts include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts. In one embodiment, the pharmaceutically acceptable salt is a hydrochloride/chloride salt.
[0095]
“Second active agent” is a low molecular weight drug or biologic which has pharmacologically effective activity, and it includes, but is not limited to, PGE2 signal inhibitors such as additional EP4 antagonists, microsomal prostaglandin E synthase (mPGES)-1 inhibitor, COX-2 inhibitors, NSAIDs, and immune checkpoint inhibitors, cancer immunotherapeutics, immune cell therapeutics, molecular-targeted antitumor drugs, alkylating agents, antimetabolites, anti-tumor antibiotics, anti-infective drugs, microtubule inhibitors, hormonal therapeutics, platinum drugs, topoisomerase inhibitors, molecular-targeted cancer therapeutics, vaccine therapeutics and so on.
[0096]
“Immune cell therapeutics” includes, but is not limited to, drugs or biologies for anti-tumor vaccine therapy, and adoptive immune cell therapy such as adoptive T-cell therapy, adoptive dendritic cell therapy, adoptive NK cell therapy, and CAR-T therapy.
[0097]
“Cancer immunotherapeutics” includes, but is not limited to, the anti-tumor drugs that targeting immune cells and molecules related to immune cells and cancer-immune cell interactions. Immune cells include, but is not limited to, B cells, T cells, regulatory T cells, natural killer cells, natural killer T cells, dendritic cells, myeloid-derived suppressor cells, monocytes and macrophages. Molecules related to immune cells and cancer-immune cell interactions include, but is not limited to, PD-1 , PD-L1 , CTLA4, TIM3, LAG3, TIGIT, BTLA, OX-40, ICOS, CD137, GITR, CD40, CD28, CD27, IL-2, IL-7, IL-15, IL-21 , GM-CSF, IL-12, IFNa, ICAM1 , VCAM1 , CD103, IDO, TDO, NOS1 , Arginase, CSF1 , FOXP3, TGFp, IL-10, BATF3, XCR1/XCL1 , STING, IFNy, CXCL9/10/11 , CXCL1/13, CCL2/5.
[0098]
“Molecular-targeted antitumor drugs” include, but are not limited to, small molecules and biologies which target specific molecules such as protein kinases, apoptosis regulators, growth factors, angiogenesis regulators, humoral receptors, transcription factors, cytokines, chemokines, receptors, enzymes, ion channels, etc. that related to the growth of cancer cells. “Molecular-targeted antitumor drugs” include, but are not limited to, Imatinib, Gefitinib, Erlotinib, Sorafenib, Sunitib, Dasatinib, Lapatinib, Nilotinib, Bortezomib, Tamoxifen, tofacitinib, crizotinib, obatoclax, navitoclax, gossypol, iniparib, Olaparib, perifosine, Apatinib, vemurafenib, dabrafenib, trametinib, PD-0332991 , LEE011 , Vintafolide, Temsirolimus, Everolimus, Vemurafenib, Trametinib, Dabrafenib, Pembrolizumab, Rituximab, Trastuzumab, Alemtuzumab, Cetuximab, Panitumumab, Bevacizumab, Ipiliumab, and Nivolumab. [0099]
“Liver cancer” includes, but is not limited to, hepatocellular carcinoma, cholangiocarcinoma, mucinous cystic neoplasm and intraductal papillary biliary neoplasm. “Liver cancer” also includes, but is not limited to, cancers in liver associated with cirrhosis, hepatitis B, hepatitis C virus infections, and alcohol consumption.
[0100]
“Melanoma” includes, but is not limited to, melanomas occurring in the skin, mouth, eye, gastrointestinal organs, liver, bone, and other organs, and includes primary melanoma and metastatic melanoma.
[0101]
“Lymphoma” includes, but is not limited to, Hodgkin’s lymphomas, non-Hodgkin lymphomas and Epstein-barr virus-associated lymphoproliferative diseases. “Lymphoma” also includes, but is not limited to, mature B cell neoplasms, mature T cell and natural killer cell neoplasms, precursor lymphoid neoplasms, and immunodeficiency-associated lymphoproliferative disorders. In particular, lymphoma includes B-cell lymphoma.
[0102]
“Leukemia” includes, but is not limited to, lymphocytic leukemia and myelogenous leukemia with acute or chronic properties. “Leukemia” also includes, but is not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, hairy cell leukemia, T-cell prolymphocytic leukemia, large granular lymphocytic leukemia, adult T-cell leukemia, and clonal eosinophilia. [0103]
The term ΈR4 signal” or ΈR4 signaling”, as used herein, means EP4 receptor-mediated cellular signal transductions such as the cyclic AMP and phosphoinositide 3-kinase (PI3K) signals and following signal transductions in association with agonistic stimulation of EP4 receptor.
Examples
[0104]
For the purpose to elucidate the anti-tumor efficacies of the compounds of the invention for the therapy of the cancers of the invention, validated mice tumor models were employed, and tested the tumor growth inhibition and the changes of body weight of mice during the experimental periods. No drug-related abnormal body weight changes or abnormal behaviors were observed in the experiments described in these Examples.
[0105]
Example 1
Compound B demonstrated almost complete inhibition of the growth of H22 hepatocellular carcinoma in a mouse liver cancer model. (Figure 1 A)
Experimental Methods
Mouse hepatocellular carcinoma H22 cells were cultured in RPMI-1640 medium containing 10% FBS, 100 U/mL penicillin and 100 mV/GhI. streptomycin. 2 x 106 cells/0.1 mL of H22 cells were inoculated to the right rib of BALB/c mice subcutaneously on Day 0. On Day 4, the mice were divided into the group (N=8) and the drug therapy was started from Day 5 for 14 days everyday. Compound B was treated at 45 mg/kg/day, bid, p.o. Tumor volume was evaluated by measuring the long and short diameter of a tumor and calculated with the equation, 0.5 x (long diameter) x (short diameter). Statistical analysis of tumor volume between groups was analyzed by One-Way ANOVA. Body weight measurements and behavioral observations of the mice were conducted prior to the start of each drug treatment.
Study Results and Conclusion
Oral dosing of Compound B at 45 mg/kg/day demonstrated 78.1% inhibition of H22 tumor growth compared to vehicle treated on Day 19 (Figure 1A). This inhibition was statistically significant. No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.
[0106]
Example 2
Compound B in combination with an anti-PD-1 antibody demonstrated combinational anti-tumor effects in inhibiting the growth of H22 hepatocellular carcinoma in a mouse cancer model. (Figure 1 B)
Experimental Methods
The same mouse model as Example 1 was used for this experiment. On day 4, mice were divided into the group (ISM 3) and the drug therapy was started from Day 5 for 12 days. Compound B was treated at 15 mg/kg/day, bid, p.o.
Anti-PD-1 antibody (Kang Long Chemicals, 695318J3) was treated at 2.5 mg/kg/day, i.p., twice a week. Tumor volume, body weight, and behavior were evaluated, and the statistical analysis of tumor volume was performed the same as Example 1.
Study Results and Conclusion
Compound B therapy at 15 mg/kg/day inhibited tumor growth with 34.5% inhibition. Anti-PD-1 antibody therapy at 2.5 mg/kg twice a week inhibited tumor growth with 33.8% inhibition on Day 17. Combination therapy of Compound B and anti-PD-1 antibody showed higher tumor growth inhibition of 58.2% inhibition. The experiment suggests the benefit of the combination therapy of Compound B with anti-PD-1 therapy or the combination of EP4 inhibitory mechanism with anti-PD-1 therapy. No drug-mediated abnormal behaviors or mean body weight change was observed throughout the experimental period.
[0107]
Example 3
Compound C demonstrates potent inhibition of the growth of H22 hepatocellular carcinoma in the mouse cancer model. (Figure 2A)
Experimental Methods
The same mouse model as Example 1 was used in this experiment. On Day 4, mice were divided into the group (N=8) and the drug therapy was started from Day 5 for 14 days everyday. Compound C was treated at 200 mg/kg/day, bid, p.o. Tumor volume, body weight, and behavior were evaluated, and the statistical analysis of tumor volume was performed the same as Example 1.
Study Results and Conclusion
Compound C therapy at 200 mg/kg/day inhibited 61.2% inhibition of H22 tumor growth compared to vehicle treated on Day 19 (Figure 2A). This inhibition was statistically significant. No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.
[0108]
Example 4 Compound C in combination with an anti-PD-1 antibody demonstrated combinational anti-tumor effects in the growth of H22 hepatocellular carcinoma in a mouse cancer model. (Figure 2B)
Experimental Methods
The same mouse model as Example 1 was used for this experiment. On Day 4, mice were divided into the group (ISM 3) and the drug therapy was started from Day 5 for 12 days. Compound C was treated at 50 mg/kg/day, bid, p.o. Anti-PD-1 antibody (Kang Long Chemicals, 695318J3) was treated at 2.5 mg/kg/day, i.p., twice a week. Tumor volume, body weight, and behavior were evaluated, and the statistical analysis of tumor volume was performed the same as Example 1.
Study Results and Conclusion
Compound C therapy at 50 mg/kg/day inhibited tumor growth with 54.2% inhibition. Anti-PD-1 antibody therapy at 2.5 mg/kg twice a week (Kang Long Chemicals, 695318J3) inhibited tumor growth with 26.6% inhibition on Day 17. Combination therapy of Compound C and anti-PD-1 antibody showed additive tumor growth inhibition with 67.3% inhibition. The experiment suggests the benefit of the combination therapy of Compound C with anti-PD-1 therapy or EP4 inhibitory mechanism with anti-PD-1 therapy. No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.
[0109]
Example 5
Compound B demonstrated an inhibition of the growth of B16F10 melanoma in a mouse cancer model. (Figure 3A) Experimental Methods
Mouse melanoma B16F10 cells were cultured in DMEM containing 10% FBS. 1 x 105 cells of B16F10 cells were inoculated to the right rib of C57BL/6J each mouse subcutaneously on Day 0. On Day 11 , mice were divided into the group (N=8) and the drug therapy was started from Day 12 for 14 days. Compound B was treated at 45 mg/kg/day, bid, p.o. Tumor volume, body weight, behavior evaluation and statistical analysis of tumor volume were performed the same way as in Example 1.
Study Results and Conclusion
Oral dosing of Compound B at 45 mg/kg/day demonstrated 20.6% inhibition of B16F10 melanoma growth compared to a vehicle treated group (P>0.05) on Day 24. No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.
[0110]
Example 6
Compound C demonstrated potent inhibition of the growth of B16F10 melanoma in a mouse cancer model. (Figure 3B)
Experimental Methods
The same mouse model as Example 5 was used for this experiment. On Day 11 , mice were divided into the group (N=8) and the drug therapy was started from day 12 for 14 days. Compound C was treated at 200 mg/kg/day, tid, p.o. Tumor volume, body weight, behavior evaluation and the statistical analysis of tumor volume were performed the same way as Example 1.
Study Results and Conclusion
Oral dosing of Compound C at 200 mg/kg/day demonstrated 36.4% inhibition of B16F10 melanoma growth compared to a vehicle treated group on Day 24, which was statistically significant inhibition (P=0.049). No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.
[0111]
Example 7
Compound B demonstrated potent inhibition of the growth of A20 B-cell lymphoma in a mouse cancer model. (Figure 4A)
Experimental Methods
The mouse B-cell lymphoma A20 cells were cultured in RPMI 1640 containing 10% FBS, 0.05 mM 2-mercaptoethanol. 3 x 105 cells of A20 cells were inoculated to the right rib of BALB/c mouse subcutaneously on day 0. On Day 7, mice were divided into the group (N=8) and the drug therapy was started from Day 8 for 14 days. Compound B was treated at 45 mg/kg/day, bid, p.o. Tumor volume, body weight, behavior evaluation and the statistical analysis of tumor volume were performed the same way as Example 1.
Study Results and Conclusion
Oral dosing of Compound B at 45 mg/kg/day demonstrated 52.1% inhibition of A20 lymphoma cell growth compared to a vehicle treated group, which was statistically significant inhibition (P<0.001) on Day 22. No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.
[0112]
Example 8
Compound C demonstrated potent inhibition of the growth of A20 B-cell lymphoma in a mouse cancer model. (Figure 4B)
Experimental Methods
The same mouse model as Example 7 was used for this experiment. On Day 7, mice were divided into the group (N=8) and the drug therapy was started from Day 8 for 14 days. Compound C was treated at 200 mg/kg/day, tid, p.o. Tumor volume, body weight, behavior evaluation and the statistical analysis of tumor volume were performed the same way as in Example 1.
Study Results and Conclusion
Oral dosing of Compound C at 200 mg/kg/day demonstrated 42.2% inhibition of A20 B-cell lymphoma cell growth compared to vehicle treated on Day 22, which was statistically significant inhibition (P=0.003). No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.
[0113]
Example 9
Compound B demonstrated potent inhibition of the growth of WEHI-3 leukemia in a mouse cancer model. (Figure 5A)
Experimental Methods
The mouse leukemia WEHI-3 cells were cultured in RPM1 1640 containing 10% FBS, 0.05 mM 2-mercaptoethanol. 3 x 105 cells of WEHI-3 cells were inoculated to the right rib of BALB/c mice subcutaneously on Day 0. On Day 7, mice were divided into the group (N=8) and the drug therapy was started from Day 8 for 8 days. Compound B was treated at 45 mg/kg/day, bid, p.o. Tumor volume, body weight, behavior evaluation and the statistical analysis of tumor volume were performed the same way as Example 1.
Study Results and Conclusion
Oral dosing of Compound B at 45 mg/kg/day demonstrated 48.4% inhibition of WEHI-3 leukemia cell growth compared to a vehicle treated group, which was statistically significant inhibition (P=0.02) on Day 16. No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.
[0114]
Example 10
Compound C demonstrated potent inhibition of the growth of WEHI-3 leukemia in a mouse cancer model. (Figure 5B)
Experimental Methods
The same mouse model as Example 9 was used for this experiment. On Day 7, mice were divided into the group (N=8) and the drug therapy was started from Day 8 for 8 days. Compound C was treated at 200 mg/kg/day, tid, p.o. Tumor volume, body weight, behavior evaluation and the statistical analysis of tumor volume were performed the same way as Example 1.
Study Results and Conclusion
Oral dosing of Compound C at 200 mg/kg/day demonstrated 61.2% inhibition of WEHI-3 leukemia cell growth compared to a vehicle treated group on Day 16, which was statistically significant inhibition (P=0.003). No drug-mediated abnormal behaviors or mean body weight changes were observed throughout the experimental period.

Claims

1. A method for the treatment of liver cancer, which comprises administering a pharmaceutically effective amount of a compound selected from the group consisting of: 4-((1 S)-1 -{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid (Compound A),
4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]-benzoic acid (Compound B), and
3-[2-(4-{2-ethyl-4,6-dimethyl-1 H-imidazo[4,5-c]pyridin-1 -yl}phenyl)ethyl]-1 -[(4-meth ylbenzene)sulfonyl]urea (Compound C), or a pharmaceutically acceptable salt thereof, to a human or an animal in need thereof.
2. The method of claim 1 , further comprising administering the pharmaceutically effective amount of the Compound A, B, or C in combination with a second active agent.
3. The method of claim 2, wherein the second active agent is at least one selected from the group consisting of an immune checkpoint inhibitor, an adoptive immune cell therapeutic, a cancer vaccine, an immuno-oncological therapeutic, a molecular-targeted antitumor drug, and a cancer chemotherapeutic.
4. The method of claim 1 , further comprising administering the pharmaceutically effective amount of the Compound A, B, or C in combination with an anti-PD-1 antibody.
5. A method for the treatment of melanoma, which comprises administering a pharmaceutically effective amount of a compound selected from the group consisting of: 4-((1 S)-1 -{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid (Compound A),
4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]-benzoic acid (Compound B), and
3-[2-(4-{2-ethyl-4,6-dimethyl-1 H-imidazo[4,5-c]pyridin-1 -yl}phenyl)ethyl]-1 -[(4-meth ylbenzene)sulfonyl]urea (Compound C), or a pharmaceutically acceptable salt thereof, to a human or an animal in need thereof.
6. The method of claim 5, further comprising administering the pharmaceutically effective amount of the Compound A, B, or C in combination with a second active agent.
7. The method of claim 6, wherein the second active agent is at least one selected from the group consisting of an immune checkpoint inhibitor, an adoptive immune cell therapeutic, a cancer vaccine, an immuno-oncological therapeutic, a molecular-targeted antitumor drug, and a cancer chemotherapeutic.
8. The method of claim 5, further comprising administering the pharmaceutically effective amount of the Compound A, B, or C in combination with an anti-PD-1 antibody
9. A method for the treatment of lymphoma, which comprises administering a pharmaceutically effective amount of a compound selected from the group consisting of: 4-((1 S)-1 -{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid (Compound A), 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]-benzoic acid (Compound B), and
3-[2-(4-{2-ethyl-4,6-dimethyl-1 H-imidazo[4,5-c]pyridin-1 -yl}phenyl)ethyl]-1 -[(4-meth ylbenzene)sulfonyl]urea (Compound C), or a pharmaceutically acceptable salt thereof, to a human or an animal in need thereof.
10. The method of claim 9, further comprising administering the pharmaceutically effective amount of the Compound A, B, or C in combination with a second active agent.
11. The method of claim 10, wherein the second active agent is at least one selected from the group consisting of an immune checkpoint inhibitor, an adoptive immune cell therapeutic, a cancer vaccine, an immuno-oncological therapeutic, a molecular-targeted antitumor drug, and a cancer chemotherapeutic.
12. The method of claim 9, further comprising administering the pharmaceutically effective amount of the Compound A, B, or C in combination with an anti-PD-1 antibody
13. A method for the treatment of B-cell lymphoma, which comprises administering a pharmaceutically effective amount of a compound selected from the group consisting of:
4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid (Compound A),
4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]-benzoic acid (Compound B), and
3-[2-(4-{2-ethyl-4,6-dimethyl-1 H-imidazo[4,5-c]pyridin-1 -yl}phenyl)ethyl]-1 -[(4-meth ylbenzene)sulfonyl]urea (Compound C), or a pharmaceutically acceptable salt thereof, to a human or an animal in need thereof.
14. The method of claim 13, further comprising administering the pharmaceutically effective amount of the Compound A, B, or C in combination with a second active agent.
15. The method of claim 14, wherein the second active agent is at least one selected from the group consisting of an immune checkpoint inhibitor, an adoptive immune cell therapeutic, a cancer vaccine, an immuno-oncological therapeutic, a molecular-targeted antitumor drug, and a cancer chemotherapeutic.
16. The method of claim 13, further comprising administering the pharmaceutically effective amount of the Compound A, B, or C in combination with an anti-PD-1 antibody
17. A method for the treatment of leukemia, which comprises administering a pharmaceutically effective amount of a compound selected from the group consisting of: 4-((1 S)-1 -{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid (Compound A),
4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]-benzoic acid (Compound B), and
3-[2-(4-{2-ethyl-4,6-dimethyl-1 H-imidazo[4,5-c]pyridin-1 -yl}phenyl)ethyl]-1 -[(4-meth ylbenzene)sulfonyl]urea (Compound C), or a pharmaceutically acceptable salt thereof, to a human or an animal in need thereof.
18. The method of claim 17, further comprising administering the pharmaceutically effective amount of the Compound A, B, or C in combination with a second active agent.
19. The method of claim 18, wherein the second active agent is at least one selected from the group consisting of an immune checkpoint inhibitor, an adoptive immune cell therapeutic, a cancer vaccine, an immuno-oncological therapeutic, a molecular-targeted antitumor drug, and a cancer chemotherapeutic.
20. The method of claim 17, further comprising administering the pharmaceutically effective amount of the Compound A, B, or C in combination with an anti-PD-1 antibody
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