WO2018102506A1 - Dérivés de tyrosine et compositions les comprenant - Google Patents

Dérivés de tyrosine et compositions les comprenant Download PDF

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Publication number
WO2018102506A1
WO2018102506A1 PCT/US2017/063865 US2017063865W WO2018102506A1 WO 2018102506 A1 WO2018102506 A1 WO 2018102506A1 US 2017063865 W US2017063865 W US 2017063865W WO 2018102506 A1 WO2018102506 A1 WO 2018102506A1
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WIPO (PCT)
Prior art keywords
cancer
tyrosine
methyl
composition
amino
Prior art date
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PCT/US2017/063865
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English (en)
Inventor
Steven Hoffman
Original Assignee
Tyme, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US15/365,120 external-priority patent/US20170080093A1/en
Priority to AU2017368135A priority Critical patent/AU2017368135A1/en
Priority to KR1020197018473A priority patent/KR20190089191A/ko
Priority to CA3045110A priority patent/CA3045110A1/fr
Priority to EP17817552.7A priority patent/EP3548086A1/fr
Priority to JP2019528632A priority patent/JP2019536783A/ja
Application filed by Tyme, Inc. filed Critical Tyme, Inc.
Priority to BR112019011033A priority patent/BR112019011033A2/pt
Priority to CN201780074235.7A priority patent/CN110062633A/zh
Priority to MX2019006326A priority patent/MX2019006326A/es
Priority to EA201991305A priority patent/EA201991305A1/ru
Publication of WO2018102506A1 publication Critical patent/WO2018102506A1/fr
Priority to IL266840A priority patent/IL266840A/en
Priority to PH12019501186A priority patent/PH12019501186A1/en
Priority to JP2022122538A priority patent/JP2022153587A/ja

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    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present inventions relate generally to compositions, kits and methods for the reduction of cellular proliferation as, for example, in the treatment of cancer.
  • Cancer treatments today include surgery, hormone therapy, radiation, chemotherapy, immunotherapy, targeted therapy, and combinations thereof. Surgical removal of cancer has advanced significantly; however, there remains a high chance of recurrence of the disease. Hormone therapy using drugs such as aromatase inhibitors and luteinizing hormone-releasing hormone analogs and inhibitors has been relatively effective in treating prostate and breast cancers. Radiation and the related techniques of conformal proton beam radiation therapy, stereotactic radiosurgery, stereotactic radiation therapy, intraoperative radiation therapy, chemical modifiers, and radio sensitizers are effective at killing cancerous cells, but can also kill and alter surrounding normal tissue.
  • Chemotherapy drugs such as aminopterin, cisplatin, methotrexate, doxorubicin, daunorubicin and others alone and in combinations are effective at killing cancer cells, often by altering the DNA replication process.
  • Biological response modifier (BRM) therapy, biologic therapy, biotherapy, or immunotherapy alter cancer cell growth or influence the natural immune response, and involve administering biologic agents to a patient such as an interferons, interleukins, and other cytokines and antibodies such as rituximab and trastuzumab and even cancer vaccines such as Sipuleucel-T.
  • Targeted therapies have been developed to fight cancer. These targeted therapies differ from chemotherapy because chemotherapy works by killing both cancerous and normal cells, with greater effects on the cancerous cells. Targeted therapies work by influencing the processes that control growth, division, and the spread of cancer cells and signals that cause cancer cells to die naturally.
  • One type of targeted therapy includes growth signal inhibitors such as trastuzumab, gefitinib, imatinib, centuximab, dasatinib and nilotinib.
  • Another type of targeted therapy includes angiogenesis inhibitors such as bevacizumab that inhibit cancers from increasing surrounding vasculature and blood supply.
  • a final type of targeted therapy includes apoptosis-inducing drugs that are able to induce direct cancer cell death.
  • Site-directed chemotherapy directs anticancer agents preferentially to cancer cells by means of a targeting molecule.
  • the targeting molecule has a specific affinity for the cancer being treated.
  • Antibodies are examples of targeting molecules that can be used to direct anticancer agents to specific cancer types.
  • An antibody may recognize an antigen that is expressed on the surface of a specific type of cancer cell. By attaching anticancer agents to the antibody, the anticancer agents can be brought specifically to the cancer cells that are being targeted.
  • the present invention provides compositions, kits, and methods for reducing undue cellular proliferation, including that associated with the treatment of cancer, and combination therapies.
  • the invention provides compositions comprising a tyrosine hydroxylase inhibitor and an anticancer agent that is chemically bonded to, or physically associated with, the tyrosine hydroxylase inhibitor.
  • Other embodiments provide methods of reducing cell proliferation and/or methods of treating cancer comprising administering an effective amount of such compositions.
  • Some embodiments also provide combination therapies that are administered in conjunction with other therapeutic agents.
  • the invention provides kits that comprise such compositions together with suitable packaging.
  • composition As used herein, the terms “component,” “composition,” “composition of compounds,” “compound,” “drug,” “pharmacologically active agent,” “active agent,” “agent,” “therapeutic,” “therapy,” “treatment,” or “medicament” are used interchangeably herein to refer to a compound or compounds or composition of matter which, when administered to a subject (human or animal) induces a desired pharmacological and/or physiologic effect by local and/or systemic action.
  • treatment or “therapy” (as well as different forms thereof) include preventative (e.g., prophylactic), curative or palliative treatment.
  • treating includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease or disorder. This condition, disease or disorder can be cancer.
  • the term "effective amount” refers to an amount effective, at dosages, and for periods of time necessary, to achieve the desired result with respect to the treatment of the relevant disorder, condition, or side effect. It will be appreciated that the effective amount of components of the present invention will vary from patient to patient not only with the particular compound, component or composition selected, the route of administration, and the ability of the components to elicit a desired result in the individual, but also with factors such as the disease state or severity of the condition to be alleviated, hormone levels, age, sex, weight of the individual, the state of being of the patient, and the severity of the pathological condition being treated, concurrent medication or special diets then being followed by the particular patient, and other factors which those skilled in the art will recognize, with the appropriate dosage being at the discretion of the attending physician. Dosage regimes may be adjusted to provide the improved therapeutic response. An effective amount is also one in which any toxic or detrimental effects of the components are outweighed by the therapeutically beneficial effects.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.
  • the disclosed compounds may be prepared in the form of pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, gly colic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • These pharmaceutically acceptable salts are prepared by methods known in the art, e.g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an amine.
  • Compounds described herein can be prepared in alternate forms. For example, many amino-containing compounds can be used or prepared as an acid addition salt. Often such salts improve isolation and handling properties of the compound. For example, depending on the reagents, reaction conditions and the like, compounds as described herein can be used or prepared, for example, as their hydrochloride or tosylate salts. Isomorphic crystalline forms, all chiral and racemic forms, N-oxide, hydrates, solvates, and acid salt hydrates, are also contemplated to be within the scope of the present invention.
  • Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compounds, including free acid, free base and zwitterions, are contemplated to be within the scope of the present invention. It is well known in the art that compounds containing both amino and carboxy groups often exist in equilibrium with their zwitterionic forms. Thus, any of the compounds described herein that contain, for example, both amino and carboxy groups, also include reference to their corresponding zwitterions.
  • stereoisomers refers to compounds that have identical chemical constitution, but differ as regards the arrangement of the atoms or groups in space.
  • administering means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body.
  • subject refers to an animal, for example a human, to whom treatment, including prophylactic treatment, with the pharmaceutical composition according to the present invention, is provided.
  • subject refers to human and non-human animals.
  • non-human animals and “non-human mammals” are used
  • vertebrates e.g., mammals, such as non-human primates, (particularly higher primates), sheep, dog, rodent, (e.g. mouse or rat), guinea pig, goat, pig, cat, rabbits, cows, horses and non-mammals such as reptiles, amphibians, chickens, and turkeys.
  • mammals such as non-human primates, (particularly higher primates), sheep, dog, rodent, (e.g. mouse or rat), guinea pig, goat, pig, cat, rabbits, cows, horses and non-mammals such as reptiles, amphibians, chickens, and turkeys.
  • inhibitor includes compounds that inhibit the expression or activity of a protein, polypeptide or enzyme and does not necessarily mean complete inhibition of expression and/or activity. Rather, the inhibition includes inhibition of the expression and/or activity of a protein, polypeptide or enzyme to an extent, and for a time, sufficient to produce the desired effect.
  • promoter includes compounds that promote the expression or activity of a protein, polypeptide or enzyme and does not necessarily mean complete promotion of expression and/or activity. Rather, the promotion includes promotion of the expression and/or activity of a protein, polypeptide or enzyme to an extent, and for a time, sufficient to produce the desired effect.
  • Chemical bonds refers to the connection of two atoms by a chemical bond.
  • a chemical bond is a bond resulting from the electronic interaction of one atom (which may be part of a molecule) with another atom (which may be part of a molecule).
  • Chemical bonds may be covalent bonds or non-covalent bonds.
  • Physical associated refers to two molecules that are maintained in close proximity by means other than a chemical bond.
  • physically associated molecules is the impregnation of one molecule into a sample of the other molecule.
  • linker refers to a chemical moiety that allows two molecules to be indirectly chemically bonded, or indirectly physically associated.
  • a linker that indirectly chemically bonds two molecules forms separate chemical bonds with each of the two molecules such that the two molecules are connected through the linker.
  • a linker that indirectly physically associates two molecules forms separate physically associations with each of the two molecules such that the two molecules are physically associated through the linker.
  • a linker can also connect two molecules by chemically bonding to one of the two molecules and physically associating with the other of the two molecule.
  • the present invention provides a chemotherapy that specifically directs anticancer agents to cancer cells. While not intending to be bound by any particular mechanism of operation, the compositions of the present invention specifically target cancer cells and thereby provide a site-directed chemotherapy. It is believed that the tyrosine hydroxylase portion of the compositions of the present invention is absorbed by cancer cells. By chemically bonding, or physically associating, the tyrosine hydroxylase inhibitor and an anticancer agent, the anticancer agent accompanies the tyrosine hydroxylase inhibitor to, and/or into, the cancer cells. In this manner, the anticancer agent is directed to cancer cells in preference to non-cancerous cells.
  • compositions comprising a tyrosine hydroxylase inhibitor and an anticancer agent that is chemically bonded to, or physically associated with, the tyrosine hydroxylase inhibitor.
  • tyrosine hydroxylase inhibitors that may be used in the compositions of the present invention include tyrosine derivatives, which typically are rapidly absorbed by most cancers and inflamed tissues.
  • the tyrosine hydroxylase inhibitor is a tyrosine derivative.
  • compositions of the present invention include one or more of methyl (2R)-2- amino-3-(2-chloro-4-hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2- amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate, H-D-Tyr(TBU)- allyl ester HC1, methyl (2i?)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl (2i?)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2i?)-2-amino-3- (4-[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2- amino-3-(2- chloro-3,4-dime
  • Anticancer agents that may be used in compositions of the present invention include any agents that are active against cancer, and include alkylating agents,
  • antimetabolites anti-microtubule agents, topoisomerase inhibitors, cytotoxic antibiotics, selective estrogen receptor modulators, aromatase inhibitors, signal transduction inhibitors, agents that modify the function of proteins that regulate gene expression and other cellular functions, drugs that induce cancer cells to undergo apoptosis, and drugs that interfere with angiogenesis.
  • Representative anticancer agents that may be used in the present invention include 5-fluorouracil, abiraterone acetate, acetylcholine, ado-trastuzumab emtansine, afatinib, aldesleukin, alectinib, alemtuzumab, alitretinoin, aminolevulinic acid, anastrozole, anastrozole, aprepitant, arsenic trioxide, asparaginase erwinia chrysanthemi, atezolizumab, axitinib, azacitidine, belinostat, bendamustine, benzyl isothiocyanate, bevacizumab, bexarotene, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, busul
  • the anticancer agent is one or more of 5-fluorouracil, capecitabine, cisplatin, erlotinib, everolimus, gemcitabine, irinotecan, lanreotide acetate, leucovorin, mitomycin C, oxaliplatin, paclitaxel, taxotere, and sunitinib malate.
  • the anticancer agent is chemically bonded to the tyrosine hydroxylase inhibitor.
  • the anticancer agent can be chemically bonded to the tyrosine hydroxylase inhibitor by a covalent bond.
  • a covalent bond between the tyrosine hydroxylase inhibitor and the anticancer agent may be formed by chemical reaction of reactive functional groups on the tyrosine hydroxylase inhibitor with reactive functional groups on the anticancer agent.
  • Reactive function groups on the tyrosine hydroxylase inhibitor may include esters, carboxylic acids, amides, amino groups, hydroxyl groups, and activated aromatic or aliphatic carbon atoms.
  • Reactive function groups on the anticancer agent may include esters, carboxylic acids, amides, amino groups, hydroxyl groups, activated aromatic or aliphatic carbon atoms, sulfides, and cyano groups.
  • reaction of functional groups on the tyrosine hydroxylase inhibitor with functional groups on the anticancer agent can result in ethers, amines, esters, amides, thioesters, thioethers, carbamates, and ureas.
  • Methods for making the types of covalent bonds required by embodiments of the present invention are generally known in the art. See, e.g. , Michael B. Smith and Jerry March, March's Advanced Organic Chemistry, Reactions, Mechanism, and Structure (John Wiley & Sons 2001).
  • An exemplary embodiment of the present invention wherein an anticancer agent is chemically bonded to a tyrosine hydroxylase inhibitor by a covalent bond is the ester that would result from condensing a hydroxyl group of capecitabine with the carboxylic acid group of a-methyl tyrosine:
  • the anticancer agent is chemically bonded to the tyrosine hydroxylase inhibitor by a non-covalent bond.
  • the non- covalent bond is an ionic bond.
  • An ionic bond between the tyrosine hydroxylase inhibitor and the anticancer agent may be formed by chemical reaction of salt-forming functional groups on the tyrosine hydroxylase inhibitor with salt-forming functional groups on the anticancer agent.
  • Salt-forming functional groups on the tyrosine hydroxylase inhibitor may include carboxylic acids, amino groups, and acidic hydroxyl groups.
  • Salt-forming functional groups on the anticancer agent may include carboxylic acids, amino groups, acidic hydroxyl groups, and acidic thiols.
  • An exemplary embodiment of the present invention wherein an anticancer agent is chemically bonded to a tyrosine hydroxylase inhibitor by a non-covalent, ionic bond is the salt that would result from reacting D-tyrosine ethyl ester with leucovorin:
  • the anticancer agent is chemically bonded to the tyrosine hydroxylase inhibitor through a linker.
  • the linker is a chemical moiety that forms chemical bonds to both the tyrosine hydroxylase inhibitor and the anticancer agent and thus separates the tyrosine hydroxylase inhibitor and the anticancer agent.
  • the present invention provides a tyrosine hydroxylase inhibitor-anticancer agent conjugate.
  • Covalent bonds between the tyrosine hydroxylase inhibitor and the linker may include, for example, carbamate bonds, amide bonds, ester bonds, amino bonds, and ether bonds formed by reaction of reactive functional groups on the tyrosine hydroxylase inhibitor with reactive functional groups on the linker.
  • Covalent bonds between the anticancer agent and the linker may include, for example, disulfide bonds, carbamate bonds, amide bonds, ester bonds, amino bonds, and ether bonds formed by reaction of reactive functional groups on the anticancer agent with reactive functional groups on the linker.
  • the linker is a chemical moiety having reactive functional groups that react with the tyrosine hydroxylase inhibitor, and reactive functional groups that react with the anticancer agent.
  • the linker is a molecule with two functional groups, one of which is capable of forming a covalent bond with a functional group on the tyrosine hydroxylase inhibitor, and the other of which is capable of forming a covalent bond with a functional group on the anticancer agent.
  • the linker is selected from aliphatic compounds having two or more reactive functional groups, aromatic compounds having two or more reactive functional groups, carbohydrates, amino acids, peptides, diamino compounds, polyamino compounds, diols, polyols, amino-alcohols, ethanolamine, diamides, polyamides, lipids, and polyethylene glycols.
  • the linker can be cleaved under physiological conditions, thereby disjoining the tyrosine hydroxylase inhibitor and the anticancer agent.
  • the linker is cleaved when the conjugate has been taken into the cancer cell.
  • the linker is cleaved by enzymes located within, or on the surface of, the cancer cell.
  • a single linker may be chemically bound to multiple anticancer agents and to a single tyrosine hydroxylase inhibitor.
  • the anticancer agent is physically associated with the tyrosine hydroxylase inhibitor.
  • the anticancer agent is physically associated with the tyrosine hydroxylase inhibitor by impregnation. Impregnation may be achieved by and applying force to a tyrosine hydroxylase inhibitor and a solid anticancer agent for a time and under conditions effective to impregnate at least one of the tyrosine hydroxylase inhibitor and the anticancer agent with the other of said tyrosine hydroxylase inhibitor and said anticancer agent.
  • Compositions formed by impregnation and methods of impregnation are set forth in U.S. Patent Application Publication No. 2015/0112116-A1, published on April 23, 2015, the contents of which are incorporated in their entirety herein.
  • the anticancer agent is physically associated with the tyrosine hydroxylase inhibitor by encapsulation.
  • the linker joins the tyrosine hydroxylase inhibitor to the anticancer agent through physical association, or through a combination of physical association and chemical bonding.
  • the anticancer agent is encapsulated within a liposome that has one or more tyrosine hydroxylase inhibitors covalently bonded to its outer surface.
  • the liposome is a linker that bonds to the tyrosine hydroxylase inhibitor by chemical (covalent) bonds, and binds to the anticancer agent by physical association (encapsulation).
  • compositions of the present invention further comprise one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients are known in the art. See, e.g., Remington's Pharmaceutical Sciences, 18 th Edition, Mack Publishing Company (1990).
  • Methods of treating cancer in a subject also are provided, as are methods of reducing undue cellular proliferation.
  • Such methods can include administering an effective amount of a composition that targets cancer cells.
  • Suitable embodiments are methods that include administering an effective amount of the above-noted composition comprising a tyrosine hydroxylase inhibitor and an anticancer agent that is chemically bonded to, or physically associated with, the tyrosine hydroxylase inhibitor.
  • Other suitable methods include administering an effective amount of the above-noted composition comprising a tyrosine hydroxylase inhibitor and an anticancer agent that is chemically bonded to, or physically associated with, the tyrosine hydroxylase inhibitor, in conjunction with one or more additional therapeutic agents.
  • compositions, with or without additional therapeutic agents may be provided in a single dosage form or any number of desired dosage forms, including in individual dosage forms.
  • Representative dosage forms include tablets, capsules, caplets, sterile aqueous or organic solutions, reconstitutable powders, elixirs, liquids, colloidal or other types of suspensions, emulsions, beads, beadlets, granules, microparticles, nanoparticles, and combinations thereof.
  • the amount of composition administered will, of course, be dependent on the subject being treated, the subject's weight, the severity of the condition being treated, the manner of administration, and the judgment of the prescribing physician.
  • Administration of the compositions, with or without additional therapeutic agents can be through various routes, including orally, nasally, subcutaneously,
  • Transdermal administration can be effected using, for example, oleic acid, 1-methyl- 2-pyrrolidone, or dodecylnonaoxyethylene glycol monoether.
  • compositions, with or without additional therapeutic agents, are administered can be a mammal, preferably a human.
  • the cancer is non-small cell lung cancer.
  • the non-small cell lung cancer is stage IV non-small cell lung cancer.
  • the cancer is ovarian cancer, breast cancer, cervical cancer, pancreatic cancer, stomach cancer, brain cancer, liver cancer, testicular cancer, leukemia, lymphoma, appendix cancer, biliary cancer, choleangiocarcinoma, colon cancer, colorectal cancer, germ cell tumor, glioma, Hodgkin's lymphoma, lung cancer, neuroblastoma, prostate cancer, renal cancer, sarcoma, thyroid cancer, tongue cancer, tonsil squamous cell carcinoma, or urothelial cancer.
  • the cancer is pancreatic cancer.
  • the present methods can include not only the disclosed administration step but also the step of assessing progression of said cancer in said subject and/or the extent of cellular proliferation.
  • the assessing step can be performed before or after the administering step.
  • Suitable embodiments can include administering the above-noted compositions comprising a tyrosine hydroxylase inhibitor and an anticancer agent that is chemically bonded to, or physically associated with, the tyrosine hydroxylase inhibitor.
  • the tyrosine hydroxylase inhibitor in the composition can be a tyrosine derivative.
  • the tyrosine derivative may be one or more of the representative tyrosine derivatives noted above.
  • the anticancer agents in the above-noted compositions include any agents that are active against cancer, and include alkylating agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors, cytotoxic antibiotics, selective estrogen receptor modulators, aromatase inhibitors, signal transduction inhibitors, agents that modify the function of proteins that regulate gene expression and other cellular functions, drugs that induce cancer cells to undergo apoptosis, and drugs that interfere with angiogenesis.
  • the anticancer agent may be one or more of the representative anticancer agents noted above.
  • Methods of treating cancer in a subject comprising administering to the subject in need thereof an effective amount of the above-noted composition comprising a tyrosine hydroxylase inhibitor and an anticancer agent that is chemically bonded to, or physically associated with, the tyrosine hydroxylase inhibitor.
  • the composition is administered orally, subcutaneously, intravenously, transdermally, vaginally, rectally or in any combination thereof.
  • the transdermal administration can be done with oleic acid, l-methyl-2-pyrrolidone, or
  • the composition is administered during a cycle consisting of five to seven days of administering the composition and one to two days of not administering the composition.
  • the composition can be administered over the course of at least six of said cycles.
  • the tyrosine hydroxylase inhibitor in the composition for treating cancer can be a tyrosine derivative.
  • the tyrosine derivative may be one or more of the representative tyrosine derivatives noted above.
  • compositions for treating cancer include any agents that are active against cancer, and include alkylating agents,
  • anticancer agent may be one or more of the representative anticancer agents noted above.
  • the subject in methods of treating cancer can be a mammal and that mammal can be a human. In some embodiments, the subject is a human.
  • Representative methods of treating cancer include those in which the cancer is non-small cell lung cancer.
  • the non-small cell lung cancer is stage IV non-small cell lung cancer.
  • the cancer is ovarian cancer, breast cancer, cervical cancer, pancreatic cancer, stomach cancer, brain cancer, liver cancer, testicular cancer, leukemia, lymphoma, appendix cancer, biliary cancer,
  • Another suitable embodiment further comprises assessing progression of said cancer in said subject.
  • the assessing step can be performed before said administering step or the assessing step can be performed after said administering step.
  • the methods of treating cancer further comprise administering one or more additional therapeutic agents.
  • additional therapeutic agents may include anticancer agents which are the same as, or different than, the anticancer agents that are components of the above-noted compositions.
  • the additional therapeutic agents are one or more of the representative anticancer agents noted above.
  • the additional therapeutic agents may include one or more additional tyrosine hydroxylase inhibitors, melanin and/or a melanin promoter, a p450 3A4 promoter, a leucine aminopeptidase inhibitor, and a growth hormone inhibitor.
  • at least two of the additional therapeutic agents i.e., melanin, promoters and/or inhibitors
  • at least three of the additional therapeutic agents are administered simultaneously.
  • Each of the additional therapeutic agents can be administered simultaneously.
  • the additional therapeutic agent is one or more tyrosine hydroxylase inhibitors.
  • Representative tyrosine hydroxylase inhibitors include tyrosine derivatives.
  • the tyrosine derivative may be one or more of the representative tyrosine derivatives noted above.
  • the additional therapeutic agents include at least one of melanin, a melanin promoter, or a combination thereof.
  • melanin can be used, one or more melanin promoters can be used, and both melanin and one or more melanin promoters can be used (either in separate dosage forms or in the same dosage form).
  • Melanin promoters according to the present invention are chemical compounds that increase the production and/or the activity of melanin. Increased melanin levels are believed to reduce inflammation (through, for example, suppression of TNF) and exclude the sequestered lymph system. Melanin is a photo catalyst, and can therefore promote chemical reactions that generate free radicals which, in turn, can become accessible to cancer cells.
  • Representative melanin promoters are methoxsalen and melanotan II.
  • the additional therapeutic agents include a p450 3A4 promoter.
  • Cytochrome p450 3A4 (which can be abbreviated as "p450 3A4") is a member of the cytochrome p450 superfamily of enzymes, and is a mixed-function oxidase that is involved in the metabolism of xenobiotics in the body. It has the widest range of substrates of all of the cytochromes.
  • Representative p450 3A4 promoters are 5,5-diphenylhydantoin (sold commercially as, for example, Dilantin), valproic acid, and carbamazepine, which are believed to induce expression of the p450 3A4 enzyme.
  • the additional therapeutic agents include leucine aminopeptidase inhibitors (alternatively known as leucyl aminopeptidase inhibitors).
  • Leucine aminopeptidases are enzymes that preferentially catalyze the hydrolysis of leucine residues at the N-terminus of peptides and/or proteins.
  • Representative leucine aminopeptidase inhibitors are N-[(25',3i?)-3-amino-2-hydroxy-4-phenylbut ryl]-L-leucine, and rapamycin.
  • the additional therapeutic agents include a growth hormone inhibitor.
  • Growth hormone such as, for example, pancreatic growth hormone
  • Representative growth hormone inhibitors are octreotide, somatostatin, and seglitide.
  • the additional therapeutic agents include D-leucine.
  • D-leucine is a stereoisomer of the naturally occurring L-leucine, the form of leucine incorporated into polypeptides and proteins.
  • Methods of reducing cell proliferation in a subject comprising administering an effective amount of a composition comprising a tyrosine hydroxylase inhibitor and an anticancer agent that is chemically bonded to, or physically associated with, the tyrosine hydroxylase inhibitor.
  • components are administered orally, subcutaneously, intravenously, transdermally, vaginally, rectally or in any combination thereof.
  • the transdermal administration can be done with oleic acid, 1- methyl-2-pyrrolidone, or dodecylnonaoxyethylene glycol monoether.
  • the composition is administered during a cycle consisting of five to seven days of administering the composition and one to two days of not administering the composition.
  • the composition can be administered over the course of at least six of said cycles.
  • the tyrosine hydroxylase inhibitor in the composition for reducing cell proliferation can be a tyrosine derivative.
  • the tyrosine derivative may be one or more of the representative tyrosine derivatives noted above.
  • the anticancer agents that may be used in compositions for reducing cell proliferation include any agents that are active against cancer, and include alkylating agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors, cytotoxic antibiotics, selective estrogen receptor modulators, aromatase inhibitors, signal transduction inhibitors, agents that modify the function of proteins that regulate gene expression and other cellular functions, drugs that induce cancer cells to undergo apoptosis, and drugs that interfere with angiogenesis.
  • the anticancer agent may be one or more of the representative anticancer agents noted above.
  • the subject in methods of reducing cell proliferation can be a mammal and the mammal can be a human. In some embodiments, the subject is a human.
  • the cancer is non-small cell lung cancer.
  • the non-small cell lung cancer is stage IV non-small cell lung cancer.
  • the cancer is ovarian cancer, breast cancer, cervical cancer, pancreatic cancer, stomach cancer, brain cancer, liver cancer, testicular cancer, leukemia, lymphoma, appendix cancer, biliary cancer, choleangiocarcinoma, colon cancer, colorectal cancer, germ cell tumor, glioma, Hodgkin's lymphoma, lung cancer,
  • the cancer is pancreatic cancer.
  • Another suitable embodiment further comprises assessing progression of said cancer in said subject.
  • the assessing step can be performed before said administering step or the assessing step can be performed after said administering step.
  • the methods of reducing cell proliferation further comprise administering one or more additional therapeutic agents.
  • additional therapeutic agents may include anticancer agents which are the same as, or different than, the anticancer agents that are components of the above-noted compositions.
  • the additional therapeutic agents are one or more of the representative anticancer agents noted above.
  • the additional therapeutic agents may include one or more additional tyrosine hydroxylase inhibitors, melanin and/or a melanin promoter, a p450 3A4 promoter, a leucine aminopeptidase inhibitor, and a growth hormone inhibitor.
  • at least two of the additional therapeutic agents i.e., melanin, promoters and/or inhibitors
  • at least three of the additional therapeutic agents are administered simultaneously.
  • Each of the additional therapeutic agents can be administered simultaneously.
  • the additional therapeutic agent is one or more tyrosine hydroxylase inhibitors.
  • Representative tyrosine hydroxylase inhibitors include tyrosine derivatives.
  • the tyrosine derivative may be one or more of the representative tyrosine derivatives noted above.
  • the additional therapeutic agents include at least one of melanin, a melanin promoter, or a combination thereof.
  • melanin can be used, one or more melanin promoters can be used, and both melanin and one or more melanin promoters can be used (either in separate dosage forms or in the same dosage form).
  • Melanin promoters according to the present invention are chemical compounds that increase the production and/or the activity of melanin. Increased melanin levels are believed to reduce inflammation (through, for example, suppression of TNF) and exclude the sequestered lymph system. Melanin is a photo catalyst, and can therefore promote chemical reactions that generate free radicals which, in turn, can become accessible to cancer cells.
  • Representative melanin promoters are methoxsalen and melanotan II.
  • the additional therapeutic agents include a p450 3A4 promoter.
  • Cytochrome p450 3A4 (which can be abbreviated as "p450 3A4") is a member of the cytochrome p450 superfamily of enzymes, and is a mixed-function oxidase that is involved in the metabolism of xenobiotics in the body. It has the widest range of substrates of all of the cytochromes.
  • Representative p450 3A4 promoters are 5,5-diphenylhydantoin (sold commercially as, for example, Dilantin), valproic acid, and carbamazepine, which are believed to induce expression of the p450 3A4 enzyme.
  • the additional therapeutic agents include leucine aminopeptidase inhibitors (alternatively known as leucyl aminopeptidase inhibitors).
  • Leucine aminopeptidases are enzymes that preferentially catalyze the hydrolysis of leucine residues at the N-terminus of peptides and/or proteins.
  • Representative leucine aminopeptidase inhibitors are N-[(25',3i?)-3-amino-2-hydroxy-4-phenylbut ryl]-L-leucine, and rapamycin.
  • the additional therapeutic agents include a growth hormone inhibitor.
  • Growth hormone such as, for example, pancreatic growth hormone
  • Representative growth hormone inhibitors are octreotide, somatostatin, and seglitide.
  • the additional therapeutic agents include D-leucine. D-leucine is a stereoisomer of the naturally occurring L-leucine, the form of leucine incorporated into polypeptides and proteins.
  • kits including a therapy that specifically targets cancer cells.
  • Representative kits comprise a composition comprising a tyrosine hydroxylase inhibitor and an anticancer agent that is chemically bonded to, or physically associated with, said tyrosine hydroxylase inhibitor together with suitable packaging for same.
  • the kit can include one or more separate containers, dividers or compartments and, optionally, informational material such as instructions for administration. For example, each
  • the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms of a composition described herein.
  • the kit can include a plurality of syringes, ampules, foil packets, or blister packs, each containing a single unit dose of a composition described herein or any of the various combinations thereof.
  • the containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight.
  • the kit optionally includes a device suitable for
  • the kit further comprises one or more additional therapeutic agents.
  • the composition e.g., a syringe, inhalant, pipette, forceps, measured spoon, dropper (e.g., eye dropper), swab (e.g., a cotton swab or wooden swab), or any such delivery device.
  • the kit further comprises one or more additional therapeutic agents.
  • the additional therapeutic agents are selected from anticancer agents which are the same as, or different than, the anticancer agents that are components of the above-noted compositions, additional tyrosine hydroxylase inhibitors, melanin, a melanin promoter, a p450 3A4 promoter, leucine aminopeptidase inhibitors, a growth hormone inhibitor, and D-leucine.
  • SM88 is a novel combination of five therapies (sirolimus, melanin, melanotan, phenytoin, and tyrosine isomers) that when administered together, has demonstrated anti-cancer activity with little to no toxicity in a preliminary study of 30 patients [J Clin Oncol 31, 2013 (suppl; abstr e22095) and Hoffman et al. GynOncol, 130(1), e43].
  • This study reports preclinical animal data related to toxicity of the tyrosine agent, a- methyl-DL-tyrosine, and possible mechanism of action.
  • AUCo-Tiast values were 717.7 (males) and 724.8 (females) hr ⁇ g/ml.
  • the difference in combined isomer concentrations in plasma between Day 1 and 27, show that the systemic exposures to the agent generally increased dose-dependently, and in a slightly less than dose-proportional manner.
  • the agent's maximum concentration levels (Cmax) were reached at 2 to 6.7 hours post-dosing. After Tmax, the agent's plasma concentrations declined gradually at a mean estimated Tl/2 value ranging from 7.9 to 9.3 hours on Day 1 and from 8.4 to 9.6 hours on Day 27.

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Abstract

L'invention concerne des compositions et des kits comprenant un inhibiteur de la tyrosine hydroxylase et un agent anticancéreux qui est chimiquement lié à, ou physiquement associé à, l'inhibiteur de la tyrosine hydroxylase. L'invention concerne également des procédés de réduction de la prolifération cellulaire chez un sujet comprenant l'administration à un sujet qui en a besoin d'une composition comprenant un inhibiteur de la tyrosine hydroxylase et un agent anticancéreux qui est lié chimiquement à, ou physiquement associé à, l'inhibiteur de la tyrosine hydroxylase.
PCT/US2017/063865 2016-11-30 2017-11-30 Dérivés de tyrosine et compositions les comprenant WO2018102506A1 (fr)

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EA201991305A EA201991305A1 (ru) 2016-11-30 2017-11-30 Производные тирозина и композиции, включающие их
CN201780074235.7A CN110062633A (zh) 2016-11-30 2017-11-30 酪氨酸衍生物以及包含所述酪氨酸衍生物的组合物
CA3045110A CA3045110A1 (fr) 2016-11-30 2017-11-30 Derives de tyrosine et compositions les comprenant
EP17817552.7A EP3548086A1 (fr) 2016-11-30 2017-11-30 Dérivés de tyrosine et compositions les comprenant
JP2019528632A JP2019536783A (ja) 2016-11-30 2017-11-30 チロシン誘導体及びそれらを含む組成物
AU2017368135A AU2017368135A1 (en) 2016-11-30 2017-11-30 Tyrosine derivatives and compositions comprising them
BR112019011033A BR112019011033A2 (pt) 2016-11-30 2017-11-30 composição, método para reduzir a proliferação celular em um indivíduo, método para tratar câncer em um indivíduo e kit
KR1020197018473A KR20190089191A (ko) 2016-11-30 2017-11-30 티로신 유도체 및 이들을 포함하는 조성물
MX2019006326A MX2019006326A (es) 2016-11-30 2017-11-30 Derivados de tirosina y composiciones que los comprenden.
IL266840A IL266840A (en) 2016-11-30 2019-05-23 History of tyrosine and preparations containing them
PH12019501186A PH12019501186A1 (en) 2016-11-30 2019-05-29 Tyrosine derivatives and composition comprising them
JP2022122538A JP2022153587A (ja) 2016-11-30 2022-08-01 チロシン誘導体及びそれらを含む組成物

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