EP3541411A1 - Pharmazeutische zusammensetzungen und verfahren zur behandlung von krebs - Google Patents

Pharmazeutische zusammensetzungen und verfahren zur behandlung von krebs

Info

Publication number
EP3541411A1
EP3541411A1 EP17808688.0A EP17808688A EP3541411A1 EP 3541411 A1 EP3541411 A1 EP 3541411A1 EP 17808688 A EP17808688 A EP 17808688A EP 3541411 A1 EP3541411 A1 EP 3541411A1
Authority
EP
European Patent Office
Prior art keywords
methyl
amino
cancer
tyrosine
propanoate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17808688.0A
Other languages
English (en)
French (fr)
Inventor
Steven Hoffman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tyme Inc
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 US15/351,966 external-priority patent/US10272068B2/en
Application filed by Tyme Inc filed Critical Tyme Inc
Publication of EP3541411A1 publication Critical patent/EP3541411A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A61K38/34—Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
    • 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.
  • BRM Biological response modifier
  • 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.
  • 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.
  • the present invention provides compositions, combination therapies, kits, and methods for reducing undue cellular proliferation, including that associated with the treatment of cancer.
  • the invention provides pharmaceutical compositions comprising at least one tyrosine hydroxylase inhibitor; at least one of melanin, a melanin promoter, or a combination thereof; at least one p450 3A4 promoter; at least one leucine aminopeptidase inhibitor; and, optionally, at least one growth hormone inhibitor.
  • the invention provides kits that comprise these components together with suitable packaging.
  • Also provided are methods of reducing cellular proliferation and/or methods of treating cancer comprising administering an effective amount of at least one tyrosine hydroxylase inhibitor; at least one of melanin, a melanin promoter, or a combination thereof; at least one p450 3A4 promoter; at least one leucine aminopeptidase inhibitor; and, optionally, at least one growth hormone inhibitor to the subject in need thereof.
  • terapéutica refers 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.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, gly colic,
  • physiologically 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 interchangeably herein and include all 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.
  • 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.
  • the present invention provides combination therapies that alter the defenses of cancerous cells to oxidative stress.
  • One class of such therapies increases free radical availability to cancerous cells.
  • a representative subclass of such therapies involves administration of pharmaceutical compositions comprising a tyrosine hydroxylase inhibitor, melanin or a melanin promoter, a p450 3A4 promoter, a leucine aminopeptidase inhibitor, and, optionally, a growth hormone inhibitor.
  • Another subclass involves administration of
  • compositions comprising melanin and either a tyrosine hydroxylase inhibitor. Particular components of the pharmaceutical composition are described below.
  • tyrosine hydroxylase inhibitors function by accumulating in cancer cells and preventing them from forming a coating of either lipids or hyaluronan. By preventing the cancer cells from forming a coating of either lipids or hyaluron, the cancer cells are believed to be made more accessible to oxidative stress.
  • Representative tyrosine hydroxylase inhibitors include tyrosine derivatives, which typically are rapidly absorbed by most cancers and inflamed tissues.
  • tyrosine derivatives 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 HCl, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2- chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4-[(2-chloro-6- fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2- amino-3-(2-chloro-3,4- dimethoxyphenyl) propanoate,
  • the present invention involves the use of 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 tyrosine hydroxylase inhibitor is mixed with melanin in the same dosage form. This association of melanin with the tyrosine hydroxylase inhibitor is believed to facilitate uptake of melanin in cancer cells because tyrosine hydroxylase inhibitors are more readily taken up by such cells.
  • melanin is solubilized in a solubilizing agent and then mixed with the tyrosine hydroxylase inhibitor by methods known in the art.
  • the solubilizing agent may be removed by standard techniques, such as evaporation, drying, etc.
  • the solubilizing agent may be a non-toxic solubilizing agent, such as hydrogen peroxide or other solubilizing agents commonly known in the art.
  • the melanin and/or the pharmaceutical composition may be further processed to optimize the pharmaceutical composition's effect on cancer cells.
  • the pharmaceutical composition may include additional active agents and/or pharmaceutical excipients.
  • the pharmaceutical compositions of the invention also 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.
  • the function of a p450 3A4 promoter in the pharmaceutical compositions of the invention is to increase the expression and/or the activity of p450 3A4.
  • the increased p450 3A4 expression and/or activity is believed to reduce cortisone and estrogen levels in the patient.
  • p450 3A4 expression and/or activity also slightly decreases blood pH, which is believed to help to preserve or enhance melanin activity.
  • 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.
  • compositions further 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. Inhibiting the expression and/or activity of leucine aminopeptidases is believed to assist in tumor reabsorption by increasing cholesterol transport to the liver.
  • aminopeptidase inhibitors deplete sensitive tumor cells of specific amino acids by preventing protein recycling, thus generating an antiproliferative effect.
  • Representative leucine aminopeptidase inhibitors are N- [(25',3i?)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine, and rapamycin.
  • the instant pharmaceutical compositions also optionally include a growth hormone inhibitor.
  • Growth hormone such as, for example, pancreatic growth hormone
  • Representative growth hormone inhibitors are octreotide, somatostatin, and seglitide.
  • the pharmaceutical compositions of the invention can further include D-leucine.
  • D-leucine is a stereoisomer of the naturally occurring L-leucine, the form of leucine incorporated into polypeptides and proteins. D-leucine cannot be incorporated into polypeptides and/or proteins. Along with the leucine aminopeptidase inhibitor, the D-leucine is believed to create a physiological environment that mimics a leucine shortage. Thus, the presence of D-leucine permits the use of lower doses of leucine aminopeptidase inhibitor in a pharmaceutical composition.
  • kits including a combination therapy that creates alterations in the defenses of cancerous cells to oxidative stress.
  • An intended suitable embodiment is a kit that includes a combination therapy that increases free radical availability to cancerous cells.
  • Representative kits comprise a tyrosine hydroxylase inhibitor, melanin and/or a melanin promoter, a p450 3A4 promoter, a leucine aminopeptidase inhibitor and, optionally, a growth hormone inhibitor of the type described above, together with packaging for same.
  • the kit can include one or more separate containers, dividers or compartments and, optionally, informational material such as instructions for administration.
  • each inhibitor or promoter can be contained in a bottle, vial, or syringe, and the informational material can be contained in a plastic sleeve or packet or provided in a label.
  • the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms of a compound described herein.
  • the kit can include a plurality of syringes, ampules, foil packets, or blister packs, each containing a single unit dose of a compound described herein or any of the various combinations thereof.
  • 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 administration of 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.
  • a device suitable for administration of 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.
  • 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 combination therapy that creates alterations in the defenses of cancerous cells to oxidative stress. Representative methods of treating cancer include administering an effective amount of a combination therapy that increases free radical availability to cancerous cells.
  • Suitable embodiments are methods that include administering an effective amount of the above- noted tyrosine hydroxylase inhibitor, melanin and/or melanin promoter, p450 3A4 promoter, leucine aminopeptidase inhibitor and, optionally, growth hormone inhibitor.
  • Other suitable methods include administering an effective amount of melanin and a tyrosine hydroxylase inhibitor.
  • Suitable methods include simultaneous or at least contemporaneous
  • tyrosine hydroxylase inhibitor melanin or a melanin promoter, p450 3A4 promoter, and leucine aminopeptidase inhibitor, at least three of them, or each of them (in each case, optionally, with a growth hormone inhibitor). It is believed to be desirable that an effective concentration of these moieties be in the subject's bloodstream at the same time, and any dosing regimen that achieves this is within the scope of the present invention.
  • the desired number of inhibitors and promoters can 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 melanin, promoters, and/or inhibitors can be through various routes, including orally, nasally, subcutaneously, intravenously, intramuscularly, trans dermally, vaginally, rectally or in any combination thereof.
  • Transdermal administration can be effected using, for example, oleic acid, l -methyl-2-pyrrolidone, or dodecylnonaoxy ethylene glycol monoether.
  • the melanin, promoters and/or inhibitors can be administered during a cycle consisting of five to seven days of administering the melanin, promoters and/or inhibitors and one to two days of not administering the melanin, promoters and/or inhibitors.
  • the melanin, promoters and/or inhibitors can be administered over the course of at least six of said cycles. It can be desirable to administer these components about two hours between meals to facilitate uptake.
  • compositions are administered can be a mammal, preferably a human.
  • 60 mg of the tyrosine derivative is administered orally and 0.25 mL of a 2 mg/mL suspension of the tyrosine derivative is administered subcutaneously; 10 mg of the methoxsalen is administered orally and 0.25 mL of a 1 mg/mL suspension of the methoxsalen is administered subcutaneously; 30 mg of the 5,5- diphenylhydantoin is administered orally; and 20 mg of the N-[(25',3i?)-3-amino-2-hydroxy-4- phenylbutyryl]-L-leucine is administered orally.
  • the combination therapy comprises: (i) a dosage form containing melanin (50 meg) and a-methyl-DL-tyrosine (75 mg); (ii) a dosage form containing 5,5-diphenylhydantoin (15 mg) and a-methyl-DL-tyrosine (75 mg); (iii) a dosage form containing 3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine (50 meg) and a-methyl-DL-tyrosine (75 mg); (iv) a dosage form containing 3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine (5 meg), melanotan II (10 meg), and 5,5-diphenylhydantoin (2 mg); and (v) a dosage form containing a- methyl-DL-tyrosine (5 mg) in NaCl bacteriostatic water.
  • the combination therapy comprises: (i) a dosage form containing melanin (50 meg) and a-methyl-DL-tyrosine (75 mg); (ii) a dosage form containing 5,5-diphenylhydantoin (15 mg) and a-methyl-DL-tyrosine (75 mg); (iii) a dosage form containing rapamycin (0.2 mg) and a-methyl-DL-tyrosine (75 mg); (iv) a dosage form containing rapamycin (0.15 meg), melanotan II (10 meg), and 5,5- diphenylhydantoin (2 mg); and (v) a dosage form containing a-methyl-DL-tyrosine (5 mg) in NaCl bacteriostatic water. Dosages that are two times greater than this, and even four times greater than this, are believed to be both safe and efficacious.
  • 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.
  • one or more of the tyrosine hydroxylase inhibitor; the melanin promoter; the p450 3A4 promoter; and the leucine aminopeptidase inhibitor is a nucleic acid, protein, antibody or antigen-binding fragment of an antibody.
  • 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 a pharmaceutical composition comprising a tyrosine hydroxylase inhibitor, melanin and/or a melanin promoter, a p450 3A4 promoter, and a leucine aminopeptidase inhibitor.
  • the pharmaceutical composition can further comprise a growth hormone inhibitor.
  • the growth hormone can be pancreatic growth hormone.
  • the growth hormone inhibitor can be octreotide or somatostatin.
  • the tyrosine hydroxylase inhibitor can be a tyrosine derivative.
  • the tyrosine derivative can be 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 HCl, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro- 3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2- amino-3-(2-chloro-3,4-dimethoxyphenyl) propan
  • the melanin promoter can be methoxsalen or melanotan II.
  • the p450 3A4 promoter can be 5,5-diphenylhydantoin.
  • the p450 3A4 promoter can be valproic acid or carbamazepine.
  • the leucine aminopeptidase inhibitor can be N-[(25',3i?)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine or rapamycin.
  • compositions of the invention can further comprise D-leucine.
  • kits comprising a tyrosine hydroxylase inhibitor, melanin and/or a melanin promoter, a p450 3A4 promoter, and a leucine aminopeptidase inhibitor, together with packaging for same.
  • the kit can further comprise a growth hormone inhibitor.
  • the growth hormone can be pancreatic growth hormone.
  • the growth hormone inhibitor can be octreotide or somatostatin.
  • the tyrosine hydroxylase inhibitor can be a tyrosine derivative.
  • the tyrosine derivative can be 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-dimethoxy phenyl) propanoate H-D-Tyr(TBU)-allyl ester HCl, methyl (2R)-2- amino-3 -(3 -chloro-4,5-dimethoxy phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3- hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2- amino-3-(2-chloro-3,4-dimethoxyphenyl
  • the melanin promoter can be methoxsalen or melanotan II.
  • the p450 3A4 promoter can be 5,5-diphenylhydantoin, valproic acid or carbamazepine.
  • the leucine aminopeptidase inhibitor can be N-[(25',3i?)-3-amino-2- hydroxy-4-phenylbutyryl]-L-leucine or rapamycin.
  • the kits of the invention can further comprise D-leucine.
  • Methods of treating cancer in a subject comprising administering an effective amount of a tyrosine hydroxylase inhibitor, melanin and/or a melanin promoter, a p450 3A4 promoter, and a leucine aminopeptidase inhibitor to the subject in need thereof.
  • the method of treating cancer can further comprise a growth hormone inhibitor.
  • at least two of the components i.e., melanin, promoters and/or inhibitors
  • at least three of the components are administered simultaneously. Each of the components can be administered simultaneously.
  • the components are 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 dodecylnonaoxyethylene glycol monoether.
  • the components are administered during a cycle consisting of five to seven days of administering the components and one to two days of not administering the components.
  • the components can be administered over the course of at least six of said cycles.
  • the tyrosine hydroxylase inhibitor can be a tyrosine derivative.
  • the tyrosine derivative can be 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-dimethoxy phenyl) propanoate H-D-Tyr(TBU)-allyl ester HC1, methyl (2R)-2- amino-3 -(3 -chloro-4,5-dimethoxy phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3- hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2- amino-3-(2-chloro-3,4-dimethoxyphenyl)
  • the tyrosine derivative is administered orally and 0.25 mL of a 2 mg/mL suspension of the tyrosine derivative is administered subcutaneously.
  • the melanin promoter can be methoxsalen.
  • 10 mg of the methoxsalen is administered orally and 0.25 mL of a 1 mg/mL suspension of the methoxsalen is administered subcutaneously.
  • the melanin promoter can also be melanotan II.
  • the p450 3A4 promoter can be 5,5- diphenylhydantoin.
  • 30 mg of the 5,5-diphenylhydantoin is administered orally.
  • the p450 3A4 promoter can also be valproic acid or carbamazepine.
  • the leucine aminopeptidase inhibitor can be N-[(25',3i?)-3-amino-2-hydroxy-4-phenylbutyryl]-L- leucine. In another suitable method, 20 mg of the N-[(25',3i?)-3-amino-2-hydroxy-4- phenylbutyryl]-L-leucine is administered orally.
  • the leucine aminopeptidase inhibitor can also be rapamycin.
  • the growth hormone can be pancreatic growth hormone.
  • the growth hormone inhibitor can be octreotide.
  • the method can further comprise administering an effective amount of D-leucine.
  • the subject can be a mammal and that mammal can be a human. Representative methods include those in which the cancer is non-small cell lung cancer. In certain aspects of the subject can be a mammal and that mammal can be a human. Representative methods include
  • 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 tyrosine hydroxylase inhibitor, the melanin promoter, the p450 3A4 promoter, and the leucine aminopeptidase inhibitor is one or more of a nucleic acid, protein, antibody or antigen-binding fragment of an antibody.
  • 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.
  • Methods of reducing cell proliferation in a subject comprising administering an effective amount of a tyrosine hydroxylase inhibitor; melanin and/or a melanin promoter; a p450 3A4 promoter; and a leucine aminopeptidase inhibitor to the subject in need thereof.
  • the method of treating cancer can further comprise a growth hormone inhibitor.
  • at least two of the components i.e. , melanin, promoters and/or inhibitors
  • at least three of the components are administered simultaneously. Each of the components can be administered simultaneously.
  • components are 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 dodecylnonaoxyethylene glycol monoether.
  • the components are administered during a cycle consisting of five to seven days of administering the components and one to two days of not administering the components.
  • the components can be administered over the course of at least six of said cycles.
  • the tyrosine hydroxylase inhibitor can be a tyrosine derivative.
  • the tyrosine derivative can be 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-dimethoxy phenyl) propanoate H-D-Tyr(TBU)-allyl ester HC1, methyl (2R)-2- amino-3 -(3 -chloro-4,5-dimethoxy phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3- hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2- amino-3-(2-chloro-3,4-dimethoxyphenyl)
  • the tyrosine derivative is administered orally and 0.25 mL of a 2 mg/mL suspension of the tyrosine derivative is administered subcutaneously.
  • the melanin promoter can be methoxsalen.
  • 10 mg of the methoxsalen is administered orally and 0.25 mL of a 1 mg/mL suspension of the methoxsalen is administered subcutaneously.
  • the melanin promoter can also be melanotan II.
  • the p450 3A4 promoter can be 5, 5- diphenylhydantoin.
  • 30 mg of the 5, 5-diphenylhydantoin is administered orally.
  • the p450 3A4 promoter can also be valproic acid or carbamazepine.
  • the leucine aminopeptidase inhibitor can be N-[(25',3i?)-3-amino-2-hydroxy-4-phenylbutyryl]-L- leucine. In another suitable method, 20 mg of the N-[(25',3i?)-3-amino-2-hydroxy-4- phenylbutyryl]-L-leucine is administered orally.
  • the leucine aminopeptidase inhibitor can also be rapamycin.
  • the growth hormone can be pancreatic growth hormone.
  • the growth hormone inhibitor can be octreotide.
  • the method can further comprise administering an effective amount of D-leucine.
  • the subject can be a mammal and the mammal can be a human. Representative methods include those in which the cancer is non-small cell lung cancer. In certain aspects of the abnormality of the subject is administered orally.
  • 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 tyrosine hydroxylase inhibitor, the melanin promoter, the p450 3A4 promoter, and the leucine aminopeptidase inhibitor is one or more of a nucleic acid, protein, antibody or antigen-binding fragment of an antibody.
  • 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.
  • compositions and combination therapies are provided.
  • Various embodiments of the present invention further relate to methods of administering a pharmaceutical composition or combination therapy to a human patient for the treatment of cancer.
  • the methods may comprise administering a pharmaceutical composition or combination therapy by generally accepted routes of
  • a pharmaceutical composition or combination therapy may be administered orally and/or subcutaneously.
  • a pharmaceutical composition or combination therapy may be administered to human patients between meals.
  • a pharmaceutical composition or combination therapy may be administered to a human patient for 5 days per week for a period of 6 weeks, creating one cycle of 30 days of treatment. Depending on the outcome after 6 weeks or one cycle of treatment, additional cycles of the pharmaceutical composition or combination therapy may be administered.
  • the present invention also provides:
  • compositions comprising a tyrosine hydroxylase inhibitor
  • melanin a melanin promoter, or a combination thereof (preferably melanin);
  • compositions comprising a tyrosine hydroxylase inhibitor and a p450 3A4 promoter; - pharmaceutical compositions comprising a tyrosine hydroxylase inhibitor and a leucine aminopeptidase inhibitor; and
  • compositions comprising melanin, a melanin promoter, or a
  • melanotan II preferably melanotan II
  • p450 3A4 promoter preferably melanotan II
  • leucine aminopeptidase inhibitor preferably leucine aminopeptidase inhibitor
  • the tyrosine hydroxylase inhibitor in such compositions preferably is a-methyl-DL-tyrosine
  • the p450 3A4 promoter preferably is 5,5-diphenylhydantoin
  • the leucine aminopeptidase inhibitor preferably is N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine.
  • kits comprising each of these pharmaceutical compositions, along with a pharmaceutical composition comprising a tyrosine hydroxylase inhibitor; as well as methods comprising administering each of the pharmaceutical compositions to a patient along with a pharmaceutical composition comprising a tyrosine hydroxylase inhibitor, preferably such that they are administered to the patient within a 24 hour period.
  • a clinical study was performed to evaluate the effectiveness, safety, acceptability, and tolerability of a combination therapy in accordance with embodiments of the present invention as a treatment for metastatic cancer.
  • the combination therapy comprised the following:
  • tyrosine hydroxylase inhibitor i.e., a-methyl-DL tyrosine
  • melanin promoter i.e., melanotan II
  • p450 3A4 promoter i.e., 5, 5-diphenylhydantoin
  • leucine aminopeptidase inhibitor i.e., rapamycin
  • EORTC European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core
  • the present invention provides methods of inducing melanin production in vivo with one or both of methoxsalen and melanotan and/or through administration of melanin.
  • melanin is believed to be beneficial because of its photocatalytic nature and its ability to convert various wavelengths of ambient or induced electromagnetic radiation into electrical energy, thus potentiating desirable reactions or dislocations.
  • melanin preferably is combined mechanically or chemically with a- methyl-DL-tyrosine prior to administration.
  • Melanin as a photocatalyst is believed to have polarity at points in its physical mass. It has been determined that small melanin particles may produce less electrical energy than larger particles, and a plurality of melanin particles tend not to accumulate in polarity - specific formations. An effective method to obtain high yield of electrical energy from melanin is to form the melanin in large, polarized particles. By implication, it is believed that nanoparticles, regardless of quantity, are not as desirable as larger particles for cancer treatment, and that larger particles have a greater capacity to be accepted by cancer cell membranes.
  • melanin is combined with a-methyl- DL-tyrosine in at least three ways.
  • Melanin can be solubilized by many methods as described in U. S. Patent No. 5,225,435, the contents of which are incorporated herein by reference.
  • One preferred method involves mixing melanin with distilled water and hydrogen peroxide to achieve a melanin concentration of at least 5 weight percent, and then placing the resulting composition in a microwave oven until it reaches a boiling point.
  • the dissolved melanin that is produced is used to infuse or saturate through the mass of ⁇ -methyl-DL-tyrosine.
  • the composition is then dried and the dry powder is used.
  • a-Methyl-DL-tyrosine is placed in distilled water with 5-benzyloxy-6- methoxy-indole and sealed for up to a month.
  • the L portion of the racemic a-methyl-DL- tyrosine is believed to convert to (DOPA) melanin.
  • the size of the melanin particle can be controlled by controlling the time of growth period.
  • the powder produced is then cleaned and dried.
  • the ratio of the racemic mix is no longer 50/50, but the utility of the chemically combined ingredients facilitates penetration of the melanin even with reduced L component and appears to offer potentially sufficient benefit.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Emergency Medicine (AREA)
EP17808688.0A 2016-11-15 2017-11-15 Pharmazeutische zusammensetzungen und verfahren zur behandlung von krebs Withdrawn EP3541411A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US15/351,966 US10272068B2 (en) 2012-01-17 2016-11-15 Pharmaceutical compositions and methods
PCT/US2017/061682 WO2018093820A1 (en) 2016-11-15 2017-11-15 Pharmaceutical compositions and methods for the treatment of cancer

Publications (1)

Publication Number Publication Date
EP3541411A1 true EP3541411A1 (de) 2019-09-25

Family

ID=60570232

Family Applications (1)

Application Number Title Priority Date Filing Date
EP17808688.0A Withdrawn EP3541411A1 (de) 2016-11-15 2017-11-15 Pharmazeutische zusammensetzungen und verfahren zur behandlung von krebs

Country Status (12)

Country Link
EP (1) EP3541411A1 (de)
JP (2) JP2019537608A (de)
KR (2) KR20190084291A (de)
CN (1) CN110167580A (de)
AU (1) AU2017361080A1 (de)
BR (1) BR112019009799A2 (de)
CA (1) CA3040922A1 (de)
EA (1) EA201991192A1 (de)
IL (1) IL266486A (de)
MX (1) MX2019005450A (de)
PH (1) PH12019500758A1 (de)
WO (1) WO2018093820A1 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3140042A1 (en) 2019-05-14 2020-11-19 Tyme, Inc. Compositions and methods for treating cancer
US20210106549A1 (en) * 2019-10-15 2021-04-15 Tyme, Inc. Pharmaceutical compositions and methods
CA3167918A1 (en) * 2020-01-17 2021-07-22 Tyme, Inc. Compositions and methods for modulating cancer
CN111358777A (zh) * 2020-02-24 2020-07-03 军事科学院军事医学研究院环境医学与作业医学研究所 一种提高外周血单个核细胞线粒体功能的方法和应用
US10905698B1 (en) 2020-05-14 2021-02-02 Tyme, Inc. Methods of treating SARS-COV-2 infections

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5225435A (en) 1990-05-18 1993-07-06 Yale University Soluble melanin
WO2006032299A1 (en) * 2004-09-24 2006-03-30 Susanna Miettinen Use of inhibitors of 24-hydroxylase in the treatment of cancer
WO2006036892A2 (en) * 2004-09-24 2006-04-06 Sapphire Therapeutics, Inc. Use of inhibitors of 24-hydroxylase in the treatment of cancer
US20130183263A1 (en) * 2012-01-17 2013-07-18 Steven Hoffman Pharmaceutical compositions and methods
CN104220057B (zh) * 2012-01-17 2017-11-03 迪美公司 药物组合物和方法
US8481498B1 (en) * 2012-01-17 2013-07-09 Steven Hoffman Pharmaceutical compositions and methods
US9585841B2 (en) * 2013-10-22 2017-03-07 Tyme, Inc. Tyrosine derivatives and compositions comprising them

Also Published As

Publication number Publication date
CA3040922A1 (en) 2018-05-24
BR112019009799A2 (pt) 2019-08-06
JP2019537608A (ja) 2019-12-26
JP2023018029A (ja) 2023-02-07
PH12019500758A1 (en) 2019-07-24
MX2019005450A (es) 2019-07-04
KR20230003314A (ko) 2023-01-05
EA201991192A1 (ru) 2019-10-31
KR20190084291A (ko) 2019-07-16
AU2017361080A1 (en) 2019-05-02
WO2018093820A1 (en) 2018-05-24
CN110167580A (zh) 2019-08-23
IL266486A (en) 2019-07-31

Similar Documents

Publication Publication Date Title
US10307465B2 (en) Pharmaceutical compositions and methods
AU2020201683A1 (en) Pharmaceutical compositions and methods
US11052068B2 (en) Pharmaceutical compositions and methods
EP3541411A1 (de) Pharmazeutische zusammensetzungen und verfahren zur behandlung von krebs
US20210106549A1 (en) Pharmaceutical compositions and methods
US20210386832A1 (en) Pharmaceutical Compositions And Methods
US11103559B2 (en) Pharmaceutical compositions and methods
EA042139B1 (ru) Фармацевтические композиции и способы лечения рака

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20190617

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20200928

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20231005