WO2019182527A1 - Methyl jasmonate derivatives as possible drug candidates for use in treatment of cancer - Google Patents

Methyl jasmonate derivatives as possible drug candidates for use in treatment of cancer Download PDF

Info

Publication number
WO2019182527A1
WO2019182527A1 PCT/TR2018/050522 TR2018050522W WO2019182527A1 WO 2019182527 A1 WO2019182527 A1 WO 2019182527A1 TR 2018050522 W TR2018050522 W TR 2018050522W WO 2019182527 A1 WO2019182527 A1 WO 2019182527A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
molecule according
group
molecule
iii
Prior art date
Application number
PCT/TR2018/050522
Other languages
French (fr)
Inventor
Mustafa Guzel
Sukran OZDATLI
Ozgecan SAVLUG
Bilgesu Onur SUCU
Original Assignee
T.C. Istanbul Medipol Universitesi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by T.C. Istanbul Medipol Universitesi filed Critical T.C. Istanbul Medipol Universitesi
Publication of WO2019182527A1 publication Critical patent/WO2019182527A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/30—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C243/32—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C265/00—Derivatives of isocyanic acid
    • C07C265/02—Derivatives of isocyanic acid having isocyanate groups bound to acyclic carbon atoms
    • C07C265/06—Derivatives of isocyanic acid having isocyanate groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C265/08—Derivatives of isocyanic acid having isocyanate groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/63—Halogen-containing esters of saturated acids
    • C07C69/635—Halogen-containing esters of saturated acids containing rings in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to the active methyl jasmonate analogues which are effective on the cancer disease and / or on the mechanisms that constitute the disease, the methods of synthesis of said analogs / derivatives and their use in the treatment of a variety of diseases, particularly for treatment of cancer and cancer-causing diseases.
  • Cancer is one of the diseases that cause the most death in the world. Ten characteristics have been identified that characterize the formation and progression of cancer. The most recently identified is the cancer metabolism. In order for the cancerous cells to grow and spread to the tissue and invade the body, they must obtain energy to feed themselves and this is possible with glucose. Therefore, serious research is being carried out on the development of therapeutic agents targeting the energy metabolism and Warburg Effect in cancer. As Warburg pointed out in 1926, cancer cells differ in their ability to obtain energy relative to normal cells, and they express specific enzymes more, one of the most important enzymes over expressed is Hexokinase-2 (HK-2).
  • HK-2 enzyme One of the most important ways of inhibiting the energy metabolism of cancer cells is the inhibition of the HK-2 enzyme.
  • chemotherapeutic agents used in the treatment of cancer patients are known to have toxicity and efficiency problems.
  • the development and use of inhibitors specific for the HK-2 target is an important requirement for both safety and high efficiency in cancer patients.
  • molecules such as Methyl Jasmonate, 2-Deoxyglucose, 2- Bromopyruvate and Lonidamine have been tried to be developed as HK-2 inhibitors, but their efficacy in clinical trials is open to question. Therefore, more effective and specific HK- 2 inhibitors are needed.
  • hexokinase-2 (HK-2) inhibitors are effective in preventing the spread of cells by acting on the energy metabolism of cancer cells.
  • the inventors of this invention have developed the original methyl jasmonate derivatives and HK-2 inhibitors with a different structure and tested their biological activity.
  • the present invention relates to one or more molecules represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII or Formula VIII; wherein said molecule is;
  • Rl is selected from a group comprising
  • R2 is selected from a group comprising -H Or
  • R4 is selected from a group comprising
  • R5 is selected from -H or is *-OH when Rl is not ;
  • Rl is selected from a group comprising
  • R2 is selected froma group comprising
  • Rl is selected from a group comprising R2 is selected from a group comprising
  • Rl is selected from a group comprising
  • the molecules according to the invention can be present in the form of prodrugs of the molecules represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII or Formula IX.
  • the said prodrugs may be formed when any hydroxyl group on the molecule according to invention is in an ester or carbonate form or when a carboxylic acid group is in the form of an ester in a molecule according to the invention such as Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII or Formula IX.
  • the aforementioned prodrugs can be converted to the active molecule in vivo, eg by hydrolysis of the ester or carbonate group.
  • the molecules according to the invention may be in the form of racemic mixture or may be rich in one enantiomer.
  • the molecules according to the invention may have at least 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee or 95% ee.
  • the molecules according to the invention may have more than one stereocenter.
  • the molecules according to the invention may be rich in one or more diastereomers.
  • the molecules according to the invention can have at least 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or 95% de.
  • the molecule according to the invention is represented by Formula 1.1.
  • the molecule according to the invention is represented by Formula 1.2.
  • the molecule according to the invention is represented by Formula 1.3.
  • the molecule according to the invention is represented by Formula 1.4.
  • the molecule according to the invention is represented by Formula 1.5.
  • the molecule of the invention is represented by Formula 1.6.
  • Formula 1.6 In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.7.
  • the molecule according to the invention is represented by Formula 1.8.
  • the molecule of the invention is represented by Formula 1.9.
  • the molecule according to the invention is represented by Formula 1.11.
  • the molecule according to the invention is represented by Formula 1.12.
  • the molecule of the invention is represented by Formula 1.13.
  • the molecule according to the invention is represented by Formula 1.14.
  • the molecule according to the invention is represented by Formula 1.15.
  • the molecule according to the invention is represented by Formula 1.16.
  • the molecule of the invention is represented by Formula 1.17.
  • the molecule of the invention is represented by Formula 1.18.
  • the molecule according to the invention is represented by Formula 1.19.
  • the molecule of the invention is represented by Formula 1.20.
  • the molecule of the invention is represented by Formula 1.21.
  • the molecule according to the invention is represented by Formula 1.22.
  • the molecule of the invention is represented by Formula 1.23.
  • the molecule according to the invention is represented by Formula 1.25.
  • the molecule according to the invention is represented by Formula II.1.
  • Formula II.1 In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula II.2.
  • the molecule of the invention is represented by Formula II.3.
  • the molecule according to the invention is represented by Formula II.4.
  • the molecule according to the invention is represented by Formula II.5.
  • the molecule of the invention is represented by Formula II.6.
  • the molecule according to the invention is represented by Formula III.1.
  • the molecule according to the invention is represented by Formula III.2.
  • the molecule according to the invention is represented by Formula III.3.
  • the molecule according to the invention is represented by Formula III.4.
  • the molecule according to the invention is represented by Formula III.5.
  • the molecule according to the invention is represented by Formula IV.1.
  • the molecule according to the invention is represented by Formula IV.2.
  • the molecule of the invention is represented by Formula V.
  • the molecules shown with Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX according to the invention can be prepared and purified using conventional methods known in the state of the art.
  • the present invention relates to the use of one or more molecules shown with Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX as an HK-2 inhibitor, wherein said molecule is;
  • Rlis selected from a group comprising R2 is selected from a group comprising o
  • R4 is selected from a group comprising
  • R5 is selected from * ° H or H ;
  • Rl is selected from a group comprising
  • R2 is selected from a group comprising
  • Rl is selected from a group comprising
  • Rl is selected from a group comprising Rl
  • the present invention relates to the use of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII and Formula IX, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of cancer.
  • the present invention relates to the use of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII and Formula IX, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment or prevention of cancer.
  • treatment refers to the prevention, reduction, alleviation, amelioration or blocking of at least one symptom that characterizes a pathological disorder in a subject that is threatened by a disorder or has a condition.
  • carcinomas solid carcinomas, squamous cell carcinomas, adenocarcinomas, sarcomas, gliomas, high-grade gliomas, blastomas, neuroblastomas, plasmacytomas, histiocytomas, melanomas, adenomas, hypoxic tumors, myeloma, metastatic cancers or cancers in general.
  • cancer that can be used in the treatment of the compounds described herein include B-cell lymphoma, T-cell lymphoma, mycosis fungoides, Hodgkin's disease, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinomas of the head and neck, kidney cancer, small cell carcinoma of the lung, non-small cell lung cancer, lung cancers, neuroblastoma / glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, quamous cell carcinoma of the mouth, throat, esophagus, colon cancer, cervical cancer , cervical carcinoma, breast cancer and epithelial cancer, kidney cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, large intestine cancer, hemotopoietic cancers; testicular cancer; colon and rectal cancers, prostate cancer or pancreatic cancer.
  • the molecules according to the invention can also be used for the treatment of pre- cancerous disorders such as cervical and anal dysplasias, other dysplasias, severe dysplasias, hyperplasia, non-typical hyperplasia and neoplasia.
  • cancer and “cancerous” as used herein refer to malignant tumors or describe the physiological condition characterized by uncontrolled cell growth.
  • the molecules of the invention find use in the treatment of cancer and/or protection from cancer disease.
  • the molecules of the present invention will preferably be administered in the form of a pharmaceutical composition.
  • compositions comprising Formula I, Formula II, Formula III, Formula IV, Formula VI, Formula VI, Formula VII, Formula VIII or Formula IX, or pharmaceutically acceptable salts thereof.
  • the pharmaceutical compositions may be prepared in such a manner that such compositions comprise Formula I, Formula II, Formula III, Formula IV, Formula V , Formula VI, Formula VII, Formula VIII or Formula IX, or pharmaceutically acceptable salts thereof as rich in one enantiomer.
  • the enantiomerically rich mixture is obtained by formation of at least 60%, preferably at least 75%, 90%, 95% or 99% of an enantiomer per mole .
  • the enriched mixture of an enantiomer may be substantially free of any other enantiomers.
  • substantially free of' means that the other enantiomer is present in an amount less than 10% or less than 5% or less than 3% or less than 2% or less than 1% of the amount of enriched enantiomer.
  • the pharmaceutical compositions can be prepared in such a way that Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII or Formula IX, or a pharmaceutically acceptable salt thereof, can be rich in a diastereomer.
  • the diastereomerically rich mixture is obtained by a composition comprising at least 60%, preferably at least 75%, 90%, 95% or 99% of a diastereomer per moles.
  • a further embodiment of the invention provides the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII or Formula IX, or pharmaceutically acceptable salts thereof, as pharmaceutical compositions for use as Hexokinase-2 inhibitors or for use in the treatment of cancer.
  • the pharmaceutical compositions comprise at least one or more excipients as well as active ingredients according to the invention.
  • the pharmaceutical composition comprising the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or pharmaceutically acceptable salts thereof as active ingredient, may contain at least one further active ingredient.
  • Other active substance can be selected from, but not limited to, a subgroup comprising anticancer agents, nucleoside analogs, antifolates, other metabolites, topoisomerase I inhibitors, anthracyclines, podophyllotoxins, taxanes, vinca alkaloids, alkylating agents, platinum compounds, antihormones, radiopharmaceuticals, monoclonal antibodies, tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, retinoids, immunoregulatory agents, histoneacetylase inhibitors and other agents.
  • mTOR mammalian target of rapamycin
  • Anticancer agents can be selected from a group comprising, docetaxel, gemcitabine, imatinib, 5-fluorouracil, 9-aminocamptothecin, amine-modified geldanamycin, doxorubicin, paclitaxel, procarbazine, hydroxyurea, meso e-chlorine, cisplatin and radionuclides (eg, 1-131, Y-90, In- 111 and Tc-99m).
  • the nucleoside analogs can be selected from a group comprising, but not limited to, azacitidine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5- fluorouracil (5-FU), gemcitabine, mercaptopurine, nelarabine, pentostatin, thioguanine, trifluridine and tipiracil.
  • Antifolates can be selected from a group comprising, but not limited to, methotrexate, pemetrexed, pralatrexed and raltitrexed.
  • Other metabolites can be selected from a group comprising, but not limited to, hydroxycarbamide.
  • Topoisomerase I inhibitors can be selected from a group comprising, but not limited to, irinotecan and topotecan.
  • Anthracyclines can be selected from a group comprising, but not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone and valrubicin.
  • Podophilotoxins can be selected from a group comprising, but not limited to, etoposide and teniposide.
  • Taxanes can be selected from a group comprising, but not limited to, cabasitaxel, docetaxel and paclitaxel.
  • Vinca alkaloids can be selected from the group comprising, but not limited to, vinblastine, vincristine, vindesin, vinflunine and vinorelbine.
  • Alkylating agents can be selected from the group comprising, but not limited to, bendamustine, chlorambucil, dacarbazine, melphalan, streptozotocin and trabestedin.
  • Antihormone compounds can be selected from a group comprising, but not limited to, abiraterone, bicalutamide, ciproteron, degarelic, exemestane, fulvestrant, goserelin, histrelin, leuprolide, mifepristone and triptorel.
  • Tyrosine kinase inhibitors can be selected from a group comprising, but not limited to, afatinib, aksitinib, bosutinib, kobimetinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, pazopanib, rucolinolinib, sunitinib and vandetanib.
  • the mammalian target (mTOR) inhibitors of rapamycin can be selected from a group comprising but not limited to everolimus and temsirolimus.
  • Retinoids can be selected from a group comprising, but not limited to, alytretinoin, bexarotene, isotretinoin, tamibarotene and tretinoin.
  • Immune system regulators may be selected from a group including, but not limited to, lenalidomide, pomalidomide and thalidomide.
  • Histone deacetylase inhibitors may be selected from a group comprising, but not limited to, belinostat, panobinostat, valproate and vorinostate.
  • Other substances can be selected from a group comprising, but not limited to, anagrelide, seritinib, dabrafenib, idelalisib, ibrutinib, palbosiklib, vemurafenib, bleomycin, bortezomib, dactinomycin, eribulin, estramustine, iksabepilone, mitomycin, procarbazine, alektinib, flucimesterone, iobenguane, imiguimod, interferon, iksazomib, lanreotide, lentinan, octreotide, omacetaxine, tegafur, gimerazil, oterasil, uracil, kombrestatin and chlorokine.
  • composition comprising the molecules of the invention can be in any suitable form based on the preferred method of administering the composition to a patient.
  • the composition comprising the molecules of the present invention can be formulated for example for oral administration in the form of liquid dispersions or aqueous or oily suspensions, or in parenteral form, for example, in forms suitable for subcutaneous, intravenous, intramuscular, intraperitoneal, intradermal, transdermal or other infusion techniques.
  • the composition comprising the molecules of the invention may also be formulated in the form of a spray tube for administration through inhalation or as a solution for administration by inhalation device or nebulizer.
  • the molecules of the present invention are preferably administered to a patient by transdermal, subcutaneous, intranasal, intravenous, intramuscular, intratumorally or by inhalation.
  • the most suitable route for administration can be determined based on the molecules of the present invention, the nature and severity of the disease and the patient's physical condition.
  • Embodiments are described here to include specific features / elements.
  • the disclosure also encompasses essentially other applications comprising or consisting of said features / elements.
  • Jasmonic acid (0.210 g, 1 mmol) was placed in a 2-necked flask and dissolved in 10 mL of toluene. After addition of 4-(Dimethylamino) pyridine (0.134 g, 1.1 mmol) and triethylamine (0.101 g, 1.1 mmol), the system was stirred under nitrogen at 110 °C. Subsequently, diphenylphosphoryl azide (0.238 mL, 1.1 mmol) was added dropwise to the mixture at 110 °C and left at reflux for 16 hours. The reaction was terminated according to LC-MS control. After toluene was evaporated, extraction with ethyl acetate was carried out with brine. After drying the organic phase over Na 2 S0 4 , the solvent was evaporated on a rotary evaporator.The compound was used without any further purification.
  • the inventors determined the IC50 value of the molecule shown in Formula 1.11 with the reference molecules and MTT tests were performed.
  • Table 1 MTT test results in HI 299 and HEK cell lines
  • the inventors determined the IC50 value in the Mia-Paca cell lines of the molecule shown by Formula 1.11 and performed the MTT tests.
  • the molecule according to the invention shown in Formula 1.11 exhibits effectiveness in each of the three cell lines when used in lower amounts than the molecules known in the state of the art. This indicates that the molecules according to the invention have higher activity.
  • the inventors have carried out MTT tests of Formula 1.3, which is a molecule according to present invention on H1299 cell lines.
  • the graphs showing the l2-hour and 24-hour results of the MTT analysis are given in Figure 1 and Figure 2, respectively.
  • Example 11 Determination of Hexokinase Enzyme Activity of Formula 1.5.
  • Formula 1.8 and Formula IX
  • substrate mixture was prepared using 0.5 mM ATP and 25 mM glucose.
  • Human hexokinase-2 enzyme (rhH -2) was prepared wp have a concentration of 7.5 ng/pL and coupling Phosphatase 4 enzyme was prepared to have a concentration of 10 pg/niL .20 pL buffer.
  • 20 pL rhHK-2, 2 pL sample and 10 pL Coupling phosphatase 4 was added respectively and then left for incubation for 10 minutes.
  • 30 pL of Malachite green reagent A 100 pL of ultra pure water
  • 30 pL malachite green reagent B was added respectively and left for incubation for 20 minutes. After incubation absorbance at 620 nrn is determined and the results are calculated according to the following equation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the active methyl jasmonate analogues which are effective on the cancer disease and / or on the mechanisms that constitute the disease, the methods of synthesis of said analogs / derivatives and their use in the treatment of a variety of diseases, particularly for treatment of cancer and cancer-causing diseases.

Description

METHYL JASMONATE DERIVATIVES AS POSSIBLE DRUG CANDIDATES FOR USE IN TREATMENT OF CANCER
Technical Field
The present invention relates to the active methyl jasmonate analogues which are effective on the cancer disease and / or on the mechanisms that constitute the disease, the methods of synthesis of said analogs / derivatives and their use in the treatment of a variety of diseases, particularly for treatment of cancer and cancer-causing diseases.
State of the Art
Cancer is one of the diseases that cause the most death in the world. Ten characteristics have been identified that characterize the formation and progression of cancer. The most recently identified is the cancer metabolism. In order for the cancerous cells to grow and spread to the tissue and invade the body, they must obtain energy to feed themselves and this is possible with glucose. Therefore, serious research is being carried out on the development of therapeutic agents targeting the energy metabolism and Warburg Effect in cancer. As Warburg pointed out in 1926, cancer cells differ in their ability to obtain energy relative to normal cells, and they express specific enzymes more, one of the most important enzymes over expressed is Hexokinase-2 (HK-2).
One of the most important ways of inhibiting the energy metabolism of cancer cells is the inhibition of the HK-2 enzyme. Currently, chemotherapeutic agents used in the treatment of cancer patients are known to have toxicity and efficiency problems. Unlike the known agents, the development and use of inhibitors specific for the HK-2 target is an important requirement for both safety and high efficiency in cancer patients. Based on this idea, molecules such as Methyl Jasmonate, 2-Deoxyglucose, 2- Bromopyruvate and Lonidamine have been tried to be developed as HK-2 inhibitors, but their efficacy in clinical trials is open to question. Therefore, more effective and specific HK- 2 inhibitors are needed.
Brief Description of the Invention
When the state of the art is examined, it is seen that hexokinase-2 (HK-2) inhibitors are effective in preventing the spread of cells by acting on the energy metabolism of cancer cells.
The inventors of this invention have developed the original methyl jasmonate derivatives and HK-2 inhibitors with a different structure and tested their biological activity.
Detailed Description of the Invention
The present invention relates to one or more molecules represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII or Formula VIII; wherein said molecule is;
A) Formula I,
Figure imgf000003_0001
Formula I
wherein; Rl is selected from a group comprising
Figure imgf000004_0001
Figure imgf000004_0002
R2, is selected from a group comprising -H Or
Figure imgf000004_0003
Figure imgf000004_0004
R4 is selected from a group comprising
Figure imgf000005_0001
R4 is null when R3 is =0;
Figure imgf000005_0002
R5 is selected from -H or is *-OH when Rl is not ; or
B) Formula II
Figure imgf000005_0003
Formula II
wherein;
Rl is selected from a group comprising
Figure imgf000005_0004
R2 is selected froma group comprising
Figure imgf000006_0001
Figure imgf000006_0002
or
C) Formula III
Figure imgf000006_0003
Formula III
wherein;
Rl is selected from a group comprising
Figure imgf000006_0004
Figure imgf000006_0005
R2 is selected from a group comprising
Figure imgf000007_0001
Figure imgf000007_0002
or
D) Formula IV
Figure imgf000007_0003
Formula IV
wherein Rl is selected from a group comprising
Figure imgf000007_0004
Figure imgf000007_0005
or
E) Formula V, or
Figure imgf000008_0001
Formula VI
G) Formula VII, or
Figure imgf000008_0002
Formula VII
H) Formula VIII, or
Figure imgf000008_0003
Formula VIII
I) Formula IX
Figure imgf000009_0001
Formula IX
or salts, hydrates, solvates, polymorphs, optical isomers, geometric isomers, enantiomers, diastereomers, and mixtures thereof.
The mark as given here indicates the point where all the Rl, R2, R3, R4, R5 groups are bonded to the structures shown with Formula I, Formula II, Formula III, Formula IV with single or double bonds from the point shown with The sign on the cyclic/ring structures indicates that this connection can be made through any atom on the ring that is capable of making connections. R groups with no sign are connected directly to the ring.
In one embodiment of the invention, the molecules according to the invention can be present in the form of prodrugs of the molecules represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII or Formula IX. The said prodrugs may be formed when any hydroxyl group on the molecule according to invention is in an ester or carbonate form or when a carboxylic acid group is in the form of an ester in a molecule according to the invention such as Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII or Formula IX. In one embodiment of the invention, the aforementioned prodrugs can be converted to the active molecule in vivo, eg by hydrolysis of the ester or carbonate group.
In one embodiment of the invention, the molecules according to the invention may be in the form of racemic mixture or may be rich in one enantiomer. For example; The molecules according to the invention may have at least 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee or 95% ee.
The molecules according to the invention may have more than one stereocenter. Thus, the molecules according to the invention may be rich in one or more diastereomers. For example, the molecules according to the invention can have at least 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or 95% de.
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.1.
Figure imgf000010_0001
Formula 1.1
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.2.
Figure imgf000011_0001
Formula 1.2
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.3.
Figure imgf000011_0002
Formula 1.3
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.4.
Figure imgf000011_0003
Formula 1.4
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.5.
Figure imgf000012_0001
Formula 1.5
In a preferred embodiment of the invention, the molecule of the invention is represented by Formula 1.6.
Figure imgf000012_0002
Formula 1.6 In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.7.
Figure imgf000013_0001
Formula 1.7
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.8.
Figure imgf000013_0002
Formula 1.8
In a preferred embodiment of the invention, the molecule of the invention is represented by Formula 1.9.
Figure imgf000013_0003
Formula 1.9 In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.10.
Figure imgf000014_0001
Formula 1.10
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.11.
Figure imgf000014_0002
Formula 1.11
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.12.
Figure imgf000014_0003
Formula 1.12
In a preferred embodiment of the invention, the molecule of the invention is represented by Formula 1.13.
Figure imgf000015_0001
Formula 1.13
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.14.
Figure imgf000015_0002
Formula 1.14
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.15.
Figure imgf000016_0001
Formula 1.15
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.16.
Figure imgf000016_0002
Formula 1.16
In a preferred embodiment of the invention, the molecule of the invention is represented by Formula 1.17.
Figure imgf000016_0003
Formula 1.17
In a preferred embodiment of the invention, the molecule of the invention is represented by Formula 1.18.
Figure imgf000017_0001
Formula 1.18
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.19.
Figure imgf000017_0002
Formula 1.19
In a preferred embodiment of the invention, the molecule of the invention is represented by Formula 1.20.
Figure imgf000017_0003
Formula 1.20
In a preferred embodiment of the invention, the molecule of the invention is represented by Formula 1.21.
Figure imgf000018_0001
Formula 1.21
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.22.
Figure imgf000018_0002
Formula 1.22
In a preferred embodiment of the invention, the molecule of the invention is represented by Formula 1.23.
Figure imgf000018_0003
Formula 1.23 In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.24.
Figure imgf000019_0001
Formula 1.24
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula 1.25.
Figure imgf000019_0002
Formula 1.24
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula II.1.
Figure imgf000019_0003
Formula II.1 In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula II.2.
Figure imgf000020_0001
Formula II.2
In a preferred embodiment of the invention, the molecule of the invention is represented by Formula II.3.
Figure imgf000020_0002
Formula II.3
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula II.4.
Figure imgf000021_0001
Formula II.4
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula II.5.
Figure imgf000021_0002
Formula II.5
In a preferred embodiment of the invention, the molecule of the invention is represented by Formula II.6.
Figure imgf000022_0001
Formula II.6
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula III.1.
Figure imgf000022_0002
Formula III.1
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula III.2.
Figure imgf000023_0001
Formula III.2
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula III.3.
Figure imgf000023_0002
Formula III.3
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula III.4.
Figure imgf000023_0003
Formula III.4
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula III.5.
Figure imgf000024_0001
Formula III.5
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula IV.1.
Figure imgf000024_0002
Formula IV.1
In a preferred embodiment of the invention, the molecule according to the invention is represented by Formula IV.2.
Figure imgf000025_0001
Formula IV.2
In a preferred embodiment of the invention, the molecule of the invention is represented by Formula V.
Figure imgf000025_0002
Formula V
Molecules, whose specific chemical structures have been given, are disclosed in order to illustrate the invention and the scope of the invention is not limited to these molecules.
The molecules shown with Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX according to the invention can be prepared and purified using conventional methods known in the state of the art. In another aspect, the present invention relates to the use of one or more molecules shown with Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX as an HK-2 inhibitor, wherein said molecule is;
A) Formula I,
Figure imgf000026_0001
Formula I
wherein;
Rlis selected from a group comprising
Figure imgf000026_0002
Figure imgf000026_0003
R2 is selected from a group comprising
Figure imgf000027_0001
o
,11.
' ^
Figure imgf000027_0002
R3 is selected from a group comprising =0 — H —OH ·>— F · ·>
R4 is selected from a group comprising
Figure imgf000027_0003
Figure imgf000027_0004
null when R3 is =0 ,
R5 is selected from * °H or H ;
or
B) Formula II
Figure imgf000027_0005
Formula II
wherein;
Rl is selected from a group comprising
Figure imgf000028_0004
R2 is selected from a group comprising
Figure imgf000028_0001
Figure imgf000028_0002
or
C) Formula III
Figure imgf000028_0003
Formula III
wherein; Rl is selected from a group comprising
Figure imgf000029_0001
om a group comprising
Figure imgf000029_0002
Figure imgf000029_0003
or
D) Formula IV
Figure imgf000029_0004
Formula IV Herein Rl is selected from a group comprising Rl
Figure imgf000030_0001
Figure imgf000030_0004
F) Formula VI, or
Figure imgf000030_0002
G) Formula VII, or
Figure imgf000030_0003
H) Formula VIII, or
Figure imgf000031_0001
I) Formula IX
Figure imgf000031_0002
Formula IX
or salts, hydrates, solvates, polymorphs, optical isomers, geometric isomers, enantiomers, diastereomers, and mixtures thereof.
In another aspect, the present invention relates to the use of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII and Formula IX, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of cancer.
In another aspect, the present invention relates to the use of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII and Formula IX, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment or prevention of cancer.
As used herein, "treatment" or "treatment" refers to the prevention, reduction, alleviation, amelioration or blocking of at least one symptom that characterizes a pathological disorder in a subject that is threatened by a disorder or has a condition. The following is a non-limiting list of different types of cancer: carcinomas, solid carcinomas, squamous cell carcinomas, adenocarcinomas, sarcomas, gliomas, high-grade gliomas, blastomas, neuroblastomas, plasmacytomas, histiocytomas, melanomas, adenomas, hypoxic tumors, myeloma, metastatic cancers or cancers in general. Specific examples of cancer that can be used in the treatment of the compounds described herein include B-cell lymphoma, T-cell lymphoma, mycosis fungoides, Hodgkin's disease, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinomas of the head and neck, kidney cancer, small cell carcinoma of the lung, non-small cell lung cancer, lung cancers, neuroblastoma / glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, quamous cell carcinoma of the mouth, throat, esophagus, colon cancer, cervical cancer , cervical carcinoma, breast cancer and epithelial cancer, kidney cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, large intestine cancer, hemotopoietic cancers; testicular cancer; colon and rectal cancers, prostate cancer or pancreatic cancer.
The molecules according to the invention can also be used for the treatment of pre- cancerous disorders such as cervical and anal dysplasias, other dysplasias, severe dysplasias, hyperplasia, non-typical hyperplasia and neoplasia.
The terms "cancer" and "cancerous" as used herein refer to malignant tumors or describe the physiological condition characterized by uncontrolled cell growth.
As disclosed herein, the molecules of the invention find use in the treatment of cancer and/or protection from cancer disease. For use in this manner, the molecules of the present invention will preferably be administered in the form of a pharmaceutical composition.
One embodiment of the invention relates to pharmaceutical compositions comprising Formula I, Formula II, Formula III, Formula IV, Formula VI, Formula VI, Formula VII, Formula VIII or Formula IX, or pharmaceutically acceptable salts thereof. The pharmaceutical compositions may be prepared in such a manner that such compositions comprise Formula I, Formula II, Formula III, Formula IV, Formula V , Formula VI, Formula VII, Formula VIII or Formula IX, or pharmaceutically acceptable salts thereof as rich in one enantiomer. The enantiomerically rich mixture is obtained by formation of at least 60%, preferably at least 75%, 90%, 95% or 99% of an enantiomer per mole .In one embodiment of the invention, the enriched mixture of an enantiomer may be substantially free of any other enantiomers. The term "substantially free of', as used herein, means that the other enantiomer is present in an amount less than 10% or less than 5% or less than 3% or less than 2% or less than 1% of the amount of enriched enantiomer.
In another embodiment of the invention, the pharmaceutical compositions can be prepared in such a way that Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII or Formula IX, or a pharmaceutically acceptable salt thereof, can be rich in a diastereomer. The diastereomerically rich mixture is obtained by a composition comprising at least 60%, preferably at least 75%, 90%, 95% or 99% of a diastereomer per moles.
A further embodiment of the invention provides the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII or Formula IX, or pharmaceutically acceptable salts thereof, as pharmaceutical compositions for use as Hexokinase-2 inhibitors or for use in the treatment of cancer. The pharmaceutical compositions comprise at least one or more excipients as well as active ingredients according to the invention.
In another embodiment of the invention, the pharmaceutical composition comprising the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or pharmaceutically acceptable salts thereof as active ingredient, may contain at least one further active ingredient. .
Other active substance can be selected from, but not limited to, a subgroup comprising anticancer agents, nucleoside analogs, antifolates, other metabolites, topoisomerase I inhibitors, anthracyclines, podophyllotoxins, taxanes, vinca alkaloids, alkylating agents, platinum compounds, antihormones, radiopharmaceuticals, monoclonal antibodies, tyrosine kinase inhibitors, mammalian target of rapamycin ( mTOR) inhibitors, retinoids, immunoregulatory agents, histoneacetylase inhibitors and other agents. Anticancer agents can be selected from a group comprising, docetaxel, gemcitabine, imatinib, 5-fluorouracil, 9-aminocamptothecin, amine-modified geldanamycin, doxorubicin, paclitaxel, procarbazine, hydroxyurea, meso e-chlorine, cisplatin and radionuclides (eg, 1-131, Y-90, In- 111 and Tc-99m).
The nucleoside analogs can be selected from a group comprising, but not limited to, azacitidine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5- fluorouracil (5-FU), gemcitabine, mercaptopurine, nelarabine, pentostatin, thioguanine, trifluridine and tipiracil.
Antifolates can be selected from a group comprising, but not limited to, methotrexate, pemetrexed, pralatrexed and raltitrexed.
Other metabolites can be selected from a group comprising, but not limited to, hydroxycarbamide.
Topoisomerase I inhibitors can be selected from a group comprising, but not limited to, irinotecan and topotecan.
Anthracyclines can be selected from a group comprising, but not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone and valrubicin.
Podophilotoxins can be selected from a group comprising, but not limited to, etoposide and teniposide.
Taxanes can be selected from a group comprising, but not limited to, cabasitaxel, docetaxel and paclitaxel.
Vinca alkaloids can be selected from the group comprising, but not limited to, vinblastine, vincristine, vindesin, vinflunine and vinorelbine.
Alkylating agents can be selected from the group comprising, but not limited to, bendamustine, chlorambucil, dacarbazine, melphalan, streptozotocin and trabestedin.
Antihormone compounds can be selected from a group comprising, but not limited to, abiraterone, bicalutamide, ciproteron, degarelic, exemestane, fulvestrant, goserelin, histrelin, leuprolide, mifepristone and triptorel. Tyrosine kinase inhibitors can be selected from a group comprising, but not limited to, afatinib, aksitinib, bosutinib, kobimetinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, pazopanib, rucolinolinib, sunitinib and vandetanib.
The mammalian target (mTOR) inhibitors of rapamycin can be selected from a group comprising but not limited to everolimus and temsirolimus.
Retinoids can be selected from a group comprising, but not limited to, alytretinoin, bexarotene, isotretinoin, tamibarotene and tretinoin.
Immune system regulators may be selected from a group including, but not limited to, lenalidomide, pomalidomide and thalidomide.
Histone deacetylase inhibitors may be selected from a group comprising, but not limited to, belinostat, panobinostat, valproate and vorinostate.
Other substances can be selected from a group comprising, but not limited to, anagrelide, seritinib, dabrafenib, idelalisib, ibrutinib, palbosiklib, vemurafenib, bleomycin, bortezomib, dactinomycin, eribulin, estramustine, iksabepilone, mitomycin, procarbazine, alektinib, flucimesterone, iobenguane, imiguimod, interferon, iksazomib, lanreotide, lentinan, octreotide, omacetaxine, tegafur, gimerazil, oterasil, uracil, kombrestatin and chlorokine.
The composition comprising the molecules of the invention can be in any suitable form based on the preferred method of administering the composition to a patient. The composition comprising the molecules of the present invention can be formulated for example for oral administration in the form of liquid dispersions or aqueous or oily suspensions, or in parenteral form, for example, in forms suitable for subcutaneous, intravenous, intramuscular, intraperitoneal, intradermal, transdermal or other infusion techniques. The composition comprising the molecules of the invention may also be formulated in the form of a spray tube for administration through inhalation or as a solution for administration by inhalation device or nebulizer. The molecules of the present invention are preferably administered to a patient by transdermal, subcutaneous, intranasal, intravenous, intramuscular, intratumorally or by inhalation. In any case, the most suitable route for administration can be determined based on the molecules of the present invention, the nature and severity of the disease and the patient's physical condition.
In the context of this specification, it is intended that the expression "comprise" also confers the expression "include"
Where technically feasible, the embodiments of the invention can be combined.
Embodiments are described here to include specific features / elements. The disclosure also encompasses essentially other applications comprising or consisting of said features / elements.
Technical references such as patents and patent applications are incorporated herein by reference.
The specific and clearly described embodiments herein may be the basis of a disclaimer, either alone or in combination with one or more other embodiments.
The invention will now be described by way of example only with reference to the following examples, which are intended to be exemplary only and are not to be construed in any way as limiting the scope of the invention.
EXAMPLES:
Example 1 : Synthesis of Formula 1.12 G3 - (Y3-methyl-l.2.4-oxadiazol-5-vf) methyl) -2- (pent-2-en-l-vf) cvclopentanonel
Figure imgf000037_0001
(i) After the solution of 1 mL of 0.5 M Jasmonic acid in DMF was added to the reaction flask, 0.55 mL of DCC in 1.0 M DMF was added. After stirring at room temperature for 30 min, 1.0 mL of 0.55 M acetamide oxime was added. The reaction mixture was stirred for 4 hours at room temperature (ii) 0.55 mL of 1 M DCC was added and heated at 115 °C. under reflux for 6 hours. The reaction was followed by the TLC and LC-MS controls and then extraction with 1N HC1, saturated NaHCCh. and DCM .The organic phase was dried with MgS04 and filtered. Purified by column chromatography using a 3: 2 solution of Ethyl Alcohol: Hexane solution .
1 H NMR (500 MHz, CDCE ) d 5.49 - 5.42 (m, 1H), 5.28 5.21 (m, 1H), 3.22 (dd, / = 15.2, 4.5 Hz, 1H), 2.87 (dd, J = 15.3) , 9.1 Hz, 1H), 2.43 - 2.38 (m, 3H), 2.38 (s, 3H), 2.37 - 2.33 (m, 1H), 2.21 - 2.15 (m, 1H), 2.15 - 2.08 (m, 1 H), 2.08-2.00 (m, 2H); 2.00 to 1.94 (m, 1H); 1.59 - 1.50 (m, 1H); 0.94 (t, J = 7.5 Hz, 3H).
13 C NMR (125 MHz, CDCE ) d 218.09 (C = O), 177.69 (C qAr ), 167.17 (C qAr ), 134.43 (CH), 124.62 (CH), 53.88 (CH), 39.30 (CH), 37.61 (CH 2 ), 30.94 (CH 2 ), 26.94 (CH 2 ), 25.52 (CH 2 ), 20.60 (CH 2 ), 14.09 (CH 3 ), 11.54 (CH 3 ).
LCMS /n/z : 249.15 (M) + .
Example 2: Synthesis of Formula 1.2 r2-(pent-2-en-l-yl)-3-((3-phenyl-L2.4-oxadiazol-5- vDmethvDcyclopentanonel
Figure imgf000038_0001
(i) Jasmonic acid (JA) (1 mmol), DCC (1 mmol) and acetone (4 mL) were stirred in the reaction flask for 30 min, followed by benzamide oxime (1 mmol) addition. The reaction mixture was stirred at room temperature for 12 hours then the solvent was evaporated (ii) KOH (1 mmol) was added to the solution of the resulting intermediate in DMSO (1 mmol) and stirred for 20-30 min at room temperature. After formation of the product was observed in LC-MS, extraction was carried out. It was purified by column chromatography using 2: 3 Ethyl Alcohol: Hexane solution mixture.
*H NMR (500 MHz, CDCls ) d 8.02 - 7.99 (m, 2H), 7.45 - 7.39 (m, 3H), 5.45-5.38 (m, 1H), 5.25 - 5.18 (m, 1H), 3.26 (dd , / = 15.2, 4.7 Hz, 1H), 2.92 (dd, / = 15.2, 9.0 Hz, 1H), 2.47 - 2.39 (m, 1H), 2.38 - 2.34 (m, / = 3.4 Hz, 2H), 2.34 - 2.30 (m, 1H), 2.22 - 2.15 (m, 1H), 2.07 (ddd, J = 18.9, 11.3, 8.9 Hz, 1H), 2.03-1.16 (m, 3H), 1.58-1.52 (m, 1H), 0.89 (t, 7 = 7.5 Hz, 3H).
13C NMR (126 MHz, CDCE ) d 218.15 (C = O), 177.98 (CqAr ), 168.40 (CqAr ), 134.49 (CH), 131.24 (CHAr ), 128.88 (CH^ X 2), 127.43 ( CH^ X 2), 126.74 (CqAr ), 124.66 (CH), 53.94 (CH), 39.40 (CH), 37.65 (CH2 ), 31.13 (CH2 ), 27.01 (CH2 ), 25.62 (CH2 ), 20.65 (CH2 ), 14.11 (CH3 ).
LCMS /n /z : 311.05 (M) +.
Example 3: Synthesis of Formula 1.3 G N -(2-morpho1inoethyl)-2-(3-oxo-2-(pent-2-en-l- vDcyclopentyl) acetamidel
Figure imgf000039_0001
Jasmonic acid (JA) (1 eq), Triethyl Amine (TEA) (2 eq), HBTU (1 eq) and ethyl acetate were added to the reaction flask and after stirring for 1 hour at room temperature, 4- (2- aminoethyl) morpholine (2 eq) was added and stirring was continued. After 12 hours, the reaction mixture was extracted and purified by column chromatography with 5 : 1
EtOAc/MeOH solvent mixture.
'H NMR (500 MHz, CDCI3 ) d 5.98 (b, 1H), 5.42 - 5.35 (m, 1H), 5.26 - 5.19 (m, 1H),
3.64 (t, 4H), 3.34 - 3.28 (m, 2H) , 2.52 (dd, J = 14.2, 4.6 Hz, 1H), 2.42 (t, J = 6.0 Hz, 2H), 2.41 - 2.38 (m, 4H), 2.32-2.25 (m, 4H), 2.20 - 2.13 ( m, 1H), 2.11 - 2.05 (m, 1H), 2.04-1.16 (m, 3H), 1.86 - 1.81 (m, 1H), 1.50-1.14 (m, 1H), 0.90 (t, / = 7.5 Hz, 3H).
13C NMR (125 MHz, CDCI3 ) d 171.14 (C = O), 133.92 (CH), 125.25 (CH), 66.85 (CH2 x2 ), 57.11 (CH2 ), 54.14 (CH), 53.35 (CH2) x2), 41.25 (CH2 ), 38.64 (CH), 37.73 (CH2 ), 35.51 (CH2 ), 27.19 (CH2 ), 25.64 (CH2 ), 20.62 (CH2 ), 14.16 (CH3 ).
LCMS m /z: 323.10 (M)+
Example 4: Synthesis of Formula 1.4 G2- (3-oxo-2- (pent-2-en-l-yl) cvclopentyl) -N-
(2.4.5-trihvdroxy-6- (hydroxymethyl) tetrahvdro-2 H -pyran-3-yl ) acetamidel
Figure imgf000039_0002
Jasmonic acid (JA) (1 eq), TEA (2 eq), HBTU (1 eq) and ethyl acetate were added to the reaction flask and after stirring for 1 hour at room temperature D-(+)-Glucosamine hydrochloride (2 eq) solution in water was added and stirring was continued. After 12 hours, the reaction mixture was extracted and purified by column chromatography with 10: 2 DCM: MeOH solvent mixture.
*H NMR (500 MHz, CD3OD) d 5.47 - 5.40 (m, 1H), 5.36 - 5.27 (m, 1H), 3.90 - 3.79 (m, 2H), 3.76-3.35 (m, 2H), 3.00 ( s, 1H), 2.87 (s, 1H), 2.68 - 2.58 (m, 1H), 2.43 - 2.19 (m, 6H), 2.13 - 2.03 (m, 3H), 2.02-1.19 (m, 1H), 1.65 - 1.52 (m, 1H), 1.36 - 1.28 (m, 1H), 0.97 (t, 7 = 7.5 Hz, 3H).
13C NMR (125 MHz, CD3OD) d 220.76 (C = O), 173.33 (C = O), 133.25 (CH), 124.96 (CH), 95.80 (CH), 91.17 (CH), 76.61 (CH), 74.63 (CH), 71.65 (CH), 61.39 (CH2), 54.04 (CH), 40.26 (CH2), 38.20 (CH), 37.23 (CH2), 26.38 (CH2), 24.81 (CH2) , 20: 13 (CH2), 12.13 (CH3).
LCMS m / z : 372.10 (M)
Example 5: Synthesis of Formula 1.21 G3- (isocyanatemethyl) -2- (pent-2-en-l-yl) cvclopentanonel
Figure imgf000040_0001
Jasmonic acid (0.210 g, 1 mmol) was placed in a 2-necked flask and dissolved in 10 mL of toluene. After addition of 4-(Dimethylamino) pyridine (0.134 g, 1.1 mmol) and triethylamine (0.101 g, 1.1 mmol), the system was stirred under nitrogen at 110 °C. Subsequently, diphenylphosphoryl azide (0.238 mL, 1.1 mmol) was added dropwise to the mixture at 110 °C and left at reflux for 16 hours. The reaction was terminated according to LC-MS control. After toluene was evaporated, extraction with ethyl acetate was carried out with brine. After drying the organic phase over Na2S04, the solvent was evaporated on a rotary evaporator.The compound was used without any further purification.
LCMS /n /z : 208 (M)+.
Example 6: Synthesis of Formula 1.22 I Methyl ((3-oxo-2- (pent-2-en-l-yl) cvclopentyl) methyl) carbamatel
Figure imgf000041_0001
3-(isocyanatemethyl)-2-(pent-2-en-l-yl) cyclopentanone (0.207 g, 1 mmol) was placed in a single necked flask and dissolved in 5 mL methanol. In this case, methanol was treated with NaH and methoxide ion was added dropwise. It was allowed to stir at room temperature. After 6 hours, the reaction was stopped after LC-MS control was done. Extraction was done with dicholorome thane and organic phase was washed with water. After drying the organic phase over Na2S04, the solvent was evaporated in a rotary evaporator. Purified by column chromatography using a 10/1.5 ethyl acetate / n-hexane solvent mixture.The pure product was obtained with 45% yield.
LCMS m /z: 240 (M) +, 257 (M + H 2 O)
Example 7: Synthesis of Formula 1.12 r2-(3-oxo-2-(pent-2-en-l-yl)cvclopentyl) acetohvdrazidel
Figure imgf000042_0001
2 mL of hydrazine monohydrate was placed into a 2-necked flask. After dropwise addition of jasmonic acid (0.210 g, 1 mmol), the system was stirred under nitrogen at 80 ° C. At the end of 3 hours, the LC-MS was control was made and the reaction was terminated. The solvent was removed by evaporation in a solvent rotary evaporator, with azeotropic mixture with toluene and water to remove excess hydrazine. This process was repeated 3 times.
LCMS /n /z : 225 (M)
Example 8: Synthesis of formula 1.23 2- (pent-2-en-l-yl)-3 -((5-phenyl-l.3.4-oxadiazol-
2-yl) methyl) cyclopentanone
Figure imgf000042_0002
(i) Formula 1.13 (0.224 g, 1 mmol) was placed into a single necked flask. Sodium acetate (0.082 g, 1 mmol) was dissolved in 3 mL of water and mixed with a solution of benzaldehyde (0.101 mL, 1 mmol) in 3 mL of methanol. The mixture was stirred at room temperature for 2 hours. The product formation was checked by LC-MS. LCMS m / z: 313 (M) + (ii) After the solvent was evaporated in vacuo, the resulting schiff base was dissolved in 5 ml. of dry l,4-dioxane. After addition of potassium carbonate (0.415 g, 3 mmol) and iodine (0.158 g, 1.25 mmol), the reaction was stirred at 80 °C. The reaction was monitored with FC-MS. At the end of the reaction, extraction with 5% Na S Ch and ethyl acetate was performed. After drying the organic phase over Na2S04, the solvent was evaporated on a rotary evaporator. Purification by column chromatography using a 3/1 ethyl acetate/n-hexane solvent mixture was carried out.
LCMS m / z: 311 (M)
Example 9: Evaluation of Biological Activity of Formula 1.11
In order to show that the molecules according to the invention are more active than the known hexokinase-2 inhibitors such as methyl jasmonate (MJ) and 2-deoxyglucose (2- DG), the inventors determined the IC50 value of the molecule shown in Formula 1.11 with the reference molecules and MTT tests were performed.
IC50 values are presented in the following table;
Figure imgf000043_0001
Table 1: MTT test results in HI 299 and HEK cell lines
In addition, the inventors determined the IC50 value in the Mia-Paca cell lines of the molecule shown by Formula 1.11 and performed the MTT tests.
Figure imgf000043_0002
Figure imgf000044_0001
Table 2: MTT test results in Mi-Paca cell line
Accordingly, the molecule according to the invention shown in Formula 1.11 exhibits effectiveness in each of the three cell lines when used in lower amounts than the molecules known in the state of the art. This indicates that the molecules according to the invention have higher activity.
Example 10: Evaluation of Biological Activity of Formula 1.3
The inventors have carried out MTT tests of Formula 1.3, which is a molecule according to present invention on H1299 cell lines. The graphs showing the l2-hour and 24-hour results of the MTT analysis are given in Figure 1 and Figure 2, respectively.
According to the results of MTT analysis, it is concluded that the molecule shown in Formula 1.3 is more active than the 2-DG and Methyl Jasmonate used as reference.
Example 11: Determination of Hexokinase Enzyme Activity of Formula 1.5. Formula 1.6. Formula 1.7. Formula 1.8 and Formula IX
Universal Enzyme Assay Kit (R&D, EA004) was used to determine the hexokinase enzyme inhibition of the synthesized molecules. This Kit, in its structure, converts ADP into AMP by coupling phosphatase and quantitatively separates inorganic phosphate. The released inorganic phosphate forms a complex with malachite green. The resulting complex ratio is proportional to the formation of AMP from ADP by phosphatase. Thus, the rate of inorganic phosphate production rate reflects the kinetics of the kinase reaction.
Accordingly, substrate mixture was prepared using 0.5 mM ATP and 25 mM glucose. Human hexokinase-2 enzyme ( rhH -2) was prepared wp have a concentration of 7.5 ng/pL and coupling Phosphatase 4 enzyme was prepared to have a concentration of 10 pg/niL .20 pL buffer. 20 pL rhHK-2, 2 pL sample and 10 pL Coupling phosphatase 4 was added respectively and then left for incubation for 10 minutes. Then 30 pL of Malachite green reagent A, 100 pL of ultra pure water, 30 pL malachite green reagent B was added respectively and left for incubation for 20 minutes. After incubation absorbance at 620 nrn is determined and the results are calculated according to the following equation.
Adjusted phosphate release * (nmol) x (1000 pmol/nmol)
Specific Activity ipmol/min/ug) , . . . . .
incubation tune tmm) x enzyme amount (pg) x coupling ratio**
* As obtained from linear curve of phosphate standard and adjusted according to control
** The coupling ratio is 0.475 under specified conditions
The results obtained accordingly are given in the table below:
Figure imgf000045_0001
Table 3: Hexokinase Enzyme Activities of the molecules according to the invention
The examples provided herein show that the molecules according to the invention exceed the known state of the art and are intended to have a higher effect than the hexokinase-2 inhibitors known in the state of the art.

Claims

1. One or more molecules represented with Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX; wherein said molecule is;
A) Formula I,
Figure imgf000046_0001
Formula I
wherein;
Rl is selected from a group comprising
Figure imgf000046_0002
Figure imgf000046_0003
R2 is selected from a group comprising — H O 1
Figure imgf000047_0001
Figure imgf000047_0002
R3 is selected from a group comprising =0, -H, -OH, -F,
Figure imgf000047_0004
Figure imgf000047_0003
Formula II
wherein; Rl is selected from a group comprising
Figure imgf000048_0005
R2 is selected from a group comprising
Figure imgf000048_0001
Figure imgf000048_0002
Formula III
wherein;
O elected from a group comprising A *— OH
Rl is s
Figure imgf000048_0003
Figure imgf000048_0004
R2 is selected from a group comprising
Figure imgf000049_0001
Figure imgf000049_0002
selected from
Figure imgf000049_0003
and
Figure imgf000049_0004
or
E) Formula V
Figure imgf000050_0001
Formula V
F) Formula VI, or
Figure imgf000050_0002
Formula VI
G) Formula VII, or
Figure imgf000050_0003
H) Formula VIII
I) Formula IX
Formula IX or salts, hydrates, solvates, polymorphs, optical isomers, geometric isomers, enantiomers, diastereomers and mixtures thereof.
2. A molecule according to claim 1 shown with Formula 1.1.
Figure imgf000051_0001
3. A molecule according to claim 1, shown with formula 1.2.
Figure imgf000051_0002
4. A molecule according to claim 1, shown with formula 1.3.
Figure imgf000052_0001
5. A molecule according to claim 1, shown with formula 1.4.
Figure imgf000052_0002
6. A molecule according to claim 1, shown with formula 1.5.
Figure imgf000052_0003
7. A molecule according to claim 1, shown with formula 1.6.
Figure imgf000053_0001
. A molecule according to claim 1, shown with formula 1.7.
Figure imgf000053_0002
A molecule according to claim 1, shown with formula 1.8
Figure imgf000053_0003
10. A molecule according to claim 1, shown with formula 1.9.
Figure imgf000053_0004
11. A molecule according to claim 1, shown with formula 1.10.
Figure imgf000054_0001
12. A molecule according to claim 1 shown with Formula 1.11.
Figure imgf000054_0002
13. A molecule according to claim 1, shown with formula 1.12.
Figure imgf000054_0003
14. A molecule according to claim 1, shown with formula 1.13.
Figure imgf000054_0004
15. A molecule according to claim 1, shown with formula 1.14.
Figure imgf000055_0001
16. A molecule according to claim 1, shown with formula 1.15.
Figure imgf000055_0002
17. A molecule according to claim 1, shown with formula 1.16.
Figure imgf000055_0003
18. A molecule according to claim 1, shown with formula 1.17.
Figure imgf000055_0004
19. A molecule according to claim 1, shown with formula 1.18.
Figure imgf000056_0001
20. A molecule according to claim 1, shown with formula 1.19.
Figure imgf000056_0002
21. A molecule according to claim 1, shown with formula 1.20.
Figure imgf000056_0003
22. A molecule according to claim 1 shown with Formula 1.21.
Figure imgf000056_0004
23. A molecule according to claim 1, shown with formula 1.22.
Figure imgf000057_0001
24. A molecule according to claim 1, shown with formula 1.23.
Figure imgf000057_0002
25. A molecule according to claim 1, shown with formula 1.24.
Figure imgf000057_0003
26. A molecule according to claim 1, shown with formula 1.25.
Figure imgf000057_0004
27. A molecule according to claim 1 shown with Formula II.1.
Figure imgf000058_0001
28. A molecule according to claim 1, shown with formula II.2.
Figure imgf000058_0002
29. A molecule according to claim 1, shown with formula II.3.
Figure imgf000058_0003
30. A molecule according to claim 1, shown with formula II.4.
Figure imgf000059_0001
31. A molecule according to claim 1, shown with formula II.5.
Figure imgf000059_0002
32. A molecule according to claim 1, shown with formula II.6.
Figure imgf000059_0003
33. A molecule according to claim 1 shown with Formula III.1.
Figure imgf000060_0001
34. A molecule according to claim 1, shown with formula III.2.
Figure imgf000060_0002
35. A molecule according to claim 1, shown with formula III.3.
Figure imgf000060_0003
36. A molecule according to claim 1, shown with formula III.4.
Figure imgf000061_0001
37. A molecule according to claim 1, shown with formula III.5.
Figure imgf000061_0002
38. A molecule according to claim 1 shown with Formula IV.1.
Figure imgf000061_0003
39. A molecule according to claim
Figure imgf000061_0004
Figure imgf000062_0001
40. Use of one or more molecules shown with Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII or Formula IX wherein;
A) Formula I,
Figure imgf000062_0002
Formula I
Rlis selected from a group comprising
Figure imgf000062_0003
Figure imgf000062_0004
Figure imgf000063_0001
R2 is selected from a group comprising
Figure imgf000063_0002
Figure imgf000063_0003
R3 is selected from a group comprising =0, -H, -OH, -F;
R4 is selected from a group comprising
Figure imgf000063_0004
, F or R4 is null when R3 is— O ,
R5 is selected from
Figure imgf000063_0005
Or B) Formula II
Figure imgf000064_0001
Formula II
wherein;
Rl is selected from a group comprising
Figure imgf000064_0002
R2 is selected from a group comprising
Figure imgf000064_0003
Figure imgf000064_0004
Formula III
wherein; Rl is selected from a group comprising
Figure imgf000065_0001
m a group comprising
Figure imgf000065_0002
Figure imgf000065_0003
or
D) Formula IV
Figure imgf000065_0004
Formula IV Herein Rl is selected from a group comprising
Figure imgf000066_0001
Figure imgf000066_0002
G) Formula VII, or
Figure imgf000066_0003
H) Formula VIII, or
Figure imgf000067_0001
or their salts, hydrates, solvates, polymorphs, optical isomers, geometric isomers, enantiomers, diastereomers and mixtures thereof as inhibitors of Hexokinase-2 (HK-2).
41. The use according to claim 40, for use in the manufacture of a medicament for use in the treatment or prevention of cancer.
42. Pharmaceutical compositions comprising Formula I, Formula II, Formula III, Formula IV, Formula VI, Formula VI, Formula VII, Formula VIII, Formula IX, or pharmaceutically acceptable salts thereof, according to claims 1-39.
43. A pharmaceutical composition according to claim 42 comprising at least one or more excipients.
44. A pharmaceutical composition according to claims 42 and 43 comprising at least one other active ingredient.
45. A pharmaceutical composition according to claim 44, wherein further active ingredient is selected from a group comprising anticancer agents, nucleoside analogues, antifolates, other metabolites, topoisomerase I inhibitors, anthracyclines, podophyllotoxins, taxanes, vinca alkaloids, alkylating agents, platinum compounds, antihormones, radiopharmaceuticals, monoclonal antibodies, tyrosine kinase inhibitors, mammalian target (mTOR) inhibitors, retinoids, immunoregulatory agents, histoneacetylase inhibitors and other agents of rapamycin.
PCT/TR2018/050522 2018-03-21 2018-09-25 Methyl jasmonate derivatives as possible drug candidates for use in treatment of cancer WO2019182527A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2018/04028 2018-03-21
TR201804028 2018-03-21

Publications (1)

Publication Number Publication Date
WO2019182527A1 true WO2019182527A1 (en) 2019-09-26

Family

ID=67987967

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2018/050522 WO2019182527A1 (en) 2018-03-21 2018-09-25 Methyl jasmonate derivatives as possible drug candidates for use in treatment of cancer

Country Status (1)

Country Link
WO (1) WO2019182527A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022537305A (en) * 2019-06-20 2022-08-25 プレシジョン ナノシステムズ インコーポレーテッド Ionizable lipids for nucleic acid delivery

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106117064A (en) * 2016-05-18 2016-11-16 中国农业大学 A kind of (instead) β farnesene analog containing jasmonic group and preparation and application thereof
US20160339026A1 (en) * 2015-10-02 2016-11-24 Senomyx, Inc. Topical compositions comprising modulators of trpm8
US20170334896A1 (en) * 2014-10-31 2017-11-23 Xiamen University Substituted Heterocyclic Derivative, Preparation Method And Use Thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170334896A1 (en) * 2014-10-31 2017-11-23 Xiamen University Substituted Heterocyclic Derivative, Preparation Method And Use Thereof
US20160339026A1 (en) * 2015-10-02 2016-11-24 Senomyx, Inc. Topical compositions comprising modulators of trpm8
CN106117064A (en) * 2016-05-18 2016-11-16 中国农业大学 A kind of (instead) β farnesene analog containing jasmonic group and preparation and application thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
GOLDIN, N. ET AL.: "Methyl jasmonate binds to and detaches mitochondria-bound hexokinase", ONCOGENE, vol. 27, no. 34, 2008, pages 4636, XP002493992 *
JIKUMARU, YUSUKE ET AL.: "Preparation and biological activity of molecular probes to identify and analyze jasmonic acid-binding proteins", BIOSCIENCE, BIOTECHNOLOGY, AND BIOCHEMISTRY, vol. 68, no. 7, 2004, pages 1461 - 1466, XP055639957 *
LI, JINGJING ET AL.: "Methyl jasmonate leads to necrosis and apoptosis in hepatocellular carcinoma cells via inhibition of glycolysis and represses tumor growth in mice", ONCOTARGET, vol. 8, no. 28, 2017, pages 45965 - 45980, XP055639966 *
SCHMIDT, ELENA YU ET AL.: "Toward Acetylene Renaissance: Functionally Rich N-Aminoindoles from Acetylene Gas, Ketones, and Hydrazines in Two Steps", ORGANIC LETTERS, vol. 21, 2019, pages 4275 - 4279, XP055639986 *
YANG, LISHENG ET AL.: "Cp* Rh (III)-Catalyzed C H bond Difluorovinylation of indoles with a, a-difluorovinyl tosylate", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 84, 2019, pages 7320 - 7330, XP055639984 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022537305A (en) * 2019-06-20 2022-08-25 プレシジョン ナノシステムズ インコーポレーテッド Ionizable lipids for nucleic acid delivery
JP7416096B2 (en) 2019-06-20 2024-01-17 プレシジョン ナノシステムズ ユーエルシー Ionizable lipids for nucleic acid delivery

Similar Documents

Publication Publication Date Title
JP5265518B2 (en) Dimers of artemisinin derivatives, their preparation and their therapeutic use
CA3139242A1 (en) Compounds for treatment of pd-l1 diseases
BR112013015241A2 (en) pyrazolyl and pyrimidinyl tricyclic enones as antioxidant inflammation modulators
EP4223751A1 (en) Benzamide compound and use thereof
WO2011153197A1 (en) Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases
CN106243183B (en) Ursolic acid-hydrogen sulfide donor reagent derivatives and its synthetic method
US6268375B1 (en) 10, 11-difluoromethylenedioxycamptothecin compounds with topoisomerase I inhibition
TW201241005A (en) Methods for synthesizing molybdopterin precursor Z derivatives
JP2022510425A (en) Decarboxylase inhibitor for the treatment of Parkinson's disease
WO2019182527A1 (en) Methyl jasmonate derivatives as possible drug candidates for use in treatment of cancer
ES2875128T3 (en) Substituted pyrazoloazepin-8-ones and their use as phosphodiesterase inhibitors
ES2874632T3 (en) Substituted pyrazoloazepin-8-ones and their use as phosphodiesterase inhibitors
EP3904357A1 (en) Spiro compound and medical uses thereof
RU2753036C1 (en) Tryptolide derivative, method for its preparation and application
KR20080066039A (en) Agent for preventing or treating pancreas cancer, ovary cancer or liver cancer containing novel water-soluble prodrug
CA2431107A1 (en) Antitumoral carbazoles
WO2001027115A1 (en) Pentacyclic taxane compounds
EP1457492B1 (en) Crystals of taxane derivative and process for their production
EP4032877A1 (en) Tetrahydroisoquinoline derivatives
JP2023535692A (en) Entero-degradable co-drugs, preparation and use thereof
US20070135436A1 (en) Chemical compounds
CN114269747B (en) 1',2' -dihydro-3'H-spiro [ cyclobutane 1,4' -isoquinoline ] -3' -one derivative and application thereof
UA80409C2 (en) Hexacyclic compounds
CN116217582A (en) Geranium tschebularium derivative and application thereof
CN115784972A (en) Ethylene diamine derivative and preparation method and application thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18910582

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18910582

Country of ref document: EP

Kind code of ref document: A1