Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D215/20—Oxygen atoms
  • C07D215/24—Oxygen atoms attached in position 8
  • C07D215/26—Alcohols; Ethers thereof
  • C07D215/32—Esters
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
  • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
  • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide 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
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/385—Saturated compounds containing a keto group being part of a ring
  • C07C49/487—Saturated compounds containing a keto group being part of a ring containing hydroxy groups
  • C07C49/493—Saturated compounds containing a keto group being part of a ring containing hydroxy groups a keto group being part of a three- to five-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
• • 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
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
  • C07F7/1804—Compounds having Si-O-C linkages
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
  • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
  • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
• • 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

• Jasmonates are a family of plant stress hormones, derived from linolenic acid by the octadecanoid pathway, which are found in minute quantities in many edible plants. Stress hormones such as the jasmonate family have evolved in plants, and are released in such times of stress such as extreme UV radiation, osmotic shock, heat shock and pathogen attack, to initiate various cascades which end in appropriate responses. Examples of members of the jasmonate family are jasmonic acid, which is crucial to intracellular signaling in response to injury, and methyl jasmonate, which causes induction of a proteinase inhibitor that accumulates at low concentrations in response to wounding or pathogenic attacks.
• PCT International Patent Publication WO 2005/054172 discloses novel halogenated jasmonate derivatives, pharmaceutical compositions comprising the derivatives, and their use for reducing cancer cell growth and for treating cancer.
• the amino acids include glycine, alanine, valine, leucine and isoleucine. (Jikumaru Y. et al. Biosci. Biotechnol. Biochem. 68, 1461-1466, 2004).
• jasmonate compounds The pharmacological activity of jasmonate compounds makes them attractive candidates as therapeutic agents for the treatment of cancer. Only very few jasmonate derivatives have been reported in the art (see, for example, Ishii et al., Leukemia, 1-7 (2004); Seto et al. Biochem. Biosc. & Biotech. 63(2), (1999); Hossain et al. Biochem. Biosci. & Biotech. 68(9), 1842, (2004)). An unmet need exists to develop jasmonate derivative compounds that are potent chemotherapeutic drugs, with a high degree of specificity towards malignant cells.
• the jasmonate derivatives are represented by the structure of formula I.
• A is selected from the group consisting ; of:
• R 1 can further represent hydrogen or unsubstituted or substituted C 1 -C 12 alkyl;
• R 5 and R 6 represents an oxygen atom which is bonded to C 6 , thereby forming an oxygen-containing 6 or 5 membered heterocyclic ring, respectively; wherein the bond between C 9 and C 10 can be a single or double bond;
• R 8 , R 9a and R 9b are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -C 12 alkyl, unsubstituted or substituted C 3 -C 8 cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, glucosyl, or R 9a and R 9b can together with the nitrogen to which they are attached form an unsubstituted or substituted heterocyclic or heteroaromatic ring optionally containing one or more additional heteroatom selected from O, N and S;
• R 11 and R 12 are each independently hydrogen or a hydroxy protecting group
• R 13 is a carboxy protecting group
• R 14 is the residue of a natural or unnatural amino acid
• the group R 13 can be any carboxy protecting group, for example methyl, together defining a methyl ester group.
• the group R 14 represents the residue of any natural or unnatural amino acid.
• a currently preferred amino acid is leucine.
• any other natural and unnatural amino acid defined herein and known to a person of skill in the part can be incorporated into the jasmonate-amino acid derivatives of the present invention
• the group A in formula I is O-COR 10 , wherein R 10 is an unsubstituted or substituted C 1 -C 12 alkyl, for example methyl.
• the group A in formula I is OR 11 wherein R 11 is hydrogen or a hydroxy protecting group such as a trialkylsilyl hydroxy protecting group.
• R 5 and R 6 together with the carbons to which they are attached form an unsubstituted C 3 -C 8 cycloalkyl or a
• R 5 and R 6 together represent a C(HaI) 2 group wherein Hal is halogen, and together with C 9 and C 10 define a halo-substituted cyclopropyl group.
• each of R 3 , R 4 , R 5 , R 6 and R 7 is hydrogen.
• the bond between C 9 and C 10 is a double bond, and each of R 3 , R 4 , R 5 , R 6 and R 7 is hydrogen.
• the bond between C 9 and C 10 is a single bond, and each of R 3 , R 4 , R 5 , R 6 and R 7 is hydrogen.
• R 6 represents an oxygen atom which is bonded to C 6 , thereby forming an oxygen- containing 5 membered heterocyclic ring.
• said compound has unexpectedly been found to be a highly potent and selective cytotoxic agent, exhibiting selective cytotoxicity towards cancer cells, while having little effect on normal cells.
• compound 11 possesses surprisingly superior properties as compared with the jasmonate glucosyl derivatives disclosed in U.S. 6,469,061.
• compositions that include a pharmaceutically acceptable carrier and, as an active ingredient, one or more of the compounds of the invention, represented by any of general formula I or by any of the specific compounds of formulas 1-11, as described above.
• the present invention additionally provides a method for inhibiting cancer cell proliferation, comprising contacting the cancer cells with a therapeutically effective amount of a compound of any of general formula I, or of formulas 1-11, as described herein.
• the compound is administered in a pharmaceutical composition.
• the present invention relates to the use of a compound of any of formulas I, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 according to the present invention in the preparation of a medicament useful for the treatment of cancer.
• the cancer to be treated is selected from the group consisting of prostate cancer, breast cancer, skin cancer, colon cancer, lung cancer, pancreatic cancer, lymphoma, leukemia, myeloma, head and neck cancer, kidney cancer, ovarian cancer, bone cancer, liver cancer or thyroid cancer.
• the cancer to be treated is selected from breast cancer, kidney cancer, stomach cancer, leukemia, including lymphoblastic leukemia, lung carcinoma, melanoma and colon cancer.
• the compounds of the present invention are jasmonate derivatives represented by the general structure of formula I:
• R 1 is selected from the group consisting of
• a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs.
• a “therapeutically effective amount” of a compound of the invention is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.
• Mixed Type cancers contain several types of cells.
• the type components may be within one category or from different categories. Some examples are: adenosquamous carcinoma; mixed mesodermal tumor; carcinosarcoma; teratocarcinoma
• cancer includes the above categories of carcinoma, sarcoma, myeloma, leukemia, lymphoma and mixed type tumors.
• cancer includes: lymphoproliferative disorders, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, bone cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, cancer of the thyroid, head and neck cancer, cancer of the central nervous system, cancer of the peripheral nervous system, skin cancer, kidney cancer, as well as metastases of all the above.
• the term may refer to: hepatocellular carcinoma, hematoma, hepatoblastoma, rhabdomyosarcoma, esophageal carcinoma, thyroid carcinoma, ganglioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, Ewing's tumor, leimyosarcoma, rhabdotheliosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (well differentiated, moderately differentiated, poorly differentiated or undifferentiated), renal cell carcinoma, hypernephroma, hypemephroid adenocarcinoma, bile duct carcinoma, choriocarcino
• compositions of the present invention can be formulated for administration by a variety of routes including oral, rectal, transdermal, parenteral (subcutaneous, intraperitoneal, intravenous, intraarterial, transdermal and intramuscular), topical, intranasal, or via a suppository.
• Such compositions are prepared in a manner well known in the pharmaceutical art and comprise as an active ingredient at least one compound of the present invention as described hereinabove, and a pharmaceutically acceptable excipient or a carrier.
• pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and, more particularly, in humans.
• the carriers may be any of those conventionally used and are limited only by chemical-physical considerations, such as solubility and lack of reactivity with the compound of the invention, and by the route of administration.
• the choice of carrier will be determined by the particular method used to administer the pharmaceutical composition.
• suitable carriers include lactose, glucose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, niicrocrystalline cellulose, polyvinylpyrrolidone, cellulose, water and methylcellulose.
• Other pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
• the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
• a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
• the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
• This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
• the solid dosage forms of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
• the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
• enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
• Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine.
• Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
• transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
• transdermal patches for the delivery of pharmaceutical agents is well known in the art.
• Alternative formulations include nasal sprays, liposomal formulations, slow- release formulations, controlled-release formulations and the like, as are known in the art.
• the jasmonate derivatives of the present invention can be used in hemodialysis such as leukophoresis and other related methods, e.g., blood is drawn from the patient by a variety of methods such dialysis through a column/hollow fiber membrane, cartridge etc, is treated with the jasmonate derivatives Ex- vivo, and returned to the patient following treatment.
• Such treatment methods are well known and described in the art. See, e.g., Kolho et al. (J. Med. Virol. 1993, 40(4): 318-21); Ting et al. (Transplantation, 1978, 25(1): 31-3); the contents of which are hereby incorporated by reference in their entirety.
• Mononuclear cells were isolated from peripheral blood of healthy donors by ficoll-hypaque density gradient centrifugation. The mononuclear cells were allowed to adhere to plastic dishes to remove macrophages. The non-adherent peripheral blood lymphocytes (PBL) were pre-incubated with 0.8 ⁇ g/mL PHA and 5 ng/mL TPA for 24 hours and then used in further experiments.
• PBL peripheral blood lymphocytes
• Optical density is directly proportional to the number of living cells in culture. Cytotoxicity (%) was calculated in the following way: [(OD of control cells - OD of drug-treated cells)/OD of control cellsJxlOO.
• Jasmonate derivatives compound 9 and compound 11, were added at concentration ranging from 0.005-0.5 mM for 24 hours. Each experimental point was performed in triplicates. Untreated cells were used as control.
• the Jasmonate- derivatives were prepared as a stock of 167 mM in 100% ethanol and dilutions in medium were prepared as described above. Optical density and percentage of
• IC 50 values being the drug concentrations necessary to inhibit colony formation by 50%, were determined by plotting compound concentration versus relative colony count. Results are depicted in Table 2. Table 2. Effect of Compound 9 tested in vitro in a clonogenic assay (TCA) in different patients' derived tumors
• md moderately differentiated
• pd poorly differentiated
• ud undifferentiated

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Public Health (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• Veterinary Medicine (AREA)
• Biotechnology (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Oncology (AREA)
• Hematology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Quinoline Compounds (AREA)
• Furan Compounds (AREA)
• Saccharide Compounds (AREA)
• Medicinal Preparation (AREA)

Priority Applications (9)

Applications Claiming Priority (4)

Related Child Applications (2)

Publications (2)

Family

ID=38038558

Family Applications (1)

Country Status (9)

Cited By (10)

Families Citing this family (5)

Family Cites Families (26)

• 2006
  • 2006-12-07 EP EP11171983A patent/EP2402321A3/en not_active Withdrawn
  • 2006-12-07 BR BRPI0619492-3A patent/BRPI0619492A2/pt not_active IP Right Cessation
  • 2006-12-07 CA CA2632653A patent/CA2632653C/en active Active
  • 2006-12-07 JP JP2008544002A patent/JP5464856B2/ja active Active
  • 2006-12-07 EP EP13159825.2A patent/EP2617714B1/en active Active
  • 2006-12-07 EP EP06821626A patent/EP1960364A2/en not_active Withdrawn
  • 2006-12-07 AU AU2006322844A patent/AU2006322844A1/en not_active Abandoned
  • 2006-12-07 ES ES13159825.2T patent/ES2576980T3/es active Active
  • 2006-12-07 US US12/095,908 patent/US20090291904A1/en not_active Abandoned
  • 2006-12-07 DK DK13159825.2T patent/DK2617714T3/da active
  • 2006-12-07 WO PCT/IL2006/001408 patent/WO2007066336A2/en not_active Ceased
• 2013
  • 2013-05-24 JP JP2013109643A patent/JP2013199483A/ja active Pending

Also Published As

Similar Documents

Legal Events