EP0750496A1 - Utilisation d'inhibiteurs de la lipoxygenase en tant qu'agents therapeutiques et d'intervention anticancereux - Google Patents

Utilisation d'inhibiteurs de la lipoxygenase en tant qu'agents therapeutiques et d'intervention anticancereux

Info

Publication number
EP0750496A1
EP0750496A1 EP95916100A EP95916100A EP0750496A1 EP 0750496 A1 EP0750496 A1 EP 0750496A1 EP 95916100 A EP95916100 A EP 95916100A EP 95916100 A EP95916100 A EP 95916100A EP 0750496 A1 EP0750496 A1 EP 0750496A1
Authority
EP
European Patent Office
Prior art keywords
derivative
epithelial cell
cancer
subject
lipoxygenase
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95916100A
Other languages
German (de)
English (en)
Inventor
James L. Mulshine
Marti Jett
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
US Department of Health and Human Services
Original Assignee
US Department of Health and Human Services
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 US Department of Health and Human Services filed Critical US Department of Health and Human Services
Publication of EP0750496A1 publication Critical patent/EP0750496A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention is in the field of the prevention and treatment of cancer. More specifically, this invention relates to the use of 5-lipoxygenase inhibitors or derivatives thereof in preventing and treating cancer.
  • Arachidonic acid is a 20-carbon polyunsaturated fatty acid derived from dietary sources. Oxygenated AA metabolites participate in a variety of biologic and pathological processes including inflammation, bronchial asthma, and shock. Activation of AA metabolism is initiated by the release of AA from the phospholipid pool by the action of enzymes or other mediators. The released AA can be metabolized by either the lipoxygenase pathway where AA is converted by fatty acid lipoxygenases into hydroperoxy derivatives, giving rise to leukotrienes, or the cycloxygenase pathway where a fatty acid transforms AA rapidly to the prostaglandin PGG 2 , which in turn is further converted enzymatically.
  • FLAP 5-lipoxygenase activating protein
  • FLAP appears to be necessary for cellular leuketriene synthesis (U.S. Patent No. 5,182,367; Miller et al. (1990) Nature 343:278-281).
  • FLAP appears to be involved in the translocation of 5-lipoxygenase from the cytosol to the membrane.
  • Other enzymes involved with the sequential metabolism of the lipoxygenase product need to be in close relationship to the 5-lipoxygenase FLAP complex.
  • FLAP and molecules of related structure may be essential to the activity of enzymes in the 5-lipoxygenase pathway as well as the other downstream enzymes required for leuketriene biosynthesis.
  • Inhibitors of the AA 5-lipoxygenase pathway have shown promise in the treatment of inflammation, asthma, and shock, with minimal side effects in pre-clinical and clinical trials (Batt, Prog. Med. Che . 29:1-63 (1992); Larson, Ann. Pharmacother. 27:898-903 (1993)). However, their use for treating or preventing cancer has never been described.
  • the present invention is directed to the use of inhibitors of 5-lipoxygenase functional activity for the treatment and prevention of epithelial cell-derived cancers.
  • the present invention is also directed to the use of inhibitors of other enzymes in the lipoxygenase pathway involved in the metabolism of AA for use in the treatment and prevention of epithelial cell-derived cancers.
  • the present invention relates to the use of lipoxygenase inhibitors in therapeutic applications, in particular to the prevention and treatment of epithelial cell-derived cancers.
  • FIG. 1(a) classic SCLC cell lines NCI-H209, NCI-H345, and NCI-H510.
  • Fig. Kb) variant SCLC cell lines NCI-N417 and NCI-H82.
  • Fig. 1(c) NSCLC cell lines NCI-H23, A549, and NCI-H1155.
  • Fig. 2 (a) classic SCLC cell lines NCI-H209 and NCI-H345.
  • Fig. 2(b) variant SCLC cell lines NCI-N417 and NCI-H82.
  • Fig. 2(c) NSCLC cell lines A549 and NCI- H1155.
  • Fig. 3 (a) classic SCLC cell lines NCI-H209 and NCI-H345.
  • Fig. 3 (b) variant SCLC cell lines NCI- N417 and NCI-H82.
  • Fig. 3(c) NSCLC cell lines A549 and 5 NCI-H1155.
  • FIG. 1 Structures of MK-886 and related structures: L-669,572, L-663,511, L-665,210, L-654,639, L-668,017 and MK-591.
  • the present invention provides a method for 5 treating or preventing an epithelial cell-derived cancer in a subject in need of such treatment or prevention which comprises administering to the subject an amount of a 5- lipoxygenase inhibitor or derivative thereof, effective to treat or prevent the epithelial cell-derived cancer.
  • the 0 present invention also provides a method for treating or preventing an epithelial cell derived cancer in a subject in need of such treatment by administering an effective amount of an inhibitor of other enzymes involved in the metabolism of arachidonic acid in the 5-lipoxygenase # pathway which comprises administering to the subject an amount of the inhibitor effective to treat or prevent a epithelial cell derived cancer.
  • treatment includes partial or total inhibition of the cancer growth, as well as partial or total destruction of the cancer cells.
  • prevention includes either preventing the onset of clinically evident cancer altogether or preventing the onset of a preclinically evident stage of cancer in individuals at risk, also intended to encompassed by this definition is the prevention of initiation for malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells.
  • the epithelial cell- derived cancer includes basal cell carcinoma, adenocarcinoma, colon cancer, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body.
  • the epithelial cell-derived cancer is lung cancer or breast cancer.
  • subject for purposes of treatment includes any human or animal subject who has any one of the known epithelial cell-derived cancers, and preferably is a human subject.
  • the subject is any human or animal subject, and preferably is a human subject who is at risk for obtaining an epithelium cell-derived cancer.
  • the subject may be at risk due to exposure to carcinogenic agents, being genetically predisposed to have the cancer, and the like.
  • Inhibitors of the 5-lipoxygenase pathway in the metabolism of arachidonic acid used in the prevention and treatment of epithelial cell derived cancers may inhibit enzyme activity through a variety of mechanisms.
  • the inhibitor may block or reverse the association of the enzyme with the membrane or inhibit the ° translocation of specific enzymes such as 5-lipoxygenase via a protein such as FLAP.
  • the inhibitors used in the methods described herein may block the enzyme activity directly by acting as a substrate for the enzyme or by depriving the enzyme of necessary cofactors. 5
  • the methods provided herein relate to the use of
  • the 5-lipoxygenase inhibitor is 2-(12-Hydroxydodeca-5, 10-diynyl)-3,5,6-
  • Derivatives are intended to encompass any compounds which are structurally related to AA861, NDGA or MK886 or which possess the substantially equivalent
  • inhibitors may include, but are not limited to, derivatives which act as co-factor antagonist, better enzymatic substrates or inhibitors of activating peptide function.
  • a derivative of MK886 may have the general formula:
  • R 1 is C ⁇ -C 6 alkyl or OH or RCO- in which R 2 is H or C,-C 6 alkyl or quinoline or a long chain hydrocarbon possessing 1-32 carbon atoms and 0-6 double bonds.
  • long chain hydrocarbons include, but are not limited to, linoleic acid (18:2) or oleic acid (18:1).
  • R 3 is C,-C 6 alkyl or R 4 S- or R 5 SO- or R 6 S0 2 - and which R 4 or R 5 or R 6 may be C,-C 6 alkyl or quinoline or a long chain hydrocarbon possessing 1-32 carbon atoms and 0-6 double bonds.
  • Examples of long chain hydrocarbon include, but are not limited to, linoleic acid (18:2) or oleic acid (18:1).
  • R 3 examples include, but are not limited to, ° t-butyl thio, cyclic propyl methylthio, phenyl sulfonyl, phenyl, methyl, phenylthiol.
  • MK886 intended to be encompassed by this invention include, but are not limited to, L- 669,572, 3-[1-(p-cholorobenzyl)-5-isopropyl-3-cyclo- 5 propylmethylthioindole-2-yl]-2,2-dimethylpropanoic acid; L-663,511 3-[1-(p-cholorobenzyl)-5-isopropyl-3- phenysulfonylindol-2-yl)-2,2-dimethylpropanoic acid, L- 665,210, 3-[l-(p-chlorobenzyl) -5-isopropyl-3- phenysulfonylindol-2-yl)-2,2-dimethylpropanoic aid; L-654- 0 639, 3 [l-(p-chlorobenzyl)-5-methoxy-3-methylindol-2-yl]- 2,2-dimethylpropanoic acid;
  • the MK886 5 derivative is 3-(1-(4-chlorobenzyl)-3-(1-butyl-thio)-5- (quinolin-2-yl-methoxy)-indol-2-yl) -2,2-dimethyl propanoic acid) (MK-591) (Tagari, et al. (1993) Agents Action 40:62- 71).
  • hydroxyurea derivatives are also used as inhibitors of 5-lipoxygenase in the prevention and treatment of epithelial cell derived cancers.
  • hydroxyurea derivatives include, but are not limited to, (N-(l- benzo(b)thien-2-ylethyl)-N-hydroxyurea) (zileuton) (Tagari, et al. (1993) Agents Action 40:62-71 herein 5 incorporated by reference.
  • inhibitors of other enzymes that metabolize arachidonic acid downstream of 5-lipoxygenase may also be used to prevent or treat epithelial cell derived cancers in a 0 subject in need of such treatment in a method which comprises administering to the subject an amount effective to prevent or treat the epithelial cell derived cancer.
  • Such inhibitors may effect the activity of the enzyme 5 either directly by acting as a substrate inhibitor or by depriving the enzyme of a cofactor.
  • the inhibitor may also act by targeting proteins such as FLAP which are responsible for the translocation of the enzymes to the membrane where the enzymes are activated.
  • the compounds utilized in the methods of the present invention may be present in the form of free bases or pharmaceutically acceptable acid addition salts thereof. Examples of suitable acids for salt formation are: methanesulfonic, sulfuric, hydrochloric, phosphoric, acetic, citric, lactic, ascorbic, maleic, and the like.
  • the administration for the above methods may be affected by means known to those skilled in the art such as oral, rectal, topical (including aerosol), intranasal, intravenous, subcutaneous, intramuscular, intrabronchial, intracavitary, or intraperitoneal routes of administration. If the cancer is localized, local administration rather than system administration is preferred. Formulation in a lipid vehicle may be used to enhance bioavailability.
  • the compound may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • Such formulations may be prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine, and the like, and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering said solution sterile.
  • the formulations may be present in unit or multi-dose containers such as sealed ampoules or vials.
  • the formulation may be presented as capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the compound may be formulated with acid-stable, base- labile coatings known in the art which begin to dissolve in the high pH small intestine. Formulation to enhance local pharmacologic effects and reduce systemic uptake are preferred.
  • Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably made isotonic. Preparations for injections may also be formulated by suspending or emulsifying the compounds in non-aqueous solvent, such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol.
  • non-aqueous solvent such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol.
  • Formulations for topical use include known gels, creams, oils, and the like.
  • the compounds may be formulated with known aerosol exipients, such as saline, and administered using commercially available nebulizers.
  • Formulation in a fatty acid source may be used to enhance biocompatibility. Aerosol delivery is the preferred method of delivery for epithelial cancers of the lung for prevention application.
  • the active ingredient may be formulated into suppositories using bases which are solid at room temperature and melt or dissolve at body temperature.
  • bases include coca butter, glycerinated gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty esters of polyethylene stearate.
  • the dosage form and amount can be readily established by reference to known cancer treatment or prophylactic regiments.
  • the dosage for the inhibitors or derivatives thereof may be from about 0.1 ng/kg to about 450 g/kg, most preferred is about 0.5 ng/kg to about 100 mg/kg, and most preferably is about 1 ng/kg to about 10 mg/kg.
  • the serum concentration of the inhibitor may be from about 1 ⁇ g/ml to about 20 ⁇ g/ml.
  • the actual dose will depend upon whether the administration is for treatment or prophylactic purposes, the route of administration, the location of the cancer, as well as the phar acokinetic properties of the individual treated.
  • the dosage will generally be lower if the compounds are administered locally rather than systemically, and for prevention rather than for treatment. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician.
  • the dosage regime or therapeutically effective amount of the inhibitor to be administrated may need to be optimized for each individual.
  • the administration of the present invention may be for either prevention or treatment purposes.
  • the methods and compositions used herein may be used alone or in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of cancer.
  • the methods and compositions described herein may be used as adjunct therapy.
  • the 5-lipoxygenase inhibitor may be administered alone or in conjunction with other antineoplastic agents or other growth inhibiting agents or other drugs or nutrients.
  • the 5- lipoxygenase inhibitor or derivatives thereof and the inhibitor of other downstream enzymes involved in the metabolism of arachidonic acid may be administered in combination with each other.
  • molecular methods may be used to inhibit the 5-lipoxygenase.
  • antisense constructs generated by methods known to those skilled in the art can be used to target the messenger RNA of the 5-lipoxygenase enzyme.
  • All books, articles or patents reference herein are incorporated by reference.
  • the present invention is described in the following Experimental Details section, which sets forth specific examples to aid in an understanding of the invention, and should not be construed to limit in any way the invention as defined in the claims which follow thereafter.
  • Example 1 Materials and Methods Cell lines: The following cell lines were used: classic small cell lung cancer (SCLC) cell lines NCI-H209, NCI-H345, and NCI-H510; variant SCLC cell lines NCI-N417 and NCI-H82; large cell carcinoma cell line NCI-H1155; adeno carcinoma cell line NCI-H23; and bronchioalveolear carcinoma cell line A549, breast cancer cell line MCF-7 (American Type Tissue Culture Rockville MD; ATCC) and a colon cancer cell line NCI-H630 (ATCC) .
  • SCLC classic small cell lung cancer
  • NCI-N417 and NCI-H82 variant SCLC cell lines NCI-N417 and NCI-H82
  • large cell carcinoma cell line NCI-H1155 adeno carcinoma cell line NCI-H23
  • bronchioalveolear carcinoma cell line A549 breast cancer cell line MCF-7 (American Type Tissue Culture Rockville MD; ATCC) and a colon cancer cell line
  • All cells were grown in RPMI-1640, supplemented with 5% fetal bovine serum (FBS) , penicillin and streptomycin (Gibco, Grand Island, NY) , and were maintained in a 5% C0 2 atmosphere at 37°C. All cell lines were free of mycoplasma contamination.
  • FBS fetal bovine serum
  • penicillin and streptomycin Gibco, Grand Island, NY
  • Biochemical compounds General lipoxygenase inhibitor Nordihydroguaiaretic acid (NDGA) and 5- lipoxygenase inhibitor AA861, are readily commercially available and were purchased from Biomol Research Laboratories (Plymouth Meeting, PA) .
  • 5-lipoxygenase inhibitor MK886 and MK-591 were obtained from Merck Frost. MK886 may be synthesized as described in Gillard, J. , et al. Can. J. Phvsiol. Pharmacol. 67:456-464 (1989)). ° Growth studies: A modification (Promega
  • AA861 was tested in a dose range of 0.5-10 ⁇ M on three classic SCLC cell lines, two variant SCLC cell lines, and three NSCLC cell lines.
  • the effect of AA861 on the in vitro growth of the specific lung cancer cell lines 0 is presented in Figures 1(a), 1(b), and 1(c).
  • AA861 significantly inhibited growth on all of the SCLC cell lines, and two out of three of the NSCLC cell lines.
  • a bronchioalveolear carcinoma, A549 was repeatedly resistant to AA861. The reason for this resistance is 5 unclear.
  • NDGA also was tested on four SCLC cell lines and two NSCLC cell lines, and the results are presented in Figures 2(a), 2(b), and 2(c).
  • NDGA inhibited the growth of all of the lung cancer cell lines tested. MK886 also was tested on four SCLC cell lines and two NSCLC cell 0 lines, and the results are presented in Figures 3(a), 3(b), and 3(c). MK886 showed similar inhibition results as NDGA. AA861 inhibited growth of MCF-7 cells relative to controls (absence of AA861) to 70% and H630 to 50%. NDGA inhibited growth of MCF-7 cells relative to controls 5 80% and H630 cells 50% relative to controls. MK886 inhibited growth of MCF7 cells 100% relative to controls.
  • the therapeutic potential of the 5-lipoxygenase inhibitor, NDGA was assessed in a heterotransplant animal model. Using conventional methodology small cell lung cancer cells (cell line NCI-209) were transplanted into nude mice. Experimental animals received a 0.1% solution
  • 25 derivatives thereof may be also be tested in the heterotransplant model. Suggested serum concentration of the inhibitor in experimental animals may be from about 1 ⁇ g/ml to about 20 ⁇ g/ml. In addition to treatment models, in vivo models of cancer prevention may also be assessed for the therapeutic potential of the inhibitors or

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une méthode de traitement d'un cancer dérivé des cellules épithéliales chez un sujet nécessitant ce type de traitement. Ladite méthode consiste à administrer au sujet un inhibiteur de la 5-lipoxygénase ou un dérivé de ce dernier en une dose efficace pour traiter un cancer dérivé des cellules épithéliales. L'invention se rapporte également à une méthode de prévention d'un cancer dérivé des cellules épithéliales chez un sujet nécessitant ce type de prévention, laquelle consiste à administrer à ce dernier un inhibiteur de la 5-lipoxygénase en une dose efficace pour prévenir le cancer dérivé des cellules épithéliales. Les inhibiteurs de la 5-lipoxygénase appropriés utiles dans les méthodes selon l'invention sont constitués, de préférence, de 2-(12(hydroxydodéca-5,10-dinyl)-3,5,6-triméthyl-1,4-benzoquinone et de dérivés de celui-ci; d'acide nordihydroguaïarétique et de dérivés de celui-ci; et d'acide 3-[1-(4-chlorobenzyl)-3-t-butyl-thio-t-isopropyl-indol-2-yl]-2-2-diméthylpropanoïque et de dérivés de celui-ci. L'invention porte également sur des dérivés d'hydroxy-urée faisant office d'inhibiteurs de la 5-lipoxygénase destinés à être utilisés dans la prévention et le traitement de cancers dérivés des cellules épithéliales.
EP95916100A 1994-03-14 1995-03-14 Utilisation d'inhibiteurs de la lipoxygenase en tant qu'agents therapeutiques et d'intervention anticancereux Withdrawn EP0750496A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US21207494A 1994-03-14 1994-03-14
US212074 1994-03-14
PCT/US1995/003337 WO1995024894A2 (fr) 1994-03-14 1995-03-14 Utilisation d'inhibiteurs de la lipoxygenase en tant qu'agents therapeutiques et d'intervention anticancereux

Publications (1)

Publication Number Publication Date
EP0750496A1 true EP0750496A1 (fr) 1997-01-02

Family

ID=22789451

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95916100A Withdrawn EP0750496A1 (fr) 1994-03-14 1995-03-14 Utilisation d'inhibiteurs de la lipoxygenase en tant qu'agents therapeutiques et d'intervention anticancereux

Country Status (4)

Country Link
EP (1) EP0750496A1 (fr)
AU (1) AU698313B2 (fr)
CA (1) CA2185448A1 (fr)
WO (1) WO1995024894A2 (fr)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19624659A1 (de) 1996-06-20 1998-01-08 Klinge Co Chem Pharm Fab Neue Pyridylalken- und Pyridylalkinsäureamide
DE19624704A1 (de) 1996-06-20 1998-01-08 Klinge Co Chem Pharm Fab Neue Pyridylalkansäureamide
US6451816B1 (en) 1997-06-20 2002-09-17 Klinge Pharma Gmbh Use of pyridyl alkane, pyridyl alkene and/or pyridyl alkine acid amides in the treatment of tumors or for immunosuppression
DE19756261A1 (de) * 1997-12-17 1999-07-01 Klinge Co Chem Pharm Fab Neue arylsubstituierte Pyridylalkan-, alken- und alkincarbonsäureamide
US6903118B1 (en) 1997-12-17 2005-06-07 Klinge Pharma Gmbh Piperazinyl-substituted pyridylalkane, alkene and alkine carboxamides
DE19756212A1 (de) 1997-12-17 1999-07-01 Klinge Co Chem Pharm Fab Neue, mit einem cyclischen Imid substituierte Pyridylalkan-, alken- und -alkincarbonsäureamide
DE19756236A1 (de) * 1997-12-17 1999-07-01 Klinge Co Chem Pharm Fab Neue piperazinylsubstituierte Pyridylalkan-, alken- und -alkincarbonsäureamide
DE19756235A1 (de) 1997-12-17 1999-07-01 Klinge Co Chem Pharm Fab Neue piperidinylsubstituierte Pyridylalkan- alken- und -alkincarbonsäureamide
EP1031564A1 (fr) 1999-02-26 2000-08-30 Klinge Pharma GmbH Inhibiteurs de la formation du nicotinamide mononucléotide et leur utilisation dans le traitement du cancer
US6756399B2 (en) 2001-06-29 2004-06-29 The United States Of America As Represented By The Department Of Health And Human Services Use of lipoxygenase inhibitors and PPAR ligands as anti-cancer therapeutic and intervention agents
GB0410103D0 (en) * 2004-05-06 2004-06-09 Biolipox Ab New method
WO2010124283A2 (fr) 2009-04-24 2010-10-28 The Jackson Laboratory Procédés et compositions liées à des tumeurs malignes hématologiques
CA2883882A1 (fr) 2012-09-07 2014-03-13 Edison Pharmaceuticals, Inc. Derives de benzoquinone de traitement de troubles lies au stress oxydatif

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5008294A (en) * 1985-02-11 1991-04-16 Chemex Pharmaceuticals, Inc. Methods of treating tumors with compositions of catecholic butanes
US4554276A (en) * 1983-10-03 1985-11-19 Pfizer Inc. 2-Amino-5-hydroxy-4-methylpyrimidine derivatives
US4880637A (en) * 1985-02-11 1989-11-14 Chemex Pharmaceuticals, Inc. Compositions of catecholic butanes with zinc
GB8619433D0 (en) * 1986-08-08 1986-09-17 Lilly Industries Ltd Pharmaceutical compounds
JPH01501791A (ja) * 1986-11-19 1989-06-22 ケメックス　ファーマシューティカルズ，インコーポレイティド 薬理学的に活性な化合物およびそれらの混合物、有機組成物および金属塩類
CA1321349C (fr) * 1986-11-21 1993-08-17 Robert Zimmerman Association therapeutique d'un piegeur de radicaux libres ou d'un inhibiteur metabolique et d'une proteine bioactive
GB9012252D0 (en) * 1990-06-01 1990-07-18 Lilly Industries Ltd Pharmaceutical compounds
GB9025514D0 (en) * 1990-11-23 1991-01-09 Wellcome Found Anti-inflammatory compounds
US5409690A (en) * 1993-06-23 1995-04-25 Chemex Pharmaceuticals, Inc. Treatment of multidrug resistant diseases in cancer cell by potentiating with masoprocol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9524894A2 *

Also Published As

Publication number Publication date
AU698313B2 (en) 1998-10-29
AU2272295A (en) 1995-10-03
CA2185448A1 (fr) 1995-09-21
WO1995024894A3 (fr) 1995-12-21
WO1995024894A2 (fr) 1995-09-21

Similar Documents

Publication Publication Date Title
US6071949A (en) Use of lipoxygenase inhibitors as anti-cancer therapeutic and intervention agents
EP0738152B1 (fr) Agents de chimioprevention ou de chimiotherapie du cancer du colon a base de derives de l'acide 2-hydroxy-5-phenylazobenzoique
US8008282B2 (en) Lipoxin analogs as novel inhibitors of angiogenesis
AU698313B2 (en) Use of lipoxygenase inhibitors as anti-cancer therapeutic and intervention agents
US6541519B2 (en) Methods and compositions for treating lipoxygenase-mediated disease states
Grabacka et al. Inhibition of melanoma metastases by fenofibrate
WO1995024894A9 (fr) Utilisation d'inhibiteurs de la lipoxygenase en tant qu'agents therapeutiques et d'intervention anticancereux
US20080207947A1 (en) Use Of Docosahexaenoic Glycerides For The Treatment Of Tumorous Diseases
AU2001251379A1 (en) Method to inhibit lipoxygenase and cancer cell proliferation
US4910224A (en) Method of modifying the lipid structure and function of cell membranes and pharmaceutical compositions for use therein
JP2016502981A (ja) ムチンが関与する疾患の処置
WO2020264246A1 (fr) Composés de carbocyanine pour cibler des mitochondries et éradiquer des cellules souches cancéreuses
JP2004504271A (ja) Ｄｆｍｏのｄ−鏡像異性体およびその癌を処置するための使用方法
JPH0753359A (ja) リポキシゲナーゼ阻害剤
US7034058B2 (en) Anti-tumor pharmaceutical composition comprising N-vanillyl fatty acid amide
WO2018203127A1 (fr) Compositions pour le traitement de tumeurs malignes et d'états précancéreux, procédés d'utilisation de celles-ci et procédés de fabrication de médicaments
US5905073A (en) Use of 2-hydroxy-5-phenylazobenzoic acid derivatives as colon cancer chemopreventative and chemotherapeutic agents
JPH1067656A (ja) 細胞接着抑制剤
US8846768B2 (en) Use of compounds isolated from Euphorbia neriifolia for treating cancer and/or thrombocytopenia
JPH09169664A (ja) 分化誘導作用を有する薬剤
WO2014115764A1 (fr) Inhibiteur d'acide lactique déshydrogénase et préparation pharmaceutique contenant celui-ci
US10526333B2 (en) Rutaecarpine analogs and applications thereof
AU604226B2 (en) Method of modifying the lipid structure function and expression of cell membranes and pharmaceutical compositions for use therein
JP2014505729A (ja) コレステロールの低減および心血管事象の低減のための、コレステロール吸収阻害剤（アゼチジノン）およびω３脂肪酸（ＥＰＡ、ＤＨＡ、ＤＰＡ）
EP2949324A1 (fr) Prévention et/ou traitement d'une blessure de reperfusion / ischémie

Legal Events

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

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19961010

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

17Q First examination report despatched

Effective date: 20041014

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 35/00 20060101ALI20060313BHEP

Ipc: A61K 31/38 20060101ALI20060313BHEP

Ipc: A61K 31/475 20060101ALI20060313BHEP

Ipc: A61K 31/405 20060101ALI20060313BHEP

Ipc: A61K 31/05 20060101ALI20060313BHEP

Ipc: A61K 31/12 20060101ALI20060313BHEP

Ipc: A61K 31/00 20060101AFI20060313BHEP

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

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

18D Application deemed to be withdrawn

Effective date: 20060830