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EP0684817A1 - Traitement du cancer - Google Patents

Traitement du cancer

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Publication number
EP0684817A1
EP0684817A1 EP94906813A EP94906813A EP0684817A1 EP 0684817 A1 EP0684817 A1 EP 0684817A1 EP 94906813 A EP94906813 A EP 94906813A EP 94906813 A EP94906813 A EP 94906813A EP 0684817 A1 EP0684817 A1 EP 0684817A1
Authority
EP
European Patent Office
Prior art keywords
group
compound
cells
cancer cells
tricyclic
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Withdrawn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
EP94906813A
Other languages
German (de)
English (en)
Inventor
Lorne J. Brandes
Ron Faculty Of Pharmaceutical Science Reid
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.)
University of Manitoba
Original Assignee
University of Manitoba
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 University of Manitoba filed Critical University of Manitoba
Publication of EP0684817A1 publication Critical patent/EP0684817A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms

Definitions

  • the present invention is concerned with the identification of compounds which increase the therapeutic index of chemotherapy drugs and which stimulate the growth of cancers, their use in the treatment of cancer and with certain novel compounds useful in such treatment.
  • phenothiazines are known to be antagonists of dopamine (D 2 ) receptors
  • interactions at many other intracellular sites, including calmodulin, protein kinase C and calcium channels may be important to their activity.
  • antidepressants are known to decrease the uptake of biogenic amine neurotransmitters into nerve endings (especially serotonin and norepinephrine) thereby increasing their concentration in synapses, a good correlation between potency to inhibit the uptake of any specific amine and potency as antidepressant agents has not been shown.
  • H IC histamine receptors
  • DPPE phenylmethyl-phenoxy] -ethanamine.HCl
  • H IC phenothiazines
  • x antagonists phenothiazines
  • serotonin (5HT- L , and 5HT 3 ) antagonists triphenylethylene antiestrogens and /3-adrenergic antagonists
  • H 2 antagonists and other imidazoles do not compete for DPPE binding, they do compete for H IC , but with lower affinity than for compounds which bind both AEBS and H IC .
  • H IC histamine functions as an intracellular messenger to mediate aggregation in blood platelets and is implicated in the proliferation of normal and malignant cells.
  • a second messenger role for histamine at H IC also has been postulated in estrogen action and in brain function.
  • H IC binding may be common to the action of many classe" of drugs, including phenothiazines, antidepressants, antiestrogens, histamine (H 1; H 2 , H 3 ) antagonists, serotonin (5HT- L , 5HT 3 ) antagonists, /3-adrenergic antagonists and antifungal agents.
  • DPPE also directly cytoprotects normal gut mucosa in vitro, an effect related to DPPE-induced increases in endogenous levels of the protective prostaglandin, PGI 2 and reversed by indomethicin.
  • tricyclic antidepressant drugs and the non-tricyclic agent, fluoxetine (ProzacTM) as well as H- L -antihistamines and ⁇ - adrenergic antagonists, also compete for the binding of 3 H-DPPE and 3 H-histamine to H IC in rat liver microsomes or brain membranes and, likewise, promote tumor growth.
  • fluoxetine ProzacTM
  • H- L -antihistamines and ⁇ - adrenergic antagonists also compete for the binding of 3 H-DPPE and 3 H-histamine to H IC in rat liver microsomes or brain membranes and, likewise, promote tumor growth.
  • a method for the treatment of cancer cells in an animal which comprises:
  • Such compounds may be prepared by any convenient procedure depending on the identity of the variable groups.
  • the compound may be made by reacting a hydroxy substituted fluoro-benzophenone with a chloro-substituted amino-substitute alkyl group.
  • Figures 1 to 10 are graphical representations of text data generated in certain experiments set forth in the Examples below.
  • any compound which inhibits normal cell proliferation while promoting malignant cell proliferation is useful and is administered in an amount sufficient to inhibit the binding of intracellular histamine in normal cells.
  • Such compounds generally exhibit a pKi of at least about 5, preferably at least about 5.5.
  • X and Y are each fluorine, chlorine or bromine
  • o and p are 0 or 1
  • R x and R 2 are each alkyl groups containing 1 to 3 carbon atoms or are joined together tc form a hetero-ring with the nitrogen atoms and n is 1, 2 or 3.
  • Pharmaceutically-acceptable salts of the diphenyl compounds may be employed.
  • benzene rings may be joined to form a tricyclic ring, in accordance with the structure:
  • n, R- t and R 2 are as described above.
  • o and p are usually 0 when Z is an alkylene group and n may be 2. In one particularly preferred embodiment of the compounds of formula I, Z is -CH 2 -, n is 2, o and p are each 0 and
  • n 2 and
  • DFPE diethylamino group.
  • This compound exhibits a potency of two to four times that of DPPE in inhibiting normal cell proliferation and promoting malignant cell proliferation in H IC binding competition assays.
  • tricyclic antidepressants e.g. amitriptyline, clomipramine, imipramine and like agents
  • non-tricyclic antidepressants e.g. fluoxetine and like agents
  • phenothiazines e.g. prochlorperazine, trifluoroperizine, chlorpromazine and like agents
  • H- L -antihistamines e.g., loratadine, hydroxyzine, phenyltoloxamine, astemizole and the like
  • imidazoles and imidazole-like compounds including H 2 antagonists, such as cimetidine and ranitidine, H 3 antagonists, such as thioperamide and antifungal agents, such as ketoconazole, and (h) triphenylethylene derivatives, such as tamoxifen.
  • H 2 antagonists such as cimetidine and ranitidine
  • H 3 antagonists such as thioperamide and antifungal agents, such as ketoconazole
  • triphenylethylene derivatives such as tamoxifen.
  • the compounds which may be employed may have a chemical structure consisting of at least two phenyl rings, linked by a rigid third phenyl or non- phenyl ring, or by a non-rigid methyl, oxygen, or other moiety, with the phenyl ring structure being linked by an ether, sulfhydryl or other ring structure or group to a basic alkylamine or imidazole or amino-imidazole side chain, for example, the carboxyamide-amino-imidazole L651582.
  • DPPE and its direct analogs may be a significantly better agent for combination with chemotherapy agents than the foregoing groups of compounds, since DPPE appears to be more potent and selective for H IC and does not interact with calmodulin, protein kinase C, or calcium channels and is only a weak antagonist at other common receptors, such as E l r 5HT and D 2 .
  • DPPE does not cause serious toxic effects in humans at clinically relevant doses to enhance chemotherapy (about 0.2-12 mg/kg, preferably less than about 10 mg/kg, with about 6 mg being an optimal dose)
  • the antidepressant group of drugs may cause cardiac arrythmias
  • x antagonists might cause marked sedation or even convulsions
  • phenothiazines may cause dyskenesias.
  • FIG. 1 shows the tumor-promoting effect DPPE (1 mg/kg or 4 mg/M 2 ) given subcutaneously once daily x 3, to seven DBA/2 mice inoculated subcutaneously with 2 x 10 2 L5178Y lymphoma cells 48 hours previously.
  • a second group of 7 tumor cell-inoculated mice served as controls (saline injections, once daily x 3) .
  • 7/7 DPPE treated animals had palpable tumors as compared to 4/7 controls.
  • mice DBA/2 mice
  • groups of 3 animals were shaved over the back and 48 hours later received a single topical application of 17 nM PMA in acetone.
  • the PMA-treated mice then received either saline (control) or DPPE (4 or 32 mg/kg at time 0 and 24 hours) .
  • Three animals painted with acetone served as vehicle controls. Forty-eight hours later, the various groups were sacrificed by C0 2 asphyxiation, the skin carefully excised, pinned to paper strips to prevent wrinkling, and immersed in formaldehyde. H and E-stained sections of skin were assessed for degree of inflammation.
  • FIG. 2 shows the potency of two tricyclic agents, namely amitriptyline and doxepin, to compete for 3 H-DPPE binding in liver microsomes.
  • the K d value for DPPE is 65 nM while the K ⁇ for doxepin is 5 ⁇ M and for amitriptyline is 10 ⁇ M.
  • Figure 4 demonstrates the tumor-promoting effects of the tricyclic agent, amitriptyline, and the non-tricyclic agent, fluoxetine, in C3H mice injected subcutaneously into the gluteal region with 1 x 10 5 C-3 fibrosarcoma cells.
  • the doses employed were equivalent to therapeutic human doses (80 mg/M 2 for amitriptyline and 20-40 mg/M 2 for fluoxetine) .
  • IC 50 10 to 20 ⁇ M
  • Figure 6A shows that propanolol (a ⁇ -adrenergic antagonist) inhibits histamine binding to H IC in microsomes and Fig re 6B shows that propanolol inhibits normal lymphocyte mitogenesis.
  • propanolol significantly increased tumor weight on Day 23, as seen in Figure 7.
  • the morpholino-analogue also was prepared using the above-described procedure, but substituting 4- (2- chloroethyDmorpholine.HCl for DEAE.HC1.
  • Example IV This Example illustrates the binding characteristics and antiproliterative properties of DPPE.
  • DFPE competes for [ 3 H] DPPE binding in rat liver microsomes with a K t value of approximately 70 nM.
  • Ki value for DFPE approximates the K d value for DPPE in the same assay.
  • DFPE competes for [ 3 H] histamine binding in rat cortical membranes with a K ⁇ value of 0.3 x 10 "6 M.
  • DFPE is approximately three times moire potent than DPPE in inhibiting histamine binding at a non-H 1# non-H 2 site (H IC ) in brain membranes (Brandes,
  • PMA phorbol myristate acetate
  • DFPE and DPPE The ability of DFPE and DPPE to inhibit/kill the growth of MCF-7 human breast cancer cells after seven days incubation at 37°C in vitro is shown in Figure 10.
  • the IC 50 value for DFPE is 3.0 x 10 "6 M. This compares with an IC 50 value for DPPE of 6.5 x 10 "6 in the same assay.
  • DFPE possesses novel antihistaminic properties, antagonizes the effects of phorbol myristate acetate on platelet aggregation, and is antiproliferative cyclotoxic to MCF-7 human breast cancer cells, all with a potency approximately three to four times greater than that of DPPE. Since DPPE has been demonstrated to be antiestrogenic in vivo, to augment the effects of tamoxifen in the rat uterus in vivo, a similar spectrum of in vivo activity is expected for DFPE, but with an overall potency two to four fold greater than that observed for DPPE. In addition DFPE may be used in place of DPPE in the cancer treatment method described herein to improve the therapeutic index of conventional chemotherapy drugs.
  • the present invention provides identification of compounds and classes of compounds which stimulate cancer growth and which enable the therapeutic index of chemotherapy agents to be improved. Novel compounds also are described. Modifications are possible within the scope of this invention.

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

Abstract

On améliore le traitement chimiothérapeutique in vivo du cancer chez un animal vivant en administrant d'abord à ce dernier un composé qui inhibe la prolifération des cellules normales tout en favorisant la prolifération de cellules malignes, plus spécifiquement un antagoniste puissant sélectif pour les récepteurs de l'histamine intracellulaire en dose suffisante pour inhiber la fixation de l'histamine intracellulaire aux récepteurs dans les cellules normales et malignes. On obtient avec ledit agent chimiothérapeutique un effet toxique accru sur les cellules cancéreuses tout en inhibant ses effets nocifs sur les cellules normales, et particulièrement les cellules de la moëlle osseuse et gastro-intestinales. De nouveaux composés tels que certains dérivés fluoro sont utilisés dans ce traitement.
EP94906813A 1993-02-17 1994-02-17 Traitement du cancer Withdrawn EP0684817A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB939303210A GB9303210D0 (en) 1993-02-17 1993-02-17 Cancer treatment
GB9303210 1993-02-17
PCT/CA1994/000087 WO1994018961A1 (fr) 1993-02-17 1994-02-17 Traitement du cancer

Publications (1)

Publication Number Publication Date
EP0684817A1 true EP0684817A1 (fr) 1995-12-06

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EP94906813A Withdrawn EP0684817A1 (fr) 1993-02-17 1994-02-17 Traitement du cancer

Country Status (6)

Country Link
EP (1) EP0684817A1 (fr)
JP (2) JP2834328B2 (fr)
KR (1) KR960700698A (fr)
AU (2) AU693780B2 (fr)
GB (1) GB9303210D0 (fr)
WO (1) WO1994018961A1 (fr)

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US5869479A (en) * 1997-08-14 1999-02-09 Schering Corporation Treatment of upper airway allergic responses
EP1073738B1 (fr) 1998-04-21 2004-09-29 Max-Planck-Gesellschaft Zur Förderung Der Wissenschaften E.V. Canal ionique k+ humaine et ses applications therapeutiques
IL139975A0 (en) * 2000-11-29 2002-02-10 Univ Ramot Anti proliferative drugs
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RU2005109421A (ru) * 2002-09-04 2005-10-20 Те Юниверсити Оф Манитоба (Ca) Лечение метастатического рака молочной железы антрациклинами и таксанами
AU2011352378B2 (en) * 2010-12-27 2016-08-04 The Curators Of The University Of Missouri Oxidosqualene cyclase as a protein target for anticancer therapeutics
WO2016116438A1 (fr) 2015-01-19 2016-07-28 Partners För Utvecklingsinvesteringar Inom Life Sciences, P.U.L.S. Ab Antihistaminique utilisé dans le traitement du cancer du sein
KR102312100B1 (ko) * 2020-06-05 2021-10-14 (주)프론트바이오 항바이러스제 및 항우울제를 유효성분으로 함유하는 암 예방 또는 치료용 약학적 조성물
KR20230018341A (ko) * 2021-07-29 2023-02-07 (주)프론트바이오 항바이러스제 및 항우울제를 유효성분으로 함유하는 암 예방 또는 치료용 약학적 조성물

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JP2834328B2 (ja) 1998-12-09
AU1480497A (en) 1997-05-15
JPH10182490A (ja) 1998-07-07
GB9303210D0 (en) 1993-03-31
WO1994018961A1 (fr) 1994-09-01
JPH08506593A (ja) 1996-07-16
AU6035294A (en) 1994-09-14
KR960700698A (ko) 1996-02-24
AU693780B2 (en) 1998-07-09

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