EP0684817A1 - Cancer treatment - Google Patents
Cancer treatmentInfo
- 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- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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.
Landscapes
- 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
Description
Claims
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 (en) | 1993-02-17 | 1994-02-17 | Cancer treatment |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0684817A1 true EP0684817A1 (en) | 1995-12-06 |
Family
ID=10730606
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP94906813A Withdrawn EP0684817A1 (en) | 1993-02-17 | 1994-02-17 | Cancer treatment |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0684817A1 (en) |
JP (2) | JP2834328B2 (en) |
KR (1) | KR960700698A (en) |
AU (2) | AU693780B2 (en) |
GB (1) | GB9303210D0 (en) |
WO (1) | WO1994018961A1 (en) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5432168A (en) * | 1993-12-27 | 1995-07-11 | University Of Manitoba | Method of treatment of hormone-unresponsive metastatic prostate cancer |
US5585492A (en) * | 1994-10-11 | 1996-12-17 | G. D. Searle & Co. | LTA4 Hydrolase inhibitors |
US6506876B1 (en) * | 1994-10-11 | 2003-01-14 | G.D. Searle & Co. | LTA4 hydrolase inhibitor pharmaceutical compositions and methods of use |
TWI221768B (en) * | 1996-08-16 | 2004-10-11 | Schering Corp | Pharmaceutical composition comprising histamine H1 receptor antagonist and histamine H3 receptor antagonist providing nasal decongestant effect |
US5869479A (en) * | 1997-08-14 | 1999-02-09 | Schering Corporation | Treatment of upper airway allergic responses |
PT1073738E (en) | 1998-04-21 | 2005-01-31 | Max Planck Ges Forderung Der W | CHANNEL OF THE IA + K OF HUMANS AND THEIR THERAPEUTIC APPLICATIONS |
IL139975A0 (en) * | 2000-11-29 | 2002-02-10 | Univ Ramot | Anti proliferative drugs |
US6630454B2 (en) * | 2001-09-10 | 2003-10-07 | Ramot At Tel-Aviv University Ltd. | Method and pharmaceutical composition for the treatment of cancer |
RU2005109421A (en) * | 2002-09-04 | 2005-10-20 | Те Юниверсити Оф Манитоба (Ca) | TREATMENT OF METASTATIC BREAST CANCER ANTHRACYCLINES AND TAXANS |
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 (en) | 2015-01-19 | 2016-07-28 | Partners För Utvecklingsinvesteringar Inom Life Sciences, P.U.L.S. Ab | Antihistamine for use in treatment of breast cancer |
KR102312100B1 (en) * | 2020-06-05 | 2021-10-14 | (주)프론트바이오 | Pharmaceutical composition for preventing or treating cancer comprising antivirals, and antidepressants thereof as active ingredients |
KR20230018341A (en) * | 2021-07-29 | 2023-02-07 | (주)프론트바이오 | Pharmaceutical composition for preventing or treating cancer comprising antivirals, and antidepressants thereof as active ingredients |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3288806A (en) * | 1964-03-23 | 1966-11-29 | Parke Davis & Co | Alpha-(aminoethoxyphenyl)-alpha-alkylstilbenes |
HU187208B (en) * | 1982-12-28 | 1985-11-28 | Richter Gedeon Vegyeszet | Process for production of new dialcil-amino-alcoxi-benzoalcohole derivates, their acid additional and quaterner soils and medical preparates consisting of them |
HU189209B (en) * | 1982-12-28 | 1986-06-30 | Richter Gedeon Vegyeszeti Gyar Rt,Hu | Process for production of new 1-/amino-alkoxi-phenil/-1-phenil propanols, of their acide additioned and quaternary salts and medical preparatives consisting of such compounds |
HU187204B (en) * | 1982-12-28 | 1985-11-28 | Richter Gedeon Vegyeszet | Process for producing new diethyl-amino-alkoxy-benzhydrol derivatives, acid additional salts, and quaternary salts and pharmaceutical compositions contatining them |
HU187205B (en) * | 1982-12-28 | 1985-11-28 | Richter Gedeon Vegyeszet | Process for preparing new derivatives of amni-ethoxy-benzyl-alcohol and salts thereof further pharmaceutical compositions containing such compounds |
ATE110966T1 (en) * | 1990-12-17 | 1994-09-15 | Univ Manitoba | IMPROVED METHOD OF TREATMENT FOR CANCER. |
-
1993
- 1993-02-17 GB GB939303210A patent/GB9303210D0/en active Pending
-
1994
- 1994-02-17 AU AU60352/94A patent/AU693780B2/en not_active Ceased
- 1994-02-17 KR KR1019950703444A patent/KR960700698A/en not_active Application Discontinuation
- 1994-02-17 JP JP6518508A patent/JP2834328B2/en not_active Expired - Lifetime
- 1994-02-17 EP EP94906813A patent/EP0684817A1/en not_active Withdrawn
- 1994-02-17 WO PCT/CA1994/000087 patent/WO1994018961A1/en not_active Application Discontinuation
-
1997
- 1997-02-20 AU AU14804/97A patent/AU1480497A/en not_active Abandoned
-
1998
- 1998-01-05 JP JP10000167A patent/JPH10182490A/en active Pending
Non-Patent Citations (1)
Title |
---|
See references of WO9418961A1 * |
Also Published As
Publication number | Publication date |
---|---|
JPH10182490A (en) | 1998-07-07 |
JP2834328B2 (en) | 1998-12-09 |
WO1994018961A1 (en) | 1994-09-01 |
AU693780B2 (en) | 1998-07-09 |
AU1480497A (en) | 1997-05-15 |
KR960700698A (en) | 1996-02-24 |
AU6035294A (en) | 1994-09-14 |
GB9303210D0 (en) | 1993-03-31 |
JPH08506593A (en) | 1996-07-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5747543A (en) | Treatment method for cancer | |
AU693780B2 (en) | Cancer treatment | |
TWI259077B (en) | Combinations of drugs for the treatment of neoplastic disorders | |
US5650425A (en) | Permanently ionic derivatives of steroid hormones and their antagonists | |
US5364843A (en) | Agents for potentiating the effects of antitumor agents and combating multiple drug resistance | |
US5998467A (en) | Medicine for oculopathy | |
US5618846A (en) | Treatment method for cancer | |
HU201731B (en) | Process for producing substituted benzamides and pharmaceutical compositions comprising such active ingredient | |
EP1123702A1 (en) | Analgesics | |
EP0682947B1 (en) | Medicament for therapeutic and prophylactic treatment of diseases caused by smooth muscle cell hyperplasia | |
JPWO2005079845A1 (en) | Migraine prophylaxis | |
WO1989005795A1 (en) | Novel antiarrhythmic agents ii | |
WO1989007441A1 (en) | 6-amino-1,2-benzopyrone antitumorigenic agents and method | |
EP0563127B1 (en) | Improved treatment method for cancer | |
US6284799B1 (en) | Cancer treatment | |
AU749157B2 (en) | Cancer treatment | |
CA2156162C (en) | Cancer treatment | |
US5432168A (en) | Method of treatment of hormone-unresponsive metastatic prostate cancer | |
JP6152387B2 (en) | Treatment of type I and type II diabetes | |
Bhatnagar et al. | Recent Developments of Antipsychotic Drugs with Phenothiazine Hybrids: A Review. | |
SU1398771A3 (en) | Method of producing substituted benzamides | |
JP2001523717A (en) | Use of substituted diphenylindanone, indane and indole compounds for treating or preventing sickle cell disease, inflammatory disease characterized by abnormal cell proliferation, diarrhea and white diarrhea | |
AU2022232452A1 (en) | Compositions and methods for treating anemia associated with a ribosomal disorder | |
KR820001235B1 (en) | Process for the preparation of alkylthiophenoxypropanolamines | |
JPH06507614A (en) | N-arylalkyl derivative of 2-aminomethyl-2,3-dihydro-1,4-benzodioxin and method for producing the same |
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: 19950913 |
|
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: 19980709 |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
|
18W | Application withdrawn |
Withdrawal date: 20020114 |