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WO2007017652A2 - Utilisation therapeutique - Google Patents

Utilisation therapeutique Download PDF

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Publication number
WO2007017652A2
WO2007017652A2 PCT/GB2006/002930 GB2006002930W WO2007017652A2 WO 2007017652 A2 WO2007017652 A2 WO 2007017652A2 GB 2006002930 W GB2006002930 W GB 2006002930W WO 2007017652 A2 WO2007017652 A2 WO 2007017652A2
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
cancer
amino
propylamine
acetamide
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.)
Ceased
Application number
PCT/GB2006/002930
Other languages
English (en)
Other versions
WO2007017652A3 (fr
Inventor
Reginald Bowie Ewesuedo
Gerardus Johannes Clemens Maria Kolvenbag
Dennis Joseph Mccarthy
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.)
AstraZeneca UK Ltd
AstraZeneca AB
Original Assignee
AstraZeneca UK Ltd
AstraZeneca AB
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 AstraZeneca UK Ltd, AstraZeneca AB filed Critical AstraZeneca UK Ltd
Publication of WO2007017652A2 publication Critical patent/WO2007017652A2/fr
Publication of WO2007017652A3 publication Critical patent/WO2007017652A3/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to arylalkyl-amines and -amides, particularly (S)- ⁇ - phenyl-2-pyridineethanamine, or pharmaceutically acceptable salts thereof, and their use in the treatment of cancer in a warm-blooded animal, such as man.
  • the invention also relates to the use of pharmaceutical compositions containing arylalkyl-amines and -amides, particularly (S)- ⁇ -phenyl-2-pyridineethanamine, or pharmaceutically acceptable salts thereof, in a method of treating cancer in a warm blooded animal, such as man, and to the use of arylalkyl-amines and -amides, particularly (S)- ⁇ -phenyl-2-pyridineethanamine, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for use in a method of treating cancer in a warm blooded animal, such as man.
  • Cancer mortality in the U.S. is estimated to account for about 600,000 a year, about one in every four deaths, second only to heart disease in percent of all deaths, and second to accidents as a cause of death of children 1-14 years of age.
  • the estimated cancer incidence in the U.S. is now about 1,380,000 new cases annually, exclusive of about 900,000 cases of non-melanotic (basal and squamous cell) skin cancer.
  • Cancer is also a major cause of morbidity in the UK with nearly 260,000 new cases (excluding non-melanoma skin cancer) registered in 1997. Cancer is a disease that affects mainly older people, with 65% of cases occurring in those over 65.
  • a glioma is defined as a tumour of the brain that begins in glial cells (a glial cell is a type of cell that surrounds nerve cells and supports/holds them in place, including astrocytes).
  • Astrocytomas tumor cells that arise from astrocytes
  • ependymomas oligodendrogliomas
  • tumours with mixtures of two or more of these cell types are common gliomas, astrocytomas being the most common.
  • Astrocytomas are the second most common type of cancer in children (Osteen, R.T. (Ed.). (1996). Cancer manual (9th ed.). Atlanta: American Cancer Society). Since 1960, the five-year survival rate for astrocytomas has increased from 18% to 30%, but in spite of this increase, the average life expectancy following an astrocytoma diagnosis is only 18 months (Silverstein, M.D., Cascino, T.L., & Harmsen, W.S. (1996).
  • the present invention aims at providing a method and/or medicament which is useful for the treatment of cancer.
  • the present invention concerns the surprising finding that (S)- ⁇ -phenyl-2-pyridineethanamine is a particularly potent anticancer agent.
  • European Patent No. 356035 discloses a large number of compounds for use in the treatment of neurodegenerative disorders, including ⁇ -phenyl-2-pyridineethanamine (referred to therein and herein as l-phenyl-2-(2-pyridinyl)ethylamine),
  • European patent No. 0633879 discloses the (S)-enantiomer of this compound ((S)- ⁇ -phenyl- 2-pyridineethanamine), its preparation and its use as a pharmaceutical, in particular in the treatment of neurodegenerative disorders.
  • the potential benefits of the above compounds in the treatment of cancer patients can include:
  • tumour cell proliferation and migration direct cytostatic effect
  • the potential benefits of the above compounds in the treatment of glioma patients can include: -protection of normal brain tissue from destruction via glutamate-mediated excitotoxicity due to glutamate release from the tumour (this might both decrease neurologic sequelae and slow tumour expansion);
  • Ari and Ar 2 independently represent phenyl substituted by one or more of amino, nitro, chlorine, bromine, hydroxy, C 1-6 alkoxy, C 1-6 alkyl or cyano; in addition one of Ar 1 or Ar 2 may represent phenyl;
  • Ri represents hydrogen or Ci -6 alkyl
  • R 2 represents hydrogen or COCH 2 NH 2 ;
  • R3 represents hydrogen or Ci -6 alkyl; in addition, when R 2 represents hydrogen, then both of Ar 1 and Ar 2 may represent phenyl, one or both of Ar 1 and Ar 2 may represent fluorophenyl or 2-, 3- or 4- pyridinyl, and Ri may represent Ci. 6 alkoxycarbonyl or trifluoromethyl; provided that:
  • This invention also relates to all stereoisomeric forms, optical enantiomeric forms and pharmaceutically acceptable acid addition salts of the compounds of formula (I).
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in a warm-blooded animal such as man.
  • a method of treating cancer which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a warm blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer in a warm blooded animal such as man.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof in the reduction of proliferation in a cancerous cell or inducing differentiation of a cancerous cell in a warm-blooded animal such as man.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the reduction of proliferation in a cancerous cell or inducing differentiation of a cancerous cell in a warm-blooded animal such as man.
  • a method for reducing proliferation in a cancerous cell or inducing differentiation of a cancerous cell which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in a warm blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier for use in the reduction of proliferation or inducing differentiation of a cancerous cell in a cancerous cell in a warm blooded animal such as man.
  • a method of inducing apoptosis in a cancerous cell which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a warm blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier for use in inducing apoptosis in a cancerous cell in a warm blooded animal such as man.
  • treatment may comprise known methods of anti- tumour therapy: surgery, radiotherapy or chemotherapy.
  • the compounds of formula (I) may be applied as a sole therapy or may involve, in addition, one or more substances and/or treatments. Therefore according to the present invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the conjoint treatment of cancer in a warm-blooded animal such as man.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the conjoint treatment of cancer in a warm-blooded animal such as man.
  • a method of conjointly treating cancer which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a warm blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutical acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier for use in the conjoint treatment of cancer in a warm blooded animal such as man.
  • the conjoint treatment we mean a treatment of an individual with two or more therapeutic agents, a compound of formula (I) being the first therapeutic agent.
  • the second (and optionally third and further) therapeutic agent can be any anti-tumour therapy, e.g. irradiation treatment, treatment with chemotherapeutic drugs, treatment with cytotoxic drugs, hormone therapy, immunotherapy, anti-angiogenic therapy and/or gene therapy.
  • the conjoint treatment comprises irradiation treatment.
  • the conjoint treatment comprises treatment with a chemotherapeutic drug.
  • Such conjoint treatment can be achieved by way of the simultaneous, sequential or separate administration of a Compound of formula (I) and the second (and optionally third or further) therapeutic agent.
  • Sequential administration includes administration of a compound of formula (I) either prior to or after the second therapeutic agent.
  • the second therapeutic agent is radiation therapy
  • a compound of formula (I) can be administered pre- or post-radiation.
  • the second therapeutic agent is a chemotherapeutic drug
  • a compound of formula (I) can be administered pre- or post- chemotherapy.
  • the compound of formula (I) is a sensitizing agent.
  • sensitizing agent we mean that a compound of formula (I) is capable of sensitizing cancer cells upon contact to the activity of the second (and optionally third and further) therapeutic agent. This enables reduction of the dosage of the second therapeutic agent compared to the dosage usually administered in the absence of the sensitizing agent to achieve an anti-cancer effect, increasing the probability of killing the tumour cells.
  • Anticancer effects may include reduction in tumour mass, inhibition of proliferation and/or increase in cytotoxicity of standard therapies, increase in survival time, delay in disease progression, thus enhancing/maintaining quality of life. Methods to determine anti-tumour effects are known to those skilled in the art.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in sensitizing cancer cells in a warm-blooded animal such as man.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in sensitizing cancer cells in a warm-blooded animal such as man.
  • a method of sensitizing cancer cells which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a warm blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutical acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier for sensitizing cancer cells in a warm blooded animal such as man.
  • the compound of formula (I) is administered throughout the entire course of the treatment, and prior to the administration of the second (and optionally third or further) therapeutic agent.
  • This enables sufficient levels of the compound of formula (I) to be present in the body at the time of administration of the second (and optionally third or further) therapeutic agent e.g. radiation treatment and/ or chemotherapy, thus sensitizing the tumour cells making them more vulnerable to the action of said second (and optionally third or further) therapeutic agent.
  • Chemotherapy may include one or more of the following categories of anti-tumour agents: (i) cell cycle inhibitory agents, for example cyclin dependent kinase (CDK) inhibitors, in particular CDK2 inhibitors; (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (for example magestrol acetate), aromatase inhibitors (for example anastrozole, letrazole, vorazole, exemetane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example goserelin acetate, luprolide), inhibitors of testosterone 5 ⁇ -dihydroreductase (for example finasteride), anti-
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical incology, such as antimetabolites (for example antifolates like methotrexate, fluoropyrimidines like 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside);antitumour antibiotics (for example anthracyclines like doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mithamycin); platinum derivatives (for example cisplatin, carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, bulsulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic agents (for example vinca alkaloids like vincrisitine and taxoids like taxol, taxotere); topoisome
  • antimetabolites
  • antiangiogenic agents that work by different mechanisms from those defined hereinbefore (for example recptor tyrosine kinases like Tie-2, inhibitors of integrin ⁇ vB3 function, angiostatin, razoxin, thalidomide), and including vascular targeting agents; and (v) differentiation agents (for example retinoic acid and vitamin D).
  • Compounds of formula I include: 1 ,2-diphenylethylamine; 1 ,2-diphenyl-2-propylamine; 1 ,2-bis(4-fluorophenyl)-2-propylamine ; 1 ,2-diphenyl-2-butylamine; (-)- 1 ,2-diphenyl-2-propylamine; (+)- 1 ,2diphenyl-2-propylamine;
  • N-methyl-l,2-diphenyl-2-propylamine l-(3-nitrophenyl)-2-phenyl-2-propylamine; l-(3-chlorophenyl-2-phenyl-2-propylamine; l-(3-bromophenyl)-2-phenyl-2-propylamine;
  • the compound of formula (I) is l-phenyl-2-(2- pyridinyl)ethylamine. In another particular embodiment, the compound of formula (I) is
  • the (S)- ⁇ -phenyl-2-pyridineethanamine is substantially free from its (R)-enantiomer.
  • substantially free from its (R)- enantiomer we mean that a sample of the (S)-enantiomer contains less than 10% by weight of the (R)-enantiomer (i.e.
  • the sample contains less than 5% by weight of the (R)-enantiomer, in another embodiment the sample contains less than 2% by weight of the (R)-enantiomer, in another embodiment the sample contains less than 1% by weight of the (R)-enantiomer, and in another embodiment the sample contains pure (S)-enantiomer.
  • Suitable pharmaceutically-acceptable salts include, for example, salts with alkali metals (such as sodium, potassium or lithium), alkaline earth metals (such as calcium or magnesium), ammonium salts, and salts with organic bases affording physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine.
  • suitable pharmaceutically-acceptable acid addition salts may be prepared by treatment with various inorganic or organic acids, such as hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, succinic, fumaric, malic, maleic, tartaric, citric, benzoic, methanesulphonic or carbonic acids .
  • the sample contains a compound of formula (I) in the form of an acid-addition salt.
  • the sample contains a compound of formula (I) in the form of the dihydrochloride salt.
  • a compound of formula (I) is in the form of the benzoate salt.
  • a compound of formula (I) is in the form of the malate salt.
  • cancer refers to endometrial cancer, liver cancer, stomach cancer, thyroid cancer, rectal cancer, oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewings tumour, neuroblastoma, Kaposis sarcoma, ovarian cancer, breast cancer, bladder cancer, colon cancer, melanoma, lung cancer (non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)), gastric cancer, head and neck cancer, brain cancer, glioma, astrocytoma, renal cancer, lymphoma and leukaemia.
  • NSCLC non small cell lung cancer
  • SCLC small cell lung cancer
  • brain cancer More particularly it refers to brain cancer, glioma, NSCLC, renal cancer, colon cancer, melanoma, leukaemia, breast cancer and ovarian cancer.
  • brain cancer More particularly it refers to glioma.
  • NSCLC nuclear-plasmin-containing cell sorting
  • renal cancer In addition, more particularly it refers to colon cancer.
  • melanoma In addition, more particularly it refers to leukaemia.
  • breast cancer In addition, more particularly it refers to ovarian cancer.
  • particularly the cancer is in a metastatic state, and more particularly the cancer produces brain metastases.
  • the cancer when the cancer is in a metastatic state, that a compound of formula (I) acts at both the primary tumour site and the metastases.
  • a compound of formula (I) both prevents, treats and inhibits metastases.
  • the cancer is in a non-metastatic state.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • the compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of the compound will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight, will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration is however preferred, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of formula (I).
  • a compound of formula (I) is administered throughout the entire course of treatment rather than as an episodic therapy, optionally in combination with radiation therapy and/or chemotherapy, and in a particular embodiment as an oral tablet formulation.
  • a compound of formula (I) particularly (S)- ⁇ -phenyl-2-pyridineethanamine, may be administered orally as a tablet once daily throughout the course of the disease, optionally in combination with radiation therapy and/or chemotherapy.
  • Clinical endpoints may include increase in survival, reduction in seizures and reduction in depression.
  • the compounds of formula (I), and pharmaceutically acceptable salts thereof may have the advantages that they are less toxic, more efficacious, are longer lasting, have a broader range of activity, are more potent, produce fewer side effects, are more easily absorbed or have other useful pharmacological properties, than compounds previously indicated in the therapeutic fields mentioned above.
  • (S)- ⁇ -phenyl-2- pyridineethanamine has excellent drug-like properties.
  • (S)- ⁇ -phenyl-2- pyridineethanamine is water soluble, renally cleared, orally bioavailable, crosses the blood brain barrier, and has low protein binding, simple metabolism and predictable pharmacokinetics.
  • (S)- ⁇ -phenyl-2-pyridineethanamine is well tolerated in both young and elderly healthy human volunteers.
  • (S)- ⁇ -phenyl-2- pyridineethanamine has predictable pharmacokinetics, which allows for multiple dosing, and a plasma half-life of 14 hours. Based on human data, its efficacy range will typically be plasma concentrations of about 0.75 to 6.0 ⁇ M.
  • (S)- ⁇ -phenyl-2-pyridineethanamine is well tolerated when administered to stroke patients (Lees, K.R., Dyker, A.G., Sharma, A., Ford, G.A., Ardon, M.E. and Grosset, D.G. Stroke 32:466-472, 2001 ; Diener, H.C.,
  • Human tumour cell lines were grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine. Typically, cells were inoculated into 96 well microtiter plates in 100 ⁇ L at plating densities ranging from 5,000 to 40,000 cells/well depending on the doubling time of individual cell lines. After cell inoculation, the microtiter plates were incubated at 37° C, 5 % CO 2 , 95 % air and 100 % relative humidity for 24 h prior to addition of Compound (A).
  • SRB Sulforhodamine B
  • GI50 measurement 50% Growth Inhibition, i.e. Compound (A) inhibited 50% of the growth over 48 hours
  • the cells will grow at an expected rate over the 48 hours.
  • the number of cells at the start of the experiment with no drag added was compared to the number of cells in the control after 48 hours (a certain number of doublings will have occurred during this time). This growth was then compared with the growth that occurred in the wells treated with Compound (A). If the growth in the Compound (A) - treated wells is only half of the rate in the control, it is marked as a "hit".
  • Ti number of cells in drug-treated wells after 48 hours of growth at the five concentration levels
  • Tz the number of cells in the well just prior to addition of drag
  • C the number of cells, after 48 hours, in the wells that received no treatment, i.e., time 48 hour control.
  • the criteria established for activity of compound (A) in this screen is greater than 50% growth inhibition of the tumour cells under the conditions of the assay.
  • the results showed (Table 1) that Compound (A) inhibits the cell growth by more than 50% of two human glioma cell lines (SNB-75 and SF-295), a renal cell line (TK-10), a leukaemia cell line (MOLT-4), three non-small cell lung cell lines (NCI H322M, HOP-62 and HOP-92), a colon cell line (HCT-116) and a melanoma cell line (LOX IMVI).
  • Table 1 Cell growth inhibition of human tumour cell lines by Compound (A). Each row represents the results from a single experiment. An active "hit” is defined by greater than 50% growth inhibition (see numbers in bold). Activity against a particular cell line is defined as meeting the greater than 50% growth inhibition in at least two separate experiments.

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  • 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)
  • Emergency Medicine (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'arylalkyl-amines et d'arylalkyl-amides, en particulier, (S)-a-phenyl-2-pyridineethanamine, ou des sels de ceux-ci pharmaceutiquement acceptables pour traiter le cancer chez un animal à sang chaud, tel que l'homme. D'autres aspects de l'invention concernent une méthode permettant de traiter le cancer, et l'utilisation d'arylalkyl-amines et d'arylalkyl-amides, en particulier, (S)-a-phenyl-2-pyridineethanamine, ou des sels de ceux-ci pharmaceutiquement acceptables pour produire un médicament utilisé dans ladite méthode de traitement du cancer.
PCT/GB2006/002930 2005-08-10 2006-08-08 Utilisation therapeutique Ceased WO2007017652A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US70691605P 2005-08-10 2005-08-10
US60/706,916 2005-08-10

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WO2007017652A2 true WO2007017652A2 (fr) 2007-02-15
WO2007017652A3 WO2007017652A3 (fr) 2007-05-31

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022047123A1 (fr) * 2020-08-28 2022-03-03 The Regents Of The University Of California Compositions et méthodes de traitement d'états pathologiques liés aux amyloïdes

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0648489A1 (fr) * 1988-08-12 1995-04-19 Fisons Corporation Arylalkylamides avec des propriétés neuroprotectives
CZ288519B6 (cs) * 1992-04-03 2001-07-11 Astra Ab (S)-alfa-Fenyl-2-pyridinethanamin, způsob jeho přípravy, farmaceutická kompozice tento enantiomer obsahující, tento enantiomer pro použití jako léčivo a použití tohoto enantiomeru pro výrobu léčiva
EP1002535A1 (fr) * 1998-10-28 2000-05-24 Hrissanthi Ikonomidou Nouvelle utilisation des antagonistes du glutamate pour le traitement du cancer

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022047123A1 (fr) * 2020-08-28 2022-03-03 The Regents Of The University Of California Compositions et méthodes de traitement d'états pathologiques liés aux amyloïdes

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