WO2008139009A1 - Pyridothiénotriazines utilisées comme composés antiangiogéniques - Google Patents

Pyridothiénotriazines utilisées comme composés antiangiogéniques Download PDF

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Publication number
WO2008139009A1
WO2008139009A1 PCT/ES2008/000315 ES2008000315W WO2008139009A1 WO 2008139009 A1 WO2008139009 A1 WO 2008139009A1 ES 2008000315 W ES2008000315 W ES 2008000315W WO 2008139009 A1 WO2008139009 A1 WO 2008139009A1
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WO
WIPO (PCT)
Prior art keywords
angiogenesis
use according
compound
formula
compounds
Prior art date
Application number
PCT/ES2008/000315
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English (en)
Spanish (es)
Inventor
Ana Rodriguez Quesada
Beatriz Martinez Poveda
Miguel Angel Medina Torres
Ramon MUÑOS CHAPULI
Antonio Fernandez Medarde
José María QUINTELA LOPEZ
Ricardo Jesús RIGUERA VEGA
Original Assignee
Universidad De Malaga
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 Universidad De Malaga filed Critical Universidad De Malaga
Publication of WO2008139009A1 publication Critical patent/WO2008139009A1/fr

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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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the present invention relates to the use of some derivatives of pyridothienotriazines as antiangiogenic compounds and their use in the manufacture of medicaments for the treatment of cancer, obesity, diabetic retinopathies, macular degeneration, hemangioma, arthritis, psoriasis and atherosclerosis.
  • Angiogenesis is the generation of new capillaries from preexisting vessels. Under physiological conditions, angiogenesis is under very strict control and only takes place during embryonic development and in processes related to the female reproductive cycle, fracture repair and wound healing. However, in many pathological processes (for example, tumor growth and its spread in metastases, ophthalmic diseases such as diabetic retinopathy and macular degeneration, hemangiomas, arthritis, psoriasis, atherosclerosis ...), the disease has been linked to an deregulated angiogenesis and continuously active (J. Nat. Med. 1995, 1, 27-31).
  • angiogenesis is a highly regulated process under physiological conditions, a lack of control in this regulation, leading to a permanent activation of angiogenesis is characteristic of a series of pathologies (which we could call "angiogenesis dependent diseases"), as we have commented previously.
  • deregulation of angiogenesis can be the direct cause or exacerbate a certain pathological condition. For example, the growth of metastasis of a solid tumor is dependent on angiogenesis.
  • R is selected from a group consisting of hydrogen, and a substituted or unsubstituted phenyl group
  • R 2 is selected from a group consisting of NH 2 , NH-lower alkyl, N- (lower alkyl ) 2 , NH-benzyl, and piperidine-benzyl, are known compounds (Eur. J. Med. Chem. 1998, 33, 887-897, J. Med. Chem. 1999, 42, 4720-4724, and Eur. J Med. Chem.
  • the present invention is directed to the use for the preparation of medicaments for the treatment of angiogenesis-dependent diseases (in particular cancer, ophthalmic diseases such as diabetic retinopathy and macular degeneration, hemangiomas, arthritis, psoriasis, atherosclerosis ...), of compounds of formula general (Ia) or (Ib), of a pharmaceutically acceptable salt, a derivative or prodrug.
  • angiogenesis-dependent diseases in particular cancer, ophthalmic diseases such as diabetic retinopathy and macular degeneration, hemangiomas, arthritis, psoriasis, atherosclerosis .
  • R 1 is selected from a group consisting of hydrogen, and a substituted or unsubstituted phenyl group
  • R 2 is selected from a group consisting of NH 2 , NH-lower alkyl, N- (alkyl lower ⁇ , NH-benzyl, and piperidine-benzyl.
  • “Lower alkyl” refers to a straight or branched chain alkyl group of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl .
  • “Halogen” includes F, Cl, Br and I.
  • references to a substituted phenyl group in the compounds of the present invention refer to the phenyl group which can be substituted in one or more positions available by one or more suitable groups, such as F, Cl, Br and L; cyano; hydroxyl; nitro; azido; alkanoyl as a C 1-6 alkanoyl group as acyl and the like; carboxamide; alkyl groups that include those having 1 to 12 carbon atoms, or 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms; alkenyl and alkynyl groups, including those groups having one or more unsaturated bonds and 2 to 12 carbon atoms, or 2 to 6 carbon atoms; alkoxy groups having one or more oxygen and 1 to about 12 carbon atoms, or 1 to about 6 carbon atoms; aryloxy groups such as phenoxy; alkylthio groups, including those having one or more thioether bonds and from 1 to about 12 carbon atoms, or from 1 to about 6 carbon atom
  • a pharmaceutically acceptable salt, a derivative or a prodrug refers to any pharmaceutically acceptable salt, ester, solvate, hydrate or any other compound that, upon administration to the recipient, is capable of producing (directly or indirectly) a compound as described here.
  • the preparation of salts, prodrugs and derivatives may be carried out by known methods.
  • salts of the compounds of formula (Ia) or (Ib) are synthesized by conventional chemical methods from compounds that They contain an acidic or basic group.
  • these salts are synthesized, for example, by reacting the free acid or base forms of said compounds with appropriate stoichiometric amounts of the base or acid in water, or in an organic solvent, or in a mixture of both.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferable.
  • acid addition salts are the addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate and the addition salts of organic acids such as, for example, acetate, maleate, fumarate, citrate, oxalate , succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • alkali addition salts are inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N 5 N-dialkylene ethanolamine, triethanolamine and de basic amino acids
  • prodrug is used in the broadest sense and refers to those derivatives that are converted in vivo into the compounds of formula (Ia) or (Ib). Such derivatives include, for example, compounds in which a free hydroxyl group is converted into an esterified derivative.
  • the compounds of formula (Ia) or (Ib) may include enantiomers depending on their asymmetry or diastereoisomers.
  • the use of isolated isomers or mixture of the isomers falls within the scope of the present invention.
  • the pharmaceutical compositions comprise a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer together with a pharmaceutically acceptable carrier, adjuvant or carrier, for administration to a patient.
  • compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) for oral, topical or parenteral administration.
  • compositions will be in oral, solid or liquid form.
  • Doses suitable for administration may be supplied in the form of tablets, capsules, syrups or solutions and may contain conventional excipients such as binding agents, for example syrups, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.
  • binding agents for example syrups, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine
  • lubricants such as
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or compressing. Remixing can be used to distribute the active agent in those compositions that use large amounts of filler. Such operations are conventional.
  • the tablets may, for example, be prepared by dry or wet granulation and optionally covered by methods well known in pharmaceutical practice, in particular with an enteric coating.
  • compositions can also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the form suitable for the dose unit.
  • Suitable excipients such as fillers, buffering agents or surfactants, may be used.
  • compositions may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred due to the convenience for the patient and the chronic nature of the diseases to be treated.
  • (Ib) will depend on the relative efficacy of the chosen compound, the severity of the disease to be treated and the patient's weight.
  • the compounds will typically be administered one or more times a day for example 1, 2, 3 or 4 times a day, with total daily doses in the range of 0.1 to 1000 mg / kg / day.
  • the compounds of formula (Ia), (Ib), and their corresponding combinations can be used with other drugs in a combination therapy.
  • the other drugs may be part of the same composition, or be supplied as an independent composition for simultaneous administration or at a different time.
  • Particularly preferred compounds of those comprised in general formulas (Ia) or (Ib) are compounds I 5 II, III, and IV:
  • Bovine aorta (BAE) cells were maintained in DMEM medium with glucose (lg / L), glutamine (2mM), penicillin (50 IU / mL), streptomycin (50 ⁇ g / mL), and amphotericin
  • FBS fetal bovine serum
  • Human umbilical cord endothelial cells were isolated from umbilical cords by collagenase digestion (J. CeIl. Biol. 1988, 107, 1589-1598) and maintained in Medium 199 containing HEPES (10 mM), L -glutamine (2 mM), heparin (10 mg / mL), penicillin (50 IU / mL), streptomycin (50 ⁇ g / mL), and amphotericin (1.25 ⁇ g / mL), supplemented with 3 mg / L of endothelial cell growth supplement (ECGS, Sigma) and 20% FBS in 5% CO 2 and 37 0 C.
  • HEPES HEPES
  • L -glutamine 2 mM
  • heparin 10 mg / mL
  • penicillin 50 IU / mL
  • streptomycin 50 ⁇ g / mL
  • amphotericin 1.25 ⁇ g / mL
  • Endothelial cell differentiation test Formation of tubular structures on Matrigel
  • Table I shows the results of the minimum concentration of compounds I-IV (MIC) that gave a complete inhibition of endothelial morphogenesis on Matrigel of BAE and HUVE cells.
  • the 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT; Sigma Chemical Co., St. Louis, MO) bromide assay was used in 96-well plates, as required. described in (Anticancer Res. 2001, 21, 3457-3460).
  • 3x10 3 BAE, 4x10 3 HUVE were incubated in a total volume of 100 ⁇ L of their respective growth media with serial dilutions of compounds I-IV. After 3 days of incubation (37 0 C, 5% CO 2 in humid) atmosphere 10 .mu.l of MTT (5 mg / ml in PBS) was added to each well and the plate was incubated 4 hours (37 0 C).
  • the resulting formazan was dissolved in 150 ⁇ L of 0.04 N HC1-2 propanol and its absorbance was read at 550 nm with the aid of a plate reader.
  • the IC 50 value was calculated as the concentration of compound that gave 50% of the cell survival of the untreated control.
  • the CAM test was carried out as described in (FASEB J. 2002, 16, 261-263).
  • Test compounds were added to a solution of 0.7% methylcellulose in water .
  • drops of 10 ⁇ L of dried this solution which was then implanted on the CAM.
  • two people independently observed the CAM using a stereomicroscope. The trial was considered positive when both people reported a significant decrease in vascularization in the treated area.
  • Table III summarizes the evaluation of angiogenesis inhibition in vivo by the CAM assay for compounds I-IV. Data appears as percent inhibition. In brackets, the number of eggs with inhibited angiogenesis in their CAMs is indicated by the total number of eggs treated.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de pyridothiénotriazines comme composés antiangiogéniques. La présente invention concerne des dérivés de pyridothiénotriazines possédant une activité antiangiogénique et leur utilisation dans la préparation de compositions pharmaceutiques ou de médicaments destinés au traitement de maladies liées au processus angiogénique, comme le cancer, l'obésité, les rétinopathies diabétiques, la dégénérescence maculaire, les hémangiomes, l'arthrite, le psoriasis et l'athérosclérose.
PCT/ES2008/000315 2007-05-10 2008-05-07 Pyridothiénotriazines utilisées comme composés antiangiogéniques WO2008139009A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EPEP073801333 2007-05-10
EP07380133 2007-05-10

Publications (1)

Publication Number Publication Date
WO2008139009A1 true WO2008139009A1 (fr) 2008-11-20

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ES (1) ES2343880B8 (fr)
WO (1) WO2008139009A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002094193A1 (fr) * 2001-05-23 2002-11-28 Hamdi Hamdi K Methodes d'inhibition de l'angiogenese

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002094193A1 (fr) * 2001-05-23 2002-11-28 Hamdi Hamdi K Methodes d'inhibition de l'angiogenese

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
QUINTELA ET AL.: "Synthesis and pharamcologcial evaluation of some 8-cyanopyrido(3',2':4,5) thieno (3,2-d)triazine derivatives as inhibitors of nitric oxide and eicosanoid byosynthesis", JOURNAL MEDICINAL CHEMISTRY, vol. 42, 1999, pages 4720 - 4724 *
QUINTELA ET AL.: "Synthesis, antihistamine and cytotoxic activity of pyridothieno- and pyridodithienotriazines", EUROPEAN JOURNAL MEDICINAL CHEMISTRY, vol. 33, 1998, pages 887 - 897 *

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Publication number Publication date
ES2343880B8 (es) 2011-12-01
ES2343880B1 (es) 2011-06-16
ES2343880A1 (es) 2010-08-11

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