WO2009104027A1 - Application thérapeutique de dérivés tricycliques aromatiques et saturés de la benzo(4,5)thiéno-(2,3-d)pyrimidine, et leurs sels thérapeutiquement acceptables - Google Patents

Application thérapeutique de dérivés tricycliques aromatiques et saturés de la benzo(4,5)thiéno-(2,3-d)pyrimidine, et leurs sels thérapeutiquement acceptables Download PDF

Info

Publication number
WO2009104027A1
WO2009104027A1 PCT/HU2008/000017 HU2008000017W WO2009104027A1 WO 2009104027 A1 WO2009104027 A1 WO 2009104027A1 HU 2008000017 W HU2008000017 W HU 2008000017W WO 2009104027 A1 WO2009104027 A1 WO 2009104027A1
Authority
WO
WIPO (PCT)
Prior art keywords
thieno
benzo
pyrimidine
phenyl
tetrahydro
Prior art date
Application number
PCT/HU2008/000017
Other languages
English (en)
Inventor
Péter BÁNHEGYI
György Kéri
László ÖRFI
Zsolt SZÉKELYHIDI
Frigyes Wáczek
Original Assignee
Vichem Chemie Kutató Kft
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 Vichem Chemie Kutató Kft filed Critical Vichem Chemie Kutató Kft
Priority to PCT/HU2008/000017 priority Critical patent/WO2009104027A1/fr
Publication of WO2009104027A1 publication Critical patent/WO2009104027A1/fr

Links

Classifications

    • 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
    • C07D495/02—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 two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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 invention relates to therapeutic application of tricyclic aromatic and saturated benzo[4,5]thieno-[2,3-d]pyrimidine derivatives, as well as to that of their therapeutically acceptable salts.
  • Rl is hydrogen, phenyl, mono-, di-. tri-, tetra- or penta-substituted phenyl, five- or six-membered substituted or unsubstituted heterocyclic group having one or more heteroatoms, advantageously pyrazole, imidazole, isoxazole furane. pyrrole, thiophene, thiazole, isothiazole, triazole, pyrane, pyridine, pyrimidine, dioxane.
  • R2 is hydrogen, linear or branched alkyl, cycloalkyl, unsubstituted or substituted phenyl group;
  • A is methylene (CH2) or methylidene (CH).
  • the invention covers also the above mentioned application of therapeutically acceptable salts of the compounds of the formula (I).
  • the compounds of the formula (I) are known but their therapeutic application is new.
  • the compounds of the formula (I) can be advantageously applied as active substances of pharmaceutical preparations of tyrosine-kinaze inhibiting effect. These preparations have advantageously anti-proliferative. anti-tumor or anti-viral effect, so they can be applied for treatment of tumorous, hyper-proliferative. viral infection diseases, as well as those pertaining to inflammatory processes.
  • the preparations can be formulated with the usual vehicles, media and auxiliary materials in any used form of pharmaceutics.
  • the EGFR-PTK Extra Growth Factor Receptor Protein Tyrosine Kinase
  • the EGFR-PTK is an enzyme belonging to the group of transmembrane (acting through the cell membrane) receptor tyrosine kinase enzymes fulfilling receptor function on the cell membrane having the task to maintain communication between the cells (as well as division and differentiation of the cells)
  • transmembrane region (acting through the membrane);
  • the molecule EGF arriving to the cell is bound on a specific binding location outside the cell resulting in that the EGFR-PTK becomes linked to a neighboring kinase, if the latter is also EGFR-PTK a homo- dimer, if it is kinase enzyme of another type then a hetero-dimer is generated, then the intracellular part of the enzyme gains kinase catalytic activity, as result thereof it catalyzes transfer of a phosphate group from the adenosine-triphosphate (ATP) molecule being present in the cell to a tyrosinic hydroxil group of an intracellular protein.
  • ATP adenosine-triphosphate
  • ATP Adenosine-triphosphate
  • ADP Adenosine-diphosphate
  • the signal arriving to the cell from outside is transmitted to the inside of the cell as result of the binding of phosphoryl radical.
  • EGFR-PTK There are four subtypes of the EGFR-PTK: EGFR, HER2 (Human EGF-Related Receptor), HER3, HER4.
  • the abnormal (usually increased) function of the inter-cell communication route mediated by EGFR-PTK is either attested or its likelihood can be demonstrated.
  • the results of increased function of cancerous cells are as follows: - proliferation of cells; - invasiveness (the ability to invade into other tissues);
  • the efficiency and the selectivity can be improved if the nitrogen atom of the pyrrole ring is changed with sulfur and/or the tetrahydro-benzene ring is aromatized.
  • the invention relates to the therapeutic application of tricyclic aromatic and saturated benzo[4,5]thieno-[2,3-d]pyrimidine compounds
  • Rl is hydrogen, phenyl, mono-, di-, tri-, tetra- or penta-substituted phenyl, five- or six-membered substituted or unsubstituted heterocyclic group containing one or more heteroatoms, advantageously imidazole, isoxazole, furane, pyrrhole, thiophene, thiazole, isothiazole, triazole, pyrane, pyridine, pyrimidine, dioxane, morpholine, thiomorpholine, pyridazine, pyrazine, piperazine group;
  • R2 is hydrogen, linear or branched alkyl, cycloalkyl, unsubstituted and substituted phenyl group;
  • A is methylene (CH2), methylidene (
  • an oxo- compound of the formula (II) containing a six-membered ring is condensed with cyan-acetic acid ethylester and elementary sulphur in watery and alcoholic medium between 60 and
  • an oxo- compound of the formula (II) containing a six-membered ring is condensed with cyan-acetic acid ethylester and elementary sulfur in watery and alcoholic medium between 60 and 100 0 C
  • the produced amine derivative of the formula (III) is transformed with formamide between 60 and 100 0 C in a ring closing reaction to a thieno-pyrimidine compound of the formula (IV) where R2 is as mentioned above then its hydroxy 1 group in the position 5 is changed to halogen with excessively applied phosphor- oxychloride by heating to 80 to 100 0 C then the compound is brought into reaction with a reagent of the formula
  • the yield is 65%.
  • the yield is 66 to 85%.
  • the analysis LCMS was performed with a liquid chromatography mass-spectrometer Waters chromatograph of type ZMD of high efficiency equipped with Waters 996 DAD UV detector, Waters 2700 automatic sampler and Waters 600 control card A column of type Supelco Discovery RP- Amide was used in gradient mode with flow rate of 3 ml/min.
  • the starting (A) solvent was: 10% of acetonitrile, 90% of water and 0.05% of
  • the B solvent was 100% of acetonitrile.
  • the gradients were 0% B, until 30 sec between 0 and 80% from 30 to 120 sec, 80% until 240 sec between 80 and 0% from 240 to 260 sec and 0% until 306 sec.
  • the injection was 5 ⁇ L.
  • the technical data of the mass-spectrometer are: Ionization: ES+/ES-, pre-heating temperature: 120 °C, temperature of desolvation: 350 °C, gas of desolvation: 400 L/min, pulverizing gas: 100 L/min, capillary: 3000 V, pulverizing voltage: 25V. Extractor: 3 V Rf, Lenses: 0.2 V, Scan: from 120 to 1000 m/z 1 sec, inter-scan delay : 0.1 s.
  • the melting points were found with an apparatus B ⁇ chi Melting Point B-540.
  • the EGFR-PTK inhibitor action and selectivity of the produced compound were found on a selectivity panel containing 20 kinase enzymes, as follows:
  • the materials for assay were prepared as stock-solution dissolved in dimethyl- sulfoxid (DMSO) of 100%, from which samples were taken and the solutions of desired concentration were prepared by dilution of samples with buffer solution.
  • DMSO dimethyl- sulfoxid
  • the kinase inhibitor action of components is given in per cents (0% - no action, 100% - complete action) in the table below.
  • the measurements were performed with three samples (in triplicate) at each concentration the results were calculated as arithmetic average of the three samples.
  • concentrations causing inhibition of 50% of the existing kinase activity were determined for the compounds having the highest selectivity and the highest effectiveness, (inhibiting concentration of 50%, IC50)
  • concentrations are given in units of nanomole/liter.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention porte sur une application thérapeutique de dérivés tricycliques aromatiques et saturés de la benzo[4,5]thiéno[2,3-d]pyrimidine et de leurs sels thérapeutiquement acceptables. Les composés selon l'invention sont particulièrement utiles comme agents actifs dans des préparations thérapeutiques à action inhibitrice de la tyrosine-kinase.
PCT/HU2008/000017 2008-02-19 2008-02-19 Application thérapeutique de dérivés tricycliques aromatiques et saturés de la benzo(4,5)thiéno-(2,3-d)pyrimidine, et leurs sels thérapeutiquement acceptables WO2009104027A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/HU2008/000017 WO2009104027A1 (fr) 2008-02-19 2008-02-19 Application thérapeutique de dérivés tricycliques aromatiques et saturés de la benzo(4,5)thiéno-(2,3-d)pyrimidine, et leurs sels thérapeutiquement acceptables

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/HU2008/000017 WO2009104027A1 (fr) 2008-02-19 2008-02-19 Application thérapeutique de dérivés tricycliques aromatiques et saturés de la benzo(4,5)thiéno-(2,3-d)pyrimidine, et leurs sels thérapeutiquement acceptables

Publications (1)

Publication Number Publication Date
WO2009104027A1 true WO2009104027A1 (fr) 2009-08-27

Family

ID=39811537

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2008/000017 WO2009104027A1 (fr) 2008-02-19 2008-02-19 Application thérapeutique de dérivés tricycliques aromatiques et saturés de la benzo(4,5)thiéno-(2,3-d)pyrimidine, et leurs sels thérapeutiquement acceptables

Country Status (1)

Country Link
WO (1) WO2009104027A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102858782A (zh) * 2010-02-26 2013-01-02 贝林格尔.英格海姆国际有限公司 用于药物组合物的具有Mnk1/Mnk2 抑制活性的4-[环烷基氧基(杂)芳基氨基]噻吩并[2,3-d]嘧啶
WO2014043866A1 (fr) 2012-09-19 2014-03-27 中国科学院福建物质结构研究所 Dérivé de thiophène[2,3-d]pyrimidine et son procédé de préparation et d'utilisation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004032716A2 (fr) * 2002-10-08 2004-04-22 Massachusetts Institute Of Technology Composes pour la modulation du transport du cholesterol
WO2006136402A1 (fr) * 2005-06-22 2006-12-28 Develogen Aktiengesellschaft Thiénopyrimidines pour compositions pharmaceutiques
JP2007084494A (ja) * 2005-09-22 2007-04-05 Oncorex Inc Ｐｉｍ−１活性阻害剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004032716A2 (fr) * 2002-10-08 2004-04-22 Massachusetts Institute Of Technology Composes pour la modulation du transport du cholesterol
WO2006136402A1 (fr) * 2005-06-22 2006-12-28 Develogen Aktiengesellschaft Thiénopyrimidines pour compositions pharmaceutiques
JP2007084494A (ja) * 2005-09-22 2007-04-05 Oncorex Inc Ｐｉｍ−１活性阻害剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BHUIYAN M M H ET AL: "SCREENING OF FUSED PYRIMIDINES AS ANTIMICROBIAL AGENTS: INHIBITORY ACTIVITIES OF SOME TETRAHYDROBENZOTHIENO-PYRIMIDINES", PAKISTAN JOURNAL OF SCIENTIFIC AND INDUSTRIAL RESEARCH,, vol. 48, no. 1, 1 January 2005 (2005-01-01), pages 37/38, XP008059930, ISSN: 0030-9885 *
TRAXLER P M ET AL: "4-(Phenyl)pyrrolopyrimidines: Potent and Selective, ATP Site Directed Inhibitors of the EGF-Receptor Protein Tyrosine Kinase", JOURNAL OF MEDICINAL CHEMISTRY, US AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 39, no. 12, 1 January 1996 (1996-01-01), pages 2285 - 2292, XP002213780, ISSN: 0022-2623 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102858782A (zh) * 2010-02-26 2013-01-02 贝林格尔.英格海姆国际有限公司 用于药物组合物的具有Mnk1/Mnk2 抑制活性的4-[环烷基氧基(杂)芳基氨基]噻吩并[2,3-d]嘧啶
WO2014043866A1 (fr) 2012-09-19 2014-03-27 中国科学院福建物质结构研究所 Dérivé de thiophène[2,3-d]pyrimidine et son procédé de préparation et d'utilisation
US9434741B2 (en) 2012-09-19 2016-09-06 Fujian Institute Of Research On The Structure Of Matter, Chinese Academy Of Sciences Thieno[2,3-d]pyrimidine derivatives, preparation method and use thereof

Similar Documents

Publication Publication Date Title
US10000490B2 (en) Inhibitors of the fibroblast growth factor receptor
EP3313849B1 (fr) Nouveaux dérivés d'hydroxyacide, leur procédé de préparation, et compositions pharmaceutiques les contenant
KR102405452B1 (ko) 섬유아세포 성장 인자 수용체의 억제
CA2832504C (fr) Composes permettant d'inhiber la proliferation cellulaire dans les cancers induits par l'egfr
US10457689B2 (en) Ammonium derivatives, a process for their preparation and pharmaceutical compositions containing them
JP6617155B6 (ja) チロシンキナーゼ阻害剤およびそれを含む医薬組成物
AU2013204563B2 (en) Compounds for inhibiting cell proliferation in EGFR-driven cancers
EP3572413B1 (fr) Dérivé de 1,2-dihydro-3h-pyrazolo[3,4-d]pyrimidin-3-one utilisé en tant qu'inhibiteur de wee1
ES2920876T3 (es) Derivados de 8-[6-[3-(amino)propoxi]-3-piridil]1-isopropilimidazo[4,5-c]quinolin-2-ona como moduladores selectivos de la cinasa de la ataxia telangiectasia mutada (atm) para el tratamiento de la enfermedad de Huntington
CN105481858B (zh) 一种含氮稠杂环化合物、其制备方法、组合物及应用
US20230061083A1 (en) Kras g12c inhibitor compound and use thereof
KR20200098598A (ko) Prmt5 억제제로서의 치환된 이중 고리형 헤테로 고리 화합물
WO2011082098A1 (fr) Inhibiteurs de lysine et arginine méthyltransférase pour le traitement du cancer
CA2995375C (fr) Compositions et procedes pour la detection de cellules cancereuses exprimant pde3a ou slfn12
AU2014250836A1 (en) Quinazolines and azaquinazolines as dual inhibitors of RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways
CN114539223B (zh) 一种含芳基并氮杂七元环类化合物及其制备方法与应用
CN108101926B (zh) 含喹啉酮的嘧啶并五元杂环类化合物、制备方法及其应用
CN116768861A (zh) Sos1蛋白降解靶向嵌合体及其组合物、制剂和用途
WO2017088755A1 (fr) Composé aminopyrimidine hétérocyclique présentant une activité antagoniste du récepteur de l'adénosine
WO2018157737A1 (fr) Inhibiteur de kinase multi-cibles
WO2009104027A1 (fr) Application thérapeutique de dérivés tricycliques aromatiques et saturés de la benzo(4,5)thiéno-(2,3-d)pyrimidine, et leurs sels thérapeutiquement acceptables
US11939344B2 (en) Spirocyclic compounds
CN111372936B (zh) Mcl-1选择性抑制剂及其制备和用途
EP1387836B1 (fr) Derives de phthalazine avec activite inhibant l'angiogenese
CN109311908A (zh) 作为Akt抑制剂的二氢吡唑氮杂卓类化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08709703

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08709703

Country of ref document: EP

Kind code of ref document: A1