WO2007121883A2 - Dérivés de 1,4:3,6-dianhydromannitol et leur utilisation - Google Patents

Dérivés de 1,4:3,6-dianhydromannitol et leur utilisation Download PDF

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Publication number
WO2007121883A2
WO2007121883A2 PCT/EP2007/003332 EP2007003332W WO2007121883A2 WO 2007121883 A2 WO2007121883 A2 WO 2007121883A2 EP 2007003332 W EP2007003332 W EP 2007003332W WO 2007121883 A2 WO2007121883 A2 WO 2007121883A2
Authority
WO
WIPO (PCT)
Prior art keywords
formulas
group
dianhydromannitol
alkyl
cycloalkyl
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/EP2007/003332
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German (de)
English (en)
Other versions
WO2007121883A3 (fr
Inventor
Lutz MÜLLER-KUHRT
Hajo Schiewe
Stefan Schunk
Herbert Waldmann
Heino Prinz
Harald Schwalbe
Krishna Saxena
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.)
Analyticon Discovery GmbH
Original Assignee
Analyticon Discovery GmbH
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 Analyticon Discovery GmbH filed Critical Analyticon Discovery GmbH
Publication of WO2007121883A2 publication Critical patent/WO2007121883A2/fr
Publication of WO2007121883A3 publication Critical patent/WO2007121883A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the invention relates to novel 1, 4: 3,6-dianhydromannitol derivatives and their medical use.
  • Protein tyrosine phosphatases represent a new target for the systemic treatment of a wide variety of human diseases. Protein tyrosine phosphatases, for example, appear to be involved in the biological processes in tumor formation, in inflammatory processes and in diabetes. Accordingly, there is a high demand for inhibitors with which to influence an activity of these enzymes.
  • R 1 is a radical selected from the group: (i) substituted or unsubstituted tetrazoyl; (ii) substituted or unsubstituted triazoyl;
  • R 2 for compounds of formulas (Ia) and (Ic) is NHR 3, wherein R 3 is a radical selected from the group (O H; (ii) alkyl or cycloalkyl;
  • R 1 selected from the group alkyl, cycloalkyl heteroaryl or aryl; or R 2 in the case of compounds of the formulas (Ib) and (Id) is OR 4, where R 4 is a radical selected from the group (vii) alkyl, cycloalkyl, heteroaryl or aryl;
  • the radical R 1 is substituted by the variants (i) - (iv), this especially includes one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heterocycloalkyl or heteroaryl.
  • alkyl includes in particular branched or unbranched substituents having 1-10 C atoms.
  • cycloalkyl includes in particular substituents with 3-6 C atoms.
  • Heteroalkyl, heterocycloalkyl or heteroaryl substituents in particular include compounds in which one or more C atoms are replaced by heteroatoms selected in each case from the group O, N, or S.
  • a combination of said substituents may define the radical R1, e.g.
  • a heteroaryl substituent bonded directly to the backbone may have an alkyl substituent attached to the aromatic ring.
  • R 1 is alternative (i) (3-pyrrolidin-1-ylmethylphenyl) tetrazol-1-yl.
  • Examples include the compounds 1a, 1c to 1e and 1g mentioned below.
  • R 1 is 5-pyridin-3-yl- [1,2,3] triazol-1-yl.
  • An example includes compound 1b below.
  • R1 is alternative (iii) thiophen-2-yl-acetylamino.
  • An example includes the compound 1f mentioned below.
  • R 1 of alternative (iv) is a pyrimidin-2-ylamino substituted in the 5-position of the pyrimidine ring with an aromatic or heteroaromatic, preferably thiophene or furan.
  • R 2 is N-cyclohexylmethyl.
  • An example includes the compound 1a mentioned below.
  • R 2 is amino.
  • An example includes compound 1b below.
  • R 2 is N-cyclohexylcarbonyl.
  • An example includes the compound 1c mentioned below.
  • R 2 is N-cyclohexylurido.
  • An example includes the compound 1d mentioned below. AnalytiCon Discovery GmbH
  • R 2 is 4-benzoylamino.
  • An example includes compound 1e below.
  • R 2 is acetylamino.
  • An example includes the compound 1f mentioned below.
  • 1,4: 3,6-dianhydromannitol derivatives selected from the group
  • the abovementioned compounds of the formulas (Ia) - (Id) or of formulas 1a to 1f are inhibitors of the protein tyrosine phosphatase Shp-2.
  • This enzyme is involved in inflammatory processes in the human body.
  • a use of a compound of the formula (Ia) - (Id) / a compound of the formulas 1a to 1f is therefore suitable for the preparation of an anti-inflammatory drug or of a protein tyrosine phosphatase inhibiting the function of Shp-2.
  • the abovementioned compounds of the formulas 1a to 1f, in particular compounds of the formulas 1a to 1d are distinguished by a particularly high affinity for the protein tyrosine phosphatase Shp-2. AnalytiCon Discovery GmbH
  • compounds of the formulas (Ia) - (Id) or compounds of the formulas 1a to 1f act as inhibitors of the protein tyrosine phosphatase PTP1B.
  • This enzyme is involved, among other things, in the pathological changes due to diabetes in the human body.
  • a use of a compound of the formulas (Ia) - (Id) / a compound of the formulas 1a to 1f is therefore suitable for the preparation of a medicament for the treatment of diabetes or a drug inhibiting the function of protein tyrosine phosphatase PTP1B.
  • the abovementioned compounds of the formulas 1b to 1f, in particular compounds of the formulas 1b to 1d are distinguished by a particularly high affinity for the protein tyrosine phosphatase PTP1B.
  • Another aspect of the invention relates to a medicament containing compounds corresponding to formulas (Ia) - (Id) or a compound of formulas 1a to 1f.
  • the medicine may also contain the usual galenical supplements.
  • the compounds 1a, 1c, 1d, 1e and 1f are accessible via the following synthesis scheme.
  • Compound 1b can be obtained by the following synthetic scheme.
  • Enzyme samples of protein tyrosine phosphatases of type SHP-2 and PTP1 B were measured with an automated measuring system.
  • the reaction volumes were 10 ⁇ l each.
  • the reaction was initiated by adding 5 ⁇ l of P-nitrophenyl phosphate to 5 ⁇ l of a solution containing the enzymes, which was previously incubated for 10 to 15 minutes with the different concentration of a double dilution series of the inhibitors.
  • the rate of reaction was monitored by the change in absorbance at a wavelength of 405 nm and correlated with control measurements without inhibitors.
  • IC 50 values were calculated by linear extrapolation of the reaction rate as a function of the logarithmic concentration.
  • the buffered solutions contained 2 mM DTE (1, 4-dithio-D, L-threitol was added on the day of the experiment from a 100 mM template) and 0.025% (v / v) of the detergent NP-40 (Calbiochem 492015). All reactions were performed in quadruplicate with identical solutions (1:10 in buffers from 10 mM stock DMSO solutions).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Diabetes (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Molecular Biology (AREA)
  • Obesity (AREA)
  • Biochemistry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne en particulier l'utilisation, comme principes actifs thérapeutiques, de dérivés de 1,4:3,6-dianhydromannitol de formules (Ia) - (Id) dans lesquelles R1 désigne un reste choisi parmi les groupes désignés ci-après : (i) tétrazoyle substitué ou non substitué; (ii) triazoyle substitué ou non substitué; (iii) thiophène-2-yl-acétylamino substitué ou non substitué; (iv) pyrimidine-2-ylamino substituée ou non substituée; et R2 désigne, pour des composés de formules (Ia) et (Ic) NHR3, où R3 désigne un reste choisi dans le groupe (O H; (ii) alkyle ou cycloalkyle; (iii) COR1 où R' est choisi parmi les groupes alkyle, hétéroaryle, aryle ou acide alkylcarboxylique; (iv) CONR'R' avec R1 et R' sélectionnés indépendamment l'un de l'autre parmi les groupes H, alkyle, cycloalkyle, hétéroaryle ou aryle; (v) CSNR'R' avec R' et R' sélectionnés indépendamment l'un de l'autre parmi les groupes H, alkyle, cycloalkyle, hétéroaryle ou aryle; (vi) SO2R' avec R1 sélectionné parmi les groupes alkyle, cycloalkyle, hétéroaryle ou aryle; ou R2 pour des composés de formules (Ib) et (Id) désigne OR4 où R4 désigne un reste choisi parmi les groupes (vii) alkyle, cycloalkyle, hétéroaryle ou aryle; (viii) CONR'R' avec R' et R' sélectionnés indépendamment l'un de l'autre parmi les groupes H, alkyle, cycloalkyle, hétéroaryle ou aryle.
PCT/EP2007/003332 2006-04-19 2007-04-05 Dérivés de 1,4:3,6-dianhydromannitol et leur utilisation Ceased WO2007121883A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006018912A DE102006018912A1 (de) 2006-04-19 2006-04-19 1,4:3,6-Dianhydromannitol-Derivate und deren Verwendung
DE102006018912.4 2006-04-19

Publications (2)

Publication Number Publication Date
WO2007121883A2 true WO2007121883A2 (fr) 2007-11-01
WO2007121883A3 WO2007121883A3 (fr) 2007-12-21

Family

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Family Applications (1)

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PCT/EP2007/003332 Ceased WO2007121883A2 (fr) 2006-04-19 2007-04-05 Dérivés de 1,4:3,6-dianhydromannitol et leur utilisation

Country Status (2)

Country Link
DE (1) DE102006018912A1 (fr)
WO (1) WO2007121883A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010130840A1 (fr) * 2009-05-15 2010-11-18 Roquette Freres Polymeres triazoles/tetrazoles issus de la cyclo addition de monomeres derives de dianhydrohexitol fonctionnalises, composes intermediaires, leurs procedes de preparation et leurs applications
JP2011514903A (ja) * 2008-03-03 2011-05-12 セノミックス インコーポレイテッド イソソルビド誘導体、ならびに香味修飾剤、食味物質、および香味強化剤としてのその使用
US9540391B2 (en) 2013-01-17 2017-01-10 Sanofi Isomannide derivatives as inhibitors of soluble epoxide hydrolase

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU724533A1 (ru) * 1977-08-02 1980-03-30 Ордена Трудового Красного Знамени Институт Органического Синтеза Ан Латвийской Сср 1-(5-Фторурацилил-1) - - глюкофурануронова кислота или ее ацилзамещенный лактон,обладающие антибластическим действием
DE19913604A1 (de) * 1999-03-25 2000-09-28 Basf Ag Chirale Verbindungen und deren Verwendung als chirale Dotierstoffe zur Herstellung von cholesterisch-flüssigkristallinen Zusammensetzungen

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011514903A (ja) * 2008-03-03 2011-05-12 セノミックス インコーポレイテッド イソソルビド誘導体、ならびに香味修飾剤、食味物質、および香味強化剤としてのその使用
CN102083836A (zh) * 2008-03-03 2011-06-01 西诺米克斯公司 异山梨醇衍生物及其作为味道调节剂、促味剂和味道增强剂的用途
EP2254891A4 (fr) * 2008-03-03 2011-07-27 Senomyx Inc Dérivés d'isosorbide et leur utilisation en tant que modificateurs de parfum, agents donnant du goût et exhausteurs de goût
US8420145B2 (en) 2008-03-03 2013-04-16 Senomyx, Inc. Isosorbide derivatives and their use as flavor modifiers, tastants, and taste enhancers
CN102083836B (zh) * 2008-03-03 2015-01-28 西诺米克斯公司 异山梨醇衍生物及其作为味道调节剂、促味剂和味道增强剂的用途
WO2010130840A1 (fr) * 2009-05-15 2010-11-18 Roquette Freres Polymeres triazoles/tetrazoles issus de la cyclo addition de monomeres derives de dianhydrohexitol fonctionnalises, composes intermediaires, leurs procedes de preparation et leurs applications
FR2945536A1 (fr) * 2009-05-15 2010-11-19 Roquette Freres Monomeres derives de dianhydrohexitol fonctionalises, intermediaires et polymeres triazoles/tetrazoles issus de leur cycloaddition, procede de preparation des differents composes et applications.
US9540391B2 (en) 2013-01-17 2017-01-10 Sanofi Isomannide derivatives as inhibitors of soluble epoxide hydrolase

Also Published As

Publication number Publication date
WO2007121883A3 (fr) 2007-12-21
DE102006018912A1 (de) 2007-10-25

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