+

WO2003033517A1 - Modulateurs de ship 1 - Google Patents

Modulateurs de ship 1 Download PDF

Info

Publication number
WO2003033517A1
WO2003033517A1 PCT/CA2002/001550 CA0201550W WO03033517A1 WO 2003033517 A1 WO2003033517 A1 WO 2003033517A1 CA 0201550 W CA0201550 W CA 0201550W WO 03033517 A1 WO03033517 A1 WO 03033517A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
salt
alkyl chain
atoms
Prior art date
Application number
PCT/CA2002/001550
Other languages
English (en)
Inventor
Raymond Andersen
David E. Williams
Alice Mui
Christopher Ong
Gerald Krystal
Original Assignee
The University Of British Columbia
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 The University Of British Columbia filed Critical The University Of British Columbia
Priority to CA002463136A priority Critical patent/CA2463136A1/fr
Priority to AT03714589T priority patent/ATE433458T1/de
Priority to ES03714589T priority patent/ES2327829T3/es
Priority to PCT/CA2003/000571 priority patent/WO2004035601A1/fr
Priority to DE60327936T priority patent/DE60327936D1/de
Priority to JP2004543854A priority patent/JP4753581B2/ja
Priority to EP03714589A priority patent/EP1554304B1/fr
Priority to CA2502293A priority patent/CA2502293C/fr
Publication of WO2003033517A1 publication Critical patent/WO2003033517A1/fr
Priority to US10/825,858 priority patent/US20040266865A1/en
Priority to US11/871,086 priority patent/US20080090909A1/en
Priority to US13/213,901 priority patent/US8765994B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to SHIP 1, a regulator of cell proliferation and survival and immune cell activity.
  • SHIP 1 inositol 5-phosphatase
  • SHIP 1 is an enzyme regulator of signaling pathways that control gene expression, cell proliferation, differentiation, activation, and metabolism, particularly of the Ras and phospholipid signaling pathways.
  • SHIP 1 disrupted (SHIP 1 -/-) mice exhibit a myeloproliferative phenotype characterized by overproduction of granulocytes and macrophages 1 .
  • SHIP 1 -/- mast cells are more prone to IgE and Steel factor induced degranulation, while SHIP 1 -/- B cells are resistant to negative regulation by Fc RIIB.
  • SHIP 1 is also involved in the pathogenesis of chronic myelogenous leukemia 2 .
  • pelorol A sesquiterpene compound termed pelorol may be obtained from various marine sponge species, including Petrosaspongia metachromia and Dactylospongia elegans.
  • This invention is based on the discovery that pelorol and related compounds are capable of modulation of SHIP 1 activity.
  • This invention provides a compound or a pharmaceutically acceptable salt thereof, the compound being capable of modulation of SHIP 1 activity, wherein the compound does not have the precise structure of pelorol but is a compound of Formula I:
  • X is selected from the group consisting of: OH, -OR, -O 2 CR, -SH, -SR, -SOCR, -NH 2 , -NHR, -NR 2 , -NR 3 + , -NHCOR, -I, -Br, -Cl, -F, -CN, -CO 2 H, -CO 2 R, -CHO, -COR, -CONH2, -CONHR, NRCOR, -CONR 2 , -COSH, -COSR-, CSOR, NO 2 , -OSO 3 H, -SO3H, , -SOR, -SO 2 R, -SO 2 NH 2 , -SO 2 NHR, and -SO 2 NR 2 ; and,
  • R is a linear, branched, or cyclic one to ten carbon, saturated, partially saturated, or unsaturated alkyl group.
  • the aromatic ring comprising Uj-U 4 includes ortho and para- quinones.
  • Ui, U 2 , U 3 and U 4 are independently CH, CX, or CRi;
  • Z is an alkyl chain of 3, A, or 5 atoms, more preferably being carbon atoms or carbons in C, CH, or CH 2 groups which have been replaced as defined;
  • W is an alkyl chain of 2 or 3 atoms, more preferably being carbon atoms or carbons in C, CH or CH groups which have been replaced as defined;
  • Y is an alkyl chain of between 1 and 3 atoms, more preferably being carbon atoms or carbons in C, CH, or CH 2 groups which have been replaced as defined.
  • Z has a chain of 4 atoms as defined; W has a chain of 2 atoms as defined; and/or Y has a chain of 1 or 2 atoms as defined. It is also even more preferred that the atoms of the chains of Z, W, and Y and the ring comprising U]-U 4 be carbon atoms.
  • This invention also provides a pharmaceutical composition for the treatment or prevention of an immune, inflammatory, or neoplastic condition or disorder comprising pelorol or another compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Such compositions may comprise two or more different compounds of Formula I, one of which may be pelorol.
  • This invention also provides a method of treatment or prevention of an immune, inflammatory, or neoplastic disorder or condition, comprising administering to a patient in need of such treatment or prevention, an effective amount of pelorol or other ⁇ compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • This invention also provides the use of pelorol or another compound of Formula I, or a pharmaceutically acceptable salt thereof, for modulation of SHIP 1 activity and for preparation of agents for the modulation of SHIP 1 activity.
  • modulation may be in vitro or in vivo.
  • Agents for in vivo use include the pharmaceutical composition described above and the modulation may be for the above described treatment or prevention of conditions or disorders.
  • Compounds of Formula I including pelorol may be prepared in whole or in part from natural sources such as by fractionating extracts of marine sponges, or synthesized according to methods as disclosed herein.
  • This invention also provides a method of making a compound of Formula I, comprising: combining a lactone of Formula II: _
  • N ⁇ -N 4 , Y, W and Z are as defined for Formula I, with an aromatic ring of Formula III:
  • Component Y in compounds of Formula I produced by the preceding method from a single compound of Formula II may have different degrees of saturation as compared to Y in the starting material (see Tables 1 and 2 for examples).
  • a compound of Formula I having an unsaturated Y may be selected and subjected to oxidizing and reduction steps to reduce the size of the ring comprising Y.
  • a preferred embodiment of the preceding method starts with an aromatic compound of Formula I comprising a (non-heterocyclic) ring of carbon atoms.
  • a preferred nucleophile (Nu) is lithium (Li) which may be substituted onto the ring for a halogen such as bromine (Br) at the same time as combination of the aromatic starting material with a compound of Formula II.
  • U U 4 are CX or CRj, with Rj preferably being limited to R as defined above.
  • Substitutents may also be protected, where appropriate with a protecting group (P) such as TBS.
  • Pelorol and other compounds having the structure of Formula I exhibit SHIP 1 agonist activity.
  • SHIP 1 neoplastic diseases such as myeloid and lymphoid leukemias, as an immunosuppressive agent and for affecting mast cell degeneration such as in the treatment or prevention of allergies.
  • Figure 1 is a graph depicting the effect of sponge extracts on SHIP 1 activity in vitro.
  • the assay was performed in 96-well microtitre plates.
  • SHIP 1 enzyme was produced with a hemagglutinin and a hexahistidine tag, from a mammalian expression vector. The His tag was employed to enhance purification.
  • SHIP 1 enzyme (lOng) was incubated with extract or DMSO for 15 minutes at room temperature before addition of 200 M inositol-l,3,4,5-tetrakisphosphate. The reaction was allowed to proceed for 20 minutes at 37 degrees C. The amount of inorganic phosphate released was then assessed by the addition of malachite green reagent followed by an absorbance measurement at 650 nm.
  • Figure 2 is a graph depicting the effect of pelorol on macrophage nitric oxide (NO) production.
  • Wild-type or SHIP 1 -/- macrophage cells were aliquoted into microtitre plates (5xl0 4 /well) and activated with 1 g/mL endotoxin in the presence or absence of PNG95-127 or DMSO carrier. The cells were incubated at 37 degrees C, 5% CO 2 for 24 hours and the culture supernatant was removed for NO determination using the Griess reagent, as shown.
  • X ⁇ -X 3 is X or Ri as defined in formula I or is H.
  • X 2 is an activating group such as OMe and NHAc.
  • ArBr is a halogen (Br) substituted benzene ring for which replacement of the halogen provides a compound of Formula III in which Nu is Li.
  • Pelorol and SHIP 1 agonist compounds of this invention exhibit anti-inflammatory actions on macrophages and mast cells in intact cell-based assays, and inhibit nitric oxide production from endotoxin activated wild-type macrophages. Results obtained for pelorol are shown in Figure 2. Such inhibition is not observed in SHIP 1 -/- macrophages. Pelorol and compounds of this invention also inhibit IgE induced mast cell degranulation.
  • compositions for use in this invention may be formulated into pharmaceutical compositions in any number of ways, which would be known to a person of skill in the art, all of which are within the scope of the invention.
  • the person of skill in the art may be expected to select appropriate pharmaceutically acceptable salts as well as appropriate pharmaceutically acceptable excipients, diluents, and carriers.
  • SHIP 1 modulators and pharmaceutical compositions of this invention may be administered to patients in need of treatment for cancer (neoplastic diseases), other cell proliferative disorders, inflammatory diseases and immune diseases.
  • neoplastic diseases such as, but not limited to, leukemias, carcinomas, sarcoma, melanomas, neuroblastoma, capillary leak syndrome and hematological malignancies are within the scope of this invention.
  • Diseases with an inflammatory component include, but are not limited to, rheumatoid arthritis, multiple sclerosis, Guillan-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, host versus graft, lupus erythematosis, Alzheimer's disease and insulin-dependent diabetes mellitus.
  • Diseases related to inappropriate activation of macrophage-related cells of the reticuloendothelial lineage include osteoporosis.

Landscapes

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

Abstract

La présente invention concerne l'utilisation de pélorol et de composés sesquiterpéniques apparentés en tant que modulateurs de l'activité de SHIP 1. L'invention concerne en outre de nouveaux composés sesquiterpéniques pouvant moduler l'activité de SHIP 1, ainsi que des procédés de synthèse de ces composés.
PCT/CA2002/001550 2001-10-17 2002-10-17 Modulateurs de ship 1 WO2003033517A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
CA002463136A CA2463136A1 (fr) 2001-10-17 2002-10-17 Modulateurs de ship 1
JP2004543854A JP4753581B2 (ja) 2002-10-17 2003-04-23 Ｓｈｉｐ１モデュレーター
ES03714589T ES2327829T3 (es) 2002-10-17 2003-04-23 Moduladores de ship 1.
PCT/CA2003/000571 WO2004035601A1 (fr) 2002-10-17 2003-04-23 Modulateurs de ship 1
DE60327936T DE60327936D1 (de) 2002-10-17 2003-04-23 Modulatoren von ship-1
AT03714589T ATE433458T1 (de) 2002-10-17 2003-04-23 Modulatoren von ship-1
EP03714589A EP1554304B1 (fr) 2002-10-17 2003-04-23 Modulateurs de ship 1
CA2502293A CA2502293C (fr) 2002-10-17 2003-04-23 Modulateurs de ship 1
US10/825,858 US20040266865A1 (en) 2001-10-17 2004-04-16 SHIP 1 modulators
US11/871,086 US20080090909A1 (en) 2001-10-17 2007-10-11 Ship 1 Modulators
US13/213,901 US8765994B2 (en) 2001-10-17 2011-08-19 Ship 1 modulators

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US32950601P 2001-10-17 2001-10-17
US60/329,506 2001-10-17

Related Child Applications (2)

Application Number Title Priority Date Filing Date
PCT/CA2003/000571 Continuation-In-Part WO2004035601A1 (fr) 2001-10-17 2003-04-23 Modulateurs de ship 1
US10/825,858 Continuation-In-Part US20040266865A1 (en) 2001-10-17 2004-04-16 SHIP 1 modulators

Publications (1)

Publication Number Publication Date
WO2003033517A1 true WO2003033517A1 (fr) 2003-04-24

Family

ID=23285735

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2002/001550 WO2003033517A1 (fr) 2001-10-17 2002-10-17 Modulateurs de ship 1

Country Status (2)

Country Link
CA (1) CA2463136A1 (fr)
WO (1) WO2003033517A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004035601A1 (fr) * 2002-10-17 2004-04-29 The University Of British Columbia Modulateurs de ship 1
WO2008022468A1 (fr) * 2006-08-24 2008-02-28 British Columbia Cancer Agency Branch Compositions et procédés servant à traiter l'insuffisance médullaire
EP2097753A4 (fr) * 2006-12-04 2010-03-10 British Columbia Cancer Agency Modulation allostérique de polypeptides ship et ses utilisations
WO2011069118A1 (fr) 2009-12-04 2011-06-09 Aquinox Pharmaceuticals Inc. Modulateurs de ship1 et méthodes associées
WO2012024682A1 (fr) * 2010-08-20 2012-02-23 The University Of British Columbia Modulateurs de ship1 et procédés associés
US8765994B2 (en) 2001-10-17 2014-07-01 The University Of British Columbia Ship 1 modulators
WO2014143561A1 (fr) 2013-03-14 2014-09-18 Aquinox Pharmaceuticals Inc. Modulateurs de ship1 et méthodes associées
WO2014158654A1 (fr) 2013-03-14 2014-10-02 Aquinox Pharmaceuticals Inc. Modulateurs de ship1 et procédés associés
US8956824B2 (en) 2006-12-04 2015-02-17 British Columbia Cancer Agency Branch Methods for identifying allosteric modulators of ship polypeptides
WO2016210146A1 (fr) 2015-06-26 2016-12-29 Aquinox Pharmaceuticals (Canada) Inc. Formes solides cristallines du sel d'acétate de (1s,3s,4r)-4-((3as,4r,5s,7as)-4-(aminométhyl)-7a-méthyl-1-méthylèneoctahydro-1h-indén-5-yl)-3-(hydroxyméthyl)-4-méthylcyclohexanol
US9540353B2 (en) 2013-01-09 2017-01-10 Aquinox Pharmaceuticals (Canada) Inc. SHIP1 modulators and methods related thereto
WO2017127753A1 (fr) 2016-01-20 2017-07-27 Aquinox Pharmaceuticals (Canada) Inc. Synthèse d'un dérivé d'indène substitué
WO2018126040A1 (fr) 2016-12-28 2018-07-05 Aquinox Pharmaceuticals (Canada) Inc. Formes solides cristallines de (1s,3s,4r)-4-((3as,4r,5s,7as)-4- (aminométhyl)-7a-méthyl-1-méthylèneoctahydro-1h-indén-5-yl)-3-(hydroxyméthyl)-4-méthylcyclohexanol
US10870648B2 (en) 2018-06-29 2020-12-22 Forma Therapeutics, Inc. Inhibiting CREB binding protein (CBP)
US11292791B2 (en) 2017-09-15 2022-04-05 Forma Therapeutics, Inc. Tetrahydro-imidazo quinoline compositions as CBP/P300 inhibitors
US11795168B2 (en) 2020-09-23 2023-10-24 Forma Therapeutics, Inc. Inhibiting cyclic amp-responsive element-binding protein (CREB) binding protein (CBP)
US11801243B2 (en) 2020-09-23 2023-10-31 Forma Therapeutics, Inc. Bromodomain inhibitors for androgen receptor-driven cancers

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007147251A1 (fr) * 2006-06-21 2007-12-27 The University Of British Columbia Composés modulateurs de la ship 1

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SOROKINA, I. B. ET AL: "Estrogen and antineoplastic activity in a series of transformed estrone and estradiol analogs", XP002230773, retrieved from STN Database accession no. 80:91450 *
HARRING SCOTT R ET AL: "Polyene cascade cyclizations mediated by BF-3 cntdot CH-3NO-2. An unusually efficient method for the direct, stereospecific synthesis of polycyclic intermediates via cationic initiation at non-functionalized 3 alkenes. An application to the total synthesis of (racemic)-taxodione.", TETRAHEDRON, vol. 50, no. 31, 1994, pages 9229 - 9254, XP002230772, ISSN: 0040-4020 *
HE W ET AL: "Novel cytokine release inhibitors. Part III: truncated analogs of tripterine", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 8, no. 24, 15 December 1998 (1998-12-15), pages 3659 - 3664, XP004150387, ISSN: 0960-894X *
IZVESTIYA AKADEMII NAUK SSSR, SERIYA BIOLOGICHESKAYA (1973), (5), 664-70 *

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8765994B2 (en) 2001-10-17 2014-07-01 The University Of British Columbia Ship 1 modulators
WO2004035601A1 (fr) * 2002-10-17 2004-04-29 The University Of British Columbia Modulateurs de ship 1
WO2008022468A1 (fr) * 2006-08-24 2008-02-28 British Columbia Cancer Agency Branch Compositions et procédés servant à traiter l'insuffisance médullaire
EP2097753A4 (fr) * 2006-12-04 2010-03-10 British Columbia Cancer Agency Modulation allostérique de polypeptides ship et ses utilisations
US8956824B2 (en) 2006-12-04 2015-02-17 British Columbia Cancer Agency Branch Methods for identifying allosteric modulators of ship polypeptides
WO2011069118A1 (fr) 2009-12-04 2011-06-09 Aquinox Pharmaceuticals Inc. Modulateurs de ship1 et méthodes associées
US8101605B2 (en) 2009-12-04 2012-01-24 Aquinox Pharmaceuticals Inc. SHIP1 modulators and methods related thereto
WO2012024682A1 (fr) * 2010-08-20 2012-02-23 The University Of British Columbia Modulateurs de ship1 et procédés associés
US9000050B2 (en) 2010-08-20 2015-04-07 The University Of British Columbia SHIP1 modulators and related methods
US9540353B2 (en) 2013-01-09 2017-01-10 Aquinox Pharmaceuticals (Canada) Inc. SHIP1 modulators and methods related thereto
US10272081B2 (en) 2013-01-09 2019-04-30 Aquinox Pharmaceuticals (Canada) Inc. SHIP1 modulators and methods related thereto
US9937167B2 (en) 2013-01-09 2018-04-10 Aquinox Pharmaceuticals (Canada) Inc. SHIP1 modulators and methods related thereto
US9765085B2 (en) 2013-03-14 2017-09-19 Aquinox Pharmaceuticals (Canada) Inc. SHIP1 modulators and methods related thereto
WO2014143561A1 (fr) 2013-03-14 2014-09-18 Aquinox Pharmaceuticals Inc. Modulateurs de ship1 et méthodes associées
WO2014158654A1 (fr) 2013-03-14 2014-10-02 Aquinox Pharmaceuticals Inc. Modulateurs de ship1 et procédés associés
US10100056B2 (en) 2013-03-14 2018-10-16 Aquinox Pharmaceuticals (Canada) Inc. SHIP1 modulators and methods related thereto
US10174046B2 (en) 2013-03-14 2019-01-08 Aquinox Pharmaceuticals (Canada) Inc. SHIP1 modulators and methods related thereto
WO2016210146A1 (fr) 2015-06-26 2016-12-29 Aquinox Pharmaceuticals (Canada) Inc. Formes solides cristallines du sel d'acétate de (1s,3s,4r)-4-((3as,4r,5s,7as)-4-(aminométhyl)-7a-méthyl-1-méthylèneoctahydro-1h-indén-5-yl)-3-(hydroxyméthyl)-4-méthylcyclohexanol
US9944590B2 (en) 2015-06-26 2018-04-17 Aquinox Pharmaceuticals (Canada) Inc. Crystalline solid forms of the acetate salt of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol
US10065920B2 (en) 2015-06-26 2018-09-04 Aquinox Pharmaceuticals (Canada) Inc. Crystalline solid forms of the acetate salt of (1S,3S,4R)-4-((3AS,4R,5S,7AS)-4-(aminomethyl)-7A-methyl-1-methyleneoctahydro-1H-inden-5-YL)-3- (hydroxymethyl)-4-methylcyclohexanol
WO2017127753A1 (fr) 2016-01-20 2017-07-27 Aquinox Pharmaceuticals (Canada) Inc. Synthèse d'un dérivé d'indène substitué
US10053415B2 (en) 2016-01-20 2018-08-21 Aquinox Pharmaceuticals (Canada) Inc. Synthesis of a substituted indene derivative
WO2018126040A1 (fr) 2016-12-28 2018-07-05 Aquinox Pharmaceuticals (Canada) Inc. Formes solides cristallines de (1s,3s,4r)-4-((3as,4r,5s,7as)-4- (aminométhyl)-7a-méthyl-1-méthylèneoctahydro-1h-indén-5-yl)-3-(hydroxyméthyl)-4-méthylcyclohexanol
US11292791B2 (en) 2017-09-15 2022-04-05 Forma Therapeutics, Inc. Tetrahydro-imidazo quinoline compositions as CBP/P300 inhibitors
US11787803B2 (en) 2017-09-15 2023-10-17 Forma Therapeutics, Inc. Tetrahydro-imidazo quinoline compositions as CBP/P300 inhibitors
US10870648B2 (en) 2018-06-29 2020-12-22 Forma Therapeutics, Inc. Inhibiting CREB binding protein (CBP)
US11254674B2 (en) 2018-06-29 2022-02-22 Forma Therapeutics, Inc. Inhibiting CREB binding protein (CBP)
US11795168B2 (en) 2020-09-23 2023-10-24 Forma Therapeutics, Inc. Inhibiting cyclic amp-responsive element-binding protein (CREB) binding protein (CBP)
US11801243B2 (en) 2020-09-23 2023-10-31 Forma Therapeutics, Inc. Bromodomain inhibitors for androgen receptor-driven cancers

Also Published As

Publication number Publication date
CA2463136A1 (fr) 2003-04-24

Similar Documents

Publication Publication Date Title
WO2003033517A1 (fr) Modulateurs de ship 1
Zucchelli et al. 5-year outcomes after coverage of soft tissue dehiscence around single implants: A prospective cohort study
Tasdemir et al. Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli
CA2870526C (fr) Analogues a cycle contraint en tant qu'inhibiteurs d'arginase
EP1246625B1 (fr) Compositions des esters de nitrate et leurs utilisation pour sedation
EP3151829B1 (fr) Nouveaux dérivés sesquiterpène et leur utilisation dans le traitement de l'inflammation et du cancer
WO2008018427A1 (fr) Dérivé d'ester de l'acide aminophosphorique et modulateur du récepteur s1p contenant ledit dérivé en tant que principe actif
US8765994B2 (en) Ship 1 modulators
EP3066106B1 (fr) Dérivés de la pantéthéine stable pour le traitement de la neurodégénérescence associée de pantothénate kinase (pkan) et procédés pour la synthèse de ces composés
AU2007262621A1 (en) SHIP 1 modulator compounds
Gnabre et al. Characterization of anti—HIV lignans
AR069225A1 (es) Procedimiento de preparacion de compuestos morfinicos
Silveira et al. Allylic thiocyanates as a new class of antitubercular agents
US20200199133A1 (en) Selective dual inhibitors of pi3 delta and gamma protein kinases
WO2013025790A2 (fr) Composés libérant no et h2s
Qian et al. Synthesis, molecular modeling and biological evaluation of guanidine derivatives as novel antitubulin agents
EP1554304A1 (fr) Modulateurs de ship 1
WO2004054569A1 (fr) Composition pharmaceutique contenant du brevifoliol destinee au traitement chimiotherapeutique d'etres humains
Yong et al. Synthesis and biological evaluation of quinazoline derivatives as potential anticancer agents (II)
EP2913321A1 (fr) Nouveaux dérivés cannabigérol
JP2015514701A (ja) ＰＩ３Ｋ−α及び／又はβの阻害剤としてのボロン酸をもったリファゲイン化合物
Fu et al. Synthesis, anti-HBV activity and renal cell toxicity evaluation of mixed phosphonate prodrugs of adefovir
Matsuya et al. Synthesis of new phorbol derivatives having ethereal side chain and evaluation of their anti-HIV activity
Liu et al. Inspired by magnolol: Design of NSAID-based compounds with excellent anti-inflammatory effects
Tolmacheva et al. Synthesis and evaluation of antiviral activities of triterpenic conjugates with 2-aminobutan-1-ol as potent microbicidal agents

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ OM PH PL PT RU SD SE SG SI SK SL TJ TM TN TR TZ UA UG US UZ VC VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZM ZW AM AZ BY KG KZ RU TJ TM AT BE BG CH CY CZ DK EE ES FI FR GB GR IE IT LU MC PT SE SK TR BF BJ CF CG CI GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2463136

Country of ref document: CA

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载