WO2011159864A1 - Analogues de jte013 et leurs procédés de préparation et d'utilisation - Google Patents

Analogues de jte013 et leurs procédés de préparation et d'utilisation Download PDF

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Publication number
WO2011159864A1
WO2011159864A1 PCT/US2011/040637 US2011040637W WO2011159864A1 WO 2011159864 A1 WO2011159864 A1 WO 2011159864A1 US 2011040637 W US2011040637 W US 2011040637W WO 2011159864 A1 WO2011159864 A1 WO 2011159864A1
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mmol
yield
compound
solution
nmr
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PCT/US2011/040637
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English (en)
Inventor
Rolf E. Swenson
Natarajan Raju
Maria E. Estrella-Jimenez
Kondareddiar Ramalingam
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Bracco Imaging S.P.A.
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Publication of WO2011159864A1 publication Critical patent/WO2011159864A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to Sphingosine-1 -phosphate (SIP) receptors and compounds used in the treatment and prevention of conditions associated with such receptors.
  • SIP Sphingosine-1 -phosphate
  • S 1P 2 levels have also been correlated with other inflammatory diseases.
  • the only S1P 2 receptor selective antagonist compound. JTE01 has been found to have poor in vivo characteristics, based at least in part on its rapid clearance.
  • One embodiment of the present invention provides JTE013 analogs having similar or greater stability than JTE013.
  • Another embodiment of the present invention provides JTE013 analogs characterized by their ability to bind to sphingosinel -phosphate receptors 2 (S I P ? ), and sphingosine- 1 -phosphate receptors 5 (S 1P 5 ).
  • JTE013 analogs that are more stable than JTE013 and which also bind to both S 1P 2 and S1P 5 .
  • the present invention also provides methods of treating or preventing diseases or conditions associated with S IP receptors, particularly S1P 2 and SIP5. Such conditions include, but are not limited to inflammatory diseases and conditions as well as diseases and conditions associated with angiogenic processes. Further embodiments of the present invention include methods of making stable JTE013 analogs, methods of making JTE013 analogs which bind to both S I Pi and S1P 5 and methods of making JTE013 analogs which are both stable and bind to both of these receptors.
  • JTE013 is the only currently available S1P 2 receptor selective antagonist compound.
  • the present inventors herein have confirmed anecdotal reports that JTE013 has very poor in vivo characteristics, based at least in part on its rapid clearance. These characteristics limit the efficacy and usefulness of JTE013 in treating and preventing sphingosine- 1 -phosphate-mediated diseases and disorders.
  • JTE013 A number of novel analogs of JTE013 were prepared. Details for making these analogs are provided in the Examples. These compounds showed unexpectedly enhanced stability to liver microsomes using a well-established in vitro model for in vivo metabolism and metabolic stability, in addition, most of these compounds unexpectedly bound to both S 1 P 2 and S IP 5 receptors.
  • These compounds have utility as therapeutic drugs for the treatment and prevention f conditions or diseases mediated by S 1 P receptors.
  • conditions and diseases include, but are not limited to a wide variety of inflammatory diseases and conditions as well as diseases and conditions mediated by angiogenesis processes.
  • novel JTE013 analog compounds according to the present invention may be used to treat or prevent atherosclerosis and conditions associated therewith, including cardiovascular and cerebrovascular diseases, such as, for example, myocardial infarction, stroke, angina and peripheral vascular disease. These compounds also may be used to treat or prevent sepsis and septic shock.
  • JTEOl 3 analogs according to the present invention also may be useful for a wide variety of other diseases including diabetes, liver cirrhosis, vascular diseases with increased permeability, and allergic reactions.
  • DFU diabetic foot ulcers
  • JTEOl 3 analogs according to the present invention may be useful in treating diabetic foot ulcers.
  • Liver cirrhosis is most commonly caused by chronic liver injury due to heavy alcohol consumption and/or chronic hepatitis C infection. Liver cirrhosis causes 27,000 deaths every year and is the twelfth leading cause of death by disease. In cirrhosis, scar tissue replaces healthy liver tissue partially blocking the flow of blood through the liver leading to portal hypertension.
  • the S 1P 2 receptor has been shown to trigger hepatic wound healing and scarring by enhancing proliferation of hepatic myofibroblasts. liMF and hepatic stellate cells.
  • SIP is shown to enhance portal pressure in isolated perfused rat liver by activating S 1P 2 in hepatic stellate cells. JTEO l 3 analogs may be useful for treating portal hypertension.
  • SIP 2 activation by S1P 2 antagonist(s) may reduce hyper-permeability and edema associated with vascular diseases.
  • SIP has also been shown to be an important regulator of allergen-induced mast cell activation due to its activation of the mitogen-activated protein kinase pathway, resulting in hexosaminidase and leukotriene release.
  • .ITE-013 has been shown to block ova 1 b u m i n - i n du cctl mast cell-dependent contraction of lun parenchymal strips from o ⁇ albumin-sensitized rats. Therefore, JTE-013 analogs may be useful in treating allergic reactions.
  • these novel analogs may be used to treat or prevent angiogenesis associated with a v ariety of ocular diseases, particularly diseases involving angiogenesis.
  • compound 83c shown below is expected to have enhanced stability.
  • JTE013 analogs described above may be formulated into pharmaceutical preparations and are useful treating or preventing conditions associated with SIP receptors, particularly SIP? and S 1P 5 .
  • Suitable pharmaceutically acceptable carriers include, but are not limited to sterile water, saline solution, buffered saline (including buffers like phosphate or acetate), alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxynethyl cellulose, polyvinylpyrrolidone and the like.
  • compositions may further comprise conventional excipients: i.e.. pharmaceutically acceptable organic or inorganic earner substances suitable for parenteral, enteral or intranasal application which do not deleteriously react with the active compounds.
  • the pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents, e.g. lubricants, preservatives, stabilizers, wetting agents, emulsi tiers, salts for influencing osmotic pressure, buffers, colorings, flavorings, and/or aromatic substances and the like which do not deleteriously react with active compounds.
  • auxiliary agents e.g. lubricants, preservatives, stabilizers, wetting agents, emulsi tiers, salts for influencing osmotic pressure, buffers, colorings, flavorings, and/or aromatic substances and the like which do not deleteriously react with active compounds.
  • the pharmaceutical composition may be prepared by any of the known procedures as described in Remington's Pharmaceutical Sciences
  • compositions may be in various forms such as tablets or solutions and may be administered by various routes including, but not limited to, parenteral ly (including intravenously, intramuscularly, subcutaneously and intraperitoneally), orally, topically (including ocular administration) nasally and via inhalation.
  • parenteral ly including intravenously, intramuscularly, subcutaneously and intraperitoneally
  • topically including ocular administration
  • Syrups, elixirs or the like may be used as sweeteners.
  • Sustained release compositions may be formulated and include those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings and the like. Other methods f delaying release of the active component also may be employed.
  • a "therapeutically effective amount" of a pharmaceutical composition is an amount which is sufficient to achieve the desired
  • the dosage required to provide an effective amount of the composition will vary, depending upon the age, health, physical conditional, sex, weight and extent of disease, f the recipient. Additionally, the dosage may be determined by the frequency of treatment and the nature and scope f the desired effect. Appropriate dosages will be determined by those of ordinary skill in the art, using routine methods.
  • the dose range is from 0.001 to 100 mg of active compound per kilogram body weight.
  • the range is from 0.01 to 50 mg. of active substance per kilogram body weight.
  • a preferred composition of the invention is for example, one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains from 1 microgram to 500 mg, more preferably from 10 to 100 mg, of the active component in each unit dose, such that a daily oral dose is from 1 nanogram to 50 milligram per kg of body weight, more preferably from 0.1 to 25 mg/kg, is thereby achieved.
  • Another preferable composition is one suitable for parenteral administration which contains from 0.5 to 100 mg of active compound per ml. more preferably from 1 to 10 mg of compound per ml of solution, such that a daily parenteral dose of from 1 nanogram to 10 mg per kg of body weight, more preferably from 0.1 to 10 mg/kg, is thereby achieved.
  • Tritylchloride (2.85 g, 10.22 mmol) was added to a solution of 2,6- dichloropyridine 61 ( 1 .63 g, 10 mmol) and d i i sopropy 1 ethyl am i ne ( 1 .42 g, 20. mL) 1 1.0 mmol) in CH 2 CI 2 (20.0 mL) and the mixture was stirred for 16 h. Concentration of methylene chloride solution gave a foamy solid, which was dissolved in ethyl acetate, was washed with water and dried under vacuum. The residue was dissolved in methanol and the solid formed was filtered and dried to give the trityl derivative. Yield 3.8 g (93.8%).
  • Acetic acid (15.0 ⁇ ) was added to a mixture of Nal (10.0 ⁇ _) and 77 (10.0 ⁇ ,) followed by chloamine T (10.0 ⁇ _ ). The reaction mixture was gently vortexed twice. After 1 5 min the reaction mixture was quenched with Na 2 S 2 0 3 (10.0 ⁇ ) and analyzed by liPLC.
  • RiNTiNH 2 .Oxalate NEt 3 , ethanol reflux, 12h; ii) RiCOCH 2 COOEt, Propionic acid, 140° C, 12h; iii) POBr 3 , anisole, 140° C, 4h; iv) R 2 NHNH 2 ; ethanol or dioxane, reflux, 20h; v) Hydrazine, Carbamate 7, Dioxane, Reflux, 12h.
  • Methyl hydrazine (5.0 equiv.) was added dropwisc to a stirred solution of 2,6-dichloro-4- alkylnicotinonitrile (1.0 equiv. ) in dioxae ( 5.0 niL/g) over a period of 10.0 min with vigorous stirring. After the addition, the reaction mixture was heated to reflux for 20h. The solution was cooled and the crystallized product was filtered and washed with ether (2x25.0 m L) and dried. Yield: 91a - 3.5 g( 89%, 20.0 mmol scale).
  • Sodium cyanoborohydride (4.0 equiv.) was added to a stirred solution of the hydrazone 92/92a (1.0 equiv.) and aqueous formaldehyde (37% in water, 10.0 equiv.) in methanol/THF mixture ( 1 : 1 - 1 0.0 niL) while the pH was kept at 5.0 - 6.0 by the addition of acetic acid. After the addition, the reaction mixture was stirred at RT for 20h. A saturated solution of sodium carbonate was added to the above reaction mixture until the pH reached about 10.0. The solution was further diluted with water and the precipitate was filtered, washed with water and air dried.
  • the crude mixture was purified by preparative HPLC [column: X-Bridge C 18 ; 250 x 19 mm; 10.0 ⁇ ; solvent A: water with 0.1% TEA v/v and solvent B: acetonitrile with 0.1 % TEA v/v; initial conditions: 5% B in A; gradient: 5 to 55% B over 50 min; elution rate: 30.0 niL/min: detection @ 220.0 nm].
  • the major peak eluted at 38.0 min was collected and freeze dried to yield the product as its TFA salt. Yield: 94 - 10.0 mg (31%, 0.059 mmol scale).
  • Acid 97 (0.2 g, 1.0 mmol) was suspended in dry toluene (10.0 ml) and thionyl chloride ( 5.0 mL) and DMF (3.5 nig, 0.05 mol ) were added and the mixture was refluxed vigorously for 24 h. The volatiles were removed under reduced pressure and the crude residue was stirred with a solution of sodium azide (2.0 g, 30.0 mmol ) in acetonitrile (5 nil ) for 2h at 40° C. The cooled reaction mixture was poured into water (100.0 mL) and extracted with EtOAc (3 x 20.0 mL). The combined organic layers were washed with water (3 x 50.0 mL) and dried (Na 2 S0 4 ).
  • the monomethylated amine (60.0 mg, 0.28 mmol) was heated with HCOOH (1.0 mL) and Ac 2 0 (0.5 mL) at 70° C for 40 h.
  • the solution was diluted with water (20.0 m L) and neutralized with saturated sodium carbonate, the aqueous solution was extracted with EtOAc (3 x 20.0 mL), the organic layers combined, washed with water (3 x 20.0 mL) and dried (Na 2 S0 4 ).
  • the solution was filtered and concentrated to a paste that was purified by a Biotage column (25.0 g) and elution with 2% methanol in DC M furnished the product as colorless paste. Yield: 42.0 mg ( 60%).
  • 101b Prepared following a similar procedure for 101a. Yield: 20.0 mg [pale yellow solid; 20%). The crude product was triturated with acetonitrile (2.0 m L) and filtered and washed with acetonitrile (3 x 2.0 mL) and air dried. The purity by HPLC was >95% and no other purification was needed. t R : 10.41 min (analytical H LC: as above; initial conditions: 2% B in
  • 101c Prepared similar to 101 a. Yield: 10.0 mg as TFA salt [14%; purified by prep. HPLC as indicated in the case of 101 a; analytical conditions: same as above for 101 a and 101b; initial conditions: 10% B; gradient: 10 to 40% B over 10.0 min; purity > 98%].
  • Tri fl uoromethanesul foni c anhydride (0.85 g, 3.0 mmol) was added dropwise under nitrogen to a stirred solution 96 (0.55g, 2.3 mmol) and triethylamine (0.51 g, 5.0 mmol) in anhydrous dichloromethane at 0° C over 10 min.
  • the reaction mixture was diluted with EtOAc (50.0 mL) and washed with ice cold water (3 x 50.0 mL) and dried (Na 2 S0 4 ). The solution was filtered, concentrated under reduced pressure and the residue was purified by a Biotage column (50. Og). Elution with 5% EtOAc in hexanes yielded the product as colorless oil. Yield: 0.55g(65%).
  • Methyl hydrazine (38.0 mg, 0.82 mmol) was added to a solution of triflate 102 (O. lg, 0.27 mmol) in a mixture of anhydrous tolucne/THF mixture (1 : 1 , 0.3 mL), and stirred at 65° C for 1 h under nitrogen.
  • the reaction mixture was diluted with EtOAc (20.0 m L) and washed with water (3 x 20.0 mL) and dried (Na 2 SC>4).
  • the solution was filtered and concentrated under reduced pressure to yield a paste that was crystallized from hexanes to provide the hydrazine as colorless solid. Yield: 45.0 mg (63%).
  • the supernatant was transferred in an Agilent autosampler vial and analyzed by LC-MS. on a Rigel C8 column (4.6 x 1 50 mm, 5 ⁇ pore size) cluted at a flow rate of 1 mL/min using an aqueous/organic gradient of 0.05% formic acid in water (A) and 0.05% formic acid in acetonitrile ( B). The following gradient was used: 100% A to 100% B in 30 min, hold 100%B for 5 min.
  • Binding affinity for S1P 2 and SlP 5 of JTE-013 analogs were evaluated. Antagonist percentage inhibition determinations were obtained by assaying sample compounds and referencing the control EC 80 wells for each GPCR profiled. We evaluated binding to S1P 2 and S1P 5 receptors. The samples were run using a "Single Addition" assay protocol. The protocol design is as follows. Master stock solution
  • sample compounds were diluted in 100% anhydrous DM SO including all dilutions. If the sample compound is provided in a different solvent all master stock dilutions are performed in the specified solvent. AH control wells contained identical solvent final concentrations as the sample compound wells.
  • sample compounds were transferred from a master stock solution into a daughter plate that was used in the assay.
  • Each sample compound was diluted into assay buffer (Ix HBSS with 20mM HEPES, 2.5mM Probenecid, and 0.4% Free Fatty Acid BSA) at an appropriate concentration to obtain final specified concentrations.
  • assay buffer Ix HBSS with 20mM HEPES, 2.5mM Probenecid, and 0.4% Free Fatty Acid BSA

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne des analogues de JTE013 qui possèdent une stabilité similaire ou supérieure à JTE013. L'invention porte en outre sur des analogues de JTE013 qui peuvent se lier à la fois à S1P2 et à S IP5, et dont certains présentent une stabilité similaire ou supérieure à JTE013. En outre, l'invention porte sur des procédés de traitement et de prévention de maladies et d'états associés aux récepteurs S1P2 et S IP5.
PCT/US2011/040637 2010-06-17 2011-06-16 Analogues de jte013 et leurs procédés de préparation et d'utilisation WO2011159864A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013148460A1 (fr) * 2012-03-26 2013-10-03 Swenson Rolf E Nouveaux antagonistes des récepteurs de la sphingosine 1-phosphate
WO2014158302A1 (fr) * 2013-03-25 2014-10-02 Swenson Rolf Eric Nouveaux antagonistes de récepteur de sphingosine 1-phosphate
WO2016191872A1 (fr) * 2015-06-01 2016-12-08 Dalhousie University Antagonistes de s1pr2 et leurs utilisations
US10058543B2 (en) 2014-06-02 2018-08-28 Dalhousie University Treatment of familial exudative vitreoretinopathy through S1PR2 inhibition
US10487082B2 (en) 2015-06-01 2019-11-26 Dalhousie University S1PR2 antagonists and uses therefor
US10858358B2 (en) 2015-06-01 2020-12-08 Dalhousie University S1PR2 antagonists and uses therefor

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US3542793A (en) * 1966-01-12 1970-11-24 Ciba Geigy Corp 4-unsubstituted-5-amino- or 5-acylamino-pyrazolo(3,4-b)pyridines
US4612318A (en) * 1982-09-22 1986-09-16 Gruppo Lepetit S.P.A. CNS-depressant and analgesic tricyclo-[pyrazolo-[3,4-6]-pyridine] derivatives and pharmaceutical compositions thereof
WO2001098301A1 (fr) * 2000-06-20 2001-12-27 Japan Tobacco Inc. Composes de pyrazolopyridine et utilisation de ces derniers en tant que medicaments
US20100068200A1 (en) * 2008-09-12 2010-03-18 The University Of Connecticut Methods and Compositions for Inhibiting Atherosclerosis and Vascular Inflammation
US20100112037A1 (en) * 2008-10-31 2010-05-06 Max Bachrach S1p receptor agonists for the treatment of cerebral malaria

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3542793A (en) * 1966-01-12 1970-11-24 Ciba Geigy Corp 4-unsubstituted-5-amino- or 5-acylamino-pyrazolo(3,4-b)pyridines
US4612318A (en) * 1982-09-22 1986-09-16 Gruppo Lepetit S.P.A. CNS-depressant and analgesic tricyclo-[pyrazolo-[3,4-6]-pyridine] derivatives and pharmaceutical compositions thereof
WO2001098301A1 (fr) * 2000-06-20 2001-12-27 Japan Tobacco Inc. Composes de pyrazolopyridine et utilisation de ces derniers en tant que medicaments
US20100068200A1 (en) * 2008-09-12 2010-03-18 The University Of Connecticut Methods and Compositions for Inhibiting Atherosclerosis and Vascular Inflammation
US20100112037A1 (en) * 2008-10-31 2010-05-06 Max Bachrach S1p receptor agonists for the treatment of cerebral malaria

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013148460A1 (fr) * 2012-03-26 2013-10-03 Swenson Rolf E Nouveaux antagonistes des récepteurs de la sphingosine 1-phosphate
CN104334556A (zh) * 2012-03-26 2015-02-04 罗尔夫·E·斯文森 新型1-磷酸鞘氨醇受体拮抗剂
JP2015524789A (ja) * 2012-03-26 2015-08-27 スウェンソン，ロルフ，イー 新規なスフィンゴシン１‐リン酸受容体アンタゴニスト
AU2013240139B2 (en) * 2012-03-26 2017-02-23 Arroyo Biosciences L.L.C. Novel sphingosine 1-phosphate receptor antagonists
CN104334556B (zh) * 2012-03-26 2017-05-17 爱若优生物科技有限公司 新型1‑磷酸鞘氨醇受体拮抗剂
WO2014158302A1 (fr) * 2013-03-25 2014-10-02 Swenson Rolf Eric Nouveaux antagonistes de récepteur de sphingosine 1-phosphate
US10058543B2 (en) 2014-06-02 2018-08-28 Dalhousie University Treatment of familial exudative vitreoretinopathy through S1PR2 inhibition
WO2016191872A1 (fr) * 2015-06-01 2016-12-08 Dalhousie University Antagonistes de s1pr2 et leurs utilisations
CN107849038A (zh) * 2015-06-01 2018-03-27 达尔豪西大学 S1pr2拮抗剂及其用途
US10487082B2 (en) 2015-06-01 2019-11-26 Dalhousie University S1PR2 antagonists and uses therefor
US10858358B2 (en) 2015-06-01 2020-12-08 Dalhousie University S1PR2 antagonists and uses therefor
AU2016273436B2 (en) * 2015-06-01 2021-01-28 Dalhousie University S1PR2 antagonists and uses therefor

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