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WO2008130319A2 - Nouveaux composés 805 - Google Patents

Nouveaux composés 805 Download PDF

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Publication number
WO2008130319A2
WO2008130319A2 PCT/SE2008/050458 SE2008050458W WO2008130319A2 WO 2008130319 A2 WO2008130319 A2 WO 2008130319A2 SE 2008050458 W SE2008050458 W SE 2008050458W WO 2008130319 A2 WO2008130319 A2 WO 2008130319A2
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
tetrahydronaphthalen
amine
chromen
dihydro
Prior art date
Application number
PCT/SE2008/050458
Other languages
English (en)
Other versions
WO2008130319A3 (fr
Inventor
Yevgeni Besidski
Alf Claesson
Gabor Csjernyik
Ylva Gravenfors
Inger Kers
Karin Skogholm
Daniel Sohn
Original Assignee
Astrazeneca Ab
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 Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2008130319A2 publication Critical patent/WO2008130319A2/fr
Publication of WO2008130319A3 publication Critical patent/WO2008130319A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/54—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • Alpha subunits are large proteins of an approximate weight of 260 kDA ( ⁇ 2000 amino acids), and are functional as voltage-gated sodium channels as monomeric structures.
  • Beta subunits are known at present. Beta subunits are smaller proteins of an approximate weight of 33-36 kDa. Beta subunits can modulate functional expression, as well as the characteristics of channel opening and closing (gating) of alpha subunits.
  • a main biophysical characteristic of voltage-gated sodium channels is the fast opening and closing (activation and inactivation) of the channel upon an appropriate voltage stimulus. These features make voltage-gated sodium channels absolutely essential in the generation of the upstroke of the action potential in most neuronal and muscle cells, and thereby central to the functionality of such tissue. Thus, inhibitory pharmacological interference with the activity of NaVs is expected to have dampening effects on excitability of such tissue. Such agents may thus be useful in the treatment of diseases that involve hyperactivity of neuronal or muscle tissue.
  • WO 97/34883, WO 99/14212, WO 99/05135 and WO 99/14213 describe compounds for use in treatment of pain.
  • the compounds described in these prior art documents bind to serotonine receptors.
  • the compounds of the present invention have little to none activity towards the serotonine receptor.
  • the compounds of the present invention also are contemplated to have an improved pharmacokinetic profile compared to the compounds in the prior art, including a higher oral bioavailability, a decreased clearance and a decreased volume of distribution. Without being bound to any theory, the difference in pharmacokinetic profile is believed to be due to the fact that the right hand side of the molecule is aromatic in the compounds of the present invention while this is not the case for the known compounds.
  • X is O or CH 2 ;
  • Ri-Y is selected from Ri-Ci -4 alkyl, Ri-Ci -4 alkylN(Ci -4 alkyl)Ci -4 alkyl, Ri-Ci -4 alkylNH, Ri- NH, Ri-C(O), Ri-O, Ri-Ci -4 alkylO, Ri -C(O)C M alkyl0 and Ri-SO 2 -O;
  • o Ri is phenyl, tetrahydroisoquinolinyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, - N(Ci -4 alkyl) 2 , -NHCi -4 alkyl, NH 2 , imidazolyl, thiazolyl or pyridinyl, which may be independently mono-, di-, or tri-substituted with Rn, Ri 2 , and/or Rn, wherein Rn, Ri 2 , and Rn are independently selected from Ci -6
  • Ri-Y is selected from 5 R 1 -methyl, Ri-CH 2 C(CH 3 ) 2 , Ri-NH Ri-C(O), Ri-O, Ri-methyl(methylamino)methyl, R 1 - ethylamino, Ri-methoxy, Ri-ethoxy, Ri- Ri-CH 2 C(CHs) 2 O, Ri-carbonylmethoxy or Ri- sulfonyloxy.
  • R 2 is phenyl, triazolyl, tetrahydroisoquinolinyl, oxazolyl, indolinyl or pyridinyl, which may be independently5 mono- or di-substituted with Ri 4 , Ri 5 , and/or Ri 6 ; wherein R H , R I 5 , and are independently selected from:
  • Another embodiment relates to a compound having the formula (Ia)
  • R 3 Is H Or W 1 CH 3 ;
  • R 2 i is H, Ci -6 alkyl, or C 3-6 cycloalkyl
  • cycloalkyl refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system.
  • the term “Ci. 6 cycloalkyl” may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • heterocycloalkyloxy refers to a heterocycloalkyl as defined avobe substituted on a oxygen molecule as for example in example 86.
  • a suitable pharmaceutically acceptable salt of the compounds of the invention is, for example, an acid-addition salt, for example a salt with an inorganic or organic acid.
  • a suitable pharmaceutically acceptable salt of the compounds of the invention is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base.
  • Other pharmaceutically acceptable salts and methods of preparing these salts may be found in, for example, Remington's Pharmaceutical Sciences (18th Edition, Mack Publishing Co.).
  • the compounds of the present invention may also exists as solvents, solvated hydrates or cocrystals.
  • a suitable base may be an organic amine base such as pyridine, 2,6-lutidine, collidine, triethylamine, morpholine, N-methylmorpholine, diazabicyclo[5.4.0]undec-7-ene or tetramethylguanidine or an alkali metal or an alkaline earth metal carbonate or hydroxide such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • the reaction may be aided by the presence of 4-dimethylaminopyridine.
  • a mouse line has been generated which through advanced molecular biology technologies eliminates the functional expression of Navl.7 in DRG neurons that express Navl.8
  • antipsychotics including for example amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone
  • urinary incontinence therapies including for example darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • GABAb modulators such as baclofen, and equivalents and pharmaceutically active salts and metabolite(s) thereof.
  • the compounds of the invention will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation, or by any other parenteral route, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • Another embodiment relates to said pharmaceutical composition according, for use in the treatment of pain or acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain.
  • Amine 21 (3S)-5-(2-pyrrolidin-l-ylethoxy)chroman-3-amine
  • Amine 22 (3S)-5-[(l-methylpyrrolidin-3-yl)oxy]chroman-3-amine
  • Triethylamine (8.8 mL, 63.2 mmol) was added to a cooled (-40 0 C) solution of (35)-3- (dibenzylamino)chroman-5-ol (15.6 g, 45.2 mmol, described in WO9914212A1) in anhydrous dichloromethane (250 mL) under an atmosphere of nitrogen.
  • a solution of0 trifluoromethanesulfonic anhydride (9.4 mL, 56.5 mmol) in anhydrous dichloromethane (70 mL) was added dropwise to the reaction mixture over 25 min. The cooling was removed, the reaction mixture was stirred until it reached room temperature, cooled again to 0 0 C and saturated aqueous sodium bicarbonate was added.
  • reaction mixture was stirred at ambient temperature for 7 h.
  • the reaction mixture was partly concentrated in vacuo and added IM hydrochloric acid until a neutral p ⁇ was reached.
  • the reaction mixture was extracted with ethyl acetate (3 x 20 mL) dried over sodium sulfate and concentrated in vacuo.
  • Gene(s) encoding the full-length protein of the voltage-gated sodium channel of interest are cloned and expressed under a suitable promoter in a suitable cell line, as well known in the art.
  • the so constructed stable cell lines are used in screening assays to identify suitable compounds active on voltage-gated sodium channels. Suitable screening assays are as follows.
  • the cell line expressing the voltage-gated sodium channel of interest is plated in conventional 96 or 384 well tissue plates at a suitable cell density (for example 40000 cells/well in 96 well plate, or 20000 cells/well in 384 well plate).
  • the cells are then repeatedly washed with a suitable Na free buffer using a suitable commercially available washer (for example EL-405 washer) until all tissue culture medium is removed from the wells.
  • a suitable Na- free buffer could have the composition (mM) Choline chloride 137, KCl 5.4, MgSO4 0.81, CaC12 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. After completion of all wash steps, cells are incubated in the suitable Na free buffer for 15 minutes.
  • a buffer rich in LiCl rich in LiCl for 60 minutes at 37 0 C.
  • the LiCl buffer is also enriched in potassium ions, causing a depolarizing stimulus to the cells.
  • Such a buffer may have the composition (mM): LiCl 100, KCl 50, MgSO4 0.81, CaC12 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition.
  • an effective concentration for example 100 ⁇ M
  • the voltage-gated sodium channel opener veratridine, or any other suitable voltage-gated sodium channel opener may be added to the medium to enhance signal detection.
  • an effective concentration for example 10 ⁇ g/ml
  • suitable scorpion venom may also be added to the medium to delay channel inactivation.
  • the assay can be complemented with compounds from a compound library. Compounds of interest are added to the Li-rich solution, one in each well. At the end of the incubation period cells are repeatedly washed with Na free buffer until all extracellular LiCl is removed. Cell lysis is obtained through incubation of cells with triton (1%) for 15 min, or any other suitable method. The resulting cell lysate is then introduced into an atomic absorption spectrophotometer, thus quantifying the amount of Li-influx during the procedure described above.
  • the described assay can be run with any atomic absorption spectrophotometer using plates of 96-well format, 384-well format, or any other conventional plate format.
  • the described assay can be applied to cell lines expressing any given one or more of the voltage-gated sodium channel alpha subunits, as well as any given combination of one of the voltage- gated alpha subunits with any one or more beta subunit.
  • the cell line of choice can be further hyperpolarised by expression of a suitable potassium leak ion channel, for example TREK-I, either by transient co-transfection or through establishment of a stable co-transfected cell line.
  • a suitable potassium leak ion channel for example TREK-I
  • the successful expression of a leak K current can be verified using traditional intracellular electrophysiology, either in whole cell patch-clamp, perforated patch-clamp or conventional two-electrode voltage- clamp.
  • a cell line of choice modified to successfully express a voltage-gated sodium channel of interest together with a suitable potassium leak ion channel transfected can then be used for screening using atomic absorptions spectrometry, as described above.
  • Electrophysiological recordings of sodium currents in cells stably expressing the voltage- gated sodium channel of interest confirms activity and provides a functional measure of the potency of compounds that specifically affect such channels.
  • Electrophysiological studies can be performed using automated patch-clamp electrophysiology platforms, like Ion Works HT, Ion Works Quattro, PatchXpress, or any other suitable platform.
  • the cell line expressing the voltage-gated sodium channel of interest is plated in appropriate well tissue plates, as provided by the manufacturer of the automated patch-clamp platforms. Suitable extracellular and intracellular buffer for such experiments are applied according to the instructions given by the manufacturer of the automated patch-clamp platforms. Cells that express the voltage-gated sodium channel protein of interest are exposed to drugs through the pipetting system integrated in the platforms.
  • a suitable voltage stimulus protocol is used to activate the voltage-gated sodium channel proteins of interest.
  • a suitable stimulus protocol may consist of eight voltage pulses, each to -20 mV and 50 ms in length, and separated from each other by 330 ms intervals at a potential of -90 mV, but may also have other suitable parameters.
  • Electrophysiological studies can also be performed using the whole cell configuration of the standard patch clamp technique as described in the literature (26).
  • cells that express the human voltage-gated sodium channel protein of interest are exposed to the drugs by conventional microperfusion systems and a suitable voltage stimulus protocol is used to activate the voltage-gated sodium channels.

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

Abstract

La présente invention concerne de nouveaux composés et une composition pharmaceutique contenant ces composés et l'utilisation desdits composés en thérapie. Cette invention porte également sur des procédés de préparation de ces composés et sur de nouveaux intermédiaires utiles dans la préparation de ces derniers.
PCT/SE2008/050458 2007-04-23 2008-04-22 Nouveaux composés 805 WO2008130319A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US91330907P 2007-04-23 2007-04-23
US60/913,309 2007-04-23

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WO2008130319A2 true WO2008130319A2 (fr) 2008-10-30
WO2008130319A3 WO2008130319A3 (fr) 2008-12-18

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012067963A1 (fr) * 2010-11-15 2012-05-24 Abbott Laboratories Inhibiteurs de nampt
WO2015006280A1 (fr) * 2013-07-10 2015-01-15 Vertex Pharmaceuticals Incorporated Amides de pipéridine fusionnés utiles en tant que modulateurs de canaux ioniques
US9302989B2 (en) 2010-11-15 2016-04-05 Abbvie Inc. NAMPT and rock inhibitors
WO2020054657A1 (fr) 2018-09-10 2020-03-19 科研製薬株式会社 Dérivé d'amide hétéroaromatique et médicament le contenant
CN112062688A (zh) * 2020-09-28 2020-12-11 绍兴兴欣新材料股份有限公司 一种n,n-二乙基乙酰胺的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997034883A1 (fr) * 1996-03-22 1997-09-25 Astra Aktiebolag Derives de 1,2,3,4-tetrahydronaphthalene substitues
WO1999005134A1 (fr) * 1997-07-25 1999-02-04 Astra Aktiebolag Derives de 1,2,3,4-tetrahydronaphthalene substitue
WO1999014213A1 (fr) * 1997-09-18 1999-03-25 Astrazeneca Ab Derives de chromane substitue
WO1999014212A1 (fr) * 1997-09-18 1999-03-25 Astrazeneca Ab Derives de chromane substitues
WO2005013914A2 (fr) * 2003-08-08 2005-02-17 Vertex Pharmaceuticals Incorporated Compositions utilisees comme inhibiteurs de canaux sodium voltage dependants
US20060025415A1 (en) * 2003-08-08 2006-02-02 Gonzalez Jesus E Iii Compositions useful as inhibitors of voltage-gated sodium channels

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997034883A1 (fr) * 1996-03-22 1997-09-25 Astra Aktiebolag Derives de 1,2,3,4-tetrahydronaphthalene substitues
WO1999005134A1 (fr) * 1997-07-25 1999-02-04 Astra Aktiebolag Derives de 1,2,3,4-tetrahydronaphthalene substitue
WO1999014213A1 (fr) * 1997-09-18 1999-03-25 Astrazeneca Ab Derives de chromane substitue
WO1999014212A1 (fr) * 1997-09-18 1999-03-25 Astrazeneca Ab Derives de chromane substitues
WO2005013914A2 (fr) * 2003-08-08 2005-02-17 Vertex Pharmaceuticals Incorporated Compositions utilisees comme inhibiteurs de canaux sodium voltage dependants
US20050137190A1 (en) * 2003-08-08 2005-06-23 Gonzalez Jesus E.Iii Compositions useful as inhibitors of voltage-gated sodium channels
US20060025415A1 (en) * 2003-08-08 2006-02-02 Gonzalez Jesus E Iii Compositions useful as inhibitors of voltage-gated sodium channels

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012067963A1 (fr) * 2010-11-15 2012-05-24 Abbott Laboratories Inhibiteurs de nampt
CN103347860A (zh) * 2010-11-15 2013-10-09 Abbvie公司 Nampt抑制剂
JP2013545750A (ja) * 2010-11-15 2013-12-26 アッヴィ・インコーポレイテッド Ｎａｍｐｔ阻害剤
US9302989B2 (en) 2010-11-15 2016-04-05 Abbvie Inc. NAMPT and rock inhibitors
US10093624B2 (en) 2010-11-15 2018-10-09 Abbvie Inc. NAMPT and ROCK inhibitors
WO2015006280A1 (fr) * 2013-07-10 2015-01-15 Vertex Pharmaceuticals Incorporated Amides de pipéridine fusionnés utiles en tant que modulateurs de canaux ioniques
JP2016526571A (ja) * 2013-07-10 2016-09-05 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ イオンチャネルのモジュレーターとしての縮合ピペリジンアミド
US10233191B2 (en) 2013-07-10 2019-03-19 Vertex Pharmaceuticals Incorporated Fused piperidine amides as modulators of ion channels
WO2020054657A1 (fr) 2018-09-10 2020-03-19 科研製薬株式会社 Dérivé d'amide hétéroaromatique et médicament le contenant
KR20210057008A (ko) 2018-09-10 2021-05-20 가껭세이야꾸가부시기가이샤 신규한 헤테로방향족 아미드 유도체 및 이를 함유하는 약제
CN112062688A (zh) * 2020-09-28 2020-12-11 绍兴兴欣新材料股份有限公司 一种n,n-二乙基乙酰胺的制备方法

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