WO2012117216A1 - N- (arylalkyl) - 1h- indole- 2 - sulfonic acid amide compounds and their therapeutic use as cannabinoid allosteric modulators - Google Patents

N- (arylalkyl) - 1h- indole- 2 - sulfonic acid amide compounds and their therapeutic use as cannabinoid allosteric modulators Download PDF

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Publication number
WO2012117216A1
WO2012117216A1 PCT/GB2012/000193 GB2012000193W WO2012117216A1 WO 2012117216 A1 WO2012117216 A1 WO 2012117216A1 GB 2012000193 W GB2012000193 W GB 2012000193W WO 2012117216 A1 WO2012117216 A1 WO 2012117216A1
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independently
compound according
treatment
present
optionally substituted
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English (en)
French (fr)
Inventor
lain Robert GREIG
Ruth Alexandra Ross
Roger Guy Pertwee
Laurent Alain Claude TREMBLEAU
Mostafa Hamed ABDEL-RAHMAN
Gemma Louise BAILLIE
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University of Aberdeen
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University of Aberdeen
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • endocannabinoids are present in peripheral tissues involved in metabolic dysfunction associated with obesity, including adipose tissue, liver, skeletal muscle and pancreas, and there is evidence for the upreguiation of the endocannabinoid system in these tissues in experimental and human obesity (see, e.g., Kunos et a/., 2009).
  • a peripherally-restricted CB1 receptor antagonist does not affect behavioural responses in mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile (see, e.g., Tarn ei a/., 2010).
  • These findings confirm a prominent role for peripheral CB1 receptors on the modulation of metabolism (see, e.g., Son ei a/., 2010).
  • sulfonamides are expected to have higher solubility than amides. If a drug is to show oral activity, it must first be dissolved, to permit absorption from the gastrointestinal tract.
  • the NISA compounds described herein may also have other advantages over the corresponding amide compounds because of their mode of action: the amide ("Org") compounds described by Price et a/., 2005, all increase the binding of the endogenous ligand, but reduce the efficacy (i.e., the ligand binds more strongly but activation of the signalling pathway is reduced).
  • the NISA compounds described herein do not increase the binding of the endogenous ligand but do reduce the efficacy (i.e., the ligand binding is not increased, but activation of the signalling pathway is reduced).
  • This not only demonstrates clear differences between the NISA compounds described herein and the corresponding amide compounds, but may also provide a therapeutic advantage, for example, to provide compounds which are more effective for long-term use, for example, by avoiding potential changes in receptor expression levels caused by desensitisation.
  • -Q 2BH if present, is independently pyrimidinyl.
  • each -W 2 is independently -NH 2 , -NHR W , -NR W 2 , or -NR WN1 R N2 .
  • each -R W4 if present, is independently aliphatic C 2- alkenyl and is optionally substituted with one or more substituents selected from: -F, -CI, -Br, -I, -CF 3 , -OH, -OR W44 , and -OCF 3 , wherein each _ R W j S independently saturated aliphatic C 1-4 alkyl.
  • each -R W44 if present, is independently -Me, -Et, -nPr, -iPr, or -tBu.
  • each -R W5 if present, is independently aliphatic C 2-4 alkynyl.
  • -R 5A if present, is independently: -F, -CI, -Br, or -Me.
  • the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form.
  • the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds.
  • the substantially purified form refers to one
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • suitable substituted ammonium ions are those derived from:
  • the method is performed in vitro.
  • the treatment is treatment of osteoporosis, Paget's disease of bone, or bone related cancer. In one embodiment, the treatment is treatment of breast cancer.
  • terapéuticaally-effective amount refers to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • an NISA compound While it is possible for an NISA compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one NISA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • the compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients.
  • the compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.
  • Formulations suitable for oral administration include liquids, solutions (e.g. , aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g. , oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
  • Formulations suitable for intranasal administration, where the carrier is a liquid include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
  • Such liquids may additionally contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
  • Method C Lithium 3-methyl-1-(phenylsulfonyl)-1 /-/-indole-2-sulfinate (ABD0945c) (6 g) was suspended in methylene chloride (50 mL) and cooled to 5°C, and
  • Method F 5-Chloro-3-methyl-1 H-indole-2-carboxylic acid (ABD0956f) (2 g) and copper powder (1.2 g) were mixed in toluene (50 mL) and purged with N 2 for 5 minutes. The mixture was microwaved for 25 minutes at 250°C. After cooling to room temperature, the reaction mixture was acidified with 6 N HCI and the copper powder was removed by filtration. The filtrate was extracted twice with EtOAc, washed with saturated NaHC0 3 solution, brine, dried over MgS0 4 , and evaporated under reduced pressure to give a crude product which was purified by flash chromatography on silica gel. 13 C NMR (CDCI 3 ): ⁇ 9.5, 1 1 1.6, 1 12.0, 1 18.4, 122.1 , 123.1 , 124.9, 129.4 and 134.6.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/GB2012/000193 2011-02-28 2012-02-24 N- (arylalkyl) - 1h- indole- 2 - sulfonic acid amide compounds and their therapeutic use as cannabinoid allosteric modulators Ceased WO2012117216A1 (en)

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GBGB1103419.6A GB201103419D0 (https=) 2011-02-28 2011-02-28

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WO2015027160A3 (en) * 2013-08-22 2015-11-05 Northeastern University Allosteric modulators of the cannibinoid 1 receptor
US9676747B2 (en) 2011-12-21 2017-06-13 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9873671B2 (en) 2014-01-16 2018-01-23 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10118914B2 (en) 2014-06-20 2018-11-06 The University Of North Carolina At Greensboro Beta-arrestin-biased cannabinoid CB1 receptor agonists and methods for making and using them
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
PL422539A1 (pl) * 2017-08-11 2019-02-25 Celon Pharma Spółka Akcyjna Związki N-arylosulfonyloindolowe do leczenia chorób OUN
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10537580B2 (en) 2015-03-19 2020-01-21 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
WO2025117672A1 (en) * 2023-12-01 2025-06-05 Hotspot Therapeutics, Inc. Indazolyl-piperidine sulfonamides and related compounds and their use in therapy

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