WO2010102663A1 - Dérivés de pipérazine destinés à être utilisés en thérapie - Google Patents

Dérivés de pipérazine destinés à être utilisés en thérapie Download PDF

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Publication number
WO2010102663A1
WO2010102663A1 PCT/EP2009/052802 EP2009052802W WO2010102663A1 WO 2010102663 A1 WO2010102663 A1 WO 2010102663A1 EP 2009052802 W EP2009052802 W EP 2009052802W WO 2010102663 A1 WO2010102663 A1 WO 2010102663A1
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methyl
sulfonyl
compound
formula
chlorophenyl
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PCT/EP2009/052802
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English (en)
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Paul John Beswick
Alister Campbell
Andrew Cridland
Robert James Gleave
Lee William Page
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Glaxo Group Limited
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Priority to PCT/EP2009/052802 priority Critical patent/WO2010102663A1/fr
Publication of WO2010102663A1 publication Critical patent/WO2010102663A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to novel piperazine derivatives with affinity for Ca v 2.2 calcium channels and which are capable of interfering with Ca v 2.2 calcium channels; to processes for their preparation; to pharmaceutical compositions containing them; and to the use of such compounds in therapy.
  • Presynaptic Ca v 2.2 (N-type) voltage-gated calcium channels in the dorsal horn of the spinal cord modulate the release of key pro-nociceptive neurotransmitters such as glutamate, substance P (SP) and calcitonin-gene-related peptide (CGRP), indicating the potential therapeutic use of Ca v 2.2 calcium channel blockers as analgesics.
  • pro-nociceptive neurotransmitters such as glutamate, substance P (SP) and calcitonin-gene-related peptide (CGRP)
  • Peptidic ⁇ -conotoxins isolated from the venom of cone snails, are selective for Ca v 2.2 calcium channels and can block SP release in the spinal cord (Smith et al. (2002) Pain, 96: 119-127). Moreover, they are antinociceptive in animal models of chronic pain following intrathecal administration (Bowersox et al. (1996) Journal of Pharmacology and Experimental Therapeutics, 279: 1243-1249; Smith et al. (2002) supra), and are effective analgesics in clinical use, particularly in the treatment of neuropathic pain (Brose et al. (1997) Clinical Journal of Pain, 13: 256-259).
  • Ca v 2.2 calcium channels are also important for normal neuronal function. Therefore, the aim is to identify novel molecules that preferentially block Ca v 2.2 under conditions of increased neuronal excitability, so-called use-dependent blockers, as is the case in chronic pain syndromes (Winquist et al. (2005) Biochemical Pharmacology, 70: 489-499).
  • WO 2007/103456 discloses a series of piperazine and piperidine derivatives for the treatment of HIV infection.
  • the present invention provides compounds with affinity for Ca v 2.2 calcium channels and which are capable of interfering with the affects of these channels. According to a first aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy:
  • R 1 is halogen, Ci -4 alkyl, Ci -3 alkoxy; n is 0, 1 , 2, 3, 4 or 5; m is 0, 1 , 2, 3 or 4;
  • X is a linker selected from -CO-, -XONH-, -XH 2 -CONH-, -XH 2 -CO-, -XO-CH 2 -O-,
  • R 2 is Ci -4 alkyl, Ci -3 alkoxy Ci -3 alkyl or hydroxy Ci -4 alkyl;
  • R 3 is hydrogen, halogen, cyano, Ci -4 alkyl, Ci -4 alkoxy or halo Ci -4 alkyl;
  • R 4 is hydrogen, halogen, cyano, Ci -4 alkoxy or halo Ci -4 alkyl
  • R 5 is hydrogen, halogen, cyano, Ci -4 alkyl or Ci -4 alkoxy; wherein at least one of R 3 , R 4 and R 5 is a group other than hydrogen; and wherein when R 3 or R 4 are bromo, R 5 is halogen, cyano, Ci -4 alkyl or Ci -4 alkoxy; with the proviso that the compound is not
  • alkyl refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms.
  • Ci -6 alkyl means a straight or branched hydrocarbon chain containing at least 1 and at most 6 carbon atoms.
  • alkyl include, but are not limited to; methyl (Me), ethyl (Et), n-propyl, i-propyl, t-butyl, n-heptyl, n- hexyl and i-hexyl.
  • C 1-3 alkoxy and C 1-4 alkoxy refers to an -O-alkyl group wherein alkyl is as defined herein.
  • C 1-4 alkoxy groups are methoxy, ethoxy, propoxy and butoxy.
  • propoxy, butoxy etc. include all straight and branched chain forms having the appropriate number of carbon atoms, e.g. propoxy includes n-propoxy and isopropoxy.
  • C 1-3 alkoxy C 1-3 alkyl refers to an -alkyl-O- alkyl group wherein alkyl is as defined herein. Examples of such groups include methoxyethyl, methoxypropyl and ethoxypropyl.
  • hydroxy C 1-4 alkyl refers to an -alkyl-OH group wherein alkyl is as defined herein. Examples of such groups include hydroxymethyl and hydroxylethyl.
  • halo C 1-4 alkyl refers an alkyl group as defined herein substituted with one or more halogen groups, for example CF 3 , CF 2 H or CF 3 CH 2 .
  • 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluoro (fluorine), chloro (chlorine), bromo (bromine) and iodo (iodine).
  • n is 0, 1 , 2 or 3. In a particular embodiment of the first aspect, n is 0, 1 or 2. In a more particular embodiment of the first aspect, n is 0 or 1. In a further embodiment of the first aspect, n is 0.
  • R 1 is selected from fluoro, chloro, bromo, methyl, methoxy, ethoxy and propoxy. In a particular embodiment of the first aspect, R 1 is selected from fluoro, chloro, ethoxy and methoxy. In a more particular embodiment of the first aspect, R 1 is fluoro.
  • m is 0, 1 , 2 or 3. In another embodiment of the first aspect, m is 1 , 2 or 3. In a particular embodiment of the first aspect, m is 1 or 2. In a more particular embodiment of the first aspect, m is 1. In one embodiment of the first aspect, R 2 is C 1-3 alkyl. In another embodiment of the first aspect, R 2 is selected from methyl, ethyl, hydroxymethyl and methoxymethyl. In a particular embodiment of the fi rrsstt aspect, R 2 is methyl or ethyl. In a more particular embodiment of the first aspect, R 2 is methyl.
  • X is selected from -CO-, -XONH-, -XH 2 - CONH-, -XH 2 -CO-, -XO-CH 2 -O-, -XO-CH 2 -, -XO-CH 2 -S-, -XON(CH 3 )- and -XH 2 - CO-NH-CH 2 - wherein * indicates bonding to the piperazine ring.
  • X is selected from -CO-, -XONH- and -XH 2 -CONH- .
  • X is -CO-.
  • R 3 is selected from hydrogen, chloro, fluoro, bromo, methyl, trifluoromethyl, cyano and methoxy. In one particular embodiment of the first aspect, R 3 is selected from hydrogen, chloro, bromo, trifluoromethyl, cyano and methoxy. In a more particular embodiment of the first aspect, R 3 is selected from chloro, trifluoromethyl and cyano, In an even more particular embodiment of the first aspect, R 3 is cyano.
  • R 4 is selected from hydrogen, methoxy, fluoro, chloro and cyano. In a particular embodiment of the first aspect, R 4 is selected from hydrogen, fluoro, methoxy and cyano. In a more particular embodiment of the first aspect, R 4 is selected from hydrogen and cyano, even more particularly, R 4 is hydrogen.
  • R 5 is selected from hydrogen, methoxy, fluoro, methyl and cyano. In a particular embodiment of the first aspect, R 5 is selected from hydrogen, methoxy and fluoro. In a more particular embodiment of the first aspect, R 5 is hydrogen.
  • R 3 is selected from chloro, trifluoromethyl and cyano
  • R 4 is selected from hydrogen and cyano and R 5 is selected from hydrogen, methoxy and fluoro.
  • R 3 is selected from chloro, trifluoromethyl and cyano
  • R 4 and R 5 both are hydrogen.
  • R 3 is cyano and R 4 and R 5 both are hydrogen.
  • m is 1 or 2 and R 2 is C 1-3 alkyl.
  • m is 1 and R 2 is C 1-3 alkyl.
  • o off the first aspect m is 1 and R 2 is methyl or ethyl, even more particularly R 2 is methyl.
  • n is 1 or 2 and R 1 is selected from fluoro, chloro, ethoxy and methoxy. In a particular embodiment of the first aspect, n is 1 or 2 and R 1 is fluoro. In a more particular embodiment of the first aspect, n is 1 and R 1 is fluoro.
  • n 0, X is selected from -CO-, -XONH-, - XH 2 -CONH-, -XH 2 -CO-, -XO-CH 2 -O-, -XO-CH 2 -, -XO-CH 2 -S-, -XON(CH 3 )- and - XH 2 -CO-NH-CH 2 - wherein * indicates bonding to the piperazine ring, m is 1 or 2, R 2 is C 1-3 alkyl, R 3 is selected from chloro, trifluoromethyl and cyano, R 4 is selected from hydrogen and cyano and R 5 is selected from hydrogen, methoxy and fluoro.
  • n O
  • X is selected from -CO-, -XONH- and -XH 2 -CONH-
  • m is 1
  • R 2 is methyl or ethyl
  • R 3 is selected from chloro, trifluoromethyl and cyano
  • R 4 and R 5 both are hydrogen.
  • n is 1 or 2
  • R 1 is selected from fluoro, chloro, ethoxy and methoxy
  • X is selected from -CO-, -XONH- and -XH 2 -CONH-
  • m is 1 or 2
  • R 2 is C 1-3 alkyl
  • R 3 is selected from chloro, trifluoromethyl and cyano
  • R 4 is selected from hydrogen and cyano
  • R 5 is selected from hydrogen, methoxy and fluoro.
  • n is 1 or 2
  • R 1 is fluoro
  • m is 1
  • R 2 is methyl or ethyl
  • R 3 is selected from chloro, trifluoromethyl and cyano
  • R 4 and R 5 both are hydrogen.
  • R 1 represents halogen
  • m represents an integer from 1 or 2
  • n represents an integer from 0 to 2;
  • X represents a linker selected from -CO-, -CONH- or -CH 2 -CONH-;
  • R 2 represents C 1-4 alkyl;
  • R 3 represents hydrogen, chloro (chlorine), fluoro (fluorine), bromo (bromine), cyano or trifluoromethyl;
  • R 4 represents hydrogen, chloro (chlorine), fluoro (fluorine), cyano, methoxy or trifluoromethyl; such that at least one of R 3 , R 4 and R 5 represents a group other than hydrogen; and R 5 represents hydrogen, methyl, chloro (chlorine) or fluoro (fluorine), such that when R 5 represents a group other than hydrogen, R 3 also represents a group other than hydrogen and such that when R 3 represents bromo (bromine), R 5 represents a group other than hydrogen.
  • n 0 or 1. In an alternative embodiment of the first aspect, n represents 0 or 2. In a further embodiment of the first aspect, n represents 0.
  • R 1 represents fluoro (fluorine).
  • m represents 1 or 2. In a further embodiment of the first aspect, m represents 1. In one embodiment of the first aspect, R 2 represents C 1-3 alkyl. In a further embodiment of the first aspect, R 2 represents methyl or ethyl. In a yet further embodiment of the first aspect, R 2 represents methyl.
  • X represents -CO-.
  • R 3 represents chloro (chlorine), fluoro (fluorine), cyano or trifluoromethyl and R 4 and R 5 both represent hydrogen.
  • R 3 represents cyano
  • R 4 represents hydrogen and R 5 represents methyl.
  • R 3 represents bromo (bromine), R 4 represents hydrogen and R 5 represents methyl.
  • R 3 represents cyano and R 4 and R 5 both represent hydrogen.
  • R 4 represents fluoro (fluorine) or methoxy. In a further embodiment of the first aspect, R 4 represents fluoro (fluorine) or methoxy and R 3 and R 5 both represent hydrogen.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof is selected from a compound of Examples 1 to 68, or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from:
  • the compound of formula (I) is 4- ⁇ [(3S)-3- Methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl ⁇ benzonitrile (E27), or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of formula (I) or a salt thereof, wherein
  • R 1 is halogen, Ci -4 alkyl, Ci -3 alkoxy; n is O, 1 , 2, 3, 4 or 5; m is 1 , 2 or 3; X is a linker selected from -CO-, -XONH-, -XH 2 -CONH-, -XH 2 -CO-, -XO-CH 2 -O-,
  • R 2 is Ci- 4 alkyl, Ci -3 alkoxy Ci -3 alkyl or hydroxy Ci -4 alkyl;
  • R 3 is hydrogen, halogen, cyano, Ci -4 alkyl, Ci -4 alkoxy or halo Ci -4 alkyl
  • R 4 is hydrogen, halogen, cyano, Ci -4 alkoxy or halo Ci -4 alkyl
  • R 5 is hydrogen, halogen, cyano, Ci -4 alkyl or Ci -4 alkoxy; wherein at least one of R 3 , R 4 and R 5 is a group other than hydrogen; and wherein when R 3 or R 4 are bromo, R 5 is halogen, cyano, Ci -4 alkyl or Ci -4 alkoxy; with the proviso that the compound is not 4- ⁇ [4-[(3-fluorophenyl)carbonyl]-3- (hydroxymethyl)-1-piperazinyl]sulfonyl ⁇ benzonitrile.
  • n is O, 1 , 2 or 3. In a particular embodiment of the second aspect, n is O, 1 or 2. In a more particular embodiment of the second aspect, n is O or 1. In a further embodiment of the second aspect, n is O.
  • R 1 is selected from fluoro, chloro, bromo, methyl, methoxy, ethoxy and propoxy. In a particular embodiment of the second aspect, R 1 is selected from fluoro, chloro, ethoxy and methoxy. In a more particular embodiment of the second aspect, R 1 is fluoro.
  • n is 1 or 2. In a particular embodiment of the second aspect, m is 1.
  • R 2 is Ci -3 alkyl. In another embodiment of the second aspect, R 2 is selected from methyl, ethyl, hydroxymethyl and methoxymethyl. In a particular embodiment of the second aspect, R 2 is methyl or ethyl. In a more particular embodiment of the second aspect, R 2 is methyl.
  • X is selected from -CO-, -XONH-, -XH 2 - CONH-, -XH 2 -CO-, -XO-CH 2 -O-, -XO-CH 2 -, -XO-CH 2 -S-, -XON(CH 3 )- and -XH 2 - CO-NH-CH 2 - wherein * indicates bonding to the piperazine ring.
  • X is selected from -CO-, -XONH- and -XH 2 - CONH-.
  • X is -CO-.
  • R 3 is selected from hydrogen, chloro, fluoro, bromo, methyl, trifluoromethyl, cyano and methoxy. In one particular embodiment of the second aspect, R 3 is selected from hydrogen, chloro, bromo, trifluoromethyl, cyano and methoxy. In a more particular embodiment of the second aspect, R 3 is selected from chloro, trifluoromethyl and cyano, In an even more particular embodiment of the second aspect, R 3 is cyano.
  • R 4 is selected from hydrogen, methoxy, fluoro, chloro and cyano. In a particular embodiment of the second aspect, R 4 is selected from hydrogen, fluoro, methoxy and cyano. In a more particular embodiment of the second aspect, R 4 is selected from hydrogen and cyano, even more particularly, R 4 is hydrogen.
  • R 5 is selected from hydrogen, methoxy, fluoro, methyl and cyano. In a particular embodiment of the second aspect, R 5 is selected from hydrogen, methoxy and fluoro. In a more particular embodiment of the second aspect, R 5 is hydrogen.
  • R 3 is selected from chloro, trifluoromethyl and cyano
  • R 4 is selected from hydrogen and cyano
  • R 5 is selected from hydrogen, methoxy and fluoro.
  • R 3 is selected from chloro, trifluoromethyl and cyano
  • R 4 and R 5 both are hydrogen.
  • R 3 is cyano and R 4 and R 5 both are hydrogen.
  • n is 1 or 2 and R 1 is selected from fluoro, chloro, ethoxy and methoxy. In a particular embodiment of the second aspect, n is 1 or 2 and R 1 is fluoro. In a more particular embodiment of the second aspect, n is 1 and R 1 is fluoro.
  • n is 0, X is selected from -CO-, -XONH-, -XH 2 -CONH-, -XH 2 -CO-, -XO-CH 2 -O-, -XO-CH 2 -, -XO-CH 2 -S-, -XON(CH 3 )- and -XH 2 -CO-NH-CH 2 - wherein * indicates bonding to the piperazine ring, m is 1 or 2, R 2 is C- ⁇ -3 alkyl, R 3 is selected from chloro, trifluoromethyl and cyano, R 4 is selected from hydrogen and cyano and R 5 is selected from hydrogen, methoxy and fluoro.
  • n O
  • X is selected from -CO-, - XONH- and -XH 2 -CONH-
  • m is 1
  • R 2 is methyl or ethyl
  • R 3 is selected from chloro, trifluoromethyl and cyano
  • R 4 and R 5 both are hydrogen.
  • n is 1 or 2
  • R 1 is selected from fluoro, chloro, ethoxy and methoxy
  • X is selected from -CO-, -XONH- and -XH 2 -CONH-
  • m is 1 or 2
  • R 2 is C 1-3 alkyl
  • R 3 is selected from chloro, trifluoromethyl and cyano
  • R 4 is selected from hydrogen and cyano
  • R 5 is selected from hydrogen, methoxy and fluoro.
  • n is 1 or 2
  • R 1 is fluoro
  • m is 1
  • R 2 is methyl or ethyl
  • R 3 is selected from chloro, trifluoromethyl and cyano
  • R 4 and R 5 both are hydrogen.
  • R 1 represents halogen
  • m represents an integer from 1 or 2
  • n represents an integer from 0 to 2;
  • X represents a linker selected from -CO-, -CONH- or -CH 2 -CONH-;
  • R 2 represents C 1-4 alkyl;
  • R 3 represents hydrogen, chloro (chlorine), fluoro (fluorine), bromo (bromine), cyano or trifluoromethyl;
  • R 4 represents hydrogen, chloro (chlorine), fluoro (fluorine), cyano, methoxy or trifluoromethyl; such that at least one of R 3 , R 4 and R 5 represents a group other than hydrogen; and R 5 represents hydrogen, methyl, chloro (chlorine) or fluoro (fluorine), such that when R 5 represents a group other than hydrogen, R 3 also represents a group other than hydrogen and such that when R 3 represents bromo (bromine), R 5 represents a group other than hydrogen.
  • n 0 or 1. In an alternative embodiment of the second aspect, n represents 0 or 2. In a further embodiment of the second aspect, n represents 0.
  • R 1 represents fluoro (fluorine).
  • n 1 or 2. In a further embodiment of the second aspect, m represents 1.
  • R 2 represents Ci -3 alkyl. In a further embodiment of the second aspect, R 2 represents methyl or ethyl. In a yet further embodiment of the second aspect, R 2 represents methyl.
  • X represents -CO-.
  • R 3 represents chloro (chlorine), fluoro (fluorine), cyano or trifluoromethyl and R 4 and R 5 both represent hydrogen.
  • R 3 represents cyano
  • R 4 represents hydrogen and R 5 represents methyl.
  • R 3 represents bromo (bromine)
  • R 4 represents hydrogen and R 5 represents methyl.
  • R 3 represents cyano and R 4 and R 5 both represent hydrogen.
  • R 4 represents fluoro (fluorine) or methoxy. In a further embodiment of the second aspect, R 4 represents fluoro (fluorine) or methoxy and R 3 and R 5 both represent hydrogen.
  • a compound of formula (I), or a salt thereof is selected from a compound of Examples 1 to 68, or a salt thereof.
  • a compound of formula (I) or a salt thereof is selected from:
  • the compound of formula (I) is 4- ⁇ [(3S)-3- Methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl ⁇ benzonitrile (E27), or a salt thereof.
  • salts of compounds of formula (I) are preferably pharmaceutically acceptable.
  • Certain compounds of formula (I) as defined in the first and second aspect may in some circumstances form acid addition salts thereof. It will be appreciated that for use in medicine compounds of formula (I) may be used as salts, in which case the salts should be pharmaceutically acceptable.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse , J. Pharm. ScL, 1977, 66, 1-19.
  • pharmaceutically acceptable salts includes salts prepared from pharmaceutically acceptable acids, including inorganic and organic acids.
  • Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Examples of pharmaceutically acceptable salts include those formed from maleic, fumaric, benzoic, ascorbic, pamoic, succinic, hydrochloric, sulfuric, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoric and nitric acids.
  • prodrugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in "Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within the compounds as defined in the first and second aspects. Therefore, in a further aspect, the invention provides a prodrug of a compound as defined in the first and second aspect.
  • Certain compounds of formula (I) as defined in the first and second aspect are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the compound of formula (I) is a compound of formula (IA):
  • the compound of formula (I) is a compound of formula (IB):
  • the subject invention also includes isotopically-labeled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluoro (fluorine), such as 3 H, 11 C, 14 C and 18 F.
  • Isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging.
  • lsotopically labeled compounds of formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds of formula (I) as defined in the first and second aspect or salts thereof are not isotopically labelled.
  • a compound of formula (I) as defined in the first and second aspect can be prepared as set forth in the following Schemes and in the examples. The following processes form another aspect of the present invention.
  • the present invention also provides a process for the preparation of a compound of formula (I) as defined in the first and second aspect or a salt thereof, which process comprises:
  • process (a) typically comprises reaction of a compound of formula (II) and (III) in the presence of a suitable solvent such as N, N- dimethylformamide) and a suitable base such as cesium carbonate optionally in the presence of an iodide source (such as potassium iodide) at a temperature between O 0 C and ambient temperature (for example ambient temperature).
  • a suitable solvent such as N, N- dimethylformamide
  • a suitable base such as cesium carbonate
  • an iodide source such as potassium iodide
  • process (a) typically comprises reaction of a compound of formula (II) and (III) in the presence of a suitable solvent (such as acetonitrile, tetrahydrofuran or dichloromethane, in the presence of a suitable base, (for example, triethylamine, di-isopropylethylamine or PS-DIEA) at O 0 C to ambient temperature (for example, room temperature).
  • a suitable solvent such as acetonitrile, tetrahydrofuran or dichloromethane
  • a suitable base for example, triethylamine, di-isopropylethylamine or PS-DIEA
  • Process (b) typically comprises reaction of a compound of formula (II) and (IV) in the presence of a suitable solvent such as dichloromethane, in the presence of a suitable base (such as triethylamine) at a temperature between O 0 C and ambient temperature (for example room temperature).
  • a suitable solvent such as dichloromethane
  • a suitable base such as triethylamine
  • Process (c) typically comprises reaction of a compound of formula (V) and (Vl) in the presence of a suitable solvent (such as dichloromethane or acetonitrile) in the presence of a suitable base, (for example triethylamine, di-isopropylethylamine or PS-DIEA) at O 0 C to ambient temperature (for example, ambient temperature).
  • a suitable solvent such as dichloromethane or acetonitrile
  • a suitable base for example triethylamine, di-isopropylethylamine or PS-DIEA
  • ambient temperature for example, ambient temperature
  • process (c) may typically comprise reaction of the intermediates in the presence of a suitable base as a solvent (for example pyridine).
  • Suitable amine protecting groups include sulfonyl (e.g. tosyl), acyl (e.g. acetyl, 2',2',2'-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g. using an acid such as hydrochloric acid) or reductively (e.g.
  • Suitable amine protecting groups include trifluoroacetyl (- COCF 3 ) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
  • Process (e) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution or amide bond formation.
  • interconversion may be interconversion for a compound of formula (I) wherein R 3 represents bromo (bromine) to a compound of formula (I) wherein R 3 represents cyano.
  • Such interconversion may be carried out by treating the bromo (bromine) compound with a cyanide salt (for example copper (I) cyanide) in a suitable solvent (such as N, N- dimethylformamide) at elevated temperatures (such as 200°C using microwave irradiation).
  • a cyanide salt for example copper (I) cyanide
  • suitable solvent such as N, N- dimethylformamide
  • interconversion may be carried out using a cyanide salt (for example zinc cyanide) in the presence of a source of a palladium catalyst (for example tris(dibenzylideneacetone)dipalladium(0) and ligand (for example 1 ,1 '- bis(diphenylphosphino)ferrocene) in a suitable solvent (such as N, N- dimethylformamide) at elevated temperatures (such as 12O 0 C).
  • a cyanide salt for example zinc cyanide
  • a source of a palladium catalyst for example tris(dibenzylideneacetone)dipalladium(0) and ligand (for example 1 ,1 '- bis(diphenylphosphino)ferrocene) in a suitable solvent (such as N, N- dimethylformamide) at elevated temperatures (such as 12O 0 C).
  • a suitable solvent such as N, N- dimethylformamide
  • Such interconversion may be carried out by treating the hydroxyalkyl compound with an alkylating agent (for example methyl iodide) in the presence of a base (such as N- phenyl-tris(dimethylamino)iminophosphorane on polystyrene resin (PS-BEMP)).
  • an alkylating agent for example methyl iodide
  • a base such as N- phenyl-tris(dimethylamino)iminophosphorane on polystyrene resin (PS-BEMP)
  • PS-BEMP polystyrene resin
  • R 2 , R 3 , R 4 , R 5 , m and L 2 are as defined above and P 1 represents a suitable protecting group such as t-butoxycarbonyl.
  • Step (i) typically comprises reacting a compound of formula (Vl) and (VII) in a suitable solvent, such as dichloromethane or acetonitrile in the presence of a base, (for example triethylamine, di-isopropylethylamine or PS-DIEA) at O 0 C to ambient temperature (for example ambient temperature).
  • a suitable solvent such as dichloromethane or acetonitrile
  • a base for example triethylamine, di-isopropylethylamine or PS-DIEA
  • ambient temperature for example ambient temperature
  • step (i) may typically be carried out using a suitable base as a solvent, (for example pyridine).
  • Step (ii) typically comprises a deprotection reaction.
  • step (ii) will typically comprise treatment with an acid, for example hydrochloric acid or trifluoroacetic acid, in a solvent (such as 1 ,4- dioxane, dichloromethane or a mixture of methanol and 1 ,4-dioxane).
  • an acid for example hydrochloric acid or trifluoroacetic acid
  • a solvent such as 1 ,4- dioxane, dichloromethane or a mixture of methanol and 1 ,4-dioxane.
  • R 2 , m, R 1 , n, X and P 1 are as defined above.
  • step (i) typically comprises reacting a compound of formula (VII) with an appropriately substituted phenyl isocyanate derivative in the presence of a suitable solvent (such as dichloromethane) in the presence of a suitable base (such as triethylamine) at a temperature between O 0 C and ambient temperature (for example ambient temperature).
  • a suitable solvent such as dichloromethane
  • a suitable base such as triethylamine
  • step (i) typically comprises reacting a compound of formula (VII) with a compound of formula (III) in a suitable solvent (such as acetonitrile, tetrahydrofuran or dichloromethane) in the presence of a suitable base (for example, triethylamine, di-isopropylethylamine or PS-DIEA) at O 0 C to ambient temperature (for example ambient temperature).
  • a suitable solvent such as acetonitrile, tetrahydrofuran or dichloromethane
  • a suitable base for example, triethylamine, di-isopropylethylamine or PS-DIEA
  • Step (ii) typically comprises a deprotection reaction which may be carried out in an analogous manner to Step (ii) above.
  • Compounds with affinity for Ca v 2.2 calcium channels may be useful in the treatment of pain, including acute pain, chronic pain, chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, cancer chemotherapy, headache, toothache and dysmenorrhea.
  • 'Chronic articular pain' conditions include rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.
  • 'Pain associated with functional bowel disorders' includes non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome.
  • 'Neuropathic pain' syndromes include: diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV- related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions.
  • neuropathic pain conditions include pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • normally non-painful sensations such as "pins and needles” (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • neurodegenerative diseases and neurodegeneration include neurodegenerative diseases and neurodegeneration, neurodegeneration following trauma, tinnitus, dependence on a dependence- inducing agent such as opiods (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine.
  • opiods e.g. morphine
  • CNS depressants e.g. ethanol
  • psychostimulants e.g. cocaine
  • Neurodegenerative diseases include dementia, particularly degenerative dementia (including senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection, meningitis and shingles); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
  • degenerative dementia including senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease
  • vascular dementia including multi-infarct dementia
  • dementia associated with intracranial space occupying lesions trauma
  • infections and related conditions including HIV infection, meningitis and shingles
  • the compounds of formula (I) as defined in the first and second aspect may also be useful for neuroprotection and in the treatment of neurodegeneration following trauma such as stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
  • Another condition which could potentially be treated by compounds of formula (I) as defined in the first and second aspect is spasticity or muscular hypertonicity.
  • the therapy is to treat any of the disorders described herein, in particular pain.
  • a method of treatment of any of the disorders herein, in particular pain in humans comprises the administration to the human in need of such treatment, an effective amount of a compound of formula (I) as defined in the first and second aspect, or a pharmaceutically acceptable salt thereof.
  • treatment includes the treatment of established disorders and also includes the prophylaxis thereof.
  • prophylaxis is used herein to mean preventing symptoms in an already afflicted subject or preventing recurrence of symptoms in an afflicted subject and is not limited to complete prevention of an affliction.
  • a pharmaceutical composition comprising a compound of formula (I) as defined in the first and second aspect, or a pharmaceutically acceptable salt thereof, adapted for use in human or veterinary medicine.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) as defined in the first and second aspect, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
  • the compound of formula (I) as defined in the first and second aspect or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful in the treatment of pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain, back pain and migraine.
  • Such therapeutic agents include for example COX-2 (cyclooxygenase-2 ) inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib, COX-189 or 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine (WO99/012930); 5-lipoxygenase inhibitors; NSAIDs (non-steroidal anti-inflammatory drugs) such as diclofenac, indomethacin, nabumetone or ibuprofen; bisphosphonates, leukotriene receptor antagonists; DMARDs (disease modifying anti-rheumatic drugs) such as methotrexate; adenosine A1 receptor agonists; sodium channel blockers, such as lamotrigine; NMDA (N-methyl-D-aspartate) receptor modul
  • the compound of formula (I) as defined in the first and second aspect or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease.
  • suitable examples of such other therapeutic agents may be agents known to modify cholinergic transmission such as 5-HT 1A antagonists, (e.g.
  • 5-HT6 antagonists M1 muscarinic agonists, M2 muscarinic antagonist, acetylcholinesterase inhibitors (e.g tetrahydroaminoacridine, donepezil or rivastigmine), or allosteric modulators, nicotinic receptor agonists or allosteric modulators, symptomatic agents such as 5-HT6 receptor antagonists, e.g. SB742457, H3 receptor antagonists e.g.
  • GSK189254 and GSK239512 5-HT4 receptor agonist, PPAR agonists, also NMDA receptor antagonists or modulators, also disease modifying agents such as ⁇ or v- secretase inhibitors (e.g. R-flurbiprofen), also AMPA positive modulators and Glycine Transporter Reuptake inhibitors.
  • ⁇ or v- secretase inhibitors e.g. R-flurbiprofen
  • AMPA positive modulators e.g. Glycine Transporter Reuptake inhibitors.
  • the compounds may be administered either sequentially or simultaneously by any convenient route.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) as defined in the first and second aspect or a pharmaceutically acceptable salt thereof together with a further therapeutic agent or agents.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the composition may contain from 0.1% to 99% by weight, preferably from 10% to 60% by weight, of the active material, depending on the method of administration.
  • the dose of the compound of formula (I) as defined in the first and second aspect or a pharmaceutically acceptable salt thereof used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months, years or even life.
  • a further aspect to the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising 0.05 to IOOOmg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 0 to 3 g more suitably 0 to 2g of at least one pharmaceutically acceptable carrier.
  • the reaction was stirred for 1.5 hours.
  • the reaction mixture was evaporated to dryness under vacuum then dissolved in MeOH.
  • the MeOH solution was loaded onto a 1Og SCX column.
  • the loaded column was then washed with 2 column volumes of MeOH and the desired product was eluted from the column with 1 M ammonia in MeOH.
  • the fraction containing eluted product was evaporated to dryness under vacuum to yield the title compound as a yellow oil (895mg, 68%).
  • reaction mixture was evaporated to dryness on the rotary evaporator and the residual white solid was triturated with ether.
  • the ether was removed by filtration and the solid collected.
  • the solid was dissolved in methanol and transferred onto a SCX column, washed with two column volumes of MeOH, then the desired product eluted with 1 M methanolic ammonia.
  • the fraction containing product was collected and evaporated to dryness on the rotary evaporator to yield the title compound as a colourless oil (215mg).
  • Example 5a Faster running enantiomer (4- ⁇ [(3S)-3-ethyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl ⁇ benzonitrile or 4- ⁇ [(3R)-3-ethyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl ⁇ benzonitrile, 16mg)
  • Example 5b Slower running enantiomer (4- ⁇ [(3S)-3-ethyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl ⁇ benzonitrile or 4- ⁇ [(3R)-3-ethyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl ⁇ benzonitrile, 16mg)
  • the crude product was purified by silica chromatography (Biotage SP4), eluting a gradient from 10-80% ethyl acetate in hexane) and the product containing fractions were dried under vacuum to yield the title compound as a white solid (100mg, 49%).
  • reaction mixture was diluted with DCM (1 OmL) and the solution was washed with saturated sodium bicarbonate solution (1 OmL, twice), then with distilled water (1OmL). The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo to yield 197 mg of transparent oil.
  • reaction mixture was diluted with DCM (1 OmL) and the solution was washed with saturated sodium bicarbonate solution (1 OmL, twice), then with distilled water (1OmL). The organic layer was dried (MgSO 4 ), filtered and reduced in vacuo to yield a transparent oil (160mg).
  • the reaction was filtered, the solution washed with water (5OmL), dried (MgSO 4 ) and the solvent removed under vacuum.
  • the crude product was purified by silica chromatography (Biotage SP4, eluting with a gradient from 20-80% ethyl acetate in hexane) and the purified product dried at 40 0 C under vacuum for 72 hours to yield the title compound as a white crystalline solid (59mg).
  • the crude product was purified by silica chromatography (Biotage SP4, eluting with a gradient from 20-80% ethyl acetate in hexane) and the purified product dried at 40 0 C under vacuum for 72 hours to yield the title compound as a white crystalline solid (99mg).
  • the crude product was purified by silica chromatography (Biotage SP4, eluting with a gradient from 20-85% ethyl acetate in hexane) and the purified product dried at 40 0 C under vacuum for five days to yield the title compound as a white crystalline solid (86mg).
  • Example 39a Faster running enantiomer (4- ⁇ [(3R)-3-[(methyloxy)methyl]-4- (phenylcarbonyl)-1-piperazinyl]sulfonyl ⁇ benzonitrile or 4- ⁇ [(3S)-3-[(methyloxy)methyl]- 4-(phenylcarbonyl)-1 -piperazinyl]sulfonyl ⁇ benzonitrile, 9mg)
  • the compounds of Table 3 are commercially available and support the first aspect of the invention.
  • the compounds are commercially available from at least one of the following suppliers: a) Enamine Ltd, Kiev, Ukraine; b) Life Chemicals Inc., (formerly I. F. Lab Inc.) Burlington, Canada; c) Asinex Ltd., Moscow, Russia; d) Chem.Div. Inc, San Diego, USA; e) Vitas-M, Moscow, Russia; f) ChemBridge Corporation, San Diego, USA; g) Zelinsky Institute of Organic Chemistry, Moscow, Russia.
  • the columns used are Waters Atlantis, the dimensions of which are 19mm x 100mm (small scale) and 30mm x 100mm (large scale).
  • the stationary phase particle size is 5 ⁇ m.
  • Aqueous solvent Water + 0.1% Formic Acid
  • the column used is a Waters Acquity BEH UPLC C18, the dimensions of which are 2.1 mm x 50mm.
  • the stationary phase particle size is 1.7 ⁇ m.
  • Aqueous solvent Water + 0.05% Formic Acid
  • Organic solvent Acetonitrile + 0.05%
  • the generic method used has a 2 minute runtime.
  • the above method has a flow rate of 1 ml/min.
  • the injection volume for the generic method is 0.5ul
  • the UV detection range is from 220 to 330nm
  • ZQ1 uses Waters MassLynx version 4.0 SP2 MSD systems use Agilent ChemStation Rev. B.01.01
  • the column used is a Waters Atlantis, the dimensions of which are 4.6mm x 50mm.
  • the stationary phase particle size is 3 ⁇ m.
  • Aqueous solvent Water + 0.1% Formic Acid
  • the above method has a flow rate of 3ml/mins.
  • the UV detection range is from 210 to 350nm
  • Biotaqe SP4® Biotage - SP4® is an automated purification system. It uses preloaded silica gel columns. The user applies their material to the top of the column and chooses solvents, gradients, flow rates, column size, collection method and eluting volumes.
  • Phase separators are a range of ISOLUTE® columns fitted with an optimized frit material that easily separates aqueous phase from chlorinated solvents under gravity.
  • an SCX cartridge was used as part of the compound purification process.
  • an ISOLUTE SCX-2 cartridge was used.
  • ISOLUTE SCX-2 is a silica-based sorbent with a chemically bonded propylsulfonic acid functional group.
  • HEK293 human embryonic kidney cells.
  • HEK293 cells were cultured in Dulbecco's modified Eagles media/F12 media (Invitrogen, Cat # 041 -95750V) containing 10% fetal bovine serum, with added L-glutamine (2 mM; Invitrogen, Cat # 25030-024) and non-essential amino acids (5%; Invitrogen, Cat # 1 1140-035).
  • HEK293 cells were transfected with two plasmid vectors for expression of the hCa v 2.2 ⁇ subunit (pCIN5- hCa v 2.2 which carries a neomycin resistance marker) and the hCa v ⁇ 3 subunit (pCIH-hCa v ⁇ 3 which carries a hygromycin resistance marker).
  • Clonal cell lines were isolated following selection in media supplemented with 0.4 mg ml "1 Geneticin G418 (Invitrogen, Cat # 10131-027) and 0.1 mg ml "1 hygromycin (Invitrogen, Cat # 10687-010).
  • clonal cell lines were assessed for Ca v 2.2 ⁇ / ⁇ 3-mediated current expression using the IonWorks planar array electrophysiology technology (described below). A clonal line was identified that gave a reasonable level of functional Ca v 2.2 ⁇ / ⁇ 3 current expression.
  • This cell line was transfected with a plasmid vector for expression of the human ⁇ 2 ⁇ 1 subunit (pCIP- ⁇ 2 ⁇ 1 which carries a puromycin resistance marker) and clonal cell lines isolated following selection in media containing 0.62 ⁇ g ml "1 puromycin (Sigma, Cat # P-7255), in addition to 0.4 mg ml "1 Geneticin G418 and 0.1 mg ml "1 hygromycin.
  • Cells were grown to 30-60% confluence in T175 flasks and maintained at 30 0 C for 24 hrs prior to recording. Cells were lifted by removing the growth media, washing with Ca 2+ free PBS (Invitrogen, Cat #14190-094) and incubating with 3 ml of warmed (37°C) TrpLE (Invitrogen, Cat # 12604-013) for 6 minutes. Lifted cells were suspended in 10 ml of extracellular buffer. Cell suspension was then placed into a 15 ml tube and centrifuged for 2 minutes at 700 rpm. After centrifugation, the supernatant was removed and the cell pellet was resuspended in 4.5 ml of extracellular solution.
  • Ca 2+ free PBS Invitrogen, Cat #14190-094
  • TrpLE Invitrogen, Cat # 12604-013
  • Test pulses stepping from the holding potential (V H ) of -90 mV to +10 mV were applied for 20 ms and repeated 10 times at a frequency of 10 Hz.
  • the test pulse protocol was performed in the absence (pre-read) and presence (post-read) of a compound. Pre- and post-reads were separated by a compound addition followed by a 3-3.5 min incubation.
  • the intracellular solution contained the following (in mM): K-gluconate 120, KCI 2OmM, MgCI 2 5, EGTA 5, HEPES 10, adjusted to pH 7.3.
  • Amphotericin was prepared as 30 mg/ml stock solution and diluted to a final working concentration of 0.2 mg ml "1 in intracellular buffer solution.
  • the extracellular solution contained the following (in m ⁇ f): Na-gluconate 120, NaCI 20, MgCI 2 1 , HEPES 10, BaCI 2 5, adjusted to pH 7.4.
  • the recordings were analysed and filtered using seal resistance (>40 M ⁇ ), resistance reduction (>35%) and peak current amplitude (>200pA) in the absence of compound to eliminate unsuitable cells from further analysis. Paired comparisons between pre-compound and post-compound additions were used to determine the inhibitory effect of each compound.
  • concentrations of compounds required to inhibit current elicited by the 1 st depolarising pulse by 50% (tonic plC50) were determined by fitting of the Hill equation to the concentration response data.
  • the use-dependent inhibitory properties of the compounds were determined by assessing the effect of compounds on the 10 th versus 1 st depolarising pulse.
  • the ratio of the 10 th over 1 st pulse was determined in the absence and presence of drug and the % use-dependent inhibition calculated.
  • the data was fitted using the same equation as for the tonic plC 50 and the concentration producing 30% inhibition (use- dependent pUD 30 ) determined.
  • the compounds of Examples 1 to 68 were tested in the hCa v 2.2 assay in the version as shown in the Examples.
  • the compounds of Examples 1 to 68 exhibited a pUD 30 value of 4.5 or more than 4.5.
  • the compounds of Examples 1 to 28, 30, 31 , 34 to 42, and 50 to 67 exhibited a pUD 30 value of 5.0 or more than 5.0.
  • the compounds of Examples 1 to 3, 12, 22, 30, 31 and 50 to 53 exhibited a pUD 30 value of 5.5 or more than 5.5.
  • the compounds of Examples 1 to 67 exhibited a mean plC 5 o value of 5.0 or less than 5.0.
  • the compounds of Examples 1 to 10, 12, 14 to 21 , 23 to 29, 31 to 67 exhibited a mean plC 5 o value of 4.5 or less than 4.5.

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Abstract

La présente invention porte sur de nouveaux dérivés de pipérazine (I) qui ont une affinité pour les canaux calciques Cav2.2 et qui sont capables d'interférer avec les canaux calciques Cav2.2 ; sur des procédés permettant de les préparer ; sur des compositions pharmaceutiques les contenant ; et sur l'utilisation de tels composés en thérapie.
PCT/EP2009/052802 2009-03-10 2009-03-10 Dérivés de pipérazine destinés à être utilisés en thérapie WO2010102663A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2011026241A1 (fr) * 2009-09-04 2011-03-10 Zalicus Pharmaceuticals Ltd. Dérivés hétérocycliques substitués pour le traitement de la douleur et de l'épilepsie
WO2017144624A1 (fr) * 2016-02-23 2017-08-31 Servicio Andaluz De Salud Dérivés de pipérazine comme agents antiviraux présentant une activité thérapeutique accrue
US10208023B2 (en) 2013-03-01 2019-02-19 Mark G. DeGiacomo Heterocyclic inhibitors of the sodium channel
US10751417B2 (en) 2017-04-20 2020-08-25 Novartis Ag Sustained release delivery systems comprising traceless linkers
US11389541B2 (en) 2018-10-03 2022-07-19 Novartis Ag Sustained delivery of angiopoetin-like 3 polypeptides

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WO2007103456A2 (fr) * 2006-03-06 2007-09-13 Trimeris, Inc. Derives de piperazine et piperidine biaryle
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WO2007111921A1 (fr) * 2006-03-23 2007-10-04 Amgen Inc. Composés d'amide 1-phénylsulfonyl-diaza hétérocyclique et leurs utilisations comme modulateurs d'hydroxystéroïde déshydrogénases
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011026241A1 (fr) * 2009-09-04 2011-03-10 Zalicus Pharmaceuticals Ltd. Dérivés hétérocycliques substitués pour le traitement de la douleur et de l'épilepsie
US10208023B2 (en) 2013-03-01 2019-02-19 Mark G. DeGiacomo Heterocyclic inhibitors of the sodium channel
WO2017144624A1 (fr) * 2016-02-23 2017-08-31 Servicio Andaluz De Salud Dérivés de pipérazine comme agents antiviraux présentant une activité thérapeutique accrue
JP2019509338A (ja) * 2016-02-23 2019-04-04 セルビシオ アンダルーサ デ サルー 治療活性が増加した抗ウイルス剤としてのピペラジン誘導体
US10751417B2 (en) 2017-04-20 2020-08-25 Novartis Ag Sustained release delivery systems comprising traceless linkers
US11389541B2 (en) 2018-10-03 2022-07-19 Novartis Ag Sustained delivery of angiopoetin-like 3 polypeptides

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