EP1828122A2 - Dérivés de n-pyrrolidin-3-yl-amide comme inhibiteurs de recaptage de la sérotonine et noradrénaline - Google Patents

Dérivés de n-pyrrolidin-3-yl-amide comme inhibiteurs de recaptage de la sérotonine et noradrénaline

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Publication number
EP1828122A2
EP1828122A2 EP05811385A EP05811385A EP1828122A2 EP 1828122 A2 EP1828122 A2 EP 1828122A2 EP 05811385 A EP05811385 A EP 05811385A EP 05811385 A EP05811385 A EP 05811385A EP 1828122 A2 EP1828122 A2 EP 1828122A2
Authority
EP
European Patent Office
Prior art keywords
pyrrolidin
methyl
alkyl
propanamide
aryl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP05811385A
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German (de)
English (en)
Inventor
Mark David Andrews
Alan Daniel Brown
Paul Vincent Fish
Michael Jonathan Fray
Mark Ian Lansdell
Thomas Ryckmans
Alan Stobie
Florian Wakenhut
David L.F. Gray
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Ltd
Original Assignee
Pfizer Ltd
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Filing date
Publication date
Priority claimed from GB0427618A external-priority patent/GB0427618D0/en
Application filed by Pfizer Ltd filed Critical Pfizer Ltd
Publication of EP1828122A2 publication Critical patent/EP1828122A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • 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

Definitions

  • This invention relates to novel amide compounds which inhibit monoamine re-uptake, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
  • the compounds of the invention exhibit activity as serotonin and/or noradrenaline re-uptake inhibitors and therefore have utility in a variety of therapeutic areas.
  • the compounds of the invention are of use in the treatment of disorders in which the regulation of monoamine transporter function is implicated, more particularly disorders in which inhibition of re-uptake of serotonin or noradrenaline is implicated.
  • the compounds of the invention are of use in disorders in which inhibition of both serotonin and noradrenaline is implicated, such as urinary incontinence.
  • the compounds of the invention are of use in disorders in which it may be desired to inhibit preferentially the reuptake of one of noradrenaline or serotonin compared with the other, such as pain, depression, premature ejaculation, ADHD or fibromyalgia.
  • the invention provides a compound of Formula (I)
  • R 1 is -H, -C 1-6 alkyl, -C(A)Y, -C 3-8 CyClOaI kyl, -aryl, -het, aryl-C 1-4 alkyl- or het-C ⁇ alkyl-, wherein the cycloalkyl, aryl or het groups are optionally substituted by at least one substituent independently selected from B;
  • A is S or O
  • Y is -H, aryl is independently selected from phenyl, naphthyl, anthracyl or phenanthryl; het is independently selected from an aromatic or non-aromatic 4-, 5- or 6- membered heterocycle which contains at least one N, O or S heteroatom, optionally fused to a 5- or 6- membered carbocyclic group or a second 4-, 5- or 6-membered heterocycle which contains at least one N, O or S heteroatom; B represents d-aalkyl-, C 1 ⁇ aIkOXy-, -OH, -halo, -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -SCF 3 , hydroxy-d.
  • R 2 is aryl 1 or het 1 , each optionally substituted by at least one substituent independently selected from D; aryl 1 is independently selected from phenyl, naphthyl, anthracyl, phenanthryl, or indanyl; het 1 is an aromatic 5 to 10 membered heterocyclic ring system which contains at least one N, O or S heteroatom, optionally containing an aryl group; D represents d ⁇ alkyl-, C 1 ⁇ aIkOXy-, -OH, -halo, -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -SCF 3 , hydroxy-d- 6 alkyl-, C M alkoxy-C ⁇ alkyl-, -SC 1-8 alkyl, d-4alkyl-S-d-»alkyl-, -aryl 2 , -het 2 , -Oaryl 2 , -Ohet 2 ,
  • aryl 2 and het 2 groups are optionally substituted by at least one group selected from E;
  • aryl 2 is independently selected from phenyl, naphthyl, anthracyl or phenanthryl;
  • het 2 is independently selected from an aromatic or non-aromatic A-, 5- or 6- membered heterocycle which contains at least one N, O or S heteroatom, optionally fused to a 5- or 6- membered carbocyclic group or a second A-, 5- or 6-membered heterocycle which contains at least one N, O or S heteroatom;
  • E represents C 1-6 alkyl-, C 3-6 cycloalkyl-, C 1 ⁇ aIkOXy-, -OCs ⁇ cycloalkyl, -halo, -CN, -OH, - CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , and - SCF 3 ;
  • R 3 is -H, C 1-8 alkylSd- 8 alkyl-, -het 3 , or het 3 -C 1-4 alkyl-, wherein the alkyl, cycloalkyl and het 3 groups are each optionally substituted by at least one substituent independently selected from G; het 3 is a non-aromatic A-, 5- or 6- membered heterocycle which contains at least one N, O or S heteroatom, optionally fused to a 5- or 6- membered carbocyclic group or a second 4-, 5- or 6- membered heterocycle which contains at least one N, O or S heteroatom;
  • G represents C h alky!-, C 1 ⁇ aIkOXy-, -OH, -halo, -CF 3 , -OCHF 2 , -OCF 3 , -SCF 3 , -CN, -CF 2 CF 3 , - CF 2 -C 1-4 alkyl, hydroxy-C 1-6 alkyl-, C 1-4 alkoxy-d- 6 alkyl- and d ⁇ alkyl-S-d ⁇ alkyl-; and the alkyl groups being optionally substituted by at least one substituent independently selected from J; J represents C 1-6 alkoxy-, -OH, -halo, -CF 3 , -OCHF 2 , -OCF 3 , -SCF 3 , -CN, -CF 2 CF 3 , -CF 2 -
  • R 3 is (CH 2 ) a' K, wherein a' is 0, 1 or 2 and K is a group selected from:
  • Z is O, S, NR 12 , (CH 2 ) V or a bond; a is 1, 2, 3 or 4; b is 1 , 2 or 3; v is 1 or 2;
  • R 10 and R 11 are each independently -H or C 1 -* alkyl-;
  • R 12 is -H, C 1-6 alkyl-, -C(O)C 1-6 alkyl, -SO 2 -C 1 ⁇ alkyl; and wherein one or more pairs of hydrogen atoms on adjacent carbon or nitrogen atoms may be replaced by a corresponding number of double bonds, provided the ring system is not aromatic;
  • R 30 is -H or C ⁇ alkyl-; and wherein one or more pairs of hydrogen atoms on adjacent carbon atoms may be replaced by a corresponding number of double bonds, provided the ring system is not aromatic;
  • f is 0, 1 , 2 or 3;
  • L is SO, SO 2 or NR 40 ;
  • R 40 is -H, C 1 ⁇ alkyl-, -C(O)C 1-6 alkyl, -SO 2 -C 1-6 alkyl; ' and wherein one or more pairs of hydrogen atoms on adjacent carbon atoms may be replaced by a corresponding number of double bonds, provided the ring system is not aromatic;
  • g is 0, 1, 2 or 3; and R 50 is -H, Ci- ⁇ alkyl-, C 1 ⁇ aIkOXy-, -OH, -halo, -CF 3 , -OCHF 2 , -OCF 3 , -SCF 3 , hydroxy-d.
  • X is a covalent bond, C 1-8 alkyl- or C 3-8 CyClOaI kyl-, wherein if X is C 3 ⁇ cycloalkyl, then R 2 -X may form a fused aryl-cycloalkyl ring system; and
  • n is 1 or 2, provided that: when n is 1 , m is O or 1 ; and when n is 2, m is O; wherein if m is 0, then * represents a chiral centre.
  • R 1 is -H.
  • n 1 and m is 0 or 1.
  • X represents a covalent bond and d-ealkyl-; preferably C 1-8 alkyl represents d ⁇ alkyl, more preferably d ⁇ alkyl, more preferably C 1-2 alkyl, and most preferably represents -CH 2 -.
  • aryl 1 represents phenyl, naphthyl, and indanyl.
  • het 1 represents furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazinyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, benzothiazolyl, cinnolinyl, phthalzinyl, indolyl and isoindolyl; preferably it represents quinolinyl, isoquinolinyl or pyridinyl; preferably it represents quinolinyl.
  • R 2 is aryl 1 or het 1 , each optionally substituted by between one and three substituents independently selected from D.
  • D represents -halo, C 1-S aIKyI-, Sd- ⁇ alkyl-, C 1-8 alkyloxy-, C ⁇ alkoxy-C ⁇ alkyl-, -aryl 2 , -Oaryl 2 , -het 2 , C 3-8 CyClOaI kyl-, -OC ⁇ alkyl-C ⁇ cycloalkyl, -CF 3 , -SCF 3 , -OCHF 2 , -CHF 2 , -OCF 2 CHF 2 , and -OCF 3 ; preferably halo represents fluoro, chloro, and bromo; preferably d- ⁇ alkyl represents C 1-4 alkyl; preferably C 1-8 alkyloxy represents methoxy, ethoxy, and propoxy; preferably aryl 2 represents phenyl; preferably Oaryl 2 represents OPh; preferably het 2 represents pyridinyl; preferably SC 1-8 alkyl
  • D represents -halo, d- ⁇ alkyl-, SC 1-8 alkyl-, C ⁇ alkyloxy-, d ⁇ alkoxy-d-ealkyl-, - aryl 2 , -Oaryl 2 , Cs- ⁇ cycloalkyI-, -Od- ⁇ alkyl-Cs- ⁇ cycloalkyl, -CF 3 , -SCF 3 , -OCF 2 CHF 2 , and -OCF 3 ; preferably halo represents fluoro, chloro, and bromo; preferably C 1-8 alkyl represents C 1-3 alkyl; preferably d ⁇ alkyloxy represents methoxy, ethoxy, and propoxy; preferably aryl 2 represents phenyl; preferably Oaryl 2 represents OPh; preferably SC ⁇ alkyl represents SMe and SEt; preferably C 3-8 cycloalkyl represents cyclopropyl, cyclobutyl and cyclopent
  • D represents -halo, C h alky!-, -Sd- ⁇ alkyl, d ⁇ alkyloxy-, -aryl 2 , -Oaryl 2 , C 3 .
  • ⁇ cycloalkyl-, -Od-salkyl-Cs- ⁇ cycloalkyl, -CF 3 , .OCF 2 CHF 2 , and -OCF 3 preferably halo represents fluoro, chloro, and bromo; preferably d ⁇ alkyl represents d.
  • alkyl preferably d ⁇ alkyloxy represents methoxy and ethoxy; preferably aryl 2 represents phenyl; preferably Oaryl 2 represents OPh; preferably SC 1-8 alkyl represents SMe and SEt; preferably Cs- ⁇ cycloalkyl represents cyclopropyl; and preferably ⁇ cycloalkyl represents OCH ⁇ cyclopropyl.
  • E represents halo; preferably chloro and fluoro; preferably fluoro.
  • R 3 represents d- ⁇ alkyl-, C 3 _ 3 cycloalkyl-, C 3 ⁇ cycloalkyl-d ⁇ alkyl-, and C 1 .
  • ⁇ alkylSCi-salkyl- preferably d ⁇ alkyl represents C 1-6 alkyl; preferably C ⁇ cycloalkyl represents C 3 . 6 cycloalkyl; preferably C 3-8 cycloalkyl-d.
  • 6 alkyl represents cyclopentylmethyl; and preferably d- ⁇ alkylSd. 8 alkyl represents CH 2 SMe.
  • G represents C 1 ⁇ aIkOXy-, -halo, -OH, and -CF 3 ; preferably halo represents fluoro; preferably C 1 ⁇ aIkOXy represents methoxy and ethoxy. In a further embodiment, G represents CF 3 .
  • net 3 represents a non-aromatic 6- membered heterocycle which contains at least one N, O or S heteroatom; preferably it represents a non-aromatic 6- membered heterocycle which contains at least one O heteroatom; preferably it represents tetrahydropyranyl.
  • the invention provides a compound of Formula (I')
  • R 1 is -H, d-ealkyl-, -C(A)Y, C 3 ⁇ cycloalkyl-, -aryl, -het, aryl-d ⁇ alkyl- or het-C ⁇ alkyl-, wherein the cycloalkyl, aryl or het groups are optionally substituted by at least one substituent independently selected from C ⁇ alkyl-, d-salkoxy-, -OH, -halo, -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -SCF 3 , hydroxy-C 1-6 alkyl-, C 1 . 4 alkoxy-C 1 .
  • R 2 is aryl or heteroaryl, each optionally substituted by at least one substituent independently selected from C ⁇ alkyl-, Ci-salkoxy-, -OH, -halo, -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -SCF 3 , hydroxy-C ⁇ alkyl-, C 1- A alkoxy-C ⁇ alkyl-, C ⁇ alkyl-S-C M alkyl-, -aryl 1 , -het 1 , -Oaryl 1 , -Ohet 1 , -Saryl 1 , -Shet 1 , -CF2CF3, -CH 2 CF 3 , - CF 2 CH 3 , Qs-ecycloalkyl-, Cs-ecycloalkyl-C ⁇ alkyl-, Cs-scycloalkyl-C ⁇ alkoxy
  • Z is O, S, NR 12 , (CH 2 )v or a bond; a is 1, 2 3 or 4; b is 1 , 2 or 3; v is 1 or 2;
  • R 10 and R 11 are each independently -H or C 1-4 alkyl-; and R 12 is -H, C 1 * alkyl-, -C(O)C 1 ⁇ alkyl, -SO 2 -C 1-6 alkyl; and wherein one or more pairs of hydrogen atoms on adjacent carbon or nitrogen atoms may be replaced by a corresponding number of double bonds, provided the ring system is not aromatic;
  • N wherein: a is 1 , 2, 3 or 4; b is 1 , 2 or 3; c is 1 or 2; and R 30 is -H or C 1-4 alkyl-; and wherein one or more pairs of hydrogen atoms on adjacent carbon atoms may be replaced by a corresponding number of double bonds, provided the ring system is not aromatic;
  • d is 0, 1 , 2 or 3;
  • J is SO, SO 2 or NR 40 ;
  • R 40 is -H, C 1 * alkyl-, C(O)C 1 - S alkyl-, -SO 2 -C 1-6 alkyl; and wherein one or more pairs of hydrogen atoms on adjacent carbon atoms may be replaced by a corresponding number of double bonds, provided the ring system is not aromatic;
  • e is O, 1 , 2 or 3;
  • R 50 is -H, C 1-8 alkyl-, C 1 ⁇ aIkOXy-, -OH, -halo, -CF 3 , -OCHF 2 , -OCF 3 , -SCF 3 , hydroxy-d. 6 alkyl-, C ⁇ alkoxy-C ⁇ alkyl- and C ⁇ alkyl-S-C ⁇ alkyl-; and
  • X is a covalent bond, C 1- ⁇ alkyl- or C 3 ⁇ cycloalkyl-, wherein if X is 3-8 cycloalkyl, then R 2 -X may form a fused aryl-cycloalkyl ring system;
  • A is S or O;
  • Y is -H, d-salkyl-, -aryl, -het, aryl-C 1J( alkyl- or het-C 1-4 alkyl-;
  • n is 1 or 2, provided that when n is 1 , m is 0 or 1 and when n is 2, m is O 1 wherein if m is 0, then * represents a chiral centre;
  • aryl and aryl 1 are each independently selected from phenyl, riaphthyl, anthracyl or phenanthryl;
  • heteroaryl is an aromatic 5- or 6- membered heterocycle which contains at least one N, O or S heteroatom,
  • R 3 is as defined above in any embodiment
  • R 4 is phenyl, naphthyl, or quinolinyl, each optionally substituted by at least one substituent independently selected from C h alky!-, C 1 ⁇ aIkOXy-, -OH, -halo, -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -SCF 3 , hydroxy-C ⁇ alkyl-,
  • X is a covalent bond, C ⁇ alkyl- or C 3 ⁇ cycloalkyl-, wherein if X is ⁇ cycloalkyl, then R 4 -X may form a fused aryl -cycloal kyl ring system; and m is O or 1 , wherein if m is O, then * represents the R or S enantiomer.
  • R 4 is phenyl, 1-naphthyl or 2-naphthyl, each optionally ' substituted by at least one substituent independently selected from C h alky!-, d- ⁇ alkoxy-, -OH, -halo, -CF 3 , -CHF 2 , -OCF 3 , -
  • aryl 1 and het 1 groups are optionally substituted by at least one group selected from C 1-6 alkyl-, C 3-6 CyClOaIKyI-, C 1-6 alkoxy-, -OC 3-6 cycloalkyl, -halo, -CN, -OH, -CF 3 , -CHF 2 , -OCF 3 , -
  • OCHF 2 hydroxyC ⁇ alkyl-, C 1-4 alkoxy-C M alkyl-, -SC 1-6 alkyl and -SCF 3 .
  • the phenyl or naphthyl groups may be substituted by one, two or three substituents.
  • m is O.
  • * represents the R or S enantiomer.
  • m is O and * represents the S enantiomer.
  • R 3 is as defined above in any embodiment
  • R 6 is phenyl, naphthyl or quinolinyl, each optionally substituted by at least one substituent independently selected from C h alky!-, C 1-8 alkoxy-, -OH, -halo, -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -SCF 3 , hydroxy-C 1-6 alkyl-, -aryl 1 , -het 1 , -Oaryl 1 , -Ohet 1 , -Saryl 1 , -Shet 1 , -CF2CF3, - CH 2 CF 3 , -CF 2 CH 3 , Qs-ecycloalkyl-, Cs-ecycloalkyl-C ⁇ alkyl-, C 3 ⁇ cycloalkyl-C 1-4 alkoxy-, Cs-scycloalkyl-O-Cv 4 alkyl-, Cs-ecycloalkyl-C ⁇ alkoxy-
  • X is a covalent bond, C ⁇ alkyl- or C 3-8 cycloalkyl-, wherein if X is 3-8 cycloalkyl, then R 6 -X may form a fused aryl-cycloalkyl ring system; and * represents the R or S enantiomer.
  • R 6 is phenyl, 1 -naphthyl or 2-naphthyl, each optionally substituted by at least one substituent independently selected from C ⁇ alkyl-, C ⁇ alkoxy-, -OH, -halo, -CF 3 , -CHF 2 , -OCF 3 , - OCHF 2 , -SCF 3 , hydroxy-Ci- ⁇ alkyl-, C ⁇ alkoxy-C ⁇ alkyl-, C ⁇ alkyl-S-C ⁇ alkyl-, -aryl 1 , -het 1 , -Oaryl 1 , -Ohet 1 , -Saryl 1 , -Shet 1 , -CF2CF3, -CH 2 CF 3 , -CF 2 CH 3 , C 3-6 cycloalkyl-, C ⁇ cycloalkyl-d.
  • aryl 1 and het 1 groups are optionally substituted by at least one group selected from C 1-6 alkyl-, Cs- ⁇ cycloalkyl-, C 1-6 alkoxy-, -OC ⁇ cycloalkyl, -halo, -CN, -OH 1 -CF 3 , -CHF 2 , -OCF 3 , - OCHF 2 , hydroxyC ⁇ alkyl-, C M alkoxy-C M alkyl-, -SC ⁇ alkyl and -SCF 3 .
  • * represents the S enantiomer.
  • the invention provides a compound selected from: ⁇ /-(Biphenyl-2-ylmethyl)-2-methyl- ⁇ /-[(3S)-pyrrolidin-3-yl]propanamide; ⁇ /-(2,4-Dichlorobenzyl)-3-methyl- ⁇ /-[(3S)-pyrrolidin-3-yl]butanamide;
  • ⁇ /-(2,4-dichlorobenzyl)-2-methyl ⁇ /-[(3S)-pyrrolidin-3-yl]butanamide; ⁇ /-(2,4-dichlorobenzyl)-2-ethyl- ⁇ /-[(3S)-pyrrolidin-3-yl]butanamide;
  • pharmaceutically and/or veterinarily acceptable derivative it is meant any pharmaceutically or veterinarily acceptable salt, solvate, ester or amide, or salt or solvate of such ester or amide, complex, polymorph, stereoisomer, geometric isomer, tautomeric form, or isotopic variation, of the compounds of formula (I), (I'), (II) or (III) or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I), (I 1 ), (H') or (IH') or an active metabolite or residue thereof.
  • pharmaceutically acceptable derivatives are salts, solvates, esters and amides of the compounds of formula (I), (I 1 ), (H') or (IH'). More preferably, pharmaceutically acceptable derivatives are salts and solvates.
  • the salts referred to above will be the pharmaceutically or veterinarily acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I), (I 1 ), (U') or (III 1 ) and the pharmaceutically or veterinarily acceptable salts thereof.
  • the aforementioned pharmaceutically or veterinarily acceptable salts include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, camsylate, citrate, hemicitrate, edisylate, hemiedisylate, esylate, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, 2-napsylate, nicotinate, nitrate, orotate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate and
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • a pharmaceutically acceptable salt of a compound of formula (I), (I'), (H') or (III 1 ) may be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
  • solvates in accordance with the invention include hydrates and solvates of the compounds of formula (I), (I'), (II 1 ) or (III').
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the pharmaceutical drug which contain two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non-ionised.
  • the compounds of formula (I), (I 1 ), (H') or (IH') may be modified to provide pharmaceutically or veterinarily acceptable derivatives thereof at any of the functional groups in the compounds. Examples of such derivatives are described in: Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538; Topics in Chemistry, Chapter 31, pp 306 - 316; and in "Design of Prodrugs" by H.
  • the compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention. For example, a claim to 2-hydroxypyridinyl would also cover its tautomeric form ⁇ -pyridonyl.
  • the present invention includes radio labelled compounds of formula (I), (I 1 ), (H') or (III 1 ).
  • polymorphism The compounds of formula (I), (I 1 ), (H') or (III 1 ) and their pharmaceutically and veterinarily acceptable derivatives may also be able to exist in more than one crystal form, a characteristic known as polymorphism. All such polymorphic forms (“polymorphs") are encompassed within the scope of the invention. Polymorphism generally can occur as a response to changes in temperature or pressure or both, and can also result from variations in the crystallisation process. Polymorphs can be distinguished by various physical characteristics, and typically the x-ray diffraction patterns, solubility behaviour, and melting point of the compound are used to distinguish polymorphs.
  • any alkyl group may be straight or branched and is of 1 to 8 carbon atoms, such as 1 to 6 carbon atoms or 1 to 4 carbon atoms, for example a methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl or t-butyl group.
  • the alkyl group contains more than one carbon atom, it may be unsaturated.
  • the term C 1-6 alkyl includes C 2-6 alkenyl and C 2 ⁇ alkynyl.
  • Ci -8 alkyl includes C 2 ⁇ alkenyl and C 2-8 alkynyl
  • the term C 1-4 alkyl includes C 2-4 alkenyl and C 2-4 alkynyl.
  • halogen is used to represent fluorine, chlorine, bromine or iodine.
  • the term het includes any aromatic, saturated or unsaturated 4-, 5- or 6- membered heterocycle which contains up to 4 heteroatoms selected from N, O and S.
  • heterocyclic groups included furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, tetrahydropyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl,
  • heterocycle includes fused heterocyclyl groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazdinyl, benzothiazolyl, phthalimido, benzodiazepinyl, indolyl and isoindolyl.
  • substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different. Further, the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • the compounds of the invention are the pharmaceutically and veterinarily acceptable derivatives of compounds of formula (I), (I 1 ), (H') or (IH'), such as the pharmaceutically or veterinarily acceptable salts or solvates of compounds of formula (1), (I 1 ), (II 1 ) or (III 1 ), (e.g. pharmaceutically or veterinarily acceptable salts of compounds of formula (I), (I 1 ), (H') or (IH')).
  • a compound of the invention which is an inhibitor of serotonin and/or noradrenaline monoamine re-uptake, having SRI or NRI IC 5 oA ⁇ i values of 50OnM or less, preferably 40OnM or less, more preferably 20OnM or less.
  • the compound has SRI and/or NRI ICs O /Ki values of 10OnM or less.
  • the compound has SRI and/or NRl lC 50 /Ki values of 5OnM or less.
  • the compound has SRI and/or NRI ICso/Ki values of 25nM or less.
  • the compound is useful for the compound to be a more potent inhibitor of the reuptake of one of serotonin or noradrenaline than the other.
  • the reuptake of noradrenaline is inhibited to greater degree than the reuptake of serotonin.
  • the reuptake of serotonin is inhibited to a greater degree than the reuptake of noradrenaline.
  • compounds of the invention which inhibit the reuptake of noradrenaline have good efficacy.
  • an embodiment of the invention provides a method of treating pain which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to the invention which is capable of inhibiting the reuptake of noradrenaline.
  • the compound of the invention may selectively inhibit the reuptake of noradrenaline or it may inhibit the reuptake of noradrenaline preferentially to the inhibition of serotonin reuptake or it may inhibit the reuptake of serotonin preferentially to the inhibition of noradrenaline reuptake.
  • there provided compounds which are more potent noradrenalin reuptake inhibitors than serotonin reuptake inhibitors are more potent noradrenalin reuptake inhibitors than serotonin reuptake inhibitors.
  • such an embodiment of the invention provides a method of treating pain which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to the invention which is capable of inhibiting the reuptake of noradrenaline to a greater extent than the reuptake of serotonin.
  • compounds of Formula (I) may be prepared from compounds of Formula (III) by reaction with an aldehyde, R 2 CHO (or a suitable ketone), in the presence of a reducing agent, followed by reaction with an acid or anhydride or acid chloride R 3 COX', where X' is OH or halo or OCOR 3 , or alternatively with an acid mixed anhydride, and deprotection.
  • R 3 , R 2 , m and n are as defined above, X is CH 2 and PG is a protecting group.
  • equimolar amounts of amine and aldehyde are typically treated with either sodium triacetoxyborohydride (STAB), NaBH 3 CN or NaBH 4 , in a suitable solvent (e.g. DCM, THF) at room temperature for 1 to 24 hours.
  • STAB sodium triacetoxyborohydride
  • a suitable solvent e.g. DCM, THF
  • an excess of a reducing agent e.g. NaBH 4 , LiAIH 4 , STAB
  • a suitable solvent e.g. THF, MeOH, EtOH, toluene
  • a drying agent e.g. molecular sieve
  • a suitable solvent e.g. toluene, xylene.
  • a further alternative involves catalytic hydrogenation in the presence of a palladium or nickel catalyst (e.g. Pd/C,
  • Raney ® Ni under an atmosphere of H 2 , optionally at elevated temperature and pressure, in a suitable solvent (e.g. EtOH).
  • a suitable solvent e.g. EtOH
  • a more specific example of the reductive amination involves treatment of the amine with the aldehyde in the presence of either 10% Pd/C, optionally in the presence of triethylamine, in ethanol under about 415 kPa (about 60psi) of hydrogen at room temperature for 18 hours.
  • Another more specific example of the reductive amination is treatment of the amine with the aldehyde in toluene at reflux under Dean-Stark conditions for 18 hours and then after concentration, treatment with an excess of sodium borohydride in methanol at room temperature for 3 hours.
  • Suitable aldehydes are either, known and available from commercial sources, or, are derivable from commercially available materials using known techniques; for example, 7-methoxy-1-methyl-naphtalene- 2-carbaldehyde can be prepared using the preparation described in WO 2004/111003.
  • this may be generated in situ by standard methodology and then reacted with the amine (IV) in the presence of triethylamine in dichloromethane at room temperature for 1 hour.
  • Suitable acids, anhydrides and acid chlorides are either, known and available from commercial sources, or, are derivable from commercially available materials using known techniques.
  • PG is a suitable amine-protecting group, preferably BOC, trifluoroacetate, benzyloxycarbonyl (Bz) or benzyl (Bn),
  • the removal of PG from (V), to form the unprotected amine (I) is performed by a method selective to the protecting group as detailed in "Protective Groups in Organic Synthesis", 3 rd edition, by TW Greene and PGM Wuts. John Wiley and Sons, Inc., 1999, incorporated herein by reference. Examples of such deprotection reactions are as follows:
  • the deprotection involves treatment of (V) with an excess of strong acid (e.g. HCI, TFA) at room temperature in a suitable solvent (e.g. DCM, EtOAc, dioxane).
  • strong acid e.g. HCI, TFA
  • a suitable solvent e.g. DCM, EtOAc, dioxane
  • the deprotection involves treatment of (V) with a base (e.g. K 2 CO 3 , Na 2 CO 3 , NH 3 , Ba(OH) 2 ) in an alcoholic solvent (e.g. MeOH, EtOH), optionally with water and optionally at elevated temperature. More specifically, when PG is trifluoroacetate, the deprotection involves treatment with K 2 CO 3 in methanol :water mixture (5:1 to 10:1) at room temperature for 18 hours (WO 2004110995).
  • a base e.g. K 2 CO 3 , Na 2 CO 3 , NH 3 , Ba(OH) 2
  • an alcoholic solvent e.g. MeOH, EtOH
  • the deprotection involves either transfer hydrogenation with a transition metal or transition metal salt hydrogenation catalyst (e.g. Pd/C, Pd(OH) 2 ) in the presence of a hydrogen donor (e.g. NH 4 + HCO 2 " ) in a polar solvent (e.g. THF, EtOH, MeOH) optionally at elevated temperature and/or pressure, or catalytic hydrogenation in the presence of a palladium or nickel catalyst (e.g. Pd/C, Raney ® Ni) under an atmosphere of H 2 , optionally at elevated temperature and pressure, in a suitable solvent.
  • a transition metal or transition metal salt hydrogenation catalyst e.g. Pd/C, Pd(OH) 2
  • a hydrogen donor e.g. NH 4 + HCO 2 "
  • a polar solvent e.g. THF, EtOH, MeOH
  • a palladium or nickel catalyst e.g. Pd/C, Raney ® Ni
  • the deprotection involves treatment with either an excess of 4M hydrogen chloride in dioxane for 18 hours at room temperature or with TFA in DCM for 20 hours at room temperature.
  • the deprotection involves treatment with K 2 CO 3 in methanohwater mixture (5:1 to 10:1) at room temperature for 18 hours.
  • the deprotection involves treatment with NH 4 + HCO 2 ' and 10% Pd/C in ethanol under gentle reflux for between 4 and 20 hours.
  • the deprotection involves treatment of (V) with a base (e.g. K 2 CO 3 , Na 2 CO 3 , NH 3 , Ba(OH) 2 ) in an alcoholic solvent (e.g. MeOH, EtOH), optionally with water and optionally at an elevated temperature.
  • a base e.g. K 2 CO 3 , Na 2 CO 3 , NH 3 , Ba(OH) 2
  • an alcoholic solvent e.g. MeOH, EtOH
  • the deprotection involves treatment with K 2 CO 3 in methanohwater mixture (5:1 to 10:1) at room temperature for 18 hours (examples of such deprotection are described in WO 2004110995).
  • compounds of Formula (I) may be prepared from compounds of Formula (III) by reaction with R 2 -X-L, where L is a leaving group, under suitable conditions.
  • the resulting compound of Formula (Vl) may then be converted to a compound of Formula (I) by amide formation and deprotection in a manner analogous to that described above in relation to Scheme 1.
  • R 2 , R 3 , X, m and n are as defined above, PG is a suitable protecting group and L is a leaving group, whose meaning will depend, inter alia, on the nature of the reaction and the specific reaction conditions employed. Suitable leaving groups will be readily apparent to the skilled person and are described in many standard organic chemistry texts, for example: “Advanced Organic Chemistry", Jerry March, Third Edition, Wiley (1985), page 587, incorporated herein by reference; they include halogen (e.g. Br) and sulfonate esters (e.g. methanesulfonate or trifluoromethanesulfonate).
  • halogen e.g. Br
  • sulfonate esters e.g. methanesulfonate or trifluoromethanesulfonate.
  • R 2 is an aryl group
  • X is alkyl
  • L is Br
  • reaction (d) is carried out in a suitable solvent, at elevated temperatures, in the presence of a 3° amine (such as Et 3 N, or H ⁇ nig's base, or NMM, or an inorganic base).
  • a 3° amine such as Et 3 N, or H ⁇ nig's base, or NMM, or an inorganic base.
  • amine (III) is treated with the arylalkylbromide in acetonitrile under gentle reflux for between 1 and 20 hours in the presence of potassium carbonate.
  • reaction (d) may be carried out in a suitable solvent, at elevated temperatures, in the presence of a palladium catalyst.
  • a palladium catalyst Such palladium mediated aryl amination reactions are well known to those skilled in the art.
  • Suitable alkyl halides are either, known and available from commercial sources, or are derivable from commercially available materials using known techniques.
  • compounds of Formula (Vl) may be prepared from a ketone of Formula (VIII) by reaction with a primary amine R 2 -X-NH 2 in the presence of a reducing agent, under suitable conditions.
  • the resulting compound of Formula (Vl) may then be converted to a compound of Formula (I) by amide formation and deprotection in a manner analogous to that described above in relation to Scheme 1.
  • R 3 , R 2 , X, m and n are as defined above and PG is a suitable protecting group.
  • the reaction (e) of the primary amine R 2 -X-NH 2 with the ketone (VIII) may conveniently be a reductive amination reaction in which the dehydration of the amine and the ketone is followed by reduction of the resultant imine, for example by a metal hydride reagent or hydrogenation, under suitable conditions.
  • reaction of the amine and the ketone is carried out in the presence of titanium (IV) tetraisopropoxide in THF at room temperature for 18 hours, followed by reduction by an excess of sodium borohydride in methanol at room temperature for 5 hours.
  • Suitable amines are either, known and available from commercial sources, or are derivable from commercially available materials using known techniques.
  • R 2 is as defined above and PG is a protecting group.
  • compounds of Formula (IV) may be prepared from a 1 ° amine of Formula (III) by reaction with a carboxylic acid or acid halide, optionally prepared in situ, R 2 COX' (where X' is OH or halo), followed by reaction with a reducing agent, such as borane.
  • a more specific example of the amide formation involves treatment of the acid with the amine in the presence of 1 -propyl phosphonic ester cyclic anhydride and in the presence of triethylamine in DCM at room temperature for 1 hour.
  • this may be generated in situ by standard methodology and then reacted with the amine (III) and triethylamine in dichloromethane at 70 0 C for 90 minutes
  • reaction (y) is a reduction of the amide to amine (IV) for example by a hydride reducing agent under suitable conditions.
  • the reduction of the amide is carried out in the presence of Borane in THF at reflux for 2 hours, followed by addition of methanol and optionally of aqueous ammonium chloride and further reflux for 4 hours before isolation of the amine (IV).
  • one or more sensitive functional groups may need to be protected and deprotected during the synthesis of a compound of Formula (I), (II) or (III). This may be achieved by conventional techniques, for example as described in "Protective Groups in Organic Synthesis", 3 rd edition, by TW Greene and PGM Wuts. John Wiley and Sons, Inc., 1999, incorporated herein by reference, which also describes methods for the removal of such groups.
  • R 2 , n and m are as defined above and Y is R 1 or a protecting group, with an acid or acyl halide: R 3 COX, wherein X is OH or halo, or an acid anhydride: (R 3 CO) 2 O, and deprotecting if necessary.
  • the compound of Formula (X) may be prepared by reacting a compound of Formula (XXI) with an aldehyde: R 2 CHO in the presence of a reducing agent.
  • the compound of Formula (X) may be prepared by reacting a compound of Formula (XXI) with a compound R 2 -X-L, where L is a leaving group, optionally selected from halide, methanesulfonate and trifluoromethanesulfonate.
  • the compound of Formula (X) may be prepared by reacting a compound of Formula (XXII) with a compound R 2 -X-NH 2 in the presence of a reducing agent.
  • Racemic compounds may be separated either using preparative HPLC and a column with a chiral stationary phase, or resolved to yield individual enantiomers utilizing methods known to those skilled in the art.
  • racemic chiral intermediate compounds may be resolved and used to prepare enantio-enriched chiral compounds of the invention.
  • the compounds of the invention may have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, are more stable, have fewer side effects or are more selective, or have other more useful properties than the compounds of the prior art.
  • the compounds of the invention are useful because they have pharmacological activity in mammals, including humans. Thus, they are useful in the treatment or prevention of disorders in which the regulation of monoamine transporter function is implicated, more particularly disorders in which inhibition of re-uptake of serotonin or noradrenaline is implicated. Furthermore, the compounds of the invention are of use in disorders in which inhibition of both serotonin and noradrenaline is implicated, such as urinary incontinence. Additionally, the compounds of the invention are of use in disorders in which it may be desired to inhibit preferentially the reuptake of one of noradrenaline or serotonin compared with the other, such as pain.
  • the compounds of the invention are useful in the treatment of urinary incontinence, such as genuine stress incontinence (GSI), stress urinary incontinence (SUI) or urinary incontinence in the elderly; overactive bladder (OAB), including idiopathic detrusor instability, detrusor overactivity secondary to neurological diseases (e.g. Parkinson's disease, multiple sclerosis, spinal cord injury and stroke) and detrusor overactivity secondary to bladder outflow obstruction (e.g. benign prostatic hyperplasia (BPH), urethral stricture or stenosis); nocturnal eneuresis; urinary incontinence due to a combination of the above conditions (e.g.
  • OAB is intended to encompass both OAB wet and OAB dry.
  • the compounds of the invention are also useful in the treatment of depression, such as major depression, recurrent depression, single episode depression, subsyndromal symptomatic depression, depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, paediatric depression, child abuse induced depression, depression in infertile women, post partum depression, premenstrual dysphoria and grumpy old man syndrome.
  • the compounds of the invention are also useful in the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease) and vascular dementia (including multi-infarct dementia), as well as dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia and vitamin deficiency; mild cognitive impairment associated with ageing, particularly age associated memory impairment (AAMI), amnestic disorder and age-related cognitive decline (ARCD); psychotic disorders, such as schizophrenia and mania; anxiety disorders, such as generalised anxiety disorder, phobias (e.g.
  • agoraphobia social phobia and simple phobias
  • panic disorder obsessive compulsive disorder
  • post traumatic stress disorder mixed anxiety and depression
  • personality disorders such as avoidant personality disorder and attention deficit hyperactivity disorder (ADHD)
  • sexual dysfunction such as premature ejaculation, male erectile dysfunction (MED) and female sexual dysfunction (FSD) (e.g.
  • FSAD female sexual arousal disorder
  • SAD seasonal affective disorder
  • eating disorders such as anorexia nervosa and bulimia nervosa
  • obesity appetite suppression
  • chemical dependencies resulting from addiction to drugs or substances of abuse such as addictions to nicotine, alcohol, ***e, heroin, phenobarbital and benzodiazepines
  • withdrawal syndromes such as those that may arise from the aforementioed chemical dependencies
  • cephalic pain such as migraine, cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with chemical dependencies or withdrawal syndromes resulting from chemical dependencies, and tension headache
  • pain Parkinson's diseases, such as dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias
  • endocrine disorders such as hyperprolactinaemia
  • vasospasm such as in the cerebral vasculature
  • Tourette's syndrome trichosted fibros syndrome
  • the compounds of the invention are also useful in the treatment of a number of other conditions or disorders, including hypotension; gastrointestinal tract disorders (involving changes in motility and secretion) such as irritable bowel syndrome (IBS), ileus (e.g. post-operative ileus and ileus during sepsis), gastroparesis (e.g. diabetic gastroparesis), peptic ulcer, gastroesophageal reflux disease (GORD, or its synonym GERD), flatulence and other functional bowel disorders, such as dyspepsia (e.g. non-ulcerative dyspepsia (NUD)) and non-cardiac chest pain (NCCP); and fibromyalgia syndrome.
  • the compounds of the invention being serotonin and/or noradrenaline reuptake inhibitors are potentially useful in the treatment of a range of disorders, including pain.
  • Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
  • the system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobio!.. 57, 1-164 for a review).
  • These sensory fibres are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus.
  • nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated).
  • A-delta fibres myelinated
  • C fibres non-myelinated.
  • the activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.
  • Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually in twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.
  • neuropathic pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • carpal tunnel syndrome e.g. painful diabetic neuropathy, postherpetic neuralgia
  • back pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.
  • Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain.
  • Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, postoperative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain.
  • Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy.
  • Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
  • Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role.
  • neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
  • the inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56).
  • Arthritic pain is the most common inflammatory pain.
  • Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407).
  • Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain.
  • Gl gastrointestinal
  • FBD functional bowel disorder
  • IBD inflammatory bowel disease
  • Gl disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain.
  • Other types of visceral pain include the pain associated with dysmenorrhoea, cystitis and pancreatitis and pelvic pain.
  • heart and vascular pain including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia;
  • head pain such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; and
  • orofacial pain including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.
  • disorders of particular interest include urinary incontinence, such as mixed incontinence, GSI and USI; pain; depression; anxiety disorders, such as obsessive-compulsive disorder and post traumatic stress disorder; personality disorders, such as ADHD; sexual dysfunction; and chemical dependencies and withdrawal syndromes resulting from chemical dependencies.
  • the invention provides:
  • a compound of the invention for use in the treatment of a disorder in which the regulation of monoamine transporter function is implicated, such as urinary incontinence;
  • a method of treatment of a disorder in which the regulation of monoamine transporter function is implicated which comprises administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment;
  • xi a method of treatment of a disorder in which the inhibition of the reuptake of serotonin or noradrenaline is implicated which comprises administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment;
  • xii) a method of treatment of a disorder in which the inhibition of the reuptake of serotonin and noradrenaline is implicated which comprises administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment; and xiii) a method of treating pain or urinary incontinence, such as GSI or USI, which comprises administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment.
  • the compounds of the invention may be administered alone or as part of a combination therapy. If a combination of therapeutic agents is administered, then the active ingredients may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • Suitable agents for adjunctive therapy include:
  • an opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, ***e, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
  • NSAID nonsteroidal antiinflammatory drug
  • NSAID nonsteroidal antiinflammatory drug
  • diclofenac diflusinal, etodolac
  • fenbufen fenoprofen
  • flufenisal flurbiprofen
  • ibuprofen indomethacin
  • ketoprofen ketorolac
  • meclofenamic acid mefenamic acid
  • meloxicam nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac
  • NSAID nonsteroidal antiinflammatory drug
  • a barbiturate sedative e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;
  • a benzodiazepine having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
  • H 1 antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; • a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231
  • an alpha-adrenergic e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, phentolamine, terazasin, prazasin or 4-amino-6,7-dimethoxy-2-(5-methane- sulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline; • a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;
  • an anticonvulsant e.g. carbamazepine, lamotrigine, topiratmate or valproate;
  • a tachykinin (NK) antagonist particularly an NK-3, NK-2 or NK-1 antagonist, e.g. ( ⁇ R,9R)-7-[3,5- bis(trif1uoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H- [1 ,4]diazocino[2,1-g][1 ,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4- triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5- (trifluoromethoxy)phenyl]
  • a muscarinic antagonist e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;
  • COX-2 selective inhibitor e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
  • a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;
  • a vanilloid receptor agonist e.g. resinferatoxin
  • antagonist e.g. capsazepine
  • beta-adrenergic such as propranolol
  • a corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HT 1B/I D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan
  • a 5-HT 2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
  • a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3- buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
  • a PDEV inhibitor such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n- propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R, 12aR)-2,3,6,7, 12, 12a- hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4- dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7- propyl-3H-imidazo[5,1-f][1 ,2,4]triazin-4-one (vardenafil), 6-[2-ethoxy-5
  • an alpha-2 -delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (1 ⁇ ,3 ⁇ ,5 ⁇ )(3- amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (SS ⁇ RJ-S-amino-S-methyl-octanoic acid,
  • mGluRI metabotropic glutamate subtype 1 receptor
  • a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,!-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
  • a noradrenaline (norepinephrine) reuptake inhibitor such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S.S)-reboxetine;
  • a dual serotonin-noradrenaline reuptake inhibitor such as venlafaxine, venlafaxine metabolite O- desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;
  • an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1-iminoethyl)amino]ethyl]-L- homocysteine, S-[2-[(1 -iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1 - iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5- heptenoic acid, 2-[[(1 R,3S)-3-amino-4- hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3- pyridinecarbonitrile; 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazo
  • a prostaglandin E 2 subtype 4 (EP4) antagonist such as N-[( ⁇ 2-[4-(2-ethyl-4,6-dimethyl-1 H- imidazo[4,5-c]pyridin-1 -yl)phenyl]ethyl ⁇ amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(1 S)- 1-( ⁇ [5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl ⁇ amino)ethyl]benzoic acid; • a leukotriene B4 antagonist; such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)- cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or D
  • a 5-lipoxygenase inhibitor such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H- pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3- pyridylmethyl),1,4-benzoquinone (CV-6504);
  • a sodium channel blocker such as lidocaine
  • a 5-HT3 antagonist such as ondansetron, granisetron, tropisetron, azasetron, dolasetron or alosetron
  • an oestrogen agonist or selective oestrogen receptor modulator e.g. HRT therapies or lasofoxifene
  • an alpha-adrenergic receptor agonist such as phenylpropanolamine or R-450
  • a dopamine receptor agonist e.g. apomorphine, teachings on the use of which as a pharmaceutical may be found in US-A-5945117
  • a dopamine D2 receptor agonist e.g. premiprixal, Pharmacia Upjohn compound number PNU95666; or ropinirole
  • a PGE1 agonist e.g. alprostadil
  • the invention thus provides, in a further aspect, a combination comprising a compound of the invention together with a further therapeutic agent.
  • the compounds of the invention can be administered alone, but in human therapy will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, dual-, controlled-release or pulsatile delivery applications.
  • the compounds of the invention may also be administered via intracavemosal injection.
  • the compounds of the invention may also be administered via fast dispersing or fast dissolving dosage forms.
  • Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine, and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine, and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium star
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the compounds of the invention, and their pharmaceutically acceptable salts may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device.
  • Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof.
  • Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients.
  • Release rate modifying excipients may be present both within the dosage form i.e. within the matrix, and/or on the dosage form, i.e. upon the surface or coating.
  • Fast dispersing or dissolving dosage formulations may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol.
  • dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug substance used i.e. where the drug substance is insoluble a fast dispersing dosage form can be prepared and where the drug substance is soluble a fast dissolving dosage form can be prepared.
  • the compounds of the invention can also be administered parenterally, for example, intravenously, intra- arterially, intraperitoneally, intrathecal ⁇ , intraventricular ⁇ , intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the daily dosage level of the compounds of the invention or salts or solvates thereof will usually be from 10 to 500 mg (in single or divided doses).
  • tablets or capsules of the compounds of the invention or salts or solvates thereof may contain from 5 mg to 250 mg of active compound for administration singly or two or more at a time, as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
  • compounds of the invention may be taken as a single dose on an "as required" basis (i.e. as needed or desired).
  • a tablet formulation could typically contain between about 0.01 mg and 500mg of a compound according to the present invention (or a salt thereof) whilst tablet fill weights may range from 50mg to 1000mg.
  • An example formulation for a 10mg tablet is illustrated:
  • This quantity is typically adjusted in accordance with drug activity and is based on the weight of the free base.
  • the compounds of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebulizer with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra- fluoro-ethane, a hydrofluoroalkane such as 1 ,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra- fluoro-ethane, a hydrofluoroalkane such as 1 ,1,1,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate.
  • a lubricant e.g. sorbitan trioleate.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff' contains from 1 to 50 mg of a compound of the invention for delivery to the patient.
  • the overall daily dose with an aerosol will be in the range of from 1 to 50 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
  • the compounds of the invention may also be formulated for delivery via an atomiser.
  • Formulations for atomiser devices may contain the following ingredients as solubilisers, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.
  • the compounds of the invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compounds of the invention may also be dermally or transdermal ⁇ administered, for example, by the use of a skin patch. They may also be administered by the ocular, pulmonary or rectal
  • the compounds can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride.
  • a preservative such as a benzylalkonium chloride.
  • they may be [5 formulated in an ointment such as petrolatum.
  • the compounds of the invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene -0 polyoxypropylene compound, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters, wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the invention may also be used in combination with a cyclodextrin.
  • Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug- cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes.
  • the cyclodextrin may be 0 used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
  • Alpha-, beta- and gamma- cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A- 94/02518 and WO-A-98/55148.
  • the daily dosage levels of compounds of formula 5 (I), (I 1 ), (N'), (III 1 ), and their pharmaceutically acceptable salts will be from 0.01 to 30 mg/kg (in single or divided doses) and preferably will be in the range 0.01 to 5 mg/kg.
  • tablets will contain 1 mg to 0.4g of compound for administration singly or two or more at a time, as appropriate.
  • the physician will in any event determine the actual dosage which will be most suitable for any particular patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are, of course only 0 exemplary of the average case and there may be instances where higher or lower doses are merited, and such are within the scope of the invention.
  • Oral administration is preferred.
  • a compound of the invention is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
  • the invention provides a pharmaceutical formulation containing a compound of the invention and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable adjuvant, diluent or carrier comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • each compound of the invention When a compound of the invention is used in combination with a second therapeutic the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • compounds of the invention are isolated following work-up in the form of the free base, but pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared using conventional means.
  • Solvates e.g. hydrates
  • a compound of the invention may be formed during the work-up procedure of one of the aforementioned process steps.
  • reaction times, number of equivalents of reagents and reaction temperatures may be modified for each specific reaction, and that it may nevertheless be necessary or desirable to employ different work-up or purification conditions.
  • 2,4-Dichlorobenzaldehyde (1.88g, 10.74mmol) was added to a solution of tert-butyl (3S)-3- aminopyrrolidine-1-carboxylate (2g, 10.74mmol) in toluene (50ml).
  • the reaction mixture was heated at reflux under Dean-Stark conditions for 18 hours, under nitrogen. It was then concentrated in vacuo and the residue was taken up in methanol (50ml).
  • the mixture was cooled down to O 0 C and then sodium borohydride (812mg, 21.48mmol) was added portionwise. The solution was stirred at 0 0 C for 30 minutes and then at room temperature for 1.5 hours. It was then quenched with water (10ml) and concentrated in vacuo.
  • the title compound (458mg, 94%) was prepared by a method similar to that described in preparation 2 using the amine described in preparation 3 and isobutyryl chloride.
  • the title compound (1.55g, 85%). was prepared by a method similar to that described in preparation 3 using tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate and 2,3-dichlorobenzaldehyde.
  • the title compound (592mg, 100%) was prepared by a method similar to that described in preparation 2 using the amine described in preparation 6 and isobutyryl chloride.
  • the title compound (4.1g, 100%) was prepared by a method similar to that described in preparation 1 using (3S)-1-benzylpyrrolidin-3-amine and 2-naphthaldehyde.
  • T3P ® 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide
  • N-bromosuccinimide (44g, 24.8mmol) was added to a solution of 1-bromo-2-methylnaphthalene (5.Og, 22.6mmol) in tnchloroetha ⁇ e (100ml). Benzoyl peroxide (44mg, 0.18mmol) was then added, and the reaction mixture was heated at 85 0 C for 21 hours. It was then quenched with a saturated aqueous solution of sodium hydrogen carbonate (100ml). The organic phase was separated, washed with brine (150ml), dried over magnesium sulphate, filtered and evaporated in vacuo. The yellow solid was triturated with pentane to yield the tile compound (4.42g, 14.7mmol, 65%).
  • 1 H-NMR (CDCI 3 , 400MHz) ⁇ : 4.85 (s, 2H) 1 7.50-7.65 (m, 3H) 1 7.80 (m, 2H), 8.38 (d, 1 H).
  • the crude material was purified by column chromatography over silica gel eluting with a solvent gradient of pentane: ethyl acetate (50:50 by volume) changing to pentane: ethyl acetate (10:90 by volume).
  • the title compound was obtained as a colourless oil (110mg, 0.31 mmol, 61%).
  • the title compound (0.252g, 70%) was prepared as a mixture of diastereoisomers by a method similar to that described in preparation 1 using tert-butyl (3S)-3-aminopyrrolidine-1 -carboxylate and 5-chloroindan- 1-one.
  • the Boc protected amine described in preparation 2 (608mg, 1.3mmol) was dissolved in dichloromethane (15ml) under nitrogen, and the mixture was treated with trifluoroacetic acid (10ml). The reaction mixture was then stirred at room temperature under nitrogen for 20 hours. It was then concentrated in vacuo and the resulting residue was taken up in dichloromethane (50ml) and washed with 1 M sodium hydroxide solution (25ml). The organic phase was separated, dried over magnesium sulphate and concentrated in vacuo. The resulting residue was suspended in diethyl ether (10ml) and 1 M hydrogen chloride in diethyl ether (5ml) was added.
  • the crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5, by volume) to yield the title product as the free base. This was taken up in dichloromethane, and 1M hydrogen chloride in diethyl ether was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The solid was azeotroped twice with diethyl ether to yield the title compound (331 mg, 86%) as an off-white solid.
  • the title compound was prepared by a method similar to that described in example 2 using the Boc protected amine described in preparation 7. Trituration with diethyl ether yielded the title compound (487mg, 100%) as a solid.
  • the compounds of the invention were evaluated for biological activity by measuring the functional inhibition of monoamine reuptake by the cognate human monoamine transporter protein in a whole cell assay (Method 1). Alternatively, the activity of a compound was determined by measuring its affinity for the human monoamine transporter protein as a function of its ability to bind and hence displace a specific ligand (Method 2).
  • Method 1 The NRI and SRI IC 50 values of the exemplified compounds were determined as described below. A selection of the results is set out below in Table 1. All of the exemplified compounds exhibited an NRI IC 50 value and/or an SRI IC 50 value of less than 100 nM; a selection are characterized in table 1. a .
  • the compounds were tested for biological activity by their ability to inhibit the uptake of serotonin and/or noradrenaline by human serotonin and/or noradrenaline transporters as follows.
  • Human embryonic kidney cells HEK-293
  • HEK-293 stably transfected with the human recombinant cDNA encoding either the human serotonin transporter (hSERT, TRAN0105) or the noradrenaline transporter (hNET, TRAN0107)
  • DMEM Dulbecco's Modified Eagle's Medium Q
  • FCS dialysed foetal calf serum
  • FCS dialysed foetal calf serum
  • test compounds were dissolved in 100% DMSO at 4mM and diluted down in 1 % DMSO in water to give appropriate test concentrations. Assays were carried out in 96-well filter bottom
  • NRI and SRI Ki values of the exemplified compounds were determined as described below. A selection of the results is set out below in Table 2. All of the exemplified compounds exhibited an NRI Ki value and/or an SRI Ki value of less than 100 nM; a selection are characterized below.
  • Table 2 The compounds were tested for biological activity by their ability to inhibit binding of selective tritiated radioligands at the human serotonin and noradrenaline transporters (SERT and NET, respectively), using scintillation proximity assay (SPA) technology.
  • the SPA binding was performed using cellular membranes prepared from cell lines expressing human cDNA encoding either SERT or NET (hSERT, hNET), using the radioligands 3 H-citalopram and 3 H-nisoxetine respectively.
  • Human embryonic kidney cells (HEK-293) expressing each transporter were maintained as a continuous culture, using standard cell culture techniques, in 50 mL of growth medium (see Media and Buffers for composition) in 225 cm 2 flasks, at 37 0 C in a humidified atmosphere with 5 % CO 2 present. Cells were passaged from a 90 % confluent monolayer at a ratio of approximately 1 :3.
  • the growth medium was removed from the monolayer and the cells were incubated with cell dissociation solution (Sigma) until signs of dissociation were observed.
  • the cells were subsequently knocked from the base of the flask and pelleted by centrifugation for storage (frozen at - 80 0 C) prior to further use.
  • Cell pellets were thawed on ice and resuspended in 3 mL of membrane preparation buffer (see Media and Buffers for composition) per 1 mL of packed cell volume, using a vortex mixer to disperse the cell pellet.
  • the suspension was homogenised for four individual 10 second intervals using a hand-held homogeniser.
  • the homogenate was then centrifuged at 1 ,075 x g for 20 minutes at 4 0 C.
  • the pooled supernatants were centrifuged at 35,000 x g for 30 minutes at 4 0 C, and the supernatants discarded.
  • the pellets (P2) were then resuspended in 1 mL of membrane preparation buffer per 1 mL of the original packed cell volume. Protein concentrations were subsequently measured and the membrane suspension was finally frozen in aliquots of set volume and stored at - 80 0 C prior to use in assays.
  • the specific SPA bead type differed for each transporter studied, wheat germ agglutinin-coated yttrium silicate (YSi WGA) SPA beads were used for hSERT and WGA-coated polyvinyltoluene (PVT WGA) SPA beads for hNET assays.
  • YSi WGA wheat germ agglutinin-coated yttrium silicate
  • PVT WGA WGA-coated polyvinyltoluene
  • the affinity of the specific radioligand for the respective transporter was determined for each membrane batch at the selected protein and bead concentrations. This was achieved by the determination of the K 0 , the concentration of free radioligand at which 50 % of the transporter binding sites were occupied.
  • the mean K 0 for a radioligand at a batch of membranes was determined from data from a minimum of three separate assays. The mean K D was subsequently used for all assays using the membrane batch profiled to enable determination of K 1 values of compounds studied using the method determined by Cheng and Prussoff (Cheng YC and Prusoff WH. Relationship between the inhibition constant (K 1 ) and the concentration of inhibitor which causes 50% inhibition of an enzymatic reaction. Biochem Pharmacol 1973; 22:2099-3108.)
  • Bead/membrane complex preparation The required amount of membrane was thawed on ice and added to a pre-determined volume of bead suspension in assay buffer. The beads were then pre-coupled by incubating the predetermined protein quantity per mg of bead on a shaker at a temperature of 4°C for 2 hours. Subsequently, the bead/membrane complex was spun down at 865 x g for 5 minutes. The resulting pellet was resuspended in assay buffer and this spin/wash step was then repeated. The final pellet was then resuspended in assay buffer at the specific concentration required for the final assay.
  • test compounds were prepared at a concentration of 4 mM in 100 % dimethyl sulphoxide (DMSO) from dry samples. Compounds were diluted in 0.75 % DMSO in ddH 2 O to give appropriate test concentrations in a 384 well plate to give a final volume of 20 ⁇ L.
  • DMSO dimethyl sulphoxide
  • the assay window (specific binding) per plate was calculated by subtracting the mean NSB readings (in counts per minute, or cpm) from the mean of total binding readings. Subsequently the cpm read per well
  • IC 50 value the concentration of compound required to inhibit 50% of the specific binding at the neurotransmitter transporter.
  • the inhibitory dissociation constant (K 1 ) value was then calculated from the IC 50 value using the Cheng-
  • the activity of a compound in the treatment of neuropathic pain may be measured according to the following test protocol.
  • CCI Chronic constriction injury
  • the CCI of sciatic nerve is performed as previously described by Bennett and Xie (Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain:33:87-107, 1988).
  • Animals are anaesthetised with a 2% isofluorane/02 mixture.
  • the right hind thigh is shaved and swabbed with 1 % iodine.
  • Animals are then transferred to a homeothermic blanket for the duration of the procedure and anaesthesia maintained during surgery via a nose cone.
  • the skin is cut along the line of the thighbone.
  • the common sciatic nerve is exposed at the middle of the thigh by blunt dissection through biceps femoris. About 7mm of nerve is freed proximal to the sciatic trifurcation, by inserting forceps under the nerve and the nerve gently lifted out of the thigh. Suture is pulled under the nerve using forceps and tied in a simple knot until slight resistance is felt and then double knotted. The procedure is repeated until 4 ligatures (4-0 silk) are tied loosely around the nerve with approx 1mm spacing. The incision is closed in layers and the wound treated with topical antibiotics.
  • Streptozocin (STZ)-induced diabetes neuropathy in the rat Diabetes is induced by a single intraperitoneal injection of streptozotocin (50mg/kg) freshly dissolved in 0.9% sterile saline. Streptozotocin injection induces a reproducible mechanical allodynia within 3 weeks, lasting for at least 7 weeks (Chen and Pan, (Chen SR and Pan HL. Hypersensitivity of Spinothalamic Tract Neurons Associated With Diabetic Neuropathic Pain in Rats. J Neurophysiol 87: 2726-2733, 2002).
  • Static allodynia is evaluated by application of von Frey hairs (Stoelting, Wood Dale, Illinois, USA.) in ascending order of force (0.6, 1, 1.4, 2, 4, 6, 8, 10, 15 and 26 grams) to the plantar surface of hind paws. Each von Frey hair is applied to the paw for a maximum of 6 sec, or until a withdrawal response occurred. Once a withdrawal response to a von Frey hair is established, the paw is re-tested, starting with the filament below the one that produced a withdrawal, and subsequently with the remaining filaments in descending force sequence until no withdrawal occurrs.
  • paw withdrawal threshold PWT
  • Static allodynia is defined as present if animals respond to a stimulus of, or less than, 4g, which is innocuous in naive rats (Field MJ, Bramwell S, Hughes J, Singh L. Detection of static and dynamic components of mechanical allodynia in rat models of neuropathic pain: are they signalled by distinct primary sensory neurones? Pain,1999;83:303-11 ).
  • Dynamic allodynia is assessed by lightly stroking the plantar surface of the hind paw with a cotton bud. To avoid recording general motor activity, care is taken to perform this procedure in fully habituated rats that are not active. At least two measurements are taken at each time point, the mean of which represents the paw withdrawal latency (PWL). If no reaction is exhibited within 15 sec the procedure is terminated and animals are assigned this withdrawal time. A pain withdrawal response is often accompanied with repeated flinching or licking of the paw. Dynamic allodynia is considered to be present if animals respond to the cotton stimulus within 8 sec of commencing stroking (Field et al, 1999).
  • the activity of a compound in the treatment of nociceptive pain may be measured according to the following test protocols.
  • Hotplate Experimental Procedure Male Sprague Dawley rats are placed on a hot plate (Ugo Basile, Italy) maintained at 55 ⁇ 5 0 C. The time between placement of the animal on the hot plate and occurrence of either licking of fore or hind paw, shaking or jumping off the surface is measured. Baseline measurements are made and animals reassessed following drug administration. The cut off time for hot plate latencies is set at 20 seconds to prevent tissue damage.
  • Ovariohysterectomy (OVX)
  • mice Female Sprague Dawley rats are placed into an anaesthetic chamber and anaesthetised with a 2% isofluorane O 2 mixture. During surgery, anaesthesia is maintained via a nose cone. OVX is performed via a midline incision (2cm in length) in the linea alba, whilst the animal is on a heat blanket. The ovarian ligaments and cervix are ligated with 5-0 silk, using a single clamp technique. The ovaries and uterus are then removed. The abdominal wall is closed using 4 simple interrupted sutures and the skin closed using 4 wound clips. Immediately after surgery animals are placed in individual plexiglass chambers.
  • Postures scored are humpback position, contraction of the muscle of the abdomen associated with inward movements of the hind limb, stretching of the body and squashing of the lower abdomen against the floor. Each of these behaviours is scored as one posture.
  • MIA Mono-lodoacetate
  • mice Female SLC, Shizuoka, Japan.
  • the mice are housed in accordance with National Institutes of Health guidelines in a vivarium maintained at 22 0 C with a 12- hour alternating light-dark cycle, and were given food and water ad libitum.
  • the sarcoma injection protocol which is used has been described. After induction of general anesthesia with an inhalation of isofluran (2%), a superficial incision is made in the skin overlying the patella, using Mora scissors. The patellar ligament is then cut, exposing the condyles of the distal femur.
  • a 30-gauge needle is inserted at the level of the intercondylar notch and into the medullary canal to create an initial core pathway. After the initial core is made, a 29-gauge needle is used to make the final pathway into the bone. A 0.5-mm depression is then made using a half-round bur in a pneumatic dental high speed handpiece, to serve as mechanical retention for the dental resin plug. Then, 20 N ⁇ -minimum essential media (Sigma; sham injection) or 20 M media containing 1 X10 5 2472 osteolytic sarcoma cells (American Type Culture Collection, Rockville, Maryland; sarcoma injection) is injected using a 29-gauge needle and a .25 cc syringe.
  • the injection site is closed with dental resin, followed by copious irrigation with filtered water.
  • Wound closure is achieved using auto wound clips (Becton Dickinson, San Jose, California). Wound clips are removed at day 5 to prevent interference with behavioral testing.
  • Static allodynia is evaluated by application of von Frey hairs (Stoelting, Wood Dale, Illinois, USA.) in ascending order of force (0.6, 1 , 1.4, 2, 4, 6, 8, 10, 15 and 26 grams) to the plantar surface of hind paws. Each von Frey hair is applied to the paw for a maximum of 6 sec, or until a withdrawal response occurrs. Once a withdrawal response to a von Frey hair is established, the paw is re-tested, starting with the filament below the one that produces a withdrawal, and subsequently with the remaining filaments in descending force sequence until no withdrawal occurrs.
  • paw withdrawal threshold PWT
  • Static allodynia is defined as present if animals respond to a stimulus of, or less than, 4g, which is innocuous in naive rats (Field MJ, Bramwell S, Hughes J, Singh L. Detection of static and dynamic components of mechanical allodynia in rat models of neuropathic pain: are they signalled by distinct primary sensory neurones? Pain,1999;83:303-11).
  • Dynamic allodynia is assessed by lightly stroking the plantar surface of the hind paw with a cotton bud. To avoid recording general motor activity, care is taken to perform this procedure in fully habituated rats that are not active. At least two measurements are taken at each time point, the mean of which represents the paw withdrawal latency (PWL). If no reaction is exhibited within 15 sec the procedure is terminated and animals are assigned this withdrawal time. A pain withdrawal response is often accompanied with repeated flinching or licking of the paw. Dynamic allodynia is considered to be present if animals respond to the cotton stimulus within 8 sec of commencing stroking (Field et al, 1999).
  • the activity of compound in the treatment of inflammatory pain may be measured according to the following test protocol.
  • CFA 300 ⁇ g of Mycobacterium Tuberculosis H37 RA (Difco Laboratories) in 100 ⁇ l_ of liquid paraffin (Wako)
  • Wako liquid paraffin
  • Hyperalgesia is induced by intraplantar injection of Lambda-carrageenin (0.1 ml of 1% w/v solution in saline, Zushikagaku).
  • the test compound (1ml of 0.1% methylcellulose/100g body weight) is given orally at 5.5 hours after the carrageenin injection.
  • the paw withdrawal threshold (gram) is measured by analgesimeter (Ugo Basile) at 3.5, 4.5, 6.5 and 7.5 hours after the carrageenin injection.
  • Thermal hyperalgesia is assessed using the rat plantar test (Ugo Basile, Comerio, Italy), according to a method modified by Hargreaves et al. (1988). Briefly, rats are habituated to the apparatus that consists of three individual Perspex boxes on a glass table. A mobile radiant heat source is located under the table and focused onto the desired paw. Paw withdrawal latencies (PWLs) are recorded three times for both hind paws of each animal, the mean of which represents baseline for left and right hind paws. The apparatus is calibrated to give a PWL of approximately 10 s in na ⁇ ve rats. To prevent tissue damage of the plantar zone, a 22.5 sec cut-off is observed. Lambda carrageenan is injected intraplantarly (100 ⁇ l, 20 mg/ml) the right hind paw and baseline recordings of PWT are taken 2 hr post administration.
  • PWLs Paw withdrawal latencies
  • the activity of a compound in the treatment of visceral pain may be measured according to the following test protocols.
  • TNBS trinitrobenzenesulfonic acid
  • mice are individually housed in polypropylene cages and kept in a regulated environment (20 ⁇ 1 0 C, 50 ⁇ 5 % humidity, with light 8:00 a.m. to 8:00 p.m.) during 7 days.
  • a balloon (5-6 cm length) is inserted by anus, and kept in position (tip of balloon 5 cm from the anus) by taping the catheter to the base of the tail.
  • Oral administration of the test compound is performed 1 h before the colonic distension cycle: the balloon is progressively inflated by steps of 5 mm Hg (0.667 kPa), from 0 to 75 mm Hg, each step of inflation lasting 30 s.
  • Each cycle of colonic distension is controlled by a standard barostat.
  • the threshold (mm Hg) corresponds to the pressure which produced the first abdominal contraction, and the cycle of distension is then discontinued.
  • the colonic threshold is determined after performance of four cycles of distension on the same animal.
  • LPS lipo-polysaccharide
  • Animals are surgically prepared for electromyography: rats are anaesthetized by intraperitoneal injection of acepromazine (0.6 mg/kg) and ketamine (120 mg/kg). Three groups of three electrodes are implanted in the abdominal external oblique musculature, just superior to the inguinal ligament. Electrodes are exteriorized on the back of the neck and protected by a glass tube attached to the skin. Animals are individually housed in polypropylene cages and kept in a temperature-controlled room (21 0 C). Food (UAR pellets, Epinay, France) and water are provided ad libitum.
  • Electromyographic recordings begin five days after surgery.
  • the electrical activity of abdominal striated muscles is recorded with an electroencephalograph machine (Mini VIII Alvar, Paris, France) using a short time constant (0.03 s) to remove low-frequency signals ( ⁇ 3 Hz) and a paper speed of 3.6 cm/min. Spike bursts are recorded as an index of abdominal contractions.
  • Distension procedure Rats are placed in plastic tunnels (6 cm diameter x 25 cm long), where they cannot move, escape, or turn around, in order to prevent damage to the balloon. Animals are accustomed to this procedure for four days before rectal distension in order to minimize stress reactions during experiments.
  • the balloon used for distension is an arterial embolectomy catheter (Fogarty, Edwards Laboratories Inc.). Rectal distension is performed by insertion of the balloon (2 mm diameter x 2 cm long) into the rectum, at 1 cm from the anus, and catheter is fixed at the base of the tail. It is inflated progressively with tepid water by steps of 0.4 ml, from 0 to 1.2 ml, each step of inflation lasting 5 min. To detect possible leakage, the volume of water introduced in the balloon is checked by complete removal with a syringe at the end of the distension period.

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  • Organic Chemistry (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Reproductive Health (AREA)
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  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyrrole Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur un composé représenté par la formule (I) et sur ses produits dérivés acceptables sur le plan pharmaceutique et/ou vétérinaire dans laquelle R1 est H, C1-6alkyl, -C(A)Y, C3.8cycloalkyl, aryl, het, aryl-C1-,alkyl ou het-Cl.4alkyl, les groupes cycloalkyle, aryle ou het étant éventuellement substitués; A est S ou O; Y est H, C1-6alkyl, aryl, het, aryl-CI.4alkyl ou het-C1_4alkyl; aryle est sélectionné indépendamment parmi phényle, naphthyle, anthracyle ou phénanthryle; het est sélectionné indépendamment parmi un hétérocycle aromatique ou non aromatique à 4, 5 ou 6 chaînons qui contient au moins un hétéroatome N, O ou S éventuellement fusionné à un groupe carbocyclique à 5 ou 6 chaînons ou un deuxième hétérocycle à 4, 5 ou 6 chaînons qui contient au moins un hétéroatome N, O ou S. R2 est aryl1 ou het1, chacun éventuellement substitué; aryl1 est sélectionné indépendamment parmi phényle, naphthyle, anthracyle, phénanthryle ou indanyle; het1 est un système de noyau hétérocyclique aromatique de 5 à 10 chaînons qui contient au moins un hétéroatome N, O or S, contenant éventuellement un groupe aryle; R3 est H, C1_8alkyl, C3_8cycloalkyl, C3- 8cycloalkyl-C1-6alkyl, C1-3alkylSC1-8alkyl, het3 ou het3-C1.4alkyl, les groupes alkyle, cycloalkyle et het3 étant chacun éventuellement substitués, het3 est un hétérocycle non aromatique à 4, 5 ou 6 chaînons qui contient au moins un hétéroatome N, O ou S, éventuellement fusionné à un groupe carbocyclique à 5 ou 6 chaînons ou un deuxième hétérocycle à 4, 5 ou 6 chaînons qui contient au moins un hétéroatome N, O ou S ; ou R3 est (CH2)a,K, où a' est 0, 1 ou 2 et K est un groupe sélectionné à partir de la formule (i) dans laquelle Z est O, S, NR12, (CH2) ou une liaison ; a est 1, 2, 3 ou 4; b est 1, 2 ou 3; v est 1 ou 2; R10 et R' sont chacun indépendamment H ou C1_4 alkyl; R12 est H, C1-6 alkyl, C(O)C1-6 alkyl, S02-C1.6 alkyl; et dans laquelle une ou plusieurs paires d'atomes d'hydrogène sur des atomes de carbone adjacents ou sur des atomes d'hydrogène peuvent être remplacées par un nombre correspondant de liaisons doubles, à condition que le système de noyau ne soit pas aromatique; à partir de la formule (ii) d'un groupe spiro carbocyclique contenant entre 6 et 12 atomes de carbone; à partir de la formule (iii) où c est 1, 2, 3 ou 4; d est 1, 2 ou 3; e est 1 ou 2; et R30 est H ou C1-4 alkyl; et où une ou plusieurs paires d'atomes d'hydrogène sur des atomes de carbone adjacents peuvent être remplacées par un nombre correspondant de liaisons doubles, à condition que le système de noyau ne soit pas aromatique ; à partir de la formule (iv) où f est 0, 1, 2 ou 3; L est SO, SO2 ou NR 40; et R40 est H, C1-6 alkyl, C(O)C1.6 alkyl, SO2-C16 alkyl; et où une ou plusieurs paires d'atomes d'hydrogène sur des atomes de carbone adjacents peuvent être remplacées par un nombre correspondant de liaisons doubles, à condition que le système d'anneau ne soit pas aromatique ; à partir de la formule (v) où g est 0, 1, 2 ou 3; et R50 est H, C1.8alkyl, C1-8alkoxy, OH, halo, CF3, OCHF2, OCF3, SCF3, hydroxy-Cl.6alkyl, C1-4alkoxy-CI.6alkyl et C1-4alkyl-S-C1-,alkyl; et à partir de l
EP05811385A 2004-12-16 2005-12-08 Dérivés de n-pyrrolidin-3-yl-amide comme inhibiteurs de recaptage de la sérotonine et noradrénaline Withdrawn EP1828122A2 (fr)

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GB0427618A GB0427618D0 (en) 2004-12-16 2004-12-16 Novel compounds
US64783905P 2005-01-27 2005-01-27
US69523805P 2005-06-28 2005-06-28
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JPWO2008029924A1 (ja) 2006-09-08 2010-01-21 大日本住友製薬株式会社 環状アミノアルキルカルボキサミド誘導体
US10512644B2 (en) 2007-03-12 2019-12-24 Inheris Pharmaceuticals, Inc. Oligomer-opioid agonist conjugates
US8173666B2 (en) 2007-03-12 2012-05-08 Nektar Therapeutics Oligomer-opioid agonist conjugates
JP2011102241A (ja) * 2008-03-04 2011-05-26 Dainippon Sumitomo Pharma Co Ltd 新規１−アミノカルボニルピペリジン誘導体

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US3577440A (en) * 1968-12-23 1971-05-04 Robins Co Inc A H 1-substituted-3-amido-pyrrolidines
US3963745A (en) * 1972-04-03 1976-06-15 A. H. Robins Company, Incorporated Method for controlling emesis with N-(1-substituted-3-pyrrolidinyl)benzamides and thiobenzamides
US4002757A (en) * 1974-12-26 1977-01-11 A. H. Robins Company, Incorporated N-(1-substituted-3-pyrrolidinyl)-4-quinolinecarboxamides
EP1125922A1 (fr) * 1998-11-02 2001-08-22 Welfide Corporation Composes de pyrrolidine et leur utilisation medicinale
IL165907A0 (en) * 2002-06-24 2006-01-15 Acadia Pharm Inc N-substituted piperidine derivatives as serotonin receptor agents

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