WO2004031191A1 - Derives de spiroether azabicyclique utilises en tant qu'antagonistes du recepteur nk-1 - Google Patents

Derives de spiroether azabicyclique utilises en tant qu'antagonistes du recepteur nk-1 Download PDF

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WO2004031191A1
WO2004031191A1 PCT/GB2002/004523 GB0204523W WO2004031191A1 WO 2004031191 A1 WO2004031191 A1 WO 2004031191A1 GB 0204523 W GB0204523 W GB 0204523W WO 2004031191 A1 WO2004031191 A1 WO 2004031191A1
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4alkyl
azabicyclo
compound
group
βalkyl
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PCT/GB2002/004523
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Ian Thomas Huscroft
Janusz Jozef Kulagowski
Piotr Antoni Raubo
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Merck Sharp & Dohme Limited
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Priority to AU2002334103A priority Critical patent/AU2002334103A1/en
Priority to JP2004540910A priority patent/JP2006503859A/ja
Priority to EP02807882A priority patent/EP1551846A1/fr
Priority to PCT/GB2002/004523 priority patent/WO2004031191A1/fr
Publication of WO2004031191A1 publication Critical patent/WO2004031191A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/22—Anxiolytics
    • 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

Definitions

  • This invention relates to a class of azabicyclic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are spiroether derivatives of l-phenyl-8-azabicyclo[3.2.1]octane, which are useful as neurokinin 1 (NK-1) receptor antagonists.
  • NK-1 neurokinin 1
  • the present invention provides compounds of the formula (I):
  • Z is -CR 9 R 10 CH 2 - or -CH 2 CR 9 R 10 -;
  • R 1 represents hydrogen, hydroxy, C ⁇ -6alkyl, C 2 -6alkenyl, C3-7cycloalkyl, C3-7cycloalkylC ⁇ -4alkyl, Ci- ⁇ alkoxy, fluoroCi- ⁇ alkoxy, hydroxyCi- ⁇ alkyl, C ⁇ -6alkoxyC ⁇ -4alkyl, Ci- ⁇ alkoxyCwalkoxy, fluoroC ⁇ -6alkoxyC ⁇ -4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylC ⁇ -4alkoxy, phenoxy, benzyloxy, cyano, halogen, NR a R b , SR a , SOR a , SO 2 R a , OSO 2 R a , NR a COR 12 , COR a , CO 2 R a or CONR a R b where R a and R b each independently represent hydrogen, C ⁇ - 4 alkyl or fluoro
  • R 3 represents hydrogen, halogen, Ci- ⁇ alkyl, fluoroCi-ealkyl, Ci- ⁇ alkoxy, fluoroCi- ⁇ alkoxy, C3-7cycloalkyl, C3-7cycloalkylC ⁇ -4alkyl, cyano, SR a , SOR a , SU2R a , NR a R b , NR a COR 12 , COR a , CO 2 R a , CONR a R b or CwaUsyl substituted by cyano, CO 2 R a or CONR a R b where R a and R b are as previously defined; or R 3 represents a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from C ⁇ -6alkyl, Ci- ⁇ alkoxy, C3-7cycloalkyl, C3-7cycloal
  • R 4 represents hydrogen, halogen, Ci- ⁇ alkyl, Ci- ⁇ alkoxy, CF3, OCF3, NO2, CN, SR a , SOR a , SO 2 R a , CO 2 R a , CONR a R b , C 2 - 6 alkenyl, C 2 -6alkynyl or Cwalkyl substituted by C ⁇ - 4 alkoxy, where R a and R b are as previously defined;
  • R 5 represents hydrogen, halogen, C ⁇ -6alkyl, CF3 or Ci- ⁇ alkoxy substituted by C ⁇ -4alkoxy;
  • R 6 represents hydrogen, hydroxy, COR a , CO 2 R a , COCONR a R , COCO 2 R a , Ci- ⁇ alkyl optionally substituted by a group selected from (CO 2 R a , CONR a R b , hydroxy, CN, COR a , NR a R , C(NOH)NR a R , CONHphenyl(C ⁇ -4alkyl), COCO 2 R a , CONHNR a R b , C(S)NR a R , CONR a C ⁇ - 6 alkylR 14 , CONR ⁇ Cs-ealkenyl, CONR ⁇ C ⁇ ealkynyl, COCONR a R b , CONR a C(NR )NR a R , CONR a heteroaryl, and phenyl optionally substituted by one, two or three substituents selected from Ci- ⁇ alkyl, Ci- ⁇ alkoxy, halogen and trifluor
  • Y is Ci- ⁇ alkylene or C3-6cycloalkyl
  • R 7 represents hydrogen or C ⁇ -4alkyl, C3-7cycloalkyl, C3-7cycloalkylC ⁇ -4alkyl, or C 2 -4alkyl substituted by C ⁇ -4alkoxy or hydroxyl
  • R 8 represents hydrogen or C-walkyl, Cwalkoxy, C3-7cycloalkyl, C3-7cycloalkylC ⁇ -4alkyl, or C2-4alkyl substituted by a group selected from C ⁇ -4alkoxy, hydroxyl, CO 2 R a , NR a R b , aryl, aryloxy, heteroaryl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R 7 , R 8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy, phenyl, benzyl or Cwalkoxy optionally substituted by a C
  • R 9 represents hydrogen, hydroxy, oxo, Ci- ⁇ alkyl, C 2 -6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC ⁇ -4alkyl, fluoroC ⁇ -6alkyl, Ci- ⁇ alkoxy, fruoroC ⁇ -6alkoxy, hydroxyCi- ⁇ alkyl, C ⁇ -6alkoxyC ⁇ -4alkyl, C ⁇ -6alkoxyC ⁇ -4alkoxy, fluoroC ⁇ -6alkoxyC ⁇ -4alkyl, C 2 -6alkenyloxy, C2-6alkynyloxy, C3-7cycloalkoxy, C3-7cycloalkylC ⁇ -4alkoxy, aryl, aryKCHsO, aryloxy, aryl(CH2)oxy, cyano, halogen, NR 7 R 8 , CH 2 NR 7 R 8 , SR 12 , SOR 12 , SO2R 12 , OSO2R
  • R 10 represents hydrogen, halogen or hydroxy
  • R 11 represents hydrogen or Ci- ⁇ alkyl
  • R 12 represents hydrogen, Ci- ⁇ alkyl, Ci- ⁇ alkoxy, fluoroCi- ⁇ alkyl or phenyl optionally substituted by one, two or three substituents selected from Ci- ⁇ alkyl, Ci- ⁇ alkoxy, halogen or trifluoromethyl;
  • R 13 represents C ⁇ -4alkyl substituted by a group selected from hydroxy, COR a , CO2R a , CONR a R b and heteroaryl, where R a is as previously defined;
  • R 14 represents OR a , CONR a R b or heteroaryl; and pharmaceutically acceptable salts or N-oxides thereof.
  • a preferred class of compound of formula (I) is that wherein R 1 is a C ⁇ -6alkoxy, fluoroCi- ⁇ alkoxy or C3-7cycloalkoxy group, or R 1 together with the group R 2 forms a 5-membered saturated ring containing one oxygen atom, which ring is optionally substituted by a methyl group.
  • a particularly preferred class of compound of formula (I) is that wherein
  • R 1 is methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fiuoroethoxy, cyclopropoxy or R 1 together with the group R 2 represents -OCH(CH 3 )CH2- or -N(CH 3 )C(O)C(CH3) 2 - to complete a 5-membered saturated ring, or -CH(OH)CH 2 OC(CH 3 )(CF3)-, -CH 2 CH2C(O)N(CH 3 )- or -CH(OH)CH 2 C(O)N(CH 3 )- to complete a 6-membered saturated ring.
  • R 1 is methoxy or cyclopropoxy.
  • R 2 is a hydrogen, fluorine or chlorine atom, especially a hydrogen atom.
  • a further preferred class of compound of formula (I) is that wherein R 3 is a hydrogen or halogen atom or a fluoroCi ealkoxy group, especially fluorine, trifluoromethoxy or 2,2,2-trifluoroethoxy, or a 5-membered aromatic heterocyclic group as previously defined. Most preferably, R 3 is trifluoromethoxy or 5-(trifluoromethyl)tetrazol-l-yl, and especially trifluoromethoxy.
  • a particularly preferred class of compound of formula (I) is that wherein R 1 is attached at the 2-position of the phenyl ring and R 3 is attached at the 5-position of the phenyl ring.
  • a further preferred class of compound of formula (I) is that wherein R 4 is a hydrogen atom or a fluorine atom.
  • Another preferred class of compound of formula (I) is that in which R 5 is a hydrogen atom.
  • a further preferred class of compound of formula (I) is that wherein R 6 is a hydrogen atom or a Ci- ⁇ alkyl group. Most especially, R 6 is hydrogen or methyl.
  • R 6 is a C ⁇ -6alkyl group, in particular CH 2 , CHXCH3) and CH2CH2 and especially CH2, substituted by a 5-membered heterocyclic ring containing 2 or 3 nitrogen atoms as previously defined.
  • the 5-membered ring is a heterocyclic ring selected from l,3-imidazol-4-yl, l,2,4-triazol-3-yl, l,2,3-triazol-4-yl, 2-oxo-l,3-imidazol-4-yl, and 3-oxo-l,2,4-triazol-5-yl, any of which rings being optionally substituted by the group -Y-NR 7 R 8 .
  • heterocyclic rings are selected from:
  • R 9 represents hydrogen, hydroxy, oxo, Ci- ⁇ alkoxy, C ⁇ -6alkoxyC ⁇ -4alkyl, hydroxyCwalkyl, cyano, NR 7 R 8 , CH 2 NR 7 R 8 , SO 2 R d , CH(OH)R 12 , COR 12 , CO 2 R 12 , CONR 7 R 8 , phenyl, heteroaryl, heteroarylC ⁇ -4alkyl or CH2OR 13 , where said phenyl is optionally substituted by one or two substituents selected from Cwalkyl, C ⁇ -4alkoxy, halogen or trifluoromethyl.
  • a further preferred class of compound of formula (I) is that wherein R 9 represents hydrogen, SO 2 R d (in particular where R d is phenyl) or CONR 7 R 8 (in particular where R 7 is C ⁇ -4alkyl or C2-4alkyl substituted by a hydroxyl or C ⁇ -2 alkoxy group and R 8 is hydrogen, Ci-4alkyl, C ⁇ -4alkoxy or C2-4alkyl substituted by a hydroxyl or C ⁇ -2alkoxy group, or R 7 and R 8 , together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino, piperazino or piperazino group substituted on the nitrogen atom by a C ⁇ - 4 alkyl, hydroxyC ⁇ -2alkyl, C ⁇ -4alkoxyC ⁇ -2alkyl, phenyl or benzyl group).
  • R 10 represents hydrogen, fluorine or hydroxy, and in particular that wherein R 10 is hydrogen.
  • Certain particularly apt compounds of the present invention include those wherein R 3 is a group selected from pyrrole, furan, thiene, pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, triazine, and tetrazole, each heteroaryl group being optionally substituted as previously defined.
  • R 3 is a group selected from pyrrole, furan, thiene, pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, triazine, and tetrazole, each heteroaryl group being optionally substituted as previously defined
  • Preferred compounds of the present invention are those wherein R 3 is a group selected from furan, pyridine, pyrazole, imidazole, oxazole, isoxazole, pyrazine, pyrimidine, thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole,
  • Particularly preferred compounds of the present invention are those wherein R 3 is a group selected from furan, pyridine, pyrimidine, 1,2,3-triazole, 1,2,4-triazole and tetrazole, each heteroaryl group being optionally substituted as previously defined.
  • R 15 is hydrogen, halogen, Ci-ealkyl, C 1-6 alkoxy, CFs, OCF 3 , NO 2 , CN, SR a , SOR a , SO 2 R a , COR a , CO 2 R a , (CH 2 ) r CONR a R b , (CH 2 )rNR a R b or (CH 2 )rNR a COR , where R a and R b are hydrogen or C ⁇ -4alkyl, and r is zero, 1 or 2.
  • R 15 is preferably hydrogen, Cwalkyl, especially methyl, CF3, (CH 2 )rCONR a R b , SOR a or SO 2 R a where R a , R and r are as previously defined. Most especially, R 15 is CF3.
  • R 1 , R 2 , R 3 and R 4 are as defined in relation to formula (I) and Z is -CR ⁇ R W CHb-.
  • Y (where present), may be a linear, branched or cyclic group.
  • Favourably Y contains 1 to 4 carbon atoms and most favourably 1 or 2 carbon atoms.
  • a particularly favourable group Y is CH 2 .
  • R 7 may aptly be a C ⁇ -4alkyl group or a C 2 -4alkyl group substituted by a hydroxyl or C ⁇ - 2 alkoxy group
  • R 8 may aptly be hydrogen or a group or a C2-4alkyl group substituted by a hydroxyl or C ⁇ - 2 alkoxy group
  • R 7 and R 8 may be linked so that, together with the nitrogen atom to which they are attached, they form an azetidinyl, pyrrolidinyl, piperidyl, morpholino, thiomorpholino, piperazino or piperazino group substituted on the nitrogen atom by a C ⁇ - 4 alkyl group or a C 2 -4alkyl group substituted by a hydroxy or C ⁇ -2 alkoxy group.
  • group NR 7 R 8 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring contains a double bond
  • a particularly preferred group is 3-pyrroline.
  • group NR 7 R 8 represents a non-aromatic azabicyclic ring system
  • such a system may contain between 6 and 12, and preferably between 7 and 10, ring atoms.
  • Suitable rings include 5-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo [3.2.2] nonyl, 6-azabicyclo [3.3.1] nonyl, 6-azabicyclo [3.2.2] decyl, 7-azabicyclo[4.3.1Jdecyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo [3.2.1] octyl.
  • R 8 represents a C2-4alkyl group substituted by a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S
  • suitable rings include azetidinyl, pyrrohdino, piperidino, piperazino, morpholino, or thiomorpholino.
  • Particularly preferred are nitrogen containing heteroaliphatic rings, especially pyrrolidino and morpholino rings.
  • moieties -Y-NR 7 R 8 include those wherein Y is CH 2 or CH2CH2 and NR 7 R 8 is amino, methylamino, dimethylamino, diethylamino, azetidinyl, pyrrolidino and morpholino.
  • Y is preferably CH2 and NR 7 R 8 is preferably dimethylamino, azetidinyl or pyrrolidino, especially dimethylamino.
  • R 10 will be absent and the group Z will in fact represent -C(O)CH2- or -CH2C(O)-.
  • alkyl or "alkoxy" as a group or part of a group means that the group is straight or branched.
  • suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
  • fluoroC ⁇ -4alkyl means a Cwalkyl group in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by fluorine atoms.
  • fluoroC ⁇ -3alkyl and fluoroC ⁇ -3alkoxy groups for example, CF3, CH2CH2F, CH 2 CHF 2 , CH2CF3, OCFs, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CFs, OCFs and OCH2CF3.
  • hydroxyCi-ealkyl means a C ⁇ -6alkyl group, in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by a hydroxy group.
  • the cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • a suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.
  • cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
  • alkenyl and alkynyl as a group or part of a group means that the group is straight or branched.
  • suitable alkenyl groups include vinyl and allyl.
  • a suitable alkynyl group is propargyl.
  • aryl as a group or part of a group means a monocyclic, fused-bicyclic or linear bicyclic aromatic ring containing 6, 10 or 12 carbon atoms, any of which rings is optionally substituted by one, two or three substituents selected from halogen, Ci- ⁇ alkyl, Ci- ⁇ alkoxy, or trifluoromethyl.
  • Particular examples of such groups include phenyl, naphthyl and biphenyl.
  • heteroaryl as a group or part of a group means a monocychc or fused-bicyclic heteroaromatic ring containing between 5 and 10 ring members, of which 1 to 4 may be heteroatoms selected from N, O and S, and wherein any of which rings is optionally substituted by one or two substituents selected from halogen, Ci- ⁇ alkyl, C ⁇ -6alkoxy, trifluoromethyl or phenyl.
  • Such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indole, benzofuran, benzthiophene, benzimidazole, benzoxazole and benzthiazole.
  • Furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, and pyridyl are particularly preferred. Where said rings are substituted, preferred substituents include methyl and phenyl groups.
  • halogen means fluorine, chlorine, bromine and iodine.
  • the most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
  • Specific compounds within the scope of this invention include:
  • the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
  • a pharmaceutically acceptable salt especially an acid addition salt.
  • the salts of the compounds of formula (I) will be non- toxic pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid.
  • Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
  • suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • the present invention includes within its scope prodrugs of the compounds of formula (I) above.
  • prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I).
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • a prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug” or “parent molecule”) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule.
  • the transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
  • the present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
  • the compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • the preferred compounds of formula (I) and (la) will have the stereochemistry of the 1, 2, 4' and 5 positions as possessed by, for instance, the compound of Example 11, i.e. as shown in formula (lb)
  • compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.
  • the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.
  • a more detailed description of pharmaceutical compositions that are suitable for the formulation of compounds of the present invention is disclosed in US patent No. 6,071,927, the content of which is incorporated herein by reference (see in particular, column 8, line 50 to column 10, line 4).
  • the present invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises bringing a compound of formula (I) into association with a pharmaceutically acceptable carrier or excipient.
  • the compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity.
  • a comprehensive listing of clinical conditions, uses and methods of treatment for which the compounds of the present invention will be useful is disclosed in US patent No. 6,071,927, the content of which is incorporated herein by reference (see, in particular, column 10, line 14 to column 22, line 18).
  • the compounds of the present invention are useful in the treatment of a variety of disorders of the central nervous system.
  • Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; and anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders.
  • the compounds of the present invention are also particularly useful in the treatment of nociception and pain.
  • pain predominates include soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, migraine, episiotomy pain, and burns.
  • soft tissue and peripheral damage such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, migraine, episiotomy pain, and burns.
  • the compounds of the present invention are also particularly useful in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; in the treatment of inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; and in the treatment of allergic disorders such as eczema and rhinitis.
  • respiratory diseases particularly those associated with excess mucus secretion
  • respiratory diseases such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm
  • inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rhe
  • the compounds of the present invention are also particularly useful in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as ulcerative colitis, Crohn's disease and irritable bowel syndrome.
  • GI gastrointestinal
  • the compounds of the present invention are also particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure.
  • the compounds of formula (I) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy; by radiation including radiation therapy such as in the treatment of cancer; and in the treatment of post-operative nausea and vomiting.
  • the excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimising the risk of unwanted side effects.
  • a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg kg, such as from about 0.05 to about 10 mg/kg per day.
  • a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • a suitable dosage level is about 0.001 to 10 mg kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • a suitable dosage level is about
  • 0.001 to 10 mg/kg per day preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
  • treatment includes prophylactic use to prevent the occurrence or recurrence of any of the aforementioned conditions.
  • compounds of formula (I) may be prepared by the reaction of a compound of formula (II)
  • Hal is chlorine, bromine or, preferably, iodine, by a reductive Heck reaction using a palladium catalyst such as palladium acetate with, for example, tri-o-tolylphosphine, dimethylformamide and tributylamine, or tetrabutylammonium chloride and dimethylformamide, and a reducing agent, preferably formic acid or a salt thereof, such as potassium formate.
  • a palladium catalyst such as palladium acetate with, for example, tri-o-tolylphosphine, dimethylformamide and tributylamine, or tetrabutylammonium chloride and dimethylformamide
  • a reducing agent preferably formic acid or a salt thereof, such as potassium formate.
  • compounds of formula (I) may be prepared by the reaction of a compound of formula (IV)
  • each R 45 is a C ⁇ -4alkyl group, preferably methyl or n-butyl groups, with a compound of formula (V)
  • R 50 is a leaving group such as triflate (-OSO 2 CF3) or a halogen atom, for example, chlorine, bromine or iodine, especially triflate, bromine or iodine.
  • the reaction is conveniently effected in the presence of lithium chloride and a transition metal catalyst such as triphenylphosphine palladium (0).
  • Suitable solvents for the reaction include an aromatic hydrocarbons, for example, toluene, polar aprotic solvents, for example, dimethylformamide, or ethers, for example, dioxan, the reaction being effected at a temperature between 80°C and the reflux temperature of the solvent. Subsequent reduction of the double bond is effected using the conditions of general process (G), below.
  • compounds of formula (I) may be prepared by the reduction of a compound of formula (VI)
  • borohydride such as Uthium borohydride or lithium triethylborohydride in tetrahydrofuran
  • a hydride such as lithium aluminium hydride or dhsobutylaluminium hydride.
  • compounds of formula (I) wherein R 1 is Ci- ⁇ alkoxy, fluoroCi- ⁇ alkoxy, C 2 -6alkenoxy, C3-7cycloalkoxy, C3-7cycloalkylCi-4alkoxy or benzyloxy, may be prepared by the interconversion of a compound of formula (I) wherein R 1 is hydroxy, hereinafter referred to as formula (Nil)
  • R a is a group of the formula R as defined in relation to formula (I) (other than H) or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine); and, if R a is a precursor group, converting it to a group R (in which process any reactive group may be protected and thereafter deprotected if desired).
  • LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine)
  • R a is a precursor group, converting it to a group R (in which process any reactive group may be protected and thereafter deprotected if desired).
  • This reaction may be performed in conventional manner, for example in an organic solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate.
  • compounds of formula (I) may be prepared by the reduction of a compound of formula (XI)
  • Suitable reducing conditions include: catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof; or reduction using trifluoroacetic acid and triethylsilane.
  • a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof
  • suitable solvent such as alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a
  • Compounds of formula (II) may prepared, for example, by the conversion of a stannane of formula (IN) to the corresponding iodide -by treatment with iodine at reduced temperature, for example, at about -78°C, in a suitable solvent such as dichloromethane.
  • the iodine may then be displaced to give the compound of formula (II) by treatment with, for example, ⁇ , '-azo- isobutyronitrile and tributyltin hydride in a suitable solvent, for example, toluene, at an elevated temperature, for example, at about 100°C.
  • compounds of formula (II) may be prepared by the cyclization of a compound of formula (XII)
  • triphenylphosphine and diethylazodicarboxylate in a suitable solvent such as tetrahydrofuran.
  • reaction is conveniently effected by catalytic hydrogenation using a metal catalyst such as palladium on calcium carbonate in the presence of a lead poison (e.g. Lindlar catalyst).
  • a metal catalyst such as palladium on calcium carbonate
  • a lead poison e.g. Lindlar catalyst
  • compounds of formula (IN) may be prepared from a compound of formula (XV)
  • R 50 is as previously defined (and is preferably a triflate group or a bromine or iodine atom), by reaction with a compound of the formula (R 45 )sSn- Sn(R 45 )3, for example, hexamethyl distannane.
  • the reaction is conveniently effected in the presence of a base, for example, lithium carbonate, and a catalyst such as triphenylphosphine palladium(O).
  • Suitable solvents for the reaction include ethers such as tetrahydrofuran, the reaction being effected at a temperature between room temperature and 100°C, for example, at about 60°C.
  • Compounds of formula (XV) may be prepared from a compound of formula (XX) by enolisation of the ketone in the presence of a base, for example, sodium hexamethyldisilazide, followed by reaction with a reagent capable of introducing a suitable leaving group, for instance, where R 50 is -OSO2OF3, using 2-[NN- bis(trifluorom.ethyls phonyl)amino]-5-cMoropyridine or triflic anhydride.
  • the reaction is conveniently effected in a suitable solvent such as an ether, for example, tetrahydrofuran at a reduced temperature, for instance, -80°C.
  • Suitable reducing conditions include: catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof; or reduction using trifluoroacetic acid and triethylsilane.
  • a metal catalyst such as palladium or platinum or hydroxides or oxides thereof
  • a suitable solvent such as alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof
  • a suitable solvent such as alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or
  • the compound of formula (XVII) is reduced using, for example, Red-AlTM in a suitable aprotic solvent such as an aromatic hydrocarbon, for example, toluene, or an ether, for example, diethyl ether, or a mixture thereof.
  • a suitable aprotic solvent such as an aromatic hydrocarbon, for example, toluene, or an ether, for example, diethyl ether, or a mixture thereof.
  • the resultant compound is then iodinated using iodine.
  • cyclisation takes place by reaction with carbon monoxide in the presence of a transition metal catalyst such as tris(dibenzylidineacetone)palladium (0) and l,4-bis(diphenylphosphino)butane, and an organic base such as a trialkylamine, for example, isopropyldiethylamine.
  • the cyclisation is conveniently effected in an aprotic solvent such as an ether, for example, te
  • reaction is conveniently effected in the presence of ethyl magnesium bromide in a suitable aprotic solvent such as an ether, for example, tetrahydrofuran.
  • a suitable aprotic solvent such as an ether, for example, tetrahydrofuran.
  • a Grignard reagent prepared from a compound of formula (III), preferably using magnesium and a bromide of formula (III).
  • the couphng reaction is conveniently effected at reduced temperature, for example, at about 0°C, using a suitable solvent such as an ether, for example, diethyl ether.
  • a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, for example, methanol or ethanol, or an ester, for example, ethyl acetate, or an organic acid, for example, acetic acid, or a mixture thereof.
  • aprotic solvent such as an aromatic hydrocarbon, for example, toluene.
  • reaction of a compound of formula (XXII) with acrylonitrile is particularly suitable for preparing compounds where the R 9 substituent is situated on either of the carbon atoms of the two-carbon bridge.
  • R 6 is a benzyl group.
  • the various reduction reactions described above may conveniently replace the benzyl group with a hydrogen atom. It will be appreciated from the discussion above that compounds of formula (I) wherein R 6 is a hydrogen atom are particularly preferred precursors to other compounds of formula (I).
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the compounds were found to be active with IC50 at the human NKi receptor of less than lOOnM on said test method.
  • the following non-limiting Examples serve to illustrate the preparation of compounds of the present invention:
  • reaction mixture was cooled to -60°C and a solution of iodine (2.5g, 9.8mmol) in toluene (35ml) was added.
  • the cold bath was removed and the mixture was stirred at ambient temperature for 30 minutes, treated with 10% aqueous Na 2 SO3 and stirred until for 1 hour.
  • the phases were separated.
  • the aqueous layer was extracted twice with ethyl acetate (2x50ml).
  • the combined organic extracts were washed with brine, dried (Na2SO 4 ) and concentrated.
  • the residue was purified by chromatography on silica gel ( ⁇ so-hexane:ethyl acetate) to give the title compound (1.88g, 66%).
  • the reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of CeliteTM.
  • the filtrate was concentrated and purified by flash chromatography to give a mixture of phenol and n-propyl derivative in ratio 3.4:1.
  • the mixture was treated with dry tetrahydrofuran (3ml) followed by diethyl azodicarboxylate (0.15ml, 0.95mmol), triphenylphosphine (293mg, l.lmmol) and methanol (0.2ml) and stirred at room temperature for 1 hour. The mixture was quenched with water (1 drop) and concentrated.
  • reaction mixture was cooled to room temperature and filtered through a pad of CeliteTM.
  • the filtrate was concentrated and purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (245mg, 62%).
  • Tetrakis(triphenylphosphine)palladium(0) 300mg, 0.26mmol was added to a degassed solution of (lR*,2R*,55*,6R*)-8-benzyl-2-(3-hydroxypropynyl)-l-phenyl- 6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 13; 1.8g, 3.7mmol) in tetrahydrofuran (50ml). The mixture was cooled to +5°C before tri-n-butyltin hydride (1.3g, 4.4mmol) was added.
  • DESCRIPTION 19 (p-ToluenesuIphonyloxy)propan-2-ol p-Toluenesulphonyl chloride (19.4g, 102mmol) was added to a stirred solution of propane-l,2-diol (30ml), triethylamine (15ml, 106mmol), N,N-dimethylamine (108mg, 0.87 mmol) in dichloromethane (100 ml) at +5°C. The mixture was stirred for 2 hours at +5°C and overnight at room temperature then diluted with diethyl ether (300ml) and washed 2M aqueous hydrochloric acid, water (twice) and brine.
  • DESCRIPTION 23b (lR*,5S*,6S*)-8-benzyl-6-(ferf-butoxycarbonyl)-l- phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one ⁇ H (360 MHz, CDCls): 7.70 (IH, dd, J 1.3Hz, 8.7Hz), 7.40-7.25 (8H, m), 6.88 (IH, dd, J 4.8Hz, 9.8Hz), 6.25 (IH, d, J 9.8Hz), 4.02 (IH, dd, J 5.0Hz, 6.0Hz), 3.65- 3.50 (3H, m), 2.60 (2H, m), 1.43 (9H, s).
  • 6S*-epimer ⁇ H (360 MHz, CDCI3): 7.50-7.20 (10H, m), 3.75 (IH, d, J 14.7Hz), 3.61 (IH, dd, J 3.5Hz, 6.3Hz), 3.52 (IH, d, J 14.8Hz), 3.46 (IH, dt, J 6.7Hz, 11.6Hz), 2.95 (IH, m), 2.90 (IH, dd, J 7.0Hz, 14.4Hz), 2.53-2.36 (2H, m), 2.26 (IH, dd, J 11.6Hz, 14.0Hz), 1.94 (IH, d, J 14.0Hz), 1.91 (IH, m), 1.46 (9H, s).
  • ⁇ ir-epimer (distinguishable signals) ⁇ H (400 MHz, CDCls): 4.07 (IH, d, J 14.9Hz), 3.48 (IH, m), 3.04 (IH, d, J 14.9Hz), 2.54 (IH, dd, J 12.3Hz, 13.7Hz), 1.46 (9H, s).
  • Lithium naphthalenide (18ml, 1.0M solution in tetrahydrofuran) was added dropwise to a -78°C stirred solution of (LR*,2R*,4'S :): , ⁇ S*,6B*)-8-benzyl-4'-(2- benzyloxy- ⁇ -trifluoromethoxyphenyl)-2',3',4', ⁇ '-tetrahydro-l-phenyl-6- phenylsulfonylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan] (Description 16; 2g, 2.7mmol) in tetrahydrofuran (20ml).
  • Tetrakis(triphenylphosphine) palladium(0) (20mg, 0,017mmol) was added to a degassed suspension of (lR*,2E*,5S*,6E*)-8-Benzyl-2',5'-dihydro-l-phenyl-6- phenylsulfonyl-4'-tributylstannylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan] (Description 18; 150mg, 0.2mmol), hthium chloride (50mg, 1.2mmol), 2-methoxy- 5-trifluoromethoxyiodobenzene (lOOmg, 0.3mmol) and copper(I) iodide (lOmg,
  • the cold bath was removed and the reaction mixture was stirred at room temperature for 30 minutes.
  • the mixture was diluted with dichloromethane and treated with small amount of saturated aqueous Na 2 SO4, stirred for 1 hour and filtered through a pad of CeliteTM.
  • the filtrate was concentrated in vacuo.
  • the residue was treated with tetrahydrofuran (3ml) followed by triphenylphosphine (220mg, 0.84mmol) and diethyl azodicarboxylate (0.1ml, 0.64mmol) and stirred at room temperature overnight.
  • the mixture was purified by chromatography on silica gel (dichloromethane.-methanol) to give the title compound (35mg, 48%).
  • HCI salt ⁇ H (400 MHz, CDCls): 10.73 (IH, d, J 4.8Hz), 8.96 (IH, d, J 4.8Hz), 7.53 (2H, m), 7.38 (3H, m), 6.97 (IH, dd, J 2.0Hz, 8.8Hz), 6.70 (IH, d, J 2.5Hz), 6.67 (IH, d, J 8.9Hz), 4.90 (IH, br s), 3.94 (IH, t, J 7.9Hz), 3.64 (3H, s), 3.61 (IH, dd, J 8.4Hz, 10.8Hz), 2.74 (IH, m), 2.64 (IH, dt, J 3.6Hz, 12.7Hz), 2.51 (IH, m), 2.40-2.25 (2H, ), 1.93-1.77 (4H, m
  • HCI salt ⁇ H (400 MHz, MeOH- ⁇ : 8.02 (2H, dm, J 8.6Hz), 7.83 (IH, m), 7.72 (2H, t, J 8.0Hz), 7.60-7.50 (5H, m), 7.03 (IH, dd, J 2.8Hz, 9.0Hz), 6.85 (IH, d, J 9.0Hz), 6.82 (IH, d, J 2.8Hz), 4.49 (IH, s), 4.38 (IH, dd, J 5.5 Hz, 9.4Hz), 3.91 (IH, t, J 7.7Hz), 3.67 (IH, m), 3.67 (3H, s), 3.03 (IH, dd, J 9.5Hz, l ⁇ .OHz), 2.81 (IH, dd, J 5.4Hz, 15.0Hz
  • Oxone 400mg, 0.65mmol was added to a stirred mixture of (lR*,2R*,4'S'*,5S :i: ,6R :I: )-2',3',4',5'-tetrahydro-4'-[2-(l-phenylthiocyclopropyloxy)-5- trifluoromethoxyphenyl]-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan] (Description 17; 88mg, 0.12mmol), wet aluminium oxide (5g of Al 2 O3 in 1ml of water, 370mg) and chloroform (5ml) at room temperature.
  • HCI salt ⁇ H (360 MHz, CDCls): 7.51 (5H, m), 7.20 (IH, d, J 9.0Hz), 7.05 (IH, ddd, J 0.9Hz, 2.8Hz, 9.0Hz), 6.85 (IH, d, J 2.8Hz), 4.07 (IH, dd, J 3.1Hz, 7.0Hz), 3.90 (IH, t, J 7.4Hz), 3.67 (IH, m), 3.60 (IH, dd, J 8.1Hz, 10.6Hz), 2.63 (IH, dddd, J 5.0Hz, 10.6Hz, 14.4Hz), 2.50-2.20 (7H, m), 1.95-1.77 (2H, m), 1.76 (IH, t, J 11.7Hz), 0.79 (2H, m), 0.60 (IH, ⁇ H (360 MHz, CDCls): 7.51 (5H, m), 7.20 (IH, d, J 9.0Hz), 7.05 (IH,
  • the mixture was hydrogenated using the Parr® apparatus at 50psi. for 20 hours.
  • the mixture was filtered through CeliteTM and the filtrate concentrated in vacuo.
  • the residue was chromatographed on silica gel eluting with 180:8:1, dicHoromethane:methanol: ammonia to yield the title compound (83mg, 86%).
  • the hydrochloride salt was prepared by treatment with ethereal HCI.
  • HCI salt ⁇ H (360 MHz, -d 4 ): 7.51 (5H, m), 6.90 (IH, s), 6.48 (0.5H, s), 6.47 (0.5H, s), 4.88 (IH, m), 4.07 (IH, m), 3.89 (0.5H, dd, J 5.3Hz, 7.9Hz), 3.87 (0.5H, dd, J 5.5Hz, 7.6Hz), 3.76 (0.5H, dd, J 8.2Hz, 9.7Hz), 3.73 (0.5H, dd, J 8.1Hz, 9.7Hz), 3.25 (IH, dd, J 8.7Hz, 15.8Hz), 2.73 (IH, dd, J 7.4Hz, 15.8Hz), 2.65 (0.5H, dd, J 4.7Hz, 10.3Hz), 2.62 (0.5H,
  • Step (a) The mixture of (lR*,2R*,4'-5*,5R*)-6-(terf-Butoxycarbonyl)-2',3',4',5'- tetrahydro-4'-(2-hydroxy- ⁇ -trifluoromethoxyphenyl)- 1-phenylspiro [8- azabicyclo[3.2.1]octane-2,2'-furan] (Example 8; 900mg, 1.73mmol), diethyl azodicarboxylate (0.37ml, 1.72mmol), triphenylphosphine (800mg, 3.0mmol), methanol (1ml) and tetrahydrofuran (10ml) was stirred at room temperature for 2 hours.
  • Step (b) A portion of the solution (2ml) was treated with morpholine (0.1 ⁇ ml, 1.72mmol), triethylamine (0.2ml, 2.7mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (140mg, 0.73mmol), and 4-N,N- dimethylaminopyridine (lOmg, O.O ⁇ mmol). The mixture was stirred for 4 days, diluted with dichloromethane, washed with 10% aqueous citric acid, dried (Na2SO 4 ) and concentrated.
  • morpholine 0.1 ⁇ ml, 1.72mmol
  • triethylamine 0.2ml, 2.7mmol
  • l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride 140mg, 0.73mmol
  • 4-N,N- dimethylaminopyridine lOmg
  • HCI salt ⁇ H (360 MHz, MeOH- ⁇ ): 7.52 (5H, m), 7.0 ⁇ (IH, dd, J 1.9Hz, 8.9Hz), 6.87 (IH, d, J 9.0Hz), 4.36 (IH, br s), 3.93 (IH, t, J 7.6Hz), 3.80-3.60 (10H, m), 3.69 (3H, s), 3.14 (IH, dd, J 10.1Hz, 14.1Hz), 2.46 (IH, dd, J 5.0Hz, 14.2Hz), 2.40 (IH, dd, J 7.6Hz, 13.2Hz), 2.30 (IH, m), 2.14 (IH, dt, J 4.5Hz, 13.7Hz), 1.97 (IH, dd, J 4.7Hz, 14.5Hz), 1.97-1.
  • Example 21 ⁇ H (360 MHz, CDC1 3 ): 7.40-7.25 (5H, m), 6.96 (IH, dd, J 2.6Hz, 8.8Hz), 6.75 (IH, d, J 2.7Hz), 6.67 (IH, d, J 9.0Hz), 3.79 (IH, t, J 7.7Hz), 3.65 (3H, s), 3.64 (IH, t, J 2.3Hz), 3.55 (IH, dd, J 7.7Hz, 10.5Hz); 3.30-3.12 (4H, m), 3.08 (3H, s), 2.77 (IH, dd, J 3.9Hz, 9.5Hz), 2.71 (IH, br), 2.54 (IH, dd, J 9.1Hz, 13.3Hz), 2.29 (IH, dd, J 7.7Hz, 12.3Hz), 2.25 (IH, dd, J 3.9Hz, 13.3Hz), 1.98 (IH, m), 1.88 (IH, m), 1.82-1
  • Example 22 ⁇ H (360 MHz, CDCI3): 7.59 (2H, dm, J 6.8Hz), 7.40-7.30 (3H, m), 6.95 (IH, dd, J 2.0Hz, 9.0Hz), 6.73 (IH, d, J2.7Hz), 6.66 (IH, d, J 8.9Hz), 3.96 (IH, t, J 7.7Hz), 3.89 (IH, br s), 3.64 (3H, s), 3.59 (IH, dd, J 8.1Hz, 10.9Hz), 3.48 (3H, m), 3.39 (2H, m), 3.33 (3H, s), 3.11 (IH, dd, J 5.3Hz, 13.7Hz), 2.95 (IH, dd, J ⁇ .6Hz, 8.7Hz), 2.38 (IH, br t, J 11.2Hz), 2.27 (IH, dd, J 9.8Hz, 13.7Hz), 2.23 (3H, s), 2.13 (IH, dd, J 8.1
  • Example 21 The hydrochloride salts of Example 21 and Example 22 were prepared by treatment with ethereal HCI.
  • HCI salt of Example 21 ⁇ H (360 MHz, MeOH-ck): 7.52 (5H, m), 7.05 (IH, dd, J 1.6Hz, 8.7Hz), 6.86 (IH, d, J 8.9Hz), 6.85 (IH, d, J 2.8Hz), 4.20 (IH, s), 3.93 (IH, t, J 7.6Hz), 3.68 (IH, m), 3.68 (3H, s), 3.42 (2H, t, J 6.1Hz), 3.40-3.15 (6H, m), 2.95 (IH, dd, J 7.7Hz, 9.8Hz), 2.64 (IH, dd, J4.6Hz, 14.2Hz), 2.40 (IH, dd, J 7.6Hz, 13.2Hz), 2.30 (IH, m), 2.10-1.80 (4H, m), 1.70-1.55 (3H, ), 1.17 (2H, s).

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Abstract

L'invention concerne des composés représentés par la formule (I), dans laquelle Z représente -CR9R10CH2- ou -CH2CR9R10-; et R1, R2, R3, R4, R5 et R6 sont tels que définis dans le descriptif. Les composés selon l'invention sont particulièrement utiles dans le traitement ou la prévention de la dépression, de l'anxiété, de la douleur, de l'inflammation, de la migraine, des vomissements ou de l'algie post-zostérienne.
PCT/GB2002/004523 2002-10-04 2002-10-04 Derives de spiroether azabicyclique utilises en tant qu'antagonistes du recepteur nk-1 WO2004031191A1 (fr)

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AU2002334103A AU2002334103A1 (en) 2002-10-04 2002-10-04 Azabicyclic spiroether derivatives as receptor antagonists
JP2004540910A JP2006503859A (ja) 2002-10-04 2002-10-04 受容体拮抗薬としてのアザ二環式スピロエーテル誘導体
EP02807882A EP1551846A1 (fr) 2002-10-04 2002-10-04 Derives de spiroether azabicyclique utilises en tant qu'antagonistes du recepteur nk-1
PCT/GB2002/004523 WO2004031191A1 (fr) 2002-10-04 2002-10-04 Derives de spiroether azabicyclique utilises en tant qu'antagonistes du recepteur nk-1

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Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0873753A1 (fr) * 1997-04-23 1998-10-28 Pfizer Inc. Utilisation des antagonistes du récepteur-NK-1 dans la fabrication d'un médicament destiné au taitement du syndrome de l'intestin irritable
WO2000073303A1 (fr) * 1999-06-01 2000-12-07 Pfizer Products Inc. Polymorphes de (2-benzhydril-1-azabicyclo[2.2.2]oct-3-yl)-isopropyl-2-methoxybenzyl)-amine citrate cristallins comme antagonistes recepteurs nk-1
WO2000078759A1 (fr) * 1999-06-22 2000-12-28 Pfizer Products Inc. Polymorphes du (2-benzhydryl-1-azabicyclo[2,2,2]oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-chlorure d'ammonium cristallin utilises en tant qu'antagonistes du recepteur de la neurokinine-1

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Publication number Priority date Publication date Assignee Title
EP0873753A1 (fr) * 1997-04-23 1998-10-28 Pfizer Inc. Utilisation des antagonistes du récepteur-NK-1 dans la fabrication d'un médicament destiné au taitement du syndrome de l'intestin irritable
WO2000073303A1 (fr) * 1999-06-01 2000-12-07 Pfizer Products Inc. Polymorphes de (2-benzhydril-1-azabicyclo[2.2.2]oct-3-yl)-isopropyl-2-methoxybenzyl)-amine citrate cristallins comme antagonistes recepteurs nk-1
WO2000078759A1 (fr) * 1999-06-22 2000-12-28 Pfizer Products Inc. Polymorphes du (2-benzhydryl-1-azabicyclo[2,2,2]oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-chlorure d'ammonium cristallin utilises en tant qu'antagonistes du recepteur de la neurokinine-1

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EP1551846A1 (fr) 2005-07-13
JP2006503859A (ja) 2006-02-02

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