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WO2004031190A1 - Azabicyclic amine derivatives as nk-1 receptor antagonists - Google Patents

Azabicyclic amine derivatives as nk-1 receptor antagonists Download PDF

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Publication number
WO2004031190A1
WO2004031190A1 PCT/GB2002/004515 GB0204515W WO2004031190A1 WO 2004031190 A1 WO2004031190 A1 WO 2004031190A1 GB 0204515 W GB0204515 W GB 0204515W WO 2004031190 A1 WO2004031190 A1 WO 2004031190A1
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Prior art keywords
phenyl
azabicyclo
octane
trifluoromethoxy
benzylamino
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French (fr)
Inventor
Janusz Jozef Kulagowski
Piotr Antoni Raubo
Christopher George Thomson
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Organon Pharma UK Ltd
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Merck Sharp and Dohme Ltd
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Priority to EP02807881A priority Critical patent/EP1551836A1/en
Priority to PCT/GB2002/004515 priority patent/WO2004031190A1/en
Priority to JP2004540909A priority patent/JP2006503858A/en
Priority to AU2002334100A priority patent/AU2002334100A1/en
Publication of WO2004031190A1 publication Critical patent/WO2004031190A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
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Definitions

  • This invention relates to a class of azabicyclic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are substituted benzylamino derivatives of l- ⁇ henyl-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):
  • X represents hydrogen or a Ci-4alkyl group optionally substituted by a hydroxy group
  • Y represents hydrogen, Ci- ⁇ alkyl or C3-7cycloalkyl
  • Z is -CR 9 R 10 CH 2 - or -CH 2 CR 9 R 10 -;
  • R represents hydrogen, fluorine, hydroxy, C ⁇ -6alkyl or Ci- ⁇ alkoxy
  • R 1 represents hydrogen, hydroxy, Ci- ⁇ alkyl, C 2 -6alkenyl, C3-7cycloalkyl, C3-7cycloalkylC ⁇ -4alkyl, Ci- ⁇ alkoxy, fluoroCi- ⁇ alkoxy, hydroxyCi- ⁇ alkyl, C ⁇ -6alkoxyC ⁇ -4alkyl, C ⁇ -6alkoxyC ⁇ -4alkoxy, fluoroC ⁇ -6alkoxyC ⁇ -4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylC ⁇ -4alkoxy, phenoxy, benzyloxy, cyano, halogen, NR a R b , SR a , SOR a , S0 2 R a , OSO 2 R a , NR a COR 12 , COR a , C0 2 R a or CONR a R b where R a and R b each independently represent hydrogen, C ⁇ - 4 alky
  • R 3 represents hydrogen, halogen, Ci- ⁇ alkyl, fluoroCi- ⁇ alkyl, Ci- ⁇ alkoxy, fluoroCi- ⁇ alkoxy, C3-7cycloalkyl, C3-7cycloalkylC ⁇ -4alkyl, cyano, SR a , SOR a , SO 2 R a , NR a R , NR a COR i2 , COR a , C0 2 R a , CONR a R b or C ⁇ alkyl substituted by cyano, CO2R 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 Ci- ⁇ alkyl, Ci- ⁇ alkoxy, C3-7cycloalkyl, C3-7cycloalkyl
  • R 4 represents hydrogen, halogen, Ci- ⁇ alkyl, Ci- ⁇ alkoxy, CF3, OCF3, NO 2 , CN, SR a , SOR a , SO 2 R a , CO 2 R a , CONR a R b , C 2 -6alkenyl, C ⁇ alkynyl or C ⁇ -4alkyl substituted by Cwalkoxy, where R a and R b are as previously defined;
  • R 5 represents hydrogen, halogen, Ci- ⁇ alkyl, CF3 or Ci- ⁇ alkoxy substituted by C ⁇ -4 alkoxy;
  • R 6 represents hydrogen, hydroxy, COR a , C0 2 R a , COCONR a R ,
  • Ci- ⁇ alkyl optionally substituted by a group selected from (CO 2 R a , CONR a R , hydroxy, CN, COR a , NR a R b , C(NOH)NR a R b , CONHphenyKCwalkyl), COCO 2 R a , CONHNR a R b , C(S)NR a R b , CONR a C ⁇ - 6 alkylR 14 , CONR H C ⁇ alkenyl, CONR U C 2 -6alkynyl, 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 trifluoromethyl); or R 6 represents a group of the formula -CH2C ⁇ CCH2NR 7 R 8 where R 7 and R
  • W is Ci- ⁇ alkylene or C3-6cycloalkyl
  • R 7 represents hydrogen or Ci-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC ⁇ -4alkyl, or C 2 -4alkyl substituted by Ci-4alkoxy or hydroxyl;
  • R 8 represents hydrogen or C ⁇ -4alkyl, C ⁇ -4alkoxy, C3-7cycloalkyl, C3-7cycloalkylC ⁇ -4alkyl, or C 2 -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 C ⁇ -4alkoxy optionally substituted by a C ⁇ -4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(
  • R 9 represents hydrogen, hydroxy, oxo, Ci- ⁇ alkyl, C2- ⁇ alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC ⁇ -4alkyl, fluoroCi-ealkyl, Ci- ⁇ alkoxy, fiuoroCi- ⁇ alkoxy, hydroxyCi- ⁇ alkyl, C ⁇ -6alkoxyC ⁇ -4alkyl, C ⁇ -6alkoxyC ⁇ -4alkoxy, C2- ⁇ alkenyloxy, C 2- 6alkynyloxy, C3-7cycloalkoxy, C3-7cycloalkylC ⁇ -4alkoxy, aryl, aryl(CH 2 ), aryloxy, aryl(CH 2 )oxy, cyano, halogen, NR 7 R 8 , CH 2 NR 7 R 8 , SR 12 , SOR* 2 , SO2R 12 , OSO2R 12 , NR a COR i2
  • 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 Ci ⁇ alkyl substituted by a group selected from hydroxy, COR a , CU2R a , CONR a R b and heteroaryl, where R a is as previously defined;
  • R i 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 X is hydrogen, methyl or hydroxymethyl, in particular, hydrogen.
  • Another preferred class of compound of formula (I) is that wherein Y is hydrogen or C ⁇ -4alkyl, in particular, hydrogen or methyl, especially hydrogen.
  • a further preferred class of compounds of formula (I) is that wherein R represents hydrogen or fluorine.
  • a preferred class of compound of formula (I) is that wherein R 1 is a
  • 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-fluoroethoxy, cyclopropoxy or R 1 together with the group R 2 represents -OCH(CH 3 )CH 2 - or -N(CH 3 )C(0)C(CH 3 )2- to complete a 5-membered saturated ring, or -CH(OH)CH 2 OC(CH g XCF3)-, -CH 2 CH2C(O)N(CH 3 )- or -CH(OH)CH 2 C(O)N(CH3)- 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- ⁇ alkoxy group, especially fluorine, trifluoromethoxy or 2,2,2-trifluoroethoxy, or a 5-membered aromatic heterocyclic group as previously defined. Most especially, R 3 is trifluoromethoxy or 5-(trifluoromethyl)tetrazol-l-yl.
  • 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- ⁇ alk l group. Most especially, R 6 is hydrogen or methyl.
  • R 6 is a Ci- ⁇ alk l group, in particular CH2, CH(CHs) 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 -W-NR 7 R 8 .
  • heterocyclic rings are selected from:
  • Another preferred class of compound of formula (I) is that wherein
  • R 9 represents hydrogen, hydroxy, oxo, Ci- ⁇ alkoxy, C ⁇ -6alkoxyC ⁇ -4alkyl, hydroxyC ⁇ -4 alkyl, cyano, NR 7 R 8 , CH 2 NR 7 R 8 , S0 2 R d , CH(OH)R 12 , COR 12 , C0 2 R 12 , CONR 7 R 8 , phenyl, heteroaryl, or CH 2 OR 13 , where said phenyl is optionally substituted by one or two substituents selected from C ⁇ -4alkyl, C ⁇ -4alkoxy, halogen or trifiuoromethyl.
  • 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 C 2 -4alkyl substituted by a hydroxyl or C ⁇ -2alkoxy group and R 8 is hydrogen, C ⁇ -4alkyl, or C2-4alkyl substituted by a hydroxyl or C ⁇ - 2 alkoxy 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 ⁇ -4alkyl, hydroxyC ⁇ -2alkyl, C ⁇ -4alkoxyC ⁇ -2alkyl, phenyl or benzyl group).
  • R 10 represents hydrogen, fluorine
  • 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, 1,3,4-oxadiazole and tetrazole, each heteroaryl group being optionally substituted as previously defined.
  • 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 ⁇ -6 alkoxy, CF3, OGF3, N0 2 , CN, SR a , SOR a , SO 2 R a , COR a , C0 2 R a , (CH 2 ) r CONR a R , (CH 2 ) r NR a R or (CH 2 ) r NR a COR b , where R a and R b are hydrogen or C1.4alk.yl, and r is zero, 1 or 2.
  • the optionally substituted tetrazolyl group is particularly preferred.
  • R l ⁇ is preferably hydrogen, C ⁇ -4alkyl, especially methyl, CF3, (CH 2 )rCONR a R b , SOR a or S0 2 R a where R a , R b and r are as previously defined. Most especially, R 15 is CF3.
  • R l ⁇ is preferably hydrogen, C ⁇ -4alkyl, especially methyl, CF3, (CH 2 )rCONR a R b , SOR a or S0 2 R a where R a , R b and r are as previously defined. Most especially, R 15 is CF3.
  • R l ⁇ is preferably hydrogen, C ⁇ -4alkyl, especially methyl, CF3, (CH 2 )rCONR a R b , SOR a or S0 2 R a where R a , R b and r are as previously defined. Most especially, R 15 is CF3.
  • R 15 is CF3.
  • R 1 , R 2 , R 3 , R 4 , X and Y are as defined in relation to formula (I) and Z is -CR 9 R i °CH 2 -.
  • W may be a linear, branched or cyclic group.
  • a particularly favourable group W is CH 2 .
  • R 7 may aptly be a C ⁇ -4alkyl group or a C 2 - 4 alkyl group substituted by a hydroxyl or C ⁇ - 2 alkoxy group
  • R 8 may aptly be hydrogen or a C ⁇ -4alkyl group or a C 2 -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 Ci-4alkyl group or a C2-4alkyl group substituted by a hydroxy or Ci-2alkoxy 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
  • R 8 represents a C 2 -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, pyrrolidino, piperidino, piperazino, morpholino, or thiomorpholino.
  • nitrogen containing heteroaliphatic rings especially pyrrolidino and morpholino rings.
  • Particularly suitable moieties -W-NR 7 R 8 include those wherein W is
  • CH 2 or CH2CH2 and NR 7 R 8 is amino, methylamino, dimethylamino, dieth lamino, azetidinyl, pyrrolidino and morpholino.
  • W is preferably CH2 and NR 7 R 8 is preferably dimethylamino, azetidinyl or pyrrolidino, especially dimethylamino.
  • 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(0)CH 2 - or -CH 2 C(0)-.
  • 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, CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , OCF 3 , OCH 2 CH 2 F, OCH 2 CHF 2 or OCH2CF3, and most especially CF 3 , OCF3 and OCH2CF3.
  • hydroxyCi- ⁇ alkyl means a Ci-ealkyl group, in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by a hydroxy group.
  • cycloalkyl groups referred to herein may represent, for example, c clopropyl, cyclobut l, 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.
  • substituents selected from halogen, Ci- ⁇ alkyl, Ci- ⁇ alkoxy, or trifluoromethyl.
  • Particular examples of such groups include phenyl, naphthyl and biphenyl. Phenyl is especially preferred.
  • heteroaryl as a group or part of a group means a monocyclic 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,
  • Ci- ⁇ alkoxy trifluoromethyl or phenyl.
  • Particular examples of such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrirnidinyl, 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.
  • the compounds of formula (I) may be prepared in the form of 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.
  • 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 ⁇ acuo 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).
  • 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 carboxylie, 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 present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.
  • 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.
  • 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
  • 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
  • the compounds of the present invention are also particularly useful in the treatment of nociception and pain.
  • Diseases and conditions in which 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.
  • 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.
  • treatment includes prophylactic use to prevent the occurrence or recurrence of any of the aforementioned conditions.
  • compounds of formula (I) may be prepared by a process (A) which comprises reacting a compound of formula (II) with a compound of formula (III):
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y and Z are as defined for formula (I), except that any reactive moiety is protected by a suitable protecting group; and LG represents a leaving group; in the presence of a base, followed by deprotection, if required.
  • Suitable leaving groups include halogen atoms, e.g. chlorine, bromine or iodine, or sulphonate derivatives such as tosylate, mesylate or triflate.
  • reaction is conveniently carried out in a suitable organic solvent, such as an ether, e.g. 1,2-dimethoxyethane, at a temperature in the region of 0°C.
  • suitable organic solvent such as an ether, e.g. 1,2-dimethoxyethane
  • Favoured bases of use in the reaction include alkali metal amides and hydrides, such as potassium bis(trimethylsilyl)amide or potassium hydride.
  • sodium hydride is used.
  • compounds of formula (I) may be prepared by the reductive amination of a compound of formula (II) with a compound of formula (W), in the presence of a reducing agent:
  • Suitable reducing agents for use in this reaction include, for example, sodium cyanoborohydride or sodium triacetoxyborohydride, or catalytic hydrogenation.
  • the reaction is conveniently effected in a suitable solvent such as acetic acid or methanol at a temperature between 0°C and 50°C, conveniently at about room temperature.
  • compounds of formula (I) wherein R 1 is Gi- ⁇ alkoxy, fluoroCi- ⁇ alkoxy, C 2 -6alkenoxy, C3-7cycloalkoxy, C3-7cycloalkylC ⁇ -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 (V)
  • Suitable bases include alkali metal hydrides, such as sodium hydride, in a suitable solvent such as dimethylformamide. The reaction is conveniently effected at about room temperature.
  • compounds of formula (I) may be prepared by the interconversion of a corresponding compound of formula (I) in which R 6 is H, hereinafter referred to as formula (VI)
  • R a is a group of the formula R 6 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).
  • 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.
  • reaction (a) reaction with lithium naphthalenide in tetrahydrofuran, the reaction being effected at reduced temperature, for example at about -78°C; or (b) in a first step, oxidation of the phenylthio moiety using, for example, oxone in the presence of aluminium oxide, the reaction being effected in a suitable solvent such as a halogenated hydrocarbon, for example, chloroform, and conveniently at room temperature, and in a second step, removal of the phenylsulfonyl moiety using, for example, sodium amalgam in the presence of disodium hydrogen orthophosphonate, the reaction being effected in a suitable solvent such as an alcohol, for example, methanol, and at a reduced temperature, for example, between 0°C and 10°C.
  • a suitable solvent such as an alcohol, for example, methanol
  • reaction is conveniently effected in two steps, firstly reacting the compound of formula (DQ with the amine, ideally in the presence of a suitable catalyst such as -toluenesulfonic acid in a suitable solvent such as an aromatic hydrocarbon, for example, toluene, followed by treatment with a reducing agent such as a borohydride, for example, sodium cyanoborohydride, sodium triacetoxyborohydride or sodium borohydride.
  • a suitable solvent such as an alcohol, for example, methanol.
  • any N-protecting group may be removed by conventional procedures well known to the skilled worker (for instance, by catalytic hydrogenation in the presence of a suitable catalyst, for example, palladium on carbon, in a suitable solvent, such as acetic acid or methanol or a mixture thereof).
  • a suitable catalyst for example, palladium on carbon
  • a suitable solvent such as acetic acid or methanol or a mixture thereof.
  • Compounds of formula (VIII) may be prepared from a compound of formula (V) by reaction with (l-iodo-cycloprop-l-yl)phenylsulfide.
  • 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.
  • Compounds of formula (DQ wherein R is fluorine may be prepared by interconversion of a corresponding compound of formula (DQ in which R is hydrogen, using conventional fluorination techniques, for example, by treatment with lithium hexamethyldisilazide, followed by reaction with N-fluorobenzenesulfonamide.
  • reaction of a compound of formula (XI) 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 exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01165.
  • the compounds were found to be active with IC50 at the human NKi receptor of less than lOOnM on said test method.
  • Lithium (175mg, 2 ⁇ mmol) was added to a solution of naphthalene ( 3.2g, 25mmol) in tetrahydrofuran (25mL), and the mixture sonicated for 2 hours. The green solution formed was then slowly added to a solution of 30 (lR*,2R*,5S*,6R*)-2-amino-8-benzyl-l-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octane (Description 8; 2.0g, 4.6mmol) in tetrahydrofuran ( ⁇ OmL), already cooled to -78°C.
  • DESCRIPTION 12 l-(Cyclopropoxy)-2-iodo-4-(trifluoromethoxy)benzene l-(Vinyloxy)-2-iodo-4-(trifluoromethoxy)benzene (Description 11; 7.6g, 10 23mmol) and chloroiodomethane ( ⁇ .4mL, 74mmol) were dissolved in 1,2-dichloroethane (40mL) and cooled to 0°C. Diethyl zinc (3.8mL, 36.8mmol) was then added dropwise.
  • DESCRIPTION 16a (l ⁇ *,5S*,6i2*)-8-benzyl-6-(fer£- butoxycarbonyl)-l-phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one ⁇ H (360 MHz, CDCls): 7.83 (IH, dd, J 1.4Hz, 8.6Hz), 7.40-7.25 (8H, m),
  • DESCRIPTION 22 (lR*,2R*,5S*,6R*)-2-Dibenzylamino-8-benzyl-6-(hydroxymethyl)-l- phenyl-8-azabicyclo [3.2.1] octane (lR*,2R*, ⁇ S*,6R*)-2-Dibenzylamino-8-benzyl-6-(hydroxycarbonyl)-l- phenyl-8-azabicyclo[3.2.1]octane (Description 21; 400mg, 0.78mmol) was dissolved in tetrahydrofuran (lOmL) and treated with lithium aluminium hydride solution (800 ⁇ L, IM, 0.8mmol) in tetrahydrofuran.
  • DESCRIPTION 29 (lR*,5S*,6R*)-8-Benzyl-6-cyano-l-phenyl-8-azabicyclo[3.2.1]oct-3- ene-2-one l ⁇ N-benzyl-3-hydroxy-2-phenylpyridinium bromide (20g, 58.3mmol), acrylonitrile (60ml, 75 ⁇ mmol) and triethylamine (20ml, 143mmol) were mixed and stirred at reflux for 20 hours in 1,4-dioxane (150ml). The mixture was partitioned between saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, dried (MgS ⁇ 4),
  • DESCRIPTIONS 33a and 33b ⁇ (a) (lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-l-phenyl-6-(l- methyl-li ⁇ -tetrazol-5-yl)-8-azabicyclo[3.2.1]octane; and (b) (lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-l-phenyl-6-(2- methyl-J?H-tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-l-phenyl-6-(iH-tetrazol- ⁇ -yl)- 0 8-azabicyclo[3.2.1]octane (Description 31; 370mg, 0.82mmol) was dissolved in a mixture of to
  • DESCRIPTIONS 36a, 36b and 36c (a) (lR*,3S*,5S*,6R*)-8-Benzyl-3-fluoro-l-phenyl-6-(*er*- butoxycarbonyl)-8-azabieyclo[3.2.1]octan-2-one; 0 (b) (lR*,3R*,5S*,6R*)-8-Benzyl-3-fluoro-l-phenyl-6-(fer£- butoxycarbonyl)-8-azabicyclo[3.2.1]octan-2-one; and (c) (lR*,5S*,6R*)-8-Benzyl-3,3-difluoro-l-phenyl-6-(fer£- butoxycarbonyl)-8-azabicyclo[3.2.1]octan-2-one To a solution of lithium hexamethyldisilazide in tetrahydrofuran (18mL, 5 IM, 18mmol) was added
  • DESCRIPTION 37 (lR*,2R*,3S*,5S*,6R*)-2-Benzylamino-8-benzyl-3-fluoro-l-phenyl-6- (£er£-butoxycarbonyl)-8-azabicyclo[3.2.1]octane (lR*,3S*,5S*,6R*)-8-Benzyl-3-fluoro-l-phenyl-6-(ferf-butoxycarbonyl)-8- azabicyclo[3.2.1]octan-2-one (Description 36a; 1.68g, 4.1mmol), titanium iso-propoxide (1.8mL, 6.2mmol) and benzylamine (520 ⁇ L, 4.7mmol) were heated together at 85°C for two hours, then cooled and diluted with methanol (30mL).
  • Diastereomer A (Most polar): ⁇ H (360 MHz, CDsOD): 7.57-7.46 (5H, m), 7.24 (IH, br d, J 8.9Hz), 7.04 (lh, d, J 8.9Hz), 6.76 (IH, br s), 4.27-4.29 (IH, m), 3.78 (3H, s), 3.49-3.40 (2H, m), 2.87-2.80 (IH, m), 2.44-2.24 (3H, m), 2.16-1.81 (4H, ), 1.29-1.21 (3H, m).
  • Diastereomer B (Least Polar): ⁇ H (400 MHz, CDsOD): 7.55-7.52 (3H, ), 7.30-7.28 (2H, m), 7.15 (IH, br d,

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Abstract

The present invention relates compounds of the formula (I), wherein X represents hydrogen or a C1-4alkyl group optionally substituted by a hydroxy group; Y represents hydrogen, C1-6alkyl or C3-7cycloalkyl; Z is -CR9R10CH2- or -CH2CR9R10-; R represents hydrogen, fluorine, hydroxy, C¿1-6?alkyl or C1-6alkoxy; and R?1, R2, R3, R4, R5 and R6¿ are as defined herein. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migaine, emesis or postherpetic neuralgia.

Description

AZABICYCLIC AMINE DERIVATIVES AS NK-1 RECEPTOR ANTAGONISTS
This invention relates to a class of azabicyclic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are substituted benzylamino derivatives of l-ρhenyl-8- azabicyclo[3.2.1]octane, which are useful as neurokinin 1 (NK-1) receptor antagonists.
The present invention provides compounds of the formula (I):
Figure imgf000002_0001
(I)
wherein
X represents hydrogen or a Ci-4alkyl group optionally substituted by a hydroxy group;
Y represents hydrogen, Ci-βalkyl or C3-7cycloalkyl;
Z is -CR9R10CH2- or -CH2CR9R10-;
R represents hydrogen, fluorine, hydroxy, Cι-6alkyl or Ci-βalkoxy;
R1 represents hydrogen, hydroxy, Ci-βalkyl, C2-6alkenyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, Ci-βalkoxy, fluoroCi-βalkoxy, hydroxyCi-βalkyl, Cι-6alkoxyCι-4alkyl, Cι-6alkoxyCι-4alkoxy, fluoroCι-6alkoxyCι-4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylCι-4alkoxy, phenoxy, benzyloxy, cyano, halogen, NRaRb, SRa, SORa, S02Ra, OSO2Ra, NRaCOR12, CORa, C02Ra or CONRaRb where Ra and Rb each independently represent hydrogen, Cι-4alkyl or fluoroCι-4alkyl;
R2 represents hydrogen, halogen, Ci-βalkyl or Ci-βalkoxy; or when R2 is adjacent to R1, they may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen, sulphur, NH or NRC, which ring is optionally substituted by one, two or three groups selected from hydroxy, Cwalkyl, Cι-3alkoxyCι-3alkyl, fiuoroCι-4alkyl, phenyl, =0 or =S, where Rc represents Cι-4alkyl, hydroxyCι-4alkyl, Cι-4alkoxyCι-4alkyl, fluoroCι-4alkyl, phenyl or benzyl.
R3 represents hydrogen, halogen, Ci-βalkyl, fluoroCi-βalkyl, Ci-βalkoxy, fluoroCi-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, cyano, SRa, SORa, SO2Ra, NRaR , NRaCORi2, CORa, C02Ra, CONRaRb or C^alkyl substituted by cyano, CO2Ra or CONRaRb where Ra and Rb are as previously defined; or R3 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 Ci-βalkyl, Ci-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, trifluoromethyl, OCF3, NO2, CN, SRa, SORa, S02Ra, CORa, C02Ra, phenyl, -(CH2)rNRaRb, -(CH2)rNRaCOR , -(CH2)rCONRaR , or CH2C(0)Ra, where Ra and R are as previously defined and r is zero, 1 or 2;
R4 represents hydrogen, halogen, Ci-βalkyl, Ci-βalkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C^alkynyl or Cι-4alkyl substituted by Cwalkoxy, where Ra and Rb are as previously defined;
R5 represents hydrogen, halogen, Ci-βalkyl, CF3 or Ci-βalkoxy substituted by Cι-4alkoxy; R6 represents hydrogen, hydroxy, CORa, C02Ra, COCONRaR ,
COCθ2 a, Ci-βalkyl optionally substituted by a group selected from (CO2Ra, CONRaR , hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONHphenyKCwalkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaCι-6alkylR14, CONRHC^alkenyl, CONRUC2-6alkynyl, COCONRaRb, CONRaC(NR )NRaR , CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from Ci-βalkyl, Ci-βalkoxy, halogen and trifluoromethyl); or R6 represents a group of the formula -CH2C≡CCH2NR7R8 where R7 and R8 are as defined below; or R6 represents Ci-βalkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by =0 or =S and optionally substituted by a group of the formula — -NR7R8 where
W is Ci-βalkylene or C3-6cycloalkyl;
R7 represents hydrogen or Ci-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, or C2-4alkyl substituted by Ci-4alkoxy or hydroxyl;
R8 represents hydrogen or Cι-4alkyl, Cι-4alkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, or C2-4alkyl substituted by a group selected from Cι-4alkoxy, hydroxyl, CO2Ra, NRaRb, aryl, aryloxy, heteroaryl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R7, R8 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 Cι-4alkoxy optionally substituted by a Cι-4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NRC moiety where Rc is as previously defined; or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or W, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R9 represents hydrogen, hydroxy, oxo, Ci-βalkyl, C2-βalkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, fluoroCi-ealkyl, Ci-βalkoxy, fiuoroCi-βalkoxy, hydroxyCi-βalkyl, Cι-6alkoxyCι-4alkyl, Cι-6alkoxyCι-4alkoxy,
Figure imgf000005_0001
C2-βalkenyloxy, C2-6alkynyloxy, C3-7cycloalkoxy, C3-7cycloalkylCι-4alkoxy, aryl, aryl(CH2), aryloxy, aryl(CH2)oxy, cyano, halogen, NR7R8, CH2NR7R8, SR12, SOR*2, SO2R12, OSO2R12, NRaCORi2, CH(OH)Ri2, COR12, CO2R12, CONR R8, CH2OR13, heteroaryl or
Figure imgf000005_0002
wherein Ra is as previously defined;
R10 represents hydrogen, halogen or hydroxy;
R11 represents hydrogen or Ci-βalkyl; R12 represents hydrogen, Ci-βalkyl, Ci-βalkoxy, fluoroCi-βalkyl or phenyl optionally substituted by one, two or three substituents selected from Ci-βalkyl, Ci-βalkoxy, halogen or trifluoromethyl;
R13 represents Ci^alkyl substituted by a group selected from hydroxy, CORa, CU2Ra, CONRaRb and heteroaryl, where Ra is as previously defined;
Ri represents ORa, CONRaRb or heteroaryl; and pharmaceutically acceptable salts or N-oxides thereof.
A preferred class of compound of formula (I) is that wherein X is hydrogen, methyl or hydroxymethyl, in particular, hydrogen. Another preferred class of compound of formula (I) is that wherein Y is hydrogen or Cι-4alkyl, in particular, hydrogen or methyl, especially hydrogen.
A further preferred class of compounds of formula (I) is that wherein R represents hydrogen or fluorine. A preferred class of compound of formula (I) is that wherein R1 is a
Ci-βalkoxy, fiuoroCi-βalkoxy or C3-7cycloalkoxy group, or R1 together with the group R2 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 R1 is methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, cyclopropoxy or R1 together with the group R2 represents -OCH(CH3)CH2- or -N(CH3)C(0)C(CH3)2- to complete a 5-membered saturated ring, or -CH(OH)CH2OC(CHgXCF3)-, -CH2CH2C(O)N(CH3)- or -CH(OH)CH2C(O)N(CH3)- to complete a 6-membered saturated ring. Most especially, R1 is methoxy or cyclopropoxy.
Another preferred class of compound of formula (I) is that wherein R2 is a hydrogen, fluorine or chlorine atom, especially a hydrogen atom.
A further preferred class of compound of formula (I) is that wherein R3 is a hydrogen or halogen atom or a fluoroCi-βalkoxy group, especially fluorine, trifluoromethoxy or 2,2,2-trifluoroethoxy, or a 5-membered aromatic heterocyclic group as previously defined. Most especially, R3 is trifluoromethoxy or 5-(trifluoromethyl)tetrazol-l-yl.
A particularly preferred class of compound of formula (I) is that wherein R1 is attached at the 2-position of the phenyl ring and R3 is attached at the 5-position of the phenyl ring.
A further preferred class of compound of formula (I) is that wherein R4 is a hydrogen atom or a fluorine atom.
Another preferred class of compound of formula (I) is that in which R5 is a hydrogen atom. A further preferred class of compound of formula (I) is that wherein
R6 is a hydrogen atom or a Ci-βalk l group. Most especially, R6 is hydrogen or methyl.
Also preferred is the class of compound of formula (I) in which R6 is a Ci-βalk l group, in particular CH2, CH(CHs) and CH2CH2 and especially CH2, substituted by a 5-membered heterocyclic ring containing 2 or 3 nitrogen atoms as previously defined. In particular, 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 -W-NR7R8.
Particularly preferred heterocyclic rings are selected from:
Figure imgf000007_0001
Figure imgf000007_0002
Another preferred class of compound of formula (I) is that wherein
R9 represents hydrogen, hydroxy, oxo, Ci-βalkoxy, Cι-6alkoxyCι-4alkyl, hydroxyCι-4alkyl, cyano, NR7R8, CH2NR7R8, S02Rd, CH(OH)R12, COR12, C02R12, CONR7R8, phenyl, heteroaryl,
Figure imgf000007_0003
or CH2OR13, where said phenyl is optionally substituted by one or two substituents selected from Cι-4alkyl, Cι-4alkoxy, halogen or trifiuoromethyl.
A further preferred class of compound of formula (I) is that wherein R9 represents hydrogen, SO2Rd (in particular where Rd is phenyl) or CONR7R8 (in particular where R7 is Cι-4alkyl or C2-4alkyl substituted by a hydroxyl or Cι-2alkoxy group and R8 is hydrogen, Cι-4alkyl,
Figure imgf000007_0004
or C2-4alkyl substituted by a hydroxyl or Cι-2alkoxy group, or R7 and R8, 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 Cι-4alkyl, hydroxyCι-2alkyl, Cι-4alkoxyCι-2alkyl, phenyl or benzyl group). Another preferred class of compounds of formula (I) is that wherein R10 represents hydrogen, fluorine or hydroxy, and in particular that wherein R10 is hydrogen.
Certain particularly apt compounds of the present invention include those wherein R3 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 R3 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, 1,3,4-oxadiazole and tetrazole, each heteroaryl group being optionally substituted as previously defined. Particularly preferred compounds of the present invention are those wherein R3 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.
An especially preferred class of compound of formula (I) is that wherein R3 is the group
Figure imgf000008_0001
where R15 is hydrogen, halogen, Ci-ealkyl, Cι-6alkoxy, CF3, OGF3, N02, CN, SRa, SORa, SO2Ra, CORa, C02Ra, (CH2)rCONRaR , (CH2)rNRaR or (CH2)rNRaCORb, where Ra and Rb are hydrogen or C1.4alk.yl, and r is zero, 1 or 2.
The optionally substituted tetrazolyl group is particularly preferred.
Rlδ is preferably hydrogen, Cι-4alkyl, especially methyl, CF3, (CH2)rCONRaRb, SORa or S02Ra where Ra, Rb and r are as previously defined. Most especially, R15 is CF3. One favoured group of compounds of the present invention are of the formula (la) and pharmaceutically acceptable salts thereof:
Figure imgf000009_0001
(la)
wherein R1, R2, R3, R4, X and Y are as defined in relation to formula (I) and Z is -CR9Ri°CH2-.
With respect to compounds of the formula (I), W (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 W is CH2.
With respect to compounds of the formula (I), R7 may aptly be a Cι-4alkyl group or a C2-4alkyl group substituted by a hydroxyl or Cι-2alkoxy group, R8 may aptly be hydrogen or a Cι-4alkyl group or a C2-4alkyl group substituted by a hydroxyl or Cι-2alkoxy group, or R7 and R8 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 Ci-4alkyl group or a C2-4alkyl group substituted by a hydroxy or Ci-2alkoxy group.
Where the group NR7R8 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring contains a double bond, a particularly preferred group is 3-pyrroline. Where the group NR7R8 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. l]hexyl, 5-azabicyclo [2.2. l]heptyl, 6-azabicyclo [3.2.1] octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo [3.3. l]nonyl,
6-azabicyclo[3.2.2]decyl, 7-azabicyclo[4.3.1]decyl,
7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially
5-azabicyclo [2.2. l]heptyl and 6-azabicyclo[3.2.1]octyl.
Where R8 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, pyrrolidino, piperidino, piperazino, morpholino, or thiomorpholino. Particularly preferred are nitrogen containing heteroaliphatic rings, especially pyrrolidino and morpholino rings. Particularly suitable moieties -W-NR7R8 include those wherein W is
CH2 or CH2CH2 and NR7R8 is amino, methylamino, dimethylamino, dieth lamino, azetidinyl, pyrrolidino and morpholino.
In particular, W is preferably CH2 and NR7R8 is preferably dimethylamino, azetidinyl or pyrrolidino, especially dimethylamino. When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.
It will be appreciated that, where R9 represents an oxo (=O) group, then R10 will be absent and the group Z will in fact represent -C(0)CH2- or -CH2C(0)-.
As used herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. As used herein, the terms "fluoroCi-βalkyl" and fluoroCι-6alkoxy" mean a Ci-βalkyl or Cι-6alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Similarly, the term "fluoroCι-4alkyl" means a Cwalkyl group in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroCι-3alkyl and fluoroCι-3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCH2CF3. As used herein, the term "hydroxyCi-βalkyl" means a Ci-ealkyl group, in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by a hydroxy group. Preferred are hydroxyCι-3alkyl groups, especially where one hydrogen atom has been replaced by a hydroxy group, for example, CH2OH, CH2CH2OH and C(CHs)2OH.
The cycloalkyl groups referred to herein may represent, for example, c clopropyl, cyclobut l, cyclopentyl or cyclohexyl. A suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.
Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
As used herein, the terms "alkenyl" and "alkynyl" as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.
As used herein, the term "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-βalkyl, Ci-βalkoxy, or trifluoromethyl. Particular examples of such groups include phenyl, naphthyl and biphenyl. Phenyl is especially preferred.
As used herein, the term "heteroaryl" as a group or part of a group means a monocyclic 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-βalkyl,
Ci-βalkoxy, trifluoromethyl or phenyl. Particular examples of such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrirnidinyl, 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.
When used herein the term "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: lR*,2R*,5S*)-2-(3,5-bis(trifluoromethyl)benzylamino)-l-phenyl-8- azabicyclo [3.2.1] octane;
(lR*,2R*,5S*)-2-(2-methoxy-5-(trifluoromethoxy)benzylamino)-l-phenyl-8- azabicyclo [3.2.1] octane;
(lR*,2R*,5S*)-2-(2-cyclopropyloxy-5-[5-(trifluoromethyl)tetrazol-l- yl]benzylamino)-l-phenyl-8-azahicyclo [3.2.1] octane;
(lR*,2R*,5S*)-2-(2-methoxy-5-(trifluoromethoxy)benzylamino)-8-benzyl-l- phenyl-8-azabicyclo [3.2.1] octane ;
(lR*,2R*,5S*)-2-(2-Cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-l- phenyl-8-azabicyclo[3.2.1]octane; (lR*,2R*,5S*,6R*)-2-(2-methoxy-5-(trifluoromethoxy)benzylamino)-l- ρhenyl-6-phenylsulphonyl-8-azabicyclo [3.2.1] octane;
(1R*,2R*,5S*,9S*)- and (lR*,2R*,5S*,9R*)-2-[l-(2-methoxy-5-
(trifluoromethoxy)phenyl)ethylamino]-l-phenyl-8-azabicyclo[3.2.1]octane;
(lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6- (hydroxymethyl)-l-phenyl-8-azabicyclo [3.2.1] octane; (lR*,2R*,5S*)-2-(2-chloro-5-(trifluoromethoxy)benzylamino)-l-phenyl-8- azabicyclo [3.2.1] octane
(lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6-
[l-(3-hydroxy)ρropyloxymethyl]-l-phenyl-8-azabicyclo[3.2.1]octane; (lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6-
( er -butoxycarbonyl)-l-phenyl-8-azabicyclo[3.2.1]octane;
(lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6-
(N-methoxy-N-methylcarboxamido)- l-phenyl-8-azabicyclo [3.2.1] octane;
(lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6- acetyl-1 -phenyl-8-azabicyclo [3.2.1] octane;
(lR*,2R*,5S*,6R*,R*) and (lR*,2R*,5S*,6R*,S*)-2-(2-cyclopropoxy-5-
(trifluoromethoxy)benzylamino)-6-( 1 -hydroxy)ethyl- 1 -phenyl-8- azabicyclo [3.2. l]octane;
(lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6- (l-hydroxy-l-methyl)ethyl-l-phenyl-8-azabicyclo[3.2.1]octane;
(lR*,2R*,5S*,6S*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6-
(lH-tetrazol-5-yl)-l-phenyl-8-azabicyclo[3.2.1]octane;
(lR*,2R*,5S*,6S*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-l- phenyl-6-(l-methyl-iH-tetrazol-5-yl)-8-azabicyclo[3.2.1]octane; (lR*,2R*,5S*,6S*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-l- phenyl-6-(2-methyl-2H-tetrazol-5-yl)-8-azabieyclo [3.2.1] octane;
(lR*,2R*,3S*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)- benzylamino)-3-fluoro-l-phenyl-6-(hydroxymethyl)-8- azabicyclo [3.2. l]octane; (lR*,2R*,5S*,6R*)-6-(bromomethyl)-2-(2-cyclopropoxy-5-
(trifluoromethoxy)benzylamino)-l-phenyl-8-azabicyclo[3.2.1]octane;
(lR*,2R*,5S*,6R*)-2-(2-cycloproρoxy-5-(trifluoromethoxy)-benzylamino)-6-
[(methylsulphonyl)methyl]-l-phenyl-8-azabicyclo[3.2.1]octane; and pharmaceutically acceptable salts thereof. In a further aspect of the present invention, the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
For use in medicine, 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. Furthermore, where the compounds of the invention carry an acidic 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 υacuo 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. In general, such 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 carboxylie, 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 and 5 positions as possessed by, for instance, the compound of Example 1, i.e. as shown in formula (lb)
Figure imgf000015_0001
(lb) It will be appreciated that the preferred definitions of the various substituents recited herein may be taken alone or in combination and, unless otherwise stated, apply to the generic formula for compounds of the present invention as well as to the preferred class of compound represented by formula (la).
The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.
Preferably 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). In particular, 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. Diseases and conditions in which 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.
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.
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. 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. Most especially, 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.
In the treatment of the conditions associated with an excess of tachykinins, 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. For example, in the treatment of conditions involving the neurotransmission of pain sensations, 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.
In the treatment of emesis, 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. In the treatment of psychiatric disorders, 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.
As used herein, the term "treatment" includes prophylactic use to prevent the occurrence or recurrence of any of the aforementioned conditions.
According to a general process (A), compounds of formula (I) may be prepared by a process (A) which comprises reacting a compound of formula (II) with a compound of formula (III):
Figure imgf000019_0001
wherein R, R1, R2, R3, R4, R5, R6, X, Y and Z are as defined for formula (I), except that any reactive moiety is protected by a suitable protecting group; and LG represents a leaving group; in the presence of a base, followed by deprotection, if required.
Suitable leaving groups include halogen atoms, e.g. chlorine, bromine or iodine, or sulphonate derivatives such as tosylate, mesylate or triflate.
The reaction is conveniently carried out in a suitable organic solvent, such as an ether, e.g. 1,2-dimethoxyethane, at a temperature in the region of 0°C. Favoured bases of use in the reaction include alkali metal amides and hydrides, such as potassium bis(trimethylsilyl)amide or potassium hydride. Suitably, sodium hydride is used. According to another general process (B), compounds of formula (I) may be prepared by the reductive amination of a compound of formula (II) with a compound of formula (W), in the presence of a reducing agent:
Figure imgf000020_0001
(IN)
Suitable reducing agents for use in this reaction include, for example, sodium cyanoborohydride or sodium triacetoxyborohydride, or catalytic hydrogenation. The reaction is conveniently effected in a suitable solvent such as acetic acid or methanol at a temperature between 0°C and 50°C, conveniently at about room temperature.
According to another general process (C), compounds of formula (I) wherein R1 is Gi-βalkoxy, fluoroCi-βalkoxy, C2-6alkenoxy, C3-7cycloalkoxy, C3-7cycloalkylCι-4alkoxy or benzyloxy, may be prepared by the interconversion of a compound of formula (I) wherein R1 is hydroxy, hereinafter referred to as formula (V)
Figure imgf000020_0002
(N) by reaction with an appropriate alkyl-, fluoroalkyl-, alkenyl-, cycloalkyl-, cycloalkylalkyl- or aralkyl-halide, especially the iodide, in the presence of a base.
Suitable bases include alkali metal hydrides, such as sodium hydride, in a suitable solvent such as dimethylformamide. The reaction is conveniently effected at about room temperature.
According to another general process (D), compounds of formula (I) may be prepared by the interconversion of a corresponding compound of formula (I) in which R6 is H, hereinafter referred to as formula (VI)
Figure imgf000021_0001
(VI)
by reaction with a compound of formula (VII):
LG-R ,'6a
(NH)
where R a is a group of the formula R6 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). 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.
Suitable alternative methods for introducing the group R6 are described, for instance, in International Patent Specification No. WO 95/18124.
According to another general process (E), compounds of formula (I) may be prepared from a compound of formula (VIII)
Figure imgf000022_0001
(VIII)
by either
(a) reaction with lithium naphthalenide in tetrahydrofuran, the reaction being effected at reduced temperature, for example at about -78°C; or (b) in a first step, oxidation of the phenylthio moiety using, for example, oxone in the presence of aluminium oxide, the reaction being effected in a suitable solvent such as a halogenated hydrocarbon, for example, chloroform, and conveniently at room temperature, and in a second step, removal of the phenylsulfonyl moiety using, for example, sodium amalgam in the presence of disodium hydrogen orthophosphonate, the reaction being effected in a suitable solvent such as an alcohol, for example, methanol, and at a reduced temperature, for example, between 0°C and 10°C.
Further details of suitable procedures will be found in the accompanying Examples.
Compounds of formula (II) in which R30 is NHY may be prepared, for example, by reaction of a compound of formula (DQ
Figure imgf000023_0001
(IX)
with an amine of the formula NHYR40 where R40 is a hydrogen atom or, more preferably, an N-protecting group such as a benzyl group. The reaction is conveniently effected in two steps, firstly reacting the compound of formula (DQ with the amine, ideally in the presence of a suitable catalyst such as -toluenesulfonic acid in a suitable solvent such as an aromatic hydrocarbon, for example, toluene, followed by treatment with a reducing agent such as a borohydride, for example, sodium cyanoborohydride, sodium triacetoxyborohydride or sodium borohydride. This second step is conveniently effected in a suitable solvent such as an alcohol, for example, methanol. Where present, any N-protecting group may be removed by conventional procedures well known to the skilled worker (for instance, by catalytic hydrogenation in the presence of a suitable catalyst, for example, palladium on carbon, in a suitable solvent, such as acetic acid or methanol or a mixture thereof). Compounds of formula (VIII) may be prepared from a compound of formula (V) by reaction with (l-iodo-cycloprop-l-yl)phenylsulfide.
Compounds of formula (DQ may be prepared from a compound of formula (X)
Figure imgf000024_0001
by catalytic hydrogenation using 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.
Compounds of formula (DQ wherein R is fluorine may be prepared by interconversion of a corresponding compound of formula (DQ in which R is hydrogen, using conventional fluorination techniques, for example, by treatment with lithium hexamethyldisilazide, followed by reaction with N-fluorobenzenesulfonamide.
Compounds of formula (X) wherein R6 is benzyl or allyl, may be prepared from a compound of formula (XI)
Figure imgf000024_0002
(or a corresponding compound wherein the O" is OH, and the compound is associated with a counterion, such as a bromide or chloride ion) by reaction with a vinyl compound of the formula R9CH=CH2, in particular where R9 is cyano, SO2R13 (especially where R13 is phenyl) or C02R13
(especially where R13 is terέ-butyl), in the presence of an organic base such as a trialkylamine, for example, triethylamine. The reaction is conveniently effected in an aprotic solvent such as an aromatic hydrocarbon, for example, toluene. The reaction of a compound of formula (XI) with acrylonitrile is particularly suitable for preparing compounds where the R9 substituent is situated on either of the carbon atoms of the two-carbon bridge.
In a preferred embodiment of the aforementioned processes, R6 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 R6 is a hydrogen atom are particularly preferred precursors to other compounds of formula (I).
Compounds of formula (III) and (rV) are either known compounds or may be prepared by methods analogous to those described herein.
It will be appreciated that the general methodology described above may be adapted, using methods that are readily apparent to one of ordinary skill in the art, in order to prepare further compounds of the present invention. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McO ie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Jol Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01165. 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:
DESCRIPTION 1
N-Benzyl-3-hydroxy-2-phenylpyridinium bromide
A suspension of 3-hydroxy-2-phenylpyridine (20g, 116mmol) in toluene (250ml) was heated at reflux for 30 minutes. Benzyl bromide (20ml) was added and the reaction mixture was heated at reflux for 6 hours then cooled using an ice bath. The solid residue was collected by filtration and washed twice with ether to give crude N-benzyl-3-hydroxy-2- phenylpyridinium bromide (36.5g, 91%) which was used in the next step without further purification. δH (360 MHz, CDCI3): 11.88 (IH, s), 9.47 (IH, d, J 7.2Hz), 8.16 (IH, d, J 8.1Hz), 8.05 (IH, dd, J 6.0Hz, 8.8Hz), 7.60-7.45 (3H, m), 7.37-7.22 (5H, m), 6.88 (2H, dd, J 6.2Hz, 7.9Hz), 5.61 (2H, s).
DESCRIPTION 2 (122*,5S*,6i2*)-8-Benzyl-l-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]oct-3-en-2-one
A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (Description 1; 4.91g, 14.3mmol), phenyl vinyl sulphone (4.2g, 25mmol), triethylamine (2.8ml, 20mmol) and 1,4-dioxane (50ml) was heated at reflux overnight. After cooling to room temperature, the reaction mixture was poured onto saturated aqueous NaHCOβ and extracted with ethyl acetate (3xl00ml). The combined organic extracts were dried (Na2S04) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 10-70%) to give the title compound (4.84g, 78%) as a yellow-orange foam. Crystallisation from ϊso-hexane:diethyl ether gave the title compound as yellow rhombs. δH (360 MHz, CDCls): 7.75-7.60 (5H, m), 7.48 (2H, t, J 7.7Hz), 7.41-7.25 (8H, m), 6.86 (IH, dd, J 4.8Hz, 9.6Hz), 6.23 (IH, d, J 9.6Hz), 4.25 (IH, d, J 4.8Hz), 3.65 (IH, d, J 13.4Hz), 3.56 (IH, dd, J 4.0Hz, 9.4Hz), 3.43 (IH, d, J 13.5Hz), 2.83 (IH, dd, J 3.9Hz, 14.9Hz), 2.56 (IH, dd, J 9.4Hz, 15.0Hz).
DESCRIPTION 3
(LR*,5S*,6i2*)-8-Benzyl-l-phenyl-6-phenylsulphonyl-8- azabicyclo [3.2.1 ] octan-2-one
10% Palladium on carbon (lg) was added as a slurry in water (2ml) to a solution of (lR*,5ιS*,6i?*)-8-benzyl-l-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]oct-3-ene-2-one (Description 2; llg, 25.6mmol) in methanol (50ml) and ethyl acetate (50ml). The mixture was hydrogenated at 30psi for one hour. The reaction mixture was filtered through a pad of Celite™. The filter cake was washed with dichloromethane (IL) and the combined filtrates concentrated in vacuo to give the title compound (10.8g, 98%). δH (400 MHz, CDCI3): 7.79 (2H, d, J 7.2Hz), 7.68 (IH, t, J 6.4Hz), 7.51 (2H, t, J 7.6Hz), 7.41-7.25 (10H, m), 3.94 (IH, br s), 3.73-3.69 (IH, d, J 14.0Hz), 3.63 (IH, t, J 7.7Hz), 3.36 (IH, d, J 14.0Hz), 2.71-2.54 (5H, m), 1.77 (IH, m).
DESCRIPTION 4 (lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-l-phenyl-6- phenylsulphonyl-8-azabicyelo[3.2.1] octane A mixture of (lR*,5S*,6R*)-8-benzyl-l-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octan-2-one (Description 3; 15. Og, 35mmol), p-toluenesulfonic acid monohydrate (50mg) and benzylamine (5.5g, δlmmol) in toluene (150mL) was heated at reflux under Dean Stark conditions for 24 hours, then cooled and the solvent removed in vacuo. The residue was dissolved in methanol (300mL) and sodium cyanoborohydride (2.3g, 36mmol) added. The solution formed was stirred 5 at room temperature for 16 hours then concentrated to. approximately A volume. Saturated aqueous sodium hydrogen carbonate solution (500mL) was added and the suspension formed was extracted with ethyl acetate (2x500mL). The extracts were dried (MgSθ4) and concentrated, before the residue was purified by silica chromatography to give the title compound
10 as a gum. δH (400 MHz, CDCls): 7.6δ-7.63 (2H, m), 7.δ9-7.δδ (IH, m), 7.δ0-7.48 (2H, m), 7.41-7.37 (4H, m), 7.32-7.21 (11H, m), 4.34 (IH, d, J 14.6Hz), 3.90 (IH, d, J 13.δHz), 3.82 (IH, m), 3.68-3.63 (2H, m), 3.48 (IH, dd, J δ.6Hz and 9.1Hz), 3.2δ (IH, d, 3.5Hz), 2.36-2.23 (3H, m), 2.04-2.00 (IH, m), 1.72- lδ 1.76 (IH, m), 0.98-1.00 (IH, m). MS (ES+) δ23 (M+H).
DESCRIPTION 5 (lR*,2R*,5S*,6R*)-2-amino-l-phenyl-6-phenylsulphonyl- 20 8-azabicyclo[3.2.1]octane
(lR*,2R*,δS*,6R*)-2-benzylamino-8-benzyl-l-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octane (Description 4; 1.73g, 3.3mmol) was dissolved in a mixture of methanol (30mL) and acetic acid (20mL), then treated with 10% palladium on charcoal (δOOmg). The suspension was hydrogenated at
2δ δOpsi hydrogen for 16 hours, then filtered and concentrated. The residue was basified with saturated sodium bicarbonate solution (lOOmL) and extracted with dichloromethane (2xl00mL). The extracts were dried (MgSθ4) and concentrated, and the residue purified by silica chromatography to give the title compound as a gum (1.10g, 3.2mmol).
30 δH (400 MHz, CDCI3): 7.87-7.85 (2H, ), 7.68-7.63 (IH, m), 7.58-7.δ3 (2H, m), 7.36-7.20 (5H, m), 4.05 (IH, t, J 2.8Hz), 3.60 (IH, dd, J 5.0Hz and 8.8Hz), 2.82 (IH, dd, J 1.6Hz and 4.7Hz), 2.δδ (IH, dd, J 8.8Hz and 14.2Hz), 2.30 (IH, dd, J δ.OHz and 14.2Hz), 1.96-1.64 (6H, m), 1.38-1.2δ (lH, m).
MS (ES+) 343 (M+H). δ
DESCRIPTION 6 (lR*,2R*,5S*)-2-amino-l-phenyl-8-azabicyclo[3.2.13octane (lR*,2R*,δS*,6R*)-2-amino-l-phenyl-6-phenylsulphonyl- 8-azabicyclo[3.2.1]octane (Description δ; l.Og, 2.9mmol) in methanol
10 (20mL) was treated with disodium hydrogen phosphate (l.βδg, 11.6mmol) and 10% sodium amalgam (2.67g), and the mixture stirred for 40 minutes. Saturated sodium bicarbonate solution (lOOmL) was then added and the suspension extracted with dichloromethane (2xl00mL). The extracts were dried (MgS04) and concentrated, and the residue purified by silica lδ chromatography to give the title compound as a gum (31δmg, 1.6mmol). δH (400 MHz, CDCls): 7.37-7.18 (5H, m), 3.69-3.67 (IH, m), 3.00 (IH, dd, J 1.4Hz and 4.5Hz), 2.30-2.22 (IH, m), 2.14-1.65 (8H, m), 1.58-1.52 (IH, m), 1.37-1.33 (IH, m). MS (ES+) 203 (M+H).
20
DESCRIPTION 7 2-Methoxy-5-(trifluoromethoxy)benzaldehyde
To 4-(trifluoromethoxy)anisole (5.0g, 26mmol) in tetrahydrofuran (lOOmL) cooled to -78°C was slowly added a solution of fert-butyllithium in
2δ pentanes (23mL, 1.7M, 39mmol). The resulting solution was stirred at -78°C for 30 minutes, before N,N'-dimethylformamide (8mL, 104mmol) was added. The solution was allowed to stir to ambient temperature and was then quenched with saturated aqueous ammonium chloride (lOOmL). The suspension formed was extracted with ethyl acetate (2xl00mL) and
30 the extracts dried (MgS04). Concentration gave a yellow oil which was purified by silica chromatography to give the title compound as an oil
(4.13g, 18.8mmol). δH (360 MHz, CDCls): 10.43 (IH, s), 7.69 (IH, d, J 3.1Hz), 7.40 (IH, dd, J
3.1 and 9.1Hz), 7.01 (IH, d, J 9.1Hz), 3.96 (3H, s). δ
DESCRIPTION 8
(lR*,2R*,5S*,6R*)-2-amino-8-benzyl-l-phenyl-6-phenylsιdphonyl-8- azabicyclo [3.2.1] octane
(lR*,2R*,δS*,6R*)-2-benzylamino-8-benzyl-l-phenyl-6-phenylsulphonyl-8- 10 azabicyclo [3.2.1] octane (Description 4; 8.34g, lβmmol) was dissolved in methanol (lδOmL) and acetic acid (lδOmL), then treated with 10% palladium on activated charcoal (2g). The suspension was then hydrogenated at δOpsi hydrogen for 16 hours, then filtered. The filtrate was concentrated in vacuo, and the oil remaining suspended in saturated lδ aqueous sodium hydrogen carbonate solution (2δ0mL). This was extracted with ethyl acetate (2x2δ0mL) and the extracts were dried (MgSθ4), then concentrated. Purification by silica chromatography yielded the title compound as a gum (3.37g, 7.8mmol). δH (360 MHz, De-DMSO): 7.73-7.67 (3H, m), 7.δ7-7.48 (δH, m), 7.39-7.3δ 20 (4H, m), 7.29-7.17 (3H, m), 4.36 (IH, d, J lδ.4Hz), 3.90 (IH, dd, J δ.4 and
9.2Hz), 3.69 (IH, d, J 15.4Hz), 3.55 (2H, s), 2.30-1.98 (4H, m), 1.61-1.57
(2H, m), 0.93-0.90 (IH, m).
MS (ES+) 433 (M+H).
25 DESCRIPTION 9
(lR*,2R*,5S*)-2-amino-8-benzyl-l-phenyl-8-azabicyclo[3.2.1]octane
Lithium (175mg, 2δmmol) was added to a solution of naphthalene ( 3.2g, 25mmol) in tetrahydrofuran (25mL), and the mixture sonicated for 2 hours. The green solution formed was then slowly added to a solution of 30 (lR*,2R*,5S*,6R*)-2-amino-8-benzyl-l-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octane (Description 8; 2.0g, 4.6mmol) in tetrahydrofuran (δOmL), already cooled to -78°C. The mixture was stirred at -78°C for 1 hour, then quenched with aqueous saturated ammonium chloride solution (δOmL). After warming to ambient temperature, the mixture was extracted with ethyl acetate (2xl00mL) and the extracts dried (MgSθ4). δ Concentration in vacuo yielded a solid, which was purified by silica chromatography to give the title compound as a gum (900mg, 3.1mmol). δH (360 MHz, CDCls): 7.4δ-7.43 (2H, m), 7.35-7.18 (8H, m), 3.98 (IH, d, J 15.1Hz), 3.27 (IH, t, J 2.8Hz), 3.00 (IH, d, J 15.1Hz), 2.52 (IH, d, J 3.6Hz), 2.33-2.14 (3H, m), 2.06-1.86 (3H, m), 1.74-1.60 (3H, m), 1.34-1.25 (IH, ). 10 MS (ES+) 293 (M+H).
DESCRIPTION 10 l-(2-Chloroethoxy)-2-iodo-4-(trifluoromethoxy)benzene
2-Iodo-4-(trifluoromethoxy)phenol (lOg, 33mmol), 2-chloroethyl-p- lδ toluenesulfonate (7.9g, 34mmol), N,N'-dimethylformamide (50mL) and potassium carbonate (9.1g, 66mmol) were stirred together at 50°C for 16 hours and then cooled. The suspension was diluted with water (lOOmL) and extracted with 60% diethyl ether/hexane (2xl00mL). The extracts were dried (MgSθ4) and concentrated to give the title compound as a solid 20 (12. lg, 33mmol). δH (360 MHz, CDCls): 6.43 (IH, d, J 2.6Hz), δ.96 (IH, dd, J 2.6 and 9.0Hz), 5.57 (IH, d, J 9.0Hz), 3.04 (2H, t, J 6.0Hz), 2.64 (2H, t, J 6.0Hz).
DESCRIPTION 11 25 l-(Vinyloxy)-2-iodo-4-(trifluoromethoxy)benzene
To l-(2-chloroethoxy)-2-iodo-4-(trifluoromethoxy)benzene (Description 10; 12. lg, 33mmol) in tetrahydrofuran (50mL) at — °C was slowly added potassium fertf-butoxide (3.7g, 33mmol). After addition was complete, the solution was allowed to stir to room temperature for 20 hours, and was 30 then quenched with water (lOOmL). The mixture was extracted with δ0% diethyl ether/hexane (2xl00mL) and the extracts dried (MgSθ4). Concentration gave an oil which was purified by silica chromatography to give the title compound as an oil (7.62g, 23mmol). δH (360 MHz, CDC13): 7.67 (IH, d, J 2.6Hz), 7.20 (IH, dd, J 2.6 and 8.8Hz), 6.96 (IH, d, J 8.8Hz), 6.δ4 (IH, dd, J 6.0 and 13.7Hz), 4.80 (IH, dd, J 2.1 δ and 13.7Hz), 4.δ6 (IH, dd, J 2.1 and 6.0Hz).
DESCRIPTION 12 l-(Cyclopropoxy)-2-iodo-4-(trifluoromethoxy)benzene l-(Vinyloxy)-2-iodo-4-(trifluoromethoxy)benzene (Description 11; 7.6g, 10 23mmol) and chloroiodomethane (δ.4mL, 74mmol) were dissolved in 1,2-dichloroethane (40mL) and cooled to 0°C. Diethyl zinc (3.8mL, 36.8mmol) was then added dropwise. The solution was allowed to warm to room temperature for 10 minutes, then cooled back to 0°C when it was quenched with saturated aqueous ammonium chloride solution (δOmL). lδ The suspension formed was extracted with δ0% diethyl ether/hexane (2xl00mL) and the extracts dried (MgSθ4). Concentration yielded a yellow oil which was purified by silica chromatography to give the title compound as a clear oil (δ.84g, 17mmol). δH (400 MHz, CDCls): 7.62 (IH, d, J 2.8Hz), 7.20 (IH, dd, J 2.8 and 9.0Hz), 20 6.96 (IH, d, J 9.0Hz), 3.81-3.77 (IH, m), 0.86-0.83 (4H, m).
DESCRIPTION 13 2-(Cyclopropoxy)-5-(trifluoromethoxy)benzaldehyde l-(Cyclopropoxy)-2-iodo-4-(trifluoromethoxy)benzene (Description 12;
2δ δ.84g, 17mmol) was dissolved in tetrahydrofuran (lδOmL) and cooled to
-78°C. Tert-bvήyl lithium solution (20mL, 1.7M in pentanes, 34 mmol) was then added dropwise. The solution was stirred at -78°C for 10 minutes, before N,N'-dimethylformamide (δ.3mL, 68mmol) was added, and the resulting solution allowed to stir to room temperature. Saturated aqueous
30 ammonium chloride solution (δOmL) was then added and the mixture extracted with diethyl ether (2xl00mL). The extracts were dried (MgS04) and concentrated to yield an oil. Purification of this by silica chromatography gave the title compound as a clear oil (3.94g, 16mmol). δH (360 MHz, CDCls): 10.34 (IH, s), 7.67-7.66 (IH, m), 7.42-7.37 (2H, ), 3.88-3.83 (IH, m), 0.90-0.87 (4H, m). δ
DESCRIPTION 14 1-Hydroxy-l- (2-methoxy-5- (triflouromethoxy) phenyl) ethane To 2-methoxy-δ-(trifluoromethoxy)benzaldehyde (l.Og, 4.5mmol) in tetrahydrofuran (lOmL) at 0°C was added a solution of methyl magnesium
10 bromide in tetrahydrofuran (1.6mL, 3M, 4.7mmol). The solution was then warmed to room temperature and quenched with saturated aqueous ammonium chloride solution (50mL). The suspension formed was extracted with ethyl acetate (2xl00mL) and the extracts were dried (MgSθ4). Concentration in vacuo yielded the title compound as an oil lδ (1.03g, 4.4mmol). δH (360 MHz, CDC13): 7.25 (IH, d, J 2.0Hz), 7.09 (IH, dd, J 2.0 and 8.9Hz), 6.84 (IH, d, J 8.9Hz), 5.10 (IH, dq, J 4.8 and 6.5Hz), 3.86 (3H, s), 2.41 (IH, d, J 4.8Hz), 1.48 (3H, d, J 6.5Hz).
20 DESCRIPTION 15
2-Methoxy-5-(triflouromethoxy)acetophenone l-Hydroxy-l-(2-methoxy-5-(triflouromethoxy)phenyl)ethane (Description 14; 1.03g, 4.4mmol) in dichloromethane (20mL) was treated with 1,1,1- triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (1.8δg, 4.4mmol) and 5 stirred at room temperature for 15 minutes. Aqueous sodium metabisulphite solution (lOmL) was added and the solution was stirred for 10 minutes. The organic layer was removed, washed with water, brine, then dried (MgSθ4). Concentration gave an oil which was purified by silica chromatography to yield the title compound as a waxy solid (840mg, 0 3.6mmol). δH (360 MHz, CDC13): 7.62 (IH, d, J 2.1Hz), 7.31 (IH, dd, J 2.1 and 9.0Hz), 6.97 (IH, d, J 9.0Hz), 3.93 (3H, s), 2.62 (3H, s).
DESCRIPTION 16 5 (lβ*,5S*,6JRS)-8-Benzyl-6-(ferf-butoxycarbonyl)-l-phenyl-8- azabicyclo[3.2.1]oct-3-en-2-one
A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (25δg, 0.74δmol), tert-hutyl acrylate (470ml), triethylamine (lδOml) and 1,4- dioxane (11) was heated at reflux for lδ hours and cooled to roo
10 temperature. The reaction mixture was poured onto saturated aqueous NaHCθ3 (11) and extracted into an 1:1 mixture of iso-hexane:diethyl ether (3xδ00ml). The combined organic extracts were dried (Na2Sθ4) and concentrated. The residue was purified by chromatography on silica gel (7δ0g, iso-hexane:diethyl ether 0-20%) to give a 2:1 mixture of lδ (lR*,δS*,6i2*)-8-benzyl-6-(fer^-butoxycarbonyl)-l-phenyl-8- azabicyclo[3.2.1]oct-3-en-2-one and (lR*,δS*,6»S,*)-8-benzyl-6-(fe^- butoxycarbonyl)-l-phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one (205g, 70%) as a yellow-orange foam. The isomers were separated on silica gel (iso- hexane: diethyl ether) and crystallised from iso-hexane:diethyl ether giving
20 yellow rhombs:
DESCRIPTION 16a: (lβ*,5S*,6i2*)-8-benzyl-6-(fer£- butoxycarbonyl)-l-phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one δH (360 MHz, CDCls): 7.83 (IH, dd, J 1.4Hz, 8.6Hz), 7.40-7.25 (8H, m),
6.91 (IH, dd, J 4.8Hz, 9.7Hz), 6.18 (IH, d, J 9.7Hz), 4.10 (IH, d, J 4.8Hz),
25 3.67 (IH, d, J 13.0Hz), 3.51 (IH, d, J 14.0Hz), 2.99 (IH, dd, J 2.6Hz,
14.2Hz), 2.84 (IH, dd, 2.6Hz, 9.0Hz), 2.39 (IH, dd, J 9.0Hz, 14.2Hz), 1.43 (9H, s). DESCRIPTION 16b: (LR*,5*S*,6S*)-8-benzyl-6-(fer£- butoxycarbonyl)-l-phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one δH (360 MHz, CDC13): 7.70 (IH, dd, J 1.3Hz, 8.7Hz), 7.40-7.2δ (8H, m), 6.88 (IH, dd, J 4.8Hz, 9.8Hz), 6.2δ (IH, d, J 9.8Hz), 4.02 (IH, dd, J δ.OHz, δ 6.0Hz), 3.6δ-3.δ0 (3H, m), 2.60 (2H, m), 1.43 (9H, s).
DESCRIPTION 17 (lJR*,5S*,6BS)-8-Benzyl-6-(ferf-butoxycarbonyl)-l-phenyl-8- azabicyclo [3.2.1 ]octan-2-one
10 A mixture of (lR*,δS*,6J?ιS)-8-benzyl-6-(terϊ-butoxycarbonyl)-l-phenyl-8- azabicylco[3.2.1]oct-3-en-2-one (Description 16; 26g, 66mmol), 10% palladium on charcoal (3.δg, 3.3mmol), ethyl acetate (δOml) and methanol (100ml) was stirred under hydrogen atmosphere (latm) at room temperature for 1 hour. The reaction mixture was treated with lδ dichloromethane (δOOml), filtered through a pad of Celite™. The filter cake was well washed with dichloromethane and the filtrate was concentrated to give the title compound as a solid (26g, 100%). The isomers were separated on silica gel (iso-hexane:ethyl acetate) and crystallised from acetone:tso-hexane yielding pure ketones as a colourless
20 crystals.
6B*-epimer: δH (360 MHz, CDCI3): 7.δ0 (2H, dm, J 7.2Hz), 7.41 (2H, d, J 7.3Hz), 7.33 (4H, m), 7.2δ (2H, m), 3.72 (IH, m), 3.70 (IH, d, J lδ.OHz), 3.44 (IH, d, J 14.6Hz), 2.91 (IH, dd, J 5.2Hz, 9.5Hz), 2.75-2.45 (5H, m), 1.97-1.87 (IH, m), 1.46 (9H, s).
2δ 6S*-epimer: δH (360 MHz, CDCI3): 7.δ0-7.20 (10H, m), 3.7δ (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).
30 3δ
DESCRIPTION 18 (lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-6-(ferf-butoxycarbonyl)- l-phenyl-8-azabicyclo[3.2.1]octane
(lR*,δS*,6R*)-8-Benzyl-6-(ter^-butoxycarbonyl)-l-phenyl-8- δ azabicyclo [3.2. l]octan-2-one (Description 17; δ.Og, 12.8mmol), p-toluenesulfonic acid monohydrate (2δmg) and benzylamine (2.1g, 20mmol) in toluene (δOmL) was heated at reflux under Dean Stark conditions for 24 hours, then cooled and the solvent removed in vacuo. The residue was dissolved in methanol (lOOmL) and sodium
10 cyanoborohydride (900mg, 14mmol) added. The solution formed was stirred at room temperature for 2 hours then concentrated to approximately XA volume. Water (δOOmL) was added and the suspension formed was extracted with ethyl acetate (2xδ00mL). The extracts were dried (MgSθ4) and concentrated, before the residue was purified by silica lδ chromatography to give the title compound (3.87g, 8mmol) as a gum. δH (360 MHz, CDCls): 7.46-7.41 (3H, m), 7.30-7.19 (12H, m), 4.31 (IH, d, J lδ.4Hz) 3.86 (IH, d, J 13.6Hz), 3.66-3.61 (3H, m), 3.08 (IH, d, J 3.1Hz), 2.73-2.70 (IH, m), 2.47-2.41 (IH, m), 2.30-2.18 (IH, m), 2.1δ-2.07(lH, m), 2.03-1.94UH, m), 1.88-1.76(1H, m), 1.41 (9H, s), 1.25-1.15 (IH, m).
20 MS (ES+) 483 (M+H).
DESCRIPTION 19 (lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-6-hydroxymethyl-l- phenyl-8-azabicyclo[3.2.1]octane
25 (lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-6-(terf-butoxycarbonyl)-l- phenyl-8-azabicyclo[3.2.1]octane (Description 18; 600mg, 1.2mmol) in dichloromethane (lOmL) was cooled to -δ°C and a solution of diisobutylaluminium hydride in dichloromethane (3mL, 1M, 3mmol) was added dropwise. The solution was allowed to stir to ambient temperature
30 over 2 hours, then dichloromethane (30mL) was added followed by saturated aqueous potassium sodium tartrate solution (δOmL). The biphasic system was stirred vigorously for 1 hour, then the organic layer removed and dried (MgSθ4). Concentration in vacuo gave a gum which was purified by silica chromatography to yield the title compound (2δ8mg, 0.63mmol). 5 δH (360 MHz, CDCls): 7.50-7.23 (15H, m), 4.48 (IH, d, J 14.1Hz), 3.94 (IH, d, J 13.6Hz), 3.77-3.δ0 (4H, m), 3.32 (IH, d, J 3.2Hz), 3.26 (IH, s), 2.48- 2.33 (IH, m), 2.16-1.72 (4H, m), 1.68-1.40 (2H, m), 1.11-1.07 (IH, m). MS (ES+) 413 (M+H).
0 DESCRIPTION 20
(lR*,2R*,5S*,6R*)-2-amino-6-hydroxymethyl-l-phenyl-8- azabicyclo[3.2.1]octane
(lR*,2R*,δS*,6R*)-2-Benzylamino-8-benzyl-6-hydroxymethyl-l-phenyl-8- azabicyclo[3.2.1]octane (Description 19; 220mg, 0.δ3mmol) was dissolved 5 in ethanol (5mL) and treated with 10% palladium on activated charcoal (lOOmg), followed by 1,4-cyclohexadiene (l.δmL). The suspension formed was heated at reflux for 24 hours, then cooled and filtered. The filtrate was concentrated in vacuo, and the oil remaining purified by silica chromatography to yield the title compound as a gum (92mg, 0.4mmol). 0 δH (360 MHz, CDCls): 7.38-7.12 (5H, m), 3.72 (IH, dd, J 3.9 and 9.9Hz),
3.δ6 (IH, s), 3.δ0 (IH, dd, 4.8 and 9.9Hz), 3.16 (IH, d, " 3.9Hz), 2.41 (IH, dd, J 9.0 and 13.1Hz), 2.28-1.88 (4H, m), 1.77 (IH, dd, J 3.9 and 13.1Hz), I.δ9-l.δ4 (IH, m), 1.43-1.38 (IH, m). MS (ES+) 233 (M+H). δ
DESCRIPTION 21 (lR*,2R*,5S*,6R*)-2-Dibenzylamino-8-benzyl-6-(hydroxycarbonyl)- l-phenyl-8-azabicyclo[3.2.1]octane (lR*,2R*,δS*,6R*)-2-Benzylamino-8-benzyl-6-(terέ-butoxycarbonyl)-l- 0 phenyl-8-azabicyclo[3.2.1]octane (Description 18; 1.8g, 3.7mmol) was dissolved in N,N'-dimethylformamide (20mL) and treated with potassium carbonate (966mg, 7mmol) and benzyl bromide (833μL, 7mmol). The suspension was stirred at ambient temperature for 16 hours, then poured into water (200mL). The mixture was extracted with ethyl acetate (2xl00mL) and the extracts were concentrated in vacuo, before being dissolved in 30% trifiuoroacetic acid/dichloromethane (δOmL). This solution was stirred for 2 hours, concentrated, and the residue was basified with saturated aqueous sodium hydrogen carbonate solution (lOOmL). The organics were extracted with dichloromethane (2xδ0mL) and the extracts were dried (MgSθ4). The solid remaining was then purified by silica chromatography to give the acid as a white foam (400mg, O.β mol). δH (360 MHz, CDC13): 7.37-7.02 (20H, m), 4.07 (IH, d, J 14.3Hz), 3.91 (IH, s), 3.42-3.40 (2H, m), 3.02-2.92 (2H, m), 2.82 (IH, d, J 14.6Hz), 2.43-2.10 (4H, m), 1.96-1.70 (4H, m). MS (ES+) 518 (M+H).
DESCRIPTION 22 (lR*,2R*,5S*,6R*)-2-Dibenzylamino-8-benzyl-6-(hydroxymethyl)-l- phenyl-8-azabicyclo [3.2.1] octane (lR*,2R*,δS*,6R*)-2-Dibenzylamino-8-benzyl-6-(hydroxycarbonyl)-l- phenyl-8-azabicyclo[3.2.1]octane (Description 21; 400mg, 0.78mmol) was dissolved in tetrahydrofuran (lOmL) and treated with lithium aluminium hydride solution (800μL, IM, 0.8mmol) in tetrahydrofuran. The resulting mixture was stirred for 16 hours, then a further portion of lithium aluminium hydride solution (200μL, IM, O.δmmol) in tetrahydrofuran was added. Stirred at 50°C for 1 hour, then cooled, and water (40μL) added, followed by 15% aqueous sodium hydroxide solution (40μL), then water (120μL). The suspension formed was filtered and the filtrate taken up in water (lOmL). This mixture was extracted with ethyl acetate (2xl0mL) and the extracts were dried (MgSθ4), before being concentrated in vacuo. The gum remaining was purified by silica chromatography to give the title compound (295mg, 0.59mmol) as a gum. δH (360 MHz, CDC13): 7.37-7.11 (18H, m), 6.89 (2H, br s), 4.20 (IH, d, J 14.7Hz), 3.83-3.71 (2H, m), 3.46-3.37 (3H, m), 3.03 (IH, d, J 14.7Hz), 2.40- δ 2.3δ (3H, m), 2.23-2.14 (3H, m), 1.82-1.78 (IH, m), 1.60.-l.δ0 (2H, m). MS (ES+) 603 (M+H).
DESCRIPTION 23 (lR*,2R*,5S*,6R*)-2-Dibenzylamino-8-benzyl-6-[l-(3- 10 hydroxy)propyloxymethyl]-l-phenyl-8-azabicyclo[3.2.1]octane
(lR*,2R*,6S*,6R*)-2-Dibenzylamino-8-benzyl-6-(hydroxymethyl)-l-phenyl- 8-azabicyclo [3.2.1] octane (Description 22; 295mg, O.δθmmol), 18-crown-6 (396mg, l.δmmol), and 3-(bromopropoxy)-ferέ-butyldimethylsilane (348μL, l.δmmol) in tetrahydrofuran (δmL) were treated with 60% sodium hydride lδ suspension in oil (60mg, l.δmmol) and stirred for 16 hours at room temperature. The mixture was poured into saturated aqueous ammonium chloride solution (δOmL) and then extracted with ethyl acetate (2x5 OmL). The extracts were dried (MgSθ4) and concentrated and the residue dissolved in tetrahydrofuran (lOmL). Tetra-n.-butylammonium fluoride
20 solution in tetrahydrofuran (3mL, IM, 3mmol) was then added and the solution stirred for 1 hour at ambient temperature. The solution was poured into water (50mL) and extracted with ethyl acetate (2xδ0mL). The extracts were dried (MgSθ4) and concentrated, and the residue purified by silica chromatography to yield the title compound (240mg, 0.43 mmol).
25 δH (360 MHz, CDCI3): 7.36-7.15 (10H, m), 7.12-7.10 (6H, m), 6.95-6.84 (4H, m), 4.20 (IH, d, J 14.7Hz), 3.78-3.70 (3H, m), 3.66-3.35 (8H, m), 3.02 (IH, d J 14.7Hz), 2.47-2.34 (3H, m), 2.26-2.10 (4H, m), 1.85-1.76 (4H, m). MS (ES+) 561 (M+H). DESCRIPTION 24 (lR*,2R*,5S*,6R*)-2-Amino-6-[l-(3-hydroxy)propyloxyπιethyl]-l- phenyl-8-azabicyclo[3.2.1]octane
(lR*,2R*,5S*,6R*)-2-Dibenzylamino-8-benzyl-6-[l-(3- δ hydroxy )propyloxymethyl]-l-phenyl-8-azabicyclo[3.2.1]octane (Description 23; 240mg, 0.43mmol) and 1,4-cyclohexadiene (812μL, 8.6mmol) were dissolved in ethanol (δmL) and treated with 10% palladium suspended on activated charcoal (lOOmg). The resulting suspension was heated at reflux for 16 hours, cooled then filtered. The filtrate was concentrated in vacuo 0 to give the title compound as a gum (71mg, 0.24mmol). δH (360 MHz, CDC13): 7.34-7.09 (5H, m), 3.79-3.68 (2H, m), 3.64-3.55 (2H, m), 3.52-3.41 (IH, m), 3.38-3.27 (IH, m), 2.50-2.38 (IH, m), 2.33-2.22 (IH, ), 2.20-1.75 (6H, ), 1.66-1.53 (IH, m), 1.51-1.34 (2H, m). MS (ES+) 291 (M+H). 5
DESCRIPTION 25 2-Bromo-l-chloro-4-(trifluoronιethoxy)benzene To anhydrous copper (II) chloride (6.3g, 47mmol) in acetonitrile (lOOmL) was added tert-butyl nitrite (6.85mL, δδmmol), followed dropwise by a 0 solution of 2-bromo-4-(trifluoromethoxy)aniline (lOg, 39mmol) in acetonitrile (15mL). The solution was stirred at ambient temperature for 1 hour then poured into hydrochloric acid (250mL, 2M). The suspension formed was extracted with diethyl ether (2x250mL) and the extracts were dried (MgS04). Concentration yielded the title compound as an oil (7.82g, 5 28mmol). δH (360 MHz, CDCI3): 7.51 (IH, d, J 3.2Hz), 7.48 (IH, d, J 8.8Hz), 7.15 (IH, dd, J 3.2 and 8.8Hz). DESCRIPTION 26 1 -Chlor o-2-vinyl-4- (trifluoromethoxy)benzene
2-Bromo-l-chloro-4-(trifluoromethoxy)benzene (Description 2δ; l.Og, 3.6mmol) and tri-n-butylvinyl tin (1.21g, 3.8mmol) were dissolved in δ toluene (20mL) and the solution was degassed for 4δ minutes with nitrogen. Tetrakis(triphenylphosphine) palladium (0) (lOOmg) was then added and the solution heated at reflux for 2 hours. Once cooled, the solution was concentrated and the residue was purified by silica chromatography to give the title compound (274mg, 1.2mmol). 0 δH (360 MHz, CDCls): 7.40-7.36 (2H, m), 7.09-7.01 (2H, m), 6.75 (IH, d, J 17.5Hz), δ.47 (IH, d, J 10.9Hz).
DESCRIPTION 27 2-Chloro-5-(trifluoromethoxy)benzaldehyde 5 l-Chloro-2-vinyl-4-(trifluoromethoxy)benzene (Description 26; 274mg,
1.2mmol) was dissolved in dichloromethane (15mL) and methanol (5mL) and the solution cooled to -78°C. Ozone was then bubbled through until the solution turned blue. Dimethyl sulfide (l L) was added and the solution allowed to stir to ambient temperature for 16 hours. 0 Concentration yielded an oil which was purified by silica chromatography to give the title compound (120mg, 0.53mmol). δH (360 MHz, CDCls): 10.44 (IH, s), 7.77 (IH, d, J 2.3Hz), 7.51 (IH, d, J 8.7Hz), 7.39 (IH, dd, J 2.3 and 8.7 Hz).
5 DESCRIPTION 28
(lR*,2R*,5S*,6R*)-2-Amino-6-(ferf-butoxycarbonyl)-l-phenyl-8- azabicyclo[3.2.1]octane
(lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-6- er^-butoxycarbonyl)-l- phenyl-8-azabicyclo[3.2.1]octane (Description 18; 7.07g, 14.7mmol) and 10% palladium on activated charcoal (2g) were taken up in methanol
(lOOmL) and acetic acid (lOOmL), and the mixture was hydrogenated at δOpsi hydrogen for 16 hours at room temperature. The suspension was filtered and the filtrate concentrated in vacuo. The residue was then suspended in saturated aqueous sodium hydrogen carbonate solution (200mL) and extracted with dichloromethane (2x400mL). The extracts 6 were dried (MgSθ4) and concentrated to give the title compound as a brown oil (4.4g, 14.6mmol). δH (360 MHz, CDCls): 7.32-7.22 (δH, m), 3.67 (IH, m), 2.84-2.82 (2H, m), 2.64 (IH, dd, J 8.5 and 12.0Hz), 2.05 (IH, dd, J 4.2 and 12.0Hz), 1.92-1.83 (2H, m), 1.69 (2H, br s), 1.66-1.62 (IH, ), 1.50-1.44 (IH, m), 1.40 (9H, s). 10 MS (ES+) 303 (M+H).
DESCRIPTION 29 (lR*,5S*,6R*)-8-Benzyl-6-cyano-l-phenyl-8-azabicyclo[3.2.1]oct-3- ene-2-one lδ N-benzyl-3-hydroxy-2-phenylpyridinium bromide (20g, 58.3mmol), acrylonitrile (60ml, 75δmmol) and triethylamine (20ml, 143mmol) were mixed and stirred at reflux for 20 hours in 1,4-dioxane (150ml). The mixture was partitioned between saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, dried (MgSθ4),
20 filtered and concentrated. The residue was chromatographed on silica gel eluting with 25, 35 and 45% diethyl ether/ϊso-hexanes to yield the title compound (4.4g, 24%). δH (400MHz, CDCls): 7.75-7.73 (2H,m), 7.48-7.28 (8H,m), 6.83 (IH, dd, J 4.8Hz, 9.7Hz), 6.24 (IH, d, J 9.7Hz), 4.12 (lH,m), 3.81 (IH, d, J 14.1Hz),
2δ 3.52 (IH, d, J 14.1Hz), 3.00 (IH, dd, J 3.5Hz, 8.3Hz), 2.80-2.69 (2H, m).
DESCRIPTION 30 (lR*,5S*,6R*)-8-Benzyl-6-cyano-l-phenyl-8-azabicyclo[3.2.1]octan-2- one
30 Palladium hydroxide (20%) (700mg) was added to a solution of
(lR*,δS*,6R*)-8-benzyl-6-cyano-l-phenyl-8-azabicyclo[3.2.1]oct-3-ene-2- one (Description 29; 7.1g, 22.6mmol) in methanol (100ml). The mixture was transferred to the Parr™ apparatus and hydrogenated at 45psi for 20 minutes. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The organic layer was separated, dried (MgS04), filtered and concentrated to yield the title compound (6.9g, 96%). δH (400MHz, CDC13): 7.75-7.73 (4H,m), 7.51-7.36 (4H,m), 7.32-7.28 (2H,m), 3.86 (lH,s), 3.83 (IH, d, J 14.4Hz), 3.51 (IH, d, J 14.4Hz), 3.03 (IH, dd, J 4.7Hz, 9.5Hz), 2.91 (IH, dd, J 9.δHz, 14.0Hz), 2.67-2.35 (4H,m), 1.92-1.85 (lH,m).
DESCRIPTION 31 (lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-l-phenyl-6-(2H-tetrazol- 5-yl)-8-azabicyclo[3.2.1]octane A mixture of (lR*,5S*,6R*)-8-benzyl-6-cyano-l-phenyl-8- azabicyclo[3.2.1]octan-2-one (Description 30; 2.3g, 7.3mmol), -toluenesulfonic acid monohydrate (5mg) and benzylamine (1.2g, llmmol) in toluene (lOmL) was heated at reflux under Dean Stark conditions for 24 hours, then cooled and the solvent removed in vacuo. The residue was dissolved in methanol (20mL) and sodium cyanoborohydride (510mg, 8mmol) added. The solution formed was stirred at room temperature for 1 hour then concentrated to approximately XA volume. Saturated aqueous sodium hydrogen carbonate solution (δOmL) was added and the suspension formed was extracted with dichloromethane (2x50mL). The extracts were dried (M Sθ4) and concentrated, before the residue was purified by silica chromatography to give the axial and equatorial amines as a mixture (1.47g, 3.6mmol). Part of this mixture (l.Og, 2.5mmol) was mixed with sodium azide (488mg, 7.5mmol) and triethylamine hydrochloride (1.03mmol) in N-methylpyrrolidinone (δmL) and heated at 150°C for 16 hours. After cooling the mixture was diluted with ethyl acetate (δOmL), washed with water (50mL) and dried (MgS04). Concentration gave a solid which was purified by silica chromatography to yield the title compound as a tan solid (723mg, l.βmmol). δH (360 MHz, CDCls): 7.46-7.13 (15H, m), 4.40 (IH, d, J 13.7Hz), 3.94 (IH, d, J 13.5Hz), 3.72 (IH, d, J 13.5Hz), 3.70 (IH, d, J 13.7Hz), 3.63 (IH, dd, J 5 3.9 and 9.3Hz), 3.47 (IH, s), 3.29 (IH, br s), 2.63 (IH, dd, J 9.3 and 13.7Hz), 2.47-2.41 (IH, m), 2.12-1.91 (3H, m), 1.38-1.34 (IH, m). MS (ES+) 451 (M+H).
DESCRIPTION 32 0 (lR*,2R*,5S*,6R*)-2-Amino-l-phenyl-6-(lJff-tetrazol-5-yl)-8- azabicyclo[3.2.1]octane
(lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-l-phenyl-6-(iH-tetrazol-5-yl)- 8-azabicyclo[3.2.1]octane (Description 31; 300mg, 0.67mmol) was dissolved in ethanol (lOmL) and treated with 1,4-cyclohexadiene (660μL, 7mmol) 5 and 10% palladium on activated charcoal (lOOmg). The resulting suspension was heated at reflux for 96 hours, cooled and filtered. The filtrate was concentrated in vacuo to give the title compound as a foam (166mg, 0.61mmol). δH (360 MHz, CD3OD): 7.47-7.29 (5H, m), 3.75-3.71 (2H, m), 3.45 (IH, d, J 0 3.4Hz), 3.09 (IH, dd, J 9.0 and 13.6Hz), 2.39-2.30 (IH, m), 2.13 (IH, dd, J 4.8 and 13.6Hz), 1.99-1.84 (2H, m), 1.77-1.69 (IH, m). MS (ES+) 271 (M+H).
DESCRIPTIONS 33a and 33b δ (a) (lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-l-phenyl-6-(l- methyl-liϊ-tetrazol-5-yl)-8-azabicyclo[3.2.1]octane; and (b) (lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-l-phenyl-6-(2- methyl-J?H-tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-l-phenyl-6-(iH-tetrazol-δ-yl)- 0 8-azabicyclo[3.2.1]octane (Description 31; 370mg, 0.82mmol) was dissolved in a mixture of toluene (5mL) and methanol (5mL), and treated with a solution of (trimethylsilyl)diazomethane in hexane (700μL, 2M, 1.4mmol). After stirring at room temperature for 15 minutes, the solution was concentrated in vacuo and the residue purified by silica chromatography, to give the two title compounds. Description 33a (57mg, 0.12mmol) (most polar): δH (400 MHz, CDC13): 7.53-7.52 (2H, m), 7.36-7.21 (13H, m), 4.37 (IH, d, J 15.0Hz), 3.92 (IH, d, J 13.5Hz), 3.86 (3H, s), 3.74-3.70 (2H, m), 3.47 (IH, br s), 3.37 (IH, dd, J 4.8 and 6.4Hz), 3.27 (IH, d, J 3.8Hz), 2.86-2.76 (IH, m), 2.54 (IH, dd, J 6.4 and 12.0Hz), 2.48-2.37 (IH, m), 2.14 (IH, dd, J 4.8 and 12.0Hz), 2.03-1.95 (IH, m), 1.29-1.24 (IH, m). MS (ES+) 465 (M+H).
Description 33b (357mg, 0.77mmol) (least polar): δH (400 MHz, CDCI3): 7.51-7.49 (2H, m), 7.32-7.13 (13H, m), 4.36 (IH, d, J 15.3Hz), 4.31 (3H, s), 3.92 (IH, d, J 13.6Hz), 3.71-3.65 (3H, m), 3.52 (IH, dd, J 6.2 and 8.2Hz), 3.22 (IH, d, J 2.8Hz), 2.57-2.56 (2H, m), 2.33-2.31 (IH, m), 2.09-1.98 (2H, m), 1.35-1.32 (IH, m). MS (ES+) 465 (M+H).
DESCRIPTION 34 (lR*,2R*,5S*,6R*)-2-Amino-l-phenyl-6-(l-methyl-lH-tetrazol-5-yl)-8- azabicyclo[3.2.1]octane
(lR*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-l-phenyl-6-(l-methyl-iH- tetrazol-δ-yl)-8-azabicyclo[3.2.1]oetane (Description 33a; δ7mg, 0.12mmol) was dissolved in ethanol (5mL) and treated with 1,4-cyclohexadiene (δmL), followed by 10% palladium on activated charcoal (50mg). The suspension formed was heated at reflux for 72 hours, then cooled and filtered. The filtrate was concentrated, and the residue taken up in ethyl acetate (2mL) and treated with ethereal hydrogen chloride (2mL, IM). The solid formed was removed by filtration, washed with diethyl ether and dried to give the crude title compound as a solid (27mg). MS (ES+) 285 (M+H). DESCRIPTION 35 (lR*,2R*,5S*,6R*)-2-Amino-l-phenyl-6-(2- ethyl-2H-tetrazol-5-yl)-8- azabicyclo[3.2.1]octane δ (lR*,2R*,5S*,6R*)-2-Benzylanιino-8-benzyl-l-phenyl-6 (2-methyl-2H- tetrazol-δ-yl)-8-azabicyclo [3.2.1] octane (Description 33b; 3δ7mg, 0.77mmol) was dissolved in ethanol (lOmL) and treated with 1,4-cyclohexadiene (5mL), followed by 10% palladium on activated charcoal (300mg). The suspension formed was heated at reflux for 72 0 hours, then cooled and filtered. The filtrate was concentrate to give the title compound as a gum (239mg, 0.67mmol). δH (400 MHz, CD3OD): 7.57-7.47 (δH, m), 4.29 (3H, s), 4.07-4.00 (IH, m), 3.92-3.87 (IH, m), 3.64-3.40 (IH, m), 2.82-2.70 (IH, m), 2.68-2.51 (2H, m), 2.22-1.98 (3H,m). 5 MS (ES+) 285 (M+H).
DESCRIPTIONS 36a, 36b and 36c (a) (lR*,3S*,5S*,6R*)-8-Benzyl-3-fluoro-l-phenyl-6-(*er*- butoxycarbonyl)-8-azabieyclo[3.2.1]octan-2-one; 0 (b) (lR*,3R*,5S*,6R*)-8-Benzyl-3-fluoro-l-phenyl-6-(fer£- butoxycarbonyl)-8-azabicyclo[3.2.1]octan-2-one; and (c) (lR*,5S*,6R*)-8-Benzyl-3,3-difluoro-l-phenyl-6-(fer£- butoxycarbonyl)-8-azabicyclo[3.2.1]octan-2-one To a solution of lithium hexamethyldisilazide in tetrahydrofuran (18mL, 5 IM, 18mmol) was added tetrahydrofuran (lOOmL), and the mixture cooled to -78°C. A solution of (lR*,5S*,6R*)-8-benzyl-l-phenyl-6-(te7 - butoxycarbonyl)-8-azabicyclo[3.2.1]octan-2-one (Description 17; 5.0g, 12.8mmol) was then slowly added. The temperature was allowed to warm to — 50°C, then was immediately stirred back to — 78°C for 30 minutes. 0 N-Fluorobenzenesulfonimide (5.7g, 18mmol) dissolved in tetrahydrofuran (50mL) was then added, and the solution was allowed to stir to -30°C for 30 minutes. Saturated aqueous ammonium chloride solution (lOOmL) was added, and the mixture was extracted with ethyl acetate (2x200mL). After drying (MgSθ4), the extracts were concentrated and the residue purified by silica chromatography to give the three products: Description 36a (1.62g, 4.0mmol) (most polar): δH (400 MHz, CDC13): 7.52-7.49 (2H, m), 7.42-7.25 (8H, m), 5.36 (IH, dt, J 9.1 and 49.7Hz), 3.82 (IH, d, J 14.6Hz), 3.83-3.78 (IH, m), 3.31 (IH, d, J 14.6Hz), 2.91 (IH, dd, 3.9 and 9.4Hz), 2.73-2.63 (3H, m), 2.50 (IH, dd, J 9.4 and 14.9Hz), 1.45 (9H,s). MS (ES+) 410 (M+H).
Description 36b (1.67g, 4.1mmol): δH (400 MHz, CDCls): 7.46-7.23 (10, m), 5.68 (IH, ddd, J 6.0, 10.8 and 50.7Hz), 3.77-3.72 (IH, m), 3.46 (IH, d, J 13.7Hz), 3.26 (IH, d, J 13.7Hz), 3.06-2.96 (IH, m), 2.83-2.72 (3H, m), 1.71-1.60 (IH, m), 1.46 (9H, s). MS (ES+) 410 (M+H).
Description 36c (1.76g, 4.1mmol) (least polar): δH (400 MHz, CDCI3): 7.62-7.50 (2H, m), 7.29-7.40 (8H, m), 3.83 (IH, t, J 4.3Hz), 3.76 (IH, d, J 14.9Hz), 3.35 (IH, d, J 14.9Hz), 3.08 (IH, dd, J 5.1 and 9.4Hz), 2.93-2.70 (3H, m), 2.62-2.50 (IH, m), 1.45 (9 H, s). MS (ES+) 428 (M+H).
DESCRIPTION 37 (lR*,2R*,3S*,5S*,6R*)-2-Benzylamino-8-benzyl-3-fluoro-l-phenyl-6- (£er£-butoxycarbonyl)-8-azabicyclo[3.2.1]octane (lR*,3S*,5S*,6R*)-8-Benzyl-3-fluoro-l-phenyl-6-(ferf-butoxycarbonyl)-8- azabicyclo[3.2.1]octan-2-one (Description 36a; 1.68g, 4.1mmol), titanium iso-propoxide (1.8mL, 6.2mmol) and benzylamine (520μL, 4.7mmol) were heated together at 85°C for two hours, then cooled and diluted with methanol (30mL). The solution was then heated to 50°C and sodium borohydride (1.06g, 28mmol) was added portionwise over 4 hours. After addition was complete, the solution was heated for a further 16 hours, then cooled and poured into aqueous sodium hydroxide solution (lOOmL, IM). The suspension formed was extracted with ethyl acetate (2xl00mL) and the extracts were dried (MgSθ4). Concentration in vacuo gave a gum which was purified by silica chromatography to give the title compound (651mg, 1.3mmol). δH (360 MHz, CDCls): 7.50-7.48 (2H, m), 7.39-7.18 (13H, m), 5.05 (IH, dm, J 47.3Hz), 4.13 (IH, d, J 15.1Hz), 4.04 (IH, d, J 13.3Hz), 3.74-3.72 (3H, m), 3.62 (IH, d, J 15.1Hz), 2.61 (IH, dd, J 4.6 and 9.1Hz), 2.48-2.36 (2H, m), 2.02 (IH, dd, J 9.1 and 13.7Hz), 1.87-1.82 (IH, m), 1.39 (9H,s). MS (ES+) 501 (M+H).
DESCRIPTION 38 (lR*,2R*,3S*,5S*,6R*)-2-Benzylamino-8-benzyl-3-fluoro-l-phenyl-6- (hydroxymethyl)-8-azabicyclo[3.2.1]octane (lR*,2R*,3S*,5S*,6R*)-2-Benzylamino-8-benzyl-3-fluoro-l-phenyl-6-(tert- butoxycarbonyl)-8-azabicyclo[3.2.1]octane (Description 36b; 651mg, 1.3mmol) was dissolved in tetrahydrofuran (lOmL) and then treated with a solution of lithium triethylborohydride in tetrahydrofuran (4mL, IM, 4mmol). The solution was stirred at room temperature for 1 hour, then poured into aqueous sodium hydroxide solution (50mL, IM). The suspension formed was extracted with ethyl acetate (2xl00mL) and the extracts were dried (MgSθ4). Concentration in vacuo gave a gum which was purified by silica chromatography to give the title compound (476mg, l.lmmol). δH (400 MHz, CDCls): 7.51-7.49 (2H, m), 7.41-7.20 (13H, m), 5.15 (IH, dm, J 47.3Hz), 4.22 (IH, d, J 14.1Hz), 4.13 (IH, d, J 12.9Hz), 3.93 (IH, t, J 4.3Hz), 3.81-3.77 (2H, m), 3.57-3.49 (IH, ), 3.37-3.34 (IH, m), 2.55 (IH, dq, 2.7 and 12.1Hz), 2.08-1.98 (2H, m), 1.78-1.72 (IH, m), 1.60-1.56 (IH, m). MS (ES+) 431 (M+H). DESCRIPTION 39 (lR*,2R*,3S*,5S*,6R*)-2-Amino-3-fluoro-l-phenyl-6- (hydroxymethyl)-8-azabicyclo[3.2.1]octane
(lR*,2R*,3S*,5S*,6R*)-2-Benzylamino-8-benzyl-3-fluoro-l-phenyl-6- 5 (hydroxymethyl)-8-azabicyclo [3.2.1] octane (Description 38; 486mg,
1.13mmol) was dissolved in ethanol (20mL) and 1,4-cyclohexadiene (2mL). 10% Palladium on activated charcoal (500mg) was added and the suspension was heated at reflux for 24 hours. After cooling and filtration, the filtrate was concentrated in vacuo to give the title compound as a gum 0 (2δ7mg, l.Ommol). δH (360 MHz, CD3OD): 7.36-7.24 (5H, m), 5.05 (IH, dm, J 47.1Hz), 3.55- 3.48 (IH, m), 3.40 (IH, d, J 6.8Hz), 2.48 (IH, dd, J 8.7 and 13.7Hz), 2.21- 2.13 (IH, m), 2.01-1.87 (2H, m), 1.40 (IH, dd, 4.5 and 13.7Hz). MS (ES+) 251 (M+H). 5
EXAMPLE 1 (lR*,2R*,5S*)-2-(3,5-bis(trifluoromethyl)benzylamino)-l-phenyl-8- azabicyclo [3.2.1] octane dihydr ochloride (lR*,2R*,5S*)-2-Amino-l-phenyl-8-azabicyclo[3.2.1]octane (Description 6; 0 97mg, 0.48mmol) and 3,5-bis(trifluoromethyl)benzaldehyde (121mg,
O.δmmol) were dissolved in 1,2-dichloroethane (lOmL) and treated with acetic acid (30μL). The solution was stirred at room temperature for 16 hours then concentrated. The residue was taken up in methanol (lOmL) and treated with sodium cyanoborohydride (60mg), then heated at 80°C δ for 2 hours, concentrated in vacuo and the residue suspended in saturated sodium bicarbonate solution (lOmL). This was extracted with dichloromethane (2xl0mL) and the extracts dried (MgSθ4), then concentrated. The residue was taken up in ethyl acetate (lOmL) and treated with ethereal hydrogen chloride (IM, 2mL). The suspension 0 formed was concentrated in vacuo and the solid remaining recrystallized from methanol/diethyl ether, to give the title compound as a white solid (167mg, 0.33mmol). δH (360 MHz, Dβ-DMSO, 340K): 7.88 (IH, s), 7.78 (2H, s), 7.43-7.39 (δH, m), 4.11 (IH, br d, J 6.7Hz), 3.70 (IH, d, J 14.3Hz), 3.28-3.24 (2H, m), δ 2.78-2.67 (IH, m), 2.30-1.91 (6H, m), 1.63 (IH, br d, J 13.1Hz). MS (ES+) 429 (M+H).
EXAMPLE 2 (lR*,2R*,5S*)-2-(2-Methoxy-5-(trifluoromethoxy)benzylamino)-l- 0 phenyl-8-azabicyclo[3.2.1]octane dihydrochloride
Prepared according to the method of Example 1 from the product of Description 6 and 2-methoxy-δ-(trifluoromethoxy)benzylaldehyde. δH (360 MHz, De-DMSO, 340K): 7.48-7.39 (5H, m), 7.23-7.21 (2H, m), 6.97- 6.94 (IH, m), 4.14-4.12 (IH, m), 3.69 (IH, d, J 14.1Hz), 3.60 (3H, s), 3.42- 5 3.34 (2H, m), 2.79-2.71 (IH, m), 2.29-1.92 (6H, m), 1.66-1.62 (IH, m). MS (ES+) 407 (M+H).
EXAMPLE 3 (lR*,2R*,5S*)-2-(2-Cyclopropyloxy-5-[5-(trifluoromethyl)tetrazol-l- 0 yl]benzylamino)-l-phenyl-8-azabicyclo[3.2.1]octane
(lR*,2R*,5S*)-2-Amino-l-phenyl-8-azabicyclo [3.2.1] octane (Description 6; 50mg, 0.2δmmol) and 2-(cyclopropoxy)-5-[5-(trifluoromethyl)tetrazol-l- yljbenzaldehyde (119mg, 0.4mmol) [See International (PCT) Patent Publication No. WO 99/24423, published 20 May 1999] were dissolved in 5 1,2-dichloroethane (5mL) and treated with acetic acid (23μL), followed by sodium triacetoxyborohydride (8δmg). The solution was stirred at ambient temperature for 16 hours, then quenched with saturated aqueous sodium hydrogen carbonate solution (50mL). The mixture was extracted with dichloromethane (2xδ0mL) and the extracts were dried (MgS04), 0 then concentrated. The residue was purified by silica chromatography to give the free base, which was taken up in ethyl acetate (lOmL) and treated with ethereal hydrogen chloride (IM, 2mL). The solid formed was removed by filtration and recrystallized from methanol/ethyl acetate to give the title compound as a white solid (84mg, O.lδmmol). δH (360 MHz, CD3OD): 7.67-7.64 (IH, m), 7.57-7.60 (7H, m), 4.35-4.33 (IH, 5 m), 4.1δ (IH, br d, J 13.4Hz), 3.88-3.86 (2H, m), 3.6δ (IH, br d, J 13.4Hz), 2.96-2.87 (IH, m), 2.61-2.54 (IH, m), 2.42-2.13 (5H, m), 1.90-1.86 (IH, m), 0.88-0.82 (4H, m), 0.77-0.69 (IH, m). MS (ES+) 485 (M+H).
10 EXAMPLE 4
(lR*,2R*,5S*)-2-(2-Methoxy-5-(trifluoromethoxy)benzylamino)-8- benzyl-l-phenyl-8-azabicyclo[3.2.1]octane dihydrochloride
(lR*,2R*,δS*)-2-amino-8-benzyl-l-phenyl-8-azabicyclo[3.2.1]octane (Description 9; lδβmg, 0.53mmol) and 2-methoxy-δ- lδ (trifluoromethoxy)benzaldehyde (132mg, O.βmmol) were dissolved in
1,2-dichloroethane (lOmL) and acetic acid (35μL), and treated with sodium triacetoxyborohydride (127mg, O.βmmol). The suspension formed was stirred at ambient temperature for 16 hours, then quenched with saturated aqueous sodium hydrogen carbonate solution (50mL). The
20 mixture was extracted with dichloromethane (2x5 OmL) and the extracts were dried (MgSθ4), then concentrated. Purification of the residue gave the desired free base which was taken up in ethyl acetate (lOmL) and treated with ethereal hydrogen chloride (IM, 2mL). The solid formed was recovered by filtration and recrystallized from methanol/diethyl ether to
25 give the title compound as a white solid (178mg, 0.3mmol). δH (360 MHz, CD3OD, 330K): 7.81(2H, br s), 7.69-7.58 (5H, m), 7.46-7.44 (3H, m), 7.30 (IH, br d, J 9.0Hz), 7.24 (IH, br s), 7.01 (IH, d, J 9.0Hz), 4.28 (IH, br d, J 13.δHz), 3.92-3.88 (2H, m), 3.63-3.61 (IH, m), 3.61 (3H, s), 3.47-3.46 (IH, m), 2.96-2.86 (2H, m), 2.66-2.12 (6H, m), 1.83-1.79 (IH, 0 m).
MS (ES+) 497 (M+H). EXAMPLE 5 (lR*,2R*,5S*)-2-(2-Cyclopropoxy-5-(trifluoromethoxy)- benzylamino)-l-phenyl-8-azabicyclo[3.2.1]octane dihydrochloride
5 (lR*,2R*,5S*)-2-Amino-l-phenyl-8-azabicyclo[3.2.1]octane (Description 6; 116mg, 0.57mmol) and 2-(cyclopropoxy)-5-(trifluoromethoxy)benzaldehyde (Description 13; lOOmg, 0.41mmol) were dissolved in 1,2-dichloroethane (5mL) and acetic acid (lmL), then treated with sodium triacetoxyborohydride (318mg, l.δmmol). The suspension formed was
10 stirred at room temperature for 4 hours, then quenched with saturated aqueous sodium hydrogen carbonate solution (2δmL). The suspension formed was extracted with dichloromethane (2x25mL) and the extracts dried (MgSθ4), then concentrated. Purification of the residue by silica chromatography yielded the free base as a gum. This was taken up in lδ ethyl acetate (lOmL) and treated with ethereal hydrogen chloride (IM,
2mL). The solid formed was recovered by filtration and washed with ethyl acetate. Drying in vacuo yielded the title compound as a white powder (130mg, 0.26mmol). δH (360 MHz, CD3OD): 7.58-7.49 (5H, m), 7.36-7.29 (2H, m), 7.23 (IH, s),
20 4.36-4.34 (IH, m), 4.12 (IH, br d, J 13.3Hz), 3.83 (IH, br s), 3.77-3.71 (IH, m), 3.69 (IH, br d, J 13.3Hz), 2.96-2.87 (IH, m), 2.66-2.57 (IH, m), 2.49- 2.12 (5H, m), 1.92-1.86 (IH, m), 0.82-0.76 (3H, m), 0.65-0.60 (IH, m). MS (ES+) 433 (M+H).
25 EXAMPLE 6
(lR*,2R*,5S*,6R*)-2-(2-Methoxy-5-(tri luoromethoxy)benzylamino)- l-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane dihydrochloride
( IR* , 2R*, 5 S*, 6R*)-2-amino- 1 -phenyl-6-phenylsulphonyl- 0 8-azabicyclo [3.2.1] octane (Description 6; 90mg, 0.26mmol) and 2-methoxy- δ-(trifluoromethoxy)benzaldehyde (116mg, 0.54 mmol) were dissolved in 1,2-dichloromethane (5mL) and acetic acid (35 μL), and treated with sodium triacetoxyborohydride (165mg, 0.78 mmol). The suspension was stirred at room temperature for 16 hours, then at 60°C for 2 hours. After cooling the mixture was poured into saturated aqueous sodium hydrogen 5 carbonate solution (20mL) and extracted with dichloromethane (2x25mL). The extracts were dried (MgSθ4) and concentrated. Purification of the residue by silica chromatography yielded the free base as a gum. This was taken up in ethyl acetate (lOmL) and treated with ethereal hydrogen chloride (IM, 2mL). The solid formed was recovered by filtration and
10 recrystallized form methanol/diethyl ether to yield the title compound as a white powder (109mg, O.lδmmol). δH (360 MHz, CD3OD): 7.90-7.88 (2H, m), 7.77-7.72 (IH, m), 7.65-7.61 (2H, m), 7.47-7.45 (3H, m), 7.35-7.29 (3H, m), 7.15 (IH, br s), 7.00-7.98 (IH, m), 4.11-4.12 (IH, m), 4.06-4.01 (2H, m), 3.83-3.79 (IH, m), 3.58 (3H, s), 3.37- lδ 3.38 (IH, m), 2.88-2.82 (IH, m), 2.14-1.96 (4H, m), 1.56-1.53 (IH, m). MS (ES+) 547 (M+H).
EXAMPLE 7
(1R*,2R*,5S*,9S*)- and (lR*,2R*,5S*,9R*)-2-[l-(2-Methoxy-5- 20 (trifluoromethoxy)phenyl)ethylamino]-l-phenyl-8- azabicyclo[3.2.1]octane dihydrochlorides
(lR*,2R*,5S*,6R*)-2-Amino-l-phenyl-8-azabicyclo[3.2.1]octane (Description 6; 78mg, 0.39mmol) and 2-methoxy-5- (triflouromethoxy)acetophenone (116mg, 0.54 m ol) were dissolved in
2δ 1,2-dichloromethane (δmL) and acetic acid (35μL), and treated with sodium triacetoxyborohydride (170mg, 0.8mmol). The suspension was stirred at room temperature for 16 hours, then at 100°C for 4 hours. After cooling the mixture was poured into saturated aqueous sodium hydrogen carbonate solution (20mL) and extracted with dichloromethane (2x25mL).
30 The extracts were dried (MgS04) and concentrated. Purification of the residue by silica chromatography yielded the free bases as a gum. The 63
diastereomers were then separated by chiral preparative HPLC. Each of the free bases were then taken up in ethyl acetate (lOmL) and treated with ethereal hydrogen chloride (IM, 2mL). The solid formed was recovered by filtration and washed with ethyl acetate to yield the two dihydrochloride salts (16mg and 4mg). Diastereomer A (Most polar): δH (360 MHz, CDsOD): 7.57-7.46 (5H, m), 7.24 (IH, br d, J 8.9Hz), 7.04 (lh, d, J 8.9Hz), 6.76 (IH, br s), 4.27-4.29 (IH, m), 3.78 (3H, s), 3.49-3.40 (2H, m), 2.87-2.80 (IH, m), 2.44-2.24 (3H, m), 2.16-1.81 (4H, ), 1.29-1.21 (3H, m).
MS (ES+) 421 (M+H).
Diastereomer B (Least Polar): δH (400 MHz, CDsOD): 7.55-7.52 (3H, ), 7.30-7.28 (2H, m), 7.15 (IH, br d,
J 8.9Hz), 6.91-6.88 (2H, m), 4.19-4.15 (IH, m), 3.38 (3H, s), 2.79-2.76, (IH, m), 2.37-1.94 (5H, m), 1.73-1.69 (IH, m), 1.33-1.26 (3H, m). MS (ES+) 421 (M+H).
EXAMPLE 8 (lR*,2R*,5S*,6R*)-2-(2-Cyclopropoxy-5-(trifluoromethoxy)- benzylamino)-6-(hydroxymethyl)-l-phenyl-8- azabicyclo[3.2.1]octane dihydrochloride
Prepared according to the method of Example 5 from the product of Description 20 and Description 13. δH (360 MHz, CD3OD): 7.56-7.48 (5H, m), 7.33-7.26 (2H, m), 7.19-7.18 (IH, m), 4.23-4.21 (IH, m), 4.06-4.01 (IH, m), 3.70-3.60 (4H, m), 3.50 (IH, dd, J 6.4 and 10.5Hz), 3.04 (IH, dd, J 9.6 and 14.4Hz), 2.65-2.65 (2H, m), 2.37- 2.31 (2H, m), 2.01-1.87 (2H, m), 0.80-0.55 (4H, m). MS (ES+) 464 (M+2H). EXAMPLE 9 (lR*,2R*,5S*)-2-(2-Chloro-5-(trifluoromethoxy)benzylamino)-l- phenyl-8-azabicyclo[3.2.1]octane dihydrochloride
(lR*,2R*,5S*)-2-Amino-l-phenyl-8-azabicyclo[3.2.1]octane (Description 6; 5 77mg, 0.38mmol) and 2-chloro-5-(trifluoromethoxy)benzaldehyde
(Description 27; 120mg, 0.53mmol) were dissolved in 1,2-dichloroethane (δmL) and acetic acid (lmL), then treated with sodium triacetoxyborohydride (128mg, O.βmmol). The suspension was stirred at room temperature for 16 hours, then diluted with methanol (5mL).
10 Sodium cyanoborohydride was added (200mg, 0.9mmol) and this solution stirred for a further 16 hours at ambient temperature. The resulting mixture was poured into saturated aqueous sodium hydrogen carbonate solution (δOmL) and extracted with dichloromethane (2x50mL). The extracts were dried (MgS04) and concentrated to yield a gum, which was lδ purified by silica chromatography. The pure free base was dissolved in ethyl acetate (lOmL) and treated with ethereal hydrogen chloride (2mL, IM). The solid formed was removed by filtration, washed with diethyl ether and dried to give the title compound as a solid (46mg, O.lmmol). δH (360 MHz, CDsOD): 7.63-7.40 (7H, m), 7.27-7.25 (IH, m), 4.30 (IH, d, J
20 6.7Hz), 3.96 (IH, d, J 14.0Hz), 3.65 (IH, br s), 3.48 (IH, d, J 14.0Hz), 2.92- 2.84 (IH, m), 2.48-2.11 (6H, m), 1.85-1.80 (IH, m). MS (ES+) 412 (M+H).
EXAMPLE 10 25 (lR*,2R*,5S*,6R*)-2-(2-Cycloproρoxy-5-(trifluoromethoxy)- benzylamino) -6- [1- (3-hydroxy)propyloxymethyl] - 1 -phenyl-8- azabicyclo[3.2.1]octane dihydrochloride
Prepared according to the method of Example 6 from the product of Description 24 and 2-cyclopropoxy-5-(trifluoromethoxy)benzaldehyde. 30 δH (360 MHz, CDC13): 7.65-7.50 (2H, m), 7.48-7.39 (3H, m), 7.29-7.26 (IH, m), 7.15-7.06 (2H, m), 4.41 (IH, br s), 4.24-4.20 (IH, m), 4.01 (IH, d, J δδ
13.1Hz), 3.89-3.62 (7H, m), 3.17-3.14 (IH, m), 2.83-2.38 (δH, ), 2.12-2.07 (IH, m), 2.01-1.96 (IH, m), 1.73-1.64 (2H, m), 0.71 (4H, d, δ.3Hz). MS (ES+) 521 (M+H).
5 EXAMPLE 11
(lR*,2R*,5S*,6R*)-2-(2-Cyclopropoxy-5-(trifluoromethoxy)- benzylamino)-6-(fer£-butoxycarbonyl)-l-phenyl-8- azabicyclo[3.2.1]octane
Prepared according to the method of Example 1 from the product of 10 Description 28 and 2-cyclopropoxy-δ-(trifluoromethoxy)benzaldehyde. δH (360 MHz, CDCls): 7.26-7.20 (5H, m), 6.99-6.97 (2H, m), 6.73 (IH, br s), 3.72 (IH, m), 3.52 (IH, d, J 14.8Hz), 3.43 (IH, m), 3.30 (IH, d, J 14.8Hz), 2.79 (IH, dd, J 4.6 and 9.2Hz), 2.59 (IH, d, J 2.9Hz), 2.41 (IH, dd, J 9.2 and 13.3Hz), 1.96 (IH, dd, 4.6Hz and 13.3Hz), 1.86-1.78 (IH, m), 1.70- lδ 1.65 (3H, m), 1.39 (9H, s), 0.66-0.64 (2H, m), 0.53-0.51 (2H, m). MS (ES+) 533 (M+H).
EXAMPLE 12 (lR*,2R*,5S*,6R*)-2-(2-Cyclopropoxy-5-(trifluoromethoxy)- 20 benzylamino) -6- (N-methoxy-N-methylcarboxamido) - 1 -phenyl-8- azabicyclo[3.2.1 ] octane
(lR*,2R*,5S*,6R*)-2-(2-Cyclopropoxy-5-(trifluoromethoxy)benzylamino)-6- (ter -butoxycarbonyι)-l-phenyl-8-azabieyclo [3.2.1] octane (Example 11; 294mg, O.δδmmol) was taken up in 30% trifluoroacetic acid in
26 dichloromethane (lOmL) and stirred at room temperature for 4 hours.
After concentration in vacuo, the residue was dissolved in dichloromethane (lδmL), and treated with triethylamine (612μL, 4.4mmol), N,0- dimethylhydroxylamine hydrochloride (107mg, l.lmmol), N,N- dimethylaminopyridine (lOmg) and l-(3-dimethylaminopropyl)-3-
30 ethylcarbodiimide hydrochloride (llδmg, O.θmmol). The solution formed was stirred at room temperature for 4 hours, then poured into water (50mL). Extraction with dichloromethane (2xδ0mL) and concentration of the dried (MgSθ ) extracts gave the crude product as a gum. Purification by silica chromatography yielded the title compound (160mg, 0.31mmol). δH (360 MHz, CDCls): 7.26-7.17 (5H, m), 7.00-6.97 (2H, m), 6.74 (IH, br s), 3.70 (3H, s), 3.53 (IH, d, J 14.8Hz), 3.45-3.28 (3H, m), 3.14 (3H, s), 2.63 (IH, m), 2.43-2.35 (2H, m), 2.08-1.97 (3H, m), 1.88-1.84 (IH, m), 1.44-1.41 (IH, m), 0.67-0.63 (2H, m), 0.54-0.51 (2H, m). MS (ES+) 520 (M+H).
EXAMPLE 13
(lR*,2R*,5S*,6R*)-2-(2-Cyclopropoxy-5-(trifluoromethoxy)- benzylamino)-6-acetyl-l-phenyl-8-azabicyclo[3.2.1]octane
(lR*,2R*,5S*,6R*)-2-(2-Cyclopropoxy-5-(trifluoromethoxy)benzylamino)-6- (N-methoxy-N-methylcarboxamido)-l-phenyl-8-azabicyclo[3.2.1]octane (Example 12; 490mg, 0.95mmol) was dissolved in tetrahydrofuran (lOmL) and cooled to 0°C. A solution of methylmagnesium chloride in tetrahydrofuran (lmL, 3M, 3mmol) was then added and the solution was stirred at 0°C for 1 hour and then allowed to stir to room temperature over 2 hours. The solution was poured into saturated aqueous ammonium chloride solution (20mL), extracted with ethyl acetate (2x20mL) and the extracts were dried (MgS04). Concentration in vacuo gave an oil which was purified by silica chromatography to give the title compound as a tan oil (356mg, 0.75mmol). δH (400 MHz, CDCls): 7.28-7.19 (5H, m), 7.01-6.98 (2H, m), 6.76 (IH, br s), 3.70 (IH, t, J 2.6Hz), 3.54 (IH, d, J 14.7Hz), 3.43 (IH, m), 3.33 (IH, d, J
14.7Hz), 3.00 (IH, dd, J 4.8 and 9.0Hz), 2.63 (IH, d, J 2.6Hz), 2.28 (IH, dd, J 9.0 and 13.2Hz), 2.18 (3H, s), 2.04-1.94 (2H, m), 1.90-1.84 (IH, m), 1.73- 1.71 (IH, m), 1.45-1.42 (IH, m), 0.67-0.63 (2H, m), 0.52-0.48 (2H, m). MS (ES+) 475 (M+H). EXAMPLE 14 (lR*,2R*,5S*,6R*,R*) and (lR*,2R*,5S*,6R*,S*)-2-(2-Cyclopropoxy-5- (trifluoromethoxy)benzylamino)-6-(l-hydroxy)ethyl-l-phenyl-8- azabicyclo[3.2.1]octane dihydrochlorides (lR*,2R*,5S*,6R*)-2-(2-Cyclopropoxy-δ-(trifluoromethoxy)benzylamino)-6- acetyl-l-phenyl-8-azabicyclo[3.2.1]octane (Example 13; 109mg, 0.23mmol) in methanol (δmL) was treated with sodium borohydride (8.7mg, 0.23mmol) and the solution was stirred for lδ minutes, before being poured into saturated aqueous sodium hydrogen carbonate solution (20mL). The solution was extracted with dichloromethane (2x20mL), and the extracts were dried (MgSθ4) then concentrated. The residue was purified by silica chromatography to give the two diastereomers. Each one was taken up in ethyl acetate (5mL) and treated with ethereal hydrogen chloride (lmL, IM). The solid formed was removed by filtration, washed with diethyl ether and dried to give the title compounds as solids (16mg of each).
Least Polar Compound: δH (400 MHz, CDsOD): 7.56-7.49 (5H, m), 7.33-7.27 (2H, m), 7.18 (IH, br s), 4.01-3.94 (IH, m), 3.69-3.62 (3H, m), 2.86 (IH, dd, J 9.2 and 14,1Hz), 2.69-2.55 (IH, m), 2.43-2.23 (4H, m), 2.03-1.89 (3H, m), 1.12 (3H, d, J 6.3Hz), 0.78-0.68 (3H, m), 0.58-0.55 (IH, m). MS (ES+) 477 (M+H). Most Polar Compound: δH (400 MHz, CD3OD): 7.54-7.42 (5H, m), 7.30-7.23 (2H, m), 7.13 (IH, br s), 3.97-3.93 (IH, m), 3.66-3.64 (4H, m), 3.03 (IH, dd, J 9.72 and 14.1Hz), 2.54-2.60 (IH, m), 2.33-2.24 (3H, m), 2.03-2.00 (IH, m), 1.91 (IH, dd, J 4.4 and 14.1Hz), 1.82-1.79 (IH, m), 1.20 (3H, d, 6.2Hz), 0.80-0.53 (4H, m). MS (ES+) 477 (M+H). EXAMPLE 15 (lR*,2R*,5S*,6R*)-2-(2-Cycloproρoxy-5-(trifluoromethoxy)- benzylamino)-6-(l-hydroxy-l-methyl)ethyl-l-phenyl-8- azabicyclo[3.2.1]octane dihydrochloride
5 (lR*,2R*,5S*,6R*)-2-(2-Cyclopropoxy-δ-(trifluoromethoxy)benzylamino)-6- acetyl-l-phenyl-8-azabicyclo[3.2.1]octane (Example 13; 132mg, 0.28mmol) in tetrahydrofuran (2mL) was cooled to -70°C and a solution of methylmagnesium chloride in tetrahydrofuran (300μL, 3M, 0.9mmol) was slowly added. After addition was complete, the solution was allowed to 0 stir to room temperature over 1 hour, and was then poured into saturated aqueous ammonium chloride solution (lOmL). Extracted with ethyl acetate (2xl0mL) and the extracts were dried (MgS04). Concentration in vacuo gave a gum which was purified by silica chromatography to give the free base. This was dissolved in ethyl acetate (lOmL) and treated with 5 ethereal hydrogen chloride (2mL, IM). The solid formed was removed by filtration, washed with diethyl ether and dried to give the title compound as a solid (33mg, 0.06mmol). δH (360 MHz, CD3OD): 7.67-7.48 (5H, m), 7.35-7.29 (2H, m), 4.47 (IH, s), 4.13-4.06 (IH, m), 3.83-3.70 (3H, m), 2.95 (IH, dd, J 8.0 and 12.8Hz), 2.71- 0 2.67 (IH, m), 2.40-2.31 (4H, m), 1.91-1.87 (IH, m), 1.33 (3H, s), 1.14 (3H, s), 0.82-0.59 (4H, m). MS (ES+) 491 (M+H).
EXAMPLE 16 δ (lR*,2R*,5S*,6S*)-2-(2-Cyclopropoxy-5-(trifluoromethoxy)- benzylamino) -6- (lH-tetrazol-5-yl) -1 -phenyl-8- azabicyclo[3.2.1]octane dihydrochloride
Prepared according to the method of Example 6 from the product of Description 32 and 2-cyclopropoxy-δ-(trifluoromethoxy)benzaldehyde. 0 δH (360 MHz, CDsOD): 7.57-7.49 (5H, m), 7.37-7.30 (2H, m), 7.21 (IH, br s), 4.54 (IH, br s), 4.11-4.08 (2H, m), 3.77-3.70 (3H, m), 3.49 (IH, dd, J 9.7 and 14.6Hz), 2.71 (IH, dd, J 5.4 and 14.7Hz), 2.58-2.36 (3H, m), 2.10-2.00 (IH, m), 0.83-0.60 (4H, m). MS (ES+) 501 (M+H).
6 EXAMPLE 17
(lR*,2R*,5S*,6R*)-2-(2-Cycloproρoxy-5-(trifluoromethoxy)- benzylamino)-l-phenyl-6-(l-methyl-lH-tetrazol-5-yl)-8- azabicyclo[3.2.1]octane dihydrochloride
Prepared according to the method of Example 5 from the product of 10 Description 34 and 2-cyclopropoxy-δ-(trifluoromethoxy)-benzaldehyde. δH (400 MHz, CD3OD): 7.52-7.47 (5H, m), 7.37-7.31 (2H, m), 7.21 (IH, d, J 2.3Hz), 4.39-4.33 (IH, m), 4.14-4.10 (IH, m), 4.09 (3H, s), 3.76-3.71 (3H, m), 3.42 (IH, dd), 2.62-2.48 (3H, m), 2.38-2.34 (IH, m), 2.07-2.00 (IH, m), 0.84-0.61 (δH, m). lδ MS (ES+) 615 (M+H).
EXAMPLE 18 (lR*,2R*,5S*,6R*)-2-(2-Cyclopropoxy-5-(trifluoromethoxy)- benzylamino)-l-phenyl-6-(2-methyl-2H-tetrazol-5-yl)-8- 20 azabicyclo[3.2.1]octane dihydrochloride
Prepared according to the method of Example 5 from the product of Description 35 and 2-cyclopropoxy-5-(trifluoromethoxy)-benzaldehyde. δH (360 MHz, CD3OD): 7.66-7.51 (5H, m), 7.35-7.29 (2H, m), 7.21 (IH, br s), 4.29 (3H, s), 4.11-4.04 (2H, m), 3.78-3.68 (3H, m), 3,48 (IH, dd, J 9.6 26 and 14.6Hz), 2.80 (IH, dd, J 4.8 and 14.6Hz), 2.76-2.38 (3H, m), 2.14-2.10 (IH, m), 0.82-0.59 (4H, m). MS (ES+) 51δ (M+H). EXAMPLE 19 (lR*,2R*,3S*,5S*,6R*)-2-(2-Cyclopropoxy-5-(trifluoromethoxy)- benzylamino)-3-fluoro-l-phenyl-6-(hydroxymethyl)-8- azabicyclo[3.2.1]octane dihydrochloride
5 Prepared according to the method of Example 5 from the product of Description 39 and 2-cyclopropoxy-5-(trifluoromethoxy)-benzaldehyde. δH (360 MHz, CD3OD): 7.56-7.51 (3H, m), 7.45-7.42 (2H, m), 7.26 (IH, d, J 9.2Hz), 7.17 (IH, dd, J 2.1 and 9.2Hz), 6.66 (IH, d, J 2.1Hz), 4.14 (IH, d, J 3.4Hz), 3.77-3.71 (IH, m), 3.70-3.68 (IH, m), 3.59 (IH, dd, J 5.0 and 0 10.5Hz), 3.45 (IH, dd, J 6.8 and 10.5Hz), 3.09 (2H, s), 2.99 (IH, dd, J 9.2 and 14.5Hz), 2.58-2.50 (IH, m), 2.40-2.29 (2H, m), 1.86 (IH, dd, J 4.7 and 14.7Hz), 0.85-0.62 (4H, m). MS (ES+) 481 (M+H).
5 EXAMPLE 20
(lR*,2R*,5S*,6R*)-6-(Bromomethyl)-2-(2-cyclopropoxy-5-
(trifluoromethoxy)benzylamino)-l-phenyl-8- azabicyclo[3.2.1]octane
(lR*,2R*,5S*,6R*)-2-(2-Cyclopropoxy-δ-(trifluoromethoxy)benzylamino)-6- 0 (hydroxymethyl)-l-phenyl-8-azabicyclo[3.2.1]octane (Example 19; 225mg, 0.49mmol) was dissolved in dichloromethane (5mL) and treated with triphenylphosphine (392mg, l.δmmol) followed by carbon tetrabromide (497mg, l.δmmol). The solution was then stirred at room temperature for 16 hours, before being poured into water (20mL), extracted with δ dichloromethane (2x20mL) and the extracts dried (MgSθ4). After concentration to approximately XA volume, the concentrated solution was applied to an acidic SCX ion exchange cartridge which was washed thoroughly with dichloromethane and ethyl acetate. The cartridge was then eluted with methanolic ammonia (200mL, 2M) and the eluant 0 concentrated in vacuo to give the title compound as a gum (208mg, 0.4mmol). δH (400 MHz, CDCls): 7.29-7.18 (5H, m), 7.06-6.99 (2H, m), 6.79 (IH, d, J 2.3Hz), 3.73-3.59 (IH, m), 3.53 (IH, d, J 14.1Hz), 3.49-3.45 (IH, m), 3.44- 3.39 (IH, m), 3.36 (IH, d, J 14.5Hz), 3.31 (IH, dd, J 6.7 and 9.8Hz), 2.64- 2.62 (IH, m), 2.44-2.37 (2H, m), 1.92-1.69 (4H, m), 1.38-1.33 (IH, m), 0.68- 0.43 (4H, m).
MS (ES+) 625 and 527 (M+H).
EXAMPLE 21 (lR*,2R*,5S*,6R*)-2-(2-Cycloproρoxy-5-(trifluoromethoxy)- benzylamino)-6-[(methylsulphonyl)methyl]-l-phenyl-8- azabicyclo[3.2.1]octane dihydrochloride
(lR*,2R*,5S*,6R*)-6-(Bromomethyl)-2-(2-cyclopropoxy-5- (trifluoromethoxy)benzylamino)-l-phenyl-8-azabicyclo[3.2.1]octane (Example 20; 200mg, 0.38mmol) was dissolved in N,N-dimethylformamide (5mL) and the solution treated with the sodium salt of methanesulfinic acid (388mg, 3.8mmol). The resulting suspension was heated at 110°C for 1 hour, then cooled and poured into water (50mL). The mixture was extracted with ethyl acetate (2x20mL), the extracts were dried (MgS04) and then concentrated to give a gum. This was purified by silica chromatography to give the pure free base, which was dissolved in ethyl acetate (lOmL). Ethereal hydrogen chloride (2mL, IM) solution was added and the solid formed was removed by filtration and recrystallized from methanol diethyl ether to give the title compound as a white powder (120mg, 0.20mmol). δH (400 MHz, CDsOD): 7.56-7.47 (5H, m), 7.33-7.27 (2H, m), 7.18 (IH, br s), 4.36 (IH, br s), 4.03 (IH, d, J 13.7Hz), 3.72-3.64 (3H, m), 3.45 (IH, dd, J 8.8 and 14.6Hz), 3.35-3.25 (2H, m), 3.10-3.04 (IH, m), 2.61-2.25 (3H, m), 2.05 (IH, dd, 5.3 and 14.6Hz), 1.97-1.93 (IH, m), 0.81-0.56 (4H, m). MS (ES+) 525 (M+H).

Claims

CLAIMS:
A compound of the formula (I):
Figure imgf000063_0001
(I)
wherein
X represents hydrogen or a
Figure imgf000063_0002
group optionally substituted by a hydroxy group; Y represents hydrogen, Ci-βalkyl or C3-7cycloalkyl;
Z is -CR9R10CH2- or -CH2CR9R10-;
R represents hydrogen, fluorine, hydroxy, Ci-6alkyl or Ci-βalkoxy;
R1 represents hydrogen, hydroxy, Ci-βalkyl, C2-6alkenyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, Ci-βalkoxy, fluoroCi-βalkoxy, hydroxyCi-βalkyl, Cι-6alkoxyCι-4alkyl, Cι-6alkoxyCι-4alkoxy, fluoroCι-6alkoxyCι-4alkyl, C2-βalkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylCι-4alkoxy, phenoxy, benzyloxy, cyano, halogen, NRaRb, SRa, SORa, S02Ra, OS02Ra, NRaCOR12, CORa, C02Ra or CONRaR where Ra and Rb each independently represent hydrogen, Ci^alkyl or fluoroCι-4alkyl;
R2 represents hydrogen, halogen, Ci-ealkyl or Ci-βalkoxy; or when R2 is adjacent to R1, they may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen, sulphur, NH or NRC, which ring is optionally substituted by one, two or three groups selected from hydroxy, Cι-4alkyl, Cι-3alkoxyCι-3alkyl, fluoroCι-4alkyl, phenyl, =0 or =S, where Rc represents
Figure imgf000064_0001
Cι-4alkoxyCι-4alkyl, fluoroCι-4alkyl, phenyl or benzyl.
R3 represents hydrogen, halogen, Ci-βalkyl, fluoroCi-βalkyl, Ci-βalkoxy, fluoroCi-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, cyano, SRa, SORa, S02Ra, NRaRb, NRaCORi2, CORa, C02Ra, CONRaRb or Cι- alkyl substituted by cyano, Cθ2Ra or CONRaRb where Ra and Rb are as previously defined; or R3 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 Ci-βalkyl, Ci-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, trifluoromethyl, OCFs, N02, CN, SRa, SORa, S02Ra, CORa, C02Ra, phenyl, -(CH2)rNRaRb, -(CH2)rNRaCORb, -(CH2)rCONRaRb, or CH2C(0)Ra, where Ra and Rb are as previously defined and r is zero, 1 or 2;
R4 represents hydrogen, halogen, Ci-βalkyl, Ci-βalkoxy, CF3, OCF3, N02, CN, SRa, SORa, S02Ra, C02Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or Cι-4alkyl substituted by
Figure imgf000064_0002
where Ra and Rb are as previously defined;
Rδ represents hydrogen, halogen, Ci-βalkyl, CF3 or Ci-βalkoxy substituted by Cι-4alkoxy;
R6 represents hydrogen, hydroxy, CORa, C02Ra, COCONRaR , COCθ2Ra, Cι-6alkyl optionally substituted by a group selected from (C02Ra, CONRaR , hydroxy, CN, CORa, NRaR , C(NOH)NRaRb, CONHphenyl(Cι-4alkyl), COC02Ra, CONHNRaRb, C(S)NRaRb, CONRaCι-6alkylRi4, CONR11C2-6alkenyl, CONR11C2-6alkynyl, COCONRaR , CONRaC(NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from Ci-βalkyl, Cι-6alkoxy, halogen and trifluoromethyl); or R6 represents a group of the formula -CH2C≡CCH2NR7R8 where R7 and R8 are as defined below; or R6 represents Ci-βalkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by =0 or =S and optionally substituted by a group of the formula -W-NR7R8 where
W is Ci-βalkylene or Cs-βcycloalkyl;
R7 represents hydrogen or Ci^alkyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, or C2-4alkyl substituted by Cι-4alkoxy or hydroxyl; R8 represents hydrogen or
Figure imgf000065_0001
Cι-4alkoxy, C3-7cycloalkyl,
C3-7cycloalkylCι.4alkyl, or C2-4alkyl substituted by a group selected from Cι-4alkoxy, hydroxyl, C02Ra, NRaRb, aryl, aryloxy, heteroaryl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R7, R8 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 Cι-4alkoxy optionally substituted by a
Figure imgf000065_0002
or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(0)2 or a second nitrogen atom which will be part of a NH or NRC moiety where Rc is as previously defined; or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or W, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R9 represents hydrogen, hydroxy, oxo, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, fluoroCi-ealkyl, Ci-βalkoxy, fluoroCi-βalkoxy, hydroxyCi-βalkyl,
Figure imgf000065_0003
Cι-6alkoxyCι-4alkoxy, fluoroCi-ealkoxyCi-ialkyl, C2-6alkenyloxy,
C2-6alkynyloxy, C3-7cycloalkoxy, C3-7cycloalkylCι-4alkoxy, aryl, aryl(CH2), aryloxy, aryl(CH2)oxy, cyano, halogen, NR7R8, CH2NR7R8, SR12, SOR*2, S02R12, OSO2R12, NRaCOR12, CH(OH)R12, COR12, C02R12, CONR R8, CH2OR13, heteroaryl or heteroarylCι-4alkyl, wherein Ra is as previously defined; R10 represents hydrogen, halogen or hydroxy;
R11 represents hydrogen or Ci-βalkyl;
R12 represents hydrogen, Ci-βalkyl, Ci-βalkoxy, fluoroCi-βalkyl or phenyl optionally substituted by one, two or three substituents selected from Ci-βalkyl, Ci-βalkoxy, halogen or trifluoromethyl; R13 represents Cι-4alkyl substituted by a group selected from hydroxy, CORa, C02Ra, CONRaRb and heteroaryl, where Ra is as previously defined;
R14 represents ORa, CONRaRb or heteroaryl; with the exception of the compound (2-methoxy-5-trifluoromethoxy- benzyl)-(l-phenyl-8-azabicyclo [3.2.1] oct-2-yl)amine; or a pharmaceutically acceptable salt or N-oxide thereof.
2. A compound as claimed in Claim 1 wherein R is hydrogen or fluorine.
3. A compound as claimed in Claim 1 or Claim 2 wherein R1 is a Ci-βalkoxy, fluoroCi-βalkoxy or C3-7cycloalkoxy group, or R1 together with the group R2 forms a 5-membered saturated ring containing one oxygen atom, which ring is optionally substituted by a methyl group.
4. A compound as claimed in any one of Claims 1 to 3 wherein R2 is a hydrogen, fluorine or chlorine atom.
5. A compound as claimed in any one of Claims 1 to 4 wherein R3 is a hydrogen or halogen atom or a fluoroCi-βalkoxy group or a δ-membered aromatic heterocyclic group as defined in Claim 1.
6. A compound as claimed in any one of Claims 1 to 6 wherein R4 is hydrogen or fluorine.
δ 7. A compound as claimed in any one of Claims 1 to 6 wherein
R5 is hydrogen.
8. A compound as claimed in any one of Claims 1 to 7 wherein R6 is hydrogen or Ci-βalkyl, or a Ci-βalkyl group substituted by a
10 δ-membered heterocyclic ring containing 2 or 3 nitrogen atoms as defined in Claim 1.
9. A compound as claimed in any one of Claims 1 to 8 wherein Z is -CR9R10CH2-. lδ
10. A compound as claimed in any one of Claims 1 to 9 wherein R9 is hydrogen, hydroxy, oxo, Ci-βalkoxy, Cι-6alkoxyCι-4alkyl, hydroxyCι- alkyl, cyano, NR7R8, CH2NR7R8, S02Rd, CH(OH)Ri2, COR 2, CO2R12, CONR7R8, phenyl, heteroaryl, heteroarylCwalkyl or CH2OR13,
20 where said phenyl is optionally substituted by one or two substituents selected from Cwalkyl, Cι-4alkoxy, halogen or trifluoromethyl.
11. A compound as claimed in any one of Claims 1 to 10 wherein R10 is hydrogen, fluorine or hydroxy.
2δ
12. A compound as claimed in any one of Claims 1 to 11 wherein X is hydrogen, methyl or hydroxymethyl.
13. A compound as claimed in any one of Claims 1 to 12 wherein 30 Y is hydrogen or Cι-4alkyl.
14. A compound of the formula (la):
Figure imgf000068_0001
da)
wherein R1, R2, R3, R4, X and Y are as defined in Claim 1 and Z is
-CR9R10CH2-; with the exception of the compound (2-methoxy-5-trifluoromethoxy- benzyl)-(l-phenyl-8-azabicyclo[3.2.1]oct-2-yl)amine; or a pharmaceutically acceptable salt thereof.
15. A compound as claimed in Claim 1 selected from the group consisting of: lR*,2R*,5S*)-2-(3,5-bis(trifluoromethyl)benzylamino)-l-phenyl-8- azabicyclo [3.2.1] octane;
(lR*,2R*,5S*)-2-(2-methoxy-5-(trifluoromethoxy)benzylamino)-l-phenyl-8- azabicyclo [3.2.1] octane;
(lR*,2R*,5S*)-2-(2-cyclopropyloxy-5-[5-(trifluoromethyl)tetrazol-l- yl]benzylamino)-l-phenyl-8-azabicyclo[3.2.1]octane;
(lR*,2R*,5S*)-2-(2-methoxy-δ-(trifluoromethoxy)benzylamino)-8-benzyl-l- phenyl-8-azabicyclo [3.2.1] octane;
(lR*,2R*,5S*)-2-(2-Cyclopropoxy-5-(trifiuoromethoxy)-benzylamino)-l- phenyl-8-azabicyclo[3.2.1]octane; (lR*,2R*,5S*,6R*)-2-(2-methoxy-δ-(trifluoromethoxy)benzylamino)-l- phenyl-6-phenylsulphonyl-8-azabicyclo [3.2.1] octane;
(1R*,2R*,5S*,9S*)- and (lR*,2R*,5S*,9R*)-2-[l-(2-methoxy-5-
(trifluoromethoxy)phenyl)ethylamino]-l-phenyl-8-azabicyclo[3.2.1]octane; (lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-δ-(trifluoromethoxy)-benzylamino)-6-
(hydroxymethyl)-l-phenyl-δ-azabicyclo [3.2.1] octane;
(lR*,2R*,5S*)-2-(2-chloro-5-(trifluoromethoxy)benzylamino)-l-phenyl-8- azabicyclo[3.2.1]octane
(lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6- [l-(3-hydroxy)propyloxymethyl]-l-phenyl-8-azabicyclo[3.2.1]octane;
(lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6-
(fer£-butoxycarbonyl)-l-phenyl-8-azabicyclo[3.2.1]octane;
(lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6-
(N-methoxy-N-methylcarboxamido)-l-phenyl-8-azabicyclo [3.2.1] octane; (lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6- acetyl- l-phenyl-8-azabicyclo [3.2.1] octane;
(lR*,2R*,5S*,6R*,R*) and (lR*,2R*,5S*,6R*,S*)-2-(2-cyclopropoxy-5-
(trifluoromethoxy)benzylamino)-6-(l-hydroxy)ethyl-l-phenyl-8- azabicyclo [3.2.1] octane ; (lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6-
(l-hydroxy-l-methyl)ethyl-l-ρhenyl-8-azabicyclo[3.2.1]octane;
(lR*,2R*,5S*,6S*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6-
(2H-tetrazol-δ-yl)-l-phenyl-8-azabicyclo [3.2.1] octane;
(lR*,2R*,5S*,6S*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-l- phenyl-6-(l-methyl-2H-tetrazol-δ-yl)-8-azabicyclo[3.2.1]octane;
(lR*,2R*,5S*,6S*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-l- phenyl-6-(2-methyl-2H-tetrazol-5-yl)-8-azabicyclo[3.2.1]octane; (lR*,2R*,3S*,δS*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)- benzylamino)-3-fluoro-l-phenyl-6-(hydroxymethyl)-8- azabicyclo[3.2.1]octane;
(lR*,2R*,5S*,6R*)-6-(bromomethyl)-2-(2-cyclopropoxy-5- (trifluoromethoxy)benzylamino)-l-phenyl-8-azabicyclo[3.2.1]octane;
(lR*,2R*,5S*,6R*)-2-(2-cyclopropoxy-5-(trifluoromethoxy)-benzylamino)-6- [(methylsulphonyl)methyl] - l-phenyl-8-azabicyclo [3.2.1] octane; or a pharmaceutically acceptable salt thereof.
16. A compound as claimed in any one of Claims 1 to 13 wherein the stereochemistry of the 1- 2-, and 5-positions is as shown in formula (lb):
Figure imgf000070_0001
(lb)
17. A compound according to any one of Claims 1 to 16 for use in therapy.
18. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 16, together with at least one pharmaceutically acceptable carrier or excipient.
19. A method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound according to Claim 1.
20. A method according to Claim 19 for the treatment or prevention of pain or inflammation, migraine, emesis, postherpetic neuralgia, depression or anxiety.
21. The use of a compound according to any one of Claims 1 to 16 for the manufacture of a medicament for the treatment or prevention of physiological disorders associated with an excess of tachykinins.
22. The use of a compound according to any one of Claims 1 to 16 for the manufacture of a medicament for the treatment or prevention of pain or inflammation, migraine, emesis, postherpetic neuralgia, depression or anxiety.
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WO2001077100A2 (en) * 2000-04-10 2001-10-18 Pfizer Products Inc. Benzoamide piperidine compounds as substance p antagonists
EP1186318A2 (en) * 2000-09-06 2002-03-13 Pfizer Products Inc. Combination, for treating depression and anxiety, containing a 5HT1d receptor antagonist and aCNS penetrant NK-1 receptor antagonist

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001077100A2 (en) * 2000-04-10 2001-10-18 Pfizer Products Inc. Benzoamide piperidine compounds as substance p antagonists
EP1186318A2 (en) * 2000-09-06 2002-03-13 Pfizer Products Inc. Combination, for treating depression and anxiety, containing a 5HT1d receptor antagonist and aCNS penetrant NK-1 receptor antagonist

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