EP1551846A1

EP1551846A1 - Azabicyclic spiroether derivatives as receptor antagonists

Info

Publication number: EP1551846A1
Application number: EP02807882A
Authority: EP
Inventors: Ian Thomas Huscroft; Janusz Jozef Kulagowski; Piotr Antoni Raubo
Original assignee: Merck Sharp and Dohme Ltd
Current assignee: Organon Pharma UK Ltd
Priority date: 2002-10-04
Filing date: 2002-10-04
Publication date: 2005-07-13
Also published as: JP2006503859A; AU2002334103A1; WO2004031191A1

Abstract

The present invention relates compounds of the formula (I): wherein Z is -CR9R10CH2- or -CH2CR9R10-; and R1, 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

AZABICYC IC SPIROETHER 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 spiroether derivatives of l-phenyl-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):

(I)

wherein

Z is -CR⁹R¹⁰CH₂- or -CH₂CR⁹R¹⁰-;

R¹ represents hydrogen, hydroxy, Cι-6alkyl, C₂-6alkenyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, Ci-βalkoxy, fluoroCi-βalkoxy, hydroxyCi-βalkyl, Cι-6alkoxyCι-4alkyl, Ci-βalkoxyCwalkoxy, fluoroCι-6alkoxyCι-4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylCι-4alkoxy, phenoxy, benzyloxy, cyano, halogen, NR^aR^b, SR^a, SOR^a, SO₂R^a, OSO₂R^a, NR^aCOR¹², COR^a, CO₂R^a or CONR^aR^b where R^a and R^b each independently represent hydrogen, Cι-₄alkyl or fluoroCι-4alkyl;

R² represents hydrogen, halogen, Cι-6alkyl 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 NR^C, which ring is optionally substituted by one, two or three groups selected from hydroxy, Cι-4alkyl, Cι-3alkoxyCι-3alkyl, fluoroCι-4alkyl, phenyl, =O or =S, where R^c is Cι-4alkyl, hydroxyCι-4aTkyl, Cι-4alkoxyCι-4alkyl, fluoroCι-4alkyl, phenyl or benzyl;

R³ represents hydrogen, halogen, Ci-βalkyl, fluoroCi-ealkyl, Ci-βalkoxy, fluoroCi-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, cyano, SR^a, SOR^a, SU2R^a, NR^aR^b, NR^aCOR¹², COR^a, CO₂R^a, CONR^aR^b or CwaUsyl substituted by cyano, CO₂R^a or CONR^aR^b where R^a and R^b 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 Cι-6alkyl, Ci-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, trifluoromethyl, OCF3, NO2, CN, SR^a, SOR^a, SO₂R^a, COR^a, CO₂R^a, phenyl, -(CH₂)rNR^aR^b, -(CH₂)rNR^aCOR^b, -(CH₂)rCONR^aR^b, or CH₂C(O)R^a, where R^a and R^b are as previously defined and r is zero, 1 or 2;

R⁴ represents hydrogen, halogen, Ci-βalkyl, Ci-βalkoxy, CF3, OCF3, NO2, CN, SR^a, SOR^a, SO₂R^a, CO₂R^a, CONR^aR^b, C₂-₆alkenyl, C₂-6alkynyl or Cwalkyl substituted by Cι-₄alkoxy, where R^a and R^b are as previously defined;

R⁵ represents hydrogen, halogen, Cι-6alkyl, CF3 or Ci-βalkoxy substituted by Cι-4alkoxy;

R⁶ represents hydrogen, hydroxy, COR^a, CO₂R^a, COCONR^aR , COCO₂R^a, Ci-βalkyl optionally substituted by a group selected from (CO₂R^a, CONR^aR^b, hydroxy, CN, COR^a, NR^aR , C(NOH)NR^aR , CONHphenyl(Cι-4alkyl), COCO₂R^a, CONHNR^aR^b, C(S)NR^aR , CONR^aCι-₆alkylR¹⁴, CONR^Cs-ealkenyl, CONR^C^ealkynyl, COCONR^aR^b, CONR^aC(NR )NR^aR , CONR^aheteroaryl, 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 Cι-6alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by =O or =S and optionally substituted by a group of the formula -Y-NR⁷R⁸ where

Y is Ci-βalkylene or C3-6cycloalkyl;

R⁷ represents hydrogen or Cι-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, or C₂-4alkyl substituted by Cι-4alkoxy or hydroxyl; R⁸ represents hydrogen or C-walkyl, Cwalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, or C2-4alkyl substituted by a group selected from Cι-4alkoxy, hydroxyl, CO₂R^a, NR^aR^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 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 Cwalkoxy 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 NR^C moiety where R^c 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 Y, 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, fluoroCι-6alkyl, Ci-βalkoxy, fruoroCι-6alkoxy, hydroxyCi-βalkyl, Cι-6alkoxyCι-4alkyl, Cι-6alkoxyCι-4alkoxy, fluoroCι-6alkoxyCι-4alkyl, C₂-6alkenyloxy, C2-6alkynyloxy, C3-7cycloalkoxy, C3-7cycloalkylCι-4alkoxy, aryl, aryKCHsO, aryloxy, aryl(CH2)oxy, cyano, halogen, NR⁷R⁸, CH₂NR⁷R⁸, SR¹², SOR¹², SO2R¹², OSO2R¹², NR^aCOR¹², CH(OH)R¹², COR¹², CO2R¹², CONR⁷R⁸, CH2OR¹³, heteroaryl or heteroarylCι-4alkyl, wherein R^a 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, COR^a, CO2R^a, CONR^aR^b and heteroaryl, where R^a is as previously defined;

R¹⁴ represents OR^a, CONR^aR^b or heteroaryl; and pharmaceutically acceptable salts or N-oxides thereof. A preferred class of compound of formula (I) is that wherein R¹ is a Cι-6alkoxy, fluoroCi-θalkoxy 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-fiuoroethoxy, cyclopropoxy or R¹ together with the group R² represents -OCH(CH₃)CH2- or -N(CH₃)C(O)C(CH3)₂- to complete a 5-membered saturated ring, or -CH(OH)CH₂OC(CH₃)(CF3)-, -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 ealkoxy group, especially fluorine, trifluoromethoxy or 2,2,2-trifluoroethoxy, or a 5-membered aromatic heterocyclic group as previously defined. Most preferably, R³ is trifluoromethoxy or 5-(trifluoromethyl)tetrazol-l-yl, and especially trifluoromethoxy.

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-εalkyl group. Most especially, R⁶ is hydrogen or methyl.

Also preferred is the class of compound of formula (I) in which R⁶ is a Cι-6alkyl group, in particular CH₂, CHXCH3) 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 -Y-NR⁷R⁸.

Particularly preferred heterocyclic rings are selected from:

Another preferred class of compound of formula (I) is that wherein R⁹ represents hydrogen, hydroxy, oxo, Ci-βalkoxy, Cι-6alkoxyCι-4alkyl, hydroxyCwalkyl, cyano, NR⁷R⁸, CH₂NR⁷R⁸, SO₂R^d, CH(OH)R¹², COR¹², CO₂R¹², CONR⁷R⁸, phenyl, heteroaryl, heteroarylCι-4alkyl or CH2OR¹³, where said phenyl is optionally substituted by one or two substituents selected from Cwalkyl, Cι-4alkoxy, halogen or trifluoromethyl.

A further preferred class of compound of formula (I) is that wherein R⁹ represents hydrogen, SO₂R^d (in particular where R^d 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, Ci-4alkyl, Cι-4alkoxy 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 compound 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

where R¹⁵ is hydrogen, halogen, Ci-ealkyl, C_1-6alkoxy, CFs, OCF₃, NO₂, CN, SR^a, SOR^a, SO₂R^a, COR^a, CO₂R^a, (CH₂)_rCONR^aR^b, (CH₂)rNR^aR^b or (CH₂)rNR^aCOR , where R^a and R^b are hydrogen or Cι-4alkyl, and r is zero, 1 or 2.

The optionally substituted tetrazolyl group is particularly preferred. R¹⁵ is preferably hydrogen, Cwalkyl, especially methyl, CF3, (CH₂)rCONR^aR^b, SOR^a or SO₂R^a where R^a, R and r are as previously defined. Most especially, R¹⁵ is CF3.

One favoured group of compounds of the present invention is of the formula (la) and pharmaceutically acceptable salts thereof:

(la)

wherein R¹, R², R³ and R⁴ are as defined in relation to formula (I) and Z is -CR^βR^WCHb-. With respect to compounds of the formula (I), Y (where present), may be a linear, branched or cyclic group. Favourably Y contains 1 to 4 carbon atoms and most favourably 1 or 2 carbon atoms. A particularly favourable group Y is 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 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 Cι-₄alkyl group or a C₂-4alkyl group substituted by a hydroxy or Cι_-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[2.1.1]hexyl, 5-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo [3.2.2] nonyl, 6-azabicyclo [3.3.1] nonyl, 6-azabicyclo [3.2.2] decyl, 7-azabicyclo[4.3.1Jdecyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo [3.2.1] octyl. 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, pyrrohdino, piperidino, piperazino, morpholino, or thiomorpholino. Particularly preferred are nitrogen containing heteroaliphatic rings, especially pyrrolidino and morpholino rings.

Particularly suitable moieties -Y-NR⁷R⁸ include those wherein Y is CH₂ or CH2CH2 and NR⁷R⁸ is amino, methylamino, dimethylamino, diethylamino, azetidinyl, pyrrolidino and morpholino.

In particular, Y 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(O)CH2- or -CH2C(O)-.

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 "fluoroCι-6alkyl" and fluoroCι-6alkoxy" mean a Ci-βalkyl or Ci-βalkoxy 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, OCFs, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CFs, OCFs and OCH2CF3.

As used herein, the term "hydroxyCi-ealkyl" means a Cι-6alkyl 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, cyclopropyl, cyclobutyl, 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 monocychc or fused-bicyclic heteroaromatic ring containing between 5 and 10 ring members, of which 1 to 4 may be heteroatoms selected from N, O and S, and wherein any of which rings is optionally substituted by one or two substituents selected from halogen, Ci-βalkyl, Cι-6alkoxy, trifluoromethyl or phenyl. Particular examples of such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indole, benzofuran, benzthiophene, benzimidazole, benzoxazole and benzthiazole. Furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, and pyridyl are particularly preferred. Where said rings are substituted, preferred substituents include methyl and phenyl groups.

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*,2i2*,4'5^,*,5S*)-2',3',4',5'-tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)-l-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] ; (lR*,2R*,4'S^:!:,5S^:i:,6R^:i:)-2',3',4^,,5'-tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo [3.2.1] octane-2,2'-furan] ;

(lR*,2Λ*,4'S*,5»S*)-4'-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)- 2',3',4',5⁵- tetrahydro-1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] ; (lR*,2R.*,4'S*,5R*)-2',3',4',5'-tetrahydro-4'-(2-isopropoxy-5- ^" trifluoromethoxyphenyl)-l-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan]; (li2*,2E*,4'S*,5i2*)-2',3',4',5'-tetrahydro-4'-(2-(2',2'-difluoro)ethoxy-5- trifluoromethoxyphenyl)-l-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan]; (lR*,2i2*,4'5^,:1;,5i2*)-2',3',4'₃5'-tetrahydro-l-phenyl-4'-[2-(2,2,2-trifluoroethoxy)-5- trifluoromethoxyphenyl)spiro [8-azabicyclo [3.2.1] octane-2,2'-fur an] ; (lR*,2B*,4'S*,5R*)-4'-[2-(2-Fluoroethoxy)-5-trifluoromethoxyphenyl]-2',3',4',5'- tetrahydro- 1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] ; (lR*,2 *,4'S*,5S*)-2',3',4',5'-tetrahydro-4'-[(2R.<S)-2,3-dihydro-2-methyl-5- trifluoromethoxybenzofuran-7-yl] -1-phenylspiro [8-azabicyclo [3.2.1] octane-2 ,2'- furan];

(lR*,2R*,4',Sf*,5R*)-2',3',4',5'-tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)-6-(morpholin-l-ylcarbonyl)-l-phenylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan]; (lR*,2R*,4'S*,5R*)-2',3',4',5'-tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)-6-(3-methoxypropylaminocarbonyl)-l-phenylspiro[8- azabicyclo [3.2.1] octane-2,2'-fur an] ;

(lR*,2R*,4'5*,5R*)-2',3',4',5'-tetrahydro-4'-(2-methoxy-5- trifluoromethoxvphenyl)-6-(3-methoxypropylaminocarbonyl)-8-m.ethyl-l- phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan]; 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 vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin. The present invention includes within its scope prodrugs of the compounds of formula (I) above. 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 carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.

The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. The preferred compounds of formula (I) and (la) will have the stereochemistry of the 1, 2, 4' and 5 positions as possessed by, for instance, the compound of Example 11, i.e. as shown in formula (lb)

( 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) and formula (lb).

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 the reaction of a compound of formula (II)

(II)

and a compound of formula (III)

(HI)

where Hal is chlorine, bromine or, preferably, iodine, by a reductive Heck reaction using a palladium catalyst such as palladium acetate with, for example, tri-o-tolylphosphine, dimethylformamide and tributylamine, or tetrabutylammonium chloride and dimethylformamide, and a reducing agent, preferably formic acid or a salt thereof, such as potassium formate.

According to another general process (B), compounds of formula (I) may be prepared by the reaction of a compound of formula (IV)

(IV)

wherein each R⁴⁵ is a Cι-4alkyl group, preferably methyl or n-butyl groups, with a compound of formula (V)

(V)

wherein R⁵⁰ is a leaving group such as triflate (-OSO₂CF3) or a halogen atom, for example, chlorine, bromine or iodine, especially triflate, bromine or iodine.

The reaction is conveniently effected in the presence of lithium chloride and a transition metal catalyst such as triphenylphosphine palladium (0). Suitable solvents for the reaction include an aromatic hydrocarbons, for example, toluene, polar aprotic solvents, for example, dimethylformamide, or ethers, for example, dioxan, the reaction being effected at a temperature between 80°C and the reflux temperature of the solvent. Subsequent reduction of the double bond is effected using the conditions of general process (G), below.

According to another general process (C), compounds of formula (I) may be prepared by the reduction of a compound of formula (VI)

(VI)

using, for example, a borohydride such as Uthium borohydride or lithium triethylborohydride in tetrahydrofuran, or a hydride such as lithium aluminium hydride or dhsobutylaluminium hydride.

According to another general process (D), compounds of formula (I) wherein R¹ is Ci-βalkoxy, fluoroCi-δalkoxy, C₂-6alkenoxy, C3-7cycloalkoxy, C3-7cycloalkylCi-4alkoxy or benzyloxy, may be prepared by the interconversion of a compound of formula (I) wherein R¹ is hydroxy, hereinafter referred to as formula (Nil)

(VII)

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 (E), 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 (VLII)

(VIII)

by reaction with a compound of formula (IX):

LG-R^6a(LX)

where R ^a is a group of the formula R as defined in relation to formula (I) (other than H) or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine); and, if R ^a is a precursor group, converting it to a group R (in which process any reactive group may be protected and thereafter deprotected if desired).

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 (F), compounds of formula (I) may be prepared from a compound of formula (X)

(X)

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 orthophosphate, 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.

According to another general process (G), compounds of formula (I) may be prepared by the reduction of a compound of formula (XI)

(XI) wherein the dotted line represents a double bond at either bond (a) or bond (b). Suitable reducing conditions include: catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof; or reduction using trifluoroacetic acid and triethylsilane.

Further details of suitable procedures will be found in the accompanying Examples.

Compounds of formula (II) may prepared, for example, by the conversion of a stannane of formula (IN) to the corresponding iodide -by treatment with iodine at reduced temperature, for example, at about -78°C, in a suitable solvent such as dichloromethane. The iodine may then be displaced to give the compound of formula (II) by treatment with, for example, α, '-azo- isobutyronitrile and tributyltin hydride in a suitable solvent, for example, toluene, at an elevated temperature, for example, at about 100°C.

Alternatively, compounds of formula (II) may be prepared by the cyclization of a compound of formula (XII)

(XII)

using triphenylphosphine and diethylazodicarboxylate in a suitable solvent such as tetrahydrofuran.

Compounds of formula (XII) may be prepared by the partial reduction of an acetylene compound of formula (XIII)

(XIII)

The reaction is conveniently effected by catalytic hydrogenation using a metal catalyst such as palladium on calcium carbonate in the presence of a lead poison (e.g. Lindlar catalyst). Other suitable methods will be readily apparent to a person of ordinary skill in the art.

Compounds of formula (XIII) may be prepared from compounds of formula (XIV)

CX )

and, for example, a Grignard reagent prepared from O-trimethylsilylpropargyl alcohol using conventional methodology, followed by removal of the hydroxy protecting group. Compounds of formula (IN) may be prepared from a compound of formula

(XIII) by reaction with a compound of the formula (R ⁵)sSnH, for example tri-(n- butyl)stannane in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium(0) in a suitable solvent such as an ether, for example, tetrahydrofuran, followed by a dehydration step using, for example, triphenylphosphine and diethylazodicarboxylate in a suitable solvent such as an ether, for example, tetrahydrofuran.

Alternatively, compounds of formula (IN) may be prepared from a compound of formula (XV)

(XV)

wherein R⁵⁰ is as previously defined (and is preferably a triflate group or a bromine or iodine atom), by reaction with a compound of the formula (R⁴⁵)sSn- Sn(R⁴⁵)3, for example, hexamethyl distannane. The reaction is conveniently effected in the presence of a base, for example, lithium carbonate, and a catalyst such as triphenylphosphine palladium(O). Suitable solvents for the reaction include ethers such as tetrahydrofuran, the reaction being effected at a temperature between room temperature and 100°C, for example, at about 60°C.

Compounds of formula (XV) may be prepared from a compound of formula (XX) by enolisation of the ketone in the presence of a base, for example, sodium hexamethyldisilazide, followed by reaction with a reagent capable of introducing a suitable leaving group, for instance, where R⁵⁰ is -OSO2OF3, using 2-[NN- bis(trifluorom.ethyls phonyl)amino]-5-cMoropyridine or triflic anhydride. The reaction is conveniently effected in a suitable solvent such as an ether, for example, tetrahydrofuran at a reduced temperature, for instance, -80°C.

Compounds of formula (VI) may be prepared by reduction of a compound of formula (XVI)

(XVI)

Suitable reducing conditions include: catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof; or reduction using trifluoroacetic acid and triethylsilane.

Compounds of formula (XVI) may be prepared from a compound of formula (XVII)

(XVII)

by a three-step process. Firstly, the compound of formula (XVII) is reduced using, for example, Red-Al™ in a suitable aprotic solvent such as an aromatic hydrocarbon, for example, toluene, or an ether, for example, diethyl ether, or a mixture thereof. The resultant compound is then iodinated using iodine. Finally cyclisation takes place by reaction with carbon monoxide in the presence of a transition metal catalyst such as tris(dibenzylidineacetone)palladium (0) and l,4-bis(diphenylphosphino)butane, and an organic base such as a trialkylamine, for example, isopropyldiethylamine. The cyclisation is conveniently effected in an aprotic solvent such as an ether, for example, tetrahydrofuran.

Compounds of formula (XVII) may be prepared by the reaction of a compound of formula (XTV) with a compound of formula (XVIII)

(XVIII)

The reaction is conveniently effected in the presence of ethyl magnesium bromide in a suitable aprotic solvent such as an ether, for example, tetrahydrofuran.

Compounds of formula (X) maybe prepared from a compound of formula (VII) by reaction with (l-iodo-cycloprop-l-yl)phenylsulfϊde.

Compounds of formula (XI) may be prepared by the dehydration of a compound of formula (XLX)

(XLX)

using an acid such as trifluoroacetic acid. The reaction is conveniently effected at a temperature between 0°C and room temperature, using a suitable organic solvent such as a halogenated hydrocarbon, for example, dichloromethane. Compounds of formula (XLX) may be prepared by the reaction of a compound of formula (XX)

(XX)

with a Grignard reagent prepared from a compound of formula (III), preferably using magnesium and a bromide of formula (III). The couphng reaction is conveniently effected at reduced temperature, for example, at about 0°C, using a suitable solvent such as an ether, for example, diethyl ether.

Compounds of formula (XX) may be prepared from a compound of formula (XIV) by a variety of processes, for instance, by the following reaction sequence (Scheme A) or by methods analogous thereto:

Scheme A

Compounds of formula (XIV) may be prepared from a compound of formula (XXI)

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 (XXI) wherein R⁶ is benzyl or allyl, may be prepared from a compound of formula (XXII)

(XXII)

(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 CO2R¹³ (especially where R¹³ is tert-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 (XXII) 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.

Where they are not commercially available, the intermediates of formula (II), (IV) and (XVIII) above may be prepared, for example, from the corresponding phenol derivative using, for example, the procedures described in the accompanying Examples, or by alternative procedures which will be readily apparent to one skilled in the art.

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 (LX) and (XXII) 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.

McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective

Groups in Organic Synthesis, John 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

O-Vinyloxy-4-trifluoromethoxybenzene

Diethyl azodicarboxylate (19ml, 121mmol) was added dropwise to a stirred solution of 4-trifluoromethoxyphenol (20.5g, llδmmol), triphenylphosphine

(31.5g, 120mmol) and 2-bromoethanol (10ml, 141mmol) at +5°C. The cold bath was removed and the reaction mixture was stirred at ambient temperature for

20 hours and concentrated in vacuo. The residue was treated with diethyl ether

(50ml) followed by hexane (200ml). The solid was filtered off and the filtrate was concentrated. The residue was treated with dichloromethane (150ml) followed by 50% aqueous NaOH (150 ml) and tetra-n-butylammonium hydrogen sulphate (40g, 118mmol). The mixture was stirred at room temperature for 3 hours, diluted with water (200ml) and layers were separated. The aqueous phase was extracted into diethyl ether. The combined organic extracts were washed with water, dried (Na SO₄) and concentrated under atmospheric pressure using a Vigreux column (300mm). The residue was distilled under reduced pressure to give the title compound (9.64g, 41%, bp. 64°C/20mm Hg) as a colourless liquid. δ_H (250 MHz, CDCls): 7.17 (2H, ), 7.01 (2H, m), 6.60 (1H, dd, J 6.1Hz, 13.7Hz), 4.79 (1H, dd, J 1.8Hz, 13.7Hz), 4.48 (1H, dd, J 1.8Hz, 6.0Hz).

DESCRIPTION 2 O-Cyclopropyloxy-4-trifluoromethoxybenzene

Diethyl zinc (24ml, neat, 235mmol) was added dropwise to a stirred solution of O-vinyloxy-4-trifluoromethoxybenzene (Description 1; 9.6g, 47mmol), diiodomethane (37.7ml, 470mmol) in dimethoxyethane (200ml) over 30 minutes. The reaction mixture was heated at reflux for 13 hours, cooled to room temperature and quenched with saturated aqueous ammonium chloride. The layers were separated and the upper aqueous phase was extracted into hexane (2x50ml). The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated under atmospheric pressure using a Vigreux column (300mm). The residue was distilled under reduced pressure to give the title compound (6.7g, 65%) as a colourless liquid. δ_H (250 MHz, CDCls): 7.13 (2H, m), 7.01 (2H, m), 3.70 (1H, m), 0.77 (4H, m).

DESCRIPTION 3 2-Cyclopropyloxy-5-trifluoromethoxybenzaldehyde A of solution of tert-butyl hthium in pentane (1.7M, 30ml, δlmmol) was added dropwise to a stirred solution of O-cyclopropyloxy-4-trifluoromethoxybenzene (Description 2; 5.2g, 23.7mmol) in tetrahydrofuran (50ml) at -78°C over 10 minutes. The mixture was stirred for 30 minutes at -78°C and DMF (8ml) was added dropwise. The reaction mixture was warmed to 0°C over 90 minutes, quenched with saturated aqueous ammonium chloride and extracted into hexane (3x30ml). The combined organic extracts were dried (Na2SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-10%) to give the title compound (4.59g, 84%) as a solid. 5H (250 MHz, CDC ): 10.35 (1H, m), 7.67 (1H, ), 7.40 (2H, m), 3.87 (1H, m), 0.87 (4H, m).

DESCRIPTION 4 2-Cyclopropylosy-5-trifluoromethoxyphenylethyrte Potassium carbonate (6.15g, 44mmol) was added to a stirred solution of 2-cyclopropyloxy-5-trifluoromethoxybenzaldehyde (Description 3; 4.4g, 17.8mmol), and acetyl diazomethyl phosphonate (6.15g, 32mmol) in dry methanol (50ml) at +5°C. The reaction mixture was stirred at +5°C for 30 minutes and at room temperature for 3.5 hours. The mixture was quenched with saturated aqueous ammonium chloride and extracted into hexane (3x30ml). The combined organic extracts were dried (Na2SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-45%) to give the title compound (4.2g, 94%). δ_H (250 MHz, CDCls): 7.31 (1H, d, J 2.7Hz), 7.24 (1H, d, J 9.0Hz), 7.18 (1H, ddd, J 0.7Hz, 1.7Hz, 9.1Hz), 3.80 (1H, ), 3.30 (1H, s), 0.85 (4H, m).

DESCRIPTION 5

N-Benzyl-3-hydroxy-2 henylpyιή.dinitιr broπιide

A suspension of 3-hydroxy-2-phenylpyridine (20g, llβmmol) 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. δ_H (360 MHz, CDCls): 11.88 (1H, s), 9.47 (1H, d, J 7.2Hz), 8.16 (1H, d, J 8.1Hz), 8.05 (1H, dd, J 6.0Hz, 8.8Hz), 7.60-7.45 (3H, ), 7.37-7.22 (5H, m), 6.88 (2H, dd, J 6.2Hz, 7.9Hz), 5.61 (2H, s).

DESCRIPTION 6 (LR*,5S*,6i?*)-8-BenzyI-l-phenyI-6-phenylsulphonyl-8- azabicyclo[3.2.1]oct-3-en-2-one A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (Description 5; 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 NaHCO3 and extracted with ethyl acetate (3x100ml). The combined organic extracts were dried (Na₂SO4) 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 iso- hexane:diethyl ether gave the product as yellow rhombs. δ_H (360 MHz, CDCls): 7.75-7.60 (5H, m), 7.48 (2H, t, J 7.7Hz), 7.41-7.25 (8H, m), 6.86 (1H, dd, J 4.8Hz, 9.6Hz), 6.23 (1H, d, J 9.6Hz), 4.25 (1H, d, J 4.8Hz), 3.65 (1H, d, J 13.4Hz), 3.56 (1H, dd, J 4.0Hz, 9.4Hz), 3.43 (1H, d, J 13.5Hz), 2.83 (1H, dd, J 3.9Hz, 14.9Hz), 2.56 (1H, dd, J 9.4Hz, 15.0Hz).

DESCRIPTION 7

(lβ*,5,S^:H,6i?*)-8-BenzyH-p]ιenyl-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*,5S*,6R*)-8-benzyl-l-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3- ene-2-one (Description 6; llg, 25.6mm.ol) 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%). δ_H (400 MHz, CDCls): 7.79 (2H, d, J 7.2Hz), 7.68 (1H, t, J 6.4Hz), 7.51 (2H, t, J 7.6Hz), 7.41-7.25 (10H, ), 3.94 (1H, br s), 3.73-3.69 (1H, d, J 14.0Hz), 3.63 (1H, t, J 7.7Hz), 3.36 (1H, d, J 14.0Hz), 2.71-2.54 (5H, m), 1.77 (1H, m).

DESCRIPTION 8 (lR*,2S*,5S*,6i2*)-8-Benzyl-2-(2-cyclopropyloxy-5- trifluoromethoxyph.enyl)ethynyl-l-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octan-2-ol

A solution of n-butyl lithium in hexanes (1.6M, 5ml, 8mmol) was added dropwise to a stirred solution of 2-cyclopropyloxy-5-trinuoromethoxyphenylethyne (Description 4; 2.0g, 8.2mmol) in tetrahydrofuran (30ml) at -78°C to form an orange solution that turned violet at the end of addition. The mixture was stirred for 10 minutes and solid anhydrous cerium(III) chloride (2g, 8.1mmol) was added. The mixture was stirred for 30 minutes at -78°C and a solution of (LR*,5iS*,6R*)-8-benzyl-l-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2- one (Description 7; 2.9g, 6.7mmol) in tetrahydrofuran (25ml) was added dropwise. The reaction mixture was warmed to 0°C over 30 minutes, stirred at 0°C for 15 minutes, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (3x100ml). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (2.4g, 53%) which was recrystallised from ethyl acetate:iso-hexane. δ_H (400 MHz, CDCls): 7.86 (2H, dm, J 7.2Hz), 7.71 (2H, dm, J 7.2Hz), 7.65 (1H, t, J 7.5Hz), 7.54 (2H, t, J 8.0Hz), 7.48 (2H, d, J 7.3Hz), 7.40-7.25 (6H, ), 7.14 (1H, d, J 9.0Hz), 7.08 (1H, dd, J 2.5Hz, 9.2Hz), 7.00 (1H, d, J 2.5Hz), 4.05 (1H, d, J 14.6Hz), 3.94 (1H, br s), 3.77 (1H, d, J 14.6Hz), 3.68 (1H, ), 3.64 (1H, t, J 8.6Hz), 3.51 (1H, br s), 2.94 (1H, dd, J 9.1Hz, 14.2Hz), 2.87 (1H, dd, J 6.7Hz, 14.2Hz), 2.21 (1H, m), 2.10 (1H, ), 1.29 (1H, m), 0.76 (2H, m), 0.66 (2H, m).

DESCRIPTION 9

(LR*,2/2*,5Sf*,6i2*)-8-Benzyl-2-[( )-2-(2-cyclopropyloxy-5- trifluoromethoxyphenyl)-2-iodoethenyl]-l-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octan-2-ol

(lR*,2₁S*,5₁S*,6R*)-8-benzyl-2-(2-cyclopropyloxy-5- trifluoromethoxyphenyl)ethynyl-l-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octan-2-ol (Description 8; 2.4g, 3.6mmol) was dissolved in hot, dry toluene (35ml), cooled to room temperature and treated with diethyl ether (15ml) followed by a solution of Red-Al^® (3.4M in toluene, 1.8ml, 6.12mmol). The mixture was stirred at room temperature for 2 hours and at +40°C for 30 minutes. The reaction mixture was cooled to -60°C and a solution of iodine (2.5g, 9.8mmol) in toluene (35ml) was added. The cold bath was removed and the mixture was stirred at ambient temperature for 30 minutes, treated with 10% aqueous Na₂SO3 and stirred until for 1 hour. The phases were separated. The aqueous layer was extracted twice with ethyl acetate (2x50ml). The combined organic extracts were washed with brine, dried (Na2SO₄) and concentrated. The residue was purified by chromatography on silica gel (ϊso-hexane:ethyl acetate) to give the title compound (1.88g, 66%). δ_H (360 MHz, CDCls): 7.84 (2H, dm, J 7.1Hz), 7.70-7.45 (7H, ), 7.40-7.25 (6H, m), 7.05 (IH, d, J 9.0Hz), 7.01 (IH, dd, J 2.3Hz, 9.0Hz), 6.52 (IH, d, J 2.3Hz),

5.90 (IH, s), 4.25 (IH, s), 4.01 (IH, d, J 14.5Hz), 3.92 (IH, br s), 3.75 (IH, d, J 14.4Hz), 3.71 (IH, m), 3.59 (IH, dd, J 7.7Hz, 9.5Hz), 2.85 (IH, dd, J 6.7Hz, 14.0Hz), 2.59 (IH, dd, J 9.1Hz, 14.0Hz), 2.31 (IH, dd, J 4.6Hz, 14.4Hz), 2.21 (IH, ddt, J 2.8Hz, 5.3Hz, 14.0Hz), 1.82 (IH, ddd, J 5.2Hz, 13.6Hz), 1.34 (IH, m), 0.80- 0.65 (4H, m).

DESCRIPTION 10 (lR*,2i2*,5S*,62?*)-8-Benzyl-4'-(2-cyclopropyloxy-5- trifl oromethoxyphenyl)-l-phenyl-6-phenylsιdphonylspiro[8- azabicyclo[3.2.1]octane-2,2'(5'H)-furan]-5'-one

A mixture of (lR*,2R.*,5-5*,6R*)-8-benzyl-2-[(Z)-2-(2-cyclopropyloxy-5- trifluoromethoxyphenyl)-2-iodoethenyl]-l-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octan-2-ol (Description 9; 690mg, 0.86mmol), 1,4- bis(diphenylphosphino)butane (45mg, O.lmmol), Pd₂(dba)3 (140mg, l.δmmol), ethyl di-iso-propyl amine (0.75ml) and tetrahydrofuran (20ml) was stirred under an atmosphere of carbon monoxide (latm) at +50°C for 24 hours. Additional portion of l,4-bis(diphenylphosphino)butane (45mg, O.lmmol) and Pd2(dba)3 (140mg, l.δmmol) were added and the mixture was stirred for an additional 24 hours. After cooling to room temperature the mixture was diluted with ethyl acetate and filtered through a pad of Celite™. The filtrate was concentrated and the residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-35%) to give the title compound (350mg, 58%). δ_H (400 MHz, CDCls): 7.89 (2H, dm, J 8.6Hz), 7.67 (IH, t, J 7.4Hz), 7.62-7.53 (4H, m), 7.48 (IH, d, J2.8Hz), 7.46 (IH, s), 7.40-7.25 (3H, ), 7.28 (IH, t, J 7.4Hz), 7.23-7.13 (4H, m), 7.09 (IH, dd, J 2.4Hz, 9.0Hz), 3.99 (IH, d, J 14.6Hz),

3.91 (IH, br s), 3.85 (IH, d, J 14.6Hz), 3.77 (IH, t, J 8.0Hz), 3.71 (IH, m), 3.13 (IH, dd, J 7.4Hz, 14.1Hz), 2.76 (IH, dd, J 8.9Hz, 14.0Hz), 2.25 (IH, ddt, J 2.7Hz, J 5.5Hz, 12.5Hz), 2.04 (IH, dt, J 6.3Hz, 13.3Hz), 1.71 (IH, dd, J 5.2Hz, 15.0Hz), 1.38 (IH, m). DESCRIPTION 11 (lR*,2J2*,4'_JK*,5S*,6i?*)-2',3^,,4',5'-Tetrahydro-4'.(2-methoxy-5- trifluoromethoxyphenyl)-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan]-5-one

A mixture of (l?2*,2ie^:!:,5S'^:i;,6R*)-8-benzyl-2'-(2-cycloprσpyloxy-5- trifluoromethoxyphenyl)-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo[3.2.1]octane-2,2'(5Η)-furan]-5'-one (Description 10; 349mg, O.δmmol), 5% palladium on charcoal (lg, lmmol) and ethanol (20ml) was stirred under hydrogen (latm) at +65°C for 2.δ hours. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and purified by flash chromatography to give a mixture of phenol and n-propyl derivative in ratio 3.4:1. The mixture was treated with dry tetrahydrofuran (3ml) followed by diethyl azodicarboxylate (0.15ml, 0.95mmol), triphenylphosphine (293mg, l.lmmol) and methanol (0.2ml) and stirred at room temperature for 1 hour. The mixture was quenched with water (1 drop) and concentrated. The residue was purified by chromatography on silica gel (ιso-hexane:ethyl acetate 0-100%) to give the title compound (180mg, 61%). δ_H (360 MHz, CDCls): 7.89 (2H, dm, J 8.2Hz), 7.60-7.40 (6H, m), 7.35 (2H, m),

7.41-7.36 (4H, m), 6.97 (IH, dd, J 2.7Hz, 9.0Hz), 6.67 (IH, d, J 9.0Hz), δ.88 (IH, d, J2.8Hz), 4.09 (IH, t, J 10.6Hz), 4.07 (IH, s), 3.67 (IH, dd, J 5.3Hz, 8.5Hz), 3.49 (3H, s), 2.60 (IH, dd, J 5.4Hz, 14.5Hz), 2.49 (IH, dd, J 8.6Hz, 14.5Hz), 2.25- 2.10 (3H, m), 1.60 (IH, m), 1.51 (IH, m).

DESCRIPTION 12 (lK*,aR*,4'-S'*,5-S*,6Z2*)-2',3^,,4',5'-Tetrahydro-4^,-(2-methoxy-5- trifl oromethoxyphenyl)-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan]-5-one l,8-Diazabicyclo[5.4.0]-undec-7-ene (0.05ml, 0.34mmol) was added to a solution of (lR*,2R*,4'R^:,:,5S*,6R^:1:)-2',3',4',5'-tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan]-5-one (Description 11; 150mg, 0.26mmol) in dichloromethane (2ml). A white precipitate formed. The mixture was stirred at room temperature overnight, then treated with hexane (2ml) and cooled to -20°C. The solid was filtered off to give the title compound (lOO g, 66%) as white crystals. δ_H (400 MHz, CDCls): 7.91 (2H, dm, J 7.2Hz), 7.68 (IH, t, J 7.6Hz), 7.58 (2H, t, J 7.8Hz), 7.51 (2H, m), 7.42 (3H, m), 7.03 (IH, dd, J 2.1Hz, 8.9Hz), 6.74 (IH, d, J 9.0Hz), 6.55 (IH, d, J 2.5Hz), 4.07 (IH, br s), 3.73 (3H, s), 3.64 (IH, dd, J 5.3Hz, 8.5Hz), 2.66 (IH, dd, J δ.3Hz, 14.5Hz), 2.68 (IH, dd, J 8.6Hz, 14.δHz), 2.24 (IH, dd, J 8.3Hz, 11.0Hz), 2.20 (IH, m), 2.00 (IH, dd, J δ.4Hz, 14.9Hz), 1.89-1.77 (2H, m), 1.65 (IH, dt, J 7.0Hz, 14.2Hz), 1.49 (IH, m).

DESCRIPTION 13 (LR*,2_R*,5-S*,6i2*)-8-Benzyl-2-(3-hydroxypropynyl)-l-phenyl-6- phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol A solution of n-butyl lithium in hexanes (1.6M, 20ml, 32mmol) was added to a stirred, -78°C solution of O-trimethylsilylpropargyl alcohol (5ml, 34.8 ol) in tetrahydrofuran (50ml). After 30 minutes a solution of (LR*,5S*,6R*)-8-benzyl-l- phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-one (Description 7; 4.6g, 10.7mmol) in tetrahydrofuran (20ml) was added. The mixture was stirred for 30 minutes then quenched by addition of saturated ammonium chloride. The mixture was diluted with ethyl acetate and washed (2x100ml) with water. The organic layer was separated and treated with a solution of tetrabutylammonium fluoride (11.5ml, 1.0M solution in tetrahydrofuran) for 20 minutes at room temperature. The solution was washed with water (2x100ml) then dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1:1, 3:2 and 2:1 ethyl acetate/iso-hexanes to yield the title compound (4.12g, 79%). δ_H(400 MHz, CDC1₃): 7.86 (2H, d, J 7.2Hz), 7.63-7.53 (5H, ), 7.4δ (2H, d, J 7.2Hz), 7.38-7.26 (6H, m), 4.07 (2H,s), 4.01 (IH, d, J 14.6Hz), 3.93 (IH, s), 3.77 (lH,s), 3.73 (IH, d, J 14.4Hz), 3.6 (IH, m), 2.86-2.81 (2H, m), 2.10-1.96 (3H, m). DESCRIPTION 14 (lR*,2i2*,5S*,6i2*)-8-Benzyl-2-[(Z)-3-hydro3∑ypropenyl]-l-phenyl-6- phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol

Lindlar catalyst (200mg) was added to a solution of (lR*,2R*,5S*,6#*)-8-benzyl- 2-(3-hydroxypropynyl)-l-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 13; 2.1g, 4.3mmol) in ethyl acetate (100ml). The mixture was stirred at room temperature for 8 hours then filtered through Celite™ and the filtrate concentrated in vacuo to yield the title compound (1.88g, 90%). δ_H (400 MHz, CDCls): 7.89 (2H, d, J 7.2Hz), 7.70 (IH, m), 7.58 (2H, m), 7.47 (2H, ), 7.39-7.24 (8H, m), 5.35 (IH, m), 5.20 (IH, d, J 14.4Hz), 4.91 (IH, br s), 4.00 (IH, d, J UA Hz), 3.96 (IH, br s), 3.83 (IH, d, J 14.4Hz), 3.77-3.63 (3H, m), 2.95 (IH, dd, J 14.0 Hz, 7.4Hz), 2.66 (IH, dd, J 9.2Hz, 4.9Hz), 2.01 (IH, m), 1.84 (IH, dd, J 5.0Hz), 1.65 (IH, td, J 5.8, 5.0Hz), 1.39 (IH, m).

DESCRIPTION 15

(lR*,2K*,5S*,622*)-8-Benzyl-2',5'-dihydro-l-phenyl-6- phenylsιιlfonylspiro[8-azabicyclo[3.2.1]octane-2,2'-fu an]

Diethylazodicarboxylate, 0.7ml, 4.4mmol was added dropwise to a +5°C solution of (LR*,2R*,6S^:i:,6R*)-8-benzyl-2-[(Z)-3-hydroxypropenyl)-l-phenyl-6- phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 14; 1.8g, 3.7mmol) and triphenylphosphine (l.lδg, 4.4mmol) in tetrahydrofuran (25ml). After 90 minutes the mixture was diluted with ethyl acetate and washed (x2) with water (100ml). The organic extracts were separated, dried (MgSO₄), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10, 20, 30 and 50% ethyl acetate/iso-hexanes to yield the title compound (1.48g, 86%) δ_H(400 MHz, CDCls): 7.86 (2H, d, J 7.9Hz), 7.65-7.51 (6H, m), 7.35-7.18 (7H, m), 5.57 (2H, br s), 4.55 (IH, d, J 14.2Hz), 4.25 (IH, d, J 14.6Hz), 3.91 (IH, d, J 16.3Hz), 3.83 (IH, s), 3.69 (IH, d, J 16.2Hz), 3.64 (IH, ), 2.88 (IH, dd, J 7.8Hz, 15.5Hz), 2.6 (IH, dd, J 10.1Hz, 16.5Hz), 2.18 (IH, m), 1.69 (2H, m). DESCREPTION 16 (LR*,2U*,4'-S*,5S*,6JR*)-8-Benzyl-4'-(2-benzyloxy-5- trifluoromethoxyphenyl)-2',3',4',5'-tetrahydro-l-ρh.enyl-6- phenylsuIfonylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan] Palladium acetate (140mg, O.βmmol) was added to a degassed suspension of (lR*,2 ?*,5S*,6 ^*)-8-benzyl-2 5'-(i-hydro-l-phenyl-6-phenylsulfonylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan] (Description 15; 2.9g, 6.15mmol), 2-benzyloχy- 5-trifluoromethoxyiodobenzene (7.3g, 18.5mmol), tetrabutylammonium chloride, (1.7g, 6.15mmol), lithium chloride (2.6g, 62mmol), triethylamine (2.6ml, 18mmol), potassium formate (1.56g, 18.5mmol), N,N-dimethylformamide (40ml) and water (3ml). The mixture was stirred at 60°C for 72 hours then partitioned between brine and ethyl acetate. The organic layer was washed (x3) with water then dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5, 10, 15 and 30% ethyl acetate/iso- hexanes to yield the title compound (2.0g, 44%). δ_H(400 MHz CDCls): 7.89 (2H, d, J 7.4Hz), 7.65 (IH, t J 5.6Hz), 7.63-7.53 (3H, m), 7.44-7.39 (4H, m), 7.33-7.20 (7H, m), 7.11 (3H, m), 6.94 (IH, dd, J 2.2Hz, 8.7Hz), 6.73-6.70 (2H, m), 4.86 (2H, AB system), 3.99 (IH, t, J 7.6Hz), 3.86-3.83 (2H, m), 3.71-3.65 (2H, m), 3.55 (IH, dd, J 8.1Hz, 10.9Hz), 2.89 (IH, dd, J 7.6Hz, 13.7Hz), 2.35 (IH, dd, J 9.0Hz, 13.7Hz), 2.12-2.04 (2H, m), 1.82 (IH, dd, J 5.0Hz, 14.8Hz), 1.72-1.42 (3H, m), 1.31-1.28 (IH, ).

DESCRIPTION 17 (LR*,2iJ*,4'S*,5S*,6JΪ*)-2',3',4^,,5'-Tetrahydro-4'-[2-(l- phenylthiocyclopropyloxy)-5-trifluoromethoxyphenyl]-l-phenyl-6- phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan]

The mixture of (lR*,2R*,4'S*,55f*,6R*)-2',3',4',5'-tetrahydro-4'-(2-hydroxy-5- trifiuoromethoxyphenyl)-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan] (Example 10; 315mg, 0.56mmol), 1-iodo-l- phenylthiocyclopropane (1.8g, 6.5mmol), silver carbonate (1.03g, 3.7mmol) and toluene (7ml) was stirred at +40°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite™. The filtrate was concentrated and purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (245mg, 62%). δ_H (400 MHz, CDCls): 7.91 (2H, dm, J 7.9Hz), 7.68 (IH, m), 7.59 (2H, ), 7.43- 7.20 (4H, m), 7.13 (IH, d, J 9.0Hz), 7.00 (IH, dd, J 2.6Hz, 9.0Hz), 6.77 (IH, d, J 2.5Hz), 4.03 (IH, br s), 3.70 (IH, t, J 7.7Hz), 3.62 (IH, dd, J 5.2Hz, 8.6Hz), 3.41 (IH, dd, J 8.3Hz, 10.7Hz), 2.51 (IH, dd, J 5.2Hz, 14.3Hz), 2.46 (IH, dd, J 8.7Hz, 14.3Hz), 2.16 (IH, dd, J 8.0Hz, 12.8Hz), 2.11 (IH, m), 1.88 (IH, m), 1.85-1.20 (3H, m).

DESCRIPTION 18 (lR*,2β*,5S*,6β*)-8-Benzyl-2',5'-dihydro-l-phenyl-6-phenyls lfonyl-4'- tributylstannylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan]

Tetrakis(triphenylphosphine)palladium(0) (300mg, 0.26mmol) was added to a degassed solution of (lR*,2R*,55*,6R*)-8-benzyl-2-(3-hydroxypropynyl)-l-phenyl- 6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 13; 1.8g, 3.7mmol) in tetrahydrofuran (50ml). The mixture was cooled to +5°C before tri-n-butyltin hydride (1.3g, 4.4mmol) was added. The mixture was allowed to warm to room temperature and stirred for a further 18 hours before triphenylphosphine (lg, 3.7mmol) and diethyl azodicarboxylate (0.65g, 3.7mmol) were added. After 3 hours the mixture was concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5 and 10% ethyl acetate/iso-hexanes to give the title compound (154mg, 5.5%). δ_H (400MHz, CDCls): 7.83 (2H, d, J 7.9Hz), 7.64 (IH, t, J 7.4Hz), 7.61-7.49 (6H, m), 7.33 (2H, t, J 7.4Hz), 7.23-7.14 (4H, m), 5.57 (IH, t, J 2.2Hz), 4.63 (IH, dd, J 2.2Hz, 13.2Hz), 4.35 (IH, dd, J2.2Hz, 13.2Hz), 3.92 (IH, d, J 14.7Hz), 3.81 (IH, br s), 3.69-3.64 (2H, m), 2.87 (IH, dd, J 7.0Hz, 14Hz), 2.55 (IH, dd, J 9.0Hz 14.0Hz), 2.20-2.11 (IH, m), 1.68-1.52 (3H, m), 1.41-1.19 (12H, ), 0.99-0.85 (9H, m), 0.80-0.72 (6H, m).

DESCRIPTION 19 (p-ToluenesuIphonyloxy)propan-2-ol p-Toluenesulphonyl chloride (19.4g, 102mmol) was added to a stirred solution of propane-l,2-diol (30ml), triethylamine (15ml, 106mmol), N,N-dimethylamine (108mg, 0.87 mmol) in dichloromethane (100 ml) at +5°C. The mixture was stirred for 2 hours at +5°C and overnight at room temperature then diluted with diethyl ether (300ml) and washed 2M aqueous hydrochloric acid, water (twice) and brine. The combined organic extracts were dried (Na₂SO4) and concentrated to give the title compound (22.8g, 97%). δ_H (360 MHz, CDCls): 7.80 (2H, m), 7.36 (2H, m), 4.08-3.96 (3H, m), 3.86 (IH, dd, J 7.0Hz, 9.8Hz), 2.45 (3H, s), 2.20 (IH, br), 1.16 (3H, d, J 6.3Hz).

DESCRIPTION 20 2-(2-Iodo-4-trifluoromethoxyphenyloxy)-l-(p- toluenesulphonyloxy)propane Diethyl azodicarboxylate (5ml, 31.8mmol) was added dropwise to a stirred solution of (p-toluenesulphonyloxy)propan-2-ol (Description 19; 7.6g, 33mmol), triphenylphosphine (9.0g, 34mmol) and 2-iodo-4-trifluoromethoxyphenol (10ml, 33mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (18.7g). δ_H (400 MHz, CDCls): 7.77 (2H, dm, J 8.2Hz), 7.60 (IH, d, J 3.1Hz), 7.30 (2H, m), 7.13 (IH, ddt, J 0.8Hz, J 3.1Hz, 9.0Hz), 6.75 (IH, d, J 9.2Hz), 4.57 (IH, m), 4.21 (IH, dd, J 6.3Hz, 10.6Hz), 4.15 (IH, dd, J4.3Hz, 10.6Hz), 2.43 (3H, s), 1.37 (3H, d, J 6.3Hz).

DESCRIPTION 21 2,3-Dihydro-2-methyl-5-trifluorom.ethoxybenzofuran 10 ml solution of (2-iodo-4-trifluoromethoxyphenyloxy)-l- - toluenesulphonyloxypropane (Description 20; 16g, 28mmol) in tetrahydrofuran (50ml) was added dropwise to a stirred mixture of magnesium turnings (5g, 208mmol) in tetrahydrofuran (20ml). 1,2-Dibromoethane (0.1ml) was added. The exotermic reaction started. The mixture was warm up to reflux and the rest of (2-iodo-4-trifluoromethoxyphenyloxy)-l-p-toluenesulphonyloxypropane solution was added dropwise. The reaction mixture was heated at reflux for 24 hours, then cooled to room temperature and quenched with 2M aqueous hydrochloric acid. The mixture was extracted with a 1:1 mixture iso-hexane:diethyl ether (3x100ml). The combined organic extracts were dried (Na2SO₄) and concentrated. The residue was purified by chromatography on silica gel (ϊso-hexane:diethyl ether 0-15%) to give the title compound (2.8g, 36%). δ_H (360 MHz, CDCls): 7.00 (IH, br s), 6.94 (IH, dm, J 8.4Hz), 6.68 (IH, d, J 8.8Hz), 4.97 (IH, m), 3.31 (IH, dd, J 8.8Hz, 15.4Hz), 2.82 (IH, dd, J 7.7Hz, 15.8Hz), 1.46 (3H, d, J 6.3Hz).

DESCRDPTION 22

2,3-Dihydro-7-iodo-2-methyl-5-trifluoromethoxybenzofur n

Iodine (2.8g, llmmol) was added in few portions to a stirred mixture of 2,3- dihydro-2-methyl-δ-trifluoromethoxybenzofuran (Description 21; 2.8g, 12.8mmol), silver(I) trifluoroacetate (3.5g, lδ.δmmol) in chloroform (60ml). The mixture was stirred at room temperature for 1 hour, filtered through a pad of Celite™ and concentrated. The residue was treated with iso-hexane (150ml), washed with aqueous sodium sulphite. The organic layer was dried (Na₂SO4) and concentrated. The residue was purified by chromatography on silica gel (iso- hexane: diethyl ether 0-4%) to give the title compound (3.76g, 85%). δ_H (400 MHz, CDCls): 7.00 (IH, dd, J 0.8Hz, 1.6Hz), 6.99 (IH, d, J 0.8Hz), 5.05 (IH, m), 3.45 (IH, dd, J 9.0Hz, 16.0Hz), 2.94 (IH, dd, J 7.8Hz, 16.0Hz), 1.52 (3H, d, J 6.3Hz).

DESCRIPTION 23 (lB^δS^βiϊ^-S-Benzyl-β^fer^-butoxycarbonyD-l-pbenyl-S- azabicyclo[3.2.1]oct-3-en-2-one

A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (255g, 0.745mol), tert-butyl acrylate (470ml), triethylamine (150ml) and 1,4-dioxane (11) was heated at reflux for 15 hours and cooled to room temperature. The reaction mixture was poured onto saturated aqueous NaHCO3 (11) and extracted into an 1:1 mixture of iso-hexane:diethyl ether (3x500ml). The combined organic extracts were dried (Na2SO₄) and concentrated. The residue was purified by chromatography on silica gel (750g, iso-hexane:diethyl ether 0-20%) to give a 2:1 mixture of (lR*,5S*,6R*)-8-benzyl-6-(tert-butoxycarbonyl)-l-phenyl-8- azabicyclo[3.2.1]oct-3-en-2-one and (LR*,5S*,6S*)-8-benzyl-6-(fert- 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 yellow rhombs: DESCRIPTION 23a: (LR*,5,S*,6_JK*)-8-benzyl-6-(ferf-butoxycarbonyl)-l- phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one δ_H (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), 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, J 2.6Hz, 9.0Hz), 2.39 (IH, dd, J 9.0Hz, 14.2Hz), 1.43 (9H, s).

DESCRIPTION 23b: (lR*,5S*,6S*)-8-benzyl-6-(ferf-butoxycarbonyl)-l- phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one δ_H (360 MHz, CDCls): 7.70 (IH, dd, J 1.3Hz, 8.7Hz), 7.40-7.25 (8H, m), 6.88 (IH, dd, J 4.8Hz, 9.8Hz), 6.25 (IH, d, J 9.8Hz), 4.02 (IH, dd, J 5.0Hz, 6.0Hz), 3.65- 3.50 (3H, m), 2.60 (2H, m), 1.43 (9H, s).

DESCRD7TION 24 (lR*,5S*,6-RS)-8-Benzyl-6-(ϊ^lerι^l-butoxycarbonyl)-l-phenyl-8- azabicyclo[3.2.1]octan-2-one

A mixture of (-LR*,55*,6R)S)-8-benzyl-6-(fert-butoxycarbonyl)-l-phenyl-8- azabicylco[3.2.1]oct-3-en-2-one (Description 23; 26g, 66mmol), 10% palladium on charcoal (3.δg, 3.3mmol), ethyl acetate (50ml) and methanol (100ml) was stirred under hydrogen atmosphere (latm) at room temperature for 1 hour. The reaction mixture was treated with dichloromethane (500ml), 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 (ϊso-hexane:ethyl acetate) and crystallised from acetone:iso-hexane yielding pure ketones as a colourless crystals.

6#*-epimer: δ_H (360 MHz, CDC1₃): 7.50 (2H, dm, J l.ZKz), 7.41 (2H, d, J 7.3Hz), 7.33 (4H, m), 7.25 (2H, m), 3.72 (IH, ), 3.70 (IH, d, J 15.0Hz), 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). 6S*-epimer: δ_H (360 MHz, CDCI3): 7.50-7.20 (10H, m), 3.75 (IH, d, J 14.7Hz), 3.61 (IH, dd, J 3.5Hz, 6.3Hz), 3.52 (IH, d, J 14.8Hz), 3.46 (IH, dt, J 6.7Hz, 11.6Hz), 2.95 (IH, m), 2.90 (IH, dd, J 7.0Hz, 14.4Hz), 2.53-2.36 (2H, m), 2.26 (IH, dd, J 11.6Hz, 14.0Hz), 1.94 (IH, d, J 14.0Hz), 1.91 (IH, m), 1.46 (9H, s). DESCRIPTION 25 (lR*,2S*,5S*,6fiS)-8-Benzyl-6-(ferf-b toxycarbonyl)-2-(3- hydroxypropynyl)-l-phenyl-8-azabicyclo[3.2.1]octan-2-ol

A solution of n-butyl lithium in hexanes (1.6M, 34ml, δδ.4mmol) was added dropwise to a stirred solution of O-trimethylsilyl propargyl alcohol (8ml, 62mmol) in tetrahydrofuran (40ml) at -78°C. This solution was added via syringe to a stirred solution of (lR*,5S*,6RS)-8-benzyl-6-(fert-butoxycarbonyl)-l-phenyl-8- azabicyclo[3.2.1]octan-2-one (Description 24; a 3:1 mixture of C6 epimers, 5g, 12.7 mmol) in tetrahydrofuran (30ml) at -78°C over 30 minutes. The reaction mixture was stirred for 1 hour and quenched with acetic acid (3.1ml), warm up to room temperature and concentrated in vacuo. The residue was treated with tetrahydrofuran (50ml) followed by 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (75ml). The mixture was stirred for 30 minutes and concentrated in vacuo. The residue was treated with ethyl acetate (200ml), washed with water and brine, dried (Na2SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (4.05g, 71%) as a 3:1 mixture of C6 epimers. 6S^*-epimer: δ_H (400 MHz, CDCls): 7.61 (2H, m), 7.40-7.20 (8H, ), 4.31 (IH, s), 4.07 (IH, s), 3.95 (IH, d, J 14.8Hz), 3.72 (IH, s), 3.05 (IH, d, J 14.9Hz), 2.96 (IH, dd, J 5.5Hz, 13.3Hz), 2.87 (IH, dd, J 5.6Hz, 9.4Hz), 2.77 (IH, dd, J 9.4Hz, 13.3Hz), 2.10-1.90 (2H, m), 1.70-1.50 (IH, m), 1.44 (9H, s). 622^*-epimer: (distinguishable signals) δ_H (400 MHz, CDCls): 7.44 (2H, m), 4.41 (IH, s), 4.09 (IH, d, J 14.8Hz), 4.06 (IH, s), 3.56 (IH, dt, J 6.3Hz, 12.5Hz), 3.47 (IH, m), 3.06 (IH, d, J 14.8Hz), 2.58 (IH, dd, J 12.1Hz, 14.1Hz), 1.46 (9H, s).

DESCRIPTION 26 (LR*,2S*,5S*,6-RS)-8-Benzyl-6-(ferf-butoxycarbonyl)-2-[(Z)-3- hydroxypropenyl]-l-phenyl-8-azabicyclo[3.2.1]octan-2-ol A mixture of (lR*,2S*,5S*,6RS)-8-benzyl-2-(3-hydroxypropynyl)-l-phenyl-6-(tert- butoxycarbonyl)-8-azabicylco[3.2.1]octan-2-ol (Description 25; a 3:1 mixture of C6 epimers, 4g, 8.9mmol), Lindlar catalyst (800mg) and ethyl acetate (30ml) was stirred under hydrogen atmosphere (latm) at room temperature for 45 minutes. The reaction mixture was filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (4.0g, 100%) as a 3:1 mixture of C6 epimers.

6S^*-epimer: δ_H (400 MHz, CDCI3): 7.40-7.20 (10H, ), 5.42-5.30 (2H, m), 5.06 (IH, br), 3.91 (IH, d, J 14.5Hz), 3.87-3.70 (2H, ), 3.67-3.57 (IH, m), 3.31 (IH, d, J 14.5Hz), 2.98-2.86 (2H, ), 2.62 (IH, dd, J 8.6Hz, 12.9Hz), 2.35 (IH, br), 1.98 (IH, m), 1.79 (IH, m), 1.59 (2H, m), 1.44 (9H, s). βir-epimer: (distinguishable signals) δ_H (400 MHz, CDCls): 4.07 (IH, d, J 14.9Hz), 3.48 (IH, m), 3.04 (IH, d, J 14.9Hz), 2.54 (IH, dd, J 12.3Hz, 13.7Hz), 1.46 (9H, s).

DESCRIPTION 27 (lR*,2i2*,5₎S*,6ieS)-8-Benzyl-6-(ferf-b toxycarbonyl)-l-phenylspiro[8- azabicyclo[3.2.1]octane-2,2'(5'H)- uran] The mixture of (lR*,2,S*,5₁S*,6RS)-8-benzyl-6-(fert-butoxycarbonyl)-2-[(Z)-3- hydroxypropenyl]-l-phenyl-8-azabicylco[3.2.1]octan-2-ol (Description 26; a 3:1 mixture of C6 epimers, 4.0g, 8.9mmol), diethyl azodicarboxylate (1.8ml, 11.4mmol), triphenylphosphine (3.6g, 13.7mmol), tetrahydrofuran (30ml) was stirred at room temperature for 15 minutes. The mixture was treated with water (0.1ml) and concentrated in vacuo. The residue was treated with diethyl ether followed by iso-hexane. The solid was filtered off and the filtrate was concentrated and purified by chromatography on silica gel (iso-hexane:diethyl ether 0-20%) to give the title compound (3.1g, 81%) as a 3:1 mixture of C6 epimers.

6#*-epimer: δ_H (400 MHz, CDCI3): 7.56 (2H, dm, J 7.2Hz), 7.42 (2H, d, J 7.4Hz), 7.27 (IH, t, J 7.2Hz), 7.20-7.15 (5H, m), 5.57 (IH, dt, J 2.4Hz, 6.3Hz), 5.45 (IH, dt, J 1.6Hz, 6.3Hz), 4.51 (IH, dt, J 2.3Hz, 12.5Hz), 4.13 (IH, dt, J 2.0Hz, 12.9Hz), 3.81 (IH, d, J 14.9Hz), 3.71 (IH, t, J 2.7Hz), 3.00 (IH, d, J 14.8Hz), 2.98-2.87 (2H, m), 2.40 (IH, dd, J 7.4Hz, 11.8Hz), 2.11 (IH, ddt, J 2.4Hz, 5.5Hz, 12.5Hz), 1.80 (IH, dt, J δ.8Hz, 14.5Hz), 1.70 (IH, dd, J 5.4Hz, 14.4Hz), 1.62-1.51 (2H, ), 1.43 (9H, s).

6S*-epimer: δ_H (360 MHz, CDCI3): 7.48 (4H, m), 7.32 (IH, t, J 7.1Hz), 7.26-7.16 (5H, m), 5.60 (IH, dt, J 2.5Hz, 6.3Hz), 5.39 (IH, dt, J 1.8Hz, 6.3Hz), 4.48 (IH, dt, J 1.8Hz, 13.0Hz), 4.06 (IH, ddd, J 1.8Hz, 2.5Hz, 13.0Hz), 3.97 (IH, d, J 14.7Hz), 3.60-3.48 (4H, m), 2.96 (IH, d, J 14.7Hz), 2.77 (IH, dd, J 4.9Hz, 13.3Hz), 2.56 (IH, dd, J 11.9Hz, 13.3Hz), 2.05 (IH, ddt, J2.4Hz, 4.9Hz, 14.0Hz) 2.00 (IH, dt, J 5.3Hz, 14.0Hz), 1.69 (IH, m), 1.60-1.50 (IH, m), 1.45 (9H, s).

DESCRIPTION 28 (lB*,222*,4'S*,5_JR*)-8-Benzyl-4'-(2-benzyloxy-5-trifluorometlιoxypheιιyl)-6- (fer -butoxycarbonyl)-2',3',4^,,5'-tetralιydro-l-phenylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan]

A mixture of (LR*,2R*,5S*,6RS)-8-benzyl-6-(feri-butoxycarbonyl)-l- phenylspiro[8-azabicyclo[3.2.1]octane-2,2'(5'H)-furan] (Description 27; 3.1g, 7.17mmol), 2-benzyloxy-5-trifluoromethoxyphenyl iodide (8.7g, 22.1mmol), tetra- n-butylammonium chloride (2.0g, 6.2mmol), lithium chloride (3.45g, 77.5mmol), potassium formate (2.8g, 33mmol), palladium(II) acetate (250mg, l.lmmol), water (0.5ml) and N,N-dimethylformamide (30ml) was stirred at +70°C for 20 hours. An additional batch of 2-benzyloxy-δ-trifluoromethoxyphenyl iodide (3.6g, 9.1mmol) and palladium(II) acetate (130mg, 0.56mmol) was added and the reaction mixture was stirred at +70°C for 24 hours. The mixture was cooled to room temperature, quenched with water and extracted into a 1:1 mixture of iso- hexane: diethyl ether (3x100ml). The combined organic extracts were dried (Na2SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-45%) to give the title compound (3g, 60%). δ_H (360 MHz, CDCls): 7.53 (2H, dm, J 7.4Hz), 7.48-7.05 (13H, m), 6.93 (IH, ddd, J 1.0Hz, 2.8Hz, 8.8Hz), 6.76 (IH, d, J 2.8Hz), 6.73 (IH, d, J 9.1Hz), 4.88 (2H, s), 4.00 (IH, t, J 7.7Hz), 3.75 (IH, d, J 14.7Hz), 3.69 (IH, br s), 3.55 (IH, dd, J 8.1Hz, 10.9Hz), 2.99-2.83 (3H, m), 2.27 (IH, dd, J 8.8Hz, 13.0Hz), 2.18 (IH, dd, J 7.7Hz, 12.3Hz), 2.02 (IH, ddt, J 2.8Hz, 5.3Hz, 12.6Hz), 1.80 (IH, dt, J 5.8Hz, 14.5Hz), 1.79 (IH, dd, J 5.3Hz, 14.4Hz), 1.60-1.46 (2H, m), 1.42 (9H, s).

EXAMPLE 1 (LR*,222*,4',S*,5i?*)-8-Benzyl-2',3',4',5'-tetrahydro-4'-[2-hydroxy-(5- trifluoromethoxy)phenyl]-l-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'- furan]

Lithium naphthalenide (18ml, 1.0M solution in tetrahydrofuran) was added dropwise to a -78°C stirred solution of (LR*,2R*,4'S^:):,δS*,6B*)-8-benzyl-4'-(2- benzyloxy-δ-trifluoromethoxyphenyl)-2',3',4',δ'-tetrahydro-l-phenyl-6- phenylsulfonylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan] (Description 16; 2g, 2.7mmol) in tetrahydrofuran (20ml). After 15 minutes the mixture was quenched with saturated ammonium chloride then warmed to room temperature. The mixture was partitioned between ethyl acetate and brine. The organic layer was separated, dried (MgSO₄), filtered and concentrated. The residue was chromatographed on silica gel eluting with 5, 10 and 20% ethyl acetate/iso- hexanes to give the title compound (0.88g, 64%). δ_H (400MHz, CDC1₃): 7.67-7.65 (2H, m), 7.44 (2H, d, J 7.3Hz), 7.40-7.08 (6H, m), 6.85 (IH, dd, J 2.0Hz, 8.6Hz), 6.72 (IH, d, J 2.6Hz), 6.68 (IH, d, J 8.7Hz), 3.91 (IH, t, J 7.3Hz), 3.84 (IH, d, J 14.2Hz), 3.61 (IH, dd, J 8.2Hz, 10.6Hz), 3.33

(lH,m), 2.83 (IH, d, J 14.3Hz), 2.43 (td, IH, 4.6Hz), 2.27-2.00 (4H, ), 1.80-1.68 (3H, m), 1.45-1.39, (2H, m), 1.28-1.23 (IH, m).

EXAMPLE 2 (LR*,2β*,4'S*,5β*)-8-Benzyl-2',3',4',5'-tetrahydro-4'-(2-isopropoxy-5- trifl oromethoxyphenyl)-l-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'- furan]

A mixture of (LR*,2R*,4'S^:1:,5R*)-8-benzyl-2',3',4',5'-tetrahydro-4'-[2-hydroxy-(5- trifluoromethoxy)phenyl]-l-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan] (Example 1; 150mg, 0.29mmol), 2-bromopropane (δδmg, 0.44mmo ) and potassium carbonate (lOO g, 0.73mmol) were stirred at 60°C in N,N-dimethylformamide, 5ml for 18 hours. After this time the mixture was poured into brine, δOml and extracted with ethyl acetate (50ml). The organic layer was washed (x3) with water then separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10% ethyl acetate/iso-hexanes to give the title compound. (87mg, 54%). δ_H (400MHz, CDCls): 7.59-7.57 (2H, m), 7.38-7.36 (2H, m), 7.26-7.11 (6H, m), 6.85 (IH, dd, J 2.1Hz, 8.8Hz), 6.69 (IH, d, J2.8Hz), 6.58 (IH, d, J 8.9Hz), 4.31 (IH, heptet, J 6.0Hz), 3.95 (IH, t, J 7.5Hz), 3.72 (IH, d, J 14.2Hz), 3.44 (IH, dd, J 8.0Hz, 10.8Hz), 3.23 (IH, ), 2.77 (IH, d, J 14.2Hz), 2.33 (IH, td, 4.6Hz, 12.6Hz), 2.24-1.97 (4H, m), 1.74-1.20 (6H, m), 1.14 (6H, m). EXAMPLE 3 (LR*,2fi*,4'S*,5.R*)-8-Benzyl-4'-[2-(2,2-difluoroethoxy)-5- trifl oromethoxypbenyU^'^'^'jδ'-tetrahydro-l-phenylspiroES- azabicyclo[3.2.1]octane-2,2'-furan] Prepared in an analogous manner to Example 2 using 2-bromo-l,l- difluoroethane as an alkylating agent. δ_H (400MHz, CDC1₃): 7.66-7.64 (2H, m), 7.44-7.42 (2H, m), 7.34-7.18 (6H, m), 6.98 (IH, dd, J 2.9Hz, 8.9Hz), 6.81 (IH, d, J 2.8Hz), 6.63 (IH, d, J 8.9Hz), 6.14-5.82 (IH, tt, J 3.7Hz, 54.6Hz), 4.02-3.94 (3H, m), 3.80 (IH, d, J 14.2Hz), 3.62 (IH, dd, J 8.0Hz, 10.9Hz), 3.33 (IH, m), 2.86 (IH, d, J 14.2Hz), 2.41-2.04 (5H, m), 1.79- 1.70 (4H, m), 1.50-1.43 (2H, ).

EXAMPLE 4 (lR*,2fi*,4'₍S*,5/2*)-8-Benzyl-2',3',4',5'-tetrahydro-l-phenyl-4'-[2-(2,2,2- trifluoroethoxy) -5-trifluoromethoxyphenyl] spiro [8- azabicyclo[3.2.1]octane-2,2'-furan]

Prepared in an analogous manner to Example 2using 2,2,2- trifluoroethyltrichloromethanesulfonate as an alkylating agent. δ_H (400MHz, CDCI3): 7.65-7.63 (2H, m), 7.44 (2H, m), 7.32-7.18 (6H, ), 6.96 (IH, m), 6.80 (IH, d, J 2.8Hz), 6.64 (IH, d, J 8.9Hz), 4.17-4.09 (2H, m), 4.02 (IH, t, J 7.5Hz), 3.80 (IH, d, J 14.2Hz), 3.52 (IH, dd, J 8.0Hz, 10.8Hz), 3.29 (IH, ), 2.82 (IH, d, 14.2Hz), 2.43-2.00 (5H, m), 1.79-1.40 (6H, ).

EXAMPLE 5 (LR*,2β*,4'S*,5_JR*)-8-Benzyl-4'-[2-(2-fluoroethoxy)-5- trifluoromethoxyphenyl]-2',3',4',5^,-tetrahydro-l-phenylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan]

Prepared in an analogous manner Example 2using l-bromo-2-fluoroethane as an alkylating agent. δ_H (400MHz, CDCls): 7.59-7.58 (2H, m), 7.38-7.36 (2H, m), 7.33-7.11 (6H, ), 6.86 (IH, m), 6.71 (IH, d, J 2.7Hz), 6.58 (IH, d, J 8.9Hz), 4.67-4.65 (IH, m), 4.57-4.55 (IH, m), 4.07-3.90 (3H, m), 3.72 (IH, d, J 14.1Hz), 3.51 (IH, dd, J 8.0Hz, 10.9Hz), 3.24 (IH, m), 2.77 (IH, d, J 14.2Hz), 2.35 (IH, m), 2.21-1.91 (4H, m), 1.77-1.33 (6H, m). EXAMPLE 6 (lfi*,222*,5S*,622*)-8-Benzyl-2',5'-dihydro-4'-(2-mLethoxy-5- trifluoromethoxyphenyl)-l-pheιιyl-6-phenylsulfonylspiro[8- azabicyclo[3.2.1]octane-2,2'- uran]

Tetrakis(triphenylphosphine) palladium(0) (20mg, 0,017mmol) was added to a degassed suspension of (lR*,2E*,5S*,6E*)-8-Benzyl-2',5'-dihydro-l-phenyl-6- phenylsulfonyl-4'-tributylstannylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan] (Description 18; 150mg, 0.2mmol), hthium chloride (50mg, 1.2mmol), 2-methoxy- 5-trifluoromethoxyiodobenzene (lOOmg, 0.3mmol) and copper(I) iodide (lOmg,

O.Oδmmol) in toluene (10ml). The mixture was heated to reflux for 18 hours. On cooling the mixture was diluted with ethyl acetate (60ml) and filtered through Celite™. The filtrate was washed with water (25ml) then dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10, 20 and 30% ethyl acetate/iso-hexanes to give the title compound (llδmg, 87%). δ_H (400MHz, CDCls): 7.86-7.83 (2H, m), 7.63-7.59 (3H, m), 7.54-7.49 (4H, m), 7.37-7.33 (2H, m), 7.27-7.04 (5H,m), 6.80 (IH, d, J 9.0Hz), 6.72 (IH, d, J 2.7Hz), 6.20 (IH, t, J 2.0Hz), 4.97 (IH, dd, J 2.1Hz, 12.4Hz), 4.60 (IH, dd, J 2.0 Hz, 12.4 Hz), 4.00 (IH, d, J 14.7Hz), 3.86 (IH, s), 3.78 (3H, s), 3.71-3.65 (2H, m), 2.86 (IH, dd J 6.7Hz, 14.0Hz), 2.60 (IH, dd, J 9.2Hz, 14.0Hz), 2.21 (IH, m), 1.83-1.65 (3H, m).

EXAMPLE 7 (lβ*,2β*,4'S*,5i2*)-8-Benzyl-2',3',4',5^,-tetrabydro-4'-[(2i2S)-2,3-dihydro-2- methyl-5-trifluoromethoxybenzofuran-7-yl]-l-phenyl-6- phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan]

A mixture of (LS*,2R*,5S*,6R*)-8-benzyl-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo[3.2.1]octane-2,2'(5'H)-furan] (Description 15; 500mg, l.Oδmmol), 2,3- dihydro-7-iodo-2-methyl-5-trifluoromethoxybenzofuran (Description 22; l.llg, 3.22mmol), tetra-n-butylammonium chloride (310 mg, 0.96mmol), lithium chloride (640mg, 1.48mmol), potassium formate (420mg, δmmol), palladium(II) acetate (47mg, 0.21mmol), water (0.2ml) and N,N-dimethylformamide (5ml) was stirred at +65°C for 24 hours. An additional batch of 2,3-dihydro-7-iodo-2- methyl-5-trifluoromethoxybenzofuran (0.7g, 2.0mmol) and palladium(II) acetate (22mg, O.lmmol) was added and the reaction mixture was stirred at +65°C for 48 hours. The mixture was cooled to room temperature, quenched with saturated aqueous NaHCOβ and extracted into diethyl ether. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane'.diethyl ether 0-45%) to give the title compound (320mg, 44%) as a 1:1 mixture of epimers. δ_H (400 MHz, CDCls): 7.89 (2H, dm, J 7.4Hz), 7.65-7.50 (8H, m), 7.33 (4H, m), 6.78 (IH, s), 6.415 (0.5H, d, J 1.6Hz), 6.410 (0.5H, d, J 1.6Hz), 4.81 (IH, m), 3.92 (IH, d, J 7.8Hz), 3.88 (2H, d, J 9.4Hz), 3.74 (IH, s), 3.71 (IH, d, J 7.8Hz), 3.70 (0.5H, m), 3.66 (0.5H, dd, J 8.2Hz, 11.0Hz), 3.21 (0.5H, dd, J 3.1Hz, 8.6Hz), 3.16 (0.5H, dd, J 3.5Hz, 11.0Hz), 2.97 (IH, dd, J 7.8Hz, 13.7Hz), 2.68 (IH, dd, J 7.4Hz, lδ.6Hz), 2.43 (IH, dd, J 9.0Hz, 13.7Hz), 2.12-1.97 (4H, m), 1.65-1.65 (2H, m), 1.49 (IH, m), 1.35 (1.5H, d, J 5.9Hz), 1.34 (1.5H, d, J 6.3Hz).

EXAMPLE 8 (LR*,2i2*,4'S*,5_JR*)-6-(ferf-Butoxycarbonyl)-2',3',4',5'-tetrahydro-4'-(2- hydroxy-5-trifluoromethoxyphenyl) -1 -phenylspiro [8- azabicyclo[3.2.1]octane-2,2'-furan] A mixture of (lR*,2R*,4'S*,5R*)-8-benzyl-4'-(2-benzyloxy-5- trifluoromethoxyphenyl)-6-(tert-butoxycarbonyl)-2',3',4',5'-tetrahydro-l- phenylsρiro[8-azabicyclo[3.2.1]octane-2,2'-furan] (Description 28; 1.065g, 1.52mmol), 10% palladium on charcoal (340mg, 0.32mmol) and ethanol (20ml) was stirred under hydrogen atmosphere (lat ) at +65°C for l.δ hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (900mg, 97%). δ_H (400 MHz, CDCls): 7.53 (2H, ), 7.40-7.30 (3H, m), 6.86 (IH, ddd, J 0.8Hz, 3.1Hz, 9.0Hz), 6.73 (IH, d, J 2.7Hz), 6.64 (IH, d, J 9.0Hz), 3.79 (IH, t, J 7.4Hz), 3.77 (IH, br s), 3.61 (IH, dd, J 8.2Hz, 9.8Hz), 2.87 (IH, dd, J 5.1Hz, 8.6Hz), 2.43 (IH, dd, J 8.6Hz, 13.7Hz), 2.39-2.31 (2H, m), 2.10 (IH, ddt, J 3.1Hz, 5.9Hz, 12.5Hz), 1.83 (IH, dd, J 5.5Hz, 14.6Hz), 1.74 (IH, dd, J 5.5Hz, 12.8Hz), 1.69-1.56 (2H, ), 1.41 (9H, s). EXAMPLE 9 (lR*,2Z2*,4'S*,5S*)-2',3',4',5'-Tetrahydro-4'-(2- ethoxy-5- trifluoromethoxyphenyl)-l-pb.enylspiro[8-azabicyclo[3.2.1]octane-2,2'- furan] A solution of Hthium aluminium hydride in tetrahydrofuran (1M, 2 ml) was added to a stirred suspension of (lR*,2R*,4'S*,5S*,6_JR*)-2',3^>,4',5'-tetrahydro-4'- (2-methoxy-5-trifluoromethoxyphenyl)-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan]-5-one (Description 12; lOOmg, 0.17mmol) in tetrahydrofuran (4ml) at +5°C. The cold bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with dichloromethane and treated with small amount of saturated aqueous Na₂SO4, stirred for 1 hour and filtered through a pad of Celite™. The filtrate was concentrated in vacuo. The residue was treated with tetrahydrofuran (3ml) followed by triphenylphosphine (220mg, 0.84mmol) and diethyl azodicarboxylate (0.1ml, 0.64mmol) and stirred at room temperature overnight. The mixture was purified by chromatography on silica gel (dichloromethane.-methanol) to give the title compound (35mg, 48%). δ_H (400 MHz, CDCls): 7.60-7.41 (3H, m), 7.33-7.25 (2H, m), 6.93 (IH, dd, J 2.0Hz, 8.8Hz), 6.74 (IH, d, J 2.5Hz), 6.67 (IH, d, J 8.9Hz), 5.70 (IH, br), 3.96 (IH, br s), 3.86 (IH, t, J 7.7Hz), 3.64 (3H, s), 3.57 (IH, dd, J 8.0Hz, 10.6Hz), 2.99 (IH, d, J 8.6Hz), 2.40-2.20 (3H, m), 1.92-1.75 (4H, m), 1.65 (IH, m), 1.50 (IH, m).

The hydrochloride salt of the title compound was prepared by treatment with etheral HCI and recrystallisation from dichloromethane:iso-hexane. HCI salt: δ_H (400 MHz, CDCls): 10.73 (IH, d, J 4.8Hz), 8.96 (IH, d, J 4.8Hz), 7.53 (2H, m), 7.38 (3H, m), 6.97 (IH, dd, J 2.0Hz, 8.8Hz), 6.70 (IH, d, J 2.5Hz), 6.67 (IH, d, J 8.9Hz), 4.90 (IH, br s), 3.94 (IH, t, J 7.9Hz), 3.64 (3H, s), 3.61 (IH, dd, J 8.4Hz, 10.8Hz), 2.74 (IH, m), 2.64 (IH, dt, J 3.6Hz, 12.7Hz), 2.51 (IH, m), 2.40-2.25 (2H, ), 1.93-1.77 (4H, m), 1.70-1.56 (2H, m). MS (ES+) 434 (M+H)⁺. EXAMPLE 10 (LR*,2i2*,4^,S*,5S*,6J2*)-2',3',4',5'-Tetrahydro-4'-(2-hydroxy-5- trifluorotαethoxyphenyl)-l-phenyl-6-pb.enyls lphonylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan] A mixture of (LR*,2R*,4'S*,5S*,6R*)-8-benzyl-2',3',4',5'-tetrahydro-4'-(2- benzyloxy-5-trifluoromethoxyphenyl)-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan] (Description 16; 2.2g, 2.97mmol), 5% palladium on charcoal (3g, 1.4mmol) and ethanol (55ml) was stirred under hydrogen atmosphere (latm) at +70°C for 70 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (1.77g, quant.). δ_H (400 MHz, CDCls): 7.90 (2H, dm, J 7.1Hz), 7.68 (IH, m), 7.58 (2H, t, J 7.8Hz), 7.52 (2H, dd, J 1.9Hz, 7.9Hz), 7.40-7.30 (3H, ), 6.86 (IH, dd, J 1.9Hz, 8.9Hz), 6.70 (IH, d, J 2.4Hz), 6.65 (IH, d, J 8.7Hz), 4.04 (IH, s), 3.83 (IH, t, J 7.7Hz),

3.70-3.65 (2H, m), 2.57 (IH, dd, J 5.3Hz, 14.4Hz), 2.53 (IH, dd, J 8.6Hz, 14.4Hz), 2.34 (IH, dd, J 7.6Hz, 12.7Hz), 2.11 (IH, m), 1.85 (IH, dd, J 5.2Hz, 14.6Hz), 1.72 (IH, m), 1.58 (IH, dd, J 5.7Hz, 14.1Hz), 1.47 (IH, t, J 12.7Hz), 1.46 (IH, m).

EXAMPLE 11

(LR*,2β*,4'S*,5S*,6i2*)-2',3',4',5'-Tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan]

The mixture of (LR*,2R*,4'S*,5S*,6R*)-2',3',4',5'-tetrahydro-4'-(2-hydroxy-5- trifluoromethoxyphenyl)-l-phenyl-6-phenylsulphonylspiro [8- azabicyclo[3.2.1]octane-2,2'-furan] (Example 10; 60mg, O.llmmol), diethyl azodicarboxylate (0.04ml, 0.25mmol), triphenylphosphine (68mg, 0.26mmol), methanol (0.2ml) and tetrahydrofuran (2ml) was stirred at room temperature overnight then concentrated in vacuo and treated with methanol (2ml) followed by 4M aqueous NaOH (0.4ml). The mixture was stirred at room temperature for 24 hours, diluted with brine and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO4) and concentrated. The residue was purified by chromatography on silica gel (isø-hexane:ethyl acetate) to give the title compound (52mg, 84%). δ_H (400 MHz, CDCls): 7.90 (2H, dm, J 7.1Hz), 7.66 (IH, m), 7.57 (2H, t, J 7.9Hz), 7.90 (2H, dd, J 1.9Hz, 8.1Hz), 7.40-7.30 (3H, m), 6.94 (IH, dd, J 2.9Hz, 9.0Hz), 6.74 (IH, d, J 2.8Hz), 6.66 (IH, d, J 8.9Hz), 4.04 (IH, t, J 2.8Hz), 3.80 (IH, t, J 7.6Hz), 3.64 (IH, m), 3.64 (3H, s), 3.5δ (IH, dd, J 8.2Hz, 10.6Hz), 2.56 (IH, dd, J 9.0Hz, 14.5Hz), 2.51 (IH, dd, J 8.6Hz, 14.5Hz), 2.30 (IH, dd, J 7.8Hz, 12.9Hz), 2.12 (IH, ddt, J 3.2Hz, 5.5Hz, 12.9Hz), 1.92 (IH, tt, J 7.4Hz, 11.0Hz), 1.82 (IH, dd, J 5.1Hz, 14.5Hz), 1.54 (IH, dt, J 5.8Hz, 13.7Hz), 1.43 (IH, m), 1.38 (IH, dd, J 11.7Hz, 12.5Hz).

The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallisation from ethyl acetate:diethyl ether. HCI salt: δ_H (400 MHz, MeOH-ά : 8.02 (2H, dm, J 8.6Hz), 7.83 (IH, m), 7.72 (2H, t, J 8.0Hz), 7.60-7.50 (5H, m), 7.03 (IH, dd, J 2.8Hz, 9.0Hz), 6.85 (IH, d, J 9.0Hz), 6.82 (IH, d, J 2.8Hz), 4.49 (IH, s), 4.38 (IH, dd, J 5.5 Hz, 9.4Hz), 3.91 (IH, t, J 7.7Hz), 3.67 (IH, m), 3.67 (3H, s), 3.03 (IH, dd, J 9.5Hz, lδ.OHz), 2.81 (IH, dd, J 5.4Hz, 15.0Hz), 2.34 (2H, dd, J 7.8Hz, 13.0Hz), 2.05-1.95 (2H, m), 1.95-1.75 (2H, m), 1.67 (IH, t, J 13.2Hz). MS (ES-) 574 (M+H)⁺.

EXAMPLE 12

(LR*,2β*,4'/S*,5-S*)-4'-(2-Cyclopropyloxy-5-trifluoromethoxyphenyl)- 2',3',4',5'-tetrahydro-l-phenylspiro[8-azabicyclo[3.2.13octane-2,2'-furan]

Oxone (400mg, 0.65mmol) was added to a stirred mixture of (lR*,2R*,4'S'*,5S^:i:,6R^:I:)-2',3',4',5'-tetrahydro-4'-[2-(l-phenylthiocyclopropyloxy)-5- trifluoromethoxyphenyl]-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan] (Description 17; 88mg, 0.12mmol), wet aluminium oxide (5g of Al₂O3 in 1ml of water, 370mg) and chloroform (5ml) at room temperature. The reaction mixture was stirred for 5 hours then filtered and concentrated to give crude disulphone (95mg). Sodium amalgam (10%, 700mg) was added in small portions to the stirred mixture of the disulphone (95mg), disodium hydrogen orthophosphate (700mg), and methanol (5ml) at +5°C. After reaction went to completion, the mixture was quenched with saturated aqueous NaHCO3, decanted and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO4) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound (34mg, 60%). δ_H (400 MHz, CDC1₃): 7.50-7.20 (5H, m), 7.04 (IH, d, J 8.9Hz), 6.96 (IH, dt, J 2.0Hz, 8.9Hz), 6.72 (IH, d, J 2.6Hz), 3.88 (IH, br s), 3.83 (IH, t, J 7.8Hz), 3.56 (IH, m), 3.50 (IH, dd, J 8.0Hz, 10.6Hz), 2.40-2.10 (4H, m), 1.90-1.70 (5H, m), 1.57 (IH, m), 1.50 (IH, t, J 11.7Hz), 0.74 (2H, m), 0.62 (2H, m).

The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallisation from ethyl acetate:iso-hexane. HCI salt: δ_H (360 MHz, CDCls): 7.51 (5H, m), 7.20 (IH, d, J 9.0Hz), 7.05 (IH, ddd, J 0.9Hz, 2.8Hz, 9.0Hz), 6.85 (IH, d, J 2.8Hz), 4.07 (IH, dd, J 3.1Hz, 7.0Hz), 3.90 (IH, t, J 7.4Hz), 3.67 (IH, m), 3.60 (IH, dd, J 8.1Hz, 10.6Hz), 2.63 (IH, ddd, J 5.0Hz, 10.6Hz, 14.4Hz), 2.50-2.20 (7H, m), 1.95-1.77 (2H, m), 1.76 (IH, t, J 11.7Hz), 0.79 (2H, m), 0.60 (IH, m), 0.53 (IH, m). MS (ES⁺) 460 (M+H) 1⁺+

EXAMPLE 13 (lβ*,2β*,4'S*,5-R*)-2',3',4',5'-Tetrahydro-4'-(2-isopropoxy-5- trifluoromethoxyphenyl)-l-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'- furan] hydrochloride

Palladium hydroxide, 20mg was added to a solution of (LR*,2R*,4'S*,5i?*)-8- benzyl-2',3',4',δ'-tetrahydro-4'-(2-isopropoxy-5-trifluoromethoxyphenyl)-l- phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan] (Example 2; 84mg, O.lδmmol) in ethanol (3ml). The mixture was hydrogenated at 45psi. using the Parr® apparatus for 4 hours. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluting with 150:8:1, dichloromethane:methanol:ammonia to give the title compound (42mg, 60%). The hydrochloride salt was prepared by treatment with ethereal HCI. δ_H (400MHz, MeOΗ.-d₄): 7.50 (5H, br s), 7.02 (IH, dd, J 2.0Hz, 9.0 Hz), 6.87-6.85 (2H, m), 4.48 (IH, heptet, J 6.0Hz), 4.06 (IH, m), 3.98 (IH, t, J 7.7Hz), 3.57 (IH, dd, J 8.0Hz, 10.8Hz), 2.63 (IH, m), 2.46-1.78 (10H, m), 1.2 (3H, d, J 6.0Hz), 1.17 (3H, d, J 6.0Hz). MS (ES)+ 462(M+H)⁺. EXAMPLE 14 (lβ*,2R*,4'S*,5JJ*)-2',3^,,4',5'-Tetrahydro-4^,-(2-(2',2'-difluoro)etlιθ-^-5- trifluoromethoxyphenyl)-l-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'- furan] hydrochloride

Prepared in an analogous manner to Example 13 from Example 3. δ_H (360MHz, MeOH-cf*): 7.51 (5H, br s), 7.08 (IH, dd, J 1.8Hz, 8.1Hz), 6.92 (IH, d, J 9.0Hz), 6.87 (IH, d, J2.7Hz), 6.25-5.94 (IH, tt, J 3.6Hz, 54.7Hz), 4.16-3.96 (4H, m), 3.68-3.63 (IH, m), 2.65-2.60 (IH, m), 2.46-1.79 (10H, m). MS (ES)⁺ 484(M+H)⁺.

EXAMPLE 15 (liJ*,222*,4'S*.5B*)-2',3',4',5'-Tetrahydro-l-phenyl-4'-[2-(2,2,2- trifluoroethoxy)-5-trifluoromethoxyph.enyl)spiro[8- azabicyclo[3.2.1]octane-2,2'-furan] hydrochloride

Prepared in an analogous manner to Example 13 from Example 4. δ_H (400MHz, MeOH-ck): 7.50 (5H, br s), 7.09 (IH, dd, J 1.9Hz, 8.6Hz), 6.94 (IH, d, J 8.9Hz), 6.90 (IH, d, J 2.4Hz), 4.47-4.40 (2H, ), 4.08-4.00 (2H, m), 3.64 (IH, t, J 8.4Hz), 2.66 (IH, m), 2.47-1.79 (10H, m). MS (ES)⁺ 502(M+H)⁺.

EXAMPLE 16 (LR*,2R*,4'S*,5/2*)-4'-[2-(2-Fluoroetlioxy)-5-trifluoromethoxyphenyl]- 2',3',4^,,5'-tetrahydro-l-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan] hydrochloride

Prepared in an analogous manner to Example 13 from Example 5. δ_H (400MHz, MeOH-d₄): 7.51 (5H, br s), 7.0δ (IH, dd, J 1.9Hz, 9.0Hz), 6.88 (IH, d, J 9.0Hz), 6.82 (IH, d, J 2.7Hz), 4.73 (IH, m), 4.61 (IH, m), 4.11 (IH, m), 4.07- 4.04 (2H, ), 4.00 (IH, t, J 7.5Hz), 3.69 (IH, dd, J 8.0Hz, 10.7Hz), 2.64-2.59 (IH, m), 2.46-2.39 (2H, m), 2.31-2.04 (4H, m), 1.94-1.79 (4H, m). MS (ES)⁺ 466(M+H)⁺. EXAMPLE 17 (li2*,2_JR*,4'β*,5,S^:l!,6iJ*)-2',3',4',5^,-Tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)-l-phenyl-6-phenylsulphonylspiro[8- azabicyclo[3.2.1]octane-2,2 Hιr an] hydrochloride 10% Palladium on carbon (lOOmg) was added as a slurry in water (1ml) to a solution of (lR*,2R*,56f*,6R*)-8-benzyl-2',5'-dihydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)-l-phenyl-6-phenylsulfonylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan] (Example 6; 113mg, 0.17mmol) in methanol (10ml). The mixture was hydrogenated using the Parr® apparatus at 50psi. for 20 hours. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluting with 180:8:1, dicHoromethane:methanol: ammonia to yield the title compound (83mg, 86%). The hydrochloride salt was prepared by treatment with ethereal HCI. δ_H (400MHz, MeOH-ώ): 8.03-8.01 (2H, m), 7.85-7.83 (IH, m), 7.83-7.81 (2H, m), 7.56-7.34 (5H, m), 7.00 (IH, m), 6.88 (IH, d, J 9.0Hz), 6.12 (IH, t, 2.2Hz), 4.54 (IH, s), 4.43 (IH, m), 4.11 (IH, m), 3.93-3.85 (IH, ), 3.69 (3H, m), 3.06-2.97 (2H, ), 2.83-2.78 (IH, m), 2.40-2.34 (IH, m), 2.13-1.81 (5H, m). MS(ES)⁺574(M+H)⁺.

EXAMPLE 18 (LR*,2β*,4^,S*,5iJ*)-2',3',4',5'-Tetrahydro-4'-[(2βS)-2,3-dihydro-2-methyl-5- trifluoromethoxybenzofuran-7-yl]-l-phenyl-6-phenylsulphonylspiro[8- azabieyclo[3.2.1]octane-2,2'-fu an] A mixture of (LR*,2R*,4'S*,5R*)-8-benzyl-2',3',4',5'-tetrahydro-4'-[(2RS)-2,3- dihydro-2-m.ethyl-5-trifluoroniethoxybenzofuran-7-yl]-l-phenyl-6- phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan] (Example 7; 200mg, 0.29mmol), 10% palladium on charcoal (375mg, 0.35mmol) and ethanol (25ml) was stirred under hydrogen atmosphere (latm) at +70°C for 30 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (160mg, 92%). δ_H (360 MHz, MeOH-ώ): 8.02 (2H, dm, J 8.1Hz), 7.82 (IH, t, J 7.3Hz), 7.72 (2H, t, J 7.8Hz), 7.33 (5H, m), 6.89 (IH, s), 6.44 (IH, br s), 4.84 (IH, m), 4.44 (IH, s), 4.37 (IH, dd, J 5.3Hz, 9.1Hz), 3.87 (IH, dt, J 8.1Hz, 13.7Hz), 3.73 (IH, q, J 9.8Hz), 3.23 (IH, dd, J 8.8Hz, 16.1Hz), 2.99 (IH, dd, J 9.5Hz, 15.1Hz), 2.77 (IH, dd, J 5.3Hz, 15.0Hz), 2.71 (IH, dd, J 7.7Hz, 16.1Hz), 2.28 (2H, m), 1.96 (2H, m), 1.80 (2H, m), 1.56 (IH, m), 1.35 (3H, d, J 6.3Hz).

EXAMPLE 19 (LR*,aR*,4^,S*,5S*)-2',3',4',5'-Tetrahydro-4'-[(2KS)-2,3-dihydro-2-methyl-5- trifluoromethoxybenzofuran-7-yl]-l-phenylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan] Sodium amalgam (10%, 2g) was added in small portions to stirred mixture of (li2*,2R.*,4'-5*,5R*)-2',3',4',5'-tetrahydro-4'-[(2R.S)-2,3-dihydro-2-methyl-5- trifluoromethoxybenzofuran-7-yl] -l-phenyl-6-phenylsulphonylspiro [8- azabicyclo[3.2.1]octane-2,2'-furan] (Example 18; 160mg, 0.26mmol), disodium hydrogen orthophosphate (500mg), methanol (10ml) at +δ°C. After reaction went to completion, the mixture was quenched with saturated aqueous NaHCO3, decanted and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound (83mg, 67%). δ_H (400 MHz, CDCls): 7.40-7.20 (5H, m), 6.79 (IH, s), 6.45 (0.5H, d, J 1.6Hz), 6.43 (0.5H, d, J 1.6Hz), 4.88 (IH, m), 3.76 (IH, m), 3.70-3.55 (2H, m), 3.21 (0.5H, dd, J 5.0Hz, 15.0Hz), 3.19 (0.5H, dd, J 4.9Hz, 15.0Hz), 2.69 (IH, dd, J 7.4Hz, 15.7Hz), 2.27 (IH, ), 2.15 (3H, m), 2.01 (IH, ddt, J2.7Hz, 5.9Hz, 12.5Hz), 1.87 (IH, ddt, J 2.7Hz, 5.1Hz, 14.1Hz), 1.81-1.48 (5H, m), 1.38 (1.5H, d, J 6.3Hz), 1.37 (1.5H, d, J 6.3Hz).

The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallisation from dichloromethane: terf-butyl methyl ether. HCI salt: δ_H (360 MHz, -d₄): 7.51 (5H, m), 6.90 (IH, s), 6.48 (0.5H, s), 6.47 (0.5H, s), 4.88 (IH, m), 4.07 (IH, m), 3.89 (0.5H, dd, J 5.3Hz, 7.9Hz), 3.87 (0.5H, dd, J 5.5Hz, 7.6Hz), 3.76 (0.5H, dd, J 8.2Hz, 9.7Hz), 3.73 (0.5H, dd, J 8.1Hz, 9.7Hz), 3.25 (IH, dd, J 8.7Hz, 15.8Hz), 2.73 (IH, dd, J 7.4Hz, 15.8Hz), 2.65 (0.5H, dd, J 4.7Hz, 10.3Hz), 2.62 (0.5H, dd, J 4.5Hz, 9.7Hz), 2.44 (IH, dd, J 4.2Hz, 12.3Hz), 2.40-20 (4H, m), 2.16 (IH, dd, J 4.0Hz, 9.7 Hz), 2.13 (IH, dd, J 4.7Hz, 9.2Hz), 2.06 (IH, dd, J 5.5Hz, 13.4Hz), 1.97-1.75 (4H, m), 1.61 (IH, m), 1.36 (3H, d, J 6.3Hz).

MS (ES+) 460 (M+H)⁺.

EXAMPLE 20 (LR*,2i2*,4^,S*,5iϊ*)-2',3',4',5'-Tetrahydro-4'-(2-methoxy.5- trifluoromethoxyphenyl)-6-(morpholin-l-ylcarbonyl)-l-phenylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan]

Step (a) - The mixture of (lR*,2R*,4'-5*,5R*)-6-(terf-Butoxycarbonyl)-2',3',4',5'- tetrahydro-4'-(2-hydroxy-δ-trifluoromethoxyphenyl)- 1-phenylspiro [8- azabicyclo[3.2.1]octane-2,2'-furan] (Example 8; 900mg, 1.73mmol), diethyl azodicarboxylate (0.37ml, 1.72mmol), triphenylphosphine (800mg, 3.0mmol), methanol (1ml) and tetrahydrofuran (10ml) was stirred at room temperature for 2 hours. A few drops of water were added and the mixture was concentrated. The residue was purified by chromatography on silica gel to give a 1:1 mixture of (LR*,2R*,4',S*,5R*)-6-(tert-butoxycarbonyl)-2',3',4',5'-tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)- 1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] and (LR*,2R*,4'S*,5R*)-6-(tert-butoxycarbonyl)-2',3',4',5'-tetrahydro-4'-(2-methoxy-5- trifluorom.ethoxyphenyl)-8-niethyl-l-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'- furan] (500mg). This mixture was treated with dichloromethane (7ml) and trifluoroacetic acid (3ml) and stirred at room temperature for 24 hours and concentrated. The residue was treated with dichloromethane (6ml) to form a solution of carboxylic acid.

Step (b) - A portion of the solution (2ml) was treated with morpholine (0.1 δml, 1.72mmol), triethylamine (0.2ml, 2.7mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (140mg, 0.73mmol), and 4-N,N- dimethylaminopyridine (lOmg, O.Oδmmol). The mixture was stirred for 4 days, diluted with dichloromethane, washed with 10% aqueous citric acid, dried (Na2SO₄) and concentrated. The residue was purified by preparative TLC on silica gel (dichloromethane:methanol) to give the title compound (2δ mg). δ_H (400 MHz, CDCls): 7.52 (2H, m), 7.35-7.25 (3H, m), 6.95 (IH, dd, J 2.0Hz, 8.9Hz), 6.78 (IH, d, J 2.6Hz), 6.67 (IH, d, J 8.9Hz), 3.83 (IH, t, J 7.4Hz), 3.77 (IH, br s), 3.71 (2H, m), 3.65 (3H, s), 3.70-3.50 (6H, m), 3.14 (IH, dd, J 5.1Hz, 8.6Hz), 2.75 (IH, br), 2.49 (IH, dd, J 8.6Hz, 13.3Hz), 2.43 (IH, dd, J 5.1Hz, 13.3Hz), 2.36 (IH, dd, J 7.8Hz, 12.5Hz), 2.19 (IH, ddt, J 2.7Hz, 5.5Hz, 12.9Hz), 1.94 (IH, tt, J 7.0Hz, 14.5Hz), 1.85 (IH, dd, J 5.1Hz, 14.1Hz), 1.74 (IH, td, J 5.5Hz, 12.9Hz), 1.58 (2H, m), 1.43 (IH, dd, J 11.8Hz, 12.1Hz).

The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallisation from dichloromethane:tert-butyl methyl ether. HCI salt: δ_H (360 MHz, MeOH-ώ): 7.52 (5H, m), 7.0δ (IH, dd, J 1.9Hz, 8.9Hz), 6.87 (IH, d, J 9.0Hz), 4.36 (IH, br s), 3.93 (IH, t, J 7.6Hz), 3.80-3.60 (10H, m), 3.69 (3H, s), 3.14 (IH, dd, J 10.1Hz, 14.1Hz), 2.46 (IH, dd, J 5.0Hz, 14.2Hz), 2.40 (IH, dd, J 7.6Hz, 13.2Hz), 2.30 (IH, m), 2.14 (IH, dt, J 4.5Hz, 13.7Hz), 1.97 (IH, dd, J 4.7Hz, 14.5Hz), 1.97-1.81 (2H, m), 1.72 (IH, t, J 12.9Hz), 1.19 (2H, s). MS (ES⁺) 547 (M+H)⁺.

EXAMPLE 21 (lR*,2β*,4'S*,5β^ii:)-2',3^,,4',5'-tetrahydro-4'-(2- ethoxy-5- trifluoromethoxyphenyl)-6-(3-methoxypropylammocarbonyl)-l- phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan]; and

EXAMPLE 22 (lβ*,2K*,4'S*,5β*)-2',3',4',5'-tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)-6-(3-Bαethoxypropylammocarbonyl)-8-methyl-l- phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan]

A portion of the solution from Step (a) of Example 20 (2ml) was treated with 3- methoxypropylamine (0.15ml, 1.94mmol), triethylamine (0.2ml, 2.7mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (300mg, 1.56mmol), and 4-N,N-dimethylajninopyridine (20mg, O.lβmmol). The mixture was stirred for 4 days, diluted with dichloromethane, washed with 10% aqueous citric acid, dried (Na₂SO4) and concentrated. The residue was purified by preparative TLC on silica gel (dichloromethane:methanol) to give (lR*,2i2*,4'iS*,5i2*)-2',3',4',δ'- tetrahydro-6-(3-methoxypropylaminocarbonyl)-4'-(2-methoxy-5- trifluoromethoxyphenyl)-l-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] (21 mg) and (lR*,2R*,4'S*,5i2*)-2',3',4',5'-tetrahydro-6-(3- methoxypropylaminocarbonyl)-4'-(2-methoxy-5-trifluorom.ethoxyphenyl)-8- methyl-l-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan] (21 mg). Example 21: δ_H (360 MHz, CDC1₃): 7.40-7.25 (5H, m), 6.96 (IH, dd, J 2.6Hz, 8.8Hz), 6.75 (IH, d, J 2.7Hz), 6.67 (IH, d, J 9.0Hz), 3.79 (IH, t, J 7.7Hz), 3.65 (3H, s), 3.64 (IH, t, J 2.3Hz), 3.55 (IH, dd, J 7.7Hz, 10.5Hz); 3.30-3.12 (4H, m), 3.08 (3H, s), 2.77 (IH, dd, J 3.9Hz, 9.5Hz), 2.71 (IH, br), 2.54 (IH, dd, J 9.1Hz, 13.3Hz), 2.29 (IH, dd, J 7.7Hz, 12.3Hz), 2.25 (IH, dd, J 3.9Hz, 13.3Hz), 1.98 (IH, m), 1.88 (IH, m), 1.82-1.72 (2H, m), 1.68-1.55 (3H, m), 1.43 (IH, t, J 12.3Hz). Example 22: δ_H (360 MHz, CDCI3): 7.59 (2H, dm, J 6.8Hz), 7.40-7.30 (3H, m), 6.95 (IH, dd, J 2.0Hz, 9.0Hz), 6.73 (IH, d, J2.7Hz), 6.66 (IH, d, J 8.9Hz), 3.96 (IH, t, J 7.7Hz), 3.89 (IH, br s), 3.64 (3H, s), 3.59 (IH, dd, J 8.1Hz, 10.9Hz), 3.48 (3H, m), 3.39 (2H, m), 3.33 (3H, s), 3.11 (IH, dd, J 5.3Hz, 13.7Hz), 2.95 (IH, dd, J δ.6Hz, 8.7Hz), 2.38 (IH, br t, J 11.2Hz), 2.27 (IH, dd, J 9.8Hz, 13.7Hz), 2.23 (3H, s), 2.13 (IH, dd, J 8.1Hz, 12.6Hz), 1.90 (IH, dd, J 4.6Hz, 13.0Hz), 1.86-1.67 (5H, m), 1.44 (IH, t, J 12.3Hz). MS (ES+) 560 (M+H)⁺.

The hydrochloride salts of Example 21 and Example 22 were prepared by treatment with ethereal HCI.

HCI salt of Example 21: δ_H (360 MHz, MeOH-ck): 7.52 (5H, m), 7.05 (IH, dd, J 1.6Hz, 8.7Hz), 6.86 (IH, d, J 8.9Hz), 6.85 (IH, d, J 2.8Hz), 4.20 (IH, s), 3.93 (IH, t, J 7.6Hz), 3.68 (IH, m), 3.68 (3H, s), 3.42 (2H, t, J 6.1Hz), 3.40-3.15 (6H, m), 2.95 (IH, dd, J 7.7Hz, 9.8Hz), 2.64 (IH, dd, J4.6Hz, 14.2Hz), 2.40 (IH, dd, J 7.6Hz, 13.2Hz), 2.30 (IH, m), 2.10-1.80 (4H, m), 1.70-1.55 (3H, ), 1.17 (2H, s). HCI salt of Example 22: δ_H (360 MHz, MeOH-Λ): 7.65-7.45 (5H, m), 7.04 (IH, ddd, J 1.1Hz, 2.6Hz, 8.8Hz), 6.86 (IH, d, J 9.1Hz), 6.83 (IH, d, J 2.9Hz), 4.30 (IH, br s), 4.04 (IH, dd, J 6.7Hz, 8.5Hz), 3.74 (IH, dd, J 8.2Hz, 10.8Hz), 3.67 (3H, s), 3.44 (2H, t, J 6.1Hz), ), 3.67 (IH, dd, J 5.5Hz, 9.9Hz), 3.40-3.15 (5H, m), 3.15 (IH, dd, J 5.8Hz, 14.6Hz), 2.86 (IH, dd, J 10.2Hz, 14.6Hz), 2.65 (3H, s), 2.43 (IH, m), 2.22 (IH, dd, J 7.0Hz, 11.7Hz), 2.17-2.01 (3H, m), 1.86-1.70 (4H, m). MS (ES⁺) 564 (M+H)⁺.

Claims

CLAIMS:

A compound of the formula (I):

(I)

wherein

Z is -CR⁹R¹⁰CH₂- or -CH₂CR⁹R¹⁰-;

R¹ represents hydrogen, hydroxy, Ci-βalkyl, C2-6alkenyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, Ci-βalkoxy, fluoroCi-βalkoxy, hydroxy Ci-βalkyl, Cι-6alkoxyCι-4alkyl, Ci-βalkoxyCwalkoxy, fluoroCι-6alkoxyCι-4alkyl, C₂-6alkenyloxy, C3-7cycloalkoxy, Cs-7cycloalkylCι-4alkoxy, phenoxy, benzyloxy, cyano, halogen, NR^aR^b, SR^a, SOR^a, SO₂R^a, OSO₂R^a, NR^aCOR¹², COR^a, CO₂R^a or CONR^aR^b where R^a and R^b each independently represent hydrogen, Cι-4alkyl or fluoroCι-4alkyl;

R² represents hydrogen, halogen, Ci-βalkyl or Ci-ealkoxy; 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 NR^C, which ring is optionally substituted by one, two or three groups selected from hydroxy, Cι-4alkyl, Cι-3alkoxyCι-3alkyl, phenyl, =O or =S, where R^c is Cι-4alkyl, hydroxyCwalkyl, Cι-4alkoxyCι-4alkyl, fluoroCι-4alkyl, phenyl or benzyl;

R³ represents hydrogen, halogen, Ci-βalkyl, fluoroCi-βalkyl, Ci-βalkoxy, fluoroCι-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, cyano, SR^a, SOR^a, SO₂R^a, NR^aR^b, NR^aCOR¹², COR^a, CO₂R^a, CONR^aR^b or substituted by cyano, CO2R²¹ or CONR^aR^b where R^a and R^b 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, SR^a, SOR^a, SO₂R^a, COR^a, CO₂R^a, phenyl, -(CH₂)rNR^aR^b,

-(CH₂)rNR^aCOR , -(CH₂)rCONR^aR^b, or CH₂C(O)R^a, where R^a and R^b are as previously defined and r is zero, 1 or 2;

R⁴ represents hydrogen, halogen, Ci-βalkyl, Ci-βalkoxy, CF3, OCF3, NO2, CN, SR^a, SOR^a, SO₂R^a, CO₂R^a, CONR^aR^b, C₂.₆alkenyl, C₂-6alkynyl or Cwalkyl substituted by Cι-4alkoxy, where R^a and R^b are as previously defined;

R⁵ represents hydrogen, halogen, Ci-βalkyl, CF3 or Ci-βalkoxy substituted by Cι-4alkoxy;

R⁶ represents hydrogen, hydroxy, COR^a, CO₂R^a, COCONR^aR , COCO₂R^a, Ci-βalkyl optionally substituted by a group selected from (CO2R^a, CONR^aR^b, hydroxy, CN, COR^a, NR^aR^b, C(NOH)NR^aR^b, CONHphenyl(Cι-4alkyl), COCO₂R^a, CONHNR^aR^b, C(S)NR^aR^b, CONR^aCι-₆alkylR¹⁴, CONR¹¹C2-₆alkenyl, CONR^C^ealkynyl, COCONR^aR , CONR^aC(NR )NR^aR^b, CONR^aheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from Cx-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 =O or =S and optionally substituted by a group of the formula -Y-NR R⁸ where

Y is Ci ealkylene or Cs-βcycloalkyl;

R⁷ represents hydrogen or Cι-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, or C₂-4alkyl substituted by Cι-4alkoxy or hydroxyl;

R⁸ represents hydrogen or Cι-4alkyl, Cι-4alkoxy, C3-7cycloalkyl, C3-7cyeloaIkylCι-4alkyl, or C_2-4alkyl substituted by a group selected from

Cι-₄alkoxy, hydroxyl, CO₂R^a, NR^aR^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 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 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 NR^C moiety where R^c 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 Y, 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-ealkyl, C₂-6alkenyl, C₂-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, fluoroCi-βalkyl, Ci-βalkoxy, fluoroCι-6alkoxy, hydroxyCi-βalkyl, Cι-6alkoxyCι-4alkyl, fluoroCι-6alkoxyCι-4alkyl, C₂-6alkenyloxy, C₂-6alkynyloxy, C3-7cycloalkoxy, C3-7cycloalkylCι-4alkoxy, aryl, aryl(CH ), aryloxy, aryl(CH₂)oxy, cyano, halogen, NR⁷R⁸, CH₂NR⁷R⁸, SR¹², SOR¹², SO₂R¹², OSO2R¹², NR^aCOR¹², CH(OH)R¹², COR¹², CO2R¹², CONR⁷R⁸, CH2OR¹³, heteroaryl or heteroarylCι-4alkyl, wherein R^a 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, Cι-6alkoxy, halogen or trifluoromethyl;

R¹³ represents Cι-₄alkyl substituted by a group selected from hydroxy, COR^a, CO₂R^a, CONR^aR^b and heteroaryl, where R^a is as previously defined;

R¹⁴ represents OR^a, CONR^aR^b or heteroaryl; and pharmaceutically acceptable salts or N-oxides thereof.

2. A compound as claimed in Claim 1 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.

3. A compound as claimed in Claim 1 or Claim 2 wherein R² is a hydrogen, fluorine or chlorine atom.

4. A compound as claimed in any one of Claims 1 to 3 wherein R³ is a hydrogen or halogen atom or a fluoroCi-ealkoxy group or a 5-membered aromatic heterocyclic group as defined in Claim 1.

5. A compound as claimed in any one of Claims 1 to 4 wherein R⁴ is hydrogen or fluorine.

6. A compound as claimed in any one of Claims 1 to 5 wherein R⁵ is hydrogen.

7. A compound as claimed in any one of Claims 1 to 6 wherein R⁶ is hydrogen or Cι-6alkyl, or a Ci-βalkyl group substituted by a 5-membered heterocyclic ring containing 2 or 3 nitrogen atoms as defined in Claim 1.

8. A compound as claimed in any one of Claims 1 to 7 wherein Z is -CR⁹R¹⁰CH₂-.

9. A compound as claimed in any one of Claims 1 to 8 wherein R⁹ is hydrogen, hydroxy, oxo, Ci-βalkoxy, Cι-6alkoxyCι-4alkyl, hydroxyCwalkyl, cyano, NR⁷R⁸, CH₂NR⁷R⁸, SO₂R^d, CH(OH)R¹², COR¹², CO₂R¹², CONR⁷R⁸, phenyl, heteroaryl, heteroarylCι-4alkyl or CH₂OR¹³, where said phenyl is optionally substituted by one or two substituents selected from Cι-4alkyl, Cι-4alkoxy, halogen or trifluoromethyl.

10. A compound as claimed in any one of Claims 1 to 9 wherein R¹⁰ is hydrogen, fluorine or hydroxy.

11. A compound of the formula (la):

(la)

wherein R¹, R², R³ and R⁴ are as defined in Claim 1 and Z is -CR⁹R¹⁰CH₂-; or a pharmaceutically acceptable salt thereof.

12. A compound as claimed in Claim 1 selected from:

(lR*,2R*,4'S*,5S^:i:)-2',3',4',5'-tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)- 1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] ;

(lR*,2R*,4'₁S*,5,S^:i;,6B*)-2',3',4',5'-tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)- l-phenyl-6-phenylsulphonylspiro [8- azabicyclo [3.2.1] octane-2,2'-fur n] ; dR*,2B*,4^,S*,5S*)-4^,-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)- 2',3',4',5'- tetrahydro-l-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan];

(LR*,2B^:1:,4'S^ϊf:,5R^:,:)-2',3',4',δ'-tetrahydro-4'-(2-isopropoxy-5- trifiuoromethoxyphenyl)- 1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-fur an] ;

(lR*,2R*,4'S*,5R*)-2',3',4',5'-tetrahydro-4'-(2-(2',2'-difluoro)ethoxy-5- trifluoromethoxyphenyl)-l-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] ; (lR*,2i2*,4'S^,*,5R*)-2',3',4',δ'-tetrahydro-l-phenyl-4'-[2-(2,2,2-trifluoroethoxy)-5- trifluoromethoxyphenyl)spiro [8-azabicyclo [3.2.1] octane-2 ,2'-furan] ;

(LR*,2R*,4'S*,5R^:!:)-4'-[2-(2-Fluoroethoxy)-5-trifluoromethoxyphenyl]-2',3',4',5'- tetrahydro-l-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan];

(LR*,2R*,4'5*,5S*)-2',3',4',5'-tetrahydro-4'-[(2R5')-2,3-dihydro-2-methyl-5- trifluoromethoxybenzofuran-7-yl] -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'- furan]; (lR*,2R*,4'S*,5R*)-2',3',4',5^,-tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)-6-(morphoπn-l-ylcarbonyl)-l-phenylspiro[8- azabicyclo [3.2.1] octane-2,2'-fur an] ;

(lR*,2R*,4'5'*,5R*)-2',3',4',5⁵-tetrahydro-4'-(2-methoxy-5- trifluoromethoxyphenyl)-6-(3-methoxyproρylaminocarbonyl)-l-phenylspiro[8- azabicyclo[3.2.1]octane-2,2'-furan];

(lR*,2R*,4'5f*,5R*)-2',3',4',5'-tetrahydro-4'-(2-methoxy-5- trifluoromLethoxyphenyl)-6-(3-methoxypropylaminocarbonyl)-8-methyl-l- phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] ; or a pharmaceutically acceptable salt thereof.

13. A compound as claimed in any one of Claims 1 to 10 wherein the stereochemistry of the 1- 2-, 4'- and 5-positions is as shown in formula (lb):

(lb)

14. A compound according to any one of Claims 1 to 13 for use in therapy.

15. A pharmaceutical composition comprising a compound as claimed in Claim 1, together with at least one pharmaceutically acceptable carrier or excipient.

16. 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.

17. A method according to Claim 16 for the treatment or prevention of pain or inflammation, migraine, emesis, postherpetic neuralgia, depression or anxiety.

18. The use of a compound according to any one of Claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of physiological disorders associated with an excess of tachykinins.

19. The use of a compound according to any one of Claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of pain or inflammation, migraine, emesis, postherpetic neuralgia, depression or anxiety.