CA2237638A1 - Spiro-piperidine derivatives and their use as tachykinin antagonists - Google Patents

Abstract

The present invention relates to compounds of formula (I), wherein R1 represents halogen, hydroxy, C1-6alkyl group optionally substituted by one to three fluorine atoms, C1-6alkoxy group optionally substituted by one to three fluorine atoms, or C1-6alkylthio optionally substituted by one to three fluorine atoms; R2 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; 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 oxygen atoms; R3 represents an optionally substituted 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur; R4, R5, R9 and R10 are a variety of substituents; R6 represents hydrogen, CORa, CO2Ra, COCONRaRb, COCO2Ra, C1-6alkyl optionally substituted by a group selected from (CO2Ra, CONRaRb, hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONHphenyl(C1-4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaC1-6alkylR12, CONR13C2-6alkenyl, CONR13C2-6alkynyl, COCONRaRb, CONRaC(NRb)NRaRb, CONRaheteroaryl, and optionally substituted phenyl) or -CH2CCCH2NR7R8 or C1-6alkyl, optionally substituted by oxo, substituted by an optionally substituted 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms; m is 0-3 and n is 0-3, with the proviso that the sum total of m+n is 2 or 3; p is zero or 1; q is 1 or 2; and when m is 1 and n is 1 or 2, the broken line represents an optional double bond; or a pharmaceutically acceptable salt thereof. The compounds are of particular use in the treatment or prevention of pain, inflammation, migraine, emesis and postherpetic neuralgia.

Description

CA 02237638 1998-0~-12 SPnRO-P~ERnDnNE DERlVAlTVES AND THEnR USE AS TAC~ ~ nNnN ANTAGONISlS

This invention relates to a class of azacyclic compounds which are 5 useful as tachykinin antagonists. More particularly, the compounds of the invention are spiro-substituted azacyclic derivatives.
The tachykinins are a group of naturally OC~:ur~illg peptides found widely distributed throughout m~mm~ n tissues, both within the central nervous system and in peripheral nervous and circulatory systems.
The tachykinins are distinguished by a conserved carboxyl-terminal se~uence:
Phe-X-Gly-Leu-Met-NH2 At present, there are three known m~mm~ n tachykinins referred to as substance P, neurokinin A (NKA, substance K, neuromedin L) and neurokinin B (NKB, neuromedin K) (for review see J.E. Maggio, Peptides (1986) 6(suppl. 3), 237-242). The current nomenclature designates the three tachykinin receptors mediating the biological ~cti~n~ of substance P, NKA and NKB as the NK1~ N K2 and N ~3 receptors, respectively.
Evidence for the use~ulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflz~mm~tory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, intl~mm~tory diseases of the gut including ulcerative colitis and Crohn's disease, ocular inJury and ocular infl~mm~tory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyper-reflexia is reviewed in "Tachykinin 3~eceptors and Tachykinin Receptor Antagonists", C.A. Maggi, R.
Patacchini, P. Rovero and A. C~iachetti, J. Auto7~. Pharmacol. (1993) ~, 23-~3.

W O 97/19084 PCT/GB96/028~3 For instance, substance P is believed inter alia to be involved in the neurotr~n.~mi.~inn of pain sensations [Otsuka et al, "Role of Substance P
as a Sensory Tr~qn.~mi~.ter in Spinal Cord and Sympathetic Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 6 13-34 (published by Pitman) and Otsuka and Y~n~ wa, "Does Substance P Act as a Pain Tr:~n.cmit.ter?" TIPS (1987) ~, 506-510~, specifically in the tr~n.qmi~.si~n of pain in migraine (B.E.B. Sandberg et al~
J. Med Ch~m, (19~i2) 25, 1009) and in arthritis [Levine et al Scie7~ce (1984) 226, 547-549]. Tachykinins have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract such as infl~mm~tory bowel disease lMantyh et al Neuroscience (1988) ~(3), 817-37 and D. Regoli in "Tre7~ds in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific Publishers, Amsterdam (1987) page 8~)] and emesis [F. D. Tattersall et al, Eur. J. Pharmacol., (1993) 250, R5-R6]. It is also hypothesised that there is a neurogenic meçhz~ni~m for arthritis in which substance P may play a role ~Kidd et al "A Neurogenic Mer.h~ni~m for Symmetrical Arthritis" in The Lancet, 11 November 1989 and Gronblad et al, "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J.
Rheumatol. (1988) 15(12), 1807-10~. Therefore, substance P is believed to be involved in the inll~mm~tory response in diseases such as rheumatoid arthritis and osteoarthritis, and fibrositis [O'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8]. Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al, Can. cJ. Pha7 macol. Physz;ol. (1988) 66, 1361-7], immunoregulation [Lotz et al, Science (1988) 241, 1218-21 and Kimball et al, J. Im7nunol. (1988) 141(10), 3564-9~ vasodilation, bronchospasm, reflex or neuronal control of the viscera ~Mantyh et al, PNAS (1988) 85, 323O-9~ and. possibly by arresting or slowing B-amyloid-mediated neurodegenerative changes ~, CYankner et al, Science (1990) 250, 279-82~ in senile dementia of the Alzheimer type, Alzheimer's disease and Down's Syndrome.

CA 02237638 1998-0~-12 Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular small cell lung cancer (SCLC~ [Langdon et al"
Cc~ncer Research (1992) 52, 4554-7].
Substance P may also play a role iIl demy~lin~t.in~ diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et al, poster C.I.N.P. XVIIIth Congress, 28th June-2nd July lg92~, and in disorders of bladder function such as bladder detrusor hyper-reflexia (lancet, 16th May 1992~ 1239).
It has furthermore been suggested that tachyl~nins have utility in the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersen~i~ivil,y disorders such as poison ivy, vasospastic diseases such as Z~ngin~ and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fasci~ iR, reflex sympathetic dy~Llo~hy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enhancement or suppression such as systemic lupus erythmatosus (European patent spe- ffl~tion no. 0 436 334), ophth~lmic disease such as conjuctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis (European patent spef~ific~ti-)n no. 0 394 989).
International (PCT) patent specification no. WO 9~/20500 (published 15th September 1994) discloses spiroazacyclic derivatives as substance P antagonists. In particular, WO 94/20500 relates to spirocyclic piperidine derivatives cont~ining a 1,8-diazaspiro[5.5]undecane core.
We have now found a further class of non-peptides which are potent antagonists of tachykinins, especially of substance P. In addition, the compounds of the present invention exhibit a high level of hepatic stability as measured by, for example, conventional liver microsome analysis.
The present invention provides compounds of the formula (I):

CA 02237638 1998-0',-12 Rl o (Cx~ ~ R2 R9 ~ ~ (C ~
~ I ~ (CH2)p - R3 (I~
wherein Rl represents a halogen atom, a hydroxy group, a Cl 6alkyl group optionally substituted by one to three ~1uorine atoms, or a Cl 6alkoxy group 5 optionally substituted by one to three ~uorine atoms, or a Cl 6alkylthio group optionally substituted by one to three ~uorine atoms;
R2 represents hydrogen, halogen, C1 6alkyl or Cl.6alkoxy;
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 10 cont~inin~ one or two oxygen atoms;
R3 represents a 5- or 6-membered aromatic heterocyclic group cont.~ining 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from Cl 6alkyl, Cl 6alkoxy, C3 7cycloalkyl, C3 7cycloalkylCl 4alkyl, 15 trifluoromethyl, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, phenyl, ~(CH2)rNRaRb~ -(CH2)rNRaCORb, ~(CH2)rCONRaRb~ or CH2C(O)Ra, where Ra and Rb are each independently hydrogen or Cl 4alkyl and r is zero, 1 or 2;
R4 represents hydrogen, halogen, C~ 6alkyl, Cl Galkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CO2:Ra, CONRaRb, C2 6alkenyl, C2 6alkynyl or 20 Cl 4alkyl substituted by Cl ~lkoxy, where Ra and Rb each independently represent hydrogen or Cl 4alkyl;
R5 represents hydrogen, halogen, Cl Galkyl, C~ ~,alkoxy substituted by C, 4alkoxy or CF3;
R6 represents hydrogen, CORa, CO2Ra, COCONRaRb, COCO2Ra, 25 Cl 6alkyl optionally substituted by a group selected from (CO2Ra, CA 02237638 1998-0~-12 CONRaRb, hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONHphenyl(Cl 4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaCl 6alkylRl2, CONRl3C~6alkenyl, CONRl3C2.6alkynyl, COCONRaRb, CONRaC(NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from Cl 6alkyl, Cl 6alkoxy, halogen and trifluoromethyl);
or R6 represents a group of the formula -CHgC_CCH2NR7R8 where R7 and R8 are as defined below;
or R6 represents Cl 6alkyl, optionally substituted by oxo, substituted by a ~-membered or 6-membered heterocyclic ring cont~ininE 1, 2 or 3 nitrogen atoms optionally substituted by =O or =S and optionally substituted by a group of the formula ZNR7R8 where Z is Cl 6alkylene or C3 6cycloalkyl;
R7 is hydrogen or Cl 4alkyl, C3 7cycloalkyl, C3 7cycloalkylCl 4alkyl, or C~4alkyl substituted by Cl 4alkoxy or hydroxyl;
R8 is hydrogen or Cl 4alkyl, C3 7cycloalkyl, C3 7cycloalkylCl 4alkyl, or ~2 4alkyl substituted by Cl 4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring cont.~ining 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 or Cl 4alkoxy optionally substituted by a C1 4alkoxy or hydroxyl group, and optionally cont~ining a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O3 or S(O32 or a second nitrogen atom which will be part of a NH
or NRC moiety where Rc is C1 4alkyl optionally substituted by hydroxy or 4 Cl-4alkoxy;
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;

CA 02237638 1998-0~-12 or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contaln an oxygen ring atom;
R9 and Rl~ each independently represent hydrogen, halogen, 5 Cl.6al:kyl, CH20Rd, oxo, CO2Ra or CONRaRb where Ra and Rb are as previously det~ined and Rd represents hydrogen, Cl 6alkyl or phenyl;
Rl2 represents ORa, CONRaRb or heteroaryl;
Rl3 represents H or Cl.~alkyl;
m is zero 1, 2 or 3;
n is zero, 1, 2, or 3, with the proviso that the sum total of m+n is 2 or 3;
p is zero or 1;
qis 1 or 2; and when m is 1 and n is 1 or 2, the broken line represents an optional double bond;
and pharmaceutically acceptable salts thereo~
A preferred class of compound of formula (I) is that wherein Rl represents a Cl 6alkyl group optionally substituted by one to three fluorine atoms, or a Cl ~alkoxy group optionally substituted by one to three fluorine atoms.
Another preferred class of compound of formula (I) is that wherein:
Rl represents a Cl Galkyl group optionally substituted by one to three ~uorine atoms, or a Cl 6alkoxy group optionally substituted by one to three fluorine atoms;
R2 represents hydrogen, halogen, Cl Galkyl or Cl.~alkoxy;
R3 represents a 6- or 6-membered aromatic heterocyclic group cont~ining 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by a group selected from Cl 6alkyl, Cl 6alkoxy, C3 7cycloalkyl, C3 7cycloaL"ylC~ 4alkyl, trifluoromethyl, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, phenyl, ~(CH2)rNRaRb~ ~(CH2)rNRaCORb~ -(CH2)rCONRaRb~ or CH2C(O)Ra, where Ra and Rb are each independently hydrogen or Cl.4alkyl and r is zero, 1 or 2;
and R6 represents hydrogen, CORa, CO2RR, COCON~aRb, COCO2Ra, Cl 6alkyl optionally substituted by a group selected from ((~02Ra, '' 6 CONRaRb, hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONHphenyl(Cl.4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb C:~ONRaCl 6alkylRl2, CONRI3C2 6alkenyl, CONRl3C2 6alkynyl, COCONRaRb, CONRaC(NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from Cl 6alkyl, Cl 6alkoxy, 10 halogen and trifluoromethyl3 or Cl 6alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring cont.s~ining 1, 2 or 3 nitrogen àtoms optionally substituted by =O or =S and optionally substituted by a group of the formula ~NR7R8 where Z, R7 and R8 are as previously defined;
1~ and pharmaceutically acceptable salts thereof.
A further preferred class of compound of the present invention is that of the formula (I') Rl R

~R3 (I') 20 wherein Rl represents a Cl.6alkyl group optionally substituted by one to three fluorine atoms, or a Cl Galkoxy group op~ionally substituted by one to three fluorine atoms;
R2 represents hydrogen or halogen;

CA 02237638 1998-0~-12 W O 97/19084 PCTtGB96/02853 R3 represents an N-linked tetrazolyl group optionally substituted by a group selected from Cl 6alkyl, C3 7cycloalkyl, C3 7cycloalkylCl 4alkyl, trifluoromethyl, SRa, SORa, SO2Ra, phenyl, NRaRb, NRaCORb or CH2C(O)Ra, where Ra and Rb are each independently hydrogen or Cl 4alkyl;
R4 represents hydrogen or halogen;
R6 represents hydrogen, CORa, (~02Ra, COCONRaRb, COCO2Ra, alkyl optionally substituted by a group selected from (CO2Ra, CONRaRb, hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONEphenyl(Cl 4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaCl 6alkylRl2, CONRl3C2 6alkenyl, CONRl3C2 6alkynyl, COCONRaRb, CONRaC(NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from Cl 6alkyl, Cl 6alkoxy, halogen and trifluoromethyl) or C, 6alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring cont~;ning 1, 2 or 3 nitrogen atoms optionally substituted by =O or =S and optionally substituted by a group of the formula ZNR7R8 where Z is C1 6alkylene or C3 6cycloalkyl;
R7 is hydrogen or Cl 4alkyl, C3 7cycloalkyl, C3 7cycloalkylCl 4alkyl, or C2 4alkyl substituted by Cl 4alkoxy or hydroxyl;
R8 is hydrogen or Cl 4alkyl, C3 7cycloalkyl, C3 7cycloalkylC1 4alkyl, or C2 4alkyl substituted by Cl 4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring c- nt~ining 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 or Cl 4alkoxy optionally substituted by a C, 4alkoxy or hydroxyl group, and optionally cont,~ining a double bond~
which ring may optionally contain an oxygen or sulphur ring atom, a group S(O3 or S(O)2 or a second nitrogen atom which will be part of a NH

CA 02237638 1998-0~-12 W O 97/19084 PCT/G~96/02853 or NRC moiety where Rc is Cl 4alkyl optionally substituted by hydroxy or Cl 4alkoxy;
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;
6 or Z, 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;
Rl2 represents ORa, CONRaRb or heteroaryl;
Rl3 represents H or Cl 6alkyl;
or a pharmaceutically acceptable salt thereo~
A particularly preferred class of compound of formula (I) is that wherein Rl is a methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy or trifluoromethoxy group, especially a methoxy group.
Another preferred class of compound of formula (I) is that wherein R2 is a hydrogen, fluorine or ~.hlf)r;ne atom, especially a hydrogen atom.
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.
Also preferred is the class of compound of formula (I) in which R9 and Rl~ are both hydrogen atoms.
A further preferred class of compound of formula ~I) is that wherein R6 is a hydrogen atom.
Also preferred is the class of compound of formula (I) in which R~i is a Cl Galkyl group, in particular CH2, C~H(CH~) and CH2CH2 and especially CH2, substituted by a 5-membered heterocyclic ring cont~ining 2 or 3 nitrogen atoms as previously defined.
In particular, the 6-membered ring is a heterocyclic ring selected from:

WO 97/19084 PCT/Gn9G~2853 H ~N ~ N ~

3/ 0~ ~ ; <~ ;

N ~ NR7Rs ~ ~ < ~
ZNR R ZNR R
Particularly preferred heterocyclic rings are selected from:
H ~ H ~ H ~

H NH N H ZNR R

H ~ N ~ ; and <
ZNR R ZNR R N ~
ZNR R

Most especially, the heterocyclic ring is selected from:

H H
N ~ ~ ~ ; and HN ~
ZNR R HN ZNR R N ~ ZNR7Rs A particularly preferred heterocyclic ring is:

CA 02237638 1998-0~-12 W O 97/19084 PCT/GB96/~28S3 N ~/
HN ~
N ZNR R

Where Rl and R2 are attached to adjacent carbon atoms and are joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring cont~ining one or two oxygen atoms, there is formed a fused ring moiety such as 2,3-dihydrobenzofuran, benzofuran, 3,4-dihydro-2H-1-benzopyran, 2H-1-benzopyran, 1,3-benzodioxole or 1,4-benzodioxan.
Particularly preferred is 2,3-dihydrobenzofuran where the oxygen atom corresponds to the position of R1.
Certain particularly apt compounds of the present invention include those wherein R3 is a group selected from pyrrole, furan, thiene, pyridine, pyrazole, imirlis7.01e, oxazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimi(lin~?, 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 ~3 is a group selected from furan, pyridine, pyrimidine, 1,2,3-triazole, 1,2,4-triazole and tetrazole, each heteroaryl group being optionally substituted as previously defined.
An especially preferred class of compound of fol-mula (I) is that wherein R3 is the group CA 02237638 1998-0=,-12 N~ R

where Rll is hydrogen, halogen, Cl.6alkyl, Cl 6alkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, (CH2)rCONRaRb~ (CH2)~NRsRb or (CH2)rNRaCORb~ where Ra and Rb are hydrogen or Cl 4alkyl, and r is zero, 1 or 2.
Another especially preferred class of compound of formula (I) is that wherein R3 is the group N~N
N~)~ Rll N

wherein Rll is as previously defined.
Rll is preferably hydrogen, Cl 4alkyl, especially methyl, CF3, (CH2)rCONRaRb~ SORa or SO2Ra where Ra, Rb and r are as previously 15 defined.
Preferably m is 1.
Preferably n is 1 or 2, especially 1.
Preferably p is zero.
Preferably q is 2.
It will be appreciated that when the broken line represents a double bond then the group -(CH2)n- should be interpreted as a -(CH)n- group.
One favoured group of compounds of the present in~ention are of the formula (Ia) and pharmaceutically acceptable salts thereof: ..

Rl R2 (Ia) wherein Rl, R2, R3, R4, R9, Rl~ and the broken line are as defined in relation to formula (I).
Another favoured group of compounds of the present invention are of the formula (Ib) and pharmaceutically acceptable salts thereof:

Rl R2 Rl~ ~ 3 3~ R

(Ib) 10 wherein Rl, R2, R3, R4, R9 and Rl~ are as defined in relation to formula (I).Another favoured group of compounds of the present invention are of the formula (Ic) and pharmaceutically acceptable salts thereof:

CA 02237638 1998-0~-12 Rl R2 Rl~ ~ 3 N ~ R
.~ ~ ~ R4 ~ 11 (Ic) wherein Rl, R2, R3, R~, R9 and Rl~ are defined in relation to formula (I), Q
is CH or N and Z, R7 and R8 are as defined in relation to formula (I).
With respect to compounds of the formulae (I) and (Ic), Z (where present), may be a linear, branched or cyclic group. Favourably Z contains 1 to 4 carbon atoms and most favourably 1 or 2 carbon atoms. A
particularly favourable group Z is CH~.
With respect to compounds of the formulae (I) and (Ic), R7 may aptly 10 be a Cl 4alkyl group or a C~4alkyl group substituted by a hydroxyl or C
2alkoxy group, R8 may aptly be a Cl 4alkyl group or a C2 4alkyl group substituted by a hydroxyl or Cl 2alkoxy group, or R7 and R8 Inay be linked so that, together with the nitrogen atom to which they are attached, they form an azetidinyl, pyrrolidinyl, piperidyl, morpholino, thiomorpholino, 15 piperazino or piperazino group substituted on the nitrogen atom by a Cl 4alkyl group or a C~.4alkyl group substituted by a hydroxy or Cl 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 s Where the group NR7R8 represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and pre~erably 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, CA 02237638 1998-0~-12 2-azabicyclo~2.2.2loctyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl, 6-azabicyclo~3.3.2]decyl, 7-azabicyclo~4.3.1]decyl, 7-azabicyclo~4.4. 1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.
6 Where ~8 represents a C2 4alkyl group substituted by a 5 or 6 ~embered heteroaliphatic ring cont~ining one or two heteroatoms selected from N, O and S, suitable rings include pyrrolidi~o, piperidino, piperazino, mo~holino, or thiomorpholino. Particularly preferred are nitrogen co~t~ining heteroaliphatic rings, especially pyrrolidino and morpholino rings.
In the group ZNR7R8, Z is preferably CH2 or CH2CH2, and especially CH2.
The group NR7R8 preferably represents amino, methyl~mino, dimethylamino, diethyl~minn, azetidinyl, pyrrolidino and morpholino.
In particular, NR7R8 is preferably dimethyl~minn, azetidinyl or pyrrolidino, especially dimethylzlmino.
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.
The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.
~5 As used herein, the terms "alkenyl" and "alkynyl" as a group or part of a group means that the group is straight or branched. ~xamples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.
As used herein, the term "heteroaryl" as a group or part of a group means a 5- or 6-membered heteroaromatic ring contS~ining 1 to 4 heteroatoms selected from N, O and S. Particular examples of such groups CA 02237638 1998-0~-12 include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imi(lz~olyl, oxazolyl, isoxazolyl, t.~ 7.01yl, isothi~7.01yl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, and tetrazolyl.
When used herein the term "halogen" means ~Luorine, chlorine, 5 bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
Speci~ic compounds within the scope of this invention include:
(6S,5R,3S~-3-(2-methoxy-5-(5-trifluoromethyVtetrazol-l-yVphenyl)-6-phenyl-1-oxa-7-aza-spiro~4.5]decane;
(6S, 5R, 3S) -3-(2-isopropoxy-5-(5-(trifluoromethyl)tetrazol- l -yVphenyV-6-phenyl-l-oxa-7-aza-spiro~4.6~decane;
(6S,5R,3S)-3-(2-methoxy-5-(tetrazol-l-yl)phenyl)-6-phenyl-l-oxa-7-aza-spiro~4.51decane;
(6S,5R,3S)-3-(2-methyl-5-(5-(tri~LuoromethyVtetrazol-l-yVphenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(6S,5R,3S)-3-(2-trifluoromethoxy-5-(5-(trifluoromethyl)tetrazol-1-Yvphenyl)-6-phenyl-l-oxa-7-aza-spiro[4~5]decane;
(6S,5R,3S)-3-(2-methoxy-3-fluoro-5-(5-(trifluoromethyl)tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(6S,6R,3S)-3-(2-methoxy-5-(1,2,4-triazol-4-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro [4. 6] decane;
(6S,5R,3S)-3-(2-methoxy-4-~uoro-5-(5-(trifluoromethyl)tetrazol-1-Yvphenyl)-6-phenyl-l-oxa-7-aza-spiro[4~5]decane;
(6S,5R,3S)-6-phenyl-3-(2-methoxy-5-(3,5-bis(trifluoromethyl)-1,2,4-triazol-4-yl)phenyl)-1-oxa-7-aza-spiro~4.5]dec-3-ene;
(6S,~R,3S)-6-phenyl-3-(5-(5-trifluoromethyl)tetrazol- 1-yl)-2,3-dihydrobenzfuran-7-yl)-1-oxa-7-aza-spiro[4.5]decane;
(6S,5R,3S)-6-phenyl-3-(5-(5-trifluoromethyl)tetrazol-1-yl)-2,3-dihydrobenzfuran-7-yl)-1-oxa-7-aza-spiro~4.5]dec-3-ene;
(6S,5R, 3S)-6-phenyl-3-(2-methoxy-5-(3,5-bis(trifluoromethyl)- 1,2,4-triazol-4-yl)phenyl)- 1-oxa-7-aza-spiro[4.5]decane;

CA 02237638 l998-0~-l2 W O 97/19084 PCT/GB96/028~3 (6S,5R,3S)-6-phenyl-3-(2-methoxy-5-(5-trifluoromethyl)isoxazol-4-yl)phenyl)-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(6S,5R,3S)-6-phenyl-3-(2-methoxy-5-(5-trifluoromethyl~isoxazol-4-yl)phenyl) l oxa 7 aza-spiro~4.5]decane;
(6S,6R,3S)-7-((2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl)-3-(2-methoxy-5-(5-(triiluoromethyVtetrazol-l-yVphenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(6S.5R~3S~-7-(2-(N,N-dimethyl~rnino)ethyl)-3-(2-methoxy-5-(5-(tri~luoromethyl)tetrazol-l-yVphenyV-6-phenyl- 1-oxa-7-aza-spiror4.5]decane;
(6S,5R,3S)-7-((lH-imill~7.ol-5-yl)methyl)-3-(2-methoxy-5-(5-(trifluoro~nethyl)tetrazol-l-yl)phenyV-6-phenyl-1-oxa-7-aza-spiro [4. 5] decane;
and pharmaceutically acceptable salts thereof.
Further preferred compounds of the present invention include:
(5R,65)-3-[2-methoxy-5-(2,4-dimethyl-lH-imir~ Ql-l-yl)phenyl]-6-phenyl-l-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-methoxy-5-(2,4-dimethyl-lH-irni-1~7c1-1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro~4.5]dec-3-ene;
(35,5R,65)-3-l2-methoxy-5-(2,4-dimethyl-lH-imi~701-1-yl)phenyl]-6-phenyl-l-oxa-7-aza-spiro[4.51decane;
(5R,65)-3-[2-methoxy-5-(4-pyridyl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-methoxy-5-(4-pyridyl)phenyl]-6-phenyl-1-oxa- /-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-~-methoxy-5-(4-pyridyl)phenyl~-6-phenyl- 1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-15-(4-pyridyl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[5-(4-pyridyl)-2-(trifluoromethoxy)phenyl]-6-phenvl-1-oxa-7-aza-spiro[4.5]dec-3-ene;

CA 02237638 1998-0~-12 5~,6$)-3-[5-(4H-1,2,4-triazol-4-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[5-(4H-1,2,4-triazol-4-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[5-(4H-1,2,4-triazol-4-yV-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(6R,6S)-3-[2-(trifluoromethoxy-5-(3-tri~luoromethyl-4H-1,2,4-triazol-4-yl)~he~yl]-6-p~enyl-1-oxa-7-~erf-~utoxyc~rbonyl)a~a-spilo~4 5]dec-3-eIle;
(5R,6S)-3-[2-(trifluoromethoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-(trifluoromethoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiror4.5]decane;
(5R,6S)-3-[2-methoxy-5-(2-trifluoromethyl-lH-imitls3~ yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-~2-methoxy-5-(2-trifluoromethyl-lH-imi~7--1-l-yl)phenyl]-6-phenyl- 1-oxa-7-aza-spiro [4. 5] dec-3-ene;
(35,5R,65)-3-[2-methoxy-5-(2-trifluoromethyl-lH-;mi~1~701-l-yl)phenyl]-6-phenyl-1-ox~-7-aza-spiro~4.5]decane;
(5R,6S)-3-[2-trifluoromethoxy-5-(2-trifluoromethyl-lH-imidazol-l-2û yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-trifluoromethoxy-5-(2-trifluoromethyl-1 H-imidazol- 1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spirol4.5]dec-3-ene;
(3S,5R,6S)-3-[2-trifluoromethoxy-5-(2-trifluoromethyl-lH-imidazol-1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-methoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenvl~-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-~2-methoxy-5-(3-trifluoromethyl-4H- 1,2,4-triazol-4-yl)phenvl]-6-phenvl-l-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-methoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenvl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;

CA 02237638 1998-0~-12 ~ - 19 -(5R,6S?-3- [2-(2-fluoroethoxy)-5-(5-trifluoromethyl-tetrazol- 1-yVphenyl3-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro~4.5]dec-3-ene;
(5R,6S)-3-[2-(2-fluoroethoxy)-5-(5-trifluoromethyl-tetrazol -1-yl)phenyl~-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-(2-fluoroethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)phenyl]-6-phenyl- 1-oxa-7-aza-spiro[4.5] decane;
(5R,6S)-3-[2-methoxy-5-(2-methyltetrazol-5-yl)phenyl]-6-phenyl-1-oxa-7-(tert ~u~ox~ r~ony~)as~-spirQ~.5~dec-~-ene;
(5R,6S)-3-r2-methoxy-5-(2-methyltetrazol-5-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro~4.5]dec-3-ene;
(5R,6S)-3- [2-methoxy-5-(1-methyltetrazol-5-yl)phenyl] -6-phenyl- 1 -oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-methoxy-5-(1-methyltetrazol-5-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-methoxy-5-(1-methyltetrazol-5-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-chloro-5-(tetrazol-1-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-chloro-5-(tetrazol-1-yl)phenyl]-6-phenyl-l-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[5-(lH-pyrazol- l-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-~tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[5-(lH-pyrazol-1-yl)-2-(trifluoromethoxy)phenyl~-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-~2-ethoxy-5-(2-trifluoromethyl-lH-imi~7ol-l-yl)phenyl]-6-phenyl-l-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5Jdec-3-ene;
(5R,6S)-3- [2-ethoxy-5-(2-trifluoromethyl- lH-imidazol- 1-yl)phenyl] -6-phenyl-l-oxa-7-aza-spiro[4.5]dec-3-ene;
(35,5R,65)-3-[2-ethoxy-5-(lH-imi~z~7.ol-l-yl)phenyl]-6-phenyl-l-oxa-7-aza-spiro[4.5]decane;

CA 02237638 1998-0~-12 (5R,6S)-3- [2-isopropoxy-5-(3-trifluoromethyl-4H- 1,2,4-triazol-4-yl)phenyl] -6-phenyl-1-oxa-7-(tert-butoxycarhonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3[2-isopropoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(35,5R,65)-3-[2-isopropoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-l-oxa-7-aza-spiro[4.5]decane;
(5R,65)-3-[2-isopropoxy-5-~2-trifluoromethyl-lH-imi(l~ol-l-yl)phenyl]-6-phenyl~l-ox~-7-~tert-butoxyc~rbonyl)~a-spiro~4.5~dec-3-elle;
(5R,65)-3-[2-isopropoxy-5-(2-trifluoromethyl-lH-imirl~7.ol-1-yl)phenyl]-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-isopropoxy-5-(2-trifluoromethyl-lH-imidazol-1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-methoxy-5-(oxazol-5-yl)phenyl~-6-phenyl- 1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,65)-3-~2-methoxy-5-(oxazol-5-yVphenyl]-6-phenyl-l-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6~)-3-[2-methoxy-5-(oxazol-5-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro~4.5]decane;
(5R,6S)-3-[2-isopropoxy-5-(oxazol-5-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro~4.5]dec-3-ene;
(5R,65)-3-[2-isopropoxy-5-(oxazol-5-yl3phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-~2-isopropoxy-5-(oxazol-5-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro [4. 5] decane;
(5R,6S)-3- [2-benzyloxy-5-(2-trifluoromethyl- lH-imidazol- 1 -yl)phenyl] -6-phenyl-1-oxa-7-(tert-butoxycarbonyl) aza-spiro[4.5]dec-3-ene;
(5R,65)-3-[2-bcnzyloxy-5-(2-trifluoromethyl-lH-imi~ zol-l-yl)phenyl]-6-phenyl- l-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-hydroxy-5-(2-trifluoromethyl- lH-imidazol- 1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5~decane;

CA 02237638 l998-0~-l2 W O 97/19084 PCT/~B96/02853 -2,1-(5R,6S) -3- [5-(1-methyl- lH- 1,2, 3-triazol-3-yl)-2-(tri_uoromethoxy)phenyl] -6-phenyl-1-oxa-7-(tert-butoxycarbonyl~aza-spiro[4.5]dec-3-ene;
(5R,6$)-3-~5-(1-methyl-lH-1,2,3-triazol-3-yl)-2-(tri~Luoromethoxy~phenyl3-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[5-(1-methyl-lH-1,2,3-triazol-3-yl)-'7-(tri~luoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiror4.5]decane;
(5R,6S)-3-[5-(2-methyl-2H-1,2,3-triazol-3-yl)-2-(tri~luoromethoxy)phenyl]-6-p,henyl~ l~oxa~7-(tert-~utoxycar~o~yl~a~a-spir~[4~ 5~dec-5-ene;
(5R,6S)-3-r5-(2-methyl-2H-1,2,3-triazol-3-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiror4.5]dec-3-ene;
(3S,5R,6S)-3-[5-(2-methyl-2H-1,2,3-triazol-3-yl)-2-(tri~luoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5~,6S) -3- [5-(pyrid-3-yl)-2-(tri~Luoromethoxy)phenyl] -6-phenyl- 1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5~dec-3-ene;
(5R,6S)-3-[5-(pyrid-3-yl)-2-(triiluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S, 5R,6,S)-3-[2-isopropoxy-5-(pyrid-3-yl)phenyl] -6-phenyl- 1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane;
(3S,5R,6S)-3-[2-isopropoxy-5-(pyrid-3-yl)phenyl]-6-phenyl-1-oxa-7-aza-20 spiro[4.5]decane;
(5R,6,~)-3-[2-methoxy-5-(lH-1,2,4-triazol-1-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-r2-methoxy-5-(lH-1,2,4-triazol-1-yl)phenyl~-6-phenyl-1-oxa-7-aza-spiro [4 . 5] dec- 3 -ene;
(3S,5R,6S)-3-[2-methoxy-5-(lH-1,2,4-triazol-1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro~4.5]decane;
(5R,6S)-3-~5-(pyrimidin-5-yl)-2-(trifluoromethoxy)phenyll-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,65)-3-[5-(pyrimidin-5-yl)-2-(trif3uoromethoxy)phenyl~-6-phenyl-1-oxa-30 7-aza-spiro[4.5]dec-3-ene;
and pharmaceutically acceptable salts thereo~

CA 02237638 1998-0~-12 W O 97/19~84 PCT/GB96/02853 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 5 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 ~ccep~able s~lts of the compounds of this invention include acid ?,llfli~.inn salts which may, for example, be formed by mi~ring a 10 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 15 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 ~lkslline earth metal salts, e.g. calcium or 20 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 itl, vacuo or bv fieeze drying or 2~ by ex~h~n~in~ the anions of an existing salt for another anion on a suitable ion ex~h ?~ n ge 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) ~ hich are readily 30 convertible iJI vivo into the required compound of formula (I).
Conventional procedures for the selection and prepara~ion of suitable W O 97/19084 PCT/GB9Gi~2853 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 5 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 meta~olic process~ such as chemiGal or en7lymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a 10 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 15 diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The compounds of the formula (I), (Ia), (Ib) and (Ic) will have the preferred stereochemistry of the 5-, 6-positions that is possessed by the 20 compound of Example 2 (i.e. 5-(R) and 6-(S)). Thus for example as shown in formula (Id) Rl ~ (c ~ ~ , R
(CH~"~ -(CHy)n ~N~ ~ )p--R~

(Id) The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in 25 association with a pharmaceutically acceptable carrier or excipient.

CA 02237638 1998-0~-12 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 inh~l~tion or insufilation.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic a~id, mag~efiium stearate, dic~.lci~lm ph~spha~;e or ~Im, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition Cont~ining a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereo~
When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
This solid preformulation composition is then subdivided into unit dosage forms of the type described above cont,~inin~ from O.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. ~ variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil CA 02237638 1998-0~-12 suspensions, and flavoured em~ inn~ with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and .~imil~r ph~rm~ceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as 5 tragacanth, ~cz~ , alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for ~lmini~tration by injection include those co~pri~ a con~polmd of formula (I)) afi the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or 10 in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. TweenTM 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span~M 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example m~nni~ol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, LiposynTM, InfonutrolT~, LipofundinTM
20 and LipiphysanTM. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almondoil) and an emulsion formed upon mi~ing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It 25 will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between ~ and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and l.O,um, particularly 0.1 and 0.5~m, and have a p~I in the range of 5.5 30 to 8Ø

CA 02237638 1998-0~-12 Particularly preferred emulsion compositions are those prepared by mi7~ing a compound of formula (I) with IntralipidTM or the components thereof (soybean oil, egg phospholipids, glycerol and water).
Compositions for inhalation or insufELation include solutions and 5 suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The li~uid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
Prefer~bly tlle con~positions are administer~d hy t~e or~l or nasal respiratory route for local or systemic effect. Compositions in preferably 10 sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing n~chin~. Solution, suspension or powder compositions may be administered, preferably ora~ly 15 or nasally, from devices which deliver the formulation in an appropriate m~nner.
The present invention futher 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 20 association with a pharmaceutically acceptable carrier or excipient.
The compounds of formula (I) are of value in the treatment of a wide variety of ~linic~l conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity.
Thus, for example, an excess of tachy~inin, and in particular 25 substance P, activity is implicated in a varietv 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 30 cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder.

_ CA 02237638 1998-0~-12 specific phobias, for example, specific ~nim~l phobias, social phobias, obsessive-co~npulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for e~mpl~, 5 schizophreniform disorders, schizoa~Eective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or halll~( in~t;ons; delerium, deme~tia, and amnestic and o~her c~gnitive or ~eurodegeneIati~e disorders, such ~s Alzheimer's disease, seIlile dementia, de~nentia of the ~l7he~mer's type~
10 vascular dementia, and other dementias, for exaInple, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson's disease and other extra-pyr~mi-l~l movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced 15 parkinsonism, neuroleptic m~lign~nt syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dys7~inesia and medication-induced postural tremour; substance-re~ated disorders arising from the use of alcohol, amphet~min~?s (or amphetamine-like substances) caffeine, ~nn~his, cocaine, hallucinogens, inh~ nts and 20 aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, intoxication, withdrawal. intoxication delerium, withdrawal delerium, persisting dementia, psvchotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders;
25 epilepsy; Down's syndrome; demyelinating diseases such as MS and ALS
and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropath~, and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; and cerebral vascular disorders due to acute or chronic 30 cerebrovascular damage such as cerebral infarction, subarachnoid haemorrhage or cerebral oedema.

CA 02237638 1998-0~-12 Tachykinin, and in particular substance P, activity is also involved in nociception and pain. The compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pain predominates, including soft tissue and 5 peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, dental pain, myofascial pain syndromes, he~ h~, episiotomy pain, and buIns; ~eep and viscexal pain, ~uch as heart pain, muscle pain, eye pain, orofacial paill, for example, o~-~nt~lgif, abdominal pain, gynaecological 10 pain, for example, dysmenorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root ~m~e, and ar~chn~iflit.i~; pain associated with carr.inom~, 15 often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low back pain; sciatica;
ankylosing spondylitis, gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of respiratory diseases, particularly those 20 associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic ~lbrosis and asthma, adult respiratory distress syndrome, and bronchospasm;
infl~mm~tory diseases such as infl~mm~tory bowel disease, psoriasis, ~lbrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn;
25 allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophth~lmi(~ diseases such as conjunctivitis, vernal conjunctivitis, and the lil~e; ophth~mi~ conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other 30 eczematoid dermatitis.

CA 02237638 1998-0~-12 -2~-Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neurogz~nglinblastomas and small cell carcinomas such as small cell lung cancer.
6 Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including inflz~mm~tory disorders and diseases of the C~I tract such as gastritis, gas1;ro(1uode~ ulcerfi~ gastric carcinomas, gastric lymphomas~ disor~lsrs associated with the neuronal control of viscera, ulcerative colitis, Crohn's disease, irritable bowel syndrome and emesis, including acute, delayed or ~nti~ ipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo"li7~iness and Meniere's disease, surgery, migraine, variations in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus;
plasma extravasation resulting from cytokine chemotherapy, disorders of 2~ bladder function such as cystitis, bladder detrusor hyper-reflexia and incontinence; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as ~ngin~, vascular headache. migraine and Reynaud's disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the tr~n~mi~sion of pain in migraine.

W O 97/19084 PCT/GB9~ 853 The compounds of formula (I) are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting.
The compounds of formula (I) are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, ra~liAt.ic-n, toxins, pregnancy, vestibular disorders, motion, ~uL~e. y, migraine, and variations in intercranial pressure. Mos~: e~pecially, the compounds of f~rmula ~1~ are of use in the treatment of emesis induced by antineoplastic (cytoto~ic) agents including those routinely used in eancer chemotherapy, and emesis induced by other pharmacological agents, for example, rolipram.
m~les of such chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethylen~imin~ compounds, alkyl sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; ~ntimetabolites, for example, folic acid, purine or pyrimidin~ antagonists; mitotic inhibitors, for example, vinca ~lk~loids and derivatives of podophyllotoxin; and cytotoxic antibiotics.
Particular examples of chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea ar~d Vomiting: Recent Research and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Florida, USA (1991) pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechloreth~mine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CC~rU), doxorubicin (adriamycin~, daunorubicin, procarbazine, mitomycin, c~-talabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al in Cancer ~reatme7it Reports (1984) 68(1), 163-172].
The compounds of formula (I) are also of use in the treatment of emesis induced by radiation including radiation therap~ such as in the CA 02237638 l998-0~-l2 treatment of cancer, or radiation .cif~kne.ss; and in the treatment of post-operative nausea and vomiting.
It will be appreciated that the compounds of formula (I) may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate or sequential use for the relief of emesis. ~uch combined preparations may ~e, for example, in the form of a twin pack.
A further as~ct ~f ~he pre.s~nt invention compri,qes the compoll~ds of formula (I) in combination with a 5-HT3 antagonist, such as ondansetron, granisetron or tropisetron, or other anti-emetic medicaments, for example, a dopamine antagonist such as metoclopramide or GABAs receptor agonists such as baclofen. Additionally, a compound of formula (I) may be ~l1mini~tered in combination with an anti-infl~mm~tory corticosteroid, such as dexamethasone, triamcinolone, triamcinolone acetonide, flunisolide, budesonide, or others such as those disclosed in US patent nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712. Dexamethasone (DecadronTM) is particularly preferred. Furthermore, a compound of formula (I) may be administered in combination with a chemotherapeutic agent such as an alkylating agent, antimetabolite, _itotic inhibitor Ol cytotoxic antibiotic, as described above. In general, the currently available dosage forms of the known therapeutic agents for use in such combinations will be suitable.
When tested in the ferret model of cisplatin-induced emesis described by F. D. Tattersall et al, in Eur. J. pharmacol., (1993) 250, R5-R6, the compounds of the present invention were found to attenuate the retching and vomiting induced by cisplatin.
The compounds of formula (I) are also particularly useful in the treatment of pain or nociception and/or infls-mm~tion and disorders associated therewith such as, for example~ neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, CA 02237638 1998-0C,-12 asthma, osteroarthritis, rheumatoid arthritis, headache and especially mlgrame.
I'he present invention further provides a compound of formula (I) for use in therapy.
According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an exceqs, of tachykinins~ especially substance P.
The present invention also provides a method for the the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises a~mini~tration to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I).
For the treatment of certain conditions it may be desirable to employ a compound according to the present invention in conjunction with another pharmzlcologically active agent. For example, for the treatment of respiratory diseases such as asthma, a compound of formula (I) may be used in con~unction with a bronchodilator, such as a ~2-adrenergic receptor agonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula (I) and the bronchodilator may be administered to a patient simultaneously, sequentially or in combination.
Likewise, a compound of the present invention may be employed with a leukotriene antagonists, such as a leukotriene D4 antagonist such 26 as a compound selected from those disclosed in European patent specification nos. 0 480 717 and 0 604 114 and in US patent nos. 4,859,692 and 5,270,324. This combination is particularly useful in the treatment of respiratory diseases such as asthma, chronic bronchitis and cough.
The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises zl~mini~tration to a patient in need thereof of an effective CA 02237638 1998-0~-12 amount of a compound of formula (I) and an effect*e amount of a bronchodilator.
The present invention also provides a composition comprising a compound of formula (I), a bronchodilator, and a pharmaceutically 5 acceptable carrier.
It will be appreciated that for the treatment or prevention of migraine, a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergot~mines or 5-HTl agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
Likewise, for the treatment of behavioural hyperalgesia, a compound of the present invention may be used in conjunction with an antagonist of N-methyl D-aspartate (NMDA), such as dizocilpine.
For the treatment or prevention of infl~mm~tory conditions in the lower urinary tract, especially cystitis, a compound of the present 1~ invention may be used in conjunction with an antiinfl~rnm~tory agent such as a brady!~inin receptor antagonist.
It will be appreciated that for the treatment or prevention of pain or nociception, a compound of the present invention may be used in conjunction with other analgesics, such as acet~minophen (paracetamol), 20 aspirin and other NSAIDs and, in particular, opioid analgesics, especially morphine. Specific anti-infl~3mm~tory agents include diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam and slllin~
~uitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, 25 diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereo~ Preferred salts of these opioid analgesics include morphine sulphate, morphine 30 hydrochloride, morphine tartrate, codeine phosphate, codeine sulphate, dihydrocodeine bitartrate, diacetylmorphine hydrochloride, hydrocodone CA 02237638 1998-0~-12 bitartrate, hydromorphone hydrochloride, levorphanol tartrate, oxymorphone hydrochloride, alfentanil hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate, meperidine hydrochloride, methadone hydrochloride, nalbuphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate (2-naphthalenesulphonic acid (~:1) monohydrate), and pentazocine hydrochloride.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an analgesic as a combined preparation for si~nultaneous, separate or sequential use in the treatment or prevention of pain or nociception.
It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents.
Suitable classes of anti-depressant agent include norepinephrine reupta~;e inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs~, reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, o~-adrenoreceptor antagonists and atypical anti-depressants.
Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof. Suitable examples of secondary amine tricyclics include:
amoxapine, desipramine, maprotiline, nortriptyline and protriptyline. and pharmaceutically acceptable salts thereof.

CA 02237638 1998-0~-12 - 3~i -Suitable selective serotonin reuptake inhibitors include: fluoxetine, ~luvox~min~., paroxetine and sertraline, and pharmaceutically acceptable salts thereo~
Suitable monoamine oxidase inhibitors include: isocarboxazid, 5 phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereo~
Suitable reversible inhibitors of monoamine oxidase include:
moclobemide, and pharmaceutically acceptable salts thereo~
Suitable serotonin and noradre~lin~ reuptake inhibitors of use in 10 the present invention include: venl~rine, and pharmaceutically acceptable salts thereof.
Suitable CRF antagonists include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/~3644, WO
94/13661, WO 94/13676 and WO 94/1367~.
Suitable atypical anti-depressants include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof.
Suitable classes of anti-anxiety agent include benzodiazepines and 5-HTlA agonists or antagonists, especially 5-HTlA partial agonists, and 20 corticotropin releasing factor (CRF) antagonists.
Suitable benzodiazepines include: alprazolam, chlordiazepoxide~
clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepa~, and pharmaceutically acceptable salts thereof.
~ uitable 5-HTlA receptor agonists or antagonists include, in 25 particular, the ~-HTlA receptor partial agonists buspirone, flesinoxan.
gepirone and ipsaperone, and pharmaceutically acceptable salts thereof.
Therefore, in a ~rther aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an anti-depressant or anti-anxiety agent, together 30 with at least one pharmaceutically acceptable carrier or excipient.

CA 02237638 1998-0~-12 In a further or alternative aspect of the present invention, there is provided a product co_prising a compound of the present invention and an anti-depressant or anti-anxiety agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of depression and/or anxiety.
The excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimi~ing the risk of unwanted side effects.
In the treatment of the con~1itio~ 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 neurotr:~n.~mi.~ion of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 _g/kg per day, and especially about 0.005 to 5 mgtkg per day. The compounds may be a-~mini.~tered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of emesis using an injectable for_ulation, a suitable dosage level is about 0.001 to 10 mg/kg per day. preferably about 0.00~ to 5 mg/kg per day, and especially 0.01 to 1 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 a-lmini~tration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discletion of the attendant physician.
According to a general process (A), the compounds according to the invention in which m is 1 and n is 1 Ol 2, may be prepaled by the reduction of a compound of formula (I) in which the broken line represents a double bond, hereinafter referred to as a compound of formula (II) Rl (C 12)q_--~C~) \=,<
R10 ~< I ~ (CE2)p--R3 (II) ~,, wherein Rl, R2, R3, R4, R5, R6, R9, Rl~, p and q are as defined in relation to formula (I).
Suitable reducing conditions include: catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides 10 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 thereo~
According to another general process (B), compounds of formula (I~
may be prepared by the interconversion of a corresponding compound of 1., formula (I) in which R~ is H, hereinafter referred to as formula (III) o (C~ R2 R ~ ~--(CH 7)n \~<

'' ~

(III) wherein Rl, R2, R3, R4, R5, R9, Rl~, m, n, p, q and the broken line are as def~ned in relation to formula (I) by reaction with a compound of formula (IV):

LG-R6s where R6a is a group of the formula RG as defined in relation to formula a) (other than EI~ or a precu~sor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen 10 atom (e.g. bromine, chlorine or iodine); and, if R6a is a precursor group, converting it to a group R6 (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 dimethylform~mi-1e in the presence 15 of an acid acceptor such as potassium carbonate.
According to another process (C), compounds of formula (I~ wherein R~ represents a 1,2,3-triazol-4-ylmethyl group substituted by CH2NR7R8, may be prepared by reaction of a compound of formula (V) Rl R2 O (C~<
(CH~)" ~ (CH~)n ~
~ N ~ (CH2)p - R
Rl~ J ~ R~

(~
with an amine of formula NHR7R8, in a suitable solvent such as an ether, for example, dioxan, at elevated temperature, for example, between ~0~C
and 100~C, in a sealed tube, or the like. This reaction is based upon that described in Chemische Berichte (1989) 122, p. 1963.

CA 02237638 1998-0~-12 According to a further process (D), compounds of formula (I) wherein R~ represents a Cl Galkyl group which is substituted by an unsubstituted or substituted 1,2,4-triazolyl group, may be prepared by reaction of an intermediate of formula (III) with a compound of formula (VI) 18 ~ NH ~ (CH2)m - Hal (VI) wherein Hal is a halogen atom, for example, bromine, chlorine or iodine, m is an integer from 1 to 6 and Rl8 is H, CON H2 or OCH3 (which is converted to an oxo substituent under the reaction conditions), in the presence of a 10 base, followed where necessary by conversion to a compound of formula (I), for example, by reduction of the CONII2 group to CH2NH2.
Suitable bases of use in the reaction include alkali metal carbonates such as, for example, potassium carbonate. The reaction is conveniently effected in an anhydrous organic solvent such as, for example, anhydrous 15 dimethylform~mi-le, preferably at elevated temperature, such as about 140~C.
~ suitable reducing agent for the group CONH2 is lithium aluminium hydride, used at between -10~C and room temperature.
According to a further process (E), compounds of formula (I) mav be 20 prepared by further interconversion processes from other compounds of formula (I) using suitable procedures. In particular, processes mav be used to vary the group R~'~. For example, compounds of formula (I) wherein RG is other than H may be prepared fiom the corresponding compounds of formula (I) wherein RG is H by reaction with a reagent 25 suitable to introduce the group RG, for example. compounds of formula (I) wherein RG is CORa may be prepared from compounds of formula (I) CA 02237638 1998-0~-12 wherein R6 is H by, for example, reaction with an appropriate acid anhydride.
Compounds of formula (I) wherein R6 is ~l.6alkyl may be prepared from corresponding compounds of formula (I) wherein R6 is CORa by 5 reduction using, for examplei borane or a borohydride such as sodium cyanoborohydride .
Compounds of formula (I) wherein R6 is Cl.6alkyl substituted by CONRa:~b may be prepared from correspo~ n~ compounds of for~ula (I) wherein R6 is Cl 6al3~yl substituted by CO2Ra by treatment with ammonia 10 or an amine of formula NRaRb.
Compounds of formula (I) wherein R6 is Cl Galkyl substituted by 5-o~ 70lyl may be prepared from compounds of formula (I) wherein R6 is Cl.6alkyl substituted by CO2Ra, where Ra represents Cl 6alkyl, by reaction with a compound of formula (VII) NOH
H N ~ R32 wherein R3~ represents H or a suitable substituent. in the presence of a base.
Suitable bases of use in the reaction include alkali metals, such as, 20 for example, sodium, and alkali metal hydrides, such as, for example, sodium hydride.
The reaction is conveniently effected in a suitable organic solvent.
Which solvents will bc appropriate will depend on the nature of the base used. For example, where the base used is an alkali metal. suitable 25 solvents will include alcohols, for example, ethanol, whereas where the base used is an alkali hydride, suitable solvents will include ethers. for example, tetrahydrofuran.

CA 02237638 1998-OF,-12 Preferably the reaction is conducted at elevated temperature, such as the reflux temperature of the chosen solvent.
~ Compounds of formula (I) wherein RG is Cl 6alkyl substituted by thiazolyl may be prepared from compounds of ~ormula (I) wherein R~ is 5 Cl 6alkyl substituted by CSNH2 by reaction with a compound of formula Hal-CH2(~(0)-R6~, where Hal is a halogen atom, such as bromine, chlorine or iodine, and R60 represents H or a suita~le substituent.
Compounds of foxmula (I? wherein R6 is Cl 6alkyl substituted by thioxotriazolyl may be prepared from compounds of formula (I) wherein R6 10 is Cl 6alkyl substituted by CONHNH2 by reaction with a compound of formula R6lNCS, wherein R6l represents H or a suitable substituent such as Cl 6alkyl, in the presence of a base.
Suitable bases of use in the reaction include organic bases such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction is 15 conveniently effected in a suitable organic solvent, such as alcohol, e.g.
butanol.
According to another general process (F), compounds of formula (I) wherein p is zero and R3 is a tetrazol-l-yl group may be prepared by reaction of intermediates of formula (VIII) Rl o (CE~.,~ R2 R ~
Rr' with ammonium chloride and sodium azide at elevated temperature, conveniently in a solvent such as dimethvlform~mi~e.

According to another general process (G), compounds of formula (I) may be prepared by a coupling reaction between a compound of formula (IX) and (X) o (c~ R2 R ~ ~ R4 R3-~CH2)p-R4 (IX) ~

wherein one of R40 and R4l is B(OH)2 or Sn(alkyl33 or a derivative thereof, and the other is a leaving group such as a halogen atom e.g. bromine or iodine, or -OSO2CF3. Where one of R40 and R4l is B(0H)2, the reaction is 10 conveniently ef~ected in the presence of a palladium (O) catalyst such as tetrakis(triphenylphosphine)palladium (O) in a suitable solvent such as an ether, for example, dimethoxyethane at an elevated temperature. Where one of R40 and R41 is Sn(alkyl)3, the reaction is convenientl~ effected in the presence of palladium (II) catalyst such as bis(triphen~-lphosphine) 15 palladium (II) chloride, in a suitable solvent such as an aromatic hydrocarbon, for example, toluene, at an elevated temperature.
According to another general process (H), compounds of formula (I) wherein R~ represents a 1,2,3-triazol-4-ylmeth- l group substituted b~
CH~NR7R8, may be prepared by reaction of a compound of formula (~I) Rl R2 o (CH.~)m ~

R9 ~ ~C ~
RI~N~ 4 (CH2)p--R
/J ~
~q// R5 (XI) with an azide, for example, sodium azide in a suitable solvent such as dimethylsulphoxide at a temperature of between 40~C and 100~C followed 5 by reduction of the carbonyl group adjacent to -NR7R8 using a suitable reducing agent such as lithium aluminium hydride at a temperature between -10~~ and room temperature, conveniently at room temperature.
According to another general process (J), compounds of formula (I) may be prepared from a compound of formula (XXII) ) nl R
2)~ R3 (XXII) by an acid catalysed intramolecular cyclisation reaction.
Suitable acids of use in the reaction include mineral acids such as 15 hydrochloric acid. The reaction is conveniently effected in a suitable organic so~vent, such as an alcohol, e.g. methanol, at an elevated temperature, for example, at the reflux temperature of the chosen solvent.
According to another general process (K), compounds of formula (I) wherein R6 represents the group -CH2C-CCH2NR7R8, may be prepared 5 from a compound of formula (XXV) (CH2)q ~ (C~)~ \~<

J ~
~/ R6 Hal ~gV~
wherein Hal is a halogen atom such as chlorine, bromine or iodine, by reaction with an amine of formula ~INR7R8 in the presence of a base.
Suitable bases of use in the reaction include alkali metal carbonates 10 such as, for example, potassium carbonate. The reaction is conveniently effected in an organic solvent such as, for example, N,N-dimethylformamide, conveniently at room temperature.
Further details of suitable procedures will be found in the accompanying Examples.
Intermediates of formula (II) are conveniently prepared by the reaction of a cornpound of formula (XII) R9 ( ~ (CH)"
~N~ '~

(XII) =

CA 02237638 1998-0~-12 W O 97/19084 PCT/GB96/~2853 wherein each R45 is a C~l 4alkyl group, preferably methyl or n-butyl groups, with a compound of formula (XIII) Rl '~, R2 Hal~
(CH2)p--R3 (XIII) wherein Hal is a ha;ogen atom, ~or e~ample, ~h~c)ri~le, ~l~omil~e o~ i~dine, 5 especially bromine.
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 aromatic hydrocarbons, for example, toluene, the reaction being effected at a 10 temperature between 80~C and the reflux temperature of the solvent.
Intermediates of formula (~II) may be prepared in a fiimil~r manner, preferably with an amino protecting group on the pyrroliflin~/piperidine nitrogen in the compound of formula (XII). Suitable amino protecting groups include alkoxycarbonyl groups such as tert-butoxycarbonyl and 15 trichloroethoxycarbonyl, aralkyloxycarbonyl groups such as benzyloxycarbonyl, or aralkyl groups such as benzyl. Removal of the protecting group is effected by conventional procedures thus, for example, tert-butoxycarbonyl groups may be removed under acidic conditions using, for example, trifluoroacetic acid; tert-butoxycarbonyl groups, together with 20 benzyloxycarbonyl and benzyl groups, may also be removed by hydrogenolysis in the presence of a catalyst, for example, palladium: and trichloroethoxycarbonvl groups may be removed with zinc dust.
Intermediates of formula (V) may be prepared from a compound of formula (XIV) o _ (CH.,)m ~ R2 g (CH2)~ ('C~<
Rl~N~ (CE2)p--R3 /J ~
~/ R5 Hal X~

wherein Hal is a halogen atom, for example, chlorine, bromine or iodine, especially chlorine, by reaction with an azide, for example, sodium azide in 5 a suitable solvent such as dimethylsulphoxide at or below room temperature.
Compounds of formula ~gIV) may be prepared by a dropwise addition of an intermediate of formula (III) to a dihaloacetylene of formula Hal-CH2-C-C-CH2-Hal where each Hal is independently chlorine, bromine 10 or iodine, especially chlorine. The reaction is conveniently effected in a suitable solvent such as dimethylformamide in the presence of a base such as potassium carbonate.
Co~npounds of formula (VI) may be prepared as described in J. Med. C.7tet7t., (1984) 27, 849.
Compounds of formula (XII) may be prepared from a compound of formula (XV) (CH,), (XV~

wherein R50 is a triflate (-OSO2CF3) group or a bromine or iodine atom. by reaction with a compound of the formula (R45)3Sn-Sn(R4b)3, for example.
hexamethyl dist~nn~ne. The reaction is conveniently effected in the presence of a base, for example, lithium carbonate, and a catalyst such as 5 triphenylphosphine palladium(0). 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 6Q~C.
Compounds of formula (XV) may be prepared from a compound of 10 formula (XVI):

o - -g (CH~ -(CH2),~

Rl~ : ,~R;7R~

(XVI) by enolisation of the ketone in the presence of a base, for example, sodium hexamethyl~ 7ide, followed by reaction with a reagent capable of 16 introducing a suitable leaving group, for instance~ whele R~~ is -OS0 7CF3, using 2-[N,N-bis(trifluoromethylsulphonyl)amino]-5-chloropylidine triflic anhydride. The reaction is conveniently effected in a suitable solvent such as an ether, for example, tetrahydrofuran al a reduced temperature, for instance, -80~C.
Compounds of formula (X~TI) may be prepaled from a compound of formula (XVII) by the following reaction sequences (Scheme ~ O1 Scheme ~3) or by methods analogous thereto (with the pl'OViSO that R9 and Rl~ are not oxo):

Scheme A

R~ ~ R ~ OPh R~

R5 Tetrahedror., (i992) R10 N R4 48:6087-6104) R~ ~
~I) R5 n-BuLi ZnC12 (Ph3P)4.Pd(0) (c~ ~ O o~ne/O~ O ~ CH
R9 ~ ~ ~;R4 (CH3)2s (XVI) Scheme B

MgCl (CHz) ~ (CH2), N ~ R4 ~(CH~,.2 R9~
Rl~ R6 ~ Grignard ~ ..... c lo~< IN ~R~

(XVII) hydroxylation KMnO4 .

O~ OH
(CH~)q1--(CHZ),Z HCl (CH2)q~(CH~OH

Rl~ N~R4 intrAmnl~elllAr R~<N~ R4 R6 ~ R5 cychsahon RG ~ R~

Swern tinn .

(CH~)q ~~c R9 1 --(CH~
Rl~~<RN~ \~R

R;
(XVI) In an alternative method, compounds of formula (XII) may be p~epared by the following reaction sequence (Scheme C) or by methods analogous thereto:

Scheme C

OTMS
~ OTMS OH J
n ~ Br- Mg- - ~ R~ ~ R4 ~I) R Rs l.TXAF
2.nBu3SnH
Pd~h3P)4 ~luene OH

O ~ OH
cX,)q ~ SnB~3 DEAD,Ph3P,THF ~ (C~
N ~ ~ ~ ~ SnBu3 R R~ ~ R Rio Rj ~ R~

o In a preferred embodiment of the aforementioned processes. RG is replaced with an amino protecting group, in particular tert-butox~-carbonyl which is conveniently removed prior to reduction of the /-aza-spiro [4.~]dec-3-ene structure (general process (A)).
In another preferred embodiment of the aforementioned processes, RG is a benzyl group. The reduction reaction described as process (~) above for the preparation of compounds of formula (I) may convenientlv replace the benzyl group with a hydrogen atom. It ~vill be appreciated CA 02237638 l998-0=.-l2 - al -from the discussion above that compounds of formula (I) wherein R6 is a hydrogen atom are particularly preferred pr:ecursors to other compounds of formula (I).
Compounds of formula (XIII) in which p is zero and R3 is an a N-linked heterocyclic group may be prepared by conventional methodology, for example, from a compound of formula (XVIII) Hal ~

(XVIII) by reaction with a suitable anhydride of the formula (R60CO)20, where R60 1~ is hydrogen or a desired substituent for the heterocycle, followed by reaction with triphenylphosphine in carbon tetrachloride, followed by the further step of (i) reaction with an azide such as sodium azide to effect the formation of a tetrazole ring; or (ii) reaction with hydrazine hydrate to ef~ect the formation of a 1,2,4-triazole ring; or (iii) reaction with aminoacetaldehyde diethyl acetal to effect the formation of an imidazole ring.
Compounds of formula (XVIII) may be prepared fiom the corresponding nitro compound by reduction using, for example, iron powder, or Raney nickel in a conventional manner.
The compounds of formula (~III) or their nitro precursors are either known compounds or may be prepared using conventional methodolOg~,r.
For compounds wherein RG is a Cl Galkyl gl'OUp substituted by a a-membered heterocycle which in turn is substituted by a ZNR7R8 group where Z is CH., certain favoured compounds of formula (I) may be prepared from a corresponding compound with a hydrogen atom in place of the ZNR7R8. Thus, for example a compound of the formula (I) wherein RG

CA 02237638 1998-0C.-12 WO 97/19084 PCT/GB96tO2853 is an imidazolinone group carrying a CH2NR7R8 moiety may be prepared from a corresponding compound lacking the CH2NR7R8 moiety by reaction with formaldehyde and an amine NHR7R8 under conventional 3~nnich reaction conditions, for example in methanol with heating. If desired a 5 pre-formed reagent such as R7R8N+=CH2.I- may be employed and a tertiary amine such as triethyl~mine used as acid acceptor.
Alternatively a compound of formula ~I~ wherein R6 is a Cl.6al~yl group sub~tituted hy an imi~ Qlinoxle group may be reacted with paraformaldehyde and an amine for example a secondary amine such as 10 pyrrolidine or morpholine to give a compound wherein the imirl~olinone ring is substituted by CH2NR7R8 where R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom or a second nitrogen atom which will be part of a NH or NRC moiety, where Rc is as previously 15 defined.
This reaction may be performed in a conventional m~nner, for instance, in a suitable solvent such as an alcohol, for example, methanol at an elevated temperature up to the boiling point of the solvent.
A further alternative method for the preparation of certain 20 compounds of formula (I) involves the reaction of an intermediate of formula (III~ as defined above with one of the compounds of formula (XIX):

LG LG LG
\
~ ~CH,,)X N ~CH~)X ~CH,,),C
(a)O~ ~ )</ ~ (c) HN ~
H Z H Z N z LG LG LG
~ X) wherein each I~G, which may be the same or different, is a leaving group, 25 such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) Ol', in particular~ a halogen atom, (e.g. bromine, chlorine or iodine), x is an integer from 1 to 6 and Z is as defined in formula (I), followed by reaction of the resultant compound with an amine NHR7R8 to complete the ZNR7R8 moiety.
This reaction is conveniently effected in an organic solvent such as dimethylform~mi(le in the presence of an acid acceptor such as potassium carbonate.
It will be appreciated that, where necessary, reactive groups may be protected, thus for example, the NH groups of an imidazolinone of formula (XIXa) may be protected by any suitable amine protecting group such as 10 an acetyl group.
Compounds of formula (VIII) may be prepared by reacting a compound of formula (XX) O (CH2)m ~ R
(CH~q ~\~/

(XX) with any suitable reagent for completing the RG moiety as described in any one of processes (B) to (E).
Compounds of formula (XX), and also compounds of formula (~TIII), may be prepared by reaction of a compound of formula (~ vith a 20 compound of formula (XXI) Eal ~
~nHCN
~ ) according to the methods described above, followed, if desired, by reduction according to the method of general process (A).
Intermed~ates of formula ~XII~ wherein n is ~ rnay ke prepared by 5 the reduction of a compound of formula (XXIII) HO\
(CH2)m 01''~' ~--R2 Rl~ R~

(XXIII) or a protected derivative thereof, using conventional methodology, for instance, by catalytic hydrogenation using a metal catalyst such as 10 palladium or platinum or oxides thereof, preferably in a solvent such as an alcohol, e.g. ethanol, or an ester, e.g. ethyl acetate.
Compounds of formula (XXIII) may be prepared by the reaction of a compound of formula (XVII) with a compound of formula (X~IV) CA 02237638 l998-05-l2 HO~
(CH2)m HC~ ~ R2 (CH2)p--R3 (XXIV) or a protected derivative thereof, by lithiation using n-butyl lithium followed by quen~hin~ with, for example, sodium dihydrogen 5 orthophosphate. The reaction is conveniently effected in a solvent such as an ether, e.g. tetrahydrofuran, at a reduced temeprature, for example, at -78~C-Compounds of formula (XVII) may be prepared by methods described in European Patent Specification No. 0 577 394-A, or by 10 analogous methods.
Compounds of formula (XXIV) are known compounds (see Chemische Berichte, (1988) 121,1315-1320) or may be prepared by methods analogous to those described therein.
Intermediates of formula (V) may be prepared from a compound of formula (XXV) by reaction with an azide, for example, sodium azide in a suitable solvent such as dimethylsulphoxide at or below room temperature .
Compounds of formula (XXV) may be prepared bv a drop~vise addition of an intermediate of formula (III) to a dihaloacetvlene of formula Hal-CII2-(~_C-CH2-Hal where each Hal is independentlv chlorine. bromine or iodine, especially chlorine. The reaction is convenientlv effected in a ~ suitable solvent such as dimethylformamide in the presence of a base such as potassium carbonate.

CA 02237638 1998-0',-12 Compounds of formula (VII), (X), (XIX) and (XXI) are known compounds or may be prepared by conventional methods or using techniques analogous to those taught herein.
It will be appreciated that compounds of the formula (I) wherein R6 contains an =O or =S substituent can exist in tautomeric forms. All such tautomeric forms and mixtures thereof are included within this invention.
Most aptly the =t:) or =S substituent in R6 is the =O substituent.
Where they are not commercially available, the intermediates of formula (IV) above may be prepared by the procedures described in the accompanying ~ m~les or by alternative procedures which will be readily apparent to one skilled in the art.
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 cxemplified 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 NKl receptor of less than l,uM on said test method.
For the avoidance of doubt, the nomenclature adhered to throughout this specification follows the general principle illustrated below:

l 2 2~ 3 7N~\~3 R~' The following non-limiting F,~:~mI~les serve to illustrate the preparation of compounds of the present invention:

~+) l-tert-Butoxvcarbonvl-2-PhenvlPiperidin-3-one To a cooled (-60~C) solution of oxalyl ~.hlnri~ll? (0.68ml, 7.8mmol) in dichlorc)methan~ ~17ml) was added dimethvl sulphoxide (0.69ml, 9.8mmol) for 10minutes before addition of (-l)1-tert-butoxycarbonyl-3-hydro~y-2-phenylpiperidine (1.8g, 6.5mmol; prepared by the method described in European Patent Spe-~ific~tion number 0 528 495-A) in dichlorornethane (7ml). The solution was stirred at -60~C for 20nLinutes, warmed to -30~C
and triethyl~n~ine (2.5mV added. The solution was warmed to room temperature then was washed with ice cold lQ% aqueous citric acid solution (40ml, twice), water and dried (M gSO4). After evaporation the residue was purified by chromatography on silica gel (eluting with hexane cont~ining an increasing proportion of ethyl acetate up to 20%) to give the title compound.
lH N~IR (250MHz, CDCl3) ~ 7.5-7.3 (5H,m), 6.8 (lH, br.s), 4.2 (lH, br.s) 3.4 (lH, m~, 2.6 (2H, m), 2.0 (2H, m), 1.54 (9H, s).

(+)(2S* . 3R*) 1 -tert-Butoxvcarbonvl-3-hvdroxv-3-(2-methvlene-3-phenoxvpropvl) -Z -phenvlpiperidine ~ tetrahydrofuran solution of 3-(chloromagnesio)-2-(phenoxymethyl)-1-propene (0.9l M, 3ml) (Louw et. al. Tetrahedron 48:6087-6104, (1992), prepared from 2.74mmol of 3-chloro-2-(phenoxymethyl)-1-propene) was slowlv added to a solution of (~)1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Desc. 1) in tetrahydrofuran (3ml).
T~e solution was stirred at room temperature for 1 hour, quenched by addition of saturated ammonium chloride solution (20ml) and extracted CA 02237638 l998-0',-l2 WO 97/19084 PCTIGB96/0285:~

with ethyl acetate (20ml). The organic phase was washed (saturated brine), dried (MgSO4), evaporated to a small volume and puri ed by chromatography on a column cont~ining silica gel (eluting with he~n~
cont~ining increasing proportions of ethyl acetate between 0% to 20%).
5 E,vaporation of the fractions gave the title compound. m/z (C1~424 (M+H), 324 (M+2H - t-BuOCO-), 368 (M+2H - t-Bu).
lH NMR (360MHz, CDCl3) o 7.48 (2H, d, J=6.9Hz), 7.35-7.2 (6H, m) 6.9-6.8~ ~3H, m), 5.~ (lH, s~, ~.16 ~2H, d, J--13.71Hz), 4.61 ~2H, ~), 4.11 (2H, m),3.17 (lH, m), 2.66 and 2.~9 (2H, AB d, J=14.0Hz), 1.95 (2H, m), 1.79 (2H, m), 1.36 (9H, s).

( I )(5R*,6.S*)-3-Methvlene-6-~henyl-1-oxa-7-(tert-butoxvcarbonYl)aza-sPiro ~4.51 decane To a cooled(-80~C) solution of (~)(2S*,3R*)1-tert-butoxycarbonyl-3-hydroxy-3-(2-methylene-3-phenoxypropyl)-2-phenylpiperidine (1.53g, 3.62mmol; Desc.2) in tetrahydrofuran (20ml) was added a solution n-butyl lithium in hexanes (2.5M, 1.45ml, 3.62mmol) followed by a solution of zinc chloride (0.5M in tetrahydrofuran, 7.24ml, 3.62mmol). The solution was allowed to warm to room temperature, tetrakis(triphenvlphosphine) palladium (0) (0.23g, 0.2mmol) added, degassed and then heated to reflux for 16 hours. After removal of the solvent by evapol~ation the residue was partitioned between ethyl acetate and 2M sodium hydroxide. The organic phase was washed with saturated brine, dried (MgSO I) and purified b~
chromatography on a column cont~ining silica gel (eluting ~ ith hexane cont~ining increasing proportions of ethyl acetate between 0% to 5%).
Evaporation of the fractions gave the title compound. lH N~IR ~360~IHz, CDCl3) ~ 7.~8 (2H, d, J=8.4Hz), 7.32-7.21 (3H, m). ~.23 (lH, s), .5.06 (lH, m)~ 4 97 (lH, m), 4.39 (2H, AB d, J=13.3Hz), 3.99(1H, dd. J=13.3, 4.48Hz), 2. 83 (lH, AB d, J=15.5Hz), 2.7 (lH, td, ~=12.5Hz 3.93Hz) 2.5 (lH,~B d, J=15.4Hz), 2.15 (2H, td, J=12.3Hz 4.4Hz), 1.69 (2H, m), 1.46 (9H,s). m/z (CI+) 329 ~M+2H- t-BuOCO).

(+)(5R*,6S*)-3-Keto-6-phenYl-1-oxa-7-(tert-butoxvcarbonYl~aza-sPiro r4.5l decane Through a cooled (-80~C) solution of (+)(6S*,5R*)-3-methylene-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5~decane (0.665g; Desc.3) in ~ichk~romethane (5ml) and methanol (5ml) was bu~bled a mixture of ozone and oxygen for 45 minutes. After the solution had been purged with nitrogen, dimethyl sulphide (0.5ml) was added and then stirred under nitrogen at room temperature for 16 hours. The solvent was removed i71 uacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), evaporated and the residue purified by chromatography on a column cont~inin~ silica gel (eluting with l~ n~
cont~ining increasing proportions of ethyl acetate between 0% to 10%).
Evaporation of the fractions gave the title compound. mlz (CI+)332 (M+H), 232 (M+2H - t-BuOCO-), 276 (M~2H- t-Bu). lH NMR (250 MHz, CDCl3) ~
7.58 (2H, d, J=6.2Hz), 7.37-7.26 (3H, m), 5.3 (lH,s), 4.15 and 4.09 (2H, AB
d, J=17.4Hz), 3.97 (lH, m), 2.80 (lH, td, J=12.9Hz and 4.0Hz), 2.74 and 2.48 (2H, AB d, J=18.1Hz), 2.29 (2H, m), 1.88-1.63 (2H, m), 1.44 (9H, s).

Dl~SCRIPTION 5 (+)(5R*.6S*)-3-Trifluoromethylsulphonvl-6-phenyl-1-oxa-7-(tert-butoxvcarbonvl)aza-spiror4.5ldec-3-ene To a cooled (-80~C) solution of lM sodium hexamethyl-liqil~37i~e (0.38ml, 0.38mmol) in tetrahydrofuran was added a solution of (+)(5R*,6S*)-3-keto-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (0.105mg, 0.319mmol; Desc.4) in tetrahydrofuran (3ml).
The solution was stirred for 1 hour at -80~(~ then a solution of 2-~N,N-bis(trifluoromethylsulphonyl)-amino]-5-chloropyridine (0.163g, 0.415mmol) in tetrahydrofuran (3ml) was added. The solution was stirred at ~80~C ~or 0.5 hours then at room temperature for 0.5 hours before being quenched by addition of saturated ammonium chloride solution and ethyl acetate. The dried (MgSO4) organic phase was purified by chromatography on a column contS~ining silica gel (eluting with hexane cont.~inin,g increasing proportions of ethyl acetate between 0% to 5%).
Evaporation of the f ractions gave the title compound. m/z (CI~) 464 (M+H), 364 (M+2H - t-BuOCO-), 408 (M+2H - t-Bu). IH NMR (360 MHz, CDCl3) 7.4 (2H, d, J=7.3Hz), 7.3-7.22 (3H, m), 6.01 (l~I, t, J-2.13Ez), 5.13 (lH, s), 4.56 and 4.26 (2H, AB dd, J=12.4Hz and 1.97Hz), 4.10 (lH, dt, J=12.6Hz and 4.22Hz), 3.00 (lH, m), 2.28-2.04 (2H, m) 1.88-1.76 (2H, m), 1.37 (9H, s).

( l )(5R*~6S*)-3-Trimethylstannyl-6-PhenYl-l-oxa-7-(tert-butoxYcarbonvl)-aza-sPiro r4.5~ dec-3-ene To a degassed solution of (1)(5R*,6S*)-3-tritluoromethylsulphonyl-6-phenyl-l-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene (0.482g, 1.04mmol; Desc.5), lithium chloride (0.264g, 6.25mmol), lithium carbonate (0.076g) and hexamethyl dist~nn~ne (0.96g, 2.9mmol) in tetrahydrofuran (lOml) was added tetrakis(triphenylphosphine) palladium(O) (0.06g). The solution was degassed and then heated at 60~C for 5 hours under nitrogen.
Water (20ml) and ethyl acetate (20ml) were added and the dried organic phase was purified by chromatography on a column containing silica gel (eluting with hexane contslining increasing proportions of ethyl acetate between 0% to 5%). Evaporation of the fractions gavethe title compound as a crystalline solid. IH NMR (360 MHz, CDCl~) ~ 7.25 (2H, d, J=7 3Hz), 7.1-7.0 (3H,m), 5.83 (lH, t, J=2.5Hz), 4.78 (lH, s), 4.48 and4.02 (2H, dd, J=12.9Hz and 2.3Hz), 3.96 (lH, dd, J=6.16Hz and 13.4Hz), 2.95 (lH, td, J=13.3Hz and 4.5Hz), 1.84 (lH, m), 1.68 (lH, m), 1.60 (2H, m), 1.19 (9H, s), O (6H, s).

2-Bromo-4-(trifluoromethvl-tetrazolyl~-anisole (a) 4-amino-2-bromoanisole A ~nixture 2-bromo-4-nitroanisole (15g, 64.6mmol) and iron powder (27.3g, 0.49mol) in water (lOOml) and glacial acetic acid (25ml) was stirred at reflux for 2 hours. The mixture was allowed to cool to ambient temperature and filtered through a pad of HY~OTM (washed with 25% acetic acid/water). The ~lltrate was extracted with ethyl acetate (2 x 2~0ml) and the organic layer was dried over sodium sulphate. Removal of the solvent in vacuo left an oil which was chromatographed on silica eluting with 40%
ethyl acetate/hexane giving the title compound as a brown solid (10.32g, 79%). Mass Spec ES+ 202 M+1.
(b) 2-Bromo-4-(tri~1uoroacetamido)anisole 4-Amino-2-bromoanisole (5g, 24.7mmol) was dissolved in dichloromethane (50ml) cont~ining triethylamine ~3.44ml, 24.7mmol).
The solution was cooled to 0~C and trifluoroacetic anhydride (3.5ml, 24.7mmol) was added slowly. The reaction was stirred at ambient temperature for 2 hours, diluted with dichloromethane (200ml) and washed with water (2 x 200ml). The organic layer was dried over sodium sulphate and the solvent was removed i71, uacuo leaving an oil.
Chromatography on silica eluting with 15-25% ethyl acetate/hexane gave the title compound as white solid (4.4g). 'H NMR (250MHz, CDCl3) ~ 7.79 (lH, d, J=2.6Hz), 7.~8 (lH, dd, J=2.6Hz and 8.9Hz), 6.90 (lH, d, J=8.9Hz), 3.90 (3H, s).
.

(c) 2-Brorno-4-(trifluorometkYl-tetrazQlYl)-anisole 2-Bromo-4-(trifluoroacetamido)anisole (4.3g, 14.4mmol) was suspended in carbon tetrachloride (80ml). The suspension was heated to 80~C and triphenylphosphine (4.~4g, 17.3mmol) was added in portions over 4 hours. The reaction was stirred at 80~C for 16 hours. The solvent was removed In vacuo and hexane (lOOml) was added to the residue and heated to reflux temperature. The suspension was allowed to cool to ambient temperature and filtered (triphenylphosphine oxide). The solvent was removed from the filtrate in vacuo leaving an oil (4.6g). The oil in NJN-dimethylform~mi-le (20ml) was added to a suspension of sodium azide ~1.24g, 19.1mmol) in N,N-dimct~ylfor~ mifl~ ~20ml) at ambient temperature. The mixture was stirred for 2 hours and poured into water (200ml). The mixture was extracted with ethyl acetate (2 x 200ml) and the combined organics were washed with water (200ml), dried over sodium sulphate and the solvent was removed in vacuo leaving a yellow oil.
Chromatography on silica eluting with 25% ethyl acetate/hexane gave the title compound as a clear oil (4.9g). lH NMR (2~0MH~ CDCl3) ~ 7.72 (lH, d, J=2.6Hz), 7.44 (lH, dd, J=2.6Hz and 8.9Hz), 7.08 (lH, d, J=8.9Hz), 4.02 (3H, s).

(3S)- l-tert-Butoxvcarbonvl-2-phenvlpiperidin-3-one To a cooled (-60~C) solution of oxalyl chloride (0.68ml, 7.8mmol~ in dicloromethane (17ml) was added dimethyl sulphoxide (0.69ml, 9.8mmol) for 10 minutes before addition of (25,3S)1-tert-butoxycarbonvl-3-hydroxy-2-phenylpiperidine (1.8g, 6.5mmol; prepared bv the method described in European Patent Specification number 0 528 496-A) in dicloromethane (7ml). The solution was stirred at -60~C for 20 minutes, warmed to -30~C
and triethylamine (2.5ml) added. The solution was warmed to room temperature then was washed with ice cold 10% aqueous citric acid solution (40ml, twice), water and dried (MgSO~). This material was used without puri~lcation on silica (enantiomeric excess >90%, chiral hplc).

2-Bromo-4-nitrophenol 4-Nitrophenol (50g) was dissolved in glacial acetic acid (400ml) and bromine (27ml) was added dropwise and stirred for 18 hours. The reaction mixture was then evaporated to dryness, and the crude product crystallised from dichloromethane h~ne to yield the title compound as white crvstals (67~. lH NM3~ (250MHz, CDC13) ~ 8.44 (] H. d, J=2.6Hz!, 8 16 (lH, dd, J=2 6 and 8.9Hz) and 7.13 (lH, d, J-9.OHz).

2-iso-Propoxv-5-nitrobromobenzene 2-Bromo-4-nitrophenol (2.5g; Desc. 9), 2-iodopropane (2.2g) and potassium carbonate (6g) were refluxed in acetone (30ml) for 18 hours.
1~ The reaction mixture was then evaporated to dryness, and taken up in ethyl acetate/water. The organic layer was washed (water, brine), dried (MgSO4) and evaporated in vacuo. Chromatography on silica eluting with 10% ethyl acetate/hexane gave the title compound (2.8g, 94%). lH NMR
(250MHz, CDCl3) ~ 8.46 (lH, s), 8.20 (lH, m), 6.93 (lH, m), 4.76 (lH, m), 1.42 (6H, d, J=7.5Hz).

2-iso-Propoxv-5-amino-bromobenzene Prepared from the compound of Description 10 according to the method of Description 7(a). IH NMR (360MHz, CDCl3) ~ 6.91 (lH, d, 3=2.7Hz), 6.78 (lH, d, J=8.6Hz), 6.57 (lH, dd, J=2.9 and 8.8Hz), 4.33 (lH, m), 1.32 (3H, d, J=5.6E~z).

2-iso-Propoxy-5-(trifluoroacetamido)-bromobenzene Prepared from the compound o~Description 11 according to the method of Description 7(b). lH NMR (360MHz, CDCl3) ~ 7.74 (~H, d, J=2.7Hz), 7.46 (lH, dd, J=2.7Hz and 8.9Hz), 6.91 (lH, d, J=8.9Hz), 4.54 (lH, m), 1.37 (3H, d, J--5.6Hz).

2-iso-Propoxy-5-(triiluoromethvl-tetrazolYl)bromobenzene Prepared from the compound of Description 12 according to the method of Description 7(c). lH NMR (360MHz, CDCl3) ~ 7.69 (lH, d, J=2.7Hz), 7.37 (lH, dd, J=2.7 and 8.9Hz), 7.04 (lH, d, J=8.9Hz), 4.6g ~lH, m), 1.46 (3H, d, J=6.1Hz).

2-Bromo-4-tetrazolvl-anisole 4-Amino-2-bromo-anisole (Desc. 7(a); 4.7g) was dissolved in triethylorthoformate (50ml), trifluoroacetic acid (1.8ml) was added and the mixture heated at reMux for 48 hours. The solvent was removed i71 VClCUO
to afford a brown solid. Sodium azide (2.25g) and acetic acid (25ml) were added and the mixture heated at reflux for 6 hours. The product was purified on flash silica eluting with dichloromethane cont~ining increasing proportions of methanol (0.25%, 0.5 and 0.75%) to give the title compound as a brown solid (3.98g, 67% yield). ~H NMR (250MHz, dG-DMSO) ~ 4.07 (3H, s), 7.50 (lH, d, J=9Hz~, 8.03 (lH, dd, J=9Hz, J=3Hz), 8.32 (lH, d, J-3Hz), 10.16 ~lH, s).

2-Bromo-4-(5-(trifluoromethvl)oxazol-4-vl)anisole Following the procedures described in J. Org. Chem, 1988, 53, 129 and J. Org. Chem., 1988, 53, 519, 3-bromo-4-methoxybenzaldehyde was converted through to the appropriately substituted hydrazine by hydrazine formation with t-butyl hydrazine, methylation on nitrogen and reaction with tritluoroacetic anhydride.
~ollowing the procedure in Heterocycles, vol 34 No 5, 1992 this 5 hydrazine (lg) was reacted with 'wet' silica to give the 5-hydroxy-5-tri~luoromethyl-3-oxazoline (0.4g); m/z (ES+) 340/342 (M+l+, 100%).
Purffled by ~Lash chromatography eluent 5%~10%~15% ethyl acetate in he~ n~?.
Dehydration of the hydroxy oxazoline (0.4g) to give the title compound (0.123g) was carried out by re~1uxing in neat POCl3 for 1 hour.
Purification by flash chromatography eluent 2l/2-5-7l/2-10% ethyl acetate in h~ ne.
lH NMR (250MHz, CDCl3~ ~,3.96 (3H, s), 6.97 (lH, d, J=8.6), 7.63 (lH, dd, J=8.5, 2.1), 7.94 (lH, d, J=2.2), 7.97 (lH, s).

4-(2,5-Bis(trifluoromethvl)-1,3,4-oxadiazol-1-vl)-2-bromoanisole 2,5-Bistrifluoromethyl-1,3,4-n~ 7ole (l.Olg) and 4-amino-2-bromoanisole were heated in a sealed tube at 110~C fol 16 hrs. The two 20 components dissolved to give a brown oil at the reaction temperature. The residue was purified on flash chromatography using eluent 5% ethyl acetate rising to 6%~10% in hexane to afford the title compound as a yellow solid (0.7g). IH NMR (250MHz, DMSO) ~ 4.07 (3H, s), 7.47 (lH, d, J=9.0), 7.97 (lH, dd, J=8.9, 2.5) 8.28 (lH, d, J=2.5). nz/:z (ES+~ 390/392 (M+l+, 100%).

2-Bromo-4-~tetrazol- 1-vl)anisole 4-Amino-2-bromoanisole (4.7g) was suspended in 30 triethylorthoformate (50ml), trifluoroacetic acid (1.8ml) was added. and the reaction was heated at reflux for 36 hrs. The triethvlorthoformate was removed i71 uacuo to afford a brown oil, which was dissolved in acetic acid (25m1), sodium azide (2.25g) was added and the mixture was heated for 4hrs. The solvent was removed in vacuo and the residue dispersed between ethyl acetate and saturated sodium hydrogen carbonate. The 5 organic layer was washed with water, brine, dried (MgSO4) and the solvent removed. Purification on flash silica eluting with 100%
dichloromethane ~0.25~/~0.5%~0.75% methanol in dichloromethane ~f~orded the tit]e compound (~4g) as a brown solid. lH NMR (250MHz, DMSO) ~ 4.06 (3H, s), 7.48 (lH, d, J=8.9) 8.03 (lH, dd, J=8.9, 2.7), 8.31 (lH, d, J=2.5), 10.15 (lH, s).

5-Amino-7-bromo-2,3-dihvdro~enzofuran a) 3-Bromo-4-(pro~-2-envl)oxvnitrobenzene 2-Bro~no-4-nitrophenol (9.2g) was dissolved in dimethylform~mi~le (50ml) and sodium hydride (2.4g) was added portionwise. The bright yellow solution was stirred until all effervescence ceased. Allyl bromide (4.7ml) was added and the resulting solution was heated at 60~C for 30 minutes. The mixture was cooled, quenched by the dropwise addition of water 30ml, then diluted with water (500ml) and extracted with ethyl acetate (3x50ml). The combined organic extracts were ~vashed with sodium hydroxide (2N), water, brine, dried (M gSO4) and evaporated. The residue was purified on silica using 5-10% ethyl acetate in hexane to afford the title compound as a crystalline solid (lOg). IH NMR (360MHz, CDC13) 4.72 (2H, d, J=6Hz), 5.37 (lH, d, J=9Hz), 5.61 (lH, d, J=15Hz), 6.94 (lH, d, J=6.5Hz), 8.18 (lH, dd, J=6.5, 2.6Hz), 8.47 (lH, J=2.6Hz).

b) 2-Bromo-6-prop-2-envl-4-nitro~henol 3-Bromo-4-(prop-2-enyl)oxynitrobenzene (8g) was heated neat at 150-190~C for lhr and at 200-210~C for lhr. The resulting black mixture was purified on silica gel using 10% ethyl acetate in hexane as eluent.
This afforded the title compound as a yellow oil which crystallised on st~n-ling (5.8g, 72%). lH NMR (360MHz, CDCl3) ~ 3.50 (2H, d, J=6.5Hz), 5.14-5.21 (2H, m), 5.91-6.03 (lH, m), 8.03 (lH, d, J=2.6Hz), 8.30 (lH, d, 5 J=2.6Hz).

c) 2-Bromo-6-(2-hvdroxvethyl~-4-nitroPhenol 2~Bromo-6 prop-2-enyl-ac-nitrophenol ~.8g3 was disss~ed in dichloromethane (30ml) and methanol (30ml) and the resulting solution 10 was cooled to -78~C. Ozone was bubbled through the solution until a faint blue coloration was observed and all starting material had leacted. The solution was purged with nitrogen, sodium borohydride (850g) was added and the solution was allowed to come to room temperature. The solvent was evaporated and the residue was dispersed between ethyl acetate and 15 HCl (lN). The ethyl acetate layer was washed with water, brine, dried (MgSO~) and concentrated. The residue was purified on silica using 2%
methanol in dichloromethane as eluent to afford the title compound as a white solid (4g). IH NMR (360MHz, CDCl3) ~ 3.03 (2H, t, J=5.4Hz), 4.06 (2H, t, J=5.5Hz), 8.01 (lH, d, J=2.6Hz), 8.35 (lH, d, J=2.6Hz).
d) 7-Bromo-~-nitro-2.3-dihvdrobenzofuran ~2-Bromo-6-(2-hydroxyethyl)-4-nitrophenol (3.12g) was dissolved in tetrahydrofuran (20ml) and was added dropwise to a cooled (0~C) solution of triphenylphosphine (4.03g) and diethylazodicarboxylate (2.43ml) in 25 tetrahydrofuran (30ml). The mixture was stirred for 3h and the sol~ent was removed i71 vacuo. The residue was purified on silica using 15% ethyl acetate in hexane as eluent to afford the title compound as a white ~ crystalline solid (2g). lH NMR (250MHz, CDCl3) ~ 3.43 (2H, t, J=8. l Hz), 4.85 (2H, t, J=9Hz), 8.03-8.05 (lH, m), 8.20-8.29 ~lH, m).

W O 97/1908~ PCT/GB96/02853 -68 ~

e) 5-Amino-7-bromo-2 3-dihydrobenzofuran 7-Bromo-5-nitro-2,3-dihydrobenzofuran (2g) was suspended in acetic acid (5ml) and water (12mV. Iron powder (3.5g) was added and the 5 mixture was heated at reflux for 3hr. The cooled mixture was cooled and filtered through celite. The filtrate was concentrated and azeotroped with toluene. The residue was purified by chromatography on silica using 10%
ethyl ace~.ate in hexane a~ eluent to al~Eord the title compound (1.3g) as an oil. lH NMR (250MHz, CDCl3) ~ 3.22 (2H, t, J=7.aHz), 3.38 (2H, br s~, 4.58 (2H, t, J=8Hz), 6.51-6.53 (lH, m), 6.63-6.64 (lH, m).

3-33romo-4-trifluoromethoxv-~niline 4-Trifluoromethoxynitrobenzene (4.1g) was suspended in water (16ml) and concentrated sulfuric acid (16ml) and warmed to 80~C with stirring. Potassium bromate (3.7g) was added portionwise over 3 hours.
The resulting mixture was heated at 80~C for a further 2 hours, cooled to room temperature and poured onto ice (lOOg). The mixture was extracted with ethyl acetate, dried (MgS04), filtered, and the solvent removed 20 i7t uacuo. The recovered solid (l.Og) was taken up in acetic acid (2.5ml) and water (lOml) and iron powder (2.0g) added. The resulting mixture was warmed to reflux for 2 hours, cooled to room temperatule and filtered through CeliteTM. The filtrate was extracted with ethyl acetate, the organic layers separated, dried (MgSO4), filtered and the sol--ent removed 25 Z,71 VCJ,CUO. Chromatography on silica gel (ethyl acetate:hexane 1:3) af~orded the title compound as a yellow oil. lH NMR (CDCl:3) ~ 6.a7 (lH, dd), 6.9 (lH, d), 7.06 (lH, dd).

W O 97/19084 PCT/G sg6/028s3 2-Bromo-4-(3-(trifluoromethvl)tetrazol- 1 -vl~trifluoroanisole The title compound was prepared from the product of Description 19 according to the method of step (b) of Description 7. l H NMR (CDCl3) â
57.54 (2 H, m ), 7.86 (lH, d, J=1.0Hz).

2-Bromo-4-(3-(tri~uoromethyl)tetrazol-1-vl)toluene The title compound was pepared from 4-amino-2-bromotoluene 10 according to the method of step (b) of Description 7. lH NMR (CDCls) ~
2.53 (3H, s), 7.32 (lH, dd, J=8.0, 1.0Hz), 7.45 (lH, d, J=8.0 H Z), 7.69 (lH, d,=1.0Hz).

(2S,3R)-l-tert-:~utoxvcarbonyl-3-(3-hvdroxypropyn-lyl)-2-phenylpiperidin-3-ol To a cooled (-~~C) solution of ethylm~gn~sium bromide (lM in tetrahydrofuran, 130ml, 130mmol) in tetrahydrofuran was added O-trimethylsilylpropargyl alcohol slowly. The reaction was stirred at 0~C
for 20 minutes and then at room temperature for 2 hours, before cooling to -10~C. To this was then added a solution of (2S)-l-tert-butoxycarkonyl-2-phenylpiperidin-3-one (Desc. 8; 30g, 108mmol) in tetrahydrofuran keeping the temperature below 5~C. The reaction was stirred at room temperature overnight, quenched by addition of water/saturated aqueous ammonium chloride (200ml/200ml) and extracted with ethyl acatate (2 x 200ml). The combined organic phases were dried (M gSO4) and evaporated to an oil.
This oil was dissolved in ethyl acatate (400 m 1) and a solution of tetrabutylammonium fluoride (lM in tetrahydrofuran, 130 ml, 130mmol) added. ~fter stirring at room temperature for 2 hours, water (200 ml) was added. and the two layers separated. The aqueous phase was further extracted with ethyl acatate (200mV, the organic layers dried (M gSO4) and evaporated to give the product as an oil (50g) which was used crude for Description 23. lH NMR (CDCl3) ~ 7.53-7.55 (2E, m), 7.19-7.35 (3H, m) ~.56 (lH, s), 4.27 (2H, s), 3.99-4.03 (lH, m) 3.25 (lH, bs), 2.77-2.81 (lH, m) 2.77 (lH, bs), 2.12-2.20 (lH, m) 1.91-1.99 (2H, m), 1.77-1.83 (lH, m), 1.39 (9H, s).

(5R.6S)-3-TributYlstannvl-6-1)henvl - 1-oxa-7-(tert-butoxvcarbonyl)aza-sPiror4.51dec-3-ene To a solution of (2S,3R)-l-t-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-phenylpiperidin-3-ol (Desc. 22; 50g) and tetrakis(triphenylphosphine)palladium (0) (2g, 1.7mmol) in toluene (600mV was added tributyltin hydride (29ml, 108mmol) dropwise. The reaction was stirred at room temperature for 2 hours, after which the solvent was evaporated to give a mixture of the two regioisomeric st~nn~nes, (2S,3R)-l-t-butoxycarbonyl-3-(3-hydroxy-2-tributylstannylpropen-lyl)-2-phenylpiperidin-3-ol and (2S,3R)-l-t-butoxycarbonyl-3-(3-hydroxy-1-tributylstannylpropen-lyl)-2-phenylpiperidin-3-ol, as an oil. This oil was dissolved in tetrahydrofuran (600ml), triphenylphosphine (26.2g, 100mmol) added, and a solution of diethyl azodicarboxylate (15.7ml, 100mmol) in tetrahydrofuran (60ml) added dropwise. The reaction was stirred at room temperature for 1 hour, the solvent evaporated, the residue dissolved in acetonitrile (500ml) and extracted with h~xane (6 x 100ml). The combined hexane layers were evaporated and the residue chromatographed on silica, eluting with 2%
eth~ l acatate in dichloromethane, to yield first the title compound, (5R,6S)-3-tributylstan7lyl-6-phenyl -1-oxa-7-(tert-butoxycarbonyl)a~a-spiro[4.5~dec-3-ene as an oil (25g) lH NMR (CDCl3) ~ 7.38-7.40 (2H, m) 7.1~-7.2a (3H, m), 5.96 (lH, t, J=2.3Hz), 4.93 (lH, s), 4.63 (lH, dd! J=2.23 and 12.9 Hz), 4.22 (lH, dd, J=2.23 and 12.9 Hz), 4.09-4.14 (lH, m). 3 09-3.17 (lH, m), 1.95-1.99 (lH, m), 1.83-1.86 (lH, m), 1.72-1.76 (2H, m), 1.40-1.51 (6H, m), 1.38 (9H, s), 1.25-1.32 (6H, m), 0.86-0.~9 (15H, m), followed by some mixed fractions (6g) and lastly the other regioisomer (~,6S)-4-tributylstannyl -6-phenyl - l -oxa- 7-~tert-buto:x~carbonyl)aza-spiro[4. 5~dec-3-5 ene (3g).

N-(3-~3rom o-4-methoxYphenvl)acetamide Acetic anhydride (3.11ml, 3.37g, 33mmol) was added dropwise to a stirred, cooled (0~C) solution of 3-bromo-4-methoxy~nilin~ (6.06g, 30mmol) in dichloromethane (60ml). The mixture was stirred at room temperature for 90 minutes, methanol (lOml) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (lOOml) and water (50ml) were added and the mixture was extracted with ethyl acetate (3 x lOOml). The combined organic fractions were washed with aqueous hydrochloric acid (lM, lOOml), saturated aqueous sodium hydrogen carbonate (l()Oml) and brine (lOOmV, dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallized fiom ethyl acetate (20ml)/hexane (50ml) and the solid was collected and dried i77, vacuo to give the title compound as a tan solid (6.41g, 88%), lH NMR (360 MHz, CDCl3) â 7.68 (lH, d, J=2.5 Hz), 7.45 (lH, dd, J=8.8, 2.5 Hz), 7.36 (lH, br s), 6.84 (lH, d, J=8.8 Hz), 3.87 (3H, s), and 2.16 (3H, s).

D~SCRIPTION 26 1-(3-Bromo-4-methoxvphenvl)-2.4-dimethvl- lH-imida~ole Sodium hydride (60% dispersion in mineral oil, O.90g, 25.2mmol) was added to a stirred, cooled (0~C) solution of N-(3-bromo-4-methoxyphenyl~acetamide (4.58g, 18.8mmol) in dimethylformamide (60ml). The mixture was stirred at 0~C for 30 minutes, then propargvl bromide (80% solution in toluene. 2.olml, 25.2mmol) was added. The CA 02237638 1998-0~-12 mixture was stirred at room temperature for 30 minutes, then water (150ml) was added. The mixture was extracted with ethyl acetate (3 x 150ml) and the combined organic fractions were washed water (4 x 150ml) and brine (150mV, dried (MgSO4) and evaporated under reduced pressure.
The residue was dissolved in acetic acid (15ml) and mercury (II) acetate (0.9Og, 2.8 m mol) and ~mmonium acetate (14.47g, 188m mol) were added.
The mixture was heated under reflux for 4 hours, cooled and poured into water (150ml). The pH was adjusted to 10.0 with saturated aqueous ammonia and the mixture was extracted with ethyl acetate (3 x 160ml).
The combined organic f:ractions were washed with brine (150ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3 (Aq.) (95:5:0.5) and the residue was recrystallized from ethyl acetate (30ml)/hesr~n~ (60ml). The solid was collected and dried in vacuo to give the title compound as a cream-coloured solid (4.98g, 94%), IH
NMR (360 MHz, CDCl3) ~ 7.48 (lH, d, J=2.6 Hz), 7.19 (lH, dd, J=8.7, 2.6 Hz), 6.95 (lH, d, J--8.7 Hz), 6.66 (lH, s), 3.95 (3H, s), 2.30 (3H, s), and 2.22(3H, s~.

4-(4-Methoxvphenvl~vridine A mixture of 4-methoxybenzene boronic acid (2g, 13.16mmol), 4-bromopyridine hydrochloride (3.84 g, 19.72mmol), diphenylphosphinobutylpalladium (II) dichloride (lOOmg), dimethoxyethane (50ml) and 2M sodium carbonate solution (30ml) were stirred at 85~C for 1.5 hours under a nitrogen atmosphere. The solution was allowed to cool to ambient temperature, diluted with ethyl acetate (150ml) and washed with water (150ml). The aqueous layer was extracted with ethyl acetate (2 x 100ml). The combined organic layers were dried over sodium sulphate and the solvents were rernoved leaving a white solid, which was chromatographed on silica gel in 70-100% ethyl acetate/hexane giving the title compound as a white solid (1.95g, 80%). lH NMR (250MHz, CDCl3) ~ 8.66-8.63 (2H, d, J=6.2Hz), 7.63-7.59 (2H, d, J=9.OHz), 7.50-7.47 (2H, d, J=6.2Hz), 7.03-6.99 (2H, d, J=9.OHz), and 3.87 (3H, s~. m/z (ES~) 186 (~+1).

4-(3-:~romo-4-methoxvphenyl)pvridine 4-(4-Methox~h.enyl)pyridine (lg5 5.4mmol) wafi dissolved in glacial acetic acid (6ml). Iron powder (30mg, 0.54mmol) was added followed by a solution of bromine (0.36mV in glacial acetic acid (3ml) slowly over 5 minutes The resulting solution was stirred at 60~C for 1 hour. A solution of bron~ine (0.13ml) in glacial acetic acid (lml) was added and stirring was contiIlued at 60~C for 1.5 hours. The solution was allowed to cool to ambient temperature, diluted with water (20ml). Excess bromine was destroyed by adding in sold sodium bisulphite until all the colour had disappeared. Solid sodium carbonate was added until the solution was basic and the resulting solution was then extracted with ethyl acetate (2 x 30ml) and dried over sodium sulphate. Removal of the solvent gave an oil which was chromatographed on silica gel in diethyl ether giving the title compound as a clear oil (0.77g, 54%). lH NMR (250MHz, CDCl3) ~ 8.66-8.62 (2H, d, J=8.6Hz), 7.87-7.86 (lH, d, J=2.2Hz), 7.61-7.56 (lH, dd, J=8.5Hz and 2.2~Iz), 7.48-7.46 (lH, d, J=8.5Hz), 7.03-6.99 (2H, d, J=8.6Hz), and 3.96 (3H, s). m/z (ES+) 264, 266 (M+1).

D~SCRIPTION 28 4-(Trifluoromethoxv)benzene boroniç acid 1-Bromo-4-(trifluoromethoxy)benzene (5g, 20.75mmol) was dissolved in tetrahydrofuran (20ml). The solution was cooled to -78~C.
n-Butyllithium (1.6M in heaxanes, 14.3ml, 22.8mmol~ was added dropwise keeping the temperature below -60~C. The reaction was sirred at -78~C for W O 97/19084 PCTtGB96/02853- 74 -1 hour. Trimethylborate (14ml, 0.125M) was added dropwise again keeping the temperature below -GO~C. The solution was allowed to warm slowly to ambient temperature and stirred for 16 hours. A 10% citric acid solution (50ml) was added, the solution was stirred for 1 hour ~nd then 5 extracted with ethyl acetate (2 x lOOml). The combined organic layers were dried over sodium sulphate and removal of the solvents gave a white solid which was chromatographed on silica in 35% ethyl acetate/hexane coIlt~inin~ 0.5% glacial acetic acid. The title compound was obtained as a white solid (3.34g, 78%). lH NMR (250MHz, CDCls) ~ 8.27-8.22 (2H, m), and 7.36-7.23 (2H, m).

4- ~4-~Trifluoromethoxvh~henvllpyridine A mixture of 4-(trifluoromethoxy)benzene boronic acid (2g, 9.7mmol), 4-bromop~rridine hydrochloride (2.83g, 14.~mmoV, diphenylphosphinobutylpalladium (II) dichloride (lOOmg), dimethoxyethane (50ml) and a 2M sodium carbonate solution (30ml) were stirred at 85~C for 2 hours. The solution was allowed to cool to ambient temperature diluted with water (lOOml), and extracted with ethyl acetate (2 x lOOml). The combined organic layers were dried over sodium sulphate. Removal of the solvents in uacuo gave an oil which was chromatographed on silica in 30% ethyl acetate/hexane giving the title compound as an oil (1.86g, 80%). lH ~MR (250MHz, CDCl3) ~ 8.72-8.70 (2H, d, J--6.2Hz), 7.69-7.63 (2H, d, J=9.6Hz), 7.49-7.47 (2H, d, J=6.2Hz), and 7.36-7.32 (2H, d, J=9.6Hz). m/z (ES+) 240 (M+l).

4-r3-Bromo-4-(trifluoromethoxv)~henvll~vridine 4-[4-(Trifluoromethoxy)phenyl]pyridine (~OOmg, 2.1mmol) was 30 suspended in water (2ml) and conc. sulphuric acid (2ml). The suspension was heated to 80~C and potassium bromate (386mg, 2.31mmol) was added in portions over 2 hours. The reaction was stirred at 80~C for a further 2 hours, allowed to cool to ambient temperature and then poured onto ice.
The solution was basified with 4N sodium hydroxide solution, extracted with ethyl acetate (2 x 30ml) and the combined organic layers were 5 washed with water. The solution was dried over sodium sulphate arld the solvent was removed in vacuo giving an oil (467mg) which was used without further puri~ tion. lH NMR (2~0MHz, CDCl3) ~ 8.70 (2H, br s), 7.9~-7.91 f~ T=2.2Hz), 7.fi~-7.fi8 (lH, dd, e7=8.FjF17, ~n~ 2 2Hz~, ancl 7.47-7.41 (3H, m). m/z (ES+) 318, 3~20 (M+1).

4-(3-Bromo-4-trifluoromethoxvPhenvl)-4H-l ,2,4-triazole The title compound was prepared from 3-bromo-4-(tri~Luoromethoxy)~niline, using the procedure of Bartlett and Humphrey in J. Chem. Soc, (1967) 1664. IH NMR (360MHz, CDCl3) ~ 7.42 (lH, dd, J=8.6 & 2.5Hz), 7.50 (lH, dd, J=8.6 & 1.3 Hz), 7.73 (lH, d, J-2.5Hz), and 8.47 (2H, s).

20 N-~3-Bromo-4-(trifluoromethoxy)phenvl~trifluoroacetamide The title compound was prepared from 3-bromo-4-(trifluoromethoxy)~niline, using the procedure from Description 7b. lH
NMR (360MHz, CDCl3) ~ 7.33 (lH, dd, J=10.1 & 1.2 Hz), 7.o8 (lH, dd.
J=8.9 & 2.6 Hz), 7.97 (lH, d, J=2.6Hz), and 8.01 (lH,br s).
2~

4-~3-Bromo-4-(trifluoromethoxv)phenvll -3-trifluoromethvl-4H - 1.2.4-triazole N-[3-Bromo-4-(trifluoromethoxy)phenvl]trifluoroacetamide (1'6g!
30 4.6mmol) was suspended in carbon tetrachloride (40ml). The suspension W O 97/19084 PCT/GB96J'~2~5 was heated to 80~C and triphenylphosphine (1.8g, 6.9mmol) was added in portions over 1 hour. The reaction was stirred at 80~C for 15 hours. The solvent was removed i7~ vacuo and hexane (100ml) was added to the residue and heated to reflux temperature. The suspension was allowed to cool to ambient temperature and filtered (triphenylphosphine oxide). The solvent was removed from the filtrate in vacuo leaving an oil (1.2g). The oil was dissolved in dry tetrahydrofuran (~ml), under a nitrogen atmQsphe~e, cooled t,o Q~C and treated with hydrazine hydrate (0.17ml, 3.3mmol). The reaction was stirred at room temperature for 10 minutes before the mixture was evaporated in uacuo. The residue was dissolved in acetic acid (20ml), treated with triethylorthoformate (~ml, 30mmol) and heated at reilux for 12 hours The black mixture was evaporated i,n uacuo, basified (NaOH, lM) and extracted with ethyl acetate (2 x 40ml). The extracts were washed with brine (20mV, dried (Na2SO4) and evaporated in uacuo to a beige solid which was purified by chromatography on silica eluting with ethyl acetate/hexane (1:1) to give the title compound as a white solid (360mg, 84%). lH NMR (360MHz, CDCl3) ~ 7.41 (1H, dd, J=8.8 & 2.6 ~Iz), 7.51 (lH, dd, J=8.8 & 1.4 Hz), 7.72 (lH, d, J=2.6Hz), and 8.36 (lE~, s).

l-r3-Bromo-4-~methoxv)phenvll-2-trifluoromethvl-lH-imidazole 2-Bromo-4-(trifluoroacetamido)anisole (Desc. 7b; 4.3g, 14.4mmol) was suspended in carbon tetrachloride (80ml). The suspension was heated to 80~C and triphenylphosphine (4.54g, 17.3mmol) was added in portions over 4 hours. The reaction mixture was stirred at 80 C for 16 hours. The solvent was removed i71 vacuo and hexane (lOOml) was added to the residue and the mixture heated to reflux temperature. The suspension was allowed to cool to ambient temperature and filtered (triphenylphosphine oxide). The solvent was removed from the filtrate i71 I

vacuo leaving an oil (4.6g). A portion of this oil (3.63g) was dissolved in tetrahydrofuran (40ml) and treated with aminoacetaldehyde diethyl acetal (5.0ml, 34mmol). The mixture was stirred at room temperature for 3 hours, concentrated in vacuo, redissolved in acetic acid (lOOml) and heated at reflux for 1 hour. The mixture was evaporated, treated with lM sodium hydroxide solution (250ml) and extracted with ethyl acetate (2 x lOOml).
The extracts were washed with brine (lOOml), combined, dried (M g~O4) and evaporated to an amber oil. Pl]rifif~t.inn by flash chromatography, eluting with ethyl acetate/he~r~n~ 2 then 2:3), gave the title compound as a tan solid (2.60g, 71%); lH NMR (250MHz, CDCl3) ~ 3.97 (3H, s), 6.98 (lH, d, J=8.7Hz), 7.12 (lH, d, J=l.lHz), 7.21 (lH, d, ~=l.lHz), 7.31 (lH, dd, J=8.7, 2.6Hz), and 7.58 (lH, d, J=2.6Hz).

DES~RIPTION 35 l~ r3-Bromo-4-(triiluoromethoxY)~henvll-2-trifluoromethYl-lH-im;~ole The title compound was prepared from N-[3-bromo-4-(trifluoromethoxy)phenyl]trifluoroacet~mi-le, using the procedure from Description 34. lH NMR (360MHz, CDCl3) ~ 7.15 (lH, d, J--1.0 Hz), 7.25 (lH, d, J=l.O Hz), 7.34-7.46 (2H, m), and 7.70 (lH, d, J=2.4 Hz). m/z (ES+) 375, 377 (M+l).

4-~3-Bromo-4-methoxyphenvl~-3-trifluoromethyl-4H - 1,2,4-triazole The title compound was prepared from from N-[3-bromo-4-(trifluoromethoxy)phenyl]trifluoroacetamide, using the procedure described in Description 33. lH NMR (360MHz, CDCl3) ~ 3.99 (3H, s), 7.02 (lH, d~ J=8.8 Hz), 7.31 (lH, dd, J=8.8 & 2.6 Hz), 7.~7 (lH, d, J=2.6Hz), s and 8.31 (lH, s). m/z (~S+) 322, 324 (M+l).

CA 02237638 1998-0',-12 3-Bromo-4-(2-hvdroxy)ethoxv nitrobenzene Sodium hydride (4.13g, O.lmol) was added portionwise to a solution of 2-bromo-4-nitrophenol (Desc. 9, 15g, 0.07moV in 6 N,N-dimethylformamide (85ml). The resulting mixture was stirred at ambient temperature for 15 minutes. 2-Bromoethanol (6.85ml, O.Omol) was added dropwise, and the resulting solution was heated at 60~C for 4 hours. The solution was allowed to cool to ambient temperature, diluted with water (150ml) and extracted with ethyl acetate (3x80ml). The combined organic fractions were washed with brine (150ml), dried (MgSO4), and evaporated in vacuo. Purification on silica, eluting with 25%-35% ethyl acetate in hexane afforded the title compound as a yellow solid (7.9g, 43%). lH NMR (250MHz, CDCl3) ~ 4.05 (2H, t, J=2.9Hz), 4.27 (2H, t, J=2.8Hz), 6.96 (lH, d, J=7.9Hz), 8.18 (lH, dd, J=7.9Hz, J=2.6Hz), 8.45 (lH, d, J=2.8Hz).

3-Bromo-4-(2-fluoro)ethoxv nitrobenzene To a cooled (-780C) suspension of 3-Bromo-4-(2-hydroxy)ethox nitrobenzene (7.9g, 30mmol) in dichoromethane (80ml) was added diethylaminosulphur trifluoride (3.88ml, 31.5mmol) . The solution was stirred at ambient temperature for 2 hours, then quenched by the dropwise addition of water (lOOml). The organic layer was separa~ed.
washed with brine (lOOml), dried (MgS04), and evaporated in vacuo.
Purification on silica, eluting with 15%-20% ethyl acetate in hexane afforded the title compound as a yellow oil (1.2g, 15%). lH NMR (2~0MHz, CDCl3) ~ 4.35 ( lH, dd, J=4.1Hz, J=2.4Hz), 4.45 (lH, dd, J= .4Hz.
J=4.1Hz), 4. / 5 (lH, dd, J=4Hz, J=5.8Hz), 4.9Ei (lH, dd, J=4Hz, J=~.8Hz), 6.98 (lH, d, J=9.1Hz~, 8.21 (lH, dd, J=2.7Hz, J=9Hz).

3-Bromo-4-(2-fluoro)ethoxvaniline Prepared from 3-Bromo-4-(2-fluoro)ethoxy nitrobenzene, using the procedure from Description 7a, but refluxing for only 5 minutes.
5 Purification on silica, eluting with 25% ethyl acetate in he~n~ afforded the title compound as a brown oil. (1.4g, 92%). m/z (~I+) 234 (M+l, 100%).

3-Bromo-4-~(2-fluoro)ethoxyltrifluoroacet~nili~le Prepared from 3-bromo-4-(2-fluoro)ethoxy aniline, using the procedure from Description 7b, to afford the title compound as a white solid (9OOmg, 80%). lH NMR (250MHz, CDCl3) ~ 4.23 (lH, t, J=4.23Hz), 4.33 (lH, t, J=4.2Hz), 4.70 (lH, t, J=4.lHz), 4.89 (lH, t, J=4.lHz), 6.93 (lH, d, J=8.9Hz), 7.62 (lH, dd, J=8.9Hz, J=2.7Hz), 7.80 (lH, d, J=2.6Hz).

3-Bromo-4- r(2-fluoro)ethoxvl - ~(5-trifluoromethvl) -tetrazol- 1 -vllbenzene Prepared from 3-bromo-4-L(2-fluoro)ethoxy]-tri~luoroacetanilide, using the procedure from Description7c, to afford the title compound as a yellow oil (540mg). lH NMR (250MHz, CDCl3) ~ 4.34 (lH, t, J=4.1Hz), 4.46 (lH, t, J=4.1Hz), 4.77 (lH, t, J=3.92Hz), 4.96 (lH, t, J=4.0Hz), 7.10 (lH, d, J=8.8Hz), 7.43 (lH, dd, J=2.6Hz, J=8.8Hz), 7.73 (lH, d, J=2.6Hz).

VESC~RIPTION 42 2-Bromo-4-(1-methvltetrazol-5-vl)anisole and 2-Bromo-4-(2-methvltetrazol-6-vl~anisole A mixture of 3-bromo-4-methox~Tbenzonitrile (9g, 42mmol), sodium azide (3.03g, 46.7mmol) and ammonium chloride (2.~g, 46.7mmol) in N,N-dimethylform~mi~e (60ml) was heated at 90~C for 18 hours. The reaction was cooled, poured onto ice (200ml) and acidified with lN HCl to pHl. The resultant solid was filtered, dried and lecrystallized from ethanollwater to give 2-bromo-4-(tetrazol-5-yl)anisole (9.2g). lH NMR
(360MHz, DMSO-dG) ~ 3.95 (3H, s), 7.3~i (lH, d, J=8.6 Hz), 8.05 (lH, d, J-8.6 Hz), 8.23 (lH, s). To a suspension of sodium hydride (60% dispersed, 1.5g, 37mmoV in N,N-dimethylform:~mitle was added the foregoing anisole 6 (6g, 32.6mmol) and the reaction stirred at room temperature for 2 hours.
The reaction was diluted with water (70ml) and the resultant solid filtered, dried and chromatographed on silica eluting with 60% ethyl acetatelhexane to give 2-bromo-4-(2-methyltetrazol-5-yl)anisole (3.2g), lH
NMR (360MHz, CDCl3) ~ 3.97 (3H, s), 4.39 (3H, s), 7.00 (lH, d, J=12.4 10Hz), 8.07 (1H, dd, J=12.4 and 3.0 Hz), 8.34 (lH, d, J=3.0 Hz); and 2-bromo-4-(1-methyltetrazol-5-yl)anisole (0.8g), lH NMR (360MHz, CDCl3) ~ 3.94 (3H, s), 4.13 (3H, s), 7.01 (lH, d, J=8.6 Hz), 7.66 (lH, dd, J=8.6 and 2.2 Hz), 7.90 (lH, d, J=2.2 Hz).

2-Bromo-4-chloro- 1 -(tetrazol- 1-vl~benzene 3-Bromo-4-chloroz~niline (3g, 14.5mmol) in acetic acid (40ml) was treated with triethylorthoformate (6ml, 36.1mmol) and heated at 70~C for 2 hours. Sodium azide (2.84g, 43.7mmol) was added portionwise over 10 20 minutes to the solution at 70~C and heating continued for a further 2.a hours. Upon cooling crystals started to appear. Water (2aml) was added and the mixture aged at 0~C for 1 hour. The solid was filtered, washed with ~-ater (25ml) and dried in uacuo at 60~C for 16 hours to give the title compound (3.08g). IH NMR (250MHz, CDCl3) ~ 7.63-7.89 (2H, m). 8.06 25 (lH, s), 9.01 (lH~ s).

DESC~IPTION 44 l-r3-:Blomo-4-(trifluoromethoxY)Phenvll-lH-Pvrazole Sodium nitrite (359mg, 5.2mmol) in water (6ml) was added 30 dropwise to a stirred, cooled (0 ~C) suspension of 3-bromo-4-trifluoromethoxy~nilin~ (Description 19) (1.02g. 4mmol) in aqueous CA 02237638 1998-0~-12 hydrochloric acid (37%, 10ml). The mixture was stirred at 0 ~C for 30 min., then added dropwise to a stirred, cooled (-5 ~C) suspension of tin (II) chloride dihydrate (4.06g, 18mmol) in aqueous hydrochloric acid (37%, 10ml). The mixture was stirred at 0 ~C for 30 min., then at room temperature for 30 min. The mixture was poured into cooled (0 ~C) aqueous sodium hydroxide (4M, 200ml) and extracted with ethyl acetate (3 x 100ml). The combined organic fractions were washed with aqueous sodium hydroxide (4M, 2 x 100ml) and brine (lOOmV, dried (M gS04) and evaporated under reduced pressure. The residue was dissolved in ethanol (lOml), cooled in ice and ethanolic hydrogen chloride (5M, 0.76ml, 3.8mmol) was added. The solvent was evaporated under reduced pressure, ethanol (50ml) and malonaldehyde bis(dimethyl acetaV (0.63ml, 0.62g, 3.8mmol) were added. The mixture was heated under reflux for 30 min., cooled and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (50ml) and water (20ml) were added and the mixture was extracted with ethyl acetate (3 x 50ml). The combined organic fractions were washed with brine (50ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (92:8) to give the title compound as a yellow oil (801mg, 6~%). lH NMR (360MHz.
CDCl3) ~ 8.04 (lH, d, J=2.6Hz), 7.90 (lH, d, J=2.4Hz), 7.74 (lH, d, J=1.8Hz), 7.68 (lH, dd, J=8.9, 2.6~Iz), 7.39 (lH, d, J=8.9Hz), and 6 50 (lH, dd, J=2.4, 1.8Hz). m/z (ES~ 307, 309 (M+1).

2-Ethoxv-5-nitrobromobenzene Iodoethane (3.7ml) was added to a mixture of 2-bromo 4-nitrophenol (4g) and potassium carbonate (5.1g) in N,N
dimethylformamide (20ml) and the mixture was stirred at room 30 temperature for 3 hours. The mixture was partitioned between water (300ml) and ethyl acetate. After extraction with EtOAc. the combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with he~r~n~ tOAc (95:5 increasing to 90: 10) to give the title compound as an oil (3.4g). lH NMR
(250MHz, CDCl3) ~ 1.54 (3H, t, J=9.1Hz), 4.21 (2H, q, J=7Hz), 6.93 (lH, d, J=9.lHz), 8.19 (lH, dd, J=9.1, 2.7Hz), and 8.47 (lH, d, J=2.7Hz).

3-Bromo-4-ethoxvaniline Prepared from the compound of Description 45 according to the method of Description 7a. lH NMR (250MHz, CDCl3) ~ 1.41 (3H, t, J=7.0Hz), 4.00 (2H, q, J=7.0Hz), 6.58 (lH, dd, J=8.6, 2.7Hz), 6.74 (lH, d, J=8.6Hz), and 6.91 (lH, d, J=2.7Hz).

N-(3 -Bromo-4-ethoxvphenYl)trifluoroacetamide Prepared from the compound of Description 46 according to the method of Description 7b. lH NMR (250MHz, CDCl3) ~ 1.47 (3H, t, J=7.0Hz), 4.10 (2H, q, J=7.0Hz), 6.88 (lH, d, J=8.9Hz), 7.48 (lH, dd.
J=8.9, 2.6Hz), and 7.75 (lH, d, J=2.6Hz).

I~ESCRIPTION 48 1-(3-Bromo-4-ethoxv~henvl)-2-trifluoromethvl- lH-imidazole Prepared from the compound of Description 47 according to the method of Description 34. lH NMR (250MHz, CDCl3~ 2 (3H, t, J=7.0Hz), 4.16 (2H, q, J=7.0Hz), 6.94 (lH, d, J=8.8Hz)~ /.11 (lH, d, J=1.2Hz), 7.21 (lH, d, J=1.2Hz), 7.27 (lH, dd, J=8.8, 2.~3Hz), and ~ 56 (lH, d, J=2.43Hz).

4-(3-Bromo-4-isopropoxvphenvl~-3-trifluoromethvl-4H- 1.2~4-triazole ~ Prepared from the compound of Description 12 accor-ling to the method of Description 33. lH NM~ (360MHz, CD(~ 1.44 (6H, d, J=6.1Hz), 4.66 (lH, sept, ~=6.1Hz), 7.00 (lH, d, J=8.8Hz), 7.25 (lH, dd, J=8.8, 2.6Hz), 7.56 (lH, d, J-2.6Hz), and 8.30 ~lH, s). m/z (ES+) 350, 352 ~+1).

DESCRIPTION ~0 1-(3-Bromo-4-isopro~ox~Phenvn-2-tri~Luoromethvl-lH-imirl~7:ole Prepared from the compound of Description 12 according to the method of Description 34.1H NMR (360MHz, CDCl3) ~ 1.43 (6H, d, J=6.0Hz), 4.63 (lH, sept, J=6.lHz), 6.96 (lH, d, J=8.8Hz), 7.10 (lH, d, J=l.lHz), 7.20 (lH, d, J=l.OHz), 7.25 (lH, dd, J=8.7, 2.6Hz), and 7.56 (lH, d, J=2.6Hz). m/z (ES+) 349, 351 (M+l).

1 -(3-Bromo-4-methoxYphenvl)oxazole Potassium t-butoxide (2.85g, 25.4mmol) was added to a cooled (0 ~C) solution of (lH-benzotriazol-l-yl)methyl isocyanide (2g, 12.7mmol) and 3-bromo-4-methoxybenzaldehyde (2.72g, 12.7mmol) in tetrahydrofuran (lOml) and ethanol (1.17g) and the mixture was stirred at 0 ~C for 2 hours.
The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (100:0 increasing to 75:25) to give the title compound (2.7g). lH NMR (250MHz, CDCl3) â 7.88 tlH, s), 7.8 (lH, d, J=2.2Hz), 7.6 (lH, dd, J=8.6, 2.2Hz), 7.2 (lH, s), 6.8 (lH, d, J=8.6Hz), and 3.8 (3H, s).
m/z (ES+) 254, 256 (M+l).

DESCRIPTION 52 _ 3-Bromo-4-isoPropoxvbenzaldehyde Potassium carbonate (10.28g, 7.4mmol) and 2-bromopropane (8.7ml) were added to 3-bromo-4-hydroxybenzaldehyde (7.46g, 3.7mmol) in N,N-dimethylform~rnifle (20ml). The mixture was stirred at room temperature for 3 hours, then partitioned between ethyl acetate and water. The organic phase was washed with brine and dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purif~ied by flash column chromatography on silica gel, eluting with h~x~ne/EtOAc (90:10 10 increasing to 80:20) to give the title compound (5.34g). lH NMR (250MHz, CDCl3) ~ 9.82 (lH, s), 8.û3 (lH, d, J=2.0Hz), 7.82-7.78 (lH, dd, J-6.0, 2.0Hz), 7.00 (lH, d, J=6.0Hz), 4.72 (lH, septet, J=6.0Hz), and 1.40 (6H, d, J=6.0Hz).

1-(3-Bromo-4-iso~ro~oxv~henyl)oxazole Prepared from the compound of Description 52 according to the method of Description 51.1H NMR (250MHz, CDCl3) ~ (7.90, lH, s3, 7.82 (lH, d, J=2.2Hz), 7.52 (lH, dd, J=8.6, 2.2Hz), 7.22 (lH, s),6.90 (lH, d, 20 J=8.6Hz), 4.64 (lH, septet, J=6.0Hz), and 1.42 (6H, d, J=6.0Hz).

DE~CRIPTION 54 1 -Benzvloxv-2-bromo-4-nitrobenzene 2-Bromo-4-nitrophenol (lOg), potassium carbonate (12.7g) and 25 benzyl bromide were dissolved in dimethylform~3mi-1e and the mixture was stirred overnight. The mixture was diluted with water (1 L) and extracted with ethyl acetate (3 x 50ml). The organic layer was washed with water, brine, dried (MgSO~) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on 30 silica gel, eluting with hexane/EtOAc (95:5) to give the title compound as a pale yellow solid, (11.8g, 77%). IH NMR (250MHz, CDCl3) ~ 8.49 (lH, d, =

J=2.7Hz), 8.17 (lH, dd, J=9.1, 2.7Hz), 7.45 (5H, m), 7.00 (lH, d, J=9.lHz), and 5.28 (2H, s).

5 4-Benzvloxv-3-bromo~nilin~
Prepared from the compound of Description 54 according to the method of Description 7a. lH NMR ~250ME~z, CDCl3) o 7.45 (5H, m), 7.24 ~1H, d, J=2-.7H~), 7.08 (1EI~ d~ ~T=8.6H7,~, fi.86 ~lH, dd, J=8.6, 2.7HZ)S 6..~6 (2H, s), and 3.77 (2H, br s). m/z (ES+) 278, 280 (M+1).

N-(2-Benz~loxy- 3-bromoPhenYl)trifluoroacetamide Prepared from the compound of Description 5~ according to the method of Description 7b. lH NMR (360MEz, CDCls) ~ 5.14 (2H, s), 6.91 (lH, d, J=7.2Hz), 7.24-7.45 (6H, m), 7.77 (lH, d, J=2.6Hz) and 7.90 (lH, s).

1-(2-Benzvloxy-3-bromophenyl)-2-(trifluoromethYl)-lH-~mi~7.Qle Prepared from the compound of Description 56 according to the method of Description 34. mlz (ES+) 397, 399 (M+1).

3-Bromo-4-(trifl uoromethoxv)benzonitrile 4-(Trifluoromethoxy)benzonitrile (5.57g, 29.8mmol) was added to 50% aqueous sulfuric acid (60ml) and the mixture was warmed to 80 ~C.
Potassium bromate (5.97g, 35.7mmol) was added in portions over 2 hours and the mixture was stirred at 80 ~C for a further 2 hours. The mixture was cooled to room temperature and poured into water (200ml). The mixture was extracted with ethyl acetate (3 x 200ml) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the title compound as an orange oil (6.0g) which contained 4-(tri~1uoromethoxy)benzonitrile (ca. 30%) as detern:lined by lH NMR. lH
NMR (250MHz, CDCl3) ~ 7.97 (lH, d, J=2.0Hz), 7.68 (lH, dd, J=8.5, 2.0Hz), and 7.42 (lH, dq, J=8.5, 1.5Hz).

D3~SCRIPTION 59 4-r3-Bromo-4-(trifluoromethoxv)~henvll-lH-1~2,3-triazole Trimethylsilyl diazomethane (2M solution in h~nes, 17.85ml, 35.7mmol) was dissolved in dieth~l ether (150ml~ and cooled to 0 ~C n-Butyl lithium (1.6M solution in h~ nas, 35.7mmol) was added dropwise over 10 minutes and the reaction stirred at 0 ~C for 20 min. Crude 3-bromo-4-(trifluoromethoxy)benzonitrile (Description 58) (6.0g) was added over 5 minutes and the mixture was stirred at 0 ~C for 1 hour. Saturated aqueous ammonium chloride (200mlj and water (l00mV were added and the mixture was extracted with ethyl acetate (3 x 200ml). The combined organic layers were dried (MgSO4) and evaporated to give an orange oil (10.lg). The residue was dissolved in ethanol (150ml) and potassium fluoride (2.09g, 36mmol) and concentrated hydrochloric acid (3.6ml) were added. The mixture was heated at reflux for 1 hour, cooled to room temperature and the ethanol was evaporated under reduced pressure.
Water (200ml) was added and the mixture was extracted with ethyl acetate (3 x 200ml). The combined organic layers were washed with brine (200ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/ether (90:10) to give the title compound as a colorless solid (4.02g, 44%). lH NMR (250MHz, CDCl3) S 8.14 (lH, d, ~J=2.1Hz), 8.00 (lH, s), 7.81 (lH, dd, J=8.5, 2.1Hz), and 7.40 (lH, dq, J=8.5, 1.4Hz). m/z (ES+) 308, 310 (M+l).

2-Methvl-4-r3-bromo-4-(trifluoromethoxv)phenYll-2H-1.2.3-triazole and 1-methvl-4-r3-bromo-4-(trifluoromethoxv)~henvn-lH-1.2.3-triazole Tetra n-butyl ammonium fLuoride solution (lM in THF, 12.5ml, 12.5mmol) was added over 5 minutes to a stirred solution of 4-~3-bromo-4-(tri~luoromethoxy)phenyl~-lH-1,2,3-triazole (Description 593 (2.73g, 8.85mmol) and dimethyl sulfate (2.10ml, 22.1 mmol) in THF (50mV The mixture was stirred for at room temperature for 1.5 hours, then water (100mV and diethyl ether (lOOmV were added. The layers were separated 10 and the aqueous layer was extracted with ether (200ml3. The combined organic layers were washed with water (lOOml) and brine (lOOml), dried ~MgSO4) and evaporated under reduced pressure. The residue was purified by ilash column chromatography on silica gel, eluting with ne/EtOAc (75:25 increasing to 50:50) to give 2-methyl-4-[3-bromo-4-15 (trifluoromethoxy)phenyl~-2H-1,2,3-triazole as a colorless solid (1.50g, 53%), lH NMR (250MHz, CDC13) ~ 8.07 (lH, d, cr=2.1Hz), 7.81 (lH, s), 7.73 (lH, dd, J=8.5, 2.1Hz), 7.36 (lH, dq, J=8.5, 1.4Hz), and 4.25 (3H, s), m/z (ES+) 322,324 (M+1), and l-methyl-4-[3-bromo-4(trifluoromethoxy)phe7tyl~-lH-1,2,3-triazole as a colorless solid (566mg, 20%), lH NMR (250MHz~
20 CDC13) d 8.12 (lH, d, J=2.1Hz), 7.8Q (lH, dd, J=8.5, 2.1Hz), 7.78 (lH. s), 7.36 (lH, dq, J=8.5, 1.5Hz), and 4.17 (3H, s), m/z (ES+) 322,324 (M+1).

3 -(4-Trifluoromethoxy~henyl)pyridine 4-(Trifluoromethoxy) pheny~ boronic acid (1.3g, 6.31mmol) was dissolved in ethylene glycol dimethyl ether (50ml). 3-Bromopyridine (lml, 9.5mmol), aqueous sodium carbonate (2M, 30mV, and Pd(dppb)Cl2 (lOOmg) were added and the reaction mixture was stirred at 85 ~C for 3 hours. The mixture was allowed to cool to room temperature, then water (200ml) was added and the mixture was extracted with ethyl acetate (3 x lOOml). The combined organic fractions were dried (MgS04) and the solvent was CA 02237638 1998-0~-12 evaporated under reduced pressure. The residue was purified by ~1ash column chromatography on silica gel, eluting with hexane/ether (60:40) to give the title compound as an oil (1.26g, 84%). lH NMR (250MHz, CDCl3) ~ t 8.84 (lH, s), 8.60 (lH, br d), 7.87 (lH, m), 7.61 (2H, m), and 7.36 (3H, m).
m/z (ES+) 240 (M+1).

3-(3-Bromo-4-trifluoromethoxv~henvl) Pvridine 3-(4-TrifluoromethoxyphenyVpyridine (Description 61) (1.26g, 5.27mmol) was suspended in aqueous sulfuric acid (50%, 16mV and cooled to O ac. Potassium bromate (0.88g, 5.27mmol) was added in portions over 2 hours and the mixture was stirred at room temperature for 40 min. The mixture was poured into ice/water and basified with aqueous sodium hydroxide (4M). The mixture was extracted with ethyl acetate (3 x lOOml) and the combined organic fr~tio~ were washed with brine, dried (M gSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ether (60:40) to give the title compound as an oil (1.2g, 74%).
lH NMR (360MHz, CDCl3) ~ 8.82 (lH, s), 8.62 (lH, d), 7.84 (2H, m), 7.54 (lH, dd, J=8.~, 2.2~z), 7.41 (2~, m). m/z (l~S+) 318, 320 ~M+1).

3-(Trimethvlstannyl)pvridine .
3-Bromopyridine (0.8g, 5.1mmol), hexamethylditin (5g, 15.3mmol), lithium chloride (1.3g, 30.6mmoV and lithium carbonate (375mg, 5.1mmol) were suspended in tetrahydrofuran (lOml~ under a nitrogen atmosphere.
Tetrakis(triphenylphosphine)palladium (O) (2~0mg, 0.25mmol) was added and the solution was stirred at 60 ~C for 16hours, allowed to cool to room temperature, filtered and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic layer was dried (Na2SO4) and the solvent was evaporated W O 97/19084 PCTtGB96/02853 ~- 89-under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with h~ne/EtOAc (90:10) to give the title compound as an oil (302mg). lH NMR (250MHz, CDCl3) X 8.66-8.62 (lH, m), 8.58-8.62 (lH, m), 7.93-7.75 (lH, m), 7.27-7.22 (lH, m), and 0.34 (9H, s). MS (ES+) 240-248 (M+l).

2-(Benzvloxv)bromobenzene A mixture of 2-bromophenol (lOg, 57.8mmoV, benzyl bromide (27.5ml, 0.23mol) and potassium carbonate (64g, 0.462mol) in N,N-dimethylform~mi(le ~70ml) was stirred at room temperature for 72 hours.
The suspension was poured into water (500ml) and extracted with ethyl acetate (2 X 300ml). The combined organic fractions were washed with water (300mV, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with he~n~/EtOAc (98:2) to give the title compound as a colourless oil (2.9g). lH NMR (250MHz, CDCl3) ~ 7.58-7.19 (8H, m), 6.95-6.81 (2H, m), and 5.16 (2H, m).

(5R,6S)-3-(2-BenzvloxvPhenvl)-6-phenvl-1-oxa-7-(tert-butoxvcarbon-rl)aza-spiror4.51dec-3-ene Prepared from the compound of Description 64 and (5R,6S)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyVaza-spiro~4.5]dec-3-ene according to the method of Example lA. lH NMR (250MHz, CDCl3) ~
7.49-7.34 (7H, m), 7.27-7.17 (4H, m), 7.10-7.06 (lH, m), 6.99-6.90 (2H, m), 6.65-6.64 (lH, t, J=2.05Hz), 5.11 (2H, dd (AB), J=11.5Hz), 6.07 (lH, s), 4.98-4.92 (lH, dd, J=12.06, 2.05Hz), 4.67-4.61 (lH, dd, J=12.06, 2.05Hz), 4.13-4.06 (lH, m), 3.18-3.10 (lH, m), 2.08-2.03 (lH, m), 1.82-1.71 (3H, m), and 1.32 (9H, s). MS (ES+) 498 (M+1).

(5R,6S)-3-(2-Hvdroxvphenvl)-6-Phenvl- 1-oxa-7-(tert-butoxvcarbonvl)aza-sPiror4.51decane (5R,6S~-3-(2-Benzyloxyphenyl)-6-phenyl- 1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene (Description 65) (450mg, 0.9mmol) was dissolved in methanol (15mV and 10% palladium on carbon (50mg) was added. The solution was shaken under hydrogen (50 psi) for 5 hours.
Thc mixturc was ~ltered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with h~x~ne/EtOAc (85:15) to give the title compound as a foam (253mg, 68%). lH NMR (360MHz, CDCl3) ~ 7.59-7.57 (2H, m), 7.34-7.29 (2H, m), 7.26-7.22 (lH, m), 7.13-7.05 (2H, m), 6.87-6.83 (lH, m), 6.77-6.74 (lH, m), 5.78 (lH, br s), 5.36 (lH, s), 4.26-4.21 (lH, dd, J=8.9, 7.1Hz), 4.01-3.g5 (lH, m), 3.94-3.89 (lH, dd, J--8.9, 7.2Hz), 3.70-3.66 (lH, m), 2.87-2.79 (lH, m), 2.50-2.44 (lH, m), 2.25-2.08 (2H, m), 1.81-1.70 (3H, m), and 1.36 (9H, s). MS (ES+) 410 (M+1).

(3S,~R,6S)-3-(5-Bromo-2-hvdroxvPhenvl)-6-Phenvl-l-oxa-7-(tert-20 butoxvcarbonvl)aza-spiro~4.5ldecane (5R,65)-3-(2-Hydroxyphenyl)-6-phenyl- 1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5~decane (I~escription 66) (lOOmg, 0.24mmol) was dissolved in a 3:2 dichloromethane/ methanol mixture (5mV.
Tetrabutylammonium perbromide (118mg, 0.24mmol) was added in 25 portions over 10 minutes and the reaction was stirred until the solution became colourless (10 min.). The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water The organic layer was dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column 30 chromatography on silica gel, eluting with hexane/EtOAc (80:20) to give the title compound as a foam (76mg). l~ NMR (360MHz. CDCl3) ~ 7.a7-W O 97/19084 PCT/GB9G/'0285 7.55 (2H, m), 7.34-7.31 (2H, m), 7.27-7.25 (lH, m), 7.21-7.16 (2H, m), 6.67-6.64 (lH, d, J=8.4Hz), 6.20 (lH, br s), 5.33 (lH, s), 4.23-4.19 (lH, dd, J=9.06 and 7.07Hz), 4.02-3.95 (lH, ~), 3.94-3.89 (lH, dd, J=9.1 and 6.57Hz), 3 61-3.57 (lH, m), 2.85-2.81 (lH, m), 2.51-2.45 (lH, m), 2.19-2.13 (2H, m), 1.80-1.73 (3H, m), and 1.36 (9H, s). MS (ES+) 488, 490 ~M+1).

(~.5R.6~-3-(~-Bromo-2-i~o~roPox~hL~nvl~-fi-nhenvl-~1 -oxa-7-(~ert-butoxvcarbonvl~aza-spiror4.5~decane To a solution of (3S,5R,6S~-3-(5-bromo-2-hydroxyphenyl)-6-phenyl-l-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Description 67) (69mg, 0.14mmol) and 2-bromopropane (63ml, 0.56mmol) in N,N-dimethylform~mi~l~ (5ml) was added potassium carbonate (157mg, 1.1 ~mmol). The solution was stirred at 50 ~C for 72 hours, allowed to cool to ambient temperature, poured into water (50ml) and extracted with ethyl acetate (2 x 50mV. The combined org~nie~fractions were washed with water, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by ~1ash column chromatography on silica gel, eluting with hexane/EtOAc (85:15) to give the title compound as an oil (68.4mg, 91%). lH NMR (360MHz, CDCl3) ~ 7.57-7.55 (2H, m), 7.34-7.23 (5H, m), 6.72-6.70 (lH, d, J=8.5Hz), 5.20 (lH, s), 4.53-4.47 (lH, m), 4.24-4.21 (lH, m), 4.01-3.98 (lH, m), 3.75-3.68 (lH, m), 3.65-3.61 (lH, m), 2.92-2.84 (lH, m), 2.41-2.35 (lH, m), 2.18-2.12 (2H, m), 1.77-1.72 (3H, m), 1.40 (9H, s), and 1.34-1.31 (6H, m). MS (ES+) 530, 532 (M+l).

3 -Bromo-4-methoxv~henvlhvdrazine A solution of sodium nitrite (3.16g, 45.8mmol) in water (30ml) was added dropwise over 30 minutes to a stirred, cooled (-5 ~C) suspension of 4-amino-2-bromoanisole (Description 7a) (7.31g, 36.2mmol) in concentrated hydrochloric acid (50ml), maint~ining the temperature below 0 ~C. The CA 02237638 l998-05-l2 mixture was stirred at ca. 0 ~C for 30 minutes then added portionwise to a suspension of tin (II) chloride dihydrate (36.87g, 163mmoV in cor~ePtrated hydrochloric acid (50ml) at -10 ~C The resulting thick paste was stirred at -2 ~C for 15 mi~., allowed to warm to room temperature over 20 minutes and stirred at room te nperature for a further 20 min. The reaction mixture was recooled, basified with aqueous sodium hydroxide (10M) and extracted with ethyl acetate (2 x 250ml). The extracts were washed with brine (260ml), combined, dried ~[gSO4) and the solvent was evaporated under reduced pressure to give 3-bromo-4-methoxyphenylhydrazine (7.27g, 93%). lH NMR (250MHz, CDCl3) ~ 3.84 (3H, s), 6.75 (lH, dd, J--8.8, 2.6Hz), 6.83 (lH, d, J=8.8Hz), and 7.11 (lH, d, J=2.6Hz).

1-(3-Bromo-4-methoxvphenvl)-5-trifluoromethvl-lH-1,2,4-triazole and 1-(3-bromo-4-methox~phenvl)-lH-1 2,4-triazole Trifluoroacet~mi(le (5.87g, 51.9mmol) and dimethylform~mitl~
dimethyl acetal (3.3ml, 62mmol) in ~ n~ (20ml) were stirred at 80 ~C
for 30 min. The the solvent was evaporated under reduced pressure to give a dark yellow oil (7.71g). A portion of this oil (5.04g) was added to a solution of 3-bromo-4-methoxyphenylhydrazine (Description 69) (4.29g, 19.8mmol) in acetic acid (40ml) and the mixture stirred at 90 ~C overnight.
The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50ml) and stirred with saturated aqueous sodium hydrogen carbonate (150ml) ~or 15 minutes. The phases were separated and the aqueou~ phase was extracted with ethyl acetate (2 x 50ml). The extracts were washed with brine (50ml), combined, dried (MgSO~) and the solvent was evaporated under reduced pressure. The residue was purified hy flash column chromatography on silica gel, eluting with h~ne/EtOAc (80:20 increasing to 25:70) to give 1-(3-bromo-4-rnethoxyphenyl)-5-trif.,uoromethyl-lH-1,~,4-trza~ole (0.194g, 3%~, lH NMR (360MHz, CDCl3) ~ 3.98 (3H, s), 7.00 ~lH, d, J=8.8Hz), 7.40 (lH, dd, J-8.8, 2.6Hz), 7.69 (lH, d, J=2.6Hz), 8.11 (lH, s), and 1-(3-bromo-4-methoxyphenyl)-lH-1,2,4-triazole (0.63g, 13%), lH NMR
(360MHz, CDCl3) ~ 3.96 (3H, s), 6.85 (lH, d, J=8.8Hz), 7.58 (lH, dd, J=8.8, 2.6Hz), 7.89 (lH, d, J=2.6Hz), 8.09 (lH, s), and 8.47 (lH, s).

5-(4-Trifluoromethoxv)~henvlpyrimi(lin~
44Trifluorom~thoxy)ph~nylboronic 23cid (2g) ar.d fi-13rom~opyrimi~
(1.7g) were dissolved ~n ethylene glycol dimethyl ether (20mV. Lithium chloride (1.22g) and sodium carbonate (2g in 10ml water) were added and the solution was purged with nitrogen (x 3). Tetrakis(triphenylphosphine) palladium (0) (200mg) was added, the mixture was purged with nitrogen (x 3) and stirred at 80 ~C for 3 hours. The mixture was cooled, diluted with water (50ml) and extracted with ethyl acetate (3 x 50ml). The combined organic fractions were washed with brine, dried (M gSO4) and the solvent wa~s evaporated under reduced pressure. The residue was purif;ed by flash column chromatography on silica gel, eluting with hexane/EtOAc (50:50) to give the title compound as an amorphous solid (1.3g) lH NMR (250MHz, CDCl3) ~ 7.39 (2H, dd, J=8.8, 0.9Hz), 7.62 (2H, dd, J=8.8, 0.9Hz), 8.95 (2H, s), and 9.30 (lH, s).

5-(3-Bromo-4-trifluoromethoxy)phenvlpvrimidine Bromine (0.13ml) and silver sulphate (0.4g) and were added to a solution of 5-(4-trifluoromethoxy)phenylpyrimi~iinP (Description 71) (0.62g, 2.6mmol) in sulphuric acid (2ml) and the reaction stirred at room temperature for 45 minutes. The reaction was cooled to 0 ~C and ice (lOg) was added. The mixture was neutralized with sodium hydroxide (4M) and filtered, wz.shing with dichloromethane. The filtrate was extracted ~,vith dichloromethane (3 x 50ml) and the combined organic fiactions were washed with aqueous sodium bisulphite (6%, 100ml) and brine, dried CA 02237638 l998-05-l2 W O 97/19084 PCT/~B96/02853 (M gSO~) and the solvent was evaporated under reduced pressure to give the title compound as an oil (0.64g).lH NMR (360MHz, CDC13) ~ 7.47 (lH, dd, J=8.5, 1.36Hz), 7.55 (lH, dd, cl=8.5, 2.2Hz), 7.87 (lH, d, J=~.2Hz), 8.93 (2H, s), and 9.26 (lH, s). MS (ES+) 319, 321 ~M+1).

EX~MPLE lA
(~3(3S*,5R*~6S*)-3-(2-MethoxY-5-(5-(trifluoromethvl)tetrazol-1-vl)phenvl)-6-~henvl-l-oxa-7-(teTt-hutoxYcarhonyl)a7~ pi~nr4~F~ ec-3-ene A mixture of (~)(5~*,6S*)-3-trimethylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro~4.5]dec-3-ene (0.2g, 0.419mmol; Desc.6),1ithium chloride (0.106g, 2.51mmol), 2-bromo-4-(trifluoromethyl-tetrazolyl)-anisole (0.16g, 0.502mmol; Desc.7) in toluene was degassed before addition of tetrakis(triphenylphosphine) palladium(0) (0.06g) degassed thoroughly the solution was heated to 110~C for 14 hours. The solution was partitioned between water and ethyl acetate and the dried organic phase was purified by chromatography on a column cont~ining silica gel (eluting with hexane cont~ining increasing proportions of ethyl acetate between 0% to 10%).
Evaporation of the fractions gave a residue which was dissolved in hexane/diethyl ether (2:1), filtered and the soluble filtrate was evaporated to givethe title compound. m/z (CI+)558 (M+H), ~58(M+~H - t-BuOCO-), 502 (M~2H - t-Bu). lH NMR (360MHz, CDCl3) ~ 7.59-7.06 ~8H, rn), 6.71 (lH, t, J=1.98Hz), 5.16 (lH, s), 4.91 and 4.56 (2H, AB dd, J=12.0Hz and 2Hz), 4.12 (lH, m), 3.97 (3H, s), 3.12 (lH, m), 2.1-2.3 (2H, m), 1.5-1.9 (3H, m), 1.36 (9H, s).
EXAMPLE lB
(+)(3$*.6~*,6S*)-3-(2-Methoxv-5-(5-(trifluoromethvl)tetrazol-1-vl)Phenvl)-6-Phen~ l-l-oxa-7-aza-spiro[4.51dec-3-ene (~)(3S*,5R*,6S*)-3-(2-Methoxy-5-(5-(trifluoromethyl)tetrazol- 1-yl)phenvl)-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro~4.5]dec-3-ene (136mg; Ex.1~) was dissolved in anhydrous trifluoroacetic acid (10r~1) for 10 minutes before evaporation to dryness and purification by chromatography on a column cont~ininF silica gel (eluting with dichloromethane cont~inin~ increasing proportions of methanollaqueous ammonia (26:1) between 0% to 5%) to give the title compound. m/z 6 (CI+)458 (M+H, 100%). lH NMR (360MHz, CDC13) ~ 7.33-7.22 (6H, m), 6.99 (lH, d, J=9.0Hz), 6.88 (lH, d, J=2.67Hz), 6.12 (lH,t, J=1.97Hz), 4.91 and 4.53 (2H, AB dd, J=12.4Hz and 2.0Hz), 4.3 (lH, s), 3.8 (3H, s), 3.38 (lHJ br.d), 3.10 (lH, br.t,), 2.3 (lH,m~, 1.91 (3Hr m).

( I )(3S*~5R*,6S*)-3-(2-Metho~v-5-(5-(trifluoromethvl)tetrazol-1-vl)Phenvl)-6-phenvl-1-oxa-7-aza-spiro~4.51decane A mixture of (+)(3S*,5R*,6S*)-3-(2-methoxy-5-(5-(trifluoromethyl)-tetrazol-l-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene (Ex.lB) and 10% palladium hydroxide/carbon in methanol (20ml) cor~t~ininE acetic acid (lml) was hydrogenated at 50psi for 4 hours. The solution was filtered, evaporated and purif;ed by chromatography on a column cont~ining silica gel (eluting with dichloromethane cont~ining increasing proportions of ~ethanol/aqueous ammonia (25:1) between 0% to 5%) to give the title compound. m/z (CI+)460 (M+H, 100%). ~H NMR (360MHz, CDCl3) â 7.41 (2H, br.d), 7.17 (3H, m), 7.06 (lH, t, J=7.5Hz), 6.88 (lH, d, J=8.82Hz), 6.17 (lH, d, J=2.62Hz), 4.19 (lH, t, J=8.22Hz), 4.02 (lH, s), 3.91 (lH, m), 3.79 (3H, s), 3.31 (lH,t, J=8.77Hz), 3.08 (lH, br.d, J=12.2Hz), 2.85 (lH, td, J=10.5Hz), 2.16 (2H,m), 1.96 (lH, dd, J=12.6Hz and 8.23Hz). 1.78 (lH, t, 26 J=ll.OHz), 1.60 (2H, m).
To a sample dissolved in methanol was added lM HCl in methanol (1 equivalent). The solution was evaporated and on addition of diethyl ether a colourless crystalline solid was formed, mp 244-246~C.

E~AMPLE 3 (35~ 5R,65)-3-(2-Methoxv-5-~5-(trifluoromethYl)tetrazol- 1-vl)Phenyl~-6-phenyl-l-oxa-7-aza-spiror4.5~decane The title compound was prepared in a manrler analogous to F',~mrle 2 using (3s~5R~6s)-3-(2-methoxy-5-(5-(trifluoromethyvtetra yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro~4,51,dec-3-ene as the starting material, which compound was prepared in an analogous fashion to Ex~mple lB u~,ing ~3S)1-~ert-butoxycarbonyl-2-phenylpiperidin-3-one (Desc.8) as the starting material instead of the racemic phenylpiperidinone described in Description 1. m/z (CI~) 460 (M+H, 100%). lH NMR (360MHz, C~DCl3) ~ 7.41 (2H, br.d), 7.17 (3H, m), 7.06 (lH, t, J--7.5Hz), 6.88 (lH, d, J=8.82Hz), 6.17 (lH, d, J=2.62Hz), 4.19 (lH, t, ~=8.22Hz), 4.02 (lH, s), 3.91 (lH, m), 3.79 (3H, s), 3.31 (lH, t, J=8.77Hz), 3.08 (lH, br.d, J=l~ ~7~), 2.85 (lH, td, J=10.5Hz), 2.16 (2H,m), 1.96 (lH, dd, J=12.6Hz and 8.23Hz), 1.78 (lH, t, J=ll.OHz), 1.60 (2H, m).
(en~n~inmeric excess 94%, chiral hplc).

(3S.6R,6S)-3-(2-IsoproPoxv-5-t5-trifluoromethvl-tetrazol- 1-vl)phenvl)-6-phenvl-1-oxa-7-(tert-butoxvcarbonvl)aza-sPiro~4.5ldec-3-ene Prepared from the compound of Description 13 and (5R,6S)-3-trimethylstannyl-6-phenyl- 1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene according to the method of Example lA. Mass Spec ES~ 586 M+1.

E~AMPL~ 4B
(3$.5R.6$)-3-(2-IsoproPoxv-5-(5-trifluoromethvl-tetrazol-1-Yl)phenYl)-6-phenvl-l-oxa-7-aza-spiror4.51dec-3-ene Prepared from the compound of Example 4A according to the method of Example lB. lH NMR (250MHz, CDC13) o 7.33-7.37 (2H, m), 7.14-7.24 (3H, m), 6.9 (2H, m), 6.20 (lH, m), 4.89 (lH, dd, J=2.1 and CA 02237638 l998-0',-l2 W O 97/19084 PCT/GB96/028~3 ll.9Hz), 4.62 (lH, m), 4.36 (lH, dd, J=2.1 and ll.9Hz), 3.77 (lH, s), 3.30 (lH, m~, 2.84 (lH, m), 1.46-2.00 (5E, m), 1.2-1.46 (6H, m).
.

(35,5R.6$)-3-(2-IsoproPoxY-5-(5-trifluoromethvl-tetrazol-1-vl~Phenvl)-6-phenvl-l-oxa-7-aza-sPiror4.6ldecane hvdrochloride Prepared from the compound of F'.~?m~le 413 according to the method of ~x~rnple 2. lH NMR (250MHz, CDCl3~ ~ 7.55 (2H. vb s), 7.15-7.06 (4H, m), 6.86 (lH, d, J=8.9Hz), 6.07 (lH, d, J=2.5Hz), 4.57 (lH, m), 4.23 (lH, t, J=8.0Hz), 3.86-4.00 (2H, m), 3.36 (lH, vb s), 3.14 (lH, t, J=9.OHz), 2.83 (lH, vb s), 2.43 (lH, vb s), 2.14 (lH, m), 1.96 (lH, m), 1.56-1.79 (3H, m), 1.32 (6H, m). Mass spec ES+ 488 (M+l).

EXAMPLl~ 6A
(3S,5R~6S)-3-(2-Methoxv-5-(tetrazol- 1-yl)phenvl)-6-phenvl- 1-oxa-7-(tert-butoxvcarbonyl)aza-spiror4.51dec-3-ene Prepared from the compound of Description 14 and (5R,6S)-3-trimethylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro~4.51dec-3-ene according to the method of ~ m~le lA, to give the title compound as a white foam (280mg; 57%) MS (13S+) 490 (M+l, 100%).

(35.5R.6S)-3-(2-Methoxv-5-(tetrazol-1-vl)~henvl~-6-Phenvl-l-oxa- I-aza-s~Piro r4.5l dec- 3 -ene Prepared from the compound of F'.~r~mple 6A according to the method of Example 1~, to give the title compound as a white foam (0.13g, 75%) MS m/z (3~S+) 390 (M+l, 90%). lH NMR (250MHz, CDCl3) ~ 1.81-2.08 (4H, m), 2.78-2.90 (lH, m), 3.45-3.34 (lH, m), 3.79 (lH, s), 3.86 (3H, s), 4.34 (lH, dd, ~J=2Hz, ~T=12Hz), 4.94 (lH, dd, J=2Hz, J=12Hz), G.20-6.23 (lH, m), 6.93-6.98 (lH, m), 7.04-7.08 (lH, m), 7.13-7.24 (3H, m), 7.34-7.46 (3H, m), 8.82 (lH, s).

(3S.5R,6Sl-3-(2-Methoxv -5-(tetrazol-l-vl~PhenYl)-6-phenyl-l-oxa-7-aza spiro r4.51 decane Prepared from the compound of ~,~mple 6B according to the 5 method of h'"r~mple 2, to give the title compound as a white foam (64mg) MS m/z (ES~) 392 (M+l, 100%). lH NMR (250MHz, CDC13) ~ 1.56-2.22 (6H, m), 2.76-2.90 (lH, m), 3.18-3.30 (2H, m), 3.68 (lH, s), 3.79 (3H, s), 3.82-3.99 (lH, rn), 4.07-4.16 ~lH; m), 6~42 (]EI, ds J=3Hz,), 6.87 (lH, d, ~=9Hz), 7.20-7.32 (3H, m), 7.39-7.45 (lH, dd, J=3Hz, 9Hz), 7.46-7.54 (2H, m), 8.61 (lH, s).

In an analogous f:~hi~n, the compounds of Table I were prepared from (5R,6S)-3-trimethylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.51dec-3-ene and the appropriate halogenated substituted phenyl 15 compound (cf. formula XIII)):

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(6$.5R~3$)-7-((2.3-Dihvdro-3-oxo-1.2.4-triazol-5-vl)methvl)-3-(2-methoxv-5-(5-(trifluoromethyl)tetrazol-1-vl)phenvl)-6-Phenvl-l-oxa-7-aza-spiro r4.51 decane The hydrochloride salt of the product of F,~m~le 3 (0.4g), N-carbomethoxy-2-chloroacetamidrazone (0.149g) and potassium carbonate (0.552g) were suspended in dimethylform~mi~l~ (5ml) at 40~C
~or 4h and then cooled to room temperature. Water (50mV and ethyl acetate (50mV were added and the organic phase was washed further with saturated brine and dried (MgSO4). After evaporation, a solution of the residue in toluene (50ml) was heated to reilux for 5h and cooled to room temperature and evaporated to dryness. The residue was purified by chromatography on silica, eluting with dichloromethane followed by 5%
methanol in dichloromethane. The fractions cont~inin~ the desired product were evaporated to dryness and the residue recrystallized from toluene to g~ive the title compound, mp 186-187~C; lH NMR (360MHz, DMSO-d6) ~

11.14~1H,s), ll.ll(lH,s), 7.51(3H, m), 7.11(3H,m), 6.87(1H, t, J=7.4Hz), 6.2(1H, d, J=2.4Hz), 4.00(1H, t, J=8.0Hz),3.80(3H, s), 3.70(1H, m), 3.22(1H, d, J=14.3Hz), 2.88(2H, m), 2.77(1h, d, ~,T=14.2Hz), 2.17(1H, td, J=ll.lHz), 2.04-1.89(3H, m), 1.74(1H, t, J=12.3Hz), 1.52-1.42(2H, m); m /~
(C~+) 557 (100%, M~H).

(65,5R.35)-7-(2-(N,N-Dimethvlamino)ethYl)-3-(2-melhoxv-6-(5-25 (trifluoromethvl)tetra~ol-1-yl)phenvl)-6-~henvl-1-oxa-7-aza-spiro ~4.51 decane The hydrochloride salt of the product of Example 3 (0.263g) was dissolved in dimethylformamide (6ml), 2-dimethvlaminoethvl chloride (82mg) and potassium carbonate (0.16g) were added. and the mixture 30 heated to 60~C for 3 hrs under an atmosphere of nitrogen. The reaction mixture was dispersed between water ~lOOml) and ethyl acetate (50ml).

The organic layer was washed with brine, dried (MgSO4) and the solvent removed in vacuo to afford a clear oil. Purification was carried by flash silica chromatography eluting with a gradient of 2% MeOH in DCM (0.3%
NH3)~3%~4% MeOH in DCM (0.3% NH3) to give the title compound.
lH NMR (360MHz, CDCl3) o 1.44(1H, td, J-13.9, 5.0Hz), 1.61(1H, bd, J=13.2Hz), 1.77(1H, dd, J-12.4, 10.6Hz), 1.89(1H, dd, J=12.8, 8.5Hz), 2.04(6H, s), 2.02-2.14(3H,n~), 2.24(1H, bt, J=11.4Hz), 2.34~2.40(2H, m), 2.1-2.~ 1H, m), 3.13(-3.~6(3H, m), ~~.8~(~H, s), 3.~ 1E, q, J=8.8Hz), 4.12(1H, t, J=8.2Hz), 6.05(1H, d, J=2.6Hz), 6.82-6.92(2H, m), 7.07-7.14(3H, m), 7.44(2H, bd, J=5.6Hz); m/z ~ES+) 531 (100%, M~H).

EX~MPLE 21 (6$.5R.35)-7-((lH-Tmi~7.ol-5-vl)methvl)-3-(2-metho~-5-(5-(trifluoromethvl)tetrazol- l-vl)Phenyl)-6-phenYl- l-oxa-7-aza-15 spiror4.5ldecane The product of Example 3 (0.3g) was dissolved in dimethylform~mi-le (6ml), ((N-p-toluenesulfonyl)-lH-imidazol-5-yl)methyl methanesulfonate (0.188g) and potassium carbonate (0.17g) were added and the reaction was heated at 60~C for 3 hrs under an atmosphere of 20 nitrogen. The reaction was diluted with water (lOOml) and extracted with ethyl acetate (3x50ml). The combined organics were washed with water, brine, dried (MgSO4) and the solvent removed i7t vacuo to afford a clear oil.
Purification was carried out by flash chromatography eluting with a gradient of 5~10~15% ethyl acetate in hexane. The tosylated protected 25 compound (0.293g) was stirred with methanolic hydrogen chloride (l.OM) (30ml) at room temperature for ll/2hr. Purification by flash chromatography eluting with 1.5~3% methanol in dichloromethane (0.3%
NH3) afforded the title compound as a white foam (0.189g).
lH Nl!~IR (360MHz, CDCl3~ ~ 1.46(1H, td, J 3.7, 12.8H), 1.59(1H, bd, J
13.5Hz), 1.8(1H, dd, J 10.7,12.4Hz), 1.92(1H, dd, J 12.5, 8.6Hz), 2.02(1H, bd, J 13.0Hz), 2.12(1H, bd, J 14.8Hz~, 2.21(1H, bt, J lO.OHz), 3.07-3.26(4H,m), 3.60(1H,d, J 14.2Hz), 3.82(3H, s), 3.88(1H, t, J 9.2Hz), 4.14(1H, t, J 8.1Hz), 6.07(1H,d, J 2.6Hz), 6.77(1H, s), 6.86(1H, d, J 8.8Hz), 6.95(1H, t, J 7.3Hz), 7.12-7.22(3H, m), 7.44-7.58~3H, m);
m/z (EI+) 540 (100%, M+H).

~AMPLE 22A
(5R.65)-3-r2-Methoxv-.~-(2,4-dimethvl-lH-imi~7,ol-l-Yl)Phen~n-6-Phen l-oxa-7-~tert-butoxvcarbonvl)aza-spiror4.51dec-3-ene Prepared from the compound of Description 25 and (SR,6S)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro~4.5]dec-3-ene according to the method of ~ mple lA. lHNMR (250MHz, CDC13) 7.46 (2H, m), 7.24 (3H, m), 7.15 (lH, dd, J=8.7 & 2.6 Hz), 6.97 (lH, d, J=8.7 Hz), 6.90 (lH, d, J=2.6 Hz), 6.69 (lH, t, J=2.0 Hz), 6.66 (lH, s), 5.16 (lH, s), 4.94 (lH, dd, J=12.0 & 2.0 Hz), 4.58 (lH, dd, J=12.0 & 2.0 Hz), 3.92 (3H, s), 2.27 (3H, s), 2.23 (3H, s), 2.87-1.41 (6H, m), and 1.37 (~H, s).
m/z (ES+) 516 (1!~+1).

E~AMPLE 22B
(5R.65)-3-r2-Methoxv-5-(2~4-dimethvl-lH-imidazol-l-vl)Phen~ll-6-phen~
l-oxa-7-aza-sp~ro~4.51dec-3-ene Prepared from the compound of F',~mple 22A according to the method of h'"r~m~le lB. lHNMR (250MHz, CDCl3) ~ 7.38 (2H, m), 7.20 (3H, m), 7.05 (lH, dd, J=8.7 & 2.6 Hz), 6.85 (lH, d, J=8.7 Hz), 6.66 (lH, d, J=2.6 Hz), 6.~9 (lH, s), 6.13 (lH, t, J=2.0 Hz), 4.86 (lH, dd, J=12.0 & 2.0 Hz), 4.32 (lH, dd, J=12.0 & 2.0 Hz), 3.82 (3H, s), 3.81 (lH, s), 3.30 (lH. m), 2.82 (lH, m), 2.75 (lH, br s), 2.22 (6H, s), and 2.18-1.62 (4H, m). m/z (ES+) 416 (M+l).

(3S.5R.65)-3-r2-Methoxy-5-(2,4-dimethvl-lH-imidazol-l-vl)PhenYn-6-phenvl-l-oxa-7-aza-spiro~4.51decane hvdrochloride Prepared ~rom the compound of ~ mple 22B accordi~ig to the method of Example 2.1HNMR (250MHz, DMSO-d6) ~ 9.64 (lH, br s), 8.93 (lH, br s), 7.47 (2H, m), 7.25 (5H, m), 7.00 (lH, d, J=8.9), 6.32 (lH, d, J=2.4), 4.42 (lH, m), 4.07 (lH, m), 3.70 (lH, m), 3.62 (3H, s), 3.46-3.01 ~4II, m), 3.00 ~ , m3, 2.25 (3H, s~, 2.2'' (3H, s~, and 2.30 1.64 (4E, m3. m/z (ES+) 418 (M+l~.

(5~,6S)-3-[2-Methoxv-5-(4-pvridvl)Phenvn-6-1~henvl-l-oxa-7-(tert-butoxvcarbonvl)aza-spiro~4.51dec-3-ene Prepared from the compound of Description 27 and (5R,6S~-3-trimethylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiroL4.53dec-3-ene according to the method of Example lA. lH NMR (250MHz, CDC13) 8.66-8.62 (2H, m), 7.61-7.46 (5H, m), 7.32-7.20 (4H, m), 7.04-6.99 (lH, m), 6.68-6.67 (lH, m), 5.19 (lH, s), 5.06-5.01 (lH, dd, J=12.0Hz and 2.0Hz), 4.71-4.65 (lH, dd, J=12.0Hz and 2.0Hz), 4.16-4.08 (lH, m), 3.93 (3H, s), 3.18-3.06 (lH, m), 2.16-2.10 (lH, m), 1.90-1.78 (3H, m3, and 1.38 (9H, s).
m/z (ES+) 499 (M+l).

(5R.6S)-3-r2-Methoxv-5-(4-pvridvl)~henvll -6-uhenvl- 1-oxa-7-aza-spiror4.51dec-3-ene Prepared fiom the compound of Example 24A according to the method of Example lB. IH NMR (360MHz, CDCl3) ~ 8 64-8.61 (2H, d, J=6.2Hz), 7.46-7.39 (3H, m), 7.37-7.35 (2H, d, J=6.2Hz), 7.22-7.15 (3H, m~, 7.13-7.12 (lH, d, J=3.2Hz), 6.91-6.89 ~lH, d, J=8.6Hz), 6.14-6.13 (lH, m), 4.94-4.90 (lH, dd, J=11.9Hz and 2.0Hz), 4.39-4.35 (1~, dd, J=11.9Hz and CA 02237638 l998-05-l2 2.0Hz), 3.82 (3H, s), 3.80 (lH, s), 3.31-3.28 (lH, m), 2.88-2.80 (lH, m), 2.76 (lH, br s), 2.08-1.98 (2H, m), 1.86-1.77 (lH, m), and 1.71-1.63 (lH, m). m/z (ES+) 399 (M~1).

E~AMPI.~ 25 (35.5R.65)-3-r2-Methoxv-5-(4-Pvridvl)~henvn-6-Phenvl-l-oxa-7-aza-spiror4.51decane Dihvdrochloride A mi~ture of (6R,6$)-3-~2-methoxy-5-(4-pyridyl)phenyl~-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene (131mg, 0.33mmol), ammonium formate (126mg, 1.97mmol) and 10% palladium on charcoal (2~mg) in methanol (lOml) was stirred at 70~C for 36 hours. The solution was allowed to cool to ambient temperature and filtered. The solvent was removed in vacuo and the residue was chromatographed on alumina (grade III) in 50% ethyl acetate/hexane giving the title compound (33mg). The dihydrochloride salt was made by treatment with an ethereal hydrogen chloride solution. lH
NMR (360MHz, DMSO-d6) ~ 9.71 (lH, m), 9.01 (lH, m~, 8.97-8.93 (2H, m), 7.95-7.91 (2H, m), (7.85-7.83 (lH, m), 7.60-7.56 (2H, m), 7.51-7.47 (3H, m), 7.12-7.10 (lH, m), 6.96 (lH, s), 4.53-4.49 (lH, m), 4.14-4.10 (lH, m), 3.87-3.83 (lH, m), 3.72 (3H, s), 3.65-3.20 (5H, m), 3.12-3.08 (lH, m), 2.10-2.05 (2H, m), and 1.92-1.81 (2H, m). m/z (~S+) 401 (M+1).

~AMPLE 26A
~5R,6S)-3- r6-(4-Pvridvl)-2-(trifluoromethoxY)Phenvll -6-Phenvl- 1 -oxa-7-(tert-butox~ carbonvl)aza-spiro~4.51dec-3-ene Prepared from the compound of Description 30 and (5R,6S)-3-trimethylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene according to the method of l~ mple lA. lH NMR (360MHz~ CDCl3) 8.66-8.63 (2H, m), 7.56-7.53 (lH, m~, 7.47-7.37 (5H, m), 7.29-7.21 (4H, m), 6.57-6.a6 (lH, m), 5.17 (lH, s), 4.99-4.96 (lH, m), 4.65-4.62 (lH, m), 4.16-4.09 (lH, m), 3.16-3.12 (lH, m), 2.15-2.11 (lH, m), 1.92-1.86 (3H. m), and 1.36 (9H, s). m/z (ES+) 5a3 (M+1).

CA 02237638 1998-0=.-12 E~Xi~DIPLE 26B
(5R.6S~-3-r5-(4-Pvridvl~-2-(tri~uoromethox~)Phenvll-6-Phenvl-l-oxa-7-aza-spiror4.5ldec-3-ene Dihvdrochloride Prepared from the compound of ~,~m~le 26A according to the 6 rnethod of Example lB. lH NMR (360MHz, DMSO-d6) ~ 9.82 (lH, br s), 9.19 (lH, br s), 8.92 (2H, br s), 8.20 (2H, br s), 7.97-7.95 (lH, m) 7.66 (lH, s), 7.55-7.48 (3H, m), 7.36-7.31 (3H, m) 6.47 (lH, s), 5.00-4.97 (lH, m), 4.68-4.6~ (lH, m), 4.51-4.47 (lH, m), 3.35-3.31 (2H, m), 3.15-3.11 (lH, m), 2.~;7-2.53 (2H, m), 2.13-2.09 (lH, m), and 1.98-1.96 (lH, m). m/z (ES+) 453 (M+l).

(5R~65)-3-[5-(4H-1,2,4-Triazol-4-vl~-2-(tri~1uoromethoxY)Phenyl~-6-PhenY
l-oxa-7-(tert-butoxvcarbonvl)aza-sPiro~4.51dec-3-ene Prepared from the compound of Description 31 and (5R,6S)-3-trimethylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.53dec-3-ene according to the method of ~.~ mI~le lA. m/z (ES+) 643 (M+l).

l~XAMPLE 27B
(5R~65)-3-~5-(4H-1,2,4-Triazol-4-vl)-2-(trifluorQmethoxv)Phenvll-6-phenvl-l-oxa-7-aza-spiro~4.5]dec-3-ene Prepared from the compound of ~ m~le 27A according to the method of F'.~mI)le lB. lH NMR (360MHz, CDCl3) ~ 1.62-1.72 (lH, m), 1.82-1.87 (lH, m), 1.98-2.11 (2H, m), 2.85 (lH, dt, J=12.5 & 2.9 Hz), 3.29-3.34 (lH, m), 3.84 (lH, s), 4.37 (lH, dd, J=12.2 & 2.1 Hz), 4.86 (lH, dd, J=12.2 & 2.1 Hz), 6.10-6.11 (lH, m), 6.82 (lH, d, J=2.7 Hz), 7.20-7.26 (4H, m), 7.33-7.40 (4H, m), and 8.36 (2H,s). m/z (ES+) 443 (M+l).

(3S,5R,6S)-3-~5-~4H-1,2,4-Triazol-4-Yl)-2-(trifluoromethoxv)~henyll-6-phenvl- l-oxa- I -aza-sPiror4.51decane hvdrochloride Prepared from the compound of ~ m~le 27B according to the method of F',~mple 2.1H NMR (360MHz, D20) ~ 1.83-1.97 (3H, m), 2.16-2.39 (3H, m), 3.24 (lH, t, J=12.9 Hz), 3.52-3.55 (lH, m), 3.59-3.64 (lH, m), 4.02 (lH, t, J=8.3 Hz), 4.24 (lH, t, 8.5 Hz), 4.44 (lH, s), 6.08 (lH, d, J=2.3 Hz), 7.21 (lH, t, J=7.4Hz), 7.31-7.42 (4H, m), 7.51 (2H, m), and 8.72 (2H,s). m/z (ES+) 445 (M+l).

E~lVlPLF~ 2~A
(5R~65)-3-r2-(TrifluoromethoxY-5-(3-trifluoromethvl-4H-1,2~4-triazol-4-vl)Phenvn-6-Phenvl-l-oxa-7-(tert-buto~sYcarbonvl~aza-s~iror4.5ldec-3-ene Prepared from the compound of Description 33 and (~R,6S)-3-trimethylstannyl-6-phenyl- 1-oxa-7-(tert-butoxycarbonyl)aza-spiro [4.5] dec-3-ene according to the method of h'.~mple lA. lH NMR (360MHz, CDCl3) 1.34 (9H, s), 1.83-1.90 (3H, m), 2.12-2.14 (lH, m), 3.14-3.17 (lH, m), 4.11-4.14 (lH, m), 4.55 (lH, dd, J=12.3 & 2.1 Hz), 4.90 (lH, dd, J=12.3 & 1.9 Hz), 5.14 (lH, s), 6.60 (lH, d, J=2.0 Hz), 7.17-7.47 (8H, m), and 8.34 (lH,s). m/z (ES+) 611 (M+l).

(5R,65~-3-~2-(Trifluoromethoxv-5-(3-trifluoromethYl-4H-1.2.4-triazol-4-vl)~henvll-6-phenvl- 1-oxa-7-aza-spiror4.5ldec-3-ene Prepared from the compound of Example 29A according to the method of Example lB. lH NMR (360MHz, CDCl3) ~ 1.65-1.68 (lH, m), 1.77-2.03 (4H, m), 2.80-2.90 (lH, m), 3.27 (lH, m), 3.77 (lH, s), 4.32 (lH, dd, J=12.1 & 2.2 Hz), 4.82 (lH, dd, J=12.0 & 2.0 Hz), 6.15-6.16 (lH, m), 6.85 (lH, d, J=2.6 Hz), 7.14-7.36 (7H, m), and 8.27 (lH.s). m/z (ES+) all (M+l).

~ oi~IP L E 30 (35~5R.65)-3-r2-~Trifluoromethoxv-5-(3-trifluoromethvl-4H-1.2.4-triazol-4-yl~Phenvll-6-phenvl-1-oxa-7-aza-s,~iro~4.51decane hvdrochloride Prepared from the compound of Example 29B according to the 6 method of l~ mI~le 2.1H NMR (360MHz, D20) o 1.80-1.97 (3H, m), 2.15-2.19 (lH, m), 2.25 (lH, m), 2.38 (lH, dd, J=13.5 & 9.6 Hz), 3.24 (lH, dt, J=13.0 & 3.3 Hz), 3.48-3.55 (2H, m), 4.07-4.14 (lH, m), 4.28 (lH, t, 8.7 Hz), 4.44 (lH, s), 5.74 (lH, d, J=2.4 Hz), Ç~.99 (lH, ~, J=7.5 H7), 7.3Q ~2H, t, J=7.8Hz), 7.39 (lH, dd, J=8.8 & 2.4 Hz), 7.44-7.52 (3H, m), and 8.74 (lH, s). m/z (ES+) 513 (M+l).

(5R,6$)-3-r2-Methoxv-5-(2-trifluoromethvl-lH-imirl~7,Ql-l-vl)~henvll-6-Phenvl-l-oxa-7-(tert-butoxvcarbonv~aza-spiro~4.51dec-3-ene Prepared from the compound of Description 34 and (5R,6S~-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene according to the method of F'.x~mple lA. lH NMR (360 MHz, CDCl3) 7.58-6.96 (lOH, m), 6.31 (lH, t, J=2.0 Hz), 5.16 (lH, s), 4.93 (lH, dd, J=12.0, 2.0 Hz), 4.67 (lH, dd, J=12.0, 2.0 Hz), 3.93 (3H, s), 3.11 (2H, ~n), 2.11 (lH, m), 1.90-1.70 (3H, m), and 1.36 (9H, s). m/z (ESt) 556 (M+l).

(5R.6S~-3-r2-Methoxv-5-(2-trifluoromethvl-lH-imi(lz~zol-l-~ henvll-6-~henvl- l-oxa-7-aza-spiro[4.51dec-3-ene Prepared from the compound of Example 31A accolding to the method of Example lB lH NMR (360MHz, CDCl3) ~ 1.79-1.83 (3H, m~, 1.96-2.0~ (2H, m), 2.82 (lH, dt, J=12.2 & 2.7 Hz), 3.25-3.29 ~lH, m), 3.76 (lH, s), 3.84 (3H, s), 4.28 (lH, dd, J=ll.9 & 2.2 Hz), 4.84 (lH, dd, J-ll.9 &
2.0 Hz), 6.15 (lH, t, J=2.0 Hz), 6.75 (lH, d, J=2.6 Hz), 6.86 (lH, d. J=8.8 CA 02237638 1998-0',-12 Hz), 7.03 (lH, d, J=1.2 Hz~, 7.13-7.19 (5H, m), and 7.35 (2H, d, J=7.6 Hz).
m/z (ES+) 456 ~M~l).

E~AMPLE 32 (35~5R.6S)-3-r2-Metho~v-5-(2-trifluoromethYl-lH-imi~ ol-1-vl)l)henvll-6-phenvl-l-oxa-7-aza-spiror4.5ldecane hvdrochloride Prepared from the compound of F.sr~ le 31B according to the methQd of Example 2. lH NMR (360MHz. D20) ~ 1.82-1.99 (3H, m), 2.19-2.26 (3H, m), 3.25 (lH, dt, J=12.8 & 2 Hz), 3.36 (lH, t, J=8.9 Hz), 3.63-3.56 (lH, m), 3.80 (3H, s), 3.99-4.04 (lH, m), 4.19 (lH, t, J~,.3 Hz), 4.41 (lH, s), 5.86 (lH, d, J=2.4Hz), 7.00 (lH, d, J=8.8 Hz), 7.10 (lH, t, J=7.5Hz), 7.20-7.23 (2H, m), 7.30-7.34 (3H, m), and 7.52-7.57 (2H, m). m/z (ES+) 458 (M+l).

(5R.6S) -3- r2-Trifluoromethoxy-5-(2-tri~1uoromethvl- lH-imidazol- 1-vl)phenvl~-6-Phenvl-l-oxa-7-(tert-butoxYcarbonvl)aza-sPiror4.51dec-3-ene Prepared from the compound of Description 35 and (aR,6S)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene according to the method of F.~r~mple lA. lH NMR (360~IHz, CDCl3) ~
1.34 (9H, s), 1.80-2.03 (3H, m), 2.09-2.20 (lH, m), 3.10-3.18 (lH, m), 4.09-4.15 (lH, m), 4.57 (lH, dd, J=12.2 & 2.2 Hz), 4.91 (lH, dd, J=12.2 & 2.0 Hz), 5.16 (lH, s), 6.57 (lH, m~, 7.14 (lH, d, J=1.2 Hz), and /.18-7.49 (9H, m). m/z (ES+) 610 (M+1).

(5R.65~-3-r2-Trifluoromethoxv-5-(2-trifluoromethvl- lH-imidazol- 1-vl~Phenvll-6-~henvl-1-oxa-7-aza-spiro~4.51dec-3-ene Prepared from the compound of ~ mple 33A according to the method of Example lB. lH NMR (360MHz, CDCl3) ~ 1.76-2.06 (4H, m), 2.83 (lH, m), 3.25-3.30 (lH, m), 3.79 (lH, s), 4.32 (lH, dd, J=12.1 & 2.2 Hz), 4.82 (lH, dd, J=12.1 & 2.1 Hz), 6.12 (lH, t, J=2.1 Hz), 6.87 (lH, d, J=2.5 Hz), 7.06 (lH,d, J=1.2 Hz), and 7.15-7.36 (8H, m). m/z (ES+) 510 (M+l).

~XAMPLE 34 (35,5R,6S)-3-r2-Tri~Luoromethoxv-5-(2-trifluoromethYl-lH-;mi-1~7.~1-l-Yl)phen~l~-6-~hen~l-1-ox~-7-~a-sPiror4fildecane hv(lrochlorid~s Prepared from the compound of Example 33B according to the method of Example 2.1H NMR (360MHz, D20) ~ 1.81-1.98 (3H, m), 2.16-2.38 (3H, m), 3.25 (lH, dt, J=12.8 & 2 Hz), 3.46 (lH, t, J=8.8 Hz), 3.52-3.55 (lH, m), 4.04-4.09 (lH, m), 4.25 (lH, t, J=8.7 Hz), 4.42 (lH, s), 5.76 (lH, d, J=2.4Hz), 7.01 (lH, t, J=7.5 Hz), 7.27-7.33 (4H, m), 7.36-7.40 (2H, m), and 7.50 (2H, m). m/z (ES+) 512 (M+l).
EXAMPLE 35~
(5R,65)-3-~2-MethoxY-5-(3-trifluoromethvl-4H-1.2.4-triazol-4-vl~phenvn-6-phenvl-l-oxa-7-(tert-hutoxycarbonvl)aza-s~iro~4.5ldec-3-ene Prepared fiom the compound of Description 36 and (5R,6S)-3-tributvlstannyl-~-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro~4.5]dec-3-ene according to the method of ~xample lA. lH NMR (250MHz, (~DCl3) 1.36 (9H, s), 1.78-1.89 (3H, m), 2.09-2 14 (lH, m), 3.06-3.20 (lH, m), 3.95 (3H, s), 4.10-4.16 (lH, m), 4.56 ~lH, dd, J=12.0 & 2.1 Hz), 4.92 (lH, dd, ~=12.0 & 2.0 Hz), 5.16 (lH, s), 6.70 (lH, t, J=2.0 Hz), 6.98 (lH, d, J=2.6 Hz), 7.02 (lH, d, J=8.8 Hz), 7.20-7.30 (4H, m), 7.45 (2H, d, J=6.6 Hz), and 8.30 (lH, s). m/z (E~;+) 557 (M~l).

(5~6 S)-3-r2-Methoxv-5-(3-trifluoromethvl-4H-1~2~4-triazol-4-Yl)Phenvll-6-phenvl-1-oxa-7-aza-spiro~4.5ldec-3-ene Prepared from the compound of l~ m~le 35A according to the method of ~ m~le lB. lH NMR (360MHz, CDCl3) ~ 1.80-1.85 (2H, m), r 1.96-2.04 (2E, m~, 2.82 (lH, dt, J=12.3 & 2.9 Hz), 3.23-3.30 (lH, m), 3.76 (lH, s), 3.85 (3H, s), 4.27 (lH, dd, J=ll.9 & 2.1 Hz), 4.83 (lH, dd, J=ll.9 &
2.0 Hz), 6.16 (lH, t, J=2.0 Hz), 6.72 (lH, d, J=2.6 Hz), 6.90 ~lH, d, J=8.8 Hz), 7.12-7.19 (4H, m), 7.35 (2H, d, J=7.1 Hz), and 8.22 (lH, s). m/z (ES~) 457 ~M+l).

EXAMPL~ 36 (35,5R~65)-3-r2-MethoxY-5-(3-trifluoromethvl-4H-1.2~4-triazol-4-Yl)phenvll-6-1~henvl-l-oxa-7-aza-spiro~4.5ldecane oxalate Prepared from the compound of F',~m~le 35B according to the method of F~ mI~le 2.1H NMR (360MHz, D20) ~ 1.75-1.81 (3H, m), 2.15-2.21 (3H, m), 3.17 (lH,m), 3.30-3.35 (lH, m), 3.44-3.47 (lH, m), 3.75 (3H, s), 3.97 (lH, t, J=9.0 Hz), 4.14 (lH, t, 8.3 Hz), 4.34 (lH, s), 5.75 (lH, d, J=2.4 Hz), 7.00 (2H, t, J--8.9 Hz), 7.20-7.27 (3H, m), 7.44-7.46 (2H, m), and 8.60 (lH, s). m/z (ES+) 459 (M+l).

(5R,6S)-3-r2-(2-fluoroethox-~)-5-~5-trifluorometh~l-tetrazol-1-vl)phenvll-6-phenvl-l-oxa-7-(tert-butoxycarbonyl)aza-s~iro~4.51dec-3-ene Prepared from the compound of Description 41 and (5R,6S)-3-trimethylstannyl-6-phenyl- 1 -oxa-7-(tert-butoxycarbonyVaza-spiro [4.5] dec-3-ene according to the method of F',~r~mI~le lA, to afford the title compound as a yellow oil (600mg, 78%). lH NMR (250MHz, CDCl3) ~ 1.35 (9H, s), 1.85 (3H, m), 2.10 (lH, m), 3.15 (lH, m), 4.10 (lH, m), 4.31 (lH, dt, J=1.8Hz, J=3Hz), 4.40 (lH, dt, J=1.9Hz, J=3Hz), 4.56 (lH, d, J=2.1Hz), 4.61 (lH, d, J=2.1Hz) ,4.73 (lH, m), 4.92 (2H, m), 4.98 (lH, d, J=2.0Hz), 5.15 (lH, s), 6.76 (lH, t, J=2.0Hz), 7.05 (lH, d, J=8.9Hz), 7.18 (lH, d, CA 02237638 l998-05-l2 W O 97/19084 PCT/GB9''~2853 J=2.6Hz), 7.21 (3H, m), 7.36 (lH, dd, J=2.6Hz, J=8.8Hz), 7.44 (2H, dd, J=1.6Hz, J=6.5Hz).

EXAMPLl~ 37B
~5R,65)-3-r2-(2-fluoroethoxv)-5-~5-trifluoromethvl-tetrazol-1-Yl)phenvll-6-phenvl-l-oxa-7-aza-sl~iro~4.51dec-3-ene The compound of ~.~r~mple 37A was stirred in lN meth~n~ HCl at ~mbic~t temperature ~r 1~ hours. The solvent was evaporated in vac~o and the residue partitioned between aqueous saturated potassium carbonate (50ml) and ethyl acetate (3x50ml). The combined organic *actions were washed with brine (50ml), dried (MgSO4) and evaporated i7t vacuo. Purification on silica, eluting with 10% methanol in dichloromethane afforded the title compound as a white solid. lH NMR
(250MHz, CDCl3) ~ 1.66 (lH, d, J=12.9Hz), 1.80 (lH, dt, J=4.3Hz, J=13.3Hz), 2.0 (lE, d, J=15.4Hz), 2.07 (lH, m), 2.82 (lH, dt, J=2.8Hz, J=12.4Hz), 2.95 (lH, broad s), 3.30 (lH, d, J=12.4Hz), 3.81 (lH, s), 4.21 (lH, m), 4.29 (lH, m), 4.36 (lH, dd, J=2.1Hz, J=12Hz), 4.71 (lH, m), 4.85 (lH, m), 4.89 (lH, dd, J=2.1Hz, J=12.1Hz), 6.27 (lH, t, J=2.1Hz), 6.92 ( 2H, m), 7.18 (3H, m), 7.26 (lH, m), 7.37 (2H, dd J=1.8Hz, J=8Hz~ m/z (CI+) 490 (M+l, 100%).

3~XAMPLE 38 (3S.5R.6S)-3~r2-(2-fluoroethoxv)-5-(5-trifluoromethvl-tetrazol-1-vl)~henvll-6-phenvl- 1 -oxa -7-aza-sPiro ~4.51 decane hvdrochloride .
Prepared from the compound of Example 37B according to the method of ~xample 2, to afford the title compound as a white solid (140mg, 41%) IH NMR (360MHz, ~DCl3) ~ 1.56 (lH, m), 1.65 (lH, m), 1.79 (lH, t, J=10.6Hz), 2.0 (lH. m), 2.17 (2H, m), 2.81 (lH, dt, J=12.3Hz), 3.24 (lH, t, J=8.9Hz), 3.28 (lH, m), 3.81 (lH, s), 3.95 (lH, t, J=9.lHz), 4.20 (2H, m).
4.26 (lH, d, J=3.8Hz), 4.69 (lH, t, J=4.1Hz), 4.82 ~lH, t. J=4.0Hz), 6.10 CA 02237638 l998-05-l2 (lH, d, J=2.5Hz), 6.87 (lH, d, J=8.8Hz), 6.98 (lH, t, J=7.5Hz), 7.13 (3H, m), 7.47 (2H, d, J=7.5Hz). m/z (CI+) 492 (M+1, 100%).
!

(5R.6S)-3-r2-MethoxY-5-(2-methVltetraZol-5-Vl)~henVll-6-~henVl-l-oXa-7-(tert-butoxvcarbonvl~aza-sPiro~4.51dec-3-ene Prepared from compound of Description 42 and (5R,6S)-3-tri~utyls~ann~-6-ph~ny]-1-o~a-7-~tert-buLo~y~ arbonvl)aza-sp~ro[46~1ec-3-ene according to the method of F7~m}~le LA. lH NMR (360MHz, CDCl3) 1.37 (9H, s), 1.83-1.88 (3H, m), 2.02-2.06 (lH, m), 3.12 (lH, m), 3.92 (3H, s), 4.13 (lH, m), 4.37 (3H, s), 4.71 (lH, d, J=12.6 Hz), 5.03 (lH, d, J=12.6 Hz), 5.17 (lH, s), 6.70 (lH, s), 7.01 (lH, d, J=8.7 Hz), 7.19-7.28 (3~I, m), 7.48 (2H, d, J=7.6 Hz), 7.83 (lH, s), 8.03 (lH, dd, J=8.7 and 2.1 Hz).

(5R.6S)-3-r2-Methoxy-5-(2-methvltetrazol-5-vl~phenvlJ-6-phenvl-1-oxa-7-aza-sPiro~4.51dec-3-ene Prepared from the compound of l~ mple 39A according to the method of F,~s~mple lB. lH NMR (360MHz, DMSO-d6) ~ 1.84-1.88 (2H, n~), 2.02-2.06 (2H, m), 3.06-3.10 (2H, m), 3.83 (3H, s), 4.39 (3H, s). 4.44 (lH, d, J=12.6 Hz), 4.58 (lH, bs) 4.96 (lH, d, J=12.6 Hz), 5.75 (lEI, s). 7.16 (lH. d, J=8.7 Hz), 7.28-7.34 (3H, m3, 7.46-7.50 (3H, m), 7.91 (lH, d, J=6.6 Hz).

E~AMPLE 40A
(5R.6S)-3-r2-Methoxv-5-(1-methvltetrazol-5-vl)Phenvll-6-phenvl-1-oxa-7-(tert-butoxvcarbonvl)aza-spiror4.51dec-3-ene Prepared from compound of Description 42 and (5R,6S)-3-tribut~vlstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spilo~4.5]dec-3-ene (Desc. 23) according to the method of F,~s~mple lA. lH N~IR (360~IHz, CDCl3) ~ (1.33 (9H, s) 1.75-1.89 (3H, m), 2.04-2.12 (lH, m), 3.09-3.17 (lH, m), 3.95 (3H, s), 4.01 (3H, s), 4.11-4.15 (lH, m), 4.63 (lH, d, J=12.1 Hz).

4.98 (lH, d, J=12.1 Hz), 5.17 (lH, s), 6.69 (lH, s), 7.07 (lLH, d, J=8.7 Hz), 7.19-7.28 (2H, m), 7.42-7.47 (3H, m), 7.61 (lH, d, J=8.7 Hz), 7.96 (lH, s).
t (5R.6S)-3-~2-Methoxv-5-(1-methvltetrazol-5-yl)phenvll-6-Phenvl-l-oxa-7-a~a-spiror4.51dec-3-ene Prepared from compound of Example 40A according to the method of Example lB. lH NMR (360MHz, CDCl3) ~ 1.86-1.96 (3H, m), 2.02-20.6 (lH, m), 2.94-3.00 (lH, m), 3.54-3.60 (lH, m), 3.98 (3H, s), 4.14 (3H, s), 4.46 (lE, d, J=12.6 Hz), 4.92 ~lH, d, J=12.6 Hz), 5.36 (lH, s), 6.06 (lH, s), 6.98 (lH, d, J-7.2 Hz), 7.16-7.36 (5H, m), 7.40-7.50 (2H, m).

(3S,5R.6S)-3- r2-Methoxv-5-(1-methvltetrazol-5-vl)~henvll -6-phenvl- 1 -oxa-7-aza-spiror4.51decane Prepared from compound of ~ mple 40B according to the method of F',~mE~le 2. lH NMR (360MHz, CDCl3) ~ 1.55-1.64 (2H, m), 2.00-2.18 (2H, m), 2.82 (lH, dt, J=12.5 and 2.6 Hz), 3.23-3.30 (2H, m), 3.54 (2H, bs), 3.74 (lH, s), 3.79 ~3H, s), 3.87 (3H, s), 3.87-3.98 (lH, m), 6.72 (lH, s), G.90 (lH, d, J=8.6 Hz), 7.14-7.32 (3H, m), 7.48-7.54 (4H, m).

(5R.6S~-3- r2-Chloro-5-(tetrazol-1-Yl)phenvll-6-phenvl-1-oxa-7-(tert-butoxvcarbonvl)aza-spiror4.51dec-3-ene 26 Prepared from compound of Description 43 and (5R,6S)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene (Desc. 23) accor~ing to the method of Example lA. lH N~[R (360~IHz, CDCl3) ~ 1.36 (9H, s), 1.81-1.93 (3H, m), 2.13-2.19 (lH, m), 3.17-3.20 (lH, m), 4.09-4.16 (lH, m), 4.59 (lH, d, J=12.3 Hz), 4.98 (lH, d, J, 12.3 Hz), 5.18 (lH, s), 6.54 (lH, s), 7.21-7.30 (3H, m), 7.46-7.48 (3H, m), 7.53-7.62 (2H, m), 8.97 (lH, m).

CA 02237638 l998-0=,-l2 3~XAMPLE 43 (5R.6S)-3-r2-Chloro-5-(tetrazol-1-vl)phenvl}-6-~henYl-l-oxa-7-aza-sPiror4.51d~cane Prepared from compound of F,~m~le 42 according to the method of ~ qmIlle 2. lH NMR (260MHz, CDC13) ~ 1.67-2.08 (4H, m), 2.86 (lH, dt, J=12.1 and 3.0 Hz), 3.27-3.32 (lH, m), 3.79 (lH, s), 4.33 (lH, d, J=12.2 Hz), 4.89 (lH, d, J=12.2 Hz), 5.98 (lH, s), 6.99 (lH,s), 7.22-7.31 (3H, m~, 7.39-7.43 ~ H, m), 7 49 (2E, s), 8.87 (lH, ~,).

(5R.65)-3-r5-(lH-Pvrazol-l-Yl)-2-(trifluoromethoxY)~3henYll-6-phenvl-l-oxa 7-(~ert-butoxvcarbonvl)aza-sPiror4.51dec-3-ene Prepared from the compound of Description 44 and (5R,6S~-3-tributylstan~yl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiroL4.5]dec-3-ene according to the method of ~,~m~le lA. lH NMR (250MHz, CDCl3) ~
7.88 (lH, d, J=2.3Hz), 7.73 (lH, d, J=1.8Hz), 7.60-7.21 (8H, m), 6.58 (lH, t, J=2.1Hz), 6.49 (lH, dd, J=2.3, 1.8Hz3, 5.15 (lH, s), 4.96 (lH, dd, J=12.3, 2.1Hz), 4.64 (lH, dd, J=12.3, 2.1Hz), 4.15 (lH, m), 3.16 (lH, m), 2.15-1.80 (4H, m), and 1.36 (9H, s~. m/z (ES+) 542 (M+l).

(5R.6S)-3-r6-(lH-Pvrazol-l-vl~-2-(trifluoromethoxY)Phen~11-6-~hen~l- l-oxa-7-aza-spiro~4.51dec-3-ene Hvdrochloride Prepared from the compound of ~ mI)le 44~ according to the method of Fxample lB. M.p. 262-265 ~C. lH NMR (250MHz, CD30D) ~
8.21 (lH, d, J=2.0Hz), 7.71 (2H, m), 7.50 (3H, m), 7.37 (4H, m), 6.54 (lH, t, J=2.0Hz), 6.31 (lH, t, J=2.0Hz), 5.00 (lH, dd, J=12.5, 2.0Hi~, 4.65 ~lH, dd, J=12.5, 2.0Hz), 4.56 (lH, s), 3.48 (lH, m), 3.25 (lH, m), and 2.38-1.96 (4H, m). m/z (ES+) 442 (M+l). Found: C, 59.39; H, 4.74; N, 8.64.
C~4H22F3N302.HCl.O.~H20 requires: C, 59.20; H, 4.97; N, 8.63%.

CA 02237638 l998-05-l2 EXAMPLE 4~A
(5R,6S)-3-r2-Ethoxv-5-(2-trifluoromethvl-lH-imi~7,nl-l-vl)phenvl~-6-phenvl-l-oxa-7-(tert-butoxvcarbonYl)aza-spiror4.51dec-3-ene Prepared from the compound of Description 48 and (5R,6S)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyVaza-spiro[4.5]dec-3-ene according to the method of ~.~mI-le lA. m/z (ES+) 570 (M+l).

lEXAMPLE 46B
(5R,65)-3-r2-Ethoxv-5-(2-tri~uorometh~l-lH-imi(1~7lol-l-vnphenyll-6 phenvl-1-oxa-7-aza-spiro~4.51dec-3-ene Prepared from the compound of F'.~ mple 45A according to the method of F'.~m~le lB. lH NMR (360MHz, CDCl3) ~ 1.46 (3H, t, J=lOHz), 1.61-2.06 (4H, m), 2.82 (lH, td, J=17.2, 3.6Hz), 3.26 (lH, dt, J=17.5, 2.7Hz), 3.76 (lH, s), 4.04 (2H, q, J=lOHz), 4.31 (lH, dd, J=17.2, 3.1Hz), 4.88 (lH, d, J=17.2, 3.1Hz), 6.20 (lH, t, J=3Hz), 6.76-6.86 (2H, m), 7.03 (lH, d, J=1.7Hz), 7.06-7.24 (4H, m), and 7.29-7.39 (2H, m). m/z (ES+) 470 ~a+l).

(3S 5R~6S)-3-r2-Ethoxv-5-(lH-imidazol-l-vl)Phenvll-6-phenvl-1-oxa-7-aza-s~iro[4.5~decane Prepared from the compound of F',~r~m~le 45B according to the method of Example 2. lH NMR (360MHz, CDCl3) ~ 1.41 (3H, t, J=6.8Hz), 1.54-1.64 (2H, m), 1.79-1.96 (2H, m) 1.97-2.22 (2H, m), 2.81 (lH, ta, J=10.0, 2.1Hz), 3.13 (lH, t, J=8.0Hz), 3.23 (lH, br d, J=9.8Hz), 3.65 (lH, s), 3.82-4.04 (3H, m), 4.14 (lH, t, J=8.0Hz), 6.08 ~lH, d, J=8.7Hz), 6.90 (lH, d, J=lHz), 6.96 (2H, m), 7.10-7.22 (3H, m), and 7.43 (2H, d, J=7.2Hz).
m/z (ES+) 472 (M+l).

(5R.65)-3-r2-IsoPropoxv-5-(3-trifluoromethvl-4H-1.2.4-triazol-4-Yl~Phen 6-phenvl-1-oxa-7-~tert-butoxvcarbonYl~aza-spiror4.51dec-3-ene Prepared from the compound of Description 49 and (5R,65)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyVaza-spiro[4.~]dec-3-ene according to the method of ~mI)le lA. lH NMR (360MHz, CDCl3) o 1.35 (9H, s), 1.40 (6H, t, J=5.7Hz), 1.79-1.84 (lH, m3, 2.09-2.12 (lH, m), 3.13~.17 ~lH, m), 4.Q~4.~5 ~E, m~, 4.~ H, dd, ~=12.2, ~ lHz), 4.~4-4.69 (lH, m), 4.93 (lH, dd, J=12.2, 2.1Hz), 5.14 (lH, s), 6.64 (lH, d, e7=2.0Hz)~ 6.64 (lH, d, J=2.0Hz), 6.98 (lH, d, cl=8.9Hz), 7.04 (lH, d, J=2.6Hz~, 7.17-7.27 (4H, m), 7.44 (lH, d, J=7.3Hz), and 8.28 (lH, s) m/z (ES+) 585 (M+l).

(5R,65)-3r2-IsoPropoxv-5-(3-tri~uoromethvl-4H-1.2.4-triazol-4-vl)~henvll-6-Phenvl-l-oxa-7-aza-sPiro~45ldec-3-ene Prepared from the compound of F~ mple 47A according to the method of F',2ZlmT)le lB. lH NMR (360MHz, CDCl3) ~ 1.34 (6H, dd, J=6.0, 1.6Hz), 1.70-1.82 (3H, m), 1.96-2.03 (2H, m), 2.82 (lH, d~;, J=12.1, 2.8Hz ), 3.76 (lH, s), 4.32 (lH, dd, J=12.0, 2.1Hz), 4.55-4.61 (lH, m), 4.86 (lH. dd, J=12.0, 2.0Hz), 6.16 (lH, t, J=2.1Hz), 6.78 (lH, d, J=2.7Hz), 6.87 (lH, d, J=8.9Hz), 7.67-7.20 (4H, m), 7.33- 7.35 (2H, m), and 8.22 (lH, s). m/z (ES+) 485 (M+l).

~XAMPLE 48 (35.5R~6Sl-3-r2-Isopropoxv-5-(3-trifluoromethvl-4H-1.2.4-triazol-4-vl)phenvll-6-phenvl-l-oxa-7-aza-spiro~4 51decane Hvdrochloride Prepared from the compound of Example 4713 according to the method of F'.~m~le 2.1H NMR (360MHz, D20) ~ 1.27-1.30 (6H, m), 1.75-1.95 (3H, m), 2.13-2.29 (3H, m), 3.18-3.25 (lH, m), 3.35 (lH, t, J=8.7Hz), 3.49-3.52 (lH, m), 4.02-4.06 (lH, m), 4.23 (lH, t, J=8.6Hz), 4.39 (lH, s), 4.67-4.63 (lH, m), 5.72 (lH, d, J=2.4Hz~, 7.01 (lH, t, J=7.5Hz), 7.09 (lH, d, J=8.9Hz~, 7.21-7.30 (3H, m), 7.48-7.50 (2H, d, J=7.4Hz), and 8.64 (lH, s). m/z (ES+) 487 (M+l).

(5R,60-3-r2-Isopro~oxv-5-(2-tIifluoromethvl-lH-;mirl~7.ol-l-vl)Phenvll-6-phenvl- :l-oxa -7-~ert-hutnxYc~rbonvl~aza-sPiror4.51dec-3-ene Prepared from the compound of Description 50 and (5R,6S)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5~dec-3-ene according to the method of l~ mple lA. lH NMR (360MHz, (~DCl3) d 1.33 (9H, s), 1.39-1.42 (6H, m), 1.79 (3H, m), 2.09 (lH, m), 3.13 (lH, m), 4.10-4.18 (lH, m), 4.57-4.67 (2H, m), 4.92-4.96 (lH, m), 5.14 (lH, s), 6.63 (lH, m), 6.94 (lH, d, J=8.85Hz), 7.07 (lH, d, J=2.5Hz), 7.09 (lH, d, J=0.9Hz), 7.18-7.25 (5H, m), 7.45 (lH, d, J=7.5Hz), and 8.28 (lH, s). m/z (ES+) 584 (M+l).

(5R.6S~-3-~2-Isopropox~-5-(2-trifluoromethvl-lH-imidazol-l-vl)phenvll-6-phen~l-1-oxa-7-azaspirol4.51dec-3-ene Prepared from the compound of Example 49A according to the method of Example lB. lH NMR (250MHz, CDCl3) d 1.33 (6H, dd, J=6.0, 2.1Hz), 1.63-1.72 (2H, m), 1.95-2.03 (2H, m), 2.82 (lH, dt, J=12.0, 3.0Hz ), 3.23-3.29 (lH, m), 3.76 (lH, s), 4.32 (lH, dd, J=12.0, 2.2Hz), 4.61-4.61 (lH, sept, J=6.0Hz), 4.86 (lH, dd, J=12.0,2.1Hz), 6.18 (lH, t, J=2.1Hz), 6.80-6.86 (2H, m), 7.04 (lH, d, J=1.29Hz), 7.07-7.21 (4H, m), and 7.33- 7.37 (2H, m). m/z (ES+) 484 (M+l).

(3$.6R.65~-3-r2-IsoProPoxv-5-(2-trifluorometh~ l-lH-imidazol-l-vl~Phenvll-6-phenvl-1-oxa-7-aza-spiror4.51decane Hvdrochloride CA 02237638 l998-05-l2 Prepared from the compound of Example 49B according to the method of l~,x~mFIle 2.1H NMR (360MHz, D20) d 1.29-1.32 (6H, m), 1.79-2.00 (3H, m), 2.18-2.28 (3H, m), 3.24-3.37 (2H, m), 3.55-3.68 (lH, m), 4.02-4.10 (lH, m), 4.23 (lH, t, J=8.4Hz), 4.41 (lH, s), 4.55-4.61 (lH, m), 5.79 (lH, d, J=2.1Hz), 7.04-7.09 (2H, m), 7.15-7.17 (2H, m), 7.24-7.33 (3H, m), and 7.51 (2H, d, J=7.3Ez). m/z (ES+) 486 (M+l).

Ed~MPLE ~lA
(5R,65)-3-~2-Methoxv-5-(oxazol-5-vl~Phenvll-6-~henYl-l-oxa-7-(ter~-butoxvcarbonYl)aza-spiror4.51dec-3-ene Prepared from the compound of Description 51 and (5R,6S)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyVaza-spiro[4.5]dec-3-ene according to the method of ~ mple lA.

(5R~65)-3-~2-Methoxv-5-(oxazol-5-vl)phenvll-6-PhenYl-l-oxa-7-aza-sPiror4.51dec-3-ene . . .
Prepared from the compound of ~ mple 5~A according to the method of ~ mple lB. lH NMR (360MHz, CDCl3) ~ 1.66 (lH, d, J=11.2Hz~, 1.8 (lH, d, J=4.4Hz), 1.92-2.08 (2H, m), 3.28 (lH, d, J=10.5Hz), 3.8 (4H, s), 4.32 (lH, dd, J=12.0, 2.1Hz), 4.88 (lH, dd, J=12.0, 2.2Hz), 6.10-6.18 (lH, m), 6.82 (lH, d, J=9.OHz), 7.2 (lH, d, J=2.0Hz), 7.10-7.24 (4H, m), 7.38-7.42 (3H, m), and 7.82 (lH, s). m/z (:ES+) 389 (M+l).

(35~5R.65)-3-r2-Methoxv-5-(oxazol-5-vl~Phenvl~-6-PhenYl-l-oxa-7-a%a-spiro ~4.5l decane J Prepared from the compound of Example 51B according to the method of F'.~mple 2. lH NMR (250MHz, CDC13) ~ 1.44-1.62 (lH, m), 1.80-1.94 (2H, m), 2.02-2.20 (2H, m), 2.62-2.76 (lH. m), 3.06-3.27 (2H, m), 3.70 (3H, s), 3.76-3.86 (2H, m), 4.02-4.15 (2H. m), 6.48 (lH, d. J=2.0Hz), 6.6 (lH, d, J=9.OHz), 7.0 (lH, s), 7.24-7.36 (4H, m), 7.62 (2H, d, J=8.0Hz), and (7.86, lH, s). m/z (ES+) 391 (M+l).

E~AMPLE 53A
(~R.65)-3-r2-IsoPro~oxv-5-(oxazol-5-vl)~henYll-6-~henYl-l-oxa-7-(tert butoxvcarbonYl)aza-sPiro~4.51dec-3-ene Prspared from the compound of Description 53 and (5R,6S)-3-tributyls~annyl-Ç;-phellyl-l -oxa-7-(tert-huto~carbonyl)aza-spiro~4.5~dec-3-ene according to the method of F.~mple L~. lH NMR (2aOMHz, CDCl3) 7.86 (lH, s), 7.56-7.22 (8H, m), 6.92 (lH, d, J=8.7Hz), 6.62 (lH, t, J=2.0Hz), 5.10 (lH, s), 5.03 (lH, dd, J=12.2, 2.0Hz), 4.76-4.64 (2H, m), 4.10 (lH, m), 3.14 (lH, m), 2.13-1.60 (4H, m), and 1.44-1.22 (15H, m). m/z (ES+) 517 (M+l).

E~AMP:LE 53B
(5R,65)-3-r2-Isopropoxv-5-(oxazol-5-vl)phenvn-6-Phenvl-l-oxa-7-aza-spiror4.5~dec-3-ene Prepared from the compound of Example 53A according to the method of Example lB. lH NMR (250MHz, CDCl3) ~ 1.2 / (6H, d, -~=6.0Hz), 2.80-1.98 (2H, m), 2.02-1.99 (lH, m), 2.50-2.42 (lH. br s). 2.94-2.86 (lH, br s), 3.50-3.48 (lH, br d, J=7.0Hz), 4.12 (lH, s), 4.5 (2H, m), 4.98 (lH, br d, J=12.4Hz), 6.03 (lH, br s), 6.81 (lH, d, J=8.8Hz), 7.08 (lH, d, J=2.1Hz), 7.22 (4H, m), 7.4 (lH, dd, J=8.6, 2.2Hz), 7.56 (2H, m), and 7.85 (lH, s). m/z (ES~) 417 (M+l).

(35.5R,65)-3-~2-Isopropoxv-5-(oxazol-5-vl)phen~ -6-phen~ l-1-ox~- /-~za-spiror4.51decane Prepared from the compound of Example 53~ according to the method of Example 2. lH NMR (250~Hz, CDCl3) ~ 1.19 (lH. m), 1.24 (3H, W O 97/19084 PCTtGB96/028S3 - 123-d, J--6Hz), 1.30 ~3H, d, J=6.0Hz), 1.50-2.01 (2H, m), 2.16 (lH, br d, J=9.OHz), 2.43 (lH, br s), 2.90 (lH, br s), 3.15 (lH, dd, J=8.3Hz, 10.3Hz), 3.50-3.42 (lH, br d, J=7.0Hz), 3.94-3.82 (lH, m), 3.99-4.10 (2H, m), 4.52 (lH, septet, J=6Hz), 6.53 (lH, s), 6.81 (lH, d, J=8.5Hz), 7.0 (lH, s), 7.43-7.22 (4H, m), 7.76-7.63 (lH, br s), and 7.83 (lH, s). m/z (ES+) 419 (M+l).

l~XAMPLE 55A
(.5~,65~-3-,r2-BenzYloxv-~6-(2-trifluorom.ethvl-lH-imid~zol-l-vl)phe~vll-fi-phenvl-l-oxa-7-(tert-butoxYcarbonYl) aza-sPiror4.51dec-3-ene Prepared from the compound of Description 57 and (5R,6S)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5~dec-3-ene according to the method of l~ m~le lA. lH NMR (360MHz, CDCl3~ ~
1.32 (9H, s), 1.71-1.84 (4H, m), 2.03-2.13 (lH, m), 3.04-3.16 (lH, m), 4.05-4.13 (lH, m), 4.60 (lH, dd), 4.91 (lH, dd), 5.09 (lH, s), 5.17(2H, q), 6.70 (lH, t), 7.04 (2H, dd), 7.11 (lH, d), 7.15-7.28 (5H, m), and 7.35-7.49 (7H, m).

(5R.65~-3-r2-Benzvloxv-6-(2-trifluoromethvl-lH-imidazol-l-vl)phenvll-6-~henvl-1-oxa-7-aza-spiror4.5ldec-3-ene Prepared from the compound of Example 55A according to the method of Example lB. m/z (ES~) 532 (M+l).

EXAMPL~ 56 26 (35.5R.6Sl-3-~2-Hvdroxv-5-(2-trifluoromethvl-lH-inni(lzl70l-l-vl)phenvll-6- phenvl-l-oxa-7-aza-s~iror4.5ldecane Hvdrochloride Prepared from the compound of Example 5~B according to the method of ~,~mple 2. lH NMR (360MHz, DMSO-d~ 1.66 (lH, t, J=12Hz), 1.70-1.81 (2H, m), 1.91-2.10 (3H, m), 3.03-3.07 (lH, m), 3.10 ~lH, t, J=8Hz), 3.25-3.2$ (lH, m), 3.820 (lH, qn, J=lOHz), 4.15 (lH, t, J---7.2Hz), 4.45 (lH, d, J=10.8Hz), 5.97 (lH, d"~=2Hz), 6.90 (lH, d, -J=8.6Hz), 7.03 (lH, dd, J=7, 2Hz), 7.10 (lH, t, J=7.5Hz), 7.23 (lH, d, J=lHz), 7.28 (lH, t, J=8Hz), 7.42 (lH, d, J=lHz), and 7.51 (lH, d, J=7Hz). m/z (ES+) 444 (M+l).

(5R.65)-3-r5-(1-Methvl-lH-1.2.3-triazol-3-Yl)-2-(trifluoromethoxY)Phenvl]
6-phenvl-1-oxa-7-(tert-butoxvcarbonvl)aza-s~iror4.5]dec-3-ene Prepared ~rom 1-methyl-4-~3-bromo-4-(trifluoromethoxy)phenyl~-lH-1,2,3-triazole (Description 60) and (5R,6S)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene according to the method of Example lA. lH NMR (250MHz, CDCl3) ~ 7.75 (lH, s), 7.74-7.67 (2H, m), 7.50-7.40 (2H, m), 7.35-7.19 (4H, m), 6.57 (lH, t, J=2.1Hz), 5.15 (lH, br s), 4.96 (lH, dd, J=12, 2.1Hz), 4.65 (lH, dd, J=12, 2.1Hz), 4.17 (3H, s), 4.15-4.05 (lH, m), 3.23-3.08 (lH, m), 2.18-2.05 (lH, m), 1.95-1.75 (3H, m), and 1.35 (9H, s). m/z (ES+) 557 (M+l).

(5R,6$)-3-r5-(1-Methvl-lH-1~2,3-triazol-3-vl)-2-(trifluoromethoxY)phenvll-6-phenvl- 1 -oxa-7-aza-spiro~4.51dec-3-ene Prepared from the compound of Example 57A according to the method of Example lB. lH NMR (250MHz, CDCl3) ~ 7.68 (lH, s), 7.60 (lH, dd, J=8.5, 2.2Hz), 7.42-7.35 (3H, m), 7.26-7.10 (4H, m), 6.16 (lH, t, J=2.1Hz), 4.88 (lH, dd, J=12, 2.1Hz), 4.42 (lH, dd, J=12, 2.1Hz), 4.15 (3H, s), 3.78 (lH, s), 3.35-3.20 (lH, m), 2.84 (lH, dt, J=12, 2.8Hz). and 2.12-1.60 (4H, m). m/z (ES+) 457 (M+l).

EXAMPLE ~8 (3S.5R,6S~-3-~5-(1-Methvl-lH-1.2 3-triazol-3-vl~-2-(trifluoromethoxv)Phenvll-6-~henvl-1-oxa-7-aza-spiror4.51decane Prepared from the compound of F"r~mrle 57B according to the method of Example 2.1H NMR (250MHz, CDCl3) ~ 7.73 (lH, dd, J=8.5, 2.1Hz), 7.60-7.50 (2H, m), 7.42 (lH, s), 7.41-7.25 (3H, m), 7.18 (lH, dq, J=8.5, 1.5Hz), 6.63 (lH, d, J=2.1Ez), 4.19 (3H, s), 4.13 (lH, t, J=8.0Hz), 3.91-3.74 (lH, m), 3.70 (~H, s), 3.35-3.20 (2H, m), 2.84 (lH, dt, J=12, 3Hz), 2.20-1.80 (4H, m), and 1.70-1.55 (2H, m). m/z (ES+) 459 (M+l).

(5R,65)-3-r5-(2-Methyl-2H-1,2~3-triazol-3-vl~-2-(triiluoromethoxv3~henYll-6-phenvl-1-oxa-7-~tert-butoxvcarbonYl)aza-spiror4.51dec-3-ene Prepared from 2-Methyl-4-[3-bromo-4-(tr~fluoromethoxy)phenyl]-2H-1,2,3-triazole (Description 60) and (5R,6S)-3-tributylstannyl-6-phen~
l-oxa-7-(tert-butoxycarbonyl)aza-spiro~4.5~dec-3-ene according to the method of ~ m~le lA. lH NMR (250MHz, CDCl3) ~ 7.79 (lH, s), 7.67 (lH, dd, J=8.5, 2.1Hz), 7.63 (lH, d, J=2.1Hz), 7.50-7.44 (2H, m), 7.36-7.18 (4H, m), 6.57 (lH, t, J=2.1Hz), 5.18 (lH, br s), 4.98 (lH, dd, J=12, 2.1Hz), 4.66 (lH, dd, cl=12, 2.1Hz), 4.25 (3H, s), 4.20-4.10 (lH, m), 3.20-3.05 (lH, m), 2.20-2.05 (lH, m), 1.95-1.78 (3H, m), and 1.37 (9H, s). m/z (ES+) 557 (M+l).

(5R,6S)-3-r5-(2-Methvl-2H-1.2.3-triazol-3-vl)-2-(trifluoromethoxv)Phenvll-6-Phen~rl-l-oxa-7-aza-spiror4.51dec-3-ene Prepared from the compound of ~ mI~le 59A according to the method of Example lB. lH NMR (250MHz, CDCl3) ~ 7.73 (lH, s), 7.58 (lH, dd, J=8.5, 2.2Hz), 7.42-7.34 (2H, m), 7.30-7.10 (5H, m), 6.12 (lH, t!
J=2.1Hz), 4.89 (lH, dd, J=12, 2.1Hz), 4.40 (lH, dd, J=12. 2.1Hz), ~.23 (3H, s), 3.79 (lH, s), 3.35-3.20 (lH, m), 2.84 (lH, dt, J=12, 2.9Hz), and 2.15-1.60 (4H, m). m/z (ES+) 457 (M+l).

CA 02237638 1998-0=,-12 EX~MPLE 60 (3S.5R.6S)-3-~5-~2-~ethvl-2H-1.2.3-triazol-3-vl)-2-(trifluoromethoxv)~henvll-6-Phenvl-l-oxa-7-aza-spiro~4.51decane Prepared from the compound of Example 59B according to the method of h'.~mple 2.1H NMR (250MHz, CDCl33 ~ 7.62-7.51 (3H, m), 7.49 (lH, s), 7.42-7.36 (3H, m), 7.17 (lH, dq, J-8.5, 1.5Hz), 6.65 (lH, d, J=2.1~1z), 4.24 (3H, s), 4.10 (l~I, t, cT=7.9Hz), 3.92-3.74 (lE~, m), 3.69 (lH, E,~, 3.32-3.22 ~ ), 2.~ ~lH, d~, J=12, 3Hz), 2.20-1.8., (4H, m~, and 1.69-1.56 (2H, m). m/z (ES+) 459 (M+1).
E~AMPLE 61A
(5R~6S)-3-~5-(Pvrid-3-yl)-2-(tri~Luoromethox~phenvll-6-Phenvl-l-oxa-7-(tert-butoxycarbonvl)aza-s~iro~4.51dec-3-ene Prepared from the compound of Description 62 and (5R,6S)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5~dec-3-ene according to the method of ~ mple lA. lH NMR (360MHz, CDCl3) ~
8.78 (lH, dd, J=4.9, 1.8Hz), 7.82 (lH, m), 7.48 (3H, m), 7.38 (3H, m), 7.24 (3H, m), 6.5~, (lH, t, J=2.1Hz), 5.16 (lH, s), 4.97 (lH, dd, J=2.1, 12.2Hz), 4.63 (lH, dd, J=2.1, 12.2Hz), 4.13 (lH, m), 3.16 (lH, m), 2.15 (lH, m), 1.86 (2H, m), 1.64 (lH, m), 1.34 (9H, s). m/z (ES+) 563 (M+l).

E~AMPLE 61B
(5R,65)-3-r5-(Pvrid-3-vl)-2-~trifluoromethoxv)~henvll-6-PhenYl-l-Qxa-7-aza-s~iror4.5ldec-3-ene Hydrochloride (5R,6S)-3-[5-(Pyrid-3-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene (Description 6LA) (230mg, 0.42mmol) was dissolved in diethylether (lOml). Ethereal HCl (2M, lOml) was added and the reaction mixture was stirred at room temperature over night. The solid was collected and dried i7luacl~o to give the title compound as a solid (175mg, 92%). lH NMR (360MHz, DMSO-d~) 9.73 (lH, m), 9.14 (lH, m), 8.96 (lH, d, J=2.0Hz), 8.67 (lH, dd, J=5.1, 1 6Hz), 8.23 (lH, d, J=7.9Hz), 7.78 (lH, dd, J=8.6, 2.3Hz), 7.6B (lH, dd, J=7.9, 5.1Hz), 7.48 (4H, m), 7.33 (3H, m), 6.42 (lH, t), 4.99 (lH, dd, J=12.5Hz), 4.66 (lH, d, J=10.4Hz), 4.50 (lH, dd, J=12.6Hz), 3.33 (lH, m), 3.13 (lH, m), 2.08 (2H, m), 1.88 (2H, m). m/z (ES+) 453 (M+l).

~35. 5~ 6S)- 3 r -Iso~ropox~ -5-(pYrid-3-~l)phe~ -6-phenYl - l-oxa-7-~er~-butoxvcarbonvl)aza-sl)iror4.51 decane (3S,5R,6S~-3-(~-Bromo-2-isopropoxyphenyl)-6-phenyl- 1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Description 68) (lOOmg, 0.19mmoV, 3-(trimethylstannyl)pyridine (Description 63) (60mg, 0.25mmol) and lithium chloride (48mg, 1.14mmol) were suspended in toluene (5ml) under a nitrogen atmosphere. Tetrakis(triphenylphosphine) palladium (0) (20mg, 0.017mmol) was added and the solution was stirred at 100 ~C for 16hours, allowed to cool to ambient temperature and filtered. The filtrate was washed with water, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (80:20) to give the title compound as an oil (33mg). lH NMR (360MHz, CDCl3) ~ 8.78 (lH, s), 8.56-8.52 (lH, m), 7.80-7.78 (lH, m), 7.57-7.54 (2H, m), 7.40-7.37 (2H, m), 7.31-7.20 (4H, m), 6.95-6.94 (lH, d, J=8.3Hz), 5.24 (lH, s), 4.65-4.58 (lH, m), 4.31-4.26 (lH, m), 4.Q3-3.97 (lH, m), 3.87-3.82 (lH, m), 3.74-3.69 (lH, m), 2.94-2.87 (lH, m), 2.44-2.39 (lH, m), 2.31-2.14 (2H, m), 1.81-1.75 (3H, m), 1.40-1.36 (6H, m), and 1.32 (9H, s). MS (ES+) 529 (M+l).

(35,6R.65)-3-r2-Isopropoxv-5-(1~Yrid-3-vl~phenvll-6-phenvl-l-oxa-7-aza-spiro r4.51 decane Dihvdrochloride .
(3$,5R,6S)-3-r2-Isopropoxy-5-(pyrid-3-vl)phenyl~-6-phenyl-1-oxa-7-(ter~-butoxvcarbonyl)aza-spiro[4.5~decane (Description 62) (29mg, W O 97/19084 PCTtG B96/02853 0.05mmol) was dissolved in diethyl ether (2ml). Ethereal hydrochloric acid (lM, 2ml) was added and the solution was stirred for 16 hours. The solid was collected and dried in vacuo to give the title compound as a solid (13mg). lH NMR (360MHz, CDCl3) ~ 9.70-9.67 (lH, m), 9.03-8.97 (lH, m), 8.84-8.78 (lH, m), 8.34-8.32 (lH, m), 8.01-8.00 (lH, m), 7.59-7.57 (3H, m), 7.47-7.43 (2H, m), 7.39-7.38 (lH, m), 7.11-7.08 (lH, d, J=8.8Hz), 6.60-6.59 (lH, d, J=2.2Hz), 4.67-4.63 (lH, m), 4.52-4.49 (lH, m), 4.18-4.14 (lH, m), 3.~-3~81 (lH, m)S 2.2~;-2~22 (2H, m), 3.13-3.07 (lH, m)) 2.13-2.07 (S~; m), 1.82-1.75 (3H, m), and 1.27-1.22 (6H, m). MS (ES~) 429 (M~l).

EXAl!.![PLE 64A
(5R.65)-3-r2-Metho~Y-5-(lH-1,2,4-tria~ol-1-vl)phenvll-6-~henvl-1-oxa-7-(tert-butoxycarbonvl)aza-spiro~4.51dec-3-ene Prepared from 1-(3-bromo-4-methoxyphenyl)-lH-1,2,4-triazole (Description 70) and (5R,6S)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene according to the method of Example lA. lH NMR (360MHz, CDCl3) ~ 1.31 (9H, s), 1.78-1.88 (3H, m), 2.08-2.14 (lH, m), 3.10-3.16 (lH, m), 3.91 (3H, s), 4.09-4.15 (lH, m), 4.64 (lH, dd, J=12.1, 2.1Hz), 4.99 (lH, dd, J=12.0, 2.0Hz), 5.17 (lH, S), 6.69 (lH. t, J=2.0Hz), 7.00 (lH, d, J=8.9Hz), 7.18-7.28 (3H, m), 7.33 (lH, d, J=2.6Hz), 7.45-7.57 (3H, m), 8.08 (lH, s), and 8.44 (lH, s). m/z (ES+) 489 ~+1).

(5R~65~-3-r2-Methoxv-5-(lH-1,2.4-triazol-1-Yl)phenvl~-6-,t~henvl-1-oxa- l-aza-spiror4.61dec-3-ene Prepared fiom the compound of Example 64A according to the method of Example lB. lH NMR (250MHz, CDCl3) ~ 1.64-1.68 (lH, m), 1.96-2.05 (3H, m), 2.83 (lH, dt, J=12.4, 2.8Hz ), 3.26-3.29 (lH, m)~ 3.78 (lH, s), 3.82 (3H, s), 4.35 (lH, dd, J=ll.9, 2.2Hz). 4.88 (lH, dd, J=ll.9, 2.1Hz), 6.19 (lH, t, J=2.0Hz), 6.89 (lH, d, J=8.8Hz), 7.04 (lH, d, J=2.7Hz), 7.11-7.21 (3H, m), 7.36-7.42 (3H, m), 8.05 (lH, s), and 8.35 (lH, s). m/z (ES+) 389 ~M+l).

(35,5R,65)-3-r2-Methoxv-5-(lH-1.2.4-triazol-1-Yl)phen~11-6-~henYl-l-oxa-7-aza-spiror4.5~decane Hvdrochloride Prepared ~om the com~o~ of ~ample 64B according to the method of l~ ple 2.1H NMR (360MHz, D20) S 1.82-1.94 (3H, m), 2.06-2.19 (3H, m), 3.21 (lH, m), 3.48-3.55 (2H, m), 3.71 (3H, s), 3.84 (lH, m), 4.10-4.13 (lH, m), 4.37 (lH, s), 6.41 (lH, s), 6.94 (lH, d, J=8.4Hz), 7.23-7.33 (4H, m), 7.47 (2H, d, J=7.1Hz), 8.34 (lH, s), and 8.78 (lH, s). m/z (ES+) 391 (M+l).

(5R,65)-3-r5-(Pyrimidin-5-yl)-2-(trifluoromethoxY~Phenvl~-6-phenyl-1-oxa-7-(tert-butoxvcarbon~l)aza-spiror4.51dec-3-ene Prepared from the compound of Description 72 and (5R,6S)-3-tributylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-20 ene according to the method of l~ mple lA. lH NMR (250MHz, CDCl3) ~
0.85 (lH, d, J=7.6Hz), 1.36 (9H, s), 1.84 (2H, m), 2.12 (lH, m), 3.2 (lH, m), 4.12 (2H, q, J=7.1E~z), 4.61 (lH, dd, J=17.1, 2.1Hz), 4.95 (lH, dd, J=17.0, l.9Hz), 5.16 (lH, s), 6.57 (lH, s), 7.29 (5H, m), 7.51 (3H, m), 8.91 (2H, s), and 9.25 (lH, s). m/z (ES+) 564 (M+l).

~6R,6$)-3-r6-(pvrimidin-5-vl)-2-(trifluolomethoxv~Phen~ -Phenvl-l-oxa-7-aza-sPiror4.61dec-3-ene Prepared from the compound of Example 66A according to the method of Example lB. lH NMR (260MHz, CDCl3) ~ 1.85 (2H, t~

W O 97/19084 PCT/GB9~ 285 J=11.9Hz), 2.93 (lH, t, J=11.5Hz), 3.52 (lH, d, J=12.0Hz), 4.46 (lH, dd, J=12.6, 2.1Hz~, 4.92 (lH, dd, J=12.6, 2.1Hz), 5.99 (lH, s), 6.98 (lH, d, J=2.2Hz), 7.3 (5H, m), 7.43 (lH, dd, J=8.56, 6.3Hz), 7.55 (lH, dd, J=6.0, 1.8Hz), 8.8 (2H, s), 9.23 (lH, s). m/z (ES+) 454 (M+l). t

Claims (30)

CLAIMS:

1. A compound of the formula (I):

wherein R1 represents a halogen atom, a hydroxy group, a C1-6alkyl group optionally substituted by one to three fluorine atoms, a C1-6alkoxy group optionally substituted by one to three fluorine atoms, or a C1-6alkylthio group optionally substituted by one to three fluorine atoms;
R2 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy;
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 oxygen atoms;
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 C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, trifuoromethyl, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, phenyl, -(CH2)rNRaRb, -(CH2)rNRaCORb, -(CH2)rCONRaRb, or CH2C(O)Ra, where Ra and Rb are each independently hydrogen or C1-4alkyl and r is zero, 1 or 2;
R4 represents hydrogen, halogen, C1-6alkyl, C1-6alkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, where Ra and Rb each independently represent hydrogen or C1-4alkyl;

R5 represents hydrogen, halogen, C1-6alkyl, C1-6alkoxy substituted by C1-4alkoxy or CF3;
R6 represents hydrogen, CORa, CO2Ra, COCONRaRb, COCO2Ra, C1-6alkyl optionally substituted by a group selected from (CO2Ra, CONRaRb, hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONHphenyl(C1-4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaC1-6alkylR12, CONR13C2-6alkenyl, CONR13C2-6alkynyl, COCONRaRb, CONRaC(NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from C1-6alkyl, C1-6alkoxy, halogen and trifluoromethyl);
or R6 represents a group of the formula -CH2C~CCH2NR7R8 where R7 and R8 are as defined below;
or R6 represents C1-6alkyl, 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 ZNR7R8 where Z is C1-6alkylene or C3-6cycloalkyl;
R7 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R8 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy, hydroxyl 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 or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH
or NRc moiety where Rc is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;

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 Z, 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 and R10 each independently represent hydrogen, halogen, C1-6alkyl, CH2ORd, oxo, CO2Ra or CONRaRb where Ra and Rb are as previously defined and Rd represents hydrogen, C1-6alkyl or phenyl;
R12 represents ORa, CONRaRb or heteroaryl;
R13 represents H or C1-6alkyl;
m is zero 1, 2 or 3;
n is zero, 1, 2, or 3, with the proviso that the sum total of m+n is 2 or 3;
p is zero or 1;
q is 1 or 2; and when m is 1 and n is 1 or 2, the broken line represents an optional double bond;
or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 wherein R1 represents a C1-6alkyl group optionally substituted by one to three fluorine atoms, or a C1-6alkoxy group optionally substituted by one to three fluorine atoms.

3. A compound as claimed in claim 1 wherein R1 represents a C1-6alkyl group optionally substituted by one to three fluorine atoms, or a C1-6alkoxy group optionally substituted by one to three fluorine atoms;
R2 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy;
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 a group selected from C1-6alkyl, Cl-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylCl 4alkyl, trifluoromethyl, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, phenyl, -(CH2)rNRaRb, -(CH2)rNRaCORb, -(CH2)rCONRaRb, or CH2C(O)Ra, where Ra and Rb are each independently hydrogen or Cl-4alkyl and r is zero, 1 or 2;
and R6 represents hydrogen, CORa, CO2Ra, COCONRaRb, COCO2Ra, Cl-6alkyl optionally substituted by a group selected from (CO2Ra, CONRaRb, hydroxy, CN, CORa, NraRb, C(NOh)NraRb, CONHphenyl(C1-4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaCl-6alkylRl2, CONRl3C2-6alkenyl, CONR13C2-6alkynyl, COCONRaRb, CONRaC(NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from Cl-6alkyl, Cl-6alkoxy, halogen and trifluoromethyl) or Cl-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 ZNR7R8 where Z, R7 and R8 are as previously defined;
or a pharmaceutically acceptable salt thereof

4. A compound as claimed in claim 1 of formula (I'):

wherein Rl represents a Cl-6alkyl group optionally substituted by one to three fluorine atoms, or a Cl-6alkoxy group optionally substituted by one to three fluorine atoms;
R2 represents hydrogen or halogen;
R3 represents an N-linked tetrazolyl group optionally substituted by a group selected from Cl-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, trifluoromethyl, SRa, SORa, SO2Ra, phenyl, NRaRb, NRaCORb or CH2C(O)Ra, where Ra and Rb are each independently hydrogen or Cl-4alkyl;
R4 represents hydrogen or halogen;
R6 represents hydrogen, CORa, CO2Ra, COCONRaRb, COCO2Ra, Cl-6alkyl optionally substituted by a group selected from (CO2Ra, CONRaRb, hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONHphenyl(Cl-4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaCl-6alkylRl2, CONRl3C2-6alkenyl, CONRl3C2-6alkynyl, COCONRaRb, CONRaC(NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from Cl-6alkyl, Cl-6alkoxy, halogen and trif1uoromethyl) or Cl-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 ZNR7R8 where Z is Cl-6alkylene or C3-6cycloalkyl;
R7 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCl-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R8 is hydrogen or Cl-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCl-4alkyl, or C2-4alkyl substituted by Cl-4alkoxy, hydroxyl 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 or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH
or NRc moiety where Rc is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
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 Z, R7 and the nitrogen atom to which they are attached from a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R12 represents ORa, CONRaRb or heteroaryl;
R13 represents H or C1-6alkyl;
or a pharmaceutically acceptable salt thereof.

5. A compound as claimed in any one of claims 1 to 4 wherein R1 is a methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy or trifluoromethoxy group.

6. A compound as claimed in any one of claims 1 to 5 wherein R2 is a hydrogen, fluorine or chlorine atom.

7. A compound as claimed in claim 1 to 3 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 defined in claim 1.

8. A compound as claimed in claim 7 wherein R3 is the group , or where Rll is hydrogen, halogen, Cl-6alkyl, Cl-6alkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, (CH2)rCONRaRb, (CH2)rNRaRb or (CH2)rNRaCORb, where Ra and Rb are hydrogen or Cl-4alkyl, and r is zero, 1 or 2.

9. A compound as claimed in any one of claims 1 to 8 wherein R4 is a hydrogen atom or a fluorine atom.

10. A compound as claimed in any one of claims 1 to 3 wherein R5 is a hydrogen atom.

11. A compound as claimed in any one of claims 1 to 10 wherein R6 is a hydrogen atom.

12. A compound as claimed in any one of claims 1 to 3 wherein R9 and Rl0 are both hydrogen atoms.

13. A compound as claimed in any one of claims 1 to 3 wherein m is 1.

14. A compound as claimed in any one of claims 1 to 3 wherein n is 1 or 2.

15. A compound as claimed in any one of claims l to 3 wherein p is zero.

16. A compound as claimed in any one of claims 1 to 3 wherein q is 2.

17. A compound selected from:
(6S,5R,3S)-3-(2-methoxy-5-(5-trifluoromethyl)tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(6S,5R,3S)-3-(2-isopropoxy-5-(5-(trifluoromethyl)tetrazol-l-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(6S,5R,3S)-3-(2-methoxy-5-(tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(6S,5R,3S)-3-(2-methyl-5-(5-(trifluoromethyl)tetrazol-l-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(6S,5R,3S)-3-(2-trifluoromethoxy-5-(5-(trifluoromethyl)tetrazol-1-yl)phenyl)-6-phenyl-l-oxa-7-aza-spiro[4.5]decane;
(6S, 5R, 3S)-3-(2-methoxy-3-fluoro-5-(5-(trifluoromethyl)tetrazol- 1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(6S,5R,3S)-3-(2-methoxy-5-(1,2,4-triazol-4-yl)phenyl)-6-phenyl-l -oxa-7-aza-spiro[4.5]decane;
(6S,5R,3S)-3-(2-methoxy-4-fluoro-5-(5-(trifluoromethyl)tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(6S,5R,3S)-6-phenyl-3-(2-methoxy-5-(3,5-bis(trifluoromethyl)-1,2,4-triazol-4-yl)phenyl)-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(6S,5R,3S)-6-phenyl-3-(5-(5-trifluoromethyl)tetrazol-1-yl)-2,3-dihydrobenzfuran-7-yl)-1-oxa-7-aza-spiro[4.5]decane;
(6S.5R,3S)-6-phenyl-3-(5-(5-trifluoromethyl)tetrazol-1-yl)-2.3-dihydlobenzfuran-7-yl)-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(6S.5R,3S)-6-phenyl-3-(2-methoxy-5-(3,5-bis(trifluoromethyl)-1,2,4-triazol-4-yl)phenyl)-1-oxa-7-aza-spiro[4.5]decane;
(6S.5R,3S)-6-phenyl-3-(2-methoxy-5-(5-trifluoromethyl)isoxazol-4-yl)phenyl)-1-oxa-7-aza-spiro[4.5]dec-3-ene;

(6S,5R,3S)-6-phenyl-3-(2-methoxy-5-(5-trifluoromethyl)isoxazol-4-yl)phenyl)-1-oxa-7-aza-spiro[4.5]decane;
(6S,5R,3S)-7-((2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-3-(2-methoxy-5-(5-(trifluoromethyl)tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(6S,5R,3S)-7-(2-(N,N-dimethylamino)ethyl)-3-(2-methoxy-5-(5-(trifluoromethyl)tetrazol-l-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(6S,5R,3S)-7-((lH-imidazol-5-yl)methyl)-3-(2-methoxy-5-(5-(trifluoromethyl)tetrazol-l-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-methoxy-5-(2,4-dimethyl-lH-imidazol-l-yl)phenyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-methoxy-5-(2,4-dimethyl-lH-imidazol-1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-methoxy-5-(2,4-dimethyl-lH-imidazol-1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-methoxy-5-(4-pyridyl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-methoxy-5-(4-pyridyl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-methoxy-5-(4-pyridyl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[5-(4-pyridyl)-2-(trifluoromethoxy)phenyl] -6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[5-(4-pyridyl)-2-(trifluoromethoxy)phenyl] -6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
5R,6S)-3-[5-(4H-1,2,4-triazol-4-yl)-2-(trifluoromethoxy)phenyl] -6-phenyl- 1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[5-(4H-1,2,4-triazol-4-yl)-2-(trifluoromethoxy)phenyl] -6-phenyl-l-oxa-7-aza-spiro[4.5]dec-3-ene;

(3S,5R,6S)-3-[5-(4H-1,2,4-triazol-4-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-(trifluoromethoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-(trifluoromethoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-(trifluoromethoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-l-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-methoxy-5-(2-trifluoromethyl-lH-imidazol-l-yl)phenyl]-6 phenyl-l-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-methoxy-5-(2-trifluoromethyl-lH-imidazol-1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-methoxy-5-(2-trifluoromethyl-lH-imidazol-1-yl)phenyl]-6-phenyl-l-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-trifluoromethoxy-5-(2-trifluoromnethyl-lH-imidazol-1-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-trifluoromethoxy-5-(2-trifluoromethyl-1H-imidazol-l-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-trifluoromethoxy-5-(2-trif1uoromethyl-lH-imidazol-1-yl)phenylJ-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-methoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-methoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-methoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-(2-fluoroethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)phenyl]-6-phenyl-l-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene:
(5R,6S)-3-[2-(2-fluoroethoxy)-5-(5-trifluoromethvl-tetrazol -1-yl)phenyl]-6-phenyl-l-oxa-7-aza-spiro[4.5]dec-3-ene;

(3S,5R,6S)-3-[2-(2-fluoroethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-methoxy-5-(2-methyltetrazol-5-yl)phenyl] -6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-methoxy-5-(2-methyltetrazol-5-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5],dec-3-ene;
(5R,6S)-3-[2-methoxy-5-(1-methyltetrazol-5-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-methoxy-5-(1-methyltetrazol-5-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-methoxy-5-(1-methyltetrazol-5-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-chloro-5-(tetrazol-1-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-chloro-5-(tetrazol-1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[5-(lH-pyrazol-l-yl-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[5-(1H-pyrazol-1-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa-7-aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-ethoxy-5-(2-trifluoromethyl-1H-imidazol-1-yl)phenyl]-6-phenyl-l-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene:
(5R,6S)-3-[2-ethoxy-5-(2-trifluoromethyl-1H-imidazo1-1-yl)pheny]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-ethoxy-5-(lH-imidazol-1-yl)phenyl]-6-phenyl-l-oxa-7-aza-spiro [4.5] decane;
(5R,6S)-3-[2-isopropoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3[2-isopropoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-l-oxa-7-aza-spiro[4.5]dec-3-ene;

(3S,5R,6S)-3-[2-isopropoxy-5-(3-trifluoromethyl-4H-1,2,4-triazol-4-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-isopropoxy-5-(2-trifluoromethyl-1H-imidazol-1-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-isopropoxy-6-(2-trifluoromethyl-1H-imidazol-1-yl)phenyl]-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-isopropoxy-5-(2-trifluoromethyl-1H-imidazol-1-yl)phenyl]-6-phenyl-oxa-7-aza-spiro[4.5]decane;
(5R,6S-3-[2-methoxy-5-(oxazol-5-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-methoxy-5-(oxazol-5-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-methoxy-5-(oxazol-6-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-isopropoxy-5-(oxazol-5-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-isopropoxy-5-(oxazol-5-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-isopropoxy-5-(oxazol-5-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[2-benzyloxy-5-(2-trifluoromethyl-1H-imidazol-1-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[2-benzyloxy-5-(2-trifluoromethyl-1H-imidazol-1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-hydroxy-5-(2-trifluoromethyl-1H-imidazol-1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[5-(1-methyl-1H-1,2,3-triazol-3-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[5-(1-methyl-1H-1,2,3-triazol-3-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;

(3S,5R,6S)-3-[5-(1-methyl- lH- 1,2,3-triazol-3-yl)-2-(trif1uoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[5-(2-methyl-2H-1,2,3-triazol-3-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[5-(2-methyl-2H-1,2,3-triazol-3-yl-2-(trifluoromethoxy)phenyl] -6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[5-(2-methyl-2H-1,2,3-triazol-3-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[5-(pyrid-3-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbony)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[5-(pyrid-3-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro [4.5] dec-3-ene;
(3S,5R,6S)-3-[2-isopropoxy-5-(pyrid-3-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane;
(3S,5R,6S)-3-[2-isopropoxy-5-(pyrid-3-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro [4.5] decane;
(5R,6S)-3-[2-methoxy-5-(1H-1,2,4-triazol-1-yl)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,65)-3-[2-methoxy-5-(lH-1,2,4-triazol-1-yl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
(3S,5R,6S)-3-[2-methoxy-5-(lH-1,2,4-triazol-1-yl)phenyl] -6-phenyl-1-oxa-7-aza-spiro[4.5]decane;
(5R,6S)-3-[5-(pyrimidin-5-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene;
(5R,6S)-3-[5-(pyrimidin-5-yl)-2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;
or a pharmaceutically acceptable salt thereof.

18. A compound as claimed in any preceding claim for use in therapy.

19. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 17 in association with a pharmaceutically acceptable carrier or excipient.

20. 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.

21. A method according to claim 20 for the treatment or prevention of pain or inflammation.

22. A method according to claim 20 for the treatment or prevention of migraine.

23. A method according to claim 20 for the treatment or prevention of emesis.

24. A method according to claim 20 for the treatment or prevention of postherpetic neuralgia.

25. The use of a compound as claimed in any one of claims 1 to 17 for the manufacture of a medicament for the treatment or prevention of a physiological disorder associated with an excess of tachykinins.

26. The use of a compound as claimed in any one of claims 1 to 17 for the manufacture of a medicament for the treatment or prevention of pain or inflammation.

27. The use of a compound as claimed in any one of claims 1 to 17 for the manufacture of a medicament for the treatment or prevention of migraine.

28. The use of a compound as claimed in any one of claims 1 to 17 for the manufacture of a medicament for the treatment or prevention of emesis.

29. The use of a compound as claimed in any one of claims 1 to 17 for the manufacture of a medicament for the treatment or prevention of postherpetic neuralgia.

30. A process for the preparation of a compound as claimed in Claim 1 which comprises:

(A), where m is 1 and n is 1 or 2, reduction of a compound of formula (I) in which the broken line represents a double bond, i.e. a compound of formula (II) wherein R1, R2, R3, R4, R5, R6, R9, R10, p and q are as defined in claim 1; or (B), interconversion of a corresponding compound of formula (I) in which R6 is a hydrogen atom, i.e. a compound of formula (III) wherein R1, R2, R3, R4, R5, R9, R10, m, n, p, q and the broken line are as defined in claim 1 by reaction with a compound of formula (IV):

LG-R6a (IV) where R6a is a group of the formula R6 as defined in claim 1 (other than H) or a precursor therefor and LG is a leaving group; and, if R6a is a precursor group, converting it to a group R6;

(C), where R6 represents a 1,2,3-triazol-4-ylmethyl group substituted by CH2NR7R8, reaction of a compound of formula (V) with an amine of formula NHR7R8; or (D), where R6 represents a C1-6alkyl group which is substituted by an unsubstituted or substituted 1,2,4-triazolyl group, reaction of an intermediate of formula (III) with a compound of formula (VI) wherein Hal is a halogen atom, m is an integer from 1 to 6 and R18 is H, CONH2 or OCH3 (which is converted to an oxo substituent under the reaction conditions), in the presence of a base, followed where necessary by conversion to a compound of formula (I); or (E), by interconversion of a compound of formula (I) into another compound of formula (I);

(F), where p is zero and R3 is a tetrazol-1-yl group, reaction of intermediates of formula (VIII) with ammonium chloride and sodium azide; or (G), a coupling reaction between a compound of formula (IX) and (X) R3-(CH2)p-R41 wherein one of R40 and R41 is B(OH)2 or Sn(alkyl)3 or a derivative thereof, and the other is a leaving group; or (H), where R6 represents a 1,2,3-triazol-4-ylmethyl group substituted by CH2NR7R8, reaction of a compound of formula (XI) with an azide, followed by reduction of the carbonyl group adjacent to -NR7R8 using a suitable reducing agent; or (J), an acid catalysed intramolecular cyclisation reaction of a compound of formula (XXII) or (K), where R6 represents the group -CH2C~CCH2NR7R8, reaction of a compound of formula (XXV) wherein Hal is a halogen atom, with an amine of formula HNR7R8 in the presence of a base, each process being followed, where necessary, by the removal of any protecting group where present;
and when the compound of formula (I) is obtained as a mixture of enantiomers or diastereoisomers, optionally resolving the mixture to obtain the desired enantiomer;
and/or, if desired, converting the resulting compound of formula (I) or a salt thereof, into a pharmaceutically acceptable salt thereof.