CA2245578A1 - Spiro-ketal derivatives and their use as therapeutic agents - Google Patents

Abstract

The present invention relates to compounds of formula (I), wherein R represents hydroxy, C1-6alkoxy, C3-6alkenyloxy, C3-6alkynyloxy, fluoro C16alkoxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, phenoxy, benzyloxy or halogen, wherein the phenyl moiety of said phenoxy or benzyloxy is optionally substituted by one, two or three of C1-6alkyl, C1-6alkoxy, halogen and trifluoromethyl; R1, R2, R3, R4, R5, R6, R9a and R9b are as defined in the specification; or R and R1 may be joined such that -R-R1- is a linkage selected from -O-CH2- and -O-CH2CH2-; m is zero, 1, 2 or 3; and n is zero, 1, 2 or 3; with the proviso that the sum total of m and n is 2 or 3; and pharmaceutically acceptable salts thereof. The compounds are of particular use in the treatment or prevention of pain, inflammation, migraine, emesis and postherpetic neuralgia.

Description

CA 0224~78 1998-08-0~

~PIRO-K~TAL DERIVATIVES AND '1'~1~1~ USE AS
THERAPEUTIC AGENTS

This invention relates to a class of spiroketal compounds which are ~ 5 useful as tachykinin antagonists. The present invention also relates to processes for their preparation, pharmaceutical compositions Cont,S~ining them, and to their use in therapy.
The tachykinins are a group of naturally oc~ulrhlg 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 sequence:
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 (1985) 6(suppl. 3), 237-242). The current nomenclature designates the three tachykinin receptors mediating the biological actions of substance P, NKA and NKB as the NKl, NK2 and NK3 receptors, respectively.
Evidence for the usefulness 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 infl~mmiqtory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, infl~mmatory 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 Receptors and Tachykinin Receptor Antagonists", C.A. Maggi, R.

CA 02245578 l998-08-05 Patacchini, P. Rovero .and A. Giachetti, J. Auton. Pharmacol. tl993) ~, 23-93.
For instance, substance P is believed inter alia to be involved in the neurotr~n.~mi~ion of pain sensations ~Otsuka et al, "Role of Substance P
5 as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "~oes Substance P Act as a Pain Transmitter?" TIPS (1987) ~, 506-510], spe~ific~lly in the tr~n~mi.~ion of pain in migraine (B.E.B. Sandberg et al, 10 eJ. Med Chem, (1982) 25, 1009) and in arthritis [Levine et al Science (1984) 226, 647-549]. Tachykinins have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract such as ;nfl~mm atory bowel disease [Mantyh et al Neuroscience (1988) ~~(3), 817-37 and D. Regoli in "Trends itl Cluster Headache" Ed. Sicuteri et al Elsevier Scientific Publishers, Amsterdam (1987) page 85)] and emesis ~F. D. Tattersall et al, Eur. cJ. Pharmacol., (1993) 250, R5-R6]. It is also hypothesised that there is a neurogenic mech~ni~m for arthritis in which substance P may play a role [Kidd et al "A Neurogenic Mech~ni.~m for. Symmetrical Arthritis" in The Lancet, 11 November 1989 and Gronblad et al, "Neuropeptides in 20 Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J.
Rheurnatol. (1988) 15(12), 1807-10~. Therefore, substance P is believed to be involved in the infl~mmatory response in diseases such as rheumatoid arthritis and osteoarthritis, and ~lbrositis [O'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8l. Other disease areas where tachykinin 25 antagonists are believed to be useful are allergic conditions [Hamelet et al,Can. ~J. Pharmacol. Physiol. (1988) 66, 1361-7], immunoregulation ~Lotz et al, Science (1988) 241~ 1218-21 and Kimball et al, ~J. Im~nu7l01. (1988) 141(10), 3564-9] vasodilation. bronchospasm, reflex or neuronal control of the viscera ~antyh et al, PNAS (1988) ~, 323~-9] andr possibly by 30 arresting or slowing B-amyloid-mediated neurodegenerative changes CA 0224~78 lsss-os-o~
wo 97/30056 PCT/Gs97/00404 ~Yankner et al, Science (1990) 250, 279-82] in senile dementia of the Alzheimer type, ~17h~imer~s disease and Down's Syndrome.
Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular snlall cell lung cancer (SCL~) ~Langdon et al, Cancer Research (1992) 52, 4554-7].
Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et al, poster C.~.N.P. XVIIIth Congress, 28th June-2nd July 1992~, and in disorders of bladder function such as bladder detrusor hyper-reflexia (Lancet, 16th May 1992, 1239).
It has furthermore been suggested that tachykinins have utility in the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersen~ y disorders such as poison ivy, vasospastic diseases such as :~n~in:~ and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy 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 specification no. 0 436 334), ophth~lm~c 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 specification no. 0 394 989).
European patent specification no. 0 577 394 (published 5th January 26 1994) discloses morpholine and thiomorpholine tachykinin receptor antagonists of the general formula R~X~ R4a ~ R2a ~ R5a Rla wherein Rla is a large variety of substituents;

R2a and R3a are inter alia hydrogen;
R4a is inter alia R6Z~

, R

R5a is z,nter al~a optionally substituted phenyl;
5 R6a, R7a and R8a are a variety of substituents;
Xa is O, S, SO or SO2;
ya iS inter alia O; and za is hydrogen or C1 4alkyl.
We have now found a further class of non-peptides which are potent 10 antagonists of tachykinins, especially of substance P.
The present invention provides compounds of the formula (I):

R'~R3 o (C~"

R9b IN 1 RJ
Rs (I) wherein R represents hydroxy, C1 Galkoxy, C3 ¢alkenyloxy, C3.Galkynyloxy, fluoroCl 6alkoxy, C3 7cycloalkoxy, C3 7cycloalkylCI 4alkoxy, phenoxy, benzyloxy or halogen, wherein the phenyl moiety of said phenoxy Ol benzyloxy is optionally substituted by one, two or thrce substituents selected from Cl Galkyl, Cl Galkoxy, halogen and trifluoromethyl;
R1 represents hydrogen, halogen, C1 Galkyl, C~Galkenyl, C~Galkynyl, C3 7cycloalkyl, C3 7cycloalkylCl 4alkyl, Cl.Galkoxy, fluoroCl Galkyl, CA 0224~78 1998-08-0~

fi~uoroCl 6alkoxy, Cl.4alkyl substituted by a Cl ~lko~y or hydroxy group, hydroxy, trimethylsilyl, nitro, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb, NRaRb, SO2NRaRb, or OCl 4alkylNRaRb, where Ra and Rb are each independently hydrogen or Cl 4alkyl;
R2 and R3 each independently represent hydrogen, halogen, Cl 6alkyl, Cl 6alkoxy substituted by Cl 4alkoxy or trifluoromethyl;
or R and R1 may be joined such that -R-Rl- is a linkage selected from -O-CH2- and -O-CH2CH2-;
or, where Rl and R2 are attached to adjacent carbon atoms, they 10 may be joined such that, together with the carbon atoms to which they are attached, there is formed a 5- or 6-membered ring optionally cont~inin~ ~
or 2 heteroatoms selected from oxygen, sulfur or nitrogen, or 1 or 2 groups selected from S(O), S(O)2 and NRa, which ring may also contain 1 or 2 double bonds, where Ra is as previously defined;
R4 represents hydrogen, halogen, Cl 6alkyl, C2 6alkenyl, C2 6alkynyl, C3 7cycloalkyl, C3 7cycloal~ylCl 4alkyl, Cl 6alkoxy, Cl.4alkyl substituted by a Cl 4alkoxy group, trifluoromethyl, nitro, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, CONRaRb where Ra and Rb are as previously defined;
R5 represents hydrogen, halogen, C1 Galkyl, Cl Galkoxy substitutcd by Cl 4alkoxy or trifluoromethyl;
RG represents hydrogen, CORa, CO2Ra, COCONRaRb, COCO2Ra, Cl Galkyl optionally substituted by a group selected from (CO2Ra, CONRaRb, hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONHphenyl(Cl 4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaC1 GalkylRl2, CONRl3C2 Galkenyl, CONRl3C~ Galkynyl, COCONRaRb, CONRaC~NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from C1 Galkyl, Cl (;alkoxy, halogen and trifluoromethyl);
or RG represents a group of the formula -CH2CsCCH2NR7R8 where R7 and R8 are as defined below;

CA 0224~78 1998-08-0~

or R6 represents Cl 6alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring contS3ining 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 6cycloaIkyl;
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 7cycloalkylCl 4alkyl, or C2 4alkyl substituted by Cl 4alkoxy, hydroxyl or a 4, 5 or 6 membered 10 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 for~n 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 1~ Cl~alkoxy or hydroxyl group, and optionally cont~ining a double bond, which ring ~ay 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 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;
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;
R9a and R9b each independently represent hydrogen or Cl 4alkyl, or R9a and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a C6 7 ring;
Rl2 represents ORa, CONRaRb or heteroaryl;
Rl3 represents H or Cl ~;alkyl;
m is zero, 1, 2 or 3; and CA 0224~78 1998-08-0~

n is zero, 1, 2 or 3; with the proviso that the sum total of m and n is 2 or 3;
and pharmaceutically acceptable salts thereo~
A preferred class of compound of formula (I) is that wherein R
5 represents hydroxy, Cl 3alkoxy, C3 salkenyloxy, phenoxy or halogen.
Particularly preferred are those compounds where R represents hydroxy or Cl 3alkoxy, and especially those where R represents hydroxy or methoxy.
Where R represents a phenoxy or benzyloxy substituent the phenyl moiety of each substituent is preferably unsubstituted.
Where R represents a halogen atom, fluorine is preferred.
A preferred class of compound of formula (I) is that wherein represents hydrogen, halogen, Cl Galkyl, C2 6alkenyl, C2.~ialkynyl, C3 7cycloalkyl, C3 7cycloalkylC1 4alkyl, Cl 6alkoxy, Cl 4alkyl substituted by a Cl 4alkoxy group, OCF3, hydroxy, tri~1uoromethyl, trimethylsilyl, nitro, CN, SRa, SORa, SO2Ra, CORa, C02Ra, CONRaRb where Ra and Rb are each independently hydrogen or Cl 4alkyl; and R2 and R3 each independently represent hydrogen, halogen, Cl ~alkyl, Cl ~alkoxy substituted by Cl 4alkoxy or trifluoromethyl Certain particularly apt compounds of the present invention include those wherein Rl is hydrogen, Cl ~alkyl, Cl 4alkoxy, halogen, fluoroC
3alkyl or fluoroCl 3alkoxy.
Most aptly R2 is hydrogen, Cl ~alkyl, Cl 4alkoxy, halogen or CF3.
Most aptly R3 is hydrogen, fluorine, chlorine or CF3 Favourably Rl is hydrogen, Cl 4alkyl, especially methyl, Cl 4alkoxy, especially methoxy, OCF3 Ol CF3.
Favourably R2 is hydrogen, fluorine, chlorine, Cl 4alkyl or CF3, especially hydrogen or CF3.
Favourably R3 is hydrogen.
Preferably R'7 is in the ~-position on the phenyl ring.
Most aptly R~ is hydrogen.
Most aptly R~ is hydrogen, fluorine, chlorine or CF3 Preferably R4 is hydrogen and R5 is 4-fluoro.
Most aptly R9a and R9b are each independently hydrogen or methyl.
Preferably R9a is hydrogen. Preferably R9b is hydrogen. Most preferably R9a and R9b are both hydrogen.
Preferably n is 1.
Preferably m is 1 or 2, especially 1.
Favourably R~ is hydrogen, Cl 3alkyl, especially CHa and CH(CH3), substituted by phenyl wherein said phenyl ring is optionally substituted by Cl salkoxy (especially methoxy) or CF3, or R6 is a group of formula -CH2C--CCH2NR7R8, or R~i is Cl 3alkyl, in particular CH2, CH(CH3) and CH2CH2 and especially CH2, substituted by a 5-membered ring.
In particular, the 5-membered ring is a heterocyclic ring selected from:

H3~ H~ N3/

H i o =~ 7 8 ZNR R

N ZNR R N~/ ; and <~ .
ZNR R ZNR R
Particularly preferred heterocyclic rings are selected from:

CA 0224=,=,78 1998-08-0=, _ 9 _ H N N
0~ ~ i o=( ~ i ~~ ~ i N HN--N H ZNR R

N~/ ; HN~ ~ ; and <~
N ZNR R N ZNR R N--\
ZNR R

Most especially, the heterocyclic ring is selected from:

N ~/ ; and HN
N N ZNR R

One favoured group of compounds of the present invention are of the formula (Ia) and pharmaceutically acceptable salts thereof:
A ~'1 ~~~~ A

N~
6 ~A3 (I~) wherein R and R~ are as defined in relation to formula (I);
Al is hydrogen, Cl 3alkyl, Cl 3alkoxy, halogen, fluoroCl 3alkyl or fluoroCl 3alkoxy;
A2 is hydrogen, halogen, Cl 4alkyl or fluoroCl 3alkyl; and A3 is hydrogen or halogen.

CA 0224~78 1998-08-0~

In particular, Al is preferably hydrogen, methyl, methoxy, OC~F3 or CF3.
In particular A2 is hydrogen, ffuorine or trifiuoromethyl.
In particular A3 is hydrogen or fluorine.
With respect to compounds of the formulae (I) and (Ia), 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 CH2.
With respect to compounds of the formulae (I) and (Ia~, R7 may aptly be a Cl 4alkyl group or a C~4alkyl group substituted by a hydroxyl or Cl 2alkoxy group, R8 may aptly be a Cl 4alkyl group or a Cl 4alkyl group substituted by a hydroxyl or Cl 2alkoxy group, or R7 and R8 may be linked so that, together with the nitrogen atom to which they are attached, they form an azetidinyl, pyrrolidinyl, piperidyl, morpholino, thiomorpholino, piperazino or piperazino group substituted on t~e nitrogen atom by a Cl 4alkyl group or a C2 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 Where the group NR7R8 represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and preferabl~,~
between 7 and 10, ring atoms. Suitable rings include 5-azabicvclo[2.1.1]hexyl, 5-azabicyclo[2.2.1~heptyl, 6-azabicyclo[3.2.1]octyl, 2-azabicycloL2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1~nonyl, 6-azabicyclo[3.2.2]decyl, 7-azabicyclo[4.3.1]decyl, 7-azabicycloL4.4. l]undecyl and 8-azabicyclo L5-4- l]dodecyl, especially 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.
Where R8 represents a C2 4alkyl glOup substituted by a 5 or 6 membered heteroaliphatic ring cont~ining one or two heteroatoms selected fiom N, O and S, suitable rings include pyrrolidino, piperidino, piperazino, CA 0224',',78 1998-08-0', morpholino, or thiomorpholino. Particularly preferred are nitrogen cont~ining heteroaliphatic rings, especially pyrrolidino and morpholino rings.
In the group ZNR7R8, Z is preferably CH2 or CH2CH2, and especially 5 CH2.
The group NR7R8 preferably represents amino, methyl~mino, dimethylamino, diethyl~mino, azetidinyl, pyrrolidino or morpholino.
In particular, NR7R8 is preferably dimethylamino, azetidinyl or pyrrolidino, especially dimethyl ~mino.
Where R and Rl are joined such that -R-Rl- is a linkage, this is preferably -O-CH2-, thereby forming a phthalan ring.
Where Rl and R2, together with the carbon atoms to which they are attached, form a 5- or 6-membered ring optionally cont~ining 1 or ~
heteroatoms selected from oxygen, sulfur or nitrogen, or 1 or 2 groups 15 selected from S(O~, ~(0)2 and NRa, and which ring may also contain 1 or 2 double bonds, it will be appreciated that the ring thus formed may be saturated, partially saturated or unsaturated. Thus, Rl and R2 may represent, for example, -OCH2CH2CH2-, -OCH2CH20-, -OCH2CH2-, -OCH20-, -NRaCH2CH2CH2-, -NRaCH2CH2-, -CH2CH2CH2CH2-, 20 -CH2CH2CH2-, -CH=CH-CH=CH-, -O-CH=CH-, -NRa-CH=CH-, -S-CH=CH-, -NRa-CH=N-, -O-CH=N-, -S-CH=N-, -N=CH-CH=CH-, -CH=N-CH=CH-. Particularly preferred linkages formcd by Rl and R2 include, -OCH2CH2CH~-,-OCH2CH20-,-OCH2CH2-,-OCH20-,-NRaCH CH2CH~-and -CH=CH-CH=CH- In these examples, Ra preferably represents a 25 hydrogen atom.
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 o~ 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, 30 n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

CA 0224~78 1998-08-0~

The cycloalkyl groups referred to herein may represent, ~or example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.
As used herein, the terms "alkenyl" and "alkynyl" as a group or part of a group means that the group is straight or branched. ~,x~mI~les of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propar~yl.
As used herein, the terms "fluoroCl 6alkyl" and "fluoroCl 6alkoxy"
means a Cl 6alkyl or Cl 6alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by a fluorine atom.
Particularly preferred are fluoroC1 3alkyl and fluoroCl 3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially (~F3 and OCF3.
When used herein the term halogen means ~luorine, chlorine, ~5 bromine and iodine. The most apt halogens are ~Luorine and chlorine of which fluorine is preferred.
Specific compounds within the scope of this invention include:
(2R,3S,9R)-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-phenyl-spiro[5.4]decane;
(2R, 3S,gR)-4-aza-4-benzyl- 1, 7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxyphenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl-1,7-dioxa-3-(4-f~uorophenyl)-9-hydroxy-9-(2-(trifluoromethyl)phenyl)spiro[5 4]decane;
(2R,3S,9R)-4-aza-4-benzyl- 1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxy-~:~-(trifluoromethyVphenyl)spiro[5.4]decane;
(2R,3S,9S)-4-aza-4-benzyl- 1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-(trifluoromethoxy)phenyl)spiro[5.4]decane;

3~) (+/-)-(2R*.3S*,9R*~-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9- (2-methylphenyl)spiro[5.4]decane;

CA 0224~78 1998-08-0~

(2R,3S,9R)-4-aza-4-benzyl-1,7-dioxa-9-(2-ethylphenyl)-3-(4-fluorophenyl)-9-hydroxy-spiro [5. 4~ decane;
(2R,3S,9R)-4-aza-4-benzyl-9-(2-chlorophenyl)-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-spiro[5.43decane;
~ 5 (2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-phenylspiro~5.4~ decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxyphenyl)spiro[5.4~decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro [5 .4] decane;
(2R,3S,9S)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxy-5-(trifluoromethyl)phenyVspiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-(tri~luoromethoxy)phenyl)spiro~ 5.4]decane;
(+/-)-(2R~,3S*,9R~)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methylphenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxyphenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-(trifluoromethyl)phenyl)-spiro~5.4]decane;
(2R,3S,9R)-4-aza-4~(4-(N,N-dimethylamino)-but-2-ynyl)-1" -dioxa-3-(4-fluorphenyl)-9-hydroxy-9-(2-methoxy-5-(tri~luoromethyl)phenyl)-spiro~5.4]decane;
(2R, 3S,9R)-4-aza-4-(5-(N,N-dimethylaminomethyl)- 1, 2, 3-triazol-4-yl)methyl-1,7-dioxa-3-(4-fluorophenyl)-9-hydrox~J-9-(2-methoxy-5-(tri~luoromethyl)phenyl)spiro[o.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-4-(l(S)-phenylethyl)-9-(2-(trifluoromethyl)phenyl)spiro[;3.4]decane;

CA 0224~78 1998-08-0~

(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-~luorophenyl)-9-hydroxy-4-(1(R)-phenylethyl)-9-(2-(trifluoromethyl)phenyVspirol5.41decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-4-((2-(tri~Luoromethyl)phenyVmethyl)-9-(2-(trifluoromethyVphenyl)-5 spiro[6.4]decane;
(+/-)-(2R~,3S*,9R~)-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-phenyl-spiro[5.4~decane;
(2R, 3S,9R~-4-aza-4-benzyl- 1, 7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-Inethoxyphenyl)spiro[5.4]decane;
10 (2R,3S,9R)-4-aza-4-benzyl-1,7-dioxa-3-(4-~1uorophenyV-9-methoxy-9-(2-(tri~1uoromethyl)phenyl)spiroL5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxy-5-(trifluoromethyl)phenyVspiror5.4]decane;
(+/-)-(2R*,3S*,9R*)-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-15 9-(2-methylphenyl)spiro~5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl-1,7-dioxa-9-(2-ethylphenyl)-3-(4-fluorophenyV-9-methoxy-spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl-9-(2-chlorophenyl)-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-spiro[5.4]decane;
20 (+/-)-(2R~,3S*,9R*)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-phenyl-spiro[6.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxyphenyl)spiro[5.43decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-25 (trifluorom~thyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-~luorophenyl)-9-methoxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methylphenyl)spiro[6.4]decane;
30 ~2R,3S,9R)-4-aza-1,7-dioxa-9-(2-ethylphenyl)-3-(4-fluorophenyl)-9-methoxy-spiro [5.4] decane;

CA 0224~78 1998-08-0~
WO 97/30~)56 PCT/GB97/00404 (2R,3S,9R)-4-aza-4-(5-(N,N-dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-(5-(N,N-dimethylaminomethyl)-1,2,3-tetrazol-4-yl)methyl- 1, 7-dioxa-3-(4-fluoropheny~)-9-methoxy-9-(2-(trifluoromethyl)phenyl)spiro[5 .4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-4-(1-(S)-phenylethyl)-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-4-(1-(R)-phenylethyl)-9-(2-methoxy-5-~trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyV-9-n:lethoxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)-4-((2-(trifluoromethyl)phenyl)methyl)-spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxy-5-15i (triflu~r~n~eth~ll)phenyl)-4-((~-(tri~1uoromethyl)phenyl)meth~zl)-spiro[5.4]decane;
(2R, 3S,9R)-4-aza- 1, 7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-4-((2-methoxyphenyl)methyl)-9-(2-methoxy-5-(trifluoromethyl)phenyl) spirol5.4]decane;
(2R,3S,9R)-9-allyloxy-4-aza-4-benzyl- 1,7-dioxa-3-(4-fluorophenyl3-9-phenyl-spiro [5.4]decane;
(2R, 3S, 9R) -4-aza-4-benzyl- 1, 7-dioxa-3- (4-fluorophenyl)-9-p henyl-9-(phenylmethyloxy)spiro[5.4]decane;
(2R,3S,9R)-4-aza- 1, 7-dioxa-3-(4-fluorophenyl)-9-phenyl-9-propyloxy-spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl-1,7-dioxa-9-fluoro-3-(4-fluorophenyl)-9-phenyl-spiro[5.4]decane;

CA 0224~i~i78 1998-08-O~i WO 97/3~056 PCT/GB97/00404 - 16 ~

(2R,3S,9R~-4-a~a-1,7-dioxa-g-~uoro-3-(4-fluorophenyl)-9-phenylspiro[5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-(hydroxymethyl)phenyl)spiro[~.4~decane;
~; [2'R- [2'a(S*), 4~CC]~ 3r~ -(4-fluorophenyl)-4"-(phenylmethyl)dispiro-[isobenzofuran- 1 (3H~, 4' (5rH)-furan-2' (3~:1), 2" -morpholine];
[2r~-[2'a(S*),4roc]]-3"-(4-fluorophenyl)dispiro[isobenzofuran- 1(3~),4'(5 furan-2' (3~ 2~r -morpholine~;
and pharmaceutically acceptable salts thereof.
In a further aspect of the present invention, the compounds of formula (I) will preferably be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention incluae acid addition salts which may, for example, be formed by mi~ing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, 2~ 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 ~lk~3line earth metal salts, e.g. calcium or magnesium salts.
The salts may be formed by conventional means, such as by reacting the ~ree base form of the product with one or more cquivalents of the CA 0224~78 l998-08-0~

appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed i7?, vacuo or by freeze drying or by e~ h~nging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I).
Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for exa~nple, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation i7t vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
The compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The preferred compounds of the formula (I) and ~Ia) will have the preferred stereochemistry of the ~-, 3- and 9-positions that is possessed by the compound of 3xample 1 (2R,3S,9R). Thus for example as shown in formula (Ib) CA 0224~78 1998-08-0~

o (c~R3 ~ ~j~ (CH ~)m 9b J' N ~ ""'~ R4 (Ib) The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in 5 association with a pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal a~rnini.qtration, or administration by inhalation or insufflation.
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 acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a so~id preformulation 15 composition cont~3ining a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof 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 20 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~ining from 0.1 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 CA 0224~78 1998 - 08 - o~

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 5 resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A 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 suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and simil~r pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include those comprising a compound of formula (I), as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or 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. ~weenTM 20, 40, 60, 80 or 85) and other sorbitans (e.g. SpanTM 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 mannitol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions mav be prepared using commercially available fat emulsions, such as IntralipidTM, LiposynTM, InfonutrolTM, LipofundinTM

CA 0224C7C778 1998-08-0C, and LipiphysanT~. 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~inE~ with a phospholipid (e.g. egg 5 phospholipids, soybean phospholipids or soybean lecithin) and water. It 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 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and 1.0~Lm, particularly 0.1 and 0.5,um, and have a pH in the range of 5.5 to 8Ø
Particularly preferred emulsion compositions are those prepared by mi~in~ a compound of formula (I) with IntralipidTM or the components thereof (soybean oil, egg phospholipids, glycerol and water).
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
Preferably the compositions are a(1rnini~tered by the oral or nasal 20 respiratory route for local or systemic effect. C~ompositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directl~ fiom the neb~ in~ device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, 25 suspension or powder compositions may be administered, pleferably orallv or nasall~, from devices which deliver the formulation in an appropriate manner.
The present invention futher provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), 30 which process comprises bringing a compound of formula (I) into association with a pharmaceutically acceptable carrier or excipient CA 0224~78 l998-08-0~

The compounds o~ 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 tachykinin, and in particular 5 substance P, activity is implicated in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and 10 cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, .
speclfic phoblas, for example, speclfic ~nlmf.l phoblas, soclal phoblas, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety 15 disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; delerium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as 20 Alzheimer's disease, senile dementia, dementia of the Al~heimer's type, vascular dementia, and other dementias, for example, 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-pyrz3mi-1z3l movement disorders such as 2~ medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induccd acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour; substance-related disorders arising ~rom the use of alcohol, amphetamines (or amphetamine-30 like substances) caffeine, cannabis, cocaine, hallucinogens, inh~l~nts andaerosol propellants, nicotine, opioids, phenylglycidine derivatives, CA 0224~78 1998-08-0~

sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, intoxication, withdrawal, intoxication delerium, withdrawal delerium, persisting dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders;
5 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 neuropathy, and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; and cerebral vascular disorders due to acute or chronic 10 cerebrovascular damage such as cerebral infarction, subarachnoid haemorrhage or cerebral oedema.
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 15 conditions in which pain predominates, including soft tissue and peripheral fl~m~ge, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, dental pain, myofascial pain syndromes, headache, episiotomy pain, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, 20 orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorlhoea, 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, 25 nerve root damage, and arachnoiditis; pain associated with carcinoma, 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 p ain .
Tachykinin, and in particular substance P, antagonists may also be 30 of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive CA 0224~78 1998-08-0~

airways disease, bronchopneumonia, chronic bronchitis, cystic fi~rosis and asthma, adult respiratory distress syndrome, and bronchospasm;
infl~mmz~tory diseases such as infl~mm~tory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn;
5 allergies such as eczema and rhinitis; hypersen~i~ivi~y disorders such as poison ivy; ophth~lmi~ diseases such as conjunctivitis, vernal conjunctivitis, and the like; ophth~lmi~ conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other 10 eczematoid dermatitis.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganglioblastomas and small cell carcinomas such as small cell lung cancer.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including infl~mm~tory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, Crohn's 20 disease, irritable bowel syndrome and emesis, including acute~ delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo, dizziness and Meniere's disease, surgery, migraine, variations in intercranial pressure, gastro-oesophageal 2O 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 30 related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological reactions such as CA 0224~78 1998-08-0~

rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus;
plasma extravasation resulting from cyto3~ine chemotherapy, disorders of 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 ~n~n~3, 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~ n of pain in 10 migraine.
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 1~ treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula (I) are of use in the treatment of emesis induced by antincoplastic (cytotoxic) 20 agents including those routinely used in cancer chemotherapy, and emesis induced by other pharmacological agents, for example, rolipram.
Examples of such chemotherapcutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as 26 nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, ~olic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinca alkaloids and derivatives of podophvllotoxin; and cytotoxic antibiotics.
Particular examples of chemotherapeutic agents are described, for 30 instance, by D. J Stewart in l~ausea a7~d Vol7titi7lg: Rece77,t Research and Cli7licaZ Adva7~ces, Eds. J. ~ucharczyk et al, CRC Press Inc., Boca Raton CA 0224~78 1998-08-0~

- 2~ -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 (CCNU), doxorubicin 5 (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al in Cancer Tr~atment Reports (1984) 68(1),163-172~.
The compounds of formula (I) are also of use in the treatment of 10 emesis induced by radiation including radiation therapy such as in the treatment of cancer, or radiation sickness; 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 15 preparation for simultaneous, separate or sequential use for the relief of emesis. ~uch combined preparations may be, for example, in the form of a twin pack.
A further aspect of the present invention comprises the compounds of formula (I) in combination with a 5-HT3 antagonist, such as 20 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 administered in combination with an anti-infl~mmatory corticosteroid, such as dexamethasone, triamcinolone, 2a triamcinolone acetonide, flunisolide, budesonide, or others such as those disclosed in ~S patent nos. 2,789,118,2,g90,401,3,048,581,3,126,375, 3,929,768,3,996,359,3,928,326 and 3,749,712. Dexamethasone (DecadronTM3 is particularly preferred. Furthermore, a compound of formula (I) may be administered in combination with a chemotherapeutic 30 agent such as an alkylating agent, antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as described above. In general, the currently available CA 0224~78 1998-08-0~
WO 97/300~;6 PCT/GB97/00404 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, R6-5 R6, the compounds of the present invention were found to attenuate theretching and vomiting induced by cisplatin.
The compounds of formula (I) are also particularly useful in the treatment of pain or nociception and/or infl~ m m ~tion and disorders associated therewith such as, for example, neuropathy, such as diabetic 10 and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis, headache and especially migraine.
The present invention further provides a compound of formula (I) for use in therapy.
According to a further or alterIlative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a me~ m.?nt for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.
The present invention also provides a method for the the treatment 20 O1 prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises at1ministration 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).
2~ For the treatment of certain conditions it may be desirable to employ a compound according to the present invention in conjunction with another pharmacologically acti~e agent. For example, for the treatment of respiratorY diseases such as asthma, a compound of formula (I) may be used in conjunction with a bronchodilator, such as a ~2-adrenergic receptor 30 agonist or tachykinin antagonist which acts at NK-2 receptors. The CA 0224~78 1998-08-0~

compound of formula (I) and the bronchodilator may be arlmini~tered to a patient simultaneously, sequentially or in combination.
Likewise, a compound of the present invention _ay be employed with a leukotriene antagonists, such as a leukotriene D4 antagonist such as a compound selected from those disclosed in European patent specification nos. 0 480 717 and 0 604114 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 10 treatment of a respiratory disease, such as asthma, which method comprises a(lmini.~tration to a patient in need thereof of an effective amount of a compound of formula (I) and an effective amount of a bronchodilator.
The present invention also provides a composition comprising a 16 compound of formula (I), a bronchodilator, and a pharmaceutically 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 ergotamines or 5-~Tl agonists, 20 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 in~mm~tory conditions in the 2~ lower urinary tract, especially cystitis, a compound of the present invention may be used in conjunction with an antiinfl~3mmatory agent such as a bradykinin 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 30 conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs and. in particular, opioid analgesics, especially CA 0224~78 1998-08-0~
WO 97/30056 PCT/GB97/01~404 morphine. Specific anti-;nfl~mm~tory agents include diclofenac, ibuprofen, indometh~in, ketoprofen, naproxen, piroxicam and sulindac.
Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof. Preferred salts of these opioid analgesics include morphine sulphate, morphine 10 hydrochloride, morphine tartrate, codeine phosphate, codeine sulphate, dihydrocodeine bitartrate, diacetylmorphine hydrochloride, hydrocodone bitartrate, hydromorphone hydrochloride, levorphanol tartrate, oxymorphone hydrochloride, alfentanil hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate, meperidine 15 hydrochloride, methadone hydrochloride, nalbuphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate (2-naphthalenesulphonic acid (1:1) monohydrate), and pentazocine hydrochloride.
Therefore, in a further aspect of the present invention, there is 20 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 25 analgesic as a combined preparation for simultaneous, 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 reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), CA 0224=,=,78 1998-08-0=, ~nonoamine oxidase inhibitors ~MAOIs), reversible inhibitors of monoamine oxidase (RIMAs~, serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, a-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:
10 amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.
Suitable selective serotonin reuptake inhibitors include: fluoxetine, fluvo~ ine, paroxetine and sertraline, and pharmaceutically acceptable salts thereo~
16 Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof.
Suitable reversible inhibitors of monoamine oxidase include:
moclobemide, and pharmaceutically acceptable salts thereof.
Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venl~f:~ine, and pharmaceutically acceptable salts thereof Suitable CRF antagonists include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO
25 94/13661, WO 94/13676 and WO 94/13677.
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 30 5-HTIA agonists or antagonists, especially 5-HTlA partial agonists, and corticotropin releasing factor ((~RF) antagonists.

CA 0224~78 1998-08-0~

Suitable benzodiazepines include: alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereof.
Suitable 5-HTlA receptor agonists or antagonists include, in particular, the 5-HTlA receptor partial agonists buspirone, ~le.sino~n, gepirone and ipsaperone, and pharmaceutically acceptable salts thereo~
Therefore, in a further 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 10 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 anti-depressant or anti-anxiety agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention 15 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.qing the risk of unwanted side effects.
In the treatment of the conditions associated with an excess of 20 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.ssion of pain sensations, a suitable dosage level is about 25 0.001 to 25 mg/kg per day, preferably about 0.005 to 1~ mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be a(lmini.~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 formulation, a 30 suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 1 mg/kg per day. The CA 0224~78 l998-08-0~

compounds may be afln~ini.~tered 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 5 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 discretion of the attendant physician.
According to a general process (A), compounds of formula (I) 10 wherein R is a hydroxy group, may be prepared from a compound of formula (II) o (CH2)"
R9a 0 ~ O
~ (CH2)m 9b J~ N '~~ ~ R4 (II) 15 wherein R~, R5, RG, R9a, R9b, m and n are as defined in relation to formula ~.
(I) by reaction with a Grignard or organolithium compound of formula ~IIIA) or (IIIB) ~M~Hal RZ

R R
(IIIA) (IIIB) wherein Rl, R2 and R3 are as defined in relation to formula (I) and Hal is a halogen atom, for example, chlorine, bromine or iodine, especially a bromine atom.

= ~

Both reactions are effected under conventional conditions, for instance, in a suitable solvent such as an ether, e.g. tetrahydrofuran, at a temperature between -90~ and -60~C, with subsequent quenching using, for example, saturated ammonium chloride solution.
According to a general process (B), compounds of formula (I) wherein R is a group selected from Cl ~alkoxy, C3 Galkenyloxy, C3.6alkynyloxy, fluoroCl 6alkoxy, C3 7cycloaIkoxy, C3 7cycloalkylCl 4alkoxy, phenoxy or benzyloxy, may be prepared from the corresponding compound of formula (I) in which R is a hydroxy group, hereinafter referred to as 10 compounds of formula (IV~

Rl~R3 o--(CH,/ ~, R9b 7 " R4 R
(I~

by reaction with a suitable alkyl halide, alkenyl halide, alkynyl halide, 15 ~luoroalkyl halide, c~Tcloalkyl halide, cycloalkylalkyl halide, phenyl halide or benzyl halide.
The reaction is conveniently effected in the presence of a base such as an alkali metal halide, for example, sodium hydride in a suitable solvent, for example an organic solvent such as N,N-dimethylformamide, 20 preferably at a temperature between 10~C and 50~C, conveniently at room temperature.
According to another general process (C), colnpounds of formula (I) wherein R is a halogen atom~ may be prepared from a corresponding compound of formula (IV) by reaction with a suitable halogenating CA 0224~78 1998-08-0~

reagent. Thus, for example, compounds wherein R is Muorine may be prepared by reaction with diethylaminosulfur trifluoride, the reaction being effected in a suitable organic solvent such as a halogenated hydrocarbon, for example, dichloromethane, at a temperature between -90~C and -60~C, for example, at about -78~C.
According to another general process (D), compounds of formula (I) wherein R6 is H may be prepared from the corresponding compound of formula (I) in which RG is a benzyl group. The reaction may be effected, for instance, under conventional conditions of catalytic hydrogenation using a palladium or platinum catalyst or an oxide thereof, the reaction being effected in a suitable solvent such as an alcohol, for example, methanol, conveniently at room temperature.
According to a further general process (E), compounds of formula (I) may be prepared from the corresponding compound of formula (I) in which R~ is H, hereinafter referred to as compounds of formula (V) Rl~R3 ~ (CH~)n~
9b ~ N ~ \~ R4 ~R5 (V) wherein R, Rl, R~, R3, R'l, R;~, R9a, R9b, m and n are as defined in relation to formula (I), by reaction with a compound of formula LG-RG~ (VI) where RG" is a group of the formula RG as defined in relation to formula (I) or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g.
brornine, chlorine or iodine); and, if RGa is a precursor group, converting it to a group R6 (in which process any reactive group may be protected and thereafter deprotected if desired).
6 This reaction may be performed in a conventional ms~nn~r, for example in an organic solvent such as dimethylform~m;de in the presence of an acid acceptor such as potassium carbonate.
According to another process (F), compounds of formula (I) wherein R6 represents a 1,2,3-triazol-4-ylmethyl group substituted by C~2NR7R8, 10 may be prepared by reaction of a compound of formula (VII) Rl~R3 O (C>~

J ~ R4 ~/ R~

N3 (VII) with an amine of formula NHR7R8, in a suitable solvent such as an ether, 15 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.
According to a further process (G), compounds of formula (I) wherein RG represents a Cl Galkyl group which is substituted by an unsubstituted 20 or substituted 1,2,4-triazolyl group, may be prepared by reaction of an intermediate of formula (V) with a compound of formula (VIII) CA 0224~78 1998-08-0~

lG J~ ~ ( CH, ) p H~ll (VIII~
-w-herein ~al is a halogen atom, foL example, bromille~ chloli~ïe o-l= iOuir~e, p is an integer from 1 to 6 and Rl8 is H, CONH2 or O~H3 (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), for example, by reduction of the CONH2 group to CH2N~I2.
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 10 dimethylformamide, preferably at elevated temperature, such as about 140~C.
A suitable reducing agent for the group CONH2 is lithium aluminium hydride, used at between -10~C and room temperature.
According to a further process (H), compounds of formula (I) may 15 also be prepared from other compounds of formula (I) using suitable interconversion procedures. In particular, interconversion processes may be used to vary the group RG. For example, compounds of formuIa (I) wherein RG is other than H may be prepared from the corresponding compounds of formula (I) wherein RG is ~I by reaction with a reagent ~0 suitable to introduce the group RG, for example, compounds of formula (I) wherein RG is CORa may be prepared from compounds of formula (I) wherein RG is H by, for example, reaction with an appropriate acid - anhydride.
Compounds of formula (I) wherein RG is Cl ~,alkyl may be prepared 25 fiom corresponding compounds of formula (I) wherein RG is CORa by reduction using, for example~ borane or a boroh~dride such as sodium cyanoborohydride Compounds of formula (I) wherein R6 is Cl 6alkyl substituted by CONRaRb may be prepared from corresponding compounds of formula (T) wherein R6 is Cl 6alkyl substituted by CO2Ra by treatment with ammonia or an amine of formula NRaRb.
Compounds of formula (I) wherein R~ is Cl 6alkyl substituted by 5-oxadiazolyl may be prepared from compounds of formula (I) wherein R6 is Cl 6alkyl substituted by CO23~a, where Ra represents Cl 6alkyl, by reaction with a compound of formula (IX) NOH

(IX) wherein R32 represents H or a suitable substituent, in the presence of a base.
Suitable bases of use in the reaction include alkali metals, such as, 15 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 20 solvents will include alcohols, for example, ethanol, whereas where the base used is an alkali hydride, suitable solvents will include ethers, for example, tetrahydrofuran.
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 Galkyl substituted by thiazolyl may be prepared from compounds of formula (I) wherein RG is Cl Galkyl substituted by CSNH2 by reaction with a compound of formula Hal-CH2C(O)-RG~, where Hal is a halogen atom, such as brornine, chlorine or iodine, and RG~ represents H Ol a suitable substituent.

Compounds of formula (I) wherein RG is Cl 6alkyl substituted by thioxotriazolyl may be prepared from compounds of formula (I) wherein R6 is Cl 6alkyl substituted by CONHNHa by reaction with a compound of formula R6lNCS, wherein R6l represents H or a suitable substituent such 5 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 conveniently effected in a suitable organic solvent, such as alcohol, e.g.
butanol.
According to another general process (J), compounds of formula (I) wherein R6 represents the group -CHaC_CCH2NR7R8, may be prepared from a compound of formula (X) 9a o (C~
~ (CHy)m Rgb~J ~ \~

~ R~
Hal wherein Hal is a halogen atom such as chlorine, bromine or iodine, by reaction with an amine of formula HNR7R8 in the presence of a base.
Suitable bases of use in the reaction include alkali metal carbonates 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.
Intermediates of formula (II~ may be preparcd by the oxidation of a compound of formula (XI) O (c~
~ (CHy)m R9~ ~ Nl / ~ R4 (XI) under conventional conditions for the oxidation of a secondary alcohol.
Particularly preferred are the conditions of the Swern oxidation, i.e.
dimethylsulfoxide and oxalyl chl~ride, which reaction is conveniently 5 effected in a halogenated hydrocarbon such as dichloromethane, preferably at a temperature below -70~C.
Compounds of formula (XI) may be prepared from a compound of formula (XII) HO
(CHy)n 9a OH
~ (CHy)m R9b N --~R4 (XII) 10 by an acid catalysed intramolecular cyclisation reaction.
Suitable acids of use in the reaction include mineral acids such as, for example, hydrochloric acid. The reaction is conveniently effected in a suitable organic solvent, such as an alcohol, for example, methanol, at elevated temeprature, for example, at the reflux temperature of the chosen 1 5 solvent.
Intermediates of formula (XII) wherein n is 1 may be prepared by the hydroxylation of a compound of formula (XIII):

CA 02245C~78 1998-08-05 R9a ~ ~ CH2 ~ (CH2),,~

R9b~7~ \~R4 R6 ~
RJ
(XIII) using conventional methodology, for instance, using osmium tetroxide and N-methylmorpholine-N-oxide, preferably in an inert solvent such as an ether, for example, tetrahydrofuran, or an alcohol, for example, isobutyl 5 alcohol, or water or a mixture thereof, conveniently at room temperature.
Compounds of formula (XIII~ may be prepared by the reaction of a compound of formula (XIV):
R~ O ~ O

R9b 1 ~ R4 (XLV) with a compound of formula (XV):
~ MgCl ~ (CH.~) ,, (XV) using conventional Grignard conditions, for example, the reaction being effected in a solvent such as an ether, e.g. tetrahydrofuran, at reduced temperature, for examplc, at -78~C.
Compounds of formula (XIV) may be prepared by methods described in European Patent Specification No. 0 577 394-A, or by analogous methods.
Compounds of formula (~1) are known compounds.
Intermediates of formula (~TII) may be prepared from a compound of formula (X) by reaction with an azide, for example, sodium azide in a CA 0224=,=,78 1998-08-0=, suitable solvent such as dimethylsulphoxide at or below room temperature.
Compounds of formula (X~ may be prepared by a dropwise addition of an intermediate of formula (V) to a dihaloacetylene of formula 5 Hal-CH2-C_C-CH2-Hal where each Hal is independently chlorine, bromine or iodine, especially chlorine. The reaction is conveniently effected in a suitable solvent such as dimethylform~mi-le in the presence of a base such as potassium carbonate.
Compounds of formula (VIII) may be prepared as described in cT. Med. Chem., (1984) 27, 849.
For compounds wherein R6 is a (:~l 6alkyl group substituted by a 5-membered heterocycle which in turn is substituted by a ZNR7R8 group where Z is (~H2, certain favoured compounds of for~ula (I) may be prepared from a corresponding compound with a hydrogen atom in place of 15 the ZNR7R8. Thus, for example a compound of the formula (I) wherein R~
is an imidazolinone group carrying a CH2NR7R8 moiety may be prepared from a corresponding compound lacking the CH2NR7R8 moiety by reaction with formaldehydc and an amine NHR7R8 under conventional M~nnich reaction conditions, for example in methanol with heating. If desired a 20 pre-formed reagent such as R7R8N+=CH2.I- may be employed and a tertiary amine such as triethylamine used as acid acceptor.
Alternatively a compound of formula ~I) wherein RG is a Cl ~,alkyl group substituted by an imi~l~701inone group may be reacted with paraformaldehyde and an amine for example a secondary amine such as 25 pyrrolidine or morpholine to give a compound wherein the imicl~olinone ring is substituted by CH2NR7R8 where R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of ~ to 7 ring atoms which may optionally contain an oxygen ring atom or a second nitrogen atom which will be part of a N~ or NRC moiety, where Rc is as previously 30 defined.

CA 0224~78 l998-08-0~
WO 97/30056 PCT/GBg7/00404 This reaction may be performed in a conventional manner, 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 compounds of formula (I) involves the reaction of an intermediate of formula (-V) as de~ined above with one of the compounds of formuia (~vïj:

LG ~ G LC~

~ ~ ~ N N ,/ (CH2)"
(a) ~L~ ~= ~ z H (c) HN ~

LG LG LG
(XVI) wherein each LG, which may be the same or different, is a leaving group, 10 such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or, in particular, a halogen atom, (e.g. bromine, chlorine or iodine), q is an integer from 1 to 6 and Z are 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 dimethylformamide in the presence of an acid acceptor such as potassium carbonate.
It will be appreciated that, whcre necessary, reactive groups may be protected, thus for example, the NH groups of an imidazolinone of formula 20 (XIIa) may be protected by any suitable amine protecting group such as an acetyl group.
- It will be further appreciated that ~imil~r methodology may be used for the preparation of compounds where the group ZNR7R8 is absent.
(~ompounds of formulae (IIIA) and (IIIB) are either known 2O compounds or may be prepared from a corresponding compound of formula (X~II) WO 97/300!;6 PCT/GB97/00404 ~R

Hal (XVII) wherein Hal is a halogen atom, for example, chlorine, bromine or iodine, especially bromine, using conventional conditions for the synthesis of Grignard reagents or organolithium reagents.
An alternative convenient method for the preparation of compounds of formula (II), in which n is 1, is that illustrated by Scheme A, below, or using methods analogous thereto:

Scheme A
Rsa OPh OPh R9bXNJ~ R4 ~ / IgCl R9~o~ ~=CH~

R (c.f. Louw et al .~\ ~
R5 TetrQhedrolt, (i992) R9b ~l ~ ~ --R4 48: ~087-(;104) R6 ~X
(XIV) R5 n-BuLi ZnCL>

(Ph3P)4.Pd(o) R ~O~ I ~>co ozone/O~~ O
R '~ ~ (CE13)~5 R ~ \ R4 (II) It will be appreciated that compounds of the formula (I) wherein RG
contains an =O or =S substituent can exist in tautomeric forms. All such CA 0224~78 1998-08-0~

tautomeric forms and mixtures thereof are included within this invention.
Most aptly the =O or =S substituent in R~; is the =O substituent.
- Where they are not commercially available, the intermediates offormula (VI) above may be prepared by the procedures described in the accompanying l~xamples 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, Protectiue 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.
Further methods suitable for adaptation to the preparation of the spiroketal compounds of the present invention are described by F. Perron and K.F. Albizati in Chem. ~ev., (1989) ~, 1617-1661.
The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No.
WO 93/01165 The compounds or, in the case of prodrugs, the parent compounds, were found to be active with IC50 at the NKI receptor of less than l~M on said test method.
For the avoidance of doubt, the nomenclature adhered to throughout this specification is based upon the following structures:
2~
3' - 2'~4' G' G nd ,~ G' r.

N ' ',, R"

The following non-limiting Examples serve to illustrate the preparation of compounds of the present invention:

(2R,3S)-4-Benzvl-3-(4-fluorophenvl)-2-hvdroxY-2-(Prop-2-envl)mor~holine (3S)-4-Benzyl-3-(4-fluorophenyl)-2-morpholinone (see International Patent Specification No. WO 95/18124) (13.6g, 47.6mmol) was dissolved in anhydrous tetrahydrofuran (200ml) and cooled to below -70~C under an inert atmosphere. Allyl magnesium chloride (26.2ml of a 2.0M solution in tetrahydrofuran; 52.4mmol) was added dropwise over 15 minutes, maint~inin~ the temperature below -70~C~. After 30 minutes, the reaction was quenched by the addition of a saturated solution of ammonium chloride and allowed to warm to room temperature. The resulting suspension was extracted with ethyl acetate (3xlOO~nl), and the combined organic extracts dried ~MgSO4) and concentrated in vacuo to yield the title compound in ~3:1 mixture of the lactols as a light yellow oil (15.3g, 98%), which was used without further purification. m/2~ (ES+) 328 (M+l, 22%), 310 (M-OH, 61), 269 (100).

(2R,3S) -4-BenzYl-2-(2,3-dihvdroxY~ProPYl-3-(4-fluorophenvl) -2-hydroxvmorpholine The alkene of Description 1 (18.9g, 57.7mmol) was stirred with 2~ osmium tetroxide (0.2g, 0.8mmol) and N-methylmorpholine N-oxide (7.78g, 6~.4mmol) in a solution of tetrahydrofulan (200mV, 2-methyl-2-propanol (120ml) and water (14ml) for 3 days at room temperature. Thc resulting black solution was diluted with ethyl acetate (200ml), water (200ml) and saturated brine (lOOml), separated and the organic fraction dried (MgSO4) and concentrated i7Z, vacllo. The resulting black oil (26g) was purified by flash silica gel chromatography eluting with ~0-100%

CA 0224=,=,78 1998-08-0=, ethyl acetate in hexane to yield the title compound as a mixture of isomers as a white foam (15.9g, 76%). Analysis Found: C, 65.22; H, 6.74; N, 3.68.
C20H24FNO4Ø5 H20 requires C, 64.84; H, 6.82; N, 3.78% m/z (ES+) 362 (M+1, 18%), 344 (l~-OH, 100).
DESCRIPTIONS 3A and 3B
(2R,3S ,9RO-4-Aza-4-benzvl- 1,7-dioxa-3-(4-fluorol~henyl) -9-hYdroxYspiro~5.41decane; and (2S,3S,9RS)-4-Aza-4-benzvl-1,7-dioxa-3-(4-fi uorophenYl) -9-hvdroxvspiro ~5.41 decane The mixture of triols of Description 2 (15.0g, 41.5mmoV was dissolved in hydrochloric acid (200ml, 6M), and methanol (lOOml) and heated at re~lux for 5 hours. The cooled solution was basified with 4N
sodium hydroxide solution and extracted with ethyl acetate (3x200ml).
The combined organic extracts were dried (MgS04) and concentrated i71 vacuo. The resulting black oil (18g) was purified by ~lash silica gel chromatography eluting with 33-66% ethyl acetate in hexane to yield the title compounds as pairs of diasteromers. The less polar isomer pair ~Description 3A), was obtained as an orange gum (7.1g, 50%). Rf 0.37 (50~/0 ethyl acetate/hexane). lH NMR (360MHz, CDCl3) ~ 0.42 (~l/2H, d, J=10.4Hz)*, 1.69 (l/2H, dd, J=13.5, 5.5Hz), 1.86 (l/2H, d, J=14.6Hz), 1.96 (l/2H, d, J=13.6Hz), 2.15 (l/2H, dd, J=14.6, 6.4Hz~, 2.30 (lH, dt, J-12.0, 3.6Hz), 2.76 (lH, d, J=13.1Hz), 2.79 (lH, d, J=13.2Hz), 3.11 (~l/2H, d, J=11.2Hz)*, 3.34 (lH, d, J=14.2Hz), 3.35-3.71 (3H, m), 3.91 (7/2H, dd, J=9.7, 3.6Hz), 3.98-4.24 (2l/2H, m), 7.01 (2xl/2H, t, J=8.8Hz), 7.08 (2xl/2H, t, J=8.7Hz~, 7.18-7.29 (5H, m), 7.54 and 7.63 (2H, 2xbr s) ~* exchanges in D~O); m,/~ (ES+) 344 (M+1, 100%).
The more polar isomer pair (Description 3B) was obtained as an orange glass (4.3g, 30%). Rf 0.25 (50% ethyl acetate/hexane). lH NMR
(360MHz, CDCl3) ~ 0.83 (2/3H, br d)*, 1.64 (l/3H, dd, J=14.0, 5.7Hz), 1.87 (2/3H, d, J=14.6Hz), 2.02 (l/3H, J=14.0Hz), 2.15 (2/3H, dd, J=14.6, 6.6Hz), 2.32-2.41 (lH, m), 2.74-2.82 (lH, m), 3.03 (l/3H, d, J=ll.OHz)*, 3.14 (2/3H, CA 0224~78 1998-08-0~

d, J=13.7Hz), 3.17 (l/3H, d, J=13.7Hz), 3.50 (l/3H, d, J=13.6Hz), 3.59 (2/3H, d, J=13.7Hz), 3.66-4.16 ({~l/3H, m), 4.33 (2/3H, br s), 7.00-7.09 (2H total, m),7.21-7.31 (5H, m), 7.41-7.52 (2H total, m) (* e~f~h~nges in D2O); m/z (ES+) 344 (M+~, 100%).
DESCRIPI'ION 4 (2R~3S)-4-Aza-4-benzYl-1.7-dioxa-3-(4-fluoro~henYl)-9-oxospLro~5.4]decane Anhydrous dimethylsulphoxide (3.4ml, 47.8mmol) dissolved in dichloromethane (lOml) was added dropwise over 10 minutes to a solution of oxalyl chloride (2.0ml, 22.9mmol) dissolved in anhydrous dichloromethane (200ml) cooled to below -70~C. The temperature was m~int~ined below -60~C during the addition and the solution stirred for a further 15 minutes at below -70~C. The alcoho~ isomer pair A (Description 3A) (6.57g, l9.1mmol) dissolved in dichloromethane (40ml) was added dropwise over 10 minutes, maint~ining the temperature below -70~C, and then stirred at this temperature for one hour. Triethylamine (13.3ml, 95.5mmol) was added dropwise over 10 minutes, and the reaction allowed to warm to room tempcrature. The resulting mixture was washed with dilute sodium bicarbonate solution (0.2M) and water (200ml) and the organic fraction dried (MgSO4) and concentrated i71 ~acuo (7.9g). The crude product was purified by flash silica gel chromatograph~ eluting with 14-20% ethyl acetate in hexane to yield the title compound as a pale yellow glass which solidified to a buff coloured solid on standing (5.2g, 80%). Analysis Found: C~, 70.29; H, 5.83; N, 4.02. C70H20FNO3 requires C, 70.37; H. 5.91; N, 4.10%. La]22D=+125.6 (c=1.04, CH7~12); lH NMR
(360MHz, CDCl3) ~ 2.31 (2H, d, J=3.0Hz), 2.35 (lH, dt, J=12.0, 3.5Hz), 2.80 (lH, d, J=12.9Hz), 2-.~3 (lH, br d, J=ll.OHz), 3 a2 (lH, s), 3.59 (lH, dq, J=10.1, 1.6Hz), 3.68 (lH, d, J=13.2Hz), 3.88 (lH. d, J=16.6Hz), 4.03 (lH, d, J=16.6Hz), 4.18 (lH, dt, J=11.7, 2.aHz), 7.0a ~lH, t, J=8.7Hz), 7.19-7.32 (5H, m), 7.58 (2H, br s); 7lt/_ (~S+) 342 (M+l, 100%).

CA 0224~78 1998-08-0~

(2R,3S.9R)-4-Aza-4-(4-chlorobut-2-vnYl)- 1,7-dioxa-3-(4-fluorophenYl)-9-hvdroxY-9-(2-methoxy-5-(trifluoromethYl)phenYl~sPiro [5.4l decane A solution of 1,4-dichlorobutyne (l96~11 2.0mmol) in DM~ (30ml) and potassium carbonate (709mg, 5.13mmol) was heated to 60~C. The morpholine of Example 12 ~731mg, 1.71mmol) as a solution in DMF (lOml) was added dropwise over 5 minutes and the reaction stirred for 3 hours.
The cooled reaction mixture was diluted with water (lOOml), extracted with ether (3x40ml), dried (MgS04) and concentrated to an orange oil 10 which was purified by flash silica gel chromatography eluting with 2:1 to 1:1 hexane:ethyl acetate to yield the title compound as a yellow oil (326mg, 37%). m/z (ES+) 514/516 (3:1, M+1, 100%).

15 (2R,3S,9R~-4-Aza-4-(4-azidobut-2-vnvl)-1.7-dioxa-3-(4-fluorophenvl)-9-hvdroxv-9-(2-methoxv-5-(trifluoromethYl)~henYl)sPiro~5.41decane Sodium azide (97mg, 1.48mmol) was added to a solution of the chloride of Description 5 (255mg, 0.49mmol) dissolved in DMSO (lOml) and stirred for 18 hours. The reaction mixture was diluted with saturated 20 ammonium chloride solution (lOOml), extracted with ethyl acetate (3x40ml), dried (MgSO4) and concentrated to a crude oil which was purified by flash silica gel chromatography eluting with 4:1 hexane:ethyl acetate to yield the title compound as an oil (232mg, 91%); ~n/~ (ES+) 521 (M+1, 100%).

(2R,3S~9R)-4-Aza-4-(4-chlorobut-2-vnvl)-1.7-dioxa-3-(4-fluorophenyl)-9-methox~r-(2-methoxv-5-(trifluoromethvl~henvl)sPiro[5.41decane The title compound was prepared from the morpholine of Example 32 30 according to the mcthod of Description 5 to yield a glass (137mg, 44%).
lH NM:I~ (360MHz, CD(~13) ~ 2.25 (lH, d, J=14.0)~ 2.53 (lH, d, J=14 0), 2 78 CA 0224~78 1998-08-0~

(lH, dd, J=11 4, 1.4), 2.93-3.01 (lH, m), 2.98 (31E~, s), 3.07 (lH, dt, J=17.4, 1.9), 3.19 (1~, dt, J=17.5, 1.8), 3.63 (lH, s), 3.67 (3H, s), 3.76 (lH, dd, J=11.5, 2.7), 3.90 (lH, d, J=9.8), 4.17 (2H, s), 4.39 (lH, dt, J=11.8, 2.8), 4.4;4 (lH, d, J=9.8), 6.81 (lH, d, J=8.6), 6.87 (2H, t, J=8.1), 7.22 (lH, d, J=2.1), 7.44 (~2H, br s), 7.45 (lH, dd, J=8.7, 1.9); m/z (ES+) 528l530 (3:1, M+l, 100%).

(2R,3S ~ 9R)-4-Aza-4-(4-azidobut-2-vnYl~- 1,7-dioxa-3-(4-fluorophenyl)-9-10 methoxY-9-(2-methoxY-5-(trifluoromethYl)~henyl)spiror5~4ldecane The title compound was prepared from the chloride of I)escription 7 according to the method of Description 6 to yield an oil (104mg, 76%). m /z (ES+) 535 (M+l, 100%).

(2R.3S,9R)-4-Aza-4-(4-chlorobut-2-vnYl)-1.7-dioxa-3-(4-FluoroPhenyl~-9-methoxy-9-(~-(tri~luoromethyl)phenvl)spiro~5.41decane The title compound was prepared from the morpholine of Example 31 according to the method of Description 5 to yield an oil (193mg, 84%).

(2R,3S,9R)-4-Aza-4-(4-azidobut-2-YnYl)-1.7-dioxa-3-(4-fluoroPhenyl)-9-methoxy-9-(2-(trifluoromethyl)~henvl)spiro~5.41decane The title compound was prepared from the chloride of Description 9 25 according to the method of Description 6 to yield an oil (166mg, 86%).

2-Bromobenzyl triisoProPvlsil~-l ether Triisopropylsilyl chloride (8.0ml, 46.0mmol) was added dropwise to a 30 solution of 2-bromobenzyl alcohol (7.0g, 39.6mmol) and imidazole (5. lg, 75.0mmol) in DMF (25ml) and the resulting solution stirred at 20~C for 18 CA 0224~78 1998-08-0~

hours. The reaction mixture was diluted with water (400ml) and extracted with ethyl acetate (3x75ml). The combined organic extracts were washed with saturated brine (lx75ml), dried (MgSO4) and concentrated to yield the title compound as a clear oil (10.2g, 78%). lH NMR (250M~z, CDCl3) 1.05-1.24 (21~I, m), 4.8~ (2H, s), 7.11 (lH, dt, ~=7.5, 1.2), 7.34 (lH, t, J=7.6), 7.48 (lH, dd, J=7.9, 1.1), 7.63 (lH, d, J=6.7).

DES~RIPTION 12 (2R,3S,9~-4-Aza-benzvl-1.7-dioxa-3-(4-fluoroPhenvl)-9-hvdroxY-9-(2-((triisopropvlsilYloxY)methvllphenYl~spiror5~4ldecane Tert-butyl lithium (1.69ml, 1.7M solution in pentane, 2.87mmol) was added dropwise to a solution of the bromide of Description 11 (2.0g, 5.85mmol) in ether (5ml) cooled to -78~C, the temperature rising to -30~C
during the addition. The benzyl ketone of Description 4 (l.Og, 2.83mmol) as a solution in ether (3ml) was added dropwise over 20 minutes and the resulting solution allowed to warm to 20~~ over ll/2 hours. The reaction was quenched by the addition of saturated ammonium chloride solution, extracted with ethyl acetate (3x40ml) and the combined organic extracts washed with saturated brine (lx40ml), dried (MgSO~) and concentrated to a yellow oil. The crude concentrate was purified by flash silica gel chromatography eluting with 19:1 hexane:ethyl acctate to yield the title compound as an oil contaminatcd with an equal mass of unreacted benzyl ketone (350mg total) and was used without further purification in Example 47; 777 /:z (ES+) 606 (M+1, 100%).
2a (2R,3S,9R)-4-Aza-4-benzyl-1,7-dioxa-3-(4-:i~luorophenvl)-9-hvdroxy-9-Phenvl-spiror5.41decane Phenyl magnesium ~romide (750111 of a 3.0M solution in ethel~, 2.25mmol) was added dropwise over 10 minutes to an ice cold solution of the benzyl l~etone of Description 4 (512mg, 1.50mmol) in tetrahydrofuran (lOml). The reaction mixture was allowed to warm to 20~C over 2 hours before being quenched with saturated ammonium chloride solution (15ml), extracted with ethyl acetate (3xl5ml), dried (MgSO4) and concentrated to dryness. The resulting crude gum (852mg) was purified by flash silica gel chromatography eluting with 7:3 hexane:ether to yield the title compound as an o~E-white foam (232mg, 37%). Analysis Found: C, 74.77; H, 6.19; N, 3.21. C2~H2~FNO3 requires C, 74.43; H, 6.26; N, 3.34%. lH NMR (360MHz, CDCl3) ~ 2.18 (lH, d, J=13.5), 2.23 (lH, d, J=13.6), 2.36 (lH, dt, J=12.1, 3.3), 2.81 (2H, t, 3=12.1), 3 54 (lH, s), 3.66 (3H, m), 4.20 (2H, m), 4.34 (lH, dt, J=11.4, 3.0), 7.05-7.12 (4H, m~, 7.19-7.26 (8H, m), 7.62 (2H, br s); m/~
(~S+) 420 (M+l, 100%).

(2R,3$,9R)-4-Aza-4-benzvl-1,7-dioxa-3-(4-fluoroPhenvl)-9-hYdroxy-9-(2-methoxvPhenvl)sPiro~5.41decane n-Butyl lithium (1.03ml, 1.6M in hexanes, 1.65mmol) was added dropwise over 2 ~ninutes to a solution of 2-hromoanisole (210~1, 1.70mmol) in tetrahydrofuran (5ml) cooled to below -70~C. The solution was maintained at this temperature and stirred for 40 minutes before the benzyl ketone of Description 4 (0.50g, 1.46mmol) as a solution in tetrahydrofuran (5ml) was added dropwise over 10 minutes maints-ining the temperature below -70~C. The solution was stirred for 10 minutes before warming to 20~C over 1 hour and quenchcd with a saturated ammonium chloride solution (20ml). The resulting suspension was extracted with ethyl acetate (3xl5ml), dried (MgSO4) and concentrated to a black gum (0.64g), which was further purified by flash silica chromatography eluting with 20% ethyl acetate in hexanc. The title compound was obtained as a pale yellow gum (0 21g, 32%) which solidified on standing. lH NMR (250MHz, CDCl3) ~ 2.03 (lH, d, J=13.0), 2.34 (lH, dt, J=11.9. 3.5), 2.61 (lH, d, J=13.0), 2.77 ~lH, d, J=13.2), 2.82 (lH, br d, J=13.5), 3.37 (3H, s), 3.55 (lH. s), 3.62-3.70 (2H, m), 4.13 (2H, d, J=1.4), CA 0224~78 1998-08-0~

4.34 (lH, dt, J=12.0, 2.5), 4.60 (lH, s), 6.73 (lH, d, J=8.2), 6.90 (lH, dt, J=7.5, 1.1), 7.05 (lH, t, J=8.8), 7.16-7.28 (7H, m), 7.52 (lH, dd, J=7.8, 1.8), 7.62 (2H, br s); m/z (ES+) 450 (M+l, 100%), 432 (M-OH, 20).

EXA~PLL 3 (2R.3S.9R)-4-Aza-4-benzvl- 1,7-dioxa-3-(4-fluorophenvl)-9-hvdroxy-9-(2-(tri~luoromethYl)PhenYl)spiro~r5.4~decane n-Butyl lithium (3.5ml of a 1.6M solution in hexanes, 5.6mmol) was added dropwise over 15 minutes to a solution of 2-(trifluoromethyl)-iodobenzene (1.47g, 5.4mmol) in ether (15mV cooled to -10~C. A~ter stirring for 1 hour, a 1.2M solution of tributoxyzirconium chloride in ether (4.7ml, 5.6}nmol) (Helv. Chr;m. Acta, 1981, 64, 1552) was added and stirring continued at 0~C for 2.5 hours. Benzyl ketone of Description 4 (616mg, 1.8mmol) as a solution in dichloromethane (6ml) was added and the reaction mixture allowed to warm to 20~C overnight. The reaction was quenched by the addition of 1.0M HCl solution (50ml), extracted with ether (3x30ml), dried (MgSO4) and concentrated to dryness. The crude oil (200mg) was purified by flash silica gel chromatography eluting with 2:1 hexane:ether to yield the title compound as a yellow oil (55mg, 6%).
lH Nl~R (CDC13) ~ 2.28 (lH, d, J=13.3), 2.22-2 40 (2H, m), 2.45 (lH, d, J=13.3), 2.81 (2H, t, J=11.8), 3.54 (lH, s), 3.66 (2H, d, J=12.8), 3.77 (lH, d, J=9.3), 4.32 (2H, m), 4.43 (l~I, d, J=9.2), 7.00 (2H, t, J-8.7), 7.13 (lH, d, J=7.4), 7.21-7.38 (7H, m), 7.58 (2H, br s), 7.68 (lH, d, J=7.3); r~l/3 (:E~S+) 488 (M+l, 100%).
EXAMPLES 4A and 4B
(2R~3S,9R)-4-Aza-4-benzvl-1,7-dioxa-3-(4-~uoroPhenYl)-9-hYdroxY-9-(2 ~ methoxv-6-(tri~1uoromethYl)PhenYl)sPiro~5 4~dccane; and ¢2R,3$,9S~-4-Aza-4-benzvl-1,7-dioxa-3-(4-~luQrophenvl)-9-hYdroxv-9-(2-methoxY-6-30 (tri~1uoromethvl)phenvl)sPiror6.4~decane CA 0224~78 1998-08-0~

2-Methoxy-5-(trifluoromethyl)iodobenzene (1.51g, 5.0mmol) and the benzyl ketone of Description 4 (1.53g, 4.5mmol) were reacted according to the method of Example 2 which gave after work up a crude oil (2.2g). The crude concentrate was purified by flash silica gel chromatography eluting 5 with 6:1 to 4:1 hexane:ethyl acetate to yield the title compound (~"rz~m~le 4A) as a white foam (846mg, 36%); lH NMR (360MHz, CDCl3) ~ 1.92 (lH, d, J=13.0), 2.33 (lH, dt, J=12.0, 3.5), 2.65 (lH, d, J=13.0), 2.76 (lH, d, J=13.2), 2.82 (lH, d, J=11.5), 3.30 (3H, s), 3.54 (lH, s), 3.64 (lH, d, J=13.0), 4.03 (lH, d, J=8.8), 4.18 (lH, d, J=8.8), 4.33 (lH, dt, J=11.8, 2.3), 4.66 (lH, s), 6.72 (lH, d, J=8.6), 7.07 (2H, t, J=8.7), 7.16-7.28 (5H, m~, 7.42 (lH, dd, J=8.9, 2.2), 7.63 (2H, br s), 7.98 (lH, d, J=2.3); 7n/z (ES+) 518 (M+l, 100%);
and the title compound (F',~mple 4B) as an oil ~170mg, 7%); 'H NMR
(360MHz, CI~Cl3) ~ 2.22 (lH, dd, J=14.3, 1.2), 2.33 (lH, dt, J=ll.9, 3.5), 2.73 (lH, d, J=14.3), 2.81 (lH, d, J=13.2), 3.52 (lH, s), 3.57 (lH, m), 3.70 (lH, d, J=13.2), 3.84 (3H, s), 3.85 (lH, d, J=9.0), 4.22 (lH, dt, J=11.8, 2.4), 4.35 (lH, d, J=9.0), 6.88 (lH, d, J=8.6), 7.12 (2H, t, J=8.7), 7.18-7.30 (5H, m), 7.48 (lH, dd, J=8.4, 1.8), 7.65 (lH, d, J=2.1), 7.71 (2H, br s); ~7t/~ (ES+)518 (M+l, 100%).
EXAMPI,E 5 (2R,3S,9R)-4-Aza-4-benzvl-1.7-dioxa-3-(4-fluoroPhenYl)-9-hvdroxy-9-(2-(trifluoromethoxy)phenyl)spiro ~5.41 decane The title compound was prepared according to the method of Example 3 to yield a yellow oil (9lmg, 10%). IH NMR (360MHz, CDCl3) ~ 2.21 (lH, d, J=13.0), 2.35 (lH, dt, J=ll.9, 3.3), 2.40 (lH, d, J=13.2), 2.77 (lH, d, J=13.3), 2.83 (lH, d, J=11.7), 3.56 (lH, s), 3.62-3.70 (2H, m~, 3.83 (lH, d, J=9.3), 4.34 (lH, dt, J=11.6, 2.1), 4.47 (lH, d, J=9.3), 4.55 (lH, s), 7.00 (2H,t, J=8.7), 7.14-7.35 (9H, m~, 7.57 (2H, br s); 77t/~ (E~+) 504 (M+l, 100%).

CA 02245578 l998-08-05 (+/-)-(2R~,3S*,9R*)-4-Aza-4-benzvl-1~7-dioxa-3-(4-fluoroPhenYl)-9-hYdroxy-~ 9-(2-methylphenyl~spiro~5.41decane The title compound was prepared according to the method of ~,~mI)le 1 to yield a white foam (355mg, 47%). Analysis Found: C, 74.64; H, 6.39;
N, 3.40. C27H2sFN03 requires C, 74.81; H, 6.51; N, 3.23%. lH NMR
(360MHz, CDC13) ~ 2.14 (3H, s), 2.27 (lH, d, J=13.2), 2.33 (lH, d, J=13.6), 2.35 (lH, dt, J=ll.9, 3.3), 2.80 (lH, d, J=13.4), 2.83 (lH, d, J=14.4), 3.57 (lH, s), 3.67 (lH, d, J=13.3), 3.86 (lH, d, J=9.3), 4.28 (lH, s), 4.33 (lH, dt, J=11.8, 2.4), 4.43 (lH, d, J=9.3), 7.00 (2H, t, J=8.8), 7.04-7.31 (9H, m), 7.58 (2H, br s); m/z (ES+) 434 (M+l, 100%).

(2R,3S.9R)-4-Aza-4-benzvl- 1,7-dioxa-9-(2-ethYlPhenYl)-3-(4-fluoroPhenyl) -9-hydroxY-spiro~5.41decane The title compound was prepared according to the method of Example 2 to yield an oil (180mg, 28%). IH NMR (360MHz, ~DCl3) ~ 1.07 (3H, t, J=7.5), 2.26-2.48 (4H, m), 2.77-2.88 (2H, m), 3.57 (lH,s), 3.64-3.72 (2H, m), 3.82 (lH, d, J=9.3), 4.32-4.38 (2~, m), 4.41 (lH, d, J=9.3), 6.98-7.08 (3H, m), 7.14-7.30 (8H, m), 7.54-7.64 (2H, br s); m/z (ES+) 449 (M+l, 100%).

(2R.3S,9R)-4-Aza-4-benzYl-9-t2-chlorophenYl)-1.7-dioxa-3-(4-fluoroPhenyl)-9-hvdroxy-spiror5.4~decane The title compound was prepared according to the method of Example 1 to yield an oil (280mg, 51%). ~ (ES+) 454 (M+l, 100%).

(2R,3S,9R)-4-Aza-1,7-dioxa-3-(4-fluoroPhenvl)-9-hYdroxy-9-Phenylspirol5.41decane CA 02245C~78 1998-08-05 The benzylamine of h'.~mple 1 (255mg, 0.61mmol) as a solution in methanol (15ml) was hydrogenated at 40 psi of hydrogen with 10% Pd-C
catalyst (160mg) for 2l/2 hours The reaction mixture was filtered through a pad of Hyflo~M and concentrated to a crude gum which was purified by flash silica gel chromatography eluting with 5% methanol in dichloromethane to yield the title compound as a glass ~76mg, 38%).
lH NMR (360MHz, CDCl3) ~i 1.7-1.9 (~2H, br s), 2.09 (lH, d, J=13.5), 2.20 (lH, dd, J--13.5, 0.9), 3.06 (lH, dd, J=12.4, 2.4), 3.22 (lH, dt, J=12.3, 3.6), 3.73 (lH, dd, J=11.2, 3 0), 3 78 (lH, d, J=9 3), 4 03 (lH, s), 4.27 (lH, d, 10 J=9.3), 4.36 (lH, dt, J=11.7, 2.7), 7.03 (2H, t, J=8.7), 7.12 (2H, m), 7.16-7.26 (3H, m), 7.47 (2H, m); m/z (E:S+) 330 (M+l, 100%), 312 (M-17, 30).

EXAMPLl~ 10 (2R,3S,9R)-4-Aza-1,7-dioxa-3-(4-fluorophenvl)-9-hYdroxv-9-(2-15 methox~henvl)sPiro~;.41decane The benzyl~mine o~~ mple 2 was hydrogenated according to the method of Example 9 to yield the title compound as a glass (9Omg, 68%).
~H NMR (360MHz, CDCl3) ~ 1.98 (lH, d, J=13.1), 2.56 (lH, d, J=13.1), 3.04 (lH, dd, J=11.6, 2.1), 3.20 ~lH, dt, 3=12.3, 3.7), 3.34 (3H, s), 3.71 (lH, dd, 20 J=ll.O, 2.6), 4.03 (lH, s), 4.17 (2H, s), 4.33 (lH, dt, 3=11.6, 3.1), 6.72 (lH, dd, J=8.2, 0.9), 6.89 (lH, dt, J=7.6, 1.1), 7.02 (2H, t, J=8.7), 7.18 (lH, dt, J=7.8, 1.8), 7.44-7.55 (3H, m); m/~ (ES+) 360 (M+1, 100%), 342 (M-17, 72), 192 (75).

(2R,3S.9R)-4-A~a-1.7-dioxa-3-(4-fluorophenvl)-9-hYdroxy-9-(2-(trifluoromethyl)phenvl~spiror5.41decane The benzylamine of Example 3 was hydrogenated according to the method of l~xample 9 to yield the title compound as a glass (21mg, 53%).
30 lH NMR (360MHz, CDCl3) ~ 2.21 (lH, d, J=13.3), 2.42 (lH, d, J=13.3), 3.0 (lH, dd, J=12.4, 2 0), 3.22 (lH, dt, J=12.3, 3.6), 3.73 (lH, dd, ~=11.2, 2.8), CA 0224~78 1998-08-0~

- 55 - .

3.89 (~H, d, J=9.4), 4.05 (lH, s), 4.34 (lH, dt, J=11.7, 2.6), 4.48 (lH, d, J=9.4), 6.94-7.00 (2H, m), 7.20 (lH, d, J=7.3), 7.31-7.47 (4H, m), 7.68 (lH, dd, J=7.5, 1.6); m/z (ES+) 398 (M+l, 100%).

(2R,3$~9R)-4-Aza-1,7-dioxa-3-(4-fluoroPhenvl)-9-hYdroxY-9-(2-methoxY-5 (trifluoromethyl)phenYl)sPiro ~5.4l decane The benzylamine of Example 4A was hydrogenated according to the method of Example 9 to yield the title compound as an oil (80mg, 70%).
lH NMR (360MHz, CDC13) ~ 1.7-2.1 (~lH, br s), 1.91 (lH, d, J=13.1), 2.59 (lH, d, J=13.0), 3.06 (lH, dd, J=12.4, 2.0), 3.22 (lH, dt, J=12.3, 3.6), 3.32 (3H, s), 3.73 (lH, dd, J=ll.l, 2.7), 4.04 (lH, s), 4.07 (lH, d, J=8.9), 4.34 (lH, dt, J=11.7, 2.9), 6.75 (lH, d, J=8.6), 7.04 (2H, t, J=8.6), 7.43-7.52 (3H, m), 7.92 (lH, d, J=2.3); m/z (ES+) 428 (M+l, 100%).

(2R.3S,9$)-4-Aza-1,7-dioxa-3-~4-fluorophenYl)-9-hvdroxY-9-(2-methoxY-5-(trifluoromethyl3phenyl)spiror5.41decane The benzylamine of Example 4B was hydrogenated according to the mthod of ~xample 9 to yield the title compound as an oil (79mg, 68%).
H NMR (360MHz, CDCl3) ~ 2.14 (lH, d, J=14.3), 2.16 (~lH, br s), 2.64 (lH, d, J=14.4), 3.02 (lH, dd, J=12.3, 2.2), 3.18 (lH, dt, J=12.2, 3.6), 3.62 (lH, dd, J=11.4, 2.8), 3.86 (3H, s), 3.91 (lH, dd, J=9.2, 1.3), 3.99 (lH, s), 4.22 (lH, dt, J=11.8, 2.6), 4.36 (lH, d, J=9.0), 6.90 (lH, d, J=8.6), 7.07 (2H, t, J=8.7), 7.49 (lH, dd, J=8.2, 1.8), 7.54-7.63 (3H, m); m/z (ES+) 428 (M+l, 100%).

E~MPLE 14 (2R,3S,9R)-4-Aza-1,7-dioxa-3-(4-~luorophenvl3-9-hvdroxY-9-(2-(tri~luoromethoxY)Phcnvl)sPiror5~4ldecane The benzyl~3mine of ~,~mple 5 was hydrogenated according to the method of Example 9 to yield the title compound as an oil (46mg, 66%).
lH NMR (360MHz, CDCls) ~ 1.7-2.1 (lH, br s), 2.18 (lH, d, J=13.1), 2.33 (lH, d, J=13.2), 3.06 (lH, dd, ~=I2.4, 2.2), 3.22 (lH, dt, J=12.3, 3.6), 3.74 (lH, dd, J=11.3, 2.9), 3.97 (lH, d, J=9.4), 4.06 (lH, s), 4.35 (lH, dt, J=11.7, 2.4), 4.48 (lH, d, J=9.5), 6.97 (2H, t, J=8.8), 7.14-7.19 (2H, m), 7.24-7.30 (lH, m), 7.39-7.46 (3H, m); m/z (ES+) 414 (M+1, 100%).

(+/-)-(2R~,3S~.9R*)-4-Aza-1.7-dioxa-3-(4-fluoroPhenvl)-9-hYdroxv-9-(2-methylphenvl)sl)iror5.4~decane The benzyl~mine of ~"c:~m~le 6 was hydrogenated according to the method~of F,~r~m~le 9 to yield the title compound as glass (105mg, 78%).
lH NMR (360MHz, CDCl3) ~ 2.19 (lH, d, J=12.9), 2.21 (3H, s), 2.31 (lH, d, 15 J=13.2), 2.9-3.3 (~2H, br s), 3.06 (lH, dd, J=11.7, 2.0), 3.21 (lH, dt, J=12.3, 3.6~, 3.72 (lH, dd, J=10.5, 2.7), 3.95 (1E~, d, J=9.3), 4.06 (lH, s), 4.34 (lH, dt, J=11.7, 3.0), 4.49 (1H, d, J=9.2~, 6.94-7.18 (6H, m), 7.42-7.47 (2H, m);
m /z (ES+) 344 (M+ 1, 100%) .

EXAMPLl~ 16 (2R,3S,9R)-4-Aza-4-(2,3-dihvdro-3-oxo-1.2.4-triazol-5-YllmethYl-1,7-dioxa-3-(4-fluoro~henYl)-9-hYdroxY-9-(2-methoxvPhen~l)spiro~5.4ldecane The morpholine of Example 10 (81mg, 0.23mmol) was heated with N-methylcarboxy-2-chloroacetamidrazone (see European Patent 25 Specification No. 0 577 394-A) (45mg, 0.271mmol) and potassium carbonate (125mg, 0.904mmol) in DMF (5ml) at 60~C for 1 hour. The cooled solution was diluted with water (25ml), extracted with ethyl acetate (3xl5ml), dried (MgSO~) and concentrated to dryness. The crude gum (110mg) was purified by flash silica gel chromatog~aph~r eluting with 6-8%
30 methanol in dichloromethane to yield the intermcdiate imidiazone, which was redissolved in xylene (2ml~ and heated at reflux for 2 hours. The CA 0224~78 1998-08-0~

crude concentrate was purified by flash silica gel chromatography eluting with 6% methanol in dichloromethane to yield the title compound as a glass (42mg, 41%). IH NMR (360MHz, CDCl3) ~ 2.05 (lH, d, J=13.1), 2.57 (lH, d, J=13.2), 2.61 (lH, m), 2.89 (lH, br d, ~=11.2), 2.95 (lH, d, J=14.~;), 3.35 (3H, s~, 3.45 (lH, d, J=14.5), 3.62 (lH, s), 3.75 (lH, br d, J=8.9), 4.14 (lH, d, J=9.0), 4.18 (lH, d, J=9.0), 4.36 (lH, dt, J=11.7, 2.1), 4.47 (lH, s), 6.71 (lH, d, J=8.2), 6.89 (lH, t, J=7.5), 7.05 (2H, t, J=8.6), 7.19 (lH, t, J=7.5), 7.50 (lH, dd, J=7.8, 1.6), 7.56 (2H, vbr s), 9.90 (lH, br s), 10.45 (lH, br s); m/z (ES+) 457 (M:~l, 32%), 439 (M-17, 15), 382 (100).

(2R,3S,9R)-4-Aza-4-(2,3-dihvdro-3-oxo-1.2.4-triazol-5-Yl)methYl-1,7-dioxa-3-(4-fluoro~henyl)-9-hYdroxY-9-(2-(trifluoromethvl)phenYl)-spiro r5.4] decane The title compound was prepared from the morpholine of ~z~mple 11 according to the method of Example 16 to yield a glass (60mg, 48%).
H NMR (360MHz, CDCl3) ~ 2.2-2.5 (lH, br s), 2.23 (lH, d, J=13.5), 2.47 (lH, d, J=13.4), 2.61 (lH, dt, J=ll 9, 3.3), 2.90 (lH, d, ~=11.3), 3.00 (lH, d, J=14.4), 3.47 (lH, d, ~=14.5), 3.61 (lH, s), 3.75 (lH, d, J=8.9), 3.81 (lH, d, J=9.3), 4.26 (lH, s), 4.35 (lH, dt, J=11.7, 2.0), 4.45 (lH, d, J=9.3), 6.99 (2H,t, J=8.6), 7.11 (lH, d, J=8.6), 7.31-7.37 (2H, m), 7.52 (2H, br s), 7.67 (lH, d,J=9.3), 10.41 (lH, s), 10.95 (lH, br s); ~ (ES+) 495 (M~l, 100%).

~2R,3S,9R)-4-~za-4-(4-(N.N-dimethYlamino)-but-2-vnvl)-1.7-dioxa-3-(4-fluorphenyl)-9-hYdroxy-9-(2-methoxv-5-(trifluoromethvl)~henvl)-spiror{;.4~decane The chloride of Description 5 (60mg, 0.12mmol) dissolved in dioxan (3mV was added to condensed dimethylamine (3ml) in a sealed tube and 30 heated at 90~C for 7 hours. The crude concentrate was purified by flash silica gel chromatography eluting with 5% methanol in dichloromethane to yield the title compound as an oil (42mg, 69%). IH NMR (360MHz, CD~13) o 1.92 (lH, d, J=13.0), 2.31 (6H, s), 2.32 (2H, s), 2.~6 (lH, d, J=13.1), 2.83 (lH, br d, J=11.6), 3.03 (lH, dt, J=12.0, 3.7), 3.29 f2H, s), 3.32 (3H, s), 3.75 (lH, s), 3.79 (lH, dd, J=11.3, 3.7), 4.06 (lH, d, J=8.9), 4.19 (lH, d, J=8.9), 4.46 (lH, dt, J=ll.~i, 2.3), 4.61 (~lH, br s), 6.75 (lH, d, J=8.6), 7.05 (2H, t, J=8.5), 7.44 (lH, dd, J=9.0, 2.6), 7.53 (2H, br s), 7.92 (lH, d, J=2.2); m/z (ES+) ~23 (M+l, 100%).

(2R.3S.9R)-4-Aza-4-(~-(N.N-dimethYlaminomethYl)-1.2~3-triazol-4-yl)methyl- 1.7-dioxa-3-(4-fluoro~henYl)-9-hvdroxY-9-(2-methoxY-5-(trifluoromethYl)phenvl)spiror5.41decane The azide of Description 6 (230mg, 0.44mmol) dissolved in tli~ n (6ml) was added to condensed dimethylamine (6ml) in a sealed tube and heated at 90~C for 7 hours. The crude concentrate was purified by ~lash silica gel chromatography eluting with 10% methanol in dichloromethane to yield the ~itle compound as a foam (155mg, 62%). lH NMR (360MHz, CDCl3) o 1.94 (lH, d, J=13.0), 2.23 ~6H, s), 2.55 (lH, m), 2.58 (lH, d, J=13.1), 2.87 (lH, d, J=11.5), 3.20 (lH, d, J=13.8), 3.34 (3H, s), 3.51 (2H, s), 3.61 (2H, t, J=6.9), 3.71 (lH, dd, J=11.3, 2.1), 4.05 (lH, d, J=8.9), 4.18 (lH, d, J=8.9), 4.32 (lH, dt, J=11.7, 2.0), 6.75 (lH, d, J=8.6), 7.09 (2H, t, J=8.6), 7.45 (lH, dd, J=8.3, 2.1), 7.62 (2H, br s). 7.91 (lH, d, J=2.2); 77~/-fES+) 566 fM+l~ 82%), 165 (100).

EXAMPLES 20A and 20B
(2R,3S,9R)-4-Aza-1~7-dioxa-3-f4-fluoloPhenYl)-9-hYdrox~r-4-(1($)-~henvlethYl)-9-(2-(trifluoromethYl)~henYl)spilor~4ldecane; and (2R,3S,9R)-4-Aza-1,7-dioxa-3-f4-fluoloPhenYl)-9-hYdroxv-4-(l(R)-phenylethvl)-9-(2-(trifluoromethvl)phenYl)sPiro~5.41decane (l-Bromoethyl)benzene (103,ul, 0.76mmol) and potassium carbonate (208mg, 1.5mmol) were added to the mo~pholine of Example 11 (150mg, CA 0224~78 1998-08-0~

0.38mmol) as a solution in DMF (7ml) and stirred for 18 hours at 20~C, then 4 hours at 75~C. The cooled reaction mixture was diluted with water (50ml), extracted with ether (3x25ml), dried (MgS04) and concentrated to a yellow oil (194mg). The crude isomers were separated by medium pressure chromatography eluting with 2:1 hexane:ether to yield the less polar title compound (Example 20A) as a white solid (39mg, 21%);
lH NMR (360MHz, CDC13) ~ 1.17 (3H, d, J=6.8), 2.24 (lH, d, J=13.3), 2.41 (lH, d, J=11.6), 2.45 (lH, d, ~=13.3), 2.65 (lH, dt, J=11.8, 3.3), 3.6~ (lH, m), 3.75 (1~, ~, J=6.8), 3.77 (lH, d, J=9.2), 3.93 (lH, s), 4.24 (lH, dt, 10 J=11.4, 1.9), 4.3~ (lH, s), 4.44 (lH, d, J=9.2), 6.99 (2H, t, J=8.8), 7.15 (lH, d, J=7.3), 7.18-7.40 (4H, m), 7.43 (2H, d, J=8.0), 7.64 (2H, br s), 7.68 (lH, dd, J=7.6, 1.6); m/z (ES~) 502 (M+1, 100%); and the morepolar title compound (Example 20B) as a glass (68mg, 36%); lH NMR (360MHz, CDCl3) ~ 1.39 (3H, d, J=7.1), 2.20 (lH, d, J=13.5), 2.30 (lH, d, J=13.4), 2.30 15 (lH, m), 3.00 (lH, d, J=11.5), 3.48 (lH, s), 3.66 (lH, d, J=9.3), 3.71 (l~I, dd, J=ll.O, 1.4), 3.82 (lH, q, ~=7.1), 4.21 (lH, s), 4.36 (2H, m), 6.95 (2H, dd, J=8.0, 1.6), 7.04 (2H, t, J=8.7), 7.05 (lH, m), 7.23-7.36 (5H, m), 7.51 (2H, br s), 7.65 (lH, dd, J=7.3, 2.0); m/~ (ES+) 502 (M+l, 100%).

EXAMPLE ~1 (2R,3S,9R)-4-Aza-1,7-dioxa-3-(4-fluoroPhenvl)-9-hvdroxy-4-((2-(trifluoromethyl)phenyl)methvl)-9-(2-(trifluoromethYl)phenyl)-spiro r5.4l decane The morpholine of Example 11 (lOOmg, 0.25mmol), 2-25 (tri~Luoromethyl)bcnzyl bromide (120mg, 0.50mmol) and potassium carbonate (138mg, l.OOmmol) were stirred in DMF (5ml) for 4 hours. The reaction mixture was diluted with water (50ml), extracted with ether, (3x25mI), dried (MgSO~) and concentrated to a crude oil (244mg) which was purified by ~lash silica gel chromatography eluting with 4:1 30 hexane:ethyl acetate to vield the title compound as a glass (99mg, 71%) WO 97/300~;6 PCT/GB97/00404 lH NMR (360MHz, CDCl3) ~ 2.29 (lH, d, J=13.3), 2.44 (lH, dt, J=12.0, 3.2), 2.47 (lH, d, J=13.3), 2.75 (lH, d, J=11.8), 3.23 (lH, dd, J=14.8, 1.8), 3.58 (lH, d, J=14.8), 3.66 (lH, s), 3.67 (lH, m), 3.79 (lH, d, J=9.3), 4.32 (lH, s), 4.36 (lH, dt, J=11.7, 2.4), 4.46 (lH, d, J=9.3), 6.95 (2H, t, J=8.8), 7.15 (lH, d, J=7.3), 7.24-7.39 (3H, m), 7.51-7.65 (~4H, m), 7.68 (lH, dd, J=7.5, 1.6), 7.96 (lH, dd, J=7.7); m/z (ES+) 556 (M+l, 100%).

EXAMPL:~ 22 (+/-)-(2R*,3S~9R~)-4-Aza-4-benzYl-1.7-dioxa-3-(4-fluorophenYl)-9-methoxY-9-PhenYl-spiro[5.41decane Sodium hydride (80mg, 60% dispersion in oil, 2.0mmol) was added to a racemic mixture of the alcohol of F,~mple 1 (250mg, 0.60mmol) dissolved in DMF (5mV. After stirring for 30 minutes, methyl iodide (370,u1, 5.96mmoV was added and the reaction stirred for between 2 and 24 hours. The reaction mixture was quenched by the addition of water (50ml, care!) extracted with ether (3x25ml), dried (MgSO4) and concentrated to a yellow solid (254mg) which was purified by flash silica gel chromatography eluting with 5:1 hexane: ethyl acetate to yield the title compound as a glass (197mg, 76%). Analysis Found: C, 75.10; H, 6.51; N, 3.38.
Cz7H2gFNO3 requ~res C, 74.81; H, 6.51; N, 3.23%~. IH NMR (360MHz, ~DGl3) ~ 2.22 (lH, d, J=14.2), 2.33 (lH, dt, J=11.9, 3.4), 2.45 (lH, d, J=14.2), 2.79 (2H, m), 3.09 (3H, s), 3.45 (lH, s), 3 64-3.70 (3H, m), 4.24 (lH, dt, J=11.7, 2.2), 4.28 (lH, d, J=9.3), 6.77-6.83 (2H, m), 6.97 (2H, t, J=8.7), 7.11-7.26 (8H, m), 7.57 (~2H, br s); m/~ (ES+) 434 (M+l, 100%), 402 (M-31, 42).

(2R.3S.9R~-4-Aza-4-benzyl- 1.7-dioxa-3-(4-fluoroPhenvl)-9-methoxv-9-(2- .
methoxvphenyl~spiror5.41decane The alcohol of Example 2 was reacted accol-ding to the method of Example 22 to yield the title compound as a pale vellow foam (466mg, CA 0224~78 1998-08-0~

71%). lH NMR (360MHz, CDC13) ~ 2.25 (lH, d, J=13.9), 2.31 (lH, dt, J=ll.9, 3.4), 2.58 (lH, dd, J=13.8, 1.0), 2.75 (lH, d, J=13.1), 2.78 (lH, br d, J=11.3), 2.97 (3H, s), 3.45 (lH, s), 3.60 (lH, d, J=13.3), 3.62-3.69 (2H, m), 3.66 (3H, s), 4 28 (lH, dt, J=11.8, 2.2), 4.52 (lH, dd, J=9.8, 0.8), 6.77-6.83 (2H, m), 6.88-6.97 (3H, m), 7.17-7.27 (6H, m), 7.56 (~2H, br s); m/z (ES+) 464 (M+l, 100%).

EXAMPL~ 4 (2R,3S.9R)-4-Aza-4-benzYl-1.7-dioxa-3-(4-iluoroPhenYl)-9-methoxv-9-(2-(trifluoromethYl)phenvl)spiror5.41decane The alcohol of ~ m~le 3 was reacted according to the method of Example 22 to yield the title compound as a solid after recrystallisation from 60/80 petrol (9lOmg, 82%). Mp. 155-157~C (petrol). lH NMR
(360MHz, CDCl3) ~ 2.29 (lH, d, J=14.7), 2.27-2.41 (lH, m), 2.56 (lH, d, J=14.7), 2.72-2.83 (2H, m), 2.96 (3H, s), 3.35 (lH, s), 3.69-3.70 (2H, m), 4.18 (lH, br t, J=11.8), 4.27 (2H, s), 6.63 (lH, d, J=7.9), 6.75 (lH, br s), 7.08 (lH, t, J=7.4), 7.16-7.46 (8H, m), 7.59 (lH, d, J=7.9).

(2R,3S,9R)-4-Aza-4-benzvl-1~7-dioxa-3-(4-fluoroPhenvl)-9-methoxv-9-(2-methoxy-a-(trifluoromethYl)phenYl)s~iroL5.4~dccane The alcohol of Example 4A was reacted according to the method of Example 22 to yield the title compound as a foam (430mg, 67%). lH NMR
(360MHz, CDCl3) ~ 2.32 (lH, dt, J=ll.9, 3.5), 2.35 (lH, d, J=14.0), 2.53 (lH, d, J=14.0), 2.75 (lH, d, J=13.1), 2.79 (IH, d, J=ll.O), 2.97 (3H, s), 3.43 (lH, s), 3.a9 (lH, d, J=13.3), 3.64 (lH, m), 3.69 (3H, s), 3.82 (lH, d, J=8.6), 6.88 (2H. t, J=8.7), 7.17-7.29 (6H, m), 7.46 (lH, dd, J=8.4, 1.6), 7.51 (~2H, br s); r7t/~ (ES+) 532 (M+l, 100%).

(+/-)-(2R~,3S*,9R~)-4-Aza-4-benzYl-1.7-dioxa-3-(4-fluorophenvl)-9-methoxY-9-(2-methvlphenyl)spiror5.41decane The alcohol of ~,~m~le 6 was reacted according to the method of Example 22 to yield the title compound as an oil (175mg, 39%) IH NMR
(360~Hz, CDCl3) ~ 2.28-2.36 (2H, m~, 2.31 (3H, s), 2.54 (lH, d, J=13.8), 2.76 (lH, d, J=13.1~, 2.79 (lH, d, J=1~.6), 2.87 (3H, s), 3.42 (lH, s), 3.63 (lH, d, J=13.2), 3.65 (lH, m), 3.89 (lH, d, J=9.3~, 4.26 (lH, dt, J=11.8, 2.5), 4.42 (lH, d, J=9.3), 6.65 (lH, d, J=7.7), 6.84 (2H, t, J=8.9), 6.90 (lH, m), 7.05 (2H, m), 7.15-7.27 (5H,m), 7.49 (~2H, br s); m/z (~S+) 448 (M+l, 100%).

(2R,3S,9R)-4-Aza-4-benzvl-1.7-dioxa-9-(2-ethvlphenvl)-3-(4-iluoro~henvl)-9-methoxy-spiro[5.41decane The alcohol of Example 7 was reacted according to the method of Example 22 to yield the title compound as a white solid (135mg, 77%).
lH NMR (360MHz, CDCl3) ~ 1.14 (l~I, t, J=7.5), 2.28-2.37 (2H, m), 2.54 (lH, d, J=13.8), 2.67-2.84 (4H, m), 2.89 (3H, s), 3.42 (lH, s), 3.60-3.69 (2H, m), 3.85 (lH, d, J=9.4), 4 25 (lH, td, J=10.6, 2.2), 4 ~1 (lH, d. J=9.4), 6.67 (lH, d, J=7.9), 6.80-6.93 (3H, m), 7.11-7.28 (7H, m), 7.47 (2H~ br s); m/_ (ES+) 462 (M~1, 100%) (2R~3S~9R)-4-Aza-4-benzvl-9-(2-chloroPhen~7l)-1.7-dioxa-3-(4-fluoroPhen~rl)-9-~ethoxy-s~iro r5.4~ decane The alcohol of F.~,qm~le 8 was reacted according to the method of ml?le 22 to yield the title compound as an oil (150mg, 51%). lH N~IR
(360MHz, CDCl3) ~ 2.31 (lH, td. J=11.9, 3.3), 2.45 (lH, d, J=1~.1), 2~68 (lH, d, J=14.1), 2.73-2~84 (2H, ~ , 2~92 (3H, s), 3.41 (lH, s), 3.60-3.69 (2H, m), 4.05 (lH, d, J=9.7), 4.23 (lH. td, J=11.7, 2.2), 4.45 (lH, d. J=9.7), 6.78-CA 02245578 lsss-os-05 wo 97/300s6 PCT/GB97/Oû404 6.86 (2H, m), 6.98 ~lH, td, J=7.5, 1.3), 7.10 (lH, td, J=7.7, 1.6), 7.16-7.28 (7H, m), 7.41-7.54 (2H, m); m/z (ES+) 468 (M+l, 100%).

(+/-)-(2R* .3S~,9R*)-4-Aza- 1,7-dioxa-3-(4-fluoroPhenYl)-9-methoxY-9-phenyl-spiror5.41decane The (+/-)-benzyl~min~? of Example 22 was hydrogenated according to the method of Example 9 to yield the title compound as an oil (138mg, 100%). lH ~MR (360MHz, CDC13) ~ 2.14 (lH, d, ~=14.2), 2.40 (lH, d, J=14 2), 3.03 (lH, dd, J=12.3, 2.2), 3.08 (3H, s), 3.20 (lH, dt, J=12.2, 3.6), 3.72 (lH, br d, J=12.1), 3.75 (lH, d, J=9.3), 3.95 (lH, s), 4.26 (lH, dt, J=12.0, 2.7), 4.31 (lH, d, J=9.7), 6.81-6.86 (2H, m), 6.90-6.96 (2H, m), 7.11-7.15 (3H, m), 7.39-7.45 (2H, m); m/z (ES+) 344 (M+l, 60%), 312 (M-31, 100).
EXAMPI,E 30 2R,3S,9R)-4-Aza-1~7-dioxa-3-~4-fluorophenvl)-9-methoxy-9-(2-methoxyphenYl)spiro ~5.4~decane The benzylamine of E~xample 23 was hydrogenated according to the method of Example 9 to yield the title compound as a yellow oil (265mg, 84%). lH NMR (360MHz, CDC13) ~ 2.18 (lH, s), 2.18 (lH, d, J=13.9), 2.54 (lH, d, J=13.9), 2.99 (3H, s), 3.00 (lH, m), 3.16 (lH, dt, J=12.2, 3.6), 3.63 (3H, s), 3.70 (lH, dd, J=11.4, 2.9), 3.82 ~lH, d, J=9.8), 3.95 (lH, s), 4.30 (lH, dt, J=11.8, 2.7), 4.55 (lH, d, J=9.8), 6.77-6.93 (4H, m), 6.98 (lH, dd, J=7.6, 1.6), 7.19 (lH, dt, J=7.8, 1.7), 7.39-7.45 (2H, m); m/~ ~ES+) 374 (M~l, 100%), 342 (M-31, 93).

(2R,3S,9R)-4-Aza-1,7-dioxa-3-(4-fluoroPhenvl~-9-methoxY-9-(2-30 (trifluoromethyl)phenYl)sPiror5.4~decane WO 97/300!;6 PCT/GB97/00404 The benzylamine of Example 24 was hydrogenated according to the mthod of ~,~m~le 9 to yield the title compound as a white solid (603mg, 90 %3. l H N M R (360 M H z, C D Cl3) ~ 2.01 (lH, br s, NH), 2.26 (lH, d, J=14.6), 2.52 (lH, d, J=14.6), 2.96 (3H, s), 3.03 (lH, dt, J=14.0, 2.0), 3.17 (lH, td, J=12.1, 4.0), 3.70 (lH, dd, J=11.4, 3.0), 3.46 (lH, s), 4.21 (lH, td, J=ll.9, 2.9), 4.30 (2H, s), 6.66-6.78 (3H, m), 7.06 (lH, t, J=7.6), 7.18-7.31 (3H, m), 7.58 (lH, d, J=7.9); m/z (ES+) 412 (M+l, 100%).

E~AMPLE 32 10 ~2R~3S,9R)-4-Aza-1,7-dioxa-3-(4-fluorophenYl)-9-methoxv-9-(2-methoxy-5-(trifluoromethylh~henyl)sPiro ~5.41 decane The benzylamine of F"r~mple 25 was hydrogenated according to the method of Example 9 to yield the title compound as an oil (272mg, 88%).
lH NMR (360MHz, CDCl3) ~ 2.26 (lH, d, J=13.9), 2.2-2.5 (~2H, br s), 2.49 15 (lH, d, J=13.7), 3.00 (3H, s), 3.03 (lH, m), 3.16 (lH, dt, J=12.2, 3.7), 3.64(3H, s), 3.71 (lH, dd, J=11.5, 2.8), 3.93 (lH, d, J=9.8), 3.96 (lH, s), 4.31 (lH, dt, J=ll.9, 2.9), 4.44 (lH, d, J=9.7), 6.81 (lH, d, J=8.6), 6.88 (2H, t, J=8.7), 7.25 (lH, d, J=2.1), 7.39-7.47 (3H, m); 771/Z ~ES+) 442 (M+l, 100%).

(2R~3S,9R)-4-Aza-1,7-dioxa-3-~4-fluorophenyl)-9-methoxy-9-(2-rnethvlphenyl)sT)iro~5.41decane The benzylamine of 33xarnple 26 was hydrogenated accor ding to the method of Example 9 to yield the title compound as a glass (35mg, 47%).
25 lH NMR (360MHz, CDCl3) ~ 2.14 (lH, d, J=13.9), 2.16 (lH, m), 2.28 (3H, s), 2.56 (lH, d, J=13.9), 2.86 (3H, s), 3.05-3.20 (2H, m), 3.76 (lH, dd, J=12.2, 2.9), 4.05 (lH, d, J=9.a), 4.13 (lH, m), 4.46 (lH, m), 4.49 (lH, d, J=9.5), 6.64 ~lH, d, J=7.6), 6.84 (2H, t, J=8.5), 6.88- ~lH, m), 7.03-7.10 (2H, m), 7.49 (2H, dd, J=8.5, 5.3); ~71/~, (ES+) 358 (M+l, 100%).

CA 0224~78 1998-08-0~

EXAMPI.E 34 (2R,3S,9R)-4-Aza-1.7-dioxa-9-(2-ethYlphenyl)-3-(4-fluorophenvl)-9-methoxv-sPiror6.41decane The benzylz~lmine of Example 27 was hydrogenated according to the method of Example 9 to yield the title compo~nd as an oil (85mg, 81%).
lH NMR (250MHz, CDCl3) ~ 1.14 (3H, t, J=10.7), 2.07 (lH, br s), 2.22 (lH, d, J=l9.9), 2.49 (lH, d, J=l9.9), 2.68 ~2H, q, J=10 8), 2.90 (3H, s), 3.02 (lH, dd, J=17.5, 3.4), 3.18 (lH, td, .,T=17.3, 5.0), 3.72 (lH, td, J=16.5, 4.2), 3.92-3.99 (2H, m), 4.27 (lH, td, J=16.9, 4.3), 4.47 (lH, d, J=13.5), 6.71 (lH, d, J=ll l), 6 76-6.96 (3H, m), 7.11-7.19 (2H, m), 7.30-7.42 (2H, m).

(2R,3S~9R)-4-Aza-4-(5-(N.N-dimethvlaminomethvl)- 1,2,3-triazol-4-yl)methyl- 1,7 -dioxa-3-(4-fluoroPhenvl)-9-methoxY-9- (2-methoxy-5-(trifluoromethvl)phenvl)spiro r5.41 decarle The title compound was prepared from the azide of Description 8 according to the method of Example 19 to yield a foam (86mg, 76%).
lH NMR (360MHz, CDCl3) ~ 2.24 (lH, d, J=14.0), 2.50 (6H, s), 2.55 (lH, d, J=14.0), 2.76 (lH, br d, J=11.2), 2.97 (3H, s), 3.24 (lH, d, J=13.9), 3.50 (lH, s), 3.55 (lH, d, J=14.0), 3.68 (lH, m), 3.69 (3H, s), 3.86 (3H, m), 4.19 (lH, dt, J=11.8, 2.1), 4.47 (lH, d, J=9.8), 6.8~ (IH, d, J=8.6), 6 95 (2H, t, J=8.5), 7.21 (lH, d, J=l.9), 7.47 (lH, dd, J=8.7, 1.9), 7.5 (~2H, br s), 7.8-8.4(~lH, br s); m/x ~ES+) 580 (M+1, 100%).

~XAMPLE 36 (2R,3S,9R)-4-Aza-4-(5-(N,N-dimethYlaminomethvl)- 1~2,3-tctrazol-4-vl)methyl- 1,7-dioxa-3-(4-fluoroPhenvl)-9-methoxY-9-(2-(trifluoromethvl)phenyl)spiro~5.41decane The title compound was prepared from the azide of Description 10 according to the method of Example 19 to vield a yellow foam (124mg, 69%). lH NM:R (3~0MHz, CDC13) ~ 2.19-2.27 (7H, m). 2.50-2 61 (2H, m), CA 0224~78 l998-08-0~

2.82 (lH~ br d, J=11.6), 2.96 (3H, s~, 3.20 (lH, d, J=14.0), 3.41 (lH, s), 3.48 (2H, s), 3.61 (lH, d, J=14.0), 3.64 (IH, br d, J=l.0), 4.16 (lH, dt, J=9.4, 2.3), 4.25 (lH, d, J=9.8), 4.29 (lH, d, J=4.3), 6.64 (lH, d, J=7.9), 6.79 (lH, br s), 7.10 (lH, t, J=7.6), 7.23 (lH, t, J=7.7), 7.60 (lH, d, J=7.9); m/z (ES+) 550 (M+l, 100%).

EXAMPLES 37A and 37B
(2R.3S~9R)-4-Aza-1,7-dioxa-3-~4-fluoroPhenvl)-9-methoxv-4-(1-(S~-phenvlethYl)-9-(2-methoxY-5-(trifluoromethYl)phenyl)sl~iror5~4~decane; and 10 (2R~3S,9R~-4-Aza-1.7-dioxa-3-(4-fluoroPhenvl)-9-methoxY-4-(l-(R)-phenvlethYl)-9-(2-methoxY-5-(trifluoromethYl)Phenyl)spiro r5.41decane The morpholine of Example 32 was reacted according to the method of Example 20 to yield the less polar title compound (Example 37A) as an oil (39mg, 25%),1H NMR (360MHz, CDC13) ~ 1.14 (3H, d, J=6.9), 2.32 (lH, 15 d, J=14.0), 2.36 (IH, d, J=11.7), 2.53 (lH, d, J=14.2), 2.62 (lH, dt, J=11.7,3.3), 2.97 (3H, s), 3.60 (lH, dd, J=ll.l, 1.7), 3.67 (lH, q, J=6.8), 3.69 (3H, s), 3.83 (2H, m), 4.17 (lH, dt, J=11.4, 2.1), 4.3 (lH, d, J=9.7), 6.81 (lH, d, J=8.6), 6.88 (2H, t, J=8.7), 7 17-7.42 (7H, m), 7.46 (lH, dd, J=8.7, 1.6), 7.58 (~2H, br s); m/z (;ES+) 546 (M+l, 100%); and the morepolar title 20 compound (Example 37B) as an oil (47mg, 30%), lH NMR (360MHz, CDCl3) ~ 1.35 (3H, d, J=7.1), 2.19-2.34 (~3H, m), 2.42 (lH, d, 14.0), 2.90 (3H, s), 2.96 (lH, d, J=11.4), 3.37 (lH, s), 3.69 (3H, s), 3.70-3.77 (3H, m), 4.28 (lH, dt, J=11.4, 2.4), 4.35 (lH, d, J=10.0), 6.80 (lH, d, J=8.6), 6.88-6.99 (4H, m), 7.16 (lH, d, J=l.9), 7.20-7.29 (3H, m), 7.41-7.49 (~4H, m);
25 1~1 /z (;~S+) 546 (M+ 1, 100%).

(2R~3S,9R)-4-Aza- 1,7-dioxa-3-(4-fluoroPhenvl)-9-methoxY-9-(2-methoxv-5-(tri~Luoromethyl)phenvl)-4-((2-(trifluorometh~tl)PhenYl)methyl)-30 s~iror~i.41 decane The title compound was prepared from the morpholine of Example 32 according to the method of F',~m~le 21 to yield a glass (67mg, 73%).
lH NMR (360MHz, CDCl3) ~ 2.32-2 43 (2H, m), 2.57 (lH, d, J=14.1), 2.71 (lH, br d, J=11 6), 2.99 (3H, s), 3.18 (lH, dd, J=14.7, 1.7) 3.50 (lH, d, J=14.9), 3.54 (lH, s), 3.65 (lH, dt, J=11.5, 1.6), 3.69 (3H, s), 3.83 (lH, d, J=9.8), 4.29 (lH, dt, J=11.8, 2.2), 4.45 (lH, d, J=9.7), 6.81-6.91 (3H, m), 7.24-7.30 (2H, m), 7.45-7.55 (~5H, m), 7.95 (lH, d, J=7.7); m/~ (ES+) 600 (M+l, 100%).

:E~AMPkE 39 (2R~3S,9R)-4-Aza-1~7-dioxa-3-(4-fluorophenvl)-9-methoxv-9-(2-methoxv-5-(trifluoromethYl)phenvl)-4-((3-(trifluoromethYl)PhenYl)methyl) spiror5.41decane The title compound was prepared from the morpholine of Example 32 according to the method of Example 21 to yield a glass ~54mg, 59%).
lH NMR (360MHz, CDCl3) ~ 2.26 (lH, d, J=14.0), 2.28 (lH, m), 2.47 (lH, d, J=14.0), 2.67 (lH, br d, J=11.4), 2.77 (lH, d, J=13.5), 2.90 (3H, s), 3.38 (lH, s), 3.54 (lH, d, J=13.6), 3.59 (lH, m), 3.62 ~3H, s), 3.76 (lH, d, J=9.8), 4.20 (lH, dt, J=11.8, 2.2), 4.35 (lH, d, J--9.8), 6.75 (lH, d, J=8.6), 6.81 (2H,t, J=8.7), 7.15 (lH, d, J=2 1), 7.28-7.41 (5H, m), 7.44 (~2H, br s): m/~ (ES~) 600 (M+l, 100%) (2R,3S~9R)-4-Aza-1,7-dioxa-3-(4-fluoro~henvl)-9-methoxv-9-(2-methoxy-5-(trifluoromethvl)Phenvl)-4-((4-(trifluoromethYl)phenvl)methYl)-spiror6.41decane The title compound was prepared from the morpholine of Example 32 according to the method of Example 21 to yield a glass (63mg, 69%).
lH NMR (360MHz, CDC13) ~ 2.34 (lH, d, J=14.0), 2.36 (lH, dt, J=ll 7, 3.4), 2.55 (lH, d, J=14.0), 2.74 (lH, br d, J=11.5), 2.84 (lH, d, J=13.7). 2.98 (3H, s), 3.46 (lH, s~, 3.62 (lH, d, J=14.3), 3.68 (lH, m), 3.70 (3H. s), 3.83 CA 0224~78 1998-08-0~
WO 97/30056 PCT/G~97/00404 (lH, d, J=9.8), 4.27 (lH, dt, ~=12.0, 2.6), 4.44 (lH, d, J=9.8), 6.83 (lH, d, J=8.6), 6.88 (2H, t, J=8.7'?, 7.23 (lH, d, J=2.1), 7.36 (2H, d, J=8.0), 7.47 (lH, dd, J=9.0, 1.9), 7.51 (4H, m); m/z (ES~) 600 (M+l, 100%).

EXA3!.!1PLE 41 (2R,3S,9R)-4-Aza-1,7-dioxa-3-(4-fluoroPhenvl)-9-methoxv-4-¢(2-methoxyphenvl)methvl)-9-(2-methoxv-5-(trifluoromethvl~PhenYl) s~iror5.41decane The title compound was prepared from the morpholine of Example 32 according to the method of Example 21 to yield an oil (63mg, 74%).
lH NMR (360MHz, C~DCl3) ~? 2.32-2.40 (2H, m), 2.53 (lH, d, J=13.9), 2.86 (lH, br d, J=11.7), 2.97 (3H, s), 3.03 (lH, d, J=13.8), 3.40 (lH, d, J=13.8), 3.46 (lH, s), 3.65 (lH, dd, J=11.4, 2.13, 3.67 ~lH, m), 3.69 (3H, s), 3.72 (3H, s), 3.81 (lH, d, J=9.8), 4.27 (lH, dt, J=11.8, 2.1), 4.41 (lH, d, J=9.8), 6.76-6.91 (5H, m), 7.15-7.25 (2H, m), 7.38 (lH, br d, J=6.g), 7.46 (lH, dd, J=8.6, 1.8), 7.50 (~2H, br s); m/z (ES+) 562 (M+l, 100%).

(2R,3S,9R)-9-Allvloxy-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-phenvl-s~iro~5.4]decane The title compound was prepared from the alcohol of Example 1 and allyl bromide according to the method of Example 22 to yield an oil (62mg, 59%). lH NMR (36(!MH~, CDCl3) ~? 2.24 (lH, d, J=14.2), 2.32 (lH, dt, J=11.8, 3.5), 2.47 (lH, d, J=14.2), 2.78 (lH, d, J=13.3), 2.78 (lH, m), 3.43 (lH, s), 3.61-3.84 (5H, m), 4.23 (lH, dt, J=11.7, 2.5), 4.28 (lH, d, J=9.2), 5.10 (lH, dq, J=10.4, 1.6), 5.28 (lH, dq, J=17.2, 1.7)? 5.83-5.93 (lH, m), 6.77-6.81 (2H, m), 6.96 (2H, t, J=8.7~?, 7.08-7.28 (8H~ m), 7.55 (~2H, br s);
m/z (ES+) 460 (M+l, 100%).

(2R,3S,9R)-4-Aza-4-benzvl- 1,7-dioxa-3-(4-fluorophenyl) -9-Phenvl-9-(phenylmethvloxY)spiror5.4~decane The title compound was prepared from the alcohol of l~ mI~le 1 and benzyl bromide according to the method of Example 22 to yield an oil which solidified on st~n~ing (99mg, 77%). lH NMR (360MHz, CDCl3~ ~
2.29 (lH, d, J=14.2), 2.35 (lH, dt, J=ll.9, 3.3), 2.58 (lH, d, J=14.2), 2.80 (2H, m), 3.45 (lH, s~, 3.64 (lH, m), 3.68 (lH, d, J=13.8), 3.79 (lH, d, J=9.3), 4.16 (lH, d, J=11.6), 4.26 (lH, dt, J=11.5, 1.7), 4.33-4.38 (2H, m), 10 6.85-6.89 (2H, m), 6.95 (2H, t, J=8.6), 7.11-7.32 (13H, m), 7.56 (~2H, br s); m/z (ES+) 510 (M+1, 100%).

(2R,3S.9R)-4-Aza-1,7-dioxa-3-(4-fluoroPhenvl)-9-PhenYl-9-propyloxy-15 spiror5.41decane The benzyl~rnin~ of F'.~r~mple 42 was hydrogenated according to the method of Example 9 to yield the title compound as an oil (27mg, 67%).
H NMR (360MHz, CDCl3) ~ 0.84 (3H, t, J=7.3), 1.54 (2H, sx, J=7.2), 1.84 (~lH, br s), 1.98 (lH, m), 2.15 (lH, d, J=14.1), 2.31 (lH, d, J=13.9), 2.40 20 (lH, d, ~=14.1), 2.94-3.23 (~4H, m), 3.66-3.70 (~lH, m), 3.82 (lH, d, J=9.2),3.93 (lH, s), 4.18-4.25 (lH, m), 4.29 (1~, d, J=9.1), 6.71-6.92 (~3H, m), 7.04-7.11 (3H, m), 7.20-7.41 (~2H, m); m/~ (ES+) 372 (M+1, 100%).

25 (2R~3S.9R~-4-Aza-4-benzYl-1.7-dioxa-9-fluoro-3-(4-fluoroPhenYl)-9-Phen sPiro ~5.41 decane Nitrogen was bubbled through a solution of the alcohol of Example 1 (250mg, 0.60mmol) in dichloromethane (6ml) in a NalgeneT~ flask for 5 minutes before cooling to -78~C. Diethylaminosulfur trifluoride (83,u1, 30 0.63mmol) was added dropwise and the solution stirred at -78~C for 4 hours. The reaction mixture was quenched at -78~C by the addition of WO 97/30056 PCT/GB97/~0404 water (20ml), diluted with dichloromethane (20ml), separated and the organic layer dried (MgSO4) and concentrated to a gum (317mg). The crude residue was purified by medium pressure silica gel chromatography eluting with 5:1 hexane:ethyl acetate to yield the title compound (~3:1 mixture of diastereomers) as the least polar component as an oil (65mg, 26%); lH NMR (360MHz, CDCl3) ~ 2.23-2.59 (~3H, m), 2.75-2.92 (~3H, m), 3.50 and 3.54 (lH total, 3:1, 2 x s), 3.61-3.78 (~21~I, m), 3.98-4.42 (~2H, m), 6.96-7.36 (12H, m), 7.54-7.68 (~2H, br s); 13C NMR (90.6MHz, CDCl3, DEPT) ~ 24.66 (CHz), 35.83 (CH2), 45.41 and 45.46 (CH2), 46.41, 46.46, 10 46.53, 46.68 and 46.83 (CH2), 54.69, 55.14, 55.83 and 56.41 (C~2), 66.88, 66.98 and 67.45 (CH), 73.25 and 73.54 (CH7), 75.33 and 75.65 (CH2), 109.6~, 109.88 and 110.63 (CH), 118.47, 118.58, 118.99, 119.46 and 119.56 (C~H), ~20.81, 121.99, 122.03, 122.59, 122.76, 123.16, 123.19, 123.23, 123.30, 123.80, 123.83 and 123.92 (CH~, 127.01, 127.09, 127.27 and 127.36 15 (CH), 13~.90 (CH); m/z (ES+) 422 (M+l, 100%), 402 ~M-19, 28).

(2R,3S~9R)-4-Aza-1,7-dioxa-9-fluoro-3-(4-fluoroPhenYl)-9-phenyl-spiro[5.41decane The benzyl~mine of Example 45 was hydrogenated according to the method of l~ mple 9 to yield the title compound as an oil (18mg, 46%);
m/~ (ES+) 332 (M+1, 18%), 102 (100) 25 (2R,3S,9R~-4-Aza-4-benzYl-1.7-dioxa-3-(4-fluoroPhenYl)-9-hYdroxy-9-(2 (hvdroxymethvl)phenyl)spiro~5.41decane The product of Description 12 (350mg) was heated at ref~ux in a solution of 1~.01 HCl (2ml) and water:ethanol (lOml, 1:1) The ethanol was removed by distillation and the aqueous residue basified (NaHCO~) and 30 extracted with ethyl acetate ~3x30ml~. The combinecl organic cxtracts were washed with water and saturated brine (lx30ml cach), dried W0971300~i6 - 71 - PCT/GB97100404 ~MgSO4) and eoneentrated to a erude oil whieh was purified by flash silica gel ehromatography eluting with 9:1 to 4:1 hexane:ethyl aeetate to yield ~ the title eompound as an oil (136mg, 52%). m/z (ES+) 450 (M+1, 100%).

~0 ~ ~0/

F~

[2'R-r2'a(5*),4'a]1-3"-(4-~uoroPhenYl)-4"-(phenvlmethvl)dispiro-risobenzofuran-1(3H3~4'(5'~)-furan-2'(3EO,2"-morpholine]
Methanesulfonyl~hlori-l~ (23~L1, 0.29mmol) was added to a solution of the diol of Example 47 (130mg, 0.29mmol) and triethylamine (81~
0.58mmol) in diehloromethane (5ml) eooled to 0~C. The resulting mixture was allowed to warm to 20~C and stirred for 18 hours. The reaetion mixture was washed sequentially with l.OM citric acid, water and saturated brine, dried (MgSO4) and concentrated to a yellow oil which was purified by flash siliea gel ehromatography eluting with 19:1 to 4:1 hexane:ethyl acetate to yield the title compound as white foam (9Omg, 72%). lH NMR (360MH~, CDCl3) ~ 2.12 (lH, d, J=14.2), 2.28-2.36 (lH, m), 2.37 (lH, d, J=14.2), 2.82 (lH, d, J=12.7), 2.77-2.88 (lH, m), 3.50 (lH, s), 3.62-3.76 (3H, m), 4.24 (lH, d, J=9.7), 4.20-4.30 (lH, m), 5.03 (2H, s), 6.09 (lH, d, J=7.4), 7.02-7.30 (lOH, m), 7.65 (2H, br s); 771/~ (ES+) 432 (M+1, 100%) .

~fo~ , F ~

r2'R-r2'a(5*).4'a]1-3"-(4-fluoroPhenYl)disPirorisobenzofuran-1(3H~.4'(~i'H)-furan-2'(3H),2"-morpholinel The benzylamine of Example 48 was hydrogenated according to the method of ~,~rnple 9 to yield the title compound as a foam (15mg, 38%).
lH NMR (360MHz, CDCl3) ~ 2.02 ~lH, d, J=14.2), 2.23 (lH, d, J=14.2), 3.05 (lH, dd, J=9.~i, 2.7), 3.21 (lH, td, J=12.3, 3.6), 3.77 (~H, d, J=9.8), 3.74-3.82 (lH, m), 4.01 (lH, s), 4.28 (lH, d, J=9.8), 4.25-4.33 (lH, m), 5.04 (2H, s), 6.19 (lH, d, J=7.5), 7.02-7.13 (4H, m), 7.17 (lH, d, J=6.6), 7.48-7.54 (2H, m); m/z (~S+) 342 (M~l, 100%).

Claims (27)

CLAIMS:

1. A compound of the formula (I):

wherein R represents hydroxy, C1-6alkoxy, C3-6alkenyloxy, C3-6-alkynyloxy, fluoroC1-6alkoxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, phenoxy, benzyloxy or halogen, wherein the phenyl moiety of said phenoxy or benzyloxy is optionally substituted by one, two or three substituents selected from C1-6alkyl, C1-6alkoxy, halogen and trifluoromethyl;
R 1 represents hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, C1-4alkyl substituted by a C1-4alkoxy or hydroxy group, hydroxy, trimethylsilyl, nitro, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, CONR aR b, NR aR b, SO2NR aR b, or OC1-4alkylNR aR b, where R a and R b are each independently hydrogen or C1-4alkyl;
R 2 and R3 each independently represent hydrogen, halogen, C1-6alkyl, C1-6alkoxy substituted by C1-4alkoxy or trifluoromethyl;
or R and R 1 may be joined such that -R-R1- is a linkage selected fLom -O-CH2- and -O-CH2CH2-:
or, where R 1 and R 2 are attached to adjacent carbon atoms, they may be joined such that, together with the carbon atoms to which they are attached, there is formed a 5- or 6-membered ring optionally containing 1 or 2 heteroatoms selected from oxygen, sulfur or nitrogen, or 1 or 2 groups selected from S(O), S(O)2 and NR a, which ring may also contain 1 or 2 double bonds, where R a is as previously defined;
R 4 represents hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, C1-4alkyl substituted by a C1-4alkoxy group, trifluoromethyl, nitro, CN, SR a, SOR a, SO2R a, COR a, CO2R a, CONR aR b where R a and R b are as previousiy defined;
R 5 represents hydrogen, halogen, C1-6alkyl, C1-6alkoxy substituted by C1-4alkoxy or trifluoromethyl;
R 6 represents hydrogen, COR a, CO2R a, COCONR aR b, COCO 2R a, C1-6alkyl optionally substituted by a group selected from (CO 2R a, CONR aR b, hydroxy, CN, COR a, NR aR b, C(NOH)NR aR b, CONHphenyl(C1-4alkyl), COCO 2R a, CONHNR aR b, C(S)NR aR b, CONR aC1-6alkylR 12, CONR 13C2-6alkenyl, CONR 13C2-6alkynyl, COCONR aR b, CONR aC(NR b)NR aR b, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from C1-6alkyl, C1-6alkoxy, halogen and trifluoromethyl);
or R 6 represents a group of the formula -CHaC~CCH2NR 7R 8 where R 7 and R 8 are as defined below;
or R 6 represents C1-6alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =O or =S and optionally substituted by a group of the formula ZNR 7R 8 where Z is C1-6alkylene or C3-6cycloalkyl;
R 7 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R 8 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 R 7, R 8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy 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 NR c moiety where R c 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;
R9a and R9b each independently represent hydrogen or C1-4alkyl, or R9a and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a C5-7 ring;
R12 represents ORa, CONR aRb or heteroaryl;
R13 represents H or C1-6alkyl;
m is zero, 1, 2 or 3; and n is zero, 1, 2 or 3; with the proviso that the sum total of m and n is 2 or 3;
or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 wherein R represents hydroxy, C1-3alkoxy, C3-5alkenyloxy, phenoxy or halogen.

3. A compound as claimed in claim 1 or claim 2 wherein R1 represents hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, C1-4alkyl substituted by a C1-4alkoxy group, OCF3, hydroxy, trifluoromethyl, trimethylsilyl, nitro, CN, SR a, SOR a, SO2R a, COR a, CO2R a, CONR a R b where R a and R b are each independently hydrogen or C1-4alkyl; and R2 and R3 each independently represent hydrogen, halogen, C1-6alkyl, C1-6alkoxy substituted by C1-4alkoxy or trifluoromethyl.

4. A compound as claimed in any one of claims 1 to 3 wherein R 1 is hydrogen, C1-4alkyl, C1-4alkoxy, halogen, fluoroC1-3alkyl or fluoroC1-3alkoxy.

5. A compound as claimed in any one of claims 1 to 4 wherein R 2 is hydrogen, C1-4alkyl, C1-4alkoxy, halogen or CF3.

6. A compound as claimed in any one of claims 1 to 5 wherein R 3 is hydrogen, fluorine, chlorine or CF3.

7. A compound as claimed in any one of claims 1 to 6 wherein R 4 is hydrogen.

8. A compound as claimed in any one of claims 1 to 7 wherein R 5 is hydrogen, fluorine, chlorine or CF3.

9. A compound as claimed in any one of claims 1 to 8 wherein R 9a and R 9b are each independently hydrogen or methyl.

10. A compound as claimed in any one of claims 1 to 9 wherein n is 1.

11. A compound as claimed in any one of claims 1 to 10 wherein m is 1 or 2.

12. A compound of formula (Ia) wherein R and R6 are as defined in claim 1;
A1 is hydrogen, C1-3alkyl, C1-3alkoxy, halogen, fluoroC1-3alkyl or fluoroC1-3alkoxy;
A2 is hydrogen, halogen, C1-4alkyl or fluoroC1-3alkyl; and A3 is hydrogen or halogen;
or a pharmaceutically acceptable salt thereof.

13. A compound as claimed in any one of claims 1 to 12 wherein R6 is hydrogen, C1-3alkyl substituted by phenyl wherein said phenyl ring is optionally substituted by C1-3alkoxy or CF3, or R6 is a group of formula -CH2C~CCH2NR7R8, or R5 is C1-3alkyl substituted by a 5-membered heterocyclic ring selected from:

; ; ;

; ;

and

14. A compound selected from:
(2R,3S,9R)-4-aza-4-benzyl-1,7-dioxa-3-(4-f1uorophenyl)-9-hydroxy-9-phenyl-spiro [5.4] decane;
(2R,3S,9R)-4-aza-4-benzyl- 1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxyphenyl)spiro [5.4] decane;
(2R,3S,9R)-4-aza-4-benzyl- 1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl- 1,7-dioxa-3-(4-fluorophenyl)-9-hydloxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4] decane;
(2R,3S,9S)-4-aza-4-benzyl- 1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-(trifluoromethoxy)phenyl)spiro[5.4]decane;
(+/-)-(2R*.3S*,9R*)-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methylphenyl)spiro[5.4]decane;
(2R,3S.9R)-4-aza-4-benzyl- 1,7-dioxa-9-(2-ethylphenyl)-3-(4-fluorophenyl)-9-hydroxy-spiro[5.4]decane;

(2R,3S,9R)-4-aza-4-benzyl-9-(2-chlorophenyl)- 1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-spiro[5.4] decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-phenylspiro[5.4]decane;
(2R,3S,9R)-4-aza- 1,7-dioxa-3 -(4-fluorophenyl)-9-hydroxy-9-(2-methoxyphenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza- 1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4] decane;
(2R,3S,9S)-4-aza- 1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-(trifluoromethoxy)phenyl)spiro[5.4]decane;
(+/-)-(2R*,3S*,9R*)-4-aza- 1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methylphenyl)spiro[5.4] decane;
(2R,3S,9R)-4-aza-4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxyphenyl)spiro[5.4] decane;
(2R,3S,9R)-4-aza-4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-(trifluoromethyl)phenyl)-spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-(4-(N,N-dimethylamino)-but-2-ynyl)-1,7-dioxa-3-(4-fluorphenyl)-9-hydroxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)-spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-(5-(N,N-dimethylaminomethyl)- 1,2,3-triazol-4-yl)methyl-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-4-(1(S)-phenylethyl)-9-(2-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza- 1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-4-(1(R)-phenylethyl)-9-(2-(trifluoromethyl)phenyl)spiro[5.4] decane:

(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-4-((2-(trifluoromethyl)phenyl)methyl)-9-(2-(trifluoromethyl)phenyl)-spiro[5.4]decane;
(+/-)-(2R*,3S*,9R*)-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-phenyl-spiro[5.4]decane;
(2R, 3S,9R)-4-aza-4-benzyl- 1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxyphenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl- 1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl- 1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4]decane;
(+/-)-(2R*,3S*,9R*)-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methylphenyl)spiro[5.4] decane;
(2R,3S,9R)-4-aza-4-benzyl-1,7-dioxa-9-(2-ethylphenyl)-3-(4-fluorophenyl)-9-methoxy-spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl-9-(2-chlorophenyl)-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-spiro[5.4]decane;
(+/-)-(2R*,3S*,9R*)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-phenyl-spiro [5.4]decane;
(2R,3S,9R)-4-aza- 1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxyphenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza- 1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4] decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methylphenyl)spiro[5.4]decane:
(2R.3S,9R)-4-aza-1,7-dioxa-9-(2-ethylphenyl)-3-(4-fluorophenyl)-9-methoxy-spiro[5.4] decane;

(2R,3S,9R)-4-aza-4-(5-(N,N-dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl- 1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-(5-(N,N-dimethylaminomethyl)-1,2,3-tetrazol-4-yl)methyl-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-4-(1-(S)-phenylethyl)-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza- 1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-4-(1-(R)-phenylethyl)-9-(2-methoxy-5-(trifluoromethyl)phenyl)spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)-4-((2-(trifluoromethyl)phenyl)methyl)-spiro[5.4] decane;
(2R,3S,9R)-4-aza- 1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)-4-((3-(trifluoromethyl)phenyl)methyl)-spiro[5.4] decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-9-(2-methoxy-5-(trifluoromethyl)phenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-methoxy-4-((2-methoxyphenyl)methyl)-9-(2-methoxy-5-(trifluoromethyl)phenyl) spiro[5.4]decane;
(2R,3S,9R)-9-allyloxy-4-aza-4-benzyl-1,7-dioxa-3-(4-fluorophenyl)-9-phenyl-spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl- 1,7-dioxa-3-(4-fluorophenyl)-9-phenyl-9-(phenylmethyloxy)spiro[5.4]decane;
(2R,3S,9R)-4-aza-1,7-dioxa-3-(4-fluorophenyl)-9-propyloxy-9-spiro[5.4]decane;
(2R,3S,9R)-4-aza-4-benzyl- 1,7-dioxa-9-fluoro-3-(4-fluorophenyl)-9-phenyl-spiro[5.4]decane;

(2R,3S,9R)-4-aza- 1,7-dioxa-9-fluoro-3-(4-fluorophenyl)-9-phenylspiro[5.4] decane;
(2R,3S,9R)-4-aza-4-benzyl- 1,7-dioxa-3-(4-fluorophenyl)-9-hydroxy-9-(2-(hydroxymethyl)phenyl)spiro[5.4]decane;
[2'R-[2'.alpha.(S*),4'.alpha.]]-3"-(4-fluorophenyl)-4"-(phenylmethyl)dispiro-[isobenzofuran-1(3H),4'(5'H)-furan-2'(3H),2"-morpholine];
[2'R-[2'.alpha.(S*),4'.alpha.]]-3"-(4-fluorophenyl)dispiro[isobenzofuran- 1(3H),4'(5'H)-furan-2'(3H),2"-morpholine];
or a pharmaceutically acceptable salt thereof.

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

16. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 14 in association with a pharmaceutically acceptable carrier or excipient.

17. 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.

18. A method according to claim 17 for the treatment prevention of pain or inflammation.

19. A method according to claim 17 for the treatment prevention of migraine.

20. A method according to claim 17 for the treatment prevention of emesis.

21. A method according to claim 17 for the treatment or prevention of postherpetic neuralgia.

22. The use of a compound as claimed in any one of claims 1 to 14 for the manufacture of a medicament for the treatment or prevention of a physiological disorder associated with an excess of tachykinins.

23. The use of a compound as claimed in any one of claims 1 to 14 for the manufacture of a medicament for the treatment or prevention of pain or inflammation.

24. The use of a compound as claimed in any one of claims 1 to 14 for the manufacture of a medicament for the treatment or prevention of migraine.

25. The use of a compound as claimed in any one of claims 1 to 14 for the manufacture of a medicament for the treatment or prevention of emesis.

26. The use of a compound as claimed in any one of claims 1 to 14 for the manufacture of a medicament for the treatment or prevention of postherpetic neuralgia.

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

(A), where R is a hydroxy group, reacting a compound of formula (II) wherein R4, R5, R6, R 9a, R 9b, m and n are as defined in claim 1 with a Grignard or organolithium compound of formula (IIIA) or (IIIB) wherein R1, R2 and R3 are as defined in claim 1 and Hal is a halogen atom;
or (B), where R is a group selected from C1-6alkoxy, C3-6alkenyloxy, C3-6alkynyloxy, fluoroC1-6alkoxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, phenoxy or benzyloxy, reacting a compound of formula (IV) with a suitable alkyl halide, alkenyl halide, alkynyl halide, fluoroalkyl halide, cycloalkyl halide, cycloalkylalkyl halide, phenyl halide or benzyl halide; or (C), where R is a halogen atom, reacting a compound of formula (IV) with a suitable halogenating reagent; or (D), where R 6 is H, debenzylating the corresponding compound of formula (I) in which R 6 is a benzyl group; or (E), reacting a compound of formula (V) wherein R, R1, R2, R3, R4, R5, R 9a, R 9b, m and n are as defined in claim 1, with a compound of formula (VI) where R 6a is a group of the formula R 6 as defined in claim 1 or a precursor therefor and LG is a leaving group; and, if R 6a is a precursor group, converting it to a group R 6; or (F), where R 6 represents a 1,2,3-triazol-4-ylmethyl group substituted by CH2NR7R8, reacting a compound of formula (VII) with an amine of formula NHR 7R 8; or (G), where R 6 represents a C1-6alkyl group which is substituted by an unsubstituted or substituted 1,2,4-triazolyl group, reacting a compound of formula (V) with a compound of formula (VIII) wherein Hal is a halogen atom, p is an integer from 1 to 6 and R 18 is H, CONH 2 or OCH 3 (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) by reduction of the CONH 2 group to CH 2NH2; or (II). interconversion of a compound of formula (I) into another compound of formula (I); or (J), where R 6 represents the group -CH2C~CCH 2NR 7R 8, reacting a compound of formula (X) wherein Hal is a halogen atom, with an amine of formula HNR 7R 8 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.