Note: Descriptions are shown in the official language in which they were submitted.
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~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.
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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
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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;
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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,
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-- 5 --
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;
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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
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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
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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:
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_ 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.
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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,
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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.
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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;
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(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;
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(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;
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- 15 -
(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
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- 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~
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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)
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WO 97/30056 PCT/GB97/00404
- 18 -
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
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WO 97/30056 PCT/GB97/00404
- 19 -
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,
WO 97/300S6 PCT/GB97/00404
- 20 -
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
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WO 97/30056 PCT/GB97/00404
- 21 -
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~
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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
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- 23 -
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
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- 24 -
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~
W097/300S6 PCT/GB97/00404
- 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
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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
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- 27 -
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
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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),
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~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.
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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
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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.
= ~
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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
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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
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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)
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lG J~ ~ ( CH, ) p H~ll
NH2
(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
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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
H2N R32
(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.
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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)
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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
R5
(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):
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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
R5
(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
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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.
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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)
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R2
~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
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- 43 -
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"
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The following non-limiting Examples serve to illustrate the
preparation of compounds of the present invention:
DESCRIPTION 1
(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).
DESCRIPTION 2
(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%
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- 45 -
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,
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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%).
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DESCRIPTION 5
(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%).
DESC3RIPTION 6
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%).
DESCRIPTION 7
(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
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(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%).
DESCRIPTION 8
(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%).
DESCRIPTION 9
(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%).
DESCRIPTION 10
(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%).
DESCRIPTION 11
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
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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
EXAMPLE 1
(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
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(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%).
EXAMPLE 2
(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),
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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
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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%).
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EXAMPLE 6
(+/-)-(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%).
EXAMPLE 7
(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%).
EXAMPLE 8
(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%).
EXAMPLE 9
(2R,3S,9R)-4-Aza-1,7-dioxa-3-(4-fluoroPhenvl)-9-hYdroxy-9-
Phenylspirol5.41decane
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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).
EXAMPLE 11
(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),
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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%).
EXAMPLE 12
(2R,3$~9R)-4-Aza-1,7-dioxa-3-(4-fluoroPhenvl)-9-hYdroxY-9-(2-methoxY-5
(trifluoromethyl)phenYl)sPiro ~5.4l decane
The benzylamine of Example 4A was hydrogenated according to the
method of Example 9 to yield the title compound as an oil (80mg, 70%).
lH NMR (360MHz, CDC13) ~ 1.7-2.1 (~lH, br s), 1.91 (lH, d, J=13.1), 2.59
(lH, d, J=13.0), 3.06 (lH, dd, J=12.4, 2.0), 3.22 (lH, dt, J=12.3, 3.6), 3.32
(3H, s), 3.73 (lH, dd, J=ll.l, 2.7), 4.04 (lH, s), 4.07 (lH, d, J=8.9), 4.34
(lH, dt, J=11.7, 2.9), 6.75 (lH, d, J=8.6), 7.04 (2H, t, J=8.6), 7.43-7.52 (3H,
m), 7.92 (lH, d, J=2.3); m/z (ES+) 428 (M+l, 100%).
EXAMPLE 13
(2R.3S,9$)-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
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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%).
EXAMPLE 16
(+/-)-(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
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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).
EXAMPLE 17
(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%).
EXAMPLE 18
~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
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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%).
EXAMPLE 19
(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,
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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%)
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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).
EXAMPLE 23
(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,
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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).
EXAMPLE 25
(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%).
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EXAMPLE 26
(+/-)-(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%).
EXAMPLE 27
(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%)
EXAMPLE 28
(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-
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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%).
EXAMPLE 29
(+/-)-(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).
EXAMPLE 31
(2R,3S,9R)-4-Aza-1,7-dioxa-3-(4-fluoroPhenvl~-9-methoxY-9-(2-
30 (trifluoromethyl)phenYl)sPiror5.4~decane
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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%).
EXAMPLE 33
(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%).
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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).
EXAMPLE 35
(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),
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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%).
EXAMPLE 38
(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
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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%)
EXAMPLE 40
(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
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(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%).
EXAMPLE 42
(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%).
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EXAMPLE 43
(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%).
EXAMPLE 44
(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%).
EXAMPLE 45
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
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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).
EXAMPLE 46
(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)
EXAMPLE 47
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
CA 02245578 1998-08-05
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%).
EXAMPLE 48
~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%) .
CA 02245578 1998-08-05
WO 97/30056 - 72 - PCTIGB97100404
EXAMPLE 49
~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%).
