Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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SPIRO-KETAL l)ERTVATIVE~ AND 'l'~ JSE ~S
THERA~UTIC AGENTS
This invention relates to a class of spiroketal compounds which are
useful as tachykinin antagonists. The present invention also relates to
processes for their preparation, pharmaceutical compositions cont~ining
the~n, arld to their use ill therapy.
The tachykinins are a group of naturally occurring peptides found
widely distributed throughout ln~mm~ n tissues, both within the central
nervous system and in periphera~ nervous and circulatory systems.
The tachykinins are distinguished by a conserved carboxyl-terminal
sequence:
Phe-X-Gly-Leu-l~et-NH2
At present, there are three known m~mm~ n tachykinins referred
1~ to as substance P, neurokinin A (NKA, substance K, neuromedin L) and
neurokinin ~3 (NKB, neuromedin K~ (for review see J E. Maggio, Peptides
(198~) 6(suppl. 3~, 237-242~. The current nomenclature designates the
three tachykinin receptors mediating the biological actions of substance P,
NI~ and NKB as the NI~l~ NK2 and N~3 receptors, respectively
Evidence for the use~ulness of tachykinin receptor antagonists in
pain, headache, especially migraine, Alzheimer's disease, multiple
sclerosis, att~nuation of morphine withdrawal, cardio~rascular changes,
oedema, such as oedema caused by thermal injury, chronic infl~n~matory
diseases such as rheumatoid arthritis asthma/bronchial h~-perreacT:ivity
and other respiratory diseases including allergic rhinitis, in Fl~mmator~r
diseases of the gut including u lcerati~e colitis and Crohn's disease, ocular
inJury and oculal inflammatory diseases, proliferati~re vitreoretinopathy,
ilritable bowel syndromne and disorders of bladder function including
~ cystitis and bladder detruser hyper-refle~ia is reviewed in "Tachykinin
30 Receptors and Tachykinin Receptor Antagonists", C.A. Maggi, R.
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Patacchini, P. Rovero and A. Giachetti, J. Auton. Pharmacol. (1993) 13,
23-93.
For instance, substance P is believed inter alia to be involved in the
neurotr~l~smi~sion of pain sensations [Otsuka et al, "Role of Substance P
~i as a Sensory Tr~n~mitter in Spinal (~ord and Sympathetic Ganglia" in
7982 Substance P in the Nervous System, Ciba Foundation Symposium 91,
13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does
Substance P Act as a Pain Transmitter?" TIPS (1987) 8,506-&10],
specifically in the tr~n.~mi~.qinn of pain in migraine (B.E:.B. Sandberg et al,
J. Med Chem., (1982) 25, 1009) and in arthritis [Levine et al Science (1984
226, E;47-549]. Tachykinins have also been implicated in gastrointestinal
(GI) disorders and diseases of the C~I tract such as infl~mrnator~r bowel
disease ,lMantyh et al Neuroscie7?,ce (1988~ 25(33, 817-37 and ~. Regoli in
"Trends i71, Cluster Headache" Ed. Sicuteri et al Elsevier Scienti~ic
~5 Publishers, Amsterdam (1987) page 85)] and emesis [F. D. Tattersall et al,
Eur. J. Pharmacol., (1993) 25(), R~-R6~. It is also hypothesised that there
is a neurogenic me~ 3ni~rn for arthritis in which substance P may pla~T a
role LKidd et al "A NeurogerLic Mec~t~ni~m for Symmetrical Arthritis" in
The La7lcet, 11 November 1989 and Gronblad et al, ''Neuropeptides in
20 Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J.
Rhell7natol. ~1988) 15(12),1807-10]. Therefore, substance P is believed to
be involved in the infl~mm~3tory response in diseases such as rheumatoid
arthritis and osteoarthritis, and f ibrositis ~O'Byrne et al, Art~ritis and
Rheur7latis77~ (1990) 33, 1023~8~ Other disease areas where tachykinin
2~ antagonists are believed to be useful are allergic conditions [~Iamelet et al,
Can. 3. Pharmacol. Physiol. (1988) 66, t 361-7~, immunoregulation ~Lotz et
a7., Science (1988) 241~ 1218-21 and I~imball e~ al, J. Immt~7l01. (1g88
l4l~10), 3~64-9] vasodilation, bronchospasm, reflex or neurollal control of
the viscera [Mantyh et c~l, PlYAS (1988~ 8~, 323~-9] and, possibly by
30 arresting or slowing B-amyloid-mediated neurodegenerative~ changes
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[Yankner et al, Science (1990) 2~0, 279-82] in senile dementia of the
Alzheimer type, Alzheimer's disease and I)ownrs Syndrome.
Tachykinin antagonists may also be useful in tlle treatment of small
cell carcinomas, in particular small cell lung cancer (SCL~) ~I.angdon et al,
Cancer Research ~1992) 52, 4554-7~.
~ubstance P may also play a role in demyelinating diseases such as
multiple sclerosis and amyotrophic lateral sclerosis ~J. Luber-Narod et al,
poster C~.I.N.P. XVlIIt~ Congress, 28th June-2nd July ~992~, and in
disorders of bladder function such as bladder detrusor hyper-reflexia
(I,ancet, 16th May 1992, 1239).
It has furthermore been suggested that tachykinins have utility in
the following disorders: depression, dysthymic disorders, chronic
obstructive airways disease, hypersensitivity disorders such as poison ivy,
vasospastic diseases such as ~n~in~ and Reynauld's disease, fibrosing and
collagen diseases such as sclero~erma and eosinophilic fascioliasis, reilex
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 specir1cation no. 0 436
334), ophth~lmi~ 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
fipecification no. 0 394 989).
European patent specifical;ion no. 0 577 394 (published 5th Januar~7
2~ :L994) discloses morpholine and thiomorpholine tachykinin receptor
antagonists of the general fvrmula
R3~ X' ~~
7~~ N Rs7~
wherein p,l'l is a large variety of substituents:
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R2a and R3~ are i71~ter al~a hydrogen;
R'li' is tnter alia
R6ZI
R
R~i is ~rl,ter alia optionally substituted E~henyl;
R~a, R7a and R8" are a variety of substituents;
~a iS 0, S, SO or SO2;
ya is in?;er alia O; and
Zll is hydrog,en or C1 ~,alkyl.
We have now found a ~urther 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!7b T~ R4 R3
R6 ~
R
~r)
wherein
Rl r eplesents hydrogen, halogen, C~ ~,alk~rl, C2 Galken~,rl, C2 Galk~n~ l.
C3 7cycloalk~rl, C3 7cycloalkylCI ~al~yl, C~ Galkox~, fluoroCI ~alkyl,
fluoroCl Galkoxy, Cl 4alkyl substituted by a ~ alkoxy or hydloxy gl~OU}~,
hydloxy, trimethylsilyl, nitro, CN, SR~, SO:Ra, SO2RI', CORI~, CO2R~,
CONRaRb. NR~R~, SO2NRaR~, or OCI,~alk~,rlNRaRb7 where Ri~ and Rl~ are
2~ each independently hydrogen or Cl 4alkyl;
~ 2 lepresents hydrogen, halogen, C~ Galk~ alkoxy substitute(l
h~y Cl ~alko~y or trifluo~omethvl;
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or, where R1 and R2 are attached to adjacent carbon atoms, they
may be joined such that, together with the carbon atoms to which they are
attached, there is formed a 5- or 6-membered ring optionally containing 1
or 2 heteroatoms selected from oxygen, sulfur o~ nitrogen, or 1 or 2 groups
5 selected ~rom S(O), S(O)2 and NRa, which ring may also contain 1 or 2
double bonds, where Ra is as previously defined;
R3 rep~ esents a 5- or 6-membered aromatic hetcrocyclic group
cont~inin~ 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and
sulphur, which group is optionally substituted by a group selected from
Cl Galkyl, Cl 6alkoxy, C3 7cycloalkyl, C3.7cycloalkylCI 4alkyl,
trifluoromethyl, OCF3, NO2, CN, SRa, SORa, S02Ra, CORa, CO2Ra, phenyl,
-(CH2)rNRaRb~ ~(CH2)rNRaCORh~ ~(CE~2)rCONRaRb~ or CH2C((~)Ra, where Ra
and Rb are each independently hydrogen or C1 4alkyl and r is zero, ~ or 2;
R4 represents hydrogen, halogen, Cl Galkyl, C2.~alkenyl, C2 Galkynyl,
~5 C3 7cycloalkyl, C3 7cycloalkylCl.4alkyl, Cl ~;alkoxy, Cl 4alkyl substitut~d by a
C~ 4alkoxy group, trifluoromethyl, nit~o, CN, ~Ra, SORa, SO2Ra, CORa,
CO2Ra, CONRaR~ where Ra and Rb are as previously defined;
R5 represents hydrogen, halogen, Cl.~alkyl, Cl (;alkoxy substituted
by C] ,~alkoxy or trifluoromethyl;
R~ represents hydrogen, CORa, CO2R~', COCONRaRb, COCO2Ra,
C1 Galkyl optionally substituted by a group selected from (CO~Ra,
CONR~qR~, hydloxy, CN, CORa, NRaRb, C~NOH~NRaRi~,
CONHphenyl(Cl 4alkyl), COCO2Ra, CONHNRaRb, C(S)NR"Rl~,
CONRa~l~alk~lRl2, CONRl3C2Galkenyl, CONR~3C~Galkynyl. COCONRaRb,
CONRaC~NRb~NRaRb, CONE~aheteroa:ryl, and phen~ l optionally substituted
by one, two or three substituents selected ~om Cl Galkyl, C~ Galkoxy,
halogen and t1ifluoromethyl~;
or RG replesents a group of the formu]a -C~7C-CC~R7R8 where
R/ and R8 are as defined below;
3~ Ol R(i represents Cl.Galkyl, optionally substituted by o~;o. substitutecl
by a 6-membeled or 6-membered heterocyclic ring ~ontainin~, ~ or 3
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nitrogen atoms optionally substituted by =O or =S and optionally
substituted by a group of the formula ZNR7R8 where
~ is Cl Galkylene or C3.~cycloalkyl;
R7 is hydrogen or Cl.4alkyl, (~3.7cycloalkyl, C3 7cycloalkylCl.,.alkyl, or
C2 lalkyl substituted by C1.4alkoxy or h~droxyl;
R8 is hydrogen or C~ 4alkyl, C3 7cycloalkyl, C3 7cycloalkyl~l ~alkyl, or
C~.4alkyl substituted by C~.4alkoxy, hydroxyl or a 4, 5 or 6 membered
heteroaliphatic ring cont,.ining one or two heteroatoms selected from N, O
and S;
or R7, R8 and the nitrogen atom to which they are attached form a
heteroaliphatic ring of 4 to 7 ring atoms, optionally suhstituted by one or
two groups selected from hydro~y or C1 4alkoxy optionally substituted by a
Cl 1~lko~y or hydroxyl group, and optionally cont~ining a douhle bond,
which ring may optionally contain an oxygen or sulphur ring atom, a
group S~O3 or S~O~2 or a second nitrogen atom which will be part of a NH
or NRC moiety where Rc is Cl.4alkyl optionally substituted by hydroxy or
Cl 4alkoxy;
or R7, R3 and the nitrogen atom to which they are attached form a
non-aromatic azabicyclic ring system of 6 to 1~ ring atoms;
or ~, R~ and the nitrogen atom to which they are attached form a
heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain a
oxygen ring atom;
R9a and R9b each independently represent hydrogen or C~ alkyl, Ol
R9~- and R9b are joined so, togethe~ ith the carbon atoms to which they are
attached, there is formed a C5., ring;
Rl~ represents ORa, CONRaRb or heteroaryl;
Rl3 represents H or Cl.~;alkyl;
m is zero, 1, 2 or 3; and
n is zero, 1, ~ or 3; with the proviso that the sum total of m and n is
~ or 3;
and pharmaceutically acceptable salts thereof.
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A preferred class of compound of formula ~I) is that wherein R1 is a
methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy or trifluorometho~y
group, especially a methoxy group.
Another preferred class of compound of formula (I) is that wherein
5 R2 is a hydrogen, fluorine or chlorine atom, especially a hydrogen atom.
A further preferred class of compound of formula (I) is that wherein
R4 is a hydrogen atom or a fluorine atom.
Another preferred class of compound of formula (I) is that in which
R5 is a hydrogen atom.
Also preferred is the class of compound of formula (I) in which R9a
and R9b are both hydrogen atoms.
Preferably n is zero.
Prefexably m is 1 or 2, especially 1.
A further preferred class of compound of formula (I) is that wherein
~5 RG is a hydrogen atom.
Also pre~erred is the class of compound of formula (I~ in which R~ is
a Cl 6alkyl group, in particular CH2, CH(C~I3) and CH2CH2 and especially
CEI2, substituted by a 5-membered heterocyclic ring con~ining 2 or 3
nitrogen atoms as previously defined.
~20 ln particular, the 5-membered ring is a heterocyclic ring selected
from:
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H H~ H
n ~3/ N N 3/
0~ ~ ; <~ ;
ZNR R
N~ NR7R8 ~; and <~
ZNR R ZNR R
Particularly prefe~red heterocyclic rings are selected ~om:
H3/ 0 =~ N~ 7 8
N ~ N ~ ; anc~ < ~/
ZNR R ZNR R N ~\
ZNR R
Most especially, the heterocyclic ring is selected from:
<\ ~ ; o=3< ~ ; an~ HN X'
ZNR R 7i zNR7R8 ~ ZNR R
A particularly preferred heterocycllc ring is
HN
'~ %NR R
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Certain particularly apt compounds of ~he present invention include
those wherein R3 is a group selected from pyrrole, furan, thiene, pyridine,
pyrazole, imidazole, oxazoIe, isoxazole, thiazole, isothiazole, pyrazine,
5 pyrimidine, pyridazine, triazole, oxadia~ole, thiadiazole, triazine, and
tetra~ole, each heteroaryl group being optional~y substituted as previously
defined.
Preferred compounds o~ the present invention are those wherein R3
is a group selecl;ed from furan, pyridine, pyrazole, imidazole, oxazole,
isoxazol~, pyrazine, pyrimi-lin~, thiazole, 1,2,3-triazole, 1,2,~-triazole,
1,2,4-oxadiazole, 1~3,~-oxadiazole and tetrazole, each heteroaryl groups
~eing optionally substituted as pre~iously defined.
Particularly pre~erred compounds of the present invention are those
wherein R3 is a group selected ~rom furan, pyridine, pyrimi-line, 1,2,3-
triazole, 1,2,4-triazole and tetrazole.
An especially preferred class of compound of ~ormula (I) is that
wherein R3 is the group
N~ R'
N
~0
where Rl~ is hydrogen, halogen, Cl ~;alkyl, Cl (ialkox~-, CF3, OCF3, NO~. CN,
SRq, SORa, SOzRa, CORa, CO2Ra, (CH2)rCONR~Rb~ (CH~)rNRaRb or
(CH2)rNRlCOR~J, where Ra and Rb are hydrogen or Cl .~alkyl, and r is zelo,
1 Ol 2
Allother esp~cially p~e~erred class of compoUllc~ of folmula (I) is that
wherein ~3 is the group
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N- N
N
wherein Rl~ is as pr~viously defined.
Rl~ is preferably hydrogen, Cl 4alkyl, especially methyl or CF3.
One favoured group of compounds of the present inYention are of the
formula (Ia~ and pharmaceutically accepta~7le salts thereof:
.~
N~ R4 R3
R
(Ia)
wherein Rl, R2, R:~, R4, R5, m and n are a~ defined in relation to formula (I).
Another favoured group of compounds of the present invention are
of the formula ~ ) and pharmaceutically acceptable salts thereo~:
Rl
O_ (C~ ~ " R
N ~ R5
:ZNR7 R8
( Ib3
wherein ~l, R', R3, R~, R~, rm and n are de~ined in relation ~o formula (I)~ Q
15 is CH Ol N and Z, R/ and R~ are as defined in relatiun t.o fo~ l~ula (I).
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With respect to compounds of thc formulae (I) and (Ib), Z (where
present), may be a linear, branchecl or cyclic group. Favourabl~ Z contains
1 to 4 carbon atoms and most favourably 1 or 2 carbon atoms. A
particularly fa~rourable group Z is C~H,
With respect to compounds of th~ formulae ~1) and (Ib), R~ may aptl~
be a Cl ~alkyl group or a C2 4alkyl group substituted by a hydroxyl or
Cl 2alkoxy group, R8 may aptly be a C~ ~all~yl group or a Cl.4all{~l group
substituted by a hydroxyl or Cl 2alkoxy group, or R~ and R8 ma~ be linked
so that, together with the nitrogen atom to which they are attached, they
form an azetidinyl, pyrrolidin~rl, piperidyl, morpholino, thiomorpholino,
piperazino or piperazino group substituted on the nitrogen atom by a
Cl 4alkyl group or a C~4alkyl group substituted by a hydroxy or Cl ~alko~y
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 azabic~ clic ring
system, such a system may contain between 6 and 12, and prefeLably
between 7 and 10, ring atoms Suitable rings include
5-azabicyclo~2.1.1]hexyl, 5-azabicyclo[~.2.1]heptyl, 6-a~abicyclo[3.2.1~octyl,
2-azabicyclo[2.2.2~octyl, ~-a~abicyclo~3.~.2~nonyl, 6-azabicycloL3.3.1]nonyl,
~i-a~abicyclo~3.2.2]decyl, 7-azabicyclo~4.3.1]decyl,
7-azabicyclo[4.4. l]undecyl and 8-azabicyclo[5.4. l]dodecyl, especially
5-azabicyclo~2.2. 13heptyl and 6-a~abicyclo[3.2. l]oct~l.
W~ere ~8 represents a (~ ~alkyl group substitute(l by ~ 5 or ~,
memhered heteroaliphatic ring containing one or two heteroatoms selected
fiom N, O and S, suitabl~ rings include pyrrolidino, piperidino, l~iperazino,
morpholino, or thiomorpholino. Particularly prefelred are nitrogen
containing heteroaliphatic rings, especiall~ pyrrolidino and morpholino
3(~ gs.
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In the group ZNR7R8, ~ is preferably CH~ or C~>CH~, and especially
CH~.
The group NR7R8 preferably represents amino, methy~amino,
dimethylamino, cliethylamino, azetidinyl, pyrrolidino and morpholino.
In particular, NR7R8 is preferably dimethylamino, azetidinyl or
pyrrolidino, especially dimethylamino.
Where Rl and R2, together with the carbon ato_s to which they are
attached, ~orm a 5~ or 6-membered ring optionally cont~inin~ 1 or 2
heteroatoms selected from oxygen, su~fur or nitrogen, or 1 or '~. groups
selected from S(O), S(O)~ and NR,a, ana which ring may also contain 1 or 2
double bonds7 it will be appreciated that the ring thus formed may be
saturated, partially saturated or unsaturated. Thus, Rl and R2 may
represent, for example, -OCH2C~2CH~.-, -OCH>CH20-, -OC~I~CE2-,
-OCH20-, -NRaCH2CH2CH2-, -NRaCH2CH2-, -C~I2(:~E2CH2CH~-,
1~ -CH2CH2CH2-, -CH=C~-CH=C~I-, -O-C~I=CH-, -NRa-CH=CH-, -S-CH=~
, -N:Ra-(~H=N-, -O-CH=N-, -S-CH=N-, -N=C~-CH=CH-. -CH=N-CH=C~I- .
Particularly pre~rred linkages formed by Rl and R2 include,
-OCH2CH2CH2-,-OC~2CH20-,-OCH2CH2-,-OCH20-,-~TRaCH~ I2CH2-
and -CH=CH-CH-CH-. In these examples, RQ preferably represents a
~0 hydrogen atonl.
As used herein, the term "alkyl" or ~Calko~y~ as a group or part of a
group means that the group is straight or branched. :~;amples of suitable
alkyl groups include methyl, ethy]., n-propyl, i-prop~-l, n-butyl, s-butyl and
t-butyl. Examples of suitable alkoxy groups include metho~y, ethoxy.
n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
The cycloalkyl groups referred to herein ma-~ represellt, for example,
cyclopropyl, cyclobutyl, cyclopentyl or cyclohex~-l. A suitable
cycloalkylalkyl group may be, for example, cyclopropylmethyl.
As used herein, the terms "alkenyl" and alkyllyl as a group or pal t
Or a group means that the group is straight or l~rallched. F,~-~mples o~
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- 13 -
suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group
is propargyl.
~s used herein, the terms "fluoroCl ~alkyl" and "fluoroCl 6alkoxy"
means a Cl ~alkyl or Cl ~all~ox~ group in which one or more (in particular,
~ to 3) hydrogen atoms have ~een replaced by a fluorine atoIn
Particularly preferred are ~luoroC~l 3alkyl and fluoro~l 3alkoxy groups, for
example, CF3, CHgCH2F, CH2CHFz, CH2CF3, OC~3, OCH2CH2F,
O~H~C~1~2 or OCH2CF3, and most especially CF3 and O(~F3.
When used herein the term halogen means fluorine, chlorine,
bromine and iodine. The most apt halogens are fluorine and chlorine of
which ~uorine is preferred.
~;pecific conlpounds within the scope of this invention include:
(2S,3$)-~-aza-1,7-dioxa-(9S)-(3-tetrazol-l-yl)phenyl-3-(4-
fLuorophenyl)spiro~ ]decane;
lEj (2S,3~;)-4-aza-1,7-dioxa-(9S)-(2-methoxy-5-(5-(trifluoromethyl)tetrazol-1-
yl))phenyl-3-(4-fluorophenyVspi~ o[4.5]decane;
~2S,3S)-4-aza-1,7-dioxa-~9S)-~2-methyl-5-(5-(trifluoromethyl)tetrazol-1-
yl))phenyl-3-(4-fluorophenyl)spiroL4.5]decane;
(2S,3S)-4-aza-1,7-dioxa-(9S)~(2-trifluoromethoxy-5-~5-
tri~1uoromethyl)tetrazol-1-yl))phenyl-3-(4-fluorophenyl)spiroL4.5]d~cane;
and pharmaceutically acceptable salts thereo~.
In a further aspect of the present invention, the compounds of
formula (I) will p~eferably be prepared in the form of a pharmaceutically
acceptable salt, especially an acid addition salt.
2~ For use in medicine, the salts of the compounds of formula (I) will be
non-toxic pharmaceutically acceptable salts. Other salts rnay, however, be
useful in the preparatioll of the compounds according to the invention Ol of
their non~toxic pharmaceutically acceptable salts Suitable
pharmaceutically acceptable salts of the compounds of this invention
30 include acid adtlition salts which may, for example, be ~ormed by ~ ing a
solution of the compound according to the invention with a solution of a
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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 thc
5 amino nitrogen atom carries a suitable organic group such as an alkyl,
alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of
the invention carry an acidic moiety, suitable pharmaceutically acceptable
salts thereof may include metal salts such as alkali metal salts, e.g.
sodium or potassium salts; and ~lk~line earth metal salts, e.g calcium or
10 magnesium salts.
The salts may be formed ~y conventional means, such as by reacting
the free ~ase form of the product with one or more equivalents of the
appropriate acid in a solvent or medium in which the salt is insoluble, Ol
in a solvent such as water which is removed i77. vacuo or by ~reeze drying or
15 by ex~h~n~;n~ the anions of an e~isting 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
20 convertible ~n viuo into the required compound of ~ormula (~).
Conventional procedures for the selection and preparation of suitable
prodrug derivatives are described, for exalnple, in "Design of Prodrugs",
ed. H. Bundgaard, Elsevier, 198~.
A p~odrug may be a pharmacologicall~y inactive derivat;ive of a
~5 biologically active ~ubstance (the "parent drug" or "parent molecule") that
requires transformation within the body in ordel to 1elease the active
drug, and that has improved delivery properties ovel the parent drug
molecule. The trans~ormation i7t vivo ma~7 be, for e~ample, as the result; of
som~ metabolic process, such as chemical or enzymatic hydrolysis of a
30 calbogylic, phosphoric or sulphate este-, or reduction or ogidation of a
susceptible ~unctiollality.
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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
5 diastereoisomers. It is to be understood that all such isomers and
mixtures thereof are encompassed within the scope of the present
}nvention.
The pre~erred compounds of the ~ormula (I), (Ia) and (Ib) will have
the preferred stereorhemi~try of the 2- and 3-position that is possessed by
10 the compound of Example 1 (i.e. 2-(S), 3-(S)). Thus for example as shown
in formula (Ic)
Rl
~ - ~ ~ R2
~~ (CH~)m \~
R~b ~ N ~ ~ R~ R3
(Ic)
The present invention further provides pharmaceutical compositions
15 comprising one or more compounds o~formula (I) in association with a
pharmaceutically acceptable carrier or excipient.
Preferabl~r the compositions accord~ to the i~lvention are in unit
dosage ~orms such as tablets, pills, capsules, powde~s, granules, solutions
or suspensions, Ol suppositories, for oral, parenteral or rectal
~0 a~lnlini.~tration, or administration by inhalation or insufflation.
For preparing solid compositions such as tablets, the principal
active ingredient is m~xed with a pharmaceutical callier, e.g. conventional
tableting ingredients such as corn stalch, lactose, suc~ose, sorbitol, talc
stearic acid, magnesium stearate, dicalcium phosphate or gums, and other
CA 02245579 1998-08-05
WO 97/30055 PCT/GB97/llO383
pharmaceutical diluents, e.g. water, to ~orm a solid preformulation
composition cont~ining 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
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 containing 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
dosage ~orm affording the advantage of prolonged action. For example, the
tablet or pill can comprise an inner dosage and an outer dosage
component, the ]atter being in the form of an envelope over the former.
The two components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permits the inner component to
pass intact into the duodenum or to be delayed in release. 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 salch materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present
invention may be incorporated ~or administration orally or by injection
include aqueous solutions, suitably flavoured syrups, a~Lueous or oil
suspensions, and flavoured emulsions with edible oils such as cottonseecl
~5 oil, sesame oil, coconut oil or peanut oil, as well as elixirs and .qimil~rpharmaceutical 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 ~o~ administration by injection include those
comprising a compound of formula (I), as the active ingredient, in
CA 02245579 1998-08-05
WO 97/30055 - 17 - PCT/G1~97100383
association with a surface-active agent ~or wetting agent or surfactant) or
in the form of an e~nulsion ~as a water-in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, non-ionic
agents, such as polyoxyethylen~sorbitarls (e.g. TweenTM 20, 4(), 60, 80 or
85) and other sorbitans ~e.g. SpanTM 20, 40, G0, 80 or 85~ ompositions
with a sur~ace-active agent will conveniently comprise between 0.~5 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 may be prepared using commercially available
fat emulsions, such as Intralipid , Liposyn , Infonutrol M, LipofundinTM
and LipiphysanTM. The active ingredient may be either dissolved in a pre-
mixed emulsion composition or alternatively it may be dissolved in an oil
(e.g. soybean oil, safflower oil, cottonseed oil, sesame oil~ corn oil or almondoil) and an emulsiorl formed upon mi~in~ with a phospholipid (e.g. egg
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 elnulsion. Suitable
emulsions will t~rpically contain up to 20% oil, fol example, between 5 and
20%. The fat emulsion will preferably comprise fat droplets between O.l
and l.O,um, particularly 0.1 and 0.5,um, and ha~e a pH in the range of 6.5
to 8Ø
Particularl~r preferred emulsion compositiolls are those prepared b~
mixing a compowld of ~orrnula (I) with IntralipidTM or the components
26 the~reof (soybean oil, egg phospholipids, glycerol and water).
Compositions for inhalation or insufflation include solutions and
suspensions in pharmaceutically acceptable, aqueous Ol organic solvents.
or mixtures thereof, and powders. The li~uid or solid coml~ositions may
contain suitable pharmaceutically acceptable excipients as se~ out ahove
Preferably the compositions are administered bV the oral or nasal
r espiratory r oute for local or svstemic effect. Compositiolls in preferabl~
CA 02245579 1998-08-05
WO 97/30055 PCT/GB97J~)0383
sterile phar~naceutically acceptable solvents may be nebulised by use of
inert gases. Nebulised solutions may be breathed directly from the
nebulising device or l;he nebulising device may be attached to a face mask,
tent or intermittent positive pressure breathing m~ hine. Solution,
suspension or powder compositions may be arlmini~tered? pre~erably orally
or nasally, 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),
10 which process comprises bring~ng a compound of ~ormula (I) into
association with a pharmaceutically acceptable carrier or excipient.
The compounds of formula (I) are of value in the treatment of a wide
variety of clinical conditions which are characterised by the presence of an
excess of tachykinin, in particular substance P, activity.
Thus, for example, an excess of tachykinin, and in particular
substance P, activity is implicated in a variety of disorders of the central
nervo~s 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,
20 or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and
cyclothymic disorder; anxiety disorders, such as panic disorder with or
without agoraphobia, agoraphobia without history of panic disorder,
specific phobias, for example. specific animal phobias, social phobias,
obsessiYe-compulsive disorder, stress disorders including post-traumatic
25 stress disorder and acute stress disorder, and generalised anxiety
disorders: schizophrenia and other psychotiG disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional disorders,
brief psychotic disorders, shared psychotic disorders and psvchotic
disorders with delusions or hallucinations; delerium, dementia, and
30 amnestic and other cognitive or neurodegenerative disorders, such as
Alzheimer's disease, senile dementia, dementia of the Alzheimer's type,
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WO 9't/30055 PCT/GB97/00383
- 19 -
vascular dementia, and other dementias, for example, due to lII~7 disease,
head trauma, Parkinson's disease, Huntington's disease, Pick's disease,
C~reutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson's
disease and other extra-pyrz~mi~ ovement disorders such as
5 medication-induced movement disorders, for e~:ample, neuroleptic-induced
parkinsonism, neuroleptic rnz3li~n~nt syndrome, neuroleptic-induced acute
dystonia, neuroleptic-induced acute akathisia, neuroleptic-irlduced tardive
dyskinesia and medication-induced postural tremour; substance-related
disorders arising from the use of alcohol, arnphetamines (or amphet~min~?-
10 like substances) caffeine, cannabis, cocaine, hallucinogens, inh~l~nts andaerosol propellants, nicotine, opioids, phenylglycidine derivatives,
sedatives, hypnotics, and anxiolytics, which substance-related disorders
include dependence and abuse, intoxication, withdrawal, intoxication
delerium, withdrawal delerium, persisting dementia, psychotic disorders,
15 mood disorders, anxiety disorders, se~ual dysfunction and sleep disorders;
epilepsy; I)own's syndxome; demyelinating diseases such as MS and ALS
and other neuropathological disorders such as peripheral neuropathy, for
example diabetic and chemotherap~r-induced neuropathy, and postherpetic
neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and
2~ other neuralgias; and cerebral vascular disorders due to acute or chronic
cerebrovascular damage such as cerebral infarction, subarachnoid
haemorrhage or cerebral oedcma.
Tachykinin, and in particular su~stance P, activit~r is also involved
in nociception and pain. The compounds of the present invention will
25 therefore be of use in the pre~rention or treatment of diseases and
conditions in which pain predominates, including soft tissue and
peripheral damage, such as acute traurna, osteoarthritis, rheumatoid
arthritis, musculo-skeletal pain, parl;icularly after trauma, spinal pain,
- dental pain, myofascial pain syndromes, headache, episiotomy pain, and
3() burns; deep and visceral pain, such as heart pain, muscle pain, e~re pain,
orofacial pain, for example, odontalgia, abdominal ~ain, gynaecological
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- 20 -
pain, for e~ample, dysmenorrhoea, and labour pain; pain associated with
nerve and root damage, such as pain associated with peripheral nerve
disorders, for example, nerve entrapment and brachial plexus avulsions,
amputation, peripheral neuropathies, tic douloureux, atypical facial pain,
5 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 pain.
Tachykinin, and in particular substance P, antagonists may also be
10 of use in the treatment of respiratory diseases, particularly those
associated with excess mucus secretion, such as chronic obstructive
airways disease, hronchopneumonia, chronic bron~hi~ , cystic ~ibrosis and
asthma, adult respiratory distress syndrome, and bronchospasm;
infl~mm~tory diseases such as intl,qmrnatory bowel disease, psoriasis,
15 fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn;
alle7 gies such as eczema and rhinitis; hypersensitivity disorders such as
poison ivy; opht.h~lmi-~. diseases such as conJunctivitis, vernal
con3unctivitis, and the like; ophthalmic conditions associated with cell
prolifcrati.on such as proli~erative vitreoretinopathy; cutaneous diseases
20 such as contact dermatitis, atopic dermatitis, urticaria, and other
eczematoid dermatitis.
Tachykinin, and in particular substance P, antagonists may also be
of use in the treatment o~ neoplasms, including breast tumours,
neuroganglioblastomas and small cell carcinomas such as small cell Lung
2~ cancer.
Tachvkinin, 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, disord~rs
30 associated with the neuronal control of viscera~ ulcerative colitis~ Crohn'~
disease, irlitable bowel syndrome and emefiis, illcludillg acutc~ delaycd or
CA 022455i9 1998-08-05
WO 9713Q055 PCTIGB~7100383
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
re:~ux disease, acid indigestion, over indulgence in food or drink, acid
stomach, waterbrash or regurgitation, heartburn, for example, episodic,
nocturnal or meal-induced ~}eartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be
of usc in the treatment of a variety of other conditions including stress
10 related somatic disorders; reflex sympathetic dystrophy such as
shoulder/hand syndrome; adverse immunological reactions such as
rejection of transplanted tissues and disorders related to imnlune
enhancement or suppression such as systemic lupus erythematosus;
plasma extravasation resulting from cytokine chemotherap~-, disorders of
15 bladder function such as cystitis, bladder detrusor hyper-re~Lexia and
incontinence; fibrosing and collagen diseases such as scleroderma and
eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and
vasospastic diseases such as angina, vascular headache, migraine and
Reynaud's disease; and pain or nociception attributable to or associated
20 with any of the foregoing conditions, especially the tr~n~n~i~sion of pain in
migraine.
The compounds o~ 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.
2~ The compounds of formula (I) are particularlv useful in the
treatment of emesis, including acute, delayed or anticipatol~- emesis. such
as emesis induced by cl emotherapy, radiation. roxins, plegnancy,
vestibular disorders, motion, surgery, migraine. and varia~ions in
- intercl anial pressure Most especially, the coml~ounds of ~ormula (I) are
30 of use in the treatment of emesis induced by antineoplastic (cytotoxic)
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WO 97/300S!; PCTfGB97/00383
- 2~ -
agents including those routinely used in cancer chemotherapy, and emesis
induced by other ph~rm~cologica~ agents, for example, rolipram.
Examples of such chemotherapeutic agents include a~kylating
agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl
sulphonates and other compounds with an alkylating action such as
nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic
acid, purine or pyrimidine antagonists; mitotic inhibitors, for example,
vinca alkaloids and derivatives of podophylloto~in; and cytotoxic
antibiotics .
Particular examples of chemotherapeutic agents are described, for
instance, by D. J. Stewart in Nausea and T~omiti77,g: Recent ~esearch and
~i7lical Adv~nces, Eds. J. Kucharczyk et a~, C:~C Press Inc., Boca Raton,
Florida, USA (lg91) pages 177-203, especially page 188. Commonly used
chemotherapeutic agents include cisplatin, dacarbazine ~DTIC),
1~ dactinomycin, mechloreth~min~ (nitrogen mustard~, streptozocin,
cyclophosph~mi-l~, carmustine (B~NU), lomustine (CCNU), doxorubicin
(adriamycin), daunorubicin, procarbazine, rnitomycin. cytarabine,
etoposide, methotre~ate, 5-fluorouracil, vinblastine, vincristine, bleom~rcin
and chlorambucil [R. J. Gralla et al in Ca71cer T~eatme7l,t Repor~s (1~84)
68(1), ~63-172].
The compounds of formula (I) are also of use in the treatment of
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 ~ormula (I) may be
presented together with another therapeutic agent ac a combined
preparation for simultaneous, separate or sequential use for the relief of
emesis. Such combined preparations may be, for e~alllple, in the form of a
twin pack.
A further aspect of the present inventiun comprises the compounds
of formula (I) in combination with a ~-HT3 antagonisr. such as
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WO 97/30055 PCT/GB97/00383
- 23 -
ondansetron, granisetron or tropisetron, or other anti-emetic
medicaments, for example, a dopamine antagonist such as metoclopramide
or GABAs receptor agonists such as baclofen. Additiona}ly, a compound of
formula (I) may be a~mini~tered in combination with an anti-
5 infl~mmatory corticosteroid. such as dexamethasone, triamcinolone,triamcinolone acetonide, flunisolide, budesonide, or others such as those
disclosed in US patent nos. 2,789,~18, 2,990,4()1, 3,048,.'i81, 3,126,375,
3,~29,768, 3,996,3~9, 3,928,326 and 3,749,712. Dexamethasone
(DecadronTM) is particularly preferred. Furthcrmore, a cornpound o~
10 formula (I) may be administered in combination with a chemothcrapeutic
agent such as an alkylating agent, antimetabolite, mitotic inhibitor or
cytotoxic antibiotic, as described above. In general, the currently available
dosage forms of the known therapeutic agents for use in such combinations
will be suita~le.
1~ When tested in the ferret model of cisplatin-induced emesis
described by F. D. Tattersall el~ al, in Eur. J. pharmcr,col., (1993) 260, R5-
R6, the compounds of the present invention were found to attenuate the
retching and vomiting induced by cisplatin.
The compounds of formula (I) are also particularly useful in the
treatment of pain or nociception andJor infl~mm?ltion and disorders
associated therewith such as, for example, neuropathy, such as diabetic
and chemotherapy-induced neuropath~T, postherpetic and other neuralgias,
asthma, osteroarthrit;s, rheumatoid arthritis, headache and especially
migraine
26 The prcsent invention further provide~ a compound of formula (I)
for use in therapy.
According to a further or alternative aspect, the present invention
provides a compound of ~ormula (I) for use in the manufacture of a
- medicament for the tleatment of physiological disorders associated with
an excess of tachykinills, especially substance P.
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WO 97/30055 PCT/GB97/00383
- 24 -
The present invention also provides a method for the the treatment
or prevention of physiological disorders associated with an excess of
tachykinins, especially substance P, which method comprises
a~mini.~tration to a patient in need thereof of a tachyl~inirL reducing
5 amount of a compound of formula (I) or a composition comprising a
compound of formula (I).
For the treatment of certain conditions it may be desirable to
employ a compound acco3~ding to the present invent;ion in conjunction with
another pharmacologically active agent. For example, for the treatment of
10 respiratory diseases such as asthma, a compound of formula (I) may be
used in conjunction with a bronchodilator, such as a ,B2-adrenergic receptor
agonist or tachykinin antagonist which acts at NK-2 receptors. The
compound o~ formula (I) and the bronchodilator may be administered to a
patient simultaneously, sequentially or in combination.
:15 Likewise, a co~pound of the present invention may be employed
with a leukotriene antagonists, such as a leukotriene D4 antagonist such
as a compound selected from those disclosed in ~uropean patent
specification nos. 0 480 717 and 0 604 114 and in US patent nos. ~,859,692
and 5,270,324. This combination is particularly useful in the treatment of
20 respiratory diseases such as asthma, chronic bronchitis and cough.
The present invention accordingly provides a method for the
treatment of a respilatory disease, such as asthma, which method
comprises a-1mi~ tration to a patient in need thereo~of an ef~ective
amount of a cnmpound of formula (I) and an effective amount of a
25 broIlchodilatol.
The present invention also provides a composition comprising a
compound of formula (I), a bronchodilator, and a pharmaceutically
acceptable caIrier.
It will be appreciated that for the treatn~ent or prevention of
3() migrain~, a compound of the present invention may be used in conjunction
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WO 97/30055 PCT/GB97/00383
- 25 -
with other anti-migraine agents, s,uch as ergotamines or 5-HTI agonists,
especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
Likewise, for the treatment of behavioural hyperalgesia, a
compound of the prcsent invention may he used in conjunction with an
antagonist of N-methyl D-aspartate (NMD~), such as di~ocilpine.
For the treatment or prevention of infl~mmatory conditions in the
lower urinary tract, especially cystitis, a compound of the present
invention may be used in conjunction with an ant.iinf',~mm~tory 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
conjunction with other analgesics, such as ace~,m~nophen (paracetamol),
aspirin and other NSAIDs and, in particular, opioid analgesics, especially
morphine. ~peci~ic anti-infl~mm~,tory agents include diclofenac,
15 ibuprofen, indomethacin, 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,
20 sufentanyl. meperidine, methadone, nalbuphine, propoxyphene and
pentazocine; or a pharmaceutically acceptable salt thereof. Preferled salts
of these opioid analgesics include morphine sulphate, morphine
hydrochloride, morphine tartrate, codeine phosphate, codeine sulphate,
dihydrocodeine bitartrate, diacetylmorphine hydrochloride, hydrocodone
25 bitartrate, hydromorphone hydrochlori~e, levorphanol tartlate,
oxymorphone hydrochloride, alfentanil hydrochloride, buprenorphine
hydrochloride, butorphanol tartrate, felltanyl citrate, meperidine
hydrochloride, methadone hydrochloride, nalbuphine hydrochloride~
- propoxyphene hydrochloride, propoxyphene napsylate
30 (2-naphthalenesulphonic acid (1:1) monohydrate), and pentazocine
hydrochloridc.
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WO 97/30Q5~; PCT/GB97/00383
- 26 -
Therefore, in a ~ur~her aspect of the present invention, there is
provided a pharmaceutical composition comprising a compound of the
present invention and an analgesic, together with at least one
pharmaceutically acceptable carrier or excipient.
In a fu~ther or alternative aspect of the present invention, there is
provided a product comprising a compound of the present invention and an
analgesic as a combined preparation for simultaneous, separate or
sequential use in the treatment or prevention of pain or nociception.
It wilI be appreciated that for the treatment of depression or
1() anxiety, a compound of the present invention may be used in conjunction
with other anti-depressant or anti-anxiety agents.
Suita~le classes of anti-depressant agent include norepinephrine
reuptake inhibitors, selective serotonin reuptake inhibitors (SSRls),
monoamine oxidase inhibitors (MAOIs), reversible inhibitors of
monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake
inhibitors (SNRIs), corticotropin releasing factor ~CRF) antagonists, a-
adrenoreceptor antagonists and atypicaI 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.
~uitable examples of secondary amine tricyclics include: amoxapine,
desipramine, maprotiline, nortriptyline and protriptyline, and
pharmaceutically acceptable salts thereo~
Suitable selective serotonin ~euptake inhibitors include: f~uoxetine~
fluvoxamine, paroxetine and sertlaline, and pharmaceutically accepta~le
salts thereo~.
Suitable monoamine oxidase inhibitors include: isocarl)oxa~id~
phenelzine, tranylcypromine and selegiline~ and pharmaceuticaIIy
3() acceptable salts thereof.
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WO 97/300S5 - 27 - PCTIGB97/00383
Suitable reversible inhibitors o~ monoamine oxidase include:
moclobemide, and pharmaceutically acceptable salts thereof.
~ uitable serotonin and noradrenaline reuptake inhibitors of use in
the present invention include: venl~f~xine, and pharmaceutically
5 acceptable salts thereof.
Suitable CRF antagonists include those compounds descri~ed in
International Patent Speci~cation Nos. WO 94/13~43, WO 94113G4~, WO
94/13661, WO 94113676 and WO 94/13677.
Suitable atypical anti-depressants include: bupropion, lithium,
10 nefazodolle, trazodone and viloxazine, and pharmaceutically acceptable
salts thereof.
Suitable classes of anti-anxiety agent include benzodiazepines and
~-HTlA agonists or antagonists, especially 5-HTl~ partiaL agonists, and
corticotropin releasing factor (CRF~ antagonists.
1~ Suitable benzodiazepines include: alprazolam, chlordiazepoxide,
clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam
and praz,epam, and pharmaceutically acceptable salts thereof.
~uitable 5-HTlA receptor agonists or antagonists include, in
particular, the ~5-HTIA reCeptOl partial agonists huspirone, ~lesinoxan,
2~) 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-depresfiant or anti-anxiety agent, together
writh at least one pharmaceutically acceptable carrier or excipient.
2 :} In a ~urther or alternati~re aspect of the present invelltion, there is
provided a product comprising a compound of the present invention and an
anti-depressant or anti-anxiety agent as a combined preparation ~or
simultaneous, separate or seqllential use ~or the treatment or prevention
of depression and/or anxiety
CA 02245579 1998-08-05
WO 97~30tlSS PCT/GB97/00383
- 28 -
The excel~ent pharmacological profile of the compounds of t;he
present invention offers the opportunity for their use in therapy at low
doses thereby minimi.~ing the risk of unwanted side effects.
In the treatment of the conditions associated with an excess of
tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in
particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about
1~ mg/kg per day.
For example, in the treatment of conditions involving the
neurotr~n.~mi.s.sion of pain sensations, a suitable dosage level is about
0.001 to 2~ mg/kg per day, preferably about 0.005 to 10 mg/kg per da~,r, and
especially about 0.005 to 5 mg/kg per day. The compounds may be
administered on a regimen of 1 to 4 times per day, preferably once or twice
per day.
In the treatment of emesis using an injectable formulation, a
~;uitable dosage level is about 0.001 to 10 mglkg per day, prefera~ly about
0.00~ to 5 mg/kg per day, and especially 0.01 to 1 mg/kg per day. The
compounds may be a~rnini.~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 ally treatment will vary not only with the particular
compounds or composition selected but also with the route of
~lmini.t;: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 ~o~ mula (I) in ~ hich
n is 1 and m is l or 2, may be prepared by the reduction of a compoulld of
rurmula (II)
CA 02245C~79 1998-08-05
WO !~7/30055 ~CT/GB97/00383
- 29 -
~gX~'~ /> ~\
~3 R4 R~
R5
aI)
wherein ~ is -CH= or -CH2CH=.
Suitable reducing conditions include: cata3ytic hydrogenation using
a metal catalyst such as palladium or platinum or hydroxides or oxides
5 thereof, preferably in a suitable solvent such as alcohol, e.g. methanol or
ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, Ol
a mixture thereof; borane in tetrahydrofuran; 9-boracyclo[3.3.1~nonane (9-
BBN) in an ether such as tetrahydrofuran; and lithium
triethylborohydride (Super-Hydride~M) in an ether such as
10 tetrahydrofuran.
According to another general process (B~, compounds of formula (I)
may be prepared by the interconversion of a corresponding compound of
formula (I) in which R~ is H, hereinafter referred to as compounds of
formula (LII)
R
g o ( C~
R9b H~--~R4 R3
~35
(III~
-
wherein Rl~ E~r7~ R3, R1, Rfi, R~3a, R9b, m and n are as defined in relation to
formula (I) b~ reaction with a compouncl of Çormula ~
CA 02245579 1998-08-05
WO 97/3005~ PCT/GB97/~0383
- 3C~ -
LG~R~;a (I~7)
where RGa is a group of the ~ormula R6 as defined in relation to formula (I
5 or a precursor there;fior and LG is a leaving group such as an alk~rl- or
arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g.
bromine, chlorine or iodine); and, if R6a is a precursor group, converting it
to a group R6 ~n which process any reactive group may be protected and
therea~ter deprotected if desired).
This reaction may be performed in conventional manner, for
e~ample in an organic solvent such as dimethyl~ormamide in the pr~sence
of an acid acceptor such as potassiu}n carbonate.
According to another process (C), compounds of formula (I) wherein
R~ represents a 1,2,3-triazol-4-ylmethyl group substituted by CH2NR7R8,
15 may be prepared by reaction of a compound of formula (V)
o _ (C~ ~ R
/~ ~ " I
~3 (V)
with an amine of formula NHR7RX, in a suitable solvent such as an ether,
20 for example, dioxan, at elevated temperatu1e, ~or example, between ~0~C
and 100~C, in a sealecl tube, Ol' the like This reactio~l is based upon t:hat~
descL~ibed in Chc777~ische Berichte (1989) 1~2. p. 1963
According to a i'urther process (V), compounds of ~ol1llula (I) whelei
R~ represents a Cl ~.alkyl group which is substitute~l by a~ nsubstitutf~d
-
CA 02245579 1998-08-05
WO 97/30055 PCT/<:~B97/00383
~ 31 -
or substituted 1,2,4-triazolyl group, may be prepared by reaction of an
intermediate o~ ~ormula (III) with a compound of formula (VI~
J~ NHN ( CH2 ) q Ha l
NH2
(VI)
5 wherei~ Hal is a halogen atom, for example, l~romine, chlorine or iodine, q
is an integer from 1 to 6 and Rl8 is ~, CONH~ Ol OCH:3 (which is converted
to an oxo substituent under the reaction conditions), in the presence o~ a
base, followed where necessary by conversion to a compound of formula ~I),
for example, by reduction of the CONH~ group to CH2NH2.
Suitable bases of use in the reaction include aLkali metal carbonates
such as, for example, potassium carbonate. The reaction is conveniently
effected in an anhydrous organic solvent such as, for exampl.e, anhydrous
dimethylformamide, preferably at elevated temperature, such as about
140~C.
A suitable reducing agent ~or the group CONH2 iS lithium
aluminium hydride, used at between -10~~ and room temperature.
~ ccording to another process ~E), compounds of formula (I~ may be
prepared fiom intermediates of formula (VII)
HO~
( f~l2 ) n
R~o~(CH2), ~R
R
(VI I )
~0
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WQ 97/300SS PCTIGB97/00383
- 32 -
by an acid catalysed intramolecular cyclisahon 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 alcohol, e.g. methanol~ at elevated
temperature, for example, at the ref~ux tempera~ure of the chosen solv~nt.
According to a further process (F), compounds of formula (I) may
also be prepared from other colnpounds of formula (I) using suitable
interconversion procedures. In particular, interconversion processes ma~r
be used to vary the group R';. F'or ~xample, compounds of formula (I)
wherein R~ is other than 1:1 may be prepared fiom the corresponding
compounds of formula ~I) wherein R~ is H by reaction with a reagent
suitable to introduce the group RG, for example, compounds of ~ormula (I)
wherein R~ is CORa may be prepared from compounds of formula (I)
wherein RG is H by, for example, reaction with an approp1iate acid
anhydride.
Compounds of formula (I) wherein RG is Gl l;alkyl may be prepared
from corresponding compounds of formula (I) wherein R'~ is CORa by
reduction using, for example, borane or a boroh~rdridc such as sodium
cyanoborohydride.
Compounds of formula (I) wherein R~ is Cl.~,alkyl substituted b~-
CONR;lRb may be prepared from corresponding compounds of formula (I)
wherein RG is Cl Galkyl substituted by CO2Ra by treatmenr with ammonia
or an amine of formula NRaR~.
Compounds of formula ~I) wherein Rc is Cl ~;alkyl substitutecl by ~-
oxadiazolyl may be prepar~d from compounds of folmula (I) wherein R~; is
Gl ~,alkyl substituted by COzRa, where Rl r~presents Gl (iall~yl, by reaction
with a compound of formula ~JIII)
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WO 97/3U05~; PCT/GBg7100383
- 33 -
NOH
~2N R32
(VIII )
- 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,
for example, sodiu~n, and alkali metal hydrides, such as, for example,
sodium hydride.
The reaction is conveniently effected in a suitable organic solvent.
Which solvents will be appropriate will depend on the nature of the base
used. For example, where the base used is an alkali metal, suitable
solvents will include alcohols, for example, ethanol, whereas where the
base used is an alkali hydride, suitable sol~ents will include ethers, for
example, tetrahydrofuran.
Preferably the reaction is conducted at elevated temperature, such
as the re~~ux temperature of the chosen solvent.
Compounds of formula (I) wherein RG is Cl.~alkyl substituted by
thiazol~Tl may be prepared from compounds o~ formula ~I) wherein R~ is
Cl.~alkyl substituted by ~SNH2 by reaction with a compound of formula
Hal-C~ C(O)-RG~, where Hal is a halogen atom, such a,s bromine, chlorine
or iodine, and RG~ represent~ H or a suitable substituent.
Compounds of formula (I) wherein E~ is Cl.Galkyl substituted b~
thio~otriazolyl may be prepared from compounds of formula (I~ wherein
is Cl (ialkvl substituted by CONHN~I2 by reaction with a compound of
formula RGlNCS, wherein RGI represents ~I or a suitable substituent such
as Cl.Galk~-l, in the presence of a base.
Suit:able bases of use in the reaction include organic bases such as~
fol example, 1,8-diazabicyclo[5 4.0]undec-7-ene (DBU) The reaction is
convenien~ly erfected in a suitable organic solvellt, such as alcohoL e.g.
butanol.
CA 02245579 1998-08-05
WO 97130055 PCTIGB97100383
- 3~ -
According to another general process (C~), compounds of formula (I)
wherein R3 is a tetrazol-l-~l group may be prepared by reaction of
intermediates of ~ormula (IX)
~ J-- (C~5)m~ R-
R~b
(I~)
with ammonium chloride and sodium a~ide at ele~7ated temperature,
conveniently in a solvent such as dimethylformamide.
According to another general process (H), compounds of formula (I:)
~0 may be prepared by a coupling reaction between a compound of formula
¢X) and ~XI)
X i (C>H2~/
R9b ~ R3-~4 1
(X) (~I)
15 wherein one of RJ~ and RJl is B(OH)2 or Sn(alkyl)3 or a clerivati~re thele~or,
and the other is a lea~ring group such as a halogen atom e.g. bromine Ol
iodine, Ol -OSO2C:F~. Where one of:R~~ and RJl is B¢OH)~ the reaction i~s
con~7enient;ly efrected in t;he presence of a palladiull~ (O~ caialyst such as
.
CA 022455i9 1998-08-05
WO 971300~;5 PCT/GB97/00383
- 3~ -
tetrakis(triphenylphosphine~palladium (0) in a suitable solvent such as an
ether, for example, dimethoxyethane at an elevated temperature. Where
one of R4~ and R41 is Sn(alkyl)3, the reaction is conveniently effected in the
presence of palladium (II) catalyst such as bis~triphenylphosphine)
5 palladium (TI) chloride, in a suitable solvent such as an aromatic
hydrocarbon, for e~ample, toluene, at an elevated temperature.
According to another general process (J~, compounds of ~ormula (I)
wherein RG represents a 1,2,3-triazol~4-ylmethyl group substituted by
CH~NR7R8, may be prepared by reaction of a compound of formula (XII)
o ~>EI~
\~ , ~(~H2)m
9~./~N~
NR7R8
(XII)
with an azide, for example, sodium azide in a suitable sol~ ellt such as
dimethylsulphoxide at a ten~perature of between 40~C ancl 1~)0~C followed
by rcduction of the carbonyl group adjacent to -NR7R~ using a suitable
reducing agent such as lithium aluminium hydride at a temperature
between -10~C and room tempe}~ature, conveniently ar room temperatule.
According to anothe1 ~eneral process (K), compounds of Lormula (I)
whe~ein RG represents the gl'Oup -CH2C-CCH2NR~R~ may be prepared
~0 ~rom a compound of fol~mula (~
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WO 97/30V55 PCT/GB97/nO383
- 36 -
R9~ ~ ~ i 2 I ~ ~ ~ R2
R J f ~ R
~/ R
Hal
~XIX)
wherein Hal is a halogen atom such as chlorine, bromine or iodine, b~
reaction with an amine of formula HNR7R~ in the presence of a base.
Suitable bases of use in the reaction include alkali metal carbonates
5 such as, for example, potassium carbonate. The leaction is conveniently
effected in an organic solvent such as, for example,
N,N-dimethylform~mide, conveniently at room temperature.
Further details of suitabIe procedures will be found in the
accompanying Examples.
Intermediates of formula ~II) are conveniently prepared b~r the
reaction of a compound of formula (XIII)
Compounds of formula (II) may be prepared by the reaction of a
compound of formula ~XIII~:
~ o~ ~R30
R~b N ~3--R~
R''
l~i (XIII)
wherein X is -CH= or -CH2CH= and R30 is a suitable leaving group such as
-0S02CF3. ~ith a boronic acid of formula (XIV):
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WO 97/3005S PCT/GB97/00383
- 37 -
~ \ 3
(OH)~B R
(XIV)
or an ester or an anhydride thereof.
The reaction is preferably eifected in the presence of a transition
metal catalyst such as tetrakis(triphenylphosphine)palladium (0) in a
suitable solvent such as an ether, for example, tetrahydrofuran or
1~2-dimethoxyethane, in ~he presence or absence of water, or an aromatic
hydrocarbon, for example, benzene The reaction is ple~erably effected in
the presence of a base such as an alkali or alkaline ealth n~etal carbonate,
~0 for example, sodium carbonate, at a suitable temperature up to reflux.
Alternatively, compounds of formula (II) ma~r be prepared by the
reaction of a compound of formula (XV)
R9 1 O ~ ~ Sn(R4~)3
~J
wherein ~ is -CH= or -CH2CH= and each R~~ is a Cl ~alkyl g~oup,
pre~rably methyl groups, with a compound of formula (X~
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WO 97/3~0~;5 PC: TIGB97/00383
R2
ll
Hal ~/\ R3
~XVI)
wherein Hal is a halogen atom, for example, chlorine, bromine or iodine,
especially bromine.
The reaction is conveniently effected in the presence of lithium
5 chloride and a transition metal catalyst such as triphenylphosphine
palladium(0). Suitable solvents for the reaction include aromatic
hydrocarbons, for e~ample, toluene, the reaction being e~fected at a
temperature b3etween 80~C and the ref~ux temperature of the solvent.
~ompounds of formula (XV~ may be prepared from a corresponding
10 compound of formula (~III) by reaction with a compound of the formula
~Rl~)3Sn-~n(~4~)3, for examplc, hexamethyl dist~3nn~ne. The reaction is
conveniently e~fected in the presence of a base, for example, lithium
carbonate, and a catalyst such as triphenylphosphine palladium(0).
Suitable solvents for the reaction include ethers, such as tetrahydrofurall.
15 the reaction being effected at a temperature between room temperature
a~d 100~C, for e~ample, at about 60~C.
Compounds of ~ormula (XIII) may be prepared from a compound of
formula ~
R~3n 0 ~ ~>= O
X '~ ,2
R~3)~ -'" ,,
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WO 97/300!j5 PCT/GB97/00383
- 39 -
by enolisation of the ketone in the presence of a base, for example, sodium
hexamethyl~ 7i~1e, followed by reaction with a reagent capable of
introducing a suitable leaving group, for instance, where R30 is -OSO2CF3,
using 2-~,N-bis(trifluoromethylsulphonyl)amino]-5-chloropyridine OIA
5 triilic anhydride. The reaction is conveniently effected in a suitable
solvent such as an ether, for example, tetrahydrofuran at a reduced
temperature, ~or instance, -78~C.
~ ornpounds of formula (XIV) and (XVI) are either known compounds
or may be prepared in a conventiona~ manner using standard methodology
lû or Inethods analogous to those described herein.
Compounds of formula ~XVII) may be prepared from a compound of
formula (XVIII) by the ~ollowing reaction sequences (Scheme A or Scheme
B) or by rnethods analogous thereto:
Scheme A
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WO 97/30055 PCT/GBg7/00383
- ~0 -
O:El
R~R~ c~)l RXO "~:u
GrignRrd condit.ions R
~5 R6
(XVIII~
0sO~
hydro~;yla~ion KM O
OH
RDa ~ ~\~ HCl F~ X ~ ~ (C~~ OH
RobXN~2 intramolecular R~l' N~R
Rs -R~ cycllsahon Rs
Swern
n~i ~ n
O
CH2)',"
R~J' --R~
:R. '
(XV~I)
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WO 97/30055 PCT/GB97/00383
~ 41 -
Scheme ~3
OPh
R~'~o o orl, <
R9b J'N J' ~ ~ ~(CM.,)J yX ~(CH;!)
R (c.f. Lo-tw et c~l, ~\~
R Tetrcthedroll, (1992) R N ~ 4
48: G08.?-Glû4) R6 ~
(xv~II! R5
n-B
ZnCl~
(P113P~4 Pd(O)
R ~ \~ R~ (C~3)~sR9~X~, ~R
(~VII)
In a preferred embodiment of the aforementioned processes, R~ is
replaced with an amino protecting gl~oup, in particular ~ert-butoxyca~-bonvl
5 which iS conveniently lemoved prior to reduction of the 4-aza-1,7-dioxa-
spiro[4.5]dec-9-ene structure ~general proces~ (A)).
In a fulther prefelled en~bodiment of the afore~llentioned processes,
RG is a benzyL group. The reduction reaction described as process (~-~) above
for the preparation of compounds of formula II) ma~? convel~ientl~T replace
1 O the benz~Tl group with a hydrogen atom. It ~-ill be appreciated from the
discussion above that compounds of formula (I) wherein R~; is a hydrogen
atom ale particularl~TT pleferled preculsors to othel~ compounds of forlllula
~Ij.
Interlllediatçs of formula (~) may be pre~aled fi~om a compoulld of
ormula (~IX) b~T reactioll with an azicle, for example~ sodium azidc in a
suitable solvent such as dimethylsulphoxide a~ or belo~T loom
tempel aturç .
CA 02245579 1998-08-05
WO 9'7/3005~; PCT/GB5~7/00383
- 42 ~
Compounds of formula (XTX) may be prepared by a dropwise
addition of an intermediate of formula ~III) to a dihaloacetylene of formula
Hal-C~2-C~ CH2-Hal where each ~al is independently chlorine, bromine
or iodine, especially chlorine. The reaction }s conveniently ef~ecte(l in a
5 suitable solvent such as dimethylformamide in the presence of a base such
as potassium carbonate.
Compounds of formula (V~) may be prepared as described in
J. Med. Chem., ~1984) 27, 849.
Intermediates of formula ~VII) wherein m is 2 may be prepared by
1~ the reduction of a compound of formula (XX):
HO~
( fH2 ) n Rl
R~XO~R
R I ~ ~ R R
~XX)
or a protected derivative thereof, uSillg conYentional methodology, fOl~
instance, by catalytic hydrogenation using a metal catalyst such as
~5 palladium or platinum or oxides thereof, preferabl~ iIl a solvent such as an
alcohol~ e.g. ~thanol, or an ester, e g. ethyl acetate.
Compounds of formula (X~) may be prepared by the reaction of a
compound of formula (~VIII) (see Schemes A an~l ~) with a compound of
formula (~
CA 02245579 1998-08-05
WO 97f3005S PCT/GB97fOO383
- 43 -
~o ~
H \f ~ R
~XXI ~
or a protected derivative thcreof, by lithiation using n-butyl lithium
foLlowed hy (luenching with, for example, sodium dihydrogen
orthophosphate. The reaction is conveniently effected in a solvent such a.s
5 an ether, e.g. tetrahydrofuran, at reduced temperature, for e~ample, at -
~8~C.
Compounds of formula (XVIII) may be prepared by methods
described in l~uropean Patent Speci~ication No. 0 577 3g4-A, Ol hy
analogous me~hods.
~0 ~ompounds of formula (XXl) are known compounds (see Chem~sche
Berichte, (1988) 1~1, 1315-1320) or may be prepared by analogous
methods.
For compounds wherein 3~ is a Cl Galkyl group substituted by a 5-
membered lleterocycle which in turn i9 substituted bv a ZNR7RS group
15 where ~ is CH:2, certain favouled compounds of ~ormula (I) may be
prcpared from a corresponding compound with a hydrogen atom in place of
the ZNR7R8. Thus, for example a compound of the formul~ herein R~;
is an imidazolinone group carrying a CH>NR~R8 moiety may he plepared
fiom a corresponding com~ound lacking the CH2NR7R~ moiety by reaction
20 wil;h f~ormaldehyde and an amine NHR7R8 under conventional ~lannich
reaction conditions, for example in methanol with heating. If desired a
~re-formed reagent such as R~ ~+=CH~ may be employed and a t;ertialy
amine such as triethylamine usecl as acid acceptor.
Alternatively ~ compound of formula (I) wllelein R~i is a Cl (ialk~,rl
~5 group substituted hy an imidazolinone group may be reacted witll
paraformaldeh~de and an amine for e}~ample a seconda1v al~ine such as
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WO 97/30055 PCT/GB97/00383
- 44 -
pyrrolidine or morpholine to give a compound wherein the imi~7.01inone
ring is substituted by CEI2NR7R8 where R7, R8 and t~e nitrogen atom to
which they are attached form a heteroaliphatic ring of 4 to 7 rillg atoms
which ma~ optionally contain an o~ygen ring atom or a second nitrogen
5 atom which will be part of a NH or NRC moiety, where Rc is as pre~iously
defined.
This reaction may be performed in a conventional manner, fol
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 furthcr alternative method for the preparation of certain
compounds of formula a) involves the reaction of an intermediate of
formula ~III) as defined above with one of the compounds of formula
(~XII):
LG l G LG
( C~ ( CH~ ~ CH2 ) p
a ) ) ~ ~= o ( b ) J~ \> ( c ) ~ X'
LG LG lG
xxI I )
wherein each LG, which r~ay l)e the same or different, is a leaving group,
~uch as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosvlate) or,
in particular, a halogen atom, (e.g bromine, chlorine or iodi~le), p is an
integer from 1 to 6 and X and Z are as defined in formula (I). rollowed b~
2() reaction of the resultant cornpound with an amine NH~ R8 to complete l:he
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.
~ t vi.7ill be app1eciated that. where neces~ar~. reactive grou~s may be
protccted~ thus for exarnplce, the NH groups of an imida~olinone of formul.l
CA 02245579 1998-08-05
WO 97/30û55 PCT/G1397/~0383
- ~5 - .
~XXIIa) may be protected by any suitable amine protecting group such as
an acetyl group.
It will be appreciated that compounds of the formu~a (I~ wherein R~i
contains an =O or =S substituent can exist in tautomeric forms. All such
tautomeric forms and mixtures thereo~ are included within this invention.
Most aptly the =O or =S su~stituent in R~ is the =O substituent.
Where the~r are not commercially available, the intermediates of
formula ~ ) above may be prepared by the procedures described in the
accompanying Examples or by alternative procedures which will be readily
lV apparent to one skilled in l;he 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 concer~ed. This may be achieved by means of conventional
protecting groups, such as those described in Protectiue Groups i~ Orgar~ic
1~ Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. (:~reene and
P.G.M. Wuts, Protect;iue Groz4ps i~l Orga~lic Sy~7,t~Lesis, ~ohn Wiley & Sons,
1~91. 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
20 spiroketal compounds of the present invention are described by F. Perron
and KF. Albizati in Chem. Rev., (1989) 89, 1~17-1661.
The exemplified compounds of this inventioll were tested b~r the
methods set out at pages 36 to 39 of International Patent Specification No.
WO 93/~llG5. The compounds or, in the case of prodlugs, t;he parent
2~ compounds, wele found to be active with IC~o at the N~l receptol Or less
than 1,uM on said test method.
:~or the avoidance of doubt, the nomenclature adhered to thl~oughout
this specification is based UpOIl the following stluctures:
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- 46 -
2~,~\, 4~
arld G ~~ 3~6~ bj'
5 N~ 3 ~ f J
The ~o:Llowing non-limiting Examples serve to illustrate the
preparation of compounds of thc present invention:
a
DESCRIPTION 1
(2:E~,3$)-4-Benzyl-3-¢4-~luoro~henYl)-2-hvdrox~-2~¢pro,~-2-en~l)mor~holin~
(3S)-4-Benzyl-3-(4-~luorophenyl)-2-morpholinone (see International
Patent Specification No. WO95/18124) (13.6g, 47.6mmol) was dissolved in
anhydrous tetrahydro~uran (200ml) and cooled to helow ~70~C under an
inert atmosphere. Allyl magnesium chloride (26.2ml of a 2.0M solution in
tetrahydrofuran; ~i2.4mmol) was added dropwise over :~ 5 millutes,
m~intaining the temperature below -70~C. After 30 minute.s, the re~cti.on
was ~uenched by the addition of a satulated solution of ammonium
la chloride and allow~d to warm to room temperature. The lesulting
suspellsion was extracted with ethyl acetate (3x:L00ml), and the combined
olganic extracts dried ¢MgSO~) and concentrated i71 VC~.CZl,O to yield the ~itlecompound in ~3:1 mixturc of the lactols as a light ~-ellov~ oil (la.3g, 98%),
~ hich was used with.out furthel purification. ~IS (~S+) m/z 328 tM+l,
2~) 22%), 310 (M-O~I, 61), 269 ~100).
DESCl~IPTIQN 2
¢ ~ R. 3 S) - 4-Be nz~rl- 2- (2 . 3-dihvdl~oxv~l~rol-vl- 3- (4- fluo~ o r~hen~ 2-
ll~Tdl~ox~rmol ~holine
2~> The alkene Or Desc~iption 1 (18.9g, ;~7.~mmol) w~s stirled with
osmium tetroxide ¢0.2g, 0~8mmol) ~nd N-meth~lmolpholille N-o~;ide
CA 02245579 1998-08-05
WO 97130055 PCT/GB97/0038:S
- 47 -
(7.78g, 66.4mmol) in a solution of tetrahydrofuran (200ml), 2-methyl-2-
propanol (120ml~ and water (14ml) for 3 days at room temperature. The
resulting black soLution was diluted with ethyl acetate (200ml), water
(200ml) and saturated brine (l~)~ml), separated and the organic fraction
dried (MgS04) and concentrated i71 vaCuo. The resulting black oil (263~)
was purified by flash silica gel chromato~raph~t eluting wil;h 50-100% ethyl
acetate in hexane to ~ield the title compound as a mI7~ture of isomers as a
white foam (15.9g, 76%).
Analysis: C20H24FNO4. 0.5 H~O requires C, 64.84; ~I, 6.82; N, 3.78;
~ound: C, 6t~.22; H, 6.74; N, 3.68%
h~S (ES~) 362 (M~-1, 18%), 344 (~-OH, 100).
DESCR~PTION 3
(2R,3S,9RS~-4-A~a-4-benzYl-1,7-dioxa-3-(4-~1uorophenYl)-9-
h~rdroxvsPiro~5,41 decane and (2S.3S,9RS~-4-Aza-4-benzYl- 1,7-dioxa-3-(4-
~lu~rophenvl)-9-hYdl oxvsPiro r5,41 decane
The mixture of triols of Description 2 (15.0g, 4~.5mmol) was
dissolved in hydrochloric acid (200~n1, 6M), and methallol (lOOml) and
heated at reflux for 5 hours. The coo~ed solution was basified with 4N
sodium h~droxide solution and extracted with eth~l acetate (3x20Qml).
The combined organic extracts were d~ied (MgSO4~ and concentrated i~1
VMCl.l,O. The resulting black oil (18g) was purified by flash si~ica gel
chromatography eluting with 33-G6"/o ethyl acetate in h~xane tc~ yield th~
title compound,~ as pai~s of diast~romers.
Isol~cr pair A, less polar, an orange gum (7.1g, 50%). R~ 0.37 (50%
e~hyl acetatelhexane). lH NMR (360MHz, CI~Cl3) ~ ().42 (~l/2H, d,
J=10.4Hz)~, 7.69 (]/2H, dd, J=13.5, G.5H~), 1.86 (l/2H~ d, J--14.6Hz), l.9G
(l~2H, d, J=13.GHz.), 2.1~ 2H, dd, ~=14.~, 6.4Hz), 2.30 (l~I, dt, J=12.0,
- 3.6Hz), 2.76 (lH, d, J=13.1H%), 2.79 (lH, cl. J=13.2Hz), 3.11 (~ 2H, d~
3~ J=11.2Hz)~, 3.34 (lH, d, J=14.2H7,), 3.35~3.71 (3H, lll), 3.91 (l/2EI, d~l, J=c3 ,,
3.6Hz), 3,98-4.29; (2]/2H, m), 7.01 (2xl/2H, l, J=8 8Hz). 7.0~ (2xl/2H, t,
CA 02245579 1998-08-05
WO 97/30055 PCT/GB97/00383
- ~8 -
J=8.7~z), 7.18-7.29 (5H, m), 7.54 and 7.63 (2H, xbr s) (~ exchanges in
D20); MS (ES~) 344 (M~l, 100%).
lsomer B, more polar, an orange glass (4.3g, 30%). Rf 0.25 (50%
ethyl acetate/hexane). l~ NMR (3Ç;0MHz, CDC13~ ~ 0.83 (2/3H, ~r d~*, 1.~i4
~l/3H, dd, J=14.0, 5.7Hz~, 1.87 (2/3H, d, J=14.6H~), 2.02 (l/3H, J=14.0Hz),
2.15 (2/3H, dd, J=14.G, 6.6Hz), 2.32-2.41 (lH, m), 2.74-2.82 (lH, m), 3.03
(l/3H, d, J=ll.OHz)*, 3.14 (2/3~, d, J=13.7Hz), 3.17 (1/3~L, d, J=13.7H~), 3.50
(l/3H, d, J=13.~Hz), 3.59 (2/3H, d, J=13.7Hz), 3.66-4.1~ (5113H, m), 4.33
(2/3H, br s), 7.00-7.09 ~2H total, m~, 7.21-7.31 (5H, m), 7.41-7.52 (ZH total,
m) (* exchanges in D20); MS (ES~) 344 (M+1, 100%).
~ESCRIPTION 4
(2R,3S)-4-A~a-4-benzYI-1.7-dioxa-3-(4-~luoro~henYl~-9-oxosl?iro~5.41decane
~nhydrous dimethylsulphoxide (3.4ml, 47.8mmol) dissolved in
dichloromethane (lOml) was added dropwise over 1~) minutes to a solution
of oxalyl chloride (2.0ml, ~2.9mmol) dissolved in anhydrous
dichloromethane (200ml) cooled to below -70~C. The temperature was
maintained below -60~C durillg the addition and the solution stirred for a
~urther 15 minutes at below -70~C~ The alcohol isomer pair A of
Desc~ iption 3 (6.57g, l9.1mmol) dissolved in dichloromethane (40ml) was
added dropwise over 10 minutes, maint~ining the temperature below
-70~C, and then s~irred at this temperatu~e for one houl. Triethylamille
(13.3ml, 9~?.5mmol) was added dropwise over 10 minutes, and the reaction
allowed to warm to room temperature. The resulting mixture was washed
2~ with dilute sodium bicalbonate solution (0.2M) and water (200ml) and the
orgallic fraction dried (MgSO~) and concentrated i7l, uacLro (7.9g). The
crude product was purified by flash silica gel chromatographv eluting with
14-~20% ethyl acetate in hexane to yield the title compound as a pale yello~
glass which solidified to a bufr coloured solid on standing (5.2g, 80%)
Analysis: C~nEl;~oFNO~ requires C~ 7Q.37; H. 5 91; N, 4.lO;
Fo~lnd: C, 70.29; H, 6.83; N. 4.02%
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~a~22D--+125.6 (c=1.04, CH2Cl2); lH NMR (360M~z, COCl3) ~ 2.31 (2H, d,
J-3.0Hz), 2.35 (lH, dt, J=12.0, 3.5Hz), 2.80 (lH. cl, J=12.9Hz), 2.S3 (lH, br
d, J=ll.OHz), 3.52 (lH, s), 3.59 (lH, dq, J=10.1. 1.6~z), 3.68 (lH, d,
J=13.2Hz~, 3.88 (lH, d, J=16.6Hz), 4.03 (lH, d. J=16.6Hz), 4.18 (l~-I, dt,
J--11.7, 2.5Hz), 7.05 (lH, t, J=8.7Hz), 7.19-7.32 (5H, m), 7.58 (2H, br s);
MS (ES+) 342 (M~l, 100%).
DESC~IPTION ~
¢2R,3S~-(4-Aza-~-benzYl-1.7-dioxa-3-~4-fluorophenYl)s~iro~5.41dec-9-en9-vl)
la tritluoromethanasulfonate
The ketolle of Description 4 (4.0g, 11.7mmol) as a solution in
anh~rdrous t~trahydrofuran (16ml) was added dropwise ovcr 10 mintes to a
solution of scdium bis(trimethylsilyl)amide (14.0ml of l.OM solution in
tetrahyd~ o~uran; 14.0mmol) cooled to below -70~C. The reaction mixture
15 was sl;irled at this temperature ~or 2 hours befole the addition of 2-[N,N-
bis(trifluoromethylsulphonyl)amino]-5-chlorop~-ridine (6.44g, l6.4mmol) in
several portions. The solution was stirred at below -70~C for l/2 hour before
being allowed to warm to room temperaturc o~elnight. The reaction was
~uenched with a saturatcd ammonium chloride solution (60ml) and
20 extracted with ethyl acetate (3x30ml). The combilled organic extracts
were dried (MgSO4) and concentrated i7~ vacuo tQ yicld a crude oil (13.2g)
which was ~urther purified by flash silica gel chl~omato~raphy eluting with
10% eth~l acetate in hexane to yield thc title co~ ound as an orange oil
(3.21g, 58%) and recovered ketone (0.61g, 13%) 'H NMR ~3~0MHz,
2~ CDCl3) a 2.33 (lH, dt, J=~2.0, 3.5Hz), 2.S3 (2II~ d, J=13.5Hz), 3.60 (lH, s)3.~8 (lH~ m), 3.73 (lH, d, J=13.4Hz), 3.94 (lH. ~Id, J=13.1, ~ Iz), 4.26
~ (lH, dt, J=11.7, 2.5Hz), 4.57 (lEI, dd, J=13 '~, '>.l~z), ~ 0 (lH, t, J=2.0Hz).
7 01 (2H, t, J=S.7Hz), 7.22-7.31 (5H, m), 7 48 ¢'~-I, bl s): MS (ES-~) 474
(M+l, 100%).
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I)ESC~IPTION 6
¢2~,3S)-4-Aza-4-benzvl-1.7-dioxa-~9S)-(3-aminophenyl)-3-(4-
f~uorophen~tl)spiror4. ~dec-9-ene
A mixture of the enol triflate of Description 5 (1.5g, 3.2mmol),
3-aminophenyl boronic acid (0.45g, 3.3mmol), lithium chloride (-102~g,
9.~mmol) and 2M sodium carbonate solution (10.8ml, 20.3mmol~ in
dimethoxyethane (30~1) was degassed for 10 minutes at 600(~.
Tetrakis~triphenylphosphine) palladium (O) (150mg) was added and ~he
reaction was stirred at 700C for 2h. The reaction was allowed to cool to
10 ambient temperature and was diluted with water (~Oml). The mixture was
extracted with ethyl acetate (3 x ~Oml) and the combined or~anics were
washed with brine, dried over magnesium sulphate and the solvents were
removed in vacuo. The residue was purified by ~lash column
chromatography on silica gel in 15-30% ethyl acetate/hexane giving the
15 title compound (740mg) as a yellow solid.
1~ NMR (2~0ME3:~, CDCl3) S 7.60-7.~4 (2H, m), 7.30-7.2~ ~5H, m), 7.07-
7 01 (lH, m), ~ 96-~.89 (2H, m), ~;.43 (lH, s), 5.87 (lH, m), 4 94-4.88 (1H,
dcl, ~=12.~z and 2.1~Iz), 4.35-4.2~ (2H, m), 3.79-3.55 (3H, m), 3.59 (2H,
s), 2.86-2.80 (2H, m), 2.41-2.33 (1H, m).
DES~RIPTION 7
~2S.3S)-4-Aza-1.7-dioxa-(9S)-(3-aminophenvl~-3-(4-fluoloPhen~
sl~iror4.51decalle
The product of Description ~ (7~0mg, 1.8mmol) was dissolved in
~o 10ml of methanol/glacial acetic acid (10:1). Ethyl acetate (30n11) was adcled
and the solution was hydrogenatecl over palladium hydloxide at 40 psi for
1Gh The catalyst ~,vas filtered and the solvents were removed in vc~cuo. the
residue was p~rtitionecl between ethyl acetate and sodium carbonate
solution. The organic layer was dried over ma~nesium sulphate and the
30 solvent was removed in Va.CZ40. The residue was purified by f1ash column
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chromatography on silica in 5% me~hano~ldichloromethane giving ~;he title
compound as an oil (39ûmg).
lH NMR (250MHz, CDCl3~ ~ 7.51-7.46 (2H, m), 7.07-6.90 (3H, m), 6.46-
6.42 (lH, dd, J-7.9~Iz and 2.3Hz), 6.22-6.19 ~lH, d, J=7.9Hz), G.00-5.98
~lH, m), 4.33-4.15 (2H, m), 4.03 (lH, s3, 3.69-3.48 (3H, m), 3.25-3.l3 (lH,
m), 3.08-3.02 (lH, m), 2.22-2.14 (lH, m), 1.74-1.~5 (lH, m).
DE~C:RTPTION 8
(2S~3S)-4-Aza-4-~uorenvlmetho~Ycarbonvl- 1,7-dioxa-~9S)-(3-aminophenyl)-
10 3-(4- uolophenvl)spiro~4.5ldecane
The product of Description 7 (380mg, 1.2mmol) was dissolved in
d}chloromethane (15ml) and ~he solutiorl was colled to 0OC.
Di-isopropylethyl~min~? (0.19ml, 1.2mmol) was added ~ollowed by
9-fluorenylmethyl chloroformatc (275mg, 1.06mmol) and the resulting
15 sol~Ltion was stirred at ambient telnper~ture for 16h. The solution was
diluted with dichloromethane (15ml~ and washed with water (30ml). The
o~ganic layer was dried over magnesium sulphate and the solvent w~s
removed in vacl~o. The residue was purified by ~lash column
chromatography on silica gel in 30-50% ethyl acetate/hexane giving the
20 title compound (4~2mg).
lH NMR (2~0MHz, CD~13) â 7.7G-7.70 (2H, m), 7.46-7.24 (5H7 m), 7.10-
7.04 (lH, m), 6.96-6.88 (2H, m), 6.57-6.53 (lH, m), G.~G-6.43 (lH:, d,
J=7.7Hz). 6.3 (lH, s), 4.G0-4.~7 (2H, m), 4.3~?-4.29 ~lH, m)~ 4.22-4.15 (lH,
m), 3.96-3.88 (2E~, m), 3.82-3.76 (2H, m), 3.7~>-3.61 (lH, m). 3.55-3.40 (lH.
2~ m), 3.38-3.21 (lH, m), 2.61-2.53 (lH, m), 1.72-1.6G (1~:, m); MS (ES~) ~51
(M+ 1).
DESCRIPTION ~
~2S,3S)-~ Aza-4-~luorenvlmetllo~{vcarbon~l-1.7-clio~ 9S~-~3-tetl.azol-1-
3~) vl)phenvl-3-(4-fluorophenvl)spiror4.r)ldecane
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The product o~Description 8 (270mg, 0.49mmoV was dissolved in
glacial acetic acid (5ml). Triet;hylorthoformate (0.2ml) was added and the
solu~ion was heated to 7~ioC and stirred for lh. Sodium azide (88.5mg,
1.36mmoI) was added in portions over 3() minutes and the resulting
solution was stirred at 7l~i~C for 4h. The solution was allowed to cool to
ambient temperature, diluted with water (50ml~ and extracted with ethyl
acetate (3 ~ 25ml). The combined organics were dried over magnesium
sulphate and the solvents were removed iJl UC~CUO. The residue was
purified by ~lash column chromatography on silica gel in 50% ethyl
acetate/hexane giving the title compound.
MS (ES~) 604 (M+1).
DESCRIPTION 10
(2S.3S)-4-Aza-4-~enzYl-1~7-dioxa-3-(4-~luorophenYl~-9-trimethYlstannanyl~
s~iror4.~1dec~9~ene
The enol triflate o~Description 5 (1.3~,g) was dissolved in
tetrahydrofuran (15ml) with lithium chloride (0.84g), lithium carbonate
(0.24g) and hexamethyldist~nn~3ne (3.21~ig) and was dcgassed thlee times
and placed under an argon atmosphere. Freshly prepared
tetraL~is(triphenylpl:losphine) palladium (O) (0.19g) was added alld the
system was degassed again. The reaction was heated at GO~C for 2h. The
tetlahydrofuran was removed i71 uacuo and tllc black lesidue was
partitioned between water and ethyl acetate. The aqueous layer was
extracted ~rith ethyl acetate (3 x lOOmlj and the combined olg~nics were
~5 washed with brine, dried over magnesium sulphate~ and the solvent was
removed i71. vacuo giving a ~rown oil. Purification was carried out on ~lash
silica gel ~Yith 0-10% ethyl acetate in he~ane as eluent. The titl~ compound
was obtained as a colourless oil which solidified on standing (1.3'3g). MS
ES-' 487 (M+l). ~H NMR (3GOMHz, CDCl~ i 7.50-7.3G ~2H, m), 7.28-7.1~ -
(5H, m), ~i.9~-G.84 (2H, m), 5.5~ (lH, m~, 4.G8-4.58 (1.~I, dd), 4.27-4.1G (1~
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td~, 3.92-3.84 (1H, m), 3.80-3.62 (2H, m), 3.49 (lEI, s), 2.8~-~.74 ~2H, m),
2.2G (lH, td), 0.00~ (9H, s).
D~SCRIPTION 11
2-Bromo-4-(3-¢trifluormethvl)tetra~ol-1-Yl)-anisole
a) 4-amino-2-bromoanisole
A mixture 2-bromo-4-nitroanisole ~15g, 64.6mmol) and iron powder
(27.3g, 0.49M) in water (lOOml) and glacial acetic acid (25ml) was stirred
at reflux for 2h. The mixture was allowed to cool to ambient temperature
ancl ~iltered through a pad of HyfloTM ~washed with 25% acetic acid/water).
The filt~ate was extracted with ethyl acetate (2 x 250ml) and the organic
layer was dried over sodium sulphate. Removal of thc solvent i7?, vacuo left
an oil which was chromatographed on silica in 40% ethyl acetate/he~ane
giving the title compound as a brown solid (10.32g, 79%). MS ~S+) 202
~+1).
~) 2-Blomo-4-(tli.fluoroac~tamido)anisole
4-Amino-2-bromoanisole (5g, 24.7mmol) vt.ras dissolved in
~ichloromethane (50ml) containing triethylamine (3.44ml, 24.7mmol). The
solution was cooled to OoC and tri~1uoroacetic anhydride (3.6ml, 24.7mmol)
was added slowly. The reaction was stirred at ambient tem3~erature for 2h,
diluted with dichloromethane (200ml) and washed with water (2 x 200ml).
T~e o1ganic layer was dried over sodium sulph~te and the sol~rent was
26 removed i7~ vaczlo leaving an oil. Chromatog~aph~ on silica in :L6-26% eth~tl
acetat~/hexane gave the title compound as white solid ~4.4g). ~H NMR
~26(}MHz COC~ 7.79 (1~, d, J=2.GHz), 7.58 ~1H, dd, J=~ Hz and
8.9~Iz~, G.~O ~lH, d, J=8.9Hz), 3.90 ~3H, s).
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c) 2~Bromo-4-(3-(trifluorometh~ tetra~ol-l-Yl)-anisole
2-Bromo-4-(trifluoroacetamido)anisole (4.3g, 14.~mmol) was
suspended in carbon tetrachloride (80ml). The suspension was heated to
80~~ and triphenylphosphine (4.~;4g, 17.3mmol3 was added in portions
5 over 4~h. The reaction was stirred at 80~C for 16h. The solvent was
removed i,77, VCI,CU,O and hexane (100ml) was added to the residue and heated
to reflux temperature. The suspension was allowed to cool to ambient
temperature and filtered (triphenylphosphine oxide). The solvent was
removed from the filtrate 77t vac~o leaving an oil ~4.6g). The oil in N,N-
10 dimethylformamide (20ml) was added to a suspension of sodium azide~1.24g, 19.1mmol) in N,N-dimethylformamide (20ml) at ambient
temperature. The mixture was stirred for 2h and poured into water
(200ml). The mixture was extracted with ethyl acetate (2x200ml) and the
combined organics were washed with water (200ml), dried over sodium
15 sulphate and the solvent was removed Ilt VC~CUO leaving a yellow oil.
Chromatography on silica in 2~% ethyl acetate/hexane gave the title
compound as a clear oil (4.9g).
1~ NMR (2~0MHz CDCl3) ~ ~.72 (1~, d, J=2.(~Hz), 7.4~ (1~, dd, J=2.6EIz
and 8.9Hz), 7.08 (lH, d, ~=8.gHz~, 4.û2 ~3H, s).
DESCRIPTION 12
~2S,3S)-4-Aza-4-benzvl-1,7-dioxa-(9$)-(2-1netho~v-5-(5-
(trif~uorometh~l)tetra~ol-l-vl~)phenYl-3-(4-fluolol~hen~l~s~iror4.~1dec-9-ene
The p~oduct of Descriptioxl 10 (0.369g, 0.75mmol), lithium chloride
2.~ (193mg, a~.5mmol) and the product of Description 11 were dissolved in
toluene (15ml) and degassed for 10 millutes at ambient temperatule.
Tetrakis(triphenylphosphine) ~alladium (03 ~mg) was aclded and the
rcaction was stirred at 110~ for 24h. The reactio}l w as allowed to cool to
ambient temperature, was diluted with ethyl acetate and washed witll
3~ water. The o~-ganic layer was drLed over sodium sul~hate a~n~ the solvent
was removed in vac~o to ~ive a vellow oil which was purifiecl by flash
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column chromatography on silica gel in 15% ethyl acetate/hexalle giving
the title compound (313mg) as a foam. MS (ESt) 668 (M+l).
DES(~ PTION 13
5 3-Bromo-4~tri~1uoromethoxy-~qnilin~ ~
4-Tri uoromethoxynitrobenzene (4.1g) was suspended in water
(16ml) and concentr~ted sulfuric acid (16ml) and warmed to 80C(~ with
stirring. Potassium bromate (3.7g) was added portionwise over 3 hours.
The resulting mixture was heated at 80~C for a further 2 hours, cooled to
10 room temperature and poured onto ice (lOOg3. The mixture was extracted
with ethyl acetate, dried ~ O~), fi~tered, and the solvent lemovecl
t71 vacuo. The recovered solid (l.Og) was taken up in acetic acid (2.5ml~
and water (lOml) and iron powder (2.0g) added. The resulting mixture
w~s warmed to reflux for 2 hours, cooled to room temperature and filtered
1~ through ~eliteTM. The filtrate was extracted with ethyl acetate, the
organic layer6 separated, dried (MgSO4), filtered and the solvent removed
if ~ V~C~LO. Chromatography on silica gel (ethyl acetate:hexane 1:3) afforded
the title compound as a ~rellow oil. lH NMR (CDCl~ .57 (lH, dd), 6.9
(lH, d), 7.06 (lH, dd).
ZO
DESCJ~IPTIQN 14
2-~3romo-4-(3-(trifluolometh~71~tetl a~ol- l-vl)tlifluoloani6vle
The title compound was pepared fi~om the product of Descliption 13
accordin~ to t~e method of step (b) of Description 11.
2~ ~H Nl~R (CD~13) ~ 7.o4 (2H, m), 7.86 (lH, d, J=l.O~Iz).
DESC:~IPTION la
2-Brnmo-4- (3-(tl if luorometh~rl)tetra~ol- 1~~ l)toluclle
The title compound was pepared from 4-~mino-2-~1olllotoluene
30 ~cordin~ to the method of step ~b~ of Description 11.
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lH NMR (CDCl3) o 2.53 (3H, s), 7.32 (1~, dd, J-8.0, 1.0Hz), 7.45 (lH, d,
J=8.0Hz), 7 69 (1H, d, J-1.0Hz).
E~MPLE~ 1
(2S,3S~-4-Aza-1~7-dioxa-(9S)-~3-tetrazol-1-~l~phenvl-3-(4-
fluorophen~ s~iror4.aldecane hvdrochloride
The prodllct of Description 9 (l OOmg, 0.26mmol) was dissolved in
dichloromethane (5ml). A 10% dimethylamine in dichloromethane (5ml)
solution was added and the solution was stirred at ambient temperature
lû for 2h. The solvent was removed i71~ uacuo and the residue was purified l~y
flash column chromatography on siltca in 5% methanol/dichloromethane
giving the free base of the title compound. This compound was dissolved in
methanol and treated ~ith a methanolic hydrochloric acid solution. The
solvent was removed i7t vacLlo giving the title compound as a ~oam.
1~ JII NMR (360MHz, ~MSO-d~ â 9.99 (lH, s), 7.71-7.6~ (3H, m), 7.43-7.37
(2~, m), 7.27-7.24 (~H, m)~ G.92-6.90 (lH, m~, 4.79 (7H, s(br)), 4.44-4.40
(1H, m), 4.22-417 (1H, m), 3.92-3.88 (1H, m), 3.8~-3.69 (~H, m), 3.42-3.38
(31~I, m), 2.47-2.43 (lH, m), 1.68-1.62 (1~I, m); ~IS (ES+) 382 (M+1).
~XAMPLE 2
(2S~3S)-4- ~za- 1,7-dioxa-(90-(2-methox~J-a-(~-(t~ if luoromethYl)tetrazol- 1 -
yl))~henvl-3-(4-~luorophen~l)s~iror4.5ldecane hvdrochloride
The product of Description 1~ (310mg, O.a5mmol) was dissolved in
methanol (30ml) containing glacial acetic aci~ (3ml~. Palladium h~droxide
~2amg) was added and the solution was hydrogenated at ~0 psi fol 4h. The
catalyst ~~ras filtered and the solvents were ren1oved i~l uacLlo~ The ~esidue
was partitioned between ethyl acetate and sodium carbonate solution. The
olganic lavel- was dried o~er sodium sulphate and the solvent was l~el~o~ed
i71 uaciLlo. The residue was purified b~ flash column chlomatography on
~ilica gel in 3% met~anol/dichlorometllane giving the ~le~e base of the title
compo~nd which was dissolved in methanol and tleat~d with a methallolic
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- 57 -
hydrochloric acid solution. Remova~ of the solvent i,7?, VCICUO and trituration
with di~thyl ether gave the title compound as a white crystalline ~olid.
M.pt. 163-165~C; MS (ES+) 480 (M+1).
E~AMPLE 3
~2S~3S~-4-Aza-1,7-dioxa-(9S)-(2-methYl-~-(5-(trifluoromethYl)tetrazol-l-
y~)~phen~Tl-3-(4-fluorophenYl)spiro~4.51decane
The title compound was prepared from the product of Descriptions
10 and 1~ according to the method of Description 12, followed by
lû reduction step according to the method of ~,~3mple 2.
1~ N~R (free base3 (CDCl3) ~ 1.59 (lH, dd, J=12.0, 8.0Hz), 1 76 (lH, br s),
2.1g (lH, dd, J=12.0, 8.0Hz), 2.27 (3H, s), 2~95 (lH, dd, J=10.0, l.OHz),
3.Q9 (lH, l~d, J=10.0, l.OHz), 3.~8 ~lH, m), 3.74 (lH, m), 3.78 (lH, s), 3.81
(1~, m), 4.05 (lH, m), 6.43 (lH, d, J=l.OHz), 6.71 (2H, m), 6.95 (lH, m),
7.1~ (lH, m), 7.43 (2H, m). MS (ES+) 465 (M+1).
:~XAMPLE 4
~2S~3S)-4-Aza-1,7-dioxa-(9S~-(2-~rifluoromethox~-6-(5-(trifluoromethvl~-
tetrazol-l-vlO~hexlyl-3-~4-fluoroPhenYl)sPiro~4~51decane
The title compound was prepared from the product of Descriptions
11} and 14 acco7~ding to the method of D~scription 12 followecl by a
reduction step according to the method of Example 2.
3H NMR (free base) ~CDCl3) ~ 7 (lH, dd, J=13.0, 7.0Hz), 1.63 (lH, l-~r s),
2.29 ~lH, dd, J=13.0, 7.0Hz), 3.00 (lH, dd, c~=12.0, l.OHz), 3.13 (lH, td,
~25 c~ .O, l.OHz), 3.~;1 (2H, m), 3.90 (2H, mj, 4.û~i (iH, m), 4.31 (lH, m), ~:;.47
~l~I, d, J=l.OH7.), 6.69 (2H, m), 7.16-7.37 (4H, m). ~IS (13~ 34 (~I+1).
.
