Note: Descriptions are shown in the official language in which they were submitted.
~ WO9S/2ll67 ~182197 F~l~ '[-13j
T~IAZOLE DERIV~TIVE8
The present invention relates to a discrete
class of substituted triazole derivatives which act on 5-
5 llydLu,~yLLyptamine (5-H~J receptors, being selective
agonists of so-called "5-HTl-like" receptors. They are
therefore useful in the treatment of ( 1 inicAl conditions
for which a selective agonist of these receptors is
indicated .
5-HT1-like receptor agonists which exhibit
selective vasoconstrictor activity have recently been
described as being o~ use in the treatm~ of migraine
(see, for example, A. Doenicke et al., The Lancet. 1988,
Vol. 1, 1309-11). The ,- c of the present
15 invention, being selective 5-HTl-like receptor agonists,
are accordingly of particular use in the treatment of
migraine and associated conditions, e. g . cluster
h~ArlA~~h.o, chronic pa~^oxysmal hemicrania, headache
associated with vascular disorders, tension headache and
20 paediatric migraine.
WO-A-94/02'L77, published on 3rd February 1994,
describes a class of substituted imidazole, triazole and
tetrazole derivatives which are stated to be selective
agonists of 5-HT1-lil~e receptors and hence to be of
25 particular use in the treatment of migraine and
associated conditions.
The present invention provides a compound of
formula I, or a sal~ or prodrug thereof:
WO 95121167 j ~ F~II~D7~ I35
~ l ~ 21 ~ 7 ` `;
-- 2 --
~J,
( , ,
10 wherein R represents 1~YdLUg~:ll or C1_6 alkyl.
As will be appreciated, the carbon atom at the
2-position of the pyrrolidine ring in the c of
formula I above is in the (S) configuration. The
of formula I above, and salts and prodrugs
15 thereof, are generically .on- -qf~ within the scope of
WO-A-94/02477. There is, however, no specific disclosure
therein of a compound co~Le~ ding to the c~ u--ds of
formula I above, i.e. compounds wherein the carbon atom
at the 2-position of the pyrrolidine ring is in the (S)
20 configuration.
For use in medicine, the salts of the
of formula I will be pharmaceutically acceptable salts.
Other salts may, however, be useful in the preparation of
the compounds according to the invention or of their
25 pharmaceutically acceptable salts. Suitable
pharmaceutically acceptable salts of the compounds of
this invention include acid addition salts which may, f or
example, be formed by mixing a solution of the compound
according to the invention with a solution of a
30 pharmaceutically acceptable acid such as hydrochloric
acid, sulphuric acid, fumaric acid, maleic acid, succinic
acid, acetic acid, benzoic acid, oxalic acid, citric
acid, tartaric acid, carbonic acid or phosphoric acid.
As used herein, the expression "Cl_6 alkyl"
35 includes straight-chained and branched alkyl groups
containing from l to 6 carbon atoms. Such groups include
_ _ _ _ _ _ _ _ _ _ _ _ _ , .
~ WO9~121167 218219 7 r~ r~ 135
methyl and ethyl, and straight-chained or branched
propyl, butyl, pentyl and hexyl. Particular alkyl groups
are methyl, ethyl, n-propyl, isopropyl and t-butyl.
The present invention includes within its scope
5 prodrugs of the compounds of formula I above. In
general, such prodru,gs will be functional derivatives of
the compounds of formula I which are readily convertible
in vivo into the required .u-1d of formula I.
Conventional procedures for the selection and preparation
lO of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard,
Elsevier, 1985.
Particular values for the group R include
hydrogen and methyl.
Specific ~ ~ within the scope of the
present invention include:
( 2S ) -2 - [ 5 - ( l, 2, 4 -triaz ol -4 -yl ) - lH- indol - 3 -
yl ] methylpyrrolidine;
(25) -N-methyl-2-[5-(1,2,4-triazol-4-yl) -lH-indol-3-
2 0 yl ] methylpyrrol idine;
and salts and prodrugs thereof.
The invention also provides pharmaceutical
compositions comprising one or more compounds of this
invention in association with a pharmaceutically
25 acceptable carrier. Preferably these compositions are in
unit dosage forms such as tablets, pills, capsules,
powders, granules, sterile parenteral solutions or
suspensions, metered aerosol or liquid sprays, drops,
ampoules, auto-injector devices or suppositories; for
30 oral, parenteral, intranasal, sublingual or rectal
administration, or for administration by inhalation or
insufflation. For preparing solid compositions such as
tablets, the principal active ingredient is mixed with a
pharmaceutical carrier, e.g. conventional tableting
35 ingredients such as corn starch, lactose, sucrose,
sorbitol, talc, stearic acid, magnesium stearate,
_ _ _ _ _ _ _ _ _ _
Wo95121167 r~ .,s~ 5
~1821~7 ~
-- 4 --
dicalcium phosphate or-gums, and other pharmaceutical
diluent6, e.g. water, to form a solid preformulation
composition containing a homogeneous mixture of a
, u-ld of the present invention, or a non-toxic
5 pharmaceutically acceptable salt thereof. When referring
to these preformulation compositions as h -, np~us~ 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
10 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 pill5 of the novel
15 composition can be coated or otherwise 1P~ to
provide a dosage form affording the advantage of
prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage ~ n~ l-L,
the latter being in the f orm of an envelope
20 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 ~ Pnllr or to be delayed in release. A
variety of materials can be used for such enteric layers
25 or coatings, such materials including a number of
polymeric acids and mixtures of polymeric acids with such
materials as shellac, cetyl alcohol and cellulose
acetate .
The liquid forms in which the novel
30 compositions of the present invention may be incorporated
for administration orally or by injection include aqueous
solutions, suitably flavoured syrups, aqueous or oil
suspensions, and flavoured emulsions with edible oils
such as cottonseed oil, sesame oil, coconut oil or peanut
35 oil, as well as elixirs and similar pharmaceutical
vehicles. suitable dispersing or suspending agents for
. _ _ . . _ .. _ . ... ,, , , , . ,, , . , _ _ _ _ _ _ _ _ _ _ _ _ _
~ WO95/21167 P~ JA.J~C 135
197
aqueous suspensions include synthetic and natural gums
such as tragacanth, acacia, alginate, dextran, sodium
caLbv,.y t_hylcellulo~e, methylcellulose, polyvinyl-
pyrrolidone or gelatin.
In the treatment of migraine, a suitable dosage
level is about 0 . Ol 1:o 250 mg/kg per day, preferably
about 0.05 to lO0 mg~'kg per day, and ~cper;~l~y about
o . oS to 5 mg/kg per day. The ~ may be
administered on a regimen of l to 4 times per day.
The ~ '~ according to this invention
wherein R is other than hydLv~ may be prepared by a
process which comprises reacting the .~ v~ of formula
IA with a . _u--d of formula II:
L - R 1 0
( I A) ( I I )
wherein RlO represents Cl_6 alkyl, and L represents a
suitable leaving group.
The leaving group L is suitably a halogen atom,
e. g. bromine or iodi~e .
3 o The reaction is conveniently carried out by
stirring the reactants under basic conditions in a
suitable solvent, for example in a dimethoxyethane and
N,N-dimethylformamide solvent system in the presence of
sodium carbonate, typically at the reflux temperature of
3 5 the solvent .
_
Wo 95/21167 . ~ ..,5.~ 135
~18219~
: `.
In an alternative ~IL'UC~ ULt:, the ~~ olln~c
according to the invention represented by formula IB:
N ~N
( I 3)
wherein -CH2R20 ~o~ u..ds to a group of formula R as
def ined above; may be prepared by a reductive amination
15 process which comprises reacting a compound of formula IA
as defined above with an aldehyde derivative of formula
R20-CI10 in the presence of a reducing agent.
An appropriate reducing agent for use in this
procedure is sodium cyanoborohydride, in which case the
20 reaction is conveniently carried out in an alcoholic
solvent such as methanol, typically in the presence of
acetic acid.
In a further procedure, the ~ , olln~lc according
to the invention wherein R is other than hydrogen,
25 including the compounds of formula IB above, may be
prepared by reacting the compound of formula III:
N~ N=
~N~
NH-NH2
( I I I )
35 with a compound of formula IV or a carbonyl-protected
form thereof:
_ _ _ , . .
~ib, _ _ 135
wo 95121 161 1 ~ I
~182197
-- 7 --
o
H N
R l o/
( IV)
10 wherein R10 is as defined above.
Suitable carbonyl-protected forms of the
compounds of formula IV include the dimethyl acetal or
ketal derivatives.
The reaction of, ,_ 'c III and IV may be
15 carried out in a sin~le step (Fischer indole synthesis)
or by an initial non-cyclising step at a lower
temperature to give a compound of formula V:
~N ~l3~N ~ N ~ L
( V )
wherein R10 as defined above; followed by cyclisation
using a suitable reagent, such as a polyphosphate ester.
The hydrazine of formula III may be prepared
30 from the corresponding aniline of formula VI:
wo95nll67 ~ 51'~ 135
218219'7'' '- --
-- 8 --
N
~!I H 2
(Vl )
by diazotisation followed by reduction. Diazotisation is
typically carried out using sodium nitrite/conc. HCl and
the resulting diazo product reduced in situ using, for
example, tin(II) chloride/conc. HCl, sodium
sulphite/conc. HC1, or sodium sulphite/conc. H2S04.
The ~_ ul-d~ of formula IA above may be
prepared by reacting a ~ _ ' of formula III as defined
above with a compound of formula VII, or a carbonyl-
protected form thereof:
H
R 3 o/
(Vl I )
wherein R3 represents hydrogen or an amino-protecting
group; folIowed, where required, by removal of the amino-
protecting group R30.
As for compound IV, suitable carbonyl-protected
forms of the compounds of formula VII include the
dimethyl acetal and ketal derivatives.
The amino-protecting group R3 , where present,
is suitably a lower alkoxycarbonyl moiety such as
t-butoxycarbonyl (BOC), which can be conveniently removed
as necessary by treatment with acid.
.... . . .... .... _ _ _ _ ,
WO 9~ 67 1 ~ v. 5 [ 135
821.97
_ g _ j ~
As with that between compounds III and IV, the
reaction between, _ ~c III and VII may be carried out
in a single step (Fischer indole synthesis) or by an
initial non-cyclising step at a lower temperature to give
5 a ~lln~l of formula VIII:
H =~
(Vl I I )
15 wherein R30 is as deEined above followed by cyclisation
using a suitable reagent, e.g. a polyphosphate ester.
The aniline derivative of formula VI may be
prepared by reacting the hydrazine derivative of formula
IX with the acetanilide of formula X:
H H H 2
Ma2N--C C--NM~2 l ll
N--N ~/\N H . C O C H 3
( IX) (X)
followed by removal of the N-acetyl protecting group.
The reaction between rn~ro~lnrlc IX and X is
conveniently effected in refluxing toluene,
advantageously in the presence of a catalytic quantity of
p-toluenesulphonic acid. Subsequent removal of the N-
acetyl protecting group is typicalIy effected in hot
aqueous 5N hydrochloric acid.
The hydrazine derivative of formula IX can be
prepared from N,N'-diformylhydrazine by reaction with
Wo 95/21167 r~ ,s,~^l3s
.j ,...
~8~1~7 - lo -
thionyl chloride/N,N-dimethylfr~r-mi-l~, as reported in J.
Chem. Soc. (C), 1967, 1664, and subsequent treatment with
sodium methoxide in methanol.
The acetanilide o~ formula X may be prepared by
5 reduction of the COL r ~ i n~ nitro c ~ ' of formula
XI:
02N~NH COCH~
(X1 )
typically by transfer hydrogenation using a 1~yd~ ~,g~1ation
15 catalyst in the presence of a hydrogen donor such as
ammonium formate, or alternatively by conventional
catalytic hydrogenation or using tin(II) chloride.
The nitro u-1d of formula XI is
commercially available from the Aldrich Ch~mirAl Company
20 Ltd., Gillingham, United Kingdom.
The preparation of a typical int~ te of
formula VII above, protected on the ring nitrogen atom by
a BOC group, is illustrated by the following reaction
scheme:
t
~ WO9~/21167 ~ 9~ r~ c~l~
-- 11 --
C~_~O H ' ~C H O ( 2 )
H BOC
~X I I )
~//--C O 2 u ~ ~H
80C aoc
(V~ IA)
The starting compound XII, L-prolinol, is
commercially available from Aldrich Chemical Company
Ltd., Gi 11 in~h~m, U.K. Step l of the reaction scheme
20 involves protection of the pyrrolidine nitrogen as the N-
BOC derivative, typically using BOC anhydride in
dichloromethane; followed by Swern oxidation (oxalyl
chloride/dimethyl sulphoxide/dichloromethane/-78-c, then
triethylamine) of the tormin~1 hydroxy group to an
25 aldehyde moiety. Step 2 involves reaction with the
Horner-Emmons reagent r~leO2C.CH2.PO(OEt)2 in the presence
of sodium hydride, using THF as the solvent. In Step 3
the side-chain double bond is reduced, conveniently by
catalytic hydrogenation over palladium-charcoal in
30 aqueous methanol; and the methyl ester moiety is then
partially reduced to an aldehyde functionality using
DIBAL-H in THF at -78 C, to give the desired product of
formula VIIA.
It will be understood that any compound of
35 formula I initially obtained from any of the above
processes may, where appropriate, subsequently be
WO 95/21167 ~ JL~ S
-- 12 --
1,,
elaborated into a further :u_~u~lld of formula I by
~Pr hni~uPc known from the art. Indeed, as will be
appreciated, the ~ u~ l of formula IA, utilised a6 an
intP -~;Ate in the above-described processes, is itself
5 a ~ __ ' in accordance with the present invention.
The following Examples illustrate the
preparation of ~ '~ according to the invention.
The ability of test _ " to bind to
5-HT1-like receptors was measured in membranes prepared
10 from pig caudate using the ~IUCt:-lUL~ described in
J. Neurosci., 1987, 7, 894. Binding was detPrm;nPd using
2 nM 5 I.ydLu,.yLLyyLamine creatinine sulphate,
5-tl,2-3H(N) ] as a radioligand. Cyanopindolol (100 nM)
and mesulergine (100 nM) were included in the assay to
15 block out 5-HT1A and 5-HTlC binding sites respectively.
The :ullc~ L~tion of the, lollnrlc of the A~ -nyillg
Examples required to displace 50% of the specific binding
(IC50) is below 1 ,uM in each case.
The activity of test .-~, u ,,,-'c as agonists of
20 the 5-HTl-like receptor was measured in terms of their
ability to mediate contraction of the sArhPn~nlc vein of
New Zealand Nhite rabbits, using the procedure described
in Arch. Pharm., 1990, 342, 111. Agonist potencies were
calculated as -loglOEC50 (pEC50) values, from plots of
25 percentage 5-HT (1 ,LM) response against the concentration
of the agonist. The olln-lc of the accompanying
Examples were found to possess pEC50 values in this assay
of not less than 5. 0 in each case.
~ WO 95/21167 2 1 8 2 1 ~ 7 . ~ 135
.
13
F.XAl\IPLE 1
(2S)-2-r5-(1.2.4-T~ ~7Al-4-y~ T-T-in~ l-3-vl~ Lvl,~ inr- l.Z5
IN~ Rl\~,nTATF, 1
4'-(1.2.~Tri~7nl-~yl)ohenvll~ ;, r
Prepared from 4~-LILL1~7' ' li(iP as described in WO 93/18029.
INTERMF~nTATF~ 2
(2S)-N-tert-:~u~ylv~ ,t,Ll,vl~vl-3-(vvrr~ in-2-yl)oro~nsll
Prepared from L-prolinol as described herein on pages 10 to 11.
(2s)-2-r5-(~ ~ 4-Trip7~l-4-vl)-1~T-in~lnl-3-vll m~ ylvvLl.. li.linr
1.25 OyDl~tr,
A solution of Tntr~rmPdis~r 1 (2.28g, 1.~ Omm~ll) and Tntrr~^~liDtP 2
(2.50g, ll.Ommol) in 4% aqlleous sulphuric acid (lOOml) was stirred at
room / ~ for 0.3h and then heated at reflux for 36h. After
cooling to room Lt~LUlJ~aLULt:, n-butanol was added and the aqueous
basified with saturated aqu~ous pVI,.3_;ULll carbonate solution. The
aqueous was sf~r~r~t~ and extracted further with n-butanol (x 3). The
combined organics were evaporated in uacuo and the residue flash
chrrnn ~togr~rhf~d on silica gel7 eluting with CH~Cl2/MeOH/NH~ (20:8:1),
to give the title-pyrrolidi7~ l.Olg, 34%). The oxalate salt was prepared,
wich crystallised out r~nts~ininF a small amount of ethanol; m.p. 118-
120C (EtOH/Et20); ~ound~ C, 55.52; H, 5.48; N, 18.17. C,5H,7Ns.
1.25(C~H204). 0.12 (C2H60) requires C, 55.29, EI, 5.29; N, 18.17%); IH
NMR (360MHz, D20) ~ 1.78 (lH, m, CH2), 1.95-2.21 (3H, m, CH2), 3.11-
3.38 (4H, m, CH2), 3.89 (lH, m, CH), 7.27 (lH, dd, J = 8.7 and 2.0Hz, Ar-
H), 7.40 (lH, s, Ar-H), 7.59 (lH, d, J = 8.7Hz, Ar-H), 7.70 (lH, d, J =
l.9Hz), 8.80 (2H, s, Ar-H).
l2 r~ J.D 5 ~ l3s
wo ss 1167 ;
2182197
14
.~AMPT,P: 2
(2s)-N-M~othvl-2-r5-(l~2~4-iriQ7nl-4-vn-lH-indol-3
yllm~lLvluy~l..li Ihnp 1.4 S~ otP
To a cooled solution of the preceding NH-pyrrolidine (free base)
(300mg, 1.12mmoV, NaCNBH3 (85mg, 1 3.~mrA~l) and acetic acid (0.16ml,
2.8mmol) in methanol (25ml) was added a solution of f~rrAol~Phyde
(llOmg, 1 35 ~1 38% w/v) in methanol (15ml). The mixture was
stirred at 0C for 1.75h and then warmed to room ' , ~ , and
stirred for 1.25h. Sat~r~tP~ K2COS solution was added and the solvent
~v~v~Led in uacuo. The aqueous was extracted with EtOAc (x 4), the
combined extracts dried ~gSO~) and the solvent removed in vacuo. The
crude product was flash ~ hed on silica gel, eluting with
CH2Cl2/MeOH/NHs (60:8:1) to give the title-product (258mg, 82%). The
1.4 sulphate salt was prepared which crystallised out ~ nt~inin~ a small
amount of ethanol, m.p. 135C; (Found: C, 45.98; H, 5.39; N, 16.32.
Cl6HIgN5. 1.4(H2SO~). 0.12 (C2H60) requires C, 45.98; H, 5.35; N,
16.51%); IH NMR (360MHz, D20) ~ 1.84-2.06 (3H, m, CH2), 2.24 (lH, m,
CH2), 2.85 (3H, s, CH3), 3.11-3.19 (2H, m, CH2), 3.38 (lH, dd, J = 14 7
and 5.9Hz, CH2), 3.62-3.73 (2H, m, CH + 1 of CH2), 7.38 (lH, dd, J = 8.7
and 2.0Hz, Ar-H), 7.48 (lH, s, Ar-H), 7.67 (lH, d, J = 8.7Hz,Ar-H), 7.84
(lH, d, J = l.9Hz, Ar-H), 9.33 (2H, s, Ar-H).
