CA2182197A1

CA2182197A1 - Triazole derivatives

Info

Publication number: CA2182197A1
Application number: CA002182197A
Authority: CA
Inventors: Victor Giulio Matassa; Francine Sternfeld; Leslie Joseph Street
Original assignee: Individual
Current assignee: Organon Pharma UK Ltd
Priority date: 1994-02-02
Filing date: 1995-01-24
Publication date: 1995-08-10
Also published as: GB9402011D0; JPH09508409A; AU1461495A; EP0741723A1; WO1995021167A1

Abstract

A compound of formula (I), or a salt or prodrug thereof wherein R represents hydrogen or C1-6 alkyl, selective agonist of 5-HT1-like receptors and is therefore useful in the treatment of clinical conditions, in particular migraine and associated conditions, for which a selective agonist of these receptors is indicated.

Description

~ 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 ` `;

~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 ~

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 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:

( 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~

( I I I ) 35 with a compound of formula IV or a carbonyl-protected form thereof:
_ _ _ , . .

~ib, _ _ 135 wo 95121 161 1 ~ I
~182197 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'' '- --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:

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~

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

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 .

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 ;

.~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).

Claims

CLAIMS:

1. A compound of formula I, or a salt or prodrug thereof:

(I) wherein R represents hydrogen or C1-6 alkyl.

2. A compound as claimed in claim 1 wherein R
represents hydrogen or methyl.

3. (2S)-2-[5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl]methylpyrrolidine; and salts and prodrugs thereof.

4. (2S)-N-Methyl-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]methylpyrrolidine: and salts and prodrugs thereof.

5. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof or a prodrug thereof in association with a pharmaceutically acceptable carrier.

6. A compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof or a prodrug thereof for use in therapy.

7. The use of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof or a prodrug thereof for the treatment and/or prevention of clinical conditions for which a selective agonist of 5-HT1-like receptors is indicated.

8. A process for the preparation of a compound as claimed in claim 1 which comprises:
(A) reacting the compound of formula IA with a compound of formula II:

L-R10 (IA) (II) wherein R10 represents C1-6 alkyl, and L represents a suitable leaving group; or (B) reacting a compound of formula IA as defined above with an aldehyde derivative of formula R20-CHO, wherein R20 represents hydrogen or C1-5 alkyl, in the presence of a reducing agent: or (C) reacting the compound of formula III:

(III) with a compound of formula IV or a carbonyl-protected form thereof:

(IV) wherein R10 is as defined above; or (D) reacting a compound of formula III as defined above with a compound of formula VII, or a carbonyl-protected form thereof:

(VII) wherein R30 represents hydrogen or an amino-protecting group; followed, where required, by removal of the amino-protecting group R30.

9. A method for the treatment and/or prevention of clinical conditions for which a selective agonist of 5-HT1-like receptors is indicated, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof.