TRIAZOLE DERIVATIVES

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: TRIAZOLE DERIVATIVES The present invention relates to a discrete class of substituted triazole derivatives which act on 5- hydroxytryptamine (5-HT) receptors, being selective agonists of so-called -'5-HTι-like" receptors. They are therefore useful in the treatment of clinical conditions for which a selective agonist of these receptors is indicated. 5-HT-L-like receptor agonists which exhibit selective vasoconstrictor activity have recently been described as being of use in the treatme--.-. of migraine (see, for example, A. Doenicke et al.. The Lancet, 1988, Vol. 1, 1309-11). The compounds of the present invention, being selective S-HT-^-like receptor agonists, are accordingly of particular use in the treatment of migraine and associated conditions, e.g. cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, tension headache and paediatric migraine. O-A-94/02477, published on 3rd February 1994, describes a class of substituted imidazole, triazole and tetrazole derivatives which are stated to be selective agonists of 5-HT-j_-like receptors and hence to be of particular use in the treatment of migraine and associated conditions. The present invention provides a compound of formula I, or a salt or prodrug thereof: ( I ) wherein R represents hydrogen or C-^.g alkyl. As will be appreciated, the carbon atom at the 2-position of the pyrrolidine ring in the compounds of formula I above is in the (S) configuration. The compounds of formula I above, and salts and prodrugs thereof, are generically encompassed within the scope of O-A-94/02477. There is, however, no specific disclosure therein of a compound corresponding to the compounds of formula I above, i.e. compounds wherein the carbon atom at the 2-position of the pyrrolidine ring is in the (S) configuration. For use in medicine, the salts of the compounds 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 pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a 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 "C-^_ alkyl" includes straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Such groups include 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 prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. Particular values for the group R include hydrogen and methyl. Specific compounds within the scope of the present invention include: (2S)-2-[5-(l,2,4-triazol-4-yl)-lH-indol-3- y1]methylpyrrolidine; (2S) -N-methyl-2-[5-(1,2,4-triazol-4-yl) -lH-indol-3- yl]methylpyrrolidine; and salts and prodrugs thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically 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 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 ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing 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 form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl- pyrrolidone or gelatin. In the treatment of migraine, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day. The compounds according to this invention wherein R is other than hydrogen may be prepared by a process which comprises reacting the compound of formula IA with a compound of formula II: ( I ) ( I D wherein R represents C-L_ 6 alkyl, and L represents a suitable leaving group. The leaving group L is suitably a halogen atom, e.g. bromine or iodine. 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 the solvent. In an alternative procedure, the compounds according to the invention represented by formula IB: ( I B) wherein -CH2R > 20 corresponds to a group of formula R as defined above; may be prepared by a reductive amination process which comprises reacting a compound of formula IA as defined above with an aldehyde derivative of formula R -CHO in the presence of a reducing agent. An appropriate reducing agent for use in this procedure is sodium cyanoborohydride, in which case the reaction is conveniently carried out in an alcoholic solvent such as methanol, typically in the presence of acetic acid. In a further procedure, the compounds according to the invention wherein R is other than hydrogen, including the compounds of formula IB above, may be prepared by reacting the compound of formula III: ( I I I ) with a compound of formula IV or a carbonyl-protected form thereof: ( IV) wherein R > ιo u is as defined above. Suitable carbonyl-protected forms of the compounds of formula IV include the dimethyl acetal or ketal derivatives. The reaction of compounds III and IV may be carried out in a single step (Fischer indole synthesis) or by an initial non-σyclising step at a lower temperature to give a compound of formula V: (V) wherein R ,1 x 0 as defined above; followed by cyclisation using a suitable reagent, such as a polyphosphate ester. The hydrazine of formula III may be prepared from the corresponding aniline of formula VI: ( V I ) 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/cone. HCl, sodium sulphite/cone. HCl, or sodium sulphite/cone. H2SO 4 . The compounds of formula IA above may be prepared by reacting a compound of formula III as defined above with a compound of formula VII, or a carbonyl- protected form thereof: (V I I ) wherein R ,30 represents hydrogen or an amino-protecting group; followed, where required, by removal of the amino- protecting group R 30 . 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 R *" -Ω, where present, is suitably a lower alkoxycarbonyl moiety such as t-butoxycarbonyl (BOC) , which can be conveniently removed as necessary by treatment with acid. As with that between compounds III and IV, the reaction between compounds 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 a compound of formula VIII: (VIII) wherein R 30 is as defined 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: ( IX) (X) followed by removal of the N-acetyl protecting group. The reaction between compounds 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 typically effected in hot aqueous 5N hydrochloric acid. The hydrazine derivative of formula IX can be prepared from N,N'-diformylhydrazine by reaction with thionyl chloride/N,N-dimethylformamide, as reported in J. Chem. Soc. (C) . 1967, 1664, and subsequent treatment with sodium methoxide in methanol. The acetanilide of formula X may be prepared by reduction of the corresponding nitro compound of formula XI: (X I ) typically by transfer hydrogenation using a hydrogenation 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 compound of formula XI is commercially available from the Aldrich Chemical Company Ltd. , Gillingham, United Kingdom. The preparation of a typical intermediate of formula VII above, protected on the ring nitrogen atom by a BOC group, is illustrated by the following reaction scheme: (XI I ) (VI IA) The starting compound XII, L-prolinol, is commercially available from Aldrich Chemical Company Ltd., Gillingham, U.K. Step 1 of the reaction scheme 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 terminal hydroxy group to an aldehyde moiety. Step 2 involves reaction with the Horner-Emmons reagent Meθ2C.CH 2 .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 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 formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art. Indeed, as will be appreciated, the compound of formula IA, utilised as an intermediate in the above-described processes, is itself a compound in accordance with the present invention. The following Examples illustrate the preparation of compounds according to the invention. The ability of test compounds to bind to 5-HTι-like receptors was measured in membranes prepared from pig caudate using the procedure described in J. Neurosci.. 1987, 1_, 894. Binding was determined using 2 nM 5-hydroxytryptamine creatinine sulphate, 5-[l,2- 3 H(N) ] as a radioligand. Cyanopindolol (100 nM) and esulergine (100 nM) were included in the assay to block out 5-HT-LA and 5-HTιc binding sites respectively. The concentration of the compounds of the accompanying Examples required to displace 50% of the specific binding (IC50) is below 1 μM in each case. The activity of test compounds as agonists of the 5-HT-L-like receptor was measured in terms of their ability to mediate contraction of the saphenous vein of New Zealand White rabbits, using the procedure described in Arch. Pharm. , 1990, 342, 111. Agonist potencies were calculated as -logioECso (PEC5 0 ) values, from plots of percentage 5-HT (1 μM) response against the concentration of the agonist. The compounds of the accompanying Examples were found to possess PEC5 0 values in this assay of not less than 5.0 in each case. EXAMPLE 1 (2-?)-2-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-yll methylpyrrol^-in p V2K Oxalate INTERMEDIATE 1 4'-(l,2,4-Triazol-4-yl)phenylhvdrazine Prepared from 4'-nitroacetanilide as described in WO 93/18029. INTERMEDIATE 2 (2--?)-N-ter,:-Butyloxycarbonyl-3-(pyrrolidin-2-yl)pro-panal Prepared from L-prolinol as described herein on pages 10 to 11. (2-S^-2-r5-α.2.4-Triazol-4-yl)-lH-indol-3-yl1 methylpyrrolidine. 1.25 Oxalate A solution of Intermediate 1 (2.28g, 13.0mmol) and Intermediate 2 (2.50g, ll.Ommol) in 4% aqueous sulphuric acid (100ml) was stirred at room temperature for 0.3h and then heated at reflux for 36h. After cooling to room temperature, n-butanol was added and the aqueous basified with saturated aqueous potassium carbonate solution. The aqueous was separated and extracted further with n-butanol (x 3). The combined organics were evaporated in vacuo and the residue flash chromatographed on silica gel, eluting with CH 2 Cl 2 /MeOH/NH 3 (20:8: 1), to give the ύtle-pyrrolidine (1.0 lg, 34%). The oxalate salt was prepared, which crystallised out containing a small amount of ethanol; m.p. 118- 120°C (EtOH/Et 2 0); (Found: C, 55.52; H, 5.48; N, 18.17. C 15 H 17 N 5 . 1.25(C 2 H 2 θ 4 ). 0.12 (C 2 H 6 0) requires C, 55.29; H, 5.29; N, 18.17%); Η NMR (360MHz, D 2 0) δ 1.78 (IH, m, CH j j), 1.95-2.21 (3H, m, CH^, 3.11- 3.38 (4H, m, CH^, 3.89 (IH, m, CH), 7.27 (IH, dd, J = 8.7 and 2.0Hz, Ar¬ il), 7.40 (IH, s, Ar-H), 7.59 (IH, d, J = 8.7Hz, Ar-H), 7.70 (IH, d, J = 1.9Hz), 8.80 (2H, s, Ar-H). EXAMPLE 2 (2-9)-N-Methyl-2-r5-(1.2.4-triazol-4-yl)-lH-indol-3- yllmethylpyrrolidine. 1.4 Sulphate To a cooled solution of the preceding NH-pyrrohdine (free base) (300mg, 1.12mmol), NaCNBH 3 (85mg, 1.35mmol) and acetic acid (0.16ml, 2.8mmol) in methanol (25ml) was added a solution of formaldehyde (HOmg, 1.35mmol, 38% w/v) in methanol (15ml). The mixture was stirred at 0°C for 1.75h and then warmed to room temperature and stirred for 1.25h. Saturated j COg solution was added and the solvent evaporated in υacuo. The aqueous was extracted with EtOAc (x 4), the combined extracts dried (MgSO^ and the solvent removed in υacuo. The crude product was flash chromatographed on silica gel, eluting with CH 2 Cl 2 MeOH/NH 3 (60:8:1) to give the title-proc-ucf (258mg, 82%). The 1.4 sulphate salt was prepared which crystallised out containing a small amount of ethanol, m.p. 135°C; (Found: C, 45.98; H, 5.39; N, 16.32. C 16 H 19 N 5 . 1.4(H 2 S0 4 ). 0.12 (C 2 H 6 0) requires C, 45.98; H, 5.35; N, 16.51%); Η NMR (360MHz, D 2 0) δ 1.84-2.06 (3H, m, CH^, 2.24 (IH, m, CHg), 2.85 (3H, s, CH 3 ), 3.11-3.19 (2H, m, CH^, 3.38 (IH, dd, J = 14.7 and 5.9Hz, CH^, 3.62-3.73 (2H, m, CH + 1 of CR-L), 7.38 (IH, dd, J = 8.7 and 2.0Hz, Ar-H), 7.48 (IH, s, Ar-H), 7.67 (IH, d, J = 8.7Hz,Ar-H), 7.84 (IH, d, J = 1.9Hz, 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 Cι_ 6 alkyl. 2. A compound as claimed in claim 1 wherein R represents hydrogen or methyl. 3. (2S)-2-[5-(l,2,4-Triazol-4-yl)-lH-indol-3- yl]methylpyrrolidine; and salts and prodrugs thereof. 4. (2S)-N-Methyl-2-[5-(1,2,4-triazol-4-yl)- lH-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-HTι-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: ( IA) (I D wherein R 10 represents C^g 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 R 0 -CHO, wherein R 20 represents hydrogen or C- j __5 alkyl, in the presence of a reducing agent; or (C) reacting the compound of formula III: NH, ( M I) with a compound of formula IV or a carbonyl-protected form thereof: ( IV) wherein R ,10 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: (V I I ) wherein R represents hydrogen or an amino-protecting group; followed, where required, by removal of the amino- protecting group R 30 . 9. A method for the treatment and/or prevention of clinical conditions for which a selective agonist of S-HT^-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.

Inventors: MATASSA VICTOR GIULIO, STERNFELD FRANCINE, STREET LESLIE JOSEPH, MATASSA, VICTOR, GIULIO, STERNFELD, FRANCINE, STREET, LESLIE, JOSEPH
Applicants: MATASSA VICTOR GIULIO, MERCK SHARP & DOHME, STERNFELD FRANCINE, STREET LESLIE JOSEPH, MATASSA, VICTOR, GIULIO, MERCK SHARP & DOHME LIMITED, STERNFELD, FRANCINE, STREET, LESLIE, JOSEPH
Application year: 1995
Main classification: C07D403
IPC codes: A61K31, A61P25, A61P43, C07D403, C07D521