+

WO1995021167A1 - Triazole derivatives - Google Patents

Triazole derivatives Download PDF

Info

Publication number
WO1995021167A1
WO1995021167A1 PCT/GB1995/000135 GB9500135W WO9521167A1 WO 1995021167 A1 WO1995021167 A1 WO 1995021167A1 GB 9500135 W GB9500135 W GB 9500135W WO 9521167 A1 WO9521167 A1 WO 9521167A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
pharmaceutically acceptable
prodrug
compounds
Prior art date
Application number
PCT/GB1995/000135
Other languages
French (fr)
Inventor
Victor Giulio Matassa
Francine Sternfeld
Leslie Joseph Street
Original Assignee
Merck Sharp & Dohme Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Sharp & Dohme Limited filed Critical Merck Sharp & Dohme Limited
Priority to EP95906416A priority Critical patent/EP0741723A1/en
Priority to AU14614/95A priority patent/AU1461495A/en
Priority to JP7520436A priority patent/JPH09508409A/en
Publication of WO1995021167A1 publication Critical patent/WO1995021167A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • 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-HT ⁇ -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.
  • the present invention provides a compound of formula I, or a salt or prodrug thereof:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
  • 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.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • R is other than hydrogen
  • R represents C-L_ 6 alkyl
  • 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.
  • 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.
  • ( 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.
  • Suitable carbonyl-protected forms of the compounds of formula IV include the dimethyl acetal or ketal derivatives.
  • reaction of compounds III and IV may be carried out in a single step (Fischer indole synthesis) or by an initial non- ⁇ yclising step at a lower temperature to give a compound of formula V:
  • 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 .
  • suitable carbonyl-protected forms of the compounds of formula VII include the dimethyl acetal and ketal derivatives.
  • the amino-protecting group R *" - ⁇ is suitably a lower alkoxycarbonyl moiety such as t-butoxycarbonyl (BOC) , which can be conveniently removed as necessary by treatment with acid.
  • BOC t-butoxycarbonyl
  • 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:
  • the aniline derivative of formula VI may be prepared by reacting the hydrazine derivative of formula IX with the acetanilide of formula X:
  • 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.
  • nitro compound of formula XI is commercially available from the Aldrich Chemical Company Ltd. , Gillingham, United Kingdom.
  • 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
  • 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.
  • 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.
  • 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.
  • test compounds to bind to 5-HT ⁇ -like receptors was measured in membranes prepared from pig caudate using the procedure described in
  • 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-HT ⁇ c binding sites respectively. The concentration of the compounds of the accompanying Examples required to displace 50% of the specific binding (IC50) is below 1 ⁇ M in each case.
  • 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 ⁇ M) 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.
  • 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 ⁇ 4 ). 0.12 (C 2 H 6 0) requires C, 55.29; H, 5.29; N, 18.17%); ⁇ NMR (360MHz, D 2 0) ⁇ 1.78 (IH, m, CH j j), 1.95-2.21 (3H, m, CH ⁇ , 3.11-
  • 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 ).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

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:
Figure imgf000004_0001
( 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:
Figure imgf000007_0001
( 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:
Figure imgf000008_0001
( 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:
Figure imgf000008_0002
( I I I ) with a compound of formula IV or a carbonyl-protected form thereof:
Figure imgf000009_0001
( IV) wherein R >ιou 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:
Figure imgf000009_0002
(V) wherein R ,1x0 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:
Figure imgf000010_0001
( 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. H2SO4. 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:
Figure imgf000010_0002
(V I I ) wherein R ,30 represents hydrogen or an amino-protecting group; followed, 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 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:
Figure imgf000011_0001
(VIII) wherein R30 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:
Figure imgf000011_0002
( 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:
Figure imgf000012_0001
(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:
Figure imgf000013_0001
(XI I )
Figure imgf000013_0002
(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.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 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,2-3H(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 (PEC50) 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 PEC50 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^-inp 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 CH2Cl2/MeOH/NH3 (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/Et20); (Found: C, 55.52; H, 5.48; N, 18.17. C15H17N5. 1.25(C2H2θ4). 0.12 (C2H60) requires C, 55.29; H, 5.29; N, 18.17%); Η NMR (360MHz, D20) δ 1.78 (IH, m, CHjj), 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), NaCNBH3 (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 jCOg 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 CH2Cl2 MeOH/NH3 (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. C16H19N5. 1.4(H2S04). 0.12 (C2H60) requires C, 45.98; H, 5.35; N, 16.51%); Η NMR (360MHz, D20) δ 1.84-2.06 (3H, m, CH^, 2.24 (IH, m, CHg), 2.85 (3H, s, CH3), 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:
Figure imgf000017_0001
( 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:
Figure imgf000018_0001
( IA) (I D
wherein R10 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 R20 represents hydrogen or C-j__5 alkyl, in the presence of a reducing agent; or
(C) reacting the compound of formula III:
Figure imgf000019_0001
NH,
( M I) with a compound of formula IV or a carbonyl-protected form thereof:
Figure imgf000019_0002
( 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:
Figure imgf000019_0003
(V I I ) wherein R 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 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.
PCT/GB1995/000135 1994-02-02 1995-01-24 Triazole derivatives WO1995021167A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP95906416A EP0741723A1 (en) 1994-02-02 1995-01-24 Triazole derivatives
AU14614/95A AU1461495A (en) 1994-02-02 1995-01-24 Triazole derivatives
JP7520436A JPH09508409A (en) 1994-02-02 1995-01-24 Triazole derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9402011A GB9402011D0 (en) 1994-02-02 1994-02-02 Therapeutic agents
GB9402011.2 1994-02-02

Publications (1)

Publication Number Publication Date
WO1995021167A1 true WO1995021167A1 (en) 1995-08-10

Family

ID=10749754

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1995/000135 WO1995021167A1 (en) 1994-02-02 1995-01-24 Triazole derivatives

Country Status (6)

Country Link
EP (1) EP0741723A1 (en)
JP (1) JPH09508409A (en)
AU (1) AU1461495A (en)
CA (1) CA2182197A1 (en)
GB (1) GB9402011D0 (en)
WO (1) WO1995021167A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7189753B1 (en) 1997-11-06 2007-03-13 Cady Roger K Preemptive prophylaxis of migraine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0497512A2 (en) * 1991-02-01 1992-08-05 Merck Sharp & Dohme Ltd. Imidazole, triazole and tetrazole derivatives
WO1993021180A1 (en) * 1992-04-10 1993-10-28 Pfizer Inc. Acylaminoindole derivatives as 5-ht1 agonists
EP0581538A1 (en) * 1992-07-30 1994-02-02 Merck Sharp & Dohme Ltd. 4-Substituted 1,2,4-triazole derivatives
WO1994002477A1 (en) * 1992-07-24 1994-02-03 Merck Sharp & Dohme Limited Imidazole, triazole and tetrazole derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0497512A2 (en) * 1991-02-01 1992-08-05 Merck Sharp & Dohme Ltd. Imidazole, triazole and tetrazole derivatives
WO1993021180A1 (en) * 1992-04-10 1993-10-28 Pfizer Inc. Acylaminoindole derivatives as 5-ht1 agonists
WO1994002477A1 (en) * 1992-07-24 1994-02-03 Merck Sharp & Dohme Limited Imidazole, triazole and tetrazole derivatives
EP0581538A1 (en) * 1992-07-30 1994-02-02 Merck Sharp & Dohme Ltd. 4-Substituted 1,2,4-triazole derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7189753B1 (en) 1997-11-06 2007-03-13 Cady Roger K Preemptive prophylaxis of migraine

Also Published As

Publication number Publication date
CA2182197A1 (en) 1995-08-10
EP0741723A1 (en) 1996-11-13
JPH09508409A (en) 1997-08-26
GB9402011D0 (en) 1994-03-30
AU1461495A (en) 1995-08-21

Similar Documents

Publication Publication Date Title
EP0778275B1 (en) Process for the preparation of imidazole, triazole and tetrazole derivatives and their use as selective 5-HT-1 receptor agonists
US5073671A (en) 1-(benzyl or pyridylmethyl)-4 or 5-aminomethyl-pyrrolidin-2-ones
EP0630374B1 (en) Imidazole, triazole and tetrazole derivatives
US5554629A (en) 4-substituted 1,2,4-triazole derivatives
EP0640085B1 (en) Fused imidazole and triazole derivatives as 5-ht1 receptor agonists
EP0096838B1 (en) 1-aryloxy-2,3,4,5-tetrahydro-3-benzazepines, a process for preparing the same and their use as medicaments
HU184727B (en) Process for preparing 3-/1-imidazolyl-alkyl/-indole derivatives
JPS6364428B2 (en)
HUT57735A (en) Process for producing benzimidazolinone derivatives and pharmaceutical compositions comprising such compounds as active ingredient
US5256664A (en) Antidepressant 3-halophenylpiperazinylpropyl derivatives of substituted triazolones and triazoldiones
US5246957A (en) N-imidazolyl derivatives of substituted indole
US5607957A (en) Imidazole, triazole and tetrazole derivatives
HU203345B (en) Process for producing ergoline derivatives and pharmaceutical compositions comprising same
WO1995021167A1 (en) Triazole derivatives
US5919783A (en) Indoline and azaindoline derivatives as 5-HT1D alpha receptor agonists
JPH09501954A (en) Imidazo [5,1-c] [1,4] benzoxazin-1-one imidazolylalkyl derivatives and processes for their preparation
US5770611A (en) Indole derivatives as 5HT1 -like agonists
EP0741722B1 (en) Triazole derivatives
US4703055A (en) Benzamides and therapeutic use thereof
US6054469A (en) Substituted tetrahydropyridine derivatives acting on 5-HT receptors
HUT60492A (en) Process for producing n-imidazolyl derivatives of substituted tetrahydrocarbazole and cyclohepta/b/-indole compounds
US6150391A (en) Diazabicyclo-octane derivatives as 5-HT receptor ligands
HU191597B (en) Process for producing of 2-/2-indalin/-imadazoline preparates and medical preparates consisting of such substances
US5047402A (en) Cyclic amides as medicaments
GB2286185A (en) Triazole derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1995906416

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 1996 676349

Country of ref document: US

Date of ref document: 19960719

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2182197

Country of ref document: CA

WWP Wipo information: published in national office

Ref document number: 1995906416

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 1995906416

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载