WO1994019326A1 - Derives d'imidazole utilises comme agonistes de recepteur 5-ht¿3? - Google Patents

Derives d'imidazole utilises comme agonistes de recepteur 5-ht¿3? Download PDF

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Publication number
WO1994019326A1
WO1994019326A1 PCT/EP1994/000512 EP9400512W WO9419326A1 WO 1994019326 A1 WO1994019326 A1 WO 1994019326A1 EP 9400512 W EP9400512 W EP 9400512W WO 9419326 A1 WO9419326 A1 WO 9419326A1
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WIPO (PCT)
Prior art keywords
ethyl
formula
pharmaceutically acceptable
compound
compound according
Prior art date
Application number
PCT/EP1994/000512
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English (en)
Inventor
Francis David King
David Malcolm Duckworth
Original Assignee
Smithkline Beecham Plc
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.)
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Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of WO1994019326A1 publication Critical patent/WO1994019326A1/fr

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Classifications

    • 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
    • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.
  • a structurally distinct class of compounds has now been discovered, which are 5-HT3 receptor agonists and are therefore of potential use in treatment or prophylaxis of CNS disorders, particularly anxiety and depression.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:
  • Ar is an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen or sulphur;
  • R 1 is OR 6 or NR 7 R 8 ;
  • R 2 , R 3 , R 4 , R5, R6, 7 anc j R8 are independently hydrogen or C j ⁇ alkyl;
  • A is an ethyl linkage optionally substituted by C ⁇ - alkyl.
  • Cj. ⁇ alkyl groups R* to R 8 may be straight-chain or branched and include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl, preferably methyl or ethyl.
  • Suitable values for Ar when Ar is a heterocyclic ring include pyridine, pyrimidine, pyrazine, pyrrole, imidazole, thiophene, furan, oxazole or thiazole.
  • Ar is thienyl or phenyl, most preferably phenyl.
  • Optional substituents for the ring Ar include halo, hydroxy, Cj. ⁇ alkoxy and Cj.galkyl. Preferred substituents are fluoro, chloro and hydroxy, most preferably Ar is unsubstituted or substituted by fluoro.
  • R 1 is suitably OR 6 or NR?R8 where R ⁇ , R and R 8 are independently hydrogen or C j .-galkyl.
  • R 1 is OR * in which R6 is C j .galkyl such as methyl or ethyl. Most preferably R* is ethoxy.
  • the group C R* is in the ortho or 2-position of the ring Ar.
  • the groups R 2 , R 3 , R 4 and R- ⁇ are suitably hydrogen or Cj. ⁇ alkyl.
  • R 2 , R 3 , R 4 and R 5 are all hydrogen.
  • the ethylene linkage A is attached to the imidazole ring at the 4-position as depicted in formula (I).
  • Particularly preferred compounds of the invention include: N-[2-(4-imidazolyl)ethyl]-N'-(2-ethoxycarbonylphenyl)urea, N-[2-(4-imidazolyl)ethyl]-N'-(2-methoxycarbonylphenyl)urea, N-[2-(4-imidazolyl)ethyl]-N'-(5-fluoro-2-methoxycarbonylphenyl)urea, N-[2-(4-imidazolyl)ethyl]-N'-(2-methoxycarbonyl-thien-3-yl)urea, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, lactic, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, ⁇ -keto glutaric, ⁇ -glycerophosphoric, and glucose- 1 -phosphoric acids.
  • conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids
  • pharmaceutically acceptable organic acids such as acetic, tartaric, lactic, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, ⁇ -keto glutaric, ⁇ -glycerophosphoric, and glucose- 1 -phosphoric acids.
  • the acid addition salt is the hydrochloride salt.
  • the compounds of the formula (I), and their pharmaceutically acceptable salts may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.
  • the compounds of the formula (I) may have chiral or prochiral centres and thus are capable of existing in a number of stereoisomeric forms including enantiomers.
  • the invention extends to each of these stereoisomeric forms (including enantiomers), and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from another by the usual methods.
  • ce ⁇ ain compounds of formula (I) can exist as tautomers.
  • the imidazole ring in formula (I) can tautomerise i.e. the hydrogen atom can be on either of the imidazole nitrogen atoms.
  • the invention extends to tautomeric forms of compounds of formula (I) and mixtures thereof.
  • the present invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises the reaction of a compound of formula (II) or a salt thereof:
  • j and J 2 are groups which react together to form a -NHCONH- linkage, and Ar, A, Rl, R 4 and R-5 are as hereinbefore defined; and thereafter optionally forming a pharmaceutically acceptable salt thereof.
  • j s NHCOL where L is a leaving group.
  • J 2 is amino.
  • Examples of leaving groups L, displaceable by a nucleophile include halogen such as chloro and bromo, imidazolyl, C]-4 alkoxy, such as CH3O and C2H5O-, PhO- or activated hydrocarbyloxy, such as CI5C6O- or CI3CO-.
  • a group L is a halide
  • the reaction is preferably carried out at non extreme temperatures in an inert non-hydroxylic solvent, such as benzene, dichloromethane, toluene, diethyl ether, tetrahydrofuran (THF) or dimethylformamide (DMF).
  • an acid acceptor such as an organic base, in particular a ternary amine, such as triethylamine, trimethylamine, pyridine or picoline, some of which can also function as the solvent.
  • the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate. Temperatures of 0°-100°C, in particular 18-80°C are suitable.
  • a group L is -4 alkoxy, phenoxy or activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as toluene or dimethylformamide. It is also preferred that the group L is CI3CO- and that the reaction is carried out in toluene at reflux temperature.
  • L is imidazolyl or chloro. It will be appreciated that when L is chloro, the resulting compound of formula (II) eliminates HCl to give the corresponding isocyanate of formula (IV):
  • Compounds of formula (II) in which L is imidazolyl can be prepared by reacting compounds of formula (V) as hereinbefore defined, with carbonyldiimidazole (CDI) in an inert solvent such as dichloromethane.
  • Pharmaceutically acceptable salts of the compounds of this invention may be formed conventionally.
  • the acid addition salts may be formed for example by reaction of the base compound of formula (I) with a pharmaceutically acceptable organic or inorganic acid.
  • the compounds of the present invention are 5-HT3 receptor agonists and it is thus believed may generally be used in the treatment or prophylaxis of CNS disorders, particularly anxiety, depression, Parkinsonism and senile dementia.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
  • Orally administrable compositions are preferred, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art, for example with an enteric coating.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyi p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.
  • the oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • the invention further provides a method of treatment or prophylaxis of CNS disorders, particularly anxiety and depression, in mammals which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • a unit dose for a 70kg adult will normally contain 0.05 to lOOOmg for example 0.1 to 500mg, of the compound of the invention.
  • Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for the treatment or prophylaxis of CNS disorders, particularly anxiety, depression, Parkinsonism and senile dementia.
  • Methylanthrinilate (1.17g) was added to phosgene solution (7.5ml of a 12.5% solution in toluene) in dry dichloromethane (12.5ml) at ambient temperature. After stirring for 15 minutes, excess phosgene was removed in vacuo. The residue was suspended in dry dichloromethane (25ml) and triethylamine (3.5ml) added. After 5 minutes histamine dihydrochloride (1.42g) was added and the reaction mixture stirred at ambient temperature for 2.5 hours. The mixture was filtered, the filtrate evaporated to dryness and the solid residue crystallised from ethanol to give the title compound (0.56g) m.p. 169 - 172°C. A sample was converted to the hydrochloride salt by treatment with methanol/dilute hydrochloric acid.
  • the compounds were evaluated for their ability to evoke von Bezold-Jarisch reflex in the anaesthetised rat.
  • Male rats, 250-350g were anaesthetised with urethane (1.25g/kg intraperitoneally) and blood pressure and heart rate recorded as described by Fozard J.R. et al., J. Cardiovasc. Pharmacol. 2, 229-245 (1980).
  • the ID50 values for the test compounds were then determined.
  • the compounds of examples 1 to 4 had ID50 values less than 100 ⁇ g/kg i.v.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Agonistes de récepteur 5-HT3 de la formule (I) dans laquelle Ar représente un noyau phényle éventuellement substitué ou un noyau hétérocyclique à 5 ou 6 éléments éventuellement substitué, contenant un ou plusieurs hétéroatomes choisis entre oxygène, azote ou soufre; R1 représente OR?6 ou NR7R8, R2, R3, R4, R5, R6, R7 et R8¿ représentent indépendamment hydrogène ou alkyle; et A représente une liaison éthyle éventuellement substituée par alkyle.
PCT/EP1994/000512 1993-02-25 1994-02-18 Derives d'imidazole utilises comme agonistes de recepteur 5-ht¿3? WO1994019326A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939303825A GB9303825D0 (en) 1993-02-25 1993-02-25 Novel compounds
GB9303825.5 1993-02-25

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WO1994019326A1 true WO1994019326A1 (fr) 1994-09-01

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5578629A (en) * 1995-03-29 1996-11-26 Merck & Co., Inc. Benzamide-containing inhibitors of farnesyl-protein transferase
WO1997036584A1 (fr) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibiteurs de transferase de farnesyl-proteine
US5922883A (en) * 1996-04-03 1999-07-13 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6028201A (en) * 1996-01-30 2000-02-22 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6034251A (en) * 1997-11-07 2000-03-07 Schering Corporation Phenyl-alkyl-imidazoles
US6090948A (en) * 1996-01-30 2000-07-18 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993014070A2 (fr) * 1992-01-10 1993-07-22 Institut National De La Sante Et De La Recherche Medicale Nouveaux derives de l'imidazole, leur preparation et leurs applications therapeutiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993014070A2 (fr) * 1992-01-10 1993-07-22 Institut National De La Sante Et De La Recherche Medicale Nouveaux derives de l'imidazole, leur preparation et leurs applications therapeutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. BERMUDEZ ET AL.: "Synthesis and 5-HT3 receptor agonist activity of arylureas derived from histamine", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 3, no. 2, 1993, OXFORD, GB, pages 205 - 208 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5578629A (en) * 1995-03-29 1996-11-26 Merck & Co., Inc. Benzamide-containing inhibitors of farnesyl-protein transferase
US6028201A (en) * 1996-01-30 2000-02-22 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6090948A (en) * 1996-01-30 2000-07-18 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036584A1 (fr) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibiteurs de transferase de farnesyl-proteine
US5922883A (en) * 1996-04-03 1999-07-13 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6034251A (en) * 1997-11-07 2000-03-07 Schering Corporation Phenyl-alkyl-imidazoles

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