WO1994019326A1

WO1994019326A1 - Imidazole derivatives as 5-ht3 receptor agonists

Info

Publication number: WO1994019326A1
Application number: PCT/EP1994/000512
Authority: WO
Inventors: Francis David King; David Malcolm Duckworth
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 1993-02-25
Filing date: 1994-02-18
Publication date: 1994-09-01
Anticipated expiration: 1995-08-25
Also published as: GB9303825D0

Abstract

5-HT3 receptor agonists of formula (I) wherein 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 OR6 or NR7R8, R2, R3, R4, R5, R6, R7 and R8¿ are independently hydrogen or alkyl; and A is an ethyl linkage optionally substituted by alkyl.

Description

IMIDAZOLE DERIVATIVES AS 5-HT3 RECEPTOR AGONISTS

This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.

A series of compounds having 5-HT3 receptor agonist activity have been disclosed by Bermudez et al, Bioorganic and Medicinal Chemistry Letters, 1993, 3, 205.

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.

Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

(i)

wherein

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;

R¹ is OR⁶ or NR⁷R⁸; R², R³, R⁴, R5, R6, 7 _ancj R8 _are independently hydrogen or C_j^alkyl; and

A is an ethyl linkage optionally substituted by C\- alkyl.

Cj.^alkyl groups R* to R⁸ 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. Preferably 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.

R¹ is suitably OR⁶ or NR?R8 where R^, R and R⁸ are independently hydrogen or C_j.-galkyl. Preferably R¹ is OR * in which R6 is C_j.galkyl such as methyl or ethyl. Most preferably R* is ethoxy. Preferably the group C R* is in the ortho or 2-position of the ring Ar. The groups R², R³, R⁴ and R-^ are suitably hydrogen or Cj.^alkyl. Preferably R², R³, R⁴ and R⁵ are all hydrogen.

Preferably 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, α-keto glutaric, α-glycerophosphoric, and glucose- 1 -phosphoric acids.

Preferably 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.

It will of course be realised that some of 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. It will be appreciated that ceπain compounds of formula (I) can exist as tautomers. For example 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.

In a further aspect 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:

•• ^{" " *} ι

• Ar - — j

^'• -V COR ,

(II)

with a compound of formula (III) or a salt thereof:

(III)

wherein j and J² are groups which react together to form a -NHCONH- linkage, and Ar, A, Rl, R⁴ and R-5 are as hereinbefore defined; and thereafter optionally forming a pharmaceutically acceptable salt thereof.

Preferably j s NHCOL where L is a leaving group. Preferably J² 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-.

If a group L is a halide, then 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). It is also preferably carried out in the presence of 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. Alternatively, 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.

If 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.

Preferably 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):

^■ Ar -V— N-***C=O

COR (IV)

in which Ar and R* are as defined in formula (I). Compounds of formula (IV) can be prepared by reaction of the corresponding amine of formula (V):

' Ar -4— NH₂

^"• A^' COR ^,

(V)

in which Ar and R are as defined in formula (I) with phosgene in an inert solvent such as dichloromethane.

Compounds of formula (III) are commercially available or can be prepared using standard procedures known in the art. For example when J² is amino, A is ethyl and attached at the 4-position and R⁴ and R-5 are both hydrogen, the resulting compound of formula (III) is histamine which is commercially available as the hydrochloride salt.

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 comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Such 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.

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.

For parenteral administration, 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. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, 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. Advantageously, 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.

An amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal. However, 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.

No adverse toxicological effects are indicated at any of the aforementioned dosage ranges.

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.

The following Examples illustrate the invention. All temperatures are recorded in degrees centigrade.

Example 1

N-[2-(4-Imida74θlyI)ethyl]-N'-(2-ethoxycarbonyIphenyl)urea hydrochloride

To a solution of carbonyl diimidazole (5g, 0.03mol) in dry dichloromethane (60ml) was added ethyl-2-aminobenzoate (4.76g, 0.029mol). After 15 minutes the solution was evaporated to dryness leaving a white solid. The solid was dissolved in dry DMF (50ml)and histamine hydrochloride (5.35g, 0.029mol) added to give a suspension, followed by triethylamine (4.1ml). The mixture was stirred overnight at ambient temperature, poured into water (600ml), and the resulting white precipitate collected. The white solid was converted into the hydrochloride salt by treatment with 5N HCl in ethanol to give the title compound (4.9g) m.p. 176 - 187°C.

NMR (d⁶ DMSO, 270 MHz):

59.82 (1H, s), 9.04 (1H, s), 8.32 (1H, dd), 7.89 (1H, dd), 7.66 (1H, t), 7.5 (2H, m), 6.99 (1H, t), 4.31 (2H, q), 3.38 (2H, m), 2.82 (2H, t), 1.32 (3H, t).

Example 2

N-[2-(4-ImidazolyI)ethyl]-N'-(2-methoxycarbonylphenyl)urea

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.

NMR (d⁶ DMSO):

δ 9.75 (1H, s), 9.05 (1H, s), 8.3 (1H, d), 7.86 (1H, dd), 7.7 (1H, t), 7.50 (1H, t), 7.46 (1H, s), 6.98 (1H, t), 3.85 (3H, s), 3.42 (2H, m), 2.84 (2H, t). Example 3

N-[2-(4-Imidazolyl)ethyl]-N'-(5-fluoro-2-methoxycarbonyIphenyI)urea

Following the procedure outlined in Example 2, 5-fluoro-2-methoxycarbonyl aniline was reacted with phosgene and histamine dihydrochloride to give the title compound m.p. 136-7°C.

Example 4

N-[2-(4-Imidazolyl)ethyl]-N'-(2-methoxycarbonyl-thien-3-yl)urea

Following the procedure outlined in Example 2, methyl-3-amino-2-thiophenecarboxylate was reacted with phosgene and histamine dihydrochloride to give the title compound m.p. 212 - 213°C.

Pharmacology

The von Bezold-Jarisch reflex

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 μg/kg i.v.

Claims

Claims:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I) wherein

R¹ is OR⁶ or NR⁷R⁸; R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are independently hydrogen or Cj .galkyl; and

A is an ethyl linkage optionally substituted by C_j-_β alkyl.

2. A compound according to claim 1 in which Ar is thienyl or phenyl.

3. A compound according to claim 2 in which RΪ is ethoxy.

4. A compound according to claim 3 in which R², R³, R⁴ and R^ are all hydrogen.

5. A compound according to claim 4 in which A is an ethyl linkage attached to the 4- position of the imidazole ring.

6. A compound according to claim 1 selected from: 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.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. A compound according to any one of claims 1 to 6 for use in therapy.

9. A compound according to any one of claims 1 to 6 for use in the treatment or prophylaxis of anxiety, depression, Parkinsonism and senile dementia.

10. 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:

1

Ar - —

^•N COR ,

(ID

with a compound of formula (III) or a salt thereof:

(HI)

wherein jl and J² are groups which react together to foim a -NHCONH- linkage, and Ar, A, R , R⁴ and R-5 are as defined in claim 1; and thereafter optionally forming a pharmaceutically acceptable salt thereof.