WO1993008185A1

WO1993008185A1 - N-aryl-n1-azabicyclo-ureas as 5-ht3 antagonists

Info

Publication number: WO1993008185A1
Application number: PCT/GB1992/001876
Authority: WO
Inventors: Francis David King; Laramie Mary Gaster
Original assignee: Smithkline Beecham Plc
Priority date: 1991-10-15
Filing date: 1992-10-13
Publication date: 1993-04-29
Also published as: GB9121835D0; AU2759892A

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein A1, A2, A3 and the carbon atoms to which they are attached form a 5- or 6-membered non-aromatic heterocyclic ring containing at least one -O-, -CO- or -N-; R1 and R2 are hydrogen or C1-6 alkyl; Y is hydrogen, halo, C1-6 alkyl or C1-6 alkoxy; L is O or NH; Z is an azabicyclic side chain; having 5-HT3 receptor antagonist activity.

Description

N-aryl-N1-azablcyclo-ureas as 5-HT3 antagoni sts

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

EP-A-235878 and 377967 (Beecham Group p.l.c.) describe phenylurea derivatives having an azabicyclic side chain and having 5-HT3 receptor antagonist activity.

A class of novel compounds has now been discovered, which compounds are 5-HT3 receptor antagonists.

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

wherein

A₁ , A₂, A₃ and the carbon atoms to which they are attached form a 5- or 6- membered non-aromatic heterocyclic ring containing at least one -0-, -CO- or -N-;

R₁ and R₂ are hydrogen or C _{1 -6} alkyl;

Y is hydrogen, halo, C _{1 -6} alkyl or C _{1 -6} alkoxy;

L is O or NH;

Z is an azabicyclic side chain;

having 5-HT3 receptor antagonist activity. Values for A₁ -A₂-A₃ include :-

CO-O-CH₂

CO-NH-CH₂

CO-CH₂-CH₂

CO-O-(CH₂)2 CO-NH-(CH₂)2

CO-CH₂-CH₂

O-CH₂-O

O-CH=N

O-CH₂-(CH₂)2

O-(CH₂)2-O

N=CH-(CH=CH)

N=CH-O

N=CH-NH

It will be appreciated that any of A₁-A₂-A₃ containing one or more hydrogen atoms, may be substituted by R₁/R₂ when C_{1 -6} alkyl.

In particular, A₁-A₂-A₃ is O-(CH₂)₂-O orCO-O-CH₂.

Suitable examples of alkyl moieties in R₁ and R₂ and Y include methyl, ethyl, n- and iso-propyl, n-, iso-, seo and tert-butyl.

Suitable examples of halo moieties include fluoro, chloro and bromo.

Suitable examples of Z are described in the art relating to 5-HT₃ receptor antagonists, ie. as follows: i) GB 2125398A (Sandoz Limited)

ii) GB 2152049A (Sandoz Limited)

iii) EP-A-215545 (Beecham Group p.l.c.)

iv) EP-A-214772 (Beecham Group p.l.c.)

v) EP-A-377967 (Beecham Group p.l.c.)

vi) WO 92/05174 (Beecham Group p.l.c.)

vii) EP-A-358903 (Dianippon)

Particular side chains of interest are depicted thus: Tropane

Granatane

Oxa/thia/aza-granatane

Quinuclidine

Isoqusnuclidme

Isogranatane

Oxa/thia-isogranatane

Isotropane

or

wherein

R is hydrogen or methyl; and X is oxygen, sulphur or nitrogen optionally substituted by C_1-6 alkyl, C_3-8 cycloalkyl, C_3-8 cycloalkyl C_1-4 alkyl, phenyl, naphthyl, phenyl C_1-4 alkyl or naphthyl C_1-4 alkyl wherein a phenyl or naphthyl moiety is optionally substituted by one or more of halo, C_1-6 alkoxy or C_1-6 alkyl.

Side chains Z of particular interest include tropane, oxagranatane and azagranatane, where R is methyl. Suitable values for N-substituents when X is N are as described in WO 92/05174 , for example, iso-propyl or ethyl.

L is preferably NH.

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, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-keto glutaric, α-glycerophosphoric, and glucose-1-phosphoric acids.

Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R_x-T wherein R_x is C_1-6 alkyl, phenyl- C_1-6 alkyl or C_5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R_x include methyl, ethyl and n- and /so-propyl; and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide and iodide.

Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.

The compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) 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) 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 the other by the usual methods.

Compounds of the formula (I) may be prepared according to the methods described in EP-A-235878 and 377967 (Beecham Group p.l.c).

The L - Z function intermediates are generally prepared from the

corresponding exocyclic keto derivative of the azabicyclic side chain, prepared by condensation methods, often using a substituted piperidine. They may be prepared by processes described in the aforementioned Patent Publications relating to values of the side chain Z. It will be realised that in the compounds of the formula (I) having a tropane, granatane or oxa/thia/aza-granatane side chain, the -COL- linkage has an eπdo orientation with respect to the ring of the bicyclic moiety to which it is attached. A mixture of endo and exo isomers of the compound of the formula (I) may be synthesised non-stereospecifically and the desired isomer separated conventionally therefrom e.g. by chromatography; or alternatively the endo isomer may if desired by synthesised from the corresponding endo form of the compound of the formula (II). Corresponding geometric isomeric pairs are possible for the isoquinuclidine, isogranatane, oxa/thia-isogranatane and isotropane side chains.

Pharmaceutically acceptable salts of the compounds of this invention may be formed conventionally.

The 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 antagonists and it is thus believed may generally be used in the treatment or prophylaxis of pain, emesis, CNS disorders and gastrointestinal disorders. Pain includes migraine, cluster headache, trigeminal neuralgia and visceral pain; emesis, includes, in particular, that of preventing vomiting and nausea associated with cancer therapy, post-operative emesis, and nausea associated with migraine. Examples of such cancer therapy include that using cytotoxic agents, such as platinum complexes including cisplatin, and also doxorubicin and

cyclophosphamide, particularly cisplatin; and also radiation treatment. CNS disorders include anxiety, psychosis, cognitive disorders such as senile dementia and age associated memory inpairment (AAMI), and drug

dependence. Gastrointestinal disorders include irritable bowel syndrome and diarrohea.

5-HT3 receptor antagonists may also be of potential use in the treatment of obesity and/or arrhythmia.

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 usually 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, injectabie 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 propyl 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 pain, emesis, CNS disorders and/or gastrointestinal disorders in mammals, such as humans, 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 1000mg for example 0.5 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 within 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 use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders. The following Examples illustrate the preparation of compounds of formula (I), and the following descriptions illustrate the preparation of intermediates.

Examples A₁-A₂-A₃ Y L Z R

E1 CO-O-CH₂ H NH tropane CH₃

E2 O-(CH₂)2-O H NH tropane CH₃

_E3 O-CH₂-CH₂ H NH tropane CH₃

E4 N=CH-(CH=CH) H NH tropane CH₃

E5 CO-O-CH₂ H NH granatane CH₃

E6 O-(CH₂)2-CH₂ H NH tropane CH₃

Description 1

7-Aminophthalide A suspension of 7-nitrophthaIide (4.6g, 0.026 mole) in ethanol (250 ml) was hydrogenated at atmospheric pressure and room temperature over 10% palladium on carbon catalyst for 16 hours. The catalyst was removed by filtration through Keiseiguhrand the filtrate concentrated in vacuo to give a white solid (3.6g).

¹H NMR (D⁶ DMSO, 250 MHz) δ: 5.22(s, 2H), 6.25(bs, 2H), 6.62(m, 2H), 7.35(t, 1 H)

Description 2 5-TrifluoroacetyIamino-1,4-benzodioxan A stirred solution of 1 ,4-benzodioxan-5-carboxylic acid (1.8g, 0.01 mole) in a mixture of trif luoroacetic acid (50 ml) and trifluoracetic anhydride (10 ml) was cooled to 0°C and sodium azide (0.91g, 0.014 mole) was added portionwise. The reaction mixture was stirred at room temperature until nitrogen evolution ceased. The solvent was removed in vacuo and the residue partitioned between water and chloroform. The chloroform layer was removed, washed with aqueous sodium carbonate solution, then water, dried (Mg SO₄) and concentrated in vacuo to give a gummy solid which was purified by column chromatography on silica using ethyl acetate as eluent. The product was isolated as a pale orange solid (1.05g)

¹ HNMR (CDCI₃ 250 MHZ) δ: 4.22-4.38(m, 4H)6.71 (dd, 1H)6.87(t, 2H)7.82(dd, 1 H)8.35(bs, 1 H) Description 3

5-Amino-1,4-benzodioxan 5-Trifluoroacetylamino-1 ,4-benzodioxan (1.05g) was dissolved in methanol (20 ml) and 10% aqueous sodium hydroxide (2 ml) was added. The mixture was heated under reflux for 4 hours then the solvent was removed in vacuo and the residue partitioned between water and chloroform. The chloroform layer was further washed with water, dried (MgSO₄) and concentrated in vacuo to give a red oil (600 mg)

1 HNMR (CDCI₃, 250 MHz) δ: 3.4-3.95(bs, 2H), 4.2-4.33(m, 4H), 6.3(bdd, 2H), 6.65(t, 1 H).

Example 1 endo-N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yI)-N'-(phthalid-7-yl)urea

A stirred solution of 7-aminophthalide (1.49g, 0.01 mole) in dry

dichloromethane (150 ml) was cooled in an ice bath. Phosgene (9.5 ml of a 12.5% solution in toluene) was added dropwise and the reaction mixture was stirred at room temperature for 10 minutes. Triethylamine (3.2 ml) was then added and the reaction mixture was stirred at room temperature for another 10 minutes.

A solution of endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (1.4g, 0.01 mole) in dry dichloromethane (20 ml) was then added and the reaction mixture was stirred at room temperature for 16 hours. Aqueous sodium carbonate solution was added and the product extracted into

dichloromethane. The dichloromethane extract was washed with water, dried (MgSO₄) and concentrated in vacuo to give a cream solid.

Recrystallisation from ethyl acetate/ether gave a white solid, (500mg) mp. 195-6°C.

¹ H NMR (CDC!₃ 250 MHz) δ: 1.7-1.9(m, 4H), 2.1-2.4(m, 7H including 2.30, s, 3H), 3.18(brs, 2H), 4.00(q, 1 H), 5.28(s, 2H), 5.38(bd, 1 H), 6.95(d, 1 H), 7.08(t, 1 H), 8.36(d, 1 H), 8.50(bs, 1H).

Example 2 endo-N-(1,4-Benzodioxan-5-yl)-N'-(8-methyl-8-azabicyclo[3.2.1]oct-3- yl)urea (E2)

A stirred solution of 5-amino-1 ,4-benzodioxan (600 mg, 0.004 mole) in dry dichloromethane (100 ml) was cooled in an ice bath. Phosgene (3.8 ml of a 12.5% solution in toluene) was added dropwise and the reaction mixture was stirred at room temperature for 10 minutes. Triethylamine (1.28 ml) was then added and the reaction mixture was stirred at room temperature for another 10 minutes. A solution of endo-8-methyl-8-azabicycio[3.2.1] octan-3-amine (560 mg, 0.004 mole) in dry dichloromethane (15 ml) was then added and the reaction mixture was stirred at room temperature for 4 hours. Aqueous sodium carbonate solution was added and the product extracted into dichforomethane. The dichloromethane extract was washed with water, dried (MgSO₄) and concentrated in vacuo to give an orange solid. Recrystallisation from ethyl acetate/ether gave a pale yellow solid, (730 mg), mp 211-212°C.

1 H NMR (CDCI₃ 250 MHZ) δ: 1.6-1.8(m, 4H), 2.02-2.28(m, 7H including 2.28, s, 3H), 3.12(brs, 2H), 4.00(q, 1 H), 4.27(m, 4H), 5.2(d, 1H), 6.45(s, 1 H), 6.6(dd, 1 H), 6.8(t, 1H), 7.36(dd, 1 H).

Following the procedures outlined in Example 1 the following compounds were prepared. endo-N-(8-Methyl-8-azabicyclo|:3.2.1]octan-3-yl)-N'-(dihydrobenzofuran-7-yl)urea (E3) endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl-N'-(quinolin-8-yl)urea

(E4) endo-N-(9-Methyl-9-aza-3-oxabicyclo[3.3.13nonan-7-yl)-N'-(1,3-dihydroisobenzofuran-7-yl-1-one)urea (E5) endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-N'-(chroman-8-yl)urea

(E6)

5-HT₃ RECEPTOR ANTAGONIST ACTIVITY Compounds are evaluated for antagonism of the von Bezold-Jarisch reflex evoked by 5-HT in the anaesthetised rat according to the following method:

Male rats 250-350g, are anaesthetised with urethane (1.25g/kg

intraperitoneally) and blood pressure and heart rate are recorded as described by Fozard J.R. et al., J. Cardiovasc. Pharmacol. 2, 229-245 (1980). A submaximal dose of 5-HT (usually 6μg/kg) is given repeatedly by the intravenous route and changes in heart rate quantified. Compounds are given intravenously and the concentration required to reduce the

5-HT-evoked response to 50% of the control response (ED₅₀) is then determined.

The ED₅₀ values were: E1 - 10, E2 - 15, E3 - 6.6

E4 - 19, E5 - 2.2, E6 - 92 μg/kg.

Claims

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

wherein

A₁ , A₂, A₃ and the carbon atoms to which they are attached form a 5- or 6- membered non-aromatic heterocyclic ring containing at least one -O-, -CO- or-N-;

R₁ and R₂ are hydrogen or C_{1 -6} alkyl;

Y is hydrogen, halo, C_{1 -6} alkyl or C_{1 -6} alkoxy;

L is O or NH;

Z is an azabicyclic side chain;

having 5-HT₃ receptor antagonist activity.

2. A compound according to claim 1 wherein the value for A₁-A₂-A₃ is selected from:

CO-O-CH₂

CO-NH-CH₂

CO-CH₂-CH₂

CO-O-(CH₂)₂

CO-NH-(CH₂)₂

CO-CH₂-CH₂

O-CH2-O

O-CH=N

O-CH₂-(CH₂)₂

O-(CH₂)₂-O

N=CH-(CH=CH)

N=CH-O

N=CH-NH

3. A compound according to claim 1 or 2 wherein Z is tropane, granatane, oxa/thia-granatane, quinuclidine, isoquinuclidine, isogranatane, oxa/thia-isogranatane or isotropane. 4. A compound selected from: endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-N'-(phthalid-7-yl)urea, endo-N-(1 ,

4-benzodioxan-5-yl)-N'-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)urea, endo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-N'-(dihydrobenzofuran-7-yl)urea, endo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl-N'-(quinolin-8-yl)urea, endo-N-(9-methyl-9-aza-3-oxabicyclo[3.3.1]nonan-7-yl)-N'-(1 ,3-dihydroisobenzofuran-7-yl-1-one)urea, endo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-N'-(chroman-8-yl)urea, and pharmaceutically acceptable salts thereof.

5. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

6. A compound according to any one of claims 1 to 4 for use as an active therapeutic substance.

7. A compound according to any one of claims 1 to 4 for use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders.

8. The use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment and/or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders.