Azetidinecarboxamide derivatives and their use in the treatment of cb1 receptor mediated disorders

This application is a U.S. National Stage application of co-pending PCT application PCT/GB2004/001831, filed Apr. 29, 2004, which claims the priority of Great Britain Patent Application No. 0310056.7, filed May 1, 2003. These applications are incorporated herein by reference in their entireties.

The present invention relates primarily to the use of azetidine-1-carboxamides in the treatment of disorders mediated by the cannabinoid CB₁receptor, particularly to the treatment of obesity and other eating disorders associated with excessive food intake.

It has been recognised that obesity is a disease process influenced by environmental factors in which the traditional weight loss methods of dieting and exercise need to be supplemented by therapeutic products (S. Parker, “Obesity: Trends and Treatments”, Scrip Reports, PJB Publications Ltd, 1996).

Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m²). Thus, the units of BMI are kg/m²and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m², and obesity as a BMI greater than 30 kg/m². There are problems with this definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this, obesity can also be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively.

As the BMI increases there is an increased risk of death from a variety of causes that is independent of other risk factors. The most common diseases with obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.

Compounds marketed as anti-obesity agents include Orlistat (Reductil®) and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorption directly and tends to produce a high incidence of unpleasant (though relatively harmless) side-effects such as diarrhoea. Sibutramine (a mixed 5-HT/noradrenaline reuptake inhibitor) can increase blood pressure and heart rate in some patients. The serotonin releaser/reuptake inhibitors fenfluramine (Pondimin®) and dexfenfluramine (Redux™) have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use. There is therefore a need for the development of a safer anti-obesity agent.

There now exists extensive pre-clinical and clinical data supporting the use of CB₁receptor antagonists/inverse agonists for the treatment of obesity.

Preparations of marijuana (Cannabis sativa) have been used for over 5000 years for both medicinal and recreational purposes. The major psychoactive ingredient of marijuana has been identified as Δ⁹-tetrahydrocannabinol (Δ⁹-THC), one of a member of over 60 related cannabinoid compounds isolated from this plant. It has been demonstrated that Δ⁹-THC exerts its effects via agonist interaction with cannabinoid (CB) receptors. So far, two cannabinoid receptor subtypes have been characterised (CB₁, and CB₂). The CB₁receptor subtype is found predominantly in the central nervous system, and to a lesser extent in the peripheral nervous system and various peripheral organs. The CB₂receptor subtype is found predominantly in lymphoid tissues and cells. To date, three endogenous agonists (endocannabinoids) have been identified which interact with both CB₁and CB₂receptors (anandamide, 2-arachidonyl glycerol and noladin ether).

Genetically obese rats and mice exhibit markedly elevated endocannabinoid levels in brain regions associated with ingestive behaviour (Di Marzo et al. 2001 Nature 410: 822-825). Furthermore, increased levels of endocannabinoids are observed upon the fasting of normal, lean animals (Kirkham et al., British Journal of Pharmacology 2002, 136(4) 550-557). Exogenous application of endocannabinoids leads to the same physiological effects observed with Δ⁹-THC treatment, including appetite stimulation (Jamshida et al., British Journal of Pharmacology 2001, 134: 1151-1154), analgesia, hypolocomotion, hypothermia, and catalepsy.

CB₁(CB₁^−/−) and CB₂(CB₂^−/−) receptor knockout mice have been used to elucidate the specific role of the two cannabinoid receptor subtypes. Furthermore, for ligands such as Δ⁹-THC which act as agonists at both receptors, these mice have allowed identification of which receptor subtype is mediating specific physiological effects. CB₁^−/−, but not CB₂^−/−, mice are resistant to the behavioural effects of agonists such as Δ⁹-THC. CB₁^−/− animals have also been shown to be resistant to both the body weight gain associated with chronic high fat diet exposure, and the appetite-stimulating effects of acute food deprivation.

These findings suggest a clear role for both endogenous and exogenous cannabinoid receptor agonists in increasing food intake and body weight via selective activation of the CB₁receptor subtype.

The therapeutic potential for cannabinoid receptor ligands has been extensively reviewed (Exp. Opin. Ther. Pat. 1998, 8, 301-313; Exp. Opin. Ther. Pat. 2000, 10, 1529-1538; Trends in Pharm. Sci. 2000, 21, 218-224; Exp. Opin. Ther. Pat. 2002, 12(10), 1475-1489).

At least one compound (SR-141716A) characterised as a CB₁receptor antagonist/inverse agonist is known to be in clinical trials for the treatment of obesity.

WO 00/15609, WO 01/64632, WO 01/64633 and WO 01/64634 disclose azetidine derivatives as CB₁receptor antagonists. WO 02/28346 discloses the association of an azetidine derivative as a CB₁receptor antagonist, and sibutramine, for the treatment of obesity.

There remains a medical need for low molecular weight CB₁receptor antagonists/inverse agonists with pharmacokinetic and pharmacodynamic properties making them suitable for use as pharmaceutical agents. There also remains a medical need for new treatments of disorders mediated by the CB₁receptor, particularly eating disorders, and particularly obesity. The object of the present invention is to provide such pharmaceutical agents and treatments.

It has now been found that certain azetidine-1-carboxamides show unexpected efficacy as anti-obesity agents. Compounds of this general formula were previously described in WO-A-99/37612 for the treatment of anxiety and epilepsy. These azetidine-1-carboxamides have been shown to selectively bind to the CB₁receptor subtype with high affinity. Such compounds have been shown to dose-dependently block the effects of an exogenously applied cannabinoid receptor agonist (eg ?⁹-THC) in mice. Furthermore, such compounds have been shown to reduce food intake and body weight gain in both rat and mouse models of feeding behaviour.

According to the present invention, there is provided a compound of formula (I)

embedded image

wherein:

R¹and R²are independently selected from aryl; and
R³is hydrogen or alkyl;
or a pharmaceutically acceptable salt or prodrug thereof,

wherein at least one of R¹and R²has a non-hydrogen substituent in the ortho-position(s) thereof relative to the point of attachment to the [—CH—O—] group.

The active compounds of formula (I) are antagonists and/or inverse agonists at the cannabinoid-1 (CB₁) receptor and are useful for the treatment, prevention and suppression of diseases mediated by the CB₁receptor. The invention is concerned with the use of these compounds to selectively antagonise the CB₁receptor and, as such, in the treatment of obesity and other disorders.

Reference in the present specification to an “alkyl” group means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl (including allyl) or alkynyl (including propargyl)) hydrocarbyl radical. Where cyclic or acyclic the alkyl group is preferably C₁to C₁₂, more preferably C₁to C₈(such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, hexyl, heptyl, octyl). It will be appreciated therefore that the term “alkyl” as used herein includes alkyl (branched or unbranched), alkenyl (branched or unbranched), alkynyl (branched or unbranched), cycloalkyl, cycloalkenyl and cycloalkynyl. A cyclic alkyl group may also be a mono-bridged or multiply-bridged cyclic alkyl group. In a preferred embodiment, a cyclic alkyl group is preferably C₃to C₁₂, more preferably C₅to C₈and an acyclic alkyl group is preferably C₁to C₁₀, more preferably C₁to C₆, more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, tertiarybutyl or sec-butyl) or pentyl (including n-pentyl and iso-pentyl), more preferably methyl.

As used herein, the term “lower alkyl” means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical wherein said cyclic lower alkyl group is C₅, C₆or C₇, and wherein said acyclic lower alkyl group is C₁, C₂, C₃or C₄. It will be appreciated therefore that the term “lower alkyl” as used herein includes lower alkyl (branched or unbranched), lower alkenyl (branched or unbranched), lower alkynyl (branched or unbranched), cycloloweralkyl, cycloloweralkenyl and cycloloweralkynyl. Preferably, a lower alkyl group is preferably selected from methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, tertiary-butyl or sec-butyl), more preferably methyl.

Reference in the present specification to an “aryl” group means a mono or bicyclic aromatic group, such as phenyl or naphthyl, and preferably a mono-cyclic aromatic group.

Reference in the present specification to a “heteroaryl” group means an aromatic group containing one or more heteroatoms, preferably 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms. Preferably the heteroatoms are selected from O, S and N, preferably from O and N. Preferably the heteroaryl group comprises 5 or 6-membered ring systems. The heteroaryl group is preferably a monocyclic or bicyclic ring system, preferably monocyclic. Examples include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl and isobenzofuryl.

Reference in the present specification to a non-aromatic heterocylic group is to a saturated or partially unsaturated 4, 5, 6 or 7-membered ring containing 1, 2 or 3 heteroatoms selected from N, O and S, preferably 1 or 2 heteroatoms, preferably selected from N and O. Examples include piperidinyl, morpholinyl, piperazinyl and pyrrolidinyl.

The alkyl, aryl and heteroaryl groups may be substituted or unsubstituted. In one embodiment, only the alkyl, aryl and heteroaryl groups defined herein as R¹to R¹⁶may be substituted. Where R⁷and R⁸together form a 5 or 6-membered ring, the ring may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 or 2 substituents. Substituents may include:

carbon containing groups such as

- alkyl
- aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl);
  
  halogen atoms and halogen containing groups such as
- haloalkyl (e.g. trifluoromethyl);
  
  oxygen containing groups such as
- alcohols (e.g. hydroxy, hydroxyalkyl, (aryl)(hydroxy)alkyl),
- ethers (e.g. alkoxy, alkoxyalkyl, aryloxyalkyl),
- aldehydes (e.g. carboxaldehyde),
- ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl),
- acids (e.g. carboxy, carboxyalkyl),
- acid derivatives such as esters
  - (e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl) and amides
  - (e.g. aminocarbonyl, mono- or dialkylaminocarbonyl, aminocarbonylalkyl, mono- or dialkylaminocarbonylalkyl, arylaminocarbonyl);
    
    nitrogen containing groups such as
- amines (e.g. amino, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl),
- azides,
- nitriles (e.g. cyano, cyanoalkyl),
- nitro;
  
  sulphur containing groups such as
- thiols, thioethers, sulphoxides and sulphones
  - (e.g. alkylthio, alkylsulfinyl, alkylsufonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl);
    
    and heterocyclic groups containing one or more, preferably one, heteroatom,
- (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl and carbolinyl).

Where an aryl group is phenyl, the phenyl may be substituted by adjacent substituents forming a 5 or 6 membered saturated ring optionally containing 1 or 2 heteroatoms, preferably selected from N, O and S, preferably from N and O. Where the saturated ring contains 2 nitrogen atoms, the ring is preferably a 6-membered ring. Where the saturated ring contains 2 oxygen atoms, the ring may be a 5- or 6-membered ring. Examples include 2,3-dihydrobenzo[b]furan-7-yl, 2,3-dihydrobenzo[b]thiophen-6-yl, 1,2,3,4-tetrahydronaphthalen-5-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl and 1,2,3,4-tetrahydroisoquinolin-8-yl.

Preferred substituents include alkyl (including haloalkyl), alkoxy (including haloalkoxy), aryl, nitrile or halo. Preferred halogen-containing groups include trifluoromethyl.

As used herein, the term “alkoxy” means alkyl-O— and “alkoyl” means alkyl-CO—.

As used herein, the term “halogen” means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine or chlorine radical.

The compounds of formula (I) may exist in a number of diastereomeric and/or enantiomeric forms. Unless otherwise stated, reference in the present specification to “a compound of formula (I)” is a reference to all stereoisomeric forms of the compound and includes a reference to the unseparated stereoisomers in a mixture, racemic or non-racemic, and to each stereoisomer in its pure form.

In the compounds of formula (I), preferably R¹and R²are independently selected from substituted or unsubstituted phenyl or naphthyl (preferably phenyl), more preferably substituted phenyl or naphthyl (preferably phenyl), more preferably phenyl or naphthyl (preferably phenyl) having 1 to 3 substituents and most preferably phenyl or naphthyl (preferably phenyl) having 1 or 2 substituents. In one embodiment the substituent groups are selected from halogen and haloalkyl (particularly trifluoromethyl). Preferably R¹and R²are selected from mono-cyclic aromatic groups.

In a preferred embodiment of the compounds of formula (I), R¹and R²are independently selected from a group of formula:

embedded image

wherein R⁴, R⁵and R⁶are independently selected from hydrogen, halo, alkyl (including haloalkyl), thioalkyl, alkoxy (including haloalkoxy), alkylsulfonyl, amino, mono- and di-alkyl amino, mono- and di-aryl amino, alkylarylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, NR¹⁴C(O)R¹⁵, NR¹⁴SO₂R¹⁶, COOR¹⁵, OC(O)R¹⁶, CONR⁷R⁸and SO₂NR⁷R⁸, wherein R⁷and R⁸are independently selected from hydrogen and alkyl or may form a 5 or 6 membered ring optionally containing 1 or 2 additional heteroatoms selected from N, O and S; and wherein R¹⁴is selected from H and lower alkyl (preferably H), R¹⁵is selected from H, alkyl, aryl and heteroaryl (preferably alkyl, preferably lower alkyl) and R¹⁶is selected from alkyl, aryl and heteroaryl (preferably alkyl, preferably lower alkyl). The groups R¹and R²may be the same or different, and in one embodiment are different.

Where R⁴, R⁵and R⁶are selected from halo, the halo group is preferably fluoro, chloro, bromo or iodo, preferably chloro or bromo. Where R⁴, R⁵and R⁶are selected from alkyl, thioalkyl, alkoxy and alkylsulfonyl, the alkyl is preferably selected from lower alkyl, and preferably from methyl and ethyl, preferably methyl. Where R⁴, R⁵and R⁶are selected from aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl, the alkyl is preferably selected from lower alkyl, and preferably from methyl and ethyl, preferably methyl. Where R⁴, R⁵and R⁶are selected from dialkylaminoalkyl, the dialkylamino fragment is preferably selected from cyclicamino, preferably from morpholino and piperazino. Where R⁴, R⁵and R⁶are selected from haloalkyl, the alkyl is preferably methyl, and the R⁴, R⁵or R⁶group is preferably trifluoromethyl. Where R⁴, R⁵and R⁶are selected from haloalkoxy, the alkyl is preferably methyl and the R⁴, R⁵or R⁶group is preferably selected from trifluoromethoxy or difluoromethoxy, preferably difluoromethoxy. Preferably one or two of R⁴, R⁵and R⁶are hydrogen. At least one of the R¹and R²groups has a non-hydrogen substituent in the ortho-position(s). The R¹or R²groups may independently have one or two non-hydrogen substituents in the ortho position(s) relative to the point of attachment to the [—CH—O—] group. Preferred ortho-substituents include halo and haloalkyl, as described herein. Particularly preferred ortho-substituents are chloro and trifluoromethyl, particularly trifluoromethyl.

Where R⁷and R⁸form a 5- or 6-membered ring, the ring is preferably 6-membered, and is preferably saturated or partially saturated, preferably saturated. Where the ring contains additional heteroatoms, these are preferably selected from N and O. Preferably there are 0 or 1 additional heteroatoms.

In the compounds of formula I, R³is selected from hydrogen or alkyl, preferably alkyl.

Where R³is selected from alkyl, preferably R³is lower alkyl, and preferably methyl, ethyl, propyl and butyl as described above. The alkyl group may be substituted or unsubstituted, and in one embodiment is substituted. One or two substituent groups may be present, preferably one substituent group. Preferred substituents are those referred to hereinabove, particularly hydroxy, alkoxy, thioalkyl, amino, mono- and dialkyl amino, alkoxycarbonyl, aryl (preferably phenyl), and heterocyclic groups including both heteroaryl and non-aromatic heterocyclic groups. Where R³is an acyclic alkyl group, it may be substituted by a cyclic alkyl group; and where R³is a cyclic alkyl group it may be substituted by an acyclic alkyl group. Where the substituent group is heteroaryl, the heteroaryl preferably is a 5- or 6-membered ring containing one or more N, O or S atoms, and preferred groups include thiophenyl, furanyl, isoxazolyl, thiazolyl and benzothiophenyl. Other preferred substituent groups include dihydrobenzofuranyl, dihydrobenzodioxinyl, tetrahydrofuranyl, pyrrolidinyl, oxopyrrolindyl and benzodioxolyl.

In one embodiment, R³is selected from:

—(CHR⁹)_n(CH₂)_mCR¹⁰R¹¹R¹²

wherein n is 0 or 1;

m is 0, 1, 2 or 3;
R⁹, R¹⁰, R¹¹and R¹²are selected from hydrogen, alkyl (preferably lower alkyl), hydroxy, alkoxy (preferably lower alkoxy), thioalkyl (preferably thio lower alkyl), amino, mono- and di-alkyl amino (preferably lower alkyl amino), alkoxycarbonyl (preferably lower alkoxy carbonyl) and R¹³;

wherein R¹³is selected from aryl, heteroaryl and non-aromatic heterocyclic optionally substituted by one or more (preferably 1 or 2, preferably 1) groups preferably selected from alkyl (preferably lower alkyl, preferably methyl), halogen (preferably fluoro, chloro and bromo), alkoxy (preferably lower alkoxy, preferably methoxy), oxo, aryl, heteroaryl and non-aromatic heterocycle.

Preferably, m is 0 or 1 or 2, preferably 0 or 1, and preferably 0.

Preferably, n is 0.

In one embodiment, at least one and more preferably two of R¹⁰, R¹¹and R¹²are selected from hydrogen. In a further embodiment, at least one and more preferably at least two of R¹⁰, R¹¹and R¹²are selected from methyl.

In a further embodiment, R³is selected from cyclic alkyl, including cyclopentyl, cyclohexyl, norbornanyl and adamantyl, preferably cyclopentyl and cyclohexyl.

Preferred R³groups are tertiary butyl, sec-butyl, isobutyl, isopropyl, n-propyl and ethyl, particularly tertiary butyl, isobutyl, sec-butyl and isopropyl, and particularly tertiary butyl.

Preferred compounds are as follows:

3-(2,4,4′-trichlorobenzhydryloxy)-N-(tert-butyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(ethyl propionate-2-yl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(tert-butyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2-thiophen-2-yl ethyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-[ethyl 4-(methylthio)butyrate-2-yl]azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(cyclopropylmethyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2,3-dihydrobenzofuran-5-yl-methyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2,5-dimethylfuran-3-yl-methyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2,3-Dihydro-benzo[1,4]dioxin-2-yl-methyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(5-methyl-isoxazol-3-yl-methyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-[(R)-sec-butyl]azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2-bromothiophen-3-yl-methyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-[(S)-sec-butyl] azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(thiophen-3-yl-methyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2-methoxyphenylmethyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2-furanylmethyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(3-ethoxypropyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2-tetrahydrofuranylmethyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(exo-2-norbornanyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(1-phenylpropyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-[(R)-a-methylbenzyl]azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-[(R)-1-(3-methoxyphenyl)ethyl]azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-[(S)-1-(3-methoxyphenyl)ethyl]azetidine-1-carboxamide
3-(4,4′-dichlorobenzhydryloxy)-N-(1-adamantyl)azetidine-1-carboxamide
3-(4,4′-dichlorobenzhydryloxy)-N-(benzo[b]thiophen-2-yl-methyl)azetidine-1-carboxamide
3-(2,2′-dichlorobenzhydryloxy)-N-(1-adamantyl)azetidine-1-carboxamide
3-(4,4′-dibromobenzhydryloxy)-N-(tert-butyl)azetidine-1-carboxamide
3-(4,4′-dibromobenzhydryloxy)-N-(1-adamantyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(n-propyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(iso-propyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(n-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(sec-butyl)azetidine-1 carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(ethyl propionate-3-yl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(ethyl 3-phenylpropionate-2-yl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(ethyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-[(S)-a-methyl-benzyl]azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(2,2,4-trimethylpent-4-yl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(cyclopentyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2,2,4-trimethylpent-4-yl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2-methylbut-2-yl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-2′-fluoro-4′-bromobenzhydryloxy]-N-(tert-butyl)azetidine-carboxamide
3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]-N-(iso-propyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]-N-(benzyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]-N-(iso-propyl)azetidine-carboxamide
3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]-N-(benzyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)benzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)benzhydryloxy]-N-(iso-propyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)benzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)benzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)benzhydryloxy]-N-(benzyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(trifluoromethoxy)benzhydryloxy]-N-(tert-butyl)azetidine 1-carboxamide
3-[2-(trifluoromethyl)-4′-(trifluoromethoxy)benzhydryloxy]-N-(iso-propyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(trifluoromethoxy)benzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(trifluoromethoxy)benzhydryloxy]-N-(benzyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(1-adamantyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(tert-amyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-methylbenzhydryloxy]-N-(1-adamantyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-methylbenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-methylbenzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-methoxybenzhydryloxy]-N-(1-adamantyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-methoxybenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]-N-(1-adamantyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(allyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]-N-(1-adamantyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]-N-(tert-butyl)azetidine—carboxamide
3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]-N-(iso-propyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]-N-(allyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]-N-(iso-propyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]-N-[(S)-a-methylbenzyl]azetidine-1-carboxamide
3-[2-(trifluoromethyl)-2′-fluoro-4′-(1-piperidinyloxomethyl)benzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-2′-fluorobenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide, and
3-[(R*)-2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide

Particularly preferred compounds are as follows:

3-(2,4,4′-trichlorobenzhydryloxy)-N-(tert-butyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(tert-butyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2-thiophen-2-yl ethyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(cyclopropylmethyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2,3-dihydrobenzofuran-5-yl-methyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2,5-dimethylfuran-3-yl-methyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2,3-Dihydro-benzo[1,4]dioxin-2-yl-methyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(5-methyl-isoxazol-3-yl-methyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-[(R)-sec-butyl]azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2-bromothiophen-3-yl-methyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-[(S)-sec-butyl]azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(thiophen-3-yl-methyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2-methoxyphenylmethyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2-furanylmethyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(3-ethoxypropyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2-tetrahydrofuranylmethyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(exo-2-norbornanyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(1-phenylpropyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-[(R)-a-methylbenzyl]azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-[(R)-1-(3-methoxyphenyl)ethyl]azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-[(S)-1-(3-methoxyphenyl)ethyl]azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(n-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(ethyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-[(S)-a-methyl-benzyl]azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(2,2,4-trimethylpent-4-yl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(cyclopentyl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2,2,4-trimethylpent-4-yl)azetidine-1-carboxamide
3-(2,4′-dichlorobenzhydryloxy)-N-(2-methylbut-2-yl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-2′-fluoro-4′-bromobenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]-N-(iso-propyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]-N-(benzyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]-N-(iso-propyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]-N-(benzyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)benzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)benzhydryloxy]-N-(iso-propyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)benzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)benzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)benzhydryloxy]-N-(benzyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(trifluoromethoxy)benzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3′-[2-(trifluoromethyl)-4′-(trifluoromethoxy)benzhydryloxy]-N-(iso-propyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(trifluoromethoxy)benzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(trifluoromethoxy)benzhydryloxy]-N-(benzyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(1-adamantyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(tert-amyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-methylbenzhydryloxy]-N-(1-adamantyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-methylbenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-methylbenzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-methoxybenzhydryloxy]-N-(1-adamantyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-methoxybenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]-N-(1-adamantyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(allyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]-N-(1-adamantyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]-N-(iso-propyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]-N-(cyclohexyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]-N-(allyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]-N-(sec-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]-N-[(S)-a-methylbenzyl]azetidine 1-carboxamide
3-[2-(trifluoromethyl)-2′-fluoro-4′-(1-piperidinyloxomethyl)benzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide
3-[2-(trifluoromethyl)-2′-fluorobenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide, and
3-[(R*)-2-(trifluoromethyl)-4′-chlorobenzhydryloxy]-N-(tert-butyl)azetidine-1-carboxamide.

According to a further aspect of the invention, there is provided for use in therapy a compound of formula (I).

According to a further aspect of the invention, there is provided the use of a compound of formula (I) in the manufacture of a medicament for the treatment of a disorder mediated by CB₁receptors.

According to a further aspect of the present invention there is provided a method of treatment of a disorder mediated by CB₁receptors comprising administration to a subject in need of such treatment an effective dose of the compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.

The disorders mediated by CB₁receptors are selected from psychosis, memory deficit, cognitive disorders, attention deficit disorder, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular injuries, head trauma, anxiety disorders, depression, stress, epilepsy, dementia, distonia, Alzheimer's disease, Huntingdon's disease, Tourette's syndrome, ischaemia, pain, Parkinson's disease, schizophrenia, substance abuse disorders especially relating to nicotine, alcohol, and opiates, smoking cessation, treatment of nicotine dependance and/or treatment of symptoms of nicotine withdrawal, gastrointestinal disorders (such as dysfunction of gastrointestinal motility or diarrhoea), obesity and other eating disorders associated with excessive food intake, and associated health complications including non-insulin dependant diabetes mellitus.

The present invention is particularly directed to psychosis, memory deficit, cognitive disorders, attention deficit disorder, migraine, anxiety disorders, stress, epilepsy, Parkinson's disease, schizophrenia, substance abuse disorders especially relating to nicotine, alcohol, and opiates, smoking cessation, treatment of nicotine dependance and/or treatment of symptoms of nicotine withdrawal, gastrointestinal disorders (such as dysfunction of gastrointestinal motility or diarrhoea), obesity and other eating disorders associated with excessive food intake, and associated health complications including non-insulin dependant diabetes mellitus.

The present invention is more particularly directed to disorders selected from psychosis, schizophrenia, cognitive disorders, attention deficit disorder, smoking cessation, gastrointestinal disorders (such as dysfunction of gastrointestinal motility or diarrhoea), obesity and other eating disorders associated with excessive food intake (including bulimia and compulsive eating disorder) and associated health complications including non-insulin dependant diabetes mellitus. The present invention is particularly directed to obesity and other eating disorders associated with excessive food intake and associated health complications including non-insulin dependant diabetes mellitus, and particularly to obesity and other eating disorders associated with excessive food intake, and especially to obesity.

In an alternative embodiment, the present invention is directed to substance abuse disorders especially relating to nicotine, alcohol, and opiates, smoking cessation, treatment of nicotine dependance and/or treatment of symptoms of nicotine withdrawal, and particularly to smoking cessation and the facilitation thereof.

In a further alternative embodiment, the present invention is directed to gastrointestinal disorders (such as dysfunction of gastrointestinal motility or diarrhoea).

In a further alternative embodiment, the present invention is directed to the treatment of Parkinson's Disease.

The present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.

As used herein, the term “treatment” as used herein includes prophylactic treatment.

As used herein, the term “prodrug” means any pharmaceutically acceptable prodrug of the compound of formula (I). For example, the compound of formula (I) may be prepared in a prodrug form wherein a free —OH group is derivatised (for example, via an ester, amide or phosphate bond) with a suitable group (the group may contain, for example, an alkyl, aryl, phosphate, sugar, amine, glycol, sulfonate or acid function) which is suitably labile so as it will be removed/cleaved (eg. by hydrolysis) to reveal the compound of formula (I) sometime after administration or when exposed to the desired biological environment.

As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of the compound of formula (I). Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, furnaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, sulfuric and methanesulfonic acids, and most particularly preferred is the methanesulfonate salt. Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.

The compound of formula (I) may be used in combination with one or more additional drugs useful in the treatment of the disorders mentioned above, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.

Compounds of formula (I) may be prepared according to the reaction scheme (where P is a nitrogen protecting group). R¹, R², and R³are as previously described. The ether (IV) may be formed by reaction of the azetidinol (II) with a benzhydrol (III, X═OH) with removal of water (for example azeotropic removal of water under standard Dean-Stark conditions). The ether (IV) may also be formed by reaction of the azetidinol (II) with a benzhydryl group substituted with a suitable leaving-group (III, X═Cl, Br, I, mesylate, tosylate) and a strong base such as sodium hydride. Formation of the azetidine (V) may be achieved by reaction of (IV) with a suitable nitrogen deprotection agent. For example, if P is a benzhydryl group, then deprotection may be carried out by treatment with 1-chloroethyl chloroformate followed by treatment with methanol. The deprotected azetidine (V) can be isolated directly as the hydrochloride salt or, upon basification, as the free-base. The urea (I) can be formed by reaction of azetidine (V) with an N-alkyl isocyanate, or an N-alkyl carbamoyl chloride and a base such as triethylamine or potassium carbonate. Alternatively, the urea may be prepared directly from the protected azetidine (IV) without isolation of the intermediate azetidine (V). For example, when P is a benzhydryl group, azetidine (IV) may be treated with phosgene followed by an amine, R³NH₂, to give urea (I) directly. Azetidine (V) may also be converted to the corresponding carbamoyl chloride (VI) by treatment with, for example, triphosgene. This intermediate carbamoyl chloride (VI) may be reacted with an amine, R³NH₂, to give the urea (I).

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The invention further provides a pharmaceutical composition comprising an effective amount of the compound of formula (I) in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining an effective amount of the compound of formula (I) with a pharmaceutically acceptable carrier or excipient.

To further increase efficacy, the composition may contain components such as dextrans or cyclodextrins or ether derivatives thereof, which aid stability and dispersion, and decrease metabolism of the active ingredient.

For compositions in which the pharmaceutically acceptable carrier comprises a cyclodextrin or an ether derivative thereof, the active ingredient is intimately mixed with an aqueous solution of the cyclodextrin or ether derivative thereof, with optional addition of further pharmaceutically acceptable ingredients before, during or after said mixing. The thus obtained solution is optionally lyophilized, and the lyophilized residue is optionally reconstituted with water.

In an embodiment of the present invention, the composition further comprises a buffer system, an isotonizing agent and water.

Compounds of formula (I) may be administered in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use including transmucosal and transdermal use, for example a cream, ointment, gel, aqueous or oil solution or suspension, salve, patch or plaster; for nasal use, for a example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository, for administration by inhalation, for example a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oil solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients, using standard techniques well known to those skilled in the art of pharmacy. Preferably, the compound is administered orally.

For oral administration, the compounds of formula (I) will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.

Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.

Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil. Alternatively, the active ingredient may be mixed with excipients, surfactants or solubilising agents such as Labrafil®, Labrasol® or Miglyol®, or appropriate mixtures thereof.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of formula (I) will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

It will be appreciated that the dosage levels used may vary over quite a wide range depending upon the compound used, the severity of the symptoms exhibited by the patient and the patient's body weight.

The invention will now be described in detail with reference to the following pharmacological examples. It will be appreciated that the examples are intended to illustrate and not to limit the scope of the present invention.

Experimental

Assay Procedures

Binding to CB₁Receptors

The binding of compounds of Formula I to recombinant human CB₁receptors was determined in vitro by standard methods, with reference to the procedure described by Rinaldi-Carmona et al. (Rinaldi-Camona, M., Pialot, F., Congy, C., Redon, E., Barth, F., Bachy, A., Breliere, J. C., Soubre, P., LeFur, G., Life Sci. 1996, 58(15), 1239-1247). Membranes were prepared from HEK293 cells expressing recombinant hCB₁receptors. Binding assays are performed in a total volume of 250 μL, containing [³H]—SR-141716A (1 nM final concentration), membranes and test compound. Non-specific binding is determined using CP55,940 (10 μM). Serial dilutions are performed starting from test compounds as 10 mM solutions in DMSO. Compounds are tested over the concentration range 10⁻¹⁰M to 10⁻⁵M. K_ivalues are calculated from IC₅₀values using the Cheng-Prusoff equation.

The thus-determined activity of compounds of formula (I) is shown in Table 1.

TABLE 1

Example
K_i(hCB₁) nM

1
4.7

4
4.5

28
80

30
19

81
2.3

94
1.3

139
0.6

140
27

Blockade of Δ⁹-THC Induced Hypolocomotion in Mice

The in vivo activity of compounds of formula (I) was assayed for ability to antagonise the reduction in locomotor behaviour induced by acute systemic administration of Δ⁹-THC in male C57B1/6 mice. The procedure was as follows.

Test compounds are assessed following acute oral or intraperitoneal administration at a dose of 30 mg/kg. Each study utilises a between-subjects design (typically n=8) and compares the effects of doses of the test agent to those of vehicle and a positive control.

The route of test compound administration, drug volume and injection-test-interval are dependent upon the compounds used. 10 min before testing, a 3 mg/kg dose Δ⁹-THC (or vehicle) is administered to mice by the i.p. route. Automated boxes (AM-1052 activity monitors, Benwick Electronics, Linton Instrumentation) are used to record photocell beam breaks as a measure of locomotor activity. The light beams are arranged on a 7 by 4 matrix on a metal grid. 16 grids are connected in series and Perspex boxes, 20 (width)×40 (length)×20 (height) cm, with a flat perforated, Perspex lid are placed in each grid. Mice are placed singly in Perspex boxes and the recording of activity in all 16 boxes starts simultaneously. The mice are left undisturbed to explore the novel activity monitor boxes for 15 minutes while beam breaks are recorded.

Locomotor activity data are subjected to one-way analysis of variance (ANOVA) with drug treatment as a between-subjects factor. A significant main effect is followed up by the performance of Dunnett's test in order to assess which treatment mean(s) are significantly different from the control mean. Significant differences between the vehicle/Δ⁹-THC group and Test compound/Δ⁹-THC groups are assessed by Newman-Keuls test. All statistical analyses were performed using Statistica Software, Version 6.0 (Statsoft Inc.) and Microsoft Excel 7.0 (Microsoft Corp.).

The thus-determined activity of compounds of formula (I) is shown in Table 2.

TABLE 2

Example
Active dose (mg/kg), route

1
30, p.o.

4
30, p.o.

81
30, p.o.

94
30, p.o.

Regulation of Feeding Behaviour

The in vivo activity of compounds of formula (I) was assayed for ability to regulate feeding behaviour by measuring food consumption in male food-deprived Lister-hooded rats as follows.

Test compounds are assessed following acute administration. Each study utilises a between-subjects design (typically n=8) and compares the effects of doses of the test agent to those of vehicle and a positive control.

The anorectic drug sibutramine, or the reference CB₁receptor antagonist, SR141716A, normally serves as a positive control. The route of drug administration, drug volume and injection-test-interval are dependent upon the compounds used. The injection-test-interval is the time between dosing and food re-presentation. Typically, animals are fasted such that at the time of food re-presentation food has been withdrawn for an 18-hour period. Food consumption is assayed at pre-determined time points (typically 1, 2 and 4 hours after administration). Food intake data are subjected to one-way analysis of variance (ANOVA) with drug as a between-subjects factor. A significant main effect is followed up by the performance of Dunnett's test in order to assess which treatment mean(s) are significantly different from the control mean. All statistical analyses were performed using Statistica Software, Version 6.0 (Statsoft Inc.) and Microsoft Excel 7.0 (Microsoft Corp.).

The thus-determined activity of compounds of formula (I) is shown in Table 3.

TABLE 3

Example
M.E.D (mg/kg), route

1
30, p.o.

4
30, p.o.

81
3, p.o.

94
10, p.o.

139
1, p.o.

Analytical Chemistry Procedures

HPLC

LC (50/80) refers to elution of a sample through an XTERRA RP18 (50 mm×4.6 mm) 5 μm column under gradient conditions. The initial eluent comprises 50% Methanol (pump-A) and 50% of a 10 mM aqueous ammonium acetate solution containing 5% IPA (pump-B) at a flow rate of 2 mL/min. After 1 min, a gradient is run over 5 min to an end point of 80% pump-A and 20% pump-B, which is isocratically maintained for a further 3 min. UV peak detection is generally carried out at a wavelength of 220 nm.

LC (80/20) refers to elution of a sample through an XTERRA RP18 (50 mm×4.6 mm) 5 μm column under isochratic conditions. The eluent comprises 80% Methanol (pump-A) and 20% of a 10 mM aqueous ammonium acetate solution containing 5% IPA (pump-B) at a flow rate of 2 mL/min over a period of 10 minutes. UV peak detection is generally carried out at a wavelength of 220 nm.

LC (CHIRAL AD) refers to elution of a sample through a CHIRALPAK AD column (250 mm×4.6 mm) 10 μm column under isochratic conditions. The eluent typically comprises 90% n-hexane and 10% 2-propanol at flow rate of 1 mL/min over a period of 40 minutes. UV peak detection is generally carried out at a wavelength of 220 nm.

¹H NMR

Proton nmr spectra were recorded on a 400 MHz Bruker spectrometer. Solutions were typically prepared in either deuterochloroform (CDCl₃) or deuterated dimethylsulfoxide (d⁶-DMSO) with chemical shifts reported in d with reference to tetramethylsilane (TMS) as an internal standard, and coupling constants reported in Hz.

Mass Spectra were acquired via loop injection on a Waters ZQ Mass Detector equipped with an Electrospray source operated in Positive/Negative Ion switching mode and a cone voltage of 25V.

SYNTHETIC EXAMPLES
Preparation of 1-benzhydryl-3-azetidinol (1)

This material was prepared according the method of Anderson and Lok (J. Org. Chem., 1972, 37, 3953—the disclosure of which is incorporated herein by reference), m.p. 111-112° C. (lit. m.p. 113° C.).

Preparation of 2,4,4′-trichlorobenzhydrol (2)

To a stirred solution of 2,4-dichlorobenzaldehyde (286 mmol) in diethyl ether (500 mL) was added 4-chlorophenylmagnesium bromide (1.0 M in diethyl ether, 286 mmol) dropwise at 0° C. over a period of 1 hour. The reaction was allowed to warm to ambient temperature, and stirred for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution (500 mL) and extracted with diethyl ether (2×500 mL), the extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by trituration with iso-hexane (500 mL) to yield the product as a white solid (60.0 g, 73%).

NMR (400 MHz, d⁶-DMSO) δ_H5.95 (1H, d, J 4.5 Hz), 6.23 (1H, d, J 4.0 Hz), 7.31 (2H, m), 7.37 (2H, m), 7.47 (1H, dd, J 2.5, 8.5 Hz), 7.55 (1H, d, J 2.0 Hz), 7.66 (1H, d, J 8.5 Hz).

Preparation of 1-benzhydryl-3-(2,4,4′-trichlorobenzhydryloxy)azetidine (3)

A solution of 2,4,4′-trichlorobenzhydrol (2) (174 mmol), p-toluenesulfonic acid (174 mmol) and 1-benzhydryl-3-azetidinol (1) (87 mmol) in toluene (700 mL) was heated at reflux under Dean-Stark conditions for 30 minutes. The solution was cooled, washed with sodium hydrogen carbonate (saturated aqueous solution, 700 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography [SiO₂; (10% ethyl acetate:isohexane)] to furnish the product as a yellow oil (22.0 g, 50%).

NMR (400 MHz, d⁶-DMSO) δ_H2.78 (1H, t, J 6.5 Hz), 2.84 (1H, t, J 6.5 Hz), 3.23 (1H, t, J 6.5 Hz), 3.31 (1H, t, J 6.5 Hz), 4.18 (1H, m), 4.39 (1H, s), 5.71 (1H, s), 7.15 (2H, m), 7.24 (4H, m), 7.32 (2H, m), 7.37 (6H, m), 7.47 (1H, m), 7.57 (2H, m).

Preparation of 3-(2,4,4′-trichlorobenzhydryloxy)azetidine (4)

To a stirred solution of 1-benzhydryl-3-(2,4,4′-trichlorobenzhydryloxy)azetidine (3) (39 mmol) in dichloromethane (400 mL) was added 1-chloroethylchloroformate (98 mmol) dropwise at 0° C. and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, then dissolved in methanol (400 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, then diluted with ethyl acetate (400 mL) and washed with sodium hydroxide (5N, 400 mL), dried (MgSO4) and concentrated in vacuo to furnish a yellow oil. The residue was purified by filtration through silica, eluting with dichloromethane, then [ethyl acetate:methanol:ammonium hydroxide (90:8:2)] to yield a yellow oil (8.0 g, 60%).

NMR (400 MHz, DMSO) δ_H3.38 (4H, bd), 4.29 (1H, m), 5.68 (1H, s), 7.32 (2H, m), 7.40 (2H, m), 7.49 (2H, m), 7.50 (1H, m), 7.60 (2H, m).

Example 1
3-(2,4,4′-trichlorobenzhydryloxy)-N-(tert-butyl)azetidine-1-carboxamide (5)

To a stirred solution of 3-(2,4,4′-trichlorobenzhydryloxy)azetidine (4) (3 mmol) in dichloromethane (10 mL) was added tert-butyl isocyanate (3 mmol) and triethylamine (catalytic amount) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was eluted through a pre-wetted (CH₂Cl₂) SCX-2 (2 g) cartridge with dichloromethane to yield the desired product as a white foam (424 mg, 33%).

NMR (400 MHz, DMSO) δ_H1.20 (9H, s), 3.54 (1H, dd, J 4.5, 8.5 Hz), 3.80 (1H, dd, J 6.5, 8.5 Hz), 4.29 (1H, m), 5.62 (1H, s), 7.34 (2H, m), 7.42 (2H, m), 7.50 (1H, m), 7.61 (1H, m), 7.64 (1H, s)

LC (50/80) 97.5%, 7.59 min

Found: C, 57.19; H, 5.30; N, 6.26, C16H14Cl3NO requires: C, 57.09; H, 5.25; N, 6.34%

Example 2
3-(2,4,4′-trichlorobenzhydryloxy)-N-(1-hydroxy-2-methylpropan-2-yl)azetidine-1-carboxamide (6)

To a stirred solution of triphosgene (5.5 mmol) in dichloromethane (50 mL) at 0° C. was added a solution of 3-(2,4,4′-trichlorobenzhydryloxy)azetidine (4) (14.6 mmol) and pyridine (16.1 mmol) in dichloromethane (50 mL) over a period of 1 hour. Reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was purified by filtration through silica, eluting with dichloromethane to yield the carbamoyl chloride intermediate as a dark orange oil. A solution of ‘carbamoyl chloride’ (2.47 mmol), triethylamine (2.47 mmol) and 2-amino-2-methyl-1-propanol (4.94 mmol) in dichloromethane was stirred at room temperature overnight. The reaction mixture was washed with water, dried (MgSO₄) and purified by chromatography [SiO₂:(1:1 ethyl acetate:isohexane)] to furnish the product as a colourless oil (352 mg, 31%).

NMR (400 MHz, d⁶-DMSO) δ_H1.13 (6H, s), 3.56(1H, dd, J 4.5, 8.5 Hz), 3.80 (1H, dd, J 6.5, 8.5 Hz) 4.30 (1H, m), 4.89 (1H, t, J 6.0 Hz), 5.48 (1H, s), 5.73 (1H, s), 7.34 (2H, m), 7.42 (2H, m), 7.51 (1H, m), 7.61 (2H, m)

MS 457 [M+H]⁺

LC (50/80) 99.4%, 6.80 min

Preparation of 2,4′-dichlorobenzhydrol (7)

To a stirred solution of 2,4′-dichlorobenzophenone (239 mmol) in methanol (400 mL) was added sodium borohydride (119 mmol) portionwise at 0° C. Reaction mixture was warmed to room temperature and stirred for 1 hour, then quenched with water and the methanol was removed under reduced pressure. The residue was diluted with dichloromethane (400 mL) and washed with water and brine, dried (MgSO₄) and concentrated in vacuo to yield the product as an orange oil (47.1 g, 78%).

NMR (400 MHz, d⁶-DMSO) δ_H5.99 (1H, d, J 4.5 Hz), 6.16 (1H, d, J 4.5 Hz), 7.35 (7H, m), 7.66 (1H, m).

Preparation of 1-benzhydryl-3-(2,4′-dichlorobenzhydryloxy)azetidine (8)

A solution of 2,4′-dichlorobenzhydrol (7) (178 mmol), p-toluenesulphonic acid (198 mmol) and 1-benzhydryl-3-azetidinol (1) (99 mmol) in toluene (500 mL) was heated at reflux in a Dean-Stark apparatus for 40 minutes. The solution was cooled, washed with sodium hydrogen carbonate (saturated aqueous solution, 700 mL), dried (MgSO₄) and concentrated in vacuo. The residue was purified by column chromatography [SiO₂; (10% ethyl acetate:isohexane)] to finish the product as a yellow oil (17.8 g, 38%).

NMR (400 MHz, d⁶-DMSO) δ_H2.78 (1H, t, J 6.5 Hz), 2.82 (1H, t, J 6.5 Hz), 3.24 (1H, t, J=5.5 Hz), 3.28 (1H, t, J 5.5 Hz), 4.17 (1H, m), 4.39 (1H, s), 5.74 (1H, s), 7.16 (2H, m), 7.25 (4H, m), 7.32 (3H, m), 7.37 (8H, m), 7.57 (1H, m).

Preparation of 3-(2,4′-dichlorobenzhydryloxy)azetidine hydrochloride (9)

To a stirred solution of 1-benzhydryl-3-(2,4′-dichlorobenzhydryloxy)azetidine (8) (38 mmol) in dichloromethane (400 mL) was added 1-chloroethylchloroformate (94 mmol) dropwise at 0° C. and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, then dissolved in methanol (400 mL) and stirred at room temperature for 2 hours. The reaction mixture was reduced in vacuo and diluted with isohexane (20 mL), diisopropyl ether (200 mL) and methanol (30 mL). Upon stirring, a precipitate formed. Filtration afforded the desired product as a white solid (10.1 g, 77%).

NMR (400 MHz, d⁶-DMSO) δ_H3.86 (2H, br d), 4.02 (2H, br d), 4.43 (1H, quintet, J 6.0 Hz) 5.86 (1H, s), 7.37 (3H, m), 7.44 (4H, m), 7.61 (1H, m), 8.98 (2H, br d).

Example 3
3-(2,4′-dichlorobenzhydryloxy)-N-(ethyl propionate-2-yl)azetidine-1-carboxamide (10)

A solution of 3-(2,4′-dichlorobenzhydryloxy)azetidine hydrochloride (9) (0.58 mmol), ethyl 2-isocyanatopropionate (0.58 mmol) and MP-carbonate (3.10 mmol/g, 1.74 mmol) in dichloromethane (3 mL) was shaken at room temperature overnight. The reaction mixture was eluted through a pre-wetted (CH₂Cl₂) SCX-2 (2 g) cartridge with dichloromethane to yield the desired product as a colourless gum (72 mg, 28%).

NMR (400 MHz, d⁶-DMSO) δ_H1.16 (3H, t, J 7.0 Hz), 1.22 (3H, d, J 7.5 Hz), 3.60 (1H, m), 3.68 (1H, m), 3.87 (1H, m), 3.95 (1H, m), 4.05 (3H, m), 4.36 (1H, m), 5.78 (1H, s), 6.65 (1H, d, J 7.5 Hz), 7.36 (3H, m), 7.41 (4H, m), 7.61 (1H, m).

LC (80/20) 96.5%, 0.80 min

Example 4
3-(2,4′-dichlorobenzhydryloxy)-N-(tert-butyl)azetidine-1-carboxamide (11)

This material was prepared, from the corresponding commercially available isocyanate, according to the method for compound (10).

NMR (400 MHz, d⁶-DMSO) δ_H1.21 (9H, s), 3.56 (1H, m), 3.63 (1H, m), 3.82 (1H, m), 3.89 (1H, m), 4.27 (1H, m), 5.62 (1H, s), 5.76 (1H, m), 7.42 (6H, m), 7.61 (1H, m)

LC (80/20) 99.5%, 6.84 min

Example 5
3-(2,4′-dichlorobenzhydryloxy)-N-(2-thiophen-2-yl ethyl)azetidine-1-carboxamide (12)

This material was prepared, from the corresponding commercially available isocyanate, according to the method for compound (10).

NMR (400 MHz, d⁶-DMSO) δ_H2.87 (2H, t, J 7.0 Hz), 3.18 (2H, m), 3.57 (1H, m), 3.65 (1H, m), 3.83 (1H, m), 3.91 (1H, m), 4.35 (1H, m), 5.77 (1H, s), 6.47 (1H, t, J 5.5 Hz), δ 6.84 (1H, m), 6.94 (1H, m), 7.30 (1H, m), 7.36 (3H, m), 7.42 (4H, m), 7.60 (1H, m).

LC (80/20) 98.5%, 1.07 min

Example 6
3-(2,4′-dichlorobenzhydryloxy)-N-(ethyl 3-phenylpropionate-2-yl)azetidine-1-carboxamide (13)

This material was prepared, from the corresponding commercially available isocyanate, according to the method for compound (10).

NMR (400 MHz, d⁶-DMSO) δ_H2.91 (2H, m), 3.58 (2H, m), 3.87 (1H, m), 4.20 (1H, m), 4.33 (1H, m), 5.76 (1H, s), 6.72 (1H, d, J 8.0 Hz), 7.20 (3H, m), 7.26 (2H, m), 7.36 (3H, m), 7.42 (4H, m), 7.60 (1H, m).

LC (80/20) 99.2%, 1.14 min

Example 7
3-(2,4′-dichlorobenzhydryloxy)-N-[ethyl 4-(methylthio)butyrate-2-yl]azetidine-1-carboxamide (14)

This material was prepared, from the corresponding commercially available isocyanate, according to the method for compound (10).

NMR (400 MHz, d⁶-DMSO) δ_H1.16 (3H, t, J 7.5 Hz), 1.87 (2H, m), 2.03 (3H, s), 2.46 (2H, m), 3.62 (1H, m), 3.70 (1H, m), 3.85-4.00 (2H, m), 4.06 (2H, m), 4.16 (1H, m), 4.37 (1H, m), 5.78 (1H, s), 6.64 (1H, m), 7.37 (3H, m), 7.47 (4H, m), 7.61 (1H, m).

LC (80/20) 99.3%, 0.99 min

Example 8
3-(2,4′-dichlorobenzhydryloxy)-N-(cyclopropylmethyl)azetidine-1-carboxamide (15)

3-(2,4′-dichlorobenzhydryloxy)azetidine hydrochloride (9) was converted to the corresponding free-base via standard methods.

To a stirred solution of triphosgene (6.6 mmol) in dichloromethane (50 mL) at 0° C. was added a solution of ‘free-base’ (17.4 mmol) and pyridine (19.2 mmol) in dichloromethane (50 mL) over a period of 1 hour. Reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was purified by filtration through silica, eluting with dichloromethane to yield a the carbamoyl chloride as a dark orange oil (5.32 g, 83%) which was used immediately.

A solution of ‘carbamoyl chloride’ (0.54 mmol), MP-carbonate (3.10 mmol/g, 1.62 mmol) and (aminomethyl)cyclopropane (0.81 mmol) in dichloromethane was shaken at room temperature overnight. The reaction mixture was eluted through a pre-wetted (CH₂Cl₂) SCX-2 (2 g) cartridge with dichloromethane to yield a colourless gum (51 mg, 22%).

MS 406 [M+H]⁺

LC (80/20) 98.9%, 0.91 min

Example 9
3-(2,4′-dichlorobenzhydryloxy)-N-(2,3-dihydrobenzofuran-5-yl-methyl)azetidine-1-carboxamide (16)