WO2009153569A2 - Cb1 receptor modulators - Google Patents

Abstract

Compounds of formula (I) suppress the normal signalling activity of cannabinoid receptor CB1 and are therefore useful inter alia in the treatment of conditions directly or indirectly associated with obesity and overweight, Wherein A₁ is -COOH or tetrazolyl; R₂, R_3, R'₂ and R'₃ are independently selected from -R₉, - CN, -F1 -Cl, -Br, -OR₉, or -SR₉; R₉ is hydrogen, C₁-C₃ alkyl, cycloalkyl, or fully or partially fluorinated C₁-C₃ alkyl; R₁ is (i) a bond, or (H) -C(R₁₀)(R₁₁)-*. -C(R₁₀)(R₁₁)-O-*. -C(R₁₀)(R₁₁)CH₂*, or -CH₂C(R₁₀)(R₁₁)-*, wherein the bond indicated by an asterisk is attached to Ring A ring; R₁₀ is hydrogen and R₁₁ is hydrogen, (C₁-C₃)alkyl or -OH; or R₁₀ and R₁₁ are both (C₁-C₃)alkyl; or R₁₀ and R₁₁ taken together with the carbon atom to which they are attached form a (C₃-C₅)cycloalkyl ring; Ring A is an aromatic ring as specified in the claims; Z₁ is a moncyclic group as specified in the claims.

Description

CB1 RECEPTOR MODULATORS

The present invention relates to compounds which are modulators of cannabinoid receptor CB1 and which suppress the normal signalling activity of such receptors. The invention further relates to compositions and methods using said compounds for the treatment of diseases or conditions which are mediated by CB1 receptor signalling activity, such as treatment of obesity and overweight, prevention of weigh gain, treatment of diseases and conditions directly or indirectly associated with obesity and overweight such as metabolic syndrome, type 2 diabetes, cardiovascular disease, metabolic dysfunctions in obese, overweight or normoweight individuals, metabolic diseases or disorders, cancers, liver diseases and other secondary diseases referred to below, as well as for the treatment of some disorders not necessarily related to obesity and overweight, such as eating disorders, addictive disorders, mental disorders, neurological disorders, sexual dysfunctions, reproductive dysfunctions, liver diseases, fibrosis-related diseases and other clinical indications referred to below. The invention also relates to pharmaceutical compositions containing the compounds of the invention, and to the use of the compounds in combination with other treatments for such disorders.

Background to the invention

The prevalence of obesity in North America and in most European countries has more than doubled in the last 20 years and over half of the adult population are now either overweight or obese. Obesity is now recognized as a chronic disease and a critical global health issue (Fiegal et al, 1998, Int. J. Obesity 22:39-47, Mokdad et al, 1999, JAMA 282:1519-1522; Halford, 2006, Appetite, 46, 6-10). The "identifiable signs and symptoms" of obesity include an excess accumulation of fat or adipose tissue, an increase in the size or number of fat cells (adipocyte differentiation), insulin resistance, increased glucose levels (hyperglycemia), increased blood pressure, elevated cholesterol and triglyceride levels and decreased levels of high-density lipoprotein. Obesity is associated with a significantly elevated risk for type 2 diabetes, coronary heart disease, stroke, hypertension, various types of cancer and numerous other major illnesses, and overall mortality from all causes (Must et al, 1999, JAMA 282:1523-1529, CaIIe et al, 1999, N. Engl. J. Med. 341 :1097-1105). A cluster of metabolic risk factors for cardiovascular disease and type 2 diabetes is often referred to as metabolic syndrome, syndrome X or insulin resistance syndrome. The major components of metabolic syndrome X include excess abdominal fat (also known as visceral, male-pattern or apple-shaped adiposity), atherogenic dyslipidemia (decreased high-density lipoprotein cholesterol (HDL-C)), elevated triglycerides), hypertension, hyperglycaemia (diabetes mellitus type 2 or impaired fasting glucose, impaired glucose tolerance, or insulin resistance), a proinflammatory state and a prothrombotic state.(cf. AHA/NHLBI/ADA Conference Proceedings, Circulation 2004; 109:551-556). Other abnormalities often associated with the metabolic syndrome include increased apolipoprotein B concentrations, low adiponectin plasma levels, small dense low-density lipoprotein (LDL) particles, hyperuricaemia, nonalcoholic fatty liver disease/hepatic steatosis, elevated liver transaminases, gamma-glutamyl- transferase and microalbuminuria.

Like obesity, the prevalence of obesity-related diseases such as diabetes also continues to rise. Weight reduction is critical for the obese patient as it can improve cardiovascular and metabolic values to reduce obesity-related morbidity and mortality (Blackburn, 1999, Am. J. Clin. Nujtr. 69:347-349, Galuska et al, 1999, JAMA 282:1576). It has been shown that 5-10% loss of body weight can substantially improve metabolic parameters such as levels of fasting and post-prandial blood glucose , HbAIc (glycosylated haemoglobin), insulin, total plasma cholesterol, low density lipoproteins (LDL), triglyceride, uric acid and blood pressure and reduce the risk for development of diabetes, cancer and cardiovascular diseases (Goldstein, 1992, J. Obesity, 6, 397-415).

Thus, a primary aim of treatment for obesity, and obesity-related disorders, is weight loss. Initially, treatments are based on diet and lifestyle changes augmented by therapy with pharmacological therapies. However, while physical exercise and reductions in dietary intake of calories can improve the obese condition, compliance with this treatment is very poor because of sedentary lifestyles and excess food consumption, especially high fat containing food. Additionally, treatment with the available pharmacological therapies to facilitate weight loss fail to provide adequate benefit to many obese patients because of experienced side effects, contraindications, or lack of positive response. Hence, there is impetus for developing new and alternative treatments for management of obesity.

Several potential anti-obesity agents are currently investigated (for a review, see Bays, 2004, Obesity Research, 12, 1197-1211) such as i) central nervous system agents that affect neurotransmitters or neural ion channels (e.g. antidepressants (bupropion), noradrenaline reuptake inhibitors (GW320659), selective 5HT 2c receptor agonists, antiseizure agents (topiramate, zonisamide), some dopamine antagonists, cannabinoid CB-1 receptor antagonists (rimonabant); ii) leptin/insulin/central nervous system pathway agents (e.g. leptin analogues, leptin transport and/or receptor promoters, CNTF (Axokine), NPY antagonists, AgRP antagonists, POMC promoters, CART promoters, MSH analogues, MC4 receptor agonists, agents that affect insulin metabolism/activity [PTP-1 B inhibitors, PPAR receptor antagonists, short-acting D2 agonist (ergoset), somatostatin agonists (octreotide), and adiponectin/Acrp30 (Famoxin or Fatty Acid Metabolic OXidation INducer)]) ; iii) gastrointestinal-neural pathway agents (e.g. agents that increase CCK and PYY activity, agents that increase GLP-1 activity (extendin 4, liraglutide, dipeptidyl peptidase IV inhibitor), agents that decrease ghrelin activity, amylin (pramlinitide), neuropeptide Y agonists) ; iv) agents that may increase resting metabolic rate (beta-3 agonists, UCP homologues, thyroid receptor agonists); and v) other more diverse agents, such as for example including (MCH) melanin concentrating hormone antagonists, phytostanol analogues, functional oils, P57, amylase inhibitors, growth hormone fragments, synthetic analogues of DHEAS (fluasterone), antagonists of adipocyte 11beta-hydroxysteroid dehydrogenase type 1 activity, CRH agonists, carboxypeptidase inhibitors, inhibitors of fatty acid synthesis (cerulenin and C75), indanones/indanols, aminosterols (trodusquemine), and other gastrointestinal lipase inhibitors (ATL962 ).

Drugs effective in obesity treatment may act by various mechanisms such as by: a reduction of food intake (e.g. by inducing satiety or satiety signals), altering metabolism (e.g. by modifying the absorption of nutrients e.g. by inhibition of fat absorption), increasing energy expenditure (e.g. increase thermogenesis), inhibition of lipogenesis or stimulation of adipocyte apoptosis. However, only few drugs are available for obesity treatment (for reviews, see Gadde and Allison, 2006, Circulation, 114, 974-984; Weigle, 2003, J Clin Endocrinol Metab., 88, 2462-2469; Schioth, 2006, CNS Neurol. Disorders Drug Targets, 5, 241-249). Sibutramine is a centrally acting mixed inhibitor of serotonin and norepinephrine presynaptic re-uptake. Orlistat is an inhibitor of gastrointestinal lipases which reduces fat absorption in the gut. Rimonabant (SR141716, Acomplia ®) is a centrally and peripherally acting cannabinoid CB1 modulator (antagonist and inverse agonist) that recently has been approved for treatment of obesity (for a review see Pagotto et al, 2006, Endocrine Reviews, 27, 73-100; for reports on phase III clinical trials see Despres et al, 2005, N. Engl. J. Med. 353, 212; van Gaal et al, 2005, Lancet, 16, 1389; Pi-Sunyer et al, 2006, JAMA, 295, 761).

Presently, two cannabinoid receptors have been characterized: CB1 , a receptor found in the mammalian brain and in a number of other sites in peripheral tissues; and CB2, a peripheral receptor found principally in cells related to the immune system. For reviews on cannabinoid CB1 and CB2 receptor modulators, see Pertwee, 2000, Exp. Opin. Invest. Drugs, 9, 1553- 1571 and Muccioli, 2005, Cur. Med. Chem., 12, 1361-1394. A substantial body of evidence indicates that CB1 antagonists (e.g. rimonabant) are able to modulate energy homeostasis and that CB1 antagonists are able to modulate food intake as well as peripherally block lipogenic processes (Pagotto et al, 2006, Endocrine Reviews, 27, 73-100; Tucci et al, 2006, Curr. Med. Chem. 13, 2669-2680; Lange and Kruse, 2004, Current Opinion in Drug Discovery & Dev., 7, 498-506). The peripheral effects of CB1 antagonists can be mediated by several target organs and mechanisms, e.g. i) liver: block of de novo lipogenesis, ii) muscles: increase in glucose uptake, iii) adipose tissue: stimulation of expression and/or secretion of adiponectin, inhibition of lipogenic enzymes, stimulation of GLUT4, generation of futile cycles, iv) pancreas: insulin regulation and v) gastrointestinal tract: stimulation of satiety signals.

Rimonabant (Acomplia ®) is approved as an adjunct to diet and exercise for treatment of obesity. While the effects on body weight and metabolic parameters (plasma triglyceride levels, HDL cholesterol levels, plasma insulin levels, HbAIc [glycosylated haemoglobin] levels, insulin resistance, and adiponectin levels) are very encouraging, there are also undesirable side effects, possibly centrally mediated (psychiatric and nervous system disorders), such as anxiety, depressive disorders, sleep disorders, nausea, and vomiting (cf. http://emc.medicines.org.uk; http://www.emea.europa.eu/humandocs/PDFs/EPAR/acomplia/AcompliaEparScientificD- en.pdf)- Accordingly, there still exists a need for alternative CB1 receptor antagonists associated with differing pharmacokinetic, pharmacological, and side-effect profiles.

The CB1 receptor has been invoked in many disease states (cf. review by Pacher et al, 2006, Pharmacol. Rev, 58, 389-462). Modulators of CB1 receptor activity can be useful in the treatment of diseases and conditions associated with CB1 receptor regulation such as obesity and overweight, prevention of weight gain (e.g. induced by medications or smoking cessation), and in the treatment of diseases and conditions directly or indirectly associated with obesity (cf. Bray, 2004, J. Clin. Endocrinol. Metab. 89, 2583-9; Manson, et al, 1995, N. Engl. J. Med. 333, 677-85; Grundy, 2004..J. Clin. Endocrinol. Metab. 89, 2595-600; Esposito et al, 2004, JAMA 291 ; 2978-84; Ejerblad et al, 2006; J. Am. Soc. Nephrol. 17, 695-702; Whitmer et al, 2005, BMJ 330 (7504), 1360) such as

- metabolic syndrome, also referred to as syndrome X or insulin resistance syndrome,

- type 2 diabetes,

- cardiovascular diseases (e.g. aneurysms, angina, arrhythmia, atherosclerosis, cardiomyopathy, cerebrovascular accident (stroke), cerebrovascular disease, congenital heart disease, congestive heart failure, myocarditis, valve disease, coronary artery disease, dilated cardiomyopathy, diastolic dysfunction, endocarditis, high blood pressure (hypertension), hypertrophic cardiomyopathy and its associated arrhythmias and dizziness, mitral valve prolapse, myocardial infarction (heart attack), venous thromboembolism, varicose veins and pulmonary embolism, proinflammatory state, increased tendency to thrombosis (prothrombotic state), and intracranial hypertension,

- metabolic dysfunctions in obese, overweight or normoweight individuals (e.g. dyslipidemia, hyperlipidemia, low HDL and/or high LDL cholesterol levels, hypertriglycerideemia, low adiponectin levels, impaired glucose tolerance, insulin resistance, increase in HbAIc [glycosylated haemoglobin] levels, diabetes mellitus, type 2 diabetes, reduced metabolic activity),

- metabolic diseases or disorders (conditions in which there is a deviation from or caused by an abnormal metabolic process; can be congenital due to inherited enzyme abnormality or acquired due to disease of an endocrine organ or failure of a metabolically important organ such as the liver.),

- cancers (e.g. colorectal cancer, breast cancer, uterine cancer, colon cancer),

- liver diseases (e.g. non-alcoholic fatty liver disease, steatohepatitis, steatosis, hepatic fibrosis, hepatic cirrhosis), and

- other secondary diseases related to obesity and overweight, such as menstrual disorders, gastroesophageal reflux disease, cholelithiasis (gallstones), hernia, urinary incontinence, chronic renal failure, hypogonadism (male), stillbirth, stretch marks, acanthosis nigricans, lymphedema, cellulitis, carbuncles, intertrigo, hyperuricemia, immobility, osteoarthritis, low back pain, meralgia paresthetica, headache, carpal tunnel syndrome, dementia, idiopathic dyspnea, obstructive sleep apnea, hypoventilation syndrome, Pickwickian syndrome, asthma, depression, low self esteem, body dysmorphic disorder, social stigmatization.

The CB1 receptor has been invoked in many disease states diseases not necessarily related to obesity and overweight such as eating disorders,

- addictive disorders (e.g. addiction to marijuana, psychostimulants, nicotine, alcohol, cocaine, and opiates),

- mental disorders (e.g. schizophrenia, schizo-affective disorder, bipolar disorders, anxiety, panic disorder),

- neurological disorders,

- sexual dysfunctions (e.g. erectile dysfunction),

- reproductive dysfunctions (e.g. polycystic ovarian syndrome, infertility),

- liver diseases (e.g., viral hepatitis, liver dysfunction in other infectious diseases, inflammatory liver diseases (e.g. autoimmune hepatitis), alcoholic liver disease, toxic liver disease, liver tumors (such as liver cell carcinoma, hepatocellular carcinoma, hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma of liver, Kupffer cell sarcoma, other sarcomas of liver), steatohepatitis, non-alcoholic fatty liver disease hepatic fibrosis, hepatic cirrhosis, cirrhotic portal hypertension, metabolic liver diseases (such as haemochromatosis, Wilson's disease, Gilbert's syndrome, Crigler-Najjar syndrome, Dubin-Johnson syndrome, Rotor's syndrome)),

- fibrosis-related diseases (such as cystic fibrosis of the pancreas and lungs, endomyocardial fibrosis, idiopathic myocardiopathy, idiopathic pulmonary fibrosis of the lung, diffuse parenchymal lung disease, mediastinal fibrosis, myleofibrosis, post- vasectomy pain syndrome, retroperitoneal fibrosis, progressive massive fibrosis, proliferative fibrosis, neoplastic fibrosis, sickle-cell anemia may cause enlargement and ultimately fibrosis of the spleen) ,

- and other clinical indications such as epilepsy, osteoporosis, rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis (UC) and Crohn disease (CD), congestive obstructive pulmonary disease (COPD), inflammation, inflammatory pain, atherosclerosis, diarrhoea, asthma, constipation, skin diseases, glaucoma and hairloss. Since obesity leads to, or significantly increases the risk of, co-morbidities involving various body systems (see Bays, 2004, Obesity Research, 12, 1197-1211) including: i) cardiovascular (hypertension, congestive cardiomyopathy, varicosities, pulmonary embolism, coronary heart disease [CHD], neurological (stroke, idiopathic intracranial hypertension, meralgia parethetica), ii) respiratory (dyspnea, obstructive sleep apnea, hypoventilation syndrome, Pickwickian syndrome, asthma), iii) musculoskeletal (immobility, degenerative osteoarthritis, low back pain), iv) skin (striae distensae or "stretch marks," venous stasis of the lower extremities, lymphedema, cellulitis, intertrigo, carbuncles, acanthosis nigricans, skin tags), v) gastrointestinal (gastro-esophageal reflux disorder, non-alcoholic fatty liver/steatohepatitis, cholelithiasis, hernias, colon cancer), vi) genitourinary (stress incontinence, obesity-related glomerulopathy, breast and uterine cancer), vii) psychological (depression and low self-esteem, impaired quality of life), and viii) endocrine (metabolic syndrome, type 2 diabetes, dyslipidemia, hyperandrogenemia in women, polycystic ovarian syndrome, dysmenorrhea, infertility, pregnancy complications, male hypogonadism)

It is also useful to combine a CB1 modulator with medications used for treatment of such diseases. It is also useful to combine a CB1 modulator with medications used for treatment of diseases which may be unrelated to obesity such as eating disorders, addictive disorders, mental disorders, neurological disorders, sexual dysfunctions, reproductive dysfunctions, liver diseases, fibrosis-related diseases, and other clinical indications which may be unrelated to obesity.

Description of the Invention

According to the invention, there is provided a compound of formula (I), or a salt or N-oxide thereof:

WHEREIN:

A₁ is -COOH or tetrazolyl;

R₂, R3, R'₂ and R'₃ are independently selected from -R₉, -CN, -F, -Cl, -Br, -OR₉, or -SR₉;

R₉ is hydrogen, C₁-C₃ alkyl, cycloalkyl, or fully or partially fluorinated Ci-C₃ alkyl;

R₁ is (i) a bond, or

(ii) -C(R₁₀)(Rn)-*, -C(R₁₀)(R_{1 I})-O-*, -C(R₁₀)(R₁₁)CH₂-*. Or -CH₂C(R₁₀)(R₁₁)-*, wherein the bond indicated by an asterisk is attached to Ring A ring;

R₁₀ is hydrogen and Ri₁ is hydrogen, (d-C₃)alkyl or -OH; or R₁₀ and R₁₁ are both (C₁- C₃)alkyl; or R₁₀ and R₁₁ taken together with the carbon atom to which they are attached form a (C₃-C₅)cycloalkyl ring;

Ring A is an aromatic ring selected from those of formulae (C1) to (C10):

wherein the bond marked (1) is attached to the A₁-R₁- radical of formula (I); the bond marked (2) is attached to the Z₁-C(=O)- radical of formula (I); the bond marked (3) is attached to the phenyl ring carrying the substituents R₂ and R₃ of formula (I); and the bond marked (4) is attached to the phenyl ring carrying the R'₂ and R'₃ substituents of formula (I);

Z₁ is a group selected from those of formulae (A) to (P):

wherein

R₄ and R₅ are independently is selected from hydrogen, (d-C₃)alkyl, -F, -Cl, -Br, -CF₃, -OCF₃, -OCH₃, -CH₃, -CN, and (C_rC₃)alkylsulfonyl;

R₆ is selected from -F, -Cl, -Br, -CF₃, -OCF₃, -OCH₃, -CH₃, -CN, and -OH.

R₇ is hydrogen and R₈ is hydrogen or (d-C₃)alkyl; or R₇ and R₈ are both (Ci-C₃)alkyl; or R₇ and R₈ taken together with the carbon atom to which they are attached form a (C₃- C₅)cycloalkyl ring;

Ri₂ is selected from hydrogen, -CH₃, -OH, and -CN; and

Ri₃ is selected from hydrogen and -CH₃.

Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) or a salt, hydrate, solvate or N-oxide thereof, together with one or more pharmaceutically acceptable carriers or excipients.

For orally administrable compounds with which the invention is concerned, it is preferable, according to known medicinal chemistry principles, to have a maximum compound molecular weight of 750, or even more preferably a maximum of 650.

The compounds with which the invention is concerned suppress the normal signalling activity of cannabinoid receptor CB1. Therefore, further aspects of the invention are:

(i) The use of a compound of formula (I) or a salt, hydrate, solvate or N-oxide thereof in the preparation of a composition for treatment of diseases or conditions which are mediated by CB1 receptor signalling activity. Examples of such diseases have been listed above.; and

(ii) A method for the treatment of diseases or conditions which are mediated by CB1 receptor signalling activity, which method comprises administering to a subject suffering such disease or condition an effective amount of a compound of formula (I) or a salt, hydrate, solvate or N-oxide thereof. Again, examples of such treatments have been listed above.

Terminology

As used herein, the term "(C_a-C_b)alkyl" wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms. Thus when a is 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.

As used herein the unqualified term "carbocyclic" refers to a mono-, bi- or tricyclic radical having up to 16 ring atoms, all of which are carbon, and includes aryl and cycloalkyl.

As used herein the unqualified term "cycloalkyl" refers to a monocyclic saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein the unqualified term "aryl" refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical, and includes radicals having two monocyclic carbocyclic aromatic rings which are directly linked by a covalent bond. Illustrative of such radicals are phenyl, biphenyl and napthyl.

As used herein the unqualified term "heteroaryl" refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O, and includes radicals having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, which are directly linked by a covalent bond. Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl and indazolyl. As used herein the unqualified term "heterocyclyl" or "heterocyclic" includes "heteroaryl" as defined above, and in addition means a mono-, bi- or tri-cyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical. Illustrative of such radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.

Unless otherwise specified in the context in which it occurs, the term "substituted" as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, (Ci-C₆)alkyl, (CrC₆)alkoxy, hydroxy, hydroxy(Ci- C₆)alkyl, mercapto, mercapto(C₁-C₆)alkyl, (CrC₆)alkylthio, halo (including fluoro, bromo and chloro), fully or partially fluorinated (C₁-C₃)alkyl, (C₁-C₃JaIkOXy or (d-CaJalkylthio such as trifluoromethyl, trifluoromethoxy, and trifluoromethylthio, nitro, nitrile (-CN), oxo, phenyl, phenoxy, monocyclic heteroaryl or heteroaryloxy with 5 or 6 ring atoms, tetrazolyl, -COOR^A, -COR^A, -OCOR^A, -SO₂R^A, -CONR^AR^B, -SO₂NR^AR^B, -NR^AR^B, OCONR^AR^B, -NR^BCOR^A, -NR^BCOOR^A, -NR^BSO₂OR^A or -NR^ACONR^AR^B wherein R^A and R^B are independently hydrogen or a (d-CeJalkyl group or, in the case where R^A and R^B are linked to the same N atom, R^A and R^B taken together with that nitrogen may form a cyclic amino ring, such as a morpholine, piperidinyl or piperazinyl ring. Where the substituent is phenyl, phenoxy or monocyclic heteroaryl or heteroaryloxy with 5 or 6 ring atoms, the phenyl or heteroaryl ring thereof may itself be substituted by any of the above substituents except phenyl, phenoxy, heteroaryl or heteroaryloxy. An "optional substituent" may be one of the foregoing substituent groups.

As used herein the term "salt" includes base addition, acid addition and quaternary salts. Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like. Those compounds (I) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesunfonic, glutamic, lactic, and mandelic acids and the like.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties. Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Compopunds of the invention may be prepared in solvate or hydrate form. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

Compounds with which the invention is concerned which may exist in one or more stereoisomeric form, because of the presence of asymmetric atoms or rotational restrictions, can exist as a number of stereoisomers with R or S stereochemistry at each chiral centre or as atropisomeres with R or S stereochemistry at each chiral axis. The invention includes all such enantiomers and diastereoisomers and mixtures thereof.

The compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (I).

So-called 'pro-drugs' of the compounds of formula (I) are also within the scope of the invention. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems. Vol. 14, ACS Symposium Series (T. Higuchi and VJ. Stella) and Bioreversible Carriers in Drug Design. Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association; CS. Larsen and J. østergaard, Design and application of prodrugs, In Textbook of Drug Design and Discovery, 3^rd Edition, 2002, Taylor and Francis ).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985). Such examples could be a prodrug of a carboxyl group (such as -CO-O-CH₂-O-CO-IBU as used in the pivampicillin prodrug of ampicillin), an amide (-CO-NH-CH₂-NAIk₂) or an amidine ( -C(=N-O-CH₃)-NH₂).

Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites include

(i) where the compound of formula I contains a methyl group, an hydroxymethyl derivative thereof (-CH₃ -> -CH₂OH):

(ii) where the compound of formula I contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH);

(iii) where the compound of formula I contains a tertiary amino group, a secondary amino derivative thereof (-NR¹R² -> -NHR¹ or -NHR²);

(iv) where the compound of formula I contains a secondary amino group, a primary derivative thereof (-NHR¹ -> -NH₂);

(v) where the compound of formula I contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and

(vi) where the compound of formula I contains an amide group, a carboxylic acid derivative thereof (-CONH₂ -> COOH).

For use in accordance with the invention, the following structural characteristics are currently contemplated, in any compatible combination, in the compounds (I):

The Group A₁

A₁ is either -COOH or tetrazolyl, but tetrazolyl is often preferred.

Ring A

Ring A has been defined above in connection with formula (I). Often, however, ring A will have formula (C1), (C5), (C9) or (C10) as defined in relation to formula (I). The Substituents R₁. R*. RS and R'a

R₂, R₃, R'₂ and R'₃ have been defined above in connection with formula (I). Often, however, R₂, R₃, R^f ₂ and R'₃ are selected from hydrogen, -F, -Cl, and -CN. In some preferred compounds (I), R₂ and R'₂ are each hydrogen, R₃ is 4-CI, and R'₃ is 2-CI.

The divalent radical -Ri-

R₁ may be a bond, or a divalent radical selected from -C(R₁₀)(Rn)-*, -C(R₁₀)(Rn)-O-^*, -C(Ri₀)(R₁₁)CH₂-^*, Or -CH₂C(R₁₀)(R₁₁)-^*, wherein the bond indicated by an asterisk is attached to Ring A ring; and R₁₀ is hydrogen and Rn is hydrogen, (Ci-C₃)alkyl such as methyl or ethyl, or -OH; or R₁₀ and Rn are both (CrC₃)alkyl such as both methyl or one methyl and the other ethyl; or R₁₀ and Rn taken together with the carbon atom to which they are attached form a (C₃-C₅)cycloalkyl ring such as a cyclopropyl ring. Often -R₁- is -CH₂-, -CH(CH₃)-, -CH(OH)-, or -CH₂O-^* wherein the bond indicated by an asterisk is attached to Ring A.

The Group Zi

Z₁ has been defined above in relation to formula (I). Often, however, Z₁ is selected from those of formulae (A), (E), (G), (J), (K) and (O) as defined in relation to formula (I), with Z₁ as formula (E) being currently a preferred type. In that latter case, (i) R₇ in Z₁ may be hydrogen or methyl, R₈ in Z₁ may be methyl or ethyl, and R₄ and R₅ in Z₁ may be independently selected from hydrogen, -F, -Cl, -Br, -CN, -CF₃, -OCF₃, and -SO₂CH₃, or (ii) R₇ in Z₁ may be hydrogen and R₈ in Z₁ may be methyl; or R₇ and R₈ in Z₁ may both be methyl; or R₇ and R₈ in Z₁ taken together with the carbon atom to which they are attached may form a cyclopropyl ring. When Z₁ has formula (E), R₇ may be hydrogen, R₈ may be methyl and the stereochemical configuration at the carbon to which R₁₀ and R₁₁ are attached may be R.

A particular class of compounds of the invention has formula (II):

wherein R₄ is hydrogen and R₅ is selected from 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 3-F, 3-CI, 3- Br, 3-CF₃, 3-OCF₃, 2-F, 2-CI, 2-Br, 2-CF₃, 2-OCF₃; or R₄ is 2-F and R₅ is selected from 6-F, 6-Cl₁ 6-Br, 6-CF₃, 6-OCF₃, 5-F, 5-Cl₁ 5-Br, 5-CF₃, 5-OCF₃, 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 3- F, 3-CI, 3-Br, 3-CF₃, 3-OCF₃; or R₄ is 3-F and R₅ is selected from 6-F, 6-Cl₁ 6-Br₁ 6-CF₃, 6- OCF₃, 5-F, 5-CI, 5-Br, 5-CF₃, 5-OCF₃, 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 2-CI, 2-Br₁ 2-CF₃, 2- OCF₃; or R₄ is 4-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6-OCF₃, 5-F, 5-CI, 5-Br, 5- CF₃, 5-OCF₃, 2-Cl₁ 2-Br, 2-CF₃, 2-OCF₃, 3-CI, 3-Br, 3-CF₃, 3-OCF₃. In this class of compounds, Ring A may be selected from, for example, those of formulae (C1), (C5), (C8) and (C9) as defined in relation to formula (I)

Other particular classes of compounds of the invention have formula (HIa)₁ (HIb)₁ (MIc) or (MId):

wherein the R₄ is hydrogen and R₅ is selected from 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 3-F, 3-CI, 3-Br, 3-CF₃, 3-OCF₃, 2-F, 2-CI, 2-Br, 2-CF₃, 2-OCF₃; or R₄ is 2-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6-OCF₃, 5-F, 5-CI, 5-Br₁ 5-CF₃, 5-OCF₃, 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 3- F, 3-CI, 3-Br, 3-CF₃, 3-OCF₃; or R₄ is 3-F and R₅ is selected from 6-F, 6-Cl₁ 6-Br, 6-CF₃, 6- OCF₃, 5-F, 5-CI, 5-Br₁ 5-CF₃, 5-OCF₃, 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 2-CI, 2-Br, 2-CF₃, 2- OCF₃; or R₄ is 4-F and R₅ is selected from 6-F, 6-CI, 6-Br₁ 6-CF₃, 6-OCF₃, 5-F, 5-CI, 5-Br, 5- CF₃, 5-OCF₃, 2-CI, 2-Br₁ 2-CF₃, 2-OCF₃, 3-CI, 3-Br₁ 3-CF₃, 3-OCF₃.

Further particular classes of compounds of the invention have formula (IVa)₁ (IVb)₁ (IVc) or (IVd):

wherein R₄ is hydrogen and R₅ is selected from 4-F, 4-Cl₁ 4-Br, 4-CF₃, 4-OCF₃, 3-F, 3-CI, 3- Br, 3-CF₃, 3-OCF₃, 2-F, 2-CI, 2-Br, 2-CF₃, 2-OCF₃; or R₄ is 2-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6-OCF₃, 5-F, 5-CI, 5-Br, 5-CF₃, 5-OCF₃, 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 3- F, 3-CI, 3-Br, 3-CF₃, 3-OCF₃; or R₄ is 3-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6- OCF₃, 5-F, 5-CI, 5-Br, 5-CF₃, 5-OCF₃, 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 2-F, 2-CI, 2-Br, 2-CF₃, 2-OCF₃; or R₄ is 4-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6-OCF₃, 5-F, 5-CI, 5-Br, 5-CF₃, 5-OCF₃, 2-F, 2-CI, 2-Br, 2-CF₃, 2-OCF₃, 3-F, 3-CI, 3-Br, 3-CF₃, 3-OCF₃.

Specific compounds of the invention include those of the Examples herein.

The compounds of the present invention act on central and peripheral cannabinoid receptor CB1. Some compounds distribute to a lesser extent to the central nervous system, i.e. the compound less readily crosses the blood-brain barrier and will be associated with fewer central nervous system mediated side-effects.

The compounds of the invention modulate the cannabinoid receptor CB1 by suppressing its natural signalling function. The compounds are therefore CB1 receptor antagonists, inverse agonists, or partial agonists.

The term "CB1 antagonist" or "cannabinoid receptor CB1 antagonist" refers to a compound which binds to the receptor, or in its vicinity, and lacks any substantial ability to activate the receptor itself. A CB1 antagonist can thereby prevent or reduce the functional activation or occupation of the receptor by a CB1 agonist such as for example the endogenous agonist N- Arachidonylethanolamine (anandamide). This term is well known in the art.

The term "CB1 inverse agonist" or "cannabinoid receptor CB1 inverse agonist" refers to a compound which binds to the receptor and exerts the opposite pharmacological effect as a CB1 receptor agonist does. Inverse agonists are effective against certain types of receptors which have intrinsic activity without the acting of a ligand upon them (also referred to as 'constitutive activity¹). This term is well known in the art. It is also well known in the art that such a CB1 inverse agonist can also be named a CB1 antagonist as the general properties of both types are equivalent. Accordingly, in the context of the present invention the term "CB1 antagonist" in general is understood as including both the "CB1 antagonist" as defined above and the "CB1 inverse agonist".

The term "CB1 partial agonist" or "cannabinoid receptor CB1 partial agonist" refers to a compound which acts upon the same receptor as the full agonist but that produces a weak maximum pharmacological response and has a low level of intrinsic activity. This term is well known in the art.

According to a preferred embodiment of the present invention, the "CB1 modulator" or "cannabinoid receptor CB1 modulator" is a CB1 antagonist or inverse agonist compound.

The compounds of the invention are useful for the treatment of diseases or conditions which are mediated by CB1 receptor signalling activity. Examples of such diseases and conditions and treatments therefor have been listed above. Without limitation, they include obesity and overweight, prevention of weight gain, treatment of diseases and conditions directly or indirectly associated with obesity (e.g. metabolic syndrome, type 2 diabetes, cardiovascular diseases, metabolic dysfunctions in obese, overweight or normoweight individuals, metabolic diseases or disorders, cancers, liver diseases and the other secondary diseases referred to above), and in the treatment of diseases and conditions not necessarily related to obesity (e.g. eating disorders, addictive disorders, mental disorders, neurological disorders, sexual dysfunctions, reproductive dysfunctions, liver diseases, fibrosis-related diseases and other clinical indications referred to above). They are useful for modulating body weight and energy consumption in mammals and for modulating major components involved in the metabolic syndrome such as excess abdominal fat, atherogenic dyslipidemia (abnormal levels of HDL-C, triglycerides, LDL, apolipoprotein B, adiponectin), hypertension, hyperglycaemia, hyperuricaemia, non-alcoholic fatty liver disease/hepatic steatosis, elevated liver transaminases, gamma-glutamyl-transferase and microalbuminuria. The compounds of the invention display varying physicochemical properties and are useful for modulating peripheral CB1 receptors and to varying degree central CB1 receptors. Those compounds of the invention associated with a lowered central action on CB1 receptors may have a reduced propensity to induce psychiatric and nervous system side-effects.

The compounds of the invention may be combined with another therapeutic agent used in treatment of obesity acting by a different mode of action such as central action on satiety or hunger signals, craving mechanisms, appetite regulation, leptin/insulin/central nervous system pathways, gastrointestinal-neural pathways, metabolic rate, energy expenditure, food intake, fat storage, fat excretion, gastrointestinal motility, lipogenesis, glucose transport, glucogenolysis, glycolysis, lipolysis, etc including modulators (inhibitors, agonists, antagonists, analogues) of monoaminergic (NA (noradrenaline), 5-HT (serotonin), DA (dopamine)) receptors or transporters, neural ion channels, leptin or leptin receptor, neuropeptide Y receptors, PP (pancreatic polypeptide), PYY, Protein YY3-36, ghrelin or ghrelin receptor, motilin or motilin receptor, orexins or orexin receptors, bombesin or bombesin-like peptide receptors, somatostatin or somatostatin receptors, MCHR1 (melanin concentrating hormone receptor 1), CNTF (ciliary neurotrophic factor), AgRP (agouti-related peptide), POMC (proopiomelanocortin), CART (cocaine and amphetamine regulated transcript), alpha-MSH (alpha-melanocyte-stimulating hormone), MC4 (melanocortin-4) or MC3 (melanocortin-3) receptor, galanin receptors, relaxin-3 receptor, GPR7 receptor, GPR119 receptor, GPR10 receptor, neuromedin U receptors, free-fatty-acid receptors, growth hormone, nesfatin-1 , opioid receptors, neuropeptide FF receptors, PTP-1 B (protein- tyrosine phosphatase), PPAR (peroxisome proliferators activated receptors) receptors, retinoid X receptor heterodimers, adiponectin also known as Acrp30 (adipocyte complement- related protein of 3OkDa), fatty acid metabolism, H (histamine) receptors, CCK-A (Cholecystokinin-A) or CCK-A receptor, GLP-1 (glucagon-like peptide-1) or GLP-1 receptor, oxyntomodulin, adrenomedullin, DPP-IV (dipeptidyl peptidase IV), amylin, beta-3-adrenergic receptor, UCP (uncoupling protein), thyroid receptor, thyroid-stimulating hormone receptor, 11beta-hydroxysteroid dehydrogenase type 1 , amylase, DHEAS (dehydroepiandrosterone sulfate), CRH (corticotropin releasing hormone) or CRH receptors, carboxypeptidase, fatty acid synthesis, HMG-CoA reductase, ileal bile acid transport, gastrointestinal lipase, P57, AMP-activated protein kinase (AMPK). The compounds of the invention may be combined with another therapeutic agent used in treatment of metabolic syndrome or obesity-related diseases such as cardiovascular (hypertension, congestive cardiomyopathy, varicosities, pulmonary embolism, coronary heart disease [CHD], liver cirrhosis), neurological (stroke, idiopathic intracranial hypertension, meralgia parethetica), respiratory (dyspnea, obstructive sleep apnea, hypoventilation syndrome, Pickwickian syndrome, asthma), musculoskeletal (immobility, degenerative osteoarthritis, low back pain, osteoporosis), skin (striae distensae or "stretch marks," venous stasis of the lower extremities, lymphedema, cellulitis, intertrigo, carbuncles, acanthosis nigricans, skin tags), gastrointestinal (gastro-esophageal reflux disorder, nonalcoholic fatty liver/steatohepatitis, cholelithiasis, hernias, colon cancer), genitourinary (stress incontinence, obesity-related glomerulopathy, breast and uterine cancer), psychological (depression and low self-esteem, impaired quality of life), and endocrine (metabolic syndrome, type 2 diabetes, dyslipidemia, hyperandrogenemia in women, polycystic ovarian syndrome, dysmenorrhea, infertility, pregnancy complications, male hypogonadism) diseases.

Use of the compounds of the invention may be combined with proper reduction in dietary calorie intake and physical exercise.

It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial, as is required in the pharmaceutical art. However, for administration to human patients, the total daily dose of the compounds of the invention may typically be in the range 1 mg to 1000 mg depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of from 10 mg to 1000 mg, while an intravenous dose may only require from 1 mg to 500 mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.

These dosages are based on an average human subject having a weight of about 60kg to 100kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly, and especially obese patients. The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. 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, glucose syrup, gelatin 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 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.

The active ingredient may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.

Synthesis

There are multiple synthetic strategies for the synthesis of the compounds (I) with which the present invention is concerned, but all rely on known chemistry, known to the synthetic organic chemist. Thus, compounds according to formula (I) can be synthesised according to procedures described in the standard literature and are well-known to the one skilled in the art. Typical literature sources are "Advanced organic chemistry, 4^th Edition (Wiley), J March, "Comprehensive Organic Transformation", 2^nd Edition (Wiley), R.C. Larock , "Handbook of Heterocyclic Chemistry", 2^nd Edition (Pergamon), A.R. Katritzky), P.G.M. Wuts and T.W. Greene "Greene^'s Protective Groups in Organic Chemistry" 4^th Edition (Wiley) review articles such as found in "Synthesis", "Ace. Chem. Res." , "Chem. Rev", or primary literature sources identified by standard literature searches online or from secondary sources such as "Chemical Abstracts" or "Beilstein".

General synthetic routes

Routes outlined below do not constitute an exhaustive list.

Experimental conditions given are generic and can be found in standard literature sources such as those cited above. Specific references are cited for information and conditions may apply to a given substrate with or without modification/optimization.

Compounds of Formula (C1d) and (C1g) can be prepared from (C1a) as shown on Scheme 1. Intermediate (C1 a) can be converted to (C1b) by bromination using NBS in suitable solvent such as carbon tetrachloride, nucleophilic displacement using potassium cyanide and partial hydrolysis with sodium hydroxide. Full hydrolysis of (C1b) under more forcing conditions (eg. heating with NaOH in ethanol) gives intermediate (C1e). Amidation of (C1b) using standard amide coupling reagents (eg. EDAC/HOBt) or via the acid choride gives (C1c) which can be transformed to tetrazole (C1d) using sodium azide in a solvent such as DMF under standard conditions. Diacid (C1e) can be converted to monoester (C1f) via a cyclic anhydride. Acid (C1f) can be converted to amide (C1g) and hydrolysed using standard conditions.

Scheme 1 Intermediate (C1a) can be prepared as shown on Scheme 2 by condensation of a suitable N- aryl benzamidine (C1 h) and ethyl-3-bromo-2-oxo-butanoate using a procedure similar to that described in WO2006067428.

Scheme 2

The compounds of Formula (C10d) and (C10g) can be prepared from (C10a) as shown on Scheme 3 using a similar series of reactions as described in Scheme 1

Scheme 3

Intermediate (C10a) can be prepared as shown on Scheme 4 by reaction of a suitable keto alkene (C10h) and ethylaminocrotonate using a procedure similar to that described in US20060189664.

Scheme 4

The compounds of Formula (C9d) and (C9g) can be prepared from (C9a) as shown on Scheme 5 using the same series of reactions as described in Scheme 1.

Scheme 5

Intermediate (C9a) can be prepared by a similar route to that described in Bioorg. Med. Chem. Lett. 2005, 15, 645 and outlined on Scheme 6. Diene (C9i) can be prepared via alkylation of ketone (C9h) with and elimination of the intermediate alcohol. Treatment with triphenylphosphine gives (C9j), which can be condensed with a suitable aldehyde to give (C9a).

Scheme 6

The compounds of Formula (C8d) and (C8g) can be prepared from (C8a) as shown on Scheme 7 using the same series of reactions as described in Scheme 1.

Scheme 7

Intermediate (C8a) can be prepared by a similar route to that described in J. Org Chem 2006, 71 , 5897 and outlined on Scheme 8. Reaction of diamine (C8e) with ester (C8f) gives pyrazine intermediate (C8a).

Scheme 8

The compounds of Formula (C5d) and (C5g) can be prepared from (C5a) as shown on Scheme 9 using the same series of reactions as described in Scheme 1.

Scheme 9 Intermediate (C5a) can be prepared by a similar route to that described in WO2003027069 and outlined on Scheme 10. Reaction of keto ester with the alpha-bromoketone followed by condensation with a suitable aniline affords pyrrole (C5a)

(C5a)

Scheme 10

The compounds of Formula (C7d) and (C7g) can be prepared from (C7a) as shown on Scheme 11. Tetrazole (C7d) can be made via alkylation of the pyrrole nitrogen using chloroacetonitrile and a base such as potassium carbonate, followed tetrazole formation using sodium azide under standard conditions. Acid (C7g) can be accessed via a standard alkylation hydrolysis protocol as shown in Scheme 11.

Scheme 11

Intermediate (C7a) can be prepared as outlined on Scheme 12, via a similar route to that described in J.Chem Soc Perkin Trans 1 2002, 622 and US20070149596. The amide of tosyl-propargyl glycine (C7h) can be prepared using standard amide coupling methods. Sonogashira coupling of the terminal alkyne (C7i) with an aryl iodide gives the aryl alkyne (C7j) which on treatment with iodine in the presence of potassium carbonate in acetonitrile affords the dihydropyrrole (C7k), which upon treatment with a base such as DBU gives the pyrrole (C7a) with concominant removal of the tosyl group.

Scheme 12

The compounds of Formula (C6d) and (C6g) can be prepared from (C6a) as shown on Scheme 13. Reduction of the carboxylic acid, conversion of the resultant alcohol to the mesylate or bromide and displacement with cyanide affords the nitrile which can be further transformed to tetrazole (C6d) or carboxylic acid (C6g) using standard methods.

Scheme 13

Intermediate (C6a) can be prepared as outlined on Scheme 14, by a similar route to that described in WO2005123686. The substituted benzoin can be treated with thionyl chloride followed by an amine to give the pyrrole precursor which can be converted to the pyrrole diester on treatment with dimethylactetylinedicarboxylate. Selective hydrolysis and amide coupling affords intermediate (C6a)

Scheme 14

The compounds of Formula (C11d) and (C11g) can be prepared from (C11a) as shown on Scheme 15 using the same series of reactions as described in Scheme 1.

Scheme 15

Intermediate (C11a) can be prepared as outlined on Scheme 16, by a similar route to that described in US2006167049. Aryl iodide (C11 h)(which can be prepared as described in Tetrahedron 2001 , 1689) can be coupled with boronic acid under standard Suzuki conditions to give the biaryl phenol (C11j), which can be converted to the corresponding trifllate and undergo a second Suzuki coupling to give (C11a).

Scheme 16

The compounds of Formula (C2d) and (C2g) can be prepared from (C2a) as shown on

Scheme 17 using the same series of reactions as described in Scheme 17.

Scheme 17

Intermediate (C2a) can be prepared as outlined on Scheme 18, by a similar route to that described in WO2003007887. Condensation of benzoin derivative with (C2c) with paraformaldehyded and formamide gives the imidazole (C2e), which can be N-alkylated then C alkylated to give the nitrile acid (C2a)

Scheme 18

The experimental section contains examples of different synthetic routes and the person skilled in the art may apply analogous routes using procedures found in the literature to make compounds represented by Formula (I).

Analysis:

¹H NMR resonances were measured on a Bruker Avance AMX 300 MHz spectrometer and chemical shifts are quoted for selected compounds in parts-per-million (ppm) downfield relative to tetramethylsilane as internal standard.

LCMS analysis was performed on an Agilent 1100 HPLC/MSD system, 254 tfa20p5: Column: Gemini C18, 5μm, 2.0x50mm. Flow: 1.2 ml/min. Gradient: 0-3^1/2 min: 10-95% acetonitrile in water, 3^1/2-4^1/2 min: 95% acetonitrile. Modifier: 0.1% TFA. MS-ionisation mode: API-ES (pos.) Data is quoted for all compounds as retention time (RT) and molecular ion (M+H)⁺ or (M-H)^'.

UPLC/MS was performed on a Waters Acquity- under standardised conditions as follows Column: ACQUITY UPLC BEH C18, 1.7μm, 2.1x50mm. Flow: 0.5 ml/min. Gradient: 0.1-1.0 min: 20-98% acetonitrile in water, 1-1.8 min: 98% acetonitrile. Modifier: 0.1% HCOOH. MS- ionisation mode: API-ES (pos. and neg. ionization)

Preparative HPLC:

This was performed with mass-directed fraction collection under standardised conditions as follows:

Column: YMC 19x100 mm; Flow: 20 mL/min. Gradient: 0-8 min: 10-70% MeCN in water, 8-9 min: 70-95% MeCN in water, 9-12 min: 95% MeCN. Modifier: 0.1% TFA; MS-ionisation mode: API-ES (pos.). Method ( 4_Acid 2min 20to98 50v.olp):

Synthesis of intermediates: Formula ^rA1l

1-(2-chlorophenyl)-2-(4-chlorophenyl)-4-carboxyethyl-5-methyl-pyrrole

A mixture of 4-chlorophenacylbromide (5g), ethylacetoacetate (2.6g) and potassium carbonate (8.8g) in acetonitrile (5OmL) was stirred at room temperature for 48h. Water (10OmL) was added and the mixture extracted with ethyl acetate (10OmL). The combined organics were dried (MgSO4) sulphate and concentrated in vacuo. The residue was dissolved in acetic acid (2OmL) and the mixture heated at reflux for 24h, diluted with water (200ml) and extracted with ethyl acetate (100ml). The organic phase was washed with water then brine, dried (MgSO4) and concentrated in vacuo. The residual oil was co-evaporated with toluene then subjected to column chromatography eluting with 3:1 heptane/ethyl acetate to give 3.48g of the title compound.

1-(2-chlorophenyl)-2-(4-chlorophenyl)-3-cvanomethyl-4-carboxy-5-methyl-pyrrole

A mixture of formaldehyde (37% solution in water) (1mL) and cone, hydrochloric acid (HmL) were added to a solution of [A1] (0.25g) in dichloromethane (1ml). The reaction mixture was stirred rapidly at room temp, for 18h.

The dichloromethane layer was separated off and added to a stirred solution of KCN (0,13g) in ethanol (2ml) and water (1ml). The mixture was stirred for 24h whereupon additional KCN

(0,13g) in water (5ml) was added and the mixture stirred for 48h.

The dichloromethane layer was separated off, dried (MgSO4), concentrated in vacuo and purified by column chromatography eluting with heptane/ethyl acetate to give 172mg of 1-(2- chlorophenyl)-2-(4-chlorophenyl)-3-cyanomethyl-4-carboxyethyl-5-methyl pyrrole

¹H NMR (300MHz., DMSO) : δ 1.39 (3H,t), 2.25 (3H,s), 3.55 81 H,d), 3.75 (1 H,d), 4.36 (2H,q), 7.00 (2h,d), 7.02 (1 H,d), 7.18 (2H,d9, 7.20 (1 H,t), 7.29 (1 H,t), 7.39 (1 H,d). LCMS (tfa20p5.m) : RT = 3.325min (M+H)⁺= 415 (M+H)⁺.

This product was dissolved in a solution of THF (6mL) and ethanol (2mL) and NaOH (25mg in 0.6mL water) was added and the mixture stirred for 24h at room temp. The mixture was diluted with water (30ml), acidified with 2M hydrochloric acid and extracted with ethyl acetate (20ml). Organic extracts were dried (MgSO4) and evapourated. in vacuo to give the title compound (100mg).

LCMS (tfa20p5.m) : RT = 2.714min. (M+H)⁺= 395 Formula TA31

1-(2-chlorophenyl)-2-(4-chlorophenyl)-3-cvanomethyl-5-methyl-pyrrole-4-carboxylic acid-4-bromobenzylamide

To a solution of [A2] (100mg) dichloromethane (5ml_) was added DMF (2 drops) and oxalylchloride (66mg). After 1 h, the solution was evaporated in vacuo and the residue was dissolved in dichloromethane (2ml). 4-bromobenzylamine (72mg in 1mL dichloromethane) was added and after 30min the mixture was concentrated in vacuo to give the crude title compound.

LCMS (tfa20p5.m): RT = 3.312min. (M+H)⁺= 552.4 Formula FA41 2-chloro-N-r4-(chloro)phenvnbenzenecarboximidamide

To sodium hexamethyldisilide (72mL of 1 M in THF) at room temperature under nitrogen was added 4-chloroaniline (1Og) dropwise with stirring. After a further 30 minutes a solution of 1- chloro-2-cyanobenzene in anhydrous THF (20ml) was added slowly. The mixture was stirred at room temp for a further 16h, poured into water (200ml) and extracted with dichloromethane (3 x 100ml). Organic extractes were dried (MgSO4) and evaporated in vacuo to a give the title compound as a solid (19.75g)

LCMS (tfa20p5.m) : RT = 1.26min, (M+H)⁺=267 Formula IΑ51

To a mixture of [A4] (5g) and 3-bromo-2-oxo-butyric acid methyl ester (4.2g) in 2-propanol was added sodium bicarbonate (5g) and the mixture was stirred at reflux for 18h The mixture was acidified by careful addition of 4M hydrochloric acid (ca. 50ml) and heated at reflux for 16h, diluted with water (200ml) and extracted with ethyl acetate (2X 200ml). The organic extracts were evaporated to dryness. The residue was dissolved in THF (100ml) and treated with 1 M sodium hydroxide solution (20ml) and methanol (20ml), stirred for 4h at 50⁰C whereupon LCMS indicated complete hydrolysis to give the acid as a single product. The mixture was diluted with water (200ml) and extracted with ethyl acetate (200ml). Organics were dried (MgSO4), filtered through a silica pad (washing with ethyl acetate + 1% acetic acid) and concentrated in vacuo to give the title compound as a solid (4.32g). 1H NMR (300MHz., CDCI₃) : δ 2.38 (3H,s), 7.04 (2H,d), 7.15-7.29 (H, m), 7.34 (1 H,d). LCMS (tfa20p5.m) : RT = 1.92min, (M+H)⁺=349

Formula TA61

1 -(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-bromomethyl-1 H-imidazole-4-carboxylic acid ethyl ester

To a solution of [A5] (2.45 g) in THF (40 mL) was CDI (1.72 g) added in portions under reflux. The solution was allowed to reflux for 30 minutes before EtOH (15 mL) was added and thereafter was the heating continued over night. The reaction mixture was allowed to cool to r.t. and the precipitate that was formed was filtered off, regaining unreacted [A5] (2g), and the solvent was removed in vacuo. The crude product was purified on a short silica colon, EtOAc/Heptane, 1 :1 , yielding 0.5 g of 2-(2-Chloro-phenyl)-1-(4-chIoro-phenyl)-5-methyl-1 H- imidazole-4-carboxylic acid ethyl ester. UPLCMS: R₄= 1.35 min. (M+H)+ = 375.0. ¹H NMR (CDCI3) δppm: 1.44 (t, 3H); 2.47 (s, 3H); 4.45 (q, 2H); 7.05-7.48 (m, 8H). To a solution of the above formed ester (0.5 g) in CCI₄ (30 mL) under nitrogen was added N- bromosuccinamide (0.26g) and AIBN (10mg). The reaction mixture was heated at reflux for 3h, and a further 100mg of NBS and the 5mg AIBN and heating continued overnight. The reaction mixture was filtered through a pad of celite and washed with CCI₄. The solvent was removed in vacuo to give 0.35 g of 1-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-bromomethyl- 1/-/-imidazole-4-carboxylic acid as foam which was used directly in the next step. 1H NMR (300MHz, CDCI3) δppm: 1.47 (t, 3H); 4.50 (q, 2H); 4.76 (br s, 2H); 7.24-7.44 (m, 8H).

Formula FA71

1 -(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-cvanomethyl-1 H-imidazole-4-carboxylic acid

To a solution of [A6] (0.35 g) in ethanol (40 mL) was added potassium cyanide (0.26 g) dissolved in water (10 mL). The reaction mixture was heated overnight at reflux, diluted with water (30 mL) and extracted with dichloromethane (2 x 40 mL). The combined organic phases were dried over magnesium sulphate, filtered, and the solvent removed in vacuo. The crude product was purified by flash chromatography, (eluent: dichloromethane/MeOH/AcOH, 90:10:1) yielding 80 mg of the title compound. 1H NMR (300MHz, CDCI3) δppm: 4.49 (br s, 2H); 7.16-7.57 (m, 8H). Formula TA81

2-(4-Chloro-phenyl)-3-(2-chloro-phenyl)-6-methyl-1 /Y-pyridine-4-carboxylic acid ethyl ester

Acetic anhydride (14ml) was added to a stirred solution of 2-chlorobenzyl-4-chlorophenyl ketone (4.37g) and N.N.N'N'-tetramethyldiaminomethane (2.02ml) in toluene (20ml) at room temp. Ethanol (20ml) was added and the mixture stirred at room temp for a further 16 hours. The mixture was diluted with TBME (4OmI)₁ washed with 4M sodium hydroxide solution (50ml) (heat) then water then brine. The organic phase was dried and evaporated in vacuo to give crude 2-(2-chlorophenyl)-3-(4-chlorophenyl)-prop-1-en-3-one oil 32703401(8.5Og) which was used directlyin the next step. Ethyl 3-aminocrotonate (1.22ml) and p-toluene sulphonic acid (73mg) were added to a solution of the crude starting material in n-butanol and the mixture was heated at reflux (116°C) for 18 hours.

The mixture was evaporated in vacuo, and the resulting oil was dissolved in TBME (50ml) washed with sodium bicarbonate solution then brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography over silica, eluting with 6:1 heptane/ethyl acetate, to give the title compound as an oil (1.8Og) UPLCMS: R_t=1.51min (M+H)⁺=386

Formula FA91

2-(4-Chloro-phenvπ-3-(2-chloro-phenyl)-6-cvanomethyl-1H-pyridine-4-carboxylic acid ethyl ester

A mixture of [A8] (0.84g), N-bromosuccinimide (NBS) (0.54g) and AIBN (50mg) in CCI₄

(5OmL) were heated at reflux for 5h. A further 0.3g of NBS was added and heating was continued overnight. After cooling, non solubles were removed by filtration, the organic phase concentrated in vacuo and the residue purified by flash chromatography (eluant 2:1 hexane/ethyl acetate) to give the title compound (1.09g)

UPLC/MS: R_t= 1.53 min (M+H)⁺=466.0

ΓAIOI

2-(4-Chloro-phenvπ-3-(2-chloro-phenyl)-6-cvanomethyl-1H-pyridine-4-carboxylic acid

A mixture of [A9] (2g) and potassium cyanide (0.54g) in ethanol (5OmL) and water (5mL) were heated to reflux overnight. Upon cooling the mixture was concentrated in vacuo and purified by chromatography (eluant 10:1 dichloromethane: methanol) to give 0.43g of the title compound.

UPLC/MS: R,= 1.24 min (M+H)⁺=383.0

Formula FAHI

2-(4-Chloro-phenyl)-3-(2-chloro-phenyl)-6-cvanomethyl-1H-pyridine-4-carboxylic acid chloride

To a mixture of [A10] in 2OmL DCM under nitrogen at ice bath temperature, was added 5 drops DMF followed by oxalyl chloride (0.23ml_) and the mixture stirred 15min at this temperature and a further 3h at room temperature and concentrated in vacuo to give 0.45g of the crude acid chloride [A11] which was used without further purification.

Formula 1A121

2-(4-Chloro-phenyl)-3-(2-chloro-phenyl)-6-cvanomethyl-pyridine-4-carboxylic acid-f(R)- 1-(2-fluoro-phenyl)-ethvπ-amide

The crude acid chloride [A11]_(55mg) was dissolved in 2ml_ DCM and added to a solution of (R)-1-(2-fluoro-phenyl)-ethylamine (22mg) and DIPEA (0.1ml_) in 2ml_ dichloromethane. The mixture was stirred overnight at room temperature, concentrated in vacuo and purified by flash chromatography (eluant 80DCM:1 MeOH) to give the title compound (24mg). UPLC/MS: R_t= 1.36 min (M+H)⁺=504.1

Intermediates [A13]-[A19] as shown in Table 1were prepared from [A11] using a similar route as described for [A12].

Table 1

Example 1

1 -(2-chlorophenyl)-2-(4-chlorophenvD- 3-(1 H-Tetrazol-5-ylmethvD- -S-methyl-pyrrole^-carboxylic acid-4-bromobenzylamide

A mixture of [A3] (65mg), sodium azide (65mg) and dimethylammonium chloride (130mg) in DMF (1 mL) were heated to 100⁰C under nitrogen for 16h. The mixture was cooled to room temp and water (5ml) was added. The resulting precipitate was filtered and washed with water to give the a crude product. A portion of this crude material was purified by prep HPLC with gradient acetonitrile/0.1% aqueous TFA elution and mass-directed fraction collection to give the title compound (4mg).

¹H NMR (300MHz., DMSO) : δ 2.10 (3H,s), 3.98 (1 H,d), 4.14 (1 H,d), 4.36 (1 H,d), 7.13-7.17 (4H,m), 7.29 (2H,d), 7.36-7.47 (3H,m), 7.46 (2H,d), 7.59 (1 H,dd).

Example 2: M -(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-f 2H-tetrazol-5-ylmethyl)-1 H- imidazol-4-vn-F4-(2-fluoro-phenvH-piperidin-1-vn-methanone

To a solution of [A7] (40 mg) in dichloromethane (1 mL) was added EDAC (31 mg) and HOBt (25 mg) and the reaction mixture was stirred for 45 minutes, whereupon DIPEA (90 μL) and 4-(2-fluoro-phenyl)-piperidine hydrochloride (23 mg) were added. The reaction mixture was stirred overnight, and NH₄CI(aq) (10 mL) and dichloromethane (10 mL) was added. The organic solvent was evaporated yielding 62 mg of {3-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5- [4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-3H-imidazol-4-yl}-acetonitrile that was used without purification. UPLCMS R_t= 1.43min, (M+1)+ = 533.1.

To the above nitrile in toluene (0.5 mL) was added trimethylsilyl azide (18 μL) and di-Λ/- butyltin oxide (29 mg) and the flask flushed with argon, before microwave heating at 160⁰C for 20 minutes. To the reaction mixture was added NaHCO₃ (aq) (10 mL), and the reaction was extracted with dichloromethane. The organic phase was recovered and the solvent removed in vacuo. The crude product was purified on preparative HPLC to give the title product. UPLCMS RT = 1.36min. (M+H)⁺ =576.1.

Examples 3-5 as shown in Table 2 were prepared from [A7] using a similar route as described for Example 2.

Table 2

Example 6

2-(4-Chloro-phenvπ-3-(2-chloro-phenyl)-6-(2H-tetrazol-5-ylmethyl)-pyridine-4- carboxylic acid-r(R)-1 -(2-fluoro-phenyl)-ethvπ-amide

To the nitrile (50mg) trimethylsilylazide (34.3mg) and tetrabuthylammonium fluoride hydrate (58.2mg) were added. The reaction was heated to 85⁰C and stirred over night. The reaction was dissolved in EtOAc/HCI (5%) and the organic phase was separated and washed with HCI (5%). The organic phase was dried with MgSO₄ and evaporated. The crude product was purified on preparative HPLC to give the tetrazole. RT = 1.28min. (M+H)⁺ =547.1

Examples 7-13 as shown in Table 3 were prepared from [A13]-[A17] respectively using a similar route as described for Example 6.

Table 3

Biological data:

Compounds were tested in the functional Cannabinoid Receptor-1 assay described below, and their IC₅₀ values for antagonizing a CB1 receptor agonist were assessed. Compounds [1], [3], [4], [5], [8], [10] and [11] I had IC₅₀ value less than 0.30 μM. Compound [2] had IC₅₀ value between 0.3 μM and 3.0 μM

Biological evaluation

Transfection and Cell Culture - The cDNA encoding the human CB1 (Cannabinoid Receptor-1) receptor (GenBank accession number NM_016083) was cloned from a human adipose tissue cDNA library and cloned into the eukaryotic expression vector pcDNA3.1 (Invitrogen).

Chinese Hamster Ovary cells (CHO-K1) stably expressing recombinant human CB 1 were generated by transfecting the plasmid containing the coding sequence of the human CB1 receptor in CHO-K1 cells, using lipofectamin, according to the manufacturer instructions. Resistant clones were selected in the presence of 600 μg/ml G418 (Life technology). Stably transfected CHO-K1 cells were maintained in Ham^'s F-12 culture medium (Invitrogen), supplemented with 10 % fetal calf serum (Invitrogen), 100 U/ml penicillin, 100 μg/ml streptomycin (Life Technology), and 600 μg/ml G418. Cannabinoid Receptor- 1 Functional assay.

Functional activities of the above examples of compounds of the invention were assessed in vitro by measuring their ability to inhibit CB1 receptor-induced [³⁵S]GTPγS binding to membranes prepared from Chinese Hamster Ovary (CHO-K1) cells expressing the human CB1 receptor (Perkin Elmer Product number ES-110-M400UA, protein accession number X54937).

The [³⁵S]GTPγS SPA (Scintillation Proximity Assay) binding assay was performed by incubating 5μg/well hCB1 -membranes with 1 nM [³⁵S]GTPγS (Perkin Elmer - NEG 030H) in the presence of various concentrations of the test compounds at room temperature for 1 hr in 96-well microtiter plates. 0.4mg/well SPA beads (PVT-WGA; RPNQ0001 Amersham Pharmacia Biotech) were then added and the incubation continued for further 30 min. on an orbital shaker. The assay buffer contained 5OmM HEPES (pH 7.5), 50 mM NaCI, 2.5 mM MgCI₂, 0.1% BSA, 1 μM GDP and 100 μg/ml Saponin. Microtiter plates were centrifuged at 1500 rpm for 5 min. and radioactivity was read immediately using a Topcounter (PerkinElmer Life Sciences). Data were analyzed and EC50 values determined by non-linear regression using the Prism software (GraphPad Software, San Diego).

Claims

Claims:

1. A compound of formula (I), or a salt or N-oxide thereof:

WHEREIN:

A₁ is -COOH or tetrazolyl;

R₂, R₃, R'₂ and R"₃ are independently selected from -R₉, -CN, -F, -Cl, -Br, -OR₉, or -SR₉;

R₉ is hydrogen, Ci-C₃ alkyl, cycloalkyl, or fully or partially fluorinated C₁-C₃ alkyl;

R₁ is (i) a bond, or

(ii) -C(R₁₀)(R₁₁)-^*, -C(R₁₀)(R₁O-O-^*, -C(R₁₀)(R₁₁)CH₂-^*, Or -CH₂C(R₁₀)(R₁₁)-^*, wherein the bond indicated by an asterisk is attached to Ring A ring;

R₁₀ is hydrogen and R₁₁ is hydrogen, (C_rC₃)alkyl or -OH; or R₁₀ and R₁₁ are both (C₁- C₃)alkyl; or R₁₀ and R₁₁ taken together with the carbon atom to which they are attached form a (C₃-C₅)cycloalkyl ring;

Ring A is an aromatic ring selected from those of formulae (C1) to (C10):

wherein the bond marked (1) is attached to the A₁-R₁- radical of formula (I); the bond marked (2) is attached to the Z₁-CK=O)- radical of formula (I); the bond marked (3) is attached to the phenyl ring carrying the substituents R₂ and R₃ of formula (I); and the bond marked (4) is attached to the phenyl ring carrying the R'₂ and R'₃ substituents of formula (I);

Z₁ is a group selected from those of formulae (A) to (P):

wherein

R₄ and R₅ are independently is selected from hydrogen, (CrC^alkyl, -F, -Cl, -Br, -CF₃, -OCF₃, -OCH₃, -CH₃, -CN, and (d-C^alkylsulfonyl;

R₆ is selected from -F, -Cl, -Br, -CF₃, -OCF₃, -OCH₃, -CH₃, -CN, and -OH.

R₇ is hydrogen and R₈ is hydrogen or (C₁-C₃JaIkYl; or R₇ and R₈ are both (d-C₃)alkyl; or R₇ and R₈ taken together with the carbon atom to which they are attached form a (C₃- C₅)cycloalkyl ring;

R₁₂ is selected from hydrogen, -CH₃, -OH, and -CN; and

R₁₃ is selected from hydrogen and -CH₃.

2. A compound as claimed in claim 1 wherein A₁ is tetrazolyl.

3. A compound as claimed in claim 1 or claim 2 wherein Ring A is selected from those of formula (C1), (C5), (C9) and (C10) as defined in claim 1.

4. A compound as claimed in any of claims 1 to 3 wherein R₂, R₃, R'₂ and R'₃ are independently selected from hydrogen, -F, -Cl, and -CN.

5. A compound as claimed in any of claims 1 to 4 wherein the radical -R₁- is -CH₂-, -CH(CH₃)-, -CH(OH)-, or -CH₂O-^* wherein the bond indicated by an asterisk is attached to Ring A.

6. A compound as claimed in any of claims 1 to 5 wherein Z₁ is selected from those of formulae (A), (E), (G), (J), (K) and (O) as defined in claim 1

7. A compound as claimed in any of claims 1 to 5 wherein Z₁ has formula (E) as defined in claim 1.

8. A compound as claimed in claim 7 wherein, in Z₁, R₇ is hydrogen or methyl, R₈ is methyl or ethyl, and R₄ and R₅ are independently selected from hydrogen, -F, -Cl, -Br, -CN, - CF₃, -OCF₃, and -SO₂CH₃.

9. A compound as claimed in claim 7 wherein, in Z₁, R₇ is hydrogen and R₈ is methyl; or R₇ and R₈ are both methyl; or R₇ and R₈ taken together with the carbon atom to which they are attached form a cyclopropyl ring.

10. A compound as claimed in claim 9 wherein R₇ is hydrogen and R₈ is methyl and the stereochemical configuration at the carbon to which R₁₀ and R₁₁ are attached is R.

11. A compound as claimed in claim 1 having formula (II):

wherein R₄ is hydrogen and R₅ is selected from 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 3-F, 3-Cl₁ 3- Br, 3-CF₃, 3-OCF₃, 2-F, 2-CI, 2-Br, 2-CF₃, 2-OCF₃; or R₄ is 2-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6-OCF₃, 5-F, 5-Cl₁ 5-Br₁ 5-CF₃, 5-OCF₃, 4-F, 4-CI, 4-Br₁ 4-CF₃, 4-OCF₃, 3- F₁ 3-Cl₁ 3-Br₁ 3-CF₃, 3-OCF₃; or R₄ is 3-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6- OCF₃, 5-F, 5-CI, 5-Br₁ 5-CF₃, 5-OCF₃, 4-F, 4-CI, 4-Br₁ 4-CF₃. 4-OCF₃, 2-CI, 2-Br₁ 2-CF₃, 2- OCF₃; or R₄ is 4-F and R₅ is selected from 6-F, 6-CI, 6-Br₁ 6-CF₃, 6-OCF₃, 5-F, 5-CI, 5-Br, 5- CF₃, 5-OCF₃, 2-CI, 2-Br, 2-CF₃, 2-OCF₃, 3-CI, 3-Br, 3-CF₃, 3-OCF₃.

12. A compound as claimed in claim 11 wherein Ring A is selected from those of formulae (C1), (C5), (C9) and (C1) as defined in claim 1

13. A compound as claimed in claim 1 having formula (Ilia), (IMb), (MIc) or (IMd):

wherein the R₄ is hydrogen and R₅ is selected from 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 3-F, 3-Cl₁ 3-Br, 3-CF₃, 3-OCF₃, 2-F, 2-CI, 2-Br, 2-CF₃, 2-OCF₃; or R₄ is 2-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6-OCF₃, 5-F, 5-CI, 5-Br, 5-CF₃, 5-OCF₃, 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 3- F, 3-CI, 3-Br, 3-CF₃, 3-OCF₃; or R₄ is 3-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6- OCF₃, 5-F, 5-CI, 5-Br, 5-CF₃, 5-OCF₃, 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 2-CI, 2-Br, 2-CF₃, 2- OCF₃; or R₄ is 4-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6-OCF₃, 5-F, 5-CI, 5-Br, 5- CF₃, 5-OCF₃, 2-CI, 2-Br, 2-CF₃, 2-OCF₃, 3-CI, 3-Br, 3-CF₃, 3-OCF₃.

14. A compound as claimed in claim 1 having formula (IVa), (IVb), (IVc) or (IVd):

wherein R₄ is hydrogen and R₅ is selected from 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 3-F, 3-CI, 3- Br, 3-CF₃, 3-OCF₃, 2-F, 2-CI, 2-Br, 2-CF₃, 2-OCF₃; or R₄ is 2-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6-OCF₃, 5-F, 5-CI, 5-Br, 5-CF₃, 5-OCF₃, 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 3- F₁ 3-CI, 3-Br, 3-CF₃, 3-OCF₃; or R₄ is 3-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6- OCF₃, 5-F, 5-CI, 5-Br, 5-CF₃, 5-OCF₃, 4-F, 4-CI, 4-Br, 4-CF₃, 4-OCF₃, 2-F, 2-CI, 2-Br, 2-CF₃, 2-OCF₃; or R₄ is 4-F and R₅ is selected from 6-F, 6-CI, 6-Br, 6-CF₃, 6-OCF₃, 5-F, 5-CI, 5-Br, 5-CF₃, 5-OCF₃, 2-F, 2-CI, 2-Br, 2-CF₃, 2-OCF₃, 3-F, 3-CI, 3-Br, 3-CF₃, 3-OCF₃.

15. A pharmaceutical composition comprising a compound as claimed in any of the preceding claims, together with one or more pharmaceutically acceptable carriers or excipients.

16. The use of a compound as claimed in any of claims 1 to 14 for the treatment of diseases or conditions which are mediated by CB1 receptor signalling activity.

17. The use as claimed in claim 16 for treatment of obesity, overweight, treatment of diseases and conditions directly or indirectly associated with obesity and overweight.

18. The use as claimed in claim 17 wherein the disease directly or indirectly associated with obesity and overweight is metabolic syndrome, type 2 diabetes, cardiovascular disease, metabolic dysfunction, metabolic disease or disorder, or liver disease.

19. The use as claimed in claim 16 for treatment of an eating disorder, an addictive disorder, a mental disorder, a neurological disorders, sexual dysfunction, reproductive dysfunction, liver disease or fibrosis-related disease.

19. A method for the treatment of diseases or conditions which are mediated by CB1 receptor signalling activity which method comprises administering to a subject suffering such disease or condition an effective amount of a compound as claimed in any of claims 1 to 14.

20. A method as claimed in claim 19 for the treatment of obesity, overweight, treatment of diseases and conditions directly or indirectly associated with obesity and overweight, which method comprises administering to a subject suffering such disease or condition an effective amount of a compound any of claims 1 to 14.

21. A method as claimed in claim 20 wherein the disease directly or indirectly associated with obesity and overweight is metabolic syndrome, type 2 diabetes, cardiovascular disease, metabolic dysfunction, metabolic disease or disorder, or liver disease.

22. A method as claimed in claim 19 for treatment of an eating disorder, an addictive disorder, a mental disorder, a neurological disorders, sexual dysfunction, reproductive dysfunction, liver disease or fibrosis-related disease.