WO2008074982A1

WO2008074982A1 - Pyrazole derivatives as modulators of cannabinoid receptor

Info

Publication number: WO2008074982A1
Application number: PCT/GB2007/004703
Authority: WO
Inventors: Martin Cooper; Jean-Marie Receveur; Thomas Hoegberg; Peter Aadal Nielsen; Jean-Michel Linget; Pia Karina Noeregaard
Original assignee: 7Tm Pharma A/S
Priority date: 2006-12-18
Filing date: 2007-12-10
Publication date: 2008-06-26
Also published as: CA2673358A1; EP2120931A1; GB0625196D0

Abstract

Compounds of formula (I) suppress the normal signalling activity of CB1 receptors, and are useful in the treatment of, for example obesity or overweight formula (I): wherein A1, A2, A5, A6, R1, R2, R3, and X are as defined in the claims.

Description

PYRAZOLE DERIVATIVES AS MODULATORS OF CANNABINOID RECEPTOR

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 11 beta-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; Schiδth, 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.orq.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.

Brief Description of the Invention

The present invention makes available a class of pyrazole compounds which modulate the activity of the cannabinoid receptor CB1. The following publications relate to other pyrazole compounds having CB1 modulatory activity: WO1997021682, WO1997019063, WO2000046209, WO2001058869, WO200129007, WO2003088968, WO2003020217, WO2004052864, , WO2005080343, WO2006067443, WO2006087480, WO 2006133926, EP00576357, EP00658546, US20030199536, US20040119972, US20040192667, US20050261281 , US20050624941 , US2006028084, US20060509367, J. Med. Chem. 1999 42, 769-776, Biochem. Pharmacol, 2000, 60, 1315- 1323, J. Med. Chem. 2003, 46, 642-645, Bioorg & Med. Chem. Lett. 2004, 14, 2393-2395, Current Med. Chem. 2005, 12, 1361-1394.

As described herein, the compounds of the invention are useful for the treatment of obesity and overweight, prevention of weight gain, and in the treatment of diseases and conditions discussed above which benefit from suppression of the normal signalling activity of CB1 receptors. As mentioned, such diseases and conditions include obesity and overweight and those directly or indirectly associated with obesity and overweight (e.g. metabolic syndrome, type 2 diabetes, cardiovascular diseases, metabolic disorders, cancers, liver diseases,and other secondary diseases) as well as some which may be unrelated 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). They are useful for modulating body weight and energy consumption in mammals and for modulating plasma parameters involved in the metabolic syndrome such as low HDL and/or high LDL cholesterol levels and/or small dense LDL particles, high triglyceride levels, low adiponectin levels and high HbAIc [glycosylated haemoglobin] levels and for modulating other characteristics of the metabolic syndrome such as impaired glucose tolerance, insulin resistance, excessive fat tissue in and around the abdomen, non-alcoholic fatty liver disease, steatohepatitis, steatosis, hepatic fibrosis, hepatic cirrhosis, liver tumors, metabolic liver diseases and high blood pressure.

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.

Pending International Patent Application No PCT/EP2005/005726 relates to compounds having CB1 receptor modulatory activity of formula:

wherein

Ai is hydrogen, -COOH, or tetrazolyl, and A₂ is hydrogen, -COOH, tetrazolyl, -CN, -CF₃, -

COR₆, -SO₂R₆, -OR₇, -NR₇R₈, -NHCOR₆, or -NR₇SO₂R₈ provided that one of A₁ and A₂ is either

-COOH or tetrazolyl;

p is O or 1 and A₃ is phenyl or cycloalkyl, either of which is optionally substituted with R₄ and/or R₅;

q is O or 1 ;

R₁ is a bond, or -(CH₂)_aBi(CH₂)_b- wherein a and b are independently O, 1 , 2 or 3 provided that a+b is not greater than 4, and B₁ is -CO-, -0-, -S-, -SO-, -SO₂-, -CH₂-, -CHOH- or -NR₇-.

R₂ is a bond, -(CH₂)_SB₁(CH₂V or -[(CH₂^B₁ (CH₂)_b]_n-A₄-[(CH₂)_cB₂(CH₂)_d]_m- wherein a, b, and B₁ are as defined for R₁; B₂ is as defined for B₁, c and d are independently 0,1 , 2 or 3; with the proviso that a+b+c+d is not greater than 6, n and m are independently O or 1 and A₄ is a monocarbocyclic or monoheterocyclic ring, having 3 to 8 ring atoms, optionally substituted with one or more of -F, -Cl, -Br, -CN, -CF₃, C₁-C₄ alkyl, cycloalkyl, -OR₉, oxo or -NR₇R₈;

R₃ is hydrogen, C₁-C₄ alkyl, cycloalkyl, -CF₃, -OR₉, -NR₇R₈, -(CH₂)_SCOR₆, -(CH₂)_SSO₂R₆, -(CH₂)_SNR₇COR₆, -(CH₂)sNR₇COOR₈, -(CH₂)_SNR₇SO₂R₆, wherein s is 1 , 2, 3 or 4;

R₄ and R₅ independently -R₉, -CN, -F, -Cl, -Br, -OR₉, -NR₇R₈, -NR₇COR₆, -NR₇SO₂R₆, -COR₆, -SR₉, -SOR₉, -SO₂R₆, -(C₁-C₄ alkyl)OR₉, -(C₁-C₄ alkyl)NR₇R₈, -(C₁-C₄ alkyl)NR₇COR₆, -(C₁-C₄ alkyl)NR₇COOR₈, -(C₁-C₄ alkyl)NR₇SO₂R₆, -(C₁-C₄ alkyl)COR₆, -(C₁-C₄ alkyl)SO₂R₆, -NR₇COOR₈, or -[N-(C₁-C₄ alkyl)]-tetrazolyl; R₆ is C₁-C₄ alkyl, cycloalkyl, -CF₃ or -NR₇R₈;

R₇ and Rs are independently hydrogen, CrC₄ alkyl or cycloalkyl; and

R₉ is hydrogen, C₁-C₄ alkyl, cycloalkyl, fully or partially fluorinated C₁-C₄ alkyl.

The compounds with which this invention is concerned differ in structure from those of PCT EP2005/005726 principally in the provision of heterocyclic alternatives to the A₃(CH₂)_P- and/or (R₄)(R₅)Ph(CH₂V radicals.

Detailed Description of the Invention

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

wherein:

A₁ is hydrogen, -COOH, or tetrazolyl, and A₂ is hydrogen, -COOH, tetrazolyl, -CN,

-CF₃, -COR₆, -SO₂R₆, -OR₉, -NR₇R₈, -NR₇COR₆, or -NR₇SO₂R₆ provided that one of A₁ and

A₂ is either -COOH or tetrazolyl;

R₁ is a bond, or a divalent radical selected from -C(R₁₀)(Rii)-^*, -C(R₁₀)(Rn)-O-^*, -C(R₁₀)(R₁₁)CH₂-*, -C(R₁₀)(R_{1 I})CH₂-O-^*, -CH₂C(R₁₀)(R₁₁)-*, -CH₂C(R₁₀)(R₁ ^-O-*, -CH₂-O-C(R₁₀)(Ri₁)-* and -C(R₁₀)(Rii)-O-CH₂-*, wherein the bond indicated by an asterisk is attached to the pyrazole ring;

either

(i) R₂ is a bond, or -C(R_1o)(R₁₁))_aB₁(C(R_1o)(R₁₁))_b- or

-[(C(R₁₀)(R₁₁))_aB₁(C(R₁₀)(R₁₁))_b]_n-A₄-[( C(R₁₀)(R₁₁))_cB₂(C(R₁₀)(R₁₁))_d]_m- wherein a and b are independently O, 1 , 2 or 3 provided that a+b is not greater than 4, B₁ and B₂ are independently -CO-, -0-, -S-, -SO-, -SO₂-, -CH₂-, -CHOH- or -NR₇-; c and d are independently 0,1 , 2 or 3; with the proviso that a+b+c+d is not greater than 6, n and m are independently 0 or 1 and

A₄ is a monocyclic carbocyclic or monocyclic heterocyclic ring, having 3 to 8 ring atoms, optionally substituted with one or more of -F, -Cl, -Br, -CN, -CF₃, C₁-C₄ alkyl, cycloalkyl, -OR₉, oxo or -NR₇R₈; and

R₃ is hydrogen, C₁-C₄ alkyl, cycloalkyl, -CF₃, -OR₉, -NR₇R₈, -(CH₂)_SCOR₆, -(CH₂)_SSO₂R6, - (CH₂)_sNR₇COR₆, -(CH₂)_SNR₇COOR_8, -(CH₂)_sNR₇SO₂R₆, wherein s is 1, 2, 3 or 4; or

(ii) the group -N(R₃)R₂-A₂ has formula (II), (III), (IV) or (V):

(B₃)_X-A₂ -f-N N— (B₄)_y-A₄-(E3₃)_χ-A₂

(H) (III)

+^» A₄-(B_g)_x-A₂ 4-N ]T)-(B₃)X-A₂ (CH₂)_k

(IV) (V) wherein x and y are independently O or 1 ,

j is 1 , 2, 3 or 4, and

k is 1 or 2.

B₃ is -C(Rio)(Rii)-, -0-, or -NR₇-, or in either orientation -0-C(R_1O)(Rn)-, or -CH₂-C(R₁₀)(R₁₁)-; and

B₄ is -C(R₁₀)(R₁₁)-, -CO- or -SO₂-; and Ring A is a fused monocyclic carbocyclic or monocyclic heterocyclic ring, having 3 to 8 ring atoms, optionally substituted with one or more of -F, -Cl, -Br, -CN, -CF₃, CrC₄ alkyl, cycloalkyl, -OR₉, oxo or -NR₇R₈;

X is a bond, -0-, -NR₇-, -S-, -CO-, or -SO₂-;

A₆ is a monocyclic ring selected from the following

A₅ is a monocyclic ring selected from the following

provided that A₅ and A₆ are not both:

R₄ and R₅ independently -R₉, -CN, -F, -Cl, -Br, -OR₉, -NR₇R₈, -NR₇COR₆, -NR₇SO₂R₆, -COR₆, -SR₉, -SOR₉, -SO₂R₆, -(C₁-C₄ alkyl)OR₉, -(C₁-C₄ alkyl)NR₇R₈,

R₆ is C₁-C₄ alkyl, cycloalkyl, -CF₃ or -NR₇R₈;

R₇ and R₈ are independently hydrogen, C₁-C₄ alkyl or cycloalkyl;

Rg is hydrogen, C₁-C₄ alkyl, cycloalkyl, fully or partially fluorinated C₁-C₄ alkyl;

R₁₀ and Rn are independently hydrogen or (C_rC₃)alkyl; or R₁₀ and R₁₁ taken together with the carbon atom to which. they are attached form a (C₃-C₅)cycloalkyl ring; and

Ri₂ is hydrogen or CrC₄ alkyl.

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.

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

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, (C_rC₆)alkyl, (C_rC₆)alkoxy, hydroxy, hydroxy(C_r C₆)alkyl, mercapto, mercapto(CrC₆)alkyl, (C_rC₆)alkylthio, halo (including fluoro, bromo and chloro), fully or partially fluorinated (C_rC₃)alkyl, (C_rC₃)alkoxy or (C_rC₃)alkylthio 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^AC0NR^AR^B wherein R^A and R^B are independently hydrogen or a (C_rC₆)alkyl 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).

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 atrόpisomeres 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 V.J. 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 divalent radical R₁

The radical Ri has been defined above in relation to formula (I). Presently it is preferred that R₁ be -C(R₁₀)(RiiK, -C(R₁₀)(Ri i)-0-*, -C(R₁₀)(R₁-_I)-O-CH₂-*, wherein the bond marked with an asterisk is attached to the pyrazole ring of compounds (I). In the radical R₁, including the preferred R-i radicals mentioned in the preceding sentence, it is currently preferred that R₁₀ is hydrogen while R₁₁ is hydrogen or methyl; or R₁₀ and R₁₁ are both methyl; or Ri₀ and R₁₁ taken together with the carbon atom to which they are attached form a cyclopropyl ring. Specific currently preferred radicals -R₁- are -CH₂-, -CH₂O-*, and -CH₂OCH₂-.

The divalent radical R₂

The radical R₂ has been defined above in relation to formula (I).

In general, when R₂, is -C(R_1o)(R₁₁))_aB₁(C(R_1o)(R₁₁))_b- or -[(C(R₁o)(Rii))aBi(C(R_1o)(Rii))]n-A₄-[( C(R₁₀)(Ri i))cB2(C(R₁₀)(Rii))]m-, Rio may be hydrogen while R-_I1 is hydrogen or methyl; or Ri₀ and Rn may both be methyl; or Ri₀ and R₁₁ taken together with the carbon atom to which they are attached may form a cyciopropyl ring.

Specific types of radical R₂ include the cases where R₂ is a bond, -(CHa)₁-S-,

*-CH₂-Ph-, *-CH(CH₃)-Ph- or *-C(CH₃)₂-Ph- wherein the bond marked with an asterisk is attached to the amide nitrogen and Ph represents a divalent phenylene radical optionally substituted with -F, -Cl, -Br, -CN, -CF₃, C₁-C₄ alkyl, cyciopropyl, -OR₉, oxo or -NR₇R₃ wherein

Rg is hydrogen, C₁-C₄ alkyl or -CF₃, and R₇ and R₈ are independently hydrogen or C₁-C₄ alkyl. In many such cases, Ph represents a 1 ,4-phenylene radical, optionally substituted as aforesaid.

In some embodiments, R₂ is one of the following:

wherein the bond attached to the amide nitrogen is indicated by an asterisk, and the phenyl ring may optionally be substituted by -F, -Cl, -Br, -CN, -CF₃, C₁-C₄ alkyl, cyciopropyl, -OR₉, oxo or -NR₇R₈ wherein Rg is hydrogen, C₁-C₄ alkyl or -CF₃, and R₇ and R₈ are independently hydrogen or C₁-C₄ alkyl.

In the case where R₂ is part of the group -N(R₃)R₂-A₂, specific types of group Include those where -N(R₃)R₂-A₂ has the formula:

and other types include those wherein the group -N(R₃)R₂-A₂ has formula:

wherein the phenyl ring is optionally substituted with -F, -Cl, -Br, -CN, -CF₃, C₁-C₄ alkyl, cycloalkyl, -ORg, oxo or -NR₇R₈. In such cases, B₃ may be, for example, -C(Rio)(Rii)-, ^{or in either} orientation -0-C(R₁₀)(Rn)-, -CH₂-C(R₁₀)(Rn)-, wherein R₁₀ and R₁₁ are independently hydrogen or methyl; or B₃ may be, for example, -NR₇-, wherein R₇ is hydrogen, methyl or cyclopropyl.

When A₄ is present in the radical R₂, A₄ may be, for example, a divalent piperidine, piperazine, piperazine optionally substituted by methyl on one of the ring nitrogens, morpholine, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or 2-oxo- pyrrolidine radical, or a divalent phenylene or monocyclic heteroarylene radical having from 5 or 6 ring atoms, optionally substituted with R₄ and/or R₅ as defined in relation to formula (I). In such cases, B-i and/or B₂ when present may be, for example -CH₂-.

The radicals A₁ and A₂

The radicals A₁ and A₂ have been defined above in relation to formula (I). At present, it is preferred that A₁ is -COOH or tetrazolyl while A₂ is hydrogen, -CN, -CF₃, -COR₆, -SO₂R₆, - OR₉, -NR₇R₈, -NR₇COR₆, ,or -NR₇SO₂R₆.

When A₂ is -SO₂R₆, -OR₉, -NR₇R₈, -NR₇COR₆, or -NR₇SO₂R₆ it is currently preferred that R₆ is selected from methyl or -CF₃; and R₇, R₈ and R₉ are independently selected from hydrogen or methyl.

In some compounds of the invention wherein the group -N(R₃)R₂-A₂ has formula (II), (III), - (IV) or (V), x and y may both be O and A₂ may be hydrogen, methyl, -CN, -OH, or -COOH.

In other compounds of the invention the group -N(R₃)R₂-A₂ is not one of formulae (II), (III), (IV) or (V), and in such cases R₃ may e, for example hydrogen.

Particular types of group -C(=O)NR₃R₂A₂ in compounds of the invention include those of formulae (A)-(R):

(G) (H) (J)

(P) (Q) (R) wherein

R₁₀ and Rn are independently hydrogen or (C_rC₃)alkyl; or Ri₀ and Rn taken together with the carbon atom to which they are attached form a (C₃-C₅)cycloalkyl ring;

R₁₅ is selected from hydrogen, -CH₃, -OH, -CN and -COOH;

R₁₆ is selected from hydrogen, -F, -CF₃, -OCF₃, -Br. -Cl, -OCH₃, -CH₃, -CN and

-COOH; R₁₇ is selected from hydrogen, -F, -CF₃, -OCF₃, -Br. -Cl, -OCH₃, -CH₃, -CN, -OH, and -

COOH;

R-_I8 and R₁₉ are independently selected from hydrogen and (C_rC₆)alkyl or R-iβ and R₁₉ taken together with the nitrogen to which they are attached form a cyclic amino ring of 4 to 7 ring atoms;

R₂₀ is selected from hydrogen, (C_rC₆)alkyl, (C_rC₆)alkylC(=O)-, (C_rC₆)alkylSθ₂-, benzyloxycarbonyl-, and -C(=0)0CH₃;

R₂₁ is selected from hydrogen, -F and -CN;

R₂₂ is selected from -CF₃, -OCF₃, -Br. -Cl, -OCH₃, -CH₃, -CN and -COOH; and

R₂₃ is selected from -CF₃, -OCF₃, -Br. -Cl, -OCH₃, -CH₃, -CN, -OH and -COOH.

Currently preferred are radicals of formulae (C)-(J), for example:

(i) Formula D, wherein Ri₂ is hydrogen and R₁₄ is methyl, trifluoromethyl, trifluoromethoxy, 3-,

4- or 5-fluoro, 3-, 4- or 5-chloro, or 3-, 4- or 5-cyano, or 6-hydroxy;

(ii) Formula E, wherein R₁₂ is hydrogen and R₁₄ is methyl, trifluoromethyl, , 4- or 5-fluoro, , 4- or 5-chloro, or, 4- or 5-cyano, or 2-, 6-hydroxy;

(iii) Formula H;

(iv) Formula L, wherein Ri₈ is hydrogen, 3-, 4- or 5-fluoro, 3-, 4- or 5-cyano, and R₂₀ is methyl, trifluoromethyl, trifluoromethoxy, 3-, 4- or 5-fluoro, 3-, 4- or 5-chloro, or 3-, 4- and 5- cyano, or 6-hydroxy;and

Formula C, wherein R₁₂ is hydroxyl, cyano or -COOH, and Ri₃ is fluoro, methyl, trifluoromethyl, cyano, or methoxy.

The linker X

X has been defined above in relation to formula (I). When X is NR₇, R₇ may be, for example, hydrogen. However, it is currently preferred that X be a bond or -O-..

The groups A₅ and A₆

These groups have been defined in relation to formula (I)

In some cases A₆ is selected from the following:

In other cases A₆ is selected from the following:

In some cases X is a bond or -O- and A₅ is selected from the following:

Substituents R₄ and R₅ may independently be selected from hydrogen, -F, -CN and -Cl.

Specific Examples of 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- Arachidonylethanolarηine (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 activity'). 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.

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 polyvinyl-pyrrolidone; 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 chemistry known to the synthetic organic chemist. Thus, compounds according to formula (I) can be synthesised according to procedures described in the standard literature that are well known to 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.

The compounds of formula (I) may be obtained by introduction of the N(R₃)R₂-A₂ moiety to a corresponding carboxylic acid or a protected form of the depicted carboxylic acid as outlined in the following scheme:

Scheme 1

Thus, the HN(R₃)R₂-A₂* moiety contains a nucleophilic nitrogen centre and the remaining part could include the final substituent, a protected version of the substituent (e.g. an ester) or a group which can be converted to the final substituent using standard procedures known to those skilled in the art (e.g. conversion of nitrile to tetrazole). Thus, compounds of formula (I) may either be obtained directly following the procedure in scheme 1 or after standard conversions such as removal of protecting groups.

The carboxylic acids can be in activated forms (e.g. acid chlorides or active esters) or alternatively the conversion can be made directly from the acid using suitable coupling reagents such as dicyclohexylcarbodiimide (DCC), and promoters such as 1- hydroxybenzotriazole (HOBT).

Compounds of formula (I) can also be obtained by following a related procedure to that described above wherein a carboxylic acid derivative (e.g. nitrile, ester or amide), or other suitable precursor is converted into the group A₁ after the amide formation. For instance as outlined in the following scheme for the conversion of nitrile intermediates of general formula [B] into compounds of formula (1 ):

Formula [B]

Such a procedure may include for instance conversion of the nitrile group to a tetrazole under standard conditions (e.g. by treatment with sodium azide and a weak acid such as dimethylamine hydrochloride in a polar solvent such as DMF) or a carboxylic acid. This latter conversion may either be achieved directly (e.g. by hydrolysis under acidic or basic conditions) or in a two step process involving initial formation of an ester or imidate (e.g. by treatment with an alcohol and anhydrous hydrogen chloride) followed by hydrolysis under standard conditions (e.g. with aqueous sodium hydroxide).

An alternative strategy for the preparation of compounds of formula (1 ) could be by introduction of the A-i moiety via.alkylation of a suitable nucleophilic center. Thus possible procedures could include those outlined in the following scheme:

Scheme 3

Wherein the R₁* moiety contains a nucleophilic oxygen, sulphur, nitrogen, or carbon, X represents an appropriate leaving group (e.g. bromo) and the group A₁ ^* could either represent the final substituent or a precursor to the final substituent such as a nitrile or ester group.

The aromatic represented by A₅ and A₆ present in compounds of formula (1 ) may be introduced at several different stages during the synthetic sequence. For instance in the case where X represents a bond, the Ar₆ moiety may be derived from the corresponding hydrazine compound Ar₆NHNH₂ following known procedures for the formation of pyrazoles. For example by the reaction with acetophenone derivatives A₅C(O)CH₂R** according to the published procedure (J. Med. Chem. 1999, 42, 769-776) and as outlined in scheme 4 to give intermediates of general formula [A]. The FV* moiety represents either the final substituent - RiA₁ or a moiety that can be converted to this by functional group interconversions well known to those skilled in the art.

Formula [A]

Scheme 4

Thus compounds of formula (1 ) may be prepared by hydrolysis of the ester to the acid followed by coupling to form the amide as described by scheme 1. Or alternatively by following a procedure such as those exemplified in schemes 2 and 3, whereby the R₁ ^** is converted to the final substituent R₁A₁ at an appropriate stage in the reaction sequence. For instance when R-i** represents methyl, this may be converted to a bromomethyl moiety by treatment with N-bromosuccinimide and a free-radical initiator (e.g. AIBN). This may be followed by subsequent conversion to a nitrile compound (e.g. by reaction with potassium cyanide) and ester hydrolysis to give intermediates of formula [B] which can be converted to compounds of formula (1) as previously described by scheme 2. Alternatively the bromomethyl compound may be treated with an alternative nucleophilic reagent, for instance reaction with an alcohol to give an ether. Further conversions to give the final substituent - R₁A₁ or a protected form of the final substituent (e.g. an ester) may subsequently be made before or after the ester hydrolysis and amide coupling steps.

Alternatively the substituent -X-A₅ may be introduced by displacement of a suitable leaving group (e.g. chloro) from the pyrazole ring, where appropriate in the presence of a suitable catalyst. For instance as illustrated in scheme 5 below, wherein the Intermediates of formula [C] may be derived by coupling the appropriate amino R₃(R₂A₂)NH and carboxylic acid compounds under standard conditions, for instance by formation of the acid chloride with oxalyl chloride. The carboxylic acid compounds may be obtained by following an analogous procedure to that described in the literature for the synthesis of related compounds (WO2004099157).^1'

Scheme 5

Hence, intermediates of formula [C] may be coupled under basic conditions with nucleophilic heterocyclic compounds [A₅-H (e.g. imidazole) OrA₅-X-H (e.g. phenol)] or with organo metallic compounds, for instance boronic acids [A₅-B(OH)₂], in the presence of a suitable catalyst [e.g. a palladium(O) complex]. Compounds of formula (1) are thus obtained by modification of the aldehyde moiety following a variety of different reaction sequences and functional group interconversions familiar to those skilled in the art. For instance, one such sequence of reactions might include conversion of the aldehyde to an alcohol by reaction with a reducing agent (e.g. sodium borohydride) followed by ether formation and possible further steps. For example, alkylation of the alcohol with ethyl bromoacetate under standard conditions (e.g. potassium hydroxide in dimethylsulphoxide) followed by hydrolysis of the ester (e.g. with aqueous sodium hydroxide solution) to give a compound where -R₁Ai is - CH₂OCH₂CO₂H.

Alternatively, compounds of formula (1) may be obtained from other compounds of formula (1 ), or closely related examples, by functional group interconversion as the final step. For instance, the substituents R₄ and R₅ can be introduced at a final stage in the aromatic rings A₅ or AQ as exemplified in the following scheme:

Scheme 5

For example, this may involve the reaction of a bromo compound with zinc cyanide in the presence of a suitable metal catalyst such as a palladium(O) complex and in a suitable solvent (e.g. 1 ,4-dioxane) to give a compound of formula (1 ) wherein R₄ is cyano and -A₅*-R₄ represents the final substituent A₅.

Such a conversion may also be made on an intermediate that can be converted to the compounds of formula (I) or on a protected version of the intermediates. Analogously, substituents may also be introduced in the R₂ moiety at the final stage of the reaction sequence.

The reactants used in the above schemes may either be described in the literature or obtained by following analogous procedures to those described in the literature, in some cases followed by simple functional group conversions familiar to those skilled in the art.

The experimental section contains examples of the 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 obtained under standardised conditions as follows:

Column; Gemini C18, 5μm, 2.0x50mm. Flow: 1.2 ml/min; Gradient: Acetonitrile in 0.1% aqueous trifluoroacetic acid: 10% - 95% acetonitrile over 3.5 minutes then 95% acetonitrile for 1.0 minute. Instrument: Agilent 1100 HPLC/MSD system, 254 nm UV detection. MS-ionisation mode: API-ES (pos. or neg.). Data is quoted for all compounds as retention time (RT) and molecular ion (M+H)⁺ or (M-H)^".

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.)

Synthesis of intermediates: Formula TAI

Intermediates of formula [A] were prepared following the procedure outlined in scheme 4 above. Partial hydrolysis of the ester moiety was observed during the reaction sequence to give the analogous carboxylic acid as a byproduct,

5-(4-Chloro-phenyl)-1-(3-chloro-pyridin-2-vD-4-methyl-1 H-pyrazole-3-carboxylic acid ethyl ester TA11 and 5-(4-chloro-phenvO-1-(3-chloro-pyridin-2-viy4-methyl-1 H-pyrazole-3- carboxylic acid.

(Z)-4-(4-Chloro-phenyl)-2-hydroxy-3-methyl-4-oxo-but-2-enoic acid ethyl ester lithium salt [Bioorganic & Medicinal Chemistry 2004, 12(2), 393-404] (1.59g, 5.78mmol) was dissolved in acetic acid (10ml) and (2-chloropyridin-2-yl)hydrazine hydrochloride (1.046g, 5.81 mmol) was added. The mixture was stirred at room temp for 3h then poured into water (20ml), stirred for 2h, the resulting solid collected by filtration and partially dried by suction. The solid was dissolved in acetic acid (10ml) and the solution heated to reflux for 18 hours, cooled to room temperature and poured into water (30ml). After stirring for 4h, the resulting precipitate was collected by filtration, washed with water then purified by recrystallisation from 2- propanol/water. The resulting solid was dried in vacuo at 5O⁰C to give the title compound

[A1] (0.625g, 29%).

1 H NMR (CDCI₃): δ 1.44 (3H,t), 2.38 (3H,s), 4.47 (2H,q), 7.16(2H,d), 7.29 (2H,d), 7.35

1 H,dd),.7.77(1 H,d), 8.47 (1 H,d).

LCMS: RT = 2.980min, (M+H)⁺ = 376.

The liquors from the recrystallisation were acidified with 2M hydrochloric acid and a precipitate formed. This was filtered, washed with water and recrystallised from 2- propanol/water (at pH2) to give the title compound 5-(4-chloro-phenyl)-1-(3-chloro-pyridin-2- yl)-4-methyl-1 H-pyrazole-3-carboxylic acid (185mg, 9%).

LCMS: RT = 2.347min, (M+H)⁺ = 348.

¹H NMR (CDCI₃): δ 2.40 (3H,s), 7.17 (2H,d), 7.31 (2H,d), 7.39 (1 H,dd), 7.82 (1 H,d), 8.48

(1H,d).

Formula fBI

5-(4-Chloro-phenylV1 -(3-chloro-pyridin-2-yl)-4-cvanomethyl-1 H-pyrazole-3-carboxylic acid

ΓBΠ:

2,2'-Azobisisobutyronitrile (0.027g, 0.16mmol) was added to a stirred solution of [A1] (0.62g, 1.65mmol) and N-bromosuccinimide (0.323g, 1.81 mmol) in tetrachloromethane (6ml) and the mixture heated to reflux for 18 hours then cooled to room temperature. The mixture was diluted with ethyl acetate (30ml), washed with saturated aqueous sodium metabisulphite solution (30ml) then 1 M aqueous sodium hydroxide solution (30ml) then brine (15ml), dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The residue was dissolved in ethanol (10ml) and a solution of potassium cyanide (3.22g, 4.94mmol) in water (5ml) was added dropwise. The mixture was stirred at 2O⁰C for 2Oh theni M aqueous sodium hydroxide solution (5ml) was added and the mixture stirred at 5O⁰C for 30 minutes. The mixture was diluted with water (25ml), acidified with 2M hydrochloric acid and extracted with ethyl acetate (25ml). Organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica, eluting with ethyl acetate/heptane (1 :1) + 1% acetic acid. Product-containing fractions were evaporated in vacuo and the residue co-evaporated with toluene to give the title compound [B1] (180mg, 29%) as a foam.

LCMS: RT = 2.145min. (M+H)⁺ = 373.

¹H NMR (CDCI₃) : 53.93 (2H,s), 7.19 (2H,d), 7.25-7.33 (1 H,m), 7.38 (2H,d), 7.42 (1 H,dd),

7.84 (1 H,d), 8.48 (1 H,d).

Formula TCI

5-Chloro-1 -(2-fluoro-phenyl)-3-[4-(4-fluoro-phenyl)-4-hvdroxy-piperidine-1 -carbonyll-1 H- pyrazole-4-carbaldehvde fC11

1-(2-Fluoro-phenyl)-5-hvdroxy-1H-pyrazole-3-carboxylic acid ethyl ester

(2-Fluoro-phenyl)-hydrazine hydrochloride (12.2Og, 75mmol) followed by potassium carbonate (20.74g, 150mmol) were added to a solution of diethylacetylene dicarboxylate (12.01ml, 75mmol) in ethanol (200ml) and the resulting suspension stirred at reflux for 5 hours. The mixture was cooled to room temperature, diluted with water (400ml) and acidified by dropwise addition of 2M hydrochloric acid. After stirring for 2 hours, the resulting solid was collected by filtration, washed with water (3x50ml) and dried in vacuo to give the sub-title compound (11.4g, 41 mmol, 55%).

LCMS: RT = 1.752min. (M+H)⁺ = 251. 5-Chloro-1-(2-fluoro-phenvπ-4-formyl-1 H-pyrazole-3-carboxylic acid ethyl ester

N,N-Dimethylformamide (4.6OmI₁ 59.5mmol) was added dropwise to a stirred solution of 1-(2- fluoro-phenyl)-5-hydroxy-1 H-pyrazole-3-carboxylic acid ethyl ester (12.4Og, 49.6mmol) in phosphorous oxychloride (55.4ml, 595mmol) at 2O⁰C under nitrogen. The mixture was heated to reflux for 4 hours then cooled to room temperature and added dropwise to an ice/water mixture (11). The mixture was stirred for 2 hours whereupon all the ice had melted and the resulting suspended solid filtered, washed with water and partially dried in vacuo to give the sub-title compound (15.01g).

LCMS: RT = 2.430min. (M+H)⁺ = 297.

5-Chloro-1 -(2-fluoro-phenyl)-4-formyl-1 H-pyrazole-3-carboxylic acid

2M Aqueous sodium hydroxide solution (50.6ml, 101.2mmol) was added to a solution of the solid from the previous step (15.Og) in tetrahydrofuran (250ml) and methanol (30ml) was added to give a homogenous solution. After 2 hours at room temperature, water (250ml) was added and the mixture extracted with ethyl acetate (250ml). The organic extracts were extracted with 1M sodium hydroxide solution (100ml). Combined aqueous extracts were acidified by addition of 4M hydrochloric acid and extracted with ethyl acetate (2x250ml). Organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo to give the sub-title compound (10.15g, 37.78mmol, 75% over 2 steps) as a solid.

LCMS: RT = 1.730min. (M+H)⁺ = 269. 1H NMR (DMSO-D₆): δ 7.49 (1 H,t), 7.61 (1 H₁T), 7.71-7.79 (2H,m), 10.36 (1 H,s).

5-Chloro-1 -(2-fluoro-phenyl)-3-r4-(4-fluoro-phenyl)-4-hvdroxy-piperidine-1 -carbonyiyi H- pyrazole-4-carbaldehvde [C11

Oxalyl chloride (1.95ml, 22.3mmol) was added to a stirred solution of 5-chloro-1-(2-fluoro- phenyl)-4-formyl-1 H-pyrazole-3-carboxylic acid (3.0Og, 11.17mmol) in dichloromethane (30ml) containing N,N-dimethyl formamide (0.03ml). After 1 h, the mixture was evaporated to dryness in vacuo and the residue redissolved in dichloromethane (25ml).

A portion of the resulting acid chloride solution (5ml, 20%) was added to a stirred solution of 4-(4-fluorophenyl)-4-hydroxy-piperidine (0.48g, 2.46mmol) and triethylamine (0.93ml, 6.7mmol) in tetrahydrofuran (5ml) at room temperature. After 1 hour, the mixture was diluted with ethyl acetate (50ml) washed with 1 M hydrochloric acid (25ml), water (25ml), 1 M sodium hydroxide solution (25ml) then brine. Organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo to give the title compound [C1] (0.75g, 75%) as a solid.

¹H NMR (CDCI₃): δ 1.72-1.78 (1 H,m), 1.86-1.92 (1 H,m), 2.09 (1 H.td), 2.23 (1 H.td), 3.38 (1 H,td), 3.67 (1 H,td), 3.90 (1 H,d,br), 4.76 (1 H,d,br), 7.06 (2H,t), 7.35 (2H,dd), 7.44-7.63 (4H₁ITi)₁ 10.09 (1 H,s). LCMS: RT = 2.36min, (M+H)⁺ = 446.

5-Chloro-1-(2-fluoro-phenyl)-4-formyl-1 H-pyrazole-3-carboxylic acid cvclohexylamide FC21

Prepared from 5-chloro-1-(2-fluoro-phenyl)-4-formyl-1 H-pyrazole-3-carboxylic acid and cyclohexylamine following an analogous procedure to that described for [C1].

¹H NMR (CDCI₃): δ 1.18-1.35 (4H,m), 1.62-1.82 (4H,m), 1.97-2.19 (2H,m), 4.01-4.15 (1 H,m), 7.32 (1 H,dd), 7.38 (1 H,d), 7.51 ( 1h,td), 2.56-2.64 (1h,m), 7.68 (1H,d,br), 10.49 (1H,s). LCMS: RT = 2.794min, (M+H)⁺ = 350.

Compounds of general formula FH

Synthesis: Compound [1.11

Oxalyl chloride (0.082ml, 0.94mmol) was added to a stirred solution of [B1] (176mg, 0.47mmol) and N,N-dimethylformamide (0.02ml) in dichloromethane (5ml) at room temperature, under nitrogen. After 2 hours, the mixture was evaporated in vacuo. The resulting acid chloride was redissolved in dichloromethane (10ml) and half of this solution was added to a suspension of 3-aminopyridine (27mg, 0.28mmol.) and triethylamine (0.099ml, 0.71 mmol) in tetrahydrofuran (5ml). The mixture was stirred at room temperature for 16 hours then filtered through an SCX-2 cartridge (2g), washing with ethyl acetate/ethanol (9.1 , 10ml). The filtrate was evaporated in vacuo to give 5-(4-chloro-phenyl)-1-(3-chloro- pyridin-2-yl)-4-cyanomethyl-1 H-pyrazole-3-carboxylic acid pyridin-3-ylamide_(64mg, 0.14mmol, 60%) as a solid.

LCMS: RT = 1.704min. (M+H)⁺ = 449.

Acetyl chloride (0.02ml, 0.28mmol) was added to a solution of the product from the previous step (64mg, 0.14mmol) in ethanol (4ml) and the mixture stirred at room temperature for 10 minutes then at 7O⁰C for 16 hours. Then solution was evaporated in vacuo and the residue redissolved in tetrahydrofuran (4ml). 1 M Aqueous sodium hydroxide solution (0.57ml, 0.57mmol) was added followed by methanol (1 ml) and the resulting solution heated at 5O⁰C for 4 hours. The mixture was diluted with water (15ml), acidified to pH 4-5 by addition of 2M hydrochloric acid and extracted with ethyl acetate (15ml) The organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The residue was subjected to column chromatography over silica, eluting with ethyl acetate + 1% acetic acid and the resulting product crystallised from ethyl acetate/heptane to give the title compound [1.1] (23mg, 35%). An analytically pure sample was obtained by preparative HPLC under standard conditions.

Compound H .21

A mixture of [C2] (100mg, 0.29mmol), [1 ,3-bis(2,6.diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(ll) dichloride (PEPPSI) (5mg, 0.01 mmol), 2- dimethylaminopyrimidine-5-boronic acid pinacol ester (78mg, 0.31 mmol) and potassium carbonate (119mg, O.δδmmol) in 1 ,4-dioxane (5ml) under argon, was heated at 6O⁰C for 16 hours. The mixture was evaporated and the residue subjected to column chromatography over silica, eluting with an ethyl acetate/heptane gradient to give 5-(2-dimethylamino- pyrimidin-5-yl)-1-(2-fluoro-phenyl)-4-formyl-1 H-pyrazole-3-carboxylic acid cyclohexylamide

(100mg, 0.23mmol, 80%).

LCMS: RT = 2.779min. (M+H)⁺ = 437.

Sodium borohydride (17mg, 0.46mmol) was added to a stirred solution of the product from the previous step (100mg, 0.23mmol) in acetonitrile (5ml). After 3 hours, water (15ml) was added, the mixture acidified by addition of 5% hydrochloric acid and extracted with dichloromethane (3x 10ml). Combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo.

The residue was dissolved in dimethylsulphoxide (1 ml) and ethyl bromoacetate (46mg,

0.27mmol) followed by potassium hydroxide (51 mg, 0.92mmol) were added The mixture was stirred at room temperature for 16 hours, diluted with water (20ml), acidified with 5% hydrochloric acid and extracted with dichloromethane (3x 10ml). Combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The crude residue was purified by preparative HPLC under standard conditions to give the title compound [1.2] (4.0mg, O.OOδmmol, 3.5%) as a solid.

Compounds of general formula [21

Synthesis

Oxalyl chloride (0.93ml, 1.06mmol) was added to stirred solution of 5-(4-chloro-phenyl)-1-(3- chloro-pyridin-2-yl)-4-methyl-1 H-pyrazole-3-carboxylic acid (byproduct from formation of [A1]) (185mg, 0.53mmol) and N.N-dimethylformamide (0.01ml) in dichloromethane (5ml), under nitrogen. After 1h, the solution was evaporated in vacuo. The residue was dissolved in dichloromethane (10ml) and half of the resulting solution was added to each mixture of either ethyl 4-aminophenylacetate (0.52g, 0.29mmol) or methyl aminobutyrate hydrochloride (34mg, 0.29mmol) and triethylamine (0.122ml, O.δδmmol) in tetrahydrofuran (5ml). The mixtures were stirred for 30 minutes then filtered through SCX-2 cartridges (2g), washing through with ethyl acetate. The resulting solutions were evaporated to dryness. The residues were dissolved in tetrahydrofuran (5ml) and 1 M aqueous sodium hydroxide solution (1.06ml, 1.06mmol) was added followed by sufficient methanol to give homogeneous solutions. After 16 hours at 20⁰C, the mixtures were each diluted with ethyl acetate (25ml) and washed 1 M hydrochloric acid (10ml) then with brine, dried over anhydrous magnesium sulphate, filtered and evaporated. The residues were recrystallised from ethyl acetate/heptane to give the title compounds [1.1] (50mg, 0.104mmol, 39%) and [2.2] (56mg, 0.129mmol, 49%).

Compounds of general formula f31

5-(4-Chloro-phenvn-1-(3-chloro-pyhdin-2-vn-4-(2H-tetrazol-5-ylmethyl)-1H-pyrazole-3- carboxylic acid 4-trifluoromethyl-benzylamide [3.11

Synthesis:

5-(4-Chloro-phenyl)-1-(3-chloro-pyridin-2-yl)-4-cyanomethyl-1 H-pyrazole-3-carboxylic acid 4- trifluoromethyl-benzylamide was prepared from the acid chloride solution from the synthesis of [1.1] and (4-trifluoromethyl)benzylamine, following the procedure described for the synthesis of [1.1]: HPLC; RT = 3.052 min. (M+H)⁺ = 530.

Sodium azide (82mg, 1.27mmol) and dimethylamine hydrochloride (155mg, 1.90mmol) were added to a solution of the product from the previous step (84mg, 0.16mmol) in N₁N- dimethylformamide (1ml) and the mixture heated to 100⁰C for 16 hours then cooled to room temperature. Water (5ml) was added, the mixture stirred for 2 hours and the resulting solid was collected by filtration, washed with water and dried in vacuo at 50⁰C. The solid was subjected to column chromatography over silica, eluting with an ethyl acetate/heptane gradient containing 1% acetic acid. The crude product was coevaporated with toluene to remove residual acetic acid then recrystallised from ethyl acetate/heptane to give the title compound [3.1] (12mg, 0.021 mmol, 13%).

¹H NMR (DMSO-D₆): 4.29 (2H,s), 4.47 (2H,d), 7.31 (2H,d), 7.42-7.49 (4H,m), 7.62-7.67 (3H,m), 8.19 (1 H,d), 8.57 (1 H,d), 9.32 (1 H,t,br). LCMS: RT = 2.917 min. (M+H)⁺ = 573.

Compounds of General Formula T41

Prepared from [B1] in a similar manner to that described for compound [3.1]

Compounds of General Formula [51

Prepared from [B1} in a similar manner to that described for compound [1.1]

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. Compound [3.1], [4.5], [5.1], [5.2] had IC₅₀ value lower than 0.3 μM. Compounds [2.1], [2.2], [4.1], [4.2], [4.3], [4.4], [4.6], [4.7], [4.8] had IC₅₀ values between 0.3 μM and 3 μM Compounds [1.1], [1.2] and [1.3] had IC₅₀ values between 3 μM and 10 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 CB1 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/mi 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 CP55940-induced [³⁵S]GTPγS binding to membranes prepared from CHO-K1 cells expressing the human CB 1 receptor (described in Transfection and Cell Culture). CP55940 is a well known non-selective CB1 and CB2 receptor agonist (e.g Felder et al., 1995, Molecular Pharmacology, (48) 443-50). Membranes were prepared by a standard procedure. Briefly, cells were harvested using 10 mM EDTA and collected by centrifugation. Pelleted cells were homogenized in ice-cold 20 mM Hepes (pH 7.4), 10 mM EDTA and protease inhibitors (Complete protease inhibitor cocktail tablet, Roche) using an Ultra Turrax Homogenizer. The homogenate was centrifuged at 14 000 rpm for 45 min. at 4⁰C. The resultant pellet was resuspended in the same buffer but with only 0.1 mM EDTA and was again centrifuged at 14 000 rpm for 45 min. at 4⁰C. The resulting pellet (membranes) was resuspended in 20 mM Hepes (pH 7.4), 0.1 mM EDTA, 2 mM MgCI₂ and protease inhibitors and protein concentration was determined by Micro BCA Protein Assay Reagent Kit (Pierce Biotechnology) according to the manufacturer instructions. 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 3 nM of CP55940 and 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 IC50 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, hydrate, solvate, single enantiomer or N-oxide thereof:

wherein:

Ai is hydrogen, -COOH, or tetrazolyl, and A₂ is hydrogen, -COOH, tetrazolyl, -CN,

A₂ is either -COOH or tetrazolyl;

R₁ is a bond, or a divalent radical selected from -C(R₁₀)(R₁₁)-^*, -C(R₁₀)(R₁-_I)-O-^*, -C(R₁₀)(R₁₁)CH₂-*, -C(R₁₀)(R₁₁)CH₂-O-*. -CH₂C(R₁₀)(R₁₁)-*, -CH₂C(R₁₀)(R₁0-O-^*. -CH₂-O-C(R₁₀)(R₁₁)-* and -C(R_1o)(R₁₁)-0-CH₂-*, wherein the bond indicated by an asterisk is attached to the pyrazole ring;

either

(i) R₂ is a bond, or -C(R_1o)(R₁₁))_aB₁(C(R_1o)(R₁₁))_b- or -[(C(R_1o)(R₁₁))_aB₁(C(R_1o)(R₁₁))_b]_n-A₄-[( C(R_1o)(R₁₁))_cB₂(C(R₁oXR₁₁))_d]_m- wherein a and b are independently O, 1 , 2 or 3 provided that a+b is not greater than 4,

B₁ and B₂ are independently -CO-, -0-, -S-, -SO-, -SO₂-, -CH₂-, -CHOH- or -NR₇-; c and d are independently 0,1 , 2 or 3; with the proviso that a+b+c+d is not greater than 6, n and m are independently O or 1 and

R₃ is hydrogen, C₁-C₄ alkyl, cycloalkyl, -CF₃, -OR₉, -NR₇R₈, -(CH₂)_SCOR₆, -(CH₂)_SSO₂R₆, - (CH₂)_SNR₇COR₆, -(CH₂)_SNR₇COOR₈, -(CH₂)_SNR₇SO₂R₆, wherein s is 1 , 2, 3 or 4; or (ii) the group -N(R₃)R₂-A₂ has formula (II), (III), (IV) or (V):

(II) (III)

(IV) (V) wherein x and y are independently 0 or 1 ,

j is 1 , 2, 3 or 4, and

k is 1 or 2.

B₃ is -C(R₁₀)(Rn)-, -O-, or -NR₇-, or in either orientation -O-C(R₁₀)(Rii)-, or -CH₂-C(R₁₀)(R₁₁)-; and

B₄ is -C(R₁₀)(R_t1)-, -CO- Or -SO₂-; and

Ring A is a fused monocyclic carbocyclic or monocyclic heterocyclic ring, having 3 to 8 ring atoms, optionally substituted with one or more of -F, -Cl, -Br, -CN, -CF₃, C₁-C₄ alkyl, cycloalkyl, -OR₉, oxo or -NR₇R₈;

X is a bond, -0-, -NR₇-, -S-, -CO-, Or -SO₂-; A₆ is a monocyclic ring selected from the following :

A₅ is a monocyclic ring selected from the following

provided that A₅ and A₆ are not both:

R₆ is C₁-C₄ alkyl, cycloalkyl, -CF₃ or -NR₇R₈;

R₇ and Rs are independently hydrogen, C₁-C₄ alkyl or cycloalkyL

Rg is hydrogen, C₁-C₄ alkyl, cycloalkyl, fully or partially fluorinated C-i -C₄ alkyl;

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

R₁₂ is hydrogen or C₁-C₄ alkyl.

2. A compound as claimed in claim 1 wherein the radical R₁ is -C(R₁₀)(Ri₁)-*, -C(R₁₀)(Rii)-O-* Or -C(R-_Io)(Ri-_I)-O-CH₂-* wherein Ri₀ is hydrogen and Ri₁ is hydrogen or methyl; or R_1O and Rn are both methyl; or Ri₀ and Rn taken together with the carbon atom to which they are attached form a cyclopropyl ring.

3. A compound as claimed in claim 1 wherein the radical -Rr is -CH₂-, -CH₂O-^*, - CH₂OCH₂-.

4. A compound as claimed in any of the preceding claims wherein A₁ is -COOH or tetrazolyl.

5. A compound as claimed in any of claims 1 to 4 wherein R₂ is a bond, -(CH₂)_1-5-, *-CH₂-Ph-, *-CH(CH₃)-Ph- or *-C(CH₃)₂-Ph- wherein the bond marked with an asterisk is attached to the amide nitrogen and Ph represents a divalent phenylene radical optionally substituted with -F, -Cl, -Br, -CN, -CF₃, C₁-C₄ alkyl, cyclopropyl, -OR₉, oxo or - NR₇R₈ wherein R₉ is hydrogen, C₁-C₄ alkyl or -CF₃, and R₇ and R₈ are independently hydrogen or C₁-C₄ alkyl.

6. A compound as claimed in claim 5 wherein Ph represents a 1 ,4-phenylene radical, optionally substituted as specified in claim 5.

7. A compound as claimed in any of the preceding claims wherein R₃ is hydrogen.

8. A compound as claimed in any of claims 1 to 4, wherein the group -N(R₃)R₂-A₂ has formula:

9. A compound as claimed in claim 8 wherein one of x and y is 0 and the other is 0 or 1.

10. A compound as claimed in claim 9 wherein x is 0, y is 0 or 1 and A₂ is -OH.

11. A compound as claimed in any of claims 1 to 4, wherein the group -N(R₃)R₂-A₂ has formula:

wherein the phenyl ring is optionally substituted with -F, -Cl, -Br, -CN, -CF₃, C₁-C₄ alkyl, cycloalkyl, -OR₉, oxo Or -NR₇R₈

12. A compound as claimed in any of claims 1 to 4, 8 or 11 wherein B₃ is present and is -C(Rio)(Rii)-, or in either orientation -0-C(R₁₀)(Rn)- or -CH₂-C(Ri₀)(R₁₁)- wherein R₁₀ and Ri₁ are independently hydrogen or methyl; or B₃ is -NR₇- wherein R₇ is hydrogen, methyl or cyclopropyl.

13. A compound as claimed in any of claims 1 to 4, 8 and 12 wherein, when B₄ is present and is -C(R₁₀)(R₁₁)- wherein R₁₀ and Ri₁ are independently hydrogen or methyl.

14. A compound as claimed in any of the preceding claims wherein A₄ is present in the radical R₂, and A₄ is a divalent piperidine, piperazine, piperazine optionally substituted by methyl on one of the ring nitrogens, morpholine, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or 2-oxo-pyrrolidine radical, or a divalent phenylene or monocyclic heteroarylene radical having from 5 or 6 ring atoms, optionally substituted with R₄ and/or R₅ as defined in claim 1, and B₁ and/or B₂ when present is/are -CH₂-.

15. A compound as claimed in any of the preceding claims wherein when A₂ is -SO₂R₆, -OR₉, -NR₇R₈, -NR₇COR₆, or -NR₇SO₂R₆, then R₆ is selected from methyl or -CF₃; and R₇, R₈ and Rg are independently selected from hydrogen or methyl.

16. A compound as claimed in any of claims 1 to 4 wherein -N(R₃)R₂-A₂ is selected from the group consisting of radicals of formulae (C)-(J):

wherein

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

R₁₃ is selected from hydrogen, -F, -CF₃, -OCF₃, -Br. -Cl, -OCH₃, -CH₃, -CN and

-COOH;

R₁₄ is selected from hydrogen, -F, -CF₃, -OCF₃, -Br. -Cl, -OCH₃, -CH₃, -CN, -OH, and -

COOH;

Ri₅ and R-_I6 are independently selected from hydrogen and (CrC₆)alkyl or R₁₅ and R₁₆ taken together with the nitrogen to which they are attached form a cyclic amino ring of 4 to 7 ring atoms;

R₁₇ is selected from hydrogen, (C_rC₆)alkyl, (C_rC₆)alkylC(=O)-, (CrC₆)alkylSO₂-, benzyloxycarbonyl-, and -C(=0)0CH₃.

17. A compound as claimed in claim 16 wherein -N(R₃)R₂-A₂ is selected from the group consisting of:

(i) Formula D, wherein R₁₂ is hydrogen and R₁₄ is methyl, trifluoromethyl, trifluoromethoxy, 3- , 4- or 5-fluoro, 3-, 4- or 5-chloro, or 3-, 4- or 5-cyano, or 6-hydroxy; (ii) Formula E, wherein Ri₂ is hydrogen and Ri₄ is methyl, trifluoromethyl, , 4- or 5-fluoro, , 4- or 5-chloro, or, 4- or 5-cyano, or 2-, 6-hydroxy;

(iii) Formula H;

(iv) Formula L, wherein Ri₈ is hydrogen, 3-, 4- or 5-fluoro, 3-, 4- or 5-cyano, and R₂₀ is methyl, trifluoromethyl, trifluoromethoxy, 3-, 4- or 5-fluoro, 3-, 4- or 5-chloro, or 3-, 4- and 5- cyano, or 6-hydroxy;

18. A compound as claimed in claim 16 wherein -N(R₃)R₂-A₂ is of Formula C, wherein Ri₂ is hydroxyl, cyano or -COOH, and R_i3 is fluoro, methyl, trifluoromethyl, cyano, or methoxy.

19. A compound as claimed in any of the preceding claims wherein A₆ is selected from the following:

20. A compound as claimed in any of claims 1 to 18 wherein A₆ is selected from the following:

21. A compound as claimed in any of the preceding claims wherein X is a bond or -O- and A₅ is selected from the following:

22. A compound as claimed in any of the preceding claims wherein R₄ and R₅ are independently selected from hydrogen, -F, -CN and -Cl.

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

24. The use of a compound as claimed in any of claims 1 to 22 for the treatment of diseases or conditions which are mediated by CB1 receptor signalling activity.

25. The use as claimed in claim 24 for treatment of obesity, overweight, treatment of diseases and conditions directly or indirectly associated with obesity and overweight.

26. The use as claimed in claim 25 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.

27. The use as claimed in claim 24 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.

28. 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 22.

29. A method as claimed in claim 28 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 as claimed in any of claims 1 to 22.

30. A method as claimed in claim 29 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.

31. A method as claimed in claim 28 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.