EP2120931A1 - Dérivés de pyrazole utilisés en tant que modulateurs du récepteur cannabinoïde - Google Patents

Dérivés de pyrazole utilisés en tant que modulateurs du récepteur cannabinoïde

Info

Publication number
EP2120931A1
EP2120931A1 EP07848451A EP07848451A EP2120931A1 EP 2120931 A1 EP2120931 A1 EP 2120931A1 EP 07848451 A EP07848451 A EP 07848451A EP 07848451 A EP07848451 A EP 07848451A EP 2120931 A1 EP2120931 A1 EP 2120931A1
Authority
EP
European Patent Office
Prior art keywords
compound
hydrogen
alkyl
formula
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07848451A
Other languages
German (de)
English (en)
Inventor
Martin Cooper
Jean-Marie Receveur
Thomas Hoegberg
Peter Aadal Nielsen
Jean-Michel Linget
Pia Karina Noeregaard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
7TM Pharma AS
Original Assignee
7TM Pharma AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 7TM Pharma AS filed Critical 7TM Pharma AS
Publication of EP2120931A1 publication Critical patent/EP2120931A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 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.
  • 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).
  • metabolic syndrome X 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).
  • apolipoprotein B concentrations 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.
  • LDL small dense low-density lipoprotein
  • a primary aim of treatment for obesity, and obesity-related disorders is weight loss.
  • treatments are based on diet and lifestyle changes augmented by therapy with pharmacological therapies.
  • pharmacological therapies 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.
  • 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.
  • anti-obesity agents 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 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
  • 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.
  • 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 e.g., lipogenesis or stimulation of adipocyte apoptosis.
  • drugs for reviews, see Gadde and Allison, 2006, Circulation, 114, 974-984; Weigle, 2003, J Clin Endocrinol Meta
  • 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 ®
  • Rimonabant 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).
  • CB1 cannabinoid receptor 1
  • CB2 a peripheral receptor found principally in cells related to the immune system.
  • 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.
  • liver block of de novo lipogenesis
  • muscles increase in glucose uptake
  • adipose tissue stimulation of expression and/or secretion of adiponectin, inhibition of lipogenic enzymes, stimulation of GLUT4, generation of futile cycles
  • pancreas insulin regulation
  • 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.
  • syndrome X insulin resistance syndrome
  • 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,
  • aneurysms e.g. aneurysms, angina, arrhythmia, atherosclerosis, cardiomyopathy, cerebrovascular accident (stroke), cerebrovascular disease, congenital heart disease, congestive heart failure, myocarditis, valve disease
  • 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
  • non-alcoholic fatty liver disease steatohepatitis, steatosis, hepatic fibrosis, hepatic cirrhosis
  • 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
  • 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) ,
  • 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
  • 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 pulmonary embolism, coronary heart disease [CHD], neurological (stroke, idiopathic intracranial hypertension, meralgia parethetica), ii) respiratory (dys
  • CB1 modulator 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • Ai is hydrogen, -COOH, or tetrazolyl
  • a 2 is hydrogen, -COOH, tetrazolyl, -CN, -CF 3 , -
  • p is O or 1 and A 3 is phenyl or cycloalkyl, either of which is optionally substituted with R 4 and/or R 5 ;
  • q O or 1 ;
  • R 1 is a bond, or -(CH 2 ) a Bi(CH 2 ) b - wherein a and b are independently O, 1 , 2 or 3 provided that a+b is not greater than 4, and B 1 is -CO-, -0-, -S-, -SO-, -SO 2 -, -CH 2 -, -CHOH- or -NR 7 -.
  • R 2 is a bond, -(CH 2 ) S B 1 (CH 2 V or -[(CH 2 ⁇ B 1 (CH 2 ) b ] n -A 4 -[(CH 2 ) c B 2 (CH 2 ) d ] m - wherein a, b, and B 1 are as defined for R 1 ; B 2 is as defined for B 1 , 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 A 4 is a monocarbocyclic or monoheterocyclic ring, having 3 to 8 ring atoms, optionally substituted with one or more of -F, -Cl, -Br, -CN, -CF 3 , C 1 -C 4 alkyl, cycloalkyl, -OR 9 , oxo or -NR 7 R 8 ;
  • R 3 is hydrogen, C 1 -C 4 alkyl, cycloalkyl, -CF 3 , -OR 9 , -NR 7 R 8 , -(CH 2 ) S COR 6 , -(CH 2 ) S SO 2 R 6 , -(CH 2 ) S NR 7 COR 6 , -(CH 2 )sNR 7 COOR 8 , -(CH 2 ) S NR 7 SO 2 R 6 , wherein s is 1 , 2, 3 or 4;
  • R 4 and R 5 independently -R 9 , -CN, -F, -Cl, -Br, -OR 9 , -NR 7 R 8 , -NR 7 COR 6 , -NR 7 SO 2 R 6 , -COR 6 , -SR 9 , -SOR 9 , -SO 2 R 6 , -(C 1 -C 4 alkyl)OR 9 , -(C 1 -C 4 alkyl)NR 7 R 8 , -(C 1 -C 4 alkyl)NR 7 COR 6 , -(C 1 -C 4 alkyl)NR 7 COOR 8 , -(C 1 -C 4 alkyl)NR 7 SO 2 R 6 , -(C 1 -C 4 alkyl)COR 6 , -(C 1 -C 4 alkyl)SO 2 R 6 , -NR 7 COOR 8 , or -[N-(C 1 -C 4 alkyl)]-t
  • R 7 and Rs are independently hydrogen, CrC 4 alkyl or cycloalkyl
  • R 9 is hydrogen, C 1 -C 4 alkyl, cycloalkyl, fully or partially fluorinated C 1 -C 4 alkyl.
  • a 1 is hydrogen, -COOH, or tetrazolyl
  • a 2 is hydrogen, -COOH, tetrazolyl, -CN
  • a 2 is either -COOH or tetrazolyl
  • R 1 is a bond, or a divalent radical selected from -C(R 10 )(Rii)- * , -C(R 10 )(Rn)-O- * , -C(R 10 )(R 11 )CH 2 -*, -C(R 10 )(R 1 I )CH 2 -O- * , -CH 2 C(R 10 )(R 11 )-*, -CH 2 C(R 10 )(R 1 ⁇ -O-*, -CH 2 -O-C(R 10 )(Ri 1 )-* and -C(R 10 )(Rii)-O-CH 2 -*, wherein the bond indicated by an asterisk is attached to the pyrazole ring;
  • R 2 is a bond, or -C(R 1o )(R 11 )) a B 1 (C(R 1o )(R 11 )) b - or
  • a and b are independently O, 1 , 2 or 3 provided that a+b is not greater than 4, B 1 and B 2 are independently -CO-, -0-, -S-, -SO-, -SO 2 -, -CH 2 -, -CHOH- or -NR 7 -; 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
  • a 4 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, -CF 3 , C 1 -C 4 alkyl, cycloalkyl, -OR 9 , oxo or -NR 7 R 8 ; and
  • R 3 is hydrogen, C 1 -C 4 alkyl, cycloalkyl, -CF 3 , -OR 9 , -NR 7 R 8 , -(CH 2 ) S COR 6 , -(CH 2 ) S SO 2 R6, - (CH 2 ) s NR 7 COR 6 , -(CH 2 ) S NR 7 COOR 8, -(CH 2 ) s NR 7 SO 2 R 6 , wherein s is 1, 2, 3 or 4; or
  • j is 1 , 2, 3 or 4, and
  • k 1 or 2.
  • B 3 is -C(Rio)(Rii)-, -0-, or -NR 7 -, or in either orientation -0-C(R 1O )(Rn)-, or -CH 2 -C(R 10 )(R 11 )-;
  • 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, -CF 3 , CrC 4 alkyl, cycloalkyl, -OR 9 , oxo or -NR 7 R 8 ;
  • X is a bond, -0-, -NR 7 -, -S-, -CO-, or -SO 2 -;
  • a 6 is a monocyclic ring selected from the following
  • a 5 is a monocyclic ring selected from the following
  • a 5 and A 6 are not both:
  • R 4 and R 5 independently -R 9 , -CN, -F, -Cl, -Br, -OR 9 , -NR 7 R 8 , -NR 7 COR 6 , -NR 7 SO 2 R 6 , -COR 6 , -SR 9 , -SOR 9 , -SO 2 R 6 , -(C 1 -C 4 alkyl)OR 9 , -(C 1 -C 4 alkyl)NR 7 R 8 ,
  • R 6 is C 1 -C 4 alkyl, cycloalkyl, -CF 3 or -NR 7 R 8 ;
  • R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl or cycloalkyl
  • Rg is hydrogen, C 1 -C 4 alkyl, cycloalkyl, fully or partially fluorinated C 1 -C 4 alkyl;
  • R 10 and Rn are independently hydrogen or (C r C 3 )alkyl; or R 10 and R 11 taken together with the carbon atom to which. they are attached form a (C 3 -C 5 )cycloalkyl ring; and
  • Ri 2 is hydrogen or CrC 4 alkyl.
  • Another aspect of the invention is a pharmaceutical composition
  • 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.
  • a method for the treatment of diseases or conditions which are mediated by CB1 receptor signalling activity 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.
  • a compound of formula (I) or a salt, hydrate, solvate or N- oxide thereof 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.
  • (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.
  • a 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • substituted as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, (C r C 6 )alkyl, (C r C 6 )alkoxy, hydroxy, hydroxy(C r C 6 )alkyl, mercapto, mercapto(CrC 6 )alkyl, (C r C 6 )alkylthio, halo (including fluoro, bromo and chloro), fully or partially fluorinated (C r C 3 )alkyl, (C r C 3 )alkoxy or (C r C 3 )alkylthio such as trifluoromethyl, trifluoromethoxy, and trifluoromethylthio, nitro, nitrile (-CN), oxo, phenyl, phenoxy, monocyclic heteroaryl or heteroaryloxy with 5 or 6 ring atoms
  • 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.
  • 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.
  • 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 pipe
  • hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
  • 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.
  • '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.
  • solvent molecules for example, ethanol.
  • '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 atr ⁇ pisomeres 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.
  • 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. ⁇ stergaard, 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).
  • 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 (-CH 3 -> -CH 2 OH):
  • R 1 has been defined above in relation to formula (I).
  • R 1 be -C(R 10 )(RiiK, -C(R 10 )(Ri i)-0-*, -C(R 10 )(R 1 - I )-O-CH 2 -*, wherein the bond marked with an asterisk is attached to the pyrazole ring of compounds (I).
  • R 10 is hydrogen while R 11 is hydrogen or methyl; or R 10 and R 11 are both methyl; or Ri 0 and R 11 taken together with the carbon atom to which they are attached form a cyclopropyl ring.
  • Specific currently preferred radicals -R 1 - are -CH 2 -, -CH 2 O-*, and -CH 2 OCH 2 -.
  • the radical R 2 has been defined above in relation to formula (I).
  • R 2 when R 2 , is -C(R 1o )(R 11 )) a B 1 (C(R 1o )(R 11 )) b - or -[(C(R 1 o)(Rii))aBi(C(R 1o )(Rii))]n-A 4 -[( C(R 10 )(Ri i))cB2(C(R 10 )(Rii))]m-, Rio may be hydrogen while R- I1 is hydrogen or methyl; or Ri 0 and Rn may both be methyl; or Ri 0 and R 11 taken together with the carbon atom to which they are attached may form a cyciopropyl ring.
  • radical R 2 include the cases where R 2 is a bond, -(CHa) 1 -S-,
  • Ph represents a divalent phenylene radical optionally substituted with -F, -Cl, -Br, -CN, -CF 3 , C 1 -C 4 alkyl, cyciopropyl, -OR 9 , oxo or -NR 7 R 3 wherein
  • Rg is hydrogen, C 1 -C 4 alkyl or -CF 3
  • R 7 and R 8 are independently hydrogen or C 1 -C 4 alkyl.
  • Ph represents a 1 ,4-phenylene radical, optionally substituted as aforesaid.
  • 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, -CF 3 , C 1 -C 4 alkyl, cyciopropyl, -OR 9 , oxo or -NR 7 R 8 wherein Rg is hydrogen, C 1 -C 4 alkyl or -CF 3 , and R 7 and R 8 are independently hydrogen or C 1 -C 4 alkyl.
  • R 2 is part of the group -N(R 3 )R 2 -A 2
  • specific types of group include those where -N(R 3 )R 2 -A 2 has the formula:
  • B 3 may be, for example, -C(Rio)(Rii)-, or in either orientation -0-C(R 10 )(Rn)-, -CH 2 -C(R 10 )(Rn)-, wherein R 10 and R 11 are independently hydrogen or methyl; or B 3 may be, for example, -NR 7 -, wherein R 7 is hydrogen, methyl or cyclopropyl.
  • a 4 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 R 4 and/or R 5 as defined in relation to formula (I).
  • B-i and/or B 2 when present may be, for example -CH 2 -.
  • a 1 and A 2 have been defined above in relation to formula (I). At present, it is preferred that A 1 is -COOH or tetrazolyl while A 2 is hydrogen, -CN, -CF 3 , -COR 6 , -SO 2 R 6 , - OR 9 , -NR 7 R 8 , -NR 7 COR 6 , ,or -NR 7 SO 2 R 6 .
  • R 6 is selected from methyl or -CF 3 ; and R 7 , R 8 and R 9 are independently selected from hydrogen or methyl.
  • x and y may both be O and A 2 may be hydrogen, methyl, -CN, -OH, or -COOH.
  • R 10 and Rn are independently hydrogen or (C r C 3 )alkyl; or Ri 0 and Rn taken together with the carbon atom to which they are attached form a (C 3 -C 5 )cycloalkyl ring;
  • R 15 is selected from hydrogen, -CH 3 , -OH, -CN and -COOH;
  • R 16 is selected from hydrogen, -F, -CF 3 , -OCF 3 , -Br. -Cl, -OCH 3 , -CH 3 , -CN and
  • R 17 is selected from hydrogen, -F, -CF 3 , -OCF 3 , -Br. -Cl, -OCH 3 , -CH 3 , -CN, -OH, and -
  • R 21 is selected from hydrogen, -F and -CN;
  • R 22 is selected from -CF 3 , -OCF 3 , -Br. -Cl, -OCH 3 , -CH 3 , -CN and -COOH;
  • R 23 is selected from -CF 3 , -OCF 3 , -Br. -Cl, -OCH 3 , -CH 3 , -CN, -OH and -COOH.
  • R 12 is hydroxyl, cyano or -COOH
  • Ri 3 is fluoro, methyl, trifluoromethyl, cyano, or methoxy.
  • X has been defined above in relation to formula (I).
  • R 7 may be, for example, hydrogen. However, it is currently preferred that X be a bond or -O-..
  • a 6 is selected from the following:
  • a 6 is selected from the following:
  • X is a bond or -O- and A 5 is selected from the following:
  • Substituents R 4 and R 5 may independently be selected from hydrogen, -F, -CN and -Cl.
  • 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.
  • 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- Arachidonylethanolar ⁇ ine (anandamide). This term is well known in the art.
  • 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”.
  • 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.
  • 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.
  • 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).
  • 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
  • diseases and conditions not necessarily related to obesity e.g. eating disorders, addictive disorders, mental disorders, neurological disorders, sexual dysfunctions
  • 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 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, herni
  • the compounds of the invention may be combined with proper reduction in dietary calorie intake and physical exercise.
  • 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.
  • 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.
  • 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.
  • 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
  • almond oil fractionated coconut oil
  • oily esters such as glycerine, prop
  • the active ingredient may also be administered parenterally in a sterile medium.
  • the drug can either be suspended or dissolved in the vehicle.
  • adjuvants such* as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the compounds of formula (I) may be obtained by introduction of the N(R 3 )R 2 -A 2 moiety to a corresponding carboxylic acid or a protected form of the depicted carboxylic acid as outlined in the following scheme:
  • the HN(R 3 )R 2 -A 2 * 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).
  • 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).
  • suitable coupling reagents such as dicyclohexylcarbodiimide (DCC), and promoters such as 1- hydroxybenzotriazole (HOBT).
  • 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).
  • R 1 * moiety contains a nucleophilic oxygen, sulphur, nitrogen, or carbon
  • X represents an appropriate leaving group (e.g. bromo) and the group A 1 * could either represent the final substituent or a precursor to the final substituent such as a nitrile or ester group.
  • the aromatic represented by A 5 and A 6 present in compounds of formula (1 ) may be introduced at several different stages during the synthetic sequence.
  • the Ar 6 moiety may be derived from the corresponding hydrazine compound Ar 6 NHNH 2 following known procedures for the formation of pyrazoles. For example by the reaction with acetophenone derivatives A 5 C(O)CH 2 R** 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 - RiA 1 or a moiety that can be converted to this by functional group interconversions well known to those skilled in the art.
  • 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 R 1 ** is converted to the final substituent R 1 A 1 at an appropriate stage in the reaction sequence.
  • 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).
  • a nitrile compound e.g. by reaction with potassium cyanide
  • ester hydrolysis to give intermediates of formula [B] which can be converted to compounds of formula (1) as previously described by scheme 2.
  • 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 - R 1 A 1 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.
  • an alternative nucleophilic reagent for instance reaction with an alcohol to give an ether.
  • Further conversions to give the final substituent - R 1 A 1 or a protected form of the final substituent e.g. an ester
  • the substituent -X-A 5 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.
  • a suitable leaving group e.g. chloro
  • the Intermediates of formula [C] may be derived by coupling the appropriate amino R 3 (R 2 A 2 )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'
  • intermediates of formula [C] may be coupled under basic conditions with nucleophilic heterocyclic compounds [A 5 -H (e.g. imidazole) OrA 5 -X-H (e.g. phenol)] or with organo metallic compounds, for instance boronic acids [A 5 -B(OH) 2 ], in the presence of a suitable catalyst [e.g. a palladium(O) complex].
  • nucleophilic heterocyclic compounds e.g. imidazole
  • a 5 -X-H e.g. phenol
  • organo metallic compounds for instance boronic acids [A 5 -B(OH) 2 ]
  • 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
  • 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.
  • the substituents R 4 and R 5 can be introduced at a final stage in the aromatic rings A 5 or AQ as exemplified in the following scheme:
  • 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 R 4 is cyano and -A 5 *-R 4 represents the final substituent A 5 .
  • a suitable metal catalyst such as a palladium(O) complex
  • a suitable solvent e.g. 1 ,4-dioxane
  • 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.
  • substituents may also be introduced in the R 2 moiety at the final stage of the reaction sequence.
  • 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.
  • N,N-Dimethylformamide (4.6OmI 1 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 2O 0 C 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).
  • 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).
  • 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).
  • 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 7O 0 C 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 5O 0 C for 4 hours.
  • 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.
  • Compounds were tested in the functional Cannabinoid Receptor-1 assay described below, and their IC 50 values for antagonizing a CB1 receptor agonist were assessed.
  • Compound [3.1], [4.5], [5.1], [5.2] had IC 50 value lower than 0.3 ⁇ M.
  • Compounds [2.1], [2.2], [4.1], [4.2], [4.3], [4.4], [4.6], [4.7], [4.8] had IC 50 values between 0.3 ⁇ M and 3 ⁇ M
  • Compounds [1.1], [1.2] and [1.3] had IC 50 values between 3 ⁇ M and 10 ⁇ M
  • the cDNA encoding the human CB1 (Cannabinoid Receptor-1) receptor 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 ⁇ g/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 ⁇ g/ml streptomycin (Life Technology), and 600 ⁇ g/ml G418.
  • CP55940-induced [ 35 S]GTP ⁇ S 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 4 0 C. 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 4 0 C.
  • the resulting pellet (membranes) was resuspended in 20 mM Hepes (pH 7.4), 0.1 mM EDTA, 2 mM MgCI 2 and protease inhibitors and protein concentration was determined by Micro BCA Protein Assay Reagent Kit (Pierce Biotechnology) according to the manufacturer instructions.
  • the [ 35 S]GTP ⁇ S SPA (Scintillation Proximity Assay) binding assay was performed by incubating 5 ⁇ g/well hCB1 -membranes with 1 nM [ 35 S]GTP ⁇ S (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 MgCI 2 , 0.1% BSA, 1 ⁇ M GDP and 100 ⁇ g/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).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Child & Adolescent Psychology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I) supprimant l'activité de signalisation normale des récepteurs CB1, et utile dans le traitement, par exemple, de l'obésité ou du surpoids: A1, A2, A5, A6, R1, R2, R3, et X étant tels que définis dans les revendications.
EP07848451A 2006-12-18 2007-12-10 Dérivés de pyrazole utilisés en tant que modulateurs du récepteur cannabinoïde Withdrawn EP2120931A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0625196.1A GB0625196D0 (en) 2006-12-18 2006-12-18 Modulators of cannabinoid receptor
PCT/GB2007/004703 WO2008074982A1 (fr) 2006-12-18 2007-12-10 Dérivés de pyrazole utilisés en tant que modulateurs du récepteur cannabinoïde

Publications (1)

Publication Number Publication Date
EP2120931A1 true EP2120931A1 (fr) 2009-11-25

Family

ID=37712324

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07848451A Withdrawn EP2120931A1 (fr) 2006-12-18 2007-12-10 Dérivés de pyrazole utilisés en tant que modulateurs du récepteur cannabinoïde

Country Status (4)

Country Link
EP (1) EP2120931A1 (fr)
CA (1) CA2673358A1 (fr)
GB (1) GB0625196D0 (fr)
WO (1) WO2008074982A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011512359A (ja) 2008-02-14 2011-04-21 アミラ ファーマシューティカルズ，インク． プロスタグランジンｄ２受容体のアンタゴニストとしての環式ジアリールエーテル化合物
US8426449B2 (en) 2008-04-02 2013-04-23 Panmira Pharmaceuticals, Llc Aminoalkylphenyl antagonists of prostaglandin D2 receptors
US8383654B2 (en) 2008-11-17 2013-02-26 Panmira Pharmaceuticals, Llc Heterocyclic antagonists of prostaglandin D2 receptors
WO2011073098A1 (fr) 2009-12-15 2011-06-23 Bayer Cropscience Ag Acides 1-(hétéroaryl)-pyrazol-4-yl-acétiques, procédés de production et utilisation desdits acides comme herbicides et régulateurs de la croissance des plantes
PL2576541T3 (pl) 2010-06-04 2016-10-31 Pochodne aminopirymidyny jako modulatory lrrk2
LT3124483T (lt) 2010-11-10 2019-09-25 Genentech, Inc. Pirazolo aminopirimidino dariniai, kaip lrrk2 moduliatoriai
MX361458B (es) 2011-08-23 2018-12-06 Asana Biosciences Llc Compuestos de pirimido-piridazinona y uso de los mismos.
EP2632919B1 (fr) 2011-09-30 2018-11-07 National Health Research Institutes Composés de pyrazole
DE102011055815A1 (de) 2011-11-29 2013-05-29 Aicuris Gmbh & Co. Kg Carboxamid-substituierte Heteroaryl-Pyrazole und ihre Verwendung
DE102012016908A1 (de) 2012-08-17 2014-02-20 Aicuris Gmbh & Co. Kg Tris-(Hetero)Aryl-Pyrazole und ihre Verwendung
HRP20220522T1 (hr) 2014-08-04 2022-06-10 Nuevolution A/S Proizvoljno kondenzirani heterociklil-supstituirani derivati pirimidina koji su korisni za liječenje upalnih, metaboličkih, onkoloških i autoimunih bolesti
MX2022007265A (es) 2019-12-20 2022-09-09 Nuevolution As Compuestos activos frente a receptores nucleares.
MX2022012260A (es) 2020-03-31 2022-11-30 Nuevolution As Compuestos activos frente a receptores nucleares.
US11613532B2 (en) 2020-03-31 2023-03-28 Nuevolution A/S Compounds active towards nuclear receptors

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2515119A1 (fr) * 2003-02-07 2004-08-19 Daiichi Pharmaceutical Co., Ltd. Derive de pyrazole
JP4041153B2 (ja) * 2003-05-07 2008-01-30 ファイザー・プロダクツ・インク カンナビノイド受容体リガンドとその使用
ITMI20041032A1 (it) * 2004-05-24 2004-08-24 Neuroscienze S C A R L Compositi farmaceutici
US20070117858A1 (en) * 2005-11-23 2007-05-24 Mingde Xia Substituted 5-heteroaryl-1-phenyl-pyrazole cannabinoid modulators

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008074982A1 *

Also Published As

Publication number Publication date
WO2008074982A1 (fr) 2008-06-26
GB0625196D0 (en) 2007-01-24
CA2673358A1 (fr) 2008-06-26

Similar Documents

Publication Publication Date Title
WO2008074982A1 (fr) Dérivés de pyrazole utilisés en tant que modulateurs du récepteur cannabinoïde
AU2007336068B2 (en) Modulators of CB1 receptors
US8173680B2 (en) Cannabinoid receptor modulators
CA2693457C (fr) Inhibiteurs de 11b-hydroxysteroide deshydrogenase
AU2008300649B2 (en) Prodrugs to thyroid hormone analogs
US20060019997A1 (en) Triazole compounds and their use as metabotropic glutamate receptor antagonists
US20080200527A1 (en) Cannabinoid Receptor Modulators
WO2008059207A1 (fr) Modulateurs d'un récepteur de cannabinoïde
WO2009153569A2 (fr) Modulateurs de récepteur cb1
CN101558058A (zh) Cb1受体调节剂

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

17P Request for examination filed

Effective date: 20090624

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

18W Application withdrawn

Effective date: 20091102