WO2008092681A1 - Ghrelin receptor modulators - Google Patents

Abstract

Compounds of Formula (IA) or (IB) modulate ghrelin receptor activity, and are useful in the treatment of, for example, obesity and eating disorders: wherein W is, in either orientation, -C(=O)N(R3)-, or -C(=O)O-; R is hydrogen or C1-C4 alkyl; R1 is selected from hydrogen, (C1-C4)alkyl, cycloalkyl, fully or partially fluorinated (C1-C4)alkyl, or -OR10; and R2 is selected from (i) hydrogen and (ii) (C1-C4)alkyl, cycloalkyl, cycloalkenyl, and non aromatic heterocyclyl, each optionally substituted by -F, -CN, C1-C4 alkyl, cyclopropyl, -NR7COR0, -NR7SO2R0, -COR0, -COOH, -SOR9, -SO2R0, -OR10, -NR7R8, or -NR7COOR8; and (iii) aryl, aryl-(C1-C2)alkyl-, heteroaryl and heteroaryl-(C1-C2 alkyl)- each optionally substituted in the ring part or R1 and R2, together with the nitrogen to which they are attached, form an optionally substituted cyclic amino group; R3 is selected from hydrogen, (C1-C4)alkyl, cycloalkyl, fully or partially fluorinated (C1-C4)aIkyl, or -OR10; and R4 is selected from (iv) hydrogen and (v) (C1-C4)alkyl, cycloalkyl, and non aromatic heterocyclyl, each optionally substituted by -F, -CN, -NR7COR0, -NR7SO2R0, -COR0, - COOH, -SOR9, -SO2R0, -OR10, -NR7R8, or -NR7COOR8; and (vi) aryl, aryl-(C1-C2)alkyl-, heteroaryl and heteroaryl-(C1-C2 alkyl)- each optionally substituted in the ring part thereof; or R3 and R4, together with the nitrogen to which they are attached, form an optionally substituted cyclic amino group; L is a linker radical of formula -(CR11R13)aB(CR12R14)b- as defined in the specification; R0, R7, R8, R9 and R10 are as defined in the specification.

Description

GHRELIN RECEPTOR MODULATORS

The present invention relates to use of a class of substituted 4-oxo-10-oxa-3-aza- tricyclo[5.2.1.0*1 ,5*]-decane and -dec-8-ene compounds which modify the normal signalling activity of the ghrelin receptor. The invention further relates to their use in, and methods for the treatment of, conditions alleviated by increased or decreased ghrelin receptor activity by administration of such compounds. The invention also relates to pharmaceutical compositions containing such compounds, and to novel members of the compound class.

Background to the invention

The prevalence of obesity in North America and in most European countries have more than doubled in the last 20 years and over half 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, strokes, 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).

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 and reduce risk factors for diabetes, cancer and cardiovascular disease such as high fasting and postprandial blood glucose, HbAIc (glycosylated haemoglobin), insulin, total plasma cholesterol, low density lipoproteins (LDL), triglycerides, uric acid and blood pressure (Goldstein, 1992, J. Obesity, 6, 397-415).

Thus, the primary aim of treatment for obesity is weight loss. Initially, treatments have been proposed which were 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 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 bromocriptine (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 receptor activity, amylin (pramlinitide), neuropeptide Y agonists) ; iv) agents that may increase resting metabolic rate (beta-3 agonists, UCP homologues, thyroid receptor agonists) ; and v) other more diverse agents, such as for example including (MCH) melanin concentrating hormone antagonists, phytostanol analogues, functional oils, P57, amylase inhibitors, growth hormone fragments, synthetic analogues of DHEAS (fluasterone), antagonists of adipocyte 11beta-hydroxysteroid dehydrogenase type 1 activity, CRH agonists, carboxypeptidase inhibitors, inhibitors of fatty acid synthesis (cerulenin and C75), indanones/indanols, aminosterols (trodusquemine), other gastrointestinal lipase inhibitors (ATL962 ).

Drugs effective in obesity treatment may act by different mechanisms such as reduction in food intake (e.g. by inducing satiety), drugs altering metabolism (such as agents modifying the absorption of nutrients e.g. inhibition of fat absorption), drugs that increase energy expenditure (e.g. increase of thermogenesis), drugs that inhibit lipogenesis or that stimulate 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 that reduces fat absorption in the gut. Rimonabant is a cannabinoid CB1 modulator 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 ).

Conversely, aging is associated with a progressive decrease in appetite and food intake. Although the reasons for the decline in food intake are multifactorial, it has been considered a physiological phenomenon of aging. Decline in food intake often occurs in healthy elderly persons predisposing them to pathological weight loss and protein-energy malnutrition, thereby increasing the risk of morbidity or mortality. In general, GH secretion declines markedly with age so that GH production after middle age is less than 15% of that during puberty. This GH deficiency is paralleled by an age-related decline in muscle mass. Adult GH deficiency can, therefore, be ameliorated through positive modulators of the ghrelin receptor.

The release of growth hormone (GH) from the pituitary gland is controlled via two separate receptor systems triggered by somatostatin and GHRH (growth hormone-releasing hormone). Growth hormone release is also influenced by separate growth hormone secretagogue (GHS) pathway. The hormone ghrelin (a Ser-acylated 28-amino acid peptide hormone) is the endogenous ligand to the growth hormone secretagogue (GHS) receptor 1a (GHS-RIa). Only acylated ghrelin is capable of binding GHS-RIa. The non-acylated form of ghrelin, des-acyl ghrelin, circulates at much higher levels in the blood and is shown to be the major form isolated from stomach. Ghrelin is a potent stimulator of growth hormone secretion and stimulates a positive energy balance after systemic administration. Total ghrelin levels are greatest in the fasting state, and those levels are reduced by an oral glucose load. Ghrelin initiates feeding in rodents and increases consummation of a buffet meal in human volunteers supporting a role of overexpression and secretion of ghrelin in the etiology of obesity (Heiman and Witcher, 2006, Metabolic Syndrome and Related Disorders, 4 (1 ), 37-42).

The hormone ghrelin induces both animals and humans to consume large quantities of food. This and the fact that ghrelin levels in the blood rises before mealtime have led to the belief that ghrelin may be part of the hunger signal that triggers eating and appetite. Ghrelin is predominantly produced and released from endocrine cells of the stomach in the pre- meal situation, and functions as an important orexigenic signal. Recently ghrelin-containing cells have been identified in the brain structure hypothalamus, close to areas known to be involved with feeding and metabolism. It has been found that ghrelin not only promotes the release of neuropeptides that trigger eating but also inhibits the release of neuropeptides that suppress eating. Based on the high constitutive signaling activity of the ghrelin receptor and the identification of ghrelin-containing neurons located in an area that receives input from brain regions that mediate circadian rhythms, it has been suggested that the ghrelin circuit may serve as the interface between the brain's circadian clock and regions that regulate appetite and energy expenditure, where it could counterbalance a large number of inhibitory hormones and neurotransmitters, such as leptin, insulin, and PYY3-36 (Neuron 37:649-661 , 2003). The role of ghrelin in triggering hunger and appetite has made the ghrelin receptor a highly interesting target in the search for antagonist or inverse agonists for treatment of obesity, obesity-related diseases and the metabolic syndrome.

Inhibition of ghrelin secretion appears to be an outcome of ingestion and nutrient absorption rather than the presence of nutrients in stomach. Inhibition of ghrelin secretion occurs only when ingested nutrients reach the jejunum. Circulating total ghrelin levels increase before meals and are suppressed immediately following each meal. A rare polymorphism in preproghrelin gene (Leu72Met) is linked to obesity and type 2 diabetes. Another rare human polymorphism, Arg51Gln is correlated with reduced plasma ghrelin levels and also is postulated to be a risk factor for type 2 diabetes. Total ghrelin levels are elevated in Prader- Willi syndrome suggesting that ghrelin hypersecretion contributes to this obese phenotype (Heiman and Witcher, 2006, Metabolic Syndrome and Related Disorders, 4 (1 ), 37-42). Exogenous administration of octanoylated ghrelin stimulates eating and that appears to be mediated by the GHS-RIa. There is also ample evidence indicating that des-acyl ghrelin participates in regulating energy balance and glucose homeostasis, in a manner that opposes actions of its parent acylated counterpart. It is conceivable that physiological (or pathological) states where a greater ratio of ghrelin to des-acyl ghrelin is observed could be associated with obesity and complications of hyperphagia such as enhanced carbohydrate utilization.

The ghrelin receptor has been invoked in many disease states that either are associated with an increased ghrelin receptor activity or a reduced ghrelin receptor activity (Kojima and Kangawa, 2005, Physiol Rev. 85(2): 495-522). Positive modulators of the ghrelin receptor activity such as ghrelin receptor agonists, partial agonists or allosteric modulators/enhancers are considered useful for treatment of diseases associated with reduced receptor activity or diseases treated with growth hormone or with ghrelin hormone such as eating disorders like cachexia (e.g. associated with COPD, CHF, cancer, AIDS, diabetic gastroparesis, IBS, chronic arthritis), anorexia, bulimia, wasting conditions (e.g. associated with AIDS, surgical stress, cachexia of critical illness, sepsis, glucocorticoid administration and cancer), gastrointestinal disorders (e.g. gastic ileus, gastric ulcer, chronic intestinal pseudo-obstruction, functional gastrointestinal disorders and inflammatory bowel diseases), reduced gastrointestinal motility (e.g. opioid induced constipation, diabetes related gastroparesis, treating gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS)), growth hormone (GH) deficiency, pathological weight loss, protein-energy malnutrition, age related osteoporosis, rheumatoid arthritis and lipodystrophy.

Oral administration of ghrelin receptor agonists, partial agonists or allosteric modulators/enhancers could substitute direct growth hormone replacement by parenteral routes.

Negative modulators of ghrelin receptor activity such as antagonists or inverse agonists are considered useful in the treatment of diseases associated with increased ghrelin receptor activation such as obesity and overweight, prevention of weight gain (e.g. induced by medications or smoking cessation), diseases associated with obesity as risk factor (e.g. metabolic syndrome, type 2 diabetes, cardiovascular disease, osteoarthritis, and some cancers), metabolic disorders (e.g. dyslipidemia, hyperlipidemia, low HDL and/or high LDL cholesterol levels, hypertriglycerideemia, low adiponectin levels, impaired glucose tolerance, insulin resistance, HbAIc [glycosylated haemoglobin], diabetes mellitus, type 2 diabetes, reduced metabolic activity, fatty liver), eating disorders and Prader-Willi syndrome.

Since obesity leads to, or significantly increases the risk of, co-morbidities involving various body systems (see Bays, 2004, Obesity Research, 12, 1197-121 1 ) including: i) cardiovascular (hypertension, congestive cardiomyopathy, varicosities, pulmonary embolism, coronary heart disease [CHD], liver cirrhosis), ii) neurological (stroke, idiopathic intracranial hypertension, meralgia parethetica), iii) respiratory (dyspnea, obstructive sleep apnea, hypoventilation syndrome, Pickwickian syndrome, asthma), iv) musculoskeletal (immobility, degenerative osteoarthritis, low back pain), v) skin (striae distensae or "stretch marks," venous stasis of the lower extremities, lymphedema, cellulitis, intertrigo, carbuncles, acanthosis nigricans, skin tags), vi) gastrointestinal (gastro-esophageal reflux disorder, nonalcoholic fatty liver/steatohepatitis, cholelithiasis, hernias, colon cancer), vii) genitourinary (stress incontinence, obesity-related glomerulopathy, breast and uterine cancer), viii) psychological (depression and low self-esteem, impaired quality of life), and ix) 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 ghrelin receptor modulator with medications used for treatment of such diseases.

The following publications relate to compounds having ghrelin receptor modulatory activity:

WO19990991 , US2005723616, EP1407779, WO2006045313, WO200049037, US2006967237, WO 2005070884, WO2006023608, WO2006045314, WO2006045319, WO2006058539, WO2006079562, WO2006010629, US2005154043, EP1486498, WO2004021984, WO2003087069, WO199407483, EP761219, EP761220, UA20060089398, WO05048916, UA20050070712, UA20050171131 , UA20050171 132, UA2005030734, WO2005049828, WO2005097830, WO2005112903, WO20051 14180, WO2006019577, WO2006020959, WO06055347, WO2006108599, WO2006122931 , WO2006009645; US20050014794, WO2005046682, WO2005097788, WO06009645, WO2006036932, WO2006079077.J. Med. Chem. 1998, 41 , 3705-3714, J. Med. Chem. 1998, 41 , 3699-3704, Bioorg & Med. Chem. Lett. 2004, 14, 5873-5876, Bioorg & Med. Chem. Lett. 2005, 15, 1789-1792, Bioorg & Med. Chem. Lett. 2004, 14, 5223-5226, Bioorg & Med. Chem. Lett. 2006, 16, 1864-1868, Bioorg & Med. Chem. Lett. 2005, 15, 1201-1204, Bioorg & Med. Chem. Lett. 2005, 15, 1825-1828, Gut, 2003, 52, 947-952, Gut, 2006, 55, 754-755, Gut, 2006, 55, 788-792, J. Med. Chem. 2006, 49, 4459-4469, J. Med. Chem. 2004, 47, 6655-6657, J. Med. Chem. 2006, 49, 2568-2578,

2-(2-Amino-2-methyl-propionylamino)-5-phenyl-pentanoic acid {1 -[1 -(4-methoxy-phenyl)-1 - methyl-2-oxo-2-pyrrolidin-1-yl-ethyl]-1 H-imidazol-4-yl}-amide (LY444711 ) is an orally active ghrelin receptor agonist from Lilly that induces adiposity by stimulating food consumption and sparing fat utilization (Bioorg & Med. Chem. Lett. 2004, 14, 5873-5876). RC-1291 is another orally available ghrelin receptor small molecule agonist from Sapphire Therapeutic that is in clinical trials for the treatment of anorexia and cachexia in cancer patients. TZP- 101 is a small molecule ghrelin receptor agonist developed by Tranzyme Pharma for postoperative ileus (POI) and other Gl motility disorders including gastroparesis that has been approved for clinical trials by FDA. Elixir has presented effects of a small molecule ghrelin receptor antagonist on food intake, weight, glucose tolerance and insulin secretion supporting its use in treatment of obesity and type 2 diabetes (Keystone meeting: Obesity: Peripheral and Central Pathways Regulating Energy Homeostasis, January 14 - 19, 2007, Keystone, Colorado).

Brief Description of the Invention

This invention is based on the finding that a class of substituted 4-oxo-10-oxa-3-aza- tricyclo[5.2.1.0^*1 ,5^*]-decane and -dec-8-ene modulates the signalling activity of the ghrelin receptor. The class contains compounds which increase, and compounds which decrease signalling activity, as well as compounds which increase or decrease such activity depending on the physiological or pathophysiological activity level of the ghrelin receptor. The compounds with which the invention is concerned are therefore useful for the treatment of conditions which are alleviated by reducing ghrelin receptor activity, such as obesity and overweight, prevention of weight gain, and obesity-related diseases, and for treatment of conditions which are alleviated by increasing ghrelin receptor activity, such as diseases characterised by weight loss, such as cachexia (e.g. associated with COPD, CHF, cancer, diabetic gastroparesis, IBS, chronic arthritis), anorexia, wasting conditions (e.g. associated with AIDS, surgical stress, cachexia of critical illness, sepsis, glucocorticoid administration and cancer), reduced gastrointestinal motility (e.g. opioid induced constipation, diabetes related gastroparesis, treating gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS)), growth hormone (GH) deficiency, pathological weight loss, protein-energy malnutrition, age-related osteoporosis, gastrointestinal diseases (e.g. for gastric ileus, gastric ulcer and inflammatory bowel diseases (IBD)), rheumatoid arthritis and lipodystrophy. In general 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, high triglyceride levels, low adiponectin levels and high HbAIc [glycosylated haemoglobin] and for modulating other characteristics of the metabolic syndrome such as impaired glucose tolerance, insulin resistance, excessive fat tissue in and around the abdomen and high blood pressure.

The substituted 4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0^*1 ,5^*]- decanes with which the invention is concerned are believed to be novel in their own right. The substituted 4-oxo-10-oxa-3- aza-tricyclo[5.2.1.0^*1 ,5^*]- dec-8-enes with which the invention is concerned are believed to be novel except for several which are available in the form of mixtures of stereochemical forms (mixtures of diastereomers or enantiomers in which no enrichment of a given form has been undertaken) from suppliers of commercial compound collections. Such collections can be obtained from ChemDiv INC™, 6605 Nancy Ridge Drive, San Diego CA 92121- 2253, USA, or from Aurora Fine Chemicals Ltd Reininghausstr. 49, A-8020 Graz, Austria. However, no pharmaceutical utility has been ascribed to the foregoing known dec-8-ene compounds, and certainly they are not known to have modulatory activity at the ghrelin receptor.

Detailed Description of the Invention

According to the invention there is provided the use of a ghrelin receptor modulating compound of formula (IA) or (IB), or a salt, hydrate, solvate, or N-oxide thereof, in the preparation of a medicament for the treatment of conditions responsive to increased or decreased ghrelin receptor activity:

wherein

W is, in either orientation, -C(=O)N(R₃)-, or -C(=O)O-;

R is hydrogen or C₁-C₄ alkyl;

R₁ is selected from hydrogen, (Ci-C₄)alkyl, cycloalkyl, fully or partially fluorinated (C₁- C₄)alkyl, Or -OR₁₀; and R₂ is selected from (i) hydrogen and (ii) (Ci-C₄)alkyl, cycloalkyl, cycloalkenyl, and non aromatic heterocyclyl, each optionally substituted by -F, -CN, C₁-C₄ alkyl, cyclopropyl, -NR₇COR₀, -NR₇SO₂R₀, -COR₀, -COOH, -SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or -NR₇COOR₈; and (iii) aryl, aryl-(C₁-C₂)alkyl-, heteroaryl and heteroaryl-(CrC₂ alkyl)- each optionally substituted in the ring part or

R₁ and R₂, together with the nitrogen to which they are attached, form an optionally substituted cyclic amino group;

R₃ is selected from hydrogen, (Ci-C₄)alkyl, cycloalkyl, fully or partially fluorinated (C₁- C₄)alkyl, or -OR₁₀; and R₄ Js selected from (iv) hydrogen and (v) (C_rC₄)alkyl, cycloalkyl, and non aromatic heterocyclyl, each optionally substituted by -F, -CN, -NR₇COR₀, -NR₇SO₂R₀, - COR₀, -COOH, -SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or -NR₇COOR₈; and (vi) aryl, aryl-(C_r C₂)alkyl-, heteroaryl and heteroaryl-(C_rC₂ alkyl)- each optionally substituted in the ring part thereof; or

R₃ and R₄, together with the nitrogen to which they are attached, form an optionally substituted cyclic amino group;

L is -(CR₁₁R₁₃)aB(CR₁₂R₁₄)b-;

a and b are independently 0,1 , 2, 3, 4, 5 or 6 provided that the sum a+b is from 2 to 8; B is a bond, -CO-, -O-, -SO₂-, a divalent phenylene or divalent cycloalkylene radical either of which being oprionally substituted by -F, -CN₁ -NR₇COR₀, -NR₇SO₂R₀, - COR₀, -COOH, -SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or -NR₇COOR₈;

subject to the provisos that (a) one R₁₁ or R₁₂ present in L may, together with R₆, form a bond or divalent radical linking the nitrogen to which R₆ is attached and a carbon atom in L, to form a A-, 5-, 6-, or 7-membered ring including the said nitrogen and carbon, and (b) R₁₁ and R₁₃ together with the carbon atom to which they are attached may form a monocyclic cycloalkyl or saturated heterocyclic ring of 3 to 7 ring atoms, and (c) R₁₂ and R₁₄ together with the carbon atom to which they are attached may form a monocyclic cycloalkyl or saturated heterocyclic ring of 3 to 7 ring atoms, then

R₁₁, R₁₂, R₁₃ and R₁₄ are each selected from hydrogen, (CrC₄)alkyl, cycloalkyl, fully or partially fluorinated (C₁-C₄)alkyl, -ORi_θl or phenyl optionally substituted by -F, - CN, -NR₇COR₀, -NR₇SO₂R₀, -COR₀, -COOH, -SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or - NR₇COOR₈;

subject to the proviso that R₆ together with one R₁₁ or R₁₂ present in L may form a bond or divalent radical linking the nitrogen to which R₆ is attached and a carbon atom in L to form a 4-, 5-, 6-, or 7-membered ring including the said nitrogen and carbon, R₅ and R₆ are independently selected from (vii) hydrogen, and (ix) (Ci-C₄)alkyl, cycloalkyl, and non aromatic heterocyclyl, each optionally substituted by -F, -CN, -NR₇COR₀, -NR₇SO₂R₀, - COR₀, -COOH, -SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or -NR₇COOR₈; and (x) aryl, aryl-(C_r C₂)alkyl-, heteroaryl and heteroaryl-(d-C₂ alkyl)- each optionally substituted in the ring part thereof; or R₅ and R₆, together with the nitrogen to which they are attached, form an optionally substituted cyclic amino group;

R₀ is (C₁-C₄)alkyl, cycloalkyl, -CF₃ Or -NR₇R₈;

R₇ and R₈ are independently hydrogen, (d-C₄)alkyl or cycloalkyl_, or R₇ and R₈ when attached to the same nitrogen atom form a cyclic amino group;

R₉ is hydrogen, (C₁-C₄JaIkVl, cycloalkyl, or fully or partially fluorinated (d-C^alkyl; and

R₁₀ is hydrogen, (CrC₄)alkyl, cycloalkyl, or fully or partially fluorinated (C_rC₄)alkyl, or optionally substituted aryl or heteroaryl. Expressed alternatively, the present invention provides a compound of formula (IA) or (IB), or a salt, hydrate, solvate, or N-oxide thereof, for the treatment of conditions responsive to increased or decreased ghrelin receptor activity

As briefly referred to above, compounds with which the invention is concerned, bind the ghrelin receptor and may increase or decrease signalling activity of that receptor. Any given compound may have the effect of increasing such activity (a positive modulator) or decreasing such activity (a negative modulator.) Some compounds of the invention may be positive or negative modulators depending on the physiological or pathophysiological activity level of the ghrelin receptor. Positive modulators may be ghrelin receptor agonists, partial agonists or allosteric modulators/enhancers. Negative modulators may be antagonists or inverse agonists. In the case of any given compound, the potency assays described below are suitable for determining whether it is a positive or negative modulator, or has positive or negative effects dependent of the endogenous concentration of ghrelin and other factors. The normal pharmaceutical development process involved detailed in vivo and clinical studies of the pharmacological effect of a given compound, and its positive or negative modulatory effect on ghrelin receptor signalling as foreshadowed by the potency assays described below may be unambiguously characterised during that routine sequence of studies.

In another aspect, the invention provides a method of treatment of conditions responsive to increased or decreased ghrelin receptor activity, comprising administering an effective amount of a compound with which the invention is concerned to a subject suffering such condition.

When the use or a method of the invention utilizes a ghrelin receptor modulating compound which increases ghrelin receptor activity in vivo the condition may be selected from eating disorders like cachexia (e.g. associated with COPD, CHF, cancer, AIDS, diabetic gastroparesis, IBS, chronic arthritis), anorexia, bulimia, wasting conditions (e.g. associated with AIDS, surgical stress, cachexia of critical illness, sepsis, glucocorticoid administration and cancer), gastrointestinal disorders (e.g. gastic ileus, gastric ulcer, chronic intestinal pseudo-obstruction, functional gastrointestinal disorders and inflammatory bowel diseases), reduced gastrointestinal motility (e.g. opioid induced constipation, diabetes related gastroparesis, treating gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS)), growth hormone (GH) deficiency, pathological weight loss, protein-energy malnutrition, age related osteoporosis, rheumatoid arthritis and lipodystrophy. When the use or a method of the invention utilizes a ghrelin receptor modulating compound which decreases ghrelin receptor activity in vivo, the condition may be selected from obesity and overweight, prevention of weight gain, weight-loss maintenance, conditions associated with obesity as risk factor metabolic disorders eating disorders, and Prader-Willi syndrome. Such conditions include (a) prevention of weight gain induced by medication or smoking cessation); and (b) a condition associated with obesity as risk factor selected from metabolic syndrome, type 2 diabetes, cardiovascular disease, osteoarthritis, and obesity related cancer; and (c) a metabolic disorder selected from dyslipidemia, hyperlipidemia, low HDL and/or high LDL cholesterol levels, hypertriglycerideemia, low adiponectin levels, impaired glucose tolerance, insulin resistance, HbAIc [glycosylated haemoglobin], diabetes mellitus, type 2 diabetes, reduced metabolic activity, and fatty liver.

The invention also includes novel compounds of formula (IA) or (IB) as defined above. More specifically, the invention provides a compound of formula (IA) or (IB) as defined above, excluding compounds of formula (IC)

wherein

A1. when R₂ is 2,3-dimethyl-cyclohexyl and R₅R₆N- is 1-ethyl-piperazin-4-yl, then R₄ is not 3,5-dichloro-, 3-methyl-, 4-isopropyl-, 3-chloro-4-fluoro-, 3-chloro-, 3,4-dimethyl-, 3,5- dimethyl- or 3-methylthio-phenyl;

B1. when R₂ is 2,3-dimethyl-cyclohexyl and R₅ReN- is morpholin-1-yl, then R₄ is not 4- isopropyl-, 3-chloro-4-fluoro-, 3-methyl-, 3-chloro-, 4-chloro-, 3-chloro-4-methyl-, 3,5- dimethyl-, or 3-methylthio-phenyl

C1. when R₂ is 2,3-dimethyl-cyclohexyl and R₅ReN- is 1-methyl-piperazin-4-yl, then R₄ is not 4-isopropyl-, or 3-chloro-4-fluoro-phenyl;

D1. when R₂ is 2,3-dimethyl-cyclohexyl and and R₅ and Re are each methyl, then R₄ is not 3,5-dichloro-, 3,5-dimethyl- or 3,4-dichloro-phenyl; E1. when R₂ is 2,3-dimethyl-cyclohexyl and R₅R₆N- is pyrrolidin-yl, then R₄ is not 3- methyl-, 3-chloro-, 4-chloro- or 3,5-dimethyl-phenyl;

F1. when R₂ is cyclohexyl and R₅R₆N- is morpholin-1-yl, then R₄ is not 3,5-dichloro-, 3,4- dichloro-, 4-bromo,4-chloro-, 3-methylthio- or 3,4-dichloro-phenyl;

G1. when R₂ is cyclohexyl and R₅ and R₆ are each methyl, then R₄ is not 3,5-dichloro-, A- phenoxy- or 4-isobutyl-phenyl;

H1. when R₂ is cyclohexyl and R₅R₆N- is 1-methyl-piperazin-4-yl, then R₄ is not 3,5- dichloro- or 4-isobutyl-phenyl;

K1. when R₂ is cyclohexyl and R₅R₆N- is piperidin-1-yl, then R₄ is not 3-methoxy, 3- chloro, 4-isobutyl-, 3,5-dimethyl- or 3-methylthio-phenyl;

L1. when R₂ is cyclohexyl and R₅R₆N- is 3-methyl-piperidin-1-yl, then R₄ is not A- methoxy-, 3-chloro-, 4-chloro-, 3-methylthio- or 4-methyl-phenyl;

M1. when R₂ is cyclohexyl and R₅ and R₆ are each ethyl, then R₄ is not 3-chloro;

N1. when R₂ is cyclohexyl and R₅R₆N- is 4-methyl-piperidin-i-yl, then R₄ is not 3-chloro-, 4-chloro- or 3-methylthio-phenyl,

01. when R₂ is cyclohexyl and R₅ is methyl and R₆ is benzyl, then R₄ is not 4-methyl;

P1. when R₂ is 2-methyl-cyclohexyl and R₅R₆N- is morpholin-1-yl, then R₄ is not 3- methoxy-, 3-methyl-, 4-isobutyl-phenyl;

Q1. when R₂ is 2-methyl-cyclohexyl and R₅R₆N- is piperidin-1-yl, then R₄ is not 3- methoxy-phenyl; and

R1. when R₂ is 2-methyl-cyclohexyl and R₅R₆N- is 3-methyl-piperidin-1-yl , then R₄ is not 3-methoxy-phenyl;

and also excluding the compound of formula (IA) wherein R₁ and R₃ are each hydrogen, R₂ is cyclohexyl, R₄ is 3,4 dichloro-phenyl, and R₅R₆N-L- is:

and also excluding compounds of formula (IA) wherein R is methyl, R₁ is hydrogen, R₂ is cyclohexyl, W is -C(=O)N(R₃)-^* wherein the bond marked with an asterisk is attached to R₄, R₄ is 3,4-dichlorophenyl, L is -CH₂CH₂- Or -CH₂CH₂CH₂-, and -NR₅R₆ is morpholinyl.

The above excluded compounds are available in the form of mixtures of stereochemical forms (mixtures of diastereomers or enantiomers in which no enrichment of a given form has been undertaken) from suppliers of commercial compound collections. Such collections can currently be obtained from ChemDiv INC™, 6605 Nancy Ridge Drive, San Diego CA 92121- 2253, USA, or from Aurora Fine Chemicals Ltd Reininghausstr. 49, A-8020 Graz, Austria. However, no pharmaceutical utility has been ascribed to the foregoing excluded compounds, and they are not known to have modulatory activity at the ghrelin receptor.

A specific class of compounds of the invention consists of those of formula (IA) as defined above wherein R₂ is not cyclohexyl, 2-methyl-cyclohexyl, or 2,3-dimethyl-cyclohexyl.

A narrower specific class of compounds of the invention consists of those of formula (IA) as defined above wherein R is hydrogen, W is -C(=O)N(R₃)-^* wherein the bond marked with an asterisk is attached to R₄, and R₄ is not 3-methoxy-, 4-methoxy- 3-chloro-, 4-chloro-, 4- bromo-, 3,4-dimethyl-, 3,5-dimethyl-, 3-methylthio-, 4-methyl-, 3-methyl-, 3,5-dichloro-, 3,4- dichloro-, 4-isopropyl-, 3-chloro-4-methyl-, 4-methoxy-, 3-methoxy-, 4-isopropyl-, 3-chloro-4- fluoro-, or 4-phenoxy-phenyl.

A further specific class of compounds of the invention consists of those of formula (IB) defined above.

A further specific class of compounds of the invention consists of those of formula (IA) and (IB) defined above, wherein W is -N(R₃) C(=O)-^* wherein the bond marked with an asterisk is attached to R₄.

The compounds with which the invention is concerned may be presented for use as a pharmaceutical composition comprising such a compound, together with one or more pharmaceutically acceptable carriers or excipients. The compounds with which the invention is concerned include salts thereof, hydrate and solvate forms, N-oxide forms, as well as forms in which one stereochemical form (diastereomer or enantiomer) predominates, for example as at least 90%, more preferably at least 95% or at least 98% by weight of the total amount of compound.

In accordance with general principles of medicinal chemistry, it is preferred that the compounds with which the invention is concerned should have a molecular weight of less than 700, and more preferably less than 600.

Stereochemistry

General and specific methods of synthesis of the compounds with which the invention is concerned will be discussed below. However, at this point it is noted that a typical 4- component reaction for the synthesis of compounds (IA), shown below using a Z-dienophile (Z-d)

will normally give rise to a mixture of stereoisomers having the carbonyl groups primarily in c/s-orientation on the central ring and primarily trans- orientation when using an E- dienophile (E-d).

Thee 2- and 6-substitud 4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0^*1 ,5^*]-decane and -dec-8-enes with which the invention is concerned have five chiral centers and thus 32 enantiomers are possible. However, due to strain in the core structure, especially in the 10-oxa bridge, only 16 enantiomers are likely to exist. The synthesis of 4-oxo-10-oxa-3-aza- tricyclo[5.2.1.0^*1 ,5^*]-decenes is known to proceed in exo fashion and the relative stereochemistry of the core structure is dictated by the dienophiles used (Z-d or E-d). Upon using a Z-dienophile (Z-d) c/s-isomers are preferably formed and selectivity towards one pair of enantiomers is usually obtained. Examples of enantiomer-pairs of c/s-diastereomers are shown below.

Upon using E-dienophile (E-d) frans-isomers are preferably formed and selectivity towards one pair of enantiomeres is usually obtained. Examples of enantiomer-pairs of trans- diastereomers are shown below.

Mixtures of stereochemical isomers may be enriched with respect to one or more such isomers by normal chromatographic and other methods.

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, pyhdazinyl, 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, (Ci-C₆)alkoxy, hydroxy, hydroxy(C_rC₆)alkyl, mercapto, mercapto(d-C₆)alkyl, (C_rC₆)alkylthio, halo (including fluoro, bromo and chloro), fully or partially fluorinated (C_rC₃)alkyl, (C₁-C₃)alkoxy or (d-CaJalkylthio such as trifluoromethyl, trifluoromethoxy, and trifluoromethylthio, nitro, nitrile (-CN), oxo, phenyl, phenoxy, monocyclic heteroaryl or heteroaryloxy with 5 or 6 ring atoms, tetrazolyl, - COOR^A, -COR^A, -OCOR^A, -SO₂R^A, -CONR^AR^B, -SO₂NR^AR^B, -NR^AR^B, -OCONR^AR^B, - NR^BCOR^A, -NR^BCOOR^A, -NR^BSO₂OR^A or -NR^ACONR^AR^B wherein R^A and R^B are independently hydrogen or a (Ci-C₆)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. Where a moiety is said to be "optionally substituted by Si, S₂, S₃ ... or S_n", wherein S₁-S_n are optional substituents, more than one of such substituents may be substituted in the moiety.

A particular type of optional substituents is referred to hereafter as R_a, and consists of -R₉, -F, -Cl, -Br, -CN, -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)SO₂R₆, or -NR₇COOR₈ wherein R₆-R₉ are as defined in relation to formulae (1A) and (IB) above.

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. Individual compounds of the invention may exist in several polymorphic forms and may be obtained in different crystal habits. The compounds may also be administered in the form of prodrugs thereof.

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

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (IA) and (IB) 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-tBu 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 (IA) and (IB), 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 (IA) and (IB):

The substituent R

R is hydrogen or C1-C4 alkyl, such as methyl, ethyl or iso-propyl. Currently preferred are compounds wherein R is methyl or, more particularly, hydrogen.

The radical -W-

W is, in either orientation, -C(=O)N(R₃)-, or -C(=0)0-. Currently preferred are compounds wherein W is, in either orientation, -C(=O)N(R₃)-. In a particular class of compounds, W is - C(=O)N(R₃)-^* wherein the bond marked with an asterisk is attached to R₄.

The substituents R₃ and R₄

When X is -N(R₃)-, either R₃ and R₄ may be separate substituents on the relevant nitrogen, or R₃ and R₄, together with the nitrogen to which they are attached, form an optionally substituted cyclic amino group.

In the latter case, R₃ and R₄, together with the nitrogen to which they are attached, may form, for example, a cyclic amino group of formula

wherein the ring contains 4 to 7 ring atoms, and Y is selected from -O-, -CO-, -SO₂-, - NR10-, -CH(R₁₀)-, -CH(OR₁₀)-, -CON(R₁₀)-, -SO₂N(R₁₀)- wherein R₁₀ is as defined in relation to formulae (IA) and (IB) above; or Y represents a fused phenyl or monocyclic - heteroaryl ring of 5 or 6 ring atoms which is optionally substituted, for example by one or more R₃ as defined above. When one or more Ri₀ is present in Y₁ such substituents may be selected from

(A) hydrogen;

(B) (Ci-C₄)alkyl such as methyl, ethyl, n- or iso-propyl;

(C) cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl;

(D) fully or partially fluorinated (CrC₄)alkyl such as trifluoromethyl;

(E) aryl such as phenyl or heteroaryl such as furanyl, thienyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazoyl, tetrazoyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, quinazolinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzotriazoyl, pyrrolopyrididyl, furopyridyl, oxazolopyridyl, imidazopyrridyl, pyrrolopyrimidinyl, pyrrolopyrazolyl, pyrrolopyridazinyl; such aryl and heteroaryl being optionally substituted with one or more substituents R₃ as defined in relation to formulae (1A) and (IB) above

When one or more optional substituents, for example one or more R₃ are present in Y, such substituents may be selected from, for example:

(a) (CrC₄)alkyl such as methyl, ethyl, n- or iso-propyl;

(b) cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl;

(c) fully or partially fluorinated (Ci-C₄)alkyl such as trifluoromethyl; (Cl) -F₁ -Cl, -Br, or -CN;

(e) -OR₉, -(C₁-C₄ alkyl)OR₉, -SR₉ or -SOR₉ wherein the -(C₁-C₄ alkyl)- part may be, for example -(CH₂)-, or -(CH₂)₂-; and R₉ is hydrogen,

(d-C₄)alkyl such as methyl, ethyl, n- or iso-propyl, cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl, fully or partially fluorinated (C_!-C₄)alkyl such as trifluoromethyl;

(f) -NR₇R₈ or -(C₁-C₄ alkyl)NR₇R₈ wherein the -(C₁-C₄ alkyl)- part may be, for example -(CH₂)-, or -(CH₂J₂-; and R₇ and R₈ are independently hydrogen,

(d-C₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl;_; or

R₇ and R₈ form a cyclic amino group such as morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, pyrrolidinyl, any of which being optionally substituted by (d-C₄)alkyl such as methyl, ethyl, n- or iso-propyl;

(g) -NR₇COR₆, -(C₁-C₄ alkyl)NR₇COR₆, -NR₇SO₂R₆, Or -(C₁-C₄ alkyl)SO₂R<₅, wherein the -(C₁-C₄ alkyl)- part may be, for example -(CH₂)-, or -(CH₂)₂-; and R₆ is (d-C₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; -CF₃; or -NR₇R₈ as discussed above; and

R₇ is hydrogen; (Ci-C₄)alkyl such as methyl, ethyl, n- or iso-propyl; or cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; (h) -COR₆, or -SO₂R₆ wherein R₆ is (C_rC₄)alkyl such as methyl, ethyl, n- or iso- propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; -CF₃; or -NR₇R₈ as discussed above;

(i) -NR₇COOR₈, -(C₁-C₄ alkyl)NR₇COOR₈, or (-(CrC₄ alkyl)NR₇SO₂Re wherein the -(C₁-C₄ alkyl)- part may be, for example -(CH₂)-, or -(CH₂)₂-; and R₆ is (CrC₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; -CF₃; or -NR₇R₈ as discussed above; and R₇ is hydrogen; (C₁-C₄)alkyl such as methyl, ethyl, n- or iso-propyl; or cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl.

Examples of monocyclic cyclic amino rings formed by R₃, R₄ and the nitrogen to which they are attached include, for example, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, pyrrolidinyl, thiomorpholine, azepane, diazepane, oxazepane, and azetidine. In such rings, a carbon atom may be substituted by oxo (=0) and a ring sulfur may be oxidized to -SO₂-, and such rings may be optionally substituted, for example by,

(C_rC₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; fully or partially fluorinated (Ci-C₄)alkyl such as trifluoromethyl;

-F, -CN, -OR₁₀, -NR₇COR₆, -COR₆, -SO₂R₆,.

When R₃ and R₄ are separate substituents on the relevant nitrogen, R₃ is selected from: hydrogen;

(C_rC₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; fully or partially fluorinated (C₁-C₄)alkyl such as trifluoromethyl; and -OR_1O wherein R_1O is a substiuent (A)-(E) as discussed above. At present, when X is -N(R₃)- and R₃ and R₄ are separate substituents on the relevant nitrogen, it is preferred that R₃ be hydrogen or methyl.

When R₃ and R₄ are separate substituents on the relevant nitrogen, R₄ is selected from: (i) hydrogen;

(ii) (C₁-C₄JaIkVl such as methyl, ethyl, n-or iso-propyl; (iii) cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (iv) aryl or aryl^d-CjJalkyl-, such as phenyl or benzyl;

(v) heterocyclyl, and heterocyclyK ^ alkyl)-, such as wherein the heterocyclyl part is non aromatic such as tetrahydropyrrolyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, pyrrolidinyl, isoxazolidine, thiomorpholine, azepane, diazepane, oxazinane, oxazepane, and azetidine or heteroaryl such as furanyl, thienyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazoyl, tetrazoyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, quinazolinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzotriazoyl, pyrrolopyrididyl, furopyridyl, oxazolopyridyl, imidazopyrridyl, pyrrolopyrimidinyl, pyrrolopyrazolyl, pyrrolopyhdazinyl;

In substituents (ii) and (iii) and in the non-aromatic heterocyclic part of substituents (v) one or more substituents may be present selected from:

-OR₁₀ wherein R₁₀ is a substiuent (A)-(E) as discussed above; -F, -CN, -COOH;

-NR₇R₈, -(C₁-C₄ alkyl)NR₇R₈ or -NR₇COOR₈ wherein the -(C₁-C₄ alkyl)- part may be, for example -(CH₂)-, or -(CH₂)₂-, and R₇ and R₈ are independently hydrogen;

(C₁-C₄JaIkVl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl, or

R₇ and R₈ when attached to the same nitrogen form a cyclic amino group such as morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, pyrrolidinyl, any of which being optionally substituted by (C_rC₄)alkyl such as methyl, ethyl, n- or iso-propyl; -COR₀, -SO₂R₀, wherein R₀ is

(C₁-C₄JaIkVl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; -CF₃; or -NR₇R₈ as discussed above; -SOR₉, wherein R₉ is hydrogen; (C₁-C₄JaIkYl such as methyl, ethyl, n- or iso-propyl; or cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; -NR₇COR₀, -NR₇SO₂R₀ wherein wherein

R₀ is (Ci-C₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl;

-CF₃; or -NR₇R₈ as discussed above; and

R₇ is hydrogen, (Ci-C₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl.

In the aryl or heteroaryl part of substituents substituents (iv) and (v), one or more Ra substituents (a)-(i) as discussed above may be present.

At present, when X is -N(R₃)- and R₃ and R₄ are separate substituents on the relevant nitrogen, currently preferred substituents R₄ include phenyl, optionally substituted with one or more substituents such as -CF₃, -F, -Cl, -OCF₃, and -CN, for example 4-CI-, 4-Br-, 4-CF₃- , 4-CF₃O-, 3,4-Cl₂-, 4-CI-3-CH₃-, 4-CI-3-CH₃O-, 4-CI-3-CF₃O-, 4-CI-3-CF₃O-, 4-CI-3-F-, 4- CF₃-3-CH₃-, 4-CF₃-3-CH₃O-, 4-CF₃-3-CF₃O-, 4-CF₃-3-F-, 4-CF₃-3-CI-, 4- CF₃O-3-CH₃-, 4- CF₃O-3-CH₃O-, 4-CF₃O-3-CF₃-, 4-CF₃O-3-F-, 4-CF₃O-3-CI-, 4-phenoxy-, 4-(4-F-phenoxy)-, 3-F-4-phenoxy-, and 3-F-4-(4-F-phenoxy)-, of which presently 4-trifluorophenyl is currently most preferred.

The substituents R₁ and R₂

R₁ and R₂ may be separate substituents on the relevant nitrogen, or R₁ and R₂, together with the nitrogen to which they are attached, may form an optionally substituted cyclic amino group.

In the latter case, R₁ and R₂, together with the nitrogen to which they are attached, may form, for example, a cyclic amino group of formula as discussed above in relation to R₃ and R₄ when they, together with the nitrogen to which they are attached, form a cyclic amino group of formula

When R₁ and R₂ are separate substituents on the relevant nitrogen, R₁ is selected from: hydrogen,

(d-C₄)alkyl such as methyl, ethyl, n-or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; fully or partially fluorinated (C_rC₄)alkyl such as trifluoromethyl; and -OR₁₀ wherein R₁₀ is

(d-C₄)alkyl such as methyl, ethyl, n-or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; fully or partially fluorinated (CrC₄)alkyl such as trifluoromethyl; aryl such as phenyl or heteroaryl such as furanyl, thienyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazoyl, tetrazoyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, quinazolinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzotriazoyl, pyrrolopyhdidyl, furopyridyl, oxazolopyridyl, imidazopyrridyl, pyrrolopyrimidinyl, pyrrolopyrazolyl, pyrrolopyridazinyl; the foregoing aryl and heteroaryl part of -OR₁₀ being optionally substituted with

(Ci-C₄)alkyl such as methyl or ethyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; fully or partially fluorinated (Ci-C₄)alkyl such as trifluoromethyl; or methoxy, ethoxy, methylenedioxy or ethylenedioxy; and

When R₁ and R₂ are separate substituents on the relevant nitrogen, R₂ is as discussed above in relation to R₄.

When R₁ and R₂ are separate substituents on the relevant nitrogen, currently preferred substituents R₁ include isopropyl, tert-butyl, cyclopropyl, cyclohexyl, and benzyl, and it is currently preferred that R₂ is hydrogen.

The linker radical L

L is -(CRiiRi3)_aB(CRi₂Ri4)b- wherein a and b are independently 0,1 , 2, 3, 4, 5 or 6 provided that the sum a+b is from 2 to 8; B is a bond, -CO-, -O-, -SO₂-, a divalent phenylene radical such as 1 ,4-, or 1 ,3-phenylene, or a divalent cycloalkylene radical such as 1-4 or 1 ,3- cyclohexylene, or 1 ,3 cyclopentylene, either of which being oprionally substituted by -F, - CN, -NR₇COR₀, -NR₇SO₂R₀, -COR₀, -COOH, -SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or - NR₇COOR₈; and (subject to the provisos that (a) one R₁₁ or R₁₂ present in L may, together with R₆, form a bond or divalent radical linking the nitrogen to which R₆ is attached and a carbon atom in L, to form a 4-, 5-, 6-, or 7-membered ring including the said nitrogen and carbon, and (b) R₁₁ and R₁₃ together with the carbon atom to which they are attached may form a monocyclic cycloalkyl or saturated heterocyclic ring of 3 to 7 ring atoms, and (c) R₁₂ and R₁₄ together with the carbon atom to which they are attached may form a monocyclic cycloalkyl or saturated heterocyclic ring of 3 to 7 ring atoms ) R₁₁, Ri₂, R13 and R₁₄ are each independently selected from: hydrogen,

(Ci-C₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; fully or partially fluorinated (CrC₄)alkyl such as trifluoromethyl;

-OR₁₀ as discussed above in relation to R₃; and phenyl optionally substituted by -F, -CN, -NR₇COR₀, -NR₇SO₂R₀, -COR₀, -COOH, -

SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or -NR₇COOR₈ wherein R₀, R₇, R₈, R₉ and R₁₀ are as defined and discussed above in relation to R₁, R₂, R₃ and R₄.

When R₁₁ or R₁₂ present in L, taken with R₆, forms a bond or divalent radical linking the nitrogen to which R₆ is attached and a carbon atom in L, to form a A-, 5-, 6-, or 7-membered ring including the said nitrogen and carbon), examples of such rings include morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, pyrrolidinyl, thiomorpholine, azepane, diazepane, oxazepane, and azetidine In such rings, a carbon atom may be substituted by oxo (=0) and a ring sulfur may be oxidized to -SO₂-.

When R₁₁ and R₁₃, or R₁₂ and R₁₄, together with the carbon atom to which they are attached form a monocyclic cycloalkyl or saturated heterocyclic ring of 3 to 7 ring atoms that ring may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, or an azetidine or piperidine ring.

At present it is preferred that L be -CH₂CH₂- or -CH₂CH₂CH₂-. Other specific examples of L include -CH₂C(CH₃)-, -CH₂CH(CH₃)CH₂-, and, in either orientation, -CH(CH₃)CH₂- and - CH(CH₃)CH₂CH₂-.

The substituents R₅ and R₆

As mentioned above, R₆, taken with one of R₁₁ or R₁₂ present in L₁ may form a bond or divalent radical linking the nitrogen to which R₆ is attached and a carbon atom in L, to form a A-, 5-, 6-, or 7-membered ring including the said nitrogen and carbon,

In other cases, R₅ and R₂ may be separate substituents on the relevant nitrogen, or R₅ and R₆, together with the nitrogen to which they are attached may form, for example, a cyclic amino group of formula as discussed above in relation to R₃ and R₄ when they, together with the nitrogen to which they are attached, form a cyclic amino group of formula

When R₅ and R₆ are separate substituents on the relevant nitrogen, R₅ and Re are independently selected from

(a) hydrogen,

(b) (C₁-C₄)alkyl such as methyl, ethyl, n-or iso-propyl;

(c) cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl;

(d) partially fluorinated (C_rC₄)alkyl such as trifluormethyl;,

(e) -OR₉, or -(C₁-C₄)alkyl-OR₉, wherein the -(CrC₄ alkyl)- part may be, for example - (CH₂)-, or -(CH₂)₂-, and Rg is hydrogen; (d-C₄)alkyl such as methyl, ethyl, n- or iso- propyl; or cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl;

(f) -(C_rC₄)alkyl)-NR₇R₈, -(C₁-C₄)alkyl)-NR₇COR₀, or -(Ci-C₄)alkyl-NR₇COOR₈, wherein the -(CrC₄ alkyl)- part may be, for example -(CH₂)-, or -(CH₂J₂-;

R₀ is (CrC₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; -CF₃; or -NR₇R₈ as discussed above; and

R₇ is hydrogen, (CrC₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl.

(g) -(CrC₄)alkyl)-NR₇SO₂R₀, -(C_rC₄)alkyl-Sθ2Ro wherein the -(C₁-C₄ alkyl)- part may be, for example -(CH₂)-, or -(CH₂)₂-; R₀ is (CrC₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; -CF₃; or -NR₇R₈ as discussed above;

(h) -(CrC₂)alkyl-aryl such as benzyl or phenylethyl, or -(CrC₂)alkyl- heterocyclyl such as wherein the heterocyclyl part is non aromatic such as tetrahydropyrrolyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, pyrrolidinyl isoxazolidine, thiomorpholine, azepane, diazepane, oxazinane, oxazepane, azetidine or heteroaryl such as furanyl, thienyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazoyl, tetrazoyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, quinazolinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzotriazoyl, pyrrolopyrididyl, furopyridyl, oxazolopyridyl, imidazopyrridyl, pyrrolopyrimidinyl, pyrrolopyrazolyl, pyrrolopyridazinyl; (each optionally substituted in the ring part thereof with one or more substituents selected from:

(a) (Ci-C₄)alkyl such as methyl, ethyl, n- or iso-propyl;

(b) cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl;

(c) fully or partially fluorinated (C₁-C₄JaIKyI such as trifluoromethyl;

(d) -F₁ -Cl₁ -Br, or -CN;

(e) -OR₉, -(C₁-C₄ alkyl)OR_9l -SR₉ or -SOR₉ wherein the -(C₁-C₄ alkyl)- part may be, for example -(CH₂)-, or -(CH₂)₂-; and R₉ is hydrogen,

(C_rC₄)alkyl such as methyl, ethyl, n- or iso-propyl, cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl, fully or partially fluorinated (C_rC₄)alkyl such as trifluoromethyl;

(f) -NR₇R₈ or -(C₁-C₄ alkyl)NR₇R₈ wherein the -(C₁-C₄ alkyl)- part may be, for example -(CH₂)-, or -(CH₂)₂-; and R₇ and R₈ are independently hydrogen,

(Ci-C₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl;, or

R₇ and R₈ form a cyclic amino group such as morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, pyrrolidinyl, any of which being optionally substituted by (C₁-C₄)alkyl such as methyl, ethyl, n- or iso-propyl;

(g) -NR₇COR₀, -(C₁-C₄ alkyl)NR₇COR_o, -NR₇SO₂R₀, or -(C₁-C₄ alkyl)S0₂Ro, wherein the -(C₁-C₄ alkyl)- part may be, for example -(CH₂)-, or - (CH₂J₂-; and

R₀ is (d-C₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; - CF₃; or -NR₇R₈ as discussed above; and R₇ is hydrogen; (C_rC₄)alkyl such as methyl, ethyl, n- or iso- propyl; or cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl;

(h) -COR₀, or -SO₂R₀ wherein R₀ is (d-C₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; -CF₃; or -NR₇R₈ as discussed above; (i) -NR₇COOR₈, -(C₁-C₄ alkyl)NR₇COOR_8l or

(-(C₁-C₄ alkyl)NR₇S0₂Ro wherein the -(C₁-C₄ alkyl)- part may be, for example -(CH₂)-, or - (CH₂)₂-; and

R₀ is (CrC₄)alkyl such as methyl, ethyl, n- or iso-propyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; -CF₃; or -NR₇R₈ as discussed above; and R₇ is hydrogen; (C_rC₄)alkyl such as methyl, ethyl, n- or iso-propyl; or cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl.

When R₅ and R₆ are separate substituents on the relevant nitrogen, currently preferred R₅ include hydrogen, methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and currently preferred R₆ include hydrogen, methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The preferred compounds have the carbonyl groups primarily in c/s-orientation (on the same side) on the central ring.

Further preferred are compounds having the carbonyl groups and the 10-oxa all primarily in c/s-orientation (on the same side) on the central ring.

Functional aspects of compounds (IA) and (IB)

The compounds with which the invention is concerned modulate the ghrelin receptor by modifying its natural signalling function. The compounds are therefore ghrelin receptor antagonists, inverse agonists, partial agonists, allosteric modulators or combinations thereof according to classical pharmacology. The term "ghrelin receptor antagonist" refers to a compound which prevent or reduce the functional activation or occupation of the receptor by ghrelin or other ghrelin receptor agonists.

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

The term "ghrelin receptor partial agonist" refers to a compound which acts upon the receptor in the same way as the full agonist but which produces a weak maximum pharmacological response and has a low level of intrinsic activity.

The term "ghrelin receptor allosteric modulator" or "ghrelin receptor allosteric enhancer" refers to a compound which binds to the receptor, and does not exert an effect alone but increases the maximum pharmacological response of an agonist (e.g. ghrelin).

The functional biological assays described below provide simple tools for initially determining whether a given compound is to increase or decrease ghrelin receptor activity. As mentioned above, the properties of a given compound finds utility depends on whether it has the capacity to increase or decrease ghrelin receptor signalling in vivo. Routine evaluation of the functionality of a candidate compound in animal models of one or more conditions which respond to increase or decrease of ghrelin receptor activity, such as are required for pharmaceutical development generally, are capable of elucidating into which of the above categories the compound falls. The compounds with which the invention is concerned may be combined with another therapeutic agent used in treatment of the specific condition in question. Where the condition is obesity, they may be used in combination with another anti-obesity agent 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, 11 beta-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).

Compounds with which the invention is concerned may be combined or administered together 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.

Compounds with which the invention is concerned may be combined with proper reduction in dietary calorie intake and physical exercise.

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

These dosages are based on an average human subject having a weight of about 60kg to 100kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly, and especially obese patients.

The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

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

Synthesis

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

Routes outlined below do not constitute an exhaustive list.

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

The compounds of Formula (IA) and (IB) wherein W is -C(=O)NR₃R₄ may be obtained by introduction of the -NR₁R₂ moiety to a corresponding carboxylic acid or a protected form of the depicted carboxylic acid as outlined in the following scheme:

Thus, the amine HNR₁R₂ moiety contains a nucleophilic nitrogen center 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. Thus, compounds of Formula I may either be obtained directly following the procedure in the above scheme 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) or 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDAC), and promoters such as 1-hydroxybenzotriazole (HOBT).

Compounds of Formula (IA) and (IB) wherein wherein W is -C(=O)NR₃R₄ can also be obtained by the following analogous procedure by reaction with HNR₃R₄ and the corresponding carboxylic acid.

The core system in Formula (IA) containing a dihydrofuran ring can be constructed by a four-component Ugi reaction according to procedures described by K. Paulvannan in Tetrahedron Letters 1999, 40, 1851-1854.

"X" in the above scheme represents N. The core moiety in Formula (IA) containing a dihydrofuran ring can also be constructed via a Diels-Alder reaction as exemplified below. The free carboxyl group can be transformed to -CO-NR₃R₄ as described above by reaction with HNR₃R₄ and finally the carboxyl ester can be hydrolysed and converted to compound (Ia) as outlined earlier by reaction with HNR₁R₂.

The unsaturated dihydrofuran system in compounds (IA) can be reduced according to standard conditions such as using hydrogen and a palladium catalyst according to the following scheme to convert compound (IA) to compound (IB). This reaction also can be carried out on an intermediate that is used for transformation into a compound (IB).

The unit -L₁-(N)R₅R₆ may be introduced in a protected or truncated version of the substituent (e.g. an aldehyde) or a group which can be converted to the final substituent using standard procedures known to those skilled in the art (e.g. reductive amination of an aldehyde). Thus, compounds of Formula Ia and Ib may either be obtained directly or after standard conversions such as removal of protecting or chemical transformation truncated groups.

An example of use of such a truncated group is shown in the following example. The masked aldehyde is deprotected under acidic conditions and the aldehyde formed is reductively aminated using well known conditions such as NaBH(OAc)₃ Or NaBH(CN)₃ at slightly acidic pH.

"X" in the above scheme represents N.

Alternatively, compounds of (IA) and (IB) may be obtained from other compounds of formula (IA) and (IB) by functional group interconversion as the final step. For instance, the substituents present in phenyl, heteroaryl, -(C₁-C₂ alkyl)aryl, -(C₁-C₂ alkyl)heteroaryl aromatic rings of R₂ and R₄ can be introduced at a final stage in the aryl ring. An example on R₄ as phenyl of such a conversion may involve reacting a bromo aryl compound with zinc cyanide in the presence of a metal catalyst such as a palladium(O) complex, to give a corresponding cyano compound (I) as illustrated in the following scheme:

Such a conversion may also be made on an intermediate that can be converted to the compounds of (IA)/(IB)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 following Examples are of specific compounds which are members of the class with which the invention is concerned.

Abbreviations

The following general abbreviations are used:

EtOAc; acetic acid ethyl ester,

DCM; dichloromethane

MeOH; methanol

THF; tetrahydrofurane

Et₂O; diethylether

SiO₂; commercial silicon dioxide for chromatographic purposes, CAS 1 12926-00-8 or similar

hrs; hours

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.

HPLC analysis was obtained under standardised conditions defined in the analysis methods. Data is quoted for all compounds as retention time (RT) and molecular ion (M+H)⁺ or (M-H)^'.

a) Synthesis Method A. Intermediate 1.

3-(2,2-Dimethoxy-ethyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-2,6- dicarboxylic acid 2-cyclohexylamide 6-[(3,4-dichloro-phenyl)-amide]

A mixture of furan-2-carbaldehyde (830 μl, 10 mmol), (Z)-3-(4-phenoxy-phenylcarbamoyl)- acrylic acid (2.62 g, 10 mmol), 2,2-dimethoxy-ethylamine (1.09 ml, 10 mmol) and isocyano- cyclohexane (1.25 ml, 10 mmol) in MeOH (20 ml) was stirred in at ambient temperature until LC-MS showed conversion to product (8 to 64 hrs). The compound was purified according the separation method E (MeOH) to give the title compound (4.0 g, 72%). LC/MS Analysis Method A: Rt 2.20 min, m/z 520 [M-OMe]

b) Synthesis Method B. Example 1.

4-Oxo-3-piperidin-4-ylmethyl-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-2,6-dicarboxylic acid 2-cyclohexylamide 6-[(3,4-dichloro-phenyl)-amide] Trifluoroacetate

Maleic anhydride (98 mg, 1 mmol) in dry THF (1 ml) was added to a solution of 3,4- dichloroaniline (162 mg, 1 mmol) in dry THF (0.5 ml) and stirred at ambient temperature over night. The reaction mixture was evaporated, and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (214 mg, 1 mmol) in MeOH (2 ml) was added, followed by furan-2-carbaldehyde (82.8 μl, 1 mmol) and isocyano-cyclohexane (122.7 μl, 1 mmol). The reaction mixture was heated to 50 ⁰C for 3 days, evaporated, redissolved in 2 M HCI in diethyl ether (2 ml), and left at ambiente temperature for 3 hrs. Evaporation and trituation with heptane gave a gray solid (487 mg, 74 %). The compound (50 mg) was purified according the separation method A to give the title compound (13.3 mg, 20%). LC/MS Analysis Method A: Rt 1.85 min, m/z 561 [M+H] c) Synthesis Method C Z)-3-(3,4-Dichloro-phenylcarbamoyl)-acrylic acid

Maleic anhydride (29.4 g, 0.3 mol) was dissolved to diethyl ether (300 ml) and 3,4-Dichloro- phenylamine (48.6, 0.3 mol) in diethyl ether (200 ml) was added during 5 minutes. The reaction mixture was stirred at room temperature for 16 hrs and participate was filtrated and dried to yield the title compound (67.9 g, 87%). Analysis Method A: Rt 2.07 min, m/z 260 [M+H];

d) Synthesis Method D Example 2.

3-[2-(3-Hydroxy-pyrrolidin-1-yl)-ethyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene- 2,6-dicarboxylic acid 2-cyclohexylamide 6-[(3,4-dichloro-phenyl)-amide] Trifluoroacetate

To an intermediate 3 (0.1 mmol, 51 mg) in DCM (1 ml) were added pyrrolidin-3-ol (0.4 mmol, 34 mg), tetrahydrofuran (1 ml) and NaBH(OAc)₃ (0.9 mmol 200 mg,). The mixture was stirred at 35-

4O⁰C for 64 hrs. The title compound was isolated using the separation method F and A (28 mg,

41 %).

Analysis Method A: Rt 1.78 min, m/z 577 [M+H]; ¹H NMR (DMSO-D6): δ 5.12

(app. dd, J =1.5, 1.5 Hz, 1 H, c/^'s-isomer)

The procedure of the synthesis method D can be performed in the variety of organic solvents, such as acetonitrile, 1 ,2-chloroethane, DCM or mixtures of of acetonitrile/DCM.

e) Synthesis Method E Intermediate 2.

2-Cvclohexylcarbamoyl-3-(2-diethylamino-ethyl)-4-oxo-10-oxa-3-aza- tricyclor5.2.1.0*1,5*1dec-8-ene-6-carboxylic acid Triethylamine salt

A mixture 2-Cyclohexylcarbamoyl-3-(2-diethylamino-ethyl)-4-oxo-10-oxa-3- azatricyclo[5.2.1.0^*1 ,5^*]dec-8-ene-6-carboxylic acid ethyl ester (198 mg, 0.5 mmol), lithium hydroxide monohydrate (30 mg, 0.7 mmol) tetrahydrofuran (3ml) and water (1 ml) was stirred at ambient temperature for 3 hrs and the title compound was isolated according the separation method G (93 mg, 50%)

Analysis Method A: Rt 0.91 min, m/z 420 [M+H]; ¹H NMR (DMSO-D6): δ 5.26 (dd, J =5, 1.5 Hz₁ 1 H₁ frans-isomer)

f) Synthesis Method F Example 3 3-(2-Diethylamino-ethyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-2,6- dicarboxylic acid 2-cyclohexylamide 6-[(3,4-dichloro-phenyl)-amide]

A mixture of intermediate 2 (0.05 mmol, 21 mg), DCM (1 ml), [dimethylamino-([1 ,2,3]triazolo[4,5- b]pyridin-3-yloxy)-methylene]dimethyl-ammonium hexafluoro phosphate (HATU₁ 0.08 mmol, 30 mg), 3,4-dichloroaniline ( 0.08 mmol, 13 mg) was stirred at ambient temperature and pH was adjusted to the 9 with di-isopropylethylamine. Mixture was stirred in at ambient temperature until LC-MS showed conversion to product (1 to 24 hrs). The title compound was isolated with separation method D (12 mg, 42 %)

Analysis Method A: Rt 2.34 min, m/z 563 [M+H]; ¹H NMR (DMSO-D6): δ 5.25 (d, J =4.5 Hz₁ 1 H₁ frans-isomer)

The procedure of the synthesis method N can as well be performed usig different peptide coupling reactans, such as 2-(6-Chloro-1 H-benzotriazole-1-yl)-1 ,1 ,3_l3-tetramethylaminium hexafluorophosphate) (HCTU) and (1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC) in the in the variety of the organic solvents, such as acetonitrile, tetrahydrofuran and N'N-dimethylformamide.

g) Synthesis Method G

Example 4

3-(2-Diethylamino-ethyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1 ,5*]decane-2,6-dicarboxylic acid 2-cyclohexylamide 6-[(4-phenoxy-phenyl)-amide]

The mixture of 3-(2-Diethylamino-ethyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0^*1 , 5^*]dec-8-ene-2,6- dicarboxylic acid 2-cyclohexylamide 6-[(4-phenoxy-phenyl)-amide] (40 mg, 0.07 mmol) and 10% palladium on charcoal (15 mg) and ethanol (7.5 ml) was stirred under 3 atmospheric pressure of hydrogen for 45 minutes. The reaction mixture was filtared and evaporated to yield the title compound (39 mg, 98%)

Analysis Method A: Rt 2.28 min, m/z 589 [M+H]; ¹H NMR (DMSO-D6): δ 4.71 (d, J=5.5 Hz₁ 1 H), 5.11 (bs, 1 H)

h) Synthesis Method H Example 5

4-Oxo-3-piperidin-3-yl-10-oxa-3-aza-tricyclo[5.2.1.0^*1,5*]dec-8-ene-2,6-dicarboxylic acid 2- cyclohexylamide 6-[(3,4-dichloro-phenyl)-amide] trifluoroacetate The 3-[2-Cyclohexylcarbamoyl-6-(3,4-dichloro-phenylcarbamoyl)-4-oxo-10-oxa-3- azatricyclo[5.2.1.0^*1 ,5^*]dec-8-en-3-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared using the procedure of synthesis method A, dissolved to MeOH and acetylchloride (1 ml) and stirred over night at room temperature. The title compound was purified using the procedures of the separation method F and A (15.2 mg 2 %)

Analysis Method A Rt: 1.77 min, m/z 547 [M+H]; 1 H NMR (DMSO-D6) : δ 5.10 (d, J = 1.60 Hz,

1 H) and 5.08 (d, J= 1.60 Hz₁ 1 H)

The procedure of the synthesis method H can as well be performed by replacing solvent after the first step by trifluoroacetic acid or mixture of trifluoroacetic acid and DCM.

i) Synthesis Method I

4-Oxo-3-(2-oxo-ethyl)-10-oxa-3-aza-tricyclo[5.2.1.0*1, 5*]decane-2,6-dicarboxylic acid 2- cyclopentylamide 6-[(4-trifluoromethyl-phenyl)-amide]

3-(2, 2-Dimethoxy-ethyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0^*1 ,5^*]decane-2,6-dicarboxylic acid 2-cyclopentylamide 6-[(4-trifluoromethyl-phenyl)-amide] (2.7 g, 5.0 mmol ) was stirred in 400 ml_ THF and 300 ml 4N HCI at 50⁰C for 3 hrs. Reaction was quenched with aqueous NaHCO₃ and extracted with EtOAc. The organic phase is concentrated to give the title compound as a white powder (2.5 g 100 %) Analysis Method A Rt: 1.85 min, m/z 494 [M+H];

i) Synthesis Method J

6-(3,4-Dichloro-phenylcarbamoyl)-3-(2-diethylamino-ethyl)-4-oxo-10-oxa-3-aza- tricyclo[5.2.1.0*1,5*]dec-8-ene-2-carboxylic acid

The mixture of 3-(2-diethylamino-ethyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0^*1 , 5*]dec-8-ene-2,6- dicarboxylic acid 2-[(4-tert-butyl-cyclohex-1-enyl)-amide] 6-[(3,4-dichloro-phenyl)-amide], (3.62 g, 5.56 mmol), aq. cncd HCI (14 ml) and THF (41 ml) was stirred at room temperature for 64 hrs. To the reaction mixture was added aq. NaHCO₃ until pH 9 was reached and the mixture was extracted with Et₂O, aqueous phase was acidified to pH 6-7 the mixture was evaporated to dryness. The residue was washed with DCM/MeOH (90/10) several times. After evaporation the compound was purified using the procedure of Separation method D.

I) Synthesis Method L (2-Amino-1,1-dimethyl-ethyl)-cyclopentyl-amine

Cyclopentylamine (7.9ml, 80 mmol) was added dropwise to acetonecyanohydrid (7.3 ml, 80 mmol) in MeOH (20 ml), reaction mixture was stirred 16 hrs at ambient temperature and evaporated yielding 9.7 g (80 %) intermediate 2-cyclopentylamino-2-methyl-propionitrile. Intermediate was dissolved to 200 ml Et₂O₁ cooled to -10 ⁰C and lithiumaluminiumhydride (2.2g, 60 mmol) was added in small portions during 30 minutes. Reaction mixture was stirred at ambient temperature for 1 hrs and cooled to -10 ⁰C, 4M aqueous NaOH (12 ml) was added dropwise, solids were filtrated trought a sodium sulphate and organic phase evaporated yielding the title compound (8.8g, 91%) that was used directly in the following steps.

m) Synthesis Method M N*1*-tert-Butyl-1-phenyl-ethane-1,2-diamine

A mixture of benzaldehyde (1.40 ml, 13.9 mmol), sodium cyanide (0.68 g, 13.9 mmol), tert- butylamine (1.45 ml, 13.9 mmol), 4N HCI (15 ml) and methanol (5 ml) was stirred at room temperature for 3 days. The intermediate was isolated using the separation method F. The residue was dissolved in ether and added to a commercially available solution of 2.3 M lithium aluminium hydride in tetrahydrofuran (7 ml, 16.1 mmol). The reaction mixture was stirred at room temperature over night, quenched by addition of 4N sodium hydroxide and the precipitate was removed by filtration and the filtrate was concentrated to give the title compound (1.70 g, 65 %). Analysis Method F Rt: 0.42 min, m/z 193 [M+H]; ¹H NMR (CD₃CW) δ 0.94 (s, 9 H) 2.59 (dd, J=12.43, 7.54 Hz, 1 H) 2.72 (dd, J=12.43, 5.84 Hz, 1 H) 3.61 (dd, J=7.63, 5.93 Hz, 1 H) 7.11 - 7.42 (m, 5 H)

n) Synthesis Method N

3-[2-(Cyclobutyl-isopropyl-amino)-ethyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1 ,5*]dec-8- ene-2,6-dicarboxylic acid 2-tert-butylamide 6-[(3-chloro-4-trifluoromethyl-phenyl)-amide] Example 6

A mixture of 3-(2-cyclobutylamino-ethyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0^*1 ,5^*]dec-8-ene-2,6- dicarboxylic acid 2-tert-butylamide 6-[(3-chloro-4-trifluoromethyl-phenyl)-amide]

(0.10 g, 0.18 mmol) and acetone (0.50 ml, 6.9 mmol) in 1 ,2-dichloroethane was stirred for 5 minutes. Sodium triacetoxyborohydride (0.075 g, 0.35 mmol) was added, and the reaction mixture was stirred at 50 ^CC for 4 hrs. The title compound was isolated using separation method

F and A (40 mg, 31%). Analysis Method E Rt: 1.36 min, m/z 61 1 [M+H]; ¹H NMR (DMSO-D6): δ

1.15 - 1.28 (m, 6 H) 1.35 (s, 9 H) 1.76 (m, 4 H) 4.56 (d, J=2.45 Hz, 1 H) 5.16 (dd, J=2.92, 1.79

Hz, 1 H) 7.52 (d, J=8.85 Hz, 1 H) 7.80 (d, J=8.85 Hz, 1 H) 8.08 (s, 1 H) 8.46 (d, J=4.52 Hz, 1 H)

10.62 (d, J=3.20 Hz, 1 H)

The procedure of the synthesis method N can as well be performed in the microwave cavity, typically at 80 ⁰C for 10 minutes. o) Synthesis Method O

3-[2-(Cyclopentyl-ethyl-amino)-ethyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1 ,5*]decane2,6- dicarboxylic acid 2-tert-butylamide 6-[(4-trifluoromethylphenyl)-amide] Example 7

3-[2-(Cyclopentyl-ethyl-amino)-ethyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1 ,5*]dec-8-ene-2,6- dicarboxylic acid 2-tert-butylamide 6-[(4-trifluoromethyl-phenyl)-amide] (10 mg) was dissolved to

THF (5 ml) and 5% platinium on charcoal (5 mg) was added. The reaction mixture was stirred under atmosphere of hydrogen (2.5 atm) for 30 minutes, filtrated and evaporated to yiled the title compound (10 mg, 99%)

Analysis Method E Rt: 1.32 min, m/z 579 [M+H]; 1 H NMR (DMSO-D6) : δ 4.55 (d, J = 4.5 Hz,

1 H) and 4.71 (app.dd, J= 5, 4 Hz, 1 H)

The procedure of the synthesis method O can as well be performed in MeOH or EtOH under at

1 atm hydrogen atmosphere for 1 to 48 hrs.

p) Synthesis Method P (i-Aminomethyl-cyclobutyO-isopropyl-amine

A mixture of cyclobutanone (0.75 ml, 10.0 mmol) and trimethylsilyl cyanide (1.26 ml, 10.0 mmol) was placed in a sealed reactor and stirred for 5 minutes. Acetic acid (1.30 ml, 15.0 mmol) and isopropylamine (1.71 ml, 20.0 mmol) were added causing an exotermic reaction. The reaction was stirred at room temperature over night and concentrated in vacuo followed by separation method F. The residue was dissolved in ether and added to a commercially available solution of 2.3 M lithium aluminium hydride in tetrahydrofuran (6 ml, 13.8 mmol). ). The reaction was stirred at room temperature over night, and quenched by addition of 4N sodium hydroxide. The precipitate was removed by filtration and the filtrate was concentrated to give the title compound (0.43 g, 30 %).

q) Synthesis Method Q Example 8

3-(2-Diethylamino-ethyl)-4-oxo-6-(4-trifluoromethyl-benzoylamino)-10-oxa-3-aza- tricyclo[5.2.1.0*1,5*]decane-2-carboxylic acid cyclohexylamide Trifluoroacetate

Synthesis method Q; Step 1 )

2-Cyclohexylcarbamoyl-3-(2-diethylamino-ethyl)-4-oxo-10-oxa-3-aza- tricyclo[5.2.1.0*1, 5*]decane-6-carboxylic acid

A mixture of 2-cyclohexylcarbamoyl-3-(2-diethylamino-ethyl)-4-oxo-10-oxa-3-aza- thcyclo[5.2.1.0^*1 ,5^*]dec-8-ene-6-carboxylic acid 4-nitro-benzyl ester (500 mg, 0.9 mmol) and 10% palladium on charcoal (50% H2O, Degussa typeE101 NEM/, 25 mg) in THF (10 ml) was stirred overnight at room temperature under one atmospheric pressure of hydrogen. The mixture was filtered and the filtrate was evaporated to dryness in vacuo at 40 °C. The residue was triturated with ether to give 325 mg (85%) of crude gray product which was used in the next step without further purification. Analysis Method A: Rt 1.3 min, m/z 422 [M+H]; (no UV signal).

Synthesis method Q; Step 2)

[2-Cyclohexylcarbamoyl-3-(2-diethylamino-ethyl)-4-oxo-10-oxa-3-aza- tricyclo[5.2.1.0*1,5*]dec-6-yl]-carbamic acid tert-butyl ester

A solution of crude 2-cyclohexylcarbamoyl-3-(2-diethylamino-ethyl)-4-oxo-10-oxa-3-aza- tricyclo[5.2.1.0^*1 ,5^*]decane-6-carboxylic acid (300 mg, 0.71 mmol) and triethylamine (0.11 ml, 0.78 mmol) in dry tert-butyl alcohol (10 ml) was stirred at room temperature in the presence of 0.4 nm molecular sieves. To the mixture was added diphenyl phosphorazidate (0.17 ml, 0.78 mmol) and the mixture was heated at 80 ⁰C for 21 h. Diethyl ether (10 ml) was added to the mixture which was then filtered. The filtrate was evaporated in vacuo to give 0.48 g of a sticky mass which was dissolved in ethyl acetate (25 ml) and washed with sat. aq. NaHCO₃ (3 x25 ml) and brine (25 ml). The organic phase was dried over Na₂SO₄, filtered and evaporated to dryness in vacuo to give 188 mg (51%) of a solid beige product. Analysis Method A: Rt 1.8 min, m/z 493 [M+H];.

Synthesis method Q; Step 3)

6-Amino-3-(2-diethylamino-ethyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1₎5*]decane-2- carboxylic acid cyclohexylamide Hydrochloride

A mixture of [2-cyclohexylcarbamoyl-3-(2-diethylamino-ethyl)-4-oxo-10-oxa-3-aza- tricyclo[5.2.1.0^*1 , 5^*]dec-6-yl]-carbamic acid tert-butyl ester (140 mg, 0.28 mmol) in 10 ml of 2 N

HCI was stirred at 50 °C for 2 h and the resulting clear solution was evaporated to dryness in vacuo at 80 ⁰C to give ~80 mg of crude product which was used in the next step without further purification.

Analysis Method A: Rt 0.5 min, m/z 393 [M+H]; (no UV signal).

Synthesis method Q; Step 4)

3-(2-Diethylamino-ethyl)-4-oxo-6-(4-trifluoromethyl-benzoylamino)-10-oxa-3-aza- tricyclo[5.2.1.0*1,5*]decane-2-carboxylic acid cyclohexylamide Trifluoroacetate

Triethylamine (200 μl, 1.44 mmol) was added to a suspension of the crude 6-amino-3-(2- diethylamino-ethyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0^*1, 5^*]decane-2-carboxylic acid cyclohexylamide hydrochloride (80 mg, 0.19 mmol, Synthesis method Q) in THF (3 ml) followed by 4-(trifluoromethyl)benzoyl chloride (151 μl, 1.0 mmol). The reaction mixture was stirred at room temperature overnight and evaporated to dryness in vacuo. The solid residue was triturated with a mixture of water (15 ml) and sat aq NaHCO₃ (5 ml). The mixture was filtered and the solid was washed with water and air-dried to give 165 mg of crude beige product of which 150 mg was purified by separation method A to give 15.7 mg (15%) as a white solid. Analysis Method A: Rt 1.93 min, m/z 565 [M+H]; ¹H NMR (DMSO-D6): δ 1.1-3.6 (m, 32H), 4.44- 4.56 (m, 3H), 7.82 (d, J = 8.43 Hz₁ 2H), 7:95 (d, J = 8.43 Hz, 2H)₁ 8.28 (d, J = 7.7 Hz, 1 H)₁ 8.52 (d, J = 7.7 Hz₁ 1 H)₁ 9.03 (br s, 1 H)

r) Synthesis Method R Example 9

3-[2-(Cyclopentyl-ethyl-amino)-ethyl]-2-(octahydro-isoquinoline-2-carbonyl)-4-oxo-10- oxa-3-aza-tricyclo[5.2.1.0*1 ,5*]dec-8-ene-6-carboxylic acid (4-trifluoromethyl-phenyl)- amide.

Synthesis method R; step 1. 2-(Cyclopentyl-ethyl-amino)-ethylamino]-furan-2-yl-acetic acid.

A mixture of (2-furyl)glyoxylic acid (2.80 g, 20 mmol) and N-ethyl-N^'-cyclopentylethylenediamine (3.1 g, 20 mmol) in MeOH (100 ml_) was stirred at room temperature for 2 h. NaBH₃CN (1.26 g, 20 mmol) and Montmorillonite K10 (2.0 g) was added and the mixture was stirred for 3 h. The reaction mixture was filtered through Celite and washed with MeOH. Concentration gave the product (5.5 g, 98%) ], which was used directly in the next step. Analysis Method A: Rt 0.35 min, m/z 281 [M+H

Synthesis method R; step 2.

2-[2-(Cyclopentyl-ethyl-amino)-ethylamino]-2-furan-2-yl-1-(octahydro-isoquinolin-2-yl)- ethanone.

The mixture of 2-(cyclopentyl-ethyl-amino)-ethylamino]-furan-2-yl-acetic acid (, 4.0 g, 14.3 mmol), decahydroisoquinoline (2.1 ml_, 14.3 mmol), N,N-diisopropylethylamine (5.0 mL, 28.6 mmol) and 2-(1 H-7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate methanaminium (5.4 g, 14.3 mmol) and acetonitrile (100 mL) was stirred over night at room temperature. The reaction mixture was concentrated and extracted from dichloromethane (200 mL) into 1 M HCI (40 mL), aqueous phase was basified and extracted with dichloromethane (200 mL). Organic phase was dried with MgSO₄, concentrated and purified by separation method D (40 g SiO₂ column, 0-10% MeOH in DCM). Yield 4.7 g (82%) Analysis Method A: Rt 1.40 min, m/z 402 [M+H];.

Synthesis method R; step 3. (4-Trifluoromethyl-phenyl)-(2,4,6-trimethoxy-benzyl)-amine

A solution of 2,4,6-trimethoxybenzaldehyde (1.96 g, 10 mmol) and 4-(trifluoromethyl)aniline (1.3 ml_, 10 mmol) in MeOH (40 ml_) was stirred at room temperature over night. Then NaBH(OAc)₃ (2.50 g, 12 mmol) was added and the mixture was stirred for additionally 2 h at room temperature. The solid was filtered and washed with MeOH (10 mL) yielding the crude product (2.78 g (81%) that was used directly in the next step. Analysis Method A: Rt 3.00 min, m/z 522 [M+C₁₀H₁₃O₃], m/z 181 [Ci₀H₁₃O₃].

Synthesis method R; step 4. (Z)-3-[(4-Trifluoromethyl-phenyl)-(2,4,6-trimethoxy-benzyl)-carbamoyl]-acrylic acid.

The mixture of maleic anhydride (0.95 g, 9.7 mmol) and (3-chloro-4-trifluoromethoxy-phenyl)- (2,4,6-trimethoxy-benzyl)-amine (2.78 g, 8.1 mmol) and diethyl ether (30 mL) was stirred over night at room temperature. The reaction mixture was concentrated and taken up in EtOAc₁ extracted into a saturated Na₂CO₃-solution, acidified with 1 M HCI and then extracted into DCM. The organic phase was passed through a phase separation filter and concentrated to give the product 1.95 g (55%), which was used directly in the next step. Analysis Method A: Rt 2.50 min, m/z 462 [M+Na], m/z 181 [Ci₀H₁₃O₃].

Synthesis method R; step 5.

The (Z)-3-[(4-Trifluoromethyl-phenyl)-(2₁4,6-trimethoxy-benzyl)-carbamoyl]-acrylic acid (483 mg, 1.1 mmol) was dissolved in acetonitrile (40 mL), isobutyl chloroformate (700 μL, 1.3 mmol) and N-ethylmorpholine (1.4, 2.6 mmol) were added and the mixture was stirred for 30 minutes. The activated carboxylic acid was added in portions over 2 h to a solution of 2-[2-(Cyclopentyl-ethyl- amino)-ethylamino]-2-furan-2-yl-1-(octahydro-isoquinolin-2-yl)-ethanone (400 mg, 1.0 mmol) in acetonitrile (10 mL) at 60 ⁰C. Resulting mixture was stirred at 60 ⁰C over night and intermediate was isolated using the procedures of separation Mehtod F and D. The mixture of the intermediate and TFA/Et₃Si/DCM (5:5:90, 10 mL) was stirred for 1 h at room temperature and the title product was isolated using the separation method F and A. ( 5.0 mg, 1 %). Analysis Method A: Rt 2.40 min, m/z 643 [M+H]; ¹H NMR (DMSO-D6): δ 5.16 (m, 1 H).

s) Synthesis Method S

Synthesis was performed using the procedure of synthesis method R, but the step 5 intermediate was isolated as such.

t) Synthesis Method T Example 10 3-{2-[Cyclobutyl(2-methoxyethyl)amino]ethyl}-4-oxo-10-oxa-3-azatricyclo[5.2.1.0*1,5*]dec- 8-ene-2,6-dicarboxylic acid 2-cyclopentylamide 6-[(4-trifluoromethylphenyl)amide]

The mixture of 3-(2-Cyclobutylaminoethyl)-4-oxo-10-oxa-3-azatricyclo[5.2.1.0^*1 ,5^*]dec-8-ene-

2,6-dicarboxylic acid 2-cyclopentylamide 6-[(4-trifluoromethylphenyl)amide] (0.18mmmol,

100mg), 2-bromoethylmethylether (0.18mmol, 25mg), potassium carbonate (0.73mmol, 101 mg) and acetonitrile (2ml) was stirred at 60^°C for 16 hrs and the title compound was purified using the procedure of separation method F and A (11.5 mg 8.9 %)

Analysis Method A Rt: 2.02 min, m/z 605 [M+H]; 1 H NMR (DMSO-D6): δ 5.12 (mp, 1 H, cis isomer)

u) Separation Method A

The separation was performed with Mass-directed fraction collection under standardised conditions as follows: Instrument: Agilent 1100 HPLC/MSD system, 254 nm UV detection; Column: YMC 19x100 mm; Flow: 20 mL/min. Gradient: 0 min: 5 to 50%, 12 min 30-95% MeCN in water; Modifier: 0.1% TFA; MS-ionisation mode: API-ES (pos.)

v) Separation Method B

The separation was performed with Mass-directed fraction collection under standardised conditions as follows: Instrument: Agilent 1100 HPLC/MSD system, 254 nm UV detection; Column: YMC 19x100 mm; Flow: 20 mL/min. Gradient: 0 min: 5 to 50%, 12 min 30-95% MeCN in water; Modifier: 50 mM NH₄HCO₃; MS-ionisation mode: API-ES (pos.)

x) Separation Method C

The separation was performed with manual fraction collection under standardised conditions as follows: Instrument: Shimadzu HPLC/MSD system;_Column: Chiralpak AD SFC 20x250 mm; Flow: 10-20 mL/min. Eluent: isocratic between 15 and 85 % of 2-propanol, ethanol or mixture of 2-propanol/ethanol in heptane or hexane Detection: UV 254 nM

y) Separation Method D

The crude product was absorbed to small amount SiO₂ and eluated trought a SiO₂ colum with mixture of MeOH₁ ethanol or EtOAc in heptan or DCM containing triethyl amine, ammonia or other basic modificator (from 0/100/0 to 45/45/10, typically 5/94/1 ).

x)Separation Method E

The precipitated solid was filtered, washed or recrystallized in the defined solvent or mixture of solvets to give the title compound. aa) Separation Method F

The reaction mixture was diluted with organic solvent (typically DCM or EtOAc) and washed with water or aqueous base (typically NH₄OH, NaHCO₃ or NaOH) and dried over the drying agent (typically Na₂SO₄ or K₂CO₃), filtrated and evaporated.

ab) Separation Method G

The reaction mixture was applied to acidic ion-exchange column and the column was washed with MeOH. The compound was eluated with MeOH containing 1 to 30 % base like aqueous NH3, triethyl amine, diethyl amine or similar, filtrated and evaporated.

ac) Separation Method H

The reaction mixture was filtrated trought a plug of inert absorbiton material (celite or Na₂SO₄) and evaporated.

ad) Analysis Method A

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.).

ae) Analysis Method B

Column; Gemini C18, 5μm, 2.0x50mm. Flow: 1.2 ml/min; Gradient: Acetonitrile in 50 mM aqueous ammonium bicarbonate: 10% - 95% acetonitrile over 3.5 minutes then 95% acetonitrile for 1.0 minute. Instrument: Agilent 1 100 HPLC/MSD system, 220 nm UV detection. MS- ionisation mode: API-ES (pos. or neg.).

af) Analysis Method E

Column; Acquity UPLC BEH, 1.7 μm, 2.1x50mm. Flow: 0.5 ml/min; Gradient: Acetonitrile in 0.1 % aqueous trifluoroacetic acid: 5% - 95% acetonitrile over 1.4 minutes then 95% acetonitrile for 0.6 minute. Instrument: Waters Acquity SQD HPLC/MSD system, photodiode array UV detection 210 - 400 nM, MS-ionisation mode: API-ES (pos. and neg.).

ag) Analysis Method F

Column; Acquity UPLC BEH, 1.7 μm, 2.1x50mm. Flow: 0.5 ml/min; Gradient: Acetonitrile in 50 mM aqueous ammonium bicarbonate: 5% - 95% acetonitrile over 1.4 minutes then 95% acetonitrile for 0.6 minute. Instrument: Waters Acquity SQD HPLC/MSD system, photodiode array UV detection 210 - 400 nM, MS-ionisation mode: API-ES (pos. and neg.). Intermediate 3.

4-Oxo-3-(2-oxo-ethyl)-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-2,6-dicarboxylic acid 2- cyclohexylamide 6-[(3,4-dichloro-phenyl)-amide]

Intermediate 1 (2.8 g, 5.0 mmol) was stirred in the mixture of tetrahydrofuran (20 ml) and 4 M aqueous HCI (20 ml) at 50 ⁰C for 4 hours. The title compound was purified according the separation method F (2.4 g, 90%) and used directly in the next steps. Analysis Method A: Rt 1.90 min, m/z 506 [M+H]

Intermediate 4.

4-Oxo-3-(2-oxo-ethyl)-10-oxa-3-aza-tricyclo[5.2.1.0*1, 5*]decane-2,6-dicarboxylic acid 2- cyclopentylamide 6-[(4-trifluoromethyl-phenyl)-amide]

The title compound was prepared using the procedure of synthesis method A and G and I and separation method F (last step 1.7 g 80%) and used directly in the next steps. Analysis Method A Rt: 1.8 min, m/z 494 [M+H];

Example 11

3-(2-Diethylamino-ethyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-2,6- dicarboxylic acid 2-amide6-[(3,4-dichloro-phenyl)-amide]

The title compound was prepared using the procedure of synthesis Method J but the reaction time was 2 hrs. The solvent were evaporated and precipitation washed with EtOAc to give the title compound (7.7 mg, 32%)

Analysis Method A Rt: 1.77 min, m/z 481 [M+H]; 1 H NMR (DMSO-DΘ): 5 5.11 (d, J = 1.5 Hz, 1 H, cis-isomer).

The commercial Examples were obtained from the ChemDiv INC™, 6605 Nancy Ridge Drive, San Diego CA 92121- 2253, USA.

Commercial Example 1

3-(3-Dipropylamino-propyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1, 5*]dec-8-ene-2,6- dicarboxylic acid 2-cyclohexylamide 6-[(3-methylsulfanyl-phenyl)-amide]

Commercial Example 2

3-[3-(4-Benzyl-piperazin-1-yl)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8- ene-2,6-dicarboxylic acid 2-cyclohexylamide 6-[(4-isolpropyl-phenyl)-amide]

Commercial Example 3

3-[2-(4-Ethyl-piperazin-1-yl)-ethyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene- 2,6-dicarboxylic acid 2-cyclohexylamide 6-[(3,4-dichloro-phenyl)-amide]

Commercial Example 4

3-(2-Diethylamino-ethyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1, 5*]dec- 8-ene-2,6-dicarboxylic acid 2-cyclohexylamide 6-[(4-phenoxy-phenyl)-amide]

Commercial Example 5

3-[3-(4-Methyl-piperazin-1-yl)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8- ene-2,6-dicarboxylic acid 2-cyclohexylamide 6-[(4-phenoxy-phenyl)-amide]

Commercial Example 6

3-(2-Azepan-1-yl-ethyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-2,6- dicarboxylic acid 2-cyclohexylamide 6-[(4-phenoxy-phenyl)-amide] Commercial Example 7

3-[2-(Benzyl-methyl-amino)-ethyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene- 2,6-dicarboxylic acid 2-cyclohexylamide 6-[(4-phenoxy-phenyl)-amide]

Commercial Example 8

3-[2-(Butyl-methyl-amino)-ethyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene- 2,6-dicarboxylic acid 2-cyclohexylamide 6-[(4-phenoxy-phenyl)-amide

Commercial Example 9

3-[2-(4-Ethyl-piperazin-1-yl)-ethyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene- 2,6-dicarboxylic acid 2-cyclohexylamide 6-[(4-phenoxy-phenyl)-amide]

Commercial Example 10

4-Oxo-3-(3-pyrrolidin-1 -yl-propyl)-10-oxa-3-aza-tricyclo[5.2.1.0*1 ,5*]dec-8-ene-2,6- dicarboxylic acid 6-[(3-chloro-4-methyl-phenyl)-amide] 2-cyclohexylamide

Commercial Example 11

3-[3-(4-Ethyl-piperazin-1-yl)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8- ene-2,6-dicarboxylic acid 2-cyclohexylamide 6-[(3,5-dichloro-phenyl)-amide]

Commercial Example 12

3-[3-(4-Methyl-piperazin-1-yl)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8- ene-2,6-dicarboxylic acid 2-cyclohexylamide 6-[(3,4-dichloro-phenyl)-amide]

Commercial Example 13

3-[3-(4-Benzyl-piperazin-1-yl)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8- ene-2,6-dicarboxylic acid 2-cyclohexylamide 6-[(3,4-dichloro-phenyl)-amide]

Commercial Example 14

3-(3-Diethylamino-propyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1, 5*]dec-8-ene-2,6- dicarboxylic acid 6-[(4-chloro-phenyl)-amide] 2-cyclohexylamide

Commercial Example 15

3-[3-(4-Benzyl-piperazin-1-yl)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8- ene-2,6-dicarboxylic acid 6-[(4-chloro-phenyl)-amide] 2-cyclohexylamide Commercial Example 16

3-[3-(Benzyl-methyl-amino)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene- 2,6-dicarboxylic acid 6-[(4-bromo-phenyl)-amide] 2-cyclohexylamide

Commercial Example 17

3-[3-(Butyl-methyl-amino)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene- 2,6-dicarboxylic acid 6-[(4-bromo-phenyl)-amide] 2-cyclohexylamide

Commercial Example 18

3-[3-(4-Benzyl-piperazin-1-yl)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8- ene-2,6-dicarboxylic acid 6-[(4-bromo-phenyl)-amide] 2-cyclohexylamide

Commercial Example 19

3-[3-(Benzyl-ethyl-amino)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene- 2,6-dicarboxylic acid 2-cyclohexylamide 6-[(3-methylsulfanyl-phenyl)-amide]

Commercial Example 20

3-[3-(4-Benzyl-piperazin-1-yl)-propyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8- ene-2,6-dicarboxylic acid 2-cyclohexylamide 6-[(3-methylsulfanyl-phenyl)-amide]

Commercial Example 21

3-(3-Diethylamino-propyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene 2,6- dicarboxylic acid 2-cyclohexylamide 6-[(4-isopropyl-phenyl)-amide]

Commercial Example 22

3-(3-Dipropylamino-propyl)-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene 2,6- dicarboxylic acid 2-cyclohexylamide 6-[(4-isopropyl-phenyl)-amide]

Commercial Example 23

3-[2-(4-Ethyl-piperazin-1-yl)-ethyl]-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene- 2,6-dicarboxylic acid 2-cyclohexylamide 6-[(4-isopropyl-phenyl)-amide]

Biological data:

Compounds were tested in the functional ghrelin receptor assay described below, and their EC/IC50 values for agonism, inverse agonism and antagonism for the ghrelin receptor were assessed. The potency in each of the two assays were grouped in four classes

A: IC₅₀ or EC₅₀ value lower than 0.1 μM.

B: IC₅₀ or EC₅₀ value between 0.1 μM and 1 μM

C: IC_5O or EC₅₀ value between 1 μM and 10 μM

D: IC50 or EC₅₀ value greater than 10 μM

N. D. (Not determined) indicates that the EC/IC₅₀ value has not been measured for the given compound.

Compounds stimulating the ghrelin receptor above the basel level (in the agonist assay) are displayed with a (+) indicating that the compound behaves as an agonist or partial agonist. Compounds inhibiting the ghrelin receptor below the basel level (in the agonist assay) are displayed with an (-) indicating that the compound behaves as an inverse agonist.

Commercial

Example 15 D D

Commercial

Example 16 D A

Commercial

Example 17 B A

Commercial

Example 18 C C

Commercial

Example 19 D A

Commercial

Example 20 C D

Commercial

Example 21 C D

Commercial

Example 22 C B

Commercial

Example 23 D A

The compound of Example 360 is a positive modulator in the above assay, indicating that the compound behaves as an agonist or partial agonist. That compound was tested in an in vivo assay to determine its effect on weight gain in mice, as follows:

Animals: 7 week old Male C57BL/6 mice from Charles River (Germany) were used in the study. Animals were single housed and granted a one-week acclimatization period. During the entire study, the animals are kept on a 12h/12h light/dark cycle (lights on at 06:00 and off at 18:00) in a temperature and humidity controlled environment, with ad libitum access to standard chow feed (Altromin standard #1324 chow; C. Petersen, Ringsted, Denmark) and tap water.

Treatment groups: On experimental day -1 the animals were randomized into four weight-matched groups (n=8).

Dosing: A three-day run-in period (days -3 to -1 ) of daily mock dosing (twice) and handling is applied to make the animals accustomed to the dosing procedure. Test compound (Example 360, 10 mg/kg) or vehicle were dosed twice daily at 07:00 and 15:00. (corresponding to 1 h and 9h inside the light-phase).

The results are summarised in Figure 1. Treatment with the compound in this assay resulted in a net weight gain in the treated group relative to the control group.

The compound of Example 369 is a negative modulator in the above assay, indicating that the compound behaves as an inverse agonist. That compound was tested in an in vivo assay to determine its effect on weight gain in mice, as follows: Animals: 8 week old male Sprague Dawley rats (approximately 200 g) were obtained from Charles River (Germany). The rats were single housed with ad libitum access to

HE diet (#12266B; Research Diets, New Jersey USA). All animals had access to tap water ad libitum. Animals were kept under a 12/12 L/D cycle (lights off at 18:00) and in temperature and humidity controlled rooms.

Treatment groups: On experimental day -1 the animals were randomized into four weight-matched groups (n=10).

Dosing: After acclimatization rats were subjected to 3 days of daily mock injections to accustom them to the dosing procedure. Test compound (Example 369, 20 mg/kg) / vehicle was administered twice daily (8AM and 16PM) for 14 days.

The results are summarised in Figure 2. Treatment with the compound in this assay resulted in a net weight loss in the treated group relative to the control group.

Claims

Claims:

1. The use of a ghrelin receptor modulating compound of formula (IA) or (IB), or a salt, hydrate, solvate, or N-oxide thereof, in the preparation of a medicament for the treatment of conditions responsive to increased or decreased ghrelin receptor activity:

wherein

W is, in either orientation, -C(=O)N(R₃)-, or -C(=O)O-;

R is hydrogen or C₁-C₄ alkyl;

Ri is selected from hydrogen, (C₁-C₄JaIKyI, cycloalkyl, fully or partially fluorinated (C₁- C₄)alkyl, or -OR₁₀; and R₂ is selected from (i) hydrogen and (ii) (d-C₄)alkyl, cycloalkyl, cycloalkenyl, and non aromatic heterocyclyl, each optionally substituted by -F, -CN, C₁-C₄ alkyl, cyclopropyl, -NR₇COR₀, -NR₇SO₂R₀, -COR₀, -COOH, -SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or -NR₇COOR₈; and (iii) aryl, aryl-(C₁-C₂)alkyl-, heteroaryl and heteroaryKd-C_∑ alkyl)- each optionally substituted in the ring part or

R₁ and R₂, together with the nitrogen to which they are attached, form an optionally substituted cyclic amino group;

R₃ is selected from hydrogen, (Ci-C₄)alkyl, cycloalkyl, fully or partially fluorinated (C₁- C₄)alkyl, or -OR₁₀; and R₄ Js selected from (iv) hydrogen and (v) (C₁-C₄)alkyl, cycloalkyl, and non aromatic heterocyclyl, each optionally substituted by -F, -CN, -NR₇COR₀, -NR₇SO₂R₀, - COR₀, -COOH, -SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or -NR₇COOR₈; and (vi) aryl, aryl-(C_r C₂)alkyl-, heteroaryl and heteroaryl-(Ci-C₂ alkyl)- each optionally substituted in the ring part thereof; or

R₃ and R₄, together with the nitrogen to which they are attached, form an optionally substituted cyclic amino group; L is -(CR₁₁R₁₃)_aB(CR₁₂R₁₄)b-;

a and b are independently 0,1 , 2, 3, 4, 5 or 6 provided that the sum a+b is from 2 to 8;

B is a bond, -CO-, -O-, -SO₂-, a divalent phenylene or divalent cycloalkylene radical either of which being oprionally substituted by -F, -CN, -NR₇COR₀, -NR₇SO₂R₀, - COR₀, -COOH, -SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or -NR₇COOR₈;

subject to the provisos that (a) one R₁₁ or R₁₂ present in L may, together with R₆, form a bond or divalent radical linking the nitrogen to which R₆ is attached and a carbon atom in L, to form a 4-, 5-, 6-, or 7-membered ring including the said nitrogen and carbon, and (b) R_1I and R₁₃ together with the carbon atom to which they are attached may form a monocyclic cycloalkyl or saturated heterocyclic ring of 3 to 7 ring atoms, and (c) R₁₂ and R₁₄ together with the carbon atom to which they are attached may form a monocyclic cycloalkyl or saturated heterocyclic ring of 3 to 7 ring atoms, then

Rii. Ri_2ι Rn and R₁₄ are each selected from hydrogen, (CrC^alkyl, cycloalkyl, fully or partially fluorinated (C₁-C₄)alkyl, -ORi₀, or phenyl optionally substituted by -F, - CN, -NR₇COR₀, -NR₇SO₂R₀, -COR₀, -COOH, -SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or - NR₇COOR₈;

subject to the proviso that R₆ together with one R₁₁ or R₁₂ present in L may form a bond or divalent radical linking the nitrogen to which R₆ is attached and a carbon atom in L to form a 4-, 5-, 6-, or 7-membered ring including the said nitrogen and carbon, R₅ and R₆ are independently selected from (vii) hydrogen, and (ix) (C₁-C₄)SIkYl, cycloalkyl, and non aromatic heterocyclyl, each optionally substituted by -F, -CN, -NR₇COR₀, -NR₇SO₂R₀, - COR₀, -COOH, -SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or -NR₇COOR₈; and (x) aryl, aryl-(C_r C₂)alkyl-, heteroaryl and heteroaryl-(C₁-C₂ alkyl)- each optionally substituted in the ring part thereof; or R₅ and R₆, together with the nitrogen to which they are attached, form an optionally substituted cyclic amino group;

R₀ is (C₁-C₄)alkyl, cycloalkyl, -CF₃ or -NR₇R₈;

R₇ and R₈ are independently hydrogen, (d-C₄)alkyl or cycloalkyl, or R₇ and R₈ when attached to the same nitrogen atom form a cyclic amino group; R₉ is hydrogen, (Ci-C₄)alkyl, cycloalkyl, or fully or partially fluorinated (d-C₄)alkyl; and

Rio is hydrogen, (Ci-C₄)alkyl, cycloalkyl, or fully or partially fluorinated (CrC₄)alkyl, or optionally substituted aryl or heteroaryl.

2. A method of treatment of conditions responsive to increased or decreased ghrelin receptor activity, comprising administering an effective amount of a compound as defined in claim 1 to a subject suffering such condition.

3. The use as claimed in claim 1 or a method as claimed in claim 2 wherein the ghrelin receptor modulating compound is one which increases ghrelin receptor activity in vivo and the condition is selected from eating disorders like cachexia (e.g. associated with COPD, CHF, cancer, AIDS, diabetic gastroparesis, IBS, chronic arthritis), anorexia, bulimia, wasting conditions (e.g. associated with AIDS, surgical stress, cachexia of critical illness, sepsis, glucocorticoid administration and cancer), gastrointestinal disorders (e.g. gastic ileus, gastric ulcer, chronic intestinal pseudo-obstruction, functional gastrointestinal disorders and inflammatory bowel diseases), reduced gastrointestinal motility (e.g. opioid induced constipation, diabetes related gastroparesis, treating gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS)), growth hormone (GH) deficiency, pathological weight loss, protein-energy malnutrition, age related osteoporosis, rheumatoid arthritis and lipodystrophy.

4. The use as claimed in claim 1 or a method as claimed in claim 2 wherein the ghrelin receptor modulating compound is one which decreases ghrelin receptor activity and the condition is selected from obesity and overweight, prevention of weight gain, weight-loss maintenance, conditions associated with obesity as risk factor metabolic disorders eating disorders, and Prader-Willi syndrome.

5. The use as claimed in claim 1 or a method as claimed in claim 2 wherein the ghrelin receptor modulating compound is one which decreases ghrelin receptor activity and the condition is selected from (a) prevention of weight gain induced by medication or smoking cessation); and (b) a condition associated with obesity as risk factor selected from metabolic syndrome, type 2 diabetes, cardiovascular disease, osteoarthritis, and obesity related cancer; and (c) a metabolic disorder selected from dyslipidemia, hyperlipidemia, low HDL and/or high LDL cholesterol levels, hypertriglycerideemia, low adiponectin levels, impaired glucose tolerance, insulin resistance, HbAIc [glycosylated haemoglobin], diabetes mellitus, type 2 diabetes, reduced metabolic activity, and fatty liver.

6. The use or method as claimed in any of the preceding claims wherein R is hydrogen or methyl.

7. The use or method as claimed in any of the preceding claims wherein, in the said compound, W is, in either orientation, -C(=O)N(R₃)-.

8. The use or method as claimed in claim 7 wherein, in the said compound, R₃ is hydrogen or methyl.

9. The use or method as claimed in claim 7 or claim 8 wherein, in the said compound, R₄ is (Ci-C₄)alkyl, cycloalkyl, or non aromatic heterocyclyl, each optionally substituted by - F, -CN, -NR₇COR₀, -NR₇SO₂R₀, -COR₀, -COOH, -SOR₉, -SO₂R₀, -OR₁₀, -NR₇R₈, or - NR₇COOR₈, wherein R₀ is methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, - CF₃ or -NR₇R₈; R₇ and R₈ are independently hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; or R₇ and R₈ when attached to the same nitrogen atom form a piperidine, morpholine, piperazine ring, the latter being optionally N-substituted by (Ci-C₄)alkyl; Rg is hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or -CF₃; and R_i0 is hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl cyclopentyl, cyclohexyl, - CF₃, or optionally substituted phenyl or monocyclic heteroaryl having 5 or 6 ring atoms.

10. The use or method as claimed in claim 7 or claim 8 wherein, in the said compound, R₄ is phenyl optionally ring-substituted by -CF₃, -F, -Cl, -OCF₃ or CN.

11. The use or method as claimed in claim 10 wherein, in the said compound, -W- is - 0(C=O)-^* with the bond marked with an asterisk being attached to R₄.

12. The use or method as claimed in any of the preceding claims wherein, in the said compound, R₁ is hydrogen and R₂ is cyclopentyl or benzyl, the latter being optionally ring- substituted by -CF₃ -F, -Cl, -OCF₃ or CN.

13 The use or method as claimed in any of the preceding claims wherein, in the said compound, L is -CH₂CH₂- or -CH₂CH₂CH₂-, -CH₂CH(CH₃)CH₂-, or in either orientation - CH(CH₃)CH₂- or -CH(CH₃)CH₂CH₂-,

14. The use or method as claimed in claim 13 wherein R₅ and R₆ are independently selected from Ci-C₄ alkyl and C₃-C₆ cycloalkyl.

15. The use or method as claimed in claim 14 wherein R₅ is isopropyl and R₆ Js cyclobutyL

16 The use or method as claimed in any of claims 1 to 12 wherein, in the said compound, -L-N(R₅)(R₆) is a piperidinyl ring, linked to the rest of the molecule via a ring carbon, and optionally substituted by F, CN, Rg or -ORg.

17. The use or method as claimed in claim 16 wherein -L-N(R₅)(R₆) is a piperidin-4-yl ring, optionally substituted by methyl, ethyl or isopropyl.

18. The use or method as claimed in any of the preceding claims wherein, in the said compound, the said compound has formula (IB).

19. A compound as defined in any of claims 1 and 7 to 18, excluding compounds of formula (IC)

wherein:

A. when R₂ is cyclohexyl and R₅R₆N- is 1 -ethyl-pyrrolidin-2-yl, then R₄ is not 3- methoxy- or 3-chloro-4-methyl-phenyl;

B. when R₂ is cyclohexyl and R₅R₆N- is morpholin-1-yl, then R₄ is not 3-methoxy-, 4- methoxy-, 3-chloro-, 4-chloro-, 4-bromo-, 3,5-dimethyl-, 3-methylthio-, 3,5-dimethyl-, 4- methyl-, 3,5-dichloro-, 4-isopropyl- or 3,4-dichloro-phenyl;

C. when R₂ is cyclohexyl and R₅R₆N- is homopiperidin-1-yl, then R₄ is not 3-methoxy-, 3-chloro-, 4-chloro-, 4-bromo- or 3-methylthio-phenyl;

D. when R₂ is cyclohexyl and R₅R₆N- is 2-methyl-piperidin-1-yl, then R₄ is not 3- methoxy-, 4-methoxy-, 4-methoxy-, 3-chloro-, 4-chloro-, 4-bromo-, or 3-methylthio-phenyl; E. when R₂ is cyclohexyl and R₅R₆N- is 2-ethyl-piperidin-i-yl, then R₄ is not 3-methoxy- , 4-methoxy- or 3-methylthio-phenyl

F. when R₂ is cyclohexyl and R₅R₆N- is piperidin-1-yl, then R₄ is not 3-methoxy-, 3- chloro-, 4-chloro-, 4-bromo-, 3,5-dimethyl-, 3-methylthio-, 3,5-dichloro-l, or 3,4-dichloro- phenyl;

G. when R₂ is cyclohexyl and R₅R₆N- is 1-ethyl-piperazin-4-yl, then R₄ is not 4-methyl- or 3,5-dichloro-phenyl;

H. when R₂ is cyclohexyl and R₅ is methyl and R₆ is benzyl, then R₄ is not 3-methoxy-, 4-methoxy-, or 3-methylthio-phenyl;

I. when R₂ is cyclohexyl and R₅ is methyl and R₆ is n-propyl, then R₄ is not 3-chloro-, 4-chloro- or 4-methyl-phenyl;

J. when R₂ is cyclohexyl and R₅ and R₆ are each ethyl, then R₄ is not 3-chloro-4- methyl-, 3,5-dimethyl-, or 4-isopropyl-phenyl;

K. when R₂ is cyclohexyl and R₅ and R₆ are each methyl, then R₄ is not 3,5-dichloro- phenyl;

L. when when R₂ is 2,3-dimethyl-cyclohexyl and R₅R₆N- is 1-ethyl-piperazin-4-yl, then R₄ is not 3-methylthio-, 3-chloro-4-fluoro; 3,5-dichloro, 3-methyl, 4-isopropyl, 3-chloro-4- fluoro, 3-chloro, 3,4-dimethyl 3,5-dimethyl, 3-methylthio;

M. when R₂ is 2,3-dimethyl-cyclohexyl and R₅R₆N- is piperidin-1-yl, then R₄ is not 3- methylthio-, 4-methoxy- or 3-methyl-, 4-isopropyl, 3-chloro-4-fluoro, 3-methyl, 3-chloro, 4- chloro, 3-chloro-4-methyl, 3,5-dimethyl, or 3-methylthiophenyl

N. when R₂ is 2,3-dimethyl-cyclohexyl and R₅R₆N- is morpholin-1-yl, then R₄ is not 3,4- dichloro-, 4-methoxy-, 3-chloro-, 4-chloro-, 3-chloro-4-methyl-, 3,4-dimethyl-, 3-methylthio-, 4-isopropyl-, 3-chloro-4-fluoro-, or 3-methyl-phenyl,

O. when R₂ is 2,3-dimethyl-cyclohexyl and R₅R₆N- is 2-methyl-piperidin-1-yl, then R₄ is not 4-methoxyphenyl; P. when R₂ is 2,3-dimethyl-cyclohexyl and R₅ and R₆ are each ethyl, then R₄ is not 3- methylthio- or 3-methyl-phenyl;

Q. when R₂ is (3) 2-methyl-cyclohexyl and R₅R₆N- is morpholin-1-yl, then R₄ is not 3- methoxy-, 4-isopropyl-, 3-methyl-phenyl,

R. when R₂ is (3) 2-methyl-cyclohexyl and R₅R₆N- is homopiperidin-1-yl, then R₄ is not 3-methoxy-phenyl;

S. when R₂ is (3) 2-methyl-cyclohexyl and R₅ is methyl and R₆ is benzyl, then R₄ is not 3-methoxy-phenyl;

T. when R₂ is (3) 2-methyl-cyclohexyl and R₅R₆N- is piperidin-1-yl, then R₄ is not 3- methoxy-phenyl;

U. when R₂ is (3) 2-methyl-cyclohexyl and R₅ and R₆ are each methyl, then R₄ is not 4- isopropyl-phenyl; and

V. when R₂ is (3) 2-methyl-cyclohexyl and R₅R₆N- is 1 -ethyl-pyrrolidin-2-yl, then R₄ is not 3-methy-phenyl;

and also excluding compounds of formula (ID)

wherein

A1. when R₂ is 2,3-dimethyl-cyclohexyl and R₅R₆N- is 1-ethyl-piperazin-4-yl, then R₄ is not 3,5-dichloro-, 3-methyl-, 4-isopropyl-, 3-chloro-4-fluoro-, 3-chloro-, 3,4-dimethyl-, 3,5- dimethyl- or 3-methylthio-phenyl; B1. when R₂ is 2,3-dimethyl-cyclohexyl and R₅R₆N- is morpholin-1-yl, then R₄ is not 4- isopropyl-, 3-chloro-4-f1uoro-, 3-methyl-, 3-chloro-, 4-chloro-, 3-chloro-4-methyl-, 3,5- dimethyl-, or 3-methylthio-phenyl

C1. when R₂ is 2,3-dimethyl-cyclohexyl and R₅R₆N- is 1-methyl-piperazin-4-yl, then R₄ is not 4-isopropyl-, or 3-chloro-4-fluoro-phenyl;

D1. when R₂ is 2,3-dimethyl-cyclohexyl and and R₅ and R₆ are each methyl, then R₄ is not 3,5-dichloro-, 3,5-dimethyl- or 3,4-dichloro-phenyl;

E1. when R₂ is 2,3-dimethyl-cyclohexyl and R₅R₆N- is pyrrolidin-yl, then R₄ is not 3- methyl-, 3-chloro-, 4-chloro- or 3,5-dimethyl-phenyl;

F1. when R₂ is cyclohexyl and R₅R₆N- is morpholin-1-yl, then R₄ is not 3,5-dichloro-, 3,4- dichloro-, 4-bromo,4-chloro-, 3-methylthio- or 3,4-dichloro-phenyl;

G1. when R₂ is cyclohexyl and R₅ and R₆ are each methyl, then R₄ is not 3,5-dichloro-, 4- phenoxy- or 4-isobutyl-phenyl;

H1. when R₂ is cyclohexyl and R₅R₆N- is 1-methyl-piperazin-4-yl, then R₄ is not 3,5- dichloro- or 4-isobutyl-phenyl;

K1. when R₂ is cyclohexyl and R₅R₆N- is piperidin-1-yl, then R₄ is not 3-methoxy, 3- chloro, 4-isobutyl-, 3,5-dimethyl- or 3-methylthio-phenyl;

L1. when R₂ is cyclohexyl and R₅R₆N- is 3-methyl-piperidin-1-yl, then R₄ is not 4- methoxy-, 3-chloro-, 4-chloro-, 3-methylthio- or 4-methyl-phenyl;

M1. when R₂ is cyclohexyl and R₅ and R₆ are each ethyl, then R₄ is not 3-chloro;

N1. when R₂ is cyclohexyl and R₅R₆N- is 4-methyl-piperidin-i-yl, then R₄ is not 3-chloro-, 4-chloro- or 3-methylthio-phenyl,

01. when R₂ is cyclohexyl and R₅ is methyl and R₆ is benzyl, then R₄ is not 4-methyl;

P1. when R₂ is 2-methyl-cyclohexyl and R₅R₆N- is morpholin-1-yl, then R₄ is not 3- methoxy-, 3-methyl-, 4-isobutyl-phenyl; Q1. when R₂ is 2-methyl-cyclohexyl and R₅R₆N- is piperidin-1-yl, then R₄ is not 3- methoxy-phenyl; and

R1. when R₂ is 2-methyl-cyclohexyl and R₅R₆N- is 3-methyl-piperidin-1-yl , then R₄ is not 3-methoxy-phenyl;

and also excluding the compound of formula (IA) wherein R₁ and R₃ are each hydrogen, R₂ is cyclohexyl, R₄ is 3,4 dichloro-phenyl, and R₅R₆N-L- is:

and also excluding compounds of formula (IA) wherein R is methyl, R₁ is hydrogen, R₂ is cyclohexyl, W is -C(=O)N(R₃)-^* wherein the bond marked with an asterisk is attached to R₄, R₄ is 3,4-dichlorophenyl, L is -CH₂CH₂- Or -CH₂CH₂CH₂-, and -NR₅R₆ is morpholinyl.

20. A compound of formula (IA) as defined in any of claims 1 and 7 to 18 wherein W is - C(=O)N(R₃)-^* wherein the bond marked with an asterisk is attached to R₄, and R₂ is not cyclohexyl, 2-methyl-cyclohexyl, or 2,3-dimethyl-cyclohexyl.

21. A compound of formula (IA) as defined in any of claims 1 and 7 to 18 wherein R is hydrogen, W is -C(=O)N(R₃)-^* wherein the bond marked with an asterisk is attached to R₄, and R₄ is not 3-methoxy-, 4-methoxy- 3-chloro-, 4-chloro-, 4-bromo-, 3,4-dimethyl-, 3,5- dimethyl-, 3-methylthio-, 4-methyl-, 3-methyl-, 3,5-dichloro-, 3,4-dichloro-, 4-isopropyl-, 3- chloro-4-methyl-, 4-methoxy-, 3-methoxy-, 4-isopropyl-, 3-chloro-4-fluoro-, or 4-phenoxy- phenyl.

22. A pharmaceutical composition as comprising a compound as claimed in any of claims 19 to 21 , together with a pharmaceutically acceptable carrier.