US20180028660A1 - Drug combinations comprising a dgat inhibitor and a ppar-agonist - Google Patents
Drug combinations comprising a dgat inhibitor and a ppar-agonist Download PDFInfo
- Publication number
- US20180028660A1 US20180028660A1 US15/627,475 US201715627475A US2018028660A1 US 20180028660 A1 US20180028660 A1 US 20180028660A1 US 201715627475 A US201715627475 A US 201715627475A US 2018028660 A1 US2018028660 A1 US 2018028660A1
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- US
- United States
- Prior art keywords
- alkyl
- aryl
- alkyloxy
- het
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Definitions
- This invention concerns novel drug combinations comprising an acyl CoA:diacylglycerol acyltransferase (DGAT) inhibitor, in particular a DGAT1 inhibitor, and a peroxisome proliferator-activated receptor (PPAR) agonist, in particular a PPAR- ⁇ agonist, pharmaceutical compositions comprising said novel drug combinations as active ingredients, as well as the use of said combinations as a medicament and for the manufacture of a medicament.
- DGAT acyl CoA:diacylglycerol acyltransferase
- PPAR peroxisome proliferator-activated receptor
- the present invention also concerns new piperidine/piperazine derivatives having DGAT inhibitory activity, in particular DGAT1 inhibitory activity.
- the invention further relates to methods for their preparation and pharmaceutical compositions comprising them.
- the invention also relates to the use of said compounds for the manufacture of a medicament for the prevention or the treatment of a disease mediated by DGAT, in particular DGAT 1.
- Triglycerides represent the major form of energy stored in eukaryotes. Disorders or imbalances in triglyceride metabolism are implicated in the pathogenesis of and increased risk for obesity, insulin resistance syndrome and type II diabetes, nonalcoholic fatty liver disease and coronary heart disease (see, Lewis, et al, Endocrine Reviews (2002) 23:201 and Malloy and Kane, Adv. Intern. Med. (2001) 47:11 1). Additionally, hypertriglyceridemia is often an adverse consequence of cancer therapy (see, Bast, et al. Cancer Medicament, 5th Ed., (2000) B. C. Decker, Hamilton, Ontario, CA).
- DGAT acyl CoA:diacylglycerol acyltransferase
- DAG 1,2-diacylglycerol
- TG triglycerides
- DGAT uniquely controlled the catalysis of the final step of acylation of diacylglycerol to triglyceride in the two major pathways for triglyceride synthesis, the glycerol phosphate and monoacylglycerol pathways. Because triglycerides are considered essential for survival, and their synthesis was thought to occur through a single mechanism, inhibition of triglyceride synthesis through inhibiting the activity of DGAT has been largely unexplored.
- mouse DGAT1 Genes encoding mouse DGAT1 and the related human homologs ARGP1 (human DGAT1) and ARGP2 (human ACAT2) now have been cloned and characterized (Cases, et al, Proc. Natl Acad. Sci . (1998) 95:13018; Oelkers, et al, J. Biol. Chem. (1998) 273:26765).
- the gene for mouse DGAT1 has been used to create DGAT knock-out mice to better elucidate the function of the DGAT gene.
- mice unable to express a functional DGAT1 enzyme are viable and still able to synthesize triglycerides, indicating that multiple catalytic mechanisms contribute to triglyceride synthesis (Smith, et al, Nature Genetics (2000) 25:87).
- Other enzymes that catalyze triglyceride synthesis for example, DGAT2 and diacylglycerol transacylase, also have been identified (Cases, et al, J. Biol. Chem. (2001) 276:38870).
- Gene knockout studies in mice have revealed that DGAT2 ⁇ lays a fundamental role in mammalian triglyceride synthesis and is required for survival.
- DGAT2 deficient mice are lipopenic and die soon after birth, apparently from profound reductions in substrates for energy metabolism and from impaired permeability barrier function in the skin. (Farese, et al., J. Biol. Chem. (2004) 279: 11767).
- Dgat1 ⁇ / ⁇ mice are resistant to diet-induced obesity and remain lean. Even when fed a high fat diet (21% fat) Dgat1 ⁇ / ⁇ mice maintain weights comparable to mice fed a regular diet (4% fat) and have lower total body triglyceride levels.
- the obesity resistance in Dgat1 ⁇ / ⁇ mice is not due to decreased caloric intake, but the result of increased energy expenditure and decreased resistance to insulin and leptin (Smith, et al, Nature Genetics (2000) 25:87; Chen and Farese, Trends Cardiovasc. Med. (2000) 10: 188; and Chen, et al, J. Clin. Invest. (2002) 109:1049).
- Dgat1 ⁇ / ⁇ mice have reduced rates of triglyceride absorption (Buhman, et al, J. Biol. Chem . (2002) 277:25474). In addition to improved triglyceride metabolism, Dgat1 ⁇ / ⁇ mice also have improved glucose metabolism, with lower glucose and insulin levels following a glucose load, in comparison to wild-type mice (Chen and Farese, Trends Cardiovasc. Med. (2000) 10: 188).
- novel compounds exhibiting DGAT inhibitory activity in particular DGAT1 inhibitory activity, and these compounds can therefore be used to prevent or treat a disease associated with or mediated by DGAT, such as for example obesity, type II diabetes, heart disease and cancer.
- the compounds of the invention differ from the prior art compounds in structure, in their pharmacological activity, pharmacological potency, and/or pharmacological profile.
- DGAT inhibitors including the DGAT inhibitors of the present invention, can be used to elevate the levels of one or more satiety hormones, in particular glucagon-like-peptide-1 (GLP-1) and therefore DGAT inhibitors, in particular DGAT1 inhibitors, can also be used to prevent or treat a disease which can benefit from elevated levels of a satiety hormone, in particular GLP-1.
- GLP-1 glucagon-like peptide 1
- GLP-1 is an intestinal hormone which generally stimulates insulin secretion during hyperglycemia, suppresses glucagon secretion, stimulates (pro) insulin biosynthesis and decelerates gastric emptying and acid secretion.
- GLP-1 is secreted from L cells in the small and large bowel following the ingestion of fat and proteins. GLP-1 has been suggested, among other indications, as a possible therapeutic agent for the management of type II non-insulin-dependent diabetes mellitus as well as related metabolic disorders, such as obesity.
- the present novel compounds make it possible to treat a disease which can benefit from elevated levels of GLP-1 with small molecules (compared to large molecules such as proteins or protein-like compounds, e.g. GLP-1 analogues).
- the peroxisome proliferator-activated receptors belong to the steroid hormone nuclear receptor superfamily of ligand-activated transcription factors that mediate the specific effects of small lipophilic compounds, such as steroids, retinoids and fatty acids, on DNA transcription. They play an important role in the regulation of lipid metabolism, in the regulation of energy homeostasis, inflammation, artherosclerosis and glucose control. Three subtypes are identified so far, namely PPAR- ⁇ , PPAR- ⁇ / ⁇ and PPAR- ⁇ . The three isoforms exhibit different tissue distribution as well as different ligand specificities.
- PPAR- ⁇ plays a crucial role in the intracellular lipid metabolism.
- the PPAR- ⁇ subtype is mainly expressed in tissues with elevated mitochondrial and peroxisomal fatty acid ⁇ -oxidation rates, that efficiently harvest energy from lipids, including liver, skeletal muscle, heart muscle, proximal tubular epithelial cells of the kidney, and brown fat (brown adipose tissue).
- PPAR- ⁇ is also present in cells of the arterial wall, in monocytes/macrophages, smooth muscle cells, endothelial cells, in hepatocytes, and in cardiac myocytes.
- PPAR- ⁇ Saturated and unsaturated fatty acids are found to be the primary natural PPAR- ⁇ ligands.
- PPAR- ⁇ can be activated by a heterogeneous group of compounds, which include natural and synthetic agonists, such as eicosanoids, leukotriene ⁇ 4 , carbaprostacyclin, nonsteroidal anti-inflammatory drugs, pirinixic acid (WY-14643; PPAR- ⁇ / ⁇ agonist), phthalate ester plasticizers, pterostilbene, fibrates or active metabolites thereof, ⁇ -substituted phenyl-propanoic acid derivatives and isoxazolyl-serine-based compounds.
- PPAR- ⁇ is induced by glucocorticoids in response to stress and follows a diurnal rhythm.
- Fibrates or active metabolites thereof such as fabric acid derivatives, are PPAR- ⁇ agonists, and have been used to treat dyslipidemia for several decades because of their triglyceride lowering and high-density lipoprotein (HDL) cholesterol elevating effects.
- Fibric acid derivatives lower the levels of triglyceride-rich lipoproteins, such as very low-density lipoproteins (VLDL), raise HDL levels, and have variable effect on low-density lipoproteins (LDL) levels.
- VLDL very low-density lipoproteins
- the effects on VLDL levels appear to result primarily from an increase in lipoprotein lipase activity, especially in muscle. This leads to enhanced hydrolysis of VLDL triglyceride content and an enhanced VLDL catabolism.
- Fibric acid agents also may alter the composition of the VLDL, for example, by decreasing hepatic production of apoC-III, an inhibitor of lipoprotein lipase activity. These compounds are also reported to decrease hepatic VLDL triglyceride synthesis, possibly by inhibiting fatty acid synthesis and by promoting fatty acid oxidation. In addition, they have been documented to be beneficial in the prevention of ischemic heart disease in individuals with dyslipidemia and they can also modestly decrease elevated fibrinogen and PAI-1 levels.
- fibrates are fenofibrate (fenofibric acid as active metabolite), ABT-335 (which is the choline salt of fenofibric acid), bezafibrate, clofibrate, ciprofibrate, etofibrate, pirifibrate, beclofibrate and gemfibrozil (PPAR- ⁇ modulator).
- a compound showing DGAT inhibitory activity in particular DGAT1 inhibitory activity
- a PPAR agonist in particular a PPAR- ⁇ agonist
- the combinations of the present invention may show synergy compared to administration of the composing ingredients alone.
- WO 2006/034441 discloses heterocyclic derivatives and their use as stearoyl CoA desaturase inhibitors (SCD-1 inhibitors).
- WO 2006/086445 relates to a combination therapy of a SCD-1 inhibitor and another drug to treat adverse weight gain.
- WO 2006/004200 and JP2007131584 relate to urea and amino derivatives having DGAT inhibitory activity.
- WO 2004/047755 relates to fused bicyclic nitrogen-containing heterocycles having DGAT inhibitory activity.
- WO2005/072740 relates to an anorectic action of a compound having DGAT inhibitory activity.
- WO 2007/071966 discloses a conjoint treatment of pyrimido-[4,5-B]oxazines showing DGAT inhibitory activity together with anti-dyslipidaemia agents such as PPAR- ⁇ agonists.
- WO2008/148851, WO2008/148840, WO2008/148849 and WO2008/148868 concern piperidine/piperazine derivatives having DGAT inhibitory activity.
- FIG. 1A shows the food intake of mice treated with a DGAT inhibitor (compound 223 of Class D—called D in FIG. 1A ), fenofibrate (F) or both, compared to the control group.
- a DGAT inhibitor compound 223 of Class D—called D in FIG. 1A
- F fenofibrate
- BL means baseline food intake
- FIG. 1B shows the food intake of DIO C57BL/6 mice fed with a high-fat diet containing fenofibrate (F) and compound 223 of Class D (D).
- FIG. 1C shows the high fat diet intake (g) of DIO C57BL/6 mice treated with a DGAT inhibitor (compound 358 of Class D), fenofibrate (F) or both, compared to the control group.
- a DGAT inhibitor compound 358 of Class D
- F fenofibrate
- FIG. 1D shows food intake of lean C57BL/6 mice fed a low-fat diet containing compound223 of Class D (D) and fenofibrate (F).
- FIG. 2A shows the change in body weight (g) of DIO C57BL/6 mice treated with a DGAT inhibitor (compound 223 of Class D 25 mpk/d), fenofibrate (31 mpk/d) or both.
- a DGAT inhibitor compound 223 of Class D 25 mpk/d
- fenofibrate 31 mpk/d
- FIG. 2B shows the body weight change of DIO C57BL/6 mice fed with a high-fat diet containing fenofibrate (F) and compound 223 of Class D (D).
- FIG. 2C shows the change in body weight (g) of DIO C57BL/6 mice fed with a high-fat diet containing DGAT inhibitor (compound 358 of Class D), fenofibrate or both.
- DGAT inhibitor compound 358 of Class D
- FIG. 2D shows food intake of lean C57BL/6 mice fed a high-fat diet containing compound 223 of Class D (D) and fenofibrate (F).
- FIG. 3A shows food intake on day 1 of DIO C57BL/6 mice fed with a high-fat diet containing compound 223 of Class D and fenofibrate (D+F).
- FIG. 3B shows day-1 food intake of mice fed a low and high-fat diet containing 0.01/0.0125 w/w compound 223 of Class D/fenofibrate (D/F).
- DIO C57BL/6 mice were acclimated to cages designed for measuring food intake.
- mice were switched to a diet with the same fat content (10 kcal % and 45 kcal % fat respectively), but supplemented with 0.01/0.0125% w/w D/F.
- the present invention relates to combinations of a DGAT inhibitor and a peroxisome proliferator-activator receptor (PPAR) agonist or a prodrug thereof
- PPAR peroxisome proliferator-activator receptor
- the present invention relates to combinations of a DGAT inhibitor and a PPAR- ⁇ agonist or a prodrug thereof.
- the present invention relates to combinations of a DGAT1 inhibitor and a PPAR agonist or a prodrug thereof.
- the present invention relates to combinations of a DGAT1 inhibitor and a PPAR- ⁇ agonist or a prodrug thereof.
- the present invention relates to combinations of a DGAT inhibitor, in particular a DGAT1 inhibitor, and a PPAR- ⁇ agonist or a prodrug thereof selected from the group of fibrates.
- the present invention relates to combinations of a DGAT inhibitor, in particular a DGAT1 inhibitor, and fenofibrate.
- the present invention relates to combinations of a PPAR agonist or a prodrug thereof and a DGAT inhibitor wherein the DGAT inhibitor is selected from
- the compounds of formula (I) as defined under a) are indicated as class A compounds
- the compounds as defined under b) are indicated as class B compounds
- the compounds as defined under c) are indicated as class C compounds
- the compounds as defined under d) are indicated as class D compounds.
- the present invention relates to combinations of a DGAT inhibitor wherein the DGAT inhibitor is selected from
- the present invention relates to combinations of a DGAT inhibitor wherein the DGAT inhibitor is selected from
- the present invention relates to combinations of a DGAT inhibitor wherein the DGAT inhibitor is selected from
- the present invention relates to any of the preceding embodiments wherein the DGAT inhibitor is selected from a compound of Class A.
- the present invention relates to any of the preceding embodiments wherein the DGAT inhibitor is selected from a compound of Class B.
- the present invention relates to any of the preceding embodiments wherein the DGAT inhibitor is selected from a compound of Class C.
- the present invention relates to any of the preceding embodiments wherein the DGAT inhibitor is selected from a compound of Class D.
- the present invention relates to any of the preceding or the following embodiments wherein the PPAR agonist or a prodrug thereof, is a PPAR- ⁇ agonist or a prodrug thereof, more in particular a fibrate, even more in particular a fenofibrate.
- the present invention relates to any of the preceding or following embodiments wherein the DGAT inhibitor is a DGAT1 inhibitor.
- the present invention also concerns methods for the preparation of compounds of class A, class B, class C or class D, and combinations or pharmaceutical compositions comprising them.
- the combinations according to the present invention are suitable for use as a medicament.
- the combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of metabolic disorders, such as obesity and/or obesity related disorders (including, but not limited to, peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome; dermatolog
- the combinations according to the present invention are particularly suitable for the treatment of prevention, in particular treatment, of obesity, type II diabetes mellitus; for suppressing appetite, for inducing satiety and/or for reducing food intake.
- the present invention also relates to the use of the combinations according to the present invention for the manufacture of a medicament for the treatment or prevention, in particular treatment, of the above mentioned diseases or conditions.
- the present invention also relates to the use of a combination of a DGAT inhibitor, in particular a DGAT1 inhibitor, and a PPAR agonist or a prodrug thereof, in particular a PPAR- ⁇ agonist or a prodrug thereof, more in particular a fibrate, even more in particular fenofibrate, for the manufacture of a medicament for the prevention or the treatment, in particular for the treatment, of a disease which can benefit from elevated levels of one or more satiety hormones, in particular GLP-1.
- the present invention also relates to a product containing a) a DGAT inhibitor, in particular a DGAT1 inhibitor, more in particular a compound of Class A, Class B, Class C or Class D, and (b) an agonist of peroxisome proliferators-activator receptor such as for example fenofibrate, as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease which can benefit from an elevated level of GLP-1 or DGAT inhibition, such as for example diabetes, in particular type II diabetes mellitus, obesity, for suppressing appetite, inducing satiety or for reducing food intake.
- a DGAT inhibitor in particular a DGAT1 inhibitor, more in particular a compound of Class A, Class B, Class C or Class D
- an agonist of peroxisome proliferators-activator receptor such as for example fenofibrate
- the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of the combinations mentioned hereinbefore or hereinafter.
- the present invention further relates to novel compounds, wherein the compound is selected from:
- novel compounds as defined in the list hereabove are indicated as compounds of group Q.
- the present invention further relates to the novel compound 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl) methyl]-benzamide (compound 358 Class D); including any stereochemically isomeric forms thereof; N-oxides thereof, pharmaceutically acceptable salts thereof or solvates thereof.
- the present invention also relates to a compound of group Q for use as a medicament.
- the present invention also relates to a compound of group Q for the prevention or the treatment of a disease mediated by DGAT, in particular the present invention relates to a compound of group Q for the prevention or the treatment of a disease which can benefit from inhibition of DGAT, in particular for the treatment of a disease which can benefit from inhibition of DGAT, in particular DGAT1.
- the present invention also relates to a compound of group Q for the prevention or the treatment, in particular for the treatment, of a disease which can benefit from elevated levels of one or more satiety hormones, in particular GLP-1.
- the present invention also relates to the use of a compound of group Q for the manufacture of a medicament for the treatment or prevention, in particular treatment, of the above mentioned diseases or conditions.
- the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound of group Q.
- C 0-3 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 0 (then it represents a direct bond) to 3 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl;
- C 1-2 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having 1 or 2 carbon atoms such as methyl, ethyl;
- C 1-4 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl; C 1-65 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 5 carbon atoms such as the group defined for C 1-4 alkyl and pentyl, 2-methylbutyl and the like; C 1-6 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the group defined for C 1-4 alkyl and for C 1-5 alkyl and hexyl, 2-methylpentyl and the like; C 1-12 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 12 carbon atoms such as the group defined for C 1-6 alkyl and hept
- halo is generic to fluoro, chloro, bromo and iodo.
- polyhaloC 1-6 alkyl as a group or part of a group is defined as C 1-6 alkyl substituted with one or more, such as for example 2, 3, 4 or 5 halo atoms, for example methyl substituted with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl, 1,1-difluoro-ethyl, 1,1-difluoro-2,2,2-trifluoro-ethyl and the like.
- halogen atoms are attached to a C 1-6 alkyl group within the definition of polyhaloC 1-6 alkyl, they may be the same or different.
- ( ⁇ O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulfonyl moiety when two of said terms are attached to a sulfur atom.
- Oxo means ⁇ O.
- the radical R 1 may be an optionally substituted 5-membered monocyclic heterocycle containing at least 2 heteroatoms, an optionally substituted 6-membered aromatic monocyclic heterocycle or an optionally substituted 5-membered heterocycle containing at least 2 heteroatoms fused with a phenyl, cyclohexyl or a 5- or 6-membered heterocycle.
- a 5-membered monocyclic heterocycle as defined hereinabove or hereinafter may be a 5-membered monocyclic non-aromatic (fully saturated or partially saturated) or aromatic heterocycle containing at least 2 heteroatom, in particular 2 or 3 heteroatoms, each independently selected from O, S, S( ⁇ O) p or N.
- unsubstituted monocyclic 5-membered heterocycles comprise, but are not limited to, non-aromatic (fully saturated or partially saturated) or aromatic 5-membered monocyclic heterocycles such as for example 1,3-dioxolanyl, imidazolidinyl, thiazolidinyl, dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadiazolidinyl, pyrazolidinyl, imidazolinyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl and the like.
- non-aromatic (fully saturated or partially saturated) or aromatic 5-membered monocyclic heterocycles such
- Optional substituents of the above heterocycles are hydroxyl; oxo; carboxyl; halo; C 1-6 alkyl optionally substituted with carboxyl, C 1-4 alkyloxy-carbonyl or aryl-C( ⁇ O)—; hydroxyC 1-6 alkyl optionally substituted with aryl or aryl-C( ⁇ O)—; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyloxy-carbonyl wherein C 1-6 alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)-aminocarbonyl; C 1-6 alkylcarbonyl; amino; mono- or di(C 1-6 alkyl)amino; R 5 R 4 N—C 1-6 alkyl; C 3-6 cycloalkyl
- a 6-membered aromatic monocyclic heterocycle as defined hereinabove or hereinafter contains at least one heteroatom, in particular 1, 2 or 3 heteroatoms, each independently selected from O, S, S( ⁇ O) p or N.
- heteroatoms in particular 1, 2 or 3 heteroatoms, each independently selected from O, S, S( ⁇ O) p or N.
- unsubstituted monocyclic 6-membered aromatic heterocycles comprise, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl and the like.
- Optional substituents of the above heterocycles are hydroxyl; oxo; carboxyl; halo; C 1-6 alkyl optionally substituted with carboxyl, C 1-4 alkyloxycarbonyl or aryl-C( ⁇ O)—; hydroxyC 1-6 alkyl optionally substituted with aryl or aryl-C( ⁇ O)—; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyloxy-carbonyl wherein C 1-6 alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; amino; mono- or di(C 1-6 alkyl)amino; R 5 R 4 N—C 1-6 alkyl; C 3-6 cycloalkyl-NR
- a 5-membered heterocycle containing at least 2 heteroatoms fused with phenyl, cyclohexyl or a 5- or 6-membered heterocycle as defined hereinabove or hereinafter may be a non-aromatic (fully saturated or partially saturated) or aromatic 5-membered heterocycle containing at least 2 heteroatoms, in particular 2 or 3 heteroatoms, each independently selected from O, S, S( ⁇ O) p or N, in particular O, S or N, more in particular O or N, fused with phenyl, cyclohexyl or a 5- or 6-membered non-aromatic (fully saturated or partially saturated) or aromatic heterocycle containing at least one heteroatom, in particular 1, 2 or3 heteroatoms, each independently selected from O, S, S( ⁇ O) p or N.
- unsubstituted bicyclic heterocycles comprise, but are not limited to, non-aromatic (fully saturated or partially saturated) or aromatic 8- or 9-membered bicyclic heterocycles such as for example 1,3-benzodioxolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl,
- Optional substituents of the above heterocycles are hydroxyl; oxo; carboxyl; halo; C 1-6 alkyl optionally substituted with carboxyl, C 1-4 alkyloxycarbonyl or aryl-C( ⁇ O)—; hydroxyC 1-6 alkyl optionally substituted with aryl or aryl-C( ⁇ O)—; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyloxy-carbonyl wherein C 1-6 alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; amino; mono- or di(C 1-6 alkyl)amino; R 5 R 4 N—C 1-6 alkyl; C 3-6 cycloalkyl-NR
- the radical Het or Het 1 as defined hereinabove may be an optionally substituted monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom, in particular 1, 2 or 3 heteroatoms, each independently selected from O, S, S( ⁇ O) p or N; or an optionally substituted bi- or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom, in particular 1, 2, 3, 4 or 5 heteroatoms, each independently selected from O, S, S( ⁇ O) p or N.
- unsubstituted monocyclic heterocycles comprise, but are not limited to, non-aromatic (fully saturated or partially saturated) or aromatic 4-, 5-, 6- or 7-membered monocyclic heterocycles such as for example azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl, hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, hexahydrodiazepin
- unsubstituted bicyclic or tricyclic heterocycles comprise, but are not limited to, non-aromatic (fully saturated or partially saturated) or aromatic 8- to 17-membered bicyclic or tricyclic heterocycles such as for example decahydroquinolinyl, octahydroindolyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, indolinyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzo-thienyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazo
- Optional substituents for Het heterocycles are hydroxyl; oxo; carboxyl; halo; C 1-6 alkyl optionally substituted with C 1-4 alkyloxy, amino or mono- or di(C 1-4 alkyl)amino; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; nitro; amino; mono- or di(C 1-4 alkyl)amino; —S( ⁇ O) p —C 1-4 alkyl.
- Optional substituents for Het 1 substituents are hydroxyl; oxo; carboxyl; halo; C 1-6 alkyl optionally substituted with carboxyl, C 1-4 alkyloxycarbonyl or aryl-C( ⁇ O)—; hydroxyC 1-6 alkyl optionally substituted with aryl or aryl-C( ⁇ O)—; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyloxy-carbonyl wherein C 1-6 alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; amino; mono- or di(C 1-6 alkyl)amino; R 6 R 5 N—C 1-6 alkyl; C 3-6 cycloalkyl-
- Examples of a 6-membered aromatic heterocycle containing 1 or 2 N atoms in the definition of R 3 (class B and class D) and R 2 (class C) are pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.
- each definition is independent.
- Het or Het 1 is meant to include all the possible isomeric forms of the heterocycles, for instance, pyrrolyl comprises 1H-pyrrolyl and 2H-pyrrolyl.
- R 1 in class B is meant to include all the possible isomeric forms of the heterocycles, for instance, pyrrolyl comprises 1H-pyrrolyl and 2H-pyrrolyl.
- the carbocycles or heterocycles covered by the terms aryl, Het, aryl 1 , Het 1 , R 1 (in class B) or R 3 (in class B, class C or class D) may be attached to the remainder of the molecule of formula (I) of class A, class B, class C or class D through any ring carbon or heteroatom as appropriate, if not otherwise specified.
- the heterocycle when the heterocycle is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like, or when the carbocycle is naphthalenyl, it may be 1-naphthalenyl, 2-naphthalenyl and the like.
- X is defined as for instance —NR x —C( ⁇ O)—, this means that the nitrogen of NR x is linked to the R 2 substituent (not applicable for class A) and the carbon atom of C( ⁇ O) is linked to the nitrogen of the ring
- Y is defined for instance as —NR x —C( ⁇ O)— in class A or class C, this means that the nitrogen of NR x is linked to the phenyl moiety and the carbon atom of C( ⁇ O) is linked to the R 1 substituent.
- the left part of the bivalent radical in the definition of Y is linked to the phenyl moiety and the right part of the bivalent radical in the definition of Y is linked to the R 1 substituent.
- substituents can be selected each independently out of a list of numerous definitions, such as for example for R 2 and R 3 in class A, R 4 and R 5 in class B and class D, and R 3 and R 4 in class C, all possible combinations are intended which are chemically possible.
- salts of the compounds of class A, class B, class C or class D are those wherein the counterion is pharmaceutically acceptable.
- salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
- the pharmaceutically acceptable salts as mentioned hereinbefore or hereinafter are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of class A, class B, class C or class D are able to form.
- the latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g.
- the salt form can be converted by treatment with alkali into the free base form.
- the compounds of class A, class B, class C or class D containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
- the pharmaceutically acceptable salts as mentioned hereinbefore or hereinafter are meant to also comprise the therapeutically active non-toxic metal or amine addition salt forms (base addition salt forms) which the compounds of class A, class B, class C or class D are able to form.
- Appropriate base addition salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g.
- primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
- salt form can be converted by treatment with acid into the free acid form.
- the term salt also comprises the quaternary ammonium salts (quaternary amines) which the compounds of class A, class B, class C or class D are able to form by reaction between a basic nitrogen of a compound of class A, class B, class C or class D and an appropriate quaternizing agent, such as, for example, an optionally substituted C 1-6 alkylhalide, arylhalide, C 1-6 alkyl-carbonylhalide, arylcarbonylhalide, or arylC 1-6 alkylhalide, e.g. methyliodide or benzyliodide.
- an appropriate quaternizing agent such as, for example, an optionally substituted C 1-6 alkylhalide, arylhalide, C 1-6 alkyl-carbonylhalide, arylcarbonylhalide, or arylC 1-6 alkylhalide, e.g. methyliodide or benzyliodide.
- C 1-6 alkyl trifluoromethanesulfonates C 1-6 alkyl methanesulfonates, and C 1-6 alkyl p-toluenesulfonates.
- a quaternary amine has a positively charged nitrogen.
- Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate, acetate, triflate, sulfate, sulfonate. The counterion of choice can be introduced using ion exchange resins.
- solvate comprises the hydrates and solvent addition forms which the compounds of class A, class B, class C or class D are able to form, as well as salts thereof Examples of such forms are e.g. hydrates, alcoholates and the like.
- N-oxide forms of the present compounds are meant to comprise the compounds of class A, class B, class C or class D wherein one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide.
- stereochemically isomeric forms as used hereinbefore or hereinafter defines all the possible stereoisomeric forms which the compounds of class A, class B, class C or class D may possess.
- chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of the basis molecular structure and their N-oxides, salts or solvates, substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers.
- a compound of class A, class B, class C or class D is for instance specified as (E)
- this means that the compound is substantially free of the (Z) isomer.
- stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration.
- Compounds encompassing double bonds can have an E (ent ought) or Z (zusammen) -stereochemistry at said double bond.
- the terms cis, trans, R, S, E and Z are well known to a person skilled in the art.
- an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center.
- the configuration of the second stereogenic center is indicated using relative descriptors [R*,R*] or [R*,S*], where the first R* is always specified as the reference center and [R*,R*] indicates centers with the same chirality and [R* ,S*] indicates centers of unlike chirality. For example, if the lowest-numbered chiral center in the molecule has an S configuration and the second center is R, the stereo descriptor would be specified as S—[R*,S*].
- the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number is arbitrarily always in the “ ⁇ ” position of the mean plane determined by the ring system.
- the position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is denominated “ ⁇ ”, if it is on the same side of the mean plane determined by the ring system, or “ ⁇ ”, if it is on the other side of the mean plane determined by the ring system.
- the compounds of (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
- the racemic compounds of class A, class B, class C or class D may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali.
- An alternative manner of separating the enantiomeric forms of the compounds of class A, class B, class C or class D involves liquid chromatography using a chiral stationary phase.
- Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
- said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
- the term “compounds of class A”, “compounds of class B”, “compounds of class C” or “compounds of class D” or any subgroup thereof, is meant to also include their N-oxide forms, their salts, their stereochemically isomeric forms and their solvates. Of special interest are those compounds of class A, class B, class C or class D which are stereochemically pure.
- PPAR agonist in particular PPAR- ⁇ agonist, is meant a compound or a prodrug thereof, or a composition containing said compound or prodrug thereof; which directly or indirectly stimulates or increases an in vivo or in vitro reaction typical for the PPAR receptor, in particular the PPAR- ⁇ receptor, e.g.
- Non-limiting examples of PPAR- ⁇ agonists or prodrugs thereof include natural and synthetic agonists, such as eicosanoids, leukotriene ⁇ 4 , carbaprostacyclin, nonsteroidal anti-inflammatory drugs, pirinixic acid (WY-14643; PPAR- ⁇ / ⁇ agonist), phthalate ester plasticizers, pterostilbene, fibrates or active metabolites thereof, ⁇ -substituted phenyl-propanoic acid derivatives, isoxazolyl-serine-based compounds.
- natural and synthetic agonists such as eicosanoids, leukotriene ⁇ 4 , carbaprostacyclin, nonsteroidal anti-inflammatory drugs, pirinixic acid (WY-14643; PPAR- ⁇ / ⁇ agonist), phthalate ester plasticizers, pterostilbene, fibrates or active metabolites thereof, ⁇ -substituted phenyl-propanoic acid derivatives,
- a preferred PPAR- ⁇ agonist or a prodrug thereof is a fibrate compound including, but not limited to fenofibrate (fenofibric acid as active metabolite), bezafibrate, clofibrate, ciprofibrate, etofibrate, ABT-335 (which is the choline salt of fenofibric acid), pirifibrate, beclofibrate or gemfibrozil (a PPAR- ⁇ modulator) and analogues, derivatives and pharmaceutically acceptable salts thereof.
- fenofibrate fenofibric acid as active metabolite
- bezafibrate clofibrate
- ciprofibrate ciprofibrate
- etofibrate etofibrate
- ABT-335 which is the choline salt of fenofibric acid
- pirifibrate beclofibrate or gemfibro
- prodrug refers to a pharmacological substance (drug) that is administered in an inactive or significantly less active form. Once administered, the prodrug is metabolised in vivo into an active metabolite.
- the prodrug fenofibrate esteer
- fenofibric acid which is the active metabolite (PPAR- ⁇ agonist).
- a preferred fibrate is fenofibrate.
- fibrates include fibric acid derivatives and pharmaceutically acceptable salts of such fibric acid derivatives.
- next embodiments of the present invention are those combinations of a DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPAR agonist, in particular a PPAR- ⁇ agonist, more in particular a fibrate, even more in particular fenofibrate; wherein the DGAT inhibitor is selected from compounds of Class A.
- Preferred embodiments of compounds of class A are:
- R 3a and R 3b each independently represent hydrogen; hydroxyl; carboxyl; halo; C 1-6 alkyl optionally substituted with hydroxyl; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; nitro; amino; mono- or di(C 1-4 alkyl)amino; C 1-4 alkylcarbonylamino; —S( ⁇ O) p —C 1-4 alkyl; and wherein R 3c represents hydrogen; hydroxyl; carboxyl; halo; C 1-6 alkyl; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy;
- R 3a and R 3b each independently represent hydrogen; hydroxyl; carboxyl; halo; C 1-6 alkyl; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; nitro; amino; mono- or di(C 1-4 alkyl)amino; —S( ⁇ O) p —C 1-4 alkyl; and wherein R 3 c represents hydrogen; hydroxyl; carboxyl; halo; C 1-6 alkyl optionally substituted with hydroxyl; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhalo-C 1-6 al
- next embodiments of the present invention are those combinations of a DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPAR agonist, in particular a PPAR- ⁇ agonist, more in particular a fibrate, even more in particular fenofibrate; wherein the DGAT inhibitor is selected from compounds of Class C.
- Preferred embodiments of compounds of class C are:
- R 3a and R 3b each independently represent hydrogen; hydroxyl; carboxyl; halo; C 1-6 alkyl; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; nitro; amino; mono- or di(C 1-4 alkyl)amino; —S( ⁇ O) p —C 1-4 alkyl; and wherein R 3c represents hydrogen; hydroxyl; carboxyl; halo; C 1-6 alkyl; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhalo-C 1-6 alkyloxy; C 1-6 alkyl
- R 3a and R 3b each independently represent hydrogen; hydroxyl; carboxyl; halo; C 1-6 alkyl; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; nitro; amino; mono- or di(C 1-4 alkyl)amino; —S( ⁇ O) p —C 1-4 alkyl; and wherein R 3c represents hydrogen; hydroxyl; carboxyl; halo; C 1-6 alkyl; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhalo-C 1-6 alkyloxy; C 1-6 alkyl
- C 2-6 alkynediyl may optionally be substituted with C 1-4 alkyloxy, C 1-4 alkylthio, hydroxyl, cyano or aryl; and wherein two hydrogen atoms attached to the same carbon atom in the definition of Z 2 may optionally be replaced by C 1-6 alkanediyl;
- R 3a and R 3b each independently represent hydrogen; hydroxyl; carboxyl; halo; C 1-6 alkyl; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; nitro; amino; mono- or di(C 1-4 alkyl)amino; —S( ⁇ O) p —C 1-4 alkyl; and wherein R 3c represents hydrogen; hydroxyl; carboxyl; halo; C 1-6 alkyl; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhalo-C 1-6 alkyloxy; C 1-6 alkyl
- R 3a and R 3b each independently represent hydrogen; hydroxyl; carboxyl; halo; C 1-6 alkyl; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; nitro; amino; mono- or di(C 1-4 alkyl)amino; —S( ⁇ O) p —C 1-4 alkyl; and wherein R 3c represents hydrogen; hydroxyl; carboxyl; halo; C 1-6 alkyl; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhalo-C 1-6 alkyloxy; C 1-6 alkyl
- the present invention also relates to a combination of
- the present invention also relates to a combination of 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl) methyl]-benzamide (compound 358 Class D), including any stereochemically isomeric form thereof, a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof;
- This reaction can be performed in a suitable solvent such as, for example, DCM.
- the present invention relates to the use of a drug combination comprising a DGAT inhibitor and a PPAR agonist or a prodrug thereof, as a medicament.
- the present invention relates to the use of a drug combination comprising a DGAT inhibitor and a PPAR- ⁇ agonist or a prodrug thereof, as a medicament.
- the present invention relates to the use of a drug combination comprising a DGAT1 inhibitor and a PPAR- ⁇ agonist or a prodrug thereof, as a medicament.
- the combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of metabolic disorders, such as obesity and/or obesity related disorders (including, but not limited to, peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome
- the combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of metabolic disorders, such as obesity and/or obesity related disorders (including, but not limited to, peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis, ketosis, dysmetabolic
- the combinations according to the present invention are suitable for for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of obesity and/or obesity related disorders, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, fatty liver, nonalcoholic fatty liver disease, liver fibrosis, non-alcoholic steatohepatitis or diabetes.
- the combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; for the treatment or prevention of obesity and/or obesity related disorders, obesity or cardiovascular diseases.
- said obesity related disorder is selected from peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia or cardiac myopathies.
- the combinations according to the present invention are suitable for reducing food intake and/or for reducing weight.
- the combinations according to the present invention are suitable for reducing food intake.
- the combinations according to the present invention are suitable for the treatment of said diseases or conditions.
- the combinations according to the present invention are suitable for use in the treatment or prevention, in particular treatment, of said diseases or conditions.
- the combinations according to the present invention are suitable for the manufacture of a medicament; in particular a medicament for the treatment or prevention, in particular the treatment, of the diseases or conditions mentioned hereinbefore.
- the present invention also relates to a product containing a) a DGAT inhibitor, in particular a DGAT1 inhibitor, more in particular a compound of Class A, Class B, Class C or Class D, and (b) an agonist of peroxisome proliferators-activator receptor or a prodrug thereof such as for example fenofibrate, as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease which can benefit from an elevated level of GLP-1 or DGAT inhibition, such as for example diabetes, in particular type II diabetes mellitus, obesity, for suppressing appetite, inducing satiety or for reducing food intake.
- a DGAT inhibitor in particular a DGAT1 inhibitor, more in particular a compound of Class A, Class B, Class C or Class D
- an agonist of peroxisome proliferators-activator receptor or a prodrug thereof such as for example fenofibrate
- Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of an above mentioned combination to warm-blooded animals, including humans.
- An effective therapeutic daily amount of a combination of PPAR agonist (or prodrug thereof)/DGAT inhibitor would be from about 0.01 mg/kg to 250 mg/kg body weight, preferably from 0.01 mg/kg to 50 mg/kg body weight, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.05 mg/kg to about 1 mg/kg body weight.
- the amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect will of course, vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
- a method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day.
- the compounds according to the invention are preferably formulated prior to administration.
- suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.
- the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of the combinations mentioned hereinbefore or hereinafter.
- compositions may be formulated into various pharmaceutical forms for administration purposes.
- compositions there may be cited all compositions usually employed for systemically administering drugs.
- an effective amount of the particular combination, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
- any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
- the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
- injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
- injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
- the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
- Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
- These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
- the combinations of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
- the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.
- the combinations of the present invention may also be topically administered in the form of drops, in particular eye drops.
- Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye drops are suitable for the administration of the present compounds.
- Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
- the exact dosage and frequency of administration depends on the particular combination of the present invention used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the combinations of the instant invention.
- the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of the combination of PPAR agonist/DGAT inhibitor, and, from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
- the different drugs of a combination or product may be combined in a single preparation together with pharmaceutically acceptable carriers or they may be present in a separate preparation together with pharmaceutically acceptable carriers.
- the present invention also relates to the use of the novel DGAT inhibitors of group Q, in particular DGAT1 inhibitors of group Q, to elevate levels of one or more satiety hormones, in particular GLP-1 levels.
- the present invention also relates to the use of a DGAT inhibitor of group Q, in particular a novel DGAT1 inhibitor of group Q, for the manufacture of a medicament for the prevention or the treatment, in particular for the treatment, of a disease which can benefit from an elevated level of one or more satiety hormones, in particular a disease which can benefit from an elevated GLP-1 level.
- GLP-1 levels are elevated in plasma or in portal blood, more in particular in plasma.
- GLP-1 plasma level or an elevated GLP-1 level in portal blood it is meant that the GLP-1 level of a subject having taken a DGAT1 inhibitor is elevated or increased compared to the subject under the same conditions but not having taken the DGAT1 inhibitor.
- GLP-1 levels are elevated in fasting conditions or postprandial, more in particular postprandial.
- Therapeutic uses for a compound which elevates GLP-1 level include, but are not limited to, improving learning, enhancing neuro-protection, and/or alleviating a symptom of a disease or disorder of the central nervous system, e.g., through modulation of neurogenesis, and e.g., Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, ALS, stroke, hemorrhage, cerebrovascular accident, ADD, and neuropsychiatric syndromes; converting liver stem/progenitor cells into functional pancreatic cells; preventing beta-cell deterioration and stimulation of beta-cell proliferation; treating pancreatitis; treating obesity; suppressing appetite and inducing satiety; treating irritable bowel syndrome or inflammatory bowel disease such as Crohn's disease and ulcerative colitis; reducing the morbidity and/or mortality associated with myocardial infarction and stroke; treating acute coronary syndrome characterized by an absence of Q-wave myocardial infarction; attenuating post-surgical catabolic changes
- ischemic myocardial stunning includes, but are not limited to, ischemic myocardial stunning; ishemic/reperfusion injury; acute myocardial infarction; left ventricular dysfunction; vascular disease; neuropathy, including periphere sensoric neuropathy associated with type II diabetes; bone-related disorders, including osteoporosis, obesity, diabetes.
- the DGAT inhibitors of group Q can also be used to provide cardioprotection.
- the present novel compounds of group Q can be used as a medicament.
- the present invention relates to a compound of group Q for use as a medicament, in particular for use as a medicament for the prevention or the treatment of a disease which can benefit from an elevated GLP-1 level.
- the present invention also relates to the use of a compound of group Q for the manufacture of a medicament for the prevention or the treatment of a disease which can benefit from an elevated GLP-1 level, such as the diseases and disorders mentioned above.
- a method of treating a warm-blooded mammal, including a human, suffering from or a method of preventing a warm-blooded mammal, including a human, to suffer from a disease which can benefit from an elevated level of GLP-1 in particular a method of treating a warm-blooded mammal, including a human, suffering from a disease which can benefit from an elevated level of GLP-1.
- Said methods comprise the administration of an effective amount of a compound of group Q to a warm-blooded mammal, including a human.
- the present invention also relates to a compound of group Q for use as a medicament, in particular for use as a medicament for the prevention or the treatment of a diseases which can benefit from inhibition of DGAT, in particular DGAT1.
- the invention also relates to a compound of group Q for the prevention or the treatment of a disease or disorder which can benefit from inhibition of DGAT, in particular DGAT1.
- Diseases or disorders which can benefit from inhibition of DGAT, in particular DGAT1 include, but are not limited to metabolic disorders, such as obesity and/or obesity related disorders (including peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis
- DGAT diseases or disorders which can benefit from inhibition of DGAT, in particular DGAT1
- diseases or disorders which can benefit from inhibition of DGAT are selected from obesity, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, fatty liver, nonalcoholic fatty liver disease, liver fibrosis, non-alcoholic steatohepatitis or diabetes, in particular type II diabetes.
- the invention also relates to a compound of group Q for use in the prevention or the treatment, in particular for use in the treatment, of a disease or disorder which can benefit from inhibition of DGAT, in particular DGAT1.
- the invention also relates to the use of a compound of group Q for the manufacture of a medicament for treating or preventing the above mentioned diseases or conditions.
- a method of treating a warm-blooded mammal, including a human, suffering from or a method of preventing a warm-blooded mammal, including a human, to suffer from a disease which can benefit from inhibition of DGAT in particular a method of treating a warm-blooded mammal, including a human, suffering from a disease which can benefit from inhibition of DGAT.
- Said methods comprise the administration of an effective amount of a compound of group Q to a warm-blooded mammal, including a human.
- the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound of group Q.
- the present invention also provides compositions for preventing or treating a disease which can benefit from an elevated GLP-1 level or which can benefit from inhibition of DGAT, in particular DGAT1, in particular for treating a disease which can benefit from elevated GLP-1 levels or which can benefit from inhibition of DGAT, in particular DGAT1.
- Said compositions comprise a therapeutically effective amount of a compound of group Q and a pharmaceutically acceptable carrier.
- novel compounds of group Q of the present invention may be formulated into various pharmaceutical forms for administration purposes.
- compositions there may be cited all compositions usually employed for systemically administering drugs.
- an effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
- any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
- the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
- injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
- injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
- the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
- Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
- These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
- the compounds of group Q of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
- the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.
- the compounds of the present invention may also be topically administered in the form of drops, in particular eye drops.
- Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye drops are suitable for the administration of the present compounds.
- Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
- the exact dosage and frequency of administration depends on the particular compound of group Q used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
- the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of the compound of group Q, and, from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
- THF tetrahydrofuran
- Et 2 O diethyl ether
- CH 3 OH methanol
- EtOAc ethyl acetate
- NaHCO 3 carbonic acid monosodium salt
- CH 2 Cl 2 ’ or ‘DCM’ dichloromethane
- CH 3 CN acetonitrile
- EtOH means ethanol
- HBTU 1-[bis(di-methylamino)methylene]-1H-benzo-triazoliumhexafluorophosphate(1)-3-oxide
- DMF means N,N-dimethyl-formamide
- DIPEA means N-ethyl-N-(1-methylethyl)-2-propanamine
- EDCI means N-(ethylcarbonimidoyl)-N
- 4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide .HCl was prepared in analogy to the free base form.
- hydrochloric acid salt 4-[4-[[[3-(1-pyrrolidinyl)phenyl]amino]carbonyl]phenyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (the tert-butoxy variant of 4-[4-(phenylmethyl)-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide) was deprotected with a HCl solution in dioxane.
- Trimethylsilanecarbonitrile (10 ml, 76.6 mmol) and ZnBr 2 (0.5 g) were added to a solution of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde (9.8 g, 43.8 mmol) in DCM (100 ml). The r.m. was stirred for 5 h at r.t. Then, the mixture was heated to 50° C. and stirred overnight. 2-chloro- ⁇ -hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetonitrile was used as a crude in the next reaction step.
- Compound 151 was prepared by analogy to compound 152, but 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (for which the synthesis protocol is described in detail in the experimental procedures for the Class D compounds) was used as starting material.
- the LCMS analyses for a number of compounds were done at the Surveyor MSQTM (Thermo Finnigan, USA) comprising a photo diode array detector (PDA; 190-800 nm) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer.
- the MS detector was configured with APCI (atmospheric pressure chemical ionization, + or ⁇ ions). Mass spectra were acquired by scanning from 45 to 1000 (of atomic mass unit) in 0.3 seconds. Typical APCI conditions use a corona discharge current of 10 ⁇ A and a cone voltage of 30 V.
- the APCI probe temperature was 640° C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with an XcaliburTM data system.
- the HPLC measurement was performed using an Agilent 1100 module comprising a pump, a diode-array detector (DAD) (wavelength used 220 nm), a column heater and a column as specified in the respective methods below.
- Flow from the column was split to a Agilent MSD Series G1946C and G1956A.
- MS detector was configured with API-ES (atmospheric pressure electrospray ionization). Mass spectra were acquired by scanning from 100 to 1000.
- the capillary needle voltage was 2500 V for positive ionization mode and 3000 V for negative ionization mode. Fragmentation voltage was 50 V. Drying gas temperature was maintained at 350° C. at a flow of 10 l/min.
- Reversed phase HPLC was carried out on a Waters XTerra MS C18 column (3.5 ⁇ m, 2.1 ⁇ 30 mm) with a flow rate of 1.0 ml/min.
- Two mobile phases (mobile phase A: 0.1% aqueous solution of formic acid; mobile phase B: CH 3 CN) were used. First, 100% A was hold for 0.1 minutes (min). Then a gradient was applied to 5% A and 95 B in 3 min and hold for 0.8 min. The injection volume was 1 ⁇ l. The column was at room temperature.
- the inhibiting activity of compounds of Class A, Class B, Class C and Class D on DGAT1 activity was screened in a single well procedure assay using DGAT1 comprising membrane preparations and DGAT1 substrate comprising micelles and determining formed radio-active triacylglycerol coming in close proximity of a flashplate surface by radioluminescence.
- DGAT1 activity is meant the transfer of coenzyme A activated fatty acids to the 3-position of 1,2-diacylglycerols, thus forming a triglyceride molecule, by enzyme DGAT1.
- human DGAT1 (NM012079.2) was cloned into the pFastBac vector, containing translation start, a FLAG-tag at the N-terminus as described in literature and a viral Kozak sequence (AAX) preceding the ATG to improve expression in insect cells. Expression was done as described in literature (Cases, S., Smith, S. J., Zheng, Y., Myers H. M., Lear, S. R., Sande, E., Novak, S., Collins, C., Welch, C. B., Lusis, A. J., Erickson, S. K. and Farese, R. V. (1998) Proc. Natl. Acad. Sci. USA 95, 13018-13023.) using SF9 cells.
- 72 h transfected SF9 cells were collected by centrifugation (13000 rpm-15 min-4° C.) and lysed in 2 ⁇ 500 ml lysisbuffer (0.1M Sucrose, 50 mM KCl, 40 mM KH 2 PO 4 , 30 mM EDTA pH 7.2. Cells were homogenized by cell disruptor. After centrifugation 1380 rpm-15 min-4° C. (SN discarded), pellet was resuspended in 500 ml lysisbuffer and total cell membranes collected by ultracentrifugation at 34000 rpm (100 000 g) for 60 min (4° C.). The collected membranes were resuspended in lysis buffer, divided in aliquots and stored with 10% glycerol at ⁇ 80° C. until use.
- ml lysisbuffer 0.1M Sucrose, 50 mM KCl, 40 mM KH 2 PO 4 , 30 mM EDTA pH 7.2. Cells were
- Step 4 of the Assay DGAT FlashPlateTM Assay
- DGAT activity in membrane preparations was assayed in 50 mM Tris-HCl (pH 7.4), 150 mM MgCl 2 , 1 mM EDTA and 0.2% BSA, containing 50 ⁇ M DAG, 32 ⁇ g/ml PC/PS and 8.4 ⁇ M [ 3 H]-oleoylCoA (at a specific activity of 30 nCi/well) in a final volume of 50 ⁇ l in 384-well format using the red shifted Basic Image FlashPlatelTM (Perkin Elmer Cat.No. SMP400).
- 10 ⁇ l enzyme mix and 10 ⁇ l substrate mix were added to 30 ⁇ l of assay buffer, optionally in the presence of 1 ⁇ l DMSO (blank and controls) or 1 ⁇ l of the compound to be tested. This r.m. was incubated for 120 min at 37° C. and the enzymatic reaction stopped by adding 20 ⁇ l of the stop mix. The plates were sealed and the vesicles allowed to settle overnight at room temperature. Plates were centrifuged for 5 min at 1500 rpm and measured in Leadseeker.
- % CTRL min (sample ⁇ LC )/( HC ⁇ LC ) Equation 1:
- HC high control
- LC low control
- sample refers to the radioluminescence value measured in the wells with substrate, enzyme and test compound at a particular concentration.
- % CTRL min values form a sigmoidal dose response descending curve and from this curve pIC 50 values were calculated ( ⁇ logIC 50 where IC 50 represents the concentration at which the test compound gives 50% inhibition of DGAT1 activity).
- the inhibiting activity of the compounds on DGAT2 was also determined in the above assay, slightly modified to obtain optimal assay conditions for DGAT2.
- the tested compounds did not show inhibiting activity for DGAT2 (Human DGAT2 (NM032564) was cloned and expressed as described in J. Biolog. Chem. 276(42), pp 38870-38876 (2001)).
- Elevation of GLP-1 plasma levels by a DGAT inhibitor can be studied as follows:
- Dogs are deprived from food for a period of 22 h. At time 0, animals are given a liquid meal, containing 18% fat (w/w), by gavage with a stomach tube. The test compound is given orally together with the meal. Afterwards, a postprandial plasma profile is determined for GLP-1. Therefore, blood is collected at predetermined time intervals in ice-cooled Vacutainers EDTA-plasma tubes and GLP-1 levels are measured in the samples taken at 0 h (just before the meal) and at 0.5, 1, 2, 4, 6, 8 and 24 h after dosing. Six dogs (3 males and 3 females) are included per dosage group and the plasma GLP-1 profile is compared with their own GLP-1 profile previously determined in the same conditions but without administration of the test compound. GLP-1 determinations in plasma are performed with a Glucagon-like peptide-1 (active) ELISA kit 96-well plate of LINCO Research.
- mice Male C57BL/6 mice were housed in individually ventilated cages under controlled temperature (21° C.), humidity (45-65%) and light (12 h-12 h reverse light/dark cycle; Lights on—6 PM-6 AM). Mice were set on 60 kcal % fat energy diet until their average body weight was over 45 grams, at which time they were switched to a 45 kcal % fat diet.
- mice were moved into modified type-2 cages with: doublewide food cup, wire grids and a tissue for bedding for several months before experiment to adapt to new housing/feeding conditions.
- Food Repsearch diets 45 kcal % diet D12451—see Scheme A
- Mice had been used to test several compounds for effects on food intake before being used in the current experiment, but had a wash-out period of at least one month before starting the current experiments.
- mice were weighted the day before trial onset.
- mice were ranked according to body weight and randomly assigned to treatments within repetitions/blocks (40 mice, 4 treatments, 10 repetitions/block, unless otherwise mentioned).
- the food intake the day before trial onset was also measured.
- mice's food (diet D12451) was replaced with the ‘inhouse’ diet made from premix D04071407px and added oil/lard, fenofibrate and/or the DGAT inhibitor.
- a and B compound 223 of Class D (also called ‘D’ in the continuation of the pharmacological examples) was used:
- Food cups were filled and weighted daily during the experiment. Body weight was recorded every 2nd or 3rd day.
- Food Intake and Body Weight data were analyzed using General Linear Models procedures appropriate for a 2 ⁇ 2 factorial design with blocking and repeated measures. Means comparisons were done using Duncan's Multiple Range test (SAS For Windows, Version 8.02; SAS®, Cary, N.C.). Results were expressed as means ⁇ SEM (standard error of the mean).
- test A the efficacy of the treatment in DIO C57BL/6 mice with only fenofibrate and only a DGAT inhibitor (compound 223 from Class D) was compared with the combined treatment with both D and fenofibrate.
- mice were assigned to one of the following treatments:
- mice fed with the compound 223 of Class D or fenofibrate-containing diet were 23.5 and 29 mpk/d respectively.
- the average daily drug intake of mice fed the compound 223 of Class D and fenofibrate-combination diet was 43.2 mg/kg/day.
- mice fed with the compound 223 of Class D and fenofibrate-containing diet were significantly greater than control mice (P ⁇ 0.05).
- body weight change of all drug treated mice was significantly different than controls.
- Mice fed with the compound 223 of Class D or fenofibrate-containing diet lost from 1-2 grams during the trial, whereas controls gained 0.6 grams.
- mice fed with the compound 223 of Class D and fenofibrate-combination diet (D+F) significantly lost more weight than mice fed with either drug alone, indicating a synergistic effect of the 2 compounds on weight loss.
- test B the efficacy of the treatment in DIO C57BL/6 mice with the fenofibrate/compound 223 from Class D combination was compared at different doses.
- fenofibrate and compound 223 of Class D were included at 0.05 and 0.04% of the diet (w/w) respectively.
- fenofibrate (F)/compound 223 of Class D (D) was included at 3 lower doses 0.05F/0.02D, 0.025F/0.02D and 0.0125F/0.01D.
- mice were assigned to one of the following treatments:
- test B The results of test B are shown in Figures B1, B2 and B3.
- the average daily drug intake of F/D was 26.0/10.4, 13.2/10.6 and 6.6/5.3 mpk/d respectively for mice fed with the high, medium and low concentration diets.
- Figure B1 it can be seen that the baseline food intake (i.e. day 0) of mice fed the 0.0125/0.01 was significantly lower than for other groups.
- all treatment groups ate significantly less than controls. (2.6 vs. 3.7 g for treated vs. controls respectively).
- Treated mice ate significantly (P ⁇ 0.05 or less) less than controls on all trial days except days 9, 14 and 15.
- FIG. B2 it can be seen that body weight change of mice fed with F/D-containing diets was significantly different from control mice by the 2 nd day of the trial (all P ⁇ 0.001). Body weight changed significantly over time (time effect, P ⁇ 0.001), and was significantly influenced by treatment (time ⁇ treatment interaction (P ⁇ 0.05).
- test C the efficacies of the treatments in DIO C57BL/6 mice with only fenofibrate and only a DGAT inhibitor (compound 358 from Class D) were compared with the combined treatment with both compound 358 of Class D and fenofibrate.
- mice fed with the compound 358 of Class D or fenofibrate-containing diet were 27 and 34 mpk/d respectively.
- the average daily drug intake of mice fed the compound 358 of Class D and fenofibrate-combination diet was 58 mg/kg/day.
- mice were moved into modified type-2 cages as described before. Once in the feeding cages, mice were adapted to a 10 kcal % fat diet for 1 week before trial 1 was started.
- mice were assigned to one of the following treatments:
- Compound 223 of Class D (D) and fenofibrate (F) were brought to a fine emulsion by stirring in the appropriate amount of soybean oil for 1 day. This was then mixed with the diet premix. After the soybean oil/drug was mixed with the premix for 15 min, the necessary amount of the lard was added to complete the diet. Diet was provided in powder form.
- mice's ‘baseline’ (BL) food intake was measured for 1 day before both Trial 1 (low-fat diet) and 2 (high-fat diet).
- mice were ranked according to their pretrial food intake and randomly assigned to treatments within repetitions/block (30 mice, 3 treatments, 8-9 repetitions/block). Several mice had low or high food intakes and were not included in the experiment.
- Food intake data were analysed using General Linear Models procedures appropriate for a randomized complete block design. Means comparisons were done using Duncan's Multiple Range test (SAS For Windows, Version 8.02; SAS®, Cary, NC). Results are expressed as means ⁇ SEM.
- mice were given 1 week to adapt to the food intake cages and a low-fat powdered diet (Research Diets D12450B-10 kcal % fat). After 1 day of baseline food intake measurement, mice's food was replaced by the same 10 kcal % fat diet containing 0/0, 0.01/0.0125 or 0.04/0.05 w/w D/F. The food cups were filled and weight daily during the 3-day experiment.
- mice fed the diet containing a 0.01/0.0125% D/F were not reduced at any time during the 3-day trial, whereas mice fed the diet containing 0.04/0.05% D/F reduced their food intake by 9% on day 1, but ate similar amounts as controls thereafter.
- the average daily drug intake of F/D was 71/57 or 17/14 mpk/d respectively for mice fed the high, and low concentration diets.
- mice were switched to a high-fat diet (D12451-45 k cal % fat) and allowed to adapt for 3 days. Once adapted, food intake was recorded for 1 day to establish a baseline food intake (for treatment allotment). The following day, mice were switched to the same 45 kcal % fat diet containing 0/0, 0.01/0.0125 or 0.02/0.05% w/w D/F (Figure D2).
- the average daily drug intake of F/D was 44/18 or 10.8/8.6 mpk/d respectively for mice fed the high, and low concentration diets.
- the DGAT inhibitor and the PPAR agonist may also be present in separate tablets.
- the active ingredient will be the DGAT inhibitor for one tablet and the PPAR agonist for the second tablet.
- An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.
- a parenteral composition is prepared by stirring 1.5% (weight/volume) of active ingredient in 0.9% NaCl solution.
Abstract
The present invention relates to combinations of a DGAT inhibitor and a peroxisome proliferator-activator receptor (PPAR) agonist or a prodrug thereof. The invention further relates to methods for preparing such combinations, pharmaceutical compositions comprising said combinations as well as the use as a medicament of said combinations.
The present invention also relates to novel DGAT inhibitors. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicament of said compounds.
Description
- This application a divisional application of U.S. patent application Ser. No. 14/793,896, filed Jul. 8, 2015, currently pending, which is a continuation application of U.S. patent application Ser. No. 12/993,491, filed Nov. 19, 2010, now U.S. Pat. No. 9,107,946, the disclosure of which is hereby incorporated by reference, which is the U.S. national stage of Application No. PCT/EP2009/ 056800, filed Jun. 3, 2009, which application claims priority from PCT/EP2008/057060, filed Jun. 6, 2008; PCT/EP2008/057008, filed Jun. 5, 2008; PCT/EP/056983, filed Jun. 5, 2008; PCT/EP2008/057011, filed Jun. 5, 2008 and EP 08170780.4, filed Dec. 5, 2008.
- This invention concerns novel drug combinations comprising an acyl CoA:diacylglycerol acyltransferase (DGAT) inhibitor, in particular a DGAT1 inhibitor, and a peroxisome proliferator-activated receptor (PPAR) agonist, in particular a PPAR-α agonist, pharmaceutical compositions comprising said novel drug combinations as active ingredients, as well as the use of said combinations as a medicament and for the manufacture of a medicament.
- The present invention also concerns new piperidine/piperazine derivatives having DGAT inhibitory activity, in particular DGAT1 inhibitory activity. The invention further relates to methods for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds for the manufacture of a medicament for the prevention or the treatment of a disease mediated by DGAT, in particular DGAT 1.
- Triglycerides represent the major form of energy stored in eukaryotes. Disorders or imbalances in triglyceride metabolism are implicated in the pathogenesis of and increased risk for obesity, insulin resistance syndrome and type II diabetes, nonalcoholic fatty liver disease and coronary heart disease (see, Lewis, et al, Endocrine Reviews (2002) 23:201 and Malloy and Kane, Adv. Intern. Med. (2001) 47:11 1). Additionally, hypertriglyceridemia is often an adverse consequence of cancer therapy (see, Bast, et al. Cancer Medicament, 5th Ed., (2000) B. C. Decker, Hamilton, Ontario, CA).
- A key enzyme in the synthesis of triglycerides is acyl CoA:diacylglycerol acyltransferase, or DGAT. DGAT is a microsomal enzyme that is widely expressed in mammalian tissues and that catalyzes the joining of 1,2-diacylglycerol (DAG) and fatty acyl CoA to form triglycerides (TG) at the endoplasmic reticulum (reviewed in Chen and Farese, Trends Cardiovasc. Med. (2000) 10: 188 and Farese, et al, Curr. Opin. Lipidol. (2000) 11:229). It was originally thought that DGAT uniquely controlled the catalysis of the final step of acylation of diacylglycerol to triglyceride in the two major pathways for triglyceride synthesis, the glycerol phosphate and monoacylglycerol pathways. Because triglycerides are considered essential for survival, and their synthesis was thought to occur through a single mechanism, inhibition of triglyceride synthesis through inhibiting the activity of DGAT has been largely unexplored.
- Genes encoding mouse DGAT1 and the related human homologs ARGP1 (human DGAT1) and ARGP2 (human ACAT2) now have been cloned and characterized (Cases, et al, Proc. Natl Acad. Sci. (1998) 95:13018; Oelkers, et al, J. Biol. Chem. (1998) 273:26765). The gene for mouse DGAT1 has been used to create DGAT knock-out mice to better elucidate the function of the DGAT gene.
- Unexpectedly, mice unable to express a functional DGAT1 enzyme (Dgat1−/− mice) are viable and still able to synthesize triglycerides, indicating that multiple catalytic mechanisms contribute to triglyceride synthesis (Smith, et al, Nature Genetics (2000) 25:87). Other enzymes that catalyze triglyceride synthesis, for example, DGAT2 and diacylglycerol transacylase, also have been identified (Cases, et al, J. Biol. Chem. (2001) 276:38870). Gene knockout studies in mice have revealed that DGAT2 μlays a fundamental role in mammalian triglyceride synthesis and is required for survival. DGAT2 deficient mice are lipopenic and die soon after birth, apparently from profound reductions in substrates for energy metabolism and from impaired permeability barrier function in the skin. (Farese, et al., J. Biol. Chem. (2004) 279: 11767).
- Significantly, Dgat1−/− mice are resistant to diet-induced obesity and remain lean. Even when fed a high fat diet (21% fat) Dgat1−/− mice maintain weights comparable to mice fed a regular diet (4% fat) and have lower total body triglyceride levels. The obesity resistance in Dgat1−/− mice is not due to decreased caloric intake, but the result of increased energy expenditure and decreased resistance to insulin and leptin (Smith, et al, Nature Genetics (2000) 25:87; Chen and Farese, Trends Cardiovasc. Med. (2000) 10: 188; and Chen, et al, J. Clin. Invest. (2002) 109:1049). Additionally, Dgat1−/− mice have reduced rates of triglyceride absorption (Buhman, et al, J. Biol. Chem. (2002) 277:25474). In addition to improved triglyceride metabolism, Dgat1−/− mice also have improved glucose metabolism, with lower glucose and insulin levels following a glucose load, in comparison to wild-type mice (Chen and Farese, Trends Cardiovasc. Med. (2000) 10: 188).
- The finding that multiple enzymes contribute to catalyzing the synthesis of triglyceride from diacylglycerol is significant, because it presents the opportunity to modulate one catalytic mechanism of this biochemical reaction to achieve therapeutic results in an individual with minimal adverse side effects. Compounds that inhibit the conversion of diacylglycerol to triglyceride, for instance by specifically inhibiting the activity of DGAT1, will find use in lowering corporeal concentrations and absorption of triglycerides to therapeutically counteract the pathogenic effects caused by abnormal metabolism of triglycerides in obesity, insulin resistance syndrome and overt type II diabetes, congestive heart failure and atherosclerosis, and as a consequence of cancer therapy.
- Because of the ever increasing prevalence of obesity, type II diabetes, heart disease and cancer in societies throughout the world, there is a pressing need in developing new therapies to effectively treat and prevent these diseases. Therefore there is an interest in developing compounds that can potently and specifically inhibit the catalytic activity of DGAT, in particular DGAT1.
- We have now unexpectedly found that novel compounds exhibiting DGAT inhibitory activity, in particular DGAT1 inhibitory activity, and these compounds can therefore be used to prevent or treat a disease associated with or mediated by DGAT, such as for example obesity, type II diabetes, heart disease and cancer. The compounds of the invention differ from the prior art compounds in structure, in their pharmacological activity, pharmacological potency, and/or pharmacological profile.
- We have also unexpectedly found that DGAT inhibitors, including the DGAT inhibitors of the present invention, can be used to elevate the levels of one or more satiety hormones, in particular glucagon-like-peptide-1 (GLP-1) and therefore DGAT inhibitors, in particular DGAT1 inhibitors, can also be used to prevent or treat a disease which can benefit from elevated levels of a satiety hormone, in particular GLP-1. Glucagon-like peptide 1 (GLP-1) is an intestinal hormone which generally stimulates insulin secretion during hyperglycemia, suppresses glucagon secretion, stimulates (pro) insulin biosynthesis and decelerates gastric emptying and acid secretion. GLP-1 is secreted from L cells in the small and large bowel following the ingestion of fat and proteins. GLP-1 has been suggested, among other indications, as a possible therapeutic agent for the management of type II non-insulin-dependent diabetes mellitus as well as related metabolic disorders, such as obesity.
- The present novel compounds make it possible to treat a disease which can benefit from elevated levels of GLP-1 with small molecules (compared to large molecules such as proteins or protein-like compounds, e.g. GLP-1 analogues).
- The peroxisome proliferator-activated receptors (PPAR) belong to the steroid hormone nuclear receptor superfamily of ligand-activated transcription factors that mediate the specific effects of small lipophilic compounds, such as steroids, retinoids and fatty acids, on DNA transcription. They play an important role in the regulation of lipid metabolism, in the regulation of energy homeostasis, inflammation, artherosclerosis and glucose control. Three subtypes are identified so far, namely PPAR-α, PPAR-β/δ and PPAR-γ. The three isoforms exhibit different tissue distribution as well as different ligand specificities.
- PPAR-α plays a crucial role in the intracellular lipid metabolism. The PPAR-α subtype is mainly expressed in tissues with elevated mitochondrial and peroxisomal fatty acid β-oxidation rates, that efficiently harvest energy from lipids, including liver, skeletal muscle, heart muscle, proximal tubular epithelial cells of the kidney, and brown fat (brown adipose tissue). PPAR-α is also present in cells of the arterial wall, in monocytes/macrophages, smooth muscle cells, endothelial cells, in hepatocytes, and in cardiac myocytes.
- Saturated and unsaturated fatty acids are found to be the primary natural PPAR-α ligands. In general, PPAR-α can be activated by a heterogeneous group of compounds, which include natural and synthetic agonists, such as eicosanoids, leukotriene β4, carbaprostacyclin, nonsteroidal anti-inflammatory drugs, pirinixic acid (WY-14643; PPAR-α/γ agonist), phthalate ester plasticizers, pterostilbene, fibrates or active metabolites thereof, α-substituted phenyl-propanoic acid derivatives and isoxazolyl-serine-based compounds. Finally, PPAR-α is induced by glucocorticoids in response to stress and follows a diurnal rhythm.
- Fibrates or active metabolites thereof such as fabric acid derivatives, are PPAR-α agonists, and have been used to treat dyslipidemia for several decades because of their triglyceride lowering and high-density lipoprotein (HDL) cholesterol elevating effects. Fibric acid derivatives lower the levels of triglyceride-rich lipoproteins, such as very low-density lipoproteins (VLDL), raise HDL levels, and have variable effect on low-density lipoproteins (LDL) levels. The effects on VLDL levels appear to result primarily from an increase in lipoprotein lipase activity, especially in muscle. This leads to enhanced hydrolysis of VLDL triglyceride content and an enhanced VLDL catabolism. Fibric acid agents also may alter the composition of the VLDL, for example, by decreasing hepatic production of apoC-III, an inhibitor of lipoprotein lipase activity. These compounds are also reported to decrease hepatic VLDL triglyceride synthesis, possibly by inhibiting fatty acid synthesis and by promoting fatty acid oxidation. In addition, they have been documented to be beneficial in the prevention of ischemic heart disease in individuals with dyslipidemia and they can also modestly decrease elevated fibrinogen and PAI-1 levels. Well-known examples of fibrates are fenofibrate (fenofibric acid as active metabolite), ABT-335 (which is the choline salt of fenofibric acid), bezafibrate, clofibrate, ciprofibrate, etofibrate, pirifibrate, beclofibrate and gemfibrozil (PPAR-α modulator).
- Because of the ever increasing prevalence of obesity, type II diabetes, heart disease and cancer in societies throughout the world, there is a pressing need in developing new therapies to effectively treat and prevent these diseases.
- We have now unexpectedly found that the combination of a compound showing DGAT inhibitory activity, in particular DGAT1 inhibitory activity, with a PPAR agonist, in particular a PPAR-α agonist, may exhibit an increased and/or accelerated effect on weight loss, compared to the effect of the DGAT inhibitor or the PPAR agonist each separately, and additional can decrease food intake. The combinations of the present invention may show synergy compared to administration of the composing ingredients alone.
- WO 2006/034441 discloses heterocyclic derivatives and their use as stearoyl CoA desaturase inhibitors (SCD-1 inhibitors).
- WO 2006/086445 relates to a combination therapy of a SCD-1 inhibitor and another drug to treat adverse weight gain.
- WO 2006/004200 and JP2007131584 relate to urea and amino derivatives having DGAT inhibitory activity.
- WO 2004/047755 relates to fused bicyclic nitrogen-containing heterocycles having DGAT inhibitory activity.
- WO2005/072740 relates to an anorectic action of a compound having DGAT inhibitory activity.
- WO 2007/071966 discloses a conjoint treatment of pyrimido-[4,5-B]oxazines showing DGAT inhibitory activity together with anti-dyslipidaemia agents such as PPAR-α agonists.
- WO2008/148851, WO2008/148840, WO2008/148849 and WO2008/148868 concern piperidine/piperazine derivatives having DGAT inhibitory activity.
-
FIG. 1A shows the food intake of mice treated with a DGAT inhibitor (compound 223 of Class D—called D inFIG. 1A ), fenofibrate (F) or both, compared to the control group. - ‘BL’ means baseline food intake.
-
FIG. 1B shows the food intake of DIO C57BL/6 mice fed with a high-fat diet containing fenofibrate (F) and compound 223 of Class D (D). -
FIG. 1C shows the high fat diet intake (g) of DIO C57BL/6 mice treated with a DGAT inhibitor (compound 358 of Class D), fenofibrate (F) or both, compared to the control group. -
FIG. 1D shows food intake of lean C57BL/6 mice fed a low-fat diet containing compound223 of Class D (D) and fenofibrate (F). -
FIG. 2A shows the change in body weight (g) of DIO C57BL/6 mice treated with a DGAT inhibitor (compound 223 of Class D 25 mpk/d), fenofibrate (31 mpk/d) or both. -
FIG. 2B shows the body weight change of DIO C57BL/6 mice fed with a high-fat diet containing fenofibrate (F) and compound 223 of Class D (D). -
FIG. 2C shows the change in body weight (g) of DIO C57BL/6 mice fed with a high-fat diet containing DGAT inhibitor (compound 358 of Class D), fenofibrate or both. -
FIG. 2D shows food intake of lean C57BL/6 mice fed a high-fat diet containing compound 223 of Class D (D) and fenofibrate (F). -
FIG. 3A shows food intake onday 1 of DIO C57BL/6 mice fed with a high-fat diet containing compound 223 of Class D and fenofibrate (D+F). -
FIG. 3B shows day-1 food intake of mice fed a low and high-fat diet containing 0.01/0.0125 w/w compound 223 of Class D/fenofibrate (D/F). DIO C57BL/6 mice were acclimated to cages designed for measuring food intake. After adaptation to either a lowfat (10 kcal % fat) or high-fat (45 kcal % fat) diet, mice were switched to a diet with the same fat content (10 kcal % and 45 kcal % fat respectively), but supplemented with 0.01/0.0125% w/w D/F. - The present invention relates to combinations of a DGAT inhibitor and a peroxisome proliferator-activator receptor (PPAR) agonist or a prodrug thereof
- In an embodiment, the present invention relates to combinations of a DGAT inhibitor and a PPAR-α agonist or a prodrug thereof.
- In an embodiment, the present invention relates to combinations of a DGAT1 inhibitor and a PPAR agonist or a prodrug thereof.
- In an embodiment, the present invention relates to combinations of a DGAT1 inhibitor and a PPAR-α agonist or a prodrug thereof.
- In an embodiment, the present invention relates to combinations of a DGAT inhibitor, in particular a DGAT1 inhibitor, and a PPAR-α agonist or a prodrug thereof selected from the group of fibrates.
- In an embodiment, the present invention relates to combinations of a DGAT inhibitor, in particular a DGAT1 inhibitor, and fenofibrate.
- In an embodiment, the present invention relates to combinations of a PPAR agonist or a prodrug thereof and a DGAT inhibitor wherein the DGAT inhibitor is selected from
- a) a compound having the formula
- including any stereochemically isomeric form thereof, wherein
- A represents CH or N;
- X represents O or NRx;
- the dotted line represents an optional bond in case A represents a carbon atom;
- Y represents a direct bond; —NRx—C(═O)—; —C(═O)—NRx—; —NRx—C(═O)—Z—; —NRx—C(═O)—Z—NRy—; —NRx—C(═O)—Z—NRy—C(═O)—; —NRx—C(═O)—Z—NRy—C(═O)—O—; —NRx—C(═O)—Z—O—; —NRx—C(═O)—Z—O—C(═O)—; —NRx—C(═O)—Z—C(═O)—; —NRx—C(═O)—Z—C(═O)—O—; —NRx—C(═O)—O—Z—C(═O)—; —NRx—C(═O)—O—Z—C(═O)—O—; —NRx—C(═O)—O—Z—O—C(═O)—; —NRx—C(═O)—Z—C(═O)—NRy—; —NRx—C(═O)—Z—NRy—C(═O)—NRy—; —C(═O)—Z—; —C(═O)—Z—O—; —C(═O)—NRx—Z—; —C(═O)—NRx—Z—O—; —C(═O)—NRx—Z—C(═O)—O—; —C(═O)—NRx—Z—O—C(═O)—; —C(═O)—NRx—O—Z—; —C(═O)—NRx—Z—NRy—; —C(═O)—NRx—Z—NRy—C(═O)—; —C(═O)—NRx—Z—NRy—C(═O)—O—;
- Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with C1-4alkyloxy, C1-4alkylthio, hydroxyl, cyano or aryl; and wherein two hydrogen atoms attached to the same carbon atom in the definition of Z may optionally be replaced by C1-6alkanediyl;
- Rx represents hydrogen or C1-4alkyl;
- Ry represents hydrogen; C1-4alkyl optionally substituted with C3-6cycloalkyl or aryl or Het; C2-4alkenyl; or —S(═O)p-aryl;
- R1 represents C1-12alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-oxyC1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl; C2-6alkynyl; C3-6cycloalkyl; aryl1; aryl1C1-6alkyl; Het1; or Het1C1-6alkyl; provided that when Y represents —NRx—C(═O)—Z—; —NRx—C(═O)—Z—NRy; —NRx—C(═O)—Z—C(═O)—NRy—; —C(═O)—Z—; —NRx—C(═O)—Z—NRy—C(═O)—NRy—; —C(═O)—NRx—Z—; —C(═O)—NRx—O—Z—; or —C(═O)—NRx—Z—NRy—; then R1 may also represent hydrogen;
- R2 and R3 each independently represent hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- R4 represents hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R6R5N—C(═O)—; R6R5N—C1-6alkyl; C3-6cycloalkyl; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; Het-O—;
- R5 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R8R7N—C1-4alkyl; C1-4alkyloxy; Het; aryl; R8R7N—C(═O)—C1-4alkyl;
- R6 represents hydrogen or C1-4alkyl;
- R7 represents hydrogen; C1-4alkyl; C1-4alkylcarbonyl;
- R8 represents hydrogen or C1-4alkyl; or
- R7 and R8 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from O, S, S(═O)p or N; and which heterocycle may optionally be substituted with C1-4alkyl;
- R9 represents hydrogen, halo, C1-4alkyl, C1-4alkyl substituted with hydroxyl;
- aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino; R6R5N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; Het-O—;
- Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio;
- polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino; R6R5N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; Het-O—;
- p represents 1 or 2;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof;
- b) a compound having the formula
- including any stereochemically isomeric form thereof, wherein
- A represents CH or N;
- the dotted line represents an optional bond in case A represents a carbon atom;
- X represents —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —S(═O)p—; C(═S)—; —NRx—C(═S)—; —Z—C(═S)—; —Z—NRx—C(═S)—; —O—C(═O)—; —C(═O)—C(═O)—;
- Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl;
- Rx represents hydrogen or C1-4alkyl;
- R1 represents a 5-membered monocyclic heterocycle containing at least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle; or a 5-membered heterocycle containing at least 2 heteroatoms fused with phenyl, cyclohexyl or a 5- or 6-membered heterocycle; wherein each of said heterocycles may optionally be substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy;
- C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)-aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino;
- R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkyl-C1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; Het-O—;
- R2 represents R3;
- R3 represents C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may optionally be substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; Het-O—;
- R4 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R7R6N—C1-4alkyl; C1-4alkyloxy; Het; aryl; R7R6N—C(═O)—C1-4alkyl;
- R5 represents hydrogen or C1-4alkyl;
- R6 represents hydrogen; C1-4alkyl; C1-4alkylcarbonyl;
- R7 represents hydrogen or C1-4alkyl; or
- R6 and R7 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms selected from O, S, S(═O)p or N; and which heterocycle may optionally be substituted with C1-4alkyl;
- R8 represents hydrogen, halo, C1-4alkyl, C1-4alkyl substituted with hydroxyl; aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl
- p represents 1 or 2;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof;
- c) a compound having the formula
- including any stereochemically isomeric form thereof, wherein
- A represents CH or N;
- the dotted line represents an optional bond in case A represents a carbon atom;
- X represents O—C(═O)—; —C(═O)—C(═O)—; —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —C(═O)—Z—; —NRx—C(═O)—Z—; C(═S)—; —S(═O)p—; —NRx—C(═S)—; —Z—C(═S)—; —Z—NRx—C(═S)—; —C(═S)—Z—; —NRx—C(═S)—Z—;
- Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl;
- Rx represents hydrogen or C1-4alkyl;
- Y represents C(═O)—NRx— or —NRx—C(═O)—;
- R1 represents adamantanyl, C3-6cycloalkyl; aryl1 or Het1;
- R2 represents hydrogen, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 6-membered aromatic heterocycle containing 1 or 2 N atoms may optionally be substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy;
- C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R4R3N—C(═O)—; R4R3N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; Het-O—;
- R3 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R6R5N—C1-4alkyl; C1-4alkyloxy; Het; Het-C1-4alkyl; aryl; R6R5N—C(═O)—C1-4alkyl;
- R4 represents hydrogen or C1-4alkyl;
- R5 represents hydrogen; C1-4alkyl; C1-4alkylcarbonyl;
- R6 represents hydrogen or C1-4alkyl; or
- R5 and R6 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from O, S, S(═O)p or N; and which heterocycle may optionally be substituted with C1-4alkyl;
- R7 represents hydrogen, halo, C1-4alkyl, C1-4alkyl substituted with hydroxyl;
- aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R4R3N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; Het-O—;
- Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy;
- C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R4R3N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; Het-O—;
- p represents 1 or 2;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof;
- or
- d) a compound having the formula
- including any stereochemically isomeric form thereof, wherein
- A represents CH or N;
- the dotted line represents an optional bond in case A represents a carbon atom;
- X represents C(═O)—; —O—C(═O)—; —C(═O)—C(═O)—; —NRx—C(═O)—; —Z1—C(═O)—; —Z1—NRx—C(═O)—; —C(═O)—Z1—; —NRx—C(═O)—Z1—; —S(═O)p—; C(═S)—; —NRx—C(═S)—; —Z1—C(═S)—; NRx—C(═S)—; —C(═S)—Z1—; —NRx—C(═S)—Z1—;
- Z1 represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl;
- Y represents NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—; —NRx—C(═O)—Z2—NRy—C(═O)—O—; —NRx—C(═O)—Z2—O—; —NRx—C(═O)—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—; —NRx—C(═O)—Z2—C(═O)—O—; —NRx—C(═O)—O—Z2—C(═O)—; —NRx—C(═O)—O—Z2—C(═O)—O—; —NRx—C(═O)—O—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—Z2—; —C(═O)—Z2—O—; —C(═O)—NRx—Z2—; —C(═O)—NRx—Z2—O—; —C(═O)—NRx—Z2—C(═O)—O—; —C(═O)—NRx—Z2—O—C(═O)—; —C(═O)—NRx—O—Z2—; —C(═O)—NRx—Z2—NRy—; —C(═O)—NRx—Z2—NRy—C(═O)—; —C(═O)—NRx—Z2—NRy—C(═O)—O—;
- Z2 represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with C1-4alkyloxy, C1-4alkylthio, hydroxyl, cyano or aryl; and wherein two hydrogen atoms attached to the same carbon atom in the definition of Z2 may optionally be replaced by C1-6alkanediyl;
- Rx represents hydrogen or C1-4alkyl;
- Ry represents hydrogen; C1-4alkyl optionally substituted with C3-6cycloalkyl or aryl or Het; C2-4alkenyl; or S(═O)p-aryl;
- R1 represents C1-12alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-oxyC1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl; C2-6alkynyl; C3-6cycloalkyl; adamantanyl; aryl1; aryl1C1-6alkyl; Het1; or Het1C1-6alkyl; provided that when Y represents —NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy; —NRx—C(═O)—Z2—C(═O)—NRy—; —C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—NRx—Z2—; —C(═O)—NRx—O—Z2—; or —C(═O)—NRx—Z2—NRy—; then R1 may also represent hydrogen;
- R2 represents hydrogen, C1-12alkyl, C2-6alkenyl or R3;
- R3 represents C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 6-membered aromatic heterocycle containing 1 or 2 N atoms may optionally be substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino;
- —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; Het-O—;
- R4 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R7R6N—C1-4alkyl; C1-4alkyloxy; Het; Het-C1-4alkyl; aryl; R7R6N—C(═O)—C1-4alkyl;
- R5 represents hydrogen or C1-4alkyl;
- R6 represents hydrogen; C1-4alkyl; C1-4alkylcarbonyl;
- R7 represents hydrogen or C1-4alkyl; or
- R6 and R7 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from O, S, S(═O)p or N; and which heterocycle may optionally be substituted with C1-4alkyl;
- R8 represents hydrogen, halo, C1-4alkyl, C1-4alkyl substituted with hydroxyl;
- aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; Het-O—;
- Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy;
- C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio;
- polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; Het-O—;
- p represents 1 or 2;
- provided that if X represents O—C(═O)—, then R2 represents R3;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof
- Hereinafter, the compounds of formula (I) as defined under a) are indicated as class A compounds, the compounds as defined under b) are indicated as class B compounds, the compounds as defined under c) are indicated as class C compounds, and the compounds as defined under d) are indicated as class D compounds.
- In an embodiment, the present invention relates to combinations of a DGAT inhibitor wherein the DGAT inhibitor is selected from
- a) a compound of class A, class B, class C, or class D;
- and
- b) a PPAR-α agonist or a prodrug thereof.
- In an embodiment, the present invention relates to combinations of a DGAT inhibitor wherein the DGAT inhibitor is selected from
- a) a compound of class A, class B, class C, or class D;
- and
- b) a fibrate.
- In an embodiment, the present invention relates to combinations of a DGAT inhibitor wherein the DGAT inhibitor is selected from
- a) a compound of class A, class B, class C, or class D;
- and
- b) fenofibrate.
- In an embodiment, the present invention relates to any of the preceding embodiments wherein the DGAT inhibitor is selected from a compound of Class A.
- In an embodiment, the present invention relates to any of the preceding embodiments wherein the DGAT inhibitor is selected from a compound of Class B.
- In an embodiment, the present invention relates to any of the preceding embodiments wherein the DGAT inhibitor is selected from a compound of Class C.
- In an embodiment, the present invention relates to any of the preceding embodiments wherein the DGAT inhibitor is selected from a compound of Class D.
- In an embodiment, the present invention relates to any of the preceding or the following embodiments wherein the PPAR agonist or a prodrug thereof, is a PPAR-α agonist or a prodrug thereof, more in particular a fibrate, even more in particular a fenofibrate.
- In an embodiment, the present invention relates to any of the preceding or following embodiments wherein the DGAT inhibitor is a DGAT1 inhibitor.
- The present invention also concerns methods for the preparation of compounds of class A, class B, class C or class D, and combinations or pharmaceutical compositions comprising them.
- The combinations according to the present invention are suitable for use as a medicament.
- The combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of metabolic disorders, such as obesity and/or obesity related disorders (including, but not limited to, peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome; dermatological conditions such as acne, psoriasis; cardiovascular diseases, such as atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis or vascular stenosis; alzheimer's disease; neoplastic diseases, such as solid tumors, skin cancer, melanoma, lymphoma or endothelial cancers, e.g., breast cancer, lung cancer, colorectal cancer, stomach cancer, other cancers of the gastrointestinal tract (e.g., esophageal cancer or pancreatic cancer), prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer or ovarian cancer.
- The combinations according to the present invention are particularly suitable for the treatment of prevention, in particular treatment, of obesity, type II diabetes mellitus; for suppressing appetite, for inducing satiety and/or for reducing food intake.
- The present invention also relates to the use of the combinations according to the present invention for the manufacture of a medicament for the treatment or prevention, in particular treatment, of the above mentioned diseases or conditions.
- The present invention also relates to the use of a combination of a DGAT inhibitor, in particular a DGAT1 inhibitor, and a PPAR agonist or a prodrug thereof, in particular a PPAR-α agonist or a prodrug thereof, more in particular a fibrate, even more in particular fenofibrate, for the manufacture of a medicament for the prevention or the treatment, in particular for the treatment, of a disease which can benefit from elevated levels of one or more satiety hormones, in particular GLP-1.
- The present invention also relates to a product containing a) a DGAT inhibitor, in particular a DGAT1 inhibitor, more in particular a compound of Class A, Class B, Class C or Class D, and (b) an agonist of peroxisome proliferators-activator receptor such as for example fenofibrate, as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease which can benefit from an elevated level of GLP-1 or DGAT inhibition, such as for example diabetes, in particular type II diabetes mellitus, obesity, for suppressing appetite, inducing satiety or for reducing food intake.
- In an embodiment, the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of the combinations mentioned hereinbefore or hereinafter.
- The present invention further relates to novel compounds, wherein the compound is selected from:
- N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide (compound 355 Class D);
- 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 151 Class C);
- 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 354 Class D);
- 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 356 Class D);
- 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 152 Class C);
- 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 358 Class D);
- 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 353 Class D);
- 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 357 Class D);
- 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 147 Class C);
- 4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 360 Class D);
- 4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 359 Class D);
- 4-[4-[[2,6-dichloro-4-[(4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 364 Class D);
- 4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 361 Class D);
- 4-[4-[[2,6-dichloro-4-[(4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 363 Class D);
- 4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 362 Class D);
- 4-[4-[[2,6-dichloro-4-[(4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 150 Class C);
- 4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 149 Class C);
- 4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 148 Class C);
- including any stereochemically isomeric forms thereof;
- N-oxides thereof, pharmaceutically acceptable salts thereof or solvates thereof.
- Hereinafter, the novel compounds as defined in the list hereabove (compounds 147 till 152 from Class C, and compounds 353 till 364 from Class D; including any stereochemically isomeric forms thereof; N-oxides thereof, pharmaceutically acceptable salts thereof or solvates thereof), are indicated as compounds of group Q.
- The present invention further relates to the novel compound 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl) methyl]-benzamide (compound 358 Class D); including any stereochemically isomeric forms thereof; N-oxides thereof, pharmaceutically acceptable salts thereof or solvates thereof.
- The present invention also relates to a compound of group Q for use as a medicament.
- The present invention also relates to a compound of group Q for the prevention or the treatment of a disease mediated by DGAT, in particular the present invention relates to a compound of group Q for the prevention or the treatment of a disease which can benefit from inhibition of DGAT, in particular for the treatment of a disease which can benefit from inhibition of DGAT, in particular DGAT1.
- The present invention also relates to a compound of group Q for the prevention or the treatment, in particular for the treatment, of a disease which can benefit from elevated levels of one or more satiety hormones, in particular GLP-1.
- The present invention also relates to the use of a compound of group Q for the manufacture of a medicament for the treatment or prevention, in particular treatment, of the above mentioned diseases or conditions.
- In an embodiment, the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound of group Q.
- The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail.
- All terms used are to be construed in accordance with the following definitions, unless the context indicates otherwise. In general, the terms are valid for the compounds of class A, class B, class C and class D, unless it is indicated that a certain definition for a term is only valid for a certain class or subset of classes.
- As used hereinbefore or hereinafter C0-3alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 0 (then it represents a direct bond) to 3 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl; C1-2alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having 1 or 2 carbon atoms such as methyl, ethyl;
- C1-4alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl; C1-65alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 5 carbon atoms such as the group defined for C1-4alkyl and pentyl, 2-methylbutyl and the like; C1-6alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the group defined for C1-4alkyl and for C1-5alkyl and hexyl, 2-methylpentyl and the like; C1-12alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 12 carbon atoms such as the group defined for C1-6alkyl and heptyl, 2-methylheptyl and the like; C1-6alkanediyl defines straight or branched chain saturated bivalent hydrocarbon radicals having from 1 to 6 carbon atoms such as methylene, 1,2-ethanediyl or 1,2-ethylidene, 1,3-propanediyl or 1,3-propylidene, 1,4-butanediyl or 1,4-butylidene, 1,5-pentanediyl and the like; C2-4alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 4 carbon atoms and having a double bond such as ethenyl, propenyl, butenyl and the like; C2-6alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and having a double bond such as the group defined for C2-4alkenyl and pentenyl, hexenyl, 3-methylbutenyl and the like; C2-6alkenediyl defines straight or branched chain bivalent hydrocarbon radicals having from 2 to 6 carbon atoms and having a double bond such as 1,2-ethenediyl, 1,3-propenediyl, 1,4-butenediyl, 1,5-pentenediyl and the like; C2-6alkynyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and having a triple bond such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like; C2-6alkynediyl as a group or part of a group defines straight or branched chain bivalent hydrocarbon radicals having from 2 to 6 carbon atoms and having a triple bond such as 1,2-ethynediyl, 1,3-propynediyl, 1,4-butynediyl, 1,5-pentynediyl and the like; C3-6cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- The term halo is generic to fluoro, chloro, bromo and iodo. As used hereinbefore or hereinafter, polyhaloC1-6alkyl as a group or part of a group is defined as C1-6alkyl substituted with one or more, such as for example 2, 3, 4 or 5 halo atoms, for example methyl substituted with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl, 1,1-difluoro-ethyl, 1,1-difluoro-2,2,2-trifluoro-ethyl and the like. In case more than one halogen atoms are attached to a C1-6alkyl group within the definition of polyhaloC1-6alkyl, they may be the same or different.
- As used herein before, the term (═O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulfonyl moiety when two of said terms are attached to a sulfur atom. Oxo means ═O.
- The radical R1, as defined hereinabove for the compounds of class B, may be an optionally substituted 5-membered monocyclic heterocycle containing at least 2 heteroatoms, an optionally substituted 6-membered aromatic monocyclic heterocycle or an optionally substituted 5-membered heterocycle containing at least 2 heteroatoms fused with a phenyl, cyclohexyl or a 5- or 6-membered heterocycle.
- A 5-membered monocyclic heterocycle as defined hereinabove or hereinafter may be a 5-membered monocyclic non-aromatic (fully saturated or partially saturated) or aromatic heterocycle containing at least 2 heteroatom, in particular 2 or 3 heteroatoms, each independently selected from O, S, S(═O)p or N. Examples of such unsubstituted monocyclic 5-membered heterocycles comprise, but are not limited to, non-aromatic (fully saturated or partially saturated) or aromatic 5-membered monocyclic heterocycles such as for example 1,3-dioxolanyl, imidazolidinyl, thiazolidinyl, dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadiazolidinyl, pyrazolidinyl, imidazolinyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl and the like. Optional substituents of the above heterocycles are hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxy-carbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)-aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; Het-O—.
- A 6-membered aromatic monocyclic heterocycle as defined hereinabove or hereinafter contains at least one heteroatom, in particular 1, 2 or 3 heteroatoms, each independently selected from O, S, S(═O)p or N. Examples of such unsubstituted monocyclic 6-membered aromatic heterocycles comprise, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl and the like. Optional substituents of the above heterocycles are hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—;
- C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; Het-O—.
- A 5-membered heterocycle containing at least 2 heteroatoms fused with phenyl, cyclohexyl or a 5- or 6-membered heterocycle as defined hereinabove or hereinafter may be a non-aromatic (fully saturated or partially saturated) or aromatic 5-membered heterocycle containing at least 2 heteroatoms, in particular 2 or 3 heteroatoms, each independently selected from O, S, S(═O)p or N, in particular O, S or N, more in particular O or N, fused with phenyl, cyclohexyl or a 5- or 6-membered non-aromatic (fully saturated or partially saturated) or aromatic heterocycle containing at least one heteroatom, in particular 1, 2 or3 heteroatoms, each independently selected from O, S, S(═O)p or N. Examples of such unsubstituted bicyclic heterocycles comprise, but are not limited to, non-aromatic (fully saturated or partially saturated) or aromatic 8- or 9-membered bicyclic heterocycles such as for example 1,3-benzodioxolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl, imidazoimidazolyl, imidazopyrazolyl, isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl, triazolotriazinyl and the like. Optional substituents of the above heterocycles are hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; Het-O—.
- The radical Het or Het1 as defined hereinabove may be an optionally substituted monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom, in particular 1, 2 or 3 heteroatoms, each independently selected from O, S, S(═O)p or N; or an optionally substituted bi- or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom, in particular 1, 2, 3, 4 or 5 heteroatoms, each independently selected from O, S, S(═O)p or N. Examples of such unsubstituted monocyclic heterocycles comprise, but are not limited to, non-aromatic (fully saturated or partially saturated) or aromatic 4-, 5-, 6- or 7-membered monocyclic heterocycles such as for example azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl, hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, hexahydrodiazepinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl and the like. Examples of such unsubstituted bicyclic or tricyclic heterocycles comprise, but are not limited to, non-aromatic (fully saturated or partially saturated) or aromatic 8- to 17-membered bicyclic or tricyclic heterocycles such as for example decahydroquinolinyl, octahydroindolyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, indolinyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzo-thienyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl, pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, oxazolo-pyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl, imidazoimidazolyl, imidazopyrazolyl; isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl, triazolotriazinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. Optional substituents for Het heterocycles are hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl. Optional substituents for Het1 substituents are hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino; R6R5N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; Het-O—.
- Examples of a 6-membered aromatic heterocycle containing 1 or 2 N atoms in the definition of R3 (class B and class D) and R2 (class C) are pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.
- When any variable occurs more than one time in any constituent (e.g. aryl, Het), each definition is independent.
- The term Het or Het1 is meant to include all the possible isomeric forms of the heterocycles, for instance, pyrrolyl comprises 1H-pyrrolyl and 2H-pyrrolyl.
- The term R1 (in class B) is meant to include all the possible isomeric forms of the heterocycles, for instance, pyrrolyl comprises 1H-pyrrolyl and 2H-pyrrolyl.
- The carbocycles or heterocycles covered by the terms aryl, Het, aryl1, Het1, R1 (in class B) or R3 (in class B, class C or class D) may be attached to the remainder of the molecule of formula (I) of class A, class B, class C or class D through any ring carbon or heteroatom as appropriate, if not otherwise specified. Thus, for example, when the heterocycle is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like, or when the carbocycle is naphthalenyl, it may be 1-naphthalenyl, 2-naphthalenyl and the like.
- Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms.
- When X is defined as for instance —NRx—C(═O)—, this means that the nitrogen of NRx is linked to the R2 substituent (not applicable for class A) and the carbon atom of C(═O) is linked to the nitrogen of the ring
- Thus the left part of the bivalent radical in the definition of X is linked to the R2 substituent and the right part of the bivalent radical in the definition of X is linked to the ring moiety
- When Y is defined for instance as —NRx—C(═O)— in class A or class C, this means that the nitrogen of NRx is linked to the phenyl moiety and the carbon atom of C(═O) is linked to the R1 substituent. Thus the left part of the bivalent radical in the definition of Y is linked to the phenyl moiety and the right part of the bivalent radical in the definition of Y is linked to the R1 substituent.
- When Y is defined as for instance —NRx—C(═O)—Z2— in class D, this means that the nitrogen of NRx is linked to the phenyl ring and the Z2 is linked to the R1 substituent. Thus the left part of the bivalent radical in the definition of Y is linked to the phenyl ring and the right part of the bivalent radical in the definition of Y is linked to R1 substituent.
- Some of the compounds of class A, class B, class C or class D may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
- Whenever used hereinbefore or hereinafter that substituents can be selected each independently out of a list of numerous definitions, such as for example for R2 and R3 in class A, R4 and R5 in class B and class D, and R3 and R4 in class C, all possible combinations are intended which are chemically possible.
- For therapeutic use, salts of the compounds of class A, class B, class C or class D are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
- The pharmaceutically acceptable salts as mentioned hereinbefore or hereinafter are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of class A, class B, class C or class D are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
- The compounds of class A, class B, class C or class D containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. The pharmaceutically acceptable salts as mentioned hereinbefore or hereinafter are meant to also comprise the therapeutically active non-toxic metal or amine addition salt forms (base addition salt forms) which the compounds of class A, class B, class C or class D are able to form. Appropriate base addition salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
- Conversely the salt form can be converted by treatment with acid into the free acid form.
- The term salt also comprises the quaternary ammonium salts (quaternary amines) which the compounds of class A, class B, class C or class D are able to form by reaction between a basic nitrogen of a compound of class A, class B, class C or class D and an appropriate quaternizing agent, such as, for example, an optionally substituted C1-6alkylhalide, arylhalide, C1-6alkyl-carbonylhalide, arylcarbonylhalide, or arylC1-6alkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as for example C1-6alkyl trifluoromethanesulfonates, C1-6alkyl methanesulfonates, and C1-6alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate, acetate, triflate, sulfate, sulfonate. The counterion of choice can be introduced using ion exchange resins.
- The term solvate comprises the hydrates and solvent addition forms which the compounds of class A, class B, class C or class D are able to form, as well as salts thereof Examples of such forms are e.g. hydrates, alcoholates and the like.
- The N-oxide forms of the present compounds are meant to comprise the compounds of class A, class B, class C or class D wherein one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide.
- It will be appreciated that some of the compounds of class A, class B, class C or class D may contain one or more centers of chirality and exist as stereochemically isomeric forms.
- The term “stereochemically isomeric forms” as used hereinbefore or hereinafter defines all the possible stereoisomeric forms which the compounds of class A, class B, class C or class D may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of the basis molecular structure and their N-oxides, salts or solvates, substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. Thus, when a compound of class A, class B, class C or class D is for instance specified as (E), this means that the compound is substantially free of the (Z) isomer.
- In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E (entgegen) or Z (zusammen) -stereochemistry at said double bond. The terms cis, trans, R, S, E and Z are well known to a person skilled in the art.
- Stereochemically isomeric forms of the compounds of class A, class B, class C or class D are obviously intended to be embraced within the scope of this invention.
- Following CAS-nomenclature conventions, when two stereogenic centers of known absolute configuration are present in a molecule, an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center. The configuration of the second stereogenic center is indicated using relative descriptors [R*,R*] or [R*,S*], where the first R* is always specified as the reference center and [R*,R*] indicates centers with the same chirality and [R* ,S*] indicates centers of unlike chirality. For example, if the lowest-numbered chiral center in the molecule has an S configuration and the second center is R, the stereo descriptor would be specified as S—[R*,S*]. If “α” and “β” are used : the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number, is arbitrarily always in the “α” position of the mean plane determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is denominated “α”, if it is on the same side of the mean plane determined by the ring system, or “β”, if it is on the other side of the mean plane determined by the ring system.
- The compounds of (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of class A, class B, class C or class D may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of class A, class B, class C or class D involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
- Whenever used hereinbefore or hereinafter, the term “compounds of class A”, “compounds of class B”, “compounds of class C” or “compounds of class D” or any subgroup thereof, is meant to also include their N-oxide forms, their salts, their stereochemically isomeric forms and their solvates. Of special interest are those compounds of class A, class B, class C or class D which are stereochemically pure.
- Whenever used hereinbefore or hereinafter, the term “compounds of group Q”, is meant to also include their N-oxide forms, their salts, their stereochemically isomeric forms and their solvates. Of special interest are those compounds group Q which are stereochemically pure.
- By PPAR agonist, in particular PPAR-α agonist, is meant a compound or a prodrug thereof, or a composition containing said compound or prodrug thereof; which directly or indirectly stimulates or increases an in vivo or in vitro reaction typical for the PPAR receptor, in particular the PPAR-α receptor, e.g. transcriptional regulation activity, as measured by an assay known to one skilled in the art such as, for example, described in Kuwabara K, Murakami K, Todo M, Aoki T, Asaki T, Mura M, and Yano J (2004) A novel selective peroxisome proliferator-activated receptor a agonist, 2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220), potently decreases plasma triglyceride and glucose levels and modifies lipoprotein profiles in KK-Ay mice. J Pharmacol Exp Ther Vol. 309, No. 3: 970-977.
- Non-limiting examples of PPAR-α agonists or prodrugs thereof include natural and synthetic agonists, such as eicosanoids, leukotriene β4, carbaprostacyclin, nonsteroidal anti-inflammatory drugs, pirinixic acid (WY-14643; PPAR-α/γ agonist), phthalate ester plasticizers, pterostilbene, fibrates or active metabolites thereof, α-substituted phenyl-propanoic acid derivatives, isoxazolyl-serine-based compounds.
- A preferred PPAR-α agonist or a prodrug thereof is a fibrate compound including, but not limited to fenofibrate (fenofibric acid as active metabolite), bezafibrate, clofibrate, ciprofibrate, etofibrate, ABT-335 (which is the choline salt of fenofibric acid), pirifibrate, beclofibrate or gemfibrozil (a PPAR-α modulator) and analogues, derivatives and pharmaceutically acceptable salts thereof.
- Whenever the term ‘prodrug’ is used within the context of this invention, this refers to a pharmacological substance (drug) that is administered in an inactive or significantly less active form. Once administered, the prodrug is metabolised in vivo into an active metabolite. For example, the prodrug fenofibrate (ester) is metabolised to fenofibric acid which is the active metabolite (PPAR-α agonist).
- A preferred fibrate is fenofibrate.
- In the present invention, fibrates include fibric acid derivatives and pharmaceutically acceptable salts of such fibric acid derivatives.
- The next embodiments of the present invention are those combinations of a DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPAR agonist, in particular a PPAR-α agonist, more in particular a fibrate, even more in particular fenofibrate; wherein the DGAT inhibitor is selected from compounds of Class A. Preferred embodiments of compounds of class A are:
- A-1) compounds of class A having the following formula (I)
- including any stereochemically isomeric form thereof, wherein
- A represents CH or N;
- X represents O or NRx;
- the dotted line represents an optional bond in case A represents a carbon atom;
- Y represents a direct bond; —NRx—C(═O)—; —C(═O)—NRx—; —NRx—C(═O)—Z—; —NRx—C(═O)—Z—NRy—; —NRx—C(═O)—Z—NRy—C(═O)—; —NRx—C(═O)—Z—NRy—C(═O)—O—; —NRx—C(═O)—Z—O—; —NRx—C(═O)—Z—O—C(═O)—; —NRx—C(═O)—Z—C(═O)—; —NRx—C(═O)—Z—C(═O)—O—; —NRx—C(═O)—O—Z—C(═O)—; —NRx—C(═O)—O—Z—C(═O)—O—; —NRx—C(═O)—O—Z—O—C(═O)—; —NRx—C(═O)—Z—C(═O)—NRy—; —NRx—C(═O)—Z—NRy—C(═O)—NRy—; —C(═O)—Z—; —C(═O)—Z—O—; —C(═O)—NRx—Z—; —C(═O)—NRx—Z—O—; —C(═O)—NRx—Z—C(═O)—O—; —C(═O)—NRx—Z—O—C(═O)—; —C(═O)—NRx—O—Z—; —C(═O)—NRx—Z—NRy—; —C(═O)—NRx—Z—NRy—C(═O)—; —C(═O)—NRx—Z—NRy—C(═O)—O—;
- Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with C1-4alkyloxy, C1-4alkylthio, hydroxyl, cyano or aryl; and wherein two hydrogen atoms attached to the same carbon atom in the definition of Z may optionally be replaced by C1-6alkanediyl;
- Rx represents hydrogen or C1-4alkyl;
- Ry represents hydrogen; C1-4alkyl optionally substituted with C3-6cycloalkyl or aryl or Het; C2-4alkenyl; or S(═O)p-aryl;
- R1 represents C1-12alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-oxyC1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl; C2-6alkynyl; C3-6cycloalkyl; aryl1; aryl1C1-6alkyl; Het1; or Het1C1-6alkyl; provided that when Y represents —NRx—C(═O)—Z—; —NRx—C(═O)—Z—NRy; —NRx—C(═O)—Z—C(═O)—NRy—; —C(═O)—Z—; —NRx—C(═O)—Z—NRy—C(═O)—NRy—; —C(═O)—NRx—Z—; —C(═O)—NRx—O—Z—; or —C(═O)—NRx—Z—NRy—; then R1 may also represent hydrogen;
- R2 and R3 each independently represent hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- R4 represents hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; R6R5N—C(═O)—; R6R5N—C1-6alkyl; C3-6cycloalkyl; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—;
- R5 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R8R7N—C1-4alkyl; C1-4alkyloxy; Het; aryl; R8R7N—C(═O)—C1-4alkyl;
- R6 represents hydrogen or C1-4alkyl;
- R7 represents hydrogen; C1-4alkyl; C1-4alkylcarbonyl;
- R8 represents hydrogen or C1-4alkyl; or
- R7 and R8 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms selected from O, S, S(═O)p or N; and which heterocycle may optionally be substituted with C1-4alkyl;
- aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—;
- Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—;
- p represents 1 or 2;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof; or
- A-2) compounds of class A or any subgroup thereof as mentioned hereinbefore as embodiment, wherein X represents NRx, in particular NH; or
- A-3) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment, wherein X represents O; or
- A-4) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein A represents N; or
- A-5) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein A represents CH, in particular wherein A represents CH and the dotted line does not represent a bond; or
- A-6) compounds of class A or any subgroup thereof as mentioned hereinbefore as embodiment wherein Y represents
- —NRx—C(═O)—; —NRx—C(═O)—Z—, —NRx—C(═O)—Z—NRy—; —NRx—C(═O)—Z—O—C(═O)—; in particular wherein Y represents —NRx—C(═O)— or —NRx—C(═O)—Z— with Z representing C1-6alkanediyl; or
- A-7) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Y represents a direct bond, in particular wherein Y represents a direct bond and R1 represents Het1; or
- A-8) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Y represents —NRx—C(═O)—, in particular wherein Y represents —NRx—C(═O)— and R1 represents Aryl1 or Het1; or
- A-9) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Y represents —NRx—C(═O)—Z—NRy—, in particular wherein Y represents
- —NRx—C(═O)—Z—NRy— and R1 represents Aryl1 or Het1; or
- A-10) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Y represents —NRx—C(═O)—Z—C(═O)—O— or —NRx—C(═O)—Z—O—C(═O)—, in particular —NRx—C(═O)—Z—O—C(═O)—; or
- A-11) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R2 or R3 each independently represent hydrogen, halo or C1-6alkyl, in particular both R2 and R3 represent halo, more in particular both R2 and R3 represent chloro or fluoro; or
- A-12) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R4 is placed in para position; or
- A-13) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R4 represents hydrogen; carboxyl; C1-6alkyloxycarbonyl; amino; mono- or di(C1-4alkyl)amino; R6R5N—C(═O)—; R6R5N—C1-6alkyl; Het-C(═O)— or HetC1-4alkyl, in particular Het-C(═O)— or HetC1-4alkyl; or
- A-14) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R4 is placed in para position and represents hydrogen; carboxyl; C1-6alkyloxy-carbonyl; amino; mono- or di(C1-4alkyl)amino; R6R5N—C(═O)—; R6R5N—C1-6alkyl; Het-C(═O)— or HetC1-4alkyl, in particular Het-C(═O)— or HetC1-4alkyl; or
- A-15) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein p represents 2; or
- A-16) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R1 represents hydrogen; C1-12alkyl; aryl1 or Het1; in particular Aryl1 or Het1; more in particular Aryl1; more in particular optionally substituted phenyl wherein the optional substituent is preferably selected from aryl, Het or C1-6alkyloxy; even more in particular phenyl; or
- A-17) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Z represents C1-6alkanediyl; or
- A-18) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Rx represents hydrogen; or
- A-19) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Ry represents hydrogen; or
- A-20) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R9 represents hydrogen; or
- A-21) compounds of class A or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R9 represents halo, C1-4alkyl, C1-4alkyl substituted with hydroxyl; or
- A-22) compounds of class A or any subgroup thereof as mentioned hereinbefore as embodiment wherein one or more, preferably all, of the following restrictions apply:
- a) X represents NH;
- b) R2 represents hydrogen, halo or C1-6alkyl; in particular halo; more in particular chloro;
- c) R3 represents hydrogen, halo or C1-6alkyl; in particular halo; more in particular chloro;
- d) R4 represents hydrogen;
- e) A represents N;
- f) the dotted line does not represent an additional bond;
- g) Y represents —NRx—C(═O)—Z—;
- h) Z represents C1-6alkanediyl;
- i) R1 represents aryl1; in particular optionally substituted phenyl; more in particular phenyl.
- j) Rx represents hydrogen; or
- A-23) compounds of class A or any subgroup thereof as mentioned hereinbefore as embodiment wherein one or more, preferably all, of the following restrictions apply:
- a) X represents NH or O;
- b) R2 represents hydrogen, halo or C1-6alkyl; in particular halo; more in particular chloro or fluoro;
- c) R3 represents hydrogen, halo or C1-6alkyl; in particular halo; more in particular chloro or fluoro;
- d) R4 represents hydrogen; carboxyl; C1-6alkyloxycarbonyl; Het-C(═O)— or HetC1-4alkyl, in particular Het-C(═O)— or HetC1-4alkyl;
- e) A represents N;
- f) the dotted line does not represent a bond;
- g) Y represents —NRx—C(═O)—; —NRx—C(═O)—Z—, —NRx—C(═O)—Z—NRy—; —NRx—C(═O)—Z—O—C(═O)—;
- h) Z represents C1-6alkanediyl;
- i) R1 represents hydrogen; C1-12alkyl; aryl1 or Het1; in particular aryl1; more in particular optionally substituted phenyl wherein the optional substituent is preferably selected from aryl, Het or C1-6alkyloxy; more in particular phenyl;
- j) Rx represents hydrogen;
- k) Ry represents hydrogen;
- l) R9 represents hydrogen;
- m) R4 is placed in para position; or
- A-24) compounds of class A selected from
- including any stereochemically isomeric form thereof;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
- The next embodiments of the present invention are those combinations of a DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPAR agonist, in particular a PPAR-α agonist, more in particular a fibrate, even more in particular fenofibrate; wherein the DGAT inhibitor is selected from compounds of Class B. Preferred embodiments of compounds of class B are:
- B-1) compounds of class B having the following formula (I)
- including any stereochemically isomeric form thereof, wherein
- A represents CH or N;
- the dotted line represents an optional bond in case A represents a carbon atom;
- X represents —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —S(═O)p—; C(═S)—; —NRx—C(═S)—; —Z—C(═S)—; —Z—NRx—C(═S)—;
- Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl;
- Rx represents hydrogen or C1-4alkyl;
- R1 represents a 5-membered monocyclic heterocycle containing at least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle; or a 5-membered heterocycle containing at least 2 heteroatoms fused with phenyl, cyclohexyl or a 5- or 6-membered heterocycle; wherein each of said heterocycles may optionally be substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy;
- C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—;
- R2 represents R3;
- R3 represents C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl may optionally be substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—;
- R4 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R7R6N—C1-4alkyl; C1-4alkyloxy; Het; aryl; R7R6N—C(═O)—C1-4alkyl;
- R5 represents hydrogen or C1-4alkyl;
- R6 represents hydrogen; C1-4alkyl; C1-4alkylcarbonyl;
- R7 represents hydrogen or C1-4alkyl; or
- R6 and R7 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms selected from O, S, S(═O)p or N; and which heterocycle may optionally be substituted with C1-4alkyl;
- aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; oxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- p represents 1 or 2;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof; or
- B-2) compounds of of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein X represents —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —S(═O)p—; —NRx—C(═S)— or 0—C(═O)—; in particular X represents —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; more in particular X represents —NRx—C(═O)— or —Z—C(═O)—; or
- B-3) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein A represents N; or
- B-4) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein A represents CH, in particular wherein A represents CH and the dotted line does not represent a bond; or
- B-5) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein RI- represents a 5-membered monocyclic heterocycle containing at least 2 heteroatoms, in particular pyrazolyl, triazolyl or oxadiazolyl; a 6-membered monocyclic aromatic heterocycle, in particular pyrimidinyl; or a 5-membered aromatic heterocycle containing at least 2 heteroatoms fused with a 5-membered heterocycle, in particular imidazopyrazolyl or imidazothiazolyl; wherein each of said heterocycles may optionally be substituted, preferably with one or two substituents. Particular substituents of said heterocycles include oxo, C1-6alkyl optionally substituted with aryl-C(═O)— or C1-4alkyloxycarbonyl; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; amino; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl;
- Het-C(═O)—; Het-C(═O)—C1-4alkyl; Het-O—; more in particular C1-6alkyl optionally substituted with aryl-C(═O)— or C1-4alkyloxycarbonyl; hydroxyC1-6alkyl optionally substituted with aryl; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; Het-NRx—; arylC1-4alkyl-NRx—; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; aryl; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl or Het; or
- B-6) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein the compound of class B is a compound of formula (I′)
- wherein R3a and R3b each independently represent hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; and wherein R3c represents hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy;
- C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cyclo-alkyl; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—. or
- B-7) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein the compound of class B is a compound of formula (I″)
- wherein R3a and R3b each independently represent hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; and wherein R3c represents hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyl-oxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonyl-amino; —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cycloalkyl; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—; or
- B-8) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein the compound of formula (I) is a compound of formula (I′) or (I″) and wherein R3a and R3b each independently represent halo, polyhaloC1-6alkyl, C1-6alkyl or C1-6alkyloxy, in particular both R3a and R3b represent halo, more in particular both R3a and R3b represent chloro; or
- B-9) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein the compound of class B is a compound of formula (I′) or (I″) and wherein R3c represents hydrogen, hydroxyl, carboxyl; halo; amino; mono- or di-(C1-4alkyl)amino; C1-6alkyl; C1-6alkyloxy; C1-6alkyloxycarbonyl; C1-6alkylthio; C1-4alkylcarbonylamino; R5R4N—C(═O)—; R5R4N—C1-6alkyl; Het-C(═O)— or HetC1-4alkyl; or R3c represents hydrogen; or
- B-10) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein p represents 2; or
- B-11) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Z represents C1-6alkanediyl, in particular CH2 or CH2—CH2; or
- B-12) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R1 represents hydrogen; or
- B-13) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R8 represents hydrogen; or
- B-14) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R8 represents halo, C1-4alkyl or C1-4alkyl substituted with hydroxyl; in particular R8 represents halo or C1-4alkyl; or
- B-15) compounds of class B or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R3 represents C3-6cycloalkyl, phenyl, naphtalenyl, 1,3-benzodioxolyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cyclo-alkyl, phenyl, naphtalenyl, 1,3-benzodioxolyl or 6-membered aromatic heterocycle may optionally be substituted with at least one substituent, in particular one or two substituents, preferably each substituent independently selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy; C1-6alkylthio; C1-6alkyloxycarbonyl; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; Het; HetC1-4alkyl; or
- B-16) compounds of class B or any subgroup thereof as mentioned hereinbefore as embodiment wherein one or more, preferably all, of the following restrictions apply :
- a) X represents —NRx—C(═O)—; or —Z—C(═O)—;
- b) the compound of class B is a compound of formula (I″), in particular a compound of formula (I″) wherein R3a and R3b represent halo; more in particular chloro; and wherein R3C represents hydrogen;
- c) A represents N;
- d) A represents CH;
- e) the dotted line does not represent a bond;
- f) Z represents C1-6alkanediyl;
- g) R1 represents a 5-membered monocyclic aromatic heterocycle containing at least 2 heteroatoms, in particular pyrazolyl or triazolyl; a 6-membered monocyclic aromatic heterocycle; or a 5-membered aromatic heterocycle containing at least 2 heteroatoms fused with a 5-membered heterocycle; each of said heterocycles optionally being substituted, in particular substituted with oxo, C1-6alkyl optionally substituted with aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl; C3-6cycloalkyl-NRx—; Het-NRx—; arylC1-4alkyl-NRx—; aryl; arylC1-4alkyl.
- h) Rx represents hydrogen;
- or
- B-17) compounds of class B or any subgroup thereof as mentioned hereinbefore as embodiment wherein one or more, preferably all, of the following restrictions apply:
- a) A represents CH or N;
- b) the dotted line does not represents a bond in case A represents a carbon atom;
- c) X represents —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—;
- d) Z represents a bivalent radical selected from C1-6alkanediyl;
- e) Rx represents hydrogen;
- f) R1 represents a 5-membered monocyclic heterocycle containing at least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle; or a 5-membered heterocycle containing at least 2 heteroatoms fused with a 5-membered heterocycle; wherein each of said heterocycles such as for example pyrazolyl, triazolyl, oxadiazolyl, pyrimidinyl, imidazopyrazolyl or imidazothienyl, may optionally be substituted with at least one substituent, in particular one or two substituents, each substituent independently being selected from oxo; C1-6alkyl optionally substituted with C1-4alkyloxycarbonyl; hydroxyC1-6alkyl optionally substituted with aryl; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; Het-NRx—; arylC1-4alkyl-NRx—; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; aryl; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; Het;
- g) R3 represents C3-6cycloalkyl, phenyl, naphtalenyl, 1,3-benzodioxolyl, or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cyclo-alkyl, phenyl, naphtalenyl, 1,3-benzodioxolyl or 6-membered aromatic heterocycle may optionally be substituted with at least one substituent, in particular one or two substituents, each substituent independently selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy; C1-6alkylthio; C1-6alkyloxycarbonyl; mono- or di(C1-4alkyl)amino; C1-4alkyl-carbonylamino; Het; HetC1-4alkyl;
- h) R4 represents hydrogen or C1-4alkyl;
- i) R5 represents hydrogen or C1-4alkyl;
- j) R8 represents hydrogen;
- k) aryl represents phenyl or phenyl substituted with at least one substituent, in particular one substituent, said substituent being selected from halo; C1-6alkyl; C1-6alkyloxy;
- l) Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; said monocyclic heterocycle optionally being substituted with C1-6alkyloxycarbonyl; or
- B-18) compounds of class B selected from
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
- The next embodiments of the present invention are those combinations of a DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPAR agonist, in particular a PPAR-α agonist, more in particular a fibrate, even more in particular fenofibrate; wherein the DGAT inhibitor is selected from compounds of Class C. Preferred embodiments of compounds of class C are:
- C-1) compounds of class C having the following formula (I)
- including any stereochemically isomeric form thereof, wherein
- A represents CH or N;
- the dotted line represents an optional bond in case A represents a carbon atom;
- X represents —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —C(═O)—Z—; —NRx—C(═O)—Z—; C(═S)—; —NRx—C(═S)—; —Z—C(═S)—; —Z—NRx—C(═S)—; —C(═S)—Z—; —NRx—C(═S)—Z—;
- Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl;
- Rx represents hydrogen or C1-4alkyl;
- Y represents C(═O)—NRx— or —NRx—C(═O)—;
- R1 represents C3-6cycloalkyl; aryl1 or Het1;
- R2 represents C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl may optionally be substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; R4R3N—C(═O)—; R4R3N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—;
- R3 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R6R5N—C1-4alkyl; C1-4alkyloxy; Het; aryl; R6R5N—C(═O)—C1-4alkyl;
- R4 represents hydrogen or C1-4alkyl;
- R5 represents hydrogen; C1-4alkyl; C1-4alkylcarbonyl;
- R6 represents hydrogen or C1-4alkyl; or
- R5 and R6 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms selected from O, S, S(═O)p or N; and which heterocycle may optionally be substituted with C1-4alkyl;
- aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—;
- Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio;
- polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—;
- p represents 1 or 2;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof; or
- C-2) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein X represents O—C(═O)—; —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —C(═O)—Z—; —NRx—C(═O)—Z—; —NRx—C(═S)—; in particular wherein X represents —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —C(═O)—Z—; —NRx—C(═O)—Z—; —NRx—C(═S)—; more in particular wherein X represents —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; even more in particular X represents —NRx—C(═O)— or —Z—NRx—C(═O)—; or X represents —NRx—C(═O)— or —Z—C(═O)—. Or X represents O—C(═O)—; —C(═O)—C(═O)—; —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; C(═S)—; —NRx—C(═S)—; —Z—C(═S)—; —Z—NRx—C(═S)—; or
- C-3) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein A represents N; or
- C-4) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein A represents CH, in particular wherein A represents CH and the dotted line does not represent a bond; or
- C-5) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R1 represents aryl1 or Het1; in particular optionally substituted phenyl, optionally substituted fluorenyl or an optionally substituted monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N, in particular S or N; more in particular phenyl or fluorenyl, said phenyl or fluorenyl optionally substituted with one or two substituents, said substituents independently selected from oxo, carboxyl, halo, C1-6alkyl optionally substituted with carboxyl or C1-4alkyloxycarbonyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, amino, aryl, Het or polyhaloC1-6alkyl; or a 4-, 5-or 6-membered non-aromatic or aromatic heterocycle, such as for example azetidinyl, thiazolidinyl, thiazolyl, pyrrolidinyl, piperidinyl, said 5- or 6-membered heterocycle optionally substituted with one or two substituents, said substituents independently selected from hydroxyl, oxo, C1-6alkyl, C1-6alkyloxycarbonyl, aryl or Het; or
- C-6) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R2 represents C3-6cycloalkyl, phenyl, 2,3-dihydro-1,4-benzodioxinyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms such as for example pyridyl, wherein said phenyl or heterocycle are optionally substituted with one to four substituents, preferably each substituent independently selected from halo, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkyloxycarbonyl, nitro, amino, mono- or di(C1-4alkyl)amino, aryloxy, R4R3N—C1-6alkyl, Het-C(═O)—C1-4alkyl; or
- C-7) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein the compound of class C is a compound of formula (I′)
- wherein R3a and R3b each independently represent hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; and wherein R3c represents hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; R4R3N—C(═O)—; R4R3N—C1-6alkyl; C3-6cycloalkyl; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; Het-O—; or
- C-8) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein the compound of class C is a compound of formula (I″)
- wherein R3a and R3b each independently represent hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; and wherein R3c represents hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; R4R3N—C(═O)—; R4R3N—C1-6alkyl; C3-6cycloalkyl; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; Het-O—; or
- C-9) compounds of class C or any subgroup thereof as mentioned hereinbefore as embodiment wherein the compound of formula (I) is a compound of formula (I′) or (I″) and wherein R3a and R3b each independently represent halo, C1-6alkyl or C1-6alkyloxy; in particular halo or C1-6alkyl; more in particular both R1a and R3b represent halo, more in particular both R3a and R3b represent chloro; or
- C-10) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein the compound of formula (I) is a compound of formula (I′) or (I″) and wherein R3c represents amino; mono- or di(C1-4alkyl)amino; R4R3N—C(═O)—; R4R3N—C1-6alkyl; Het-C(═O)— or HetC1-4alkyl; or R3c represents hydrogen; or
- C-11) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein p represents 2; or
- C-12) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Z represents C1-6alkanediyl or C2-6alkenediyl, in particular C1-6alkanediyl, more in particular CH2—; or
- C-13) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Rx represents hydrogen; or
- C-14) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Y represents NRx—C(═O)—; or
- C-15) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Y represents C(═O)—NRx—; or
- C-16) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R7 represents hydrogen; or
- C-17) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R7 represents halo, C1-4alkyl or C1-4alkyl substituted with hydroxyl; in particular halo; or
- C-18) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein aryl represents phenyl or phenyl substituted with halo, C1-6alkyl, polyhaloC1-6alkyl or C1-6alkyloxycarbonyl; or
- C-19) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; or a bicyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N, in particular N; said monocyclic heterocycle or said bicyclic heterocycle optionally being substituted with one or two substituents, each substituent independently being selected from oxo; or C1-6alkyl; or
- C-20) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein one or more, preferably all, of the following restrictions apply:
- a) X represents —NRx—C(═O)—; —Z—NRx—C(═O)—; or —NRx—C(═S)—;
- b) R1 represents aryl1 or Het1;
- c) R2 represents C3-6cycloalkyl, phenyl or 2,3-dihydro-1,4-benzodioxinyl, wherein said phenyl is optionally substituted with one to four substituents, each substituent independently selected from halo, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkyloxycarbonyl, nitro, amino, mono- or di(C1-4alkyl)amino, aryloxy;
- d) A represents N;
- e) A represents CH;
- f) Z represents C1-6alkanediyl or C2-6alkenediyl;
- g) Rx represents hydrogen.
- h) aryl1 represents phenyl or fluorenyl, said phenyl or fluorenyl optionally substituted with halo, C1-6alkyl or polyhaloC1-6alkyl;
- i) Het1 represents a 4-, 5-or 6-membered non-aromatic or aromatic heterocycle, such as for example azetidinyl, thiazolidinyl, thiazolyl, pyrrolidinyl, piperidinyl, said 5- or 6-membered heterocycle optionally substituted with hydroxyl, oxo, C1-6alkyl, C1-6alkyloxycarbonyl, aryl or Het;
- j) Y represents NRx—C(═O)—;
- k) R7 represents hydrogen; or
- C-21) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein one or more, preferably all, of the following restrictions apply :
- a) A represents CH;
- b) A represents N;
- c) the dotted line represents a bond in case A represents a carbon atom;
- d) the dotted line doesn't represents a bond in case A represents a carbon atom;
- e) X represents O—C(═O)—; —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —NRx—C(═S)—;
- f) Z represents C1-6alkanediyl;
- g) Rx represents hydrogen;
- h) Y represents C(═O)—NRx— or —NRx—C(═O)—;
- i) R1 represents aryl1 or Het1;
- j) R2 represents C3-6cycloalkyl, phenyl, 2,3-dihydro-1,4-benzodioxinyl, or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, 2,3-dihydro-1,4-benzodioxinyl, or 6-membered aromatic heterocycle containing 1 or 2 N atoms may optionally be substituted with at least one substituent, in particular one to four substituents, each substituent independently selected from halo; C1-6alkyl; C1-6alkyloxy; C1-6alkylthio; C1-6alkyloxycarbonyl; nitro; mono- or di(C1-4alkyl)amino; R4R3N—C1-6alkyl; aryloxy; Het-C(═O)—C1-4alkyl;
- k) R3 represents C1-4alkyl;
- l) R4 represents C1-4alkyl;
- m) R7 represents hydrogen or halo;
- n) aryl represents phenyl or phenyl substituted with halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxycarbonyl;
- o) aryl1 represents phenyl or fluorenyl; each of said phenyl or fluorenyl optionally substituted with one or two substituents, each substituent independently being selected from oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl or C1-4alkyloxycarbonyl; C1-6alkyloxy; C1-6alkyloxy-carbonyl; amino; aryl; Het;
- p) Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N; or a bicyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from N; said monocyclic heterocycle or said bicyclic heterocycle optionally being substituted with one or two substituents, each substituent independently being selected from oxo or C1-6alkyl;
- q) Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from S or N; said monocyclic heterocycle optionally being substituted with at least one substituent, in particular one or two substituents, each substituent independently being selected from hydroxyl; oxo; C1-6alkyl; C1-6alkyloxy-carbonyl; aryl; Het;
- r) p represents 2; or
- C-22)compounds of class C selected from
- including any stereochemically isomeric form thereof;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof; or
- C-23) compounds of formula (I), wherein the compound is selected from
- 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 151 Class C);
- 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 152 Class C);
- 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 147 Class C);
- 4-[4-[[2,6-dichloro-4-[(4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 150 Class C);
- 4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 149 Class C);
- 4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 148 Class C); including any stereochemically isomeric form thereof;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof; or
- C-24) compounds of class C or, whenever possible, any subgroup thereof as mentioned hereinbefore as embodiment wherein R2 represents hydrogen, C1-6alkyl or C2-6alkenyl.
- The next embodiments of the present invention are those combinations of a DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPAR agonist, in particular a PPAR-α agonist, more in particular a fibrate, even more in particular fenofibrate; wherein the DGAT inhibitor is selected from compounds of Class D. Preferred embodiments of compounds of class D are:
- D-1) compounds of class D having the following formula (I)
- including any stereochemically isomeric form thereof, wherein
- A represents CH or N;
- the dotted line represents an optional bond in case A represents a carbon atom;
- X represents C(═O)—; —NRx—C(═O)—; —Z1—C(═O)—; —Z1—NRx—C(═O)—; —C(═O)—Z1—; —NRx—C(═O)—Z1—; —S(═O)p—; C(═S)—; —NRx—C(═S)—; —Z1—C(═S)—; —Z1—NRx—C(═S)—; —C(═S)—Z1—; —NRx—C(═S)—Z1—;
- Z1 represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl;
- Y represents NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—; —NRx—C(═O)—Z2—NRy—C(═O)—O—; —NRx—C(═O)—Z2—O—; —NRx—C(═O)—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—; —NRx—C(═O)—Z2—C(═O)—O—; —NRx—C(═O)—O—Z2—C(═O)—; —NRx—C(═O)—O—Z2—C(═O)—O—; —NRx—C(═O)—O—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—Z2—; —C(═O)—Z2—O—; —C(═O)—NRx—Z2—; —C(═O)—NRx—Z2—O—; —C(═O)—NRx—Z2—C(═O)—O—; —C(═O)—NRx—Z2—O—C(═O)—; —C(═O)—NRx—O—Z2—; —C(═O)—NRx—Z2—NRy—; —C(═O)—NRx—Z2—NRy—C(═O)—; —C(═O)—NRx—Z2—NRy—C(═O)—O—;
- Z2 represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or
- C2-6alkynediyl may optionally be substituted with C1-4alkyloxy, C1-4alkylthio, hydroxyl, cyano or aryl; and wherein two hydrogen atoms attached to the same carbon atom in the definition of Z2 may optionally be replaced by C1-6alkanediyl;
- Rx represents hydrogen or C1-4alkyl;
- Ry represents hydrogen; C1-4alkyl optionally substituted with C3-6cycloalkyl or aryl or Het; C2-4alkenyl; or S(═O)p-aryl;
- R1 represents C1-12alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-oxyC1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl; C2-6alkynyl; C3-6cycloalkyl; aryl1 ; aryl1C1-6alkyl; Het1; or Het1C1-6alkyl; provided that when Y represents —NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy; —NRx—C(═O)—Z2—C(═O)—NRy—; —C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—NRx—Z2—; —C(═O)—NRx—O—Z2—; or —C(═O)—NRx—Z2—NRy—; then R1 may also represent hydrogen;
- R2 represents hydrogen, C1-6alkyl, C2-6alkenyl or R3;
- R3 represents C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl may optionally be substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—;
- R4 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R7R6N—C1-4alkyl; C1-4alkyloxy; Het; aryl; R7R6N—C(═O)—C1-4alkyl;
- R5 represents hydrogen or C1-4alkyl;
- R6 represents hydrogen; C1-4alkyl; C1-4alkylcarbonyl;
- R7 represents hydrogen or C1-4alkyl; or
- R6 and R7 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms selected from O, S, S(═O)p or N; and which heterocycle may optionally be substituted with C1-4alkyl;
- aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—;
- Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl;
- Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from O, S, S(═O)p or N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently being selected from hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—; Het-O—;
- p represents 1 or 2;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof; or
- D-2) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein X represents C(═O)—C(═O)—; O—C(═O)—; —NRx—C(═O)—; —Z1—C(═O)—; —Z1—NRx—C(═O)—; —C(═O)—Z1—; —NRx—C(═O)—Z1—; —S(═O)p—; —NRx—C(═S)—; in particular X represents —NRx—C(═O)—; —Z1—C(═O)—; —Z1—NRx—C(═O)—; —C(═O)—Z1—; —NRx—C(═O)—Z1—; —S(═O)p—; —NRx—C(═S)—; more in particular X represents —NRx—C(═O)—; —Z1—C(═O)—; —C(═O)—Z1—; —Z1—NRx—C(═O)—; —NRx—C(═S)— or —S(═O)p—; even more in particular X represents —NRx—C(═O)— or —Z1—NRx—C(═O)—; even more in particular —NRx—C(═O)—; or
- D-3) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein A represents N; or
- D-4) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein A represents CH, in particular wherein A represents CH and the dotted line does not represent a bond; or
- D-5) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein R1 represents
- C3-6cycloalkyl; adamantanyl; aryls; aryl1C1-6alkyl; Het1; or Het1C1-6alkyl;aryl1; in particular aryl1C1-6alkyl; Het1; or Het1C1-6alkyl; more in particular aryls; aryl1C1-6alkyl; Het1; or Het1C1-6alkyl, wherein said aryl1 or Het1 represent phenyl, naphthalenyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, furanyl, imidazolyl, thienyl, pyridyl; each of said cycles representing aryl1 or Het1 being optionally substituted with one or two substituents; in particular with aryl, C1-6alkyl, arylC1-4alkyl, hydroxyl, halo, polyhaloC1-6alkyl, C1-6alkyloxy, nitro, C1-6alkyloxycarbonyl, —S(═O)2—C1-4alkyl; more in particular with aryl, C1-6alkyl, arylC1-4alkyl, halo, C1-6alkyloxy, C1-6alkyloxycarbonyl, —S(═O)2—C1-4alkyl. More in particular R1 represents aryl1 wherein aryl1 represents preferably optionally substituted phenyl. Even more in particular R1 represents phenyl substituted with C1-6alkyloxy, e.g. methoxy; or
- D-6) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein R1 represents
- C1-12alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-oxyC1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl; C2-6alkynyl; provided that when Y represents —NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy; —NRx—C(═O)—Z2—C(═O)—NRy—; —C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—NRx—Z2—; —C(═O)—NRx—O—Z2—; or —C(═O)—NRx—Z2—NRy—; then
- R1 may also represent hydrogen; or
- D-7) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein R2 represents C1-12alkyl; in particular C1-6alkyl; or
- D-8) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein R2 represents C1-6alkyl or R3; in particular wherein R2 represents R3 and said R3 represents phenyl, naphthalenyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle containing 1 or 2 N atoms, each of said cycles, in particular phenyl, being optionally substituted with one to five substituents, said substituents being in particular halo, C1-6alkyl optionally substituted with hydroxy, polyhaloC1-6alkyl, C1-6alkylthio, polyhaloC1-6alkyloxy, carboxyl, hydroxyl, C1-6alkylcarbonyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, nitro, R5R4N—C(═O)—, R5R4N—C1-6alkyl, HetC1-4alkyl, Het-C(═O)—C1-4allkyl, Het-C(═O)—; said substituents being more in particular halo, C1-6alkyl optionally substituted with hydroxy, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, carboxyl, hydroxyl, C1-6alkylcarbonyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkyloxycarbonyl, nitro, R5R4N—C1-6alkyl, HetC1-4alkyl; more in particular wherein R2 represents phenyl substituted with one, two or three substituents, preferably three substituents, each substituent being selected from halo, e.g. chloro, or HetC1-4alkyl, e.g. pyrrolidinylmethyl; or
- D-9) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein the compound of class D is a compound of formula (I′)
- wherein R3a and R3b each independently represent hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; and wherein R3c represents hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cycloalkyl; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; Het-O—; or
- D-10) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein the compound of class D is a compound of formula (I″)
- wherein R3a and R3b each independently represent hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; and wherein R3c represents hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cycloalkyl; aryl; aryloxy; aryl-C(═O)—C1-4alkyl; arylC1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; Het-O—; or
- D-11) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein the compound of class D is a compound of formula (I′) or (I″) and wherein R3a and R3b each independently represent halo, C1-6alkyl or C1-6alkyloxy; in particular halo or C1-6alkyl; more in particular both R1a and R3b represent halo, more in particular both R3a and R3b represent chloro; or
- D-12) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein the compound of formula (I) is a compound of formula (I′) or (I″) and wherein R3c represents amino; mono- or di(C1-4alkyl)amino; R5R4N—C(═O)—; R5R4N—C1-6alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl or HetC1-4alkyl; or R3c represents hydrogen; more in particular wherein R3c represents amino; mono- or di(C1-4alkyl)amino; R5R4N—C(═O)—; R5R4N—C1-6alkyl; Het-C(═O)— or HetC1-4alkyl; or R3c represents hydrogen; even more in particular wherein R3c represents HetC1-4alkyl, e.g. pyrrolidinylmethyl; or D-13) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein p represents 2; or
- D-14) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein Y represents —NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy; —NRx—C(═O)—Z2—NRy—C(═O)—O—; —NRx—C(═O)—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—O—; —NRx—C(═O)—O—Z2—C(═O)—O—; —NRx—C(═O)—O—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—NRx—Z2—; —C(═O)—NRx—Z2—O—; —C(═O)—NRx—Z2—C(═O)—O—; —C(═O)—NRx—Z2—O—C(═O)—; —C(═O)—NRx—O—Z2—; —C(═O)—NRx—Z2—NRy—; —C(═O)—NRx—Z2—NRy—C(═O)—; —C(═O)—NRx—Z2—NRy—C(═O)—O—; or wherein Y represents NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy; —NRx—C(═O)—Z2—NRy—C(═O)—; —NRx—C(═O)—Z2—NRy—C(═O)—O—; —NRx—C(═O)—Z2O—; —NRx—C(═O)—Z2—C(═O)—O—; —NRx—C(═O)—Z2—C(═O)—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—Z2—; or wherein Y represents NRx—C(═O)—Z2— or —NRx—C(═O)—Z2—NRy; or wherein Y represents —NRx—C(═O)—Z2—NRy—C(═O)—O— or —NRx—C(═O)—Z2—C(═O)—O—. More in particular Y represents —NRx—C(═O)—Z2—; or
- D-15) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein Y represents NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—; —NRx—C(═O)—Z2—NRy—C(═O)—O—; —NRx—C(═O)—Z2—O—; —NRx—C(═O)—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—O—; —NRx—C(═O)—Z2—C(═O)—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—Z2—; —C(═O)—NRx—Z2—; —C(═O)—NRx—Z2—O—; or
- D-16) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein Z2 represents C1-6alkanediyl or C2-6alkenediyl; in particular C1-6alkanediyl; more in particular methylene; or
- D-17) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein Z1 represents C1-6alkanediyl, optionally substituted with hydroxyl or amino, or wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl; in particular wherein Z1 represents C1-6alkanediyl; or
- D-18) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein Rx represents hydrogen; or
- D-19) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein Ry represents hydrogen or C1-4alkyl or C2-4alkenyl or S(═O)p-aryl; or
- D-20) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein R8 represents hydrogen; or
- D-21) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein R8 represents halo, C1-4alkyl or C1-4alkyl substituted with hydroxyl; or
- D-22) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein aryl represents phenyl or phenyl substituted with one or two substituents, preferably each substituent independently selected from halo, C1-6alkyl, polyhaloC1-6alkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl or nitro; or
- D-23) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein Het1 represents a monocyclic non-aromatic or aromatic heterocycle or a bicyclic non-aromatic heterocycle, each of said cycles may optionally be substituted. In particular Het1 represents morpholinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, piperidinyl, furanyl, imidazolyl, thienyl, pyridyl, 1,3-benzodioxolyl, tetrahydropyranyl, each of said heterocycles optionally being substituted with one or two substituents, preferably each substituent independently being selected from halo, C1-6alkyl, C1-6alkyloxycarbonyl, —S(═O)p—C1-4alkyl, aryl, arylC1-4alkyl, polyhaloC1-6alkyl, C1-6alkyloxy, nitro; more preferably each substituent independently being selected from halo, C1-6alkyl, C1-6alkyloxycarbonyl, —S(═O)p—C1-4alkyl, aryl, arylC1-4alkyl; or
- D-24) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein aryl1 represents phenyl, naphthalenyl or phenyl substituted with one or two substituents, preferably each substituent independently being selected from hydroxyl, halo, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl or Het; or D-25) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein Het is a monocyclic non-aromatic or aromatic heterocycle, each of said heterocycles may optionally be substituted. In particular, Het is piperidinyl, pyrrolidinyl, piperazinyl, pyridyl, morpholinyl, each of said heterocycles optionally being substituted with one substituent, preferably the substituent is selected from C1-6alkyl, C1-6alkyl substituted with C1-4alkyloxy, —S(═O)p—C1-4alkyl, C1-6alkylcarbonyl; or
- D-26) compounds of class D or any subgroup thereof as mentioned hereinbefore as embodiment wherein one or more, preferably all, of the following restrictions apply:
- a) X represents —NRx—C(═O)—; —Z′-C(═O)—; —Z1—NRx—C(═O)—; —C(═O)—Z′—; —S(═O)p-; —NRx—C(═S)—;
- b) R2 represents C1-6alkyl or R3, with R3 representing phenyl, naphthalenyl or 1,3-benzodioxolyl, each of said cycles being optionally substituted with one to five substituents, said substituents being in particular halo, C1-6alkyl optionally substituted with hydroxy, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, carboxyl, hydroxyl, C1-6alkylcarbonyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkyloxycarbonyl, nitro, R5R4N—C1-6alkyl, HetC1-4alkyl.
- c) A represents N;
- d) A represents CH;
- e) Y represents NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy; —NRx—C(═O)—Z2—NRy—C(═O)—; —NRx—C(═O)—Z2—NRy—C(═O)—O—; —NRx—C(═O)—Z2—O—; —NRx—C(═O)—Z2—C(═O)—O—; —NRx—C(═O)—Z2—C(═O)—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—Z2—;
- f) Z1 represents C1-6alkanediyl optionally substituted with hydroxy;
- g) Ry represents hydrogen; C1-4alkyl optionally substituted with C3-6cycloalkyl or aryl; C2-4alkenyl; or S(═O)p-aryl;
- h) aryl1 represents phenyl, said phenyl optionally substituted with C1-6alkyl, halo, polyhaloC1-6alkyl, C1-6alkyloxy, nitro, C1-6alkyloxycarbonyl;
- i) Het1 represents a 5-or 6-membered non-aromatic or aromatic heterocycle, such as for example morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, furanyl, imidazolyl, thienyl, pyridyl, said 5- or 6-membered heterocycle optionally substituted with aryl, C1-6alkyl, arylC1-6alkyl, halo, polyhaloC1-6alkyl, C1-6alkyloxycarbonyl, —S(═O)2-C1-4alkyl; or
- D-27) compounds of class D having the following formula
- wherein one or more, preferably all, of the following restrictions apply :
- a) A represents CH or N;
- b) X represents —O—C(═O)—; —C(═O)—C(═O)—; —NRx—C(═O)—; —Z′-C(═O)—; —Z1—NRx—C(═O)—; —C(═O)—Z′—; —S(═O)p—; —NRx—C(═S)—;
- c) Z1 represents C1-6alkanediyl; wherein said C1-6alkanediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl;
- d) Y represents NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—; —NRx—C(═O)—Z2—NRy—C(═O)—O—; —NRx—C(═O)—Z2—O—; —NRx—C(═O)—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—O—; —NRx—C(═O)—Z2—C(═O)—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—Z2—; —C(═O)—NRx—Z2—; —C(═O)—NRx—Z2—O—;
- e) Z2 represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with C1-4alkyloxy, C1-4alkylthio, hydroxyl, cyano or aryl; and wherein two hydrogen atoms attached to the same carbon atom in the definition of Z2 may optionally be replaced by C1-6alkanediyl;
- f) Rx represents hydrogen or C1-4alkyl;
- g) Ry represents hydrogen; C1-4alkyl; C2-4alkenyl; or S(═O)p-aryl;
- h) R1 represents C1-12alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-oxyC1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl; C2-6alkynyl; C3-6cycloalkyl; adamantanyl; aryl1; Het1; or Het1C1-6alkyl; provided that when Y represents —NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy; —NRx—C(═O)—Z2—C(═O)—NRy—; —C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—NRx—Z2—; —C(═O)—NRx—O—Z2—; or —C(═O)—NRx—Z2—NRy—; then R1 may also represent hydrogen;
- i) R2 represents C1-12alkyl or R3;
- j) R3 represents phenyl, naphtalenyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said phenyl, naphtalenyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle containing 1 or 2 N atoms may optionally be substituted with at least one substituent, in particular one, two, three, four or five substituents, each substituent independently selected from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl; C1-6alkylcarbonyl; nitro; R5R4N—C(═O)—; R5R4N—C1-6alkyl; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—;
- k) R4 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R7R6N—C1-4alkyl; Het-C1-4alkyl; R7R6N—C(═O)—C1-4alkyl;
- l) R5 represents hydrogen or C1-4alkyl;
- m) R6 represents C1-4alkyl or C1-4alkylcarbonyl;
- n) R7 represents hydrogen or C1-4alkyl; or
- o) R6 and R7 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from O or N;
- p) R8 represents hydrogen, halo, C1-4alkyl substituted with hydroxyl;
- q) aryl represents phenyl or phenyl substituted with at least one substituent, in particular one or two substituents, each substituent independently being selected from halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy; nitro;
- r) aryl1 represents phenyl or naphthalenyl; wherein phenyl may optionally be substituted with one or two substituents, each substituent independently being selected from hydroxyl; halo; C1-6alkyl; C1-6alkyloxy; C1-6alkyloxy-carbonyl or Het;
- s) Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N, in particular N; said monocyclic heterocycle optionally being substituted with one substituent, said substituent being selected from C1-6alkyl optionally substituted with C1-4alkyloxy; C1-6alkylcarbonyl or —S(═O)p—C1-4alkyl;
- t) Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N, in particular N, O or S; or a bicyclic non-aromatic heterocycle containing at least one heteroatom each independently selected from O, S, S(═O)p or N, in particular O; said monocyclic heterocycle or said bicyclic heterocycle optionally being substituted with one or two substituents, each substituent independently being selected from halo; C1-6alkyl; C1-6alkyloxy-carbonyl; —S(═O)p—C1-4alkyl; aryl; or arylC1-4alkyl;
- u) p represents 2; or
- D-28) compounds of class D selected from
- including any stereochemically isomeric form thereof;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof or
- D-29) compounds of class D selected from
- including any stereochemically isomeric form thereof;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof or
- D-30) compounds of class D selected from:
- N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide (compound 355 Class D);
- 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 354 Class D);
- 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 356 Class D);
- 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 358 Class D);
- 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 353 Class D);
- 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 357 Class D);
- 4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 360 Class D);
- 4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 359 Class D);
- 4-[4-[[2,6-dichloro-4-[(4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 364 Class D);
- 4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 361 Class D);
- 4-[4-[[2,6-dichloro-4-[(4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 363 Class D);
- 4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 362 Class D);
- N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyliphenyl]-4-methoxy-benzeneacetamide (compound 352 Class D);
- N-[4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide (compound 351 Class D);
- 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 267 Class D);
- including any stereochemically isomeric form thereof;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
- In an embodiment, the present invention also relates to a combination of
- including any stereochemically isomeric form thereof;
- a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof; and fenofibrate.
- In an embodiment, the present invention also relates to a combination of 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl) methyl]-benzamide (compound 358 Class D), including any stereochemically isomeric form thereof, a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof;
- and fenofibrate.
-
- I) Class A compounds
- The general preparation of the compounds of Class A is described in WO2008/148851, the content of which is enclosed by reference in the present application.
- II) Class B compounds
- The general preparation of the compounds of Class B is described in WO2008/148840, the content of which is enclosed by reference in the present application.
- III) Class C compounds
- The general preparation of the compounds of Class C is described in WO2008/148849, the content of which is enclosed by reference in the present application.
- IV) Class D compounds
- The general preparation of the compounds of Class D is described in WO2008/148868, the content of which is enclosed by reference in the present application.
- In addition to the general procedures described in WO2008/148868, intermediates of Class D of formula (XI) can also be prepared from an intermediate of formula (LXIV) in the presence of an acid such as, for example, an HCl solution. The reaction may be performed in the presence of a suitable solvent such as, for example, dioxane. Intermediates of formula (LXIV) wherein R2 contains Het-C1-4alkyl as substituent (Het is defined as a saturated N-containing heterocycle such as, for example, pyrrollidinyl) and wherein Xi is a direct bond, said intermediates being represented by formula (LXIV-a) can be prepared by reacting an intermediate of formula (LXV) in het presence of a saturated N-containing heterocycle such as, for example, pyrrolidine, and water. Intermediates of formula (LXV) can be prepared by reacting an intermediate of formula (LXII) wherein R2 contains Het-C1-4alkyl as substituent, hereby named (LXII-a), in the presence of tetrabromomethane and a catalyst such as, for example, triphenylphosphine.
- This reaction can be performed in a suitable solvent such as, for example, DCM.
- As already indicated above, the present invention relates to the use of a drug combination comprising a DGAT inhibitor and a PPAR agonist or a prodrug thereof, as a medicament.
- In particular, the present invention relates to the use of a drug combination comprising a DGAT inhibitor and a PPAR-α agonist or a prodrug thereof, as a medicament.
- In particular, the present invention relates to the use of a drug combination comprising a DGAT1 inhibitor and a PPAR-α agonist or a prodrug thereof, as a medicament.
- In particular, the combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of metabolic disorders, such as obesity and/or obesity related disorders (including, but not limited to, peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome; dermatological conditions such as acne, psoriasis; cardiovascular diseases, such as atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis or vascular stenosis; alzheimer's disease; neoplastic diseases, such as solid tumors, skin cancer, melanoma, lymphoma or endothelial cancers, e.g., breast cancer, lung cancer, colorectal cancer, stomach cancer, other cancers of the gastrointestinal tract (e.g., esophageal cancer or pancreatic cancer), prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer or ovarian cancer.
- In an embodiment, the combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of metabolic disorders, such as obesity and/or obesity related disorders (including, but not limited to, peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome; dermatological conditions such as acne, psoriasis; cardiovascular diseases, such as atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis or vascular stenosis.
- In an embodiment, the combinations according to the present invention are suitable for for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of obesity and/or obesity related disorders, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, fatty liver, nonalcoholic fatty liver disease, liver fibrosis, non-alcoholic steatohepatitis or diabetes.
- In an embodiment, the combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; for the treatment or prevention of obesity and/or obesity related disorders, obesity or cardiovascular diseases.
- In an embodiment, said obesity related disorder is selected from peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia or cardiac myopathies.
- In an embodiment, the combinations according to the present invention are suitable for reducing food intake and/or for reducing weight.
- In an embodiment, the combinations according to the present invention are suitable for reducing food intake.
- In an embodiment, the combinations according to the present invention are suitable for the treatment of said diseases or conditions.
- In an embodiment, the combinations according to the present invention are suitable for use in the treatment or prevention, in particular treatment, of said diseases or conditions.
- In an embodiment, the combinations according to the present invention are suitable for the manufacture of a medicament; in particular a medicament for the treatment or prevention, in particular the treatment, of the diseases or conditions mentioned hereinbefore.
- The present invention also relates to a product containing a) a DGAT inhibitor, in particular a DGAT1 inhibitor, more in particular a compound of Class A, Class B, Class C or Class D, and (b) an agonist of peroxisome proliferators-activator receptor or a prodrug thereof such as for example fenofibrate, as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease which can benefit from an elevated level of GLP-1 or DGAT inhibition, such as for example diabetes, in particular type II diabetes mellitus, obesity, for suppressing appetite, inducing satiety or for reducing food intake.
- In view of the utility of the combinations of the present invention, there is provided a method of treating warm-blooded animals, including humans, suffering from or a method of preventing warm-blooded animals, including humans, to suffer from any one of the diseases or conditions mentioned hereinbefore.
- Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of an above mentioned combination to warm-blooded animals, including humans.
- Those of skill in the treatment of such diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount of a combination of PPAR agonist (or prodrug thereof)/DGAT inhibitor would be from about 0.01 mg/kg to 250 mg/kg body weight, preferably from 0.01 mg/kg to 50 mg/kg body weight, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.05 mg/kg to about 1 mg/kg body weight. The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect will of course, vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
- A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior to administration. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.
- In an embodiment, the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of the combinations mentioned hereinbefore or hereinafter.
- The combinations of the present invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular combination, as the active ingredient, is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
- The combinations of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.
- The combinations of the present invention may also be topically administered in the form of drops, in particular eye drops. Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye drops are suitable for the administration of the present compounds.
- It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
- The exact dosage and frequency of administration depends on the particular combination of the present invention used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the combinations of the instant invention.
- Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of the combination of PPAR agonist/DGAT inhibitor, and, from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
- In all previous embodiments, the different drugs of a combination or product may be combined in a single preparation together with pharmaceutically acceptable carriers or they may be present in a separate preparation together with pharmaceutically acceptable carriers.
- As already indicated above, the present invention also relates to the use of the novel DGAT inhibitors of group Q, in particular DGAT1 inhibitors of group Q, to elevate levels of one or more satiety hormones, in particular GLP-1 levels. The present invention also relates to the use of a DGAT inhibitor of group Q, in particular a novel DGAT1 inhibitor of group Q, for the manufacture of a medicament for the prevention or the treatment, in particular for the treatment, of a disease which can benefit from an elevated level of one or more satiety hormones, in particular a disease which can benefit from an elevated GLP-1 level. In particular, GLP-1 levels are elevated in plasma or in portal blood, more in particular in plasma. By elevated GLP-1 levels, e.g. elevated GLP-1 plasma level or an elevated GLP-1 level in portal blood, it is meant that the GLP-1 level of a subject having taken a DGAT1 inhibitor is elevated or increased compared to the subject under the same conditions but not having taken the DGAT1 inhibitor. In particular GLP-1 levels are elevated in fasting conditions or postprandial, more in particular postprandial.
- Therapeutic uses for a compound which elevates GLP-1 level include, but are not limited to, improving learning, enhancing neuro-protection, and/or alleviating a symptom of a disease or disorder of the central nervous system, e.g., through modulation of neurogenesis, and e.g., Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, ALS, stroke, hemorrhage, cerebrovascular accident, ADD, and neuropsychiatric syndromes; converting liver stem/progenitor cells into functional pancreatic cells; preventing beta-cell deterioration and stimulation of beta-cell proliferation; treating pancreatitis; treating obesity; suppressing appetite and inducing satiety; treating irritable bowel syndrome or inflammatory bowel disease such as Crohn's disease and ulcerative colitis; reducing the morbidity and/or mortality associated with myocardial infarction and stroke; treating acute coronary syndrome characterized by an absence of Q-wave myocardial infarction; attenuating post-surgical catabolic changes; treating hibernating myocardium or diabetic cardiomyopathy; suppressing plasma blood levels of norepinepherine; increasing urinary sodium excretion, decreasing urinary potassium concentration; treating conditions or disorders associated with toxic hypervolemia, e.g., renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, and hypertension; inducing an inotropic response and increasing cardiac contractility; treating polycystic ovary syndrome; treating respiratory distress; improving nutrition via a non-alimentary route, i.e., via intravenous, subcutaneous, intramuscular, peritoneal, or other injection or infusion; treating nephropathy; treating left ventricular systolic dysfunction, e.g., with abnormal left ventricular ejection fraction; inhibiting antro-duodenal motility, e.g., for the treatment or prevention of gastrointestinal disorders such as diarrhea, postoperative dumping syndrome and irritable bowel syndrome, and as premedication in endoscopic procedures; treating critical illness polyneuropathy (CIPN) and systemic inflammatory response syndrome (SIRS); modulating triglyceride levels and treating dyslipidemia; treating organ tissue injury (e.g. brain tissue injury) caused by reperfusion of blood flow following ischemia; improving the function of ischemic and reperfused brain tissue; treating coronary heart disease risk factor (CHDRF) syndrome.
- Further diseases which can benefit from an elevated GLP-1 level, include, but are not limited to, ischemic myocardial stunning; ishemic/reperfusion injury; acute myocardial infarction; left ventricular dysfunction; vascular disease; neuropathy, including periphere sensoric neuropathy associated with type II diabetes; bone-related disorders, including osteoporosis, obesity, diabetes. Because of the effect on GLP-1, the DGAT inhibitors of group Q can also be used to provide cardioprotection.
- References supporting the above indications include Experimental Neurology, Vol. 203(2), pp 293-301 (2007); U.S. Pat. No. 7,186,683; J. Pharm. Exp. Ther. vol. 312, No. 1, pp 303-308 (2005); Diabetes, vol. 54, pp 146-151 (2005); US2007/0021339, which are incorporated herein by reference.
- In view of the DGAT inhibitory activity, in particular the DGAT1 inhibitory activity, the present novel compounds of group Q can be used as a medicament. In particular, the present invention relates to a compound of group Q for use as a medicament, in particular for use as a medicament for the prevention or the treatment of a disease which can benefit from an elevated GLP-1 level. In particular, the present invention also relates to the use of a compound of group Q for the manufacture of a medicament for the prevention or the treatment of a disease which can benefit from an elevated GLP-1 level, such as the diseases and disorders mentioned above.
- In view of the DGAT inhibitory activity of the compounds of group Q, there is provided a method of treating a warm-blooded mammal, including a human, suffering from or a method of preventing a warm-blooded mammal, including a human, to suffer from a disease which can benefit from an elevated level of GLP-1, in particular a method of treating a warm-blooded mammal, including a human, suffering from a disease which can benefit from an elevated level of GLP-1. Said methods comprise the administration of an effective amount of a compound of group Q to a warm-blooded mammal, including a human.
- In view of the DGAT inhibitory activity, in particular the DGAT1 inhibitory activity, the present invention also relates to a compound of group Q for use as a medicament, in particular for use as a medicament for the prevention or the treatment of a diseases which can benefit from inhibition of DGAT, in particular DGAT1.
- The invention also relates to a compound of group Q for the prevention or the treatment of a disease or disorder which can benefit from inhibition of DGAT, in particular DGAT1. Diseases or disorders which can benefit from inhibition of DGAT, in particular DGAT1 include, but are not limited to metabolic disorders, such as obesity and/or obesity related disorders (including peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome; dermatological conditions such as acne, psoriasis; cardiovascular diseases, such as atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis or vascular stenosis; neoplastic diseases, such as solid tumors, skin cancer, melanoma, lymphoma or endothelial cancers, e.g., breast cancer, lung cancer, colorectal cancer, stomach cancer, other cancers of the gastrointestinal tract (e.g., esophageal cancer and pancreatic cancer), prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer or ovarian cancer; or other diseases and conditions that are sensitive or responsive to modulation, in particular inhibition, of DGAT function, in particular DGAT1 function.
- Particular diseases or disorders which can benefit from inhibition of DGAT, in particular DGAT1, are selected from obesity, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, fatty liver, nonalcoholic fatty liver disease, liver fibrosis, non-alcoholic steatohepatitis or diabetes, in particular type II diabetes.
- The invention also relates to a compound of group Q for use in the prevention or the treatment, in particular for use in the treatment, of a disease or disorder which can benefit from inhibition of DGAT, in particular DGAT1.
- In an embodiment the invention also relates to the use of a compound of group Q for the manufacture of a medicament for treating or preventing the above mentioned diseases or conditions.
- In view of the DGAT inhibitory activity of the compounds of group Q, there is provided a method of treating a warm-blooded mammal, including a human, suffering from or a method of preventing a warm-blooded mammal, including a human, to suffer from a disease which can benefit from inhibition of DGAT, in particular a method of treating a warm-blooded mammal, including a human, suffering from a disease which can benefit from inhibition of DGAT. Said methods comprise the administration of an effective amount of a compound of group Q to a warm-blooded mammal, including a human.
- In an embodiment, the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound of group Q.
- The present invention also provides compositions for preventing or treating a disease which can benefit from an elevated GLP-1 level or which can benefit from inhibition of DGAT, in particular DGAT1, in particular for treating a disease which can benefit from elevated GLP-1 levels or which can benefit from inhibition of DGAT, in particular DGAT1. Said compositions comprise a therapeutically effective amount of a compound of group Q and a pharmaceutically acceptable carrier.
- The novel compounds of group Q of the present invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
- The compounds of group Q of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.
- The compounds of the present invention may also be topically administered in the form of drops, in particular eye drops. Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye drops are suitable for the administration of the present compounds.
- It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
- The exact dosage and frequency of administration depends on the particular compound of group Q used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
- Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of the compound of group Q, and, from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
- The following examples are intended to illustrate the present invention.
- Hereinafter, the term ‘THF’ means tetrahydrofuran, ‘Et2O’ means diethyl ether, ‘CH3OH’ means methanol, ‘EtOAc’ means ethyl acetate, ‘NaHCO3’ means carbonic acid monosodium salt, ‘CH2Cl2’ or ‘DCM’ means dichloromethane, ‘CH3CN’ means acetonitrile, ‘EtOH’ means ethanol, ‘HBTU’ means 1-[bis(di-methylamino)methylene]-1H-benzo-triazoliumhexafluorophosphate(1)-3-oxide, ‘DMF’ means N,N-dimethyl-formamide, ‘DIPEA’ means N-ethyl-N-(1-methylethyl)-2-propanamine, ‘HOBt’ or ‘HOBT’ means 1-hydroxy-1H-benzotriazole, ‘EDCI’ means N-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine monohydrochloride, ‘DMSO’ means dimethylsulfoxide, ‘m.p.’ means melting point, ‘MeOH’ means methanol, ‘Et3N’ means triethylamine, ‘eq.’ means equivalent, ‘r.m.’ means reaction mixture, ‘r.t.’ means room temperature, ‘h’ means hour(s), ‘min’ means minute(s), and ‘TFA’ means trifluoroacetic acid.
- Experimental Procedures for the Class A Compounds
- The experimental procedures for the preparation of the compounds of Class A, are described in WO2008/148851, the content of which is enclosed by reference in the present application.
- Experimental Procedures for the Class B Compounds
- The experimental procedures for the preparation of the compounds of Class B, are described in WO2008/148840, the content of which is enclosed by reference in the present application.
- Experimental Procedures for the Class C Compounds
- The experimental procedures for the preparation of the compounds of Class C, are described in WO2008/148849, the content of which is enclosed by reference in the present application.
- In addition, some typical examples of Class C compounds are described below.
- Intermediates (Class C)
-
- Pd/
C 10% (1 g) was suspended in MeOH (150 ml) under N2 flow. 4-[4-(phenylmethyl)-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (5.62 g, 0.0126 mol; prepared according to the teachings described in WO2008/148849) was added and the r.m. was stirred at 50° C. under H2 atmosphere until 1 eq. of H2 was absorbed. The catalyst was filtered off over diatomaceous earth (Dicalite®). The solvent was evaporated and co-evaporated with toluene. The residue was stirred in Et2O and filtered off. The product was dried (50° C., 18 h, in vacuo). Yield: 4.23 g of 4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (96%). - 4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide .HCl was prepared in analogy to the free base form. For the preparation of the hydrochloric acid salt, 4-[4-[[[3-(1-pyrrolidinyl)phenyl]amino]carbonyl]phenyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (the tert-butoxy variant of 4-[4-(phenylmethyl)-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide) was deprotected with a HCl solution in dioxane.
-
- A solution of 1-bromo-2-chloro-4-(chloromethyl)-benzene (25.2 g, 105.03 mmol) and Et3N (16.1 ml, 115.53 mmol) in THF (150 ml) was stirred at r.t. Pyrrolidine (8.2 g, 115.53 mmol) was added dropwise. The r.m. was stirred overnight at r.t. and was then concentrated in vacuo. The residue was taken up into water and extracted with CH2Cl2 (3×100 ml). The combined organic layer was washed with saturated NaHCO3 and brine, and was then dried (MgSO4), filtered and the solvent was evaporated in vacuo. Yield: 25.8 g of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (90% yield, crude product; used in next reaction step, without further purification).
-
- Reaction under N2 atmosphere. A solution of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (25.8 g, 93.96 mmol) in THF (200 ml) was stirred at −78° C. for 15 min. A 2.5 M n-BuLi solution in hexane was added to the mixture over a period of 15 min. After 30 min, a solution of DMF (7.3 ml, 93.96 mmol) in THF (50 ml) was added dropwise to the mixture. The reaction temperature was allowed to rise to r.t. slowly, and the mixture was stirred overnight. The reaction was quenched by the addition of water at 0° C. The mixture was extracted with EtOAc (3×150 ml). The combined organic layer was washed with brine, dried (MgSO4), filtered and the solvent was evaporated in vacuo.
- Yield: 20.3 g of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde (97%, crude Yield:). The crude product was used for next step directly without further purification.
-
- Trimethylsilanecarbonitrile (10 ml, 76.6 mmol) and ZnBr2 (0.5 g) were added to a solution of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde (9.8 g, 43.8 mmol) in DCM (100 ml). The r.m. was stirred for 5 h at r.t. Then, the mixture was heated to 50° C. and stirred overnight. 2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetonitrile was used as a crude in the next reaction step.
-
- A mixture of 2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetonitrile (10.9 g, 43.8 mmol) in concentrated HCl (50 ml) was stirred and refluxed for 24 h. The mixture was cooled and the solvent was evaporated. The crude product was purified by preparative HPLC (Synergi: 250×20 mm; Mobile Phase: 0-30% CH3CN in H2O (0.1% TFA); Flow
- Rate: 80 ml/min; Finished Time: 30 min). The desired fraction was collected and the organic phase was evaporated to give a yellow oil. Yield: 6.2 g of 2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (TFA-salt), used as such in the next reaction step (52.5%; TFA-salt).
- Final Compounds (Class C)
- Preparation of Compound 152
- A mixture of 2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (1.1 g, 2.87 mmol), 4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide .HCl (1.1 g, 2.87 mmol), EDCI (0.55 g, 2.87 mmol), HOBT (0.39 g, 2.87 mmol) and Et3N (1.6 ml, 11.48 mmol) in DCM (50 ml) was stirred overnight at r.t. Water was added to the mixture, and the organic layer was separated. The aqueous layer was extracted with DCM (3×30 ml).
- The combined organic layer was washed with brine, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/
MeOH 30/1). The product fractions were collected and the solvent was evaporated. Yield: 0.8 g of crude compound 152 (purity 82% on LCMS). The crude compound 152 was purified by neutral high performance liquid chromatography (Column: Daisopak 250×20 mm; Mobile Phase: 80-100% CH3CN in water; Flow Rate: 14 ml/min; Finished Time: 15 min). The desired fraction was collected and evaporated in vacuo. Yield: 0.4 g of compound 152 (23%). - Compound 151 was prepared by analogy to compound 152, but 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (for which the synthesis protocol is described in detail in the experimental procedures for the Class D compounds) was used as starting material.
- Compounds 147, 148, 149 and 150 were also prepared by analogy to compound 152, starting from the appropriate starting materials.
- Experimental Procedures for the Class D Compounds
- The experimental procedures for the preparation of the compounds of Class D, are described in WO2008/148868, the content of which is enclosed by reference in the present application.
- In addition, some typical examples of Class D compounds are described below.
- Intermediates (Class D)
-
- A mixture of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde (prepared according to the teachings in WO2008/148868) (10.0 g, 44.70 mmol) and tetrabromomethane (22.2 g, 67.05 mmol) in DCM (300 ml) was stirred at 0° C. A solution of triphenylphosphine (35.2 g, 134.10 mmol) in DCM (500 ml) was added. The mixture was stirred for 30 min at 0° C. The mixture was concentrated in vacuo. The residue was taken up into CHC13, and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue (crude 1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl[methyl]-pyrrolidine) was used as such in the next reaction step.
-
- A mixture of pyrrolidine (150 ml) and water (15 ml) was stirred at r.t. 1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl[methyl[-pyrrolidine (crude, max. 44.70 mmol) was added to the mixture and subsequently, the mixture was stirred overnight at r.t. The solvent was evaporated, yielding 1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine as a crude that was used as such in the next reaction step.
-
- A solution of 1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine (crude, max. 44.70 mmol) in dioxane (100 ml) was stirred at r.t. A 6 M HCl solution was added.
- The mixture was stirred and refluxed for 3 days. The mixture was concentrated in vacuo. The residue was taken up in water and the mixture was brought to
pH 10 with a 4 N NaOH solution. The solution was washed with diethyl ether (3×40 ml). The aqueous layer was acidified topH 3 with a 6 N HCl solution. The mixture was concentrated in vacuo. The residue was purified by neutral high performance liquid chromatography (Column: Lana 300×50 mm, 10 μm; Mobile Phase: 0-20% CH3CN in water; Flow Rate: 80 ml/min; Finished Time: 25 min). The desired fraction was collected and evaporated in vacuo. Yield: 2.8 g of 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (25% yield over last 3 steps). - 2,6-Dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetyl chloride .HCl was prepared by analogy to 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid by using the appropriate reaction conditions well known to those skilled in the art.
- 2,6-Dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid .HCl was prepared by analogy to 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid by using the appropriate reaction conditions well known to those skilled in the art.
-
- A mixture of 3,5-dimethoxybenzenemethanamine (3.34 g, 20 mmol), 4-(4-carboxyphenyl)-1-piperazinecarboxylic acid, 1-(1,1-dimethylethyl) ester (6.13 g, 20 mmol), EDCI (4.2 g, 22 mmol), HOBT (2.97 g, 22 mmol), N(CH2CH3)3 (12 ml) and DCM (80 ml) was stirred overnight at r.t. The solvent was evaporated. The residue was purified by column chromatography (eluent: petroleum ether/
EtOAc 2/1). The desired fractions were collected and the solvent was evaporated. Yield: 5.3 g of 4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (58.24% yield). -
- 4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (5.2 g, 11.4 mmol) was dissolved in HCl/dioxane (100 ml) and the reaction solution was stirred overnight. The solvent was evaporated. The solid residue was washed with petroleum ether and dried. Yield: 4.2 g of N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide (HCl-salt) as a crude (97.7%). 1 g of the crude product was purified by preparative HPLC (YMC: 250×80 mm; Mobile Phase: 10-35% CH3CN % in H2O (0.1% TFA); Finished Time: 25 min). The desired fractions were collected and solvent was evaporated. The residue was neutralized with an aqueous NaHCO3 solution and extracted with EtOAc. The separated organic layer was washed with brine, dried (Na2SO4), filtered and the solvent was evaporated to yield a white solid. Yield: 0.4 g of N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide (HCl-salt).
- Final Compounds (Class D)
- Preparation of Compound 353
- A mixture of 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (0.94 g, 3.70 mmol) and N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide (HCl-salt) (1.5 g, 3.83 mmol) in DCM (20 ml) was stirred at r.t. Et3N (1.3 ml, 9.58 mmol) was added to the mixture. Then EDCI (0.73 g, 3.83 mmol) and HOBT (0.52 g, 3.83 mmol) were added to the mixture. The mixture was stirred overnight at r.t. The mixture was washed with water, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2/CH3OH 20/1). The product fractions were collected and the solvent was evaporated. Yield: 0.78 g of compound 353 (36%).
- Preparation of
compound 358 - A mixture of 2,6-dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetyl chloride .HCl and 2,6-dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid .HCl (1.29 g of the mixture) was added portionwise to a stirring mixture of N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide .HCl (1.406 g, 0.00358 mol) and NaHCO3 (0.993 g, 0.0118 mol) in CH3CN (60 ml; dried on molecular sieves). The r.m. was stirred under N2 atmosphere for 4 h. Subsequently, Et3N (1 ml) and HBTU (1.358 g, 0.00358 mol) were added and the r.m. was stirred at r.t. for 65 h. Then, the mixture was poured into stirring H2O (300 ml) and this aqueous mixture was stirred for 20 min. The product was filtered off and washed with H2O (3×). The product was stirred in boiling 2-propanol (70 ml), filtered off hot, and the filtrate was left standing for 3 h (crystallization started after 5 min). The product was filtered off, washed with 2-propanol (3×), and dried (50° C., in vacuo) to yield 1.12 g of compound 358 (50%). An additional amount of compound 358 (0.481 g) was obtained by evaporation of the filtrate and purification of the residue by HPLC. The desired fractions were evaporated and crystallized from boiling 2-propanol again.
- Compounds 354, 355, 359, 360, 361, 362, 363 and 364 from Class D were prepared by analogy to compound 353, starting from the appropriate starting materials.
- Compounds 356 and 357 from Class D were prepared by analogy to compounds 152 from Class C, starting from the appropriate starting materials.
- The tables below list compounds of class A, class B, class C or class D. The novel compounds of group Q (compounds 147 till 152 from Class C and compounds 353 till 364 from Class D) are enclosed in class C and class D.
- Table for the Class A compounds
- Tables for the Class B compounds
-
TABLE B1 Co. No. A X R1 Rq 1 N H— 2 N H— 3 N H— 4 N H— 5 N H— 6 N H— 7 CH H— 8 N H— 9 N H— 10 N H— 11 N H— 12 N H— 13 N H— 14 N H— 15 N H— 16 N H— 17 N H— 18 N H— 19 N H— 20 N H— 21 N H— 22 N H— 23 N H— 24 N H— 25 N H— 26 N H— 27 N H— 28 N H— 29 N H— 30 N H— 31 N H— 32 N H— 33 N H— 34 N H— 35 N H— 36 N H— 37 N H— 38 N H— 39 N H— 40 N H— 41 N H— 42 N H— 43 N H— 44 CH H— 45 N H— 46 CH H— 47 N H— 48 CH H— 49 N H— 50 CH H— 51 N H— 52 N H— 53 N 54 N 55 N 56 N 57 N HOCH2— 58 N 59 N HOCH2— 60 N 61 N HO— 62 N HO— 63 N 64 N 65 N - Tables for the Class C compounds
-
TABLE C3 Co. no. X R 2 6 —C═O 68 —NH—C═S 8 —NH—C═S 69 —NH—C═O (CH3)3—C— 5 —NH—C═O 70 —NH—C═O 71 —NH—C═O 72 —NH—C═O 73 —NH—C═O 74 —NH—C═O 75 —NH—C═O 76 —NH—C═O 77 —NH—C═O 78 —NH—C═O 79 —NH—C═O 80 —NH—C═O 81 —NH—C═O 82 —NH—C═O 83 —NH—C═O 84 —NH—C═O 85 —NH—C═O 86 —NH—C═O 87 —NH—C═O 88 —NH—C═O 89 —NH—C═O 90 —NH—C═O 91 —NH—C═O 92 —NH—C═O 93 —NH—C═O 94 —NH—C═O 9 —NH—C═O 95 —NH—C═O 96 —NH—C═O 97 —NH—C═O 98 —NH—C═O 99 —NH—C═O 100 —NH—C═O 101 —NH—C═O 102 —NH—C═O 103 —NH—C═O 104 —NH—C═O 105 —NH—C═O 106 —NH—C═O -
TABLE C6 Comp. no. X R2 R1a R1a′ R1b R1c R7 131 —CH2—C═O H H H H 134 —CH2—C═O Cl Cl H H H 135 —CH2—NH—C═O Cl Cl H H H 133 —NH—C═O H H H —OCH3 F 130 NH C═O H H H H 147 —CH2—C═O H H H H 148 —CH2—C═O H H H H 149 —CH2—C═O H H H H 150 —CH2—C═O H H H H 151 —CH2—C═O H H H H 152 —CH(OH)—C═O H H H H 129 —NH—C ═O H H H H 132 —CH2—C═O H H H H - Tables for the Class D compounds
-
TABLE D1 Co. No. 33 Co. No. 34 Co. No. 18 Co. No. 35 Co. No. 36 Co. No. 37 Co. No. 17 Co. No. 38 Co. No. 39 Co. No. 40 Co. No. 41 Co. No. 42 Co. No. 43 Co. No. 44 Co. No. 45 Co. No. 2 Co. No. 10 Co. No. 46 Co. No. 12 Co. No. 47 Co. No. 48 Co. No. 49 Co. No. 50 Co. No. 51 Co. No. 13 Co. No. 24 Co. No. 52 Co. No. 53 Co. No. 19 Co. No. 54 Co. No. 27 Co. No. 55 Co. No. 56 Co. No. 57 Co. No. 189 Co. No. 8 Co. No. 3 Co. No. 29 Co. No. 58 Co. No. 28 Co. No. 59 Co. No. 60 Co. No. 61 Co. No. 62 Co. No. 63 Co. No. 64 Co. No. 11 Co. No. 65 Co. No. 66 Co. No. 67 Co. No. 68 Co. No. 71 Co. No. 70 Co. No. 73 Co. No. 72 Co. No. 75 Co. No. 74 Co. No. 77 Co. No. 76 Co. No. 79 Co. No. 78 Co. No. 81 Co. No. 80 Co. No. 83 Co. No. 82 Co. No. 85 Co. No. 84 Co. No. 87 Co. No. 86 Co. No. 89 Co. No. 88 Co. No. 91 Co. No. 90 Co. No. 93 Co. No. 92 Co. No. 95 Co. No. 94 Co. No. 97 Co. No. 96 Co. No. 99 Co. No. 98 Co. No. 101 Co. No. 100 Co. No. 103 Co. No. 102 Co. No. 105 Co. No. 104 Co. No. 107 Co. No. 106 Co. No. 109 Co. No. 108 Co. No. 111 Co. No. 110 Co. No. 113 Co. No. 112 Co. No. 115 Co. No. 114 Co. No. 117 Co. No. 116 Co. No. 119 Co. No. 118 Co. No. 121 Co. No. 120 Co. No. 20 Co. No. 122 Co. No. 124 Co. No. 123 Co. No. 126 Co. No. 125 Co. No. 128 Co. No. 127 Co. No. 130 Co. No. 129 Co. No. 132 Co. No. 131 Co. No. 134 Co. No. 133 Co. No. 136 Co. No. 135 Co. No. 138 Co. No. 137 Co. No. 140 Co. No. 139 Co. No. 142 Co. No. 141 Co. No. 144 Co. No. 143 Co. No. 1 Co. No. 145 Co. No. 147 Co. No. 146 Co. No. 149 Co. No. 148 Co. No. 151 Co. No. 150 Co. No. 153 Co. No. 152 Co. No. 155 Co. No. 154 Co. No. 157 Co. No. 156 Co. No. 159 Co. No. 158 Co. No. 161 Co. No. 160 Co. No. 162 Co. No. 23 Co. No. 164 Co. No. 163 Co. No. 14 Co. No. 165 Co. No. 167 Co. No. 166 Co. No. 169 Co. No. 168 Co. No. 171 Co. No. 170 Co. No. 4 Co. No. 172 Co. No. 174 Co. No. 173 Co. No. 175 Co. No. 32 Co. No. 177 Co. No. 176 Co. No. 179 Co. No. 178 Co. No. 180 Co. No. 26 Co. No. 182 Co. No. 181 Co. No. 7 Co. No. 22 Co. No. 185 Co. No. 183 Co. No. 31 Co. No. 184 Co. No. 186 Co. No. 16 Co. No. 187 Co. No. 30 Co. No. 188 Co. No. 6 Co. No. 190 Co. No. 5 Co. No. 15 Co. No. 191 Co. No. 193 Co. No. 192 Co. No. 195 Co. No. 194 Co. No. 196 Co. No. 9 Co. No. 198 Co. No. 197 Co. No. 200 Co. No. 199 Co. No. 201 Co. No. 21 Co. No. 203 Co. No. 202 Co. No. 205 Co. No. 204 Co. No. 207 Co. No. 206 Co. No. 209 Co. No. 208 Co. No. 211 Co. No. 210 Co. No. 213 Co. No. 212 Co. No. 215 Co. No. 214 Co. No. 217 Co. No. 216 Co. No. 219 Co. No. 218 Co. No. 221 Co. No. 220 Co. No. 222 Co. No. 25 Co. No. 223 Co. No. 224 Co. No. 225 Co. No. 226 Co. No. 227 Co. No. 228 Co. No. 229 Co. No. 230 Co. No. 231 Co. No. 232 Co. No. 233 Co. No. 234 Co. No. 235 Co. No. 236 Co. No. 237 Co. No. 238 Co. No. 239 Co. No. 240 Co. No. 241 Co. No. 242 Co. No. 243 Co. No. 244 Co. No. 245 Co. No. 246 Co. No. 247 Co. No. 248 Co. No. 249 Co. No. 250 Co. No. 251 Co. No. 252 Co. No. 253 Co. No. 254 Co. No. 255 Co. No. 256 Co. No. 257 Co. No. 258 Co. No. 259 Co. No. 260 Co. No. 261 Co. No. 262 Co. No. 263 Co. No. 264 Co. No. 265 Co. No. 266 Co. No. 267 Co. No. 268 Co. No. 269 Co. No. 270 Co. No. 271 Co. No. 272 Co. No. 273 Co. No. 274 Co. No. 275 Co. No. 276 Co. No. 277 Co. No. 278 Co. No. 279 Co. No. 280 Co. No. 281 Co. No. 282 Co. No. 283 Co. No. 284 Co. No. 285 Co. No. 286 Co. No. 287 Co. No. 288 Co. No. 289 Co. No. 290 Co. No. 291 Co. No. 292 Co. No. 293 Co. No. 294 Co. No. 295 Co. No. 296 Co. No. 297 Co. No. 298 Co. No. 299 Co. No. 300 Co. No. 301 Co. No. 302 Co. No. 303 Co. No. 304 Co. No. 305 Co. No. 306 Co. No. 307 Co. No. 308 Co. No. 309 Co. No. 310 Co. No. 311 Co. No. 312 Co. No. 313 Co. No. 314 Co. No. 315 Co. No. 317 Co. No. 318 Co. No. 319 Co. No. 321 Co. No. 322 Co. No. 323 Co. No. 324 Co. No. 325 Co. No. 326 Co. No. 327 Co. No. 328 Co. No. 329 Co. No. 330 Co. No. 331 Co. No. 332 Co. No. 333 Co. No. 334 Co. No. 335 Co. No. 336 Co. No. 337 Co. No. 338 Co. No. 339 Co. No. 340 Co. No. 341 Co. No. 342 Co. No. 343 Co. No. 344 Co. No. 345 Co. No. 346 Co. No. 347 Co. No. 348 Co. No. 349 Co. No. 350 Co. No. 351 Co. No. 352 Co. No. 223a Co. No. 353 Co. No. 354 Co. No. 355 Co. No. 356 Co. No. 357 Co. No. 358 Co. No. 359 Co. No. 360 Co. No. 361 Co. No. 362 Co. No. 363 Co. No. 364 R*, S* relative stereochemistry - Analytical Part
- Analytical Data for the Compounds of Group Q (Compounds 147-152 from Class C and Compounds 353-364 from Class D):
- LCMS
- For (LC)MS-characterization of the compounds of the present invention, the following methods were used.
- General Procedure A
- The LCMS analyses for a number of compounds were done at the Surveyor MSQ™ (Thermo Finnigan, USA) comprising a photo diode array detector (PDA; 190-800 nm) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with APCI (atmospheric pressure chemical ionization, + or − ions). Mass spectra were acquired by scanning from 45 to 1000 (of atomic mass unit) in 0.3 seconds. Typical APCI conditions use a corona discharge current of 10 μA and a cone voltage of 30 V. The APCI probe temperature was 640° C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with an Xcalibur™ data system.
- General Procedure B
- The HPLC measurement was performed using an Agilent 1100 module comprising a pump, a diode-array detector (DAD) (wavelength used 220 nm), a column heater and a column as specified in the respective methods below. Flow from the column was split to a Agilent MSD Series G1946C and G1956A. MS detector was configured with API-ES (atmospheric pressure electrospray ionization). Mass spectra were acquired by scanning from 100 to 1000. The capillary needle voltage was 2500 V for positive ionization mode and 3000 V for negative ionization mode. Fragmentation voltage was 50 V. Drying gas temperature was maintained at 350° C. at a flow of 10 l/min.
-
Method 1 - In addition to general procedure A: Reversed phase HPLC was carried out on a Waters XTerra MS C18 column (3.5 μm, 2.1×30 mm) with a flow rate of 1.0 ml/min. Two mobile phases (mobile phase A: 0.1% aqueous solution of formic acid; mobile phase B: CH3CN) were used. First, 100% A was hold for 0.1 minutes (min). Then a gradient was applied to 5% A and 95 B in 3 min and hold for 0.8 min. The injection volume was 1 μl. The column was at room temperature.
-
Method 2 - In addition to general procedure B: Reversed phase HPLC was carried out on a YMC-Pack ODS-AQ, 50×2.0
mm 5 μm column with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: water with 0.1% TFA; mobile phase B: CH3CN with 0.05% TFA) were used. First, 90% A and 10% B was hold for 0.8 min. Then a gradient was applied to 20% A and 80% B in 3.7 min and hold for 3 min. Typical injection volumes of 2μl were used. Oven temperature was 50° C. (MS polarity: positive) -
Method 3 - In addition to general procedure B: Reversed phase HPLC was carried out on an Ultimate XB-C18, 50×2.1
mm 5 μm column with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase C: 10 mmol/L NH4HCO3; mobile phase D: CH3CN) were used. First, 90% C and 10% D was hold for 0.8 min. Then a gradient was applied to 20% C and 80% D in 3.7 min and hold for 3 min. Typical injection volumes of 2μl were used. Oven temperature was 50° C. (MS polarity: positive) -
Method 4 - In addition to general procedure B: Reversed phase HPLC was carried out on an Ultimate XB-C18, 50×2.1
mm 5 μm column with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase C: 10 mmol/L NH4HCO3; mobile phase D: CH3CN) were used. First, 100% C was hold for 1 min. Then a gradient was applied to 40% C and 60% D in 4 min and hold for 2.5 min. Typical injection volumes of 2 μl were used. Oven temperature was 50° C. (MS polarity: positive) - Melting Points
- For a number of compounds (147-150 of Class C; 358-364 of Class D), m.p. were determined by using a Gallenkamp apparatus from Sanyo Gallenkamp.
- For a number of compounds (151-152 of Class C; 353-357 of Class D), m.p. were determined with a WRS-2A melting point apparatus that was purchased from Shanghai Precision and Scientific Instrument Co. Ltd. Melting points were measured with a linear heating up rate of 0.2-5.0° C./min. The reported values are melt ranges. The maximum temperature was 300° C.
-
TABLE Y (LC) MS analytical data and m.p. - Rt means retention time (in minutes); [MH]+ means the protonated mass of the compound (free base); Method refers to the method used for (LC) MS; ‘dec.’ means decomposition. Comp. Nr. Rt [MH]+ Method m.p. (° C.) 147 - Class C 1.62 620 1 262-263 148 - Class C 1.60 663 1 180-182 149 - Class C 1.63 677 1 250-252 150 - Class C 1.68 713 1 240-242 151 - Class C 3.41 586 2 224.1-225.4 152 - Class C 4.84 602 3 138.7-140.9 353 - Class D 3.49 591 2 126.6-128.1 354 - Class D 3.23 600 2 206.3-209.4 355 - Class D 3.42 561 2 153.3-155.2 356 - Class D 3.10 616 2 134.4-137.0 357 - Class D 5.65 607 4 dec. at 124.8 358 - Class D 1.57 625 1 199-200 359 - Class D 1.61 677 1 240-241 360 - Class D 1.52 668 1 159-160 361 - Class D 1.53 691 1 164-166 362 - Class D 1.51 682 1 123-126 363 - Class D 1.61 727 1 241-243 364 - Class D 1.56 718 1 152-154 - Analytical data for the other Class A, Class B, Class C and Class D compounds are listed in WO2008/148851, WO2008/148840, WO2008/148849 and WO2008/148868, the contents of which are enclosed by reference in the present application.
- Pharmacological Example
- All mpk (mg/kg/day) values mentioned in the measurements described below, were estimated based on average food intake and average body weight.
- A) Measurement of Inhibition of DGAT1 Activity by the Compounds of Class A, Class B, Class C and Class D
- The inhibiting activity of compounds of Class A, Class B, Class C and Class D on DGAT1 activity was screened in a single well procedure assay using DGAT1 comprising membrane preparations and DGAT1 substrate comprising micelles and determining formed radio-active triacylglycerol coming in close proximity of a flashplate surface by radioluminescence.
- Said assay is described in full detail in WO2006/067071, the content of which is incorporated herein by reference.
- By DGAT1 activity is meant the transfer of coenzyme A activated fatty acids to the 3-position of 1,2-diacylglycerols, thus forming a triglyceride molecule, by enzyme DGAT1.
-
Step 1 Of the Assay: Expression of DGAT1 - human DGAT1 (NM012079.2) was cloned into the pFastBac vector, containing translation start, a FLAG-tag at the N-terminus as described in literature and a viral Kozak sequence (AAX) preceding the ATG to improve expression in insect cells. Expression was done as described in literature (Cases, S., Smith, S. J., Zheng, Y., Myers H. M., Lear, S. R., Sande, E., Novak, S., Collins, C., Welch, C. B., Lusis, A. J., Erickson, S. K. and Farese, R. V. (1998) Proc. Natl. Acad. Sci. USA 95, 13018-13023.) using SF9 cells.
-
Step 2 of the Assay: Preparation of DGAT1 Membranes - 72 h transfected SF9 cells were collected by centrifugation (13000 rpm-15 min-4° C.) and lysed in 2×500 ml lysisbuffer (0.1M Sucrose, 50 mM KCl, 40 mM KH2PO4, 30 mM EDTA pH 7.2. Cells were homogenized by cell disruptor. After centrifugation 1380 rpm-15 min-4° C. (SN discarded), pellet was resuspended in 500 ml lysisbuffer and total cell membranes collected by ultracentrifugation at 34000 rpm (100 000 g) for 60 min (4° C.). The collected membranes were resuspended in lysis buffer, divided in aliquots and stored with 10% glycerol at −80° C. until use.
-
Step 3 OF THE ASSAY: Preparation of DGAT Substrate Comprising Micelles - Materials
-
- a) 1,2-dioleoyl-sn-glycerol, 10 mg/ml (1,2-diacylglycerol (DAG)) Dissolve in acetonitrile; evaporate the acetonitrile solution under nitrogen and reconstitute in chloroform at a final concentration of 10 mg/ml.
- b) L-α-phosphatidylcholine, 1 mg/ml (phosphatidylcholine (PC)) Dissolve in chloroform at a final concentration of 1 mg/ml and store at 4° C.
- c) L-α-phosphatidyl-L-serine, 1 mg/ml (phophatidylserine (PS))
- Dissolve in chloroform at a final concentration of 1 mg/ml and store at 4° C.
- Method
- Add 1 ml dioleoyl-sn-glycerol (10 mg/ml) to 10 ml of L-α-phosphatidylcholine (1 mg/ml) and 10 ml of L-α-phosphatidyl-L-serine (1 mg/ml) in a thick glass recipient. Evaporate under nitrogen and put on ice for 15 min. Reconstitute in 10 ml Tris/HCl (10 mM, pH 7.4) by sonication on ice. The sonification process includes sonification cycles of 10 seconds in the sonification bath followed by 10 seconds cool down on ice and repeating this sonification cycle till a homogeneous solution is obtained (takes about 15 min). The thus obtained micelles are stored at −20° C. till later use and contain DAG at a final concentration of 1.61 mM.
-
Step 4 of the Assay: DGAT FlashPlate™ Assay - Materials
- a) Assaybuffer
-
- 50 mM Tris-HCl (pH 7.4), 150 mM MgCl, 1 mM EDTA, 0.2% BSA.
- b) N-ethylmaleimide, 5M
-
- Dissolve 5 g into a final volume of 8 ml DMSO 100% and store at −20° C. in aliquots till later use.
- c) Substrate mix (for 1 384 well plate=3840 μl)
- 612 μl micelles stock (51 μM final)
- 16.6 μl oleoylCoA 9.7 mM
- 23 μl [3H]-oleoylCoA (49 Ci/mmol, 500 μCi/ml)
- 3188.4 μl Tris pH 7.4, 10 mM
- d) Enzyme mix (for 1 384 well plate=3520 μl) (5 μg/ml)
-
- Add 11.73 μl of DGAT membrane stock (1500 pg/ml stock) to 3508 μl assay buffer.
- e) Stop mix (for 1 384 well plate=7.68 ml) (250 mM)
-
- Add 384 μl of N-ethylmaleimide (5M) to 3.456 ml DMSO 100%, and further dilute 3.84 ml of said solution with 3.84
ml DMSO 10%.
- Add 384 μl of N-ethylmaleimide (5M) to 3.456 ml DMSO 100%, and further dilute 3.84 ml of said solution with 3.84
- Method
- DGAT activity in membrane preparations was assayed in 50 mM Tris-HCl (pH 7.4), 150 mM MgCl2, 1 mM EDTA and 0.2% BSA, containing 50 μM DAG, 32 μg/ml PC/PS and 8.4 μM [3H]-oleoylCoA (at a specific activity of 30 nCi/well) in a final volume of 50 μl in 384-well format using the red shifted Basic Image FlashPlatel™ (Perkin Elmer Cat.No. SMP400).
- In detail, 10 μl enzyme mix and 10 μl substrate mix were added to 30 μl of assay buffer, optionally in the presence of 1 μl DMSO (blank and controls) or 1 μl of the compound to be tested. This r.m. was incubated for 120 min at 37° C. and the enzymatic reaction stopped by adding 20 μl of the stop mix. The plates were sealed and the vesicles allowed to settle overnight at room temperature. Plates were centrifuged for 5 min at 1500 rpm and measured in Leadseeker.
- Experiments with different concentrations of the test compound were performed and curves were calculated and drawn based on % CTRLmin (% of normalized control). % CTRLmin was calculated according to
equation 1, -
% CTRLmin=(sample−LC)/(HC−LC) Equation 1: - where HC (high control) refers to the median of radioluminescence value measured in the wells with enzyme and substrate but without test compound, LC (low control) refers to median background radioluminescence value measured in the wells with substrate without enzyme and without test compound, and sample refers to the radioluminescence value measured in the wells with substrate, enzyme and test compound at a particular concentration.
- The calculated % CTRLmin values form a sigmoidal dose response descending curve and from this curve pIC50 values were calculated (−logIC50 where IC50 represents the concentration at which the test compound gives 50% inhibition of DGAT1 activity).
- All the tested compounds of Class A, C and D showed pIC50 values between 5 and 9.
- All the tested compounds of Class B showed pIC50 values between 5 and 8.5.
- In order to determine selectivity of the present compounds for DGAT1 compared to DGAT2, the inhibiting activity of the compounds on DGAT2 was also determined in the above assay, slightly modified to obtain optimal assay conditions for DGAT2. The tested compounds did not show inhibiting activity for DGAT2 (Human DGAT2 (NM032564) was cloned and expressed as described in J. Biolog. Chem. 276(42), pp 38870-38876 (2001)).
- For a selected number of compounds, the pIC50 values are shown in Table E.
-
TABLE E pIC50 values Co. Nr. pIC50 151 - 6.50 Class C 152 - 7.45 Class C 147 - 7.41 Class C 148 - 8.04 Class C 149 - 8.21 Class C 150 - 8.22 Class C 353 - 6.59 Class D 354 - 6.19 Class D 355 - 6.04 Class D 356 - 7.13 Class D 357 - 7.26 Class D 358 - 7.59 Class D 359 - 7.55 Class D 360 - 8.12 Class D 361 - 7.87 Class D 362 - 8.04 Class D 363 - 7.94 Class D 364 - 8.24 Class D 352 - 6.45 Class D 351 - 6.62 Class D 267 - 6.97 Class D - Pharmacological data for the other Class A, Class B, Class C and Class D compounds are listed in WO2008/148851, WO2008/148840, WO2008/148849 and WO2008/148868, the contents of which are enclosed by reference in the present application.
- B) In Vivo Study for Effect of Test Compound on GLP-1 Plasma Levels
- Elevation of GLP-1 plasma levels by a DGAT inhibitor can be studied as follows:
- Dogs are deprived from food for a period of 22 h. At
time 0, animals are given a liquid meal, containing 18% fat (w/w), by gavage with a stomach tube. The test compound is given orally together with the meal. Afterwards, a postprandial plasma profile is determined for GLP-1. Therefore, blood is collected at predetermined time intervals in ice-cooled Vacutainers EDTA-plasma tubes and GLP-1 levels are measured in the samples taken at 0 h (just before the meal) and at 0.5, 1, 2, 4, 6, 8 and 24 h after dosing. Six dogs (3 males and 3 females) are included per dosage group and the plasma GLP-1 profile is compared with their own GLP-1 profile previously determined in the same conditions but without administration of the test compound. GLP-1 determinations in plasma are performed with a Glucagon-like peptide-1 (active) ELISA kit 96-well plate of LINCO Research. - C) Food Intake/Body Weight Effect of DGAT/Fenofibrate Combination
- General Procedure
- Male C57BL/6 mice were housed in individually ventilated cages under controlled temperature (21° C.), humidity (45-65%) and light (12 h-12 h reverse light/dark cycle; Lights on—6 PM-6 AM). Mice were set on 60 kcal % fat energy diet until their average body weight was over 45 grams, at which time they were switched to a 45 kcal % fat diet.
- For the purpose of Tests A, B and C, the mice were moved into modified type-2 cages with: doublewide food cup, wire grids and a tissue for bedding for several months before experiment to adapt to new housing/feeding conditions. Food (Research diets 45 kcal % diet D12451—see Scheme A) was provided in powdered form in a food hopper located off the front of the cage. Mice had been used to test several compounds for effects on food intake before being used in the current experiment, but had a wash-out period of at least one month before starting the current experiments.
-
Scheme A: Composition of control diet (high-fat) and premix (used for adding drug) Control Diet Added during D12451 Premix diet preparation Ingredient g/kg diet D04071407px g/kg diet Casein, 80 Mesh 233.1 233.1 L-Cystine 3.5 3.5 Corn Starch 84.8 84.8 Maltodextrin 10 3.5 3.5 Sucrose 201.4 201.4 Cellulose 58.3 58.3 Soybean Oil 29.1 29.1 Lard 206.8 104.9 102 Mineral Mix S10026 11.7 11.7 DiCalcium Phosphate 15.1 15.1 Calcium Carbonate 6.4 6.4 Potassium Citrate, 1 H20 19.2 19.2 Vitamin Mix 11.7 11.7 Choline Bitartrate 2.3 2.3 FD&C Red Dye #40 0.1 - Compound 223 of Class D (Tests A and B) or compound 358 (Test C) of Class D, and/or fenofibrate (also called ‘F’ in the continuation of the pharmacological examples) were brought to a fine emulsion by stirring in the appropriate amount of soybean oil for 1 day. This was then mixed with the diet premix (Scheme A). The diet premix was formulated to contain none of the necessary soybean oil, and only half the final amount of lard. The soybean oil, and the rest of the lard was added in-house during diet preparation. After the soybean oil/drug was mixed with the premix for 15 min, the remainder of the lard was added to complete the diet. Diet was provided in powder form.
- The mice were weighted the day before trial onset. For treatment allocation, mice were ranked according to body weight and randomly assigned to treatments within repetitions/blocks (40 mice, 4 treatments, 10 repetitions/block, unless otherwise mentioned). The food intake the day before trial onset was also measured.
- At trial onset, mice's food (diet D12451) was replaced with the ‘inhouse’ diet made from premix D04071407px and added oil/lard, fenofibrate and/or the DGAT inhibitor. In tests A and B compound 223 of Class D (also called ‘D’ in the continuation of the pharmacological examples) was used:
- Food cups were filled and weighted daily during the experiment. Body weight was recorded every 2nd or 3rd day.
- Food Intake and Body Weight data were analyzed using General Linear Models procedures appropriate for a 2×2 factorial design with blocking and repeated measures. Means comparisons were done using Duncan's Multiple Range test (SAS For Windows, Version 8.02; SAS®, Cary, N.C.). Results were expressed as means±SEM (standard error of the mean).
- Test A
- In test A, the efficacy of the treatment in DIO C57BL/6 mice with only fenofibrate and only a DGAT inhibitor (compound 223 from Class D) was compared with the combined treatment with both D and fenofibrate.
- For the purpose of test A, the mice were assigned to one of the following treatments:
- 45 kcal % fat diet (Control)
- 45 kcal % fat diet+0.05% fenofibrate (F)
- 45 kcal % fat diet+0.04% compound 223 from Class D (D)
- 45 kcal % fat diet+0.04% compound 223 from Class D+0.05% fenofibrate (D+F)
- The results of test A are shown in Figures A1 and A2.
- In figure A1 it can be seen that except for 1 or 2 days out of the 12 day trial, food intake of mice fed with the compound 223 of Class D (D) or fenofibrate-containing (F) diet was not significantly less than control mice. In contrast, food intake of mice fed with the compound 223 of Class D and fenofibrate-containing (D+F) diet was significantly less (P<0.05) on 9 out of 12 days. The cumulative food intake of the compound 223 of Class D group (D) and the fenofibrate group (F) was not significantly less than the control group when compared by Duncans Multiple Range test (3.2% and 7.5% respectively); whereas food intake of the group with the compound 223 of Class D and fenofibrate-containing (D+F) diet was significantly less (23%) than all other groups (P<0.05). When cumulative intake was analysed as a 2×2 factorial design, there was a significant DGAT effect and fenofibrate effect (P<0.005), but there was also a significant DGAT (compound 223 from Class D) x fenofibrate interaction, indicating that the combined effect was larger than the main effect of either alone (P<0.05) (synergistic effect).
- The average daily drug intake of mice fed with the compound 223 of Class D or fenofibrate-containing diet was 23.5 and 29 mpk/d respectively. The average daily drug intake of mice fed the compound 223 of Class D and fenofibrate-combination diet was 43.2 mg/kg/day.
- In figure A2 it can be seen that by
day 2, body weight loss of mice fed with the compound 223 of Class D and fenofibrate-containing diet was significantly greater than control mice (P<0.05). Byday 4, body weight change of all drug treated mice was significantly different than controls. Mice fed with the compound 223 of Class D or fenofibrate-containing diet lost from 1-2 grams during the trial, whereas controls gained 0.6 grams. In contrast, mice fed with the compound 223 of Class D and fenofibrate-combination diet (D+F) significantly lost more weight than mice fed with either drug alone, indicating a synergistic effect of the 2 compounds on weight loss. Whenday 12 weight loss was analysed by a 2×2 factorial design, the main effect of DGAT and fenofibrate were both significant (P<0.001), but DGAT x fenofibrate interaction was also significant (type 3 SS, P<0.05). This test supports the increased effect on weight loss of the combination diet when compared with single treatment. - At the end of test A, blood was collected under isoflurane anesthesia for serum biochemistry determinations. There was no indication of enhanced liver enzymes with the combination diet. Blood glucose and serum triglyceride levels were consistently lower in the (D+F) diet group than the control group.
- Test B
- In test B, the efficacy of the treatment in DIO C57BL/6 mice with the fenofibrate/compound 223 from Class D combination was compared at different doses. In test A, fenofibrate and compound 223 of Class D were included at 0.05 and 0.04% of the diet (w/w) respectively. In test B, fenofibrate (F)/compound 223 of Class D (D) was included at 3 lower doses 0.05F/0.02D, 0.025F/0.02D and 0.0125F/0.01D.
- For the purpose of test B, the mice were assigned to one of the following treatments:
- 45 kcal % fat diet (Control)
- 45 kcal % fat diet+0.02% D+0.05% F (0.05F/0.02D)
- 45 kcal % fat diet+0.02% D+0.025% F (0.025F/0.02D)
- 45 kcal % fat diet+0.01% D+0.0125% F (0.0125F/0.01D)
- The results of test B are shown in Figures B1, B2 and B3.
- The average daily drug intake of F/D was 26.0/10.4, 13.2/10.6 and 6.6/5.3 mpk/d respectively for mice fed with the high, medium and low concentration diets. In Figure B1, it can be seen that the baseline food intake (i.e. day 0) of mice fed the 0.0125/0.01 was significantly lower than for other groups. During the first day of exposure to the drug-containing diets, all treatment groups ate significantly less than controls. (2.6 vs. 3.7 g for treated vs. controls respectively). Treated mice ate significantly (P<0.05 or less) less than controls on all trial days except
days - In
FIG. B2 , it can be seen that body weight change of mice fed with F/D-containing diets was significantly different from control mice by the 2nd day of the trial (all P<0.001). Body weight changed significantly over time (time effect, P<0.001), and was significantly influenced by treatment (time×treatment interaction (P<0.05). - In figure B3, food intake of all treatment groups on
day 1 is shown. All groups ate about 30% less than controls regardless of dietary D/F combination. - It can be concluded that compound 223 of Class D in combination with fenofibrate, reduced food intake in diet-induced obese mice for almost 2 weeks. This reduction in food intake was accompanied with a significant weight change when compared to controls. Control mice gained almost 2 grams during the first 5 days of the experiment. It appeared that mice had lost some weight during adaptation to the feeding cages. Although they regained most of this weight prior to the trial, some control mice clearly still regained weight during the first week of the experiment. This was not the case for mice treated with the combination of compound 223 of Class D and fenofibrate, even when the 2 were combined in the diet at 0.01 and 0.0125 w/w respectively. These results suggest that fenofibrates may reduce the efficacious dose of a DGAT inhibitor and prolong the time a DGAT inhibitor will reduce food intake.
- Test C
- In test C, the efficacies of the treatments in DIO C57BL/6 mice with only fenofibrate and only a DGAT inhibitor (compound 358 from Class D) were compared with the combined treatment with both
compound 358 of Class D and fenofibrate. - For the purpose of test C, the 32 DIO mice (n=8/group, average starting weight
- 46.5 g) were assigned to one of the following treatments:
- 45 kcal % fat diet (Control)
- 45 kcal % fat diet+0.05% fenofibrate (F)
- 45 kcal % fat diet+0.04
% compound 358 from Class D - 45 kcal % fat diet+0.04
% compound 358 from Class D+0.05% fenofibrate (F) - The results of test C are shown in Figures C1 and C2.
- In figure C1 it can be seen that food intake of mice fed with a diet containing only compound 358 of Class D or a diet only containing fenofibrate, was not significantly less than control mice. Food intake of mice fed with the
compound 358 of Class D+fenofibrate-containing diet was only significantly less (P<0.05) from controls ondays 1 to 3, due to an increase in food intake above baseline levels in control mice rather than a decrease in intake ofcompound 358+fenofibrate-treated mice. The 21-day cumulative food intake of all drug-treated mice turned out not to be significantly less than the control group, although there was a tendency for mice fedcompound 358 of Class D and fenofibrate-containing diet to eat less. - The average daily drug intake of mice fed with the
compound 358 of Class D or fenofibrate-containing diet was 27 and 34 mpk/d respectively. The average daily drug intake of mice fed thecompound 358 of Class D and fenofibrate-combination diet was 58 mg/kg/day. - When analysed as a 2×2 factorial experiment (figure C2), both DGAT and fenofibrate treated mice gained less weight than controls (21 days body weight change, both main effects P<0.05). The combination of the 2 treatments resulted in a weight loss corresponding to the additive effect of both (interaction P>0.05, no synergistic effect).
- D) Short-Term Food Intake Effect of DGAT/Fenofibrate Combination in Lean C57BL/6 Mice.
- In Test A and Test B, it was demonstrated that DGAT inhibition (compound 223 of Class D, also called 13′) in combination with fenofibrate (F) significantly reduced food intake and body weight of diet-induced obese mice fed a high-fat diet to a greater degree than when either compound was administered alone. To further evaluate the mechanism of action of this food intake reduction, it was evaluated whether combined treatment with a DGAT inhibitor (compound 223 of Class D) and fenofibrate reduce food intake in mice fed with a low-fat diet.
- For the experiment, animals were moved into modified type-2 cages as described before. Once in the feeding cages, mice were adapted to a 10 kcal % fat diet for 1 week before
trial 1 was started. - For the purpose of this test, the mice were assigned to one of the following treatments:
- Low Fat Diets (
Trial 1; figure D1): - 10 kcal % fat diet (Control)
- 10 kcal % fat diet+0.01% D+0.0125% F (0.01% D/0.0125% F)
- 10 kcal % fat diet+0.04% D+0.05% F (0.04% D/0.05% F)
- High Fat Diet (
Trial 2; figure D2) - 45 kcal % fat diet (Control)
- 45 kcal % fat diet+0.01% D+0.0125% F (0.01% D/0.0125% F)
- 45 kcal % fat diet+0.02% D+0.05% F (0.02% D/0.05% F)
- Compound 223 of Class D (D) and fenofibrate (F) were brought to a fine emulsion by stirring in the appropriate amount of soybean oil for 1 day. This was then mixed with the diet premix. After the soybean oil/drug was mixed with the premix for 15 min, the necessary amount of the lard was added to complete the diet. Diet was provided in powder form.
- Mice's ‘baseline’ (BL) food intake was measured for 1 day before both Trial 1 (low-fat diet) and 2 (high-fat diet). For treatment allocation, mice were ranked according to their pretrial food intake and randomly assigned to treatments within repetitions/block (30 mice, 3 treatments, 8-9 repetitions/block). Several mice had low or high food intakes and were not included in the experiment.
- Food intake data were analysed using General Linear Models procedures appropriate for a randomized complete block design. Means comparisons were done using Duncan's Multiple Range test (SAS For Windows, Version 8.02; SAS®, Cary, NC). Results are expressed as means ±SEM.
- Trial 1: Food Intake of Lean Mice Fed a Low-Fat Diet
- Mice were given 1 week to adapt to the food intake cages and a low-fat powdered diet (Research Diets D12450B-10 kcal % fat). After 1 day of baseline food intake measurement, mice's food was replaced by the same 10 kcal % fat diet containing 0/0, 0.01/0.0125 or 0.04/0.05 w/w D/F. The food cups were filled and weight daily during the 3-day experiment.
- In figure D1 (Trial 1), it can be seen that food intake of mice fed the diet containing a 0.01/0.0125% D/F was not reduced at any time during the 3-day trial, whereas mice fed the diet containing 0.04/0.05% D/F reduced their food intake by 9% on
day 1, but ate similar amounts as controls thereafter. - The average daily drug intake of F/D was 71/57 or 17/14 mpk/d respectively for mice fed the high, and low concentration diets.
- Trial 2: Food Intake of Lean Mice Fed a High-Fat Diet
- At the termination of
trial 1, mice were switched to a high-fat diet (D12451-45 k cal % fat) and allowed to adapt for 3 days. Once adapted, food intake was recorded for 1 day to establish a baseline food intake (for treatment allotment). The following day, mice were switched to the same 45 kcal % fat diet containing 0/0, 0.01/0.0125 or 0.02/0.05% w/w D/F (Figure D2). - In Figure D2, it is shown that food intake of mice fed the diets containing a 0.01/0.0125% and 0.02/0.05% D/F was significantly reduced compared to controls, especially on
day 1. Thereafter lean mice adapted more quickly than was generally been observed with obese mice. Byday 2, mice were eating 90% of control values. - The average daily drug intake of F/D was 44/18 or 10.8/8.6 mpk/d respectively for mice fed the high, and low concentration diets.
- It can be seen from figure D3 that food intake during the first 24 h of exposure to the drug-supplemented diet (0.01% D/ 0.0125% F) was significantly reduced in mice fed a high-fat diet (24% below control levels), but not in mice fed a low-fat diet (4% below control levels). These results clearly indicate that a certain amount of dietary fat is necessary for the feeding suppressive effects of D/F.
- E) Composition Examples
- “Active ingredient” (a.i.) as used throughout these examples relates to, unless otherwise is indicated,
- a) a combination of a DGAT inhibitor and a PPAR agonist or a prodrug thereof; in particular to any one of the exemplified DGAT inhibitors combined with a fibrate; or
- b) a compound of group Q.
- Typical examples of recipes for the formulation of the invention are as follows:
- 1. Tablets
-
Active ingredient 5 to 100 mg Di-calcium phosphate 20 mg Lactose 30 mg Talcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg - In addition to tablets wherein both the DGAT inhibitor and the PPAR agonist are comprised together in 1 tablet, the DGAT inhibitor and the PPAR agonist may also be present in separate tablets. In that case, the active ingredient will be the DGAT inhibitor for one tablet and the PPAR agonist for the second tablet.
- 2. Suspension
- An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and
water ad 1 ml. - 3. Injectable
- A parenteral composition is prepared by stirring 1.5% (weight/volume) of active ingredient in 0.9% NaCl solution.
- 4. Ointment
-
Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g White petroleum 15 g Water ad 100 g
Claims (13)
1. A combination of a PPAR-α agonist or a prodrug thereof and a DGAT inhibitor wherein the DGAT inhibitor is selected from
a) a compound having the formula
including any stereochemically isomeric form thereof, wherein
A represents CH or N;
X represents O or NRx;
the dotted line represents an optional bond in case A represents a carbon atom;
Y represents a direct bond; —NRx—C(═O)—; —C(═O)—NRx—; —NRx—C(═O)—Z—;
—NRx—C(═O)—Z—NRy—; —NRx—C(═O)—Z—NRy—C(═O)—; —NRx—C(═O)—Z—NRy—C(═O)—O—;
—NRx—C(═O)—Z—O—; —NRx—C(═O)—Z—O—C(═O)—; —NRx—C(═O)—Z—C(═O)—;
—NRx—C(═O)—Z—C(═O)—O—; —NRx—C(═O)—O—Z—C(═O)—; —NRx—C(═O)—O—Z—C(═O)—O—;
—NRx—C(═O)—O—Z—O—C(═O)—; —NRx—C(═O)—Z—C(═O)—NRy—;
—NRx—C(═O)—Z—NRy—C(═O)—NRy—; —C(═O)—Z—; —C(═O)—Z—O—; —C(═O)—NRx—Z—;
—C(═O)—NRx—Z—O—; —C(═O)—NRx—Z—C(═O)—O—; —C(═O)—NRx—Z—O—C(═O)—;
—C(═O)—NRx—O—Z—; —C(═O)—NRx—Z—NRy—; —C(═O)—NRx—Z—NRy—C(═O)—;
or —C(═O)—NRx—Z—NRy—C(═O)—O—;
Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with C1-4alkyloxy, C1-4alkylthio, hydroxyl, cyano or aryl; and wherein two hydrogen atoms attached to the same carbon atom in the definition of Z may optionally be replaced by C1-6alkanediyl;
Rx represents hydrogen or C1-4alkyl;
Ry represents hydrogen; C1-4alkyl optionally substituted with C3-6cycloalkyl or aryl or Het; C2-4alkenyl; or S(═O)p-aryl;
R1 represents C1-12alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-oxyC1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl; C2-6alkynyl; C3-6cycloalkyl; aryls; aryl1C1-6alkyl; Het1; or Het1C1-6alkyl; provided that when Y represents —NRx—C(═O)—Z—; —NRx—C(═O)—Z—NRy; —NRx—C(═O)—Z—C(═O)—NRy—; —C(═O)—Z—; —NRx—C(═O)—Z—NRy—C(═O)—NRy—; —C(═O)—NRx—Z—; —C(═O)—NRx—O—Z—; or —C(═O)—NRx—Z—NRy—; then R1 may also represent hydrogen;
R2 and R3 each independently represent hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; or —S(═O)p—C1-4alkyl;
R4 represents hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R6R5N—C(═O)—; R6R5N—C1-6alkyl; C3-6cycloalkyl; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; or Het-O—;
R5 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R8R7N—C1-4alkyl; C1-4alkyloxy; Het; aryl; or R8R7N—C(═O)—C1-4alkyl;
R6 represents hydrogen or C1-4alkyl;
R7 represents hydrogen; C1-4alkyl; or C1-4alkylcarbonyl;
R8 represents hydrogen or C1-4alkyl; or
R7 and R8 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from the group consisting of O, S, S(═O)p and N; and which heterocycle may optionally be substituted with C1-4alkyl;
R9 represents hydrogen; halo; C1-4alkyl; or C1-4alkyl substituted with hydroxyl;
aryl represents phenyl or phenyl substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl,
C1-4 alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6 alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino; R6R5N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; and Het-O—;
Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6 alkyloxy optionally substituted with C1-4 alkyloxy; C1-6 alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino; R6R5N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; and Het-O—;
p represents 1 or 2;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof;
b) a compound having the formula
including any stereochemically isomeric form thereof, wherein
A represents CH or N;
the dotted line represents an optional bond in case A represents a carbon atom;
X represents —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —S(═O)p—; C(═S)—;
—NRx—C(═S)—; —Z—C(═S)—; —Z—NRx—C(═S)—; —O—C(═O)—; or —C(═O)—C(═O)—;
Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl;
Rx represents hydrogen or C1-4alkyl;
R1— represents a 5-membered monocyclic heterocycle containing at least 2 heteroatoms;
a 6-membered aromatic monocyclic heterocycle; or a 5-membered heterocycle containing at least 2 heteroatoms fused with phenyl, cyclohexyl or a 5- or 6-membered heterocycle; wherein each of said heterocycles may optionally be substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)-aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkyl-C1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; and Het-O—;
R2 represents R3;
R3 represents C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may optionally be substituted with at least one substituent, each substituent independently selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cycloalkyk C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
R4 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R7R6N—C1-4alkyl; C1-4alkyloxy; Het; aryl; or R7R6N—C(═O)—C1-4alkyl;
R5 represents hydrogen or C1-4alkyl;
R6 represents hydrogen; C1-4alkyl; or C1-4alkylcarbonyl;
R7 represents hydrogen or C1-4alkyl; or
R6 and R7 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms selected from the group consisting of O, S, S(═O)p and N; and which heterocycle may optionally be substituted with C1-4alkyl;
R8 represents hydrogen halo C1-4alkyl; or C1-4alkyl substituted with hydroxyl;
aryl represents phenyl or phenyl substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl
p represents 1 or 2;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof;
c) a compound having the formula
including any stereochemically isomeric form thereof, wherein
A represents CH or N;
the dotted line represents an optional bond in case A represents a carbon atom;
X represents O—C(═O)—; —C(═O)—C(═O)—; —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —C(═O)—Z—; —NRx—C(═O)—Z—; C(═S)—; —S(═O)p—; —NRx—C(═S)—; —Z—C(═S)—; —Z—NRx—C(═S)—; —C(═S)—Z—; or —NRx—C(═S)—Z—;
Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl;
Rx represents hydrogen or C1-4alkyl;
Y represents C(═O)—NRx— or —NRx—C(═O)—;
R1 represents adamantanyl; C3-6cycloalkyl; aryl1 or Het1;
R2 represents hydrogen, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 6-membered aromatic heterocycle containing 1 or 2 N atoms may optionally be substituted with at least one substituent, each substituent independently selected from the group consisting of hydroxyl; carboxyl; halo; C1-6 alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R4R3N—C(═O)—; R4R3N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
R3 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R6R5N—C1-4alkyl; C1-4alkyloxy; Het; Het-C1-4alkyl; aryl; or R6R5N—C(═O)—C1-4alkyl;
R4 represents hydrogen or C1-4alkyl;
R5 represents hydrogen; C1-4alkyl; or C1-4alkylcarbonyl;
R6 represents hydrogen or C1-4alkyl; or
R5 and R6 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from the group consisting of O, S, S(═O)p Of and N; and which heterocycle may optionally be substituted with C1-4alkyl;
R7 represents hydrogen; halo; C1-4alkyl7 or C1-4alkyl substituted with hydroxyl;
aryl represents phenyl or phenyl substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4 alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6 alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R4R3N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R4R3N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
p represents 1 or 2;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof;
or
d) a compound having the formula
including any stereochemically isomeric form thereof, wherein
A represents CH or N;
the dotted line represents an optional bond in case A represents a carbon atom;
X represents C(═O)—; —O—C(═O)—; —C(═O)—C(═O)—; —NRx—C(═O)—; —Z1—C(═O)—; —Z1—NRx—C(═O)—; —C(═O)—Z1—; —NRx—C(═O)—Z1—; —S(═O)p—; C(═S)—; —NRx—C(═S)—; —Z1—C(═S)—; —Z1—NRx—C(═S)—; —C(═S)—Z1—; or —NRx—C(═S)—Z1—;
Z1 represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl;
Y represents NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—; —NRx—C(═O)—Z2—NRy—C(═O)—O—; —NRx—C(═O)—Z2-0—; —NRx—C(═O)—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—; —NRx—C(═O)—Z2—C(═O)—O—; —NRx—C(═O)—O—Z2—C(═O)—; —NRx—C(═O)—O—Z2—C(═O)—O—; —NRx—C(═O)—O—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—Z2—; —C(═O)—Z2—O—; —C(═O)—NRx—Z2—; —C(═O)—NRx—Z2—O—; —C(═O)—NRx—Z2—C(═O)—O—; —C(═O)—NRx—Z2—O—C(═O)—; —C(═O)—NRx—O—Z2—; —C(═O)—NRx—Z2—NRy—; —C(═O)—NRx—Z2—NRy—C(═O)—; or —C(═O)—NRx—Z2—NRy—C(═O)—O—;
Z2 represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with C1-4alkyloxy, C1-4alkylthio, hydroxyl, cyano or aryl; and wherein two hydrogen atoms attached to the same carbon atom in the definition of Z2 may optionally be replaced by C1-6alkanediyl;
Rx represents hydrogen or C1-4alkyl;
Ry represents hydrogen; C1-4alkyl optionally substituted with C3-6cycloalkyl or aryl or Het; C2-4alkenyl; or S(═O)p-aryl;
R1 represents C1-12alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-oxyC1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl; C2-6alkynyl; C3-6cycloalkyl; adamantanyl; aryls; aryl1C1-6alkyl; Het1; or Het1C1-6alkyl; provided that when Y represents —NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy; —NRx—C(═O)—Z2—C(═O)—NRy—; —C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—NRx—Z2—; —C(═O)—NRx—O—Z2—; or —C(═O)—NRx—Z2—NRy—; then R1 may also represent hydrogen;
R2 represents hydrogen; C1-12alkyl; C2-6alkenyl; or R3;
R3 represents C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 6-membered aromatic heterocycle containing 1 or 2 N atoms may optionally be substituted with at least one substituent, each substituent independently selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
R4 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R7R6N—C1-4alkyl; C1-4alkyloxy; Het; Het-C1-4alkyl; aryl; or R7R6N—C(═O)—C1-4alkyl;
R5 represents hydrogen or C1-4alkyl;
R6 represents hydrogen; C1-4alkyl; or C1-4alkylcarbonyl;
R7 represents hydrogen or C1-4alkyl; or
R6 and R7 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from the group consisting of O, S, S(═O)p and N; and which heterocycle may optionally be substituted with C1-4alkyl;
R8 represents hydrogen; halo; C1-4alkyl; or C1-4alkyl substituted with hydroxyl;
aryl represents phenyl or phenyl substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
p represents 1 or 2;
provided that if X represents O—C(═O)—, then R2 represents R3;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof
2. The combination according to claim 1 wherein the DGAT inhibitor has the following formula
including any stereochemically isomeric form thereof, wherein
A represents CH or N;
X represents O or NRx;
the dotted line represents an optional bond in case A represents a carbon atom;
Y represents a direct bond; —NRx—C(═O)—; —C(═O)—NRx—; —NRx—C(═O)—Z—; —NRx—C(═O)—Z—NRy—; —NRx—C(═O)—Z—NRy—C(═O)—; —NRx—C(═O)—Z—NRy—C(═O)—O—; —NRx—C(═O)—Z—O—; —NRx—C(═O)—Z—O—C(═O)—; —NRx—C(═O)—Z—C(═O)—; —NRx—C(═O)—Z—C(═O)—O—; —NRx—C(═O)—O—Z—C(═O)—; —NRx—C(═O)—O—Z—C(═O)—O—; —NRx—C(═O)—O—Z—O—C(═O)—; —NRx—C(═O)—Z—C(═O)—NRy—; —NRx—C(═O)—Z—NRy—C(═O)—NRy—; —C(═O)—Z—; —C(═O)—Z—O—; —C(═O)—NRx—Z—; —C(═O)—NRx—Z—O—; —C(═O)—NRx—Z—C(═O)—O—; —C(═O)—NRx—Z—O—C(═O)—; —C(═O)—NRx—O—Z—; —C(═O)—NRx—Z—NRy—; —C(═O)—NRx—Z—NRy—C(═O)—; or —C(═O)—NRx—Z—NRy—C(═O)—O—;
Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with C1-4alkyloxy, C1-4alkylthio, hydroxyl, cyano or aryl; and wherein two hydrogen atoms attached to the same carbon atom in the definition of Z may optionally be replaced by C1-6alkanediyl;
Rx represents hydrogen or C1-4alkyl;
Ry represents hydrogen; C1-4alkyl optionally substituted with C3-6cycloalkyl or aryl or Het; C2-4alkenyl; or S(═O)p-aryl;
R1 represents C1-12alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-oxyC1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl; C2-6alkynyl; C3-6cycloalkyl; aryls; aryl1 C1-6alkyl; Het1; or Het'C1-6alkyl; provided that when Y represents —NRx—C(═O)—Z—; —NRx—C(═O)—Z—NRy; —NRx—C(═O)—Z—C(═O)—NRy—; —C(═O)—Z—; —NRx—C(═O)—Z—NRy—C(═O)—NRy—; —C(═O)—NRx—Z—; —C(═O)—NRx—O—Z—; or —C(═O)—NRx—Z—NRy—; then R1 may also represent hydrogen;
R2 and R3 each independently represent hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; or —S(═O)p—C1-4alkyl;
R4 represents hydrogen; hydroxyl; carboxyl; halo; C1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R6R5N—C(═O)—; R6R5N—C1-6alkyl; C3-6cycloalkyl; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; or Het-O—;
R5 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R8R7N—C1-4alkyl; C1-4alkyloxy; Het; aryl; or R8R7N—C(═O)—C1-4alkyl;
R6 represents hydrogen or C1-4alkyl;
R7 represents hydrogen; C1-4alkyl; or C1-4alkylcarbonyl;
R8 represents hydrogen or C1-4alkyl; or
R7 and R8 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from the group consisting of O, S, S(═O)p and N; and which heterocycle may optionally be substituted with C1-4alkyl;
R9 represents hydrogen; halo; C1-4alkyl; or C1-4alkyl substituted with hydroxyl;
aryl represents phenyl or phenyl substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4 alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6 alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino; R6R5N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; and Het-O—;
Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6 alkyloxy optionally substituted with C1-4 alkyloxy; C1-6 alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino; R6R5N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; and Het-O—;
p represents 1 or 2;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof
3. The combination according to claim 1 wherein the DGAT inhibitor has the following formula
including any stereochemically isomeric form thereof, wherein
A represents CH or N;
the dotted line represents an optional bond in case A represents a carbon atom;
X represents —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —S(═O)p—; C(═S)—; —NRx—C(═S)—; —Z—C(═S)—; —Z—NRx—C(═S)—; —O—C(═O)—; or —C(═O)—C(═O)—;
Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl;
Rx represents hydrogen or C1-4alkyl;
R1 represents a 5-membered monocyclic heterocycle containing at least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle; or a 5-membered heterocycle containing at least 2 heteroatoms fused with phenyl, cyclohexyl or a 5- or 6-membered heterocycle; wherein each of said heterocycles may optionally be substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)-aminocarbonyl; C1-6alkylcarbonyl; amino; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkyl-C1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—; aryl-C(═O)—C1-4alkyl; Het; HetC1-4alkyl; Het-C(═O)—; Het-C(═O)—C1-4alkyl; and Het-O—;
R2 represents R3;
R3 represents C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may optionally be substituted with at least one substituent, each substituent independently selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
R4 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R7R6N—C1-4alkyl; C1-4alkyloxy; Het; aryl; or R7R6N—C(═O)—C1-4alkyl;
R5 represents hydrogen or C1-4alkyl;
R6 represents hydrogen; C1-4alkyl; or C1-4alkylcarbonyl;
R7 represents hydrogen or C1-4alkyl; or
R6 and R7 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms selected from the group consisting of O, S, S(═O)p and N; and which heterocycle may optionally be substituted with C1-4alkyl;
R8 represents hydrogen halo; C1-4alkyl; or C1-4alkyl substituted with hydroxyl;
aryl represents phenyl or phenyl substituted with at least one substituent, one, two, three, four or five substituents, each substituent independently being each substituent independently being selected the group consisting of from hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl
p represents 1 or 2;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
4. The combination according to claim 1 wherein the DGAT inhibitor has the following formula
including any stereochemically isomeric form thereof, wherein
A represents CH or N;
the dotted line represents an optional bond in case A represents a carbon atom;
X represents O—C(═O)—; —C(═O)—C(═O)—; —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —C(═O)—Z—; —NRx—C(═O)—Z—; C(═S)—; —S(═O)p—; —NRx—C(═S)—; —Z—C(═S)—; —Z—NRx—C(═S)—; —C(═S)—Z—; or —NRx—C(═S)—Z—;
Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl;
Rx represents hydrogen or C1-4alkyl;
Y represents C(═O)—NRx— or —NRx—C(═O)—;
R1 represents adamantanyl, C3-6cycloalkyl; aryl1 or Het1;
R2 represents hydrogen, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 6-membered aromatic heterocycle containing 1 or 2 N atoms may optionally be substituted with at least one substituent, each substituent independently selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6 alkyl; C1-6 alkyloxy optionally substituted with C1-4 alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R4R3N—C(═O)—; R4R3N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; et-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
R3 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R6R5N—C1-4alkyl; C1-4alkyloxy; Het; Het-C1-4alkyl; aryl; or R6R5N—C(═O)—C1-4alkyl;
R4 represents hydrogen or C1-4alkyl;
R5 represents hydrogen; C1-4alkyl; or C1-4alkylcarbonyl;
R6 represents hydrogen or C1-4alkyl; or
R5 and R6 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from the group consisting of O, S, S(═O)p and N; and which heterocycle may optionally be substituted with C1-4alkyl;
R7 represents hydrogen halo; C1-4alkyl; or C1-4alkyl substituted with hydroxyl;
aryl represents phenyl or phenyl substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R4R3N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio;
polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R4R3N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
p represents 1 or 2;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof
5. The combination according to claim 1 wherein the DGAT inhibitor has the following formula
including any stereochemically isomeric form thereof, wherein
A represents CH or N;
the dotted line represents an optional bond in case A represents a carbon atom;
X represents C(═O)—; —O—C(═O)—; —C(═O)—C(═O)—; —NRx—C(═O)—; —Z1—C(═O)—; —Z1—NRx—C(═O)—; —C(═O)—Z1—; —NRx—C(═O)—Z1—; —S(═O)p—; C(═S)—; —NRx—C(═S)—; —Z1—C(═S)—; —Z1—NRx—C(═S)—; —C(═S)—Z1—; or —NRx—C(═S)—Z1—;
Z1 represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl;
Y represents NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—; —NRx—C(═O)—Z2—NRy—C(═O)—O—; —NRx—C(═O)—Z2-0—; —NRx—C(═O)—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—; —NRx—C(═O)—Z2—C(═O)—O—; —NRx—C(═O)—O—Z2—C(═O)—; —NRx—C(═O)—O—Z2—C(═O)—O—; —NRx—C(═O)—O—Z2—O—C(═O)—; —NRx—C(═O)—Z2—C(═O)—NRy—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—Z2—; —C(═O)—Z2—O—; —C(═O)—NRx—Z2—; —C(═O)—NRx—Z2—O—; —C(═O)—NRx—Z2—C(═O)—O—; —C(═O)—NRx—Z2—O—C(═O)—; —C(═O)—NRx—O—Z2—; —C(═O)—NRx—Z2—NRy—; —C(═O)—NRx—Z2—NRy—C(═O)—; or —C(═O)—NRx—Z2—NRy—C(═O)—O—;
Z2 represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with C1-4alkyloxy, C1-4alkylthio, hydroxyl, cyano or aryl; and wherein two hydrogen atoms attached to the same carbon atom in the definition of Z2 may optionally be replaced by C1-6alkanediyl;
Rx represents hydrogen or C1-4alkyl;
Ry represents hydrogen; C1-4alkyl optionally substituted with C3-6cycloalkyl or aryl or Het; C2-4alkenyl; or S(═O)p-aryl;
R1 represents C1-12alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-oxyC1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl; C2-6alkynyl; C3-6cycloalkyl; adamantanyl; aryls; aryl1C1-6alkyl; Hee; or Het1C1-6alkyl; provided that when Y represents —NRx—C(═O)—Z2—; —NRx—C(═O)—Z2—NRy; —NRx—C(═O)—Z2—C(═O)—NRy—; —C(═O)—Z2—; —NRx—C(═O)—Z2—NRy—C(═O)—NRy—; —C(═O)—NRx—Z2—; —C(═O)—NRx—O—Z2—; or —C(═O)—NRx—Z2—NRy—; then RI- may also represent hydrogen;
R2 represents hydrogen, C1-12alkyl, C2-6alkenyl or R3;
R3 represents C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 6-membered aromatic heterocycle containing 1 or 2 N atoms may optionally be substituted with at least one substituent, each substituent independently selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R5R4N—C(═O)—; R5R4N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
R4 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R7R6N—C1-4alkyl; C1-4alkyloxy; Het; Het-C1-4alkyl; aryl; or R7R6N—C(═O)—C1-4alkyl;
R5 represents hydrogen or C1-4alkyl;
R6 represents hydrogen; C1-4alkyl; or C1-4alkylcarbonyl;
R7 represents hydrogen or C1-4alkyl; or
R6 and R7 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from the group consisting of O, S, S(═O)p and N; and which heterocycle may optionally be substituted with C1-4alkyl;
R8 represents hydrogen halo; C1-4alkyl; or C1-4alkyl substituted with hydroxyl;
aryl represents phenyl or phenyl substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
aryl1 represents phenyl, naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl or fluorenyl optionally substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4 alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl;
Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl, C1-4alkyloxycarbonyl or aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R5R4N—C1-6alkyl; C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—;
p represents 1 or 2;
provided that if X represents O—C(═O)—, then R2 represents R3;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof
6. The combination according to claim 4 wherein the DGAT inhibitor is selected from:
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide;
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide;
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide;
4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide;
4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide;
4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide;
including any stereochemically isomeric form thereof;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
7. The combination according to claim 5 wherein the DGAT inhibitor is selected from:
N4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide;
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;
4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;
4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;
4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;
4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;
4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;
4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;
N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide;
N4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide;
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;
including any stereochemically isomeric form thereof;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
8. The combination according to claim 1 wherein the PPAR-α agonist or a prodrug thereof is a fibrate.
9. The combination according to claim 8 wherein the fibrate is fenofibrate.
10. A combination according to claim 1 for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of metabolic disorders, such as obesity and/or obesity related disorders (including, but not limited to, peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome; dermatological conditions such as acne, psoriasis; cardiovascular diseases, such as atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis or vascular stenosis; alzheimer's disease; neoplastic diseases, such as solid tumors, skin cancer, melanoma, lymphoma or endothelial cancers, e.g., breast cancer, lung cancer, colorectal cancer, stomach cancer, other cancers of the gastrointestinal tract (e.g., esophageal cancer or pancreatic cancer), prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer or ovarian cancer.
11. The combination according to claim 10 for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; for the treatment or prevention of obesity and/or obesity related disorders, diabetes or cardiovascular diseases.
12-15. (canceled)
16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a combination according to claim 1 .
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PCT/EP2008/056983 WO2008148840A1 (en) | 2007-06-08 | 2008-06-05 | Piperidine/piperazine derivatives |
PCT/EP2008/057008 WO2008148849A2 (en) | 2007-06-08 | 2008-06-05 | Piperidine/piperazine derivatives |
PCT/EP2008/057011 WO2008148851A1 (en) | 2007-06-08 | 2008-06-05 | Piperidine/piperazine derivatives |
PCT/EP2008/057060 WO2008148868A1 (en) | 2007-06-08 | 2008-06-06 | Piperidine/piperazine derivatives |
EPPCT/EP2008/057060 | 2008-06-06 | ||
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US12/993,491 US9107946B2 (en) | 2008-06-05 | 2009-06-03 | Drug combinations comprising a DGAT inhibitor and a PPAR-agonist |
US14/793,896 US9724418B2 (en) | 2008-06-05 | 2015-07-08 | Drug combinations comprising a DGAT inhibitor and a PPAR-agonist |
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KR100777169B1 (en) | 2001-01-29 | 2007-11-16 | 시오노기세이야쿠가부시키가이샤 | Medicinal preparation containing 5-methyl-1-phenyl-2-1h-pyridone as active ingredient |
JP5467862B2 (en) | 2006-03-31 | 2014-04-09 | ノバルティス アーゲー | New compounds |
JO2972B1 (en) | 2007-06-08 | 2016-03-15 | جانسين فارماسوتيكا ان. في | Piperidine/Piperazine derivatives |
CA2687912C (en) | 2007-06-08 | 2015-11-03 | Janssen Pharmaceutica N.V. | Piperidine/piperazine derivatives |
JP5464709B2 (en) | 2007-06-08 | 2014-04-09 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Piperidine / piperazine derivatives |
RU2470017C2 (en) | 2007-06-08 | 2012-12-20 | Янссен Фармацевтика Н.В. | Piperidine/piperazine derivatives |
AR066169A1 (en) | 2007-09-28 | 2009-07-29 | Novartis Ag | DERIVATIVES OF BENZO-IMIDAZOLES, USEFUL FOR DISORDERS ASSOCIATED WITH THE ACTIVITY OF DGAT |
JP5579170B2 (en) | 2008-06-05 | 2014-08-27 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Pharmaceutical combination comprising a DGAT inhibitor and a PPAR agonist |
WO2011002067A1 (en) * | 2009-07-02 | 2011-01-06 | 武田薬品工業株式会社 | Heterocyclic compound and use thereof |
EP2709609B1 (en) | 2011-05-17 | 2017-10-04 | Shionogi & Co., Ltd. | Heterocyclic compounds |
WO2013049621A1 (en) * | 2011-09-29 | 2013-04-04 | The Board Of Regents Of The University Of Oklahoma | Ophthalmic compositions comprising ppar-alpha agonists and methods of production and use thereof |
AR091858A1 (en) | 2012-07-25 | 2015-03-04 | Sova Pharmaceuticals Inc | CISTATIONIN-g-LIASA INHIBITORS (CSE) |
CA2937365C (en) | 2016-03-29 | 2018-09-18 | F. Hoffmann-La Roche Ag | Granulate formulation of 5-methyl-1-phenyl-2-(1h)-pyridone and method of making the same |
FR3050112B1 (en) | 2016-04-15 | 2020-09-04 | Soc Civ Immobiliere Gecinq | USE OF FENOFIBRIC ACID IN THE TREATMENT OF HEPATIC DISEASES |
CN109153663B (en) * | 2016-05-27 | 2021-08-13 | 百时美施贵宝公司 | Triazolones and tetrazolones as ROCK inhibitors |
EP3558992A4 (en) * | 2016-12-15 | 2020-12-02 | ONO Pharmaceutical Co., Ltd. | Activator of trek (twik related k+ channels) channels |
JP7254703B2 (en) | 2017-01-27 | 2023-04-10 | ジェンフィ | ROR gamma modulators and uses thereof |
CN106957280B (en) * | 2017-03-13 | 2019-02-15 | 洛阳师范学院 | Ether-type aryl bridged piperazine derivatives and its salt, preparation method and the purposes in preparation treatment anti-tumor drug |
KR20200121800A (en) * | 2018-01-05 | 2020-10-26 | 싸이브렉사 1, 인크. | Compounds, compositions and methods for the treatment of diseases related to tissues suffering from acidic or hypoxic diseases |
Family Cites Families (83)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1383906A (en) | 1971-02-22 | 1974-02-12 | Bdh Pharmaceuticals Ltd | Pyridazinones |
JPS5692887A (en) | 1979-12-05 | 1981-07-27 | Sumitomo Chem Co Ltd | N-substituted imidazole derivative |
DE3338846A1 (en) | 1982-10-29 | 1984-05-03 | Toyama Chemical Co. Ltd., Tokyo | NEW 4-OXO-1,4-DIHYDRONICOTINE ACID DERIVATIVES AND SALTS THEREOF, METHOD FOR THEIR PREPARATION AND ANTIBACTERIAL AGENTS WITH A CONTENT THEREOF |
GB8729083D0 (en) | 1987-12-12 | 1988-01-27 | Pfizer Ltd | Triazole antifungal agents |
JP2969359B2 (en) | 1989-01-13 | 1999-11-02 | 武田薬品工業株式会社 | Cyclic amine compounds |
DE4317093A1 (en) | 1993-05-21 | 1994-11-24 | Basf Ag | Low molecular weight and polymeric liquid crystalline benzotriazoles and their use |
TW286317B (en) | 1993-12-13 | 1996-09-21 | Hoffmann La Roche | |
US5639754A (en) | 1994-07-12 | 1997-06-17 | Janssen Pharmaceutica N.V. | Urea and thiourea derivatives of azolones |
FR2722788B1 (en) | 1994-07-20 | 1996-10-04 | Pf Medicament | NOVEL PIPERAZIDES DERIVED FROM ARYL PIPERAZINE, PROCESSES FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME |
KR100233202B1 (en) | 1994-09-30 | 1999-12-01 | 가나이 쓰도무 | Magnetic recording/reproducing device having high-speed reproduction mode |
BR9605309A (en) | 1995-01-11 | 1997-10-14 | Samjin Pharmaceutical Co | Compositions of piperazine derivatives |
AU699148B2 (en) | 1995-08-10 | 1998-11-26 | Merck & Co., Inc. | 2,5-substituted aryl pyrroles, compositions containing such compounds and methods of use |
DE69627006T2 (en) | 1995-08-10 | 2004-01-15 | Merck & Co Inc | 2-SUBSTITUTED ARYL PYRROLS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND THEIR USE |
GB9702213D0 (en) | 1996-02-24 | 1997-03-26 | Zeneca Ltd | Chemical compounds |
HN1997000027A (en) | 1996-12-06 | 1997-06-05 | Pfizer Prod Inc | DERIVATIVES OF 6-PHENYL PIRIDIL - 2 AMINE |
JPH11139969A (en) | 1997-08-07 | 1999-05-25 | Tanabe Seiyaku Co Ltd | Pharmaceutical composition |
DE19743435A1 (en) | 1997-10-01 | 1999-04-08 | Merck Patent Gmbh | Benzamidine derivatives |
CN1309654A (en) | 1998-07-20 | 2001-08-22 | 默克专利股份有限公司 | Biphenyl derivs. |
GB9826412D0 (en) | 1998-12-03 | 1999-01-27 | Glaxo Group Ltd | Chemical compounds |
AUPP999799A0 (en) | 1999-04-27 | 1999-05-20 | Fujisawa Pharmaceutical Co., Ltd. | New compound |
SK16602001A3 (en) | 1999-05-21 | 2003-03-04 | Pfizer Products Inc. | New pharmaceutical combinations for NOS inhibitors |
IL146403A0 (en) | 1999-06-22 | 2002-07-25 | Neurosearch As | Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds |
PE20011089A1 (en) | 2000-02-10 | 2001-10-04 | Pharmacia And Upjhon Company | OXAZOLIDINONE THIOAMIDES WITH PIPERAZIN-AMIDE SUBSTITUTES |
GB0013378D0 (en) * | 2000-06-01 | 2000-07-26 | Glaxo Group Ltd | Use of therapeutic benzamide derivatives |
WO2001095856A2 (en) | 2000-06-15 | 2001-12-20 | Chaconne Nsi Co., Ltd. | Urea derivative useful as an anti-cancer agent and process for preparing same |
GB2363792A (en) | 2000-06-21 | 2002-01-09 | Portela & Ca Sa | Nitrocatechols |
US20030060472A1 (en) | 2000-06-21 | 2003-03-27 | Learmonth David Alexander | Novel substituted nitrocatechols, their use in the treatment of some central and peripheral nervous system disorders and pharmaceutical compositions containing them |
JO2654B1 (en) | 2000-09-04 | 2012-06-17 | شركة جانسين فارماسوتيكا ان. في | Polyarylcarboxamides useful as lipid lowering agents |
US7186683B2 (en) | 2000-09-18 | 2007-03-06 | Sanos Bioscience A/S | Use of GLP for the treatment, prevention, diagnosis, and prognosis of bone-related and nutrition-related disorders |
AUPR201600A0 (en) | 2000-12-11 | 2001-01-11 | Fujisawa Pharmaceutical Co., Ltd. | Quinazolinone derivative |
DE10063008A1 (en) | 2000-12-16 | 2002-06-20 | Merck Patent Gmbh | carboxamide |
NZ526697A (en) | 2001-01-16 | 2005-05-27 | Astrazeneca Ab | Therapeutic heterocyclic compounds |
JO2390B1 (en) | 2001-04-06 | 2007-06-17 | شركة جانسين فارماسوتيكا ان. في | Lipid lowering biphenulcarboxamides |
DE10204116A1 (en) | 2002-02-01 | 2003-08-07 | Bayer Cropscience Ag | DELTA · 1 · -pyrrolines |
KR20040090978A (en) | 2002-03-13 | 2004-10-27 | 얀센 파마슈티카 엔.브이. | Sulfonyl-derivatives as novel inhibitors of histone deacetylase |
CA2476296C (en) | 2002-03-13 | 2011-02-22 | Janssen Pharmaceutica N.V. | Amino-derivatives as inhibitors of histone deacetylase |
WO2003082864A2 (en) | 2002-04-01 | 2003-10-09 | Cadila Healthcare Limited | Antiinfectve compounds, process for their preparation and pharmaceutical compositions containing them |
TWI319387B (en) | 2002-04-05 | 2010-01-11 | Astrazeneca Ab | Benzamide derivatives |
US7842693B2 (en) | 2002-06-12 | 2010-11-30 | Chemocentryx, Inc. | Substituted piperazines |
AU2003253141A1 (en) | 2002-08-22 | 2004-03-11 | Orchid Chemicals And Pharmaceuticals Ltd | Novel antibacterial agents |
AU2003293006A1 (en) | 2002-11-22 | 2004-06-18 | Japan Tobacco Inc. | Fused bicyclic nitrogen-containing heterocycles |
US20040192728A1 (en) | 2003-02-03 | 2004-09-30 | Ellen Codd | Quinoline-derived amide modulators of vanilloid VR1 receptor |
DE10306250A1 (en) * | 2003-02-14 | 2004-09-09 | Aventis Pharma Deutschland Gmbh | Substituted N-aryl heterocycles, processes for their preparation and their use as pharmaceuticals |
US7223788B2 (en) | 2003-02-14 | 2007-05-29 | Sanofi-Aventis Deutschland Gmbh | Substituted N-aryl heterocycles, process for their preparation and their use as medicaments |
AR044152A1 (en) | 2003-05-09 | 2005-08-24 | Bayer Corp | RENTAL DERIVATIVES, METHOD OF PREPARATION AND USE FOR THE TREATMENT OF OBESITY |
EP1635832A2 (en) | 2003-06-06 | 2006-03-22 | Merck & Co., Inc. | Combination therapy for the treatment of diabetes |
KR20060056944A (en) | 2003-07-14 | 2006-05-25 | 아레나 파마슈티칼스, 인크. | Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto |
CA2534675C (en) | 2003-08-11 | 2013-07-23 | F. Hoffmann-La Roche Ag | Piperazine with or-substituted phenyl group and their use as glyt1 inhibitors |
JP2005206492A (en) | 2004-01-21 | 2005-08-04 | Sankyo Co Ltd | Sulfonamide compound |
WO2005072740A2 (en) | 2004-01-30 | 2005-08-11 | Japan Tobacco Inc. | Anorectic compounds |
JP4787529B2 (en) | 2004-04-09 | 2011-10-05 | 大塚製薬株式会社 | Pharmaceutical composition |
WO2006004200A1 (en) | 2004-07-02 | 2006-01-12 | Sankyo Company, Limited | Urea derivative |
MX2007000791A (en) | 2004-08-03 | 2007-03-23 | Wyeth Corp | Indazoles useful in treating cardiovascular diseases. |
CN100360525C (en) | 2004-09-16 | 2008-01-09 | 中国科学院上海药物研究所 | Novel oxazolidone derivative, its preparing method and use |
TW200624427A (en) | 2004-09-20 | 2006-07-16 | Xenon Pharmaceuticals Inc | Heterocyclic derivatives and their use as therapeutic agents |
GB0421908D0 (en) | 2004-10-01 | 2004-11-03 | Angeletti P Ist Richerche Bio | New uses |
WO2006044775A2 (en) | 2004-10-15 | 2006-04-27 | Bayer Pharmaceuticals Corporation | Preparation and use of biphenyl-4-yl-carbonylamino acid derivatives for the treatment of obesity |
CN101437514B (en) | 2004-10-22 | 2012-04-25 | 詹森药业有限公司 | Inhibitors of C-FMS kinase |
NZ555683A (en) * | 2004-12-14 | 2010-09-30 | Astrazeneca Ab | Oxadiazole derivatives as dgat inhibitors |
NZ554516A (en) | 2004-12-22 | 2010-07-30 | Janssen Pharmaceutica Nv | Diacylglycerol acyltransferase assay |
GT200600046A (en) | 2005-02-09 | 2006-09-25 | COMBINATION THERAPY | |
GB0505084D0 (en) | 2005-03-11 | 2005-04-20 | Glaxo Group Ltd | Compounds |
US7759339B2 (en) | 2005-03-31 | 2010-07-20 | Takeda San Diego, Inc. | Hydroxysteroid dehydrogenase inhibitors |
WO2006106326A1 (en) | 2005-04-06 | 2006-10-12 | Astrazeneca Ab | Substituted heterocycles and their use as chk1, pdk1 and pak inhibitors |
AU2006236155A1 (en) | 2005-04-19 | 2006-10-26 | Bayer Pharmaceuticals Corporation | Aryl alkyl acid derivatives for and use thereof |
BRPI0611956A2 (en) * | 2005-06-11 | 2018-07-31 | Astrazeneca Ab | compound, use thereof, pharmaceutical composition, and process for preparing a compound |
EP1904525A4 (en) | 2005-06-30 | 2009-10-21 | Ipsen Pharma | Glp-1 pharmaceutical compositions |
JP2007131584A (en) | 2005-11-11 | 2007-05-31 | Sankyo Co Ltd | New benzoxazole derivative |
EP1966183A4 (en) * | 2005-12-20 | 2010-12-29 | Merck Frosst Canada Ltd | Heteroaromatic compounds as inhibitors of stearoyl-coenzyme a delta-9 desaturase |
JP2009520786A (en) | 2005-12-22 | 2009-05-28 | アストラゼネカ アクチボラグ | Pyrimido- [4,5-B] -oxazine for use as a DGAT inhibitor |
EP1810974A1 (en) | 2006-01-18 | 2007-07-25 | Ludwig-Maximilians-Universität München | Preparation and use of magnesium amides |
TW200804364A (en) | 2006-02-22 | 2008-01-16 | Boehringer Ingelheim Int | New compounds |
US7728031B2 (en) | 2006-02-24 | 2010-06-01 | Abbott Laboratories | Octahydro-pyrrolo[3,4-b]pyrrole derivatives |
JPWO2007102392A1 (en) | 2006-03-03 | 2009-07-23 | 塩野義製薬株式会社 | MMP-13 selective inhibitor |
US8258129B2 (en) | 2006-07-06 | 2012-09-04 | Boehringer Ingelheim International Gmbh | 4-heterocycloalkylpyri(mi)dines, process for the preparation thereof and their use as medicaments |
EP1918285A1 (en) * | 2006-11-03 | 2008-05-07 | Merck Sante | Diazepane-acetamide derivatives as selective 11beta-HSD1 inhibitors |
GB0706793D0 (en) * | 2007-04-05 | 2007-05-16 | Evotec Ag | Compounds |
MX2009012285A (en) * | 2007-05-22 | 2009-12-15 | Via Pharmaceuticals Inc | Diacylglycerol acyltransferase inhibitors. |
JO2972B1 (en) | 2007-06-08 | 2016-03-15 | جانسين فارماسوتيكا ان. في | Piperidine/Piperazine derivatives |
RU2470017C2 (en) * | 2007-06-08 | 2012-12-20 | Янссен Фармацевтика Н.В. | Piperidine/piperazine derivatives |
JP5464709B2 (en) * | 2007-06-08 | 2014-04-09 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Piperidine / piperazine derivatives |
CA2687912C (en) | 2007-06-08 | 2015-11-03 | Janssen Pharmaceutica N.V. | Piperidine/piperazine derivatives |
JP5579170B2 (en) | 2008-06-05 | 2014-08-27 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Pharmaceutical combination comprising a DGAT inhibitor and a PPAR agonist |
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EP2296659B1 (en) | 2016-12-21 |
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US20110112111A1 (en) | 2011-05-12 |
US20150320741A1 (en) | 2015-11-12 |
CA2725933C (en) | 2018-01-16 |
TWI460175B (en) | 2014-11-11 |
US9107946B2 (en) | 2015-08-18 |
AU2009253892A1 (en) | 2009-12-10 |
WO2009147170A2 (en) | 2009-12-10 |
AU2009253892B2 (en) | 2015-07-30 |
AR073450A1 (en) | 2010-11-10 |
US9724418B2 (en) | 2017-08-08 |
JP5579170B2 (en) | 2014-08-27 |
JP2011522000A (en) | 2011-07-28 |
PE20100083A1 (en) | 2010-02-17 |
UY31863A (en) | 2010-01-05 |
CA2725933A1 (en) | 2009-12-10 |
PE20140572A1 (en) | 2014-05-16 |
TW201014846A (en) | 2010-04-16 |
ES2617619T3 (en) | 2017-06-19 |
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