EP1853580A1 - Methylphenylcarbamic acid 5-(4-isobutyl-2,6,-dioxopiperazin-1-yl)pyridinyl-2-yl ester and salts as hormone sensitive lipase inhibitors - Google Patents

Methylphenylcarbamic acid 5-(4-isobutyl-2,6,-dioxopiperazin-1-yl)pyridinyl-2-yl ester and salts as hormone sensitive lipase inhibitors

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Publication number
EP1853580A1
EP1853580A1 EP06708221A EP06708221A EP1853580A1 EP 1853580 A1 EP1853580 A1 EP 1853580A1 EP 06708221 A EP06708221 A EP 06708221A EP 06708221 A EP06708221 A EP 06708221A EP 1853580 A1 EP1853580 A1 EP 1853580A1
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EP
European Patent Office
Prior art keywords
compound
compounds
acid
ester
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06708221A
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German (de)
French (fr)
Inventor
Johannes Cornelis De Jong
Poul Jacobsen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP1853580A1 publication Critical patent/EP1853580A1/en
Withdrawn legal-status Critical Current

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the present invention relates to the novel compounds mentioned in claim 1 , below, to pharmaceutical compositions comprising these compounds, to the use of these compounds as pharmaceutical compositions, and to methods of treatment employing these compounds and compositions.
  • the present compounds show strong inhibition of hormone sensitive lipase. As a result, the compounds are useful for the treatment and/or prevention of diseases and disorders related to hormone sensitive lipase.
  • the overall energy homeostasis of a mammalian system requires a high degree of regulation to ensure the availability of the appropriate substrate at the appropriate time.
  • Plasma glucose levels rise during the post-prandial state, to return to pre-prandial levels within 2-3 hours. During these 2-3 hours, insulin promotes glucose uptake by skeletal muscle and adipose tissue and decreases the release of free fatty acids (FFA) from adipocytes, to ensure that the two substrates do not compete with each other.
  • FFA free fatty acids
  • HSL Hormone-sensitive lipase
  • Insulin leads to the inactivation of HSL with a subsequent fall in plasma FFA levels during the post-prandial state, followed by the activation of the enzyme when the insulin concentration falls and catecholamines rise during the post-absorptive period.
  • the activation of HSL leads to an increase in plasma FFA, as they become the main source of energy during fasting.
  • HSL activation-inactivation of HSL is primarily mediated through the cAMP-protein kinase A and AMP-dependent kinase pathways.
  • cAMP-protein kinase A a compound like nicotinic acid and its derivatives, that decrease the activation of HSL via these pathways and cause a decrease in lipolysis that leads to a reduction in the FFA levels.
  • These drugs have a beneficial effect in the utilization of glucose and in the normalization of the excess triglyceride synthesis seen in patients with elevated FFA. However, since these pathways are used by other processes in the body, these drugs have severe side effects.
  • Formula XXXXIVa-b (claim 266, right hand formula) in the international patent application with the international publication number WO 03/051841 (Novo Nordisk A/S) relates to certain carbamic acid 2-pyridyl esters.
  • WO 2004/111031 (Novo Nordisk A/S) relates to certain methylphenyl- carbamic acid 2-pyridyl esters. None of these two applications mentions specifically the compounds prepared in example 1 or 2 below.
  • the object of this invention is to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative, for example: i) to provide compounds and pharmaceutical compositions that inhibit the lipolytic activity of HSL, ii) provide compounds which have good pharmaceutical properties such as solubility, bioavailability and specificity.
  • treatment means the management and care of a patient having developed a disease, condition or disorder, as well as the management and care of an individual at risk of developing the disease, condition or disorder prior to the clinical onset of said disease, condition or disorder.
  • the purpose of treatment is to combat the disease, condition or disorder, as well as to combat the development of the disease, condition or disorder.
  • Treatment includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.
  • the term "effective amount” as used herein means a dosage which is sufficient in order for the treatment of the patient to be effective compared with no treatment.
  • modulate as used herein means to influence, i.e. to modulate a parameter means to influence that parameter in a desired way. Examples are to modulate insulin secretion from beta cells and to modulate the plasma level of free fatty acids.
  • medicament means a pharmaceutical composition suitable for administration of the pharmaceutically active compound to a patient.
  • pharmaceutically acceptable means suited for normal pharmaceutical applications, i.e. giving rise to no adverse events in patients etc.
  • the present invention relates to the compounds mentioned in claim 1 below.
  • the present invention relates to a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • aspects and features of this invention are the following embodiments a) through bb): a) A pharmaceutical composition as described herein in unit dosage form, comprising from about 0.05 to about 2000 mg, preferably from about 0.1 to about 500 mg and even more preferable from about 1.0 to about 100 mg of said compound according to this invention or pharmaceutically acceptable salt thereof.
  • a compound according to this invention for the preparation of a pharmaceutical composition for the treatment or prevention of any disorder where it is desirable to a) modulate the plasma level of free fatty acids, glycerol, LDL-cholesterol, HDL-cholesterol, insulin and/or glucose; and/or b) modulate intracellular triacylglycerol and cholesterol ester stores, intracellular level of fatty acids, fatty acid esters such as diacylglycerols, phosphatidic acids, long chain acyl-
  • CoA ' as well as citrate or malonyl-CoA; and/or c) increase insulin sensitivity in adipose tissue, skeletal muscle, liver or pancreatic ⁇ cells; and/or d) modulate insulin secretion from pancreatic ⁇ cells.
  • said disorder is selected from the group consisting of insulin resistance, diabetes type 1 , diabetes type 2, metabolic syndrome X, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, atheroschlerosis, hypertension, abnormalities of lipoprotein metabolism and any combination thereof
  • k) The use of a compound according to this invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of hyperlipidemia.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxylnaphthoates, glycerophosphat
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium, zinc, calcium salts and the like.
  • amines and organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethyl- amine, propylamine, butylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N- methyl-D-glucamine, guanidine and the like.
  • cationic amino acids include lysine, arginine, histidine and the like.
  • Acid addition salts wherever applicable are prepared by treatment with strong acids in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
  • Examples of specific salts of the compound of formula I are: a trifluoroacetic acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester; the hydrochloric acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester; hydrobromic acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester; hydroiodic acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester; phosphoric acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2
  • polymorphs of compounds of this invention forming part of this invention may be prepared by crystallization of a compound of this invention under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formula I.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the invention also encompasses active metabolites of the present compounds.
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula I or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.
  • the invention relates to the use of compounds of formula I or their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of disorders where a decreased level of plasma FFA is desirable, such as the conditions mentioned above.
  • the present invention relates to a method of treating and/or preventing type 2 diabetes, insulin resistance, metabolic syndrome X, impaired glucose tolerance, dyslipidemia and abnormalities of lipoprotein metabolism.
  • the present invention relates to the use of one or more compounds of formula I, or pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for the treatment and/or prevention of type 2 diabetes, insulin resistance, metabolic syndrome X, impaired glucose tolerance, dyslipidemia and abnormalities of lipoprotein metabolism.
  • the present compounds are useful for the delaying or prevention of the progression from impaired glucose tolerance to type 2 diabetes.
  • the present compounds are useful for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
  • the present compounds reduce triglyceride levels and are accordingly useful for the treatment and/or prevention of ailments and disorders such as diabetes and/or obesity.
  • the compounds of this invention are useful for the treatment of hyperglycemia, elevated HbA 10 level, hyperinsulinemia, type 1.5 diabetes, latent autoimmune diabetes in adults, maturity onset diabetes, beta-cell apoptosis, hemochromatosis induced diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome X, insulin resistance, impaired lipid tolerance, cystic fibrosis related diabetes, polycystic ovarian syndrome, and gestational diabetes.
  • the compounds of this invention are useful for the treatment of obesity, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, hypertension, essential hypertension, acute hypertensive emergency, arteriosclerosis, atherosclerosis, restenosis, intermittent claudication (atherosclerosis oblitterens), cardiovascular disease, cardiomyopathy, cardiac hypertrophy, left ventricular hypertrophy, coronary artery disease, early coronary artery disease, heart insufficiency, exercise tolerance, chronic heart failure, mild chronic heart failure, arrhythmia, cardiac dysrythmia, syncopy, heart attack, myocardial infarction, Q-wave myocardial infarction, stroke, acute coronary syndrome, angina pectoris, unstable angina, cardiac bypass reocclusion, diastolic dysfunction, systolic dysfunction, non-Q-wave cardiac necrosis, catabolic changes after surgery, acute pancreatitis, and irritable
  • the compounds of this invention are useful for increasing the number of beta-cells in a patient, increasing the size of beta-cells in a patient or stimulating beta-cell proliferation, modulating beta-cell function and insulin secretion in a patient in need thereof, which method comprises administration of an effective amount of a compound of this invention to a patient in need thereof.
  • the compounds of the invention are also useful for reducing body weight in a patient in need thereof.
  • the compounds of the invention are also useful for weight neutral treatment of above mentioned diseases.
  • the compounds of the invention are also useful for redistributing fat in a patient in need thereof.
  • the compounds of the invention are also useful for redistributing central fat in a patient in need thereof.
  • the compounds of the invention are also useful for reducing or preventing central obesity.
  • the compounds of the invention are also useful for reducing postprandial serum lipid excursions.
  • the compounds of the invention are also useful for the treatment of fatty acid oxidation disorders such as MCAD.
  • the compounds of this invention are believed to be useful for the treatment of a disease, condition or disorder wherein cholesterol is a precursor.
  • diseases, conditions or disorders may relate to testosterone, for example, male contraception, excessive testosterone levels, PCOS and prostate cancer. They may also relate to Cortisol or corticotropin, for example, Cushing disease.
  • the compounds of the invention are also useful for the treatment of cancer.
  • the compounds of this invention may be useful for the treatment of insulinoma (pancreatic islet cell tumors), for example, malignant insulinomas and multiple insulinomas, adipose cell carcinomas, for example, lipocarconoma.
  • the compounds of the invention are also useful for the treatment of phaechromocytoma and other diseases with increased catecholamine incretion.
  • the compounds of the invention are also useful for the treatment of prostate cancer, for example, adenocarcinoma.
  • the compounds of this invention may be useful for the treatment of hepatic steatosis.
  • the compounds of this invention may be useful for the treatment of cirrhosis.
  • the compounds of this invention may be useful for the treatment of AIDS or an AIDS related diseases, condition or disorders
  • the compounds of this invention may be useful for the treatment of lipodystrophy
  • the compounds of this invention may be useful for the treatment of lactic acidosis.
  • the compounds of the present invention are expected to be useful for the treatment of CNS diseases, conditions or disorders.
  • the compound of the present invention may be used for the treatment of Parkinson's disease, Alzheimer's disease, ADHD (Attention Deficit Hyperactivity Disorder), feeding disorders such as bulimia and anorexia, depression, anxiety, cognitive memory disorders, age related cognitive decline, mild cognitive impairment and schizophrenia.
  • the compounds of the present invention may be useful for the treatment of inflammatory disorders, for example, rheumatoid arthritis, psoriasis, systemic inflammatory response syndrome, sepsis and the like.
  • the present compounds may also be administered in combination with one or more further pharmacologically active substances, for example, selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • further pharmacologically active substances for example, selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT
  • the antiobesity agent is leptin.
  • the antiobesity agent is dexamphetamine or amphetamine.
  • the antiobesity agent is fenfluramine or dexfenfluramine. In still another embodiment the antiobesity agent is sibutramine.
  • the antiobesity agent is orlistat.
  • the antiobesity agent is mazindol or phentermine.
  • Suitable antidiabetics comprise insulin, exendin-4, GLP-1 (glucagon like peptide-1) and derivatives thereof such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise sulphonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenosis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as HMG CoA inhibitors (statins), compounds lowering food intake, RXR agonists and agents acting on the ATP-dependent potassium channel of the ⁇ -cells.
  • the present compounds are administered in combination with a sulphonylurea, for example, tolbutamide, glibenclamide, glipizide or glicazide.
  • a sulphonylurea for example, tolbutamide, glibenclamide, glipizide or glicazide.
  • the present compounds are administered in combination with a biguanide, for example, metformin.
  • a biguanide for example, metformin.
  • the present compounds are administered in combination with a meglitinide, for example, repaglinide or senaglinide.
  • a meglitinide for example, repaglinide or senaglinide.
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor, for example, miglitol or acarbose.
  • the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the ⁇ -cells, for example, tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells for example, tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
  • the present compounds may be administered in combination with nateglinide.
  • the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent, for example, cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent for example, cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • the present compounds are administered in combination with more than one of the above-mentioned compounds, for example, in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, alatriopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennar
  • any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or more further pharmacologically active substances are considered to be within the scope of the present invention.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well- known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
  • Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
  • composition in unit dosage form comprises from about 0.05 to about 2000 mg, preferably from about 0.1 to about 500 mg of the compound of formula I pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is for oral, nasal, transdermal, pulmonal, or parenteral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • a compound of the invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the compound with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above.
  • Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
  • solutions of the present compounds in sterile aqueous solution aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono- glycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • compositions formed by combining the compounds of the invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
  • These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • a typical tablet which may be prepared by conventional tabletting techniques may in the core contain 5 mg of active compound (as free compound or salt thereof), 1.5 mg of colloidal silicon dioxide (Aerosil), 70 mg of cellulose, microcrystalline (Avicel) and 7.5 mg of modified cellulose gum (Ac-Di-SoI) and magnesium stearate q.s. and a coating with approximately 9 mg of HPMC and approximately 0.9 mg of Mywacett 9-40 T (acylated monoglyceride used as plasticizer for film coating).
  • the compounds of this invention may be administered to a patient which is a mammal, especially a human in need thereof. Such mammals include also animals, both domestic animals, for example, household pets, and non-domestic animals such as wildlife.
  • the present compounds may be administered in combination with further pharmacologically active substances, for example, an antidiabetic or other pharmacologically active material, including other compounds for the treatment and/or prevention of insulin resistance and diseases, wherein insulin resistance is the pathophysiological mechanism.
  • further pharmacologically active substances for example, an antidiabetic or other pharmacologically active material, including other compounds for the treatment and/or prevention of insulin resistance and diseases, wherein insulin resistance is the pathophysiological mechanism.
  • the compounds according to the invention may be administered in combination with antiobesity agents or appetite regulating agents.
  • the compounds of this invention can be prepared by methods known per se. PHARMACOLOGICAL METHODS
  • Compounds of this invention may be evaluated in vitro for their efficacy and potency to inhibit HSL, and such evaluation may be performed as described below.
  • HSL Hormone-sensitive lipase
  • the Hormone-sensitive lipase was provided by Dr. Cecilia Holm, from Lund University
  • the substrates used are: 3 H-labeled triolein (TO) from Amersham, Buckinghamshire, U.K. cat No. TRA191 ; 5-20 Ci/mmol dissolved in toluene, triolein (Sigma, Cat. No.
  • PC phosphatidyl choline
  • Pl phosphatidyl inositol
  • 3190.1 Assay for determination of percent inhibition of hormone sensitive lipase by compound at 10 ⁇ M sample concentration.
  • a lipid emulsion with fluorochrome-labeled triacylglyceride and phospholipid is used as substrate with a standard concentration of highly purified HSL (12 ⁇ g/mL initial concentration corresponding to 600ng/mL final concentration).
  • BSA is added as product acceptor.
  • the transfer of the fluorochrome from the lipid phase to the water (BSA) phase changes the fluorescent properties of the fluorochrome. The changes can be monitored on a fluorimeter with an excitation wavelength of 450nm and an emission wavelength of 545nm.
  • Compound and HSL (20 ⁇ L compound, 10 ⁇ L enzyme and 70 ⁇ L PED-BSA buffer) is pre- incubated for 30min at 25°C before addition of substrate (100 ⁇ L). Amount of formed product is measured after 120min incubation at 37 0 C.
  • Results are given as percent activity relative to a non-inhibited sample (no compound).
  • 3190.2 Assay for determination of IC 50 value for the inhibition of hormone sensitive lipase by compound. Standard concentrations of compound are 100 ⁇ M and 5-fold dilutions (initial concentration corresponding to 10 ⁇ M final concentration and 5-fold). A lipid emulsion with fluorochrome-labeled triacylglyceride and phospholipid is used as substrate with a standard concentration of highly purified HSL (12 ⁇ g/ml_ initial concentration corresponding to 600ng/ml_ final concentration). BSA is added as product acceptor. The transfer of the fluorochrome from the lipid phase to the water (BSA) phase changes the fluorescent properties of the fluorochrome. The changes can be monitored on a fluorimeter with an excitation wavelength of 450nm and an emission wavelength of 545nm.
  • Compound and HSL (20 ⁇ L compound, 10 ⁇ L enzyme and 70 ⁇ L PED-BSA buffer) is pre- incubated for 30 min at 25°C before addition of substrate (100 ⁇ L). Amount of formed product is measured after 120min incubation at 37°C. Results are given as IC 50 values after 4PL fit of obtained activity data.
  • the HPLC pump was connected to two eluent reservoirs containing:
  • the analysis was performed at 40 °C by injecting an appropriate volume of the sample
  • HPLC conditions detector settings and mass spectrometer settings which were used are as follows:

Abstract

Novel methylphenylcarbamic acids, pharmaceutical compositions comprising them and use thereof in the treatment and/or prevention of diseases and disorders related to hormone sensitive lipase. More particularly, the compounds are useful for the treatment and/or prevention of diseases and disorders in which modulation of the activity of hormone sensitive lipase is beneficial.

Description

METHYLPHENYLCARBAMIC ACID
5-(4-ISOBUTYL-2,6,-DIOXOPIPERAZIN-l-YL) PYRIDINYL-2-YL ESTER ANS SALTS AS
HORMONE SENSITIVE LIPASE INHIBITORS
FIELD OF THE INVENTION
The present invention relates to the novel compounds mentioned in claim 1 , below, to pharmaceutical compositions comprising these compounds, to the use of these compounds as pharmaceutical compositions, and to methods of treatment employing these compounds and compositions. The present compounds show strong inhibition of hormone sensitive lipase. As a result, the compounds are useful for the treatment and/or prevention of diseases and disorders related to hormone sensitive lipase.
BACKGROUND OF THE INVENTION
The overall energy homeostasis of a mammalian system requires a high degree of regulation to ensure the availability of the appropriate substrate at the appropriate time. Plasma glucose levels rise during the post-prandial state, to return to pre-prandial levels within 2-3 hours. During these 2-3 hours, insulin promotes glucose uptake by skeletal muscle and adipose tissue and decreases the release of free fatty acids (FFA) from adipocytes, to ensure that the two substrates do not compete with each other. When plasma glucose levels fall, an elevation in plasma FFA is necessary to switch from glucose to fat utilization by the various tissues.
In individuals with insulin resistance, FFA levels do not fall in response to insulin, as they do in normal individuals, preventing the normal utilization of glucose by skeletal muscle, adipose and liver. Furthermore, there is a negative correlation between insulin sensitivity and plasma FFA levels. Hormone-sensitive lipase (HSL) is an enzyme, expressed in adipose tissue, macrophages, muscle, adrenal, testis and islets (Kraemer and Shen, J. Lipid Res. 2002, 43, 1585-1594). In the adipocytes HSL catalyses the conversion of triglycerides to glycerol and fatty acids. It is through the regulation of this enzyme that the levels of circulating FFA are modulated. Insulin leads to the inactivation of HSL with a subsequent fall in plasma FFA levels during the post-prandial state, followed by the activation of the enzyme when the insulin concentration falls and catecholamines rise during the post-absorptive period. The activation of HSL leads to an increase in plasma FFA, as they become the main source of energy during fasting.
The activation-inactivation of HSL is primarily mediated through the cAMP-protein kinase A and AMP-dependent kinase pathways. There are compounds like nicotinic acid and its derivatives, that decrease the activation of HSL via these pathways and cause a decrease in lipolysis that leads to a reduction in the FFA levels. These drugs have a beneficial effect in the utilization of glucose and in the normalization of the excess triglyceride synthesis seen in patients with elevated FFA. However, since these pathways are used by other processes in the body, these drugs have severe side effects. Formula XXXXIVa-b (claim 266, right hand formula) in the international patent application with the international publication number WO 03/051841 (Novo Nordisk A/S) relates to certain carbamic acid 2-pyridyl esters. WO 2004/111031 (Novo Nordisk A/S) relates to certain methylphenyl- carbamic acid 2-pyridyl esters. None of these two applications mentions specifically the compounds prepared in example 1 or 2 below.
The object of this invention is to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative, for example: i) to provide compounds and pharmaceutical compositions that inhibit the lipolytic activity of HSL, ii) provide compounds which have good pharmaceutical properties such as solubility, bioavailability and specificity.
DEFINITIONS
The terms "disease", "condition" and "disorder" as used herein are used interchangeably to specify a state of a patient which is not the normal physiological state of man. The term "treatment" as used herein means the management and care of a patient having developed a disease, condition or disorder, as well as the management and care of an individual at risk of developing the disease, condition or disorder prior to the clinical onset of said disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder, as well as to combat the development of the disease, condition or disorder. Treatment includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.
The term "effective amount" as used herein means a dosage which is sufficient in order for the treatment of the patient to be effective compared with no treatment. The term "modulate" as used herein means to influence, i.e. to modulate a parameter means to influence that parameter in a desired way. Examples are to modulate insulin secretion from beta cells and to modulate the plasma level of free fatty acids.
The term "medicament" as used herein means a pharmaceutical composition suitable for administration of the pharmaceutically active compound to a patient. The term "pharmaceutically acceptable" as used herein means suited for normal pharmaceutical applications, i.e. giving rise to no adverse events in patients etc.
DESCRIPTION OF THE INVENTION
In one aspect, the present invention relates to the compounds mentioned in claim 1 below. In another aspect the present invention relates to a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. Further specific embodiments, aspects and features of this invention are the following embodiments a) through bb): a) A pharmaceutical composition as described herein in unit dosage form, comprising from about 0.05 to about 2000 mg, preferably from about 0.1 to about 500 mg and even more preferable from about 1.0 to about 100 mg of said compound according to this invention or pharmaceutically acceptable salt thereof. b) A pharmaceutical composition as described herein for use as a medicament for inhibiting the lipolytic activity of hormone-sensitive lipase against triacylglycerols, diacylglycerols, cholesterol acyl esters or steroid acyl esters, said composition comprising a compound according to this invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. c) A pharmaceutical composition as described herein which is for oral administration. d) A pharmaceutical composition as described herein which is for nasal, transdermal, pulmonal, or parenteral administration. e) The use of a compound according to this invention for the preparation of a pharmaceutical composition. f) Use of a compound according to this invention for inhibition of hormone sensitive lipase. g) The use of a compound according to this invention for preparation of a pharmaceutical composition for inhibition of the lipolytic activity of hormone-sensitive lipase against triacylglycerols, diacylglycerols, cholesterol acyl esters or steroid acyl esters. h) The use of a compound according to this invention for the preparation of a pharmaceutical composition for the treatment or prevention of any disorder where it is desirable to a) modulate the plasma level of free fatty acids, glycerol, LDL-cholesterol, HDL-cholesterol, insulin and/or glucose; and/or b) modulate intracellular triacylglycerol and cholesterol ester stores, intracellular level of fatty acids, fatty acid esters such as diacylglycerols, phosphatidic acids, long chain acyl-
CoA's as well as citrate or malonyl-CoA; and/or c) increase insulin sensitivity in adipose tissue, skeletal muscle, liver or pancreatic β cells; and/or d) modulate insulin secretion from pancreatic β cells. i) The above use wherein said disorder is selected from the group consisting of insulin resistance, diabetes type 1 , diabetes type 2, metabolic syndrome X, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, atheroschlerosis, hypertension, abnormalities of lipoprotein metabolism and any combination thereof, j) The use of a compound according to this invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of dyslipidemia. k) The use of a compound according to this invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of hyperlipidemia.
I) The use of a compound according to this invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of hyperglycemia. m) The use of a compound according to this invention for lowering HbA10. n) The use of a compound according to this invention for the preparation of a pharmaceutical composition for the treatment and/or prevention impaired glucose tolerance, o) The use of a compound according to this invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of metabolic syndrome X. p) The use of a compound according to this invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of atheroschlerosis. q) The use of a compound according to this invention for the preparation of a pharmaceutical composition for delaying or prevention of the progression from impaired glucose tolerance to diabetes type 2. r) The use of a compound according to this invention for the preparation of a pharmaceutical composition for delaying or prevention of the progression from non-insulin requiring diabetes type
2 to insulin requiring diabetes type 2. s) The use according to any one of the above indications wherein a further antidiabetic, antiobesity, antihypertensive or appetite regulating drug is used. t) The use according to any one of the above indications, wherein metformin is also used. u) The preparation of a pharmaceutical composition for the treatment and/or prevention of diabetes type 2. v) A method of treating a disorder of a patient as described herein where modulation of the activity of hormone-sensitive lipase is desired, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to this invention or a pharmaceutically acceptable salt thereof, w) A method of treating a disorder of a patient as described herein where lowering of the activity of hormone-sensitive lipase is desired, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to this invention or a pharmaceutically acceptable salt thereof, x) The above methods wherein said administration is carried out by the oral, nasal, transdermal, pulmonal, or parenteral route. y) The above methods wherein said disorder is selected from the group consisting of insulin resistance, diabetes type 1 , diabetes type 2, metabolic syndrome X, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, atheroschlerosis, hypertension, abnormalities of lipoprotein metabolism and any combination thereof, z) Any one of the above methods wherein the therapeutically effective amount of the compound is from about 0.05 to about 2000 mg, preferably from about 0.1 to about 500 mg and even more preferable from about 1.0 to about 100 mg of said compound per day. aa) Any one of the above methods wherein a further antidiabetic, antiobesity, antihypertensive or appetite regulating drug is administered to the patient, bb) Any one of the above methods wherein metformin is also administered to the patient. The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxylnaphthoates, glycerophosphates, ketoglutarates and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium, zinc, calcium salts and the like. Examples of amines and organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethyl- amine, propylamine, butylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N- methyl-D-glucamine, guanidine and the like. Examples of cationic amino acids include lysine, arginine, histidine and the like.
Acid addition salts wherever applicable are prepared by treatment with strong acids in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
Examples of specific salts of the compound of formula I are: a trifluoroacetic acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester; the hydrochloric acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester; hydrobromic acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester; hydroiodic acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester; phosphoric acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin- 2-yl ester; sulfuric acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin- 2-yl ester; a nitric acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin- 2-yl ester; formic acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin- 2-yl ester; acetic acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin- 2-yl ester; trichloroacetic acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)- pyridin-2-yl ester; propionic acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 - yl)pyridin-2-yl ester; benzoic acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 - yl)pyridin-2-yl ester; methanesulfonic acid salt of methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxo- piperazin-1 -yl)pyridin-2-yl ester; ethanesulfonic acid salt of methylphenylcarbamic acid 5-(4-isobutyl- 2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester; benzenesulfonic acid salt of methylphenylcarbamic acid 5- (4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester and p-toluenesulfonic acid salt of methylphenyl- carbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester,
Various polymorphs of compounds of this invention forming part of this invention may be prepared by crystallization of a compound of this invention under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula I or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.
Furthermore, the invention relates to the use of compounds of formula I or their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of disorders where a decreased level of plasma FFA is desirable, such as the conditions mentioned above. In another aspect, the present invention relates to a method of treating and/or preventing type 2 diabetes, insulin resistance, metabolic syndrome X, impaired glucose tolerance, dyslipidemia and abnormalities of lipoprotein metabolism.
In a still further aspect, the present invention relates to the use of one or more compounds of formula I, or pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for the treatment and/or prevention of type 2 diabetes, insulin resistance, metabolic syndrome X, impaired glucose tolerance, dyslipidemia and abnormalities of lipoprotein metabolism.
In a still further aspect, the present compounds are useful for the delaying or prevention of the progression from impaired glucose tolerance to type 2 diabetes.
In a still further aspect, the present compounds are useful for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
In another aspect, the present compounds reduce triglyceride levels and are accordingly useful for the treatment and/or prevention of ailments and disorders such as diabetes and/or obesity. In still another aspect, the compounds of this invention are useful for the treatment of hyperglycemia, elevated HbA10 level, hyperinsulinemia, type 1.5 diabetes, latent autoimmune diabetes in adults, maturity onset diabetes, beta-cell apoptosis, hemochromatosis induced diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome X, insulin resistance, impaired lipid tolerance, cystic fibrosis related diabetes, polycystic ovarian syndrome, and gestational diabetes.
In still another aspect, the compounds of this invention are useful for the treatment of obesity, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, hypertension, essential hypertension, acute hypertensive emergency, arteriosclerosis, atherosclerosis, restenosis, intermittent claudication (atherosclerosis oblitterens), cardiovascular disease, cardiomyopathy, cardiac hypertrophy, left ventricular hypertrophy, coronary artery disease, early coronary artery disease, heart insufficiency, exercise tolerance, chronic heart failure, mild chronic heart failure, arrhythmia, cardiac dysrythmia, syncopy, heart attack, myocardial infarction, Q-wave myocardial infarction, stroke, acute coronary syndrome, angina pectoris, unstable angina, cardiac bypass reocclusion, diastolic dysfunction, systolic dysfunction, non-Q-wave cardiac necrosis, catabolic changes after surgery, acute pancreatitis, and irritable bowel syndrome In still another aspect, the compounds of this invention may be useful for the treatment of diabetic retinopathy, background retinopathy, preproliferative retinopathy, proliferative retinopathy, macular edema, cataracts, nephropathy, nephrotic syndrome, diabetic nephropathy, microalbuminuria, macroalbuminuria, neuropathy, diabetic neuropathy, distal symmetrical sensorimotor polyneuropathy, and diabetic autonomic neuropathy.
In still another aspect, the compounds of this invention are useful for increasing the number of beta-cells in a patient, increasing the size of beta-cells in a patient or stimulating beta-cell proliferation, modulating beta-cell function and insulin secretion in a patient in need thereof, which method comprises administration of an effective amount of a compound of this invention to a patient in need thereof.
The compounds of the invention are also useful for reducing body weight in a patient in need thereof.
The compounds of the invention are also useful for weight neutral treatment of above mentioned diseases. The compounds of the invention are also useful for redistributing fat in a patient in need thereof.
The compounds of the invention are also useful for redistributing central fat in a patient in need thereof.
The compounds of the invention are also useful for reducing or preventing central obesity. The compounds of the invention are also useful for reducing postprandial serum lipid excursions.
The compounds of the invention are also useful for the treatment of fatty acid oxidation disorders such as MCAD. In still another aspect, the compounds of this invention are believed to be useful for the treatment of a disease, condition or disorder wherein cholesterol is a precursor. Such diseases, conditions or disorders may relate to testosterone, for example, male contraception, excessive testosterone levels, PCOS and prostate cancer. They may also relate to Cortisol or corticotropin, for example, Cushing disease.
The compounds of the invention are also useful for the treatment of cancer. Thus, the compounds of this invention may be useful for the treatment of insulinoma (pancreatic islet cell tumors), for example, malignant insulinomas and multiple insulinomas, adipose cell carcinomas, for example, lipocarconoma. The compounds of the invention are also useful for the treatment of phaechromocytoma and other diseases with increased catecholamine incretion.
The compounds of the invention are also useful for the treatment of prostate cancer, for example, adenocarcinoma.
In still another aspect, the compounds of this invention may be useful for the treatment of hepatic steatosis.
In still another aspect, the compounds of this invention may be useful for the treatment of cirrhosis.
In still another aspect, the compounds of this invention may be useful for the treatment of AIDS or an AIDS related diseases, condition or disorders In still another aspect, the compounds of this invention may be useful for the treatment of lipodystrophy
In still another aspect, the compounds of this invention may be useful for the treatment of lactic acidosis.
In yet another aspect, the compounds of the present invention are expected to be useful for the treatment of CNS diseases, conditions or disorders.
Thus, the compound of the present invention may be used for the treatment of Parkinson's disease, Alzheimer's disease, ADHD (Attention Deficit Hyperactivity Disorder), feeding disorders such as bulimia and anorexia, depression, anxiety, cognitive memory disorders, age related cognitive decline, mild cognitive impairment and schizophrenia. In yet another aspect, the compounds of the present invention may be useful for the treatment of inflammatory disorders, for example, rheumatoid arthritis, psoriasis, systemic inflammatory response syndrome, sepsis and the like.
The present compounds may also be administered in combination with one or more further pharmacologically active substances, for example, selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
Thus, in a further aspect of the invention the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents. Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR (retinoid X receptor) modulators or TR β agonists.
In one embodiment of the invention the antiobesity agent is leptin.
In another embodiment the antiobesity agent is dexamphetamine or amphetamine.
In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine. In still another embodiment the antiobesity agent is sibutramine.
In a further embodiment the antiobesity agent is orlistat.
In another embodiment the antiobesity agent is mazindol or phentermine.
Suitable antidiabetics comprise insulin, exendin-4, GLP-1 (glucagon like peptide-1) and derivatives thereof such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
The orally active hypoglycaemic agents preferably comprise sulphonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenosis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as HMG CoA inhibitors (statins), compounds lowering food intake, RXR agonists and agents acting on the ATP-dependent potassium channel of the β-cells. In one embodiment of the invention the present compounds are administered in combination with insulin.
In a further embodiment the present compounds are administered in combination with a sulphonylurea, for example, tolbutamide, glibenclamide, glipizide or glicazide.
In another embodiment the present compounds are administered in combination with a biguanide, for example, metformin.
In yet another embodiment the present compounds are administered in combination with a meglitinide, for example, repaglinide or senaglinide. In a further embodiment the present compounds are administered in combination with an α-glucosidase inhibitor, for example, miglitol or acarbose.
In another embodiment the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the β-cells, for example, tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
Furthermore, the present compounds may be administered in combination with nateglinide.
In still another embodiment the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent, for example, cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine. In a further embodiment the present compounds are administered in combination with more than one of the above-mentioned compounds, for example, in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, alatriopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
It should be understood that any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or more further pharmacologically active substances are considered to be within the scope of the present invention. The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen. Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well- known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
The therapeutic dose of the compound will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art. The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. In one embodiment the composition in unit dosage form, comprises from about 0.05 to about 2000 mg, preferably from about 0.1 to about 500 mg of the compound of formula I pharmaceutically acceptable salt thereof.
In a still further embodiment the pharmaceutical composition is for oral, nasal, transdermal, pulmonal, or parenteral administration.
For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration. The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of the invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the compound with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
For parenteral administration, solutions of the present compounds in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono- glycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
The pharmaceutical compositions formed by combining the compounds of the invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion. If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. A typical tablet which may be prepared by conventional tabletting techniques may in the core contain 5 mg of active compound (as free compound or salt thereof), 1.5 mg of colloidal silicon dioxide (Aerosil), 70 mg of cellulose, microcrystalline (Avicel) and 7.5 mg of modified cellulose gum (Ac-Di-SoI) and magnesium stearate q.s. and a coating with approximately 9 mg of HPMC and approximately 0.9 mg of Mywacett 9-40 T (acylated monoglyceride used as plasticizer for film coating). The compounds of this invention may be administered to a patient which is a mammal, especially a human in need thereof. Such mammals include also animals, both domestic animals, for example, household pets, and non-domestic animals such as wildlife.
In a further aspect of the invention, the present compounds may be administered in combination with further pharmacologically active substances, for example, an antidiabetic or other pharmacologically active material, including other compounds for the treatment and/or prevention of insulin resistance and diseases, wherein insulin resistance is the pathophysiological mechanism.
Furthermore, the compounds according to the invention may be administered in combination with antiobesity agents or appetite regulating agents.
The compounds of this invention can be prepared by methods known per se. PHARMACOLOGICAL METHODS
Compounds of this invention may be evaluated in vitro for their efficacy and potency to inhibit HSL, and such evaluation may be performed as described below.
ASSAYS
Hormone-sensitive lipase (HSL)
Materials. The Hormone-sensitive lipase was provided by Dr. Cecilia Holm, from Lund University
Sweden or produced and purified by Novo Nordisk (NN) using the reagents and protocols used by Dr. Holm. The substrates used are: 3H-labeled triolein (TO) from Amersham, Buckinghamshire, U.K. cat No. TRA191 ; 5-20 Ci/mmol dissolved in toluene, triolein (Sigma, Cat. No. T-1740), fluorochrome- labeled triacylglyceride (c/s-octadec-9-enoic acid 2-[12-(7-nitrobenzo[1 ,2,5]oxadiazol-4-ylamino)- dodecanoyloxyl-i -c/s-octadec-θ-enoyloxymethylethyl ester) prepared by Novo Nordisk (NN) by conventional methods, and 1 ,3-(di[3H]-stearin), 2-(PEG-Biotin)glycerol prepared in collaboration with Amersham Pharmacia Biotech, UK and described in WO 01/073442. Phosphatidyl choline (PC) and phosphatidyl inositol (Pl) are from Sigma (St Luis MO cat. Nos. P-3556 and P-5954, respectively). All other reagents are of commercial grade and obtained from various commercial sources.
Methods.
3190.1 : Assay for determination of percent inhibition of hormone sensitive lipase by compound at 10μM sample concentration. A lipid emulsion with fluorochrome-labeled triacylglyceride and phospholipid is used as substrate with a standard concentration of highly purified HSL (12μg/mL initial concentration corresponding to 600ng/mL final concentration). BSA is added as product acceptor. The transfer of the fluorochrome from the lipid phase to the water (BSA) phase changes the fluorescent properties of the fluorochrome. The changes can be monitored on a fluorimeter with an excitation wavelength of 450nm and an emission wavelength of 545nm.
Compound and HSL (20μL compound, 10μL enzyme and 70μL PED-BSA buffer) is pre- incubated for 30min at 25°C before addition of substrate (100μL). Amount of formed product is measured after 120min incubation at 370C.
Results are given as percent activity relative to a non-inhibited sample (no compound).
3190.2: Assay for determination of IC50 value for the inhibition of hormone sensitive lipase by compound. Standard concentrations of compound are 100μM and 5-fold dilutions (initial concentration corresponding to 10μM final concentration and 5-fold). A lipid emulsion with fluorochrome-labeled triacylglyceride and phospholipid is used as substrate with a standard concentration of highly purified HSL (12μg/ml_ initial concentration corresponding to 600ng/ml_ final concentration). BSA is added as product acceptor. The transfer of the fluorochrome from the lipid phase to the water (BSA) phase changes the fluorescent properties of the fluorochrome. The changes can be monitored on a fluorimeter with an excitation wavelength of 450nm and an emission wavelength of 545nm.
Compound and HSL (20μL compound, 10μL enzyme and 70μL PED-BSA buffer) is pre- incubated for 30 min at 25°C before addition of substrate (100μL). Amount of formed product is measured after 120min incubation at 37°C. Results are given as IC50 values after 4PL fit of obtained activity data.
For the compound prepared in example 1 below (methylphenylcarbamic acid 5-(4-isobutyl-2,6- dioxopiperazin-1 -yl)pyridin-2-yl ester), the IC50 value was 23 nM.
HPLC-MS
The following instrumentation was used: - Hewlett Packard series 1100 G1312A Bin Pump
- Hewlett Packard series 1100 Column compartment
- Hewlett Packard series 1100 G13 15A DAD diode array detector
- Hewlett Packard series 1100 MSD
- Sedere 75 Evaporative Light Scattering detector
The instrument was controlled by HP Chemstation software.
The HPLC pump was connected to two eluent reservoirs containing:
A: 0.05% TFA in water
B: 0.05% TFA in acetonitrile
The analysis was performed at 40 °C by injecting an appropriate volume of the sample
(preferably 1 μl) onto the column, which is eluted with a gradient of acetonitrile.
After the DAD the flow is divided yielding approximately 1 ml_/min to the ELS and 0.5 ml_/min to the MS.
The HPLC conditions, detector settings and mass spectrometer settings which were used are as follows:
Method A:
Column Waters Xterra MS Ci8 5μm 3 mm id x 50 mm
Gradient 5% - 100% acetonitrile linear during 7.5 min at 1.5ml/min
Detection 210 nm (analogue output from DAD) ELS (analogue output from ELS) MS lonisation mode API-ES, Scan 100-1000 amu step 0.1 amu
Example 1
Methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester
A solution of (carboxymethylisobutylamino)acetic acid trifluoroacetic acid salt (17.0 g, 56.1 mmol), triethylamine (7.8 mL, 56.1 mmol) and 1 ,1 '-carbonyldiimidazole (20.0 g, 123 mmol) in tetra- hydrofuran (200 mL) was heated to reflux for 15 minutes. Methylphenyl-carbamic acid 5-aminopyridin-
2-yl ester (13.6 g, 56.1 mmol) was added and reflux was continued for 1 hour. Extra 1 ,1 '-carbonyldi- imidazole was added in small portions until complete conversion was observed (HPLC-MS). The solvent was evaporated in vacuo and the residue was filtered over a short pad of silica gel (ethyl acetate/dichloromethane 50/50). Evaporation of the solvent yielded a solid, which was crystallised twice from ethyl acetate/heptane, yielding the title compound (12.14 g, 55% yield). Melting point: 124-
125 0C.
1H NMR (400 MHz, CDCI3): S= 0.96 (d, 6H), 1.82 (m, 1 H), 2.29 (d, 2H), 3.43 (br.s, 3H), 3.52 (s, 4H),
7.13 (br.s, 1 H), 7.27 (m, 1 H), 7.39 (m, 4H), 7.56 (br.d, 1 H), 8.17 (s, 1 H); HPLC-MS (Method A): mlz =
397 (MH-H)+; Rt = 3.59 min.
Example 2
Methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester trifluoroacetic acid salt
Step A
A solution of Λ/-((tert-butyloxy)carbonyl)iminodiacetic acid (4.66 g, 20.0 mmol) in Λ/,Λ/-dimethyl- formamide (150 mL) was treated with 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.95 g, 20.6 mmol) at room temperature. Stirring was continued for 1 hour followed by the addition of methylphenylcarbamic acid 5-aminopyridin-2-yl ester (4.87 g, 20.0 mmol). After stirring overnight 1 ,1 '- carbonyldiimidazole (3.24 g, 20.0 mmol) was added to the reaction mixture. Stirring was continued for 1 hour and most of the solvent was removed by evaporation in vacuo (around 100 mL). Water (300 mL) was added slowly, while cooling the solution in an ice-bath. The solids were collected by suction, washed twice with water and dried overnight in a vacuum oven at 50 0C, yielding 4-[6-(methylphenyl- carbamoyloxy)pyridin-3-yl]-3,5-dioxopiperazine-1 -carboxylic acid te/t-butyl ester (6.65 g, 74% yield).
Step B
A solution of 4-[6-(methylphenylcarbamoyloxy)pyridin-3-yl]-3,5-dioxopiperazine-1 -carboxylic acid tert- butyl ester (6.34 g, 14.4 mmol) in 10% trifluoroacetic acid in dichloromethane (100 mL) was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo, yielding a thick oil. The residue was dissolved in a small amount of dichloromethane. Ether was added slowly with stirring, yielding a white solid, which was isolated by suction, washed with ether and dried in a vacuum oven, yielding methylphenylcarbamic acid 5-(2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester trifluoroacetic acid salt (6.02 g, 92% yield).
Step C
A solution of methylphenylcarbamic acid 5-(2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester trifluoroacetic acid salt (50 mg, 0.11 mmol), sodium hydrogencarbonate (23 mg, 0.28 mmol), 1 -bromo-2-methyl- propane (60 mg, 0.44 mmol) and a catalytic amount of sodium iodide in Λ/,Λ/-dimethylformamide (1 ml_) was stirred overnight at 80 0C. The product was purified by preparative HPLC, yielding the title compound (15 mg, 27% yield) as an oil.
1H NMR (300 MHz, CDCI3): δ= 0.95 (d, 6H), 1.82 (m, 1 H), 2.31 (d, 2H), 3.44 (br.s, 3H), 3.54 (s, 4H), 7.16 (br.s, 1 H), 7.27 (m, 1 H), 7.37 (m, 4H), 7.56 (br.d, 1 H), 8.17 (s, 1 H); HPLC-MS (Method A): mlz = 397 (MH-H)+; Rt = 3.98 min.

Claims

1. A compound of formula I
also designated methylphenylcarbamic acid 5-(4-isobutyl-2,6-dioxopiperazin-1 -yl)pyridin-2-yl ester or a pharmaceutically acceptable salt thereof.
2. A compound according to the previous claim which is a salt of the compound of formula I.
3. A compound according to the previous claim which is any one of the specific salts mentioned specifically above, taken one by one.
4. The use of a compound of formula I or a pharmaceutically acceptable salt thereof as medicament (or a compound of formula I or a pharmaceutically acceptable salt thereof for use as a medicament).
5. The use of a compound of formula I or a pharmaceutically acceptable salt thereof for preparing a medicament for treatment of any of the diseases mentioned above.
6. A pharmaceutical composition comprising a compound as defined in any one of the preceding compound claims together with a pharmaceutically acceptable carrier or diluent.
7. A pharmaceutical composition according to any one of the above embodiments a) through d).
8. A use according to any one of the above embodiments e) through t).
9. The preparation according to the above embodiment u).
10. A method according to any one of the above embodiments v) through bb).
11. Any novel feature or combination of features described herein.
EP06708221A 2005-02-15 2006-02-13 Methylphenylcarbamic acid 5-(4-isobutyl-2,6,-dioxopiperazin-1-yl)pyridinyl-2-yl ester and salts as hormone sensitive lipase inhibitors Withdrawn EP1853580A1 (en)

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