WO2011151434A1 - Nouveaux composés, leurs compositions pharmaceutiques et méthodes d'utilisation dans le traitement de troubles métaboliques - Google Patents

Nouveaux composés, leurs compositions pharmaceutiques et méthodes d'utilisation dans le traitement de troubles métaboliques Download PDF

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Publication number
WO2011151434A1
WO2011151434A1 PCT/EP2011/059179 EP2011059179W WO2011151434A1 WO 2011151434 A1 WO2011151434 A1 WO 2011151434A1 EP 2011059179 W EP2011059179 W EP 2011059179W WO 2011151434 A1 WO2011151434 A1 WO 2011151434A1
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Prior art keywords
cyclopropyl
phenyl
thiazol
amino
cyclopentylmethyl
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PCT/EP2011/059179
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English (en)
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Hamid Hoveyda
Guillaume Dutheuil
Mohamed El Bousmaqui
Jérôme BERNARD
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Euroscreen S.A.
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Publication of WO2011151434A1 publication Critical patent/WO2011151434A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to novel compounds including their pharmaceutically acceptable salts, solvates and prodrugs, which are useful as therapeutic compounds, particularly in the treatment and/or prevention of type 2 diabetes mellitus and conditions that are often associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.
  • Type 2 diabetes mellitus is an increasing, worldwide public health problem associated with devastating pathologies such as lipid disorders including dyslipidemia, hypertension, obesity, and atherosclerosis (Wild et al, Diabetes Care 27, pp 1047-1053, 2004).
  • T2D is primarily characterized by insulin resistance and hyperglycemia.
  • Insulin resistance is defined as a decreased response of peripheral tissues to insulin action. Insulin resistance has been recognized as an integral feature of metabolic syndrome, a condition encompassing glucose intolerance, obesity, dyslipidemia and atherosclerosis.
  • Hyperinsulinemia and delayed clearance of glucose in an oral glucose tolerance test (OGTT) are hallmarks of insulin resistance in patients.
  • Dyslipidemia is characterized by high levels of triglycerides and/or LDL (bad cholesterol) or low levels of HDL (good cholesterol). Dyslipidemia is a key risk factor for cardiovascular diseases.
  • Drug therapies are available to address both T2D and dyslipidemia. Specifically, statins, fibrates and nicotinic acid or combinations thereof are often considered as a first line therapy in dyslipidemia whereas metformin, sulphonylureas and thiazolidinediones are three, widely-used classes of oral anti-diabetic drugs (Tenenbaum et al., Cardiovascular Diabetology, 5, pp20-23, 2006). Although theses therapies are widespread in their use, the common appearance of adverse effects or lack of efficacy after long-term use causes concern. Moreover, the growing patient population suffering from T2D, dyslipidemia and associated metabolic diseases creates a demand for new entrants able to overcome the limitations of the current therapeutics.
  • T2D patients having T2D have a resistance to the effects of insulin in stimulating glucose and lipid metabolisms in the main insulin-sensitive tissues, which are muscle, liver and adipose tissue. Therefore the compounds of the invention showing benefit in both glucose and lipid metabolisms, represent a real advantage and an added value for the treatment of T2D and conditions that are often associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.
  • the invention encompasses compounds of general Formula I, their pharmaceutically acceptable salts and solvates as well as methods of use of such compounds or compositions.
  • the compounds of the invention are generally disclosed by the application WO 2010/066682 but none is specifically exemplified therein.
  • the invention provides compounds of general formula
  • W is C or N;
  • X is CH or N;
  • Y is CH, or Y is N under the condition that X is CH;
  • R 1 is C3-C4 alkyl or C3-C6 cycloalkyl;
  • R 1 is H or methyl;
  • R 2 is C 1 -C4 alkyl or C3-C5 cycloalkyl
  • R 3 is H, methyl, or methoxy
  • R 4 is selected from (i) -OR 7 , (ii) dimethylamino, (iii) 5-membered heterocyclyl, (iv) 5- membered heteroaryl, each of said heterocyclyl or heteroaryl ring may be further substituted by: a) one or two methyl group(s), and/or
  • R 4 forms together with R 3 a 5 to 6-membered heterocyclyl or 5-membered heteroaryl ring fused to the heteroaryl moiety they are attached to, each of said 5 to 6-membered heterocyclyl or 5-membered heteroaryl ring may be further substituted by: d) one, two or three methyl group(s), and/or
  • R 5 is H or fluoro when W is C or R 5 is absent when W is N;
  • R 6 is H, fluoro, chloro, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy or C 1 -C 2 haloalkoxy;
  • R 7 is methyl, C 1 -C3 alkyloxyethyl optionally substituted by one methyl group.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the invention further provides methods of treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH) comprising the administration of a therapeutically effective amount of a compound or pharmaceutically acceptable salt, solvate or prodrug of formula (I), to a patient in need thereof.
  • the patient is a warm-blooded animal, more preferably a human.
  • the invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof as a medicament.
  • the medicament is used for the treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, , metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).
  • NASH nonalcoholic steatohepatitis
  • the disease is type II diabetes, a lipid disorder such as dyslipidemia, hypertension, obesity, or atherosclerosis and its sequelae.
  • the invention relates to compounds of formula I, as well as their pharmaceutically acceptable salts, solvates and prodrugs.
  • Preferred compounds of formula I and pharmaceutically acceptable salts, solvates, and prodrugs thereof are those wherein:
  • W is C; and/or Y is CH; and/or
  • R 1 is propan-l-yl, propan-2-yl, cyclopropyl, cyclobutyl or cyclopentyl, preferably R 1 is propan-l-yl, propan-2-yl or cyclopentyl; and/or
  • R 1 is H
  • R 2 is cyclopropyl
  • R 3 forms together with R 4 a pyrrolidinyl, oxazolidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl or triazolyl moiety fused to the heteroaryl ring they are attached to, each of said moieties being optionally substituted by one oxo group and/or up to three methyl groups, or R 3 is methyl and R 4 is methoxy, or R 3 is H and R 4 is methoxy, (2- methoxyethyl)oxy optionally substituted by one methyl group, (2-isopropoxyethyl)oxy, dimethylamino, 2-oxopyrrolidin-l-yl optionally substituted by one methyl or one or two fluoro group(s), pyrazol-l-yl, 3,5-dimethylpyrazol-l-yl, preferably R 3 forms together with R 4 a 2-oxopyrrolidinyl, 2-oxo-oxazolidiny
  • R 5 is H or fluoro, and/or
  • R 6 is H, fluoro, chloro, methoxy, -OCHF 2 , -OCF 3 , preferably R 6 is H or chloro, more preferably R 6 is H.
  • preferred compounds of Formula I are those of formula la:
  • W is as defined above in respect to formula I, preferably W is C;
  • R 1 is as defined above in respect to formula I, preferably R 1 is propan-l-yl, propan-2-yl, cyclopropyl, eye lo butyl or cyclopentyl, more preferably R 1 is propan-l-yl, propan-2-yl or cyclopentyl;
  • R 3 and R 4 are as defined above in respect to formula I, preferably R 3 forms together with R 4 a 1 ,3 , 3-trimethyl-2-oxopyrrolidinyl, N-methyl-2-oxo-oxazolidinyl, 1 ,4-dimethyl-2- oxopiperazinyl, 4-methyl-3-oxomorpholinyl, N-methylpyrrolyl, 1-methylpyrazolyl or 1- methyltriazolyl moiety fused to the heteroaryl ring they are attached to, or R 3 is methyl and R 4 is methoxy, or R 3 is H and R 4 is methoxy, (2-methoxyethyl)oxy, (S)-2- methoxypropoxy, ((R)- 1 -methoxypropan-2-yl)oxy, (2-isopropoxyethyl)oxy, dimethylamino, 2-oxopyrrolidin-l-yl, 3-methyl-2-oxopyrrolidin-yl, 3-methyl
  • R 3 forms together with R 4 a l,3,3-trimethyl-2-oxopyrrolidinyl, N-methyl-2-oxo- oxazo lidinyl , 1 , 4-dimethyl-2-oxopiperazinyl, 4-methyl-3-oxomorpholinyl, N- methylpyrrolyl when X is N, 1-methylpyrazolyl or 1-methyltriazolyl moiety fused to the heteroaryl ring they are attached to; or R 3 is methyl and R 4 is methoxy; or
  • R 3 is H and R 4 is methoxy when R 1 is propan-l-yl, propan-2-yl, cyclopropyl, eye lo butyl, or when one of X or Y is N,
  • R 3 is H and R 4 is (2-methoxyethyl)oxy, (S)-2-methoxypropoxy, ((R)-l-methoxypropan-2- yl)oxy, (2-isopropoxyethyl)oxy; or
  • R 3 is H and R 4 is dimethylamino when X is N; or
  • R 3 is H and R 4 is 2-oxopyrrolidin-l-yl when R 1 is propan-2-yl or cyclobutyl or when R 1 is cyclopentyl and X is N; or
  • R 3 is H and R 4 is 3-methyl-2-oxopyrrolidin-l-yl, 3-fluoro-2-oxopyrrolidin-l-yl, pyrazol-1- yl, 3,5-dimethylpyrazol-l-yl; still more preferably R 3 forms together with R 4 a N-methyl-2-oxo-oxazolidinyl, N- methylpyrrolyl when X is N, 1-methylpyrazolyl moiety fused to the heteroaryl ring they are attached to, or
  • R 3 is methyl and R 4 is methoxy, or
  • R 3 is H and R 4 is methoxy when R 1 is propan-l-yl, propan-2-yl, cyclopropyl, cyclobutyl, or when one of X or Y is N; or
  • R 3 is H and R 4 is (2-methoxyethyl)oxy, (S)-2-methoxypropoxy, ((R)-l-methoxypropan-2- yl)oxy, 2-oxopyrrolidin-l-yl, 3,5-dimethylpyrazol-l-yl, even more preferably R 3 forms together with R 4 a N-methylpyrrolyl moiety fused to the heteroaryl ring it is attached to when X is N, or
  • R 3 is H and R 4 is dimethylamino when X is N; or
  • R 3 is H and R 4 is methoxy when R 1 is propan-l-yl, propan-2-yl, cyclopropyl, cyclobutyl, or when one of X or Y is N; or R 3 is H and R 4 is (2-methoxyethyl)oxy or 2-oxopyrrolidin-l-yl;
  • R 5 is as defined above in respect to formula I, preferably R 5 is H;
  • R 6 is H, fluoro, chloro, methoxy, -OCHF 2 , -OCF 3 , preferably R 6 is H or chloro, more preferably R 6 is H.
  • Preferred compounds of formula la are those of formulae Ia-1, Ia-2, Ib-1 and Ib-2
  • Preferred compounds of formulae Ia-1, and Ia-2 are those wherein one of X or Y is N and the other one is CH.
  • Preferred compounds of formulae Ib-1, and Ib-2 are those wherein both X and Y are CH.
  • Preferred compounds of formulae Ia-3 and Ia-4 are those wherein one of X or Y is N and the other one is CH.
  • Preferred compounds of formulae Ib-3, and Ib-4 are those wherein both X and Y are CH.
  • Preferred compounds of formulae Ia-5 and Ia-6 are those wherein one of X or Y is N and the other one is CH.
  • Preferred compounds of formulae Ib-5 and Ib-6 are those wherein both X and Y are CH.
  • Preferred compounds of formula Ia-7 are those wherein W is C and R 5 is H, preferably those wherein W is C and R 5 is H and one of X or Y is N and the other one is CH.
  • the compounds of formula I can be prepared by different ways with reactions known by the person skilled in the art. Reaction schemes as described in the example section illustrate by way of example different possible approaches.
  • the compounds of the invention are therefore useful in the prevention and/or treatment of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).
  • dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance,
  • Preferred diseases are type II diabetes, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.
  • the diseases are type II diabetes and a lipid disorder such as dyslipidemia.
  • the invention also provides for a method for delaying in patient the onset of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH) comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt, solvate, and prodrug thereof to a patient in need thereof.
  • dyslipidemia such as mixed or diabetic dyslipidemia, hyper
  • the patient is a warm-blooded animal, more preferably a human.
  • the invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for treating a patient and/or preventing a patient from developing a disease selected from the group consisting of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).
  • a disease selected from the group consisting of type II diabetes, obesity, dys
  • Preferred diseases are type II diabetes, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.
  • the disease are type II diabetes and a lipid disorder such as dyslipidemia.
  • the patient is a warm-blooded animal, more preferably a human.
  • the compounds of the invention may be administered as part of a combination therapy.
  • compositions and medicaments which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt, solvate, or prodrug thereof as active ingredient, additional therapeutic agents and/or active ingredients.
  • Such multiple drug regimens may be used in the treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).
  • the use of such combinations of therapeutic agents is especially pertinent with respect to the treatment of the above-mentioned list of diseases within a patient in need of treatment or one at risk of becoming such a patient.
  • the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of Formula I or their pharmaceutical acceptable salts, solvates, or prodrugs in the form of monotherapy, but said methods and compositions may also be used in the form of multiple therapy in which one or more compounds of Formula I or their pharmaceutically acceptable salts, solvates, or prodrugs are coadministered in combination with one or more other therapeutic agents such as those described in detail further herein.
  • Examples of other active ingredients that may be administered in combination with a compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and either administered separately or in the same pharmaceutical composition include but are not limited to:
  • PPARy agonists and partial agonists including both glitazones and non- glitazones (e. g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY-300512 and LY-818;
  • glitazones and non- glitazones e. g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY-300512 and LY-818;
  • Dipeptidyl peptidase IV (DP-IV) inhibitor such as MK-0431 and LAF-237;
  • a-glucosidase inhibitors such as acarbose
  • agents which improve a patient's lipid profile such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins), (ii) bile acid sequestrants (cholestyramine, colestipol and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) cholesterol absorption inhibitors such as for example ezetimibe, (vi) acyl CoAxholesterol acyltransferase (ACAT)inhibita
  • PPARa/ ⁇ dual agonists such as muraglitazar, tesaglitazar, farglitazar and JT-501;
  • PPAR5 agonists such those disclosed in W097/28149;
  • Antiobesity compounds such as fenfluramine, dextenfluramine, phentiramine, subitramine, orlistat, neuropeptide Y5 inhibitors, MC4R agonists, cannabinoid receptor 1 antagonists/inverse agonists and ⁇ 3 adrenergic receptor agonists;
  • (m)Agents intended for use in inflammatory conditions such as aspirin, nonsteroidal, anti-inflammatory drugs, glucocorticoids, azulfidine and cyclo- oxygenase 2 selective inhibitors;
  • the above combinations include combinations of a compound of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof not only with one other active compound but also with two or more active compounds.
  • Non limiting examples include combinations of compounds having Formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPAR agonists, PTP-1B inhibitors, DP-IV inhibitors and anti-obesity compounds.
  • the compound of Formula I, a pharmaceutically acceptable salt, solvate, or prodrug thereof and other therapeutic active agents may be administered in terms of dosage forms either separately or in conjunction with each other, and in terms of their time of administration, either serially or simultaneously.
  • the administration of one component agent may be prior to, concurrent with, or subsequent to the administration of the other component agent(s).
  • the invention also provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
  • the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt, solvate, or prodrug thereof as active ingredient, additional therapeutic agents and/or active ingredients.
  • Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as active ingredient.
  • the invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the manufacture of a medicament.
  • the medicament is used for treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).
  • NASH nonalcoholic steatohepatitis
  • Preferred diseases are type II diabetes, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.
  • the disease are type II diabetes and a lipid disorder such as dyslipidemia.
  • the compounds of the invention may be used in monotherapy or in combination therapy.
  • the invention provides the use of a compound of the invention or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the manufacture of a medicament for at least one of the purposes described above, wherein said medicament is administered to a patient in need thereof, preferably a warm-blooded animal, and even more preferably a human, in combination with at least one additional therapeutic agent and/or active ingredient.
  • the compounds of the inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.
  • Such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, micro crystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and prop
  • the formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc..
  • the compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
  • the pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • unit dosages will contain between 0,05 and 1000 mg, and usually between 1 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.
  • the active compound of the invention will usually be administered between 0.01 to 100 mg per kilogram, more often between 0.1 and 50 mg, such as between 1 and 25 mg, for example about 0.5, 1, 5, 10, 15, 20 or 25 mg, per kilogram body weight of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
  • groups may be substituted, such groups may be substituted with one or more substituent(s), and preferably with one, two or three substituents.
  • substituents may be selected from but not limited to, for example, the group comprising halogen, hydroxyl, oxo, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.
  • alkyl, aryl, or cycloalkyl each being optionally substituted with -- or "alkyl, aryl, or cycloalkyl, optionally substituted with -- encompasses “alkyl optionally substituted with. "aryl optionally substituted with?” and “cycloalkyl optionally substituted with?”.
  • halo or halogen means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro.
  • alkyl by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C n H2 n +i wherein n is a number greater than or equal to 1.
  • alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms,.
  • Alkyl groups may be linear or branched and may be substituted as indicated herein.
  • Suitable alkyl groups include methyl, ethyl, n-propyl which comprises propan-l-yl and propan-2-yl, /-propyl, n-butyl, /-butyl, s-butyl and /-butyl, pentyl and its isomers (e.g. n-pentyl, /so-pentyl), and hexyl and its isomers (e.g. n-hexyl, /so-hexyl).
  • Preferred alkyl groups include methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, s-butyl and /-butyl.
  • alkylene When the suffix "ene” (“alkylene”) is used in conjunction with an alkyl group, this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups.
  • alkylene includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1,2-dimethylethylene.
  • haloalkyl alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
  • Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 , 1 , 1- trifluoroethyl and the like.
  • cycloalkyl as used herein is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures.
  • Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.
  • heterocycloalkyl where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as "heterocycloalkyl” or “heterocyclyl”.
  • heterocyclyl refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone).
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • the rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
  • Non limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2- imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2- oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro- 2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3 ,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4- dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl
  • aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic.
  • the aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein.
  • Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2- yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1- or 2-pentalenyl, 4- o r 5-indanyl, 5-, 6-, 7- o r 8-tetrahydronaphthyl, 1,2,3,4- tetrahydronaphthyl, 1 ,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl.
  • heteroaryl ring where at least one carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.
  • heteroaryl refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.
  • Non-limiting examples of such heteroaryl include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,l-b][l,3]thiazolyl, thieno [3, 2-b] furanyl, thieno[3,2-b]thiophenyl, thieno[2,3- d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[
  • X is selected from: X is selected from: X is selected from: Y is selected from:
  • X is selected from: X is selected from:
  • biaryl designates two aryl moieties as defined herein linked via a single bond.
  • Non-limiting examples of such biaryl moieties include biphenyl.
  • heteroaryl designates two heteroaryl moieties as defined herein or a heteroaryl moiety and an aryl moity as defined herein linked via a single bond.
  • heterobiaryl moieties include pyridinylphenyl which is meant to include (2-pyridinyl)phenyl, (3-pyridinyl)phenyl and (4-pyridinyl)phenyl, bipyridinyl.
  • alkylamino as used herein means an amino group substituted with one or two alkyl groups. This includes monoalkylamino and dialkylamino groups.
  • the compounds of Formula I and subformulae thereof contain at least one asymmetric center and thus may exist as different stereoisomeric forms . Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non racemic mixtures as well.
  • a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- Interscience, 1994), incorporated by reference with regard to stereochemistry.
  • bonds from an asymmetric carbon in compounds of the present invention may be depicted herein using a solid line (— ), a zigzag line ( ⁇ ww ), a solid wedge ( ), or a dotted wedge ( ).
  • a solid line to depict bonds from an asymmetric carbon atom is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended.
  • the use of either a solid or dotted wedge to depict bonds from an asymmetric carbon atom is meant to indicate that only the stereoisomer shown is meant to be included.
  • the compounds of the invention may also contain more than one asymmetric carbon atom.
  • the use of a solid line to depict bonds from asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended.
  • the compounds of the invention may be in the form of pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • pharmaceutically acceptable salts include hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.
  • the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention.
  • the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH, OH)
  • the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
  • compositions of Formula I may be prepared by one or more of these methods:
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • references to compounds of formula I include references to salts, solvates, multi- component complexes and liquid crystals thereof.
  • the compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labeled compounds of formula I.
  • salts of the compounds of the invention are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention.
  • non-pharmaceutically acceptable salts which may for example be used in the isolation and/or purification of the compounds of the invention.
  • salts formed with optically active acids or bases may be used to form diastereo isomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.
  • the invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I.
  • prodrug means the pharmacologically acceptable derivatives of compounds of formula I such as esters whose in vivo biotransformation product is the active drug.
  • Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo.
  • Suitable prodrugs for the purpose of the invention include carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters as well as compounds of formula I in which the COOH moiety is replaced by a substituent Z selected from table 2 below.
  • Table 2 Table 2
  • predrug means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the predrug reaches the area of the body where administration of the drug is indicated.
  • patient refers to a warm-blooded animal, more preferably a human, who/which is awaiting or receiving medical care or is or will be the object of a medical procedure.
  • human refers to suject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).
  • treat means to include alleviating or abrogating a condition or disease and/or its attendant symptoms.
  • prevent refers to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient's risk of acquiring a condition or disease.
  • therapeutically effective amount means the amount of active agent or active ingredient which is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.
  • administration means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.
  • pharmaceutically acceptable is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.
  • pharmaceutical vehicle means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered.
  • pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.
  • lipid disorder means any plasma lipid disorder including but not limited to dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia and hypertriglyceridemia.
  • TLC Analytical thin layer chromatography
  • HPLC-MS spectra were obtained on Agilent LCMS using Electropsray ionization (ESI).
  • the Agilent instrument includes an Autosampler 1200, a binary pump 1100, a 5 wave length detector 1100 and a 6100 Single Quad.
  • the column used was an XBridge CI 8, 4.6 x 50 mm, 3.5 ⁇ .
  • Eluent was a mixture of solution A (0.1% TFA in H 2 0) and solution B (0.1% TFA in MeCN). Gradient was applied at a flow rate of 2 mL min -1 as follows: gradient A: held the initial conditions of 5% solution B for 1 min, increased linearly to 95% solution B in 4 min, held at 95% during 1 min, returned to initial conditions in 0.5 min and maintained for 1 min; gradient B: held the initial conditions of 5% solution B for 1 min, increased linearly to 60% in 10 min, increased linearly to 95% in 0.5 min, held at 95% during 3 min, returned to initial conditions in 0.5 min and maintained for 1 min.
  • ee Determination of ee was performed on an Agilent 1100 (binary pump and 5 wavelengths detector) with manual or automatic (Autosampler 1100) injection. Columns used were CHIRALPAK IA CHIRALPAK IB or CHIRALPAK IC in isocratic mode. Mixtures of eluents were selected depending on the separation obtained of enantiomers or diastereosiomers. Usual mixtures were:
  • Method A compound was characterized on a CHIRALPAK I A column (isocratic mode) using a mixture of hexane and dichloromethane (65/35) acidified by 0.4% of TFA at a flow rate of 1.2 mL/min, and confirmed on a CHIRALPAK IC column (isocratic mode) using a mixture of heptane and Ethyl acetate (75/25) acidified by 0.1% of TFA at lmL/min.
  • Method B compound was characterized on a CHIRALPAK IC column (isocratic mode) using a mixture of heptane and ethyl acetate (70/30) acidified by 0.1% of TFA at a flow rate of lmL/min.
  • Method C compound was characterized on a CHIRALPAK IC column (isocratic mode) using a mixture of heptane and ethanol (95/5) acidified by 0.1% of TFA at a flow rate of 1.5mL/min.
  • Preparative HPLC purifications were carried out on Fractionlynx instrument, from Waters.
  • This instrument consists of a Fraction Collector, a 2767 Sample Manager, a pump control a module II, a 515 HPLC Pump, a 2525 Binary Gradient Module, a Switching Valve, a 2996 Photodiode Array Detector and a Micromass ZQ.
  • the column used was a Waters Sunfire CI 8 Eluent was a mixture of solution A (0.1 % TFA in H 2 0) and solution B (0.1 % TFA in MeCN). The gradient was adapted depending on impurities present in samples, to allow sufficient separation between impurities and target compound.
  • Solvents, reagents and starting materials were purchased from well known chemical suppliers such as for example Sigma Aldrich, Acros Organics, Fluorochem, Eurisotop, VWR International, and the following abbreviations are used:
  • NFSI N-fluorobenzenesulfonimide
  • NaHMDS Sodium hexamethyldisilazane
  • PE Petroleum ether
  • TFA Trifluoroacetic acid
  • (S)-4-benzyloxazolidin-2-one 2.2 was acylated using mixed anhydride 2.1 to furnish intermediate 2.3. Diastereo selective alkylation of 2.3 with tert-butylbromoacetate yielded intermediates 2.4 which upon auxiliary cleavage provided intermediates 1.1.
  • Acetophenone intermediates 5.1 can be prepared as described in Scheme 7.
  • 2-amino-4-aryl-5-fluorothiazole intermediates can be prepared from 2-amino-4- aryl-thiazole intermediates using the conditions described in Chem. Res. Toxicol. 2007, 1954-1965.
  • 5-amino-3-(hetero)biarylthiadiazole may be synthesized as was done for the 2- amino-4-(hetero)biarylthiazole using Suzuki coupling approach from 5-amino-3- bromothiadiazole which may be obtained using the methodology suggested in Scheme 9.
  • Step 1 synthesis of (S)-4-benzyl-3-(3-cyclopentylpropanoyl)oxazolidin-2-one
  • Solution B n-Butyllithium (2.5M/hexane, 134 mL, 0.33 mol) was added dropwise over 20 min to a stirred solution of (S)-4-benzyl-2-oxazolidinone (59.2 g, 0.33 mol) in dry THF (600 mL) at -78°C under a nitrogen atmosphere. The yellow solution was allowed to warm to ⁇ 0°C and stirred for 1 hour, after which time a white gelatinous precipitate had formed.
  • Solution A was re-cooled to -78°C and solution B added via cannula over 2.5 hours.
  • Extra THF 200 mL was added to solution B to aid cannula transfer of the more viscous final portion.
  • the resulting white suspension was allowed to warm to RT slowly overnight.
  • the mixture was cooled in an ice bath and saturated aqueous ammonium chloride (500 mL) added slowly, followed by water (400 mL) to dissolve any precipitated salts, and Et 2 0 (500 mL).
  • the separated organic layer was dried (Na 2 S0 4 ) and evaporated in vacuo to leave a yellow oil (1 10 g).
  • Step 2 synthesis of (R)-tert-butyl 4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3- (cyclopentylmethyl)-4-oxobutanoate
  • intermediate lb (R)-2-(2-(tert-butoxy)-2-oxoethyl)-4-methylpentanoic acid
  • intermediate lc (R)-4-(tert-butoxy)-2-(cyclobutylmethyl)-4-oxobutanoic acid
  • intermediates Id (R)-4-(tert-butoxy)-2-(cyclopropylmethyl)-4-oxobutanoic acid and le: (R)-2-(2-(tert-butoxy)-2-oxoethyl)hexanoic acid, were synthesized using general method A (step 2 and 3 ) from a mixture of (S)-4-benzyl-3-(3- cyclopropylpropanoyl)oxazolidin-2-one and (S)-4-benzyl-3-hexanoyloxazolidin- 2-one which was synthesized as follows:
  • intermediate 2i N-cyclopropyl-4-(2-(6-methoxypyridin-3 -yl)phenyl)thiazo 1-2- amine from (6-methoxypyridin-3-yl)boronic acid.
  • General Method C synthesis of intermediate 2b N-cyclopropyl-4-(2-(5- methoxypyrazin-2-yl)phenyl)thiazol-2-amine
  • intermediate 2e 6-(2-(2-(cyclopropylamino)thiazol-4-yl)phenyl)-3- methyloxazolo[4,5-b]pyridin-2(3H)-one from 6-bromo-3-methyloxazolo[4,5- b]pyridin-2(3H)-one which was synthesize d from 6-bromooxazolo[4,5- b]pyridin-2(3H)-one using iodomethane and sodium hydride as described for intermediate 2d,
  • intermediate 2f N-cyclopropyl-4-(2-(6-methoxy-5-methylpyridin-3- yl)phenyl)thiazol-2-amine from 5 -bromo-2-methoxy-3 -methylpyridine
  • intermediate 2g 7-(2-(2-(cyclopropylamino)thiazol-4-yl)phenyl)- 1 ,4-dimethyl- 3 ,4-dihydropyrido [2,3 -b]pyrazin-2( lH)-one from 7-bromo- 1 ,4-dimethyl-3 ,4- dihydropyrido[3,2-b]pyrazin-2(lH)-one which was synthesized from 7-bromo- 3,4-dihydropyrido[3,2-b]pyrazin-2(lH)-one using iodomethane and sodium hydride as described for intermediate 2d,
  • intermediate 21 N-cyclopropyl-4-(2-(5-methyl-5H-pyrrolo[2,3-b]pyrazin-2- yl)phenyl)thiazol-2-amine from 2-bromo-5-methyl-5H-pyrrolo[2,3-b]pyrazine
  • intermediate 2m N-cyclopropyl-4-(2-(5 -(dimethylamino)pyrazin-2- yl)phenyl)thiazol-2-amine from 5-bromo-N,N-dimethylpyrazin-2-amine which was synthesized from 5-bromopyrazin-2-amine using iodomethane and sodium hydride as described for intermediate 2d,
  • intermediate 2n N-cyclopropyl-4-(2-( 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridin-5 - yl)phenyl)thiazol-2-amine from 5-bromo-l -methyl- lH-pyrazolo[3,4-b]pyridine which was synthesized from 5-bromo-lH-pyrazolo[3,4-b]pyridine using iodomethane and sodium hydride as described for intermediate 2d,
  • intermediate 2 7-(2-(2-(cyclopropylamino)thiazol-4-yl)phenyl)-4-methyl-2H- pyrido[3,2-b][l,4]oxazin-3(4H)-one from 7-bromo-4-methyl-2H-pyrido[3,2- b][l,4]oxazin-3(4H)-one which was synthesized from 7-bromo-2H-pyrido[3,2- b][l,4]oxazin-3(4H)-one using iodomethane and sodium hydride as described for intermediate 2d,
  • the RM was stirred for 30 min at -78°C and then a solution of NFSI (3.49 mmol, 1.1 g) in THF (5 mL) was added dropwise. The RM was stirred at -78°C for 30 min and allowed to warm up to RT. EtOAc (20 mL) and 5 mL of a saturated aqueous solution of NH 4 C1 was added and organic layer was wached with brine, dried over magnesium sulfate and evaporated to dryness to yield l-(5-bromopyridin-2-yl)-3-fluoropyrrolidin-2-one as a yellow oil to be used as such in the next step. Y:400 mg (quantitative),
  • intermediate 2v 4-(2-(6-( 1 H-pyrazol- 1 -yl)pyridin-3 -yl)phenyl)-N- cyclopropylthiazol-2-amine from 5 -bromo-2-( 1 H-pyrazol- 1 -yl)pyridine
  • intermediate 2w N-cyclopropyl-4-(2-(6-methoxypyridazin-3-yl)phenyl)thiazol- 2-amine from 3-bromo-6-methoxypyridazine.
  • Step 1 synthesis of (R)-tert-butyl 3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- (2-methoxyethoxy)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoate
  • Step 2 synthesis of Example 1: compound n°l : (R)-3-(cyclopentylmethyl)-4- (cyclopropyl(4-(2-(6-(2-methoxyethoxy)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid
  • To a solution of (R)-tert-butyl 3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2- methoxyethoxy)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoate (0.18 mmol, 139 mg) in DCM (2 mL) was added TFA (1 mL).
  • Examples 2 to 27 were synthesized using general method D and intermediates described above.
  • Example 2 compound n°2 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5- methoxypyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2b.
  • Example 3 compound n°3 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3,5- dimethyl- 1 H-pyrazol- 1 -yl)pyridin-3 -yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2c.
  • Example 4 compound n°4 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l,3,3- trimethyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid was synthesized from intermediates la and 2d.
  • Example 5 compound n°5 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(3-methyl-2- oxo-2,3-dihydrooxazolo[4,5-b]pyridin-6-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2e.
  • Example 6 compound n°6 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-methoxy- 5-methylpyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2f using general method E and further preparative HPLC purification.
  • Example 7 compound n°7 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l,4- dimethyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2g.
  • Example 8 compound n°8 (R)-3-(cyclobutylmethyl)-4-(cyclopropyl(4-(2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lc and 2h.
  • Example 9 compound n° 9 (R)-3-(cyclobutylmethyl)-4-(cyclopropyl(4-(2-(6- methoxypyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lc and 2i.
  • Example 10 compound n°l l (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5-(2- methoxyethoxy)pyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2j.
  • Example 11 compound n° 12 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3- methyl-2-oxopyrrolidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2k.
  • Example 12 compound n° 1 3 (R)-3-(cyclopropyl(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)carbamoyl)-5-methylhexanoic acid was synthesized from intermediates lb and 2i.
  • Example 13 compound n°14 (R)-3-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin- 3-yl)phenyl)thiazol-2-yl)carbamoyl)-5-methylhexanoic acid was synthesized from intermediates lb and 2h.
  • Example 14 compound n° 15 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5- methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 21.
  • Example 15 compound n°16 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5- (dimethylamino)pyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2m.
  • Example 16 compound n°17 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- methyl-lH-pyrazolo[3,4-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2n.
  • Example 17 compound n°18 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- methyl- 1 H-[ 1 ,2,3]triazolo[4,5-b]pyridin-6-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2o.
  • Example 18 compound n° 19 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(4- methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2p.
  • Example 19 compound n°20 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-((S)-2- methoxypropoxy)pyridin-3 -yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2q.
  • Example 20 compound n°21 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2- isopropoxyethoxy)pyridin-3 -yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2r.
  • Example 21 compound n°22 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(((R)- 1 -methoxypropan-2-yl)oxy)pyridin-3 -yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2s.
  • Example 22 compound n°23 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5-(2- oxopyrrolidin- 1 -yl)pyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2t.
  • Example 23 compound n°24 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3- fluoro-2-oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2u.
  • Example 24 compound n°25 (R)-4-((4-(2-(6-(lH-pyrazol-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid was synthesized from intermediates la and 2v.
  • Example 25 compound n°26 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- methoxypyridazin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2w.
  • Example 26 compound n°27 (R)-3-(cyclopropyl(4-(2-(5-methoxypyrazin-2- yl)phenyl)thiazol-2-yl)carbamoyl)-5-methylhexanoic acid was synthesized from intermediates lb and 2b.
  • Example 27 compound n°33: (R)-3-(cyclopropyl(4-(2-(6-methoxypyridazin-3- yl)phenyl)thiazol-2-yl)carbamoyl)-5-methylhexanoic acid was synthesized from intermediates lb and 2w.
  • Example 28 compound n°29 : (R)-3-((4-(2-(6-(lH-pyrazol-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)carbamoyl)-5-methylhexanoic acid was synthesized from intermediates lb and 2w.
  • Example 29 compound n°37: (R)-4-(cyclopropyl(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-3 -(cyclopropylmethyl)-4-oxobutanoic acid and compound n° 38 : (R)-3-(cyclopropyl(4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)carbamoyl)heptanoic acid were synthesized from a mixture of intermediates le/ld and 2i and further preparative HPLC purification.
  • Figure 1 represents the inhibition of in-vivo lipolysis following the injection of compounds 13 and 15 in mice.
  • the blood glucose area under the curve (AUC) between time t-15 min and time tl20 min was calculated (GraphPad Prism software).
  • preferred compounds of the invention When tested in the above-described assay, preferred compounds of the invention showed a % of AUC inhibition > 11%, indicating that the compounds of invention are able to significantly reduce the level of blood glucose.
  • mice Male C57BL/6N wild-type are housed one per cage in a room maintained on a 12h light/dark cycle under constant temperature (22-25°C) with ad libitum access to food and water.
  • the anti-lipolytic effects of the compounds of the invention are studied in awake mice. Animals are fasted overnight before experimental use. On the day of the experiment, animals are put in metabolic cages and left undisturbed to acclimate to the environment for l-2h. Blood samples are taken at indicated time points from the intraorbital retrobulbar plexus. A 1% sodium citrate saline solution is used to flush the lines. A pre-treatment blood sample is obtained from each animal to determine baseline values for free fatty acids (FFA) and triglycerides (TG).
  • FFA free fatty acids
  • TG triglycerides
  • Blood samples will be centrifuged at 4000 x g, at 4°C, 15 min the resulting plasma will be transferred into non-coated tubes and stored at - 80°C until analyses.
  • the plasma is thawed at 4°C for determinations of FFA and TG using commercial kits (Wako Chemicals).
  • the compounds n° 13 and 15 administered orally inhibit, 15 minutes following the dosing, in vivo FFA baseline at the concentration of 50mg/kg from normal diet fed mice in comparison to the vehicle ( Figure 1).
  • P450-GloTM Screening assay (Promega) are used to evaluate the potential of the compounds of the invention to inhibit cytochrome P450 isoforms (CYP 1 A2 # V9770, 2C9 # V9790, 2C19 # V9880, 2D6 # V9890, 3A4 # V9910).
  • cytochrome P450 isoforms CYP 1 A2 # V9770, 2C9 # V9790, 2C19 # V9880, 2D6 # V9890, 3A4 # V9910
  • These assays employ luminogenic CYP450 probe substrates that are derivatives of beetle luciferin, a substrate for luciferase enzymes. The derivatives are converted by P450s cytochrome to luciferin, which in turn reacts with luciferase to produce an amount of light that is directly proportional to the activity of the P450.
  • P450- GloTM assays are performed in two steps, the P450- GloTM subtrates are first converted by cytochrome P450 enzyme to a luciferin product which is then detected as a luminescent signal from a luciferase reaction.
  • the cytochrome P450 mixture with cytochrome P450 enzyme and a P450- GloTM substrate is prepared at pH 7.4 in a P04 buffer at the optimal concentration for each cytochrome P450 isoform.
  • the compounds of the invention Dose response curve from ⁇ to 30nM
  • Luciferin- Free water+0.1% DMSO is used as negative control and known inhibitor as positive control.
  • the reactions are initiated by adding the NADPH regeneration system and are performed at 37°C (incubation time as describe in the table below).
  • Luciferin detection reagent is added to stop cytochrome P450 activity and initiate the D-luciferin detection reaction.
  • the IC 50 value (compound concentration required to inhibit cytochrome activity by 50%) of the compound of the invention were then determined.
  • preferred compounds of the invention When tested in the above-described assay, preferred compounds of the invention showed an IC 50 ⁇ ⁇ on all five cytochrome P450 iso forms, indicating no or a weak CYP450 activity inhibition by the compounds of the invention.

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Abstract

La présente invention concerne de nouveaux composés de formule (I) et leur utilisation dans le traitement de maladies métaboliques.
PCT/EP2011/059179 2010-06-04 2011-06-03 Nouveaux composés, leurs compositions pharmaceutiques et méthodes d'utilisation dans le traitement de troubles métaboliques WO2011151434A1 (fr)

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WO2014203217A1 (fr) 2013-06-21 2014-12-24 Lupin Limited Composés hétérocycliques substitués utiles en tant que modulateurs de crac
CN107032992A (zh) * 2017-04-05 2017-08-11 华东师范大学 一种(r)‑4‑(叔丁氧基)‑2‑(环戊基甲基)‑4‑氧代丁酸的合成方法
US9790231B2 (en) 2013-06-24 2017-10-17 Lupin Limited Chromane and chromene derivatives and their use as CRAC modulators

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014203217A1 (fr) 2013-06-21 2014-12-24 Lupin Limited Composés hétérocycliques substitués utiles en tant que modulateurs de crac
US9725463B2 (en) 2013-06-21 2017-08-08 Lupin Limited Substituted heterocyclic compounds as CRAC modulators
US9790231B2 (en) 2013-06-24 2017-10-17 Lupin Limited Chromane and chromene derivatives and their use as CRAC modulators
CN107032992A (zh) * 2017-04-05 2017-08-11 华东师范大学 一种(r)‑4‑(叔丁氧基)‑2‑(环戊基甲基)‑4‑氧代丁酸的合成方法

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