Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
  • C07D213/40—Acylated substituent nitrogen atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
  • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals

Definitions

• the present disclosure relates to novel compounds, compositions containing same and methods for treating or preventing a condition associated with a deficient insulin secretion such as diabetes and metabolic syndrome in a subject in need thereof.
• GL/FFA cycling intermediate, DAG is thought to activate Munc-13-1 , a vesicle priming protein, and also C-kinase enzymes, which play an important role in the exocytosis of insulin granules in ⁇ -cell.
• GL/FFA cycling and lipolysis derived monoacylglycerols (MAG) act as regulators of insulin secretion.
• a method for increasing insulin secretion in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or solvate thereof.
• MAG monoacylglyceride
• a compound as defined herein or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prevention of a disease or condition described above or herein or for inhibiting ABHD6 or increasing insulin secretion or increasing a level of monoacylglyceride (MAG) in a cell of a subject, preferably in pancreatic ⁇ -cells.
• MAG monoacylglyceride
• compositions as defined herein or use in the treatment or prevention of a disease or condition described above or herein or for inhibiting ABHD6 or increasing insulin secretion or increasing a level of monoacylglyceride (MAG) in a cell of a subject, preferably in pancreatic ⁇ -cells.
• MAG monoacylglyceride
• R2, R3, R4 and R5 are H or an independently selected substituent as defined herein.
• each of R7 and R8 is independently selected from H, C1-3 alkyl or fluoride.
• each of R7 and R8 is independently selected from H or C1-3 alkyl.
• X is CH.
• R1 is C1-6 linear or C3-6 branched alkyl, C3-6 cycloalkyi, C2-6 linear or branched alkenyl or aryl.
• R1 is C1-3 linear alkyl, C3 branched alkyl, C3 cycloalkyi, or optionally substituted phenyl.
• R1 is C1-3 linear or C3 branched alkyl.
• R1 is an optionally substituted phenyl. In one embodiment, in compound of formula I, II or III or a pharmaceutically acceptable salt or solvate thereof, R1 is methyl, ethyl, n-propyl, i-propyl, cyclopropyl or optionally substituted phenyl.
• R1 is methyl, ethyl, n-propyl, i-propyl or cyclopropyl.
• R6 is H, C1-6 linear alkyl or C3-6 branched alkyl, C3-6 cycloalkyl.
• R6 is H, methyl, ethyl, n-propyl, i-propyl or cyclopropyl.
• a compound of formula I, II or III or a pharmaceutically acceptable salt or solvate thereof wherein X is CH, R1 is C 1-6 linear or C3-6 branched alkyl, C3-6 cycloalkyl, or optionally substituted phenyl and R6 is H, C1-6 linear alkyl or C3-6 branched alkyl, C3-6 cycloalkyl.
• a first sub-selection of the previous embodiment is, when the compound (such as compound of formula I or II) comprises R2, R3, R4, R5, R7 and R8, that each of these variable are H.
• a compound of formula I, II or III or a pharmaceutically acceptable salt or solvate thereof wherein X is CH, R1 is C1-3 linear alkyl, C3 branched alkyl, or optionally substituted phenyl and R6 is H, C1 -3 linear alkyl, C3 branched alkyl or C3 cycloalkyl.
• a first sub-selection of the previous embodiment is, when the compound (such as compound of formula I or II) comprises R2, R3, R4, R5,
• R7 and R8, that each of these variable are H.
• a compound of formula I, II or III or a pharmaceutically acceptable salt or solvate thereof wherein X is CH, R1 is C1-3 linear or C3 branched alkyl and R6 is H, C1-3 linear alkyl, C3 branched alkyl or C3 cycloalkyl.
• a first sub-selection of the previous embodiment is, when the compound (such as compound of formula I or II) comprises R2, R3, R4, R5, R7 and R8, that each of these variable are H.
• a compound of formula I, II or III or a pharmaceutically acceptable salt or solvate thereof wherein X is CH, R1 is methyl, ethyl, n-propyl, i-propyl, cyclopropyl or optionally substituted phenyl and R6 is H, methyl, ethyl, n-propyl, i-propyl or cyclopropyl.
• a first sub-selection of the previous embodiment is, when the compound (such as compound of formula I or II) comprises R2, R3, R4, R5, R7 and R8, that each of these variable are H.
• a compound of formula I, II or III or a pharmaceutically acceptable salt or solvate thereof wherein X is N, R1 is R1 is C1-3 linear or C3 branched alkyl and R6 is H, C1-3 linear alkyl, C3 branched alkyl or C3 cycloalkyl.
• a first sub-selection of the previous embodiment is, when the compound (such as compound of formula I or II) comprises R2, R3, R4, R5, R7 and R8, that each of these variable are H.
• a compound of formula I, II or III or a pharmaceutically acceptable salt or solvate thereof wherein X is N, R1 is methyl, ethyl, n-propyl, i-propyl, cyclopropyl or optionally substituted phenyl I and R6 is H, methyl, ethyl, n-propyl, i-propyl or cyclopropyl.
• a first sub-selection of the previous embodiment is, when the compound (such as compound of formula I or II) comprises R2, R3, R4, R5, R7 and R8, that each of these variable are H.
• each of these variable can be H.
• cycloalkyl represents optionally substituted cyclic hydrocarbon moiety having 3 to 10 carbon atoms.
• Examples of “cycloalkyl” groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• Lower cycloalkyls comprise 3 to 6 or preferably 3 carbon atoms.
• alkenyl, and alkynyl groups include but are not limited to, allyl, vinyl, acetylenyl, ethylenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, hexatrienyl, heptenyl, heptadienyl, heptatrienyl, octenyl, octadienyl, octatrienyl, octatetraenyl, propynyl, butynyl, pentynyl and hexynyl.
• alkoxy represents an alkyl, alkenyl or alkynyl moiety, respectively, which is covalently bonded to the adjacent atom through an oxygen atom.
• examples include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, trifluoromethoxy and neohexyloxy.
• aryloxy represents an aryl moiety, which is covalently bonded to the adjacent atom through an oxygen atom. Examples include but are not limited to phenoxy, dimethylphenoxy, aminophenoxy, anilinoxy, naphthoxy, anthroxy, phenanthroxy or biphenoxy.
• heterocycle represents a 3 to 11 membered optionally substituted saturated, unsaturated, partially saturated or aromatic cyclic moiety wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (O), sulfur (S) or nitrogen (N).
• Heterocycles may be monocyclic or polycyclic rings. Heterocycles may be 3 to 6 membered monocyclic ring or 5 to 6 membered monocyclic ring. Heterocycles may be 7 to 12 membered bicyclic ring or 9 to 10 membered bicyclic ring.
• heterocycles include but are not limited to azepinyl, aziridinyl, azetyl, azetidinyl, diazepinyl, dithiadiazinyl, dioxazepinyl, dioxolanyl, dithiazolyl, furanyl, isooxazolyl, isothiazolyl, imidazolyl, morpholinyl, morpholino, oxetanyl, oxadiazolyl, oxiranyl, oxazinyl oxazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidyl, piperidino, pyridyl, pyranyl , pyrazolyl, pyrrolyl, pyrrolidinyl, thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl, thiazolyl,
• Halogen atom is specifically a fluorine atom, chlorine atom, bromine atom or iodine atom; preferably the halogen is a fluoride.
• the term "optionally substituted", “optionally substituent” or “substituent” preferably represents halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, -NR40R41 , -C(O)NR40R41 , -NR40COR41 , carboxy, azido, cyano, hydroxyl, nitro, nitroso, -OR40, -SR40, -S(O) 0-2 R40, -C(O)R40, -C(O)OR40 and -SO 2 NR40R41 ; wherein R40 and R41 are each independently H, C1- 6alkyl, C2-6alkenyl or C2-6alkynyl.
• the term "optionally substituted”, “optionally substituent” or “substituent” preferably represents halogen, C1-6alkyl, C2-6alkenyl, C1-6 alkoxy, - NR40R41 , -C(O)NR40R41 , -NR40COR41 , carboxy, hydroxyl, nitro, -SR40, -S(O) 0 - 2 R40, -C(O)R40, -C(O)OR40 and -SO 2 NR40R41 ; wherein R40 and R41 are each independently H, or C1-6alkyl.
• subject refers to both human and non-human subjects. Preferably the subject is human.
• the compounds in accordance with the present disclosure can contain more than one chiral centre.
• the compounds of the present invention may thus exist in the form of different diastereomers. All such diastereomers and mixtures thereof are included within the scope of the invention.
• the single diastereomer can be obtained by methods well known in the art, such as HPLC, crystalisation and chromatography.
• pharmaceutically acceptable salts of the compounds of the present disclosure are derived from pharmaceutically acceptable inorganic and organic acids and bases.
• Salts derived from appropriate bases include alkali metal, alkaline earth metal or ammonium salts.
• the salt(s) must be "acceptable" in the sense of not being deleterious to the recipient thereof.
• the pharmaceutically acceptable salts of the compounds of this disclosure can be synthesized from the compounds of this disclosure which contain a basic or acidic moiety by conventional chemical methods.
• the salts of the basic compounds are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
• the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base.
• Solvate means that a compound as defined herein incorporates one or more pharmaceutically acceptable solvents including water to give rise to hydrates.
• the solvate may contain one or more molecules of solvent per molecule of compound or may contain one or more molecules of compound per molecule of solvent.
• Illustrative non-limiting examples of hydrates include monohydrate, dihydrate, trihydrate and tetrahydrate or semi- hydrate.
• the solvent may be held in the crystal in various ways and thus, the solvent molecule may occupy lattice positions in the crystal, or they may form bonds with salts of the compounds as described herein.
• the solvate(s) must be "acceptable" in the sense of not being deleterious to the recipient thereof.
• the solvation may be assessed by methods known in the art such as Loss on Drying techniques (LOD). It will be appreciated by those skilled in the art that the compounds in accordance with the present disclosure can exist in several different crystalline forms due to a different arrangement of molecules in the crystal lattice. This may include solvate or hydrate (also known as pseudopolymorphs) and amorphous forms. All such crystalline forms and polymorphs are included within the scope of the disclosure.
• the polymorphs may be characterized by methods well known in the art. Examples of analytical procedures that may be used to determine whether polymorphism occurs include: melting point (including hot-stage microscopy), infrared (not in solution), X-ray powder diffraction, thermal analysis methods (e.g. differential scanning calorimetry (DSC) differential thermal analysis (DTA), thermogravimetric analysis (TGA)), Raman spectroscopy, comparative intrinsic dissolution rate, scanning electron microscopy (SEM).
• DSC differential scanning calorimetry
• DTA differential thermal analysis
• the sulfur atom can be at different oxidation levels, ie. S, SO, or S0 2 . All such oxidation levels are within the scope of the present disclosure.
• the nitrogen atom can be at different oxidation levels, ie. N or NO. All such oxidation levels are within the scope of the present disclosure.
• the uses, methods and compositions described herein wherein the compound is any compound as defined herein including any of compounds defined in formula I, II and III.
• the compounds provided herein may be useful in the treatment of a condition associated with a lowered level of insulin secretion.
• these conditions are commonly linked by the fact that the afflicted subject produces a lower plasma level of insulin than a healthy subject (e.g. normoglycemic), such that the afflicted subject become hyperglycemic.
• a healthy subject e.g. normoglycemic
• the pancreatic ⁇ -cells of the afflicted subject secrete less insulin that the pancreatic ⁇ -cells of the healthy subject.
• Insulin resistance is a condition in which body cells become less sensitive to the glucose- lowering effects of insulin. Insulin resistance in muscle and fat cells reduces glucose uptake (and so local storage of glucose as glycogen and triglycerides, respectively), whereas insulin resistance in liver cells results in reduced glycogen synthesis and storage and a failure to suppress glucose production and release into the blood. Insulin resistance normally refers to reduced glucose-lowering effects of insulin. However, other functions of insulin can also be affected. For example, insulin resistance in fat cells reduces the normal effects of insulin on lipids and results in reduced uptake of circulating lipids and increased hydrolysis of stored triglycerides. Increased mobilization of stored lipids in these cells elevates free fatty acids in the blood plasma.
• Diabetes can be divided into two broad type of diseases: type I and type II diabetes.
• Metabolic syndrome is generally used to define a constellation of abnormalities that is associated with increased risk for the development of type II diabetes and atherosclerotic vascular disease.
• Related conditions and symptoms include, but are not limited to, fasting hyperglycemia (diabetes mellitus type II or impaired fasting glucose, impaired glucose tolerance, or insulin resistance), high blood pressure; central obesity (also known as visceral, male-pattern or apple-shaped adiposity), overweight with fat deposits mainly around the waist; decreased HDL cholesterol; elevated triglycerides.
• Associated diseases can also include hyperuricemia, fatty liver (especially in concurrent obesity) progressing to non-alcoholic fatty liver disease, polycystic ovarian syndrome (in women), and acanthosis nigricans.
• "deficient insulin secretion” means insufficient insulin secretion.
• the condition associated with an insufficient insulin secretion is at least one of the following condition: diabetes (such as type I and II diabetes) and metabolic syndrome.
• the compounds suitable for certain uses as described herein may be viewed as those either being able to upregulate monoacylglyceride (MAG) level or increases the value of the MAG level with respect a control value and/or as being able to inhibit ABHD6 polypeptide activity or expression in the pancreatic ⁇ -cells of a subject in need thereof.
• MAG is 2-monoacylglycerol.
• MAG is -monoacylglycerol.
• the "acyl" portion of said acylglycerol is not particularly limited and is a hydrocarbon chain from 2 to 26 carbons, straight or branched, saturated or unsaturated with one or more double bond, of either E or Z stereochemistry where applicable.
• the compound are selectively inhibiting ABHD6 versus diacylglycerol lipase in at least one effective concentration.
• the compound activity and/or selectivity will result in a increased insulin secretion in the subject.
• the compound in a method or use as defined herein, can be any compound as defined herein with the possible exception of any one of compounds i) to iv) as provided herein.
• the proviso can be any of i) to iv) or a combination of said compounds thereof.
• the method or use of a compounds defined herein for inhibiting ABHD6 in a subject in need thereof is comprising a therapeutically effective amount of a compound I, II or III or a pharmaceutically acceptable salt or solvate thereof, provided that it is other than compound i) and iv).
• excipient(s) for use in pharmaceutical compositions in accordance with the disclosure must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the formulation and not being deleterious to the recipient thereof.
• the present disclosure provides a combination comprising a therapeutically effective amount of a compound, as defined herein, and a therapeutically effective amount of at least one or more therapeutic agents useful in the method of the present disclosure.
• the amount of a compound of the description required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition for which treatment is required and the age and condition of the patient and will be ultimately at the discretion of the attendant physician.
• the desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day.
• the compounds can, for example, be administered orally, mucosally (including sublingual, buccal, rectal, nasal or vaginal administrations), parenterally (including subcutaneous injection, bolus injection, intraarterial, intravenous, intramuscular, intrasternal injection or infusion administrations techniques), by inhalation spray, transdermal, such as passive or iontophoretic delivery, or topical administration, in the form of a unit dosage of a pharmaceutical composition containing aneffective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers.
• mucosally including sublingual, buccal, rectal, nasal or vaginal administrations
• parenterally including subcutaneous injection, bolus injection, intraarterial, intravenous, intramuscular, intrasternal injection or infusion administrations techniques
• transdermal such as passive or iontophoretic delivery
• topical administration in the form of a unit dosage of a pharmaceutical composition containing aneffective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers.
• the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy.
• the methods for preparing a pharmaceutical composition can include the steps of bringing into association the compound as defined herein and pharmaceutically acceptable carriers and then, if necessary, shaping the product into the desired formulation, including applying a coating when desired.
• compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion.
• Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
• the tablets may be coated according to methods well known in the art.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
• the compounds may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
• parenteral administration e.g. by injection, for example bolus injection or continuous infusion
• the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile water or saline, before use.
• the compounds and combinations as defined herein may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
• the powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e.g. gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
• the compounds of the present disclosure can be prepared according to the procedures denoted in the following reaction Scheme. Examples or modifications thereof using readily available starting materials, reagents, and conventional procedures or variations thereof well-known to a practitioner of ordinary skill in the art of synthetic organic chemistry. Specific definitions of variables in the Schemes are given for illustrative purposes only and are not intended to limit the procedures described.
• the starting materials and reagents used in preparing these compounds generally are either available from commercial sources or are prepared by synthetic chemistry in accordance with methods described for example in as R. C. LaRock, Comprehensive Organic Transformations, 2.sup.nd edition Wiley- VCH, New York 1999; and Organic Reactions, Wiley & Sons: New York, 1991 , Volumes 1-40.
• the compounds and or intermediates can be isolated and purified if necessary using known methods such as distillation, crystallization and chromatography.
• the compounds of formula (1) and (2) depicted in scheme 1 below can be obtained from a commercial source or prepared in accordance with known synthetic chemistry methods.
• a compound of formula (1) can be reacted with a proper "activating" reagent to form compound of formula (1-1 ) in which L is a leaving group suitable for the following step such as a halogen (e.g. chloride) or hydroxysuccinimide.
• R10 can be -(CO)NHR6' or a precursor thereof, wherein R6' is H, a protecting group or R6 as defined herein and R4 and R5 are as defined herein.
• a particular selection of the compounds of the present disclosure is illustrated by formula (III) defined hereinbefore.
• the compounds of formula (1a) and (2a) depicted in scheme 2 below can be obtained from a commercial source or prepared in accordance with known synthetic chemistry methods.
• a compound of formula (1 a) can be reacted with a reagent of formula (4) in a suitable solvent (such as CH 3 CN) and in the presence of a base (such as Et 3 N) to provide the intermediate compound (1-1a).
• a suitable solvent such as CH 3 CN
• a base such as Et 3 N
• X, R1 and R6 are as defined herein.
• a particular example of such substituents is when R1 is a phenyl, a methyl or isopropyl; when R6 is H, a methyl or a cyclopropyl and X is CH or N.
• DSC ⁇ , ⁇ '-Disuccinimidyl carbonate
• HOBt Hydroxybenzotriazole
• EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
• TLC Thin layer chromatography
• THF Tetrahydofuran
• DMF ⁇ , ⁇ -Dimethylformamide
• TFA trifluoroacetic acid
• RT Room temperature
• Ph phenyl
• Ac acetyl
• MeOH Methanol
• Et Ethyl
• AcOH acetic acid
• DMSO Dimethyl sulfoxide.
• WWL70 (corresponding to compound #1 in table 1 above) was obtained from Cayman Chemical Company. Orlistat was purchased from Sigma.
• the crude product (650 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC- 002(Agilent)): Column, SunFire Prep C18, 19*150mm 5um; mobile phase, water and acetonitrile (10.0% acetonitrile up to 80.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 2 min); Detector, uv 220 & 254nm. The title compound was obtained as a white solid.
• the crude product (650 mg) was purified by Prep-HPLC with the following conditions (1#- Pre-HPLC-002(Agilent)): Column, SunFire Prep C18, 19*150mm 5um; mobile phase, water and acetonitrile (10.0% acetonitrile up to 80.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 2 min); Detector, uv 220 & 254nm. The title compound was obtained as a white solid.
• the resulting solution was extracted with 20 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum.
• the crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-002(Agilent)): Column, Xbridge Prep C18, 5um, 19*150mm; mobile phase, water and CH 3 CN (45.0% CH 3 CN up to 75.0% in 10 min, hold 100.0% in 1 min, hold 45.0% in 2 min); Detector, uv 220 & 254 nm. The title compound was obtained as a white solid.
• INS 832/13 ⁇ -cell extracts (whole cell) were prepared by sonication in Krebs-Ringer
• INS832/13 cells (Hohmeir et al. Diabetes (2000) 49 pp424-430,) were cultured at 37°C in a humidified atmosphere containing 5% C0 2 in RPMI 1640 with sodium bicarbonate, supplemented with 10% (v/v) fetal calf serum (Wisent), 10 mM HEPES, pH 7.4, 2 mM L-glutamine, 1 mM sodium pyruvate and 50 ⁇ ⁇ -mercaptoethanol (complete RPMI). Cells were grown to 80% confluence. Media were changed to RPMI 1640 containing 3 mM glucose supplemented as the complete RPMI 24 h prior to the experiments. Insulin secretion incubations were conducted in Krebs- Ringer bicarbonate buffer containing 10 mM HEPES, pH 7.4 (KRBH).
• INS832/13 cells were washed in KRBH containing 1 mM glucose and 0.5% defatted BSA (KRBH 1 G/0.5%BSA) and pre-incubated for 45 min in KRBH 1 G/0.5%BSA in presence of pharmacological agents (at indicated concentrations) or vehicle (DMSO).
• pharmacological agents at indicated concentrations
• DMSO vehicle
• WWL70 an inhibitor of ABHD6
• other compounds identified in table 1 and/or orlistat (lipase inhibitor)
• the compounds were added first in pre-incubation media and then during incubation at 1 to 20 ⁇ concentration (see Table-2) at 2 mM and 10 mM glucose.
• Insulin secretion from INS832/13 cells was measured from 2-h static incubations in KRBH containing various glucose concentrations, 0.5% defatted BSA and pharmacological agents or vehicle (DMSO), with or without 35 mM KCI or 0.3 mM palmitate, as specified (see Peyot et al. , 2009-Adipose Triglyceride Lipase Is Implicated in Fuel- and Non-fuel-stimulated Insulin Secretion— J Biol Chem, 284: pp. 16848-16859). The experiments were done 3 times, with triplicates of each measurement.
• Example 8 In vivo experiment: In this experiment— CD1 strain mice were injected once with streptozotocin (100 mg/kg body wt) to induce mild diabetes. After 4 weeks, the mice were fasted overnight and oral glucose tolerance test (OGTT) was done. Half the animals (5) received ABHD6 inhibitor, WWL70 for the three days prior to OGTT, daily, intraperitoneatly (at 5mg/kg body weight) and the other half received only vehicle. For OGTT, glucose was given by gavage (2g / kg body wt), followed by blood collection at indicated time points (on the graph) for the analysis of blood glucose (by glucometer) and plasma insulin (by ELISA).
• OGTT glucose tolerance test
• mice that received compound 1 (VWVL70) were able to control their blood glucose levels better than the mice which were given vehicle. This is related to the increase in plasma insulin levels in mice that received compound 1 — indicating that the compound increases insulin secretion in the presence of glucose and thus able to control glycemia.

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• 2012
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