WO2013026587A1 - Dérivés de pyrolidin-3-yl-amine 1,4 disubstituée et leur utilisation pour le traitement de troubles métaboliques - Google Patents

Dérivés de pyrolidin-3-yl-amine 1,4 disubstituée et leur utilisation pour le traitement de troubles métaboliques Download PDF

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WO2013026587A1
WO2013026587A1 PCT/EP2012/057964 EP2012057964W WO2013026587A1 WO 2013026587 A1 WO2013026587 A1 WO 2013026587A1 EP 2012057964 W EP2012057964 W EP 2012057964W WO 2013026587 A1 WO2013026587 A1 WO 2013026587A1
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preparation
phenyl
pyrrolidin
methyl
piperidin
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PCT/EP2012/057964
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English (en)
Inventor
Oscar Barba
Lisa Sarah Bertram
Emma Louise Carswell
Susan Helen Davis
Peter Timothy Fry
Robert James Gleave
Revathy Perpetua Jeevaratnam
Craig Johnstone
John Keily
Martin James Procter
Karen Lesley Schofield
Alan John William Stewart
Simon Andrew Swain
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Prosidion Limited
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Publication of WO2013026587A1 publication Critical patent/WO2013026587A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention is directed to therapeutic compounds useful for the treatment of metabolic disorders including type II diabetes.
  • the present invention is 5 directed to compounds which have activity as agonists of GPR1 19.
  • Drugs aimed at the pathophysiology associated with non-insulin dependent type II diabetes have many potential side effects and do not adequately address the dyslipidaemia and hyperglycaemia in a high proportion of patients. Treatment is often focused at individual patient needs using diet, exercise, hypoglycaemic agents and insulin, but there is a0 continuing need for novel antidiabetic agents, particularly ones that may be better tolerated with fewer adverse effects.
  • metabolic syndrome places people at high risk of coronary artery disease, and is characterized by a cluster of risk factors including central obesity (excessive fat tissue in the abdominal region), glucose intolerance, high triglycerides and low5 HDL cholesterol, and high blood pressure.
  • central obesity excessive fat tissue in the abdominal region
  • glucose intolerance high triglycerides
  • low5 HDL cholesterol low5 HDL cholesterol
  • Obesity is characterized by an excessive adipose tissue mass relative to body size.
  • body fat mass is estimated by the body mass index (BMI; weight (kg)/height0 (m) 2 ), or waist circumference.
  • BMI body mass index
  • Individuals are considered obese when the BMI is greater than 30 and there are established medical consequences of being overweight. It has been an accepted medical view for some time that an increased body weight, especially as a result of abdominal body fat, is associated with an increased risk for diabetes, hypertension, heart disease, and numerous other health complications, such as arthritis, stroke, gallbladder5 disease, muscular and respiratory problems, back pain and even certain cancers.
  • GPR119 (previously referred to as GPR116) is a GPCR identified as SNORF25 in0 WO00/50562 which discloses both the human and rat receptors, US 6,468,756 also discloses the mouse receptor (accession numbers: AAN95194 (human), AAN95195 (rat) and A 95196 (mouse)).
  • GPR1 19 is expressed in the pancreas, small intestine, colon and adipose tissue. The expression profile of the human GPR1 19 receptor indicates its potential utility as a target for the treatment of diabetes.
  • GPR119 agonists have been shown to stimulate the release of GLP-1 from the GI tract. In doing so, GPR119 agonists (1) enhance glucose-dependent insulin release from the pancreas leading to improvements in oral glucose tolerance; (2) attenuate disease progression by increasing ⁇ -cell cAMP concentrations; and (3) induce weight loss possibly through GLP-1 's ability to reduce food intake.
  • DPP-IV Dipeptidyl peptidase IV
  • GLP- 1 Dipeptidyl peptidase IV
  • DPP-IV inhibitors are of use for the treatment of type II diabetes, examples of DPP-IV inhibitors include vildagliptin, sitagliptin, alogliptin and saxagliptin.
  • WO 2009/034388, WO 2010/103333, WO 2010/103334 and WO 2010/103333 disclose dual GPR119 agonists and DPP-IV inhibitors.
  • the compounds of the invention preferably have dual activity as agonists of GPR1 19 and inhibitors of DPP-IV
  • the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof:
  • A is a para-linked phenyl, pyridinyl, pyrimidinyl, pyrazinyl or triazinyl;
  • R1 is hydrogen, halo, cyano, Ci _4alkyl, C ⁇ ⁇ haloalkyl, Ci _4alkoxy or
  • N-pyridonyl optionally substituted by one or more groups independently selected from halo, methyl or halomethyl groups
  • R3 is C3_5cycloalkyl, 4 to 6 membered saturated heterocyclyl (comprising 1 or 2 ring heteroatoms selected from ⁇ , O and S) or Ci _4alkyl wherein the C3_ cycloalkyl and Ci _ 4alkyl are optionally substituted by one to three groups independently selected from halo, cyano, hydroxy or Ci ⁇ alkoxy;
  • p and q are each 0, 1 or 2, provided that 0 ⁇ p+q ⁇ 2;
  • Z is selected from the group consisting of:
  • heteroaryl ring or fused bicyclic system optionally substituted by one or two groups independently selected from halo, cyano, C1 .4 alkyl, Ci _4haloalkyl, Ci _4alkoxy, Ci _4hydroxyalkyl, Ci _4alkoxyCi _4alkyl, heterocyclyl (a 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from N , O and S), heterocyclyl Ci .
  • heterocyclyl is a 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from N, O and S
  • C3_ cycloalkyl optionally substituted by Ci _4 alkyl, C i .4 alkoxy or halo
  • R4 is selected from the group consisting of:
  • R7 is hydrogen, halo, C ⁇ .2 alkyl, C ⁇ ⁇ haloalkyl or C ⁇ .3 alkoxy;
  • (la) p and q are independently 0, 1 or 2 provided that p+q does not exceed 2, i.e., forming a 4-, 5- or 6-membered ring.
  • p and q may be the same, i.e., forming a 4- or 6-membered ring.
  • p and q are both 1, therefore the compounds of the invention may have the formula:
  • A is suitably pyridine, pyrimidine or pyrazine typically pyridine or pyrimidine, e.g., 2- or 3-pyridyl or 2- or 5-pyrimidinyl, where the 2-, 3- or 5- refers to the point of attachment of the pyrrolidine ring (X being attached in the para position and R 1 being attached at any suitable position).
  • R1 is suitably hydrogen, halogen or cyano.
  • R ⁇ is preferably hydrogen.
  • R ⁇ may optionally be substituted by 1, 2 or 3 substituents.
  • R ⁇ is optionally substituted by 1 or 2 substituents and in further embodiments it is substituted by 2 or 3 substituents.
  • R ⁇ is preferably optionally substituted by 1, 2, or 3 substituents independently selected from halo and methyl.
  • R ⁇ is preferably optionally substituted by 1 or 2 substituents independently selected from halo and methyl.
  • R ⁇ is suitably phenyl substituted by 1, 2 or 3 groups selected from halo and methyl groups.
  • R ⁇ is suitably phenyl substituted by 2 or 3 halo groups.
  • Halo is suitably fluoro.
  • R ⁇ may be an optionally substituted phenyl or pyridyl, e.g.
  • R ⁇ examples include phenyl, 2-pyridinyl, 4-fluoro-2-pyridinyl, 5-fluoro-2-pyridinyl, 4- methyl-2-pyridinyl, 5-methyl-2-pyridinyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4- trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6- trifluorophenyl, 2-fluoro-5-methylphenyl and 2,4-difluoro-5-methylphenyl.
  • R3 may suitably be C3_ cycloalkyl or Ci _4 alkyl wherein the Ci _4 alkyl is optionally substituted by one to three groups independently selected from halo, cyano, hydroxy or Ci _2alkoxy.
  • Suitable examples of include methyl, ethyl, n-propyl, i-propyl, cyclopropyl, CH 2 CH 2 OCH 3 and CH 2 CF 3 .
  • Z is -C(0)OR ⁇ . In further embodiments Z is C(0)R ⁇ . In still further embodiments it is S(0)2R ⁇ .
  • R4 may suitably be C ⁇ alkyl, C ⁇ _ alkoxyC2-6alkyl, C3_ cycloalkyl or C3.
  • R ⁇ examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl or t-butyl, cyclopropyl and 1-methylcyclopropyl.
  • R ⁇ is propyl, especially isopropyl.
  • Z may be a heteroaryl group optionally substituted by one or two groups selected from halo, C 1.4 alkyl, Ci _4haloalkyl, Ci _4alkoxy, Ci _4alkoxyCi _4alkyl, Ci ⁇ hydroxyalkyl,
  • Ci _4haloalkyls are perfluoroalkyls, e.g. CF 3 , CF2Me and CHF 2
  • suitable heteroaryl groups include oxadiazole, pyrimidine, pyridazine, thiazole, tetrazole, benzothiazole and thiadiazole, e.g., oxadiazole and pyrimidine.
  • Z may comprise l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5- yl, pyrimidin-2-yl or a 2H-tetrazol-5-yl, which may be substituted by any of the aforementioned substituents.
  • Z is a substituted heteroaryl
  • suitable substituents include ethyl, i-propyl, t- butyl, cyclopropyl, chloro, 1-methylcyclopropyl, CF 3 , CH 2 F, CF 2 H, CH(OMe)Me, C(Me) 2 OH, C(Me) 2 F, CF 2 Me, CH 2 OMe and 2-tetrahydrofuranyl.
  • R ⁇ is preferably hydrogen.
  • the molecular weight of the compounds of the invention is suitably less than about 800, typically less than about 600.
  • the invention also includes isotopically labeled compounds, which are similar to those recited in formulae (I), (la) and (lb) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3 ⁇ 4, ⁇ C, and ⁇ F.
  • Isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 ⁇ 4, l ⁇ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 ⁇ 4, and carbon-14, i.e., ⁇ C, isotopes are particularly preferred for their ease of preparation and detectability. and isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging.
  • isotopically labeled compounds of formula (I), (la) and (lb) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds of formula (I), (la) and (lb) or salts thereof are not isotopically labelled.
  • alkyl means carbon chains which may be linear or branched. Examples of alkyl groups include ethyl, propyl, isopropyl, butyl, sec- and tert-butyl. Such alkyl groups may in some embodiments be substituted with one or more halo groups, particularly fluoro.
  • cycloalkyl refers to a 3 to 6 C saturated carbocycle moiety e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • heterocyclyl refers to a 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from N, O and S.
  • heterocycles include tetrahydrofuran, pyrrolidine, tetrahydropyran, piperidine, oxetane and azetidine.
  • heteroaryl refers to a 5- or 6-membered aromatic heteroaryl ring optionally containing one or more, e.g. 1 , 2 or 3 heteroatoms selected from N, O and S, or a 8 to 10 membered fused aromatic bicyclic system optionally containing one or more, e.g.
  • heteroaryl rings 1, 2 or 3 heteroatoms selected from N, O and S.
  • heteroaryl rings include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazolyl and benzothiazolyl.
  • Reference to para-linked in relation to ring A refers to the relative positions of the carbonyl group and the pyrrolidine group.
  • Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the present invention includes all stereoisomers of the compounds of the invention and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically drawn or stated otherwise.
  • the present invention includes any possible solvates and polymorphic forms.
  • a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone or the like can be used.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • organic non-toxic bases from which salts can be formed include arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trimethamine and the like.
  • the compound of the invention When the compound of the invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, trifluoroacetic acid and the like.
  • the compounds of the invention are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis).
  • R 3 , R 4 , R 5 , R 6 , R 7 , A, Z, p, q and r are as defined for formula (I).
  • PG is a protecting group
  • LG is a leaving group
  • Hal is halogen
  • Het is heteroaryl.
  • Esters of formula (V) can be prepared by S A T displacement of suitable haloaromatic compounds of formula (III) with amines of formula (IV) under standard conditions, for example, DBU and DMSO at 80 - 100°C.
  • Acids of formula (VI) can be prepared from esters of formula (V) under standard conditions, for example, LiOH, water and methanol at room temperature.
  • Amides of formula (II) can be prepared from acids of formula (VI) with amines of formula (VII) under standard amide coupling conditions, for example, HOBT and EDCI, in a suitable solvent, such as DCM.
  • Sulfonamides of formula (XIV) can be prepared from amines of formula (VIII) and sulfonyl chlorides of formula (XIII) under standard conditions, for example, triethylamine in a suitable solvent, such as DCM. Removal of the protecting group PG from the amine functionality in compounds of formula (XIV) can be achieved using standard conditions well known to those skilled in the art.
  • Compounds of formula (VII) where Z is heteroaryl can be prepared as outlined in Scheme 6.
  • Compounds of formula (XVI) can be prepared by S displacement of suitable haloaromatic compounds of formula (XV) with amines of formula (VIII) under standard conditions, for example, DBU and DMSO at 80 - 100°C.
  • compounds of formula (XVI) can be prepared by reaction of suitable haloaromatic compounds of formula (XV) with amines of formula (VIII) under Buchwald-Hartwig conditions, such as, Pd2(dba and ⁇ in a suitable solvent, such as toluene at 1 10°C. Removal of the protecting group PG from the amine functionality in compounds of formula (XVI) can be achieved using standard conditions well known to those skilled in the art.
  • VIM XV XVI VII Compounds of formula (IV) where R 2 is N-pyridonyl can be prepared as outlined in Scheme 7.
  • Compounds of formula (XVIII) can be prepared from alcohols of formula (XVII) under standard conditions, for example, methanesulfonyl chloride and triethylamine in a suitable solvent, such as, THF at 0°C.
  • Diazabicyclo compounds of formula (XIX) can be prepared from compounds of formula (XVIII) by treatment with sodium hydride in a suitable solvent, such as, THF at 0°C.
  • Compounds of formula (XX) can be prepared from compounds of formula (XIX), pyrid-2-one and potassium tert-butoxide in a suitable solvent, such as, ⁇ in a microwave reactor at 100°C. Removal of the protecting group PG' from the amine functionality in compounds of formula (XX) can be achieved using standard conditions well known to those skilled in the art.
  • the compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1 ,000, compounds and more preferably 10 to 100 compounds of formula (I).
  • Compound libraries may be prepared by a combinatorial "split and mix” approach or by multiple parallel synthesis using either solution or solid phase chemistry, using procedures known to those skilled in the art.
  • labile functional groups in the intermediate compounds e.g. hydroxy, carboxy and amino groups
  • the protecting groups may be removed at any stage in the synthesis of the compounds of formula (I) or may be present on the final compound of formula (I).
  • a comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in, for example, Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts, (1991) Wiley-Interscience, New York, 2 nd edition.
  • the compounds of the invention are useful as GPR1 19 agonists, e.g. for the treatment and/or prophylaxis of diabetes.
  • the compounds of the invention will generally be administered in the form of a pharmaceutical composition.
  • the compounds of the invention may also be useful as dual GPR1 19 agonists/DPP- IV inhibitors, e.g. for the treatment and/or prophylaxis of diabetes.
  • the compounds of the invention will generally be administered in the form of a pharmaceutical composition.
  • the invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, in combination with a pharmaceutically acceptable carrier.
  • composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the invention also provides a pharmaceutical composition for the treatment of disease by modulating GPR1 19 and optionally DPP-IV, resulting in the prophylactic or therapeutic treatment of diabetes, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of the invention, or a pharmaceutically acceptable salt thereof.
  • compositions may optionally comprise other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds of the invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • a pharmaceutical carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous).
  • compositions can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion.
  • the compound of the invention, or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy.
  • such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • the compounds of the invention can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • any convenient pharmaceutical media may be employed.
  • water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or lOOOmg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, using a compound of the invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient
  • dosage levels on the order of O.Olmg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day.
  • obesity may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day. It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the compounds of the invention may be used in the treatment of diseases or conditions in which GPRl 19 and optionally DPP-IV play a role.
  • the invention also provides a method for the treatment of a disease or condition in which GPRl 19 and optionally DPP-IV play a role comprising a step of administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • diseases or conditions diabetes, obesity, impaired glucose tolerance, insulin resistance and diabetic complications such as neuropathy, nephropathy, retinopathy, cataracts, cardiovascular complications and dyslipidaemia).
  • the compounds of the invention may also be used for treating metabolic diseases such as metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and hypertension.
  • the invention also provides a method for the treatment of type II diabetes, comprising a step of administering to a patient in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method for the treatment of obesity, metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension comprising a step of administering to a patient in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition as defined above.
  • the invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition as defined above.
  • treatment includes both therapeutic and prophylactic treatment.
  • the compounds of the invention may exhibit advantageous properties compared to known compounds or combination therapies for the treatment of diabetes.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof, may be administered alone or in combination with one or more other therapeutically active compounds.
  • the other therapeutically active compounds may be for the treatment of the same disease or condition as the compounds of the invention or a different disease or condition.
  • the therapeutically active compounds may be administered simultaneously, sequentially or separately.
  • the compounds of the invention may be administered with other active compounds for the treatment of obesity and/or diabetes, for example insulin and insulin analogs, gastric lipase inhibitors, pancreatic lipase inhibitors, sulfonyl ureas and analogs, biguanides, a2 agonists, glitazones, PPAR- ⁇ agonists, GPR40 agonists, mixed PPAR- ⁇ / ⁇ agonists, RXR agonists, fatty acid oxidation inhibitors, a-glucosidase inhibitors, ⁇ -agonists, phosphodiesterase inhibitors, lipid lowering agents, glycogen phosphorylase inhibitors, antiobesity agents e.g.
  • pancreatic lipase inhibitors MCH-1 antagonists and CB-1 antagonists (or inverse agonists), amylin antagonists, lipoxygenase inhibitors, somostatin analogs, glucokinase activators, glucagon antagonists, insulin signalling agonists, PTP1B inhibitors, gluconeogenesis inhibitors, antilypolitic agents, GSK inhibitors, galanin receptor agonists, anorectic agents, CCK receptor agonists, leptin, serotonergic/dopaminergic antiobesity drugs, reuptake inhibitors e.g.
  • sibutramine CRF antagonists, CRF binding proteins, thyromimetic compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-1 inhibitors or sorbitol dehydrogenase inhibitors.
  • Combination therapy comprising the administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one other agent represents a further aspect of the invention.
  • the present invention also provides a method for the treatment of diabetes in a mammal, such as a human, which method comprises administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another agent, to a mammal in need thereof.
  • the invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another agent for the treatment of diabetes.
  • the invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in combination with another agent, for the treatment of diabetes.
  • the compound of the invention, or a pharmaceutically acceptable salt thereof, and the other agent(s) may be co-administered or administered sequentially or separately.
  • Co-administration includes administration of a formulation which includes both the compound of the invention, or a pharmaceutically acceptable salt thereof, and the other agent(s), or the simultaneous or separate administration of different formulations of each agent. Where the pharmacological profiles of the compound of the invention, or a pharmaceutically acceptable salt thereof, and the other agent(s) allow it, coadministration of the two agents may be preferred.
  • the invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another agent in the manufacture of a medicament for the treatment of diabetes.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and another antiobesity agent, and a pharmaceutically acceptable carrier.
  • the invention also encompasses the use of such compositions in the methods described above.
  • Gradient information 0.0-0.3 min 100% H 2 0; 0.3 ⁇ 1.25 min: Ramp up to 10% H 2 O-90% MeCN; 4.25-4.4 min: Ramp up to 100% MeCN; 4.4-4.9 min: Hold at 100% MeCN; 4.9-6.0 min: Return to 100% H 2 O.
  • the mass spectra were obtained using an electrospray ionisation source in either the positive (ES + ) or negative (ES ⁇ ) ion modes.
  • LCMS-method 2 Phenomenex Kinetex C18 column (3.0x30mm, 2.6 ⁇ , flow rate l .OmL/min) eluting with a H 2 0-MeCN solution containing 0.1% HCO 2 H over 2 min with UV detection at 220 nm.
  • Gradient information 0.0-0.1 min 2% MeCN 98% H 2 0 to 5% MeCN 95% H 2 0; 0.1-1.50 min: Ramp up to 100% MeCN; 1.5-1.75min: Hold at 100% MeCN; 1.75-1.8min: 100% MeCN to 2% MeCN 98% H 2 0 ; 1.8-2.0 min: Hold at 2% MeCN 98% H 2 0.
  • the mass spectra were obtained using an electrospray ionisation source in both the positive (ES + ) or negative (ES ⁇ ) ion modes.
  • LCMS-method 3 data were obtained as follows: Xbridge C18 column (3.0 x 150mm, 5 ⁇ , flow rate l .OmL/min) eluting with an MeCN-lOmM NH 4 HCO 3 solution over 5 min with UV detection at 215 - 350nm. Gradient information: 0-0.1 min: hold at 5% MeCN 95% NH4HCO3; 0.1 -3.0 min: 5% MeCN 95%NH4HC0 3 to 5% NH4HCO3 95% MeCN; 3.0- 3.9min: hold at 5% NH4HCO3 95% MeCN.
  • the mass spectra were obtained using an electrospray ionisation source in the positive (ES + ) mode.
  • LCMS -method 4 data were obtained as follows: Xbridge Ci 8 column (2.1 x 50mm, 2.5 ⁇ , flow rate 0.8mL/min) eluting with an MeCN-lOmM NH 4 HCO 3 solution over 1.5 min with UV detection at 215 - 350nm. Gradient information: 0-0.8 min: 98% MeCN 2% NH4HCO3 to 98% NH4HCO3 2% MeCN; 0.8-1.2min: hold at 98% NH4HCO3 2% MeCN. The mass spectra were obtained using an electrospray ionisation source in the positive (ES ⁇ ) mode.
  • Preparative HPLC purification was carried out using either a standard or basic method.
  • Standard method Gemini-NX Ci 8 column (21.2 x 100mm, 5 ⁇ , flow rate 20mL/min) eluting with a H 2 0-MeCN solution containing 0.1% HC0 2 H using a 10 minute gradient with UV detection at 220 nm.
  • Preparation 31 [l-(3-Ethyl-[l,2,4] eridin-4-yl]-methyl-amine
  • Preparation 171 [(3 ⁇ ,45)-1- ⁇ 5-[ ⁇ 1-[3-(1,1- ⁇ - ⁇ 1)-[1,2,4] ⁇ 3 ⁇ 3 ⁇ 1-5 ⁇ 1]- piperidin-4-yl ⁇ -(2,2,2-trifluoro-ethyl)-carbamoyl]-pyrimidin-2-yl ⁇ -4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid teri-butyl ester
  • the title compound was prepared by reacting 2-[(3R,45')-3-iert- butoxycarbonylamino-4-(2,5-difluoro-phenyl) ⁇ yrrolidin-l-yl] ⁇ yrimidine-5-carboxylic acid (Preparation 80) with ?ra «s- ⁇ l-[3-(l ,l-difluoro-ethyl)-[l,2,4]oxadiazol-5-yl]-3-fluoro- piperidin-4-yl ⁇ -methyl-amine (Procedure 30) employing a procedure similar to that outlined in Preparation 95 to afford the title compound as a mixture of diastereoisomers.
  • Preparation 176 [(3/?,45)-4-(2,4-Difluoro-5-methyl-phenyl)-l-(5- ⁇ [l-(3-isopropyl- [ 1 ,2 ,4] oxa diazol-5-yl)-piperidin-4-yl] -methyl-carbamoyl ⁇ -pyrimidin-2 -yl)-pyr r olidin-3 - yl]-carbamic acid teri-b
  • Preparation 180 [(3/?,45)-l-(5- ⁇ [l-(5-Chloro-pyrimidin-2-yl)-piperidin-4-yl]-ethyl- carbamoyl ⁇ -pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester
  • Acetic anhydride (665mL, 7.05mol) was added in one portion to l-(2,5-difluoro- phenyl)-2-nitro-ethanol (Preparation 187, 672g, 3.31mol) at 0 °C under argon.
  • DMAP 28.3g, 0.23mol was added and the solution darkened in colour.
  • the reaction was warmed to r.t. over 18 h.
  • the reaction mixture was cautiously poured into NaHC(3 ⁇ 4 (sat. aq., 3.5L) and stirred to form a yellow solid.
  • the slurry was stirred for 30 min at r.t. before filtering.
  • the solid was washed with NaHC(3 ⁇ 4 (sat.
  • the resulting paler yellow solution was stirred at -10 °C for 1 h before quenching cautiously with aHC0 3 (sat. aq., 1 L). The two batches were combined and the layers partitioned. The DCM layer was washed with water (2L) then brine (2L), dried over MgS0 4 and evaporated to give 209g of an orange oil. The material was purified by dry flash chromatography eluting with DCM to afford the title compound.
  • Triethylamine (244mL, 1.75mol) was added to a solution of l-benzyl-4-(2,5- difluoro-phenyl)-pyrrolidin-3-ylamine (Preparation 190, 252g, 0.87mol) in THF (3.8L) and the cloudy light brown solution was cooled to 0 °C.
  • Di-tert-butyldicarbonate (229g, 1.05mol) was added in one portion and the suspension warmed to room temperature over 18 h. The THF was removed by evaporation and the off-white slurry taken up into EtOAc (2.5L).
  • Nitromethane (274mL, 5.10mol) was added in one portion to a solution of 2,4,5- trifluorobenzaldehyde (680g, 4.25mol) in MeOH (7.2L) in a 10 L jacketed vessel.
  • the solution was cooled to 0 °C (jacket -10 °C) and a solution of NaOH (204g, 5.10mol) in water (680mL) was added over 30 min. A 5 °C exotherm was observed.
  • the solution was stirred for 30 min (jacket 0 °C) after which time a white precipitate had formed.
  • Half of the material was transferred to a second vessel and both slurries stirred for a further 30 min becoming very thick.
  • Acetic anhydride (849mL, 8.99mol) was added to 2-nitro-l -(2,4,5-trifluoro-phenyl)- ethanol (Preparation 194, 935g, 4.22mol) at 0 °C under argon.
  • DMAP 36g, 0.30mol was added in one portion and the solution darkened in colour. The temperature reached 50 °C over 20 min before cooling back to 0 °C. The solution was allowed to warm to r.t. over 18 h. The reaction mixture was cautiously poured into aHC0 3 (sat. aq., 6L) and stirred to form a yellow solid. The slurry was stirred for 30 min at r.t. before filtering and washing with NaHCCh (sat.
  • Triethylamine (210mL, 1.51mol) was added to l-benzyl-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-3-ylamine (Preparation 197, 23 lg, 0.75mol) in THF (1.8L) and the light brown cloudy solution was cooled to 0 °C.
  • Di-tert-butyldicarbonate (198g, 0.91mol) was added in one portion and the suspension warmed to room temperature over 18 h. The suspension was concentrated and the off-white slurry dissolved into EtOAc (2.5L). The solution was washed with water (3 x 1L) and brine (1L) then dried over MgS0 4 and evaporated to give a pale yellow oil.
  • Preparation 205 [(S ⁇ -l-IS-CCyclopropyl-il-IS-Cl-methoxy-l-methyl-ethyl)- [l,2,4]oxadiazol-3-yl]-piperidin-4-yl ⁇ -carbamoyl)-pyrimidin-2-yl]-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl -carbamic acid tert-but l ester
  • reaction mixture was diluted with EtOAc (50mL) and water (20mL); aqueous layer was back-extracted with more EtOAc, then the organics were combined, washed with brine (20mL), dried (MgS0 4 ), filtered and concentrated in vacuo.
  • Example 1 2-[(3/?,45)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine- 5-carboxylic acid cyclopropyl-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- amide hydrochloride
  • Example 2 2-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid [l-(3-iso ropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-methyl-amide
  • Example 3 2-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid ethyl-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amide hydrochloride
  • Example 4 2-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid ⁇ l-[3-(l-fluoro-l-methyl-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl ⁇ - methyl-amide hydrochloride
  • Example 84 2- [(3/?,45)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l -yl] - pyrimidine-5-carboxylic acid [l-(3-ethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-methyl- amide hydrochloride
  • Example 85 2-[(3/?,4S)-3-Amino-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-l-yl]- pyrimidine-5-carboxylic acid [l-(3-ethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-methyl- amide hydrochloride
  • Example 86 2-[(3/?,4S)-3-Amino-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-l-yl]- pyrimidine-5-carboxylic acid [l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- methyl-amide hydrochloride
  • Example 87 2-[(3/?,4S)-3-Amino-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-l-yl]- pyrimidine-5-carboxylic acid ethyl-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4- yl]-amide hydrochloride
  • Example 89 2-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid cyclopropyl- ⁇ l-[5-(l-methoxy-l-methyl-ethyl)-[l,2,4]oxadiazol-3-yl]- piperidin-4-yl ⁇ -amide hydrochloride
  • Example 90 2-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid cyclopropyl- ⁇ l-[5-(l,l-difluoro-ethyl)-[l,2,4]oxadiazol-3-yl]-piperidin- 4-yl ⁇ -amide hydrochloride
  • Example 91 2-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid cyclopropyl- ⁇ l-[(/?)-5-(tetrahydro-furan-3-yl)-[l,2,4]oxadiazol-3-yl]- piperidin-4-yl ⁇ -amide h drochloride
  • Example 92 2-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid cyclopropyl- ⁇ l-[(5)-3-(tetrahydro-furan-3-yl)-[l,2,4]oxadiazol-5-yl]- piperidin-4-yl ⁇ -amide
  • Example 94 2-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid cyclopropyl-[l-(2-ethyl-2H-tetrazol-5-yl)-piperidin-4-yl]-amide hydrochloride
  • Example 95 2-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid cyclopropyl- ⁇ l-[3-(tetrahydro-pyran-4-yl)-[l,2,4]oxadiazol-5-yl]- piperidin-4-yl ⁇ -amide
  • Example 96 2-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid cyclopropyl- ⁇ l-[3-(l-methoxy-cyclopropyl)-[l,2,4]oxadiazol-5-yl]- piperidin-4-yl ⁇ -amide
  • Example 97 2-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid cyclopropyl- ⁇ l-[(5)-3-(tetrahydro-furan-2-yl)-[l,2,4]oxadiazol-5-yl]- piperidin-4-yl ⁇ -amide hydrochloride
  • Example 98 2-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid cyclopropyl- ⁇ l-[(/?)-3-(tetrahydro-furan-2-yl)-[l,2,4]oxadiazol-5-yl]- piperidin-4-yl ⁇ -amide h drochloride
  • Example 99 5-[(3/?,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrazine-2- carboxylic acid ⁇ l-[3-(l,l-difluoro-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl ⁇ -methyl- amide hydrochloride
  • Example 100 6-[(3 J R,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-7V- ⁇ l-[3-(l,l- difluoro-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl ⁇ -7V-methyl-nicotinamide hydrochloride
  • Example 101 6-[(3/?,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-5-cyano-iV-
  • the biological activity of the compounds of the invention may be tested in the following assay systems:
  • GPR119 cAMP Assay A stable cell line expressing recombinant human GPR1 19 was established and this cell line was used to investigate the effect of compounds of the invention on intracellular levels of cyclic AMP (cAMP).
  • the cell monolayers were washed with phosphate buffered saline and stimulated at 37°C for 30 min with various concentrations of compound in stimulation buffer plus 1% DMSO. Cells were then lysed and cAMP content determined using the Perkin Elmer AlphaScreenTM (Amplified Luminescent Proximity Homogeneous Assay) cAMP kit. Buffers and assay conditions were as described in the manufacturer's protocol.
  • DPP-IV activity was measured by monitoring the cleavage of the fluorogenic peptide substrate, H-Gly-Pro-7-amino-4-methylcoumarin (GP-AMC) whereby the product 7-amino-
  • 4-methylcoumarin is quantified by fluorescence at excitation 380 nm and emission 460 nm.
  • Asn29-Pro766 was purchased from BioMol.
  • HIT-T15 cells (passage 60) were obtained from ATCC, and were cultured in
  • HIT-T15 cells were plated in standard culture medium in 96-well plates at 100,000 cells/ 0.1 mL/ well and cultured for 24 h and the medium was then discarded. Cells were incubated for 15min at room temperature with ⁇ ⁇ stimulation buffer (Hanks buffered salt solution, 5mM HEPES, 0.5mM IBMX, 0.1% BSA, pH 7.4). This was discarded and replaced with compound dilutions over the range 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 ⁇ in stimulation buffer in the presence of 0.5% DMSO. Cells were incubated at room temperature for 30 min.
  • ⁇ ⁇ stimulation buffer Hors buffered salt solution, 5mM HEPES, 0.5mM IBMX, 0.1% BSA, pH 7.4
  • 75 uL lysis buffer (5mM HEPES, 0.3% Tween-20, 0.1% BSA, pH 7.4) was added per well and the plate was shaken at 900 rpm for 20 min. Particulate matter was removed by centrifugation at 3000rpm for 5 min, then the samples were transferred in duplicate to 384-well plates, and processed following the Perkin Elmer AlphaScreen cAMP assay kit instructions. Briefly 25 ⁇ reactions were set up containing 8 ⁇ sample, 5 ⁇ acceptor bead mix and 12 ⁇ detection mix, such that the concentration of the final reaction components is the same as stated in the kit instructions. Reactions were incubated at room temperature for 150 min, and the plate was read using a Packard Fusion instrument.
  • Measurements for cAMP were compared to a standard curve of known cAMP amounts (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000 nM) to convert the readings to absolute cAMP amounts. Data was analysed using XLfit 3 software. Representative compounds of the invention were found to increase cAMP at an EC5 0 of less than 10 ⁇ . Compounds showing an EC5 0 of less than 1 ⁇ in the cAMP assay may be preferred.
  • HIT-T15 cells are plated in standard culture medium in 12-well plates at 106 cells/ 1 ml/ well and cultured for 3 days and the medium then discarded. Cells are washed x 2 with supplemented Krebs-Ringer buffer (KRB) containing 1 19 mM NaCl, 4.74 mM KC1, 2.54 mM CaCl 2 , 1.19 mM MgS0 4 , 1.19 mM KH 2 P0 4 , 25 mM NaHC0 3 , 10 mM HEPES at pH 7.4 and 0.1% bovine serum albumin. Cells are incubated with 1ml KRB at 37°C for 30 min which is then discarded.
  • KRB Krebs-Ringer buffer
  • Compounds of the invention preferably increase insulin secretion at an EC5 0 of less than 10 ⁇ .
  • the effects of compounds of the invention on oral glucose (Glc) tolerance may be evaluated in male Sprague-Dawley rats. Food is withdrawn 16 h before administration of Glc and remains withdrawn throughout the study. Rats have free access to water during the study. A cut is made to the animals' tails, then blood (1 drop) is removed for measurement of basal Glc levels 60 min before administration of the Glc load. Then, the rats are weighed and dosed orally with test compound or vehicle (20% aqueous hydroxypropyl-yS- cyclodextrin) 45 min before the removal of an additional blood sample and treatment with the Glc load (2 g kg 1 p.o.).
  • Blood samples are taken from the cut tip of the tail 5, 15, 30, 60, 120, and 180 min after Glc administration. Blood glucose levels are measured just after collection using a commercially available glucose-meter (OneTouch® UltraTM from Lifescan). Compounds of the invention preferably statistically reduce the Glc excursion at doses ⁇ 100 mg kg -1 .
  • the effects of compounds of the invention on oral glucose (Glc) tolerance were evaluated in male C57B1/6 or male ob/ob mice. Food was withdrawn 5 h before
  • mice had free access to water during the study. A cut was made to the animals' tails, then blood (20 ⁇ ,) was removed for measurement of basal Glc levels 45 min before administration of the Glc load. Then, the mice were weighed and dosed orally with test compound or vehicle (20% aqueous hydroxypropyl-yS-cyclodextrin or 25% aqueous Gelucire 44/14) 30 min before the removal of an additional blood sample (20 ⁇ ) and treatment with the Glc load (2-5 g kg 1 p.o.). Blood samples (20 ⁇ ) were then taken 25, 50, 80, 120, and 180 min after Glc administration.
  • the 20 blood samples for measurement of Glc levels were taken from the cut tip of the tail into disposable micro-pipettes (Dade Diagnostics Inc., Puerto Rico) and the sample added to 480 ⁇ , of haemolysis reagent. Duplicate 20 ⁇ , aliquots of the diluted haemolysed blood were then added to 180 ⁇ , of Trinders glucose reagent (Sigma enzymatic (Trinder) colorimetric method) in a 96-well assay plate. After mixing, the samples were left at room temperature for 30 min before being read against Glc standards (Sigma glucose/urea nitrogen combined standard set). Compounds of the invention statistically reduced the Glc excursion at doses ⁇ 100 mg kg -1 , for example at a dose of 30 mg kg 1 the compound of Example 6 showed a > 40% reduction in the Glc excursion.

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Abstract

L'invention porte sur des composés thérapeutiques répondant à la formule générale (I) qui sont utiles pour le traitement de troubles métaboliques, notamment le diabète de type II. Les composés ont une activité comme agonistes du GPR1 19. Les composés ayant une stéréochimie telle que dans la formule (Ia) peuvent également faire preuve d'activité d'inhibition de la DPP-IV.
PCT/EP2012/057964 2011-08-22 2012-05-01 Dérivés de pyrolidin-3-yl-amine 1,4 disubstituée et leur utilisation pour le traitement de troubles métaboliques WO2013026587A1 (fr)

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CN110099898A (zh) * 2016-10-24 2019-08-06 优曼尼蒂治疗公司 化合物及其用途
CN111303083A (zh) * 2020-03-31 2020-06-19 安徽中羰碳一工业技术有限责任公司 一种3-氨甲基四氢呋喃的合成方法
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof

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CN110099898B (zh) * 2016-10-24 2023-07-25 优曼尼蒂治疗公司 化合物及其用途
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