WO2011128394A1 - 5-(pyrrolidine-1-carbonyl) pyrrolidine 3-substituée et ses dérivés à usage dans le traitement de troubles métaboliques - Google Patents

5-(pyrrolidine-1-carbonyl) pyrrolidine 3-substituée et ses dérivés à usage dans le traitement de troubles métaboliques Download PDF

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Publication number
WO2011128394A1
WO2011128394A1 PCT/EP2011/055864 EP2011055864W WO2011128394A1 WO 2011128394 A1 WO2011128394 A1 WO 2011128394A1 EP 2011055864 W EP2011055864 W EP 2011055864W WO 2011128394 A1 WO2011128394 A1 WO 2011128394A1
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WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
compound according
alkyl
mmol
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PCT/EP2011/055864
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English (en)
Inventor
Oscar Barba
William Gattrell
Donald Smyth
Simon Swain
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Prosidion Limited
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Publication of WO2011128394A1 publication Critical patent/WO2011128394A1/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
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • R5 is hydrogen or Cl-4alkyl
  • said l ,2,4-oxadiazol-3-yl, 1 ,2,4-oxadiazol-5-yl or tetrazol-5-yl may be substituted by C 1.4 alkyl, such as propyl (e.g., 3-isopropyl-l ,2,4-oxadiazol-5-yl, 5-isopropyl-l ,2,4-oxadiazol-3- yl or 2-isopropyl-2H-tetrazol-5-yl), C ⁇ .4 haloalkyl,such as difluoromethyl or fluoromethylethyl, Ci .5 hydroxyalkyl (e.g.
  • Pyridin-2-yl or pyrimidin-2-yl may be unsubstituted or substituted with one or more halo groups, e.g. 5-chloro- or 5-fluoro- pyrimidin- or pyridine-2-yl, C i .4 alkyl, such as ethyl, propyl or butyl (e.g. 5-isopropyl- or 5-ethylpyrimidin-2-yl or 5-isopropylpyridin-2-yl), .
  • halo groups e.g. 5-chloro- or 5-fluoro- pyrimidin- or pyridine-2-yl, C i .4 alkyl, such as ethyl, propyl or butyl (e.g. 5-isopropyl- or 5-ethylpyrimidin-2-yl or 5-isopropylpyridin-2-yl), .
  • R 3 may be hydrogen or methyl.
  • isotopically labeled compounds of formula (I) and (la) 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) and (la) or salts thereof are not isotopically labelled.
  • 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.
  • Esters of formula (VIII) can be prepared by reaction of compounds of formula (VI) with anilines or phenols of formula (VII) under standard conditions, such as K 2 C0 3 in DMF at 80°C.
  • Compounds of formula (III) as described above can be prepared by saponification of esters of formula (VIII) under standard conditions, for example, LiOH in 5: 1 methanol / water.
  • Ketones of formula (XV) can be prepared from alkynes of formula (XIV) by treatment with mercury oxide and sulphuric acid in methanol / water at 80°C. Treatment of ketones of formula (XV) with diethylaminosulfur trifluoride in a suiable solvent, such as DCM, gives difluoro compounds of formula (XVI).
  • alcohols of formula (XVII) can be prepared by treatment of ketones of formula (XV) under standard conditions, for example, sodium borohydride in methanol. Treatment of alcohols of formula (XVII) with diethylaminosulfur trifluoride in a suitable solvent, such as DCM, gives monofluoro compounds of formula (XVIII).
  • 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 syntheses using either solution or solid phase chemistry, using procedures known to those skilled in the art.
  • the compounds of the invention are useful as GPR119 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.
  • composition is comprised of a pharmaceutically acceptable carrier and a nontoxic therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • Methanesulfonic acid 3-[l-(3-iert-butyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]propyl ester (Preparation 47) was condensed with 6 -hydro xy-2 -methylnicotinic acid ethyl ester employing a similar method to that outlined in Preparation 7, but using MEK as the solvent, and heating the reaction for 16 h. The product was hydrolysed, employing a method similar to that outlined in
  • Purification method A The crude mixture was passed directly down an SCX cartridge, eluting with MeOH followed by NH 4 OH in MeOH. The basic fraction was collected and concentrated in vacuo to afford the title compound as the free amine.
  • Purification method B As purification method A but the product was purified further by preparative HPLC to afford the title compound as the trifluoroacetate salt.
  • Purification method C As purification method B. After preparative HPLC the product was passed down a second SCX cartridge, eluting with MeOH followed by NH 4 OH in MeOH. The basic fraction was collected and concentrated in vacuo to afford the title compound as the free amine.
  • Example 2 The building block used in the synthesis of Example 2 was prepared employing the methods outlined in WO2007/003962.
  • the building block used in the synthesis of Examples 4, 6, 7, 14 and 24 were prepared employing the methods outlined in WO2008081205.
  • the building blocks used in the synthesis of Examples 5, 9, 10 and 20 were prepared employing the methods outlined in WO2008/081207:
  • the biological activity of the compounds of the invention may be tested in the following assay systems:
  • DPP-IV activity was measured by monitoring the cleavage of the fluoro genie 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.
  • Assays were carried out in 96-well plates (Black OptiPlate-96F) in a total volume of 100 ⁇ ⁇ per well consisting of 50 mM Tris pH 7.6, 100 ⁇ GP-AMC, 10-25 ⁇ recombinant human DPP-IV and a range of inhibitor dilutions in a final concentration of 1 % DMSO. Plates were read in a fluorimeter after 30 min incubation at 37°C.
  • Recombinant human DPP-IV residues Asn29-Pro766 was purchased from BioMol.
  • Compounds of the invention of formula (la) generally have an IC 50 of ⁇ 20 ⁇ .
  • HIT -T 15 cells (passage 60) were obtained from ATCC, and were cultured in RPMI1640 medium supplemented with 10% fetal calf serum and 30 nM sodium selenite. All experiments were done with cells at less than passage 70, in accordance with the literature, which describes altered properties of this cell line at passage numbers above 81 (Zhang HJ, Walseth TF, Robertson RP. Insulin secretion and cAMP metabolism in HIT cells. Reciprocal and serial passage-dependent relationships. Diabetes. 1989 Jan;38(l):44-8).
  • 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.
  • HIT -T 15 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 EC 50 of less than 10 ⁇ .
  • Blood samples (20 ⁇ are then taken 25, 50, 80, 120, and 180 min after Glc administration.
  • the 20 ⁇ ⁇ blood samples for measurement of Glc levels are 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 are then added to 180 ⁇ ⁇ of Trinders glucose reagent (Sigma enzymatic (Trinder) colorimetric method) in a 96-well assay plate. After mixing, the samples are left at room temperature for 30 min before being read against Glc standards (Sigma glucose/urea nitrogen combined standard set).
  • Compounds of the invention preferably statistically reduce the Glc excursion at doses ⁇ 100 mg kg -1 .

Abstract

La présente invention se rapporte à des composés thérapeutiques de formule (I) ayant une activité d'agonistes de GPR119 et utiles au traitement de troubles métaboliques, y compris le diabète de type II.
PCT/EP2011/055864 2010-04-14 2011-04-13 5-(pyrrolidine-1-carbonyl) pyrrolidine 3-substituée et ses dérivés à usage dans le traitement de troubles métaboliques WO2011128394A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1006166.1A GB201006166D0 (en) 2010-04-14 2010-04-14 Compounds for the treatment of metabolic disorders
GB1006166.1 2010-04-14

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5069813B2 (ja) * 2010-10-14 2012-11-07 第一三共株式会社 アシルベンゼン誘導体
WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5069813B2 (ja) * 2010-10-14 2012-11-07 第一三共株式会社 アシルベンゼン誘導体
JP2012224640A (ja) * 2010-10-14 2012-11-15 Daiichi Sankyo Co Ltd アシルベンゼン誘導体
WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique

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