WO2011071840A1 - Inhibitors of diacylglycerol acyltransferase - Google Patents

Inhibitors of diacylglycerol acyltransferase Download PDF

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Publication number
WO2011071840A1
WO2011071840A1 PCT/US2010/059158 US2010059158W WO2011071840A1 WO 2011071840 A1 WO2011071840 A1 WO 2011071840A1 US 2010059158 W US2010059158 W US 2010059158W WO 2011071840 A1 WO2011071840 A1 WO 2011071840A1
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Prior art keywords
benzazepin
dihydro
imidazo
mmol
compound
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PCT/US2010/059158
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English (en)
French (fr)
Inventor
Macklin Brian Arnold
Thomas James Beauchamp
Emily Jane Canada
Erik James Hembre
Jianliang Lu
John Robert Rizzo
John Mehnert Schaus
Qing Shi
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Eli Lilly And Company
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Priority to EP10799154.9A priority Critical patent/EP2509981B1/en
Priority to AU2010328410A priority patent/AU2010328410B2/en
Priority to JP2012543187A priority patent/JP5631411B2/ja
Priority to BR112012013918A priority patent/BR112012013918A2/pt
Priority to CN201080055334.9A priority patent/CN102666543B/zh
Priority to ES10799154.9T priority patent/ES2509922T3/es
Priority to EA201200868A priority patent/EA020128B1/ru
Priority to CA2783684A priority patent/CA2783684C/en
Priority to MX2012006646A priority patent/MX2012006646A/es
Priority to KR1020127014795A priority patent/KR101395428B1/ko
Publication of WO2011071840A1 publication Critical patent/WO2011071840A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention provides compounds that inhibit diacylglycerol acyltransferase 1 (DGAT-1).
  • DGAT-1 a key enzyme in triglyceride synthesis may provide a novel approach to treating obesity and/or improving insulin sensitivity.
  • DGAT is reported to be an excellent target for a small molecule inhibitor, only a limited number of compounds have been reported to inhibit DGAT-1 activity. No known DGAT- 1 inhibitors are approved for pharmaceutical use. Hence, there is a need for more small molecules that inhibit DGAT- 1.
  • DGAT-1 inhibitor compounds having a desirable pharmacological profile.
  • thianecarboxamides Cycloalkyl, lactam, lactone, and related compounds are reported in W098/28268 (We et.al.) as inhibitors of ⁇ -amyloid peptide release for use in the treatment of Alzheimer's Disease.
  • Acylbenzazepines are disclosed in US patent 5,696,111 (Balwin etal.) as compounds that may be used to treat arrhythmias.
  • the presently claimed imidazo-benzazepines are structurally diverse from those of Cheng, We, and Balwin.
  • Azepinone compounds are reported to be modulators of DGAT in WO 2010/056496, published 20 May 2010.
  • the azepinone compounds reported in WO 2010/056496 are structurally diverse from the presently claimed imidazo-benzazepines.
  • Compounds of this invention are potent inhibitors of DGAT- 1.
  • This invention provides a desired novel treatment option acting through a pharmacological mechanism that is unique compared to commercially available treatments. Further, certain compounds of this invention selectively inhibit DGAT- 1 as compared to DGAT-2.
  • the pharmacological profile of compounds of this invention, as selective DGAT- 1 inhibitors, can be particularly desirable for use in the treatment of obesity and/or improving insulin sensitivity.
  • This invention provides compounds of formula I:
  • R 1 is selected from the group consisting of H, F, CI, -CF 3 , -CH 3 , -OH,
  • R 2 is selected from the group consisting of H and -CH 3 ;
  • R 3 is selected from the group consisting of H and -CH 3 ; provided that at least one of the group consisting of R 2 and R 3 is H; and
  • n 1, 2, or 3.
  • this invention provides compounds of formula I
  • R 1 is selected from the group consisting of H, F, CI, -CF 3 , -CH 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH(CH 3 ) 2 , -O-cyclopropyl, -0-CH 2 -phenyl, -OC(H)F 2 , and -OCF 3; n is 1 or 3; and R 2 and R 3 are each H.
  • this invention provides compounds of formula I
  • R 1 is selected from the group consisting of H, F, CI, -CF 3 , -CH 3 , -OH, -OCH 3 ,
  • n 1.
  • this invention provides compounds of formula I
  • R 1 is selected from the group consisting of H, F, CI, -CF 3 , -CH 3 , -OH,
  • n 3.
  • this invention provides compound of the formula I
  • R 1 is selected from the group consisting of H, F, CI, -CF 3 , -CH 3 , -OH, -0(Ci-C 4 alkyl), -O-cyclopropyl, -0-CH 2 -phenyl, -OC(H)F 2 , and -OCF 3 ; n is 3; and R 3 is H.
  • this invention provides compound of the formula I
  • R 1 is selected from the group consisting of H, F, CI, -CF 3 , -CH 3 , -OH, -0(Ci-C 4 alkyl), -O-cyclopropyl, -0-CH 2 -phenyl, -OC(H)F 2 , and -OCF 3 ; n is 1; and R 3 is H.
  • R 1 is selected from the group consisting of F, CI, -CF 3 , -CH 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 ,
  • R 1 is selected from the group consisting of F, CI, and -0(Ci-C 4 alkyl) are preferred.
  • the compounds of formula I may be in the form of a racemic mixture.
  • the preferred isomer is the "R" stereo form, illustrated herein below as Formula II.
  • this invention provides compounds of formula I having the following isomeric conformation, illustrated as formula II:
  • Compounds of formula I may be synthesized and the R and the S isomers may then separated by chiral chromatography. Compounds of formula I may be synthesized using chiral synthesis to specifically synthesize the preferred R isomer.
  • a further embodiment of this invention provides the use of a compound as claimed by the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diabetes and/or obesity.
  • Another embodiment of the invention is a compound as claimed by the present invention, or a salt thereof, for use in treating obesity.
  • a further embodiment of this invention is a compound as claimed herein or a pharmaceutically acceptable salt thereof for use in therapy.
  • a further embodiment of the invention is a compound as claimed by the present invention, or a pharmaceutically acceptable salt thereof for use in the treatment of diabetes.
  • the invention relates to a compound as claimed by the present invention for use in improving insulin sensitivity in a mammal.
  • This invention provides a method for treating obesity in a mammal, comprising the step of administering to the mammal a compound as claimed by the present invention or a pharmaceutically acceptable salt thereof.
  • This invention provides a method for treating diabetes and/or improving insulin sensitivity in a mammal, comprising the step of administering to the mammal a compound as claimed by the present invention or a pharmaceutically acceptable salt thereof.
  • a further embodiment of this invention is a method for treating dyslipidemia in a mammal comprising the step of administering to the mammal a compound as claimed by the present invention or a pharmaceutically acceptable salt thereof.
  • a further embodiment of this invention is a method for treating acne in a mammal comprising the step of administering to the mammal a compound as claimed by the present invention or a pharmaceutically acceptable salt thereof.
  • a further embodiment of this invention is a method for treating hepatitis C virus (HCV) infection comprising the step of administering to the mammal a compound as claimed by the present invention or a pharmaceutically acceptable salt thereof.
  • HCV hepatitis C virus
  • the present invention also relates to pharmaceutical compositions comprising a compound as claimed by the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a further embodiment is a pharmaceutical composition of the present invention further comprising a second pharmaceutical agent.
  • the present invention relates to formulations comprising a compound as claimed by the present invention, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and hydroxypropyl methylcellulose.
  • a further embodiment is a pharmaceutical formulation wherein the hydroxyproyl methylcellulose is hydroxypropyl methylcellulose acetate succinate (HPMC-AS-L).
  • HPMC-AS-L hydroxypropyl methylcellulose acetate succinate
  • a further embodiment is a process for preparing a formulation comprising contacting a compound as claimed by the present invention, or a pharmaceutically acceptable salt thereof, with hydroxypropylmethyl cellulose.
  • a further embodiment is a process for preparing a pharmaceutical formulation wherein the hydroxymethyl cellulose is hydroxypropyl methylcellulose acetate succinate (HPMC-AS-L).
  • “Pharmaceutically-acceptable salt” refers to salts of the compounds of the invention considered to be acceptable for clinical and/or veterinary use. These salts may be prepared by methods known to the skilled artisan. Pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al, HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES,
  • compositions administered by a variety of routes.
  • pharmaceutically acceptable carrier means that the carrier, diluent, excipients and salt are pharmaceutically compatible with the other ingredients of the composition. Most preferably, these compositions are for oral administration.
  • Pharmaceutically acceptable compositions and processes for preparing same are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19 th ed., Mack Publishing Co., 1995).
  • the compounds of the invention can be prepared using the methods illustrated in
  • N,N-Dimethylformamide (DMF); Methyl tert-butyl ether (MTBE); tetrahydrofuran (THF); simulated moving bed (SMB) chromatography; methanol (MeOH); lithium hydroxide (LiOH); N-methyl-2- pyrrolidone (NMP); copper iodide (Cul); [l,3-Bis(2,6-diisopropylphenyl)imidazol-2- ylidene] (3-chloropyridyl) Pd (II) dichloride : Cu(I) iodide (PEPPSITM); N,N- Dimethylethylamine (DMEA); and 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6
  • R 1 is selected from the group consisting of H, F, CI, -CF 3 , -CH 3 , -OH, -0(Ci-C 4 alkyl), -O-cyclopropyl, -0-CH 2 -phenyl, -OC(H)F 2 , and -OCF 3 . More preferably, R 1 is -0(Ci-C 4 alkyl) or CI. Most preferably, R 1 is -OCH 2 CH 3 or CI.
  • the collection of isomer 1 is from 0.4-0.9 min and collection of isomer 2 is from 2.4-4.2 min.
  • the desired isomer (Isomer 2; R isomer) is the second eluter: benzyl N-[(4R)-5,6-dihydro-4H-imidazo[l,2-a][l]benzazepin-4- yl]carbamate. Concentrate the product containing fractions under reduced pressure to give the title compound (615 g, 73%) as a white solid: MS (m/z): 334 (M+l).
  • R 1 is selected from the group consisting of H, F, CI, -CF 3 , -CH 3 , -OH, -0(Ci-C 4 alkyl), -O-cyclopropyl, -0-CH 2 -phenyl, -OC(H)F 2 , and -OCF 3 ;
  • R 2 is selected from the group consisting of H and CH 3 ;
  • R 4 is CH 2 CH 3 .
  • Preparations 32 and 35 are purified by recrystallization from ethanol.
  • Preparations 33 and 34 are purified by flash
  • Preparation 36 may be used without purification.
  • Preparation 37 is purified by recrystallization from methanol.
  • Example 3 The Examples in Table 3 may be prepared essentially as described by the method of Example 3.
  • HATU hexafluorophosphate
  • N,N-dimethylformamide 4 mL
  • Add diisopropylethylamine (0.21 mL, 1.19 mmol) and stir the reaction for approximately 16 hours at ambient temperature under nitrogen. Dilute the reaction with ethyl acetate, wash with saturated sodium bicarbonate and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure. Purify the residue by flash chromatography (3% ammonia (2M) solution in methanol/dichloromethane) to give the title compound (131.0 mg, 68%): MS (m/z): 405 (M+l).
  • Example 17 may be prepared essentially as described by the method in Example MS (m/z): 387 (M+l). Yield 63%.
  • R 1 is selected from the group consisting of H, F, CI, -CF 3 , -CH 3 , -OH, -0(Ci-C 4 alkyl), -O-cyclopropyl, -0-CH 2 -phenyl, -OC(H)F 2 , and -OCF 3 ;
  • R 2 is selected from the group consisting of H and CH 3 ;
  • Preparation 48 may be prepared essentially as described by the method of Preparation 47, but using 5,6-dihydro-4H-imidazo[l,2-a][l]benzazepin-4-amine.
  • Preparation 49 may be prepared essentially as described by the method of Preparation 47 but using l-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (commercially available). Purify by flash chromatography using a gradient within the range of 20-90% ethyl acetate/hexane. MS (m/z): 411 (M+l).
  • Preparation 51 may be prepared essentially as described by the method of Preparation 50 but using tert-butyl N-[l-(5,6-dihydro-4H-imidazo[l,2-a][l]benzazepin-4- ylcarbamoyl)cyclopentyl]carbamate. MS (m/z): 311 (M-l).
  • Preparation 52 may be prepared essentially as described by the method of Preparation 50, but using tert-butyl N-[l-(5,6-dihydro-4H-imidazo[l,2-a][l]benzazepin- 4-ylcarbamoyl)cyclopropyl]carbamate. MS (m/z): 283 (M+l).
  • Example 4 may be prepared essentially as described by the method of Example 18 but using the reagents listed in column 3.
  • dichloromethane/dichloromethane gradient ranging from 0-80%.
  • HATU hexafluorophosphate
  • DIEA diisopropylethylamine
  • Example 5 may be prepared essentially as described by the method of Example 21 using the reagent in Column 3 in place of 4-chlorobenzoic acid and using approximately 16 hour reaction times using chiral and racemic amines. Purification is done by flash chromatography using either (Method 1; Examples 22, 23, 24, 25, 27, 28, 29, 30, 31 and 32): a 3-5% ammonia (2M) solution in methanol in
  • Examples 26 an ethyl acetate/hexane gradient ranging from 25-90%.
  • the racemic mixture may be separated and the isomers isolated by the chromatography conditions listed under Methods A, B, C, D, E and F.
  • Racemic mixtures may be separated into the R and S isomers.
  • Conditions for chiral chromatography :
  • Eluent isocratic conditions with a range of 20-30% ethanol with a 0.2% isopropyl amine modifier and CO2.
  • Examples (second column) are separated into Isomers 1 (R Isomer) and 2 (S Isomer) using the chromatographic methods A, B, C, D, E and F.
  • Examples 29, 30, 20, 8 and 6 are separated using Method A;
  • Examples 10, 13, 18, 19 and 15 are separated using Method B;
  • Examples 14, 12 and 1 1 are separated using Method C;
  • Example 7 is separated using Method D;
  • Example 9 is separated using Method E;
  • Preparation 47 is separated using Method F. Isomers 1 (R Isomer) and 2 (S Isomer), the Example number of the Isomer, and the retention times of the isomers are shown in Column 1.
  • Table 7 may be prepared essentially as described by the Method in Example 49. Table 7
  • Scheme J depicts an alternate procedure for the synthesis of N-[l-[[(4R)-5,6- dihydro-4H-imidazo[l,2-a][l]benzazepin-4-yl]carbamoyl]cyclopropyl]-4-ethoxy- benzamide.
  • dichloromethane Combine the organic layers, and stir for 0.5 to 1 h at 15 to 25 °C. Filter through a pad of silicon dioxide (20 kg), and wash the pad with 60 kg of
  • ethanol/methanol/N,N-diethylmethylamine 70:30:0.1 v:v:v; Feed: -173 g crude/L in eluent (mobile phase); Extract: 220.60 niL/min; Raffmate: 46.22 niL/min; Eluent: 245.03 niL/min; Feed: 21.80 niL/min; Recycling: 382.38 niL/min; Period: 1.00 minutes;
  • Recrystallization of ethyl l-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylate Charge an 800 L reactor with crude ethyl l-[(4- ethoxybenzoyl)amino]cyclopropanecarboxylate (14.19 kg) and dichloromethane (144kg). Stir the mixture 25 ⁇ 2 °C for 30 minutes to give a clear solution. Add Hexanes (191 kg) over a period of 30 minutes into the above solution. Stir the resulting product slurry at 25 ⁇ 2 °C for 20 minutes, then remove dichloromethane by vacuum distillation at 20 ⁇ 5 °C.
  • Dissolve the first portion in 1 1 kg of dichloromethane and concentrate again at 55 °C and 600 to 200 mbar. After evaporating to dryness, dissolve the resulting solid in 1 1 kg dichloromethane and the resulting solution is sampled for NMR determination of residual ethanol. Evaporate to dryness at 55 °C and p 600 to 200 mbar. Re-dissolve in 11 kg dichloromethane. Transfer organic solution to a new drum, rinse the rotavap with 5.5 kg dichloromethane and combine the rinse solution with the first concentrate.
  • dichloromethane and then combine with the other concentrate solutions. Inertize a 160 L reactor and transfer to the reactor. Charge reactor at 20 °C with 34 L of dichloromethane, 10.4 kg of l-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylic acid and 17.5 L of triethylamine. Cool the resulting solution to -20 °C within 50 minutes. Add 27 L of T3P slowly to the reaction mixture via addition tank within 3 hrs at -20 °C. Stir the reaction for 9 hrs at -18 °C. Warm the reaction to -3 °C within 40 minutes. Add 42 L of water within 45 minutes, allowing the temperature to rise to 6 °C forming a bright yellow suspension.
  • reaction mixture After 45 minutes at 20 °C, the reaction mixture is still a suspension. Add 17 L of dichloromethane to achieve complete dissolution of solids after 20 minutes. After phase separation (25 minutes), remove the aqueous layer (pH 8) and wash the organic dichloromethane phase with 43 L of water. After phase separation, remove the aqueous layer (pH 9). Wash the organic dichloromethane layer a second time with 42 L of water. After phase separation (15 minutes), transfer the organic layer to a new drum. Wash the aqueous layers and transfer into the reactor and wash two times with 21 L of
  • DGAT-1 enzyme assay Inhibitors of DGAT-1 are identified with an in vitro enzymatic assay which uses recombinant human DGAT- 1 expressed in sf9 insect cells as an enzyme source.
  • DGAT- 1 enzyme is produced by infecting cells with recombinant baculovirus containing a DGAT-1 expression vector. After 48hr infection cells are harvested by centrifugation, resuspended in cold 20mM NaCl, and disrupted with a Dounce homogenizer. Fifteen milliliters of 20mM NaCl are added to a cell pellet for each liter of infected cell suspension. DNA in the homogenate is sheared by pulling the cell extract through a 25 gauge needle.
  • DGAT-1 activity in the baculovirus infected cell homogenate is compared to homogenate from uninfected cells to assess background enzymatic activity associated with sf9 cells.
  • Assays are performed in 96 well plates using a modification of the assay described by Coleman (Methods in Enzymology 209. pp98-102 (1992)). Briefly, compounds are tested in a 1 :3 serial dilution scheme from 100 ⁇ to 1.7 nM final concentration.
  • the enzyme reaction mixture contains substrates 250 ⁇ 1 ,2-sn-diacylglycerol (Avanti Polar Lipids), 5 ⁇ 14 C oleoyl CoA, and 45 ⁇ oleoyl CoA in an aqueous buffer containing 150 mM Hepes buffer pH7.4, 0.7% vol/vol Triton® X-100 and CompleteTM protease inhibitors. Two micrograms of sf9 homogenate is used per reaction well. The total reaction volume is 50 ⁇ .
  • Adipocyte Triglyceride Synthesis Assay This assay measures the ability of compounds to inhibit triglyceride synthesis in intact mouse 3T3-L1 adipocytes.
  • Undifferentiated 3T3-L1 cells are cultured in 96 well plates at a density of 25,000 cells per well using standard tissue culture conditions. After two days in culture, the cells are differentiated to adipocytes by placing them in media supplemented with 0.5mM 1- methyl-3-isobutylxanthine (IBMX), 10 ⁇ g/mL insulin and ⁇ ⁇ dexamethasone. After five days in culture, cells are grown in media supplemented only with 10 ⁇ g/mL insulin. Assays are performed after cells have been in culture 12 days. To begin the assay, culture media is removed from the cells and replaced with 50 ⁇ OptiMEM® media containing 0.375 ⁇ /well 14 C acetate.
  • IBMX 1- methyl-3-isobutylxanthine
  • Assays are performed after cells have been in culture 12 days. To begin the assay, culture media is removed from the cells and replaced with 50 ⁇ OptiMEM® media containing 0.375 ⁇ /well 14 C a
  • Cells are then incubated at 37°C in 7.5% C0 2 for 4 hours. At the end of this incubation, media is removed, cells are washed once with Hank's balanced salts, and 25 ⁇ of 0.7% Triton® X-100 is added to each well and allowed to extract the cells for 5 minutes. At the end of this period, 75 ⁇ of a solution containing 58.8% isopropanol, 14.7% n-heptane, 1 1.5% water, 12.5% ethanol, and 2.5% IN sodium hydroxide is added to each well and plates are shaken on an orbital shaker for 2 minutes. 100 ⁇ of heptane is then added and plates are shaken for another 2 minutes.
  • Concentration response curves and EC5 0 values for compounds are derived from the raw data using ActivityBase (IDBS) data analysis software. Compounds are tested substantially by the adipocyte triglyceride synthesis assay method described herein.
  • Oil bolus absorption model Based on the experiments of Buhman et al. (Journal of Biological Chemistry 277 pp25474-25479 (2002)) which demonstrated that DGAT-1 is involved in lipid absorption from the small intestine, an in vivo model of DGAT- 1 inhibition was developed which measures plasma triglyceride levels following oral administration of an olive oil bolus to rats.
  • Compounds are administered via oral gavage in a vehicle of 10% ethanol/90% corn oil at a volume of 1 ml/kg.
  • a 0.5 ml blood sample is collected via the tail vein.
  • a 3.0 ml bolus of olive oil is administered by oral gavage.
  • a final blood sample is collected from the tail vein 6 hours after compound administration.
  • Plasma is prepared from blood samples by centrifugation and analyzed for both triglyceride content, using a Hitachi 912 clinical chemistry analyzer, and test compound levels. The effective dose that reduces the increase in plasma triglyceride by 50% (ED50) and 80% (EDso) is determined.
  • DGAT-1 inhibition is indicative of the ability of the test compound to inhibit the increase in plasma triglyceride that occurs between hours 4 and 6 of the study (between 14 and 16 hours in the modified model) in vehicle treated (control) animals.
  • compound is administered 14 hours prior to the first blood sample collection and oil bolus administration. The final blood sample is collected at 16 hours after dosing.
  • the 10% ethanol/90% corn oil vehicle is administered, without compound, at 10 hours after compound dosing to be consistent with the shorter duration version of the model.
  • Compounds are tested substantially by the oil bolus absorption rat model method described herein.
  • the data are analyzed using meta-analysis.
  • the overall ED50 (ED 8 o) is estimated as the weighted average of ED 50 (ED 80 ) from individual studies, with the weights being the inverse of variance of EDso (ED 8 o) estimates.
  • the homogeneity Q-test is performed. If the test is significant at 0.10 level, a mixed-effect model is used to include both inter- study and intra-study variability.
  • the weights are adjusted to the inverse of the sum of inter-study variance and the intra-study variance of EDso (ED 8 o) from individual studies.
  • the inter-study variance is estimated by the Paule-Mandel estimator.
  • QNMR quantitative nuclear magnetic resonance
  • Compound dosing twice daily, commences after 7 days of vehicle dosing. Animals are given compound 30 minutes prior to the dark phase of the dark/light cycle and, if desired, again 5.5 hours into the dark phase. Compound dosing continues for 15 to 22 days during which time food intake and body weight are measured daily. On day 14 of the experiment, body composition is measured for a second time by QNMR. On day 15, terminal bleeds are taken from two animals per test group at 0, 2, 4, and 6 hours after the final dose for measurement of test compound levels in plasma.
  • the data are analyzed using a meta-analysis.
  • the measure of treatment effect in the meta- analysis is the group mean difference between treatment and control group.
  • the measure of treatment effect is %CFICFC itself.
  • the overall treatment effect is estimated as the weighted average of treatment effect from individual studies, with the weights being the inverse of variance of individual study's treatment effect estimates. The homogeneity Q-test is performed. If the test is significant at 0.10 level, then a mixed-effect model is used to include both inter-study and intra-study variability.
  • the weights are adjusted to the inverse of the sum of inter-study variance and the intra-study variance of treatment effect estimates from individual studies.
  • the inter-study variance is estimated by the Paule-Mandel estimator. (References: Sutton, A.J., Jones, D.R., Abrams, K.R., Sheldon, T.A., and Song, F., Methods for Meta-analysis in Medical Research London, John Wiley, ISBN 0-471-49066-0 (2000). Dersimonian R., and Kacker, R., Random-effects model for meta-analysis of clinical trials: An update, Contemporary Clinical Trials 28 pl05-l 14 (2007). Compounds are tested substantially by the diet-induced obese mouse model method described herein.
  • Tables 12, 13 and 14 display the results of the mean percent gain (positive) or loss (minus) in body weight, fat mass, and food intake for N-[l-[[(4R)-5,6-dihydro-4H- imidazo[l,2-a][l]benzazepin-4-yl]carbamoyl]cyclopropyl]-4-ethoxy-benzamide
  • Tables 15, 16 and 17 display the results of the mean percent gain (positive) or loss (minus) in body weight, fat mass, and food intake for 4-Chloro-N-[l-[[(4R)-5,6-dihydro- 4H-imidazo[l,2-a][l]benzazepin-4-yl]carbamoyl]cyclopropyl]benzamide (Examples 2, 21, 58).
  • Film casting Prepare sample using 350.12 mg of HPMC-AS-L, 150 mg of N-[l- [[(4R)-5,6-dihydro-4H-imidazo[l,2-a][l]benzazepin-4-yl]carbamoyl]cyclopropyl]-4- ethoxy-benzamide and 5 mL of 50/50 MeOH/Acetone solution as the solvent. Distribute portions of the solution among flat bottom Petri dishes that have been preheated to about 60 °C. Store the films in a vacuum oven at 55 °C for 3.5 hours to remove all residual solvent.
  • the HPMC polymers form an elastic film that, while easily removed, does not form a handleable powder making additional particle size reduction difficult. Grind samples with a mortar and pestle to form a uniform agglomerate size.

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US8895737B2 (en) 2010-07-16 2014-11-25 Shashank Shekhar Process for preparing antiviral compounds
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US9255074B2 (en) 2010-07-16 2016-02-09 Abbvie Inc. Process for preparing antiviral compounds
WO2020239074A1 (zh) * 2019-05-31 2020-12-03 南京明德新药研发有限公司 作为rip-1激酶抑制剂的双并环类化合物及其应用
RU2800652C2 (ru) * 2019-05-31 2023-07-25 Медшайн Дискавери Инк. Бициклическое соединение в качестве ингибитора rip-1 киназы и его применение

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Publication number Priority date Publication date Assignee Title
US8841487B2 (en) 2010-07-16 2014-09-23 Abbvie Inc. Phosphine ligands for catalytic reactions
US8895737B2 (en) 2010-07-16 2014-11-25 Shashank Shekhar Process for preparing antiviral compounds
US8975443B2 (en) 2010-07-16 2015-03-10 Abbvie Inc. Phosphine ligands for catalytic reactions
US9200021B2 (en) 2010-07-16 2015-12-01 Abbvie Inc. Phosphine ligands for catalytic reactions
US9255074B2 (en) 2010-07-16 2016-02-09 Abbvie Inc. Process for preparing antiviral compounds
US9266913B2 (en) 2010-07-16 2016-02-23 Abbvie Inc. Phosphine ligands for catalytic reactions
US9381508B2 (en) 2010-07-16 2016-07-05 Abbvie Inc. Phosphine ligands for catalytic reactions
US9434698B2 (en) 2010-07-16 2016-09-06 Abbvie Inc. Process for preparing antiviral compounds
US9669399B2 (en) 2010-07-16 2017-06-06 Abbvie Inc. Phosphine ligands for catalytic reactions
US9732045B2 (en) 2010-07-16 2017-08-15 Abbvie Inc. Process for preparing antiviral compounds
WO2020239074A1 (zh) * 2019-05-31 2020-12-03 南京明德新药研发有限公司 作为rip-1激酶抑制剂的双并环类化合物及其应用
CN114008038A (zh) * 2019-05-31 2022-02-01 南京明德新药研发有限公司 作为rip-1激酶抑制剂的双并环类化合物及其应用
CN114008038B (zh) * 2019-05-31 2023-01-24 南京明德新药研发有限公司 作为rip-1激酶抑制剂的双并环类化合物及其应用
RU2800652C2 (ru) * 2019-05-31 2023-07-25 Медшайн Дискавери Инк. Бициклическое соединение в качестве ингибитора rip-1 киназы и его применение

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