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WO2006067224A2 - Nouveaux composes - Google Patents

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Publication number
WO2006067224A2
WO2006067224A2 PCT/EP2005/057132 EP2005057132W WO2006067224A2 WO 2006067224 A2 WO2006067224 A2 WO 2006067224A2 EP 2005057132 W EP2005057132 W EP 2005057132W WO 2006067224 A2 WO2006067224 A2 WO 2006067224A2
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WO
WIPO (PCT)
Prior art keywords
spiro
benzodioxine
piperidin
phenyl
acetamide
Prior art date
Application number
PCT/EP2005/057132
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English (en)
Other versions
WO2006067224A3 (fr
Inventor
Emma Barker
Annika Jenmalm Jensen
Erik Nordling
Andrew Proud
Martin Slater
Mikael Weber
Original Assignee
Biovitrum Ab (Publ)
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE0403160A external-priority patent/SE0403160D0/sv
Application filed by Biovitrum Ab (Publ) filed Critical Biovitrum Ab (Publ)
Publication of WO2006067224A2 publication Critical patent/WO2006067224A2/fr
Publication of WO2006067224A3 publication Critical patent/WO2006067224A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, the use of the compounds for the preparation of medicaments against orexin-1 receptor-related disorders and orexin-2 receptor-related disorders, and methods for the prophylaxis and treatment of orexin-1 receptor-related disorders and orexin-2 receptor-related disorders.
  • orexins/hypocretins are two neuropeptides encoded by the common precursor preproorexin.
  • Mammalian orexin-A is a 33 amino acid peptide with two intrachain disulfide bonds
  • orexin-B is a 28 amino acid linear peptide (Sakurai et al. (1998) Cell 92: 573-585).
  • the orexins are mainly expressed in the lateral hypothalamus, an area known to be active in the regulation of food intake, but since orexin neurons project widely to different brain areas, other physiological roles are also implicated.
  • GPCR G protein-coupled receptor class
  • OX-IR and OX-2R have different and complementary distribution (Trivedi et al. (1998) FEBS Lett. 438: 71-75); Marcus et al. (2001) J. Comp. Neurol. 435: 6-25). It has been shown that alpha- and beta-cells in pancreatic islets express orexin-A, and that both cell types express OX-IR receptors (Ouedraogo et al. (2003) Diabetes 52: 111-117). Orexin-A increases glucagon secretion and decreases glucose-stimulated insulin release from isolated islets. Furthermore, orexin-A infusion increases plasma glucagon and glucose levels and decreases plasma insulin in fasted rats.
  • LHA The lateral hypothalamic area
  • the lateral hypothalamic area has long been known to affect hunger and ingestive behavior as well as the regulation of sleep-wakefulness (Bernardis & Bellinger (1996) Neurosci. Biobehav. Rev. 20: 189-287).
  • Administration of orexin into the LHA of rodents in the early light-phase stimulates food intake in a dose-dependent manner (Sakurai et al. (1998) Cell 92: 573-585; Haynes et al. (1999) Peptides 20: 1099-1105; Yamanaka et al. (2000) Brain Res. 859: 404-409.).
  • leptin administration can only partially block orexin-induced food intake in rats (Zhu et al. (2002) Physiol. Behav. 77: 251-257). Orexin neurons have been shown to project to the arcuate nucleus and to innervate NPY neurons (Broberger et al. (1998) J. Comp. Neurol. 402: 460-474). I.c.v. injection of orexin elicits c-Fos expression in these neurons suggesting that orexin-induced feeding may occur in part via NPY pathways (Yamanaka et al. (2000) Brain Res. 859: 404-409).
  • narcolepsy a disease characterized by disorganization of the vigilance state. Patients suffer from excessive daytime sleepiness, cataplexy, and disturbed REM sleep patterns. Recently, it was shown that the activity of isolated orexin neurons is inhibited by glucose and leptin and stimulated by ghrelin, and the orexin expression in normal as well as ob/ob mice correlates negatively with changes in blood glucose, leptin, and food intake. Orexin neuron ablated mice fail to respond to fasting with increased vigilance and activity. This indicates a link between energy balance and orexin-mediated arousal (Yamanaka et al. (2003) Neuron 38: 701-713).
  • mice with a genetic ablation of the OX-2R exhibit several of the characteristics of narcolepsy (Tokita et al. (2001) Sleep 24: A20-21; Willie et al. (2003) Neuron 38: 715-730). In contrast, OX-IR ablated mice do not have an overt behavioral phenotype and exhibit only an increased fragmentation of sleep-wake cycles (Kisanuky et al. (2001) Sleep 24: A22).
  • spiro[benzodioxane] compounds of the general Formula I are active as antagonists of orexin receptors, in particular the human orexin- 1 receptor, and potentially useful in the prophylaxis and treatment of orexin- 1 receptor-related disorders and orexin-2 receptor-related disorders.
  • this invention provides a compound of the Formula I, wherein
  • Formula I n and m are, independently, 0 or, preferably, 1 ;
  • a and Y are independently CH 2 , O or NR 2 , wherein R 2 is H or Ci-Cg alkyl, provided that one of A and Y is CH 2 , and the other one is O or NR 2 , and provided that when m is 0, then Y is CH 2 ; R 1 is
  • X is CH or N, provided that when R 1 is (c) or (d), not more than two of the groups X are N; R 3 and R 4 are independently Cj-Cg alkoxy; R 5 is H, halogen, C j -Cg alkyl, or C j -Cg alkoxy; R 6 , which is bonded to R 1 in a position wherein X is CH, is (a) - R7-CO-(CH 2 ) p -Ar, (b) - R 7 -CO-CH 2 -O-Ar,
  • R 7 is O or NH
  • R 8 is H or Ar
  • Ar is aryl or heteroaryl, Ar being optionally independently substituted with one or more of halogen, C j -
  • R 10 which is bonded to R 1 in a position wherein X is CH, is H or NH2; and pharmaceutically acceptable salts, hydrates, solvates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.
  • A is NH and Y is CH 2 .
  • R 1 is (c) or (d), such as phenyl or quinoline, in particular phenyl, and substituted with R 6 .
  • R 7 is preferably NH.
  • R 6 is (d), (e) or (f), then R 7 is preferably O.
  • R 6 is (a), (d), (e) or (f), then p is preferably 1.
  • R 6 is (d), then R 8 is preferably Ar.
  • Ar is preferably phenyl or indole. Further, Ar is preferably independently substituted with one or more Ci-Cg alkoxy groups.
  • Examples of preferred compounds of Formula I include those wherein R 6 is any one of the following groups :
  • R that are independently selected from: H, halogen, Ci-Cg alkyl, or Ci-Cg alkoxy or haloalkyl.
  • Preferred compounds of Formula I are those having the Formula II:
  • n and m are, independently, 0 or, preferably, 1 ;
  • a and Y are independently CH2, O or NR 2 , wherein R 2 is H or Cj-Cg alkyl, provided that one of A and Y is CH2, and the other one is O or NR 2 , and provided that when m is 0, then Y is CH2;
  • R 6 is selected from:
  • More preferred compounds are those having the Formula III:
  • R 6 is selected from:
  • Another object of the present invention is a compound as mentioned above for use in therapy, especially for use in the prophylaxis or treatment of an orexin-1 receptor-related disorder or an orexin-2 receptor-related disorder.
  • Another object of the present invention is a pharmaceutical formulation comprising a compound as mentioned above as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier, especially for use in the prophylaxis or treatment of an orexin-1 receptor-related disorder or an orexin-2 receptor-related disorder.
  • Another object of the present invention is a method for treating a human or animal subject suffering from an orexin-1 receptor-related disorder.
  • the method can include administering to a subject (e.g., a human or an animal, dog, cat, horse, cow) in need thereof an effective amount of one or more compounds of any of the formulae herein, their salts, or compositions containing the compounds or salts.
  • a subject e.g., a human or an animal, dog, cat, horse, cow
  • the methods delineated herein can also include the step of identifying that the subject is in need of treatment of the orexin-1 receptor-related disorder or an orexin-2 receptor-related disorder. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).
  • Another object of the present invention is a method for the prophylaxis of an orexin-1 receptor-related disorder or an orexin-2 receptor-related disorder, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.
  • Another object of the present invention is a method for modulating (e g, promoting or inhibiting) orexin-1 receptor activity or orexin-2 receptor related activity, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.
  • Another object of the present invention is a method for suppressing food intake, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.
  • Another object of the present invention is a method for suppressing appetite, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.
  • Another object of the present invention is a method for reducing weight, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.
  • Another object of the present invention is a method for reducing weight gain, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.
  • Another object of the present invention is an method for treating drug or alcohol addiction (e.g., addiction to an opiate such a morphine) or reducing the severity of one or more symptoms of drug withdrawal, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.
  • drug or alcohol addiction e.g., addiction to an opiate such a morphine
  • reducing the severity of one or more symptoms of drug withdrawal comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.
  • Another object of the present invention is the use of a compound as mentioned above for the manufacture of a medicament for use in the prophylaxis or treatment of an orexin-1 receptor-related disorder or an orexin-2 receptor-related disorder.
  • orexin-1 receptor-related disorders and orexin-2 receptor-related disorders are obesity and related disorders such as diabetes type II, dyslipidemia and the metabolic syndrome; cardiovascular diseases such as atherosclerotic vascular disease, angina pectoris, myocardial infarction and stroke; and sleeping disorders such as insomnia or narcolepsy.
  • the compounds according to the invention may also be useful for blocking the emetic response, i.e. useful in the treatment of nausea and vomiting.
  • aryl in the present description refers to a hydrocarbon ring system (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms, and having at least one aromatic ring.
  • aryloxy refers to an aryl group bonded to an oxygen atom. Examples of aryls are phenyl, pentalenyl, indenyl, indanyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl and pyrenyl.
  • heteroaryl means in the present description a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium as part of the ring system.
  • heteroaryloxy refers to a heteroaryl group bonded to an oxygen atom.
  • heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline (i e 2,3- dihydroindole), isoindoline (i.e.
  • 1,3-dihydroisoindole benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzopyrazole; benzothiazole, 2,1,3-benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-l,4-benzoxazine, 1,5- naphthyridine, 1,8-naphthyridine, pyrido[3,2-b]thiophene, tetralin, methylenedioxyindole, 2,3-dihydrobensofuran, 2,3-dihydrobensotiofen, 1,3- benzoxathiole, acridine, fenazine and xanthene. Unless otherwise stated or
  • C ⁇ alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms.
  • Examples of said lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
  • C 1-6 -alkyl For parts of the range "C 1-6 -alkyl" all subgroups thereof are contemplated such as C 1-5 -alkyl, C 1-4 - alkyl, Ci- 3 -alkyl, Ci -2 -alkyl, C 2-6 -alkyl, C 2-5 -alkyl, C 2-4 -alkyl, C 2-3 -alkyl, C 3-6 -alkyl, C 4-5 - alkyl, etc.
  • C 1-6 alkoxy (or alternatively “CpCg alkoxy”) denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms.
  • Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
  • C 1-6 -alkoxy For parts of the range "C 1-6 -alkoxy" all subgroups thereof are contemplated such as C 1-5 -alkoxy, C 1-4 -alkoxy, C 1-3 -alkoxy, C ⁇ -alkoxy, C2 -6 -alkoxy, C2 -5 -alkoxy, C2 -4 -alkoxy, C2 -3 -alkoxy, C 3-6 -alkoxy, C 4-5 -alkoxy, etc.
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • Synthesis commences with an acetalisation reaction of a hydroxyphenol derivative and a protected piperidinone to form the spiro[benzodioxane-piperidine] scaffold.
  • Suzuki coupling with different boronic acids afforded the desired N-protected compounds, which were in some cases reacted further with electrophiles such as carboxylic acids and aliphatic halides.
  • HPLC was run on HPlOOO (Agilent) using System A : ACE 3 C8-column, 50x3 mm, 1 mL/min acetonitrile/water with 0.1% TFA at 40°C , System B : YMC-column or System C : Xterra column 3.5 ⁇ m Cl 8, 3x50 mm with 0.01 M NH 4 HCO 3 , pH 10 - CH 3 CN gradient.
  • System A ACE 3 C8-column, 50x3 mm, 1 mL/min acetonitrile/water with 0.1% TFA at 40°C
  • System B YMC-column
  • System C Xterra column 3.5 ⁇ m Cl 8, 3x50 mm with 0.01 M NH 4 HCO 3 , pH 10 - CH 3 CN gradient.
  • HPLC was also run on using a Waters Xterra MS Cl 8 column (100 x 4.6 mm, 5 ⁇ ) eluting with a gradient of 5% CH 3 CN in 95% water to 95% CH 3 CN in 5% water (0.2% TFA buffer) over 3.5 min, then 95% CH 3 CN in 5% water (0.2% TFA buffer) for a further 2.5 min at a flow rate of 3 ml/min on a Waters 600E or Gilson system with monitoring at 254 nm.
  • Preparative HPLC was performed on a Gilson system equipped with Xterra 5 ⁇ m, C8, 19 x 50 mm column using 0.05 M NH 4 HCO 3 , pH 10 - CH 3 CN gradient with a flow of 25 mL/min or ACE 5 C8 using acetonitrile/water with 0.1% TFA.
  • the tert-butyl carbamate was dissolved in DCM (ImI) and TFA (0.25ml) was added. The mixtures were stirred at room temperature over night. The samples were concentrated and purified by preparative HPLC.
  • This compound was prepared according to general procedure B2 from tert-butyl 6-bromo-rH,4H-spiro[l,3-benzodioxine-2,4'-piperidine]-r-carboxylate (825 mg), 3- hydroxyphenylboronic acid (312 mg), NaHCU3 (475 mg), PdCl2dppf (77 mg).
  • This compound was prepared according to general procedure E from 2- bromoacetamide (11 mg). All material was used for the next step (hydrolysis of the ethyl carbamate).
  • This compound was prepared according to general procedure E from Nl -[3- (trifluoromethyl)phenyl]-2-chloroacetamide (25 mg). All material was used for the next step (hydrolysis of the t-butyl carbamate).
  • This compound was prepared according to general procedure E from N-(2- chloroethyl)morpholine hydrochloride (20 mg). All material was used for the next step (hydrolysis of the t-butyl carbamate).
  • This compound was prepared by the general synthetic procedure A from 5- bromo-2-hydroxybenzyl alcohol and tert-butyl 4-oxopiperidine carboxylate. Yield: 1.21 g, 42% of the title compound as an oil.
  • NMR shows mostly the pinacol ester but also the boronic acid. Yield 0.9 g as a white powder.
  • This mixture (0.160 g, 0.37 mmol), tert-butyl 6-bromo-l'H,4H-spiro[l,3- benzodioxine-2,4'-piperidine]-r-carboxylat . (0.100 g, 0.26 mmol), NaHCO 3 (0.100 g, 1.2 mmol), water (1 mL) and tetrakis palladium (0.020 g, 0.017 mmol) were dissolved in DME (4 mLl) and heated in the microwave at 130°C for 20 minutes.
  • This compound was prepared from the ethylcarbamate (53 mg, Intermediate 4) by the general procedure C to afford 25 mg of the title compound.
  • This compound was prepared from tert-butyl 6-(3-aminophenyl)-l'H,4H- spiro[l,3-benzodioxine-2,4'-piperidine]-r-carboxylate by the general synthetic procedure F.
  • the amides were further purified by preparative HPLC with an Xterra column (0.05 M NH4HCO3, pH 10 / acetonitrile, 25 mL / min). Boc-deprotection was made with DCM (0.8 mL) and TFA (0.2 mL) for ca 35 min. Evaporation of the solvent and preparative HPLC (Xterra) gave 3.3 mg of the title compound.
  • the product was dissolved in 1 mL EtOH and 0.3 mL 6M NaOH was added. The mixture was heated at 100°C over night, after which the solvent was removed. The residue was dissolved in DCM/MeOH 9:1x0.4% NH3(aq) and was run through a silica plug using the same solvent mixture as eluent. The solvent was removed and 1.2 mg (3 %) of the title compound was obtained.
  • This compound was prepared using a similar procedure as for Example 12 to afford 25 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 17 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 36 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 49 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 14 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 21 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 14 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 25 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 19 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 30 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 10 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 34 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 12 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 14 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 6.5 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 20 mg of the product.
  • This compound was prepared using the general synthetic procedure G to afford 28 mg of the product.
  • This compound was prepared using the general synthetic procedure G to afford 29 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 4 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 10 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 18 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 15 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 22 mg of the product.
  • This compound was prepared using a similar procedure as for Example 43 to afford 25 mg of the product.
  • This compound was prepared using a similar procedure as for Example 43 to afford 25 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 17 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 19 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 12 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 19 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 17 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 12 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 20 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 20 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 18 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 8 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 17 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 18 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 19 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 19 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 4 mg of the product.
  • EXAMPLE 70 2-pyridin-4-yl-N-[3-(4H-spiro[l,3-benzodioxine-2,4'-piperidin]-6-yl)phenyl]acetamide,
  • This compound was prepared using a similar procedure as for Example 12 to afford 12 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 15 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 17 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 25 mg of the product.
  • This compound was prepared using a similar procedure as for Example 12 to afford 23 mg of the product.
  • HEK293EBNA Human embryonic kidney cells stably expressing OX-IR seeded in 96- or 384- well plates are pre-loaded with Ca 2+ sensing probe Fluo-4AM fluorescent dye for 60 min before addition of test compounds (10 ⁇ M for primary screen). Fluorescent intensity, which is a measurement OfCa 2+ concentration inside the cells, is recorded using a Fluorometric imaging plate reader (FLIPR 98R 96-well format or FLIPR 3, 384- well format, Molecular Devices) and inhibition of the peak response evoked by orexin-A (EC 70 concentration) is calculated.
  • FLIPR 98R 96-well format or FLIPR 3, 384- well format Fluorometric imaging plate reader
  • Kj Potency determinations are performed utilizing the same functional assay as described for primary screening, applying the compounds in the concentration range of 340 pM to 20 ⁇ M and recording the concentration resulting in a 50% inhibition of orexin-A induced Ca 2+ release (IC 50 ) and from there calculating the inhibition constant (Kj).
  • K 1 IC 50 /(l+[S]/Km) (Cheng, Y.C. & Prushoff, W.H. (1973) Biochem. Pharmacol. 22:3099- 3108).
  • Compounds of Formula (I) exhibit K 1 values for human OX-IR in the range from 30 nM to > 2 ⁇ M (See Table I). TABLE I

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Abstract

L'invention concerne des composés de formule (I) dans laquelle R1, A, Y, n et m ont la signification indiquée dans la description, des procédés de préparation desdits composés, des compositions pharmaceutiques les comprenant, et l'utilisation desdits composés et compositions dans la prophylaxie ou le traitement de troubles associés au récepteur de l'orexine 1 et de troubles associés au récepteur de l'orexine 2. A titre d'exemples pour lesdits troubles, on peut citer l'obésité et les troubles associés de type diabète de type II, la dyslipidémie et le syndrome métabolique, les maladies cardiovasculaires de type maladie vasculaire athéroscléreuse, angine de poitrine, infarctus du myocarde et AVC, la toxicomanie, et les troubles du sommeil.
PCT/EP2005/057132 2004-12-23 2005-12-22 Nouveaux composes WO2006067224A2 (fr)

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WO2008008517A2 (fr) 2006-07-14 2008-01-17 Merck & Co., Inc. Diazépans pontés antagonistes du récepteur de l'oréxine
WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
WO2008069997A1 (fr) 2006-12-01 2008-06-12 Merck & Co., Inc. Antagonistes des récepteurs de l'orexine sous forme de composés de diazépane substitués
WO2008147518A1 (fr) 2007-05-23 2008-12-04 Merck & Co., Inc. Antagonistes de récepteur d'orexine pipéridyl pipéridine
WO2008150364A1 (fr) 2007-05-23 2008-12-11 Merck & Co., Inc. Antagonistes du récepteur de la cyclopropylpyrrolidine orexine
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010003624A2 (fr) 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
WO2010043592A1 (fr) * 2008-10-15 2010-04-22 Revotar Biopharmaceuticals Ag Inhibiteurs de la lipase destinés à être utilisés dans le traitement de l’obésité
WO2010044441A1 (fr) * 2008-10-17 2010-04-22 塩野義製薬株式会社 Dérivé amide d'acide acétique ayant une activité inhibitrice d'une lipase endothéliale vasculaire
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
WO2012080220A1 (fr) * 2010-12-13 2012-06-21 Katholieke Universiteit Leuven, K.U. Leuven R&D Nouveaux composés pour le traitement de maladies neurodégénératives
WO2012120051A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés benzyl-oxathiazine substitués avec adamantane ou noradamantane, médicaments contenant ces composés et leur utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120050A1 (fr) 2011-03-08 2012-09-13 Sanofi Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, médicaments contenant ces composés et leur utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120058A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des groupes benzyle ou hétérométhylène, leur procédé de production, leur utilisation comme médicament ainsi que produits pharmaceutiques les contenant et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120057A1 (fr) 2011-03-08 2012-09-13 Sanofi Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, agent pharmaceutique contenant ces composés et leur utilisation
US9156819B2 (en) 2011-10-19 2015-10-13 Merck Sharp & Dohme Corp. 2-pyridyloxy-4-nitrile orexin receptor antagonists
US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US9499517B2 (en) 2012-02-07 2016-11-22 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
WO2017194548A1 (fr) 2016-05-10 2017-11-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de maladies inflammatoires auto-immunes
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
US10894789B2 (en) 2016-02-12 2021-01-19 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators

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AU2003299648A1 (en) * 2002-12-12 2004-06-30 Janssen Pharmaceutica, N.V. Substituted 4-phenyl-(1,3)-dioxanes
GB0313762D0 (en) * 2003-06-13 2003-07-23 Biofocus Plc Compound libraries

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008008517A2 (fr) 2006-07-14 2008-01-17 Merck & Co., Inc. Diazépans pontés antagonistes du récepteur de l'oréxine
WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
US7951797B2 (en) 2006-12-01 2011-05-31 Merck Sharp & Dohme Corp. Substituted diazepan orexin receptor antagonists
WO2008069997A1 (fr) 2006-12-01 2008-06-12 Merck & Co., Inc. Antagonistes des récepteurs de l'orexine sous forme de composés de diazépane substitués
EP2392572A1 (fr) 2006-12-01 2011-12-07 Merck Sharp & Dohme Corp. Antagonistes des récepteurs de l'orexine sous forme de composés de diazépane substitués
WO2008150364A1 (fr) 2007-05-23 2008-12-11 Merck & Co., Inc. Antagonistes du récepteur de la cyclopropylpyrrolidine orexine
US8242121B2 (en) 2007-05-23 2012-08-14 Merck Sharp & Dohme Corp. Pyridyl piperidine orexin receptor antagonists
WO2008147518A1 (fr) 2007-05-23 2008-12-04 Merck & Co., Inc. Antagonistes de récepteur d'orexine pipéridyl pipéridine
US8569311B2 (en) 2007-05-23 2013-10-29 Merch Sharp & Dohme Corp. Pyridyl piperidine orexin receptor antagonists
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010003624A2 (fr) 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
WO2010043592A1 (fr) * 2008-10-15 2010-04-22 Revotar Biopharmaceuticals Ag Inhibiteurs de la lipase destinés à être utilisés dans le traitement de l’obésité
WO2010044441A1 (fr) * 2008-10-17 2010-04-22 塩野義製薬株式会社 Dérivé amide d'acide acétique ayant une activité inhibitrice d'une lipase endothéliale vasculaire
JPWO2010044441A1 (ja) * 2008-10-17 2012-03-15 塩野義製薬株式会社 血管内皮リパーゼ阻害活性を有する酢酸アミド誘導体
US8957219B2 (en) 2008-10-17 2015-02-17 Shionogi & Co., Ltd. Acetic acid amide derivative having inhibitory activity on endothelial lipase
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
WO2012080220A1 (fr) * 2010-12-13 2012-06-21 Katholieke Universiteit Leuven, K.U. Leuven R&D Nouveaux composés pour le traitement de maladies neurodégénératives
US9284271B2 (en) 2010-12-13 2016-03-15 Katholieke Universiteit Leuven, K.U. Leuven R&D Compounds for the treatment of neurodegenerative diseases
WO2012120050A1 (fr) 2011-03-08 2012-09-13 Sanofi Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, médicaments contenant ces composés et leur utilisation
WO2012120051A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés benzyl-oxathiazine substitués avec adamantane ou noradamantane, médicaments contenant ces composés et leur utilisation
WO2012120058A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des groupes benzyle ou hétérométhylène, leur procédé de production, leur utilisation comme médicament ainsi que produits pharmaceutiques les contenant et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120057A1 (fr) 2011-03-08 2012-09-13 Sanofi Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, agent pharmaceutique contenant ces composés et leur utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
US9156819B2 (en) 2011-10-19 2015-10-13 Merck Sharp & Dohme Corp. 2-pyridyloxy-4-nitrile orexin receptor antagonists
US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US9499517B2 (en) 2012-02-07 2016-11-22 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
US9896452B2 (en) 2012-02-07 2018-02-20 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
US10894789B2 (en) 2016-02-12 2021-01-19 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
US11434236B2 (en) 2016-02-12 2022-09-06 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
US12084437B2 (en) 2016-02-12 2024-09-10 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
WO2017194548A1 (fr) 2016-05-10 2017-11-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de maladies inflammatoires auto-immunes

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