WO2007114916A2 - Composés d'arylbenzylpipéridine - Google Patents

Composés d'arylbenzylpipéridine Download PDF

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Publication number
WO2007114916A2
WO2007114916A2 PCT/US2007/008291 US2007008291W WO2007114916A2 WO 2007114916 A2 WO2007114916 A2 WO 2007114916A2 US 2007008291 W US2007008291 W US 2007008291W WO 2007114916 A2 WO2007114916 A2 WO 2007114916A2
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phenyl
compound
methyl
piperidin
branched
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PCT/US2007/008291
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English (en)
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WO2007114916A3 (fr
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Mohammad Marzabadi
Chien-An Chen
Jiang Yu
Michael Reitman
Andersen Kim
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H. Lundbeck A/S
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Publication of WO2007114916A2 publication Critical patent/WO2007114916A2/fr
Publication of WO2007114916A3 publication Critical patent/WO2007114916A3/fr

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    • 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

Definitions

  • the present invention relates to compounds that are ligands at the MCHl receptor, and as such are useful to treat depression, anxiety or obesity.
  • MCH Melanin-concentrating hormone
  • MCHl The link between MCHl and the effects of MCH on feeding was suggested by reports on the phenotype of the MCHl knockout mice. Independent groups generated knock-out mice with the targeted deletion of the MCHl receptor. The phenotype of these mice was lean, hyperphagic and hypermetabolic, with increased resistance to diet-induced obesity (D. J. Marsh, et al., Proc. Natl. Acad. Sci. 2002, 99, 3240-3245). These observations evidence that MCHl antagonists are useful to treat obesity.
  • SNAP-7941 a selective MCHl small molecule antagonist
  • Pharmacological blockade of the MCHl receptor with SNAP-7941 produced a profile similar to clinically used anti-depressants and anxiolytics in behavioral models of depression and/ or anxiety: the rat forced-swim, rat social interaction and guinea pig maternal-separation vocalization tests.
  • the objective of the present invention is to provide compounds that are ligands at the MCHl receptor.
  • the present invention relates to compounds of Formula I.
  • each X 1 , X 2 , X 3 , X 4 and X 5 is independently CR 3 or N, provided that if one X is N then the remaining X are each CR 3 ;
  • each U 1 , U 2 , U 3 and U 4 is independently CR 4 or N, provided that if one U is N then the remaining U are each CR 4 ;
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently CR 5 or N, provided that if two Y are each N then the remaining Y are each CR 5 ;
  • Z is S(O) n or O
  • R 1 is straight chained or branched C 1 -C 7 alkyl
  • R 2 is straight chained or branched C 1 -C7 alkyl, C 3 -C7 cycloalkyl or straight chained or branched Ci -C 7 alkoxy;
  • each R 3 is independently H, straight chained or branched Ci-C 7 alkyl, straight chained or branched Ci -C 7 fluoroalkyl, straight chained or branched C 1 -C 7 alkoxy, F, Cl, Br or I;
  • each R 4 is independently H, straight chained or branched Ci-C 7 alkyl, straight chained or branched Ci-C 7 fluoroalkyl, straight chained or branched Ci-C 7 alkoxy, F, Cl, Br or I;
  • each R 5 is independently H, CH 3 , F, Cl or Br;
  • n is an integer from 0 to 2 inclusive;
  • the compound is selected from one of the specific compounds disclosed in the Experimental Section.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.
  • the present invention also provides a process for making a pharmaceutical composition comprising admixing a compound of Formula I and a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating a subject suffering from depression comprising administering to the subject a therapeutically effective amount of a compound of Formula I.
  • the present invention further provides a method of treating a subject suffering from anxiety comprising administering to the subject a therapeutically effective amount of a compound of Formula I.
  • the present invention further provides a method of treating a subject suffering from obesity comprising administering to the subject a therapeutically effective amount of a compound of Formula I.
  • the present invention is directed to the use of a compound of Formula I for the manufacture of a medicament for treating a subject suffering from depression, anxiety or obesity.
  • the term "straight chained or branched Ci-C 7 alky I" refers to a saturated hydrocarbon having from one to seven carbon atoms inclusive. Examples of such substituents include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl- 1-propyl and n-heptyl.
  • the term “straight chained or branched Ci -C 4 alkyl” refers to a saturated hydrocarbon having from one to four carbon atoms inclusive.
  • the term "straight chained or branched Ci-C 7 fluoroalkyl” refers to a saturated hydrocarbon having from one to seven carbon atoms inclusive substituted with one or more fluorine atoms. Examples of such substituents include, but are not limited to, trifluoromethyl, pentafluoroethyl, 1-fluoroethyl and 1 ,2-difluoroethyl and 2,3-difluoroheptyl. Similarly, the term “straight chained or branched C1-C4 fluoroalkyl” refers to a saturated hydrocarbon having from one to four carbon atoms inclusive substituted with one or more fluorine atoms per carbon atom.
  • straight chained or branched C1-C7 alkoxy refers to a saturated alkoxy group having from one to seven carbon atoms inclusive with the open valency on the oxygen. Examples of such substituents include, but are not limited to, methoxy, ethoxy, n-butoxy, t- butoxy and n-heptyloxy.
  • straight chained or branched Ci -C 4 alkoxy refers to a saturated alkoxy group having from one to four carbon atoms inclusive with the open valency on the oxygen.
  • C 3 -C 7 cycloalkyl refers to the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane.
  • the aromatic ring containing Y 1 , Y 2 , Y 3 and Y 4 refers to the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, in which the aromatic ring may be optionally substituted with one ore more CH3, F, Cl or Br.
  • the compound of example 2a has the following structure:
  • This compound is constructed from Formula I wherein R 1 is methyl; wherein R 2 is methoxy; wherein each X 1 , X 2 , X 3 , X 4 and X s is independently CR 3 ; wherein each R 3 is independently H or F; wherein each U 1 , U 2 , U 3 and U 4 is CR 4 ; wherein R 4 is H; wherein each Y 1 , Y 2 , Y 3 and Y 4 is CR 5 ; wherein each R 5 is independently H or F; wherein Z is S(O) n ; and wherein n is 2.
  • the invention further provides certain embodiments of the present invention that are described below.
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently CR 5 or N, provided that if one Y is N then the remaining Y are each CR 5 .
  • each U 1 , U 2 , U 3 and U 4 is independently CR 4 ; and each R 4 is independently H, straight chained or branched Ci-C 4 alkyl, F, CI, Br or I.
  • each X 1 , X 2 , X 3 , X 4 and X 5 is independently CR 3 ; and each R 3 is independently H, straight chained or branched Ci-C 4 alkyl, straight chained or branched Ci- C 4 alkoxy, F, Cl, Br or I.
  • Z is O.
  • R 1 is straight chained or branched Ci-C 4 alkyl; and each R 4 is H.
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently CR 5 ;
  • R 1 is CH 3 ; and
  • R 2 is straight chained or branched Cj-C 4 alkyl.
  • Z is S(O) n .
  • R 1 is straight chained or branched Ci-C 4 alkyl; and each R 4 is H.
  • each R 3 is independently H, straight chained or branched Ci-C 4 alkyl, straight chained or branched Ci-C 4 alkoxy, F or Cl.
  • R 2 is straight chained or branched Cj-C 4 alkoxy.
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently CR 5 ; and R 1 is CH 3 .
  • R 2 is straight chained or branched C1-C 4 alkyl.
  • R 1 is CH 3 .
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently CR S ; and n is 0.
  • the present invention is directed to the use of a compound as defined above for the manufacture of a medicament for treating a subject suffering from depression.
  • the present invention is directed to the use of a compound as defined above for the manufacture of a medicament for treating a subject suffering from anxiety.
  • the present invention is directed to the use of a compound as defined above for the manufacture of a medicament for treating a subject suffering from obesity.
  • the present invention also comprises salts of the present compounds, typically, pharmaceutically acceptable salts.
  • Such salts include pharmaceutically acceptable acid addition salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-tol
  • the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • Racemic forms may be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Separation of such diastereomeric salts can be achieved, e.g. by fractional crystallization.
  • the optically active acids suitable for this purpose may include, but are not limited to d- or 1- tartaric, madelic or camphorsulfonic acids. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix.
  • the compounds of the present invention may also be resolved by the formation and chromatographic separation of diastereomeric derivatives from chiral derivatizing reagents, such as, e.g., chiral alkylating or acylating reagents, followed by cleavage of the chiral auxiliary. Any of the above methods may be applied either to resolve the optical antipodes of the compounds of the invention per se or to resolve the optical antipodes of synthetic intermediates, which can then be converted by methods described herein into the optically resolved final products which are the compound of the invention.
  • chiral derivatizing reagents such as, e.g., chiral alkylating or acylating reagents
  • optical isomers may be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in Enantiomers, Racemates, and Resolutions, John Wiley and Sons, New York 1981. Optically active compounds were also be prepared from optically active starting materials.
  • the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances.
  • prodrugs will be functional derivatives of the compounds of Formula I which are readily convertible in vivo into the required compound of Formula I.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
  • the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section and a pharmaceutically acceptable carrier.
  • the compounds of the invention may be administered alone or in combination . with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • Suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
  • Typical oral dosages range from about 0.001 to about 100 mg/kg body weight per day.
  • Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
  • typical doses are in the order of half the dose employed for oral administration.
  • the present invention also provides a process for making a pharmaceutical composition
  • a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.
  • the compound utilized in the aforementioned process is one of the specific compounds disclosed in the Experimental Section.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • a compound of Formula I contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of Formula I with a molar equivalent of a pharmaceutically acceptable acid.
  • suitable organic and inorganic acids are described above.
  • solutions of the compounds of Formula I in sterile aqueous solution aqueous propylene glycol, aqueous vitamin £ or sesame or peanut oil may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the compounds of Formula I may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • sustained release material such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the compounds of Formula I are ligands at the MCHl receptor.
  • the present invention provides a method of treating a subject suffering from depression which comprises administering to the subject a therapeutically effective amount of a compound of this invention.
  • This invention further provides a method of treating a subject suffering from anxiety which comprises administering to the subject a therapeutically effective amount of a compound of this invention.
  • This invention also provides a method of treating a subject suffering from obesity which comprises administering to the subject a therapeutically effective amount of a compound of this invention.
  • the subject is a human being. The invention will be better understood from the Experimental Details which follow.
  • representative reagents such as bases or solvents.
  • bases include but are not limited to K 2 CO 3 , Et 3 N or DIPEA (Diisopropylethylamine).
  • TLC Thin-layer chromatography
  • reagents used in the experimental section such as 2-chlorothiophenol, potassium carbonate, 3-chloroperoxybenzoic acid, 4-fluoroacetophenone, methanesulfonyl chloride, methyl chloroformate, 2,2,6,6-tetramethylpiperidine, sodium borohydride and nitronium tetrafluoroborate were purchased from the Aldrich Chemical Company, Lancaster, Maybridge or Oakwood.
  • the compounds of Formula I may be synthesized according to the procedures described in Scheme 1.
  • the compounds of Formula ⁇ and III are commercially available or may be synthesized by one skilled in the art.
  • the ketones of Formula IV are prepared via aromatic nucleophilic reaction of activated 4-halo-ketones of Formula II and phenyl or pyrindyl thiols of Formula III in the presence of base under reflux or microwave conditions. If Z is S(O) n , the corresponding sulfoxides IVb and sulfones IVc may be prepared via sequential oxidations of IVa by mCPBA.
  • the compounds of Formula IV may be coupled with the amine of Formula V to afford the compounds of the invention.
  • ketones of Formula IV may be prepared via Ullmann type reactions.
  • reaction conditions in connection with Ullmann type reactions see T. Kondo, et al., Chem. Rev., 2000, 100, 3205-3220 and the references cited therein.
  • Scheme 2 See T. Kondo, et al., Chem. Rev., 2000, 100, 3205-3220 and the references cited therein.
  • the compounds of Formula I may be synthesized according to the procedures described in Scheme 2.
  • the intermediates of Formula IV may be reduced to the alcohols of Formula VI, which may be treated with mesylchloride in the presence of triethylamine in CH 2 Cl 2 to afford the mesylates of Formula VII.
  • the mesylates may be coupled with the amines of Formula V to afford the compounds of the invention.
  • the compounds of Formula I may be synthesized according to the procedures described in Scheme 3.
  • the compounds of Formula VQI which are commercially available or synthesized by those skilled in the art, may be treated with NBS to afford the bromides of Formula IX.
  • the bromides may be coupled with the amines of Formula V to afford the compounds of the invention.
  • the amines of Formula V may be prepared according to the procedures described in Scheme 4.
  • the compounds of Formula X may be coupled with fer/-butyl 4-(3- aminoaryl)piperidinecarboxylate of Formula XI to afford the N-Cbz protected intermediates of Formula XII.
  • the Cbz group is removed to provide the compounds of Formula XV, which may be coupled with acid chlorides or chloroformates to yield the intermediates of Formula XVI.
  • the Boc group is removed to afford the amines of Formula V.
  • the nitro compounds of Formula XIII may be used.
  • Formula XI may be prepared according to the procedures described in P. R. Eastwood, Tetrahedron Lett., 2000, 41, 3705-3708 and references cited therein. Scheme 5
  • N-Cbz bromo or iodo intermediates of Formula X may be prepared according to the procedures described in Scheme 5.
  • the amino group of the commercially available starting materials of Formula XVII may be protected by treatment with benzyl chloroformate in the presence of base to afford the intermediates of Formula X.
  • ⁇ f-Cbz protected intermediates X may be prepared from the corresponding acids of Formula XVIII using diphenylphosphoryl azide via a Curtius type rearrangement, followed by trapping the isocyanates with benzyl alcohol to afford the compounds of Formula X.
  • the intermediates of Formula XIII may be prepared according to the procedures described in Scheme 6.
  • the 3-bromo or 3-iodo nitro intermediates of Formula XIII are available from commercial sources or may be prepared from the corresponding bromo or iodo precursors XIX by nitration methods or from the corresponding nitro compounds of Formula XX by bromination methods.
  • the compounds of the invention may be prepared according to the procedures as outlined in Scheme 7.
  • the compounds of Formula XV may be coupled with the benzophenones of Formula IV in the presence of Ti(OPr) 4 to provide the advanced intermediates of Formula XXI.
  • compounds of Formula XV may be coupled with the mesylates of Formula VII or benzyl bromides of Formula IX in the presence of base to provide the advanced intermediates of Formula XXI.
  • the advanced intermediates of Formula XXI may be treated with acid chlorides or chloroformates under standard coupling conditions to afford the compounds of Formula I.
  • Methanesulfonyl chloride (182 mg, 1.60 mmol) was added dropwise to a solution of l-[4- (3,4-difluoro-benzenesulfonyl)-phenyl]-ethanol (395 mg, 1.32 mmol) and TEA (268 mg, 1.60 mmol) in CH2CI2 and cooled to 0 0 C in an ice bath. The reaction was stirred for 30 min. The mixture was diluted with additional CH2CI 2 and washed with 2% HCl, water, saturated aqueous NaHCCb and brine.
  • 2-Bromo-5-fluoro-4-nitro toluene 2-bromo-5-fluoro toluene (15.0 g, 10.0 mL, 79.0 mmol) was added to a solution of nitronium tetrafluoroborate (11.6 g, 87.0 mmol) in CH 2 Cl 2 (60.0 mL) over 5 min. After refluxing for 4.5 h, the mixture was cooled to rt and poured into ice water (150 mL). The mixture was extracted with CH 2 Cl 2 (3 X 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product (18.3 g).
  • Step 1 Bromine (21.1 mL, 0.393 mol) was added dropwise over —20 min to a mixture of 2-hydroxy-5-nitropyridine (50.0 g, 0.358 mol) in water (7 L), which was warmed to 40 0 C. After stirring at 40 0 C for 2.5 h, the mixture was cooled to 10 0 C and the crude product was isolated by filtration.
  • Step 2 To a cooled (0-5 0 C) mixture of 3-bromo-2-hydroxy-5-nitropyridine (47.0 g, 0.214 mol) and quinoline (13.7 g, 0.107 mol) was added POCI 3 (26.0 mL, 0.278 mol) dropwise over ⁇ 10 min (the mixture was difficult to stir initially but became less viscous as the reaction progressed and the mixture warmed). After stirring at 120 0 C for 3.5 h, the mixture was cooled to 100 0 C and water (90 mL) was added. The resulting mixture was stirred vigorously while cooling to 0-5 0 C.
  • Step 3 NaH (as a 60 % dispersion in oil, 2.32 g, 58.0 mmol) was added over 5 min to a cooled (15 0 C) solution of diethyl malonate (8.8 mL; 58.0 mmol) in diethyl ether (110 mL). 3-Bromo-2-chloro-5-nitropyridine (12.5 g, 52.6 mmol) was added in four portions over -15 min (an exotherm to 26 0 C was observed), followed by removal of diethyl ether in vacuo to give a red oil. After stirring the resulting red oil at 114 0 C for 1 h 15 min, H 2 SO 4 (6M, 67.0 mL) was added.
  • the resulting mixture was heated at reflux for 8 h then cooled to 0 0 C and the pH value was adjusted to 7 with 25 % KOH aqueous solution (135 mL).
  • the resulting mixture was stirred in an ice bath for 25 min and the crude product was collected and washed with water (50 mL) by filtration.
  • the crude product was stirred in CH 2 Cl 2 (350 mL) for 30 min and the impurity was removed by filtration.
  • the organic layer was dried over Na 2 SO 4 , filtered and concentrated to give the impure product as red oil.
  • the red oil was dissolved in CH 2 Cb (100 mL) and Hexane (200 mL).
  • Benzyl 5-bromo-3-pyridinyl carbamate To a suspension of 5-bromonicotinic acid (20.0 g, 99.0 mmol) in toluene (200 mL) was added diphenylphosphoryl azide (25.6 mL, 118.8 mmol) and Et3N (16.6 mL, 118.8 mmol). After stirring at rt for 30 min, benzyl alcohol (15.4 mL, 148.5 mmol) was added. The mixture was stirred at rt for 1 h and refluxed overnight. After cooling to it, the reaction mixture was washed with H 2 O, saturated aqueous NaHCC> 3 and brine.
  • Titanium (IV) isopropoxide 39 mg, 0.14mmol was added to a stirred solution of N-(4- methyl-3-(piperidin-4-yl)phenyl)isobutyrarnide (30 mg, 0.12 mmol) and l-[4-(4-Chloro- phenylsulfanyl)-phenyl]-ethanone (19mg, 0.12 mmol) in dry THF (1 mL). The mixture was stirred in a sealed glass tube under argon at rt for 24 h. A solution of NaBH 4 (l lmg, 0.29mmol) in ethanol (1.5m L) was added and stirred for an additional 18 h.
  • Example Ib N-[3-(l - ⁇ l-[4-(4-Chloro-benzenesulfinyl)-phenyI]-ethyl ⁇ -piperidin-4-yl)-4- methyl-phenyl]-isobutyramide.
  • Example Id [3-(l- ⁇ l-[4-(4-Chloro-phenylsulfanyl)-phenyl]-ethyl ⁇ -piperidin-4-yl)-4-methyI- phenylj-carbamic acid methyl ester.
  • Example Ie [3-(l- ⁇ l-[4-(4-chloro-benzenesulfinyl)-phenyl]-ethyl ⁇ -piperidin-4-yl)-4-methyl- phenylj-carbamic acid methyl ester.
  • Example 2b N-(l- ⁇ l-[4-(3,4-Difluoro-benzenesulfonyI)-phenyl]-ethyI ⁇ -2-methyl- l,2,3,4,5,6-hexahydro-[3,4]bipyridinyl-5-yl)-isobutyrarnide.
  • Example 2c (l- ⁇ l-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-ethyl ⁇ -2-methyl-l,2,3,4,5,6- hexahydro-[3,4]bipyridinyl-5-yl)-carbamic acid ethyl ester.
  • the pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
  • tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine prepare tablets.
  • adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • tritiated SNAP-7941 to membranes harvested from CHO cells expressing cloned rat MCHl receptors was determined in vitro.
  • the radiochemical synthesis of tritiated SNAP-7941 was performed by Amersham Pharmacia Biotech, Cambridge, Wales.
  • SNAP-7941 from rat MCHl expressing membranes.
  • the compound and radioligand were incubated with the membranes at 25 0 C for 90 min. Incubation was terminated by rapid vacuum filtration over GF/C glass fiber filters, presoaked in 5 % PEI using 50 ⁇ M Tris pH 7.4 as wash buffer. In all experiments, nonspecific binding was defined using 10 pM of tritiated SNAP-7941.
  • the binding affinities for the compounds in the present invention, described herein, at the MCHl receptor were determined to be 100 nM or less.
  • the Ki values were determined to be 30 nM or less.
  • the Ki values were determined to be 10 nM or less.

Abstract

La présente invention concerne des composés d'arylbenzylpipéridine constituant des ligands au niveau du récepteur MCHI. L'invention propose une composition pharmaceutique comprenant une quantité thérapeutiquement suffisante d'un composé de l'invention et un excipient pharmaceutiquement admis. L'invention concerne également un procédé permettant de traiter un sujet soufrant de dépression, par administration d'une quantité thérapeutiquement efficace d'un composé de l'invention. L'invention concerne aussi un procédé permettant de traiter un sujet soufrant d'anxiété, par administration d'une quantité thérapeutiquement efficace d'un composé de l'invention. L'invention concerne en outre un procédé permettant de traiter un sujet soufrant d'obésité, par administration d'une quantité thérapeutiquement efficace d'un composé de l'invention. Enfin, l'invention concerne l'utilisation d'un composé de l'invention pour la fabrication d'un médicament pour le traitement d'un sujet souffrant de dépression, d'anxiété ou d'obésité.
PCT/US2007/008291 2006-04-04 2007-04-02 Composés d'arylbenzylpipéridine WO2007114916A2 (fr)

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US78949006P 2006-04-04 2006-04-04
US60/789,490 2006-04-04

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WO2007114916A2 true WO2007114916A2 (fr) 2007-10-11
WO2007114916A3 WO2007114916A3 (fr) 2008-07-31

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
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
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

Citations (1)

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Publication number Priority date Publication date Assignee Title
US6727264B1 (en) * 2001-07-05 2004-04-27 Synaptic Pharmaceutical Corporation Substituted anilinic piperidines as MCH selective antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6727264B1 (en) * 2001-07-05 2004-04-27 Synaptic Pharmaceutical Corporation Substituted anilinic piperidines as MCH selective antagonists

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
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
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

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