WO2007114902A2 - Composés d'alkylthiobenzylpipéridine - Google Patents

Composés d'alkylthiobenzylpipéridine Download PDF

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Publication number
WO2007114902A2
WO2007114902A2 PCT/US2007/008142 US2007008142W WO2007114902A2 WO 2007114902 A2 WO2007114902 A2 WO 2007114902A2 US 2007008142 W US2007008142 W US 2007008142W WO 2007114902 A2 WO2007114902 A2 WO 2007114902A2
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Prior art keywords
phenyl
compound
methyl
benzyl
piperidin
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PCT/US2007/008142
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English (en)
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WO2007114902A3 (fr
Inventor
Mohammad Marzabadi
Kim Andersen
Bin Chen
Michael Reitman
Yu Jiang
Eman Eldemenky
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H.Lundbeck A/S
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Publication of WO2007114902A2 publication Critical patent/WO2007114902A2/fr
Publication of WO2007114902A3 publication Critical patent/WO2007114902A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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, hyperphag ⁇ c and hypermetabolic, with increased resistance to diet-induced obesity (D. J. Marsh, et al., Proc. Natl. Acad. ScL, 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. Accordingly, the present invention relates to compounds of Formula I.
  • 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 ;
  • R 1 is straight chained or branched Ci-C 7 alkyl, C 3 -C 7 cycloalkyl or C 2 -C7 cyclic ether;
  • R 2 is H or straight chained or branched C1-C7 alkyl
  • R 3 is straight chained or branched Ci-C 7 alkyl, C3-C7 cycloalkyl or straight-chained or branched Ci-C 7 alkoxy;
  • 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 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 C 1 -C 7 alkyl” 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-propy], 2-methyl-l -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 Ci-C 4 fluoroalkyl” refers to a saturated hydrocarbon having from one to four carbon atoms inclusive substituted with one or more fluorine atoms.
  • the term "straight chained or branched Ci-C 7 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. Similarly, the term “straight chained or branched Cj-C 4 alkoxy” refers to a saturated alkoxy group having from one to four carbon atoms inclusive with the open valency on the oxygen.
  • C3-C 7 cycloalkyl refers to the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane.
  • C 2 -C 7 cyclic ether refers to the group consisting of oxirane, oxetane, tetrahydrofuran, tetrahydropyran, oxepane and oxecane with the open valency on a carbon of the cyclic ring.
  • 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 or more CH 3 , F, Cl or Br.
  • the compound of example 2a has the following structure:
  • This compound is constructed from Formula I wherein R 1 is tetrahydropyranyl; wherein R 2 is H; wherein R 3 is methoxy; 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 s is independently H or CH 3 ; and wherein n is 2.
  • the present invention further provides certain embodiments 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, CH 3 , F 5 Cl, Br or I.
  • R 2 is H or straight chained or branched C1-C4 alkyl.
  • R 1 is C2-C 7 cyclic ether.
  • R 1 is tetrahydropyranyl; and each R 4 is H.
  • R 1 is C3-C 7 cycloalkyl.
  • R 1 is straight chained or branched C 1 -C7 alkyl.
  • R 1 is straight chained or branched Ci -C 4 alkyl; and each R 4 is H.
  • R 3 is straight chained or branched Ci -C 4 alkoxy.
  • R 3 is straight chained or branched C1-C4 alkyl.
  • R 2 is straight chained or branched C1-C4 alkyl.
  • R 2 is CH 3 ; each Y 1 , Y 2 , Y 3 and Y 4 is independently CR 5 ; and each R 5 is independently H, CH3 or F.
  • R 2 is H.
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently CR 5 ; each R 5 is independently H, CH 3 or F; and n is 2.
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently CR 5 ; each R 5 is independently H, CH3 or F; 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
  • inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in S. M. Berge, et al., J. Pharm. ScL, 1977, 66, 2, the contents of which are hereby incorporated by reference.
  • 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. In general, 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
  • Optically active compounds may 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.
  • compositions 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 tree 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 E 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.
  • the pharmaceutical compositions formed by combining the compounds of Formula I and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • 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.
  • 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-propanethiol, 4- fluorobenzaldehyde, potassium carbonate, 3-chloroperoxybenzoic acid, 4- fluoroacetophenone, methyl magnesium bromide, methanesulfonyl chloride, methyl chloroformate, 4-chlorotetrahydropyran, N-bromosuccinimide, nitronium tetrafluoroborate were purchased from Aldrich Sigma. Cyclopentanethiol was purchased from TCI International.
  • the compounds of Formula I may be synthesized according to the procedures described in Scheme 1.
  • the compounds of Formula II and III are commercially available or may be synthesized by one skilled in the art.
  • the aldehydes/ ketones of Formula IV are prepared via aromatic nucleophilic reaction of activated 4-halo-benzaldehydes/ ketones of Formula II and alkylthiols of Formula HI in the presence of base under reflux or microwave conditions.
  • 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 VI to afford the compounds of the invention.
  • the conversion of the aldehydes to ketones may be obtained via the Weinreb amide intermediate. For reaction conditions in connection with the Weinreb amide, see S. Nahm and S.M. Weinreb, Tetrahedron Lett., ⁇ 981 , 22, 3815-3818.
  • aldehydes/ ketones of Formula IV may be prepared via Ullmann type reactions.
  • Ullmann type reactions 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 V, 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 VI 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 VIII 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 VI to afford the compounds of the invention.
  • the amines of Formula VI may be prepared according to the procedures described in Scheme 4.
  • the compounds of Formula X may be coupled with tert-buty ⁇ 4-(3- aminoaryl)piperidinecarboxy!ate 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 VI.
  • the nitro compounds of Formula XIII may be used.
  • N-Cbz bromo or iodo intermeditaes 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.
  • N-Cbz protected intermediates of Formula 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.
  • nitration (a) nitration, (b) bromination.
  • the nitro-bromo or iodo intermediates of Formula XIII may be prepared according to the procedures described in Scheme 6.
  • the 3-bromo or 3-iodo compounds of Formula XIII are available from commercial sources or may be prepared from the corresponding bromo or iodo compounds XIX by nitration methods or from the corresponding nitro intermediates of Formula XX by bromination methods.
  • General information regarding aromatic nitration is described in the following references: J. G. Hoggett, et al. s Nitration and Aromatic Reactivity, Cambridge University Press, London, 1971; K. Schofield, Aromatic Nitration, Cambridge University Press, London, 1980; and G. A. Olah, et al., Nitration: Methods and Mechanism, (Ed.: H. Feuer), VCH Publishers, New York, 1989.
  • the compounds of the invention may be prepared according to the procedures as outlined in Scheme 7.
  • compounds of Formula XXI 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 XXII.
  • the advanced intermediates of Formula XXII may be treated with acid chlorides or chloroformates under standard coupling conditions to afford the compounds of Formula I. Preparation of intermediates
  • Methanesulfonic acid l-[4-(propane-2-sulfonyl)-phenyl]-ethyl ester Methanesulfonyl chloride (2.00 eq, 3.06 mmol, 0.240 raL) was added to a solution of l-[4-(propane-2- sulfonyl)-phenyl]-ethanol (1.53 mmol, 0.350 g) and Et 3 N (3.00 eq, 4.59 mmol, 0.640 mL) in
  • terf-butyl 4-(4,4,5,5-tetramethyM,3,2-dioxaborolan-2-yl)-l,2,5,6-tetrahydropyridine carboxylate of Formula XI was prepared according to the procedures described by P. R. Eastwood, Tetrahedron Lett., 2000, 41, 19, 3705-3708 and references cited therein.
  • 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 CH2CI2 (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 POCl 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.
  • 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 it for 30 min, benzyl alcohol (15.4 mL, 148.5 mmol) was added. The mixture was stirred at it for 1 h and refluxed overnight. After cooling to rt, the reaction mixture was washed with H 2 O, saturated aqueous NaHCO 3 and brine.
  • Example Ia iV-(4-Methyl-3- ⁇ 1 -[4-(propane-2-sulfonyl)-benzyl]-piperidin-4-yl ⁇ -phenyl)- isobutyramide.
  • Acetic acid (24.0 mg, 0.400 mmol) and sodium triacetoxyborohydride (169 mg, 0.800 mmol) were added to a solution of N-(4-methyl-3-piperidin-4-yl-phenyl)-isobutyramide (114 mg, 0.440 mmol) and 4-(propane-2-sulfonyl)-benzaldehyde (84.8 mg, 0.400 mmol) in CH 2 Cl 2 (5.00 mL) at rt. Stirring was continued under nitrogen at rt for 10 h. Saturated aqueous ⁇ aHC ⁇ 3 and CH 2 CI 2 (20 mL) were added. The phases were separated.
  • Example Ib ⁇ 3-[l-(4-Isopropylsulfanyl-benzyl)-piperidin-4-yl]-4-methyl-phenyl ⁇ - carbamic acid methyl ester.
  • Example Ic N- ⁇ 3-[ 1 -(4-Isopropylsulfanyl-benzy l)-piperid in-4-yl]-4-methyl-phenyl ⁇ - isobutyramide.
  • Example Id N- ⁇ 3-[l -(4-Cyclopentanesulfonyl-benzyl)-piperidin-4-yl]-4-fluoro-phenyl ⁇ - isobutyramide.
  • Example I (3- ⁇ t-[4-(Pro ⁇ ane-2-sulfonyl)-benzyl]-piperidin-4-yl ⁇ -phenyl)-carbamic acid methyl ester.
  • Example 2a (4-Methyl-3- ⁇ 1 -[4-(tetrahydro-pyran-4-sulfonyl)-benzyl]-piperidin-4-yl ⁇ - phenyl)-carbamic acid methyl ester.
  • Example 2b N-(4-Methyl-3- ⁇ 1 -[4-(tetrahydro-pyran-4-sulfonyl)-benzyl]-piperidin-4-yl ⁇ - phenyl)-isobutyramide.
  • F Foorrmmuullaattiioonnss T Thhee pphhaa ⁇ rmaceutical 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.
  • the affinity of the compounds was measured by their ability to displace tritiated 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 nM Tris pH 7.4 as wash buffer. In all experiments, nonspecific binding was defined using 10 pM of tritiated SNAP-7941.
  • MCHl receptor were determined to be 500 nM or less. For the majority of the compounds, the Ki values were determined to be 100 nM or less. For some compounds, the Ki values were determined to be 10 nM or less.

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  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne des composés d'alkylthiobenzylpipéridine 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/US2007/008142 2006-04-04 2007-04-02 Composés d'alkylthiobenzylpipéridine WO2007114902A2 (fr)

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WO2007114902A3 WO2007114902A3 (fr) 2008-07-03

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Cited By (7)

* 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
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
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
CN103848767A (zh) * 2014-01-27 2014-06-11 华东师范大学 一种芳基硫醚类化合物的合成方法
CN114539073A (zh) * 2022-02-18 2022-05-27 郑州萃智医药科技有限公司 3-溴-2-氯-4,6-二氟苯胺的合成方法

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

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 (7)

* 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
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
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
CN103848767A (zh) * 2014-01-27 2014-06-11 华东师范大学 一种芳基硫醚类化合物的合成方法
CN114539073A (zh) * 2022-02-18 2022-05-27 郑州萃智医药科技有限公司 3-溴-2-氯-4,6-二氟苯胺的合成方法

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