WO2007002126A1 - Alkylsulfamide - Google Patents

Alkylsulfamide Download PDF

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Publication number
WO2007002126A1
WO2007002126A1 PCT/US2006/024043 US2006024043W WO2007002126A1 WO 2007002126 A1 WO2007002126 A1 WO 2007002126A1 US 2006024043 W US2006024043 W US 2006024043W WO 2007002126 A1 WO2007002126 A1 WO 2007002126A1
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WO
WIPO (PCT)
Prior art keywords
methyl
pyridyl
compound
cyclohexyl
amino
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PCT/US2006/024043
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English (en)
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WO2007002126A8 (fr
Inventor
Vrej Jubian
Mathivanan Packiarajan
Hermogenes Jimenez
Emily Reinhard
Original Assignee
H. Lundbeck A/S
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
Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Priority to AU2006262319A priority Critical patent/AU2006262319A1/en
Priority to MX2007015998A priority patent/MX2007015998A/es
Priority to CA002613377A priority patent/CA2613377A1/fr
Priority to EA200800111A priority patent/EA200800111A1/ru
Priority to JP2008518334A priority patent/JP2008546787A/ja
Priority to BRPI0612270A priority patent/BRPI0612270A2/pt
Publication of WO2007002126A1 publication Critical patent/WO2007002126A1/fr
Publication of WO2007002126A8 publication Critical patent/WO2007002126A8/fr
Priority to IL187894A priority patent/IL187894A0/en
Priority to NO20080411A priority patent/NO20080411L/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to compounds that are ligands at the neuropeptide Y Y5 receptor, and as such are useful to treat disorders such as depression, anxiety and obesity.
  • Neuropeptide Y is a 36 amino acid neuropeptide expressed in the peripheral and central nervous system. This peptide is a member of the pancreatic polypeptide family, which also includes pancreatic polypeptide (PP) and peptide YY (PYY). Moreover, the biological effects of NPY are mediated through its interaction with receptors that belong in the superfamily of G protein-coupled receptors.
  • NPY receptor subtypes have been cloned: Y1 (D. Larhammar, et al., J. Biol. Chem., 1992, 267, 10935-10938); Y2 (C. Gerald, et al., J. Biol. Chem., 1995, 270, 26758-26761); Y4 (J. Bard, et al., J. Biol. Chem., 1995, 270, 26762-26765); Y5 (C. Gerald, et al., J. Biol. Chem., 1995, 270, 26758-26761); and y6 (P. Gregor, et al., J. Biol.
  • NPY exerts numerous physiological effects, On the basis of animal studies, it is evident that a contributory relationship exists between NPY and its receptors with disorders such as depression, anxiety and obesity. For instance, NPY expression is shown to be sensitive to energy status while NPY administration reduces energy expenditure, and another significant ability of NPY is to acutely stimulate feeding (S. Kalra, et al., Endocr. Rev., 1999, 20, 68-100).
  • the NPY Y5 receptor has also been shown to be a receptor subtype responsible for NPY-induced food intake (C. Gerald, et al., Nature, 1996, 382, 168-171).
  • NPY neuropeptide Y
  • depression and anxiety the link between NPY and mood disorders such as depression and anxiety is established in the literature.
  • rats subjected to chronic mild stress exhibit anhedonia, a feature of clinical depression (P. Willner, et al., Eur. J. Pharmacol., 1997, 340, 121-132); they also contain elevated levels of NPY mRNA in hypothalamus accompanied by a reduction in hippocampus (V. Sergeyev, et al., Psychopharmacology, 2005, 178, 115-124).
  • the behavioral changes associated with chronic mild stress are reversed by a variety of antidepressants (P. Willner, et al., Eur. J. Pharmacol., 1997, 340, 121-132).
  • agents capable of regulating Y5 receptor function are therefore predicted to be useful for treating depression.
  • NPY neuropeptide Y
  • maternally separated rats display an anxious and depressive phenotype throughout adulthood (R. Huot, Psychopharmacology, 2001 , 158, 366-73); they also contain elevated levels of NPY-like immunoreactivity in hypothalamus accompanied by a reduction in hippocampus and cortex (P. Jimenez-Vasquez, Brain Res. Dev., 2001,
  • rats subjected to fear conditioning display increased anxiety-like behavior; they also contain elevated levels of NPY in hypothalamus, amygdala and nucleus accumbens accompanied by a reduction in frontal cortex.
  • the behavioral changes produced by fear conditioning can be reversed by treatment with anxiolytic drugs.
  • both the anxiety-like behavior and altered expression of NPY were reversed by treatment with diazepam (R.
  • NPY plays a role in anxiety, and that agents capable of regulating NPY and/or receptor function particularly in limbic regions are useful for treating anxiety.
  • Y5 is a NPY receptor expressed in limbic regions (M. Wolak, et al., J. Comp. Neurol., 2003, 22, 285-311 ; and K. Nichol, et al., J. Neurosci., 1999, 19, 10295-10304). Accordingly, agents capable of regulating Y5 receptor function are therefore predicted to be useful for treating anxiety.
  • NPY Y5 small molecule ligands for the treatment of these disorders.
  • a compound In addition to possessing the appropriate pharmacological elements to move forward in the clinic, a compound should have favorable ADME properties such as metabolic stability. Issues relating to drug-drug interactions and toxicity should also be addressed. Metabolic stability of a drug may be predicted by its clearance rate in liver microsomes. Additionally, the cytochrome P450s (CYPs) play a role in metabolism, and CYP inhibition may be used to predict the potential risks of drug-drug interactions and/or toxicity.
  • CYPs cytochrome P450s
  • the objective of the present invention is to provide compounds that are ligands at the NPY Y5 receptor.
  • the present invention relates to compounds of Formula I.
  • R 1 is H or Ci-C 6 straight chained or branched alkyl
  • R 2 is Ci-Ce straight chained or branched alkyl
  • R 1 , R 2 and the carbon to which they are attached may form C 3 -C 6 cycloalkyl
  • R 3 is H or methyl
  • R 4 is 2-pyridyl, 3-pyridyl or pyrazinyl, wherein the 2-pyridyl, 3-pyridyl or pyrazinyl may be substituted with methyl;
  • R 5 is H or methyl
  • m is an integer from 0 to 2 inclusive
  • 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 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 term "straight chained or branched CrC 6 alkyl” refers to a saturated hydrocarbon having from one to six carbon atoms inclusive. Examples of such substituents include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl,
  • straight chained or branched CrC 4 alkyl refers to a saturated hydrocarbon having from one to four carbon atoms inclusive. Examples of such substituents include, but are not limited to, methyl, ethyl and 1-propyl.
  • C 3 -C 6 cycloalkyl refers to a saturated cyclohydrocarbon ring having from three to six carbon atoms inclusive. Included within this term are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the compound of example 2b has the following structure:
  • This compound is constructed from Formula I wherein R 1 , R 2 and the carbon to which they are attached form cyclopropyl; R 3 is H; m is 1 ; n is 0; R 4 is 2-pyridyl; and R 5 is H. Additionally, the invention further provides for certain embodiments of the present invention that are described below.
  • R 5 is H.
  • R 5 is methyl
  • R 3 is H;
  • R 4 is 2-pyridyl or pyrazinyl, wherein the 2-pyridyl or pyrazinyl may be substituted with methyl;
  • m is 0 or 1; and
  • n is 0 or 1.
  • R 1 is H or Ci-C 4 straight chained or branched alkyl; and R 2 is
  • Ci-C 4 straight chained or branched alkyl isoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-C 4 straight chained or branched alkyl.
  • R 1 is H, methyl or ethyl
  • R 2 is methyl or ethyl
  • R 4 is 2- pyridyl, wherein the 2-pyridyl may be substituted with methyl.
  • R 1 is methyl and R 2 is methyl.
  • n 1
  • R 1 , R 2 and the carbon to which they are attached form C 3 -C 6 cycloalkyl.
  • R 4 is 2-pyridyl
  • R 1 is H or Ci-C 4 straight chained or branched alkyl
  • R 2 is Ci-
  • R 3 is H;
  • R 4 is 3-pyridyl or pyrazinyl, wherein the 3-pyridyl or pyrazinyl is substituted with methyl;
  • m is 0 or 1 ; and
  • n is 0 or 1.
  • R 1 is H or CrC 4 straight chained or branched alkyl
  • R 2 is Ci-C 4 straight chained or branched alkyl
  • R 3 is H
  • R 4 is 2-pyridyl, wherein the 2-pyridyl may be substituted with methyl
  • m is 0 or 1
  • n is 0 or 1.
  • R 1 is methyl; R 2 is methyl; and n is 0.
  • R 1 is methyl; R 2 is methyl; and m is 0.
  • R 4 is 3-pyridyl, wherein the 3-pyridyl is substituted with methyl.
  • R 3 is H; m is 0 or 1 ; and n is 0 or 1 ; and R 4 is 2-pyridyl or pyrazinyi, wherein the 2-pyridyl or pyrazinyl may be substituted with methyl.
  • R 1 is H or CrC 4 straight chained or branched alkyl.
  • R 2 is Ci-C 4 straight chained or branched alkyl.
  • R 1 is H, methyl or ethyl
  • R 2 is methyl or ethyl
  • R 4 is 2-pyridyl
  • n 1
  • R 1 , R 2 and the carbon to which they are attached form cyclopropyl or cyclobutyl; and n is 0.
  • 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 /- 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, 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 compounds of the invention.
  • 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 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
  • routes 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 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 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.
  • 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 NPY Y5 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.
  • the present invention 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 further 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 present invention is directed to use of a compound of Formula I for the preparation of a pharmaceutical composition for treating a subject suffering from depression.
  • This invention further provides for use of a compound of Formula I for the preparation of a pharmaceutical composition for treating a subject suffering from anxiety.
  • This invention also provides for use a compound of Formula I for the preparation of a pharmaceutical composition for treating a subject suffering from depression.
  • ⁇ -haloketone of Formula XXII refers to a ketone with the halogen being chloro, bromo or iodo.
  • ⁇ -Haloketones are commercially available. For instance, 2-bromo-1-(2-pyridyl)ethan-1-one and 2-bromo-1-(3-pyridyl)ethan-1-one are sold by Aldrich.
  • ketones may be halogenated in the ⁇ position with bromine, chlorine, or iodine to afford ⁇ - haloketones (V. De Kimpe, The Chemistry of ⁇ -Haloketones, ⁇ -Haloaldehydes, and ⁇ -Haloimines; Wiley: New York, 1988).
  • ⁇ -haloketones may be synthesized from carboxylic acids by treatment of the acid with TMS-diazomethane followed by Cl 2 or Br 2 treatment.
  • 'PG' as defined in Scheme 5 is used to designate a 'protecting group'.
  • One skilled in the art would be able to select the appropriate protecting group for a particular reaction.
  • Methods for protection and deprotection of such groups are well known in the art, and may be found in T. Green, et al., Protection Groups in Organic Synthesis, 1991 , 2 nd Edition, John Wiley & Sons, New York.
  • Method-A Luna C18 Column, 5% to 95% Acetonitrile/ H 2 O with 0.05% formic acid
  • Method-B Luna C18 Column, 15% to 85% Acetonitrile/ H 2 O with 0.05% formic acid
  • Method-C Luna C8 Column, 15% to 85% Methanol in water with 0.05% ammonium formate
  • Method-D C18 column, Neutral pH, 20 % to 90 % Acetonitrile/ H 2 O with 0.2 % Ammonium formate
  • Method-E C18 Column, Acidic pH, 20 % to 90 % Acetonitrile/ H 2 O with 0.2 % AcOH.
  • TLC Thin-layer chromatography
  • the compounds of Formula I may be synthesized according to the procedures described in Scheme 1.
  • the compounds of Formula Il are commercially available or may be synthesized by one skilled in the art.
  • the intermediates of Formula Vl may be synthesized according to the procedures outlined in Scheme 2.
  • the starting materials of Formula IX are commercially available or may be synthesized by one skilled in the art.
  • the amino acids of Formula IX may be coupled with (R 1 )(R 2 )(R 3 )CSO 2 CI to afford the intermediates of Formula X which are further converted to the Cbz-protected amines of Formula XII.
  • the amino acids of Formula IX may be converted into the mono-Cbz protected intermediates of Formula Xl.
  • the amines of Formula Xl are coupled with (R 1 )(R 2 )(R 3 )CSO 2 CI to afford the compounds of Formula XII.
  • the Cbz group of Formula XII is removed to afford the intermediates of Formula Vl.
  • the intermediates of Formula Vl may be converted to the compounds of the invention by using the procedures described in Scheme 1.
  • the compounds of Formula I may be synthesized according to the procedures outlined in Scheme 3.
  • the Cbz group of Formula III is removed to afford the intermediates of Formula IV. These intermediates are converted to the thioureas of Formula XIII.
  • the thiazole ring is formed to afford the compounds of Formula XIV.
  • the BOC group is removed to afford the amines of Formula XV.
  • the compounds of the invention are synthesized by coupling of the amines with (R 1 )(R 2 )(R 3 )CSO 2 CI.
  • the sulfonamides of Formula Vl may also be synthesized according to the procedures outlined in Scheme 5.
  • the compounds of Formula XVI are reacted with (R 1 )(R 2 )(R 3 )CS(O)C1 to afford the sulfinamides of Formula XVII.
  • These compounds are oxidized to the intermediates of Formula XVIII.
  • the protecting group is removed to form the intermediates of Formula Vl.
  • the intermediates of Formula Vl may be converted to the compounds of the invention by using the procedures described in Scheme 1.
  • Scheme 1 For representative reaction conditions, see S. Weinreb, J. Org. Chem., 1997, 62, 8604-8608; J. Ellman, Tetrahedron Lett., 2001, 42, 1433-1436; B. Sharpless, Org. Lett., 1999, 1, 783-786; and WO 01/37826.
  • the ⁇ -haloketones of Formula XXII may be synthesized according to the procedures described in Scheme 6.
  • the acids of Formula XIX are commercially available or may be synthesized by one skilled in the art.
  • the acids of Formula XIX may be converted to the corresponding acid chlorides of Formula XX.
  • the acid chlorides may be treated with trimethylsilyldiazomethane or ethylmagnesiumbromide to afford the intermediates of Formulas XXI (wherein R 5 is H) or XXIV (wherein R 5 is methyl), respectively.
  • These intermediates may be converted to the ⁇ -haloketones of Formula XXII, wherein R 5 is H or methyl, respectively.
  • the acids of Formula XIX may be converted to the corresponding Weinreb amides of Formula XXIII which are further converted to the ⁇ -haloketones of Formula XXII using ethylmagnesium bromide (wherein R 5 is methyl).
  • R 5 is methyl
  • R 5 is H.
  • the moiety R* is used to denote that the 2-pyridyl, 3-pyridyl or pyrazinyl group is optionally substituted with methyl.
  • the variable X is used to denote CH or N.
  • the ⁇ -haloketones of Formula XXII may be synthesized according to the procedures described in Scheme 7 from the starting materials of Formula XXV.
  • the cyano compounds are treated with ethylmagnesium bromide to afford the intermediates of Formula XXIV, wherein R 5 is methyl.
  • R 5 is H.
  • the intermediates of Formula XXIV are further converted to the ⁇ -haloketones of Formula XXII.
  • R* is used to denote that the 2-pyridyl, 3-pyridyl or pyrazinyl group is optionally substituted with methyl.
  • the variable X is used to denote CH or N.
  • the mixture was removed from the ice bath, warmed to 10 0 C and then slowly heated to 70 0 C. After 15 h, nitrogen evolution was observed to be finished and the solution color turned to yellow.
  • the mixture was cooled to 47 0 C and benzyl alcohol (22.8 mL, 0.220 mol) was added.
  • the mixture was heated to 110 0 C and stirred overnight.
  • the mixture was cooled to 50 0 C and concentrated in vacuo to obtain amber solids.
  • the solids were treated with deionized water (400 mL) and EtOAc (150 mL). The mixture was shaken for 10 min and the layers were isolated. The aqueous layer was extracted several times with EtOAc. The organic layers were combined, dried and concentrated in vacuo.
  • N-[fra/7s-4-( ⁇ [(methylethyl)sulfonyl]amino ⁇ methyl)cyclohexyl](phenylmethoxy) carboxamide lsopropyl sulfonyl chloride (6.6 g, 46 mmol) was added drop wise to a solution containing N-[ ⁇ a/?s-4-(aminomethyl)cyclohexyl](phenylmethoxy) carboxamide (1 1 g, 42 mmol), TEA (7.0 g, 70 mmol) in anhydrous CH 2 CI 2 (150 mL) at 0 0 C. The reaction was allowed to warm to rt and stirred overnight.
  • N,N-diisopropyl-N-ethylamine (0.52 ml, 3.0 mmol) was added to a solution of [trans- 4-(aminomethyl)cyclohexyl](4-(2-pyridyl)(1,3-thiazol-2-yl))amine (578 mg, 2.00 mmol) in CH 2 CI 2 at -78 0 C.
  • Ethanesulfonyl chloride (0.19 mL, 2.0 mmol) was then added slowly to the solution and stirring was continued for 45 min. The reaction was allowed to warm to rt then stirred for an additional 3 h. Saturated aqueous NaHCO 3 was added to the reaction mixture and stirred for 15 min.
  • 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 may 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.
  • 125 I-PYY and small molecule ligand competitors were also diluted to desired concentrations in supplemented binding buffer. Individual samples were then prepared in 96-well polypropylene microtiter plates by mixing 125 I-PYY, competing peptides or supplemented binding buffer (25 ⁇ l_), and finally, membrane suspensions (200 ⁇ l_).
  • the binding affinities for the compounds in the present invention, exemplified above, at the NPY Y5 receptor were determined to be 75 nM or less.
  • the Ki values are 10 nM or less, and for a group of compounds the Ki values are 5 nM or less.

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Abstract

La présente invention concerne des dérivés d'alkylsulfamide qui se lient au récepteur du NPY Y5. L'invention concerne une composition pharmaceutique qui comprend une quantité thérapeutiquement efficace d'un composé de l'invention et un vecteur pharmaceutiquement acceptable. La présente invention concerne également une composition pharmaceutique fabriquée en mélangeant une quantité thérapeutiquement efficace d'un composé de l'invention et un vecteur pharmaceutiquement acceptable. La présente invention concerne en outre un procédé de fabrication d'une composition pharmaceutique comprenant la combinaison d'une quantité thérapeutiquement efficace d'un composé de l'invention et d'un vecteur pharmaceutiquement acceptable. La présente invention concerne aussi un procédé de traitement d'un sujet soufrant de dépression qui comprend l'administration au sujet d'une quantité d'un composé de l'invention concernée. La présente invention concerne aussi un procédé de traitement d'un sujet soufrant d'anxiété qui comprend l'administration au sujet d'une quantité d'un composé de l'invention concernée. La présente invention concerne aussi un procédé de traitement d'un sujet souffrant d'obésité qui comprend l'administration au sujet d'une quantité d'un composé de l'invention concernée.
PCT/US2006/024043 2005-06-23 2006-06-21 Alkylsulfamide WO2007002126A1 (fr)

Priority Applications (8)

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AU2006262319A AU2006262319A1 (en) 2005-06-23 2006-06-21 Alkyl sulfonamide derivatives
MX2007015998A MX2007015998A (es) 2005-06-23 2006-06-21 Derivados de alquilsulfonamida.
CA002613377A CA2613377A1 (fr) 2005-06-23 2006-06-21 Alkylsulfamide
EA200800111A EA200800111A1 (ru) 2005-06-23 2006-06-21 Алкилсульфонамидные производные
JP2008518334A JP2008546787A (ja) 2005-06-23 2006-06-21 アルキルスルホンアミド誘導体
BRPI0612270A BRPI0612270A2 (pt) 2005-06-23 2006-06-21 composto, composição farmacêutica, e, uso de um composto
IL187894A IL187894A0 (en) 2005-06-23 2007-12-04 Alkyl sulfonamide derivatives
NO20080411A NO20080411L (no) 2005-06-23 2008-01-22 Alkylsulfonamiddderivater

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US11/159,794 2005-06-23

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007125952A1 (fr) 2006-04-28 2007-11-08 Shionogi & Co., Ltd. Derive amine ayant une activite antagoniste du recepteur y5 du npy
WO2009054434A1 (fr) 2007-10-25 2009-04-30 Shionogi & Co., Ltd. Dérivé d'amine présentant une activité antagoniste du récepteur npy y5 et son utilisation
US8227618B2 (en) 2009-04-23 2012-07-24 Shionogi & Co., Ltd. Amine-derivatives having NPY Y5 receptor antagonistic activity and the uses thereof
WO2012147764A1 (fr) * 2011-04-27 2012-11-01 塩野義製薬株式会社 Dérivé hétérocyclique aromatique à cycle à 5 chaînons ayant une activité antagoniste du récepteur npy y5

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6989379B1 (en) * 1999-04-22 2006-01-24 H. Lundbick A/S Selective NPY (Y5) antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6989379B1 (en) * 1999-04-22 2006-01-24 H. Lundbick A/S Selective NPY (Y5) antagonists

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007125952A1 (fr) 2006-04-28 2007-11-08 Shionogi & Co., Ltd. Derive amine ayant une activite antagoniste du recepteur y5 du npy
US9139518B2 (en) 2006-04-28 2015-09-22 Shionogi & Co., Ltd. Amine derivative having NPY Y5 receptor antagonistic activity
US9150507B2 (en) 2006-04-28 2015-10-06 Shionogi & Co., Ltd. Amine derivative having NPY Y5 receptor antagonistic activity
WO2009054434A1 (fr) 2007-10-25 2009-04-30 Shionogi & Co., Ltd. Dérivé d'amine présentant une activité antagoniste du récepteur npy y5 et son utilisation
US8299265B2 (en) 2007-10-25 2012-10-30 Shionogi & Co., Ltd. Amine derivatives having NPY Y5 receptor antagonistic activity and the uses thereof
US8227618B2 (en) 2009-04-23 2012-07-24 Shionogi & Co., Ltd. Amine-derivatives having NPY Y5 receptor antagonistic activity and the uses thereof
WO2012147764A1 (fr) * 2011-04-27 2012-11-01 塩野義製薬株式会社 Dérivé hétérocyclique aromatique à cycle à 5 chaînons ayant une activité antagoniste du récepteur npy y5
US8916594B2 (en) 2011-04-27 2014-12-23 Shionogi & Co., Ltd. 5-membered ring heteroaromatic derivatives having NPY Y5 receptor antagonistic activity
RU2605207C2 (ru) * 2011-04-27 2016-12-20 Шионоги Энд Ко., Лтд. Гетероциклическое производное с ароматическим 5-членным циклом, обладающее активностью антагониста рецептора npy y5
KR101893237B1 (ko) 2011-04-27 2018-08-29 시오노기세야쿠 가부시키가이샤 Ｎｐｙ ｙ5 수용체 길항 작용을 갖는 5원환 방향족 복소환 유도체

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AR054480A1 (es) 2007-06-27
AU2006262319A1 (en) 2007-01-04
CA2613377A1 (fr) 2007-01-04
CN101203499A (zh) 2008-06-18
IL187894A0 (en) 2008-03-20
BRPI0612270A2 (pt) 2016-09-06
WO2007002126A8 (fr) 2007-03-01
MX2007015998A (es) 2008-03-07

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