WO2011011506A1 - Composés oxazépine spirocyclique en tant qu'inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase - Google Patents

Composés oxazépine spirocyclique en tant qu'inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase Download PDF

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WO2011011506A1
WO2011011506A1 PCT/US2010/042732 US2010042732W WO2011011506A1 WO 2011011506 A1 WO2011011506 A1 WO 2011011506A1 US 2010042732 W US2010042732 W US 2010042732W WO 2011011506 A1 WO2011011506 A1 WO 2011011506A1
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oxazepine
benzo
spiro
dihydro
piperidine
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PCT/US2010/042732
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English (en)
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Jr. Gerald W. Shipps
Zhiwei Yang
Robert West
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Schering Corporation
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to certain 4,5-dihydro-3H-spiro[benzo[b]-
  • [1 ,4]oxazepine compounds, compounds 1-45 described herein, also referred to as the "Spirocyclic Oxazepine Compounds"
  • compositions comprising at least one Spirocyclic Oxazepine Compound
  • methods of using Spirocyclic Oxazepine Compounds for treating or preventing disorders such as non-insulin dependent (Type 2) diabetes, insulin resistance, hyperglycemia, a lipid disorder, obesity, fatty liver disease, or a skin disorder.
  • SCD Stearoyl-coenzyme A desaturase
  • the major products of SCD are palmitoyl-CoA and oleoyl-CoA, which are formed by desaturation of palmitoyl- CoA and stearoyl-CoA, respectively.
  • Oleate is found to be the major monounsaturated fatty acid of membrane phospholipids, triglycerides, cholesterol esters, wax esters and alkyl-1 ,2-diacylglycerol.
  • the ratio of saturated to unsaturated fatty acids is one of the factors influencing membrane fluidity and its alteration is important in diseases like aging, cancer, diabetes, obesity, and neurological, vascular and heart diseases (Biochem. Biophys. Acta., 431 , 469-480 (1976); J. Biol. Chem., 268, 6823-6826 (1993); Diabetes, 40, 280-289 (1991 ); Neurochem Res., 26, 771-782 (1994); Arthritis Rheum., 43, 894-900 (2000); Cancer Lett, 173, 139-144 (2001 )).
  • highly homologous isoforms of SCD exist differing primarily in tissue distribution. For instance, in mice, four SCD isoforms have been identified, while two SCD isoforms have been found in humans, SCD1 and SCD5. In humans, adipose and liver tissue show highest expression of SCD1 , while brain and pancreatic tissues show highest expression of SCD5. Flowers and Ntambi (2008) Curr. Opin. Lipidol. 19, 248.
  • mice In vivo studies in mice support the central role of SCD in both fatty acid metabolism and metabolic conditions. Mice strains with a naturally occurring mutation in one of the isoforms of SCD, SCD1 , and mice which have a targeted disruption in the SCD1 gene show reduced fatty acid and triglyceride synthesis in response to a high carbohydrate diet as compared to the amounts in wild type mice. Furthermore, mice which have a targeted disruption in the SCD1 gene show reduced body adiposity, increased insulin sensitivity and resistance to diet-induced obesity. Ntambi and Miyazaki (2003) Curr. Opin. Lipidol. 14, 255.
  • mice which were injected intraperitoneally with SCD-1 targeted antisense oligonucleotide showed improved insulin sensitivity and prevented occurrence of obesity in the mice in response to high fat diets.
  • modulation of SCD represents a promising therapeutic strategy for the treatment of obesity and related metabolic disorders.
  • mice further suggest that SCD1 activity is important to maintaining the normal functioning of the skin and eyelid as a result of its major role in lipid synthesis within sebaceous and meibomian glands.
  • SCD1 activity is important to maintaining the normal functioning of the skin and eyelid as a result of its major role in lipid synthesis within sebaceous and meibomian glands.
  • mice carrying a naturally occurring mutation in the SCD1 gene Zheng et a/. (1999) Nature Genet 23, 268) and mice which have a targeted disruption in the SCD1 gene (Miyazaki et al. (2001) J. Nutr. 131 , 2260) develop skin and eye abnormalities. These changes include hair loss as well as atrophy of the sebaceous and meibomian glands.
  • sebaceous glands secrete an oily substance called sebum which is distributed onto the skin surface which decreases the skin's stratum corneum layer's permeability and prevents the skin from cracking. These glands are present in all areas of the skin except for the palms of the hands and soles of the feet. The highest concentration of sebaceous glands occurs on the scalp and face.
  • sebum plays, many individuals experience excess sebum production which condition is associated with increased incidence of dermatological conditions such as acne or seborrheic dermatitis.
  • excess sebum production detracts from the cosmetic appearance of the skin and hair by causing the skin to look shiny, greasy or oily and hair to look limp and dirty. Decreasing the production of sebum will alleviate oily skin and hair in
  • the present invention discloses methods of using a Compound of the Formula (I),
  • Oxazepine Compounds are set forth below in Table 1 in the Examples section.
  • the invention also provides a method for treating a disorder selected from non-insulin dependent (Type 2) diabetes, insulin resistance,
  • hyperglycemia a lipid disorder, obesity, fatty liver disease, or a skin disorder comprising administering a Spirocyclic Oxazepine Compound, or a
  • the disorder is disorder is a lipid disorder, which is dyslipidemia, hyperlipidemia, atherosclorosis, hypercholesterolemia, low LDL, or high LDL.
  • the disorder being treated is a skin disorder.
  • the pharmaceutical compositions can be useful for treating non-insulin dependent (Type 2) diabetes, insulin resistance, hyperglycemia, a lipid disorder, obesity, fatty liver disease, or a skin disorder in a subject in need of such treatment.
  • the present invention provides Spirocyclic Oxazepine Compounds, pharmaceutical compositions comprising at least one Spirocyclic Oxazepine Compound, and methods of using the Spirocyclic Oxazepine Compounds for treating a metabolic disorder or skin disease in a patient, e.g., a human patient.
  • Patient includes both human and animals.
  • “Mammal” means humans and other mammalian animals.
  • any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. And any one or more of these hydrogen atoms can be deuterium.
  • protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et a/, Protective Groups in Organic Synthesis (1991 ), Wiley, New York.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S.
  • prodrug means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • prodrugs are provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C-i- C 8 )alkyl, (C 2 -Ci 2 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alk)alkyl, (C 2 -Ci 2 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C- ⁇ -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 - C 6 )alkoxycarbonyloxymethyl, N-(C- ⁇ -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C r C 6 )alkanoyl, ⁇ -amino(CrC 4 )alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ - aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (Ci-C-io)alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ - aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H, (C r C ⁇ )alkyl or benzyl,—
  • R-carbonyl RO-carbonyl
  • NRR'- carbonyl where R and R' are each independently (Ci-C-io)alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ - aminoacyl, -C(
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution- phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical ScL, 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1 ), article 12 (2004); and A. L. Bingham et al, Chem. Comm ⁇ n., 603-604 (2001 ).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • the compounds of Formula I can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
  • Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonat.es (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • alkali metal salts such as sodium, lithium, and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • salts with organic bases for example, organic amines
  • organic amines such as dicyclohexylamines, t-butyl amines
  • salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g., decyl, lauryl,
  • esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C 1-4 alkyl, or C 1-4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4)
  • the phosphate esters may be further esterified by, for example, a C-i ⁇ o alcohol or reactive derivative thereof, or by a 2,3-di (C 6 -24)acyl glycerol.
  • Compounds of Formula I, and salts, solvates, esters and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
  • the compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • Diastereomeric mixtures can be separated into their individual
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs, such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and
  • keto-enol and imine-enamine forms of the compounds are included in the invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 CI and 123 I, respectively.
  • Certain isotopically-labelled compounds of Formula (I) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes.
  • those labeled with positron-emitting isotopes like 11 C or 18 F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123 I can be useful for application in Single photon emission computed tomography (SPECT).
  • PET Positron Emission Tomography
  • SPECT Single photon emission computed tomography
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time
  • lsotopically labeled compounds of Formula (I) in particular those containing isotopes with longer half lives (T1/2 >1 day)
  • T1/2 >1 day can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the
  • the present invention further includes the compounds of Formula (I) in all their isolated forms.
  • the above-identified compounds are intended to encompass all forms of the compounds such as, any solvates, hydrates, stereoisomers, and tautomers thereof.
  • the compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be inhibitors of SCD1.
  • BOC or Boc is fe/t-butyloxycarbonyl
  • DIBAL is diisobutylaluminum hydride
  • DlEA is N,N-Diisopropylethylamine
  • DMF is dimethylformamide
  • EDC is 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide
  • EtOAc is ethyl acetate
  • HOBT 1-hydroxybenzotriazole
  • NaBH(OAc) 3 sodium
  • the present invention provides methods of using a Compound of the Formula (I)
  • the compound is selected from one of compounds 1-45 (described herein below), for treating and/or preventing certain diseases and conditions described below in a patient in need of such treatment.
  • compounds 1-45 described herein below
  • the structural formulas and names of compounds 1-45 are set forth below in Table 1 of the Examples.
  • the Compounds of Formula (I) may be prepared from known or readily prepared starting materials, following methods known to one skilled in the art of organic synthesis. Methods useful for making the Compounds of Formula (I) are set forth in in Schemes 1 and 2. Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis. All stereoisomers and tautomeric forms of the compounds are contemplated.
  • Spirocyclic Oxazepine Compounds of Formula (I) may require protection of certain functional groups (i.e., derivatization for the purpose of chemical compatibility with a particular reaction condition). Suitable protecting groups for the various functional groups of these compounds and methods for their installation and removal can be found in Greene et al., Protective Groups in Organic Synthesis, Wiley-lnterscience, New York, (1999).
  • the starting materials used and the intermediates prepared using the methods set forth in the schemes below may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and alike. Such materials can be characterized using conventional means, including physical constants and spectral data.
  • Scheme 1 illustrates the preparation of benzo-fused oxazepine starting material A-4 from hydroxyphenylethanones.
  • Intermediate A1 is synthesized using substituted hydroxyphenylethanones as starting materials.
  • the crude product A1 is converted into the corresponding oxime A2 using hydroxylamine hydrochloride.
  • Reductive rearrangement of oxime A2 by DlBAL gives intermediate A3.
  • the crude, de-protected product is reacted with BOC 2 O without purification to give intermediate A4.
  • intermediate A3 a side product, intermediate A3'
  • Scheme 2 illustrates the alkylation of N-1 of the benzo-fused oxazepine intermediate A4 to give the intermediate A5, and the acylation of N-6 of the benzo-fused oxazepine core.
  • the acylation reaction can be used in the preparation of Compounds of the Formula (I), wherein R 2 is C(O)Y, wherein Y is alkyl or cycloalkyl, or wherein R 2 is
  • N-1 of the benzo-fused oxazepine core of intermediate A4 can be alkylated with an R 1 alkylene group, e.g., R 1 methylene, by reductive amination to afford the BOC-protected intermediate A5.
  • Intermediate A5 is de-protected under acidic conditions, and the free amine can be coupled with carboxylic acids give compounds A7.
  • the intermediate A6 can be coupled with an appropriate isocyanate moiety to prepare compounds of the invention wherein the piperidine N atom forms part of urea moiety.
  • Stearoyl-CoA desaturase assays were performed in according to Talamo and Bloch. See Talamo, BR & Bloch, K, A new assay for fatty acid desaturation," 29 Anal. Biochem.300-304 (1969). Assays were run in triplicate in 100- ⁇ l volumes of 100 mM TrisHCI, pH 7.3, containing 20 ⁇ M Stearoyl-CoA , 2 mM ⁇ -NADH, and 50 ⁇ g of protein from a HepG2 cell P2 pellet. Since SCD-1 is the only isoform of SCD expressed in these cells, the assay is specific for SCD-1 with these cells as the source of enzyme.
  • Reaction mixtures were incubated fifteen minutes at 25°C and reactions were then stopped with a volume of trichloroacetic acid giving a final concentration of 0.2%. After five minutes, a 90- ⁇ l volume was transferred to a Millipore Multiscreen HTS 96-well filtration plate (MSHVN4B50) containing 125 ⁇ of 10% charcoal in each well, to which vacuum had been previously applied. Plates were shaken fifteen minutes and then filtered into a collection plate. Fifty- ⁇ l volumes of filtrate were transferred to another plate containing 150 ⁇ of MicroScint 40 for counting on a TopCount scintillation counter. Total activity was determined in reaction mixtures containing 2% DMSO and blank with a standard inhibitor at 10 ⁇ 4 M. Test compounds were run at five concentrations from 10 "5 to 10 "9 M and IC 50 values were interpolated from the data.
  • MSHVN4B50 Millipore Multiscreen HTS 96-well filtration plate
  • IC 50 data for the compounds of the present invention i.e., compounds 1-45 are provided below in Table 1 wherein A is 0.5-49 nM, B is 50-499 nM, C is 500-10,000 nM, and D is >10,000 nM.
  • the Spirocyclic Oxazepine Compounds are useful in human and veterinary medicine.
  • the Spirocyclic Oxazepine Compounds are useful in a method of inhibiting the stearoyl-coenzyme A delta-9 desaturase enzyme (SCD) in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound.
  • SCD stearoyl-coenzyme A delta-9 desaturase enzyme
  • Oxazepine Compounds are therefore useful to control, prevent, and/or treat conditions and diseases mediated by high or abnormal SCD enzyme activity.
  • the Spirocyclic Oxazepine Compounds can be administered to a patient in need of treatment for a metabolic or skin disease/disorder.
  • the general value of the compounds of the invention in inhibiting, the activity of SCD can be determined, for example, using the assay described above in Example 1.
  • the general value of the compounds in treating disorders and diseases may be established in industry standard animal models for demonstrating the efficacy of compounds in treating, for example, acne, obesity, diabetes or elevated triglyceride or cholesterol levels or for improving glucose tolerance.
  • the assay described in Luderschmidt et al. Effects of cyproterone acetate and carboxylic acid derivatives on the sebaceous glands of the Syrian hamster, 258(2) Arch Dermatol Res. 185-91 (1977).
  • the present invention provides a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment, which comprises administering to said patient an effective amount of a Spirocyclic Oxazepine Compound or a pharmaceutically salt or solvate thereof.
  • the present invention provides a method of treating non-insulin dependent diabetes mellitus (Type 2 diabetes) in a mammalian patient in need of such treatment comprising administering to the patient an antidiabetic effective amount of a Spirocyclic Oxazepine Compound,
  • the present invention provides a method of treating obesity in a mammalian patient in need of such treatment comprising administering to said patient a Spirocyclic Oxazepine Compound in an amount that is effective to treat obesity.
  • the present invention provides a method of treating metabolic syndrome and its sequelae in a mammalian patient in need of such treatment comprising administering to said patient a Spirocyclic
  • Oxazepine Compound in an amount that is effective to treat metabolic syndrome and its sequelae.
  • the sequelae of the metabolic syndrome include hypertension, elevated blood glucose levels, high triglycerides, and low levels of HDL cholesterol.
  • the present invention provides a method of treating a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL in a mammalian patient in need of such treatment comprising
  • the present invention provides a method of treating atherosclerosis in a mammalian patient in need of such treatment comprising administering to said patient a Spirocyclic Oxazepine Compound in an amount effective to treat atherosclerosis.
  • the present invention provides a method of treating cancer in a mammalian patient in need of such treatment comprising administering to said patient a Spirocyclic Oxazepine Compound in an amount effective to treat cancer.
  • the invention provides a method for treating a skin disorder, including but not limited to eczema, acne, psoriasis, keloid scar formation or prevention, oily skin, shiny or greasy-looking skin, seborrheic dermatitis, disorders related to production or secretions from mucous membranes, such as monounsaturated fatty acids, wax esters, and the like in a mammalian patient in need of such treatment comprising administering to the patient a Spirocyclic Oxazepine Compound in an amount that is effective to treat such a skin disorder.
  • the skin disorder being treated is acne.
  • the present invention provides a method of treating a cosmetic condition such as greasy or oily-looking hair, comprising
  • the present invention provides a method of treating a condition selected from the group consisting of (1 ) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9)
  • hypercholesterolemia (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome, (22) sleep-disordered breathing, (23) a skin disorder, (24) greasy or oily-looking hair, (25) metabolic syndrome, and (26) other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment comprising administering to the patient a Spirocyclic Oxazepine Compound in an amount that is effective to treat said condition.
  • the present invention provides a method of delaying the onset of a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11 ) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) fatty liver disease, (21 ) polycystic ovary syndrome, (22) sleep-disordered breathing, (23) a skin disorder, (24) greasy or oily-looking hair, (25) metabolic syndrome, and (26) other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment comprising administering to the patient a Spir
  • the present invention provides a method of reducing the risk of developing a condition selected from the group consisting of (1 ) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)
  • hypertriglyceridemia (9) hypercholesterolemia, (10) low HDL levels, (11 ) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome, (22) sleep-disordered breathing, (23) a skin disorder, (24) greasy or oily-looking hair, (25) metabolic syndrome, and (26) other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment comprising administering to the patient a Spirocyclic Oxazepine Compound in an amount that is effective to reduce the risk of developing said condition.
  • the invention provides a method for treating a condition where increasing lean body mass or lean muscle mass is desired, such as is desirable in enhancing performance through muscle building, comprising administering to a patient in need of such treatment an amount of a Spirocyclic Oxazepine Compound effective treating such condition.
  • CPT I or CPT II carnitine palmitoyltransferase deficiency
  • Such treatments are useful in humans and in animal husbandry, including for administering to bovine, porcine or avian domestic animals or any other animal to reduce triglyceride production and/or provide leaner meat products and/or healthier animals.
  • the present methods for treating or preventing a viral infection or a virus-related disorder can further comprise the administration of one or more additional therapeutic agents which are not Spirocyclic
  • the compounds of the present invention may be used in combination with one or more other agents in the treatment, prevention, suppression or amelioration of diseases or conditions for which the Spirocyclic Oxazepine Compounds or the other agents may have utility, where the combination of the drugs together are safer or more effective than either agent alone.
  • Such other agent(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a Spirocyclic Oxazepine Compound.
  • a Spirocyclic Oxazepine Compound is used
  • the combination therapy may also include therapies in which the Spirocyclic Oxazepine Compound and one or more other agents are administered on different overlapping schedules.
  • the Spirocyclic Oxazepine Compound when used in combination with one or more other therapeutic agents, the Spirocyclic
  • Oxazepine Compounds and the other therapeutic agents may be used in lower doses than when each is used singly.
  • compositions of the present invention include those that contain one or more other therapeutic agents, in addition to a Spirocyclic Oxazepine Compound.
  • Examples of other therapeutic agents that may be administered in combination with a Spirocyclic Oxazepine Compound, and either administered separately or in the same pharmaceutical composition include, but are not limited to:
  • DPP-IV dipeptidyi peptidase IV
  • insulin sensitizers including (i) PPAR-gamma-agonists, such as the glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555,
  • PPAR-gamma-agonists such as the glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555,
  • PPAR alpha/gamma dual agonists such as KRP-297, muraglitazar, naveglitazar, Galida, TAK-559
  • PPAR gamma agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate)
  • SPPAR-gammaM's selective PPAR-gamma-modulators
  • sulfonylureas and other insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, and meglitinides, such as nateglinide and repaglinide;
  • .alpha-glucosidase inhibitors such as acarbose and miglitol
  • glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;
  • GLP-1 GLP-1 , GLP-1 analogues or mimetics, and GLP-1 receptor agonists, such as exendin-4 (exenatide), liraglutide (N.N-2211 ), CJC-1131 , LY-307161 , and those disclosed in WO 00/42026 and WO 00/59887;
  • GIP and GIP mimetics such as those disclosed in WO 00/58360, and GIP receptor agonists;
  • PACAP PACAP, PACAP mimetics, and PACAP receptor agonists such as those disclosed in WO 01/23420;
  • cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii) sequestrants
  • cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR-alpha agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPAR-alpha/.
  • gamma dual agonists such as naveglitazar and muraglitazar
  • inhibitors of cholesterol absorption such as beta- sitosterol and ezetimibe
  • acyl CoA.cholesterol acyltransferase inhibitors such as avasimibe
  • antioxidants such as probucol
  • antiobesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Yi or Y 5 antagonists, CB1 receptor inverse agonists and antagonists, .beta 3 adrenergic receptor agonists, melanocortin-receptor agonists, in particular melanocortin-4 receptor agonists, ghrelin antagonists, bombesin receptor agonists (such as bombesin receptor subtype-3 agonists), and melanin-concentrating hormone (MCH) receptor antagonists;
  • MCH melanin-concentrating hormone
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • antihypertensive agents such as ACE inhibitors (enalapril, lisinopril, captopril, quinapril, tandolapril), A-Il receptor blockers (losartan, candesartan, irbesartan, valsartan, telmisartan, and eprosartan), beta blockers and calcium channel blockers;
  • GKAs glucokinase activators
  • r inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib;
  • retinoids such as etretinate, tretinoin, and aliretinoin
  • Spirocyclic Oxazepine Compounds include those disclosed in U.S. Patent No. 6,699,871 ; WO 02/076450; WO 03/004498; WO 03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO 03/002530; WO 03/002531 ; WO 03/002553; WO 03/002593; WO 03/000180; WO 03/082817; WO
  • DPP-IV inhibitor compounds include isoleucine
  • Antiobesity compounds that can be combined with the Spirocyclic Oxazepine Compounds include fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Yi or Y 5 antagonists, cannabinoid CB1 receptor antagonists or inverse agonists, melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists, ghrelin antagonists, bombesin receptor agonists, and melanin-concentrating hormone (MCH) receptor antagonists.
  • MCH melanin-concentrating hormone
  • Neuropeptide Y5 antagonists that can be combined with the Spirocyclic Oxazepine Compounds include those disclosed in U.S. Patent No. 6,335,345 and WO 01/14376; and specific compounds identified as GW 59884A; GW 56918OA; LY366377; and CGP-71683A.
  • Cannabinoid CB1 receptor antagonists that can be combined with
  • Spirocyclic Oxazepine Compounds include those disclosed in PCT Publication WO 03/007887; U.S. Patent No. 5,624,941 , such as rimonabant; PCT
  • One particular aspect of combination therapy relates to a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia,
  • hypertriglyceridemia, and dyslipidemia in a mammalian patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a Spirocyclic Oxazepine Compound and an HMG-CoA reductase inhibitor.
  • this aspect of combination therapy concerns a method of treating a condition selected from the group consisting of
  • HMG-CoA reductase inhibitor is a statin selected from the group consisting of lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, and rosuvastatin.
  • Another aspect of the invention relates to a method of reducing the risk of developing a condition selected from the group consisting of
  • hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, and the sequelae of such conditions comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a Spirocyclic Oxazepine Compound and an HMG-CoA reductase inhibitor.
  • the invention provides a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprising administering to said patient an effective amount of a Spirocyclic Oxazepine Compound and an HMG-CoA reductase inhibitor.
  • the HMG-CoA reductase inhibitor is a statin selected from the group consisting of: lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, and rosuvastatin.
  • the invention provides a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment, comprising administering to said patient a Spirocyclic Oxazepine Compound, a statin-type HMG-CoA reductase inhibitor, and further administering a cholesterol absorption inhibitor.
  • the cholesterol absorption inhibitor is ezetimibe.
  • the invention provides a method for treating acne in a human patient in need of such treatment, comprising administering to said patient a Spirocyclic Oxazepine Compound and an antibiotic, such as tetracycline or clindamycin.
  • an antibiotic such as tetracycline or clindamycin.
  • the antibiotic is useful for eradicating the effect of the microorganism, Propionibacte ⁇ um acnes, which contributes to developing acne.
  • the invention provides a method for treating acne in a human patient in need of such treatment, comprising administering to said patient a Spirocyclic Oxazepine Compound and a retinoid, such as etretinate, tretinoin, and aliretinoin.
  • a Spirocyclic Oxazepine Compound and a retinoid, such as etretinate, tretinoin, and aliretinoin.
  • the invention provides a method for treating acne in a human patient in need of such treatment, comprising administering to said patient a Spirocyclic Oxazepine Compound and estrogen or progesterone.
  • Oxazepine Compound to the second agent may be varied and will depend upon the effective dose of each agent. Generally, an effective dose of each will be used. Thus, for example, when a Spirocyclic Oxazepine Compound is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 :1000, preferably about 200:1 to about 1 :200. Combinations of a Spirocyclic Oxazepine Compound and other therapeutic agents will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the Spirocyclic Oxazepine Compound and other therapeutic agents may be administered separately or in conjunction.
  • the administration of one therapeutic agent may be prior to,
  • compositions and Administration are concurrent to, or subsequent to the administration of other agent(s).
  • compositions which comprise at least one Spirocyclic Oxazepine Compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and at least one pharmaceutically acceptable carrier.
  • the Spirocyclic Oxazepine Compounds can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle.
  • the present invention provides pharmaceutical compositions comprising an effective amount of at least one Spirocyclic Oxazepine Compound and a pharmaceutically acceptable carrier.
  • the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional
  • the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may be comprised of from about 0.5 to about 95 percent inventive composition.
  • Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.
  • Liquid form preparations include solutions, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral injection.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Liquid form preparations may include compositions suitable for topical applications, such as are used for dermatological applications.
  • the Spirocyclic Oxazepine Compound is present in a vehicle containing propylene glycol:transcutanol:ethanol (20:20:60, v/v/v) and propylene glycoLethanol (30:70, v/v).
  • the Spirocyclic Oxazepine Compound may be present in the topical composition at
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • a pharmaceutically acceptable carrier such as an inert compressed gas.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • the Spirocyclic Oxazepine Compounds of the present invention may also be delivered transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols, foams and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • the Spirocyclic Oxazepine Compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-oxide
  • the Spirocyclic Oxazepine Compound is administered intravenously.
  • the Spirocyclic Oxazepine Compound is administered sublingually.
  • the Spirocyclic Oxazepine Compound is administered topically, for example, for use in treating a skin disorder of the type described above.
  • the Spirocyclic Oxazepine Compound is administered topically, for example, for use in treating a skin disorder of the type described above.
  • Oxazepine Compound is a component of topical composition which can take the form of solutions, salves, creams, ointments, in liposomal formulations, sprays, gels, lotions, aerosols, foams, emulsions, or any other formulation routinely used in dermatology.
  • topical compositions can be administered using a patch, e.g., of the matrix type, or a roller stick, as are conventional in the art for this purpose.
  • a pharmaceutical preparation comprising at least one Spirocyclic Oxazepine Compound is in unit dosage form.
  • the preparation is subdivided into unit doses containing effective amounts of the active components.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1 % to about 99% of the Spirocyclic Oxazepine Compound(s) by weight or volume. In various embodiments, the present compositions can contain, in one embodiment, from about 1 % to about 70% or from about 5% to about 60% of the Spirocyclic Oxazepine
  • the quantity of Spirocyclic Oxazepine Compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 2500 mg. In various embodiments, the quantity is from about 10 mg to about 1000 mg, 1 mg to about 500 mg, 1 mg to about 100 mg, and 1 mg to about 50 mg.
  • the total daily dosage may be divided and
  • the daily dosage is administered in portions during the day if desired.
  • the daily dosage is administered in one portion.
  • the total daily dosage is administered in two divided doses over a 24 hour period.
  • the total daily dosage is administered in three divided doses over a 24 hour period.
  • the total daily dosage is administered in four divided doses over a 24 hour period.
  • the amount and frequency of administration of the Spirocyclic Oxazepine Compound will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. Generally, a total daily dosage of the Spirocyclic Oxazepine
  • Compound is in the range of from about 0.1 to about 3000 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of administration.
  • the dosage is from about 1 to about 300 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 10 to about 3000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 100 to about 3000 rng/day,
  • the dosage is from about 500 to about 3000 mg/day,
  • the Spirocyclic Oxazepine Compound will vary, but typically the compound will be present in a pharmaceutically acceptable composition in an amount of from about 0.01 to 50 w/w%, and more typically from about 0.1 to 10 w/w%. In some embodiments, the formulation may be applied to the affected area from 1 to 4 times daily.
  • compositions of the invention can further comprise one or more additional therapeutic agents, selected from those listed above herein.
  • compositions comprising: (i) at least one Spirocyclic Oxazepine Compound or a
  • compositions are together effective to treat disease or disorder associated with aberrant SCD activity.
  • compositions of the invention a
  • composition which comprise:
  • DPP-IV dipeptidyl peptidase IV
  • insulin sensitizers including (i) PPAR gamma agonists, such as the glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555,
  • PPAR gamma agonists such as the glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555,
  • PPAR alpha/gamma dual agonists such as KRP-297, muraglitazar, naveglitazar, Galida, TAK-559
  • PPAR alpha agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate)
  • SPPAR gamma M's selective PPAR gamma modulators
  • sulfonylureas and other insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, and meglitinides, such as nateglinide and repaglinide;
  • alpha-glucosidase inhibitors such as acarbose and miglitol
  • glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;
  • GLP-1 GLP-1 , GLP-1 analogues or mimetics, and GLP-1 receptor agonists, such as exendin-4 (exenatide), liraglutide (N.N-2211 ), CJC-1131 , LY-307161 , and those disclosed in WO 00/42026 and WO 00/59887;
  • GIP and GIP mimetics such as those disclosed in WO 00/58360, and GIP receptor agonists;
  • PACAP PACAP, PACAP mimetics, and PACAP receptor agonists such as those disclosed in WO 01/23420;
  • cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii) sequestrants
  • cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR alpha agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPAR alpha/gamma dual agonists, such as naveglitazar and muraglitazar, (vi) inhibitors of cholesterol absorption, such as beta- sitosterol and ezetimibe, (vii) acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe, and (viii) antioxidants, such as probucol;
  • PPAR delta agonists such as those disclosed in WO 97/28149;
  • antiobesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y 1 or Y 5 antagonists, CB1 receptor inverse agonists and antagonists, beta 3 adrenergic receptor agonists, melanocortin-receptor agonists, in particular melanocortin-4 receptor agonists, ghrelin antagonists, bombesin receptor agonists (such as bombesin receptor subtype-3 agonists), and melanin-concentrating hormone (MCH) receptor antagonists;
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • antihypertensive agents such as ACE inhibitors (enalapril, lisinopril, captopril, quinapril, tandolapril), A-Il receptor blockers (losartan, candesartan, irbesartan, valsartan, telmisartan, and eprosartan), beta blockers and calcium channel blockers;
  • GKAs glucokinase activators
  • r inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib;
  • antibiotic agents such as tetracycline and clindamycin
  • retinoids such as etretinate, tretinoin, and aliretinoin
  • kits comprising a therapeutically effective amount of at least one Spirocyclic Oxazepine Compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • kit comprising an amount of at least one Spirocyclic Oxazepine Compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more active ingredients result in a desired therapeutic effect.
  • the at least one Spirocyclic Oxazepine Compound and the at least one additional therapeutic agent are provided in the same container. In one embodiment, the at least one Spirocyclic Oxazepine Compound and the at least one additional therapeutic agent are provided in separate containers.
  • Another aspect of this invention is a kit containing the at least one
  • Spirocyclic Oxazepine Compound (and any additional therapeutic agents) packaged for retail distribution i.e., an article of manufacture or a kit.
  • Such articles will be labeled and packaged in a manner to instruct the patient how to use the product.
  • Such instructions will include the condition to be treated, duration of treatment, dosing schedule, etc.

Abstract

La présente invention porte sur certains composés 4,5-dihydro-3H-spiro[benzo[b]-[1,4]oxazépine de la formule (I), dans laquelle les composés sont tels que décrits ci-dessus. De plus, l'invention porte sur des compositions comprenant au moins un tel composé, et sur des procédés d'utilisation des composés pour traiter ou prévenir des troubles tels que les diabètes ne dépendant pas de l'insuline (type 2), une résistance à l'insuline, une hyperglycémie, un trouble lipidique, l'obésité, une stéatose hépatique ou une affection cutanée.
PCT/US2010/042732 2009-07-23 2010-07-21 Composés oxazépine spirocyclique en tant qu'inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase WO2011011506A1 (fr)

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WO2013056148A2 (fr) 2011-10-15 2013-04-18 Genentech, Inc. Procédés d'utilisation d'antagonistes de scd1
US10973810B2 (en) 2017-01-06 2021-04-13 Yumanity Therapeutics, Inc. Methods for the treatment of neurological disorders
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