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Abstract

Description

SPIROCYCUC OXAZEPlNE COMPOUNDS AS STEAROYL-COENZYME A DELTA-9 DESATURASE INHIBITORS

FIELD OF THE INVENTION

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, and 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.

BACKGROUND OF THE INVENTION

Stearoyl-coenzyme A (CoA) desaturase (SCD) is involved in the de novo synthesis of monounsaturated fats from saturated fatty acids (see e.g., Ntambi (1999) J. Lipid Res. 40, 1549 for a review). 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 )).

Depending on the species, 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.

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. In view of the experimental evidence described above, modulation of SCD represents a promising therapeutic strategy for the treatment of obesity and related metabolic disorders.

In addition to the above-described findings, studies in 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. Both 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.

In humans, 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. Despite the important functions that sebum plays, many individuals experience excess sebum production which condition is associated with increased incidence of dermatological conditions such as acne or seborrheic dermatitis. Even in individuals without acne, 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

individuals experiencing these conditions.

In view of the findings described above, there is a need for identifying molecules that modulate SCD activity and are useful for the treatment of metabolic disorders, such as obesity and type 2 diabetes, and skin disorders such as acne.

SUMMARY OF THE INVENTION

In one aspect, the present invention discloses methods of using a Compound of the Formula (I),

wherein the compound is selected from one of the 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. The structural formulas and names of compounds 1-45 (herein referred to as the "Spirocyclic

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

pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, to a patient, e.g., a human patient, in need of such treatment. For instance, in some embodiments, the disorder is disorder is a lipid disorder, which is dyslipidemia, hyperlipidemia, atherosclorosis, hypercholesterolemia, low LDL, or high LDL. In other embodiments, the disorder being treated is a skin disorder.

The present invention further provides pharmaceutical compositions comprising an effective amount of at least one Spirocyclic Oxazepine

Compound or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and a pharmaceutically acceptable carrier. In some embodiments, 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 details of the invention are set forth in the accompanying detailed description below.

Although any methods and materials similar to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and the claims. All patents and publications cited in this specification are incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION

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.

Definitions and Abbreviations

As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following

meanings:

"Patient" includes both human and animals. "Mammal" means humans and other mammalian animals.

It should also be noted that 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.

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.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.

As used herein, the term "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.

Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "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. A discussion of the use of prodrugs is 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.

For example, if a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, 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- C₈)alkyl, (C₂-Ci₂)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- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C-ι-C₂)alkylamino(C2-C₃)alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci-C₂)alkyl, N,N-di (C_r

C₂)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C₂- C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C-ι-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁- C₆)alkoxycarbonyloxymethyl, N-(C-ι-C₆)alkoxycarbonylaminomethyl, succinoyl, (C_rC₆)alkanoyl, α-amino(CrC₄)alkanyl, arylacyl and α-aminoacyl, or α- aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)₂, -P(O)(O(Cr Ce)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.

If a compound of Formula (I) incorporates an amine functional group, 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, (C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α- aminoacyl, -C(OH)C(O)OY¹ wherein Y¹ is H, (C_rC_β)alkyl or benzyl,—

C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C_rC₆)alkyl, carboxy (C₁- Ce)alkyl, amino(CrC₄)alkyl or mono-N— or di-N,N-(C-i-C₆)alkylaminoalkyl,— C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵ is mono-N^ or di-N, N-(C₁- C₆)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.

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 H₂O.

One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, 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. Commυn., 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. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein.

Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. 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.

Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1 ) 1 -19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D, C. on their website). These disclosures are incorporated herein by reference thereto.

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. 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.

All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Pharmaceutically acceptable 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_1-4alkyl, or C_1-4alkoxy 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) phosphonate esters and (5) mono-, di- or triphosphate esters. 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 (C₆-24)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

diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. 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

converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

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

diastereomeric forms, are contemplated within the scope of this invention.

Also, for example, all 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. Examples of 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 ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶CI and ¹²³I, respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) 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. E.g., those labeled with positron-emitting isotopes like ¹¹C or ¹⁸F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like ¹²³I can be useful for application in Single photon emission computed tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e., ²H) 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. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) 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. Additionally, 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), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the

Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.

Polymorphic forms of the compounds of Formula I, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention.

The present invention further includes the compounds of Formula (I) in all their isolated forms. For example, 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.

The following abbreviations are used below and have the following meanings: 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 is 1-hydroxybenzotriazole; and NaBH(OAc)₃ is sodium

triacetoxyborohydride.

The Compounds of Formula (1)

The present invention provides methods of using a Compound of the Formula (I)

wherein 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. The structural formulas and names of compounds 1-45 are set forth below in Table 1 of the Examples.

Methods For Making the Compounds of Formula (I)

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.

The starting materials and reagents described in in Schemes 1 and 2 below are either available from commercial suppliers such as Sigma-Aldrich (St. Louis, MO) and Acros Organics Co. (Fair Lawn, NJ), or can be prepared using methods well-known to one skilled in the art of organic synthesis.

One skilled in the art of organic synthesis will also recognize that the synthesis of the 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.

Scheme 1

The preparation of Intermediate A4 is modified from the procedure described in Willand et a/., Synthesis and Structural Studies of a Novel Scaffold for Drug Discovery: A 4,5-dihydro-3H-spiro[1,5-benzoxazepine-2,4'-pipehdine, 45 Tetrahedron Lett. 1051-1054 (2004), hereinafter "Willand et al."

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. After removing the benzyl protecting group of intermediate using palladium-catalyzed reduction, the crude, de-protected product is reacted with BOC₂O without purification to give intermediate A4.

In some embodiments in the synthesis of intermediate A3, a side product, intermediate A3'

is recovered in addition to the fully reduced intermediate, A3, Treating the mixture of A3' and A3 with lithium aluminum hydride in a suitable solvent, e.g., tetrahydrofuran, converts the mixture to the fully reduced 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 R² is C(O)Y, wherein Y is alkyl or cycloalkyl, or wherein R² is

Scheme 2

The N-1 of the benzo-fused oxazepine core of intermediate A4 can be alkylated with an R¹ alkylene group, e.g., R¹ 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.

Using the methods described in Schemes 1 and 2, compounds 1-45 can be prepared.

EXAMPLES EXAMPLE 1

Stearoyl-CoA desaturase Assay

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-μl volumes of 100 mM TrisHCI, pH 7.3, containing 20 μM Stearoyl-CoA , 2 mM β-NADH, and 50 μg 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-μl volume was transferred to a Millipore Multiscreen HTS 96-well filtration plate (MSHVN4B50) containing 125 μ\ 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-μl volumes of filtrate were transferred to another plate containing 150 μ\ 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 IC₅₀ values were interpolated from the data.

Stearoyl CoA desaturase assay data was determined for the compounds of the present invention using the above-described method. IC₅₀ 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.

Table 1

Compound Name IC₅₀

N-(2-oxo-2-(5-(4-phenoxybenzyl)- A 4,5-dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)ethyl)acetamide

N-(2-(5-(4-isopropoxybenzyl)-4,5- A dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-2- oxoethyl)acetamide

N-(2-(5-(biphenyl-4-ylmethyl)-4,5- A dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]- 1 '-yl )-2- oxoethyl)acetamide

N-(2-(5-(4-tert-butylbenzyl)-4,5- B dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-2- oxoethyl)acetamide

N-(2-(5-(4-isopropylbenzy!)-4,5- B dihydro-3H- spiro[benzo[b][1 ,4)oxazepine-2,4'-

piperidine]-1'-yl)-2- oxoethyl)acetamide

4-(5-(4-isopropylbenzyl)-4,5- B dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4"- piperidine]-1 '-yl)-4-oxobutanamide

4-(5-(biphenyI-4-ylmethy!)-4,5- B dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-4-oxobutanamide

4-(5-(4-isopropoxybenzyl)-4,5- B dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-4-oxobutanarnide

N-(2-(5-(2-ethylbenzyl)-4,5- B dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1 '-yl)-2- oxoethyl)acetamide

N-(benzo[c][1 ,2,5]thiadiazol-4-yi)- B

5-(biphenyl-4-ylmethyl)-4,5- dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1 '-carboxamide

3-(5-(4-tert-butylbenzyl)-4,5- B dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-3- oxopropanenitrile

N-(benzo[c][1 ,2,5]thiadiazol-4-yl)- B

5-(4-tert-butyl benzyl )-4,5-dihydro- 3H-spiro[benzo[b][1 ,4]oxazepine- 2,4'-piperidine]-1 '-carboxamide methyl 4-((1 '-(2-acetamidoacetyl)- B 3H-spiro[benzo[b][1 ,4]oxazepine- 2,4'-piperidine]-5(4H)- yl)methyl)benzoate

N-(2-(5-(2,3-dimethylbenzyl)-4,5- B dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-2- oxoethyl)acetamide

4-oxo-4-(5-(4-phenoxybenzyl)-4,5- B dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1 '-yl)butanamide

N-(2-(5-((5-(3-chlorophenyl)furan-

2-yl)methyl)-4,5-dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-2-oxoethyl)furan-

2-carboxamide

N-(2-oxo-2-(5-(4-(pyridin-2- yl)benzyl)-4,5-dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)ethyl)acetamide

N-(2-(5-(3-fluoro-2-methylbenzyl)- 4,5-dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-2- oxoethyl)acetamide

N-(benzo[c][1 ,2,5]thiadiazol-4-yl)- 5-(4-phenoxybenzyI)-4,5-dihydro- 3H-spiro[benzo[b][1 ,4]oxazepine- 2,4'-piperidine]-1 '-carboxamide

N-(2-(5-(2,5-difluorobenzyl)-4,5- C dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-2-

oxoethyl)acetamide

C '-

'-

'-

'-

N-(2-(5-(4-ethylbenzyl)-4,5- dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-2- oxoethyl)benzamide

N-(2-oxo-2-(5-(3-phenylpropyl)- 4,5-dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)ethyl)acetamide

N-(2-(5-(3-methoxybenzyl)-4,5- dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-2- oxoethyl)acetamide

N-(2-(5-(2-ethoxybenzyl)-4,5- C dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-2-

oxoethyl)acetamide

4-(5-(2-ethylbenzyl)-4,5-dihydro- 3H-spiro[benzo[b][1,4]oxazepine-

2,4'-piperidine]-1'-yl)-4- oxobutanamide

N-(2-oxo-2-(5~(thiophen-2- ylmethyl)-4,5-dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)ethyl)acetamide

3-(5-(biphenyl-4-ylmethyl)-4,5- dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-3- oxopropanenitrile

3-(5-(4-isopropylbenzyl)-4,5- dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-3- oxopropanenitrile

5-(4-ethylbenzyl)-N-(4- fluorophenyl)-4,5-dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1 '-carboxamide

(2S,3S)-methyl 2-(5-(4- ethylbenzyl)-4,5-dihydro-3H-

HN "CH3 spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-r-ylcarboxamido)-3- methylpentanoate

43

N-(2-(5-(4-ethylbenzyl)-4,5- B dihydro-3H- spiro[benzo[b][1 ,4]oxazepine-2,4'- piperidine]-1'-yl)-2- oxoethyl)acetamide

Uses of the Spirocyclic Oxazepine Compounds

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. The Spirocyclic

Oxazepine Compounds are therefore useful to control, prevent, and/or treat conditions and diseases mediated by high or abnormal SCD enzyme activity. For instance, 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. Alternatively, 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. For instance, for testing whether the compounds are capable of modulating sebaceous gland function and sebum secretion, 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).

In one embodiment, 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.

In another embodiment, 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,

In another embodiment, 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.

In yet another embodiment, 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.

In another embodiment, 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

administering to said patient a Spirocyclic Oxazepine Compound in an amount that is effective to treat said lipid disorder.

In yet another embodiment, 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.

In yet another embodiment, 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. In still another embodiment, 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. In particular instances the skin disorder being treated is acne.

In addition, the present invention provides a method of treating a cosmetic condition such as greasy or oily-looking hair, comprising

administering to the patient a Spirocyclic Oxazepine Compound in an amount that is effective to treat such cosmetic condition.

In another embodiment, 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.

In still another embodiment, 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 Spirocyclic Oxazepine Compound in an amount that is effective to delay the onset of said condition.

In another embodiment, 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.

In another aspect, 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.

Myopathies and lipid myopathies such as carnitine palmitoyltransferase deficiency (CPT I or CPT II) are also included as such conditions. 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. Combination Therapy

In another embodiment, 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

Oxazepine Compounds.

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. When a Spirocyclic Oxazepine Compound is used

contemporaneously with one or more other therapeutic agents, a

pharmaceutical composition in unit dosage form containing such other agents and the Spirocyclic Oxazepine Compound is preferred. However, 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. In some embodiments, 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.

Accordingly, as discussed further below, the pharmaceutical

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:

(a) dipeptidyi peptidase IV (DPP-IV) inhibitors;

(b) insulin sensitizers including (i) PPAR-gamma-agonists, such as the glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555,

rosiglitazone, balaglitazone, and the like) and other PPAR ligands, including 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), and selective PPAR-gamma-modulators (SPPAR-gammaM's), such as disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO

2004/020408, and WO 2004/066963; (ii) biguanides such as metformin and phenformin, and (iii) protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors;

(c) insulin or insulin mimetics;

(d) sulfonylureas and other insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, and meglitinides, such as nateglinide and repaglinide;

(e) .alpha-glucosidase inhibitors (such as acarbose and miglitol);

(f) glucagon receptor antagonists, such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;

(g) 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;

(h) GIP and GIP mimetics, such as those disclosed in WO 00/58360, and GIP receptor agonists;

(i) PACAP, PACAP mimetics, and PACAP receptor agonists such as those disclosed in WO 01/23420;

(j) 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;

(k) PPAR-delta agonists, such as those disclosed in WO 97/28149;

(I) antiobesity compounds, such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Yi or Y₅ antagonists, CB1 receptor inverse agonists and antagonists, .beta₃ 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;

(m) ileal bile acid transporter inhibitors;

(n) 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;

(o) 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;

(p) glucokinase activators (GKAs), such as those disclosed in WO 03/015774; WO 04/076420; and WO 04/081001 ;

(q) inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1 , such as those disclosed in U.S. Pat. No. 6,730,690; WO 03/104207; and WO

04/058741 ;

(r) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib;

(s) inhibitors of fructose 1 ,6-bisphosphatase, such as those disclosed in

U.S. Patent Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476. (t) antibiotic agents, such as tetracycline and clindamycin;

(u) retinoids, such as etretinate, tretinoin, and aliretinoin; and

(v) estrogen and progesterone. Dipeptidyl peptidase-IV inhibitors that can be combined with the

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

03/000181 ; WO 04/007468; WO 04/032836; WO 04/037169; and WO

04/043940. Specific DPP-IV inhibitor compounds include isoleucine

thiazolidide (P32/98); NVP-DPP-728; LAF 237; P93/01 ; and saxagliptin (BMS 477118).

Antiobesity compounds that can be combined with the Spirocyclic Oxazepine Compounds include fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Yi or Y₅ 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.

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

Publication WO 02/076949, such as SLV-319; U.S. Patent No. 6,028,084; PCT Publication WO 98/41519; PCT Publication WO 00/10968; PCT Publication WO 99/02499; U.S. Patent No. 5,532,237; U.S. Patent No. 5,292,736; PCT Publication WO 03/086288; PCT Publication WO 03/087037; PCT Publication WO 04/048317; PCT Publication WO 03/007887; PCT Publication WO

03/063781 ; PCT Publication WO 03/075660; PCT Publication WO 03/077847; PCT Publication WO 03/082190; PCT Publication WO 03/082191 ; PCT

Publication WO 03/087037; PCT Publication WO 03/086288; PCT Publication WO 04/012671 ; PCT Publication WO 04/029204; PCT Publication WO

04/040040; PCT Publication WO 01/64632; PCT Publication WO 01/64633; and PCT Publication WO 01/64634.

Melanocortin-4 receptor (MC4R) agonists useful in combination with the Spirocyclic Oxazepine Compounds include, but are not limited to, those disclosed in U.S. Patent No. 6,294,534, U.S. Patent Nos. 6,350,760, 6,376,509, 6,410,548, 6,458,790, U.S. Patent No. 6,472,398, U.S. Patent No. 5,837,521 , U.S. Patent No. 6,699,873, which are hereby incorporated by reference in their entireties; in US Patent Application Publication Nos. US 2002/0004512,

US2002/0019523, US2002/0137664, US2003/0236262, US2003/0225060, US2003/0092732, US2003/109556, US 2002/0177151 , US 2002/187932, US 2003/0113263, which are hereby incorporated by reference in their entireties; and in WO 99/64002, WO 00/74679, WO 02/15909, WO 01/70708, WO

01/70337, WO 01/91752, WO 02/068387, WO 02/068388, WO 02/067869, WO 03/007949, WO 2004/024720, WO 2004/089307, WO 2004/078716, WO 2004/078717, WO 2004/037797, WO 01/58891 , WO 02/070511 , WO

02/079146, WO 03/009847, WO 03/057671 , WO 03/068738, WO 03/092690, WO 02/059095, WO 02/059107, WO 02/059108, WO 02/059117, WO

02/085925, WO 03/004480, WO 03/009850, WO 03/013571 , WO 03/031410, WO 03/053927, WO 03/061660, WO 03/066597, WO 03/094918, WO

03/099818, WO 04/037797, WO 04/048345, WO 02/018327, WO 02/080896, WO 02/081443, WO 03/066587, WO 03/066597, WO 03/099818, WO

02/062766, WO 03/000663, WO 03/000666, WO 03/003977, WO 03/040107, WO 03/040117, WO 03/040118, WO 03/013509, WO 03/057671 , WO

02/079753, WO 02/092566, WO 03/093234, WO 03/095474, and WO

03/104761.

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.

More particularly, this aspect of combination therapy concerns 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 wherein the 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 is disclosed 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.

In another aspect, 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. In particular embodiments, the HMG-CoA reductase inhibitor is a statin selected from the group consisting of: lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, and rosuvastatin.

In another aspect, 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. In particular embodiments, the cholesterol absorption inhibitor is ezetimibe.

In another aspect, 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. The antibiotic is useful for eradicating the effect of the microorganism, Propionibacteήum acnes, which contributes to developing acne.

In another aspect, 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.

In another aspect, 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.

When administering a second therapeutic agent in combination with a Spirocyclic Oxazepine Compound, the weight ratio of the Spirocyclic

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.

In such combinations the Spirocyclic Oxazepine Compound and other therapeutic agents may be administered separately or in conjunction. In addition, the administration of one therapeutic agent may be prior to,

concurrent to, or subsequent to the administration of other agent(s). Compositions and Administration

This invention is also directed to pharmaceutical 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.

When administered to a patient, 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. In the pharmaceutical compositions and methods of the present invention, 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

pharmaceutical practices. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18^th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. For example, for oral

administration in the form of tablets or capsules, 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.

Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the 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. For instance, in one embodiment, 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). In some embodiments, the Spirocyclic Oxazepine Compound may be present in the topical composition at

concentrations of between about 1.5% to about 2.0% (w/v).

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.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

For preparing suppositories, 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.

Additionally, the 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

therapeutic effects, i.e., anti-cancer activity and the like. 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.

In one embodiment, the Spirocyclic Oxazepine Compound is

administered orally.

In another embodiment, the Spirocyclic Oxazepine Compound is administered intravenously.

In still another embodiment, the Spirocyclic Oxazepine Compound is administered sublingually.

In another embodiment, the Spirocyclic Oxazepine Compound is administered topically, for example, for use in treating a skin disorder of the type described above. Typically, in such embodiments, the Spirocyclic

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. Such 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.

In one embodiment, a pharmaceutical preparation comprising at least one Spirocyclic Oxazepine Compound is in unit dosage form. In such 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

Compound(s) by weight or volume.

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.

For convenience, the total daily dosage may be divided and

administered in portions during the day if desired. In one embodiment, the daily dosage is administered in one portion. In another embodiment, the total daily dosage is administered in two divided doses over a 24 hour period. In another embodiment, the total daily dosage is administered in three divided doses over a 24 hour period. In still another embodiment, the total daily dosage is administered in four divided doses over a 24 hour period.

For administration to human patients, 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. In one embodiment, the dosage is from about 1 to about 300 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 10 to about 3000 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 100 to about 3000 rng/day,

administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 500 to about 3000 mg/day,

administered in a single dose or in 2-4 divided doses.

For dermatological administration, such as for the treatment of a skin disorder, he dose of 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.

The compositions of the invention can further comprise one or more additional therapeutic agents, selected from those listed above herein.

Accordingly, in one embodiment, the present invention provides compositions comprising: (i) at least one Spirocyclic Oxazepine Compound or a

pharmaceutically acceptable salt, solvate, ester or prodrug thereof; (ii) one or more additional therapeutic agents that are not a Spirocyclic Oxazepine Compound; and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the composition are together effective to treat disease or disorder associated with aberrant SCD activity.

In certain embodiments the compositions of the invention, a

pharmaceutical composition is disclosed which comprise:

(1 ) a Spirocyclic Oxazepine Compound; (3) a pharmaceutically acceptable carrier; and (3) a compound selected from the group consisting of:

(a) dipeptidyl peptidase IV (DPP-IV) inhibitors;

(b) insulin sensitizers including (i) PPAR gamma agonists, such as the glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555,

rosiglitazone, balaglitazone, and the like) and other PPAR ligands, including 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), and selective PPAR gamma modulators (SPPAR gamma M's), such as disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO

2004/020408, and WO 2004/066963; (ii) biguanides such as metformin and phenformin, and (iii) protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors;

(c) insulin or insulin mimetics;

(d) sulfonylureas and other insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, and meglitinides, such as nateglinide and repaglinide;

(e) alpha-glucosidase inhibitors (such as acarbose and miglitol);

(f) glucagon receptor antagonists, such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;

(g) 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;

(h) GIP and GIP mimetics, such as those disclosed in WO 00/58360, and GIP receptor agonists;

(i) PACAP, PACAP mimetics, and PACAP receptor agonists such as those disclosed in WO 01/23420;

(j) 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;

(k) PPAR delta agonists, such as those disclosed in WO 97/28149; (I) antiobesity compounds, such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists, CB1 receptor inverse agonists and antagonists, beta₃ 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;

(m) ileal bile acid transporter inhibitors;

(n) 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;

(o) 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;

(p) glucokinase activators (GKAs), such as those disclosed in WO 03/015774; WO 04/076420; and WO 04/081001 ;

(q) inhibitors of 11 beta-hydroxysteroid dehydrogenase type 1 , such as those disclosed in U.S. Pat. No, 6,730,690; WO 03/104207; and WO

04/058741 ;

(r) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib;

(s) inhibitors of fructose 1 ,6-bisphosphatase, such as those disclosed in

U.S. Patent Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476;

(t) antibiotic agents, such as tetracycline and clindamycin;

(u) retinoids, such as etretinate, tretinoin, and aliretinoin; and

(v) estrogen and progesterone.

Kits

Another aspect of this invention is a kit 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. Yet another aspect of this invention is a 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. In one

embodiment, 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.

The present invention is not to be limited by the specific embodiments disclosed in the examples that are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

A number of references have been cited herein, the entire disclosures of which are incorporated herein by reference.

Claims

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Citations (124)

• 2010
  • 2010-07-21 WO PCT/US2010/042732 patent/WO2011011506A1/en active Application Filing

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