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  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
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  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07C59/40—Unsaturated compounds
  • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
  • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
  • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

• the present invention relates to compounds capable of modulating the
• G-protein-coupled receptor GPR40 compositions comprising the compounds, and methods for their use for controlling insulin levels in vivo and for the treatment of conditions such as type II diabetes, hypertension, ketoacidosis, obesity, glucose intolerance, and hypercholesterolemia and related disorders associated with abnormally high or low plasma lipoprotein, triglyceride or glucose levels.
• GPR40 is a member of the gene superfamily of G-protein coupled receptors
• GPCRs are membrane proteins characterized as having seven putative transmembrane domains that respond to a variety of molecules by activating intra-cellular signaling pathways critical to a diversity of physiological functions.
• GPR40 was first identified as an orphan receptor (i.e., a receptor without a known ligand) from a human genomic DNA fragment. Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun. 239: 543-547. GPR40 is highly expressed in pancreatic ⁇ cells and insulin-secreting cell lines. of the G q family of intra-cellular signaling proteins and concomitant induction of elevated calcium levels.
• a condition or disorder such as type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer or edema.
• the compounds of the invention have the general formula (I): Q-L'-P-L ⁇ M-X-L ⁇ A I wherein Q is hydrogen, aryl, heteroaryl, (C ⁇ -C 6 )alkyl or (C 2 -C 6 )heteroalkyl; L 1 is a bond, (d-C ⁇ alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) m , NCR 1 ), C(O)-(C 5 -C 7 )heterocycloalkylene, (C ⁇ -C 4 )alkylene-SO 2 N(R 2 ), (C ⁇ -C 4 )alkylene-N(R 2 )SO 2 or C(O)N(R ); P is an aromatic ring, a heteroaromatic ring, (C 3 -C 8 )heterocycloalkylene or (C 3 -C 8 )cycloalkylene; L 2 is a bond
• the present invention provides a compound having the formula (lb):
• R 21 is -H, -OH, -NHS(O 2 )CH 3 , heteroaryl, or -NH- A heteroaryl
• R is -(C 2 .C 8 )alkyl, -(C 3 -C 8 )alkenyl, -NR R , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, c ⁇ , or C-C-R 25 ; or optionally where Z is a nitrogen atom, R is -H; R and R are independently -H, -(C ⁇ -C 5 )alkyl, or -(Ci- C 5 )oxyalkyl; R 25 is -H, -(C ⁇ -C 5 )alkyl, -hetero(C ⁇ -C 5 )alkyl, -(C r C 5 )oxyalkyl, substituted or unsubstit
• the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula I, la, lb or II.
• a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease atherosclerosis, kidney disease, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, thrombotic disorders, dermatopathy, dyspepsia, hypoglycemia, hypertension, cancer and edema comprising administering to a subject in need thereof a therapeutically effective amoxmt of a compoxmd of formula I, la, lb or II.
• the invention provides methods for treating or preventing a disease or condition responsive to the modulation of GPR40 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, la, lb or II.
• the invention provides methods for treating or preventing a disease or condition mediated, regulated or influenced by pancreatic ⁇ cells comprising administering to a subject in need thereof a therapeutically effective amoxmt of a compoxmd of formula I, la, lb or II.
• the invention provides methods for modulating GPR40 function in a cell, comprising contacting a cell with a compound of formula I, la, lb or II.
• the invention provides methods for modulating GPR40 function comprising contacting GPR40 with a compound of formula I, la, lb or II. [018] In another aspect, the invention provides methods for modulating circulating insulin concentration in a subject, comprising administering a compound of formula I, la, lb or II to the subject. [019] Other objects, features and advantages of the invention will become apparent to those skilled in the art from the following description and claims.
• FIG. 1 provides a scheme for synthesis of exemplary compounds of the invention. 5. DETAILED DESCRIPTION OF THE INVENTION
• treat are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms and alleviating.
• prevention refers to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a subject from acquiring a condition or disease or reducing a subject's risk of acquiring a condition or disease.
• terapéuticaally effective amount refers to that amount of the compound that will elicit the biological or medical response of a tissue, system, or subject that is being sought.
• therapeutically effective amount includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated in a subject.
• the therapeutically effective amount in a subject will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.
• the "subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
• the terms "modulate”, “modulation” and the like refer to the ability of a compoxmd to increase or decrease the function or activity of GPR40 either directly or indirectly.
• Inhibitors are compounds that, for example, bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction, such as, for instance, antagonists.
• Activators are compounds that, for example, bind to, stimulate, increase, activate, facilitate, enhance activation, sensitize or up regulate signal transduction, such as agonists for instance. Modulation may occur in vitro or in vivo.
• GPR40-mediated condition or disorder refers to a condition or disorder characterized by inappropriate, for example, less than or greater than normal, GPR40 activity.
• a GPR40-mediated condition or disorder may be completely or partially mediated by inappropriate GPR40 activity.
• a GPR40-mediated condition or disorder is one in which modulation of GPR40 results in some effect on the underlying condition or disease (e.g., a GPR40 modulator results in some improvement in patient well-being in at least some patients).
• Exemplary GPR40-mediated and metabolic disorders e.g., diabetes, type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, thrombotic disorders, metabolic syndrome, syndrome X and related disorders, e.g., cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia and edema.
• alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (e.g., Ci. o means one to ten carbons).
• alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
• alkenyl by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C 2 .C 8 means two to eight carbons) and one or more double bonds.
• alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl) and higher homologs and isomers thereof.
• alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C 2 -C 8 means two to eight carbons) and one or more triple bonds.
• alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers thereof.
• alkylene by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH 2 CH 2 CH 2 CH 2 -.
• an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 12 or fewer carbon atoms being preferred in the present invention.
• a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
• heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized.
• the heteroatom(s) O, N and S may be placed at any position of the heteroalkyl group.
• Up to two heteroatoms may be consecutive, such as, for example, -CH -NH-OCH 3 .
• a prefix such as (C 2 -C 8 ) is used to refer to a heteroalkyl group
• the number of carbons (2 to 8, in this example) is meant to include the heteroatoms as well.
• a C 2 -heteroalkyl group is meant to include, for example, -CH 2 OH (one carbon atom and one heteroatom replacing a carbon atom) and -CH 2 SH.
• a heteroalkyl group is a oxyalkyl group.
• (C 2 .C 5 )oxyalkyl is meant to include, for example -CH 2 -O-CH (a C 3 -oxyalkyl group with two carbon atoms and one oxygen replacing a carbon atom), -CH 2 CH 2 CH 2 CH 2 OH, and the like.
• heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 CH 2 - and -CH2-S-CH2-CH2-NH-CH 2 -.
• heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
• heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
• cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
• heterocycloalkyl examples include l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, _ __ 4 ⁇ rph ⁇ n ⁇ tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
• cycloalkylene and “heterocycloalkylene,” by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkylene” and “heteroalkylene,” respectively.
• cycloalkylene and heterocycloalkylene are meant to be included in the terms “alkylene” and “heteroalkylene,” respectively.
• one or more heteroatoms can occupy positions at which the heterocycle is attached to the remainder of the molecule.
• a cycloalkylene or heterocycloalkylene will have from 3 to 9 atoms forming the ring, more typically, 4 to 7 atoms forming the ring, and even more typically, 5 or 6 atoms will form the cycloalkylene or hetercycloalkylene ring.
• halo or halogen
• substituents mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
• terms such as “haloalkyl” are meant to include alkyl substituted with halogen atoms which can be the same or different, in a number ranging from one to (2m' + 1), where m' is the total number of carbon atoms in the alkyl group.
• halo(C ⁇ -C 4 )alkyl is meant to include trifluoromethyl, 2,2,2-trifiuoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
• haloalkyl includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m' + 1) halogen atoms).
• perhaloalkyl means, unless otherwise stated, alkyl substituted with (2m' + 1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group.
• perhalo(C ⁇ -C 4 )alkyl is meant to include trifluoromethyl, pentachloroethyl, l,l,l-trifluoro-2-bromo-2-chloroethyl, and the like.
• aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
• heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized.
• a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
• Non-limiting examples of aryl and heteroaryl groups include phenyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-pyridyl, 3 -pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyrimidinyl, 4-pyrimidinyl, 5 -pyrimidinyl, 3 -pyrid
• aryl refers to a phenyl or naphthyl group which is unsubstituted or substituted.
• heteroaryl refers to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl or quinolyl group which is unsubstituted or substituted.
• aryl when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
• arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
• R', R" and R'" each independently refer to hydrogen, unsubstituted (C ⁇ -C 8 )alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C ⁇ -C 4 )alkyl, or aryl-(C 1 -C )alkyl groups.
• R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a " 5- - r - Dlred ⁇ nl.
• an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted.
• alkyl is meant to include groups such as trihaloalkyl (e.g., -CF 3 and -CH 2 CF ).
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CH 2 -, -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 3.
• One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) s -X-(CH 2 )r, where s and t are independently integers of from 0 to 3, and X is -O-, - ⁇ - ' -!- - - : i!0)2NR'-.
• the substituent R' in -NR'- and -S(O) 2 NR'- is selected from hydrogen or unsubstituted (C ⁇ -C 6 )alkyl. Otherwise, R' is as defined above.
• the term "heteroatom” is meant to include oxygen (O), nitrogen (N), and sulfur (S).
• bioisostere of -CO 2 H is meant that the the substituent -CO 2 H may be optionally replaced with bioisosteric replacements such as:
• pharmaceutically acceptable salt is meant to include a salt of the active compound which is prepared with relatively nontoxic acids or bases, depending on the particular substituents foxmd on the compound described herein.
• a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
• pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
• an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
• Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the .
• compoxmds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
• the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
• the parent form of the compoxmd differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.
• the invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the invention.
• prodrags can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment.
• prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
• Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
• the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
• a wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
• solvate refers to a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. , ' "' 52
• a stereomerically pure a compound having two chiral centers will be substantially free of other diastereomers of the compound.
• a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95%) by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
• stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
• Various compounds of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention.
• the compoxmds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
• the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine- 125 ( 125 I) or carbon- 14 ( 14 C).
• Radio labled compoxmds are useful as therapeutic or prophylactic agents, research reagents, e.g., GPR40 assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
• a class of compounds that modulate GPR40 is described herein. Depending on the biological environment (e.g., cell type, pathological condition of the subject, etc.), these compounds can modulate, e.g., activate or inhibit, the actions of GPR40. By modulating GPR40, the compounds find use as therapeutic agents capable of regulating insulin levels in a subject. The compounds find use as therapeutic agents for modulating diseases and conditions responsive to modulation of GPR40 and/or mediated by GPR40 and/or mediated by pancreatic ⁇ cells.
• diseases and conditions include diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, cancer, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, nephropathy, thrombotic disorders, diabetic neuropathy, diabetic retinopathy, dermatopathy, dyspepsia and edema. Additionally, the compounds are useful for the treatment and/or prevention of complications of these diseases and disorders (e.g., type II diabetes, sexual dysfunction, dyspepsia and so forth).
• complications of these diseases and disorders e.g., type II diabetes, sexual dysfunction, dyspepsia and so forth.
• the compoxmds of the invention are believed to exert their effects by interacting with GPR40, the mechanism of action by which the compounds act is not a limiting embodiment of the invention.
• Compounds contemplated by the invention include, but are not limited to, the exemplary compounds provided herein.
• the present invention provides a compound having the formula (I): Q-L -P-L 2 -M-X-L 3 -A I where Q, L , P, L , M, X, L and A are defined below.
• Q is hydrogen, aryl, heteroaryl, (C ⁇ -C 6 )alkyl or (C 2 -C 6 )heteroalkyl.
• Q is aryl
• Q is 4-(trifluoromethyl)phenyl or -tolyl.
• L 1 is a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) m , NCR 1 ),
• L 1 is a bond, (C ⁇ -C )alkylene
• L 1 is a bond, O or NCR 1 ).
• L 1 is a bond
• P is an aromatic ring, a heteroaromatic ring, (C 3 -C 8 )heterocycloalkylene or
• (C 3 -C 8 )cycloalkylene In certain embodiments where P is an aromatic ring, the term aromatic includes aryl. In other embodiments where P is a heteroaromatic ring, the term heteroaromatic includes heteroaryl.
• P is an aromatic ring or a heteroaromatic ring.
• P is a monocyclic aromatic ring or a moncyclic heteroaromatic ring.
• P is a selected from the group consisting of benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboliiie, isoquinoline, quinoxaline and quinoline.
• P can be benzene, naphthalene, pyrrole, pyrazine, pyridine, pyrimidine, pyridazine, purine, indole, carboliiie, isoquinoline, quinoxaline or quinoline.
• P is a benzene, thiazole, or oxazole ring.
• L 1 is a bond, O or N(R ! ) and P is an aromatic ring or a heteroaromatic ring.
• L 2 is a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O,
• L 2 is a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, S(0) m , N(R X ), C(O)N(R 2 ), SO 2 N(R 2 ), (C ⁇ -C 4 )alkylene-C(O)N(R 2 ), (C 2 -C 4 )alkenylene-C(O)N(R 2 ), (C ⁇ -C 4 )alkylene-SO 2 N(R 2 ) or (C 2 -C 4 )alkenylene-SO 2 N(R 2 ).
• L 2 is (C 2 -C 6 )heteroalkylene. [076] In some embodiments, L 2 is (C 2 -C 4 )heteroalkylene. 1 1 [077] In some embodiments, L is a bond, O or N(R ) and L is (C 2 -C 6 )heteroalkylene. [078] In certain embodiments, L 2 is oxymethylene or thiomethylene. 1 9 [079] In preferred embodiments, L is a bond and L is oxymethylene or thiomethylene.
• M is an aromatic ring, a heteroaromatic ring, (C 5 -C 8 )cycloalkylene, aryl(C ⁇ -C 4 )alkylene or heteroaryl(C ⁇ -C )alkylene.
• aromatic includes aryl.
• heteroaromatic includes heteroaryl.
• M is an aromatic ring or a heteroaromatic ring.
• M is a (C 5 -C 8 )cycloalkylene.
• M is a monocyclic aromatic, a monocyclic heteroaromatic ring or (C 5 -C 8 )cycloalkylene.
• M is an unsubstituted monocyclic aromatic ring or an unsubstituted monocyclic heteroaiOmatic ring.
• M is a benzene ring or a heteroaromatic ring.
• M is a benzene ring.
• P is an aromatic ring or a heteroaromatic ring and M is an aromatic ring, a heteroaromatic ring or (C 5 -C 8 )cycloalkylene.
• X is CR 3 R 4 , N(R 5 ), O or S(O) lake.
• X is CR 3 R 4 or N(R 5 ).
• X is CHR 3 .
• M is a substituted or unsubstituted benzene ring and X is/?
• M is an aromatic ring, a heteroaromatic ring or (C 5 -C 8 )cycloalkylene and X is CR 3 R 4 or 1N(R 5 ).
• " 93 ⁇ ' P is an aromatic ring or a heteroaromatic ring and X is CR 3 R 4 or N(R 5 ).
• L is a bond, (C ⁇ -C 5 )alkylene or (C 2 -C 5 )heteroalkylene, provided that L is not a bond when L 2 is a bond.
• L 3 is (C ⁇ -C 5 )alkylene or (C 2 -C 5 )heteroalkylene. [096] In certain embodiments, L 3 is (Ci-C 3 )alkylene. [097] In some embodiments, L 3 is methylene. [098] In certain embodiments, L is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl. [099] In certain embodiments, X is CR 3 R 4 or N(R 5 ), and L 3 is substituted or unsubstituted methylene.
• L 2 is (C 2 -C 4 )heteroalkylene and L 3 is (C ⁇ -C 3 )alkylene.
• L is a bond, O or N(R ), L is (C 2 -C 4 )heteroalkylene and L is (C ⁇ -C 3 )alkylene.
• A is -CO 2 H, tetrazol-5-yl, -SO 3 H, -PO 3 H 2 , -SO 2 NH 2 , -C(O)NHSO 2 CH 3 , -CHO, -C(O)R 6 , -C(O)NHR 6 , -C(O)NHOR 7 , thiazolidinedion-yl, hydroxyphenyl or pyridyl.
• A is a bioisostere of -CO 2 H.
• A is -C0 2 H or tetrazol-5-yl, -C(O)NHSO 2 CH 3 or -C(O)NHR 6 .
• A is -CO 2 H or tetrazol-5-yl.
• A is -CO 2 H or a salt thereof.
• P is an aromatic ring or a heteroaromatic ring and A is -CO 2 H.
• X is CR 3 R 4 or N(R 5 ) and A is -CO 2 H.
• M is an aromatic ring, a heteroaromatic ring or (C 5 -C 8 )cycloalkylene and A is -CO 2 H or tetrazol-5-yl.
• M is an aromatic ring, a heteroaromatic ring or (C 5 -C 8 )cycloalkylene
• X is CR 3 R 4 or N(R 5 )
• L 3 is (C 1 -C 5 )alkylene or (C 2 -C 5 )heteroalkylene and A is -CO 2 H.
• R 1 is (C ⁇ -C 6 )alkyl, aryl(d-C 3 ) alkyl or (C 2 -C 6 )heteroalkyl. [0112] In certain embodiments, R 1 is or (C 2 -C 6 )heteroalkyl. [0113] R 2 is hydrogen, (C ⁇ -C 6 )alkyl or (C 2 -C 6 )heteroalkyl.
• R 3 is cyano, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, -NR 8 R 9 , -C(O)NR 10 R ⁇ , -NR 12 C(O)R 13 or -NR 12 S(O) p R 13 .
• R is cyano, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or -NR 8 R 9 .
• R is cyano, heteroaryl, (C 2 -C 6 ) alkenyl or (C 2 -C 6 )alkynyl. [0118] In certain embodiments, R is (C 2 -C 8 )alkyl, (C 3 -C 8 )alkenyl or (C 3 -C 8 )alkynyl. [0119] In some embodiments, R 3 is aryl or heteroaryl. [0120] In certain preferred embodiments, R is tetrazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxazolyl, pyrrolyl, thienyl or prop-1-ynyl.
• R is tetrazolyl, thiazolyl, or prop-1-ynyl.
• R 4 is hydrogen, cyano, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -Cg)alkenyl or (C 2 -C 8 )alkynyl.
• O ptionally, R 3 and R are combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing from zero to three heteroatoms selected from N, O and S.
• the ring formed by combining R 3 and R 4 may be a saturated or unsaturated ring.
• R 4 is hydrogen or methyl.
• R is hydrogen.
• R is cyano, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )alkynyl or -NR 8 R 9 and R 4 is hydrogen.
• R 5 is hydrogen, aryl, heteroaryl, (C ⁇ -Cg)alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or (C 3 -C 8 )cycloalkyl.
• R 6 is heteroaryl.
• R 7 is hydrogen or (CrC ⁇ alkyl.
• R 8 and R 9 are independently hydrogen, (C ⁇ -C 5 )alkyl, oxy(C ⁇ -C 5 )alkyl or carboxy(C ⁇ -C 5 )alkyl.
• R 8 and R 9 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S.
• the ring formed by combining R 8 and R 9 may be a saturated, unsaturated or aromatic ring.
• " ? ]" '' ' ! independently selected from hydrogen, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl and (C 3 -C 8 )heterocycloalkyl.
• R 10 and R 11 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S.
• the ring formed by combining R 10 and R 11 may be a saturated, unsaturated or aromatic ring.
• R 13 is aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl or
• CR 3 R 4 and R 3 is cyano, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or -NR 8 R 9 .
• A is -CO 2 H
• X is CR R and R is cyano, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or -NR 8 R 9 .
• P and M are benzene, at least two of L , X and
• the compounds of formula I do not include
• compounds of formula I do not include compounds wherein P is a 1,2-azole ring when Q is aryl or heteroaryl, L 1 is a bond, M is a monocyclic aromatic ring, X is N(R 5 ), O or S(O) n , and A contains a carbonyl group.
• compounds of formula I do not include compounds wherein P is furan or thiophene when Q is aryl, L 1 is a bond, M is an aromatic ring, X is CR 3 R 4 , O or S(O) n and A contains a carbonyl group.
• the compounds of the invention include pharmaceutically acceptable salts, solvates or prodrugs thereof.
• ester prodrugs are preferred.
• divalent groups such as C(O)N(R 2 ), SO 2 N(R 2 ),(d-C 4 )alkylene-C(O)N(R 2 ) and the like, both possible orientations of the groups are permitted.
• the carbon atom may be attached to P or to M, as shown: O O Q-L 1 -P-C-N-M-X-L 3 -A or Q-L 1 -P-N-C-M-X-L 3 -A R 2 R 2
• the alkylene group may be attached to P or to M, as shown:
• the present invention provides a compound having the formula (la):
• Q is substituted or unsubstituted benzene
• L 1 is a bond, (C ⁇ -C 4 )alkylene, O or S(O) m .
• P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, pyridine, pyrimidine, , resort , . '' pyri a£i ⁇ eV e ⁇ tKia' ,” l S !
• benzimidazole indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline.
• Q is hydrogen, aryl, heteroaryl or (C ⁇ -C 6 )alkyl
• L 1 is a bond, (C ⁇ -C 4 )alkylene, O or S(O) m .
• L 3 is (C ⁇ -C 5 )alkylene. In certain embodiments, L 3 is methylene.
• R is cyano, aryl, heteroaryl, (C 2 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, -NR 8 R 9 , -C(O)NR 10 R n , -NR 12 C(O)R 13 or -NR 12 S(O) p R 13 and R 4 is hydrogen, cyano, aryl, heteroaryl, (C ⁇ -Cg)alkyl, (C 2 -C 8 )alkenyl or (C 2 -C 8 )alkynyl.
• R is cyano, an unsubstituted aryl or heteroaryl monocyclic ring, (C 2 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, or -C(O)NR 10 R ⁇ , R 4 is hydrogen, and P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline.
• R is cyano, an unsubstituted aryl or heteroaryl monocyclic ring, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, -C(O)NR 10 R U , R 4 is hydrogen, and L 3 is methylene.
• Q is aryl, heteroaryl, (C ⁇ -C 6 )alkyl or (C 2 -C 6 )heteroalkyl
• L 1 is a bond, (C ⁇ -C 4 )alkylene, (C 2 -C 4 )heteroalkylene, S(O) m , N(R 1 ), (C ⁇ -C 4 )alkylene-SO 2 N(R 2 ), (C 1 -C 4 )alkylene-N(R 2 )SO 2 or C(O)N(R 2 )
• P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxa
• P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, furan, thiophene, ' p i ine, ! y ⁇ m'e, pyrf a i erbenzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline.
• R 5 is an unsubstituted or substituted benzene.
• the present invention provides a compound having the formula (II):
• R 21 is -H, -OH, -NHS(O 2 )CH 3 , heteroaryl, or -NH-heteroaryl.
• R 21 is -OH, -NHS(O 2 )CH 3 , -NH-tetrazolyl, or tetrazolyl.
• R is tetrazolyl, pyrimidinyl, or pyridinyl.
• R 21 is -OH, or a salt thereof.
• R 22 is -H, -(C 2 .C 8 )alkyl, -(C 3 -C 8 )alkenyl, -NR 23 R 24 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, — c — N 5 or ⁇ C ⁇ C-R 25 _
• R 22 is unsubstituted aryl or unsubstituted heteroaryl.
• R 22 is substituted aryl and the substitution onto the aryl is unsubstituted -(C ⁇ -C 5 )alkyl, -(C ⁇ -C 5 )oxyalkyl, or -halo(C 1 -C 5 )alkyl.
• R 22 is C ⁇ C-R and R 25 is -(C ⁇ -C 5 )alkyl having 0 or 1 heteroatoms.
• R 22 is — C ⁇ CCH 3 .
• R 23 and R 24 are independently -H, -(C C 5 )alkyl, or -(C ⁇ -C 5 )oxyalkyl.
• R 25 is -H, -(C ⁇ -C 5 )alkyl, -hetero(C ⁇ -C 5 )alkyl, -(C ⁇ -C 5 )oxyalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• R 25 is -(C ⁇ -C 5 )alkyl,-(C ⁇ -C 5 )oxyalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. " " l7'3]' '' " • "" il R is -hetero(C ⁇ -C 5 )alkyl that does not contain Si. 9 [0174] In some embodiments, R is unsubstituted phenyl. [0175] In other embodiments, R 25 is a substituted phenyl. [0176] In prefened embodiments, R 25 is methyl. H -C- or -N- [0177] Z is I ' .
• Z is nitrogen. In other embodiments, Z is carbon. [0178] L is -O-, -S-, or -N(R 26 )-. In some embodiments, L is -O-. In other embodiments, L is -S-. In other embodiments, L is -N(R 26 )-. [0179] In certain embodiments, Z is nitrogen and L is -N(R )-. [0180] R 26 is -H , -(C ⁇ -C 5 )alkyl, substituted or unsubstituted aryl(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• R 26 is -H , substituted or unsubstituted aryl(C ⁇ -C ⁇ 0 )alkyl or substituted or unsubstituted aryl. [0182] In some embodiments, R 26 is -H. [0183] In other embodiments, R 26 is substituted or unsubstituted phenyl.
• Y is -CH 2 -.
• L is -O- or -S-
• Y is -CH 2 -, -CH 2 CH 2 -.
• W is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
• W can be a ring such as a benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline or quinoline., and so forth.
• W is a substituted or unsubstituted monocyclic aryl ring or a substituted or unsubstituted monocyclic heteroaryl ring.
• W is substituted or unsubstituted fused aryl bicyclic ring or substituted or unsubstituted fused heteroaryl bicyclic ring.
• " '" is"a ⁇ - f err ere !fl sed aryl bicyclic ring or an 8- to 11 -membered fused heteroaryl bicyclic ring.
• W is a substituted or unsubstituted 5- or 6-membered aryl ring or substituted or unsubstituted 5- or 6-membered heteroaryl ring.
• the substituting group can be a halogen, substituted or unsubstituted (C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted hetero(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted halo(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl(C ⁇ -C 10 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• W is a 5-membered ring having two or more heteroatoms.
• W is a 5-membered ring having two or more heteroatoms.
• R 27 is substituted or unsubstituted (C ⁇ -C 10 )alkyl, substituted or unsubstituted hetero(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted halo(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• W is a substituted or unsubstituted phenyl.
• Z is carbon and R 22 is -(C 2 -C 8 )alkyl, -(C 3 -C 8 )alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C ⁇ C-R 25 _
• R 22 is C ⁇ C-R 5 R 2S i s -hetero(C 1 -C 5 )alkyl, L is -O- or -S-, then any heteroatom in R 25 is not Si.
• R 21 is -OH
• L is -O-
• Y is -CH 2 -
• W is
• R 22 is C ⁇ C-R 25 ⁇ then R 25 is not -H.
• L is -N(R 26 )-
• Z is nitrogen
• R 22 is a phenyl
• R is hydrogen or a phenyl and W is a phenyl, then Y is not -C(O)-. H — C—
• a compound of the invention can be an S-enantiomer, an R-enantiomer, or a mixture of both an S-enantiomer and an R-enantiomer.
• a compound is an S-enantiomer.
• R 21 is -OH; L is -O-, or -S-; and Y is -CH 2 - , or
• W is not a 1,2-azole ring.
• the present invention provides a compound having the formula (III):
• R 22 , L, Y, and W are as defined with regard to formula II above.
• R 22 is -H, -(C 2 -C 3 )alkyl, -NR 23 R 24 , or substituted or unsubstituted phenyl.
• L is -O-, -S-, or -N(R 26 )-.
• R 26 is -H , substituted or unsubstituted aryl(C 1 -C ⁇ o)alkyl or substituted or unsubstituted aryl.
• W is a substituted or unsubstituted 5- or 6-membered aryl ring or substituted or unsubstituted 5- or 6-membered heteroaryl ring with the proviso if
• R 22 is phenyl, L is -O-, -S-, or -N(R 26 )-, and W is a benzene ring then Y may not be -C(O)-.
• L is -N(R 26 )-, and R 26 is hydrogen. l j . k b ⁇ nents, W is not a 1,2-azole ring.
• the compound of formula III is selected from the group consisting of
• the present invention provides a compound of formula II or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 21 is
• R 23 and R 24 are independently -H, -(C 1 -C 5 )alkyl, or -(C ⁇ -C 5 )oxyalkyl;
• R 25 is -H, -(C ⁇ -C 5 )alkyl,
• W is a substituted or unsubstituted 5- or 6- membered aryl ring or substituted or unsubstituted
• the present invention provides compounds according to formula (IN):
• R 25 is methyl
• L is -O- or -S- and Y is -CH 2 - or -CH 2 CH 2 -. 2 9] l -" W is a 5-membered ring selected from the group consisting of
• R is substituted or unsubstituted (C 1 -C ⁇ 0 )alkyl, substituted or unsubstituted hetero(C 1 .C ⁇ o)alkyl, substituted or unsubstituted halo(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted a ⁇ yl(C 1 -C ⁇ 0 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• R 27 is substituted phenyl.
• R 27 is unsubstituted phenyl.
• the present invention provides compounds according to formula (V):
• R 21 is -OH, or a salt thereof.
• W is substituted phenyl.
• W is substituted with substituted or unsubstituted
• (C 1 -C ⁇ 0 )alkyl substituted or unsubstituted hetero(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted halo(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted aryl(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• W is a 5-membered ring selected from the group consisting of
• R 27 is hydrogen, substituted or unsubstituted (C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted ' er ⁇ C yl, l utet r xmsubstituted halo(CrC 10 )alkyl, substituted or unsubstituted aryl(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• a compound of formula N is a racemate.
• the compound of formula N comprises a mixture of (S) and (R) enantiomers.
• the present invention provides compounds having the formula (Na):
• R 25 and W are defined in paragraph [0215] above.
• R 25 is methyl.
• W is a 5-membered ring selected from the group consisting of
• R 27 is hydrogen, substituted or unsubstituted (C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted hetero(C ⁇ -C 10 )alkyl, substituted or unsubstituted halo(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted aryl(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• the compound of formula VI comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula VI comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula VI comprises a mixture of S- and R-enantiomers. [0234] In certain embodiments, the present invention provides compounds according to formula (VII):
• each R 28 is independently selected from the group consisting of substituted or unsubstituted (C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted hetero(C 1 -C ⁇ 0 )alkyl, substituted or unsubstituted halo(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted aryl(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, the subscript q is an integer from 0 to 5, and R 25 is as defined above in paragraph [0215]. [0235] In some embodiments, the subscript q is 0, 1, or 2. 8
• R is a methoxy, ethoxy, trihalomethyl, methyl, halo, or cyano group and the subscript q is 1 or 2.
• R is a phenyl, methoxyphenyl, methylphenyl, trihalomethylphenyl, benzyl, phenoxy, ethoxyphenyl, cyanophenyl, halophenyl, halobenzyl, pyridyl, methoxybenyl, or pyryl group and the subscript q is 1 or 2.
• R 25 is methyl
• the compound of formula VII comprises a stereomerically pure S-enantiomer.
• the compound of formula VII ⁇ " ' c tn rises ' a eTC ⁇ me cal y pu e' R-enantiomer.
• the compound of formula VII comprises a mixture of S- and R-enantiomers.
• the formula is selected from the group consisting of
• the present invention provides compounds according to formula (VIII):
• T is a direct bond, (C ⁇ -C 5 )alkylene, hetero(C ⁇ -C 5 )alkylene, O, C(O)-(C 5 -C 7 )heterocycloalkylene, (C C 4 )alkylene-SO 2 NH, or (C ⁇ -C 4 )alkylene-NHSO 2 .
• T is a direct bond, substituted or unsubstituted (C ⁇ _C 5 )alkyl or substituted or unsubstituted hetero(C ⁇ -C 5 )alkyl.
• Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
• Ar is a benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline or quinoline.
• R 22 is ⁇ " C ⁇ C_CH3 , [0247] In some embodiments, R 21 is -OH. [0248] In certain embodiments, T is a direct bond and Ar is a substituted or unsubstituted benzene ring. [0249] In some embodiments, W is phenyl. [0250] In other embodiments, W is a 5-membered ring selected from the group consisting of
• R 27 is Ar-T-.
• the compound of formula VIII comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula VIII comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula VIII comprises a mixture of S- and R-enantiomers.
• the present invention provides compounds according to formula (IX)
• the compound has the formula:
• the compound is selected from the group consisting of: or a salt thereof.
• the present invention provides compounds, for example, of formula III, IV, VI, VII, or IX, that include a bioisostere of -CO 2 H in place of
• the invention provides compounds according to the above formulas so long as the compound is not one of the following acids, or salt thereof, including:
• the compounds of the invention can be prepared by a variety of synthetic or semisynthetic techniques.
• FIG. 1 and the Examples in Section 6 below provide a variety of synthesis routes to the compounds provided herein.
• Appropriate starting materials can be prepared by techniques known or apparent to those of skill in the art or the starting materials may be commercially available.
• One of skill in the art will understand that the synthetic routes can be modified to use different starting materials or alternative reagents and that suitable adjustments in conditions (e.g., temperatures, solvents, etc.) can be made to accomplish the desired transformations.
• protecting groups may be necessary for the preparation of certain compounds and will n( '" t e aware- t ose'co t ⁇ b ' OTnpatible with a selected protecting group. Accordingly, the exemplary methods and the examples described herein are illustrative of the present invention and are not to be construed as limiting the scope thereof.
• compositions suitable for pharmaceutical use comprising one or more compounds of the invention and a pharmaceutically acceptable carrier, excipient or diluent.
• composition as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• pharmaceutically acceptable it is meant that the carrier or excipient is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula II, wherein R 22 comprises an alkynyl 1 containing Si, and where R , L, Y, and W are as defined above in formula II.
• the Si atom is substituted with up to three alkyl groups.
• R 22 is ⁇ C ⁇ C-Si ( CH 3 ) 3
• Composition formulation may improve one or more pharmacokinetic properties (e.g., oral bioavailability, membrane permeability) of a compound of the invention (herein referred to as the active ingredient).
• compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
• the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
• the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
• compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or "' e ixirs'.
• S o i ⁇ ⁇ n nfe ⁇ ied ⁇ For oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
• Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
• Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
• Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbit
• the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
• preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
• coloring agents such as sucrose or saccharin.
• flavoring agents such as sucrose or saccharin.
• sweetening agents such as sucrose or saccharin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
• Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
• the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents.
• Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
• Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
• This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• compositions may also be administered in the form of suppositories for rectal administration of the drug.
• a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• Such materials are cocoa butter and polyethylene glycols.
• creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the invention are employed.
• topical application is also meant to include the use of mouthwashes and gargles.
• compositions and methods of the invention may further comprise other therapeutically active compounds, as noted herein, useful in the treatment of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
• other therapeutically active compounds as noted herein, useful in the treatment of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidos
• the invention provides methods of treating or preventing a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.
• the disease or condition is type II diabetes.
• the present invention provides a method for treating a disease or condition responsive to the modulation of GPR40 comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.
• the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, " '" nyperl ⁇ p eiS ⁇ ray ⁇ dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
• the disease or condition is type II diabetes.
• the disease or condition is obesity.
• the disease or condition is hyptertension.
• the compound or composition is administered orally.
• the compound or composition is administered parentally.
• the compound or composition is administered in combination with a second therapeutic agent.
• the second therapeutic agent is an insulin sensitizing agent, such as metformin or a thiazolidinedione, for example.
• the invention provides methods of treating or preventing a disease or disorder responsive to modulation of GPR40 comprising administering to a subject having such a disease or disorder, a therapeutically effective amoxmt of one or more of the subject compounds or compositions.
• the invention provides methods of treating or preventing a GPR40-mediated condition, disease or disorder comprising administering to a subject having such a condition, disease or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions.
• the invention provides methods of modulating GPR40 comprising contacting a cell with one or more of the subject compounds or compositions.
• a cell that constitutively expresses GPR40 is contacted with one or more of the subject compounds or compositions.
• a cell to be contacted can be made to express or overexpress GPR40, for example, by expressing GPR40 from heterologous nucleic acid introduced into the cell or, as another example, by upregulating the expression of GPR40 from nucleic acid endogenous to the cell.
• the compounds of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal;, local) "routes' d a- - ⁇ sl:a o ⁇ - l ⁇ --t y I e formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
• parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection or implant
• topical e.g., transdermal;, local
• the invention also contemplates administration of the compounds of the invention in a depot formulation, in which the active ingredient is released over a defined time period.
• a depot formulation in which the active ingredient is released over a defined time period.
• an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses.
• the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
• a suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day.
• the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.
• the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
• the compounds of the invention can be combined or used in combination with other agents useful in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds of the invention are useful, including type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular _ >( ' ⁇ rseafee ' j atte ds !
• compositions of the invention include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound of the invention.
• Examples of other therapeutic agents that may be combined with a compound of the invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) cholesterol lowering agents such as HMG- CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and other statins), bile acid sequestrants (e.g., cholestyramine and colestipol), vitamin B 3 (also known as nicotinic acid, or niacin), vitamin B 6 (pyridoxine), vitamin B ⁇ 2 (cyanocobalamin), fibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate and benzafibrate), probucol, nitroglycerin, and inhibitors of cholesterol absorption (e.g., beta- sitosterol and acylCoA-cholesterol acyltransferase
• the weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Combinations of a compound of the invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. [0299] In another aspect, the present invention provides a method for modulating circulating insulin concentration in a subject, comprising administering a compound or composition of the invention. ( >
• the insulin concentration is increased. [0301] In other embodiments, the insulin concentration is decreased. [0302] In certain embodiments, a compound, or composition comprising a compound, according to formula II wherein R 22 comprises an alkylyl containing Si, and 91 where R , L, Y, and W are as defined above in formula II, may be used. [0303] In some embodiments, the Si atom is substituted with up to three alkyl groups.
• R 22 is — C ⁇ C-Si ( CH 3 ) 3
• (+/-)-5-[l-(4-Hydroxy-phenyl)-but-2-ynyl]-2,2-dimethyl-[l,3]dioxane-4,6- dione (1.2).
• (+/-)-3-(4-Hydroxy-phenyl)-hex-4-ynoic acid (1.3).
• a IL RB flask was charged with compound 1.2 (37 g), diethyl ketone (160 mL), and water (80 mL). The suspension was heated to reflux for 48h. After cooling, the aqueous layer was saturated layer was dried over MgSO 4 , filtered, and concentrated to a light brown oil which was crystallized from hot ethyl acetate:hexanes (1 :2).
• the salt was re-suspended in 2 L of 2-propanol and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16h. A small sample of the salt was decomposed with aqueous acid and the free carboxylic acid was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1 % TFA in 90:10 hexanes:2-propanol) and was found to have 75% ee. The salt was re-suspended in 1.5 L of 2-propanol and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16h. This material was found to have 96% ee by chiral HPLC.
• Example 9 [0330] The following compounds were prepared by methods similar to those described in Example 3. TABLE 4
• Example 10 [0331] The following compounds were prepared by methods similar to those described in Examples 3-5. The carboxylic acids corresponding to 10.2 and 10.5 were prepared according to the method of Huang et al. (2003) J. Amer. Chem. Soc. 22: 6653- 6655, and Admas et al. (1973) Org. Synth. Coll. Nol. N: 107, 109, respectively. TABLE 5
• (+/-)-3-(4-[(4-methoxyphenyI)methoxy]phenyI)-hex-4-ynoic acid (12).
• compound 12.2 (13.8 g, 37.5 mmol) under nitrogen was added 1-propynylmagnesium bromide in THF (0.5 N, 97.5 mL) over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred for 20 minutes, quenched with saturated aqueous NH 4 C1 (50 mL) and extracted with ethyl acetate (3 x 50 mL).
• Ester 15.1 (3.19 g, 9 mmol) was taken up in glacial acetic acid (100 mL) in a 250 mL RB Flask, and the suspension was heated to reflux for 16h. The solvent was removed under reduced pressure, and the residue was re-dissolved in ethyl acetate (200 mL). The solution was washed with 1 N HCl( aq) (200 mL) and saturated brine (200 mL), dried over MgSO 4 and concentrated to a thick yellow oil, to which was added 2-methylbenyl bromide (2.57 g, 13.9 mmol), cesium carbonate (6.03 g, 18.5 mmol) and DMF (20 mL).
• Compoxmd 15.2 was dissolved in a mixture of 24 mL methanol and 24 mL isopropanol with the aid of sonication. The solution was filtered into a 50 mL glass vial. The racemic 15.2 was resolved with chiral normal phase HPLC using a ChiralTech AD semi-preparative column (2.0 cm X 25.0 cm), eluting isocratically with hexane/isopropanol (92:8) at a flow rate 20 mL/min. Each injection contained 50 mg of ester 15 (1 mL). The absorbance at 220 nm was used for detection. Both enantiomers were collected. After 36 injections, the separated enantiomers were dried to give white solids.
• Phosphorous oxychloride (0.72 mL, 7.8 mmol) was added dropwise to an oven-dried 100 mL pear-shaped flask charged with 18.1 (1.8 g, 7.00 mmol) and dichloromethane (20 mL). The reaction was refluxed under nitrogen atmosphere for 30 minutes and then cooled to room temperature. The reaction was washed with water (2 x 250 mL) and the combined aqueous layers were back extracted with DCM (2 x 25 mL). The combined organic layers were washed with brine and dried (Na 2 SO 4 ).
• the reaction was stirred at 0° C for an hour, and was then allowed to gradually warm to room temperature overnight.
• the reaction mixture was partitioned between ice water and ethyl acetate.
• the aqueous layer was extracted 2 additional times with 25 mL ethyl acetate.
• Saturated NaHCO 3 was then added to the aqueous layer and the aqueous layer was extracted a third time with ethyl acetate.
• the combined organic layers were washed with saturated NaHCO 3 and concentrated under reduced pressure.
• Example 36 [0410] The following compounds were prepared according to the methods described in Example 35. TABLE 13
• the resulted ester was then hydrolyzed with LiOH (2.0 equiv.) in a 1 : 1 : 1 mixture of MeOH, THF, and water for 2h at 25 °C.
• the reaction mixture was acidified with IN HCl, extracted with CH 2 C1 2 and concentrated to give the pure acid.
• Scheme 42.2 a. TMSCHN 2 , MeOH, benzene, r.t, 1h; b. K 2 C0 3 , DMF, r.t, overnight; c. LiOH/THF, MeOH, and water, r.t, 2h.
• the amine (60 mg, 0.15 mmol) was treated with excess formaldehyde (2 equiv.), NaBH(OAc) 3 (85 mg, 0.4 mmol) and catalytic amoxmt of AcOH in DMF overnight (14-16h) at 25 °C.
• the product was purified by reverse phase HPLC. MS ESI m/e: 424.1 (M + H).
• the methyl ester was hydrolyzed with LiOH (19mg, 0.45 mmol) in a 3 mL of 1 : 1 : 1 mixture of MeOH, THF, and water for 2h at 25 °C.
• the reaction mixture was acidified with IN HCl, extracted with CH 2 C1 2 and concentrated to give the pure acid (42.14) (23 mg).
• Example 46 The following compounds were prepared according to methods analogous to those described in Example 45: 3-(4-fluorophenyl)-3-[4-(4'-trifluoromethyl-biphenyl-3- ylmethoxy)-phenyl] -propionic acid (46.1), 3-(4-fluorophenyl)-3-[4-(4-methyl-2-p-tolyl- thiazol-5-ylmethoxy)-phenyl] -propionic acid (46.2) and 3-(4-fluorophenyl)-3- ⁇ 4-[2-(3- trifluoromethyl-phenoxy) -ethoxy] -phenyl ⁇ -propionic acid (46.3).
• (+/-)-3- ⁇ 4-[3-(4-Chloro-2-methylphenyl)phenyl]-methoxyl)phenyl ⁇ -3-(4- fluorophenyl)-propanoic acid (47). LiOH (48 mg, 2 mmol) was added to the THF-H 2 O (1/1, 4mL) solution of compound 47.2 (104 mg, 0.2 mmol ). The reaction mixture was stirred at room temperature overnight. IN HCl( aq ) was added to acidify the mixture to pH 3 at 0 °C.
• (+/-)-Methyl 3-(4-hydroxyphenyl)-3-(thiophen-2-yl)propanoate (52.2).
• a 500 mL flask was equipped with a magnetic stir bar, nitrogen inlet, nitrogen outlet and placed in a room temperature water bath.
• Compound 52.1 (5.00 g, 15.1 mmol) was added to the flask along with anhydrous THF (150 mL). After purging with nitrogen for 30 min, a solution of thiophene-2-yl-magnesium bromide in THF (1 M, 18.1 mL) was added by cannula.
• reaction mixture was stirred for 1.5 h and quenched with aqueous NH 4 C1 (1 M, 100 mL) diluted with ethyl acetate (100 mL).
• aqueous NH 4 C1 (1 M, 100 mL) diluted with ethyl acetate (100 mL).
• the aqueous layer was acidified to pH ⁇ 2 with Cone. HCl and extracted with ethyl acetate (150 mL x 2).
• the extract was washed with brine and concentrated.
• the residue was dissolved in 100 mL of 10: 1 DMF-water heated to 100°C for 8 h.
• the reaction was cooled and the diluted with 500 mL water and extracted with ethyl acetate (150 mL x 3).
• (+/-)-Methyl 3-(4-hydroxyphenyl)-3-(3-methylthiophen-2-yl)propanoate (54.1).
• a 500 mL flask was equipped with a magnetic stir bar, nitrogen inlet, nitrogen outlet and placed in a room temperature water bath.
• Compound 52.1 (5.00 g, 15.1 mmol) was added to the flask along with anhydrous THF (150 mL). After purging with nitrogen for 30 min, a solution of 3-mefhylthiophen-2-yl-magnesium bromide in THF (1 M, 18.1 mL) was added by cannula.
• reaction mixture was stirred for 1.5 h, quenched with aqueous NH 4 C1 (1 M, 100 mL) and diluted with ethyl acetate (100 mL).
• the aqueous layer was acidified to pH ⁇ 2 with Cone. HCl and extracted with ethyl acetate (150 mL x 2).
• the extract was washed with brine and concentrated.
• the residue was dissolved in 100 mL of 10:1 DMF-water and heated to 100 °C for 8 h.
• the reaction mixture was cooled, diluted with 500mL water, and extracted with ethyl acetate (150 mL x 3).
• Compoxmd 60 was obtained from compound 60.3 according to the method of Example 58. 6.61
• Example 61 [0524] The following compounds were prepared from compound 60 according to the methods described in Example 18. Table 20
• (+/-)-3-[4-(2' -Butoxy-5'-methyl-biphenyI-4-ylmethoxy)-phenyl]-3-(l- methyl-lH-pyrazol-5-yl) pjropionic acid (63.5).
• a 25 mL pear-shaped flask was charged with ethanol (1 mL), compound 63.3 (20 mg, 0.04 mmol), and 2N NaOH (aq ) (2 mL, 4.0 mmol). The resulting mixture was stirred overnight at room temperature.
• the mixture was acidified to a pH of 3 with 1UST HCl and extracted with ethyl acetate (2 x 10 mL).
• (+/-)-3-(l-Methyl-lH-pyrazol-3-yl)-3-(4-((4-methyl-2-p-tolylthia-zol-5- yl)methoxy)phenyl) propanoic acid (64.1).
• 1H NMR (400MHz) (CDC1 3 ) ⁇ 7.84 (m, 2H); 7.12 (m, 5H); 6.89 (m, 2H); 5.92 (s, IH); 5.13 (s, 2H); 4.46 (q, IH, J 6 Hz); 3.88 s, 3H); 3.23 (m, IH); 2.98 (m, IH); 2.50 (s, 3H); 2.39 (s, 3H).
• MS ESI (neg.) m/e: 446.2 (M - H).
• (+/-)-3-(l-Methyl-lH-pyrazol-3-yI)-3-[4-(4'-trifluoromethyl-biphenyl-3- ylmethoxy)-phenyl]-propionic acid (64.3).
• MS ESI (neg.) m/e: 479.2 (M - H).
• (+/-)-3-(l-Methyl-lH-pyrazol-5-yl)-3-[4-(4'-trifluoromethyl-biphenyl-3- ylmethoxy)-phenyI]-propionic acid (64.4).
• a cell-based aequorin assay may be employed to characterize the modulatory activity of compounds on the GPR40 signaling pathway.
• CHO cells are transfected in a 15 cm plated containing 14 million cells with 5 ⁇ g of GPR40 expression vector and 5 ⁇ g of Aequorin expression vector (Euroscreen) using Lipofectamine 2000
• H/HBSS Hepes
• BSA bovine serum albumin
• HSA fatty acid-free human serum albumin
• Coelantrazine is added to 1 ug/mL and the cells are incubated for 2 hours at room temperature. Cells are gently mixed every 15 minutes.
• Table 21 presents representative data (EC 50 values) obtained for exemplary compounds of the invention for the relative activation of human GPR40.
• the stereoismers in Table 21 are as specified, i.e., S-enantiomers or
• R-enantiomers and if not specified, are mixtures of S-enantiomers and R-enantiomers.
• the present invention provides the S-enantiomers, the R-enantiomers, and mixtures of both S-enantiomers and R-enantiomers including racemates of each compound prepared according to the synthetic methods described herein or adapted with the necessary minor modifications from these methods. 6.66 Example 66: Insulin Secretion Assay [0550] C57/B16 mice are euthanized with carbon dioxide gas. The pancreatic bile duct is clamped proximal to the duodenum and then cannulated.
• H/HBSS containing 0.75 mg/ml collagenase XI (Sigma) is then infused into the pancreas through the cannula.
• the pancreas is excised and then incubated at 37°C for 13 minutes to complete enzymatic digestion.
• the collagenase digestion is quenched in H/HBSS containing 1% BSA and washed once in the same buffer.
• Islets can be purified using density gradient centrifugation using Histopaque (Sigma) and are hand-picked under a stereomicroscope. [0551] Islets are cultured overnight in Roswell Park Memorial Institute (RMPI) media containing 10% fetal bovine serum and 50 uM beta-mercaptoethanol. Following overnight culture, islets are incubated in Dulbecco's Modifcation of Eagle's medium (DMEM) containing 2.8 mM glucose for one hour.
• DMEM Dulbecco's Modifcation of Eagle's medium
• islets are incubated in DMEM containing 12.5 mM glucose and test compounds for one hour. Insulin released into the culture medium from the islets is measured using an insulin ELISA.
• All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

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• 2005
  • 2005-02-24 KR KR1020067019713A patent/KR20070004769A/ko not_active Withdrawn
  • 2005-02-24 US US10/591,214 patent/US7816367B2/en active Active
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  • 2005-02-24 WO PCT/US2005/005815 patent/WO2005086661A2/en not_active Ceased
  • 2005-02-24 ES ES05723623T patent/ES2433466T3/es not_active Expired - Lifetime
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  • 2005-02-24 CN CNA2005800127092A patent/CN1946666A/zh active Pending
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• 2006
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  • 2006-09-20 CR CR8642A patent/CR8642A/es not_active Application Discontinuation
  • 2006-09-26 NO NO20064362A patent/NO20064362L/no not_active Application Discontinuation
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