EP1879860A2 - Derives de 1,4-diphenyl-3-hydroxyalkyl-2-azetidinone utilises dans le traitement de l'hypercholesterolemie - Google Patents

Derives de 1,4-diphenyl-3-hydroxyalkyl-2-azetidinone utilises dans le traitement de l'hypercholesterolemie

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Publication number
EP1879860A2
EP1879860A2 EP06759488A EP06759488A EP1879860A2 EP 1879860 A2 EP1879860 A2 EP 1879860A2 EP 06759488 A EP06759488 A EP 06759488A EP 06759488 A EP06759488 A EP 06759488A EP 1879860 A2 EP1879860 A2 EP 1879860A2
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EP
European Patent Office
Prior art keywords
compound according
pharmaceutical formulation
loweralkyl
phenyl
cholesterol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP06759488A
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German (de)
English (en)
Inventor
Eduardo Martinez
John J. Talley
Daniel P. Zimmer
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Microbia Inc
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Microbia Inc
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Publication date
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Publication of EP1879860A2 publication Critical patent/EP1879860A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the invention relates to a chemical genus of l,4-diphenyl-3-hydroxyalkyl-2- azetidinones useful in the treatment of hypercholesterolemia and other disorders.
  • the present invention relates to of 1 ,4-diphenyl-3-hydroxyalkylazetidin-2- one derivatives useful in treating hypercholesteremia and other disorders.
  • the invention relates to compounds of formula
  • R 1 represents one, two, three, four or five residues chosen independently from H, halogen, -OH, -O-loweralkyl, loweralkyl, OCF 2 H, OCF 3 , CF 2 H, CH 2 F, methylenedioxy, ethylenedioxy, -CN, CF 3, nitro, -SH, -S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, -PO 3 H 2 , - SO 3 H, -B(OH) 2 , a sugar, a
  • R 200 represents one, two, three, four or five residues chosen independently from H, halogen, -OH, -O-loweralkyl, loweralkyl, OCF 2 H, OCF 3 , CF 2 H, CH 2 F, methylenedioxy, ethylenedioxy, -CN, CF 3, nitro, -SH, -S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, -PO 3 H 2 , - SO 3 H, -B(OH) 2 , -OSO 2
  • Ar is aryl or heteroaryl;
  • R 220 represents one, two, three, four or five residues chosen independently from H, halogen, -OH, -O-loweralkyl, loweralkyl, OCF 2 H, OCF 3 , CF 2 H, CH 2 F, methylenedioxy, ethylenedioxy, -CN, CF 3 , nitro, -SH, -S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, -PO 3 H 2 , - SO 3 H,
  • R 3 is selected from the group consisting of -C(OH)(R 6 )CH 3 and (C 1 -C 19 ) saturated hydrocarbon substituted with at least one hydroxyl group; wherein R is selected from hydrogen and (C 1 -C 6 ) alkyl;
  • R 4 and R 5 are independently selected from the group consisting of H and (C 1 -C 6 ) alkyl, or taken together any two of R 4 , R 5 and R 6 form a saturated carbocycle of four to seven members, optionally substituted with one or more OH;
  • R 8 and R 9 are each residues independently selected from the group of a sugar, a glucuronide, a polyol, and a sugar carbamate;
  • R 3 is other than CH 2 OH or (CH 2 ) 2 OH
  • R 3 may additionally be H.
  • R 1 represents one, two, three, four or five residues chosen independently from H, halogen, -OH, -O-loweralkyl, loweralkyl, OCF 2 H, OCF 3 , CF 2 H, CH 2 F, methylenedioxy, ethylenedioxy, -CN, CF 3 , nitro, -SH, -S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, -PO 3 H 2 , - SO 3 H, -B(OH) 2 , a sugar,
  • R 2 represents one, two, three, four or five residues chosen independently from H, halogen, -OH, -O-loweralkyl, loweralkyl, OCF 2 H, OCF 3 , CF 2 H, CH 2 F, methylenedioxy, ethylenedioxy, -CN, CF 3 , nitro, -SH, -S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, -PO 3 H 2 , -
  • R 22 represents one, two, three, four or five residues chosen independently from H, halogen, -OH, -O-loweralkyl, loweralkyl, OCF 2 H, OCF 3 , CF 2 H, CH 2 F, methylenedioxy, ethylenedioxy, -CN, CF 3, nitro, -SH, -S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, -PO 3 H 2 , - SO 3 H, -B(OH) 2 , a sugar, a
  • R is selected from the group consisting of -C(OH)(R )CH 3 and (C 1 -C 19 ) saturated hhyyddrrooccaarrbboonn ssuubbssttiittuutteedd wwiittrh. at least one hydroxyl group; wherein R 6 is selected from hydrogen and (C 1 -C 6 ) alkyl;
  • R 4 and R 5 are independently selected from the group consisting of H and (C 1 -C 6 ) alkyl, or taken together any two of R 4 , R 5 and R 6 form a saturated carbocycle of four to seven members, optionally substituted with one or more OH;
  • R 3 is other than CH 2 OH or (CH 2 ) 2 OH
  • R 3 may additionally be H.
  • the compounds described herein can be included in pharmaceutical formulations comprising a pharmaceutically acceptable carrier and one or more of: (1) a dyslipidemic agent, (2) an anti-diabetic agent, (3) an anti-hypertensive agent, (4) an anti-obesity agent, (5) an agent used to treat autoimmune disorders, (6) an agent used to treat demylenation and its associated disorders, (7) an agent used to treat Alzheimer's disease, (8) a blood modifier, (9) a hormone replacement agent/composition, (10) a chemotherapeutic agent, (11) a peptide which mitigates one or more symptoms of atherosclerosis, (12) an anti-cancer agent, (13) an agent used to treat bone loss and associated disorders, and (14) other agents.
  • the compounds and pharmaceutical formulations described herein can be used in methods for treating a condition for which a cholesterol absorption inhibitor is indicated; preventing or treating a cholesterol related disease; inhibiting the absorption of or reducing plasma or tissue concentration of one or more sterols or stanols; preventing or treating sistoserolemia; preventing or treating vascular diseases/disorders and conditions, dyslipidemia, mixed dyslipidemia, hypo ⁇ - lipoproteinemia, LDL pattern B, LDL pattern A, primary dysbetalipoproteinemia (Frederickson Type IH), hyperlipidemia (including but not limited to hypercholesterolemia, hypertriglyceridemia, sitosterolemia), hypertension, angina pectoris, cardiac arrhythmias, congestive heart failure, and stroke; reducing the incidence of cardiovascular disease-related events; preventing or treating vascular conditions and associated thrombotic events; preventing or treating vascular inflammation; reducing blood plasma or serum concentrations of C-reactive protein; preventing, treating, or
  • the invention relates to an article of manufacture comprising a container, instructions, and a pharmaceutical formulation as described above.
  • the instructions are for the administration of the pharmaceutical formulation for a purpose chosen from: treating a condition for which a cholesterol absorption inhibitor is indicated; preventing or treating a cholesterol related disease; inhibiting the absorption of or reducing plasma or tissue concentration of one or more sterols or stanols; preventing or treating sistoserolemia; preventing or treating vascular diseases/disorders and conditions, dyslipidemia, mixed dyslipidemia, hypo ⁇ -lipoproteinemia, LDL pattern B, LDL pattern A, primary dysbetalipoproteinemia (Frederickson Type Hf), hyperlipidemia (including but not limited to hypercholesterolemia, hypertriglyceridemia, sitosterolemia), hypertension, angina pectoris, cardiac arrhythmias, congestive heart failure, and stroke; reducing the incidence of cardiovascular disease-related events; preventing or treating vascular conditions and associated thrombotic events;
  • R 1 represents one, two, three, four or five residues chosen independently from H, halogen, -OH, -O-loweralkyl, loweralkyl, OCF 2 H, OCF 3 , CF 2 H, CH 2 F, methylenedioxy, ethylenedioxy, -CN, CF 3 , nitro, -SH, -S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, allcylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, -PO 3 H 2 , - SO 3 H, -B(OH) 2 , a sugar
  • R 2 represents one, two, three, four or five residues chosen independently from H, halogen, -OH, -O-loweralkyl, loweralkyl, OCF 2 H, OCF 3 , CF 2 H, CH 2 F, methylenedioxy, ethylenedioxy, -CN, CF 3 , nitro, -SH, -S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, -PO 3 H 2 , - SO 3 H, -B(OH) 2 , a sugar,
  • R 22 represents one, two, three, four or five residues chosen independently from H, halogen, -OH, -O-loweralkyl, loweralkyl, OCF 2 H, OCF 3 , CF 2 H, CH 2 F, methylenedioxy, ethylenedioxy, -CN, CF 3, nitro, -SH, -S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, -PO 3 H 2 , - SO 3 H, -B(OH) 2 , a sugar, a
  • R 3 is selected from the group consisting of -C(OH)(R 6 )CH 3 and (C 1 -C 19 ) saturated hydrocarbon substituted with at least one hydroxy! group; wherein R 6 is selected from hydrogen and (C 1 -C 6 ) alkyl;
  • R 4 and R 5 are independently selected from the group consisting of H and (C 1 -C 6 ) alkyl, or taken together any two of R 4 , R 5 and R 6 form a saturated carbocycle of four to seven members, optionally substituted with one or more OH;
  • R 3 is other than CH 2 OH or (CH 2 ) 2 OH
  • R 3 may additionally be H.
  • R 4 and R 5 are H; and R 3 is a linear or branched saturated hydrocarbon chain substituted with one hydroxy! residue.
  • R 4 and R 5 are H; and R 3 is C 3 -C 10 hydrocarbon substituted with one or more OH.
  • More specific embodiments include:
  • R 4 and R 5 together form a carbocycle of 4-7 members substituted with OH; and R 3 is H, having the chemical formula shown below:
  • R 7 represents one, two, three or four residues chosen independently from (C 1 - C 10 ) saturated hydrocarbon, H, halogen and -OH.
  • R 4 and R 5 together form a carbocycle of 4-7 members; and R 3 is selected from a linear or branched saturated hydrocarbon chain substituted with one hydroxyl residue, a non-limiting example of which is shown below:
  • R 7 represents one, two, three or four residues chosen independently from (C 1 - C 10 ) saturated hydrocarbon, H, halogen and -OH.
  • the genus of formula I may be conveniently subdivided into two related subgenera, according to selection of the R 2 residue; having chemical formulae II and III as shown below:
  • R la is selected from halogen and H
  • R ,2a a is selected from hydroxy and -O-lower alkyl
  • Ar represent aryl or heteroaryl
  • R represents one, two, three or four residues chosen independently from H, halogen, -OH, -O-loweralkyl, loweralkyl, OCF 2 H, OCF 3 , CF 2 H, CH 2 F, methylenedioxy, ethylenedioxy, -CN, CF 3; nitro, -SH, -S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, aUcylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy, -PO 3 H 2 , -SO 3 H, -B(OH) 2 , a sugar,
  • Subgenus II further comprises compounds in which R la is halogen and R »2 z a a is selected from hydroxy and methoxy.
  • R la is F;
  • R 2a is OH;
  • R 2b is H, having chemical formula, as shown below:
  • Subgenus II comprises compounds wherein R and R are H and R is C 3 - C 1O hydroxylated saturated hydrocarbon.
  • R la is F;
  • R 2a is OH;
  • R 2b is H and
  • R 3 is 2-hydroxyethyl cyclohexyl derivative, having chemical formulae as shown below:
  • R 1 is F; R 2a is hydroxy!; R 2b is H; R 4 and R 5 are H; and R 3 is 2-hydroxypropyl, having the chemical formula shown below:
  • Subgenus II further comprises compounds in which R 2a is hydroxy and R 2 is glucitol; having chemical formula shown below:
  • Subgenus II further comprises compounds in which R 1 is H; R 2a is hydroxy and R 2b is glucitol; R 4 and R 5 are H; and R 3 is 2-hydroxyethyl cyclohexane, having chemical formula shown below:
  • R 1 is H; R 2a is hydroxy; R 2b is glucitol; R 4 and R 5 are H; and R 3 is 2-hydroxy heptane, having chemical formula shown below:
  • the glucitol may be in meta position vis a vis the azetidinone.
  • the genus of formula I further comprises compounds of subgenus III comprising 4-biaryl species.
  • R 1 is H;
  • R is hydroxy;
  • R and R 5 are H, having chemical formula shown below:
  • R 1 is H; R 2b is hydroxy; R 4 and R 5 are H; and R 3 is 2- hydroxyethyl cyclohexane, having chemical formula shown below:
  • R 1 is H; R 2 and R 2b are hydroxy; R 4 and R 5 are H; and R 3 is 2-hydroxyethyl cyclohexane having a chemical formula as shown below:
  • R 1 is H; R 2 and R 2b are hydroxy; R 4 and R 5 are H; and R 3 is 2-hydroxy heptane, having a chemical formula as shown below:
  • R 2b is hydroxy; and R 2 is phosphonic acid, having chemical formula as shown below:
  • R 1 is H; R 2b is hydroxy; R 4 and R 5 are H; and R 3 is 2- hydroxyethyl cyclohexane; and R 2 is phosphonic acid, having chemical formula as shown below:
  • R 1 is H; R 2b is hydroxy; R 4 and R 5 are H; and R 3 is 2- hydroxy heptane; and R 2 is phosphonic acid, having chemical formula as shown below:
  • R is hydroxy; and R is glucitol, having chemical formula as shown below:
  • R 1 is H; R 2b is hydroxy; R 4 and R 5 are H; and R 3 is 2-hydroxyethyl cyclohexane; and R 2 is glucitol in the para position, having chemical formula as shown below:
  • R 1 is H; R 2b is hydroxy; R 4 and R 5 are H; and R 3 is 2-hydroxy heptane; and R 2 is glucitol in the para position, having chemical formula as shown below:
  • R 1 is H; R 2b is hydroxy; R 4 and R 5 are H; and R 3 is 2- hydroxyethyl cyclohexane; and R 2 is glucitol in the meta position, having chemical formula as shown below:
  • R 1 is H; R 2b is hydroxy; R 4 and R 5 are H; and R 3 is 2-hydroxy heptane; and R 2 is glucitol in the meta position, having chemical formula as shown below:
  • Some of the compounds of the invention may contain basic or acidic residues, allowing them to be presented as salts.
  • pharmaceutically acceptable salt refers to salts whose counter ion derives from pharmaceutically acceptable non-toxic acids and bases.
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include inorganic acids, organic acids and, in the case of quats, water (which formally furnishes the hydroxide anion).
  • Examples include hydroxide, acetate, benzenesulfonate (besylate), benzoate, bicarbonate, bisulfate, carbonate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, glycolate, bromide, chloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, trifluoroacetate, p-toluenesulfonate, acetamidobenzoate, adipate, alginate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, calcium edetate, camphorate, camsylate, caprate, caproate, caprylate, cinnamate, cyclamate, dichloroacetate
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include ammonium, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • base addition salts includes those made from: arecoline, arginine, barium, benethamine, benzathine, betaine, bismuth, clemizole, copper, deanol, diethylamine, diethylaminoethanol, epolamine, ethylenediamine, ferric, ferrous, glucamine, glucosamine, histidine, hydrabamine, imidazole, isopropylamine, manganic, manganous, methylglucamine, morpholine, morpholineethanol, n-ethylmorpholine, n-ethylpiperidine, piperazine, piperidine, polyamine resins, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trolamine, and tromethamine.
  • the present invention further provides methods for treating a condition for which a cholesterol absorption inhibitor is indicated; preventing or treating a cholesterol related disease; inhibiting the absorption of or reducing plasma or tissue concentration of one or more sterols or stands; preventing or treating sistoserolemia; preventing or treating vascular diseases/disorders and conditions, dyslipidemia, mixed dyslipidemia, hypo ⁇ -lipoproteinemia, LDL pattern B, LDL pattern A, primary dysbetalipoproteinemia (Frederickson Type IH), hyperlipidemia (including but not limited to hypercholesterolemia, hypertriglyceridemia, sitosterolemia), hypertension, angina pectoris, cardiac arrhythmias, congestive heart failure, and stroke; reducing the incidence of cardiovascular disease-related events; preventing or treating vascular conditions and associated thrombotic events; preventing or treating vascular inflammation; reducing blood plasma or serum concentrations of C-reactive protein; preventing, treating, or ameliorating symptoms of Alzheimer's Disease (AD);
  • AD Alzheimer
  • the compounds described herein may inhibit cholesterol absorption and thus reduce cholesterol levels in vivo.
  • the compositions and therapeutic methods described herein are useful for treating any condition for which a cholesterol absorption inhibitor is indicated.
  • the compositions and pharmaceutical formulations described herein can lead to one or more of: reduced blood plasma or serum concentrations of low-density lipoprotein cholesterol (LDL-C); reduced blood plasma or serum concentrations of very low-density lipoprotein cholesterol (VLDL-C); reduced blood plasma or serum concentrations of intermediate-density lipoprotein cholesterol (IDL-C); reduced concentrations of cholesterol and cholesterol ester in the blood plasma or serum; reduced blood plasma or serum concentrations of apolipoprotein B; reduced blood plasma or serum concentrations of triglycerides; increased clearance of triglycerides; increased blood plasma or serum concentrations of high density lipoprotein cholesterol (HDL-C); reduced blood plasma or serum concentrations of non high-density lipoprotein cholesterol (non HDL-C); reduced levels of lipoprotein
  • LDL-C
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof) to prevent or treat a cholesterol related disease.
  • additional agents e.g., one or more dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof
  • Cholesterol related diseases include but are not limited to diseases involving elevated levels of LDL cholesterol, diseases involving regulation of LDL receptors, diseases involving reduced levels of HDL cholesterol, dyslipidemia, diseases involving elevated levels of non-esterified fatty acids, diseases involving reduced or deficient lipoprotein lipase levels or activity (including reductions or deficiencies resulting from lipoprotein lipase mutations), diseases involving elevated levels of ketone bodies (e.g., ⁇ -OH butyric acid), hyperlipidemia, elevated LDL Pattern B, elevated LDL Pattern A, primary dysbetalipoproteinemia (Frederickson Type III), hypercholesterolemia, hypo ⁇ .-lipoproteinemia (low HDL cholesterol syndrome), hyperlipoproteinemia, elevated Lp(a) levels, hypertriglyceridemia (including Frederickson typse IV and V), other aberrations of apolipoprotein B metabolism, homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia, presumed familial combined
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof) to inhibit the absorption of or reduce plasma or tissue concentration of one or more sterols (referring to, for example: (from any source and in any form: ⁇ , ⁇ and ⁇ saturated or hydrogenated sterols including all natural or synthesized forms and derivatives thereof, and isomers including but not limited to cholesterol, sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrassicasterol), desmosterol, chalinosterol, poriferasterol, clionasterol, ergosterol, coprosterol, codisterol, isofucosterol, fucosterol, clerosterol, nervisterol, lathosterol, stellasterol, spinasterol, chond
  • Sterols and stanols also include free sterols and stanols, esterified sterols and stanols with aliphatic or aromatic acids (thereby forming aliphatic or aromatic esters, respectively), phenolic acid esters, cinnamate esters, ferulate esters, phytosterol and phytostanol glycosides and acylated glycosides or acylglycosides.
  • the sterols and stanols encompasses all analogues, which may further have a double bond at the 5-position in the cyclic unit as in most natural sterols, or one or more double bonds at other positions in the rings (for example, 6,7, 8(9), 8(14), 14 5/7) or no double bonds in the cyclic unit as in stanols.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof) to prevent or treat sistoserolemia in patients who are either at risk of developing sistoserolemia or already exhibit sistoserolemia, for example, as described in US20020169134.
  • Sitosterolemia is a genetic lipid storage disorder characterized by increased levels of sitosterol and other plant sterols in the plasma and other tissues due to increased nonselective intestinal absorption of sterols and decreased hepatic removal.
  • sitosterolemia can exhibit one or more of the following conditions: tendon and tuberous xanthomas, arthritis, hemolytic episodes, accelerated atherosclerosis and myocardial infarctions, and can die at an early age due to extensive coronary atherosclerosis (see Nguyen et al. 1991 Journal of Lipid Research, 32: 1941-1948).
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more anti-hypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof) to prevent or treat vascular diseases/disorders and conditions (including but not limited to arteriosclerosis, atherosclerosis, acute vascular syndromes, peripheral arterial disease, cardiovascular disease, cerebrovascular disease (e.g., cerebral infarction or stroke (caused by vessel blockage or hemmorage), or transient ischemia attack (TIA), syncope, atherosclerosis of the intracranial and/or extracranial arteries, and the like), renovascular disease, mesenteric vascular disease, pulmonary vascular disease, ocular vascular disease, microvascular disease (such as nephropathy, neuropathy, retinopathy), and peripheral vascular disease), hyperlipidemia (including but not limited to hypercholesterolemia, hypertrig
  • Vascular disease is a term that broadly encompasses all disorders of blood vessels including small and large arteries and veins and blood flow.
  • arteriosclerosis a condition associated with the thickening and hardening of the arterial wall.
  • Arteriosclerosis of the large vessels is referred to as atherosclerosis.
  • Atherosclerosis is the predominant underlying factor in vascular disorders e.g., coronary artery disease, aortic aneurysm, arterial disease of the lower extremities and cerebrovascular disease.
  • Other vascular conditions frequently coexist with cholesterol levels associated with atherosclerosis. These may include hypertension, angina and/or arrhythmia.
  • Vascular conditions may be caused or aggravated by hypertension which is defined as persistently high blood pressure.
  • Elevated blood pressure is a risk factor for atherosclerosis, cardiovascular and cerebrovascular disease.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more anti-hypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof) to reduce the incidence of cardiovascular disease-related events, for example, as described in US20050080071.
  • additional agents e.g., one or more anti-hypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof
  • additional agents e.g., one or more anti-hypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof
  • additional agents e.g., one or more anti-hypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof
  • CVD clinically evident
  • NCEP ATP m low density lipoprotein (LDL-C) goal for patients with CHD or CHD risk equivalent is ⁇ 100 mg/dL (2.59 mrnol/L), for individuals with two or more risk factors is ⁇ 130 mg/dL (3.37 mmol/L) and for individuals with fewer than two risk factors is ⁇ 160 mg/dL (4.14 mmol/L).
  • CHD or CHD risk equivalent is ⁇ 100 mg/dL (2.59 mrnol/L)
  • risk factors is ⁇ 130 mg/dL (3.37 mmol/L)
  • individuals with fewer than two risk factors is ⁇ 160 mg/dL (4.14 mmol/L).
  • cardiovascular event includes but is not limited to fatal and non-fatal acute major coronary events, coronary revascularization procedures, myocardial revascularization procedures, peripheral vascular disease, stable angina and cerebrovascular insufficiency e.g., stroke.
  • acute major coronary event includes fatal myocardial infarction, witnessed and unwitnessed cardiac death and sudden death occurring from 1 hour up to 24 hours after collapse, non-fatal myocardial infarction including definite acute Q-wave myocardial infarction, non-Q-wave myocardial infarction, and silent subclinical (remote) myocardial infarction, and unstable angina pectoris.
  • Myocardial infarction includes recurrent myocardial infarction, Q-wave myocardial infarction, non-Q-wave myocardial infarction and silent subclinical (remote) myocardial infarction.
  • the compounds and formulations described herein can used alone or in combination therapy with one or more additional agents (e.g., one or more blood modifiers, antihypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof) to reduce the risk of mortality following a myocardial infarction or other cardiovascular or acute major coronary event.
  • additional agents e.g., one or more blood modifiers, antihypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof
  • the compound or formulation e.g., compound of the invention with a statin (e.g., atorvastatin, rosuvastatin, simvastatin, lovastatin)
  • a statin e.g., atorvastatin, rosuvastatin, simvastatin, lovastatin
  • the compound or formulation is administered within 6, 12, 18, 24, 36, or 48 hours after hospital admission for a myocardial infarction or other cardiovascular or acute major coronary event (Fonarow GC 2005 Chest 128:3641-51).
  • the compound or formulation is administered within 24 hours after hospital admission.
  • the compound or formulation is administered at any time before hospital discharge.
  • the formulation consists, consists essentially of, or comprises ezetimibe.
  • the formulation consists, consists essentially of, or comprises Vytorin (ezetimibe and simivastatin). In some embodiments the formulation consists, consists essentially of, or comprises ezetimibe and one or more blood modifiers, anti-hypertensive agents, dyslipidemic agents (e.g., a statin such as atorvastatin, rosuvastatin), peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof.
  • a statin such as atorvastatin, rosuvastatin
  • peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof.
  • the compounds and formulations described herein can used alone or in combination therapy with one or more additional agents (e.g., one or more blood modifiers, anti-hypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof) to reverse or partially reverse the build-up of plaque in coronary arteries and thus may be associated with reduced plaque volume.
  • additional agents e.g., one or more blood modifiers, anti-hypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof
  • administration of the compounds or formulations described herein stops the progression of heart diease, leads to regression of heart disease.
  • the formulation consists, consists essentially of, or comprises ezetimibe.
  • the formulation consists, consists essentially of, or comprises Vytorin (ezetimibe and simivastatin).
  • the formulation consists, consists essentially of, or comprises ezetimibe and one or more blood modifiers, anti-hypertensive agents, dyslipidemic agents (e.g., a statin such as atorvastatin, rosuvastatin), peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof.
  • a statin such as atorvastatin, rosuvastatin
  • peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more blood modifiers, anti-hypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof) to prevent or treat vascular conditions and associated thrombotic events as described, for example, in US20020147184.
  • additional agents e.g., one or more blood modifiers, anti-hypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof
  • vascular conditions and associated thrombotic events as described, for example, in US20020147184.
  • vascular diseases and conditions are often associated with thrombotic events sometimes resulting in myocardial infarction, stroke and ischemic attack.
  • a thrombotic event is one associated with the formation or presence of a thrombus (e.g., blood clot).
  • Thrombotic events include but are not limited to arterial thrombosis, coronary thrombosis, heart valve thrombosis, coronary stenosis, stent thrombosis and graft thrombosis.
  • Blood clots associated with thrombic events result from an aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements and frequently cause vascular obstruction at the point of their formation. Blood coagulation is a process consisting of a complex interaction of various blood components, or factors, which eventually gives rise to a fibrin clot.
  • SMCs smooth muscle cells
  • Thrombosis and or SMC proliferation are also involved in restenosis, which is the re-occlusion of the blood vessel or valve after surgical treatment e.g., angioplasty or bypass grafts.
  • the compounds and pharmaceutical formulations described herein can be used to prevent or treat restenosis.
  • the compounds and pharmaceutical formulations described herein can also be used to improve coagulation homeostasis (including reducing plasminogen activating inhibitor (PAT)-I activity, reducing fibrinogen, managing high levels of fibrinogen, promoting fibrinolysis, and/or reducing platelet aggregation, and/or improving endothelial function).
  • PAT reducing plasminogen activating inhibitor
  • the compounds and pharmaceutical formulations described herein can used as coatings on surgical devices (e.g., catheters) and implants (e.g., stents) to reduce the risk of restenosis and thrombosis associated with invasive procedures used in the treatment of cardiovascular diseases.
  • surgical devices e.g., catheters
  • implants e.g., stents
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more anti-hypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof) to prevent or treat vascular (e.g., cardiovascular, cerebrovascular, peripheral vascular, renovascular disease, mesenteric vascular, pulmonary vascular disease, ocular vascular) inflammation in a subject in need of such treatment, for example, as described in US20030119757 and to reduce blood plasma or serum concentrations of C-reactive protein (CRP) in a subject in need of such treatment, for example, as described in US20030119757.
  • vascular e.g., cardiovascular, cerebrovascular, peripheral vascular, renovascular disease, mesenteric vascular, pulmonary vascular disease, ocular vascular
  • CRP C-reactive protein
  • Vascular inflammation can lead to atherosclerosis or coronary heart disease.
  • Atherosclerosis is often indicated by a thickening and build-up of plaque in the arteries and typically occurs when the innermost layer of an artery, the endothelium, becomes damaged by cholesterol, toxins, oxidants, infectious agents and the like.
  • the damaged endothelial cells in the artery walls produce adhesion molecules that allow white blood cells to accumulate in the vessel wall. Fats and cholesterol also build-up with the white blood cells causing inflammation of the artery.
  • Such build-up can thicken to a point where the artery becomes vulnerable to blockage from a clot resulting in heart attack or stroke.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy to slow the progression or cause regression of atherosclerotic plaques or lesions in, for example, coronary arteries, carotid arteries, the peripheral arterial system.
  • Vascular inflammation often precedes the development and the continual process of atherosclerotic coronary heart disease.
  • Vascular inflammation beginning with an injury or change in the endothelial wall of the artery, may cause an alteration in the intimal layer that increases platelet adhesion to the endothelium.
  • Vascular stimuli to mammals e.g., cellular injury or inflammation, may lead to the production of various proteins, commonly called acute response proteins, in the body.
  • CRP C- reactive protein
  • CRP Cerethelial artery disease
  • a survey of 388 British men aged 50-69 the prevalence of coronary artery disease increased 1.5 fold for each doubling of CRP level (Mendall et al. (1996) BMJ. 312:1061-1065).
  • Multiple prospective studies have also demonstrated that baseline CRP is a good marker of future cardiovascular events (Riker et al. 1998. J Investig Med. 46:391-395).
  • CRP C-reactive Protein
  • Chlamydia American Heart Assoc. Scientific Sessions 2000.
  • Patients with levels greater 3.4 mg/dL of c-reactive protein were reported to be in the highest quartile of risk.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more agents used to treat Alzheimer's disease, other agents, including combinations thereof) to prevent, treat, or ameliorate symptoms of Alzheimer's Disease (AD), regulate production or levels of at least one amyloid ⁇ (A ⁇ ) peptide and/or regulate the amount of ApoE isoform 4 in the bloodstream and/or brain of a subject, for example, as described in US2003013699 and US6080778.
  • additional agents e.g., one or more agents used to treat Alzheimer's disease, other agents, including combinations thereof
  • AD Alzheimer's Disease
  • a ⁇ amyloid ⁇
  • compositions can be administered to a subject that exhibits no symptoms of AD, has AD, has a family history of AD or dementia illness, is a human, is a human and has trisomy 21 (Down's syndrome), is a human and carries one or more mutations in the genes that encode ⁇ amyloid precursor protein (presenilin-1 or presinilin-2), is a human and carries the Apolipoprotein E isoform 4 gene, is a human and is greater than about 40 years of age, is a human and is greater than about 60 years of age.
  • the subject can have an elevated blood cholesterol level, a total serum cholesterol level that is at least about 200 mg/dl, a total low density lipoprotein (LDL) level that is greater than about 100 mg/dl.
  • LDL total low density lipoprotein
  • the subject has an elevated level of at least one A ⁇ peptide in the bloodstream and/or brain
  • the subject has an elevated level of A ⁇ -42 in the bloodstream and/or brain
  • has a level of A ⁇ -42 peptide greater than about 30 pM in the bloodstream has a level of A ⁇ -42 peptide greater than about 40 pM in the bloodstream
  • the subject has a level of A ⁇ -40 peptide greater than about 200 pM in the bloodstream, has a level of A ⁇ -40 peptide greater than about 400 pM in the bloodstream, has a level of A ⁇ -40 peptide ranging from about 200 pM to about 800 pM in the bloodstream, has a level of A ⁇ -40 peptide greater than about 10
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more agents used to treat Alzheimer's disease, other agents, including combinations thereof) to enhance memory or to prevent, treat, or ameliorate symptoms of one or more of dementia, vascular dementia, Huntington's Disease, hydrocephalus, amnesia, AIDs-related dementia, Pick's Disease, Creutzfeldt- Jakob Syndrome, electroconvulsive therapy, Huntington's disease, amyotropic lateral sclerosis, Down syndrome, mental retardation, Parkinson's Disease, mild cognitive impairment, and memory loss.
  • additional agents e.g., one or more agents used to treat Alzheimer's disease, other agents, including combinations thereof
  • additional agents e.g., one or more agents used to treat Alzheimer's disease, other agents, including combinations thereof
  • additional agents e.g., one or more agents used to treat Alzheimer's disease, other agents, including combinations thereof
  • additional agents e.g., one or more agents used to
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more anti-obesity agents, other agents, including combinations thereof) to prevent or treat obesity in a subject in need of such treatment, for examples as described in US20030119428.
  • Obesity is a common medical problem in developed countries and is a risk factor for other illnesses, e.g., hypertension, diabetes, degenerative arthritis and myocardial infarction.
  • Weight loss medications may be appropriate for use in selected patients who are obese or who are overweight with co-morbid conditions.
  • One measure for defining obesity is known as a body mass index (BMI), which is weight in kilograms divided by height in meters squared.
  • BMI body mass index
  • a BMI of 18.5 to 24.9 is generally classified as normal, a BMI of 25.0 to 29.9 is generally classified as overweight and a BMI of 30 or greater is generally classified as obese.
  • obesity may be defined as the top percentile, e.g., 15 percent, of a population's weight for a given height. Such definitions of obesity, however, are not a measure of body composition and different people may have higher or lower levels of body fat or muscle mass for their height. Nevertheless, these definitions of obesity are useful characterizations for general populations of people.
  • Xanthomas are benign fatty tumors associated with the accumulation of fatty materials under the surface of the skin and are often associated with those who have high triglyceride and cholesterol levels.
  • Xanthoma itself may be indicative of an underlying disease e.g., diabetes, primary biliary cirrhosis, some types of cancer, or hypercholesterolemia.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more anti-hypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof) to prevent or minimize muscular degeneration and related side effects associated with certain HMG-CoA reductase inhibitors (statins), for example, as described in US20030119808.
  • Muscle degeneration encompasses all side effects relating to muscle degradation, aches, and/or weakness that may be associated with the administration of certain statins, including rhabdomyolysis and/or myopathy.
  • Rhabdomyolysis is the destruction or degeneration of skeletal muscle tissue that is accompanied by the release of muscle cell contents (as myoglobin and potassium) into the bloodstream resulting in hypovolemia, hyperkalemia, and sometimes acute renal failure.
  • muscle cell contents as myoglobin and potassium
  • Certain statins allegedly have caused severe muscle degeneration in patients; cerivastatin allegedly has been associated with deaths due to rhabdomyolysis.
  • Myopathies which refer to disorders of muscle tissue or muscles include muscle aches and muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values over ten times the upper limit of normal.
  • CPK creatine phosphokinase
  • Risk of myopathy may be increased during use of high dose statins and/or when statins are administered with other drugs e.g., fibrates, niacin, azole, antifungals, erythromycin, and cyclosporin.
  • the subjects to which the compound or pharmaceutical formulation is administered include those that have or are at risk for a vascular condition, a cardiovascular condition, hypercholesterolemia, atherosclerosis, arteriosclerosis. Suitable subjects include those having no history of clinically evident heart disease as well as those having a history of clinically evident heart disease.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one more anti-diabetic agents, anti-hypertensive agents, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, other agents, including combinations thereof) to prevent or treat diabetes and associated conditions in a subject in need of such treatment, for example, as described in US20040214811.
  • Diabetes mellitus commonly called diabetes, refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose, referred to as hyperglycemia.
  • Type 1 diabetes also referred to as insulin-dependent diabetes or IDDM
  • Type 2 diabetes also referred to as noninsulin dependent diabetes or NIDDM
  • Type 1 diabetes is the result of an absolute deficiency of insulin, the hormone that regulates glucose utilization.
  • Type 1 diabetes has two forms: Immune-Mediated Diabetes Mellitus, which results from a cellular mediated autoimmune destruction of the ⁇ cells of the pancreas; and Idiopathic Diabetes Mellitus, which refers to forms of the disease that have no known etiologies.
  • Type 2 diabetes is a disease characterized by insulin resistance accompanied by relative, rather than absolute, insulin deficiency.
  • Diabetes and associated conditions include but are not limited to Type 1 diabetes, Type 2 diabetes, gestational diabetes mellitus (GDM), maturity onset of diabetes of the young (MODY), pancreatitis, polycystic ovarian disease, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, Syndrome X, dysmetabolic syndrome and related diseases, diabetic complications (including retinopathy, neuropathy, nerphropathy) and sexual dysfunction.
  • GDM gestational diabetes mellitus
  • MODY maturity onset of diabetes of the young
  • pancreatitis polycystic ovarian disease
  • impaired glucose tolerance insulin resistance
  • hyperglycemia hyperinsulinemia
  • elevated blood levels of fatty acids or glycerol elevated blood levels of fatty acids or glycerol
  • obesity Syndrome X
  • dysmetabolic syndrome and related diseases diabetic complications (including retinopathy, neuropathy, nerphropathy) and sexual dysfunction.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one more agents used to treat autoimmune disorders, other agents, including combinations thereof) to prevent or treat at least one autoimmune disorder in a subject in need of such treatment, for example, as described (including the rationale for the therapy) in US20040092499.
  • additional agents e.g., one more agents used to treat autoimmune disorders, other agents, including combinations thereof
  • Autoimmune disorders include, but are not limited to: Alopecia Areata, Ankylosing Spondylitis, Antiphospholipid Syndrome, aplastic anemia, myelodysplastic syndromes, paroxysmal nocturnal hemoglobulinemia, pure red cell aplasia, chronic neutropenias, amegakaryocytic thrombocytopenia, antiphospholipid syndromes, autoimmune thrombocytopenia, autoimmune hemolytic syndromes, antiphospholipid syndromes, autoimmune gastritis, achlorhydria, Autoimmune Addison's Disease, Autoimmune Diabetes, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Autoimmune chronic Hepatitis, Autoimmune hypophysitis, Autoimmune orchiditis, autoimmune ovarian failure, Behcet's Disease, Bullous Pemphigoid, Cardiomyopathy, Celiac Sprue-Dermatitis, Cicatrical pemphigoid, Chronic Fat
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one more agents used to treat demylenation and its associated disorders, other agents, including combinations thereof) to prevent or treat demyelination and associated disorders in a subject in need of such treatment, for example, as described (including the rationale for the therapy) in US20040092500.
  • Nerve fibers are wrapped with multiple layers of insulation known as myelin sheath. Demyelination can occur through disease and results in the destruction or removal of the myelin sheath.
  • Primary demyelinating disorders include but are not limited to multiple sclerosis, acute disseminated encephalomyelitis, adrenoleukodystrophy, adrenomyeloneuropathy, Leber's hereditary optic atrophy and HTLV-associated myelopathy.
  • Other disorders associated with demyelination include but are not limited to Tay-Sachs disease, Niemann-Pick disease, Gaucher's disease and Hurler's syndrome; or stroke, inflammation, immune diseases, metabolic disorders, poison or drugs.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more chemotherapeutic agents, anti-cancer agents, other agents, including combinations thereof) to prevent or treat cholesterol associated tumors in patients who are either at risk of developing a cholesterol-associated tumor or already exhibit a cholesterol associated tumor, for example, as described in US20040116358.
  • the compounds of the invention may reduce both cholesterol levels in vivo and epoxycholesterol formation and thereby inhibit initiation and progression of benign and malignant cholesterol-associated tumors or cholesterol-associated cell growth or cell-masses.
  • the tumors may be benign cholesterol-associated tumors or cholesterol-associated cell growth or cell-masses including but not limited to benign tumors associated with prostate, colon, endometrial, or breast tissues or prostate, colon, breast, or endometrial cancer.
  • the compounds and pharmaceutical formulations described herein, for example, are useful to prevent or treat benign prostatic hypertrophy.
  • the tumors may be malignant cholesterol-associated tumors or cholesterol-associated cell growth or cell-masses including but not limited to malignant tumors associated with prostate, colon, endometrial, or breast tissues or prostate, colon, breast, or endometrial cancer.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more chemotherapeutic agents, anti-cancer agents, other agents, including combinations thereof) for one or more of: inhibiting the expression of at least one multiple ("multi")-drug resistance gene or protein in an animal cell, enhancing the effectiveness of a chemotherapeutic agent in an animal having cancer, and reversing a multi-drug resistance phenotype exhibited by an animal cell all of which are, for example, described in WO05/030225.
  • Co-administration (though not necessarily concurrent or proximal consecutive) of cholesterol absorption inhibitors and chemotherapeutic agents can inhibit the expression of multi-drug resistance genes.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy in one or more of: a) treating or alleviating a cancer; b) preventing, treating or alleviating tumour growth; c) inhibiting or reducing the expression of one or more multiple drug resistance genes; d) inhibiting or reducing the production of one or more proteins expressed by multiple drug resistance genes; e) enhancing the effectiveness of a chemotherapeutic agent in treating a cancer; and f) sensitizing a cell to one or more chemotherapeutic agents.
  • Multiple drug resistance genes include but are not limited to ABCBl (MDR-I), ABCA2 (ABC2), ABCB2 (TAP), ABCB3 (TAP), ABCCl (MRP-I), and ABCC3 (MRP-3).
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., dyslipidemic agents, anti-diabetic agents, anti-hypertensive agents, anti-obesity agents, agents used to treat autoimmune disorders, agents used to treat demylenation and its associated disorders, agents used to treat Alzheimer's disease, blood modifiers, hormone replacement agent/compositions, chemotherapeutic agents, peptides which mitigate one or more symptoms of atherosclerosis, anti-cancer agents, agents used to treat bone loss and associated disorders, other agents, including combinations therof) to modulate lipid raft structure (for example by reducing the level of cholesterol in the lipid raft), for example, as described (including the related rationale) in WO05023305.
  • additional agents e.g., dyslipidemic agents, anti-diabetic agents, anti-hypertensive agents, anti-obesity agents, agents used to treat autoimmune disorders, agents used to treat demylen
  • Lipid rafts are discrete microdomains in the plasma membrane which are rich in sphingolipids and contain ordered cholesterol (Field et al., J. Biol. Chem., 1997,272, 4276-4280). hi a number of cells, it has become clear that certain membrane associated proteins preferentially partition into these lipid rafts (Foster, de Hoog and Mann, PNAS, 2003,100, 5813-8). These include various seven transmembrane domain receptors and their associated G proteins and various proteins that are attached to the inner membrane leaflet through lipid moieties such as prenylation, including small molecular weight G proteins, such as Ras, Rac, cdc42 and Rho.
  • lipid rafts Disruption of lipid rafts results in an uncoupling of efficient signal transduction through receptors such as G protein coupled receptors, the T cell receptor and the high affinity IgE receptor.
  • receptors such as G protein coupled receptors, the T cell receptor and the high affinity IgE receptor.
  • Compounds which modulate lipid raft structure may be useful in the treatment or prophylaxis of a wide variety of diseases and conditions.
  • lipid raft structure such as respiratory tract/obstructive airways diseases and disorders (including: acute-, allergic, hatrophic rhinitis or chronic rhinitis (such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca), rhinitis medicamentosa, membranous rhinitis (including croupous, fibrinous and pseudomembranous rhinitis), scrofulous rhinitis, perennial allergic rhinitis, seasonal rhinitis (including rhinitis nervosa (hay fever) and vasomotor rhinitis), antitussive activity, asthma (such as bronchial, allergic, intrinsic, extrinsic and dust asthma particularly chronic or inveterate asthma (e.g., late asthma and airways hyper-responsiveness)),
  • a disease or condition associated with lipid raft structure such as respiratory tract/obstructive airways diseases and disorders
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents (e.g., one or more dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, hormone replacement agents/compositions, anti-cancer agents, chemotherapeutic agents, agents used to treat bone loss and associated disorders, other agents, including combinations thereof) to prevent or treat osteopenia disorders (bone loss disorders) in subjects in need of such treatment.
  • additional agents e.g., one or more dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, hormone replacement agents/compositions, anti-cancer agents, chemotherapeutic agents, agents used to treat bone loss and associated disorders, other agents, including combinations thereof
  • osteopenia disorders bone loss disorders
  • cardiovascular disease e.g., Gas-6, osteocalcin, matrix gammacarboxy glutamate protein and protein S function in both bone formation and arterial calcification.
  • Bone loss disorders and associated conditions include but are not limited to: osteoporosis, Paget's disease (osteitis deformans), bone loss, bone fractures, bone segmental defects, abnormally increased bone turnover, conditions associated with bone fracture or deficiency, rheumatoid arthritis (including bone loss attendant rheumatoid arthritis), osteoarthritis, osteolysis (including familial expansile osteolysis and periprostetic osteolysis), osteolytic metastases, osteolytic bone disease, metastatic bone disease, osteosarcoma, osteonecrosis, osteogenesis imperfecta, osteomyelitis (e.g., an infectious lesion in bone leading to bone loss), cleidocranial dysplasia (CCD), prosthetic loosening, periodontal disease (e.g., periodontitis) and defects, and other tooth repair processes, tooth loss, primary or secondary hyparathyroidism, hypercalcemia (including hypercalcemia of malignancy, and multiple myeloma), cartilage defects or disorders (including carti
  • Osteoporosis includes primary osteoporosis, secondary osteoporosis, medication- induced osteoporosis (e.g., corticosteroid-induced osteoporosis, transplant-bone disease), age-related osteoporosis in females or males, post-menopausal osteoporosis, glucocorticoid-induced osteoporosis, idiopathic osteoporosis, disease-induced arthritis (e.g., rheumatoid arthritis induced), disuse osteoporosis and arthritis, diabetes-related osteoporosis, endocrine osteoporosis (hyperthyroidism, hyperparathyroidism, Cushing's syndrome, and acromegaly), hereditary and congenital forms of osteoporosis (osteogenesis imperfecta, homocystinuria, Menkes' syndrome, and RiIe- Day syndrome) and osteoporosis due to immobilization of extremities.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy in one more of the following: enhancing/promoting bone formation; preventing bone loss; repair of bone defects and deficiencies, such as those occurring in closed, open and nonunion fractures; prophylactic use in closed and open fracture reduction; promotion of bone healing in plastic surgery; stimulation of bone ingrowth into non-cemented prosthetic joints and dental implants; elevation of peak bone mass in perimenopausal women; prevention or treatment of growth deficiencies; prevention or treatment of increased bone formation during distraction osteogenesis; prevention or treatment of any condition that benefits from stimulation of bone formation; repair of congenital, trauma-induced or surgical resection of bone (for instance, for cancer treatment), and in cosmetic surgery; treatment of wound healing or tissue repair; treatment of subjects undergoing facial reconstruction surgery; treatment of subjects undergoing orthopedic or oral surgery; alleviation of bone pain; prevention or treatment of localized bone loss associated with periprosthetic osteolysis and bone fractures, etc.; rapid inhibition of bone resorption in a subject while obtaining a rapid reduction of bone turnover and biomarkers
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy to stimulate bone regeneration.
  • the bone regeneration may be following reconstruction of bone defects in cranio-maxillo facial surgery, or following an implant into bone, for example a dental implant, bone supporting implant, or prosthesis.
  • the bone regeneration may also be following a bone fracture.
  • the compounds and pharmaceutical formulations described herein can be used alone or in combination therapy with one or more additional agents for preventing and treating malignant lesions (such as ductal carcinoma in situ of the breast and lobular carcinoma in situ of the breast), premalignant lesions (such as fibroadenoma of the breast and prostatic intraepithelial neoplasia (PIN) 5 gastrointestinal malignancies, liposarcomas and various other epithelial tumors (including breast, prostate, colon, ovarian, gastric and lung), cancer-induced asthenia (fatigue), irritable bowel syndrome, Crohn's disease, gastric ulceritis, and gallstones, and HIV infection, other infectious diseases, drug-induced lipodystrophy, and proliferative diseases such as psoriasis, for example, as described in US20050085497.
  • malignant lesions such as ductal carcinoma in situ of the breast and lobular carcinoma in situ of the breast
  • premalignant lesions such as fibroadenoma of
  • cancers including but not limited to human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary a
  • cancers including but not limited to human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcom
  • compositions and pharmaceutical formulations described herein can be administered alone or in combination therapy with one or more additional agents (e.g., one or more hormone replacement agents/compositions, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, anti-hypertensive agents, anti-diabetic agents, anti-obesity agents, other agents, including combinations thereof) to post-menopausal women, for example, as described in US20030119796.
  • additional agents e.g., one or more hormone replacement agents/compositions, dyslipidemic agents, peptides which mitigates one or more symptoms of atherosclerosis, anti-hypertensive agents, anti-diabetic agents, anti-obesity agents, other agents, including combinations thereof
  • compositions and pharmaceutical formulations described herein can be administered alone or in combination therapy with one or more additional agents to, for example, (1) a subject in need of or who has undergone an organ transplant (e.g., a kidney transplant), (2) a subject who is either at risk of developing systemic lupus erythematosus or already exhibits systemic lupus erythematosus, (3) a subject who has undergone or is undergoing hemodialysis, (4) a subject who is either at risk of developing hyperhomocysteine levels or already exhibits hyperhomocysteine levels, (5) a subject who is either at risk of developing hypothyroidism or already exhibits hypothyroidism, (6) a subject who is either at risk of developing obstructive liver disease or already exhibits obstructive liver disease, (7) a subject who is either at risk of developing kidney disease or already exhibits kidney disease, (8) a subject who has undergone cardiac bypass surgery, and (9) a subject who has undergone per organ transplant (e.
  • the compounds and pharmaceutical formulations described herein can be administered alone or in combination therapy with one or more additional agents to a non-human animal for a veterinary use for treating, preventing, or managing a disease or disorder disclosed herein.
  • non-human examples include cows, horses, sheep, pigs, cats, dog, mice, rats, rabbits, guinea pigs, and fowl species (e.g., chicken, turkey, duck, goose, quail).
  • the compounds and pharmaceutical formulations described herein can be used to reduce the fat content of livestock to produce leaner meats and to reduce the cholesterol content of eggs by administering the compounds to a chicken, quail, or duck hen.
  • the compounds and pharmaceutical formulations described herein can be administered via the animals' feed or orally as a drench composition.
  • Certain compounds of the invention may have the additional advantage that they suppress serum cholesterol and/or LDL levels while themselves not being appreciably absorbed into the mammalian circulation upon oral administration. As a result of the low-to-insignificant serum levels, fewer side-effects, such as drug-drug interactions, are observed.
  • Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. When not otherwise restricted, the term refers to alkyl of 20 or fewer carbons. Lower alkyl refers to alkyl groups of 1, 2, 3, 4, 5 and 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Preferred alkyl and alkylene groups are those Of C 20 or below (e.g.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3, 4, 5, 6, 7, and 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.
  • C 1 to C 20 hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl.
  • phenylene refers to ortho, meta or para residues of the formulae:
  • C 1 to C 20 saturated hydrocarbon refers to straight, branched, cyclic configurations and combinations thereof. According to the present invention the saturated hydrocarbon is hydroxylated.
  • the saturated hydrocarbon may be hydroxylated at 1, 2, 3, or 4 positions; preferably at one position.
  • Examples of saturated hydrocarbons include structures of the following formulae:
  • Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.
  • Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like.
  • the term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 1196, but without the restriction of fl27(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds).
  • thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively.
  • Polyol refers to a compound or residue having a plurality of -OH groups. Polyols may be thought of as alkyls in which a plurality of C-H bonds have been replaced by C-OH bonds. Common polyol compounds include for example glycerol, erythritol, sorbitol, xylitol, mannitol and inositol. Linear polyol residues will generally be of the empirical formula -C y H ⁇ 1 O y , and cyclic polyol residues will generally be of the formula -C y H 2y-1 O y . Those in which y is 3, 4, 5 and 6 are preferred. Cyclic polyols also include reduced sugars, such as glucitol.
  • Acyl refers to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include formyl, acetyl, propionyl, isobutyryl, t-butoxycarbonyl, benzoyl, benzyloxycarbonyl and the like.
  • Lower-acyl refers to groups containing one to four carbons.
  • Aryl and heteroaryl refer to aromatic or heteroaromatic rings, respectively, as substituents.
  • Heteroaryl contains one, two or three heteroatoms selected from O, N, or S. Both refer to monocyclic 5- or 6-membered aromatic or heteroaromatic rings, bicyclic 9- or 10-membered aromatic or heteroaromatic rings and tricyclic 13- or 14- membered aromatic or heteroaromatic rings.
  • Aromatic 6, 7, 8, 9, 10, 11, 12, 13 and 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5, 6, 7, 8, 9 and 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benziniidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl and the like. [0076] Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc.
  • alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, diallcylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.
  • saccharose any carbohydrate comprised of one or two saccharose groups.
  • the monosaccharide sugars (often called simple sugars) are composed of chains of 2-7 carbon atoms.
  • One of the carbons carries aldehydic or ketonic oxygen, which may be combined in acetal or ketal forms.
  • the remaining carbons usually have hydrogen atoms and hydroxyl groups (or protecting groups for hydroxyl, such as acetate).
  • sugars are arabinose, ribose, xylose, ribulose, xylulose, deoxyribose, galactose, glucose, mannose, fructose, sorbose, tagatose, fucose, quinovose, rhamnose, manno-heptulose and sedoheptulose.
  • disaccharides are sucrose, lactose, maltose, and cellobiose.
  • the general term "sugar” refers to both D-sugars and L-sugars.
  • the sugar may also be protected.
  • the sugar may be attached through oxygen (as in US patent 5,756,470) or through carbon (as in PCT WO 2002066464), the disclosures of both of which are incorporated herein by reference.
  • Reduced C-attached sugars or C-glycosyl compounds are also encompassed by the invention.
  • the reduced sugars e.g. glucitol
  • alditols are polyols having the general formula HOCH 2 [CH(OH)J n CH 2 OH (formally derivable from an aldose by reduction of the carbonyl group.
  • uronic acid refers to derivatives formed by the oxidation of the alchohol group of an aldose to acid.
  • oxidation of glucose results in glucuronic acid and galacturonic acid is a uronic acid derivative of galactose.
  • glucuronide is also used in its normal sense to refer to a glycoside of glucuronic acid.
  • prodrug refers to a compound that is made more active in vivo. Commonly the conversion of prodrug to drug occurs by enzymatic processes in the liver or blood of the mammal. Many of the compounds of the invention may be chemically modified without absorption into the systemic circulation, and in those cases, activation in vivo may come about by chemical action (as in the acid-catalyzed cleavage in the stomach) or through the intermediacy of enzymes and microflora in the gastrointestinal GI tract.
  • the compounds of this invention can exist in forms in which one isotope of a particular atom may be replaced with a different isotope of that same atom.
  • “hydrogen” may be 1 H, 2 H or 3 H
  • "carbon” may be 12 C, 13 C, or 14 C
  • nitrogen maybe 14 N or 15 N
  • “oxygen” maybe 16 0, 17 O or 18 O
  • the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine, iodine and chlorine include 3 H, 14 C, 35 S, 18 F, 32 P, 33 P, 125 I, and 36 Cl, respectively.
  • Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention.
  • Tritiated, i.e. 3 H, and carbon-14, i.e., 14 C 5 radioisotopes are particularly preferred for their ease in preparation and detectability.
  • Radiolabeled compounds of the invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non- radiolabeled reagent.
  • the compounds of the invention can also exist in other labeled forms.
  • US20020009714 discloses methods of labeling and uses of labeled cholesterol absorption inhibitors.
  • the labels can be primary labels (where the label comprises an element which is detected directly) or secondary labels (where the detected label binds to a primary label, e.g., as is common in immunological labeling).
  • An introduction to labels, labeling procedures and detection of labels is found in Introduction to Immunocytochemistrv, (2d ed.) Polak and Van Noorden,, Springer Verlag, N. Y. (1997) and in Handbook of Fluorescent Probes and Research Chemicals, Haugland (1996), a combined handbook and catalogue published by Molecular Probes, Inc., Eugene, Oreg.
  • Primary and secondary labels can include undetected elements as well as detected elements.
  • Useful primary and secondary labels in the present invention can include spectral labels, which include fluorescent labels such as fluorescent dyes (e.g., fluorescein and derivatives such as fluorescein isothiocyanate (FITC) and Oregon GreenTM, rhodamine and derivatives (e.g., Texas red, tetramethylrhodamine isothiocyanate (TRITC), etc.), digoxigenin, biotin, phycoerythrin, AMCA, CyDyesTM and the like), radiolabels (including those described above), enzymes (e.g., horseradish peroxidase, alkaline phosphatase etc.) spectral colorimetric labels such as colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads.
  • fluorescent labels such as fluorescent dyes (e.g., fluorescein and derivatives such as fluor
  • the label may be coupled directly or indirectly to the compound of the invention according to methods well known in the art.
  • a wide variety of labels may be used, with the choice of label depending on sensitivity required, ease of conjugation with the compound, stability requirements, available instrumentation, and disposal provisions.
  • a detector which monitors a protein/inhibitory agent interaction is adapted to the particular label which is used.
  • Typical detectors include spectrophotometers, phototubes and photodiodes, microscopes, scintillation counters, cameras, film and the like, as well as combinations thereof. Examples of suitable detectors are widely available from a variety of commercial sources known to persons of skill.
  • Nonlimiting examples of labels include those which utilize 1) chemiluminescence (using horseradish peroxidase or alkaline phosphatase with substrates that produce photons as breakdown products) with kits being available, e.g., from Molecular Probes, Amersham, Boehringer-Mannheim, and Life Technologies/Gibco BRL; 2) color production (using both horseradish peroxidase or alkaline phosphatase with substrates that produce a colored precipitate) (kits available from Life Technologies/Gibco BRL, and Boehringer-Mannheim); 3) fluorescence (e.g., using Cy-5 (Amersham), fluorescein, and other fluorescent tags); 5) radioactivity.
  • Other methods for labeling and detection will be readily apparent to one skilled in the art.
  • the label is a fluorescent label.
  • Fluorescent labels have the advantage of requiring fewer precautions in handling, and being amendable to high-throughput visualization techniques (optical analysis including digitization of the image for analysis in an integrated system comprising a computer).
  • Preferred labels are typically characterized by one or more of the following: high sensitivity, high stability, low background, low environmental sensitivity and high specificity in labeling.
  • Fluorescent moieties which are incorporated into the labels of the invention, are generally are known, including Texas red, digoxigenin, biotin, 1- and 2- aminonaphthalene, p,p'-diaminostilbenes, pyrenes, quaternary phenanthridine salts, 9- aminoacridines, p,p'-diaminobenzophenone imines, anthracenes, oxacarbocyanine, merocyanine, 3-aminoequilenin, perylene, bis-benzoxazole, bis-p-oxazolyl benzene, 1,2-benzophenazin, retinol, bis-3-aminopyridinium salts, hellebrigenin, tetracycline, sterophenol, benzimidazolylphenylamine, 2-oxo-3-chromen, indole, xanthen, 7- hydroxycoumarin, phenoxazine, calicy
  • fluorescent tags are commercially available from the SIGMA chemical company (Saint Louis, Mo.), Molecular Probes, R&D systems (Minneapolis, Minn.), Pharmacia LKB Biotechnology (Piscataway, NJ.), CLONTECH Laboratories, Inc. (Palo Alto, Calif.), Chem Genes Corp., Aldrich Chemical Company (Milwaukee, Wis.), Glen Research, Inc., GIBCO BRL Life Technologies, Inc. (Gaithersberg, Md.), Fluka ChemicaBiochemika Analytika (Fluka Chemie AG, Buchs, Switzerland), and Applied Biosystems (Foster City, Calif), as well as many other commercial sources known to one of skill.
  • the labels may be covalently bound to the compounds of the invention by a tether group.
  • the tether group can be any moiety capable of covalently linking to the inhibitors and to the labels.
  • Preferred groups are substituted or unsusbstituted alkylene, alkenylene or alkynylene of 1 to 10 carbon atoms, more preferably 1 to 4 carbon atoms. Particularly preferred groups are unsusbstituted alkynylenes.
  • the terms "methods of treating or preventing” mean amelioration, prevention or relief from the symptoms and/or effects associated with lipid disorders.
  • preventing refers to administering a medicament beforehand to forestall or obtund an acute episode or, in the case of a chronic condition to diminish the likelihood or seriousness of the condition.
  • prevent is not an absolute term, hi the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended in applicants' claims.
  • reference to "treatment” of a patient is intended, to include prophylaxis.
  • mammal is used in its dictionary sense.
  • the term “mammal” includes, for example, mice, hamsters, rats, cows, sheep, pigs, goats, and horses, monkeys, dogs (e.g., Canis familiar is), cats, rabbits, guinea pigs, and primates, including humans.
  • the compounds described herein contain two or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • Each chiral center maybe defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, as well as, their racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
  • enantiomeric excess is related to the older term “optical purity” in that both are measures of the same phenomenon.
  • the value of ee will be a number from 0 to 100, zero being racemic and 100 being pure, single enantiomer.
  • a compound which in the past might have been called 98% optically pure is now more precisely described as 96% ee; in other words, a 90% ee reflects the presence of 95% of one enantiomer and 5% of the other in the material in question.
  • a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
  • Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluenesulfonyl and methanesulfonyl respectively.
  • a comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled “Standard List of Abbreviations" is incorporated herein by reference.
  • the present invention provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
  • the most suitable route may depend upon the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • AU methods include the step of bringing into association a compound of the invention or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier, which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • the pharmaceutical compositions may include a "pharmaceutically acceptable inert carrier", and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, "Pharmaceutically acceptable carrier” also encompasses controlled release means.
  • compositions of the present invention may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must, of course, be compatible with the compound of the invention to insure the stability of the formulation.
  • excipients for use as the pharmaceutically acceptable carriers and the pharmaceutically acceptable inert carriers and the aforementioned additional ingredients include, but are not limited to:
  • BINDERS polyethylene oxide, corn starch, citric acid monohydrate, potato starch, other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, methyl cellulose, pre-gelatinized starch (e.g., STARCH 1500® and STARCH 1500 LM®, sold by Colorcon, Ltd.), hydroxypropyl methyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose (e.g., AVICELTM, such as, AVICEL-PH- 101TM, -103TM and -105TM, sold by FMC Corporation, Marcus Hook,
  • FILLERS talc, sodium choloride, aluminum oxide, iron oxides (e.g., yellow, black, red), red ferric oxide, yellow ferric oxide, magnesium carbonate, magnesium hydroxide, magnesium aluminate, aluminum magnesium hydroxide, calcium carbonate (e.g., granules or powder), calcium dihydroxide, dibasic calcium phosphate, dibasic calcium phosphate anhydrous, triacetin, lactose, hydrous lactose, tribasic calcium phosphate, calcium sulfate (e.g., granules or powder), microcrystalline cellulose, silicified microcrystalline cellulose, soybean lecithin, xanthar gum, silicic anhyride, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, or mixtures thereof;
  • iron oxides e.g., yellow, black, red
  • red ferric oxide
  • DISINTEGRANTS agar-agar, alginic acid, calcium carbonate, simethicone emulsion, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, crospovidone, povidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums, or mixtures thereof;
  • SURFACTANTS Tween 80 or polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene sorbitan, or mixtures thereof;
  • LUBRICANTS calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, palmitic acid, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil ⁇ e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, syloid silica gel (AEROSIL 200, W.R.
  • AEROSIL 200 AEROSIL 200, W.R.
  • ANTI-CAKING AGENTS calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, or mixtures thereof;
  • ANTIMICROBIAL AGENTS benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium chloride, cresol, chlorobutanol, dehydroacetic acid, ethylparaben, methylparaben, phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, polysorbate, sorbic acid, thimersol, thymo, or mixtures thereof;
  • COATING AGENTS sodium carboxymethyl cellulose, cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl methyl cellulose phthalate, methylcellulose, polyethylene glycol (e.g., polyethylene glycol 8000, polyethylene glycol 3000), polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnuba wax, candellilla wax, microcrystalline wax, or mixtures thereof;
  • COLORANTS FD&C blue no.l, D&C yellow #10 aluminum lake, FD&C yellow #6/sunset yellow FCF aluminum lake, FD&C carmine aluminum lake and FD&C blue #1, or mixtures thereof; and
  • ANTIOXIDANTS butylated hydroxyanisole, sodium ascorbate, sodium metabisulfate, malic acid, citric acid, ascorbic acid, butylated hydroxytoluene, vitamin C, propyl gallate, or mixtures thereof.
  • Solid oral dosage forms may optionally be treated with coating systems (e.g., Opadry® fx film coating system, for example Opadry® blue (OY-LS-20921), Opadry® white (YS-2-7063), Opadry® white (YS-1-7040), and black ink (S-l-8106).
  • coating systems e.g., Opadry® fx film coating system, for example Opadry® blue (OY-LS-20921), Opadry® white (YS-2-7063), Opadry® white (YS-1-7040), and black ink (S-l-8106).
  • the dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
  • a dosage unit (e.g., an oral dosage unit) can include from, for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g., 1 mg, 2 mg, 3 mg, 4mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg) of a compound described herein.
  • 1 to 30 mg, 1 to 40 mg 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg,
  • Combination therapy can be achieved by administering two or more agents, each of which is formulated and administered separately, or by administering two or more agents in a single formulation.
  • Other combinations are also encompassed by combination therapy.
  • two agents can be formulated together and administered in conjunction with a separate formulation containing a third agent. While the two or more agents in the combination therapy can be administered simultaneously, they need not be.
  • administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks.
  • the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.
  • Combination therapy can also include two or more administrations of one or more of the agents used in the combination.
  • Combination therapy can also include the administration of two or more agents via different routes or locations. For example, (a) one agents is administered orally and another agents is administered intravenously or (b) one agent is administered orally and another is administered locally into the site of injury (e.g., an artery). In each case, the agents can either simultaneously or sequentially.
  • the compounds described herein can be used in therapeutic combination with one or more dyslipidemic agents.
  • Suitable dyslipidemic agents for use in therapeutic combination with a compound described herein includebile acid sequestrants such as cholestyramine (a styrene-divinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids, such as Questran® or Questran Light® cholestyramine which are available from Bristol- Myers Squibb), colesevelam hydrochloride (such as WelChol® Tablets (polyallylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide) which are available from Sankyo), colestipol (a copolymer of diethylenetriamine and 1-chloro- 2,3-epoxypropane, such as Colestid® tablets which are available from Pharmacia
  • HMG-CoA reductase inhibitors are dyslipidemic agents that can be used in therapeutic combinations with compounds described herein.
  • Suitable HMG-CoA reductase inhibitors for use in therapeutic combination with a compounds described herein include: atorvastatin (Lipitor®; disclosed inUS4681893, US5385929 and US5686104), atorvastatin calcium (disclosed in US5273995), dihydrocompactin, (disclosed in US4450171), bervastatin (disclosed in US5082859), carvastatin, cerivastatin (Baycol®; disclosed in US5006530, US5502199, and US5177080), crilvastatin, dalvastatin/ RG 12561 (disclosed in EP738510A2), fluvastatin (Lescol®; disclosed in US4739073 and US534772), glenvastatin, fluindostatin/ XU 62-320 (disc
  • HMG-CoA reductase inhibitors where an open-acid form can exist
  • salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein.
  • Pharmaceutically acceptable salts with respect to the HMG-CoA reductase inhibitor includes non-toxic salts of the compounds which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, l-p-chlorobenzyl-2-pyrrolidine- l'-yl-methylbenzim- idazole, diethylamine, piperazine, and tris(hydroxymethyl) aminomethane.
  • a suitable organic or inorganic base particularly those formed from cations such as sodium, potassium, aluminum
  • salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamao
  • Prodrugs of HMG CoA reductase inhibitors are also dyslipidemic agents.
  • the prodrug is a lipophilic ester comprising an ester prodrug linkage to the HMG-like moiety of the statin drug and a lipophilic group described, for example, in WO05023305.
  • Lipophilic alcohols available which may be used to form such statin prodrugs include, but are not limited to, methanol, ethanol, propan- l-ol, propan-2-ol, butan-1-ol, butan-2-ol, pentan-1-ol, hexan-1-ol, heptan-1-ol, octan- l-ol, nonan-1-ol, decan-1-ol, 2-ethyl-hexan-l-ol, 3,3, 5-trimethyl-cycloliexanol, 2- ethoxy- ethaiiol, and menthol.
  • lipophilic ester statin prodrugs include but are not limited to (3R, 5R)-3, 5- Dihydroxy-7- (2-isopropyl-4, 5-diphenyl- 3-phenylcarbamoyl-pyrrol-l-yl)-heptanoic acid, (E)-(3R, 5S)-3, 5-Dihydroxy-7-(l- isopropyl-3-phenyl-lH-indol-2-yl)-hept-6-enoic acid, (E)- (3R, 5S)-3, 5-Dihydroxy-7- [4-isopropyl-2- (methanesulfonyl-methyl-amino)-6-phenyl- pyrimidin-5-yl] -hept-6- enoic acid, (E)- (3R, 5S)-7- (2-Cyclopropyl-4-phenyl-quinolin-3-yl)- 3,5-dihydroxy- hept-6-enoic acid, (E)
  • Hydroxylated statin forms and ester prodrugs thereof as described, for example, in WO05023305 are also dyslipidemic agents.
  • Hydroxylated statins include but are not limited to (3R, 5R)-3-, 5-Dihydroxy- 7- [2- (4-hydroxy-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l- yl] - heptanoic acid, (E)- (3R, 5S)-3, 5-Dihydroxy-7- [3- (4-hydroxy-phenyl)-l-isopropyl- IH- indol-2-yl] -hept-6-enoic acid, (E)- (3R, 5S)-3, 5 -Dihydroxy-7- [4- (4-hydroxy- phenyl)-6- isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-hept-6- en
  • Ester prodrugs of hydroxylated statins are of the general formul X-Y, where is X is a hydroxylated statin (e.g., (3R, 5R)-3-, 5 -Dihydroxy-7- [2- (4-hydroxy-phenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrol-1-yl] -heptanoic acid, (E)- (3R, 5S)-3, 5-Dihydroxy-7- [3- (4- hydroxy-phenyl)-l-isopropyl-lH-indol-2-yl]-hept-6-enoic acid, (E)- (3R, 5S)-3, 5- Dihydroxy-7- [4- (4-hydroxy-phenyl)-6-isopropyl-2- (methanesulfonyl-methyl- amino)- pyrimidin-5-yl] -hept-6-enoic acid, (E)- (3R, 5S
  • Lipid modulating agents are dyslipidemic agents which function as high density lipoprotein (HDL), including synthetic HDL which contains lipid such as phosphotidyl choline, phosphatidyl serine, phosphatidyl ethanolamine, and other phospholipids in combination with HDL associated proteins such as ApoA-I or variants thereof including ApoAI-Milano (Rl 73C) and biologically active peptides derived therefrom, the ApoA-I Paris variant (Rl 51C), the reverse lipid transport (RLT) peptides, enzymes associated with HDL such as paraoxonase, and apo E, alone or formulated in combination with liposomes or emulsions (an example of a liposomal formulation is found in WO95/23592), see, for example, US20030109442 and US20050096307.
  • HDL high density lipoprotein
  • synthetic HDL which contains lipid such as phosphotidyl choline, phosphat
  • HDL associated proteins include sequences present in HDL associated proteins that associate with HDL and synthetic peptides having equivalent binding or functional characteristics.
  • HDL-associated proteins further include apolipoproteins such as Apo E, proApoA-I, ApoA-IParis, ApoA-IL proApoA-II, Apo A-IV, ApoC-I, ApoC-II, ApoC-III, including variants thereof which have been modified to include one or more sulfhydral groups, as described by Bielicki and Oda, Biochemistry 41 :2089-2096 (2002).
  • apolipoproteins such as Apo E, proApoA-I, ApoA-IParis, ApoA-IL proApoA-II, Apo A-IV, ApoC-I, ApoC-II, ApoC-III, including variants thereof which have been modified to include one or more sulfhydral groups, as described by Bielicki and Oda,
  • HDL-associated proteins further include paraoxonase, cholesteryl ester transfer protein, Lecithin Cholesterol Acyltransferase (LCAT), phospholipid transfer protein, including combinations thereof complexed with and without lipid.
  • HDL-associated proteins can be used alone, in combination, complexed to one or more lipids alone or in combination complexed to one or more lipids.
  • Non limiting examples include complexes comprising Apo A-I and lipid, complexes comprising paraoxanase and lipid, and complexes comprising ApoA-I, paraoxonase and lipid.
  • HDL-associated proteins and lipids can be mixed in an aqueous solution in appropriate ratios complexed by methods known in the art and including freeze-drying, detergent solubilization followed by dialysis, microfluidization, sonication, and homogenization. Complex efficiency can be optimized, for example, by varying pressure, ultrasonic frequency, or detergent concentration.
  • An example of a detergent commonly used to prepared HDL-associated protein-lipid complexes is sodium cholate. In some cases it is desirable to mix the lipid and the HDL-associated protein prior to administration.
  • Lipids may be in solution or in the form of liposomes or emulsions formed using standard techniques such as sonication or extrusion.
  • Sonication is generally performed with a tip sonifier, such as a Branson tip sonifier, in an ice bath. Typically, the suspension is subjected to several sonication cycles. Extrusion may be carried out by biomembrane extruders, such as the Lipex Biomembrane Extruder. Defined pore size in the extrusion filters may generate unilamellar liposomal vesicles of specific sizes. The liposomes may also be formed by extrusion through an asymmetric ceramic filter, such as a Ceraflow Microfilter, commercially available from the Norton Company, Worcester Mass. or through a polycarbonate filter or other types of polymerized materials (i.e. plastics) commonly known.
  • asymmetric ceramic filter such as a Ceraflow Microfilter, commercially available from the Norton Company, Worcester Mass. or through a polycarbonate filter or other types of polymerized materials (i.e. plastics) commonly known.
  • the dyslipidemic agent comprises an HDL- associated protein with little or no lipid.
  • lipids include phospholipids (such as soy phosphatidylcholine, egg phosphatidylcholine, soy phosphatidylglycerol, egg phosphatidylglycerol, palmitoyl-oleoyl-phosphatidylcholine distearoylphosphatidylcholine, distearoylphosphatidylglycerol, phosphatidylcholine, phosphatidylglycerol, sphingomyelin, phosphatidylserine, phosphatidic acid, N-(2,3- di(9-(Z)-octadecenyloxy))-prop- 1 -yl-N,N,N-trimethylammonium chloride, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine,
  • phospholipids
  • lipids suitable for use are well known to persons of skill in the art and are cited in a variety of well known sources, e.g., McCutcheon's Detergents and Emulsif ⁇ ers and McCutcheon's Functional Materials, Allured Publishing Co., Ridgewood, NJ. Generally, it is desirable that the lipids are liquid-crystalline at 37 0 C, 35°C, or 32°C.
  • the concentration of the lipid in the formulation may vary. Persons of skill may vary these concentrations to optimize treatment with different lipid components or of particular patients. ApoAl is combined with lipid in a ratio by weight of between 1 :0.5 to 1 :3. In certain embodiments, more lipid being preferred for clearance of cholesterol.
  • the lipid modulating agent is ETC-216, which is a synthetic HDL complex composed of 14 mg/mL of recombinant apolipoprotein A-I Milano and 13 mg/niL of l-palmitoyl-2- oleoyl phosphatidyl choline (POPC) complex in sucrose-mannitol-phosphate buffer solution (sterile 6.4% sucrose, 0.8% mannitol in 6 mmol/L phosphate buffer, pH 7.4) (Esperion Therapeutics, Inc.), as a ready to inject solution or saline.
  • ETC-216 is a synthetic HDL complex composed of 14 mg/mL of recombinant apolipoprotein A-I Milano and 13 mg/niL of l-palmitoyl-2- oleoyl phosphatidyl choline (POPC) complex in sucrose-mannitol-phosphate buffer solution (sterile 6.4% sucrose, 0.8% mannitol in 6
  • dyslipidemic agents which can be used a therapeutic combination with a compound described herein include:
  • apolipoprotein E (apoE) and isoforms thereof including that produced by the methods disclosed in WO04/108922 and US5834596;
  • apolipoprotein A and isoforms thereof including that produced by the methods disclosed in WO04/108922;
  • ApoA-I agonists including the peptides described in US6004925 and US6037323;
  • HMG-CoA synthase inhibitors such as L-659,699 ((E 5 E)-I l-[3'R-(hydroxy-methyl)-4'- oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoic acid) and those disclosed in US5120729, US5064856, and US4847271;
  • cholesterol absorption inhibitors such as plant sterols, plant stanols and/or fatty acid estesrs of plant stanols such as sitostanol ester used in Benecol® margarine, stanol esters, beta-sitosterol, sterol glycosides such as tiqueside, (3R,4S)-l-(4-fluorophenyl)- 3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one (Zetia®), and the compounds disclosed in USRE37721, WO9302048, WO05044256, WO05033100, WO05021495, WO05021497, WO05009955, WO05000353, WO04087655, WO04000804, WO04000803, WO02050068, WO02050060, WO02050027, WO04
  • phytoestrogen compounds such as disclosed in WO00/30665 including isolated soy bean protein, soy protein concentrate or soy flour as well as an isoflavone such as genistein, daidzein, glycitein or equol, or phytosterols, phytostanol or tocotrienol as disclosed in WO00/015201;
  • an ⁇ -glucosidase inhibitor an aldose reductase inhibitor and/or an LDL catabolism promoter such as disclosed in EP 1022272;
  • a matrix metalloproteinase inhibitor including but not limited to ( ⁇ )4-(4'-Chloro- biphenyl-4-yl)-4-hydroxy-butyric acid, (L)-2-(Dibenzofuran-2-sulfonylamino)-3 - mercapto-propionic acid, (L)-2-(Dibenzofuran-2-sulfonylamino)-3 -methyl-butyric acid, (L)-2-(Dibenzofuran-2-sulfonylamino)-3-phenyl- ⁇ ropionic acid, (L)-2- (Dibenzofuran-2-sulfonylamino)-3-tritylsulfanyl-propionic acid, (L)-2-(Dibenzofuran- 2-sulfonylamino)-4-methyl-pentanoic acid, (S)-2-(4'-Amino-biphenyl-4- sulfonylamino
  • an LDL-receptor inducer or a steroidal glycoside such as disclosed in US5698527 and GB2304106;
  • LUV (large unilamellar vesicles) products including ETC-588 (Pfizer);
  • acyl coenzyme A-cholesterol acyl transferase (ACAT) inhibitors such as avasimibe (Current Opinion in Investigational Drugs. 3(9):291-297 (2003)), eflucimibe, HL-004, lecimibe, (DuP-I), KY505, SMP 797, TS-962 (Taisho Pharmaceutical Co. Ltd), F- 1394, CS-505 (pactimibe), F-12511, K-10085 and YIC-C8-434, CL-277,082 (Clin Pharmacol Ther.
  • ACAT acyl coenzyme A-cholesterol acyl transferase
  • CETP inhibitors such as JTT 705 identified as in Nature 406, (6792):203-7 (2000), torcetrapib (CP-529,414 described in US20030186952 and WO00/017164), CP 532,632, BAY63-2149, CeTi-I, SC 591, SC 795 (Pharmacia), SC 744 (Pharmacia) and the like including those described in Current Opinion in Investigational Drugs. 4(3):291-297 (2003) and those disclosed in J. Antibiot, 49(8): 815-816 (1996), and Bioorg. Med. Chem.
  • antioxidants such as probucol (and related compounds disclosed in US3674836), probucol derivatives such as AGI- 1067 (and other derivatives disclosed in US6121319 and US6147250), tocopherol, ascorbic acid, retinol (as disclosed in WO94/15592), ⁇ -carotene, selenium, vitamin C and pharmaceutically acceptable salts and esters thereof;
  • an antihomocysteine agent such as folic acid, folate, vitamin E, vitamin B 6 , vitamin B 12 and pharmaceutically acceptable salts and esters thereof;
  • PP ARa agonists such as those disclosed in US6028109 (fluorophenyl compounds), WO00/75103 (substituted phenylpropionic compounds), WO98/43081 and fibric acid derivatives (fibrates) such as beclofibrate, benzafibrate, bezafibrate (CAS PvN 41859- 67-0, see US3781328), binifibrate (CAS RN 69047-39-8, see BE884722), ciprofibrate (CAS RN 52214-84-3, see US3948973), clinofibrate (CAS RN 30299-08-2, see US3716583), clofibrate (such as ethyl 2-(p-chlorophenoxy)-2-methyl-propionate, e.g., Atromid-S® capsules (Wyeth-Ayerst), clofibric acid, etofibrate, pirifi
  • FXR receptor modulators such as GW 4064 (described in WO00/37077, Glaxo Group Limited), SR 103912, 3-deoxychenodeoxycholic acid, QRX-401 (QuatRx), (E)-and (Z)-guggulsterone, chenodeoxycholic acid (CDCA), 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), compounds disclosed in WO05056554 (including the compounds specifically named in claims 3, 7, 9, 11, 13, 17, 19, 21 23, 27, 29, 31, 33, 35, 37, 39, and 41), compounds disclosed in US6906057 (such as (Z)-5-[2-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronapthalen-2-yl)-2-(trimethylsilyl)vinyl]thiophene-2-carboxylic acid, (Z)-5-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronapthalen-2-yl
  • LXR receptor modulators such as ⁇ -hydroxycholesterol, 25-hydroxycholesterol, 27- hydroxy-cholesterol, 4 ⁇ -hydroxycholesterol, 24-hydroxycholesteroI, 20(S)- hydroxycholesterol, 22(R)-hydroxycholesterol, 20,22-dihydroxycholesterol, GW 3965, T9013137, and XTC0179628, and those disclosed in US20030125357, WO03/045382, WO03/053352, WO03/059874, and the like;
  • HM74 and HM74A (human HM74A is Genbank Accession No. AY148884 and rat HM74A is EMM_patAR098624) receptor agonists such as nicotinic acid (niacin) and derivatives thereof (e.g., compounds comprising a pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers, where available) including but not limited to those disclosed in Wise et al (2003) J. Biol. Chem.
  • 9869 e.g., 5-methylpyrazole-3-carboxylic acid and acifran (4,5-dihydro-5-methyl-4-oxo-5-phenyl-2-furan carboxylic acid pyradine-3 -acetic acid)
  • trans-metanicotine epibatidine or one of its analogs, pyridol or derivatives thereof, piperidine alkaloids (such as lobeline and analogs thereof) and imidacloprid or one of its analogs, 5-methyl nicotinic acid, nicotinuric acid, aluminum nicotinate, nicoclonate, nicomol, niceritrol, oxiniacic acid, nicofuranose, acipimox (5- methylpyrazine-2-carboxylic acid 4-oxide), Niaspan® (niacin extended-release tablets; Kos) and those which can be easily identified by one skilled in the art which bind to and agonize the
  • bile acid reabsorption inhibitors such as BARI 1453, SC435, PHA384640, S8921, AZD7706, and the like;
  • PPAR ⁇ agonists such as GW 501516, and GW 590735, and those disclosed in US5859051 (acetophenols), WO03/024395, W097/28149, WO01/79197, WO02/14291, WO02/46154, WO02/46176, WO02/076957, WO03/016291, WO03/033493, WO99/20275 (quinoline phenyl compounds), WO99/38845 (aryl compounds), WO00/63161 (1,4-disubstiruted phenyl compounds), WO01/00579 (aryl compounds), WO01/12612, WO05/028453, & WO01/12187 (benzoic acid compounds), and WO97/31907 (substituted 4-hydroxy-phenylalconic acid compound);
  • sterol biosynthesis inhibitors such as DMP-565;
  • SREBP-I sterol regulating element binding protein-I
  • a sphingolipid such as ceramide, or neutral sphingomyelenase (N-SMase) or fragment thereof
  • N-SMase neutral sphingomyelenase
  • triglyceride synthesis inhibitors such as ceramide, or neutral sphingomyelenase (N-SMase) or fragment thereof
  • MTTP or MTP microsomal triglyceride transport (MTTP or MTP) inhibitors, such as inplitapide
  • HMG-CoA reductase gene expression inhibitors e.g., compounds that decrease HMG-CoA reductase expression by affecting (e.g., blocking) transcription or translation of HMG-CoA reductase into protein or compounds that may be biotransformed into compounds that have the aforementioned attributes by one or more enzymes in the cholesterol biosynthetic cascade or may lead to the accumulation of an isoprene metabolite that has the aforementioned activities (such regulation is readily determined by those skilled in the art according to standard assays (Methods of Enzymology, 110:9-19 1985))) such as those disclosed in US5041432 (certain 15- substituted lanosterol derivatives) and E. I.
  • Mercer (1993) Prog. Lip. Res. 32:357 oxygenated sterols that suppress the biosynthesis of HMG-CoA reductase); squalene epoxidase inhibitors such as NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten- 4-y- nyl )-3-[(3,3'-bithiophen-5-yl)methoxy]benzene-methanamine hydrochloride); low density lipoprotein (LDL) receptor inducers such as MD-700 (Taisho Pharmaceuticals, LY295427 (Eli Lilly), HOE-402 (an imidazolidinyl-pyrimidine derivative that directly stimulates LDL receptor activity, see Huettinger et al (1993) Arterioscler. Thromb. 13:1005); platelet aggregation inhibitors; 5-LO or FLAP inhibitors;
  • LDL low density lipoprotein
  • PPAR- ⁇ activators such as 2,4-dichlorophenoxyacetic acid, 2,4,5- trichlorophenoxyacetic acid, 2-methyl-4-chlorophenoxyacetic acid, 2-phenoxy-2- methylpropanoic acid ethyl ester, 2-(4-bromophenoxy)-2-methylpropanoic acid ethyl ester, 2-(4-iodophenoxy)-2-methylpropanoic acid ethyl ester, 2-(2-chlorophenoxy)-2- methylpropanoic acid ethyl ester, 2-(3-chlorophenoxy)-2-methylpropanoic acid ethyl ester, 2-(4-chlorophenoxy)-2-methylpropanoic acid ethyl ester, 2-(4-(4- chlorophenyl)phenoxy)-2-methylpropanoic acid ethyl ester, 2-(4-(4- chlorobenzoyl)phenoxy)-2-methylpropa
  • PPAR modulators including compounds that may have multiple functionality for activating various combinations of PP ARa, PPAR ⁇ , and PPAR ⁇
  • PPAR modulators such as those disclosed in US6008237, US6248781, US6166049, WO00/12491, WO00/218355, WO00/23415, WO00/23416, WO00/23425, WO00/23442, WO00/23445, WO00/23451, WO00/236331, WO00/236332, WO00/238553, WO00/50392, WO00/53563, WO00/63153, WO00/63190, WO00/63196, WO00/63209, WO00/78312, WO00/78313, WO01/04351, WO01/14349, WO01/14350, WO01/16120, WO01/17994, WO01/21181, WO01/21578, WO01/25181, WO01/25225
  • Factor Xa modulators such as those disclosed in WO03/047517, WO03/047520, WO03/048081; ileal bile acid transport ("IBAT”) inhibitors (or apical sodium co-dependent bile acid transport (“ASBT”) inhibitors) such as benzothiepines (including 1,2- benzothiazepines; 1,4- benzothiazepines; 1,5-benzothiazepines; 1,2, 5- benzothiadiazepines);
  • IBAT ileal bile acid transport
  • ASBT apical sodium co-dependent bile acid transport
  • IBAT inhibitors include but are not limited to compounds (e.g., those in claim 1 and the named examples) described in WO93/16055, WO94/18183, WO94/18184, WO96/05188, WO96/08484, WO96/16051, WO97/33882, WO98/38182, WO99/35135, WO98/40375, WO99/64409, WO99/64410, WO00/01687, WO00/47568, WO00/61568, DE 19825804, WO00/38725, WOOO/38726, WO00/38727 (including those compounds with a 2,3,4,5-tetrahydro-l-benzothiepine 1,1-dioxide structure), WO00/38728, WO00/38729, WO01/66533, WO02/50051, EP0864582 (e.g., (3R, 5R)-3- butyl-3-ethyl-l,l-di
  • ATP citrate lyase inhibitors including those disclosed in US5447954;
  • PPAR ⁇ activators such as disclosed in WOO 1/00603 (thiazole and oxazole derivates (e.g., CAS RN 317318-32-4), WO97/28149 (fluoro, chloro and thio phenoxy phenylacetic), US5093365 (non-1-oxidizable fatty acid analogues), and WO99/04815; and other dyslipidemic agents such as benfluorex, ⁇ -Benzylbutyraimde, colmestrone, detaxtran, dextran sulphate sodium, eicosopentanoic acid, eritadenine, furazabol, meglutol, ⁇ -Oryzanol, pantethine and derivatives thereof (as disclosed, for example, in US20050101565), pentaerythritol tetraacetate, ⁇ -phenylbutyramide, pirozadil, sultosilic acid, tiadenol
  • the compounds described herein can be used in therapeutic combination with one or more anti-diabetic agents, including but not limited to:
  • PPAR ⁇ agonists such as glitazones (e.g., WAY-120,744, AD 5075, balaglitazone, ciglitazone, darglitazone (CP-86325, Pfizer), englitazone (CP-68722, Pfizer), isaglitazone (MIT/J&J), MCC-555 (Mitsibishi disclosed in US5594016), pioglitazone (such as such as ActosTM pioglitazone; Takeda), rosiglitazone (AvandiaTM; Smith Kline Beecham), rosiglitazone maleate, troglitazone (Rezulin®, disclosed in US4572912), rivoglitazone (CS-OIl, Sankyo), GL-262570 (Glaxo Welcome), BRL49653 (disclosed in WO98/05331), CLX-0921, 5-BTZD, GW-0207, LG-100641,
  • biguanides such as metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride, such as GlucophageTM, Bristol-Myers Squibb); metformin hydrochloride with glyburide, such as GlucovanceTM, Bristol-Myers Squibb); buformin (Imidodicarbonimidic diamide, N-butyl-); etoformine (l-Butyl-2- ethylbiguanide, Schering A.
  • metformin hydrochloride N,N-dimethylimidodicarbonimidic diamide hydrochloride, such as GlucophageTM, Bristol-Myers Squibb
  • metformin hydrochloride with glyburide such as GlucovanceTM, Bristol-Myers Squibb
  • buformin Imidodicarbonimidic diamide, N-butyl-
  • etoformine l-Butyl-2- ethylbig
  • metformin salt forms including where the salt is chosen from the group of, acetate, benzoate, citrate, ftimarate, embonate, chlorophenoxyacetate, glycolate, palmoate, aspartate, methanesulphonate, maleate, parachlorophenoxyisobutyrate, formate, lactate, succinate, sulphate, tartrate, cyclohexanecarboxylate, hexanoate, octanoate, decanoate, hexadecanoate, octodecanoate, benzenesulphonate, trimethoxybenzoate, paratoluenesulphonate, adamantanecarboxylate, glycoxylate, glutarnate, pyrrolidonecarboxylate, naphthalenesulphonate, 1-glucosephosphate, nitrate, sulphite, dithionate and phosphate), and phenformin;
  • SGLT2 inhibtors including those disclosed in US6414126 and US6515117; an aP2 inhibitor such as disclosed in US6548529; insulin secreatagogues such as linogliride, A-4166, forskilin, dibutyrl cAMP, isobutylmethylxanthine (IBMX), and pharmaceutically acceptable salts and esters thereof; fatty acid oxidation inhibitors, such as clomoxir, and etomoxir, and pharmaceutically acceptable salts and esters thereof;
  • A2 antagonists such as midaglizole, isaglidole, deriglidole, idazoxan, earoxan, and fluparoxan, and pharmaceutically acceptable salts and esters thereof; insulin and related compounds (e.g., insulin mimetics) such as biota, LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente), Lys-Pro insulin, GLP-I (1-36) amide, GLP-I (73-7) (insulintropin, disclosed in US5614492), LY-315902 (Lilly), GLP-I (7-36)-NH2), AL-401 (Autoimmune), certain compositions as disclosed in US4579730, US4849405, US4963526, US5642868, US5763396, US5824638, US5843866, US6153632, US6191105, and WO 85/05029, and primate, rodent,
  • HumulinTM human insulin rDNA origin
  • HumulinTM human insulin rDNA origin
  • non-thiazolidinediones such as JT-501 and farglitazar (GW-2570/GI- 262579), and pharmaceutically acceptable salts and esters thereof;
  • PPAR ⁇ / ⁇ dual agonists such as AR-HO39242 (Aztrazeneca), GW-409544 (Glaxo- Wellcome), BVT-142, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297 (Kyorin Merck; 5-[(2,4-Dioxo thiazolidinyl)methyl] methoxy-N-[[4- (trifluoromethyl)phenyl] methyljbenzamide), L-796449, LR-90, MK-0767 (Merck/Kyorin/Banyu), SB 219994, muraglitazar (BMS), tesaglitzar (Astrazeneca), reglitazar (JTT-501) and those disclosed in WO99/16758, WO99/19313, WO99/20614, WO99/38850, WO00/23415, WO00/23417, WO00/23445, WO00/50414, WO01
  • VPAC2 receptor agonists VPAC2 receptor agonists
  • GLK modulators such as those disclosed in WO03/015774; retinoid modulators such as those disclosed in WO03/000249;
  • GSK 3 ⁇ /GSK 3 inhibitors such as 4-[2-(2-bromophenyl)-4-(4-fluorophenyl-lH- imidazol-5-yl]pyridine and those compounds disclosed in WO03/024447, WO03/037869, WO03/037877, WO03/037891, WO03/068773, EP1295884, EP1295885, and the like; glycogen phosphorylase (HGLPa) inhibitors such as CP-368,296, CP-316,819, BAYR3401, and compounds disclosed in WO01/94300, WO02/20530, WO03/037864, and pharmaceutically acceptable salts or esters thereof;
  • HGLPa glycogen phosphorylase
  • ATP consumption promotors such as those disclosed in WO03/007990;
  • TRB3 inhibitors vanilloid receptor ligands such as those disclosed in WO03/049702; hypoglycemic agents such as those disclosed in WO03/015781 and WO03/040114; glycogen synthase kinase 3 inhibitors such as those disclosed in WO03/035663 agents such as those disclosed in WO99/51225, US20030134890, WO01/24786, and WO03/059870; insulin-responsive DNA binding protein-1 (IRDBP-I) as disclosed in WO03/057827, and the like; adenosine A2 antagonists such as those disclosed in WO03/035639, WO03/035640, and the like;
  • PPAR ⁇ agonists such as GW 501516, GW 590735, and compounds disclosed in JP10237049 and WO02/14291; dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucine thiazolidide, NVP- DPP728A (l-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)- pyrrolidine, disclosed by Hughes et al, Biochemistry, 38(36), 11597-11603, 1999), P32/98, NVP-LAF-237, P3298, TSL225 (tryptophyl- 1,2,3, 4-tetrahydro-isoquinoline- 3-carboxylic acid, disclosed by Yamada et al, Bioorg.
  • DP-IV dipeptidyl peptidase IV
  • valine pyrrolidide TMC-2A/2B/2C
  • CD-26 inhibitors FE999011, P9310/K364, VIP 0177, DPP4, SDZ 274-444
  • 2-cyanopyrrolidides and 4- cyanopyrrolidides as disclosed by Ashworth et al, Bioorg. & Med. Chem. Lett., Vol. 6, No.
  • GLP-I agonists such as exendin-3 and exendin-4 (including the 39 aa peptide synthetic exendin-4 called Exenatide®), and compounds disclosed in US2003087821 and NZ 504256, and pharmaceutically acceptable salts and esters thereof;
  • peptides including amlintide and Symlin® (pramlintide acetate); and glycokinase activators such as those disclosed in US2002103199 (fused heteroaromatic compounds) and WO02/48106 (isoindolin-1-one-substituted propionamide compounds).
  • the compounds described herein can be used in therapeutic combination with one or more anti-hypertensive agents, including but not limited to:
  • thiazides e.g., chlorthalidone, cyclothiazide (CAS RN 2259-96-3), chlorothiazide (CAS RN 72956-09-3, which maybe prepared as disclosed in US2809194
  • dichlorophenamide hydroflumethiazide, indapamide, polythiazide, bendroflumethazide, methyclothazide, polythiazide, trichlormethazide, chlorthalidone, indapamide, metolazone, quinethazone, althiazide (CAS RN 5588-16-9, which may be prepared as disclosed in British Patent No.
  • benzthiazide (CAS RN 91- 33-8, which maybe prepared as disclosed in US3108097), buthiazide (which maybe prepared as disclosed in British Patent Nos. 861,367), and hydrochlorothiazide), loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, and torasemide), potassium sparing agents (e.g., amiloride, and triamterene (CAS Number 396-01-0)), and aldosterone antagonists (e.g., spironolactone (CAS Number 52-01-7), epirenone, and the like); ⁇ -adrenergic blockers such as Amiodarone (Cordarone, Pacerone), bunolol hydrochloride (CAS RN 31969-05-8, Parke-Davis), acebutolol ( ⁇ N-[3-Acetyl-4-[2- hydroxy-3-[(l methylethyl)a
  • Atenolol e.g., Tenormin®, AstraZeneca
  • carteolol hydrochloride e.g., Cartrol® Filmtab®, Abbott
  • Celiprolol hydrochloride CAS RN 57470-78-7, also see in US4034009
  • cetamolol hydrochloride CAS RN 77590-95-5, see also US4059622
  • labetalol hydrochloride e.g., Normodyne®, Schering
  • esmolol hydrochloride e.g., Brevibloc®,Baxter
  • levobetaxolol hydrochloride e.g., BetaxonTM Ophthalmic Suspension, Alcon
  • levobunolol hydrochloride e.g., Betagan® Liquifilm® with C CAP® Compliance Cap, Allergan
  • nadolol e.g., Nadolol, Corgard,
  • dexpropranolol hydrochloride (2-Propanol, l-[l-methylethy)- amino]-3-(l-naphthalenyloxy)-hydrochloride (CAS RN 13071-11-9), diacetolol hydrochloride (Acetamide, N-[3-acetyl-4-[2-hydroxy-3-[(l-methyl- ethyl)amino]propoxy] [phenyl]-, monohydrochloride CAS RN 69796-04-9), dilevalol hydrochloride (Benzamide, 2-hydroxy-5-[l-hydroxy-2-[l-methyl-3- phenylpropyl)amino]ethyl]-, monohydrochloride, CAS RN 75659-08-4), exaprolol hydrochloride (2-Propanol, l-(2-cyclohexylphenoxy)-3-[(l-methylethyl)amino]-
  • perindopril erbumine such as 2S,3aS,7aS-l-[(S)-N-[(S)-l-Carboxybutyl]alanyl]hexahydro-2- indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine (1:1), e.g., Aceon®, Solvay
  • perindopril Servier, disclosed in Eur. J. clin. Pharmacol. 31:519 (1987)
  • quanipril disclosed in US4344949
  • spirapril Schering, disclosed in Acta. Pharmacol. Toxicol. 59 (Supp.
  • the compounds described herein can be used in therapeutic combination with one or more anti-obesity agents, including but not limited to:
  • HSD-I 11-beta hydroxy steroid dehydrogenase type 1 inhibitors, such as BVT 3498, BVT 2733, 3-(l-adamantyl)-4-ethyl-5-(ethylthio)- 4H-l,2,4-triazole, 3-(l- adamantyl)-5-(3,4,5-trimethoxyphenyl)-4-methyl-4H-l,2,4-triazole, 3- adamantanyl- 4,5,6,7,8,9,10,1 l,12,3a-decahydro-l,2,4-triazolo[4,3-a][l ljannulene, and those compounds disclosed in WO01/90091, WO01/90090, WO01/90092 and WO02/072084;
  • 5HT antagonists such as those in WO03/037871, WO03/037887, and the like;
  • 5HTIa modulators such as carbidopa, benserazide and those disclosed in US6207699, WO03/031439, and the like; 5HT2c (serotonin receptor 2c) agonists, such as BVT933, DPCA37215, JK264, PNU 22394, WAY161503, R-1065, SB 243213 (Glaxo Smith Kline) and YM 348 and those disclosed in US3914250, WO00/77010, WO02/36596, WO02/48124, WO02/10169, WO01/66548, WO02/44152, WO02/51844, WO02/40456, and WO02/40457;
  • 5HT6 receptor modulators such as those in WO03/030901, WO03/035061, WO03/039547, and the like; acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001) and Japanese Patent Application No. JP 2000256190; anorectic bicyclic compounds such as 1426 (Aventis) and 1954 (Aventis), and the compounds disclosed in WO00/18749, WO01/32638, WO01/62746, WO01/62747, and WO03/015769;
  • CB 1 (cannabinoid-1 receptor) antagonist/inverse agonists such as rimonabant (Acomplia; Sanofi), SR-147778 (Sanofi), SR-141716 (Sanofi), BAY 65-2520 (Bayer), and SLV 319 (Solvay), and those disclosed in patent publications US4973587, US5013837, US5081122, US5112820, US5292736, US5532237, US5624941, US6028084, US6509367, US6509367, US20060069080 (specifically including those referenced or disclosed by formulae in paragraphs 28-168), WO96/33159, WO97/29079, WO98/31227, WO98/33765, WO98/37061, WO98/41519, WO98/43635, WO98/43636, WO99/02499, WO00/10967, WOOO/10968, WO01/09120, WO01/588
  • CCK-A cholecystokinin-A agonists, such as AR-R 15849, GI 181771 (GSK), JMV- 180, A-71378, A-71623 and SR146131 (Sanofi), and those described in US5739106;
  • CNTF Central neurotrophic factors
  • GI-181771 Gaxo-SmithKline
  • SR146131 Sanofi Synthelabo
  • butabindide PD170,292, and PD 149164 (Pfizer)
  • CNTF derivatives such as Axokine® (Regeneron), and those disclosed in WO94/09134, WO98/22128, and WO99/43813; dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucine thiazolidide, valine pyrrolidide, NVP-DPP728, LAP237, P93/01, P 3298, TSL 225 (tryptophyl-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid; disclosed by Yamada et al, Bioorg. & Med. Chem. Lett.
  • DP-IV dipeptidyl peptidase IV
  • WO99/38501 WO99/46272, WO99/67279 (Probiodrug), WO99/67278 (Probiodrug), WO99/61431 (Probiodrug), WO02/083128, WO03/000180, WO03/000181, WO03/000250, WO03/002530, WO03/002531, WO03/002553, WO03/002593, WO03/004498, WO03/004496/WO03/017936, WO03/024942, WO03/024965, WO03/033524, WO03/037327 and EP1258476; growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, MK-0677 (Merck), SM-130686, CP-424391 (Pfizer), LY 444,711 (Eli Lilly), L-692,429 and L-163,255
  • H3 (histamine H3) antagonist/inverse agonists such as thioperamide, 3-(lH-imidazol- 4-yl)propyl N-(4-pentenyl)carbamate), clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and A331440, O-[3-(lH-imidazol-4-yl)propanol]carbamates (Kiec-Kononowicz, K. et al., Pharmazie, 55:349-55 (2000)), piperidine-containing histamine H3-receptor antagonists (Lazewska, D.
  • leptin derivatives such as those disclosed in US5552524, US5552523, US5552522, US5521283, WO96/23513, WO96/23514, WO96/23515, WO96/23516, WO96/23517, WO96/23518, WO96/23519, and WO96/23520; leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); lipase inhibitors, such as tetrahydrolipstatin (orlistat/Xenical®), Triton WRl 339, RHC80267, lipstatin, teasaponin, diethylumbelliferyl phosphate, FL-386, WAY- 121898
  • leptin derivatives such as those disclosed in US5552524, US5552523, US5552522, US5521283, WO96/23513, WO96/23514
  • Mc4r (melanocortin 4 receptor) agonists such as CHIR86036 (Chiron), ME-10142, ME-10145, and HS-131 (Melacure), and those disclosed in PCT publication Nos. WO99/64002, WO00/74679, WO01/991752, WO01/25192, WO01/52880, WO01/74844, WO01/70708, WO01/70337, WO01/91752, WO02/059095, WO02/059107, WO02/059108, WO02/059117, WO02/06276, WO02/12166, WO02/11715, WO02/12178, WO02/15909, WO02/38544, WO02/068387, WO02/068388, WO02/067869, WO02/081430, WO03/06604, WO03/007949, WO03/009847, WO03/009850,
  • Mc5r (melanocortin 5 receptor) modulators such as those disclosed in WO97/19952, WOOO/15826, WO00/15790, US20030092041; melanin-concentrating hormone 1 receptor (MCHR) antagonists, such as T-226296 (Takeda), SB 568849, SNP-7941 (Synaptic), and those disclosed in patent publications WO01/21169, WO01/82925, WO01/87834, WO02/051809, WO02/06245, WO02/076929, WO02/076947, WO02/04433, WO02/51809, WO02/083134, WO02/094799, WO03/004027, WO03/13574, WO03/15769, WO03/028641, WO03/035624, WO03/033476, WO03/033480, JP13226269, and JP1437059; mGluR5 modulators such as those
  • NE (norepinephrine) transport inhibitors such as GW 320659, despiramine, talsupram, and nomifensine;
  • NPY 1 antagonists such as BDBP3226, J-115814, BIBO 3304, LY-357897, CP- 671906, GI-264879A, and those disclosed in US6001836, WO96/14307, WO01/23387, WO99/51600, WO01/85690, WO01/85098, WO01/85173, and WO01/89528;
  • NPY5 neuropeptide Y Y5
  • antagonists such as 152,804, GW-569180A, GW- 594884A, GW-587081X, GW-548118X, FR235208, FR226928, FR240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, LY-366377, PD- 160170, SR- 120562A, SR-120819A, JCF-104, and H409/22 and those compounds disclosed in patent publications US6140354, US6191160, US6218408, US6258837, US6313298, US6326375, US6329395, US6335345, US6337332, US6329395, US6340683, EP01010691, EP-01044970, WO97/19682, WO97/20820, WO97/20821, WO97/20822, WO97/20823,
  • opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone, naloxone, and naltrexone and those disclosed in WO00/21509
  • opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone, naloxone, and naltrexone and those disclosed in WO00/21509
  • exin antagonists such as SB-334867-A and those disclosed in patent publications WO01/96302, WO01/68609, WO02/44172, WO02/51232, WO02/51838, WO02/089800, WO02/090355, WO03/023561, WO03/032991, and WO03/037847;
  • PDE inhibitors e.g., compounds which slow the degradation of cyclic AMP (cAMP) and/or cyclic GMP (cGMP) by inhibition of the phosphodiesterases, which can lead to a relative increase in the intracellular concentration of cAMP and cGMP; possible PDE inhibitors are primarily those substances which are to be numbered among the class consisting of the PDE3 inhibitors, the class consisting of the PDE4 inhibitors and/or the class consisting of the PDE5 inhibitors, in particular those substances which can be designated as mixed types of PDE3/4 inhibitors or as mixed types of PDE3/4/5 inhibitors) such as those disclosed in patent publications DE1470341, DE2108438, DE2123328, DE2305339, DE2305575, DE2315801, DE2402908, DE2413935, DE2451417, DE2459090, DE2646469, DE2727481, DE2825048, DE2837161, DE2845220, DE2847621, DE2934747, DE
  • Neuropeptide Y2 (NP Y2) agonists include but are not limited to: peptide YY and fragments and variants thereof (e.g., YY3-36 (PYY3-36 ) (N. Engl. J. Med. 349:941, 2003; CAS RN.
  • PYY agonists such as those disclosed in WO03/026591, WO03/057235, and WO03/027637; serotonin reuptake inhibitors, such as, paroxetine, fluoxetine (Prozac®), fluvoxamine, sertraline, citalopram, and imipramine, and those disclosed in US6162805, US6365633, WO03/00663, WO01/27060, and WO01/162341; thyroid hormone ⁇ agonists, such as QRX-431 (QuatRx), GC-24 (described in US 20040110154), KB-2611 (KaroBioBMS), and those disclosed in WO02/15845, WO97/21993, WO99/00353, GB98/284425, U.S. Provisional Application No. 60/183,223, and Japanese Patent Application No. JP 2000256190;
  • serotonin reuptake inhibitors such as, paroxetine, fluoxetine (Prozac®), flu
  • UCP-I uncoupling protein- 1
  • 2, or 3 activators such as phytanic acid, 4-[(E)-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-l-propenyl]benzoic acid (TTNPB), retinoic acid, and those disclosed in WO99/00123; ⁇ 3 (beta adrenergic receptor 3) agonists, such as AJ9677/TAK677 (Dainippon/Takeda), L750355 (Merck), CP331648 (Pfizer), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353, Trecadrine, Zeneca D7114, N-5984 (Nisshin Kyorin), LY-377604 (Lilly), SR 59119A,
  • the compounds described herein can be used in therapeutic combination with one or more agents used to treat autoimmune disorders including, but not limited to: (a) disease modifying antirheumatic drugs, including methotrexate, gold salts, D- penicillamine, hydroxychloroquine, auranofm, sulfsalazine; (b) nonsteroidal anitinflammatory drugs, including indomethacin, naproxen, diclofenac, ibuprofen, aspirin and aspirin analogs, acetaminophen; (c) COX-2 selective inhibitors, including celecoxib, rofecoxib, etoricoxib, valdecoxib, lumiracoxib; (d) COX-I inhibitors; (e) immunosuppressives, including calcineurin inhibitors such as cyclosporine and FK506; p70 kinase inhibitors such as sirolimus and rapamycin; inosine monophosphate dehydr
  • the compounds described herein can be used in therapeutic combination with one or more agents used to treat demylenation and its associated conditions including, but not limited to: beta-interferon (such as Avonex®,Biogen, Inc. and Betaseron®, Berlex Laboratories), which can decrease the frequency and occurrence of flare-ups and slow the progression to disability, glatiramer acetate (such as Copaxone®, Teva Neuroscience, Inc.), which can reduce the frequency of relapses, and/or administration of corticosteroids, such as prednisone (available from Roxane), to relieve acute symptoms.
  • beta-interferon such as Avonex®,Biogen, Inc. and Betaseron®, Berlex Laboratories
  • glatiramer acetate such as Copaxone®, Teva Neuroscience, Inc.
  • corticosteroids such as prednisone (available from Roxane)
  • the compounds described herein can be used in therapeutic combination with one or more agents used to treat Alzheimer's disease including, but not limited to: cholinesterase inhibitors (such as donepezil hydrochloride (such as Aricept® (Pfizer)), rivastigmine tartrate (such as Exelon (Novartis)), tacrine (such as Cognex® (Parke-Davis)), galanthamine and derivatives thereof (Janssen), metrifonate (Bayer Corp.), epigalanthamine, norgalanthamine, fasciculin, metrifonate, heptyl- physostigmine, norpyridostigmine, nomeostigmine, ipidacrine (Nikken Chemicals Co.
  • cholinesterase inhibitors such as donepezil hydrochloride (such as Aricept® (Pfizer)
  • rivastigmine tartrate such as Exelon (Novartis)
  • tacrine such as Cognex® (Parke
  • TAK-147 & T-82 (SS Pharmaceutical Co. Ltd.), methanesulfonyl fluoride, CHF-2819, phenserine, physostigmine (Forest Laboratories, Inc.), huperzine, cymserine (Anonyx Inc.), tolserine (National Institutes of Health), ER- 127528 (Eisai Co.
  • muscarinic receptor agonists such as aceclide, pilocarpine, oxotremorine, arecaidine, 5-methylfurmethiodide, cevimeline, PD- 151832 (Pfizer Inc.), YM-796 (Yamanouchi Pharmaceutical Inc.), P-58 (Phytopharm pic) and combinations thereof
  • M2 muscarinic receptor antagonists such as minaprine, montirelin (Grunenthal GmbH), T-588 (Toyama Chemical Co.
  • choline uptake stimulators such as MKC-231 (Mitsubishi-Tokyo Pharmaceuticals Inc)
  • nicotinic cholinergic receptor agonists such as altinicline, (SIBIA Neurosciences Inc.), SEB- 1553A, ABT-089 (disclosed in US5278176, Abbot), nicotine patch, GRS-21, TC- 2403 and combinations thereof
  • anti-A ⁇ vaccines such as AN-1792
  • ⁇ -secretase inhibitors or ⁇ -secretase inhibitors such as Asn 670 ,Sta 671 ,Val 672 -Amyloid ⁇ /A4 Protein Precursor ⁇ (662-675) (catalog no.
  • H-4948; Bachem presenilin-1, presenilin-2 and derivatives thereof comprising one or more conservative substitutions
  • amyloid aggregation inhibitors such as reumacon (Conpharm AB), NC-531 (Neurochem hie), PPI-1019 (Praecis Pharmaceuticals Inc.) and combinations thereof
  • amyloid precursor protein antisense oligonucleotides such as NS-2330
  • human stem cells such as NS-2330
  • nootropic agents such as oxiracetam (ISF Societa Per Azioni), pramiracetam (Warner Lambert), idebenone (Takeda Chemical Inds.
  • SL-25.1188, Ro-41-1049 (Roche Holding AG), and combinations thereof), estrogens and estrogen receptor ligands, NMDA receptor antagonists (such as ketamine, phencyclidine, dizocilpine, tiletamine, dextromethorphan, amantadine, methadone, dextropropoxyphene, ketobemidone, memantine, ipenoxazone (Nippon Chemiphar Co. Ltd.
  • Jun N-terminal kinase (JNK) inhibitors Jun N-terminal kinase (JNK) inhibitors, copper/zinc chelators (such as clioquinol (PN Gerolymatos SA)), 5-HT1 a receptor agonists (such as AP-159 (Asahi Kasei Corp)), NGF stimulators (such as xaliprodene (Sanofi-Synthelabo)), neuroprotective agents (such as citicholine, GS-1590 (Leo Pharmaceutical Products Ltd.) A/S, CPI-1189 (Centaur Pharmaceuticals Inc.), SR-57667 (Sanofi-Synthelabo) and combinations thereof), H 3 histamine receptor antagonists (such as GT-2016 and GT-2331 (both available from Gliatech, Inc.) and combinations thereof), calpain inhibitors, poly ADP ribose polymerase inhibitors, prolylendopeptidase inhibitors (such as ONO- 1603 (
  • ⁇ modulators such as neurocalc (Apollo Biopharmaceuticals Inc)), corticortropin releasing factor receptor antagonists (such as NBI-113 (Neurocrine Biosciences, Inc)), corticortropin releasing factor binding protein inhibitors, GABA modulators (such as NGD 97-1 (Neurogen Corp)), GABA-A receptor antagonists, GABA-B receptor antagonists, neuroimmunophilin ligands, sigma receptor ligands (such as igmesine (Pfizer)), galanin receptor ligands, imidazoline/alpha adrenergic receptor antagonists (such as efaroxan (Reckitt & Colman PLC)), vasoactive intestinal peptide receptor agonists (such as stearyl-NIe-VTP), benzodiazepine receptor inverse agonists (such as S-8510 (Shionogi & Co.
  • GABA modulators such as NGD 97-1 (Neurogen Corp)
  • cannabinoid receptor agonists such as dronabinol (Unimed Pharmaceuticals Inc)), thyrotropin releasing hormone receptor agonists (such as taltireline (Tanabe Seiyalcu Co. Ltd) and protirelin (Talceda Chemical Inds., Inc.)
  • protein kinase C inhibitors such as 5-HT3 receptor antagonists (such as GYKI-46903), prostaglandin receptor antagonists, topoisomerase II inhibitors (such as iododoxorubicin (Pharmacia & Upjohn AB)), steroid receptor ligand (such as GL- 701 (Prestara)), nitric oxide modulators, RAGE inhibitors (such as ALT-711 (Alteon Inc)), dopamine receptor agonists (such as speramine), statine compounds disclosed in US20050090449, corticosteroid receptor antagonist (such as anticort) and combinations thereof.
  • the compounds described herein can be used in therapeutic combination with one or more blood modifiers, i.e., agents capable of altering the number of platelets per a given volume of blood, inhibiting platelet function, including but not limited to platelet adhesion, aggregation or factor release, or reducing platelet count in patients with abnormally high levels in certain hematological malignancies to levels approximating normal levels capable of impacting negatively upon the formation of blood clots, and decreasing blood viscosity.
  • blood modifiers i.e., agents capable of altering the number of platelets per a given volume of blood, inhibiting platelet function, including but not limited to platelet adhesion, aggregation or factor release, or reducing platelet count in patients with abnormally high levels in certain hematological malignancies to levels approximating normal levels capable of impacting negatively upon the formation of blood clots, and decreasing blood viscosity.
  • Blood modifiers useful in the present invention include but are not limited to anti-coagulants, antithrombotic agents, fibrinogen receptor antagonists, platelet inhibitors, platelet aggregation inhibitors, lipoprotein-associated coagulation inhibitor, hemorrheologic agents, Factor Vila inhibitors, Factor Xa inhibitors, and combinations thereof. Tests showing the efficacy of the therapy and the rationale for the combination therapy with blood modifiers are described, for example, in US20020147184. [00133] Anti-coagulant agents are agents which inhibit the coagulation pathway by impacting negatively upon the production, deposition, cleavage and/or activation of factors essential in the formation of a blood clot.
  • Useful anti-coagulant agents include but are not limited to argatroban (2-Piperidinecarboxylic acid, l-[(2S)-5- [(aminoiminomethyl)amino]-l-oxo-2-[[(l,2,3,4-tetrahydro-3-methyl-8- quinolinyl)sulfonyl]amino]pentyl]4-methyl-, CAS RN 74863-84-6), bivalirudin (CAS RN 128270-60-0), dalteparin sodium (heparin) e.g., Fragmin® Injection (Pharmacia & Upjohn), desirudin (Hirudin (Hirudo medicinalis isoform HVl), 63-desulfo CAS RN 120993-53-5), dicumarol (2H-l-Benzopyran-2-one, 3,3'-methylenebis[4-hydroxy- CAS RN 66-76-2 e.g., Mebaral® (Sanofi-S
  • Anti-thrombotic agents are agents which prevent the formation of a blood thrombus.
  • a thrombus is an aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation.
  • anti-thrombotic agents include, but are not limited to: melagatran; ximelagatran (Exanta®); anagrelide hydrochloride (6,7- dichloro-l,5-dihydroimidazo[2,l-b]quinazolin-2(3H)-one monohydrochloride monohydrate) e.g., Agrylin® (Shire US)); Tinzaparin sodium as described above; cilostazol (6-[4-(l-cyclohexyl-lH -tetrazol-5-yl)butoxy]-3,4-dihydro-2(l H )- quinolinone, CAS-73963-72-1, e.g., Pletal® (Pharmacia & Upjohn); Dalteparin sodium (as described above); danaparoid sodium, e.g., Orgaran® Injection (Organon); compounds disclosed in WO99/45913; Abciximab is the (Fab fragment of
  • Abciximab binds to the glycoprotein (GP) Ilb/IIIa (( ⁇ ) ⁇ b ( ⁇ ) 3 ) receptor of human platelets and inhibits platelet aggregation.
  • Abciximab also binds to the vitronectin (( ⁇ )v ( ⁇ ) 3 ) receptor found on platelets and vessel wall endothelial and smooth muscle cells, e.g., Abciximab, Reopro® (LiIy)); ifetroban (Benzenepropanoic acid, 2-[[(lS,2R,3S,4R)-3-[4-[(pentylamino)carbonyi]- 2-oxazolyl]-7 oxabicyclo[2.2.1]hept-2-yl]methyl]-CAS RN 143443-90-7, disclosed in US5100889); Bivalirudin as described above; Cilostazol as described above; efegatran sulfate (L-Prolinamide, N-methyl-D
  • lotrafiban hydrochloride (1H-1,4- Benzodiazepine-2-acetic acid, 7-([4,4'-bipiperidm]-l-ylcarbonyl)-2,3,4,5-tetrahydro4- methyl-3-oxo-, monohydrochloride, (2S)-)CAS RN 179599-82-7
  • Fibrinogen receptor antagonists are those agents which inhibit the common pathway of platelet aggregation.
  • Suitable fibrinogen receptor antagonists include but are not limited toroxifiban acetate as described above; lotrafiban hydrochloride as described above, sibrafiban as described above, monoclonal antibody 7E3 (Fab fragment of the chimeric human-murine monoclonal antibody 7E3. binds to the glycoprotein (GP) Ilb/IIIa (( ⁇ )i b ( ⁇ ) 3 ) receptor of human platelets and inhibits platelet aggregation); orbofiban, (beta.
  • Platelet inhibitors are those agents that impair the ability of mature platelets to perform their normal physiological roles (i.e., their normal function). Platelets are normally involved in a number of physiological processes such as adhesion, for example, to cellular and non-cellular entities, aggregation, for example, for the purpose of forming a blood clot, and release of factors such as growth factors (e.g., platelet-derived growth factor (PDGF)) and platelet granular components.
  • growth factors e.g., platelet-derived growth factor (PDGF)
  • PDGF platelet-derived growth factor
  • Suitable platelet inhibitors include, but are not limited to CS-747 (Eli Lilly); eptifibatide (Integrilin®); clopidogrel bisulfate, (Thieno[3,2-c]pyridine-5(4H)-acetic acid, ⁇ -(2- chlorophenyl)-6,7-diliydro-, methyl ester, ( ⁇ S)-, sulfate (1:1), e.g., Plavix® (Sanofi- Synthelabo)); indomethacin, such as Indocin® IV.
  • CS-747 Eli Lilly
  • eptifibatide Integrilin®
  • clopidogrel bisulfate (Thieno[3,2-c]pyridine-5(4H)-acetic acid, ⁇ -(2- chlorophenyl)-6,7-diliydro-, methyl ester, ( ⁇ S)-, sulfate (1:1)
  • Platelet aggregation inhibitors as used herein refer to those compounds which reduce or halt the ability of platelets to associate physically with themselves or with other cellular and non-cellular components, thereby precluding the ability of a platelet to form a thrombus.
  • Suitable platelet aggregation inhibitors include but are not limited to beraprost, (lH-Cyclopenta[b]benzofuran-5-butanoic acid, 2,3,3a,8b- tetrahydro-2-hydroxy-l-(3-hydroxy4-methyl-l-octen-6-ynyl)-, CAS RN 88430-50-6); acadesine, (lH-Imidazole-4-carboxamide, 5-amino-l ⁇ -D-ribofuranosyl-, CAS RN 2627-69-2);beraprost sodium, (lH-Cyclopenta[b]benzofuran-5-butanoic acid, 2,3,3a,8b-tetrahydro-2-hydroxy-l-(3-hydroxy4-methyl-l-octen-6-ynyl)-, monosodium salt, CAS RN 88475-69-8); ciprostene calcium, (Pentanoic acid, 5-[(
  • Hemorrheologic agent as used herein describes those compounds which improve the flow properties of blood by decreasing its viscosity.
  • a suitable hemorrheologic agent of the present invention is pentoxifylline (lH-Purine-2,6-dione, 3,7-dihydro-3,7-dimethyl-l-(5-oxohexyl)-(9Cl) (CA INDEX NAME) Theobromine, l-(5-oxohexyl)- ,CAS RN 6493-05-6 e.g., Trentali® (Aventis)).
  • Pentoxifylline and its metabolites improve the flow properties of blood by decreasing its viscosity. In patients with chronic peripheral arterial disease, this increases blood flow to the affected microcirculation and enhances tissue oxygenation. The precise mode of action of pentoxifylline and the sequence of events leading to clinical improvement are still to be defined. Pentoxifylline administration has been shown to produce dose-related hemorrheologic effects, lowering blood viscosity, and improving erythrocyte flexibility. Leukocyte properties of hemorrheologic importance have been modified in animal and in vitro human studies. Pentoxifylline has been shown to increase leukocyte deformability and to inhibit neutrophil adhesion and activation. Tissue oxygen levels have been shown to be significantly increased by therapeutic doses of pentoxifylline in patients with peripheral arterial disease.
  • LACI Lipoprotein-associated coagulation inhibitor
  • tissue factor inhibitor is a natural inhibitor of thromboplastin (tissue factor) induced coagulation (US5110730 and US5106833 described tissue factor and are hereby incorporated by reference their entireties).
  • LACI is a protease inhibitor and has 3 Kunitz domains, two of which are known to interact with factors VII and Xa respectively, while the function of the third domain is unknown.
  • Kunitz domains two of which are known to interact with factors VII and Xa respectively, while the function of the third domain is unknown.
  • Many of the structural features of LACI can be deduced because of its homology with other well studies proteases.
  • LACI is not an enzyme, so it probably inhibits its protease target in a stoichiometric manner; namely, one of the domains of LACI inhibits one protease molecule (see US606374).
  • Factor Vila Inhibitors as used herein are those agents which inhibit activated Factor Vila from acting to contribute to the formation of a fibrin clot.
  • Suitable Factor Vila Inhibitors include but are not limited to, 4H-31-benzoxazin-4-ones, 4H-3,1- benzoxazin-4-thiones, quinazolin-4-thiones, benzothiazin-4-ones described in US6180625, imidazolyl-boronic acid-derived peptide analogues as described in US5639739, TFPI-derived peptides described in US6180625.
  • Additional suitable Factor Vila Inhibitors include but are not limited to Naphthalene-2-sulfonic acid ⁇ l-[3-(aminoimmomethyl)-benzyl]-2-oxo-pyrrolidm-3- (S)-yl ⁇ amide trifluoroacetate, dibenzofuran-2-sulfoic acid ⁇ l-[3-(aminomethyl)- benzyl]-5-oxo-pyrrolidin-3-yl ⁇ -amide, tolulene-4-sulfonic acid ⁇ l-[3- (aminoiminomethyl)-benzyl]-2-oxo-pyrrolidin-3-(S)-yl ⁇ -aniide tribluoroacetate, 3,4- dihydro- lH-isoquinoline-2-sulfonic acid ⁇ l-[3-(aminoimmomethyi)-benzyl]-2-oxo- pyrrolin-3-(S)-yl ⁇ -amide triblu
  • Factor Xa inhibitors as used herein are those agents which inhibit activated Factor X from acting to contribute to the formation of a fibrin clot.
  • Suitable agents for use in the present invention as Factor Xa inhibitors include but are not limited to disubstituted pyrazolines, disubstituted triazo lines as described in US6191159, lipoprotein-associated coagulation inhibitor (LACI) (as described above), low molecular weight heparins described as below, heparinoids described as below, benzimidazolines, benzoxazolinones, bensopiperazinones, indanones, as described in U.S. Pat. No.
  • Peptidic factor Xa inhibitors such as the leech-derived, 119-amino acid protein antistasin and the soft tick derived protein TAP (tick anticoagulant peptide) accelerate clot lysis and prevented reocclusion when given as adjuncts to thrombolysis (Melloff et al., Circulation Research 70:1152-1160 (1992); Sitko et al., Circulation 85:805-815 (1992)).
  • TAP tick anticoagulant peptide
  • the peptide ecotin is another selective, reversible, tight-binding inhibitor of factor Xa that exhibits protein anticoagulant activity (Seymour et al., Biochemistry 33:3949-3959 (1994); WO94/20535, Sep. 14, 1994).
  • Ixodidae, argasin and ancylostomatin are other representative peptidic factor Xa inhibitors isolated from animals that feed on blood (Markwardt, Thrombosis and Hemostasis 72: 477-479 (1994).
  • peptidic Factor Xa inhibitors which may be used in the present invention are listed below with their CAS RN (Chemical abstract services registry number). These include Proteinase inhibitor, antistasin, CAS RN 110119-38-5; tick anticoagulant peptide, (Proteinase inhibitor, TAP) CAS RN 129737-17-3; ecotin, (Proteinase inhibitor, ecotin) CAS RN 87928-05; argasin, CAS RN 53092-89-0 ;ancylostomatin , CAS RN 11011-09-9; Lcodidae (as described in Markwardt, 1994).
  • Low molecular weight heparins refer to agents derived from heparins which reduces the incidence of bleeding when compared with standard heparin.
  • Heparins are glycosaminoglycans. MW range from 2000-10000. They may be produced from porcine intestinal mucosa and except for nadroparan, are all sodium salts.
  • a suitable heparinoid of the present invention includes but is not limited to enoxaparin, nardroparin, dalteparin, certroparin, parnaparin, reviparin, tinzaparin and combinations thereof.
  • Heparinoid is a modified form of heparin which reduces the incidence of bleeding when compared with standard heparin.
  • a suitable heparinoid of the present invention includes but is not limited to Danaparoid CAS RN 308068-55-5, (e.g., Orgaran Injection Organon).
  • the compounds described herein can be used in therapeutic combination with one or more hormone replacement agents/compositions including, but not limited to androgens, estrogens, progestins, their pharmaceutically acceptable salts and derivatives thereof.
  • hormone replacement agents/compositions including, but not limited to androgens, estrogens, progestins, their pharmaceutically acceptable salts and derivatives thereof.
  • androgen and estrogen combinations include but are not limited to the combination of esterified estrogens (sodium estrone sulfate and sodium equilin sulfate) and methyltestosterone (17-hydroxy-17-methyl-, (17B)- androst-4-en-3-one) available from Solvay Pharmaceuticals, Inc., Marietta, Ga., under the tradename Estratest.
  • estrogens and estrogen combinations include but are not limited to: (a) the blend of nine (9) synthetic estrogenic substances including sodium estrone sulfate, sodium equilin sulfate, sodium 17 ⁇ -dihydroequilin sulfate, sodium 17 ⁇ -estradiol sulfate, sodium 17 ⁇ -dihydroequilin sulfate, sodium 17 ⁇ -dihydroequilenin sulfate, sodium 17 ⁇ -dihydroequilenin sulfate, sodium equilenin sulfate and sodium 17 ⁇ - estradiol sulfate; available from Duramed Pharmaceuticals, Inc., Cincinnati, Ohio, under the tradename Cenestin; (b) ethinyl estradiol (19-nor- 17 ⁇ -pregna-l,3,5(10)-trien-20-yne-3,17-diol; available by Schering Plough Corporation, Kenilworth, NJ., under the tradename Est
  • progestin and estrogen combinations include but are not limited to: (a) the combination of estradiol (estra-1,3,5 (10)-triene-3,17 ⁇ -diol hemihydrate) and norethindrone (17 ⁇ - acetoxy-19-nor-17 ⁇ -pregn-4-en-20-yn-3-one); which is available from Pharmacia & Upjohn, Peapack, NJ., under the tradename Activella; (b) the combination of levonorgestrel (d(-)- 13 ⁇ -ethyl- 17 ⁇ -ethinyl- 17 ⁇ -hydroxygon-4-en-3 - one) and ethinyl estradial; available from Wyeth-Ayerst under the tradename Alesse, from Watson Laboratories, Inc., Corona, Calif, under the tradenames Levora and Trivora, Monarch Pharmaceuticals, under the tradename Nordette, and from Wyeth- Ayerst under the tradename Triphasil; (c) the combination of
  • progestins examples include norethindrone; available from ESI Lederle, Inc., Philadelphia, Pa., under the tradename Aygestin, from Ortho-McNeil under the tradename Micronor, and from Watson under the tradename Nor-QD; norgestrel; available from Wyeth-Ayerst under the tradename Ovrette; micronized progesterone (pregn-4-ene-3, 20-dione); available from Solvay under the tradename Prometrium; and medroxyprogesterone acetate; available from Pharmacia & Upjohn under the tradename Pro vera. Tests showing the efficacy of the therapy and the rationale for the combination therapy with hormone replacement agents/compositions are presented in US20030119796.
  • the compounds described herein can be used in therapeutic combination with one or more chemotherapeutic agents including but not limited to hydrophobic, and heterocyclic cancer chemotherapeutic agents such as adriamycin (doxorubicin), phosphates, colcemid, etoposide, paclitaxel, bisantene, vincristine, and vinblastine.
  • chemotherapeutic agents including but not limited to hydrophobic, and heterocyclic cancer chemotherapeutic agents such as adriamycin (doxorubicin), phosphates, colcemid, etoposide, paclitaxel, bisantene, vincristine, and vinblastine.
  • Tests showing the efficacy of the therapy and the rationale for the combination therapy with chemotherapeutic agents are described, for example, in WO05/030225.
  • the compounds described herein can be used in therapeutic combination with a the peptide which mitigates one or more symptoms of atherosclerosis as described, for example, in US20040266671, US6664230, US20030045460, US20030171277, US20030229015, US20040254120, WO/04034977, WO/02015923, and WO/05016280.
  • the compounds described herein can be used in therapeutic combination with an anti-cancer agent, including but not limited to: steroidal or non steroidal antiandrogens (such as finasteride (Proscar®), cyproterone acetate (CPA), flutamide (4'-nitro-3'-trifluorormethyl isobutyranilide), bicalutamide (Casodex®), and nilutamide), estrogens, diethylstilbestrol (DES), conjugated estrogens (such as Premarin®), Taxanes (such as paclitaxel (Taxol®), docetaxel (Taxotere®), 7-O- methylthio-methylpaclitaxel (disclosed in US5646176), 3'-tert-butyl-3'-N-tert- butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N-debenzoyl-4-O-methoxycarbonyl- pac
  • C-4 methyl carbonate paclitaxel (disclosed in WO 94/14787), and formulations containing taxanes, for examples those disclosed in US6395770, US6380405, and US6239167), epothilones (such as epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxyepothilone B, [1S-[1R*,3R*(E),7R*,1OS*, 11R*,12R*,16S*]]-7,1 l-dihydroxy-8,8,10,12,16- ⁇ entamethyl-3-[l-methyl-2-(2- - methyW-thiazoly ⁇ ethenylJ ⁇ -aza- ⁇ -oxabicyclotM.l.OJhepta-decane-S ⁇ -dione (disclosed in WO 99
  • microtuble-disruptor agents microtuble-disruptor agents, alkylating agents, anti-metabolites, epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers, growth inhibitors, hormonal/antihormonal therapeutic agents, haematopoietic growth factors, the anthracycline family of drugs, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, discodermolide, the pteridine family of drugs, diynenes, aromatase inhibitors, podophyllotoxins, doxorubicin, carminomycin, daunorubicin, idarubicin, dactinomycin, plicamycin, vinorelbine, aminopterin, methotrexate, methopterin, dichlor
  • selective estrogen receptor modulator includes both estrogen agonist and estrogen antagonists and refers to compounds that bind with the estrogen receptor, inhibit bone turnover and prevent bone loss.
  • estrogen agonists are compounds capable of binding to the estrogen receptor sites in mammalian tissue, and mimicking the actions of estrogen in one or more tissue.
  • Estrogen antagonists are compounds capable of binding to the estrogen receptor sites in mammalian tissue, and blocking the actions of estrogen in one or more tissues.
  • SERMs include but are not limited to tamoxifen (and associated compounds disclosed in US4536516); 4-hydroxytamoxifen (and associated compounds disclosed in US4623660); raloxifene (and associated compounds disclosed in US4418068, US5393763, US5457117, US5478847, and US5641790); droloxifene; idoxifene (and associated compounds disclosed in US4839155); lasofoxifene; TSE-424 (and other compounds disclosed in US5998402, US5985910, US5780497, US5880137, EP0802183A1); LY353381; LYl 17081; toremifene (and other compounds disclosed in US4696949 and US4996225); centchroman (and other compounds disclosed in US3822287); fulvestrant; 4-[7-(2,2-dimethyl-l -oxopropoxy-4-methyl-2-[4-[2-(l - piperidinyl)e
  • the compounds described herein can be used in therapeutic combination with an agent used to treat bone loss and associated disorders including but not limited to: (1) SERMs (including those described above); (2) bisphosphonates including but not limited to alendronic acid and alendronate/MK-217/(Fosamax®)/alendronate sodium/alendronate monosodium trihydrate including sodium, potassium, calcium, magnesium or ammonium salts thereof (alendronic acid and alendronate are disclosed in US4922007, US5019651, US5510517, and US564849)1; also); Yamanouchi compound YM 175/incadronate/cimadronate (cycloheptylaminomethylene-1,1- bisphosphonic acid, US4970335); l,l-dichloromethylene-l,l-diphosphonic acid (clodronic acid), and the disodium salt (clodronate, Procter and Gamble), as described in Belgium Patent 672,205 (1966) and J.
  • SERMs including those
  • HMG- CoA reductase inhibitors including those described above
  • integrin receptor antagonists including those described in US20040162304
  • osteoblast anabolic agents e.g., agents that build bone such as parathyroid horomone (PTH) or its amino terminal fragments (PTHrP-(I -36); Syed et al.
  • vitamin D which includes, but is not limited to, vitamin D 3 (cholecalciferol), vitamin D 2 (ergocalciferol);l ⁇ -hydroxy vitamin D;25- hydroxy vitamin D;l ⁇ ,25-dihydroxy vitamin D; and dihydroxy vitamin D; (12) synthetic vitamin D analogues (non-naturally occurring compounds that act like vitamin D); (13) compounds disclosed in US5280040; and (14) serotonin reuptake inhibitors (including those described above).
  • the compounds described herein can be used in therapeutic combination with other agents including but not limited to: a thromboxane A2 (Tx A2) antagonist; a CRTH2 receptor modulator (such as Ramatroban/Baynas/BAY u3405 which exhibits both TxA2 and CRTH2 antagonistic activity); ranitine; bosentan; a tyrosine kinase inhibitor such as disclosed in WO00/053605; a selective androgen receptor modulator (SARM) inlcuding LGD-2226 (Ligand) or those compounds disclosed in WO03/011824; coenzyme QlO such as disclosed in US5316765, US4933165, and US4929437; an agent that upregulates type DI endothelial cell nitric acid syntase such as disclosed in WO00/003746; a chondroprotective compound such as a polysulfated glycosaminoglycan (PSGAG)
  • an HMG-CoA reductase inhibitor e.g., a statin such as atorvastatin, atorvastatin calcium, rosuvastatin, rosuvastatin calcium, simvastatin
  • a fibrate e.g., fenofibrate(Tricor®)
  • niacin including derivatives and extended release formulations (e.g., Niaspan®) thereof
  • a glitazone e.g., rosiglitazone maleate (Avandia®), piogilitazone hydrochloride(Actos®)
  • a calcium channel blocker e.g., amlodipine besylate (Norvasc®)
  • an angiotensin ⁇ receptor antagonist e.g., valsartan (Diovan®, Diovan HCT® (valsartan and hydrochlorothi
  • HMG-CoA reductase inhibitor e.g., a statin
  • a fibrate e.g., a glitazone, niacin or a derivative thereof, a calcium channel blocker, an angiotensin II receptor antagonist, a biguanide, a sulfonylurea in a single pharmaceutical composition.
  • an HMG-CoA reductase inhibitor e.g., a statin
  • a fibrate e.g., a glitazone, niacin or a derivative thereof, a calcium channel blocker, an angiotensin II receptor antagonist, a biguanide, a sulfonylurea
  • an angiotensin II receptor antagonist e.g., a statin
  • biguanide e.g., a biguanide
  • sulfonylurea e.g., a statin
  • a dosage unit that will, when administered according to a particular dosage schedule (e.g., a dosage schedule specifying a certain number of units and a particular timing for administration), deliver the same dosage of each component as would be administered if the patient was being treated with only a single component.
  • a dosage schedule e.g., a dosage schedule specifying a certain number of units and a particular timing for administration
  • a dosage unit that will deliver a dosage of one or more components that is greater than that which would be administered if the patient was being treated only with a single component.
  • the pharmaceutical composition can include additional ingredients including but not limited to the excipients described herein, hi certain embodiments, one or more therapeutic agents of the dosage unit may exist in an extended or control release formulation and additional therapeutic agents may not exist in extended release formulation.
  • one or more therapeutic agents of the dosage unit may exist in an extended or control release formulation and additional therapeutic agents may not exist in extended release formulation.
  • a compound described herein may exist in the same dosage unit with fenofibrate (an extended release fibrate agent).
  • a compound described herein may exist in the same dosage unit with one or more additional agents including a controlled release formulation of torcetrapib.
  • a pharmaceutical composition can include 1 % to 20% by weight of a compound described herein; from 1% to 80% by weight of an HMG-CoA reductase inhibitor such as atorvastatin, atorvastatin calcium, dihydrocompactin, bervastatin, carvastatin, cerivastatin, crilvastatin, dalvastatin, fluvastatin, glenvastatin, fluindostatin, velostatin, lovastatin, mevastatin, compactin, pitavastatin, pravastatin, rivastatin, rosuvastatin, rosuvastatin calcium, simvastatin, simvastatin, and CI-981; and from 0.01% to 2% by weight of a stabilizing agent such as butylated hydroxyanisole (BHA).
  • an HMG-CoA reductase inhibitor such as atorvastatin, atorvastatin calcium, dihydrocompactin, bervastatin
  • composition may optionally include of one or more of croscarmellose sodium, citric acid, ascorbic acid and propyl gallate.
  • the composition can include or exclude one or more of citric acid, ascorbic acid and pre-gelatinized starch.
  • a single dosage unit such as a tablet or capsule should weigh from 50 mg to 1000 mg (for example, including from 100 mg to 800 mg).
  • a dosage unit can include from, for example, 1 to 500 mg, 2 mg to 500 mg, 1 to 300 mg, 1 to 100 mg, 5 mg to 100 mg, 1 to 30 mg, 1 to 40 mg, 5 mg to 20 mg, 1 mg, 2 mg, 3 mg, 4mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg of a compound described herein; from 5 mg to 80 mg (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg and 80 mg) of a statin (e.g., atorvastatin, ator
  • the dosage unit comprises 5 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin. In certain embodiments, the dosage unit comprises 10 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin.
  • the dosage unit comprises 15 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin, hi certain embodiments, the dosage unit comprises 20 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin. In certain embodiments, the dosage unit comprises 25 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin.
  • the dosage unit comprises 30 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin, hi certain embodiments, the dosage unit comprises 35 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin, hi certain embodiments, the dosage unit comprises 40 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin, hi certain embodiments, the dosage unit comprises 45 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin, hi certain embodiments, the dosage unit comprises 50 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin
  • the dosage unit comprises 85 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin. In certain embodiments, the dosage unit comprises 90 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin. In certain embodiments, the dosage unit comprises 95 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin.
  • the dosage unit comprises 100 mg of a compound described herein and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg of a statin.
  • a daily dose can include 5-100 mg (e.g., 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg) of a compound described herein and 5, 10, 20, 30, 40, 50, 60, 70 or 80 mg of a statin.
  • the statin is selected from the group consisting of atorvastatin, atorvastatin calcium, rosuvastatin, rosuvastatin calcium and simvastatin.
  • the dosage unit and daily dose are equivalent.
  • the dosage unit is administered with food at anytime of the day, without food at anytime of the day, with food after an overnight fast (e.g., with breakfast), at bedtime after a low fat snack.
  • the dosage unit is administered once a day, twice a day, three times a day, four times a day.
  • the dosage unit can include from 0.0005 mg to 0.001 mg of propyl gallate per mg of statin.
  • the dosage unit can include from 0.01 mg to 16 mg, and particularly from 0.02 mg to 0.16 mg of BHA, and additionally may be include from 0.001 mg to 0.05 mg, and particularly from 0.005 mg to 0.04 mg of propyl gallate.
  • the dosage unit can additionally include from 1 mg to 640 mg, and particularly from 15 mg to 120 mg of microcrystalline cellulose; from 0.5 mg to 80 mg, and particularly from 2 mg to 16 mg of HPMC; from 0.1 mg to 32 mg, and particularly from 1.5 to 12 mg of magnesium stearate; and lactose.
  • Croscarmellose sodium may optionally be included as a component in the composition.
  • an oral dosage unit may contain from 0 mg to 80 mg of croscarmellose sodium, and particularly from 3 mg to 24 mg of croscarmellose sodium.
  • Citric acid may optionally be included as a component in the composition.
  • an oral dosage unit may contain from 0 mg to 80 mg, and particularly from 0.25 mg to 2 mg of citric acid.
  • lactic acid, malic acid, succinic acid, tartaric acid and EDTA may optionally be included in the dosage unit.
  • An inert component such as lactose can be added to bring the unit dosage form to a desired total weight.
  • the dosage unit can optionally comprise other agents such as 1, 2, 3, or more of a fibrate, niacin (including derivatives thereof), a glitazone, a calcium channel blocker, an angiotensin II receptor antagonist, a biguanide, and a sulfonylurea.
  • a dosage unit (e.g., an oral dosage unit) can include, for example, from 1 to 500 mg, 2 mg to 500 mg, 1 to 300 mg, 1 to 100 mg, 5 mg to 100 mg, 1 to 30 mg, 1 to 40 mg, 5 mg to 20 mg, 1 mg, 2 mg, 3 mg, 4mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg of a compound described herein and from 10 mg to 150 mg (e.g., 10 mg, 20 mg, 30 mg, 40 mg, 48 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 130 mg, 140 mg, 145 mg, 150 mg) of a fibrate (e.g., 10
  • the dosage unit comprises 5 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate. rn certain embodiments, the dosage unit comprises 10 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate. In certain embodiments, the dosage unit comprises 15 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 20 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 25 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 30 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 35 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate. In certain embodiments, the dosage unit comprises 40 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate. In certain embodiments, the dosage unit comprises 45 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 50 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 55 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 60 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 65 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 70 mg of a compound described herein andlO, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 75 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 80 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 85 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 90 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the dosage unit comprises 95 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate. [00159] In certain embodiments, the dosage unit comprises 100 mg of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • a daily dose can include 5-100 mg (e.g., 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg) of a compound described herein and 10, 20, 30, 40, 48, 50, 60, 70, 80, 90, 100, 120, 130, 140, 145, or 150 mg of a fibrate.
  • the fibrate is fenofibrate (Tricor®).
  • the dosage unit and daily dose are equivalent.
  • the dosage unit is administered with food at anytime of the day, without food at anytime of the day, with food after an overnight fast (e.g., with breakfast), at bedtime after a low fat snack.
  • the dosage unit is administered once a day, twice a day, three times a day, four times a day.
  • the dosage unit can optionally comprise other agents such as 1, 2, 3, or more of an HMG CoA reductase inhibitor (e.g.a statin), niacin (including derivatives thereof), a glitazone, a calcium channel blocker, an angiotensin ⁇ receptor antagonist, a biguanide, and a sulfonylurea.
  • a dosage unit (e.g., an oral dosage unit) can include, for example, from 1 to 500 mg, 2 mg to 500 mg, 1 to 300 mg, 1 to 100 mg, 5 mg to 100 mg, 1 to 30 mg, 1 to 40 mg, 5 mg to 20 mg, 1 mg, 2 mg, 3 mg, 4mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg of a compound described herein and from 1 mg to 60 mg (e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45
  • the dosage unit comprises 5 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone.
  • the dosage unit comprises 10 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone.
  • the dosage unit comprises 15 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone.
  • the dosage unit comprises 20 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone. In certain embodiments, the dosage unit comprises 25 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone. In certain embodiments, the dosage unit comprises 30 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone.
  • the dosage unit comprises 35 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone.
  • the dosage unit comprises 40 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone.
  • the dosage unit comprises 45 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone.
  • the dosage unit comprises 50 mg of a compound described herein and
  • the dosage unit comprises 55 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone. In certain embodiments, the dosage unit comprises 60 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone.
  • the dosage unit comprises 65 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone. In certain embodiments, the dosage unit comprises 70 mg of a compound described herein andl,
  • the dosage unit comprises 75 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone. In certain embodiments, the dosage unit comprises 80 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone.
  • the dosage unit comprises 85 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone. In certain embodiments, the dosage unit comprises 90 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone. In certain embodiments, the dosage unit comprises 95 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone.
  • the dosage unit comprises 100 mg of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone.
  • a daily dose can include 5-100 mg (e.g., 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg) of a compound described herein and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or 60 mg of a glitazone.
  • the glitazone is rosiglitazone maleate (Avandia®).
  • the glitazone is pioglitazone (Actos®).
  • the dosage unit and daily dose are equivalent, hi various embodiments, the dosage unit is administered with food at anytime of the day, without food at anytime of the day, with food after an overnight fast (e.g., with breakfast), at bedtime after a low fat snack, hi various embodiments, the dosage unit is administered once a day, twice a day, three times a day, four times a day.
  • the dosage unit can optionally comprise other agents such as 1, 2, 3, or more of an HMG CoA reductase inhibitor (e.g.a statin), a fibrate, niacin (including derivatives thereof), a calcium channel blocker, an angiotensin II receptor antagonist, a biguanide, and a sulfonylurea.
  • a dosage unit (e.g., an oral dosage unit) can include, for example, from 1 to 500 mg, 2 mg to 500 mg, 1 to 300 mg, 1 to 100 mg, 5 mg to 100 mg, 1 to 30 mg, 1 to 40 mg, 5 mg to 20 mg, 1 mg, 2 mg, 3 mg, 4mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg of a compound described herein and from 100 mg to 2000 mg (e.g., 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,
  • the dosage unit comprises 10 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of niacin or a derivative thereof.
  • the dosage unit comprises 15 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of niacin or a derivative thereof, hi certain embodiments, the dosage unit comprises 20 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of niacin or a derivative thereof, hi certain embodiments, the dosage unit comprises 25 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850
  • the dosage unit comprises 35 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of niacin or a derivative thereof.
  • the dosage unit comprises 40 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of niacin or a derivative thereof.
  • the dosage unit comprises 45 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of niacin or a derivative thereof, hi certain embodiments, the dosage unit comprises 50 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of niacin or a derivative thereof, hi certain embodiments, the dosage unit comprises 55 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850
  • the dosage unit comprises 80 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of niacin or a derivative thereof.
  • the dosage unit comprises 85 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of m ' acin or a derivative thereof.
  • the dosage unit comprises 90 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of niacin or a derivative thereof.
  • the dosage unit comprises 95 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of niacin or a derivative thereof, hi certain embodiments, the dosage unit comprises 100 mg of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of niacin or a derivative thereof.
  • a daily dose can include 5-100 mg (e.g., 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg) of a compound described herein and 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of niacin or a derivative thereof, hi certain embodiments the niacin derivative is Niaspan® (niacin extended release tablets), hi certain embodiments the dosage unit and daily dose are equivalent, hi various embodiments, the dosage unit is administered with food at anytime of the day, without food at anytime of the day, with food after an overnight fast (e.g., with breakfast), at bedtime after a low fat snack, hi various embodiments, the dosage unit is administered once a day, twice a day, three times a day, four times a day.
  • the dosage unit can optionally comprise other agents such as 1, 2, 3, or more of an HMG CoA reductase inhibitor (e.g.a statin), a fibrate, a glitazone, a calcium channel blocker, an angiotensin II receptor antagonist, a biguanide, and a sulfonylurea.
  • an HMG CoA reductase inhibitor e.g.a statin
  • a fibrate e.g. a statin
  • a glitazone e.g. a calcium channel blocker
  • an angiotensin II receptor antagonist e.g. a biguanide
  • a sulfonylurea e.g. a statin
  • a dosage unit (e.g., an oral dosage unit) can include, for example, from 1 to 500 mg, 2 mg to 500 mg, 1 to 300 mg, 1 to 100 mg, 5 mg to 100 mg, 1 to 30 mg, 1 to 40 mg, 5 mg to 20 mg, 1 mg, 2 mg, 3 mg, 4mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg of a compound described herein and from 1 mg to 15 mg (e.g., 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 12.5 mg, 13 mg, 14 mg, 15 mg) of a compound described
  • the dosage unit comprises 5 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker. In certain embodiments, the dosage unit comprises 10 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker. In certain embodiments, the dosage unit comprises 15 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker.
  • the dosage unit comprises 20 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker. In certain embodiments, the dosage unit comprises 25 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker, m certain embodiments, the dosage unit comprises 30 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker, hi certain embodiments, the dosage unit comprises 35 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker.
  • the dosage unit comprises 40 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker. In certain embodiments, the dosage unit comprises 45 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker. In certain embodiments, the dosage unit comprises 50 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker.
  • the dosage unit comprises 55 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker. In certain embodiments, the dosage unit comprises 60 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker, hi certain embodiments, the dosage unit comprises 65 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker, hi certain embodiments, the dosage unit comprises 70 mg of a compound described herein andl, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker, hi certain embodiments, the dosage unit comprises 75 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker
  • the dosage unit comprises 90 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker, hi certain embodiments, the dosage unit comprises 95 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker, hi certain embodiments, the dosage unit comprises 100 mg of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker.
  • a daily dose can include 5-100 mg (e.g., 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg) of a compound described herein and 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mg of a calcium channel blocker.
  • the calcium channel blocker is amlodipine (Norvasc®; amlodipine beslylate).
  • the dosage unit and daily dose are equivalent.
  • the dosage unit is administered with food at anytime of the day, without food at anytime of the day, with food after an overnight fast (e.g., with breakfast), at bedtime after a low fat snack.
  • the dosage unit is administered once a day, twice a day, three times a day, four times a day.
  • the dosage unit can optionally comprise other agents such as 1, 2, 3, or more of an HMG CoA reductase inhibitor (e.g.a statin), a f ⁇ brate, niacin (including derivatives thereof), a glitazone, an angiotensin II receptor antagonist, a biguanide, and a sulfonylurea.
  • an HMG CoA reductase inhibitor e.g.a statin
  • a f ⁇ brate e.g. f ⁇ brate
  • niacin including derivatives thereof
  • a glitazone e.g., an angiotensin II receptor antagonist, a biguanide, and a sulfonylurea.
  • a dosage unit (e.g., an oral dosage unit) can include, for example, from 1 to 500 mg, 2 mg to 500 mg, 1 to 300 mg, 1 to 100 mg, 5 mg to 100 mg, 1 to 30 mg, 1 to 40 mg, 5 mg to 20 mg, 1 mg, 2 mg, 3 mg, 4mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg of a compound described herein and from 20 mg to 400 mg (e.g., 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg
  • the dosage unit comprises 5 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist.
  • the dosage unit comprises 10 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist.
  • the dosage unit comprises 15 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist.
  • the dosage unit comprises 20 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist, hi certain embodiments, the dosage unit comprises 25 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist, hi certain embodiments, the dosage unit comprises 30 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320
  • the dosage unit comprises 55 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist.
  • the dosage unit comprises 60 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist.
  • the dosage unit comprises 65 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist.
  • the dosage unit comprises 70 mg of a compound described herein and20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist.
  • the dosage unit comprises 75 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist.
  • the dosage unit comprises 80 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist.
  • the dosage unit comprises 85 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist, hi certain embodiments, the dosage unit comprises 90 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist, hi certain embodiments, the dosage unit comprises 95 mg of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 380, or 400
  • a daily dose can include 5-100 mg (e.g., 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg) of a compound described herein and 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 320, 340, 360, 380, or 400 mg of an angiotensin II receptor antagonist.
  • the angiotensin II receptor antagonist is valsartan (Diovan®).
  • the dosage unit further comprises a diuretic (e.g., hydrocholorothiazide). In certain embodiments the dosage unit and daily dose are equivalent.
  • the dosage unit is administered with food at anytime of the day, without food at anytime of the day, with food after an overnight fast (e.g., with breakfast), at bedtime after a low fat snack.
  • the dosage unit is administered once a day, twice a day, three times a day, four times a day.
  • the dosage unit can optionally comprise other agents such as 1, 2, 3, or more of an HMG CoA reductase inhibitor (e.g.a statin), a fibrate, niacin (including derivatives thereof), a glitazone, a calcium channel blocker, a biguanide, and a sulfonylurea.
  • a dosage unit (e.g., an oral dosage unit) can include, for example, from 1 to 500 mg, 2 mg to 500 mg, 1 to 300 mg, 1 to 100 mg, 5 mg to 100 mg, 1 to 30 mg, 1 to 40 mg, 5 mg to 20 mg, 1 mg, 2 mg, 3 mg, 4mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg of a compound described herein and from 100 mg to 3000 mg (e.g., 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1250 mg,
  • the dosage unit comprises 5 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide. In certain embodiments, the dosage unit comprises 10 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 15 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 20 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 25 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 30 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 35 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 40 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 45 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 50 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 55 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 60 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 65 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 70 mg of a compound described herein andlOO, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 75 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 80 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 85 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 90 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 95 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the dosage unit comprises 100 mg of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • a daily dose can include 5-100 mg (e.g., 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg) of a compound described herein and 100, 200, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, or 3000 mg of a biguanide.
  • the biguanide is metformin (metformin hydrochloride, (Glucophage®, Glucophage® XR)).
  • the dosage unit and daily dose are equivalent.
  • the dosage unit is administered with food at anytime of the day, without food at anytime of the day, with food after an overnight fast (e.g., with breakfast), at bedtime after a low fat snack, hi various embodiments, the dosage unit is administered once a day, twice a day, three times a day, four times a day.
  • the dosage unit can optionally comprise other agents such as 1, 2, 3, or more of an HMG CoA reductase inhibitor (e.g.a statin), a fibrate, niacin (including derivatives thereof), a glitazone, a calcium channel blocker, an angiotensin II receptor antagonist, and a sulfonylurea.
  • a dosage unit (e.g., an oral dosage unit) can include, for example, from 1 to 500 mg, 2 mg to 500 mg, 1 to 300 mg, 1 to 100 mg, 5 mg to 100 mg, 1 to 30 mg, 1 to 40 mg, 5 mg to 20 mg, 1 mg, 2 mg, 3 mg, 4mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg of a compound described herein and from 1 to 40 mg (e.g., 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25
  • the dosage unit comprises 5 mg of a compound described herein and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 mg of a sulfonylurea. In certain embodiments, the dosage unit comprises 10 mg of a compound described herein and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 mg of a sulfonylurea, hi certain embodiments, the dosage unit comprises 15 mg of a compound described herein and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 mg of a sulfonylurea.
  • the dosage unit comprises 20 mg of a compound described herein and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 mg of a sulfonylurea, hi certain embodiments, the dosage unit comprises 25 mg of a compound described herein and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 mg of a sulfonylurea.
  • the dosage unit comprises 30 mg of a compound described herein and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 mg of a sulfonylurea, hi certain embodiments, the dosage unit comprises 35 mg of a compound described herein and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 mg of a sulfonylurea, hi certain embodiments, the dosage unit comprises 40 mg of a compound described herein and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 mg of a sulfonylurea, hi certain embodiments, the dosage unit comprises 45 mg of a compound described herein and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 mg of a sulfonylurea, hi certain embodiments, the dosage unit comprises 50 mg
  • the dosage unit comprises 95 mg of a compound described herein and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 mg of a sulfonylurea. In certain embodiments, the dosage unit comprises 100 mg of a compound described herein and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 mg of a sulfonylurea.
  • a daily dose can include 5-100 mg (e.g., 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg) of a compound described herein and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 mg of a sulfonylurea.
  • the sulfonylurea is glipizide (Glucotrol® Glucotrol XL®).
  • the sulfonylurea is glyburide (Micronase®, Glynase Prestab®, Diabeta®).
  • the dosage unit and daily dose are equivalent.
  • the dosage unit is administered with food at anytime of the day, without food at anytime of the day, with food after an overnight fast (e.g., with breakfast), at bedtime after a low fat snack.
  • the dosage unit is administered once a day, twice a day, three times a day, four times a day.
  • the dosage unit can optionally comprise other agents such as 1, 2, 3, or more of an HMG CoA reductase inhibitor (e.g.a statin), a fibrate, niacin (including derivatives thereof), a glitazone, a calcium channel blocker, an angiotensin II receptor antagonist, and a biguanide.
  • Sterols and stands include but are not limited to those described herein. Plant sterols and stands (e.g., beta-sitosterol) have been used as dietary supplements to reduce serum cholesterol levels. Plant sterol can be esterified to create stanol esters (also referred to as stands), which are also used as food additives. Sterols are typically derived from agricultural sources, such as corn, soy- based, and pine tree mixtures. Stanols can be created through the reaction of the sterol with the suitable acid. Suitable acids include saturated, unsaturated, and polyunsaturated acids.
  • Suitable acids include but are not limited to, stearic, butyric, lauric, palmitic, oleic, linoleic, linolenic, docohexanoic acid, and the like. Suitable methods for preparing these esters are well known in the art, see, e.g., US5502045 and US5723747. Sterols and sterol esters can be formulated a self-dispersing particles that are small enough to be effective when administered by ingestion (see, e.g., US6387411, US6376481 and US20040033202).
  • Sterols and/or sterol esters in particle form can be combined with a compound described herein to create useful pharameutical compositons which can also include other agents such as 1, 2, 3, or more of an HMG-CoA reductase inhibitor (e.g., a statin such as atorvastatin, atorvastatin calcium, rosuvastatin, rosuvastatin calcium, simvastatin), a fibrate (e.g., fenofibrate(Tricor®)), niacin (including derivatives and extended release formulations (e.g., Niaspan®) thereof), a glitazone (e.g., rosiglitazone maleate (Avandia®), piogilitazone hydrochloride(Actos®)), a calcium channel blocker (e.g., amlodipine besylate (Norvasc®)), an angiotensin II receptor antagonist (e.g., vals
  • the pharmaceutical composition can include additional ingredients such as stabilizers or bulking agents.
  • the sterol particles in the composition can have any suitable size, e.g., 10-150 microns in diameter. However, to improve absorption in the body it can be desirable to use much smaller particles, e.g., less than 2000 nm in diameter as explained in US20040033202.
  • compositions that include a compound described herein can include sterol nanoparticles, such as sitosterol and/or phytosterol nanoparticles, which have an effective average particle size of less than about 2000 nm, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 urn, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm, as measured by light-scatter
  • the particles can be created by methods which include: milling, precipitation and homogenization.
  • homogenization methods are described in US5510118.
  • the method includes dispersing sterol particles in a liquid dispersion medium in which the sterol is poorly soluble, followed by subjecting the dispersion to homogenization to reduce the particle size of the sterol to the desired effective average particle size.
  • the sterol particles are preferably reduced in size in the presence of at least one surface stabilizer.
  • the sterol particles can be contacted with one or more surface stabilizers either before or after attrition.
  • Other compounds, such as a diluent can be added to the sterol/surface stabilizer composition before, during, or after the size reduction process.
  • Dispersions can be manufactured continuously or in a batch mode.
  • Surface stabilizers can be used in the formulations. Suitable surface stabilizers include: cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hypromellose, carboxymethylcellulose sodium, methylcellulose, hydroxye
  • Polycosanol compositions are complex mixtures of concentrated n-alkyl alcohols derived from, e.g., sugar cane and the wax of honey bees. Polycosanol compositions are reported to produce cholesterol lowering effects within the first 6-8 weeks of use. According to US20030232796, at a daily polycosanol dosage of 10 mg taken at night, LDL cholesterol levels typically drop by 20-25% within the first six months of use. At a dosage of 20 mg, LDL levels typically drop by 25-30%. HDL levels typically increase by 15-25% only after two months of use.
  • Polycosanol can include fatty acid components including: 1-Octacosanol, 1-Triacontanol, 1-Tetracosanol, and 1- Hexacosanol. Typical usage levels range from 500-10,000 micrograms per serving/dose.
  • Typical commercially available commercial compositions are 90% minimum fatty alcohols of (a) 1-Tetracosanol: 0-10%; (b) 1-Hexacosanol: 2-15%; (c) 1-Heptacosanol: 0-0.5%; (d) 1-Octacosanol: 55-70%; (e) 1-Nonacosanol: 0-10%; (f) 1-Triacontanol: 5-20%; (g) 1-Dotriacontanol: 0.1-10%; and (h) 1-Tetratriacontanol: 0.1-10%.
  • Polycosanol compositions can be formulated as described above for stanols both with respect to particle size and overall formulation.
  • the formulation can include other agents such as 1, 2, 3, or more of an HMG-CoA reductase inhibitor (e.g., a statin such as atorvastatin, atorvastatin calcium, rosuvastatin, rosuvastatin calcium, simvastatin), a fibrate (e.g., fenofibrate(Tricor®)), niacin (including derivatives and extended release formulations (e.g., Niaspan®) thereof), a glitazone (e.g., rosiglitazone maleate (Avandia®), piogilitazone hydrochloride(Actos®)), a calcium channel blocker (e.g., amlodipine besylate (Norvasc®)), an angiotensin II receptor antagonist (e.g., valsartan (Diovan®, Diovan HCT® (valsartan and hydrochlorothiazi)
  • acidic and basic active ingredients can react with each other and acidic active ingredients can facilitate the degradation of acid labile substances.
  • acidic and basic substances can be physically separated as two distinct or isolated layers in a compressed tablet, or in the core and shell of a press- coated tablet.
  • the therapeutic combinations described herein can be formulated as a tablet or capsule comprising a plurality of beads, granules, or pellets. All active ingredients including the vitamins of the combination are formulated into granules or beads or pellets that are further coated with a protective coat, an enteric coat, or a film coat to avoid the possible chemical interactions. Granulation and coating of granules or beads is done using techniques well known to a person skilled in the art. At least one active ingredient can present in a controlled release form. Finally these coated granules or beads are filled into hard gelatin capsules or compressed to form tablets.
  • microtablets of the individual agents can be prepared using well known pharmaceutical procedures of tablet making like direct compression, dry granulation or wet granulation. Individual microtablets can be filled into hard gelatin capsules.
  • a final dosage form may comprise one or more microtablets of each individual component.
  • the microtablets may be film coated or enteric coated.
  • the therapeutic combinations described herein can be formulated as a capsule comprising one or more microtablets and powder, or one or more microtablets and granules or beads.
  • some active ingredients of a said combination can be formulated as microtablets and the others filled into capsules as a powder, granules, or beads.
  • the microtablets may be film coated or enteric coated. At least one active ingredient can be presented in controlled release form.
  • the therapeutic combinations described herein can be formulated wherein the active ingredients are distributed in the inner and outer phase of tablets.
  • few interacting components are converted in granules or beads using well known pharmaceutical procedures in prior art.
  • the prepared granules or beads (inner phase) are then mixed with outer phase comprising the remaining active ingredients and at least one pharmaceutically acceptable excipient.
  • the mixture thus comprising inner and outer phase is compressed into tablets or molded into tablets.
  • the granules or beads can be controlled release or immediate release beads or granules, and can further be coated using an enteric polymer in an aqueous or non-aqueous system, using methods and materials that are known in the art.
  • the therapeutic combinations described herein can be formulated as single dosage unit comprising suitable buffering agent. All powdered ingredients of said combination are mixed and a suitable quantity of one or more buffering agents is added to the blend to minimize possible interactions.
  • the agents described herein, alone or in combination, can be combined with any pharmaceutically acceptable carrier or medium. Thus, they can be combined with materials that do not produce an adverse, allergic or otherwise unwanted reaction when administered to a patient.
  • the carriers or mediums used can include solvents, dispersants, coatings, absorption promoting agents, controlled release agents, and one or more inert excipients (which include starches, polyols, granulating agents, macrocrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like), etc. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques.
  • the agents can be a free acid or base, or a pharmacologically acceptable salt thereof. Solids can be dissolved or dispersed immediately prior to administration or earlier. In some circumstances the preparations include a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injection can include sterile aqueous or organic solutions or dispersions which include, e.g., water, an alcohol, an organic solvent, an oil or other solvent or dispersant (e.g., glycerol, propylene glycol, polyethylene glycol, and vegetable oils).
  • the formulations may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • Pharmaceutical agents can be sterilized by filter sterilization or by other suitable means
  • Suitable pharmaceutical compositions in accordance with the invention will generally include an amount of the active compound(s) with an acceptable pharmaceutical diluent or excipient, such as a sterile aqueous solution, to give a range of final concentrations, depending on the intended use.
  • an acceptable pharmaceutical diluent or excipient such as a sterile aqueous solution.
  • the techniques of preparation are generally well known in the art, as exemplified by Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Company, 1995.
  • the agent can be in the form of a pharmaceutically acceptable salt.
  • Such salts are prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • examples of salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • the salt can be an ammonium, calcium, magnesium, potassium, or sodium salt.
  • salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, benethamine, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, diethanolamine, ethanolamine, ethylenediamine, N- ethymiorpholine, N-ethylpiperidine, epolamine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, meglumine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and trolamine, tromethamine.
  • other salts include tris, arecoline, arginine, barium, betaine, bismuth, chloroprocaine, cho
  • the agents of the invention can be administered orally, e.g., as a tablet or cachet containing a predetermined amount of the active ingredient, pellet, gel, paste, syrup, bolus, electuary, slurry, capsule; powder; granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, via a liposomal formulation (see, e.g., EP736299) or in some other form.
  • a liposomal formulation see, e.g., EP736299
  • Orally administered compositions can include binders, lubricants, inert diluents, lubricating, surface active or dispersing agents, flavoring agents, and humectants.
  • Orally administered formulations such as tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • the agents of the invention can also be administered by captisol delivery technology, rectal suppository or parenterally.
  • the agents described herein can be either in their free form or as a salt can be combined with a polymer such as polylactic-glycoloic acid (PLGA), poly-(I)-lactic- glycolic-tartaric acid (P(I)LGT) (WO01/12233), polyglycolic acid (US3773919), polylactic acid (US4767628), poly(M-caprolactone) and poly(alkylene oxide) (US20030068384) to create a sustained release formulation.
  • PLGA polylactic-glycoloic acid
  • P(I)LGT poly-(I)-lactic- glycolic-tartaric acid
  • WO01/12233 polyglycolic acid
  • US3773919 polylactic acid
  • US4767628 poly(M-caprolactone)
  • poly(alkylene oxide) US20030068384
  • Such formulations can be used within implants that release a compound of the invention and/or another agent over a period of a few days, a few weeks or several months depending on the polymer, the particle size of the polymer, and the size of the implant (see, e.g., US6620422 and WO05/011769).
  • sustained release formulations are described in EP0467389, WO93/241150, US5612052, WO97/40085, WO03/075887, WO01/01964, US5922356, WO94/155587, WO02/074247, WO98/25642, US5968895, US6180608, US20030171296, US20020176841, US5672659, US5893985, US5134122, US5192741, US5192741, US4668506, US4713244, US5445832 US4931279, US5980945, WO02/058672, WO9726015, WO97/04744, and US20020019446.
  • microparticles of compound are combined with microparticles of polymer.
  • US6011011 and WO94/06452 described a sustained release formulation providing either polyethylene glycols (e.g., PEG 300 and PEG 400) or triacetin.
  • WO03/053401 describes a formulation which may both enhance bioavailability and provide controlled release of the agent within the GI tract.
  • Matrix devices are a common device for controlling the release of various agents.
  • the agents described herein are generally present as a dispersion within the polymer matrix, and are typically formed by the compression of a polymer/drug mixture or by dissolution or melting.
  • the dosage release properties of these devices may be dependent upon the solubility of the agent in the polymer matrix or, in the case of porous matrices, the solubility in the sink solution within the pore network, and the tortuosity of the network.
  • the matrix imbibes water and forms an aqueous-swollen gel that entraps the agent. The matrix then gradually erodes, swells, disintegrates or dissolves in the GI tract, thereby controlling release of one or more of the agents described herein.
  • the agent is released by diffusion through an inert matrix.
  • Agents described herein can be incorporated into an erodible or non-erodible polymeric matrix controlled release device.
  • an erodible matrix is meant aqueous- erodible or water-swellable or aqueous-soluble in the sense of being either erodible or swellable or dissolvable in pure water or requiring the presence of an acid or base to ionize the polymeric matrix sufficiently to cause erosion or dissolution.
  • the erodible polymeric matrix When contacted with the aqueous environment of use, the erodible polymeric matrix imbibes water and forms an aqueous-swollen gel or matrix that entraps the agent described herein.
  • aqueous-swollen matrix gradually erodes, swells, disintegrates or dissolves in the environment of use, thereby controlling the release of a compound described herein to the environment of use.
  • Nonlimiting examples of such devices are disclosed in U. S. Patent Application Serial No. 09/495,059 filed January 31, 2000.
  • the erodible polymeric matrix into which an agent described herein can be incorporated may generally be described as a set of excipients that are mixed with the agent following its formation that, when contacted with the aqueous environment of use imbibes water and forms a water-swollen gel or matrix that entraps the drug form. Drug release may occur by a variety of mechanisms, for example, the matrix may disintegrate or dissolve from around particles or granules of the agent or the agent may dissolve in the imbibed aqueous solution and diffuse from the tablet, beads or granules of the device.
  • water- swellable, erodible, or soluble polymer which may generally be described as an osmopolymer, hydrogel or water-swellable polymer.
  • Such polymers may be linear, branched, or crosslmked.
  • the polymers maybe homopolymers or copolymers. In certain embodiments, they may be synthetic polymers derived from vinyl, acrylate, methacrylate, urethane, ester and oxide monomers.
  • polysaccharides e.g., chitin, chitosan, dextran and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum and scleroglucan), starches (e.g., dextrin and maltodextrin), hydrophilic colloids (e.g., pectin), phosphatides (e.g., lecithin), alginates (e.g., ammonium alginate, sodium, potassium or calcium alginate, propylene glycol alginate), gelatin, collagen, and cellulosics.
  • polysaccharides e.g., chitin, chitosan, dextran and pullulan
  • Cellulosics are cellulose polymer that has been modified by reaction of at least a portion of the hydroxyl groups on the saccharide repeat units with a compound to form an ester-linked or an ether-linked substituent.
  • the cellulosic ethyl cellulose has an ether linked ethyl substituent attached to the saccharide repeat unit, while the cellulosic cellulose acetate has an ester linked acetate substituent.
  • the cellulosics for the erodible matrix comprises aqueous-soluble and aqueous-erodible cellulosics can include, for example, ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC).
  • EC ethyl cellulose
  • MEC methylethyl cellulose
  • CMC carboxymethyl cellulose
  • CMEC hydroxyethyl cellulose
  • HPC hydroxyprop
  • the cellulosics comprises various grades of low viscosity (MW less than or equal to 50,000 daltons, for example, the Dow MethocelTM series E5, El 5LV, E50LV and KlOOLY) and high viscosity (MW greater than 50,000 daltons, for example, E4MCR, ElOMCR, K4M, Kl 5M and KlOOM and the MethocelTM K series) HPMC.
  • low viscosity MW less than or equal to 50,000 daltons
  • high viscosity MW greater than 50,000 daltons
  • E4MCR, ElOMCR, K4M, Kl 5M and KlOOM MW greater than 50,000 daltons
  • Other commercially available types of HPMC include the Shin Etsu Metolose 90SH series.
  • the choice of matrix material can have a large effect on the maximum drug concentration attained by the device as well as the maintenance of a high drug concentration.
  • the matrix material can be a concentration-enhancing polymer, for example, as described in WO05/011634.
  • erodible matrix material examples include, but are not limited to, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid (EUDRAGITO, Rohm America, Inc., Piscataway, New Jersey) and other acrylic acid derivatives such as homopolymers and copolymers of butylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate, (2- dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.
  • pullulan polyvinyl pyrrolidone
  • polyvinyl alcohol polyvinyl acetate
  • glycerol fatty acid esters polyacrylamide
  • polyacrylic acid copolymers of ethacrylic acid or meth
  • the erodible matrix polymer may contain a wide variety of the same types of additives and excipients known in the pharmaceutical arts, including osmopolymers, osmagens, solubility-enhancing or-retarding agents and excipients that promote stability or processing of the device.
  • the agents of the present invention may be administered by or incorporated into a non-erodible matrix device.
  • an agent described herein is distributed in an inert matrix.
  • the agent is released by diffusion through the inert matrix.
  • materials suitable for the inert matrix include insoluble plastics (e.g methyl acrylate-methyl methacrylate copolymers, polyvinyl chloride, polyethylene), hydrophilic polymers (e.g., ethyl cellulose, cellulose acetate, crosslinked polyvinylpyrrolidone (also known as crospovidone)), and fatty compounds (e.g., carnauba wax, microcrystalline wax, and triglycerides).
  • insoluble plastics e.g methyl acrylate-methyl methacrylate copolymers, polyvinyl chloride, polyethylene
  • hydrophilic polymers e.g., ethyl cellulose, cellulose acetate, crosslinked polyvinylpyrrolidone (also known as cro
  • Matrix controlled release devices may be prepared by blending an agent described herein and other excipients together, and then forming the blend into a tablet, caplet, pill, or other device formed by compressive forces.
  • Such compressed devices may be formed using any of a wide variety of presses used in the fabrication of pharmaceutical devices. Examples include single-punch presses, rotary tablet presses, and multilayer rotary tablet presses, all well known in the art. See for example, Remington: The Science and Practice of Pharmacy, 20th Edition, 2000.
  • the compressed device may be of any shape, including round, oval, oblong, cylindrical, or triangular.
  • the upper and lower surfaces of the compressed device may be flat, round, concave, or convex.
  • the device when formed by compression, has a strength of at least 5 Kiloponds (Kp)/cm 2 (for example, at least 7 Kp/cm 2 ).
  • Strength is the fracture force, also known as the tablet hardness required to fracture a tablet formed from the materials, divided by the maximum cross-sectional area of the tablet normal to that force.
  • the fracture force may be measured using a Schleuiiiger Tablet Hardness Tester, Model 6D.
  • the compression force required to achieve this strength will depend on the size of the tablet, but generally will be greater than about 5 kP/cm . Friability is a well-know measure of a device's resistance to surface abrasion that measures weight loss in percentage after subjecting the device to a standardized agitation procedure.
  • Friability values of from 0.8 to 1.0% are regarded as constituting the upper limit of acceptability.
  • Devices having a strength of greater than 5 kP/cm 2 generally are very robust, having a friability of less than 0. 5%.
  • Other methods for forming matrix controlled-release devices are well known in the pharmaceutical arts. See for example, Remington: The Science and Practice of Pharmacy, 20th Edition, 2000.
  • the agents described herein may also be incorporated into an osmotic control device.
  • Such devices generally include a core containing one or more agents as described herein and a water permeable, non-dissolving and non-eroding coating surrounding the core which controls the influx of water into the core from an aqueous environment of use so as to cause drug release by extrusion of some or all of the core to the environment of use.
  • the coating is polymeric, aqueous-permeable, and has at least one delivery port.
  • the core of the osmotic device optionally includes an osmotic agent which acts to imbibe water from the surrounding environment via such a semi-permeable membrane.
  • the osmotic agent contained in the core of this device may be an aqueous-swellable hydrophilic polymer or it may be an osmogen, also known as an osmagent.
  • Pressure is generated within the device which forces the agent(s) out of the device via an orifice (of a size designed to minimize solute diffusion while preventing the build-up of a hydrostatic pressure head).
  • osmotic control devices are disclosed in U. S. Patent Application Serial No. 09/495,061. [00191] Osmotic agents create a driving force for transport of water from the environment of use into the core of the device.
  • Osmotic agents include but are not limited to water- swellable hydrophilic polymers, and osmogens (or osmagens).
  • the core may include water-swellable hydrophilic polymers, both ionic and nonionic, often referred to as osmopolymers and hydrogels.
  • the amount of water-swellable hydrophilic polymers present in the core may range from about 5 to about 80 wt% (including for example, 10 to 50 wt%).
  • Nonlimiting examples of core materials include hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic) acid, poly (methacrylic) acid, polyvinylpyrrolidone (PVP) and crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers and PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate, vinyl acetate, and the like, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, x
  • hydrogels comprising interpenetrating networks of polymers that may be formed by addition or by condensation polymerization, the components of which may comprise hydrophilic and hydrophobic monomers such as those just mentioned.
  • Water-swellable hydrophilic polymers include but are not limited to PEO, PEG, PVP, sodium croscarmellose, HPMC, sodium starch glycolate, polyacrylic acid and crosslinked versions or mixtures thereof.
  • the core may also include an osmogen (or osmagent).
  • the amount of osmogen present in the core may range from about 2 to about 70 wt% (including, for example, from 10 to 50 wt%).
  • suitable osmogens are water-soluble organic acids, salts and sugars that are capable of imbibing water to thereby effect an osmotic pressure gradient across the barrier of the surrounding coating.
  • Typical useful osmogens include but are not limited to magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate, mannitol, xylitol, urea, sorbitol, inositol, raffinose, sucrose, glucose, fructose, lactose, citric acid, succinic acid, tartaric acid, and mixtures thereof.
  • the osmogen is glucose, lactose, sucrose, mannitol, xylitol, sodium chloride, including combinations thereof.
  • the core may include a wide variety of additives and excipients that enhance the performance of the dosage form or that promote stability, tableting or processing.
  • additives and excipients include tableting aids, surfactants, water- soluble polymers, pH modifiers, fillers, binders, pigments, disintegrants, antioxidants, lubricants and flavorants.
  • Nonlimiting examples of additives and excipients include but are not limited to those described elsewhere herein as well as microcrystalline cellulose, metallic salts of acids (e.g., aluminum stearate, calcium stearate, magnesium stearate, sodium stearate, zinc stearate), pH control agents (e.g., buffers, organic acids, organic acid salts, organic and inorganic bases), fatty acids, hydrocarbons and fatty alcohols (e.g., stearic acid, palmitic acid, liquid paraffin, stearyl alcohol, and palmitol), fatty acid esters (e.g., glyceryl (mono-and di-) stearates, triglycerides, glyceryl (palmiticstearic) ester, sorbitan esters (e.g., sorbitan monostearate, saccharose monostearate, saccharose monopalmitate, sodium stearyl fumarate), polyoxyethylene sorbitan esters), surfact
  • Nonlimiting examples of disintegrants are sodium starch glycolate (e. g., ExplotabTM CLV, (microcrystalline cellulose (e. g., AvicelTM), microcrystalline silicified cellulose (e.g., ProSolv TM ), croscarmellose sodium (e. g., Ac-Di-Sol TM ).
  • agent described herein is a solid amorphous dispersion formed by a solvent process
  • such additives may be added directly to the spray-drying solution when forming an agent described herein/concentration-enhancing polymer dispersion such that the additive is dissolved or suspended in the solution as a slurry, Alternatively, such additives may be added following the spray-drying process to aid in forming the final controlled release device.
  • a nonlimiting example of an osmotic device consists of one or more drug layers containing an agent described herein, such as a solid amorphous drug/polymer dispersion, and a sweller layer that comprises a water-swellable polymer, with a coating surrounding the drug layer and sweller layer.
  • an agent described herein such as a solid amorphous drug/polymer dispersion
  • a sweller layer that comprises a water-swellable polymer, with a coating surrounding the drug layer and sweller layer.
  • Each layer may contain other excipients such as tableting aids, osmagents, surfactants, water-soluble polymers and water-swellable polymers.
  • Such osmotic delivery devices may be fabricated in various geometries including bilayer (wherein the core comprises a drug layer and a sweller layer adjacent to each other), trilayer (wherein the core comprises a sweller layer sandwiched between two drug layers) and concentric (wherein the core comprises a central sweller agent surrounded by the drug layer).
  • the coating of such a tablet comprises a membrane permeable to water but substantially impermeable to drug and excipients contained within.
  • the coating contains one or more exit passageways or ports in communication with the drug-containing layer(s) for delivering the drug agent.
  • the drug-containing layer(s) of the core contains the drug agent (including optional osmagents and hydrophilic water-soluble polymers), while the sweller layer consists of an expandable hydrogel, with or without additional osmotic agents.
  • the tablet When placed in an aqueous medium, the tablet imbibes water through the membrane, causing the agent to form a dispensable aqueous agent, and causing the hydrogel layer to expand and push against the drug-containing agent, forcing the agent out of the exit passageway.
  • the agent can swell, aiding in forcing the drug out of the passageway. Drag can be delivered from this type of delivery system either dissolved or dispersed in the agent that is expelled from the exit passageway.
  • the rate of drag delivery is controlled by such factors as the permeability and thickness of the coating, the osmotic pressure of the drug-containing layer, the degree of hydrophilicity of the hydrogel layer, and the surface area of the device.
  • the thickness of the coating will reduce the release rate, while any of the following will increase the release rate: increasing the permeability of the coating; increasing the hydrophilicity of the hydrogel layer; increasing the osmotic pressure of the drug-containing layer; or increasing the device's surface area.
  • Other materials useful in forming the drag-containing agent include HPMC, PEO and PVP and other pharmaceutically acceptable carriers.
  • osmagents such as sugars or salts, including but not limited to sucrose, lactose, xylitol, mannitol, or sodium chloride, may be added.
  • Materials which are useful for forming the hydrogel layer include sodium CMC, PEO (e.g., polymers having an average molecular weight from about 5,000,000 to about 7,500,000 daltons), poly (acrylic acid), sodium (polyacrylate), sodium croscarmellose, sodium starch glycolat, PVP, crosslinked PVP, and other high molecular weight hydrophilic materials.
  • the delivery port(s) or exit passageway(s) may be located on the side of the tablet containing the drag agent or may be on both sides of the tablet or even on the edge of the tablet so as to connect both the drug layer and the sweller layer with the exterior of the device.
  • the exit passageway(s) may be produced by mechanical means or by laser drilling, or by creating a difficult-to-coat region on the tablet by use of special tooling during tablet compression or by other means.
  • the osmotic device can also be made with a homogeneous core surrounded by a semipermeable membrane coating, as in US3845770.
  • the agent described herein can be incorporated into a tablet core and a semipermeable membrane coating can be applied via conventional tablet-coating techniques such as using a pan coater.
  • a drug delivery passageway can then be formed in this coating by drilling a hole in the coating, either by use of a laser or mechanical means.
  • the passageway may be formed by rupturing a portion of the coating or by creating a region on the tablet that is difficult to coat, as described above.
  • an osmotic device comprises: (a) a single-layer compressed core comprising: (i) an agent described herein, (ii) a hydroxyethylcellulose, and (iii) an osmagent, wherein the hydroxyethylcellulose is present in the core from about 2.0% to about 35% by weight and the osmagent is present from about 15% to about 70% by weight; (b) a water- permeable layer surrounding the core; and (c) at least one passageway within the water-permeable layer (b) for delivering the drug to a fluid environment surrounding the tablet.
  • the device is shaped such that the surface area to volume ratio (of a water-swollen tablet) is greater than 0.6 mm "1 (including, for example, greater than 1.0 mm "1 ).
  • the passageway connecting the core with the fluid environment can be situated along the tablet band area.
  • the shape is an oblong shape where the ratio of the tablet tooling axes, i.e., the major and minor axes which define the shape of the tablet, are between 1.3 and 3 (including, for example, between 1.5 and 2.5).
  • the combination of the agent described herein and the osmagent have an average ductility from about 100 to about 200 Mpa, an average tensile strength from about 0.8 to about 2.0 Mpa, and an average brittle fracture index less than about 0.2.
  • the single-layer core may optionally include a disintegrant, a bioavailability enhancing additive, and/or a pharmaceutically acceptable excipient, carrier or diluent. Nonlimiting examples of such devices are disclosed, for example, in U. S. provisional Patent Application Serial No. 60/353,151. [00201] In certain embodiments, entrainment of particles of agents described herein in the extruding fluid during operation of such osmotic device is desirable.
  • the agent drug form is dispersed in the fluid before the particles have an opportunity to settle in the tablet core.
  • a disintegrant that serves to break up the compressed core into its particulate components.
  • standard disintegrants include materials such as sodium starch glycolate (e. g. , ExplotabTM CLV), microcrystalline cellulose (e. g., Avicel TM ), microcrystalline silicified cellulose (e. g., ProSoIv T ) and croscarmellose sodium (e. g., Ac-Di-SolTM), and other disintegrants known to those skilled in the art. Depending upon the particular formulation, some disintegrants work better than others.
  • non-gelling, non-swelling disintegrants provide a more rapid dispersion of the drug particles within the core as water enters the core.
  • non-gelling, non-swelling disintegrants are resins, for example, ion-exchange resins.
  • the resin is Amberlite IRP 88 (available from Rohm and Haas, Philadelphia, PA).
  • the disintegrant is present in amounts ranging from about 1-25% of the core agent.
  • Water-soluble polymers are added to keep particles of the agent suspended inside the device before they can be delivered through the passageway(s) (e.g., an orifice).
  • High viscosity polymers are useful in preventing settling.
  • the polymer in combination with the agent is extruded through the passageway(s) under relatively low pressures. At a given extrusion pressure, the extrusion rate typically slows with increased viscosity.
  • Certain polymers in combination with particles of the agent described herein form high viscosity solutions with water but are still capable of being extruded from the tablets with a relatively low force, hi contrast, polymers having a low weight-average, molecular weight ( ⁇ about 300,000) do not form sufficiently viscous solutions inside the tablet core to allow complete delivery due to particle settling.
  • Settling of the particles is a problem when such devices are prepared with no polymer added, which leads to poor drug delivery unless the tablet is constantly agitated to keep the particles from settling inside the core. Settling is also problematic when the particles are large and/or of high density such that the rate of settling increases.
  • the water-soluble polymers for such osmotic devices do not interact with the drug.
  • the water-soluble polymer is a non-ionic polymer.
  • a nonlimiting example of a non-ionic polymer forming solutions having a high viscosity yet still extrudable at low pressures is NatrosolTM 250H (high molecular weight hydroxyethylcellulose, available from Hercules Incorporated, Aqualon Division, Wilmington, DE; MW equal to about 1 million daltons and a degree of polymerization equal to about 3,700). Natrosol 25 OHTM provides effective drug delivery at concentrations as low as about 3% by weight of the core when combined with an osmagent.
  • Natrosol 250HTM NF is a high- viscosity grade nonionic cellulose ether that is soluble in hot or cold water.
  • the viscosity of a 1% solution of Natrosol 250H using a Brookfield LVT (30 rpm) at 25°C is between about 1, 500 and about 2,500 cps.
  • hydroxyethylcellulose polymers for use in these monolayer osmotic tablets have a weight-average, molecular weight from about 300,000 to about 1.5 million.
  • the hydroxyethylcellulose polymer is typically present in the core in an amount from about 2.0% to about 35% by weight.
  • an osmotic device is an osmotic capsule.
  • the capsule shell or portion of the capsule shell can be semipermeable.
  • the capsule can be filled either by a powder or liquid consisting of an agent described herein, excipients that imbibe water to provide osmotic potential, and/or a water-swellable polymer, or optionally solubilizing excipients.
  • the capsule core can also be made such that it has a bilayer or multilayer agent analogous to the bilayer, trilayer or concentric geometries described above.
  • Coated swellable tablets comprise a tablet core comprising an agent described herein and a swelling material, preferably a hydrophilic polymer, coated with a membrane, which contains holes, or pores through which, in the aqueous use environment, the hydrophilic polymer can extrude and carry out the agent.
  • the membrane may contain polymeric or low molecular weight water-soluble porosigens. Porosigens dissolve in the aqueous use environment, providing pores through which the hydrophilic polymer and agent may extrude.
  • porosigens are water-soluble polymers such as HPMC, PEG, and low molecular weight compounds such as glycerol, sucrose, glucose, and sodium chloride, hi addition, pores may be formed in the coating by drilling holes in the coating using a laser or other mechanical means, m this class of osmotic devices, the membrane material may comprise any film-forming polymer, including polymers which are water permeable or impermeable, providing that the membrane deposited on the tablet core is porous or contains water-soluble porosigens or possesses a macroscopic hole for water ingress and drug release.
  • Embodiments of this class of sustained release devices may also be multilayered, as described, for example, in EP378404.
  • the osmotic controlled- release device may comprise a soft-gel or gelatin capsule formed with a composite wall and comprising the liquid formulation where the wall comprises a barrier layer formed over the external surface of the capsule, an expandable layer formed over the barrier layer, and a semipermeable layer formed over the expandable layer.
  • a delivery port connects the liquid formulation with the aqueous use environment.
  • the osmotic controlled release devices of the present invention can also comprise a coating, hi certain embodiments, the osmotic controlled release device coating exhibits one or more of the following features: is water-permeable, has at least one port for the delivery of drug, and is non-dissolving and non-eroding during release of the drug formulation, such that drug is substantially entirely delivered through the delivery port(s) or pores as opposed to delivery primarily via permeation through the coating material itself. Delivery ports include any passageway, opening or pore whether made mechanically, by laser drilling, by pore formation either during the coating process or in situ during use or by rupture during use. hi certain embodiments, the coating is present in an amount ranging from about 5 to 30 wt% (including, for example, 10 to 20 wt%) relative to the core weight.
  • One form of coating is a semipermeable polymeric membrane that has the port(s) formed therein either prior to or during use. Thickness of such a polymeric membrane may vary between about 20 and 800 ⁇ m (including, for example, between about 100 to 500 ⁇ m). The diameter of the delivery port (s) may generally range in size from 0.1 to 3000 ⁇ m or greater (including, for example, from about 50 to 3000 ⁇ m in diameter). Such port(s) may be formed post-coating by mechanical or laser drilling or may be formed in situ by rupture of the coatings; such rupture may be controlled by intentionally incorporating a relatively small weak portion into the coating.
  • Delivery ports may also be formed in situ by erosion of a plug of water- soluble material or by rupture of a thinner portion of the coating over an indentation in the core, hi addition, delivery ports may be formed during coating, as in the case of asymmetric membrane coatings of the type disclosed in US5612059 and US5698220.
  • the delivery port may be formed in situ by rupture of the coating, for example, when a collection of beads that may be of essentially identical or of a variable agent are used. Drug is primarily released from such beads following rupture of the coating and, following rapture, such release may be gradual or relatively sudden.
  • the agent maybe chosen such that the beads rapture at various times following administration, resulting in the overall release of drag being sustained for a desired duration.
  • Coatings may be dense, microporous or asymmetric, having a dense region supported by a thick porous region such as those disclosed in US5612059 and US5698220.
  • the coating can be composed of a water- permeable material.
  • the coating may be composed of either a water-permeable or a water-impermeable material.
  • the coating is composed of a porous water-impermeable material, water permeates through the pores of the coating as either a liquid or a vapor.
  • Nonlimiting examples of osmotic devices that utilize dense coatings include US3995631 and US3845770.
  • Such dense coatings are permeable to the external fluid such as water and may be composed of any of the materials mentioned in these patents as well as other water-permeable polymers known in the art.
  • the membranes may also be porous as disclosed, for example, in US5654005 and US5458887 or even be formed from water-resistant polymers.
  • US5120548 describes another suitable process for forming coatings from a mixture of a water-insoluble polymer and a leachable water-soluble additive.
  • the porous membranes may also be formed by the addition of pore-formers as disclosed in US4612008.
  • vapor-permeable coatings may even be formed from extremely hydrophobic materials such as polyethylene or polyvinylidene difluorid that, when dense, are essentially water-impermeable, as long as such coatings are porous.
  • Materials useful in forming the coating include but are not limited to various grades of acrylic, vinyls, ethers, polyamides, polyesters and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration such as by crosslinking.
  • Nonlimiting examples of suitable polymers (or crosslinked versions) useful in forming the coating include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxiated ethylene- vinylacetate, EC, PEG, PPG, PEG
  • the coating agent comprises a cellulosic polymer, in particular cellulose ethers, cellulose esters and cellulose ester-ethers, i.e., cellulosic derivatives having a mixture of ester and ether substituents
  • the coating materials are made or derived from poly (acrylic) acids and esters, poly (methacrylic) acids and esters, and copolymers thereof
  • the coating agent comprises cellulose acetate
  • the coating comprises a cellulosic polymer and PEG
  • the coating comprises cellulose acetate and PEG.
  • Coating is conducted in conventional fashion, typically by dissolving or suspending the coating material in a solvent and then coating by dipping, spray coating or by pan-coating, hi certain embodiments, the coating solution contains 5 to 15 wt% polymer.
  • Typical solvents useful with the cellulosic polymers mentioned above include but are not limited to acetone, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, nitroethane, nitropropane, tetrachloroethane, 1,4- dioxane, tetrahydrofuran, diglyme, water, and mixtures thereof.
  • Pore-formers and non- solvents such as water, glycerol and ethanol
  • plasticizers such as diethyl phthalate
  • Pore-formers and their use in fabricating coatings are described, for example, in US5612059.
  • Coatings may also be hydrophobic microporous layers wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed, for example, in US5798119.
  • Such hydrophobic but water- vapor permeable coatings are typically composed of hydrophobic polymers such as polyalkenes, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.
  • Hydrophobic microporous coating materials include but are not limited to polystyrene, polysulfones, polyethersulfones, polyethylene, polypropylene, polyvinyl chloride, polyvinylidene fluoride and polytetrafluoroethylene.
  • Such hydrophobic coatings can be made by known phase inversion methods using any of vapor-quench, liquid quench, thermal processes, leaching soluble material from the coating or by sintering coating particles, hi thermal processes, a solution of polymer in a latent solvent is brought to liquid-liquid phase separation in a cooling step. When evaporation of the solvent is not prevented, the resulting membrane will typically be porous.
  • Such coating processes may be conducted by the processes disclosed, for example, in US4247498, US4490431 and US4744906.
  • Osmotic controlled-release devices may be prepared using procedures known in the pharmaceutical arts. See for example, Remington: The Science and Practice of Pharmacy, 20th Edition, 2000.
  • the agents described herein may be provided in the form of microparticulates, generally ranging in size from about lO ⁇ m to about 2mm (including, for example, from about lOO ⁇ m to lmm in diameter).
  • Such multiparticulates may be packaged, for example, in a capsule such as a gelatin capsule or a capsule formed from an aqueous-soluble polymer such as HPMCAS, HPMC or starch; dosed as a suspension or slurry in a liquid; or they may be formed into a tablet, caplet, or pill by compression or other processes known in the art.
  • Such multiparticulates may be made by any known process, such as wet- and dry- granulation processes, extrusion/spheronization, roller-compaction, melt-congealing, or by spray-coating seed cores.
  • the agent described herein and optional excipients may be granulated to form multiparticulates of the desired size.
  • Other excipients such as a binder (e. g., microcrystalline cellulose), may be blended with the agent to aid in processing and forming the multiparticulates.
  • a binder such as microcrystalline cellulose may be included in the granulation fluid to aid in forming a suitable multiparticulate.
  • the resulting particles may themselves constitute the therapeutic composition or they may be coated by various film-forming materials such as enteric polymers or water-swellable or water-soluble polymers, or they may be combined with other excipients or vehicles to aid in dosing to patients.
  • a compound described herein can be provided in an immediate release formulation together with a fibrate (e.g., Tricor) or a CETP inhibitor (e.g., torcetrapib) in a controlled release format.
  • a compound described herein can be provided together with an HMG CoA reductase inhibitor in an immediate release formulation.
  • a compound described herein can be coformulated with an HMG CoA reductase inhibitor in the immediate release formulation described in WO05/011634 (page 29, line 31 to page 33 (entire page).
  • a compound described herein is provided in a controlled release format together with another agent (e.g., an HMG CoA reductase inhibitor) in an immediate release formulation.
  • another agent e.g., an HMG CoA reductase inhibitor
  • one or more agents described herein can be provided in an immediate release formulation together with one or more other agents (for example, a fibrate and/or torcetrapib) in a controlled release format.
  • the agents can be administered, e.g., by intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, topical, sublingual, intraarticular (in the joints), intradermal, buccal, ophthalmic (including intraocular), intranasaly (including using a cannula), or by other routes.
  • the agents can be administered orally, e.g., as a tablet or cachet containing a predetermined amount of the active ingredient, gel, pellet, paste, syrup, bolus, electuary, slurry, capsule, powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion, via a micellar formulation (see, e.g., WO 97/11682) via a liposomal formulation (see, e.g., EP 736299,WO 99/59550 and WO 97/13500), via formulations described in WO 03/094886 or in some other form.
  • a micellar formulation see, e.g., WO 97/11682
  • a liposomal formulation see, e.g., EP 736299,WO 99/59550 and WO 97/13500
  • Orally administered compositions can include binders, lubricants, inert diluents, lubricating, surface active or dispersing agents, flavoring agents, and humectants.
  • Orally administered formulations such as tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • the agents can also be administered transdermally (i.e. via reservoir-type or matrix-type patches, microneedles, thermal poration, hypodermic needles, iontophoresis, electroporation, ultrasound or other forms of sonophoresis, jet injection, or a combination of any of the preceding methods (Prausnitz et al. 2004, Nature Reviews Drug Discovery 3:115)).
  • the agents can be administered locally, for example, at the site of injury to an injured blood vessel.
  • the agents can be coated on a stent.
  • the agents can be administered using high- velocity transdermal particle injection techniques using the hydrogel particle formulation described in U.S. 20020061336. Additional particle formulations are described in WO 00/45792, WO 00/53160, and WO 02/19989.
  • An example of a transdermal formulation containing plaster and the absorption promoter dimethylisosorbide can be found in WO 89/04179.
  • WO 96/11705 provides formulations suitable for transdermal administration.
  • the agents can be administered in the form a suppository or by other vaginal or rectal means.
  • the agents can be administered in a transmembrane formulation as described in WO 90/07923.
  • the agents can be administered non-invasively via the dehydrated particles described in U.S. 6,485,706.
  • the agent can be administered in an enteric-coated drug formulation as described in WO 02/49621.
  • the agents can be administered intranasaly using the formulation described in U.S. 5,179,079.
  • Formulations suitable for parenteral injection are described in WO 00/62759.
  • the agents can be administered using the casein formulation described in U. S. 20030206939 and WO 00/06108.
  • the agents can be administered using the particulate formulations described in U.S. 20020034536.
  • the agents can be administered by pulmonary route utilizing several techniques including but not limited to intratracheal instillation (delivery of solution into the lungs by syringe), intratracheal delivery of liposomes, insufflation (administration of powder formulation by syringe or any other similar device into the lungs) and aerosol inhalation.
  • Aerosols e.g., jet or ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-powder inhalers (DPIs)
  • MDIs metered-dose inhalers
  • DPIs dry-powder inhalers
  • Aerosol formulations are stable dispersions or suspensions of solid material and liquid droplets in a gaseous medium and can be placed into pressurized acceptable propellants, such as hydrofluroalkanes (HFAs, i.e. HFA- 134a and HFA-227, or a mixture thereof), dichlorodifluoromethane (or other chlorofluocarbon propellants such as a mixture of Propellants 11, 12, and/or 114), propane, nitrogen, and the like.
  • HFAs hydrofluroalkanes
  • HFA- 134a and HFA-227 or a mixture thereof
  • dichlorodifluoromethane or other chlorofluocarbon propellants such as a mixture of Propellants 11, 12, and/or 114
  • propane nitrogen, and the like.
  • Pulmonary formulations may include permeation enhancers such as fatty acids, and saccharides, chelating agents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g., benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5% but possibly up to 20%, by weight). Ethanol is commonly included in aerosol compositions as it can improve the function of the metering valve and in some cases also improve the stability of the dispersion. Pulmonary formulations may also include surfactants which include but are not limited to bile salts and those described in U.S.
  • the surfactants described in U.S. 6,524,557 e.g., a C8-C16 fatty acid salt, a bile salt, a phospholipid, or alkyl saccharide are advantageous in that some of them also reportedly enhance absorption of the compound in the formulation.
  • dry powder formulations comprising a therapeutically effective amount of active compound blended with an appropriate carrier and adapted for use in connection with a dry-powder inhaler.
  • Absorption enhancers which can be added to dry powder formulations of the present invention include those described in U.S. 6,632,456.
  • WO 02/080884 describes new methods for the surface modification of powders. Aerosol formulations may include U.S.
  • Pulmonary formulations containing stable glassy state powder are described in U.S. 20020141945 and U.S. 6,309,671.
  • Other aerosol formulations are described in EP 1338272A1 WO 90/09781, U. S. 5,348,730, U.S. 6,436,367, WO 91/04011, and U.S. 6,294,153 and U.S. 6,290,987 describes a liposomal based formulation that can be administered via aerosol or other means.
  • Powder formulations for inhalation are described in U.S. 20030053960 and WO 01/60341.
  • the agents can be administered intranasally as described in U.S. 20010038824.
  • Solutions of medicament in buffered saline and similar vehicles are commonly employed to generate an aerosol in a nebulizer.
  • Simple nebulizers operate on Bernoulli's principle and employ a stream of air or oxygen to generate the spray particles.
  • More complex nebulizers employ ultrasound to create the spray particles. Both types are well known in the art and are described in standard textbooks of pharmacy such as Sprowls' American Pharmacy and Remington's The Science and Practice of Pharmacy.
  • Other devices for generating aerosols employ compressed gases, usually hydrofluorocarbons and chlorofluorocarbons, which are mixed with the medicament and any necessary excipients in a pressurized container, these devices are likewise described in standard textbooks such as Sprowls and Remington.
  • the agent can be incorporated into a liposome to improve half-life.
  • the agent can also be conjugated to polyethylene glycol (PEG) chains.
  • PEG polyethylene glycol
  • Methods for pegylation and additional formulations containing PEG-conjugates i.e. PEG-based hydrogels, PEG modified liposomes
  • the agent can be administered via a nanocochleate or cochleate delivery vehicle (BioDelivery Sciences International).
  • the agents can be delivered transmucosally (i.e. across a mucosal surface such as the vagina, eye or nose) using formulations such as that described in U.S. 5,204,108.
  • the agents can be formulated in microcapsules as described in WO 88/01165.
  • the agent can be administered intra-orally using the formulations described in U.S. 20020055496, WO 00/47203, and U.S. 6,495,120.
  • the agent can be delivered using nanoemulsion formulations described in WO 01/91728A2.
  • proteins e.g., nitric oxide synthase isoforms, HDL associated proteins such as ApoA-I or Apo A-I Milano
  • peptides e.g., peptides which mitigates one or more symptoms of atherosclerosis, peptides and peptide analogues that mimic the structural and pharmacological properties of human ApoA-I, Exenatide®.
  • the recombinant or purified protein is administered together with a compound described herein.
  • genes encoding the protein or peptide to be delivered may be administered, rather than the protein.
  • Gene transfer can be obtained using direct transfer of genetic material, in a plasmid or viral vector, or via transfer of genetic material in cells or carriers such as cationic liposomes.
  • Such methods are well known in the art and readily adaptable for use in the therapies described herein.
  • studies by Wolff et al., Biotechniques 11:474-85 (1991) demonstrate injection of naked DNA into muscle allows long term and low expression levels of proteins coded for within the DNA sequence.
  • Administration of naked DNA to smooth muscle layers can be achieved by use of an intramural device, such as an INFILTRATORTM and allow expression of the proteins or their alpha helical domains to treat the injured vessel.
  • Transfer vectors can be any nucleotide construction used to deliver genes into cells (e.g., a plasmid), or as part of a general strategy to deliver genes, e.g., as part of recombinant retrovirus or adenovirus (Ram et al. Cancer Res. 53:83-88, (1993)).
  • Appropriate means for transfection, including viral vectors, chemical transfectants, or physico-mechanical methods such as electroporation and direct diffusion of DNA, are described by, for example, Wolff, J. A., et al., Science, 247, 1465-1468, (1990); and Wolff, J. A. Nature, 352, 815-818, (1991).
  • Plasmid or viral vectors are agents that transport the gene into a cell without degradation and may include a promoter yielding expression of the gene in the cell into which it is delivered, hi certain embodiments vectors are derived from either a virus or a retrovirus.
  • Viral vectors include but are not limited to those derived from Adenovirus, Adeno-associated virus, Herpes virus, Vaccinia virus, Polio virus, AIDS virus, neuronal trophic virus, Sindbis and other RNA viruses, including these viruses with the HIV backbone. Vectors from other viral families which share the properties of these viruses may make them suitable for use as vectors.
  • Retroviral vectors include but are not limited to those derived from include Murine Maloney Leukemia virus, MMLV, and retroviruses that express the desirable properties of MMLV as a vector. In certain emobodiments where non-proliferating cells are involved, retroviral vectors are not used. Retroviral vectors, in general, are described by Verma, I. M., Retroviral vectors for gene transfer, hi MICROBIOLOGY- 1985, American Society for Microbiology, pp. 229-232, Washington, (1985). Examples of methods for using retroviral vectors for gene therapy are described in US4868116, US4980286, WO90/02806, WO 89/07136 and Mulligan, (Science 260:926-932 (1993)).
  • Adenovirus vectors are relatively stable and easy to work with, have high titers, and can be delivered in aerosol formulation, and can transfect non-dividing cells.
  • the construction of replication-defective adenoviruses has been described (Berkner et al., J. Virology 61:1213-1220 (1987); Massie et al, MoI. Cell. Biol. 6:2872-2883 (1986); Haj-Ahmad et al., J. Virology 57:267-274 (1986); Davidson et al., J.
  • Adenoviral derived vectors are limited in the extent to which they can spread to other cell types, since they can replicate within an initial infected cell, but are unable to form new infectious viral particles. Recombinant adenoviruses have been shown to achieve high efficiency gene transfer after direct, in vivo delivery to airway epithelium, hepatocytes, vascular endothelium, CNS parenchyma and a number of other tissue sites (Morsy, J. Clin. Invest.
  • Pox viral vectors can be used in the gene transfer techniques described herein.
  • the viral/retroviral vector used in the gene transfer techniques described herein have been engineered so as to suppress the immune response of the host organism, elicited by the viral antigens.
  • these vectors carry coding regions for Interleukin 8 or 10.
  • the viral/retroviral vectors described herein have one or more of the early genes removed and a gene or gene/promotor cassette inserted into the viral genome in place of the removed viral DNA.
  • the inserted genes in viral/retroviral vectors usually contain promoters, and/or enhancers to help control the expression of the desired gene product.
  • a promoter is generally a sequence or sequences of DNA that function when in a relatively fixed location in regard to the transcription start site.
  • a promoter contains core elements required for basic interaction of RNA polymerase and transcription factors, and may contain upstream elements and response elements.
  • Promoters controlling transcription from vectors in mammalian host cells may be obtained from various sources, for example, the genomes of viruses such as: polyoma, Simian Virus 40 (SV40), adenovirus, retroviruses, hepatitis-B virus and most preferably cytomegalovirus, or from heterologous mammalian promoters, e.g., beta actin promoter.
  • the early and late promoters of the SV40 virus are conveniently obtained as an SV40 restriction fragment which also contains the SV40 viral origin of replication (Fiers et al., Nature, 273:113 (1978)).
  • the immediate early promoter of the human cytomegalovirus is conveniently obtained as a Hindm E restriction fragment (Greenway, P. J. et al., Gene 18:355-360 (1982)). Promoters from the host cell (to which the viral vector is being transferred) or related species also are useful herein.
  • Enhancer generally refers to a sequence of DNA that functions at no fixed distance from the transcription start site and can be either 5' (Laimins, L. et al., Proc. Natl. Acad. Sci. 78:993 (1981)) or 3' (Lusky, M. L., et al., MoI. Cell Bio. 3:1108 (1983)) to the transcription unit. Furthermore, enhancers can be within an intron (Banerji, J. L. et al., Cell 33:729 (1983)) as well as within the coding sequence itself (Osborne, T. F., et al., MoI. Cell Bio. 4:1293 (1984)).
  • Enhancers function to increase transcription from nearby promoters. Enhancers also often contain response elements that mediate the regulation of transcription. Promoters can also contain response elements that mediate the regulation of transcription. Enhancers often determine the regulation of expression of a gene. While many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, ⁇ -fetoprotein and insulin), typically one will use an enhancer from a eukaryotic cell virus.
  • Enhancers include but are not limited to the SV 40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers.
  • the promotor and/or enhancer may be specifically activated either by light or specific chemical events which trigger their function.
  • Systems can be regulated by reagents such as tetracycline and dexamethasone.
  • reagents such as tetracycline and dexamethasone.
  • irradiation such as gamma irradiation, or alkylating chemotherapy drugs.
  • the promoter and/or enhancer region act as a constitutive promoter and/or enhancer to maximize expression of the region of the transcription unit to be transcribed.
  • the promoter and/or enhancer region is active in all eukaryotic cell types. Promoters include but are not limited to the CMV promoter (650 bases), SV40 promoters, cytomegalovirus (full length promoter), and retroviral vector LTF.
  • Expression vectors used in eukaryotic host cells may also contain sequences necessary for the termination of transcription which may affect mRNA expression. These regions are transcribed as polyadenylated segments in the untranslated portion of the mRNA encoding tissue factor protein. The 3' untranslated regions also include transcription termination sites.
  • the transcription unit also contains a polyadenylation region (e.g., that derived from the SV40 early polyadenylation signal consisting of about 400 bases). One benefit of this region is that it increases the likelihood that the transcribed unit will be processed and transported like mRNA.
  • the identification and use of polyadenylation signals in expression constructs is well established.
  • homologous polyadenylation signals are used in the transgene constructs.
  • the transcribed units contain other standard sequences alone or in combination with the above sequences improve expression from, or stability of, the construct.
  • the viral/retroviral vectors can include nucleic acid sequence encoding a marker product. This marker product is used to determine if the gene has been delivered to the cell and once delivered is being expressed.
  • suitable selectable markers for mammalian cells are dihydrofolate reductase (DHFR), thymidine kinase, neomycin, neomycin analog G418, hydromycin, and puromycin. When such selectable markers are successfully transferred into a mammalian host cell, the transformed mammalian host cell can survive if placed under selective pressure.
  • the compounds and pharmaceutical formulations described herein may be contained in a kit.
  • the kit may include single or multiple doses of two or more agents, each packaged or formulated individually, or single or multiple doses of two or more agents packaged or formulated in combination.
  • one or more agents can be present in first container, and the kit can optionally include one or more agents in a second container.
  • the container or containers are placed within a package, and the package can optionally include administration or dosage instructions.
  • a kit can include additional components such as syringes or other means for administering the agents as well as diluents or other means for formulation.
  • kits can comprise: a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier, vehicle or diluent; and b) a container or packaging.
  • the kits may optionally comprise instructions describing a method of using the pharmaceutical compositions in one or more of the methods described herein (e.g., preventing or treating vascular diseases/disorders and conditions (including but not limited to arteriosclerosis, atherosclerosis, cardiovascular disease, cerebrovascular disease, renovascular disease, mesenteric vascular disease, pulmonary vascular disease, ocular vascular disease and peripheral vascular disease), hyperlipidemia (including but not limited to hypercholesterolemia, hypertriglyceridemia, sitosterolemia), hypertension, angina, cardiac arrhythmias, congestive heart failure, and stroke).
  • vascular diseases/disorders and conditions including but not limited to arteriosclerosis, atherosclerosis, cardiovascular disease, cerebrovascular disease, renovascular disease, mesenteric vascular disease, pulmonary
  • the kit may optionally comprise a second pharmaceutical composition comprising one or more additional agents chosen from (1) a dyslipidemic agent, (2) an anti-diabetic agent, (3) an anti-hypertensive agent, (4) an anti-obesity agent, (5) an agent used to treat autoimmune disorders, (6) an agent used to treat demylenation and its associated disorders, (7) an agent used to treat Alzheimer's disease, (8) a blood modifier, (9) a hormone replacement agent/composition, (10) a chemotherapeutic agent, (11) a peptide which mitigates one or more symptoms of atherosclerosis, (12) an anti-cancer agent, and (13) an agent used to treat bone loss and associated disorders and a pharmaceutically acceptable carrier, vehicle or diluent.
  • the pharmaceutical composition comprising the compound described herein and the second pharmaceutical composition contained in the kit may be optionally combined in the same pharmaceutical composition.
  • a kit includes a container or packaging for containing the pharmaceutical compositions and may also include divided containers such as a divided bottle or a divided foil packet.
  • the container can be, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is in turn contained within a box.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a “daily dose” can be a single tablet or capsule or several tablets or capsules to be taken on a given day.
  • a daily dose of one or more compositions of the kit can consist of one tablet or capsule while a daily dose of another one or more compositions of the kit can consist of several tablets or capsules.
  • a kit can take the form of a dispenser designed to dispense the daily doses one at a time in the order of their intended use. The dispenser can be equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory-aid is a mechanical counter which indicates the number of daily doses that have been dispensed.
  • a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • This model is based on models described by Burnett et al, (Burnett, DA. Caplen, MA, Browne, ME, Zhau, H., Altmann, SW., Davis, HR Jr., Clader, JW. Bioorg. Med. Chem. Lett. 2002,12(3):315-8) and Sparrow et al, (Sparrow, CP., Patel, S., Baffle, J., Chao, Y-S., Hernandez, M., Lam, M-H., Montenegro, J., Wright, SD., Detmers, PA. J. Lipid Res. 1999 40: 1747-1757).
  • mice Female Sprague-Dawley rats weighing 150-25Og are separated into groups of 3 and fasted overnight. The animals (4-6/group) are dosed perorally with 300 ⁇ L test compounds in olive oil or suitable vehicle. Thirty minutes later, 3-5 microCuries 3 H-cholesterol per rat are delivered perorally in 300 ⁇ L olive oil . After three hours, 200 ⁇ L serum is collected, vortexed with scintillation fluid, and measured for radioactivity in a scintillation counter. Percent inhibition is defined as 100*(l- Ctes/C ct ri ), where C test and C ctr i refer to 3 H levels in serum for the test compound and for the vehicle only control, respectively. Percent inhibition values are reported for a fixed dose. The ED 50 is the dose at which the half-maximal effect on serum 3 H levels is observed for a given test compound.
  • mice weighing 20-3Og are separated into groups of 3-8 and fasted overnight.
  • the animals (3-8/group) are dosed perorally with 200 ⁇ L test compound in olive oil or suitable vehicle.
  • 3-5 microCuries H- cholesterol per mouse are delivered perorally in 200 ⁇ L olive oil.
  • 100 ⁇ L serum is collected, vortexed with scintillation fluid, and measured for radioactivity in a scintillation counter.
  • Percent inhibition and ED 50 are defined as in the Rat Cholesterol Absorption Model above.
  • Hamsters are separated into groups of six and given a controlled cholesterol diet (Purina Chow #5001 containing 0.5% cholesterol) for seven days. Diet consumption is monitored to determine dietary cholesterol exposure in the face of test compounds. The animals are dosed with the test compound once daily beginning with the initiation of diet. Dosing is by oral gavage of 0.2 mL of corn oil alone (control group) or solution (or suspension) of test compound in corn oil. All animals moribund or in poor physical condition are euthanized. After seven days, the animals are anesthetized by intramuscular (IM) injection of ketamine and sacrificed by decapitation.
  • IM intramuscular
  • Blood is collected into vacutainer tubes containing EDTA for plasma lipid analysis and the liver excised for tissue lipid analysis. Lipid analysis is conducted as per published procedures (Schnitzer-Polokoff, R., et al, Comp. Biochem. Physiol, 1991 99A, 4, 665-670) and data are reported as percent reduction of lipid versus control.
  • Compounds are prepared in suitable formulations for oral and intravenous administration. Compounds are administered via intravenous injection (tail vein (rat), femoral vain (hamster), peripheral vain (monkey), cephalic vein (dog)) and orally (via a capsule (dogs) or gavage (all others)) to independent groups of test animals which are either fasted overnight or non-fasted. Serum or plasma is collected at various time points and assayed for the presence of compounds using an LC/MS/MS detection method.
  • Experiment samples are either diluted 15-fold in 30% acetonitrile in water, injected onto an in-line sample extraction cartridge (Waters Oasis HLB Direct Connect) and loaded onto a reverse phase HPLC column fitted with a appropriate guard column or prepared using a protein crash, dried under nitrogen, resuspended in 30% acetonitrile in water and loaded onto a reverse phase HPLC column fitted with a appropriate guard column. Samples are eluted from the reverse phase HPLC column with a gradient. A Micromass Quattro Micro (Waters Corporation, Milford, MA) triple quadrupole mass spectrometer operated in MRM mode is used for detection.
  • MRM mode Micromass Quattro Micro
  • Concentrations are calculated based on a standard concentration curve of compound or standard curves generated using peak area ratio of compound to internal standard vs. concentration.
  • MassLynx software Waters, Corporation, Milford, MA
  • a concentration versus time plot is generated from the data in Microsoft Excel, Summit Software PK Solutions 2.0, GraphPad Prism (GraphPad Software, Inc., San Diego, CA) or WinNonlin Professional Version 4.1 (Pharsight Corporation, Mountain View, CA) to generate pharmacokinetic curves.
  • ACAT cholesterol acyltransferase
  • Formation of 14 C-cholesteryl oleate is determined by separation of the ACAT assay reaction products by thin-layer chromatography (TLC) and visualization by phosphorimaging. Percent inhibition is calculated for each compound dose, and IC 50 values are determined using GraphPad Prism by regression analysis of percent inhibition plotted as a function of the logarithmic value of the sample concentration.
  • mice Three hours after administration of the tritiated radioligand, animals are euthanized by CO 2 overdose, the small intestine dissected, flushed with cold saline, and placed into an empty tube on ice. The small intestine is cut into ⁇ 6 cm segments. The intestinal epithelial mucosa is extruded from each segment, homogenized in PBS, and the radioactivity in the homogenate is counted by liquid scintillation counting. Results are normalized for protein content of the homogenates. Tritiated radioligand binding to the hamster small intestine in the presence and absence of test compound is determined by calculating the average bound radioactivity per mg of protein (DPM/mg) for each treatment group. Percent tritiated radioligand binding is calculated for each compound using the formulas:
  • a desirable medicament would inhibit cholesterol absorption without affecting the acute absorption of other important molecules of dietary origin.
  • Such a cholesterol absorption inhibitor would not interfere with the absorption of triglyceride, progesterone, ethinyl estradiol, vitamin A, vitamin D, or taurocholic acid.
  • cholestyramine which is in clinical use to lower serum cholesterol, sequesters bile acids in the intestine, ultimately leading to a decrease in plasma cholesterol by upregulating the synthesis of bile acids from cholesterol in the liver.
  • Two side effects of cholestyramine are gastrointestinal discomfort and the sequestration of fat-soluble vitamins.
  • ezetimibe a known cholesterol absorption inhibitor, does not appear to affect fat-soluble vitamin absorption in humans. In addition, ezetimibe does not inhibit the absorption of taurocholic acid, suggesting that certain cholesterol absorption inhibitors can lower serum cholesterol without inhibiting the ileal Na + /bile acid cotransporter.
  • Assays can also be performed using the known cholesterol absorption inhibitor molecule, (3R,4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one is for comparison.
  • rat cholesterol absorption model groups of five rats receive each of the compounds of the invention alone (1 mg/kg) or in combination with (3R,4S)-l-(4- fluorophenyl)-3 - [(3 S)-3 -(4-fluorophenyl)-3 -hydroxypropyl] -4-(4- hydroxyphenyl)azetidin-2-one (each at lmg/kg) or vehicle (olive oil) via oral gavage. Serum radioactivity (DPM) is measured and the average values are plotted.
  • DPM Serum radioactivity
  • the compounds of the invention can be tested to determine their effects on general activity (e.g., behavioural, autonomic and motor capabilities), for example, using Irwin's method (Psychopharmacologia - 1968 13:222-57). Briefly, groups of rodents receive a single administration of vehicle or different doses of test compound by oral gavage. Irwin observations are performed at 30, 60, 90, 180 and 300 minutes post dosing. Animals are generally observed 7 days post dosing. Electrophysiological Assays
  • hERG channels are expressed in a human embryonic kidney (HEK293) cell line that lacks endogenous I ⁇ r - HEK293 cells are stably transfected with hERG cDNA. Stable transfectants are selected by coexpression with the G418-resistance gene incorporated into the expression plasmid. Selection pressure is maintained by including G418 in the culture medium.
  • Cells are cultured in Dulbecco's Modified Eagle Medium / Nutrient Mixture F- 12 (D-MEM/F-12) supplemented with 10% fetal bovine serum, 100 U/mL penicillin G sodium, 100 ⁇ g/mL streptomycin sulfate and 500 ⁇ g/mL G418. Cells are maintained in tissue culture incubators at 37 0 C in a humidified 95% air, 5% CO 2 atmosphere, with stocks maintained in cryogenic storage. Cells used for electrophysiology are plated in plastic culture dishes.
  • Test solution reference substance (E-4031, 500 nm) and positive control (terfenadine, 60 nm) are prepared fresh daily in HEPES -buffered physiological saline (HB-PS) solution (composition in mM): NaCl, 137; KCl, 4.0; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH. All test and control solutions also contain 0.3% dimethylsulfoxide (DMSO). Thus the vehicle control solution is HB-PS + DMSO > 0.3%.
  • DMSO dimethylsulfoxide
  • Micropipette solution for whole cell patch clamp recordings is composed of (mM): potassium aspartate, 130; MgCl 2 , 5; EGTA, 5; ATP, 4; HEPES, 10; pH adjusted to 7.2 with KOH. The recording is performed at a temperature of 35 + 2 0 C.
  • Micropipettes for patch clamp recording are made from glass capillary tubing using a P-97 micropipette puller (Sutter Instruments, Novato, CA). A commercial patch clamp amplifier is used for whole cell recordings. Before digitization, current records are low-pass filtered at one-fifth of the sampling frequency.
  • Steady state is defined by the limiting constant rate of change with time (linear time dependence). The steady state before and after test article application is used to calculate the percentage of current inhibited at each concentration. Percent activation at each concentration in the test group is compared with the vehicle control group using one-way ANOVA followed by Dunnett's multiple comparison test (JMP Version 5.0.1, SAS Institute, Gary, NC).
  • Test compound at different concentrations is applied to cells to deterimine effect on hERG current amplitude.
  • the average value of 3 cells for each group ⁇ standard error of the mean (SEM) is determined and compared to the positive control terfenadine, a known hERG channel inhibitor.
  • a solid state transducer for dP/dT is placed in the left cardiac ventricle, and an epicardial electrode is put into place.
  • the test compound is infused followed by terfenadine at progressively higher doses, beginning at 1 ⁇ g/kg/min for 15 minutes and increased incrementally until a cardiovascular collapse ensues.
  • Parameters measured are: blood pressure, heart rate, dP/dT, and the QT-interval. From the QT interval and the heart rate, a QTc interval may be calculated. Measurements of hemodynamics and electrical activity are made in response to the test compound and to control.
  • potassium and cycle length can be assessed using standard microelectrode techniques in canine Purkinje fibers (Gintant et al. 2001 J.Cardiovasc.Pharmacol. 37:607-618) and in rabbit Purkinje fibers (Lu et al. 2002 Europ.J.Pharaiacol. 452:183- 192).
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures, hi these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
  • the starting materials in the case of suitably substituted azetidinones, may be obtained by the methods described in WO 02/50027, WO 97/16424, WO 95/26334, WO 95/08532 and WO 93/02048, the disclosures of which are incorporated herein by reference.
  • Example 1 Preparation of (3R,4S)-4-(3,3'-dihydroxybiphenyl-4-yl)-3-[(3R)- 3 -hydroxyoctyl] - 1 -phenylazetidin-2-one (10).
  • the compound 5-oxodecanoic acid (1) is asymmetrically reduced with Bakers' yeast to (5i?)-5-hydroxydecanoic acid (2a) according to published procedure, (Utaka, M.; Watabu, H.; Takeda, A. J. Org. Chem. 1987, 52, 4363-4368). If the pH is maintained at greater than 6, (6i?)-6-pentyltetrahydro-2H-pyran-2-one (3) generally does not form.
  • Treatment of 2a with two equivalents of tert-butyldimethylsilyl chloride and base followed by careful hydrolysis with dilute aqueous lithium hydroxide in methanol gives protected alcohol 2b.
  • Treatment of 2b with pivaloyl chloride followed by reaction with (4 * S)-(+)-4-phenyl-l,3-oxazolidin-2-one gives compound 4.
  • 2-Hydroxy-4-bromobenzaldehyde 5 is prepared by reaction of 3- bromophenol with paraformaldehyde in the presence of magnesium chloride and excess triethylamine in acetonitrile. Condensation of 5 with aniline gives the desired imine 6 that is converted to the benzyl protected derivative 7 upon treatment with benzyl bromide and potassium carbonate in DMF.
  • Example 2 Synthesis of (lS)-l,5-anhydiO-l-(3'-hydroxy-4'- ⁇ (2S,3R)-3- [(3R)-3-hydroxyoctyl]-4-oxo-l-phenylazetidin-2-yl ⁇ biphenyl-4-yl)-D-glucitol (17).
  • Example 3 Synthesis of (3'-hydroxy-4'- ⁇ (2S,3R)-3-[(3R)-3-hydroxyoctyl]-4- oxo-l-phenylazetidin-2-yl ⁇ bi ⁇ henyl-4-yl)phosphonic acid (21).
  • Suzuki coupling of 20 with 9 gives the expected biphenyl derivative that is deprotected by hydrogenolysis over palladium on carbon and finally treatment with bromotrimethylsilane and aqueous HF treatment gives the desired product 21.
  • Example 4 Synthesis of 2,6-anhydro-l-deoxy-l-(3-hydroxy-4- ⁇ (2S,3R)-3- [(3R)-3-hydroxyoctyl]-4-oxo-l-phenylazetidin-2-yl ⁇ phenyl)-D-glycero-D-gulo- heptitol (26).
  • Example 5 Synthesis of (3R,4S)-3-[(3S)-3-cyclohexyl-3-hydroxypropyl]-4- (3,3'-dihydroxybiphenyl-4-yl)- 1 -phenylazetidin-2-one (32); (IS)-1 ,5-anhydro-l -(4'- ⁇ (2S,3R)-3-[(3S)-3-cyclohexyl-3-hydiOxypropyl]-4-oxo-l-phenylazetidin-2-yl ⁇ -3'- hydroxybiphenyl-4-yl)-D-glucitol (33); (4 1 - ⁇ (2S,3R)-3-[(3S)-3-cyclohexyl-3- hydroxypropyl]-4-oxo-l-phenylazetidm-2-yl ⁇ -3'-hydroxybiphenyl-4-yl)phosphonic acid (34); and 2,
  • the scheme commences with the asymmetric reduction of 5-cyclohexyl-5- oxopentanoic acid (27) with Bakers' yeast to (S ⁇ -S-cyclohexyl-S-hydroxypentanoic acid (28a) according to the published procedure, (Utaka, M.; Watabu, H.; Takeda, A. J. Org. Chetn. 1987, 52, 4363-4368).
  • 28a Treatment of 28a with two equivalents oftert- butyldimethylsilyl chloride and base followed by careful hydrolysis with dilute aqueous lithium hydroxide in methanol gives protected alcohol 28b.
  • Example 6 Synthesis of (lS)-l,5-anhydro-l-(3'-hydroxy-4'- ⁇ (2S,3R)-3- [(3R)-3-hydroxyoctyl]-4-oxo-l-phenylazetidin-2-yl ⁇ biphenyl-3-yl)-D-glucitol (39).
  • Suzuki coupling of 38 with 9 gives the expected biphenyl derivative, which is deprotected by first hydrolysis in aqueous methanol and triethylarnine, then hydrogenolysis over palladium on carbon and finally treatment with aqueous HF to give the desired product 39.

Abstract

L'invention concerne un genre chimique de 1,4-diphényl-3-hydroxyalkyl-2-azétidinones utilisé dans le traitement de l'hypercholestérolémie et des troubles associés, ayant une formule (I).
EP06759488A 2005-05-10 2006-05-10 Derives de 1,4-diphenyl-3-hydroxyalkyl-2-azetidinone utilises dans le traitement de l'hypercholesterolemie Withdrawn EP1879860A2 (fr)

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