WO2013037984A1 - Conjugués anti-inflammatoires et antioxydants permettant de traiter les troubles métaboliques - Google Patents

Conjugués anti-inflammatoires et antioxydants permettant de traiter les troubles métaboliques Download PDF

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WO2013037984A1
WO2013037984A1 PCT/EP2012/068178 EP2012068178W WO2013037984A1 WO 2013037984 A1 WO2013037984 A1 WO 2013037984A1 EP 2012068178 W EP2012068178 W EP 2012068178W WO 2013037984 A1 WO2013037984 A1 WO 2013037984A1
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alkyl
formula
hydrogen
hydroxy
alkoxy
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Julio Cesar Castro Palomino Laria
Luc Marti Clauzel
Antonio Zorzano Olarte
Silvia Garcia Vicente
Alec Mian
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Genmedica Therapeutics Sl
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C07C327/34—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups with amino groups bound to the same hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • Oxidative stress and inflammation are implicated in the pathogenesis of metabolic diseases, diabetes, obesity, dyslipidemia and their associated cardiovascular complications.
  • oxidative stress is a common pathogenic factor leading to insulin resistance, beta-cell dysfunction, impaired glucose tolerance, and type 2 diabetes mellitus.
  • inflammation clinical studies suggest that acute hyperglycemia results in elevated levels of circulating inflammatory cytokines such as TNFalpha, IL6, and IL18.
  • mitochondria During hyperglycemia and/or hyperlipidemia, mitochondria generate cellular energy through TCA cycle activity and the associated electron transport chain of the inner mitochondrial membrane. However, while mitochondria generate elevated ATP production, mitochondria can also generate significant reactive oxygen species (ROS) and reactive nitrogen species (RNS).
  • ROS reactive oxygen species
  • RNS reactive nitrogen species
  • Cells are equipped with several antioxidant enzymes to neutralize ROS and RNS. For example, superoxide anions are enzymatically converted to hydrogen peroxide by a manganese superoxide dismutase (MnSOD) within mitochondria. Hydrogen peroxide can then be rapidly removed by the mitochondrial enzyme glutathione (GSH) peroxidase.
  • GSH glutathione
  • a further antioxidant enzyme, catalase is the hydrogen peroxide detoxifying enzyme founded exclusively in peroxisomes. Glutathione (GSH) is probably the most important defense with which the cell is equipped, for scavenging ROS generated by mitochondria metabolism and excess free radicals produced secondary to hyperglyc
  • ROS reactive oxygen species
  • pancreatic beta-cells have relatively low levels of free radical detoxification and redox regulating enzymes such as superoxide dismutase, glutathione peroxidase, catalase and thioredoxin.
  • free radical detoxification and redox regulating enzymes such as superoxide dismutase, glutathione peroxidase, catalase and thioredoxin.
  • ROS concentration in beta-cells may increase rapidly, damaging the beta-cells.
  • the production of ROS, and subsequent oxidative stress contributes to beta-cell deterioration observed in type 2 diabetes.
  • ROS is also considered a strong stimulus for the release of cytokines and increased superoxide can promote inflammation through NF-kB activation.
  • oxidative stress and associated activation of NF-kB leading to chronic inflammation and insulin resistance is essential in the processes implicated in the pathogenesis of diabetes and its progression.
  • Salicylates or aspirin-like drugs, are some of the most commonly used anti-inflammatory agents. For more than two decades, the anti-inflammatory properties of aspirin have been almost exclusively attributed to blocking prostaglandin synthesis via inhibition of cyclo-oxygenase activity. Recently, aspirin and sodium salicylate have been found to inhibit the activation of the transcription factor NF-kB. High doses of salicylate are thought to inhibit NF-kB and its upstream activator, the 1KB kinase beta (IKKbeta).
  • the present invention relates to conjugates comprised of an anti-inflammatory agent and an anti-oxidant agent.
  • the conjugates of the present invention are useful for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, and metabolic disorders, such as any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood (LADA), metabolic syndrome, hyperglycemia, and insulin sensitivity.
  • the conjugates are also useful for reducing advanced glycated end products (AGEs), ROS, lipid peroxidation, tissue and plasma TNFalpha and IL6 levels, and for delaying or preventing cardiovascular complications associated with atherosclerosis.
  • AGEs advanced glycated end products
  • ROS lipid peroxidation
  • conjugates of the present invention are useful for protecting pancreatic beta-cells, preventing their impairment or failure and subsequent lower insulin secretion.
  • the anti-inflammatory agent and antioxidant agent as provided herein are covalently bonded directly to each other or covalently bonded directly to the same linker.
  • the compounds of the present invention show additive or synergistic effects relative to treatment with an antioxidant agent alone or an antiinflammatory agent alone.
  • the additive or synergistic effect improves the anti-diabetic effect while reducing side effects associated with monotherapy.
  • treatment with GMC- 299 improves anti-diabetic effects while lowering the risk of gastric bleeding, associated with salicylic acid, and/or tinnitus, associated with N-acetylcysteine.
  • the present invention provides compounds of Formula (I)-(XI), as defined herein.
  • the present invention provides pharmaceutical compositions comprised of a compound of Formula (I)-(XI) and at least one pharmaceutically acceptable carrier.
  • the compounds of Formula (I)-(XI) and the pharmaceutical compositions comprised of Formula (I)-(XI) and at least one pharmaceutically acceptable carrier are useful for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, Latent Autoimmune Diabetes of Adulthood (LADA), metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance.
  • COPD Chronic Obstructive Pulmonary Disease
  • LADA Latent Autoimmune Diabetes of Adulthood
  • the compounds and pharmaceutical compositions of the present invention are useful for protecting pancreatic beta-cells, preventing their impairment or failure and subsequent lower insulin secretion. Also, the compounds and pharmaceutical compositions of the present invention are also useful for reducing free fatty acids (FFA), triglycerides, advanced glycated end products (AGEs), ROS, lipid peroxidation, tissue and plasma TNFalpha and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis.
  • FFA free fatty acids
  • AGEs advanced glycated end products
  • ROS lipid peroxidation
  • tissue and plasma TNFalpha and IL6 levels or for delaying or preventing cardiovascular complications associated with atherosclerosis.
  • the present invention provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, Latent Autoimmune Diabetes of Adulthood (LADA), metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formula (I)-(XI) or a pharmaceutical composition comprised of a compound of Formula (I)-(XI) and at least one pharmaceutically acceptable carrier.
  • COPD Chronic Obstructive Pulmonary Disease
  • LADA Latent Autoimmune Diabetes of Adulthood
  • the present invention also provides methods for reducing free fatty acids (FFA), triglycerides, advanced glycated end products (AGEs), ROS, lipid peroxidation, tissue and plasma TNFalpha and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formula (I)-(XI) or a pharmaceutical composition comprised of a compound of Formula (I)-(XI) and at least one pharmaceutically acceptable carrier.
  • FFA free fatty acids
  • AGEs advanced glycated end products
  • ROS lipid peroxidation
  • tissue and plasma TNFalpha and IL6 levels or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formula (I)-(XI)
  • the present invention provides methods for protecting pancreatic beta-cells, preventing their impairment or failure and subsequent lower insulin secretion in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formula (I)-(XI) or a pharmaceutical composition comprised of a compound of Formula (I)-(XI) and at least one pharmaceutically acceptable carrier.
  • the present invention provides uses for compounds of Formula (I)-(XI), or pharmaceutical compositions comprised of a compound of Formula (I)-(XI) and at least one pharmaceutically acceptable carrier, for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, Latent Autoimmune Diabetes of Adulthood (LADA), metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance in a mammal or human patient.
  • COPD Chronic Obstructive Pulmonary Disease
  • the present invention also provides uses for compounds of Formula (I)-(XI), or pharmaceutical compositions comprised of a compound of Formula (I)-(XI) and at least one pharmaceutically acceptable carrier, for preparing, or for the manufacture of, a medicament for reducing free fatty acids (FFA), triglycerides, advanced glycated end products (AGEs), ROS, lipid peroxidation, tissue and plasma TNFalpha and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient.
  • FFA free fatty acids
  • AGEs advanced glycated end products
  • ROS lipid peroxidation
  • tissue and plasma TNFalpha and IL6 levels or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient.
  • the present invention also provides uses for compounds of Formula (I)-(XI), or pharmaceutical compositions comprised of a compound of Formula (I)-(XI) and at least one pharmaceutically acceptable carrier, for preparing, or for the manufacture of, a medicament for protecting pancreatic beta-cells, preventing their impairment or failure and subsequent lower insulin secretion, in a mammal or human patient.
  • Figure 1 shows the glycemia levels after treatment with a compound according to one embodiment of the invention identified in the figure legend in db/db mice.
  • Figure 2 shows the effect on body weight after treatment with a compound according to one embodiment of the invention identified in the figure legend in db/db mice.
  • Figure 3 illustrated the fluid and food intake of db/db mice after treatment with a compound according to one embodiment of the invention identified in the figure legend.
  • Figure 4 shows the effect on the pancreas weight in db/db mice after treatment with a compound according to one embodiment of the invention identified in the figure legend. Also shown is the pancreas weight as a percentage of body weight, and the pancreas insulin level after treatment with the compound according to one embodiment of the invention identified in the figure legend.
  • Figure 5 shows the effect on the epididymal (epi) white adipose tissue (WAT) weight in db/db mice after treatment with a compound according to one embodiment of the invention identified in the figure legend. Also shown is epi WAT weight as a percentage of body weight.
  • Figure 6 illustrates the effect on intraperitoneal insulin tolerance (ipITT) and intraperitoneal glucose tolerance (ipGTT) in db/db mice after treatment with a compound according to one embodiment of the invention identified in the figure legend.
  • Figure 7 shows the fasting glycemia levels in db/db mice at day 15, 20 and 23 after treatment with a compound according to one embodiment of the invention identified in the figure legend.
  • Figure 8 shows the fasting insulinemia levels in db/db mice at day 15, and 23 after treatment with a compound according to one embodiment of the invention identified in the figure legend.
  • Figure 9 illustrates the total glycemia and total insulinemia in db/db mice at day 27 after treatment with a compound according to one embodiment of the invention identified in the figure legend.
  • Figure 10 shows the level of plasma C-peptide, plasma Adiponectin, plasma triacylglycerol (plasma TAG), and plasma non-esterified fatty acids (plasma NEFA) in db/db mice after treatment with a compound according to one embodiment of the invention identified in the figure legend.
  • Figure 11 shows the level of plasma C-Reactive Protein (plasma CRP) and percent of Hb lAc in db/db mice after treatment with a compound according to one embodiment of the invention identified in the figure legend.
  • plasma CRP plasma C-Reactive Protein
  • Figure 12 shows the plasma cholesterol levels (total, HDL, and LDL) in db/db mice after treatment with a compound according to one embodiment of the invention identified in the figure legend.
  • the present invention provides compounds, reagents, pharmaceutical compositions and methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, and metabolic disorders in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); and R7, Re, R9, Xj, and L are as defined as described with respect to Formula (I) below.
  • COPD Chronic Obstructive Pulmonary Disease
  • the compound of Formula (I) is (S)-2-acetamido-4-(2',4'-difluoro-4- hydroxybiphenylcarbonylthio)butanoic acid (GMC-299):
  • GMC-299 is described in more detail in the Examples, below.
  • the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood (LADA), in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R] is hydrogen or acetyl; R 2 , R 3 , 4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ⁇ is formula (i); and R 7 , R 8 , R9, Xi, and L are defined as described with respect to Formula (I) below.
  • LADA Latent Autoimmune Diabetes of Adulthood
  • the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); and R 7 , R 8 , R3 ⁇ 4 X b and L are defined as described with respect to Formula (I) below.
  • the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood (LADA), in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; Rg is formula (i); and R 7 , R 8 , R9, Xi , and L are defined as described with respect to Formula (I) below.
  • LADA Latent Autoimmune Diabetes of Adulthood
  • the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); and R 7 , R 8 , R9, Xi, and L are defined as described with respect to Formula (I) below.
  • a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-d
  • a method for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); R 7 is (Ci-C6)alkoxy, hydroxy, or NZ9Z1 0 wherein Z9 and Z1 0 are hydrogen; R 8 is hydrogen; R 9 is (C C 6 )alkylcarbonyl; X, is S; and L is CH 2 CH 2 .
  • the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood (LADA), in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); R 7 is (C)-C 6 )alkoxy, hydroxy, or NZ9Z10 wherein Z 9 and Z1 0 are hydrogen; R 8 is hydrogen; R9 is (Ci-C6)alkylcarbonyl; Xi is S; and L is CH 2 CH 2 .
  • the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); R 7 is (Ci-C6)alkoxy, hydroxy, or NZ9Z10 wherein Z 9 and ⁇ ) 0 are hydrogen; R 8 is hydrogen; R9 is (Ci-C 6 )alkylcarbonyl; Xi is S; and L is CH 2 CH 2 .
  • the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood (LADA), in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); R 7 is (Ci-C6)alkoxy, hydroxy, or NZ9Z1 0 wherein Z9 and Z
  • the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is formula (i); R 7 is (Ci-C6)alkoxy, hydroxy, or NZ9Z1 0 wherein Z 9 and Z10 are hydrogen; Rg is hydrogen; R9 is (Ci-C 6 )alkylcarbonyl; X, is S; and L is CH 2 CH 2 .
  • a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutical
  • a method for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); R 7 is amino, ethoxy, methoxy, or hydroxy; Rg is hydrogen; R9 is acetyl; Xi is S; and L is CH 2 CH 2 .
  • the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R5 is formula (i); R 7 is amino, ethoxy, methoxy, or hydroxy; R 8 is hydrogen; R 9 is acetyl; Xi is S; and L is CH 2 CH 2 .
  • the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; Re is formula (i); R is amino, ethoxy, methoxy, or hydroxy; Rg is hydrogen; R9 is acetyl; X ⁇ is S; and L is CH 2 CH 2 .
  • a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluoropheny
  • the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is formula (i); R 7 is amino, ethoxy, methoxy, or hydroxy; R 8 is hydrogen; R9 is acetyl; Xi is S; and L is CH 2 C3 ⁇ 4.
  • the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is formula (i); R 7 is amino, ethoxy, methoxy, or hydroxy; R 8 is hydrogen; R9 is acetyl; X
  • a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R
  • a method for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient which includes the step of administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyI; and R 6 is 3-acetamido-3- carboxypropy lth i o :
  • the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ⁇ is hydrogen or acetyl; R 2 , R 3 , R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R6 is 3-acetamido-3-carboxypropylthio.
  • a conjugate of Formula (I) or a pharmaceutically acceptable salt thereof
  • the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R6 is 3-acetamido-3-carboxypropylthio.
  • a conjugate of Formula (I) or a pharmaceutically acceptable salt thereof
  • the inventive methods include treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R) is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R6 is (S)-3-acetamido-3-carboxypropylthio.
  • a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R) is hydrogen or acetyl; R 2 , R 3 , R4,
  • the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ⁇ is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R 6 is (S)-3- acetam ido-3 -carboxypropylthio.
  • a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ⁇ is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-di
  • the present invention provides methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient that comprises administering to the mammal or patient in need of such treatment a therapeutically effective amount of GMC-299.
  • the inventive methods include treating dyslipidemia, insulin resistance, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of GMC-299.
  • the present invention provides methods for treating beta-cell dysfunction in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of GMC-299.
  • the present invention provides methods for treating hyperglycemia in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of GMC-299.
  • the present invention provides methods for reducing free fatty acids in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of GMC-299.
  • the present invention provides methods for reducing triglycerides in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of GMC-299.
  • the present invention provides methods for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of GMC-299.
  • the inventive methods include treating dyslipidemia, insulin resistance, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and GMC-299.
  • the present invention includes methods for treating beta-cell dysfunction in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and GMC-299.
  • the present invention includes methods for treating hyperglycemia in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and GMC-299.
  • the present invention includes methods for reducing free fatty acids in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and GMC-299.
  • the present invention includes methods for reducing triglycerides in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and GMC-299.
  • the present invention provides methods for reducing advanced glycated end products and lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins, in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and GMC-299.
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ⁇ 5 is formula (i); and R 7 , R g , R 9 , Xi, and L are as defined in Formula (I) of the Summary section.
  • the present invention provides uses for conjugates of Formula
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein R ⁇ is hydrogen or acetyl; R 2 , R 3 , R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; Re is formula (i); and R 7 , R 8 , R9, X] , and L are as defined in Formula (1) of the Summary section.
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); and R 7 , R 8 , R9, Xi, and L are as defined in Formula (I) of the Summary section.
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is formula (i); and R 7 , Re, R9, Xi , and L are as defined in Formula (I) of the Summary section.
  • Formula (I) Formula (I)
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein R ⁇ is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; Re is formula (i); R 7 is (Ci-C6)alkoxy, hydroxy, or NZ9Z10 wherein Z 9 and Z10 are hydrogen; R 8 is hydrogen; R 9 is (Ci-C 6 )alkylcarbonyl; Xi is S; and L is CH 2 CH 2 .
  • the present invention provides uses for conjugates of Formula
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is formula (i); R 7 is (Ci-Ce)alkoxy, hydroxy, or NZ9Z10 wherein Z 9 and Z, 0 are hydrogen; R 8 is hydrogen; R 9 is (C r C 6 )alkylcarbonyl; X, is S; and L is CH 2 CH 2 .
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R6 is formula (i); R 7 is (C, -C6)alkoxy, hydroxy, or NZ9Z10 wherein Z 9 and Z10 are hydrogen; R 8 is hydrogen; R 9 is (Cj-C6)alkylcarbonyl; X ⁇ is S; and L is CH 2 CH 2 .
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R] is hydrogen or acetyl; R 2 , R 3 , R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); R 7 is (C] -C6)alkoxy, hydroxy, or NZ9Z10 wherein Z 9 and ⁇ ] 0 are hydrogen; R 8 is hydrogen; R9 is (C,-C 6 )alkylcarbonyl; Xi is S; and L is CH 2 CH 2 .
  • Formula (I) is hydrogen or acetyl
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); R 7 is amino, ethoxy, methoxy, or hydroxy; R 8 is hydrogen; R9 is acetyl; X) is S; and L is CH 2 CH 2 .
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein R ⁇ is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen, trifluoromethyl, or 2.4-difluorophenyl; R 6 is formula (i); R 7 is amino, ethoxy, methoxy, or hydroxy; R 8 is hydrogen; R9 is acetyl; Xi is S; and L is CH 2 CH 2 .
  • the present invention provides uses for conjugates of Formula
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R 5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R ⁇ 5 is formula (i); R 7 is amino, ethoxy, methoxy, or hydroxy; R 8 is hydrogen; R 9 is acetyl; Xi is S; and L is CH 2 CH 2 .
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ⁇ is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 6 is formula (i); R 7 is amino, ethoxy, methoxy, or hydroxy; Rs is hydrogen; R9 is acetyl; X] is S; and L is CH2CH2.
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein R ⁇ is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R 6 is (S)-3-acetamido-3-carboxypropylthio.
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, and any form of diabetes mellitus including type I and type II diabetes, in a patient, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and 3 ⁇ 4 is (S)-3 -acetam ido-3 -carboxypropylthio.
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein R ⁇ is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R3 ⁇ 4 is (S)-3-acetamido-3- carboxypropylthio.
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R3, R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R6 is (S)-3-acetamido-3-carboxypropylthio.
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R5 are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R 6 is (S)-3- acetam i do-3 -carboxypropy lth i o .
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, and metabolic disorders in a mammal or patient, wherein the conjugate of Formula (I) is GMC-299.
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, beta-cell dysfunction, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the conjugate of Formula (I) is GMC-299.
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for treating hyperglycemia in a patient, wherein the conjugate of Formula (I) is GMC-299.
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing free free fatty acids in a patient, wherein the conjugate of Formula (I) is GMC-299. In certain embodiments, the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing triglycerides in a patient, wherein the conjugate of Formula (I) is GMC-299.
  • the present invention provides uses for conjugates of Formula (I) for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the conjugate of Formula (I) is GMC-299.
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating dyslipidemia, insulin resistance, elevated free fatty acids, elevated triglycerides, beta-cell dysfunction, hyperglycemia, metabolic syndrome, and any form of diabetes mellitus including type I and type II diabetes and Latent Autoimmune Diabetes of Adulthood, in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is GMC-299.
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating hyperglycemia in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is GMC-299.
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing free fatty acids in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is GMC-299.
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing triglycerides in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is GMC-299.
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for reducing advanced glycated end products and/or lipid peroxidation including, but not limited to, oxidation of low-density lipoproteins in a patient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the conjugate of Formula (I) is GMC-299.
  • the present invention provides conjugates of Formula (I)
  • Ri is hydrogen, (C i-C 6 )alkylcarbonyl, or A;
  • R 2 , R 3 , R4, and R 5 are independently hydrogen, (Ci -Ce)alkoxy, (Ci -C 6 )alkoxycarbonyl, (C i -C6)alkoxysulfonyl, (C i-Ce)alkyl, (Ci-C 6 )alkylcarbonyl, (Ci -Ce)alkylcarbonyloxy,
  • halo(Ci -C 6 )alkyl halogen, hydroxy, hydroxy(Ci-C6)alkyl, mercapto, nitro, phenyl, -NZ]Z 2 , or (NZ, Z 2 )carbonyl, wherein the phenyl is optionally substituted with 1 , 2, 3, 4, or 5 groups that are independently Ci -Cg)alkoxy, (C
  • , Z 2 , Z 3 , and Z 4 are independently hydrogen, (C i -Ce)alkyl, or (Ci -Ce)alkylcarbonyl; is
  • R 7 is (Ci -C 6 )alkoxy, (Ci -C 6 )alkyl, (C C 6 )alkylthio, hydroxy, -NZ Z,o, or -O-phenyl, wherein the phenyl is optionally substituted with 1 , 2, 3, 4, or 5 groups that are independently (Ci-C 6 )alkoxy, (Ci-C6)alkoxycarbonyl, (Ci-Ce)alkyl, (Ci -C6)alkylcarbonyl,
  • Rg is hydrogen or (Ci-C 6 )alkyl;
  • R is hydrogen, (d -C 6 )alkyl, or (Ci -C6)alkylcarbonyl:
  • Rio is (C r C 6 )alkoxy, (C r C 6 )alkyl, (Ci-C 6 )alkylthio, hydroxy, or -NZ 9 Zi 0 ;
  • Z 9 and Z10 are independently hydrogen, (Ci -C 6 )alkyl, or (C r C 6 )alkylcarbonyl;
  • X, and X 2 are independently O or S;
  • Ria is hydrogen, (C
  • R3a, Ria, and Rs a are independently hydrogen, (Ci -C6)alkoxy,
  • Z, a , Z 2a , Z 3a , and Z 4a are independently hydrogen, (Ci -C 6 )alkyl, or
  • Rib is hydrogen, (Ci-C6)alkylcarbonyl, or C;
  • R2b, R-3b, R4b, and Rsb are independently hydrogen, (C, -C6)alkoxy,
  • halo(C] -C 6 )alkyl halogen, hydroxy, hydroxy(Ci -C 6 )alkyl, mercapto, nitro, phenyl, -NZ 3b Z4b, or (NZ 3 bZ4b)carbonyl;
  • Z,b, Z 2b , Z 3 b, and Z 4 b are independently hydrogen, (Ci-C 6 )alkyl, or
  • Xi and X 2 are S.
  • R 2 , R 3 , R4 and R 5 are H.
  • R 2a , R 2 b, R3a, 3b, 4a > I1 ⁇ 4» Rs a and Rsb are H.
  • R3 is trifluoromethyl, and R 2 , R4 and R 5 are H.
  • R3 a and R3b are trifluoromethyl, and R 2a , ⁇ , Rsa, R2b, R4b and R 5 b are H.
  • R4 is 2,4-difluorophenyl
  • R 2 , R 3 and R5 are H.
  • R4 a and R) are 2,4-difluorophenyl
  • R 2a , R 3a , R 5a , R 2 b, R3b and R 5 b are H.
  • the present invention provides conjugates of Formula (I) wherein R, is hydrogen or acetyl; R 2 , R3, Ri, and R 5 are independently hydrogen, halo(C,-C 6 )alkyl, halogen, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, (Ci -C6)alkoxysulfonyl,
  • R is formula (i); R 7 is (Ci -C 6 )alkoxy, (C, -C 6 )alkyl, (Ci-C 6 )alkylthio, hydroxy, or -NZ 9 Zi 0 ; R» is hydrogen or (C,-C 6 )alkyl; R 9 is (Ci-C6)alkylcarbonyl; Xi is O or S; and Z3, Z 4 , Z 9 , and 10 are independently hydrogen, (C r C6)alkyl, or (Ci-C 6 )alkylcarbonyl.
  • Xi is S.
  • the present invention provides conjugates of Formula (I) wherein R, is hydrogen or acetyl; R 2 , R 3 , t, and R5 are independently hydrogen or phenyl, wherein the phenyl is optionally substituted with 1 or 2 groups that are independently halo(Ci-C6)alkoxy, halo(C r C 6 )alkyl, or halogen; R6 is formula (i); R 7 is (Ci-C 6 )alkoxy or hydroxy; Rg is hydrogen or (CpC 6 )alkyl; R 9 is (Ci-C6)alkylcarbonyl; and Xi is O or S. In certain such embodiments, Xi is S.
  • the present invention provides conjugates of Formula (I) wherein Ri is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen or phenyl, wherein the phenyl is optionally substituted with 1 or 2 halogen groups; R 6 is formula (i); R 7 is ethoxy, methoxy, or hydroxy; Rg is hydrogen or methyl; R9 is acetyl; and X] is O or S. In certain such embodiments, Xi is S.
  • the present invention provides conjugates of Formula (I) wherein R] is hydrogen or acetyl; one of R 2 , R3, R4, and R 5 is 2,4-difluorophenyl and the rest are hydrogen; R 6 is formula (i); R 7 is hydroxy; R 8 is hydrogen; R 9 is acetyl; and Xi is S 2 .
  • the present invention provides conjugates of Formula (I) wherein R
  • the present invention provides conjugates of Formula (I) wherein R
  • the present invention provides conjugates of Formula (I) wherein R] is hydrogen or acetyl; R 2 , R 3 , R4, and R 5 are independently hydrogen or trifiuormethyl; R 6 is formula (i); R is ethoxy, methoxy, or hydroxy; Rg is hydrogen or methyl; R 9 is acetyl; and X
  • the present invention provides conjugates of Formula (I) wherein R] is hydrogen or acetyl; one of R 2 , R 3 , R4, and R5 ais trifiuormethyl and the rest are hydrogen; R 6 is formula (i); R 7 is hydroxy; Rg is hydrogen; R 9 is acetyl; and X) is S.
  • Representative conjugates of Formula (I) include, but are not limited to, the compounds shown below, in which L is CH 2 CH 2 and R ⁇ is hydrogen or acetyl.
  • the present invention provides pharmaceutical compositions omprised of a compound of Formula (I), as shown above, and at least one pharmaceutically cceptable carrier.
  • the present invention provides conjugates of Formula (II)
  • R 2 , R3, R4, R5, Re, Ria, R-2a, R 3a , R4a, and R 5a are as defined in Formula (I) of the Summary section, provided that when 3 ⁇ 4 is hydroxy then R] a is B, as defined in Formula (I) of the Summary section.
  • the present invention provides conjugates of Formula (II) wherein R 2 , R3, R4, R5, are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; Re is as defined in Formula (I) of the Summary section; R ]a is hydrogen or acetyl; and R 2a , R3a, R4a, and R 5a , are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl.
  • the present invention provides conjugates of Formula (II) wherein R 3 ⁇ 4 R 3 , R4, R5, are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl;
  • Re is (S)- 3-acetamido-3-carboxypropylthio;
  • R -3-acetamido-3-carboxypropylthio or (+/-)-3- acetamido-3-carboxypropylthio;
  • Ri a is hydrogen or acetyl; and one of R 2a , R3a> R4a, and R 5a is C(0)-R6a and the rest are hydrogen; and e a is as defined in Formula (I).
  • Xi and X 2 are S.
  • R 2 , R3, 4 and R 5 , R 2a , R3a, 3 ⁇ 4a and R 5a are H.
  • R 2 b, R3b, R4b and R 5 b are H.
  • R3 and R 3a are trifluoromethyl, and R 2 , R 2a , R4, ia, R5 and R 5a are H.
  • R 3 b is trifluoromethyl, and R3 ⁇ 4, R4b and R 5 b are H.
  • R4 and R4 a are 2,4-difluorophenyl, and R 2 , R3.
  • R 5 R 2a , 3a and R 5a are H.
  • R4b is 2,4-difluorophenyl, and R 2 b, R3b and R 5 b are H.
  • Representative conjugates of Formula (II) include, but are not limited to, the com ounds shown below, in which L is CH 2 CH 2 and Ri a is hydrogen or acetyl.
  • the present invention provides pharmaceutical compositions comprised of a compound of Formula (II), as shown above, and at least one pharmaceutically acceptable carrier.
  • the presen invention provides conjugates of Formula (III)
  • R 2 , R 3 , R4, R 5 , R6, R 2a , R 3a , R4a, Rs 3 ⁇ 4 Rib, R2b, 3b, Rib, and R 5b are as defined in Formula (I) of the Summary section, provided that when R$ is hydroxy then Rib is C, as defined in Formula (I) of the Summary section.
  • the present invention provides conjugates of Formula (III) wherein R 2 , R 3 , R4, R5, are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R is (S)- 3-acetamido-3-carboxypropylthio; R 2a , R 3a , ia, and Rs a , are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; R 2 b, R 3b , Rtb, and R 5 b, are independently hydrogen, trifluoromethyl, or 2,4-difluorophenyl; and R ⁇ is hydrogen or acetyl.
  • Xi and X 2 are S.
  • R 2 , R 3 , R4 and R 5 , R 2a , R 3a , R4a, R 5a R 2 b, R3b, »b and R 5b are H.
  • R 3 , R 3a and R 3b are trifluoromethyl, and R 2 , R 2a , R 2 b, R4, R4a, 4b, Rs, R 5a and R 5 b are H.
  • R4, i a and t b are 2,4-trifluoromethyl, and R 2 , R 2a , R 2 b, R3, R 3a , R3b, R5, Rsa and R 5 b are H.
  • Representative conjugates of Formula (III) include, but are not limited to, the compounds s
  • the present invention provides pharmaceutical compositions comprised of a compound of Formula (III), as shown above, and at least one pharmaceutically acceptable carrier.
  • the present invention provides conjugates of Formula (IV)
  • R.7 is (Ci-C6)alkoxy, (Ci-C6)alkyl, (Ci-C6)alkylthio, hydroxy, -NZ9Z10, or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci -C6)alkoxy, (Ci-C 6 )alkoxycarbonyl, (Ci-C6)alkyl, (Ci-C6)alkylcarbonyl,
  • R8 is hydrogen or (Ci -C 6 )alkyl
  • R9 is hydrogen, (d-C 6 )alkyl, or (Ci-C 6 )alkylcarbonyl;
  • Rio is (Ci-C6)alkoxy, (Ci-C6)alkylthio, hydroxy, or -NZ 9 Z
  • Xi and X 2 are independently O or S;
  • L is CH 2 CH 2 ;
  • Z 9 and Zio are independently hydrogen, (d-Ceialkyl, or (C
  • Xj and X 2 are S.
  • Representative conjugates of Formula (IV) include, but are not limited to, the compounds shown below, in which L is CH 2 CH 2 .
  • the present invention provides pharmaceutical compositions comprised of a compound of Formula (IV), as shown above, and at least one pharmaceutically acceptable carrier.
  • the present invention provides conjugates of Formula (V)
  • R 7 is (Ci-C6)alkoxy, (Ci-C6)alkyl, (Ci-C6)alkylthio, hydroxy, -NZ 9 Z 10 , or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C, -C6)alkoxy, (Ci-C 6 )alkoxycarbonyl, (Ci-C 6 )alkyl, (Ci-C 6 )alkylcarbonyl,
  • Rs is hydrogen or (Ci-C 6 )alkyl
  • R 9 is hydrogen, (Ci -C6)alkyl, or (Ci-C6)alkylcarbonyl;
  • Rio is (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, hydroxy, or
  • Xi and X 2 are independently O or S;
  • L is CH 2 CH 2 ;
  • o are independently hydrogen, (C
  • Xi and X 2 are S.
  • Representative conjugates of Formula (V) include, but are not limited to, the compounds shown below, in which L is CH 2 CH 2 .
  • the present invention provides pharmaceutical compositions comprised of a compound of Formula (V), as shown above, and at least one pharmaceutically acceptable carrier.
  • the present invention provides conjugates of Formula (VI)
  • R ? is (Ci -C6)alkoxy, (Ci -C6)alkyl, (Ci-C 6 )alkylthio, hydroxy, -NZ 9 Z10, or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C 6 )alkoxy, (Ci-C 6 )alkoxycarbonyl, (Ci-C 6 )alkyl, (Ci-C 6 )alkylcarbonyl,
  • R 8 is hydrogen or (Ci-C6)alkyl
  • R 9 is hydrogen, (Ci-C 6 )alkyl, or (Ci-C 6 )alkylcarbonyl;
  • Rio is (Ci-Ce)alkoxy, (Ci-C6)alkylthio, hydroxy, or -NZ9Z 10 ;
  • Xi and X 2 are independently O or S;
  • L is CH 2 CH 2 ;
  • Z9 and Z10 are independently hydrogen, (Ci-C6)alkyl, or (Ci-C6)alkylcarbonyl.
  • Xi and X 2 are S.
  • Representative conjugates of Formula (VI) include, but are not limited to, the compounds shown below, in which L is CH 2 CH 2 .
  • the present invention provides pharmaceutical compositions comprised of a compound of Formula (VI), as shown above, and at least one pharmaceutically acceptable carrier.
  • the present invention provides conjugates of Formula (VII)
  • R 7 is (Ci-C6)alkoxy, (Ci-C6)alkyl, (C] -C6)alkylthio, hydroxy, -NZ9Z 10 , or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci-C 6 )alkoxy, (Ci-C6)alkoxycarbonyl, (C] -C6)alkyl, (Ci-C 6 )alkylcarbonyl,
  • Rg is hydrogen or (C, -C6)alkyl
  • R 9 is hydrogen, (C] -C6)alkyl, or (C
  • Rio is (Ci-C 6 )alkoxy, (C r C6)alkylthio, hydroxy, or -NZ 9 Zio;
  • Xi and X 2 are independently O or S;
  • L is CH 2 CH 2 ;
  • Zg and Zio are independently hydrogen, (C
  • Xi and X 2 are S.
  • Representative conjugates of Formula (VII) include, but are not limited to, the compounds shown below, in which L is CH2CH 2 .
  • the present invention provides pharmaceutical compositions comprised of a compound of Formula (VII), as shown above, and at least one
  • R 7 is (Ci-C6)alkoxy, (Ci-C 6 )alkyl. (Ci-C6)alkylthio, hydroxy, -NZ9Z10, or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (Ci -C6)alkoxy, (Ci-C6)alkoxycarbonyl, (Ci -C6)alkyl, (Ci -C6)alkylcarbonyl,
  • R 8 is hydrogen or (Ci -Ca)alkyl
  • R 9 is hydrogen, (Ci-C 6 )alkyl, or (Ci -C6)alkylcarbonyl;
  • Rio is (Ci-C6)alkoxy, (Ci-C6)alkylthio, hydroxy, or -NZ 9 Z
  • Xi and X 2 are independently O or S; L is CH 2 CH 2 ; and
  • Z 9 and Z 10 are independently hydrogen, (Ci-C6)alkyl, or (Ci-C6)alkylcarbonyl.
  • Xi and X 2 are S.
  • Representative conjugates of Formula (VIII) include, but are not limited to, the pounds shown below, in which L is CH 2 CH 2 .
  • the present invention provides pharmaceutical compositions comprised of a compound of Formula (VIII), as shown above, and at least one pharmaceutically acceptable carrier.
  • the present invention provides conjugates of Formula (IX) wherein R ⁇ is
  • R 7 is (Ci-C6)alkoxy, (Ci-C6)alkyl, (Ci-C6)alkylthio, hydroxy, -NZ9Z10, or -O-phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently (C, -C6)alkoxy, (Ci-C 6 )alkoxycarbonyl, (Ci-C6)alkyl, (C]-C6)alkylcarbonyl,
  • R 8 is hydrogen or (Ci -C6)alkyl
  • R9 is hydrogen, (Ci-C6)alkyl, or (Ci-C6)alkylcarbonyl;
  • Rio is (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, hydroxy, or -NZ 9 Zi 0 ;
  • Xi and X 2 are independently O or S;
  • L is CH 2 CH 2 ;
  • Z 9 and Z10 are independently hydrogen, (C,-C 6 )alkyl, or (C, -C6)alkylcarbonyl.
  • Xi and X 2 are S.
  • Representative conjugates of Formula (IX) include, but are not limited to, the compounds shown below, in which L is CH 2 CH 2 .
  • the present invention provides pharmaceutical compositions comprised of a compound of Formula (IX), as shown above, and at least one pharmaceutically acceptable carrier.
  • the present invention also provides conjugates of Formula (X)
  • R-20 is (C, -C4)alkoxy, hydroxy, or NZ 2 oZ 2 i ;
  • Z 2 o and Z 2) are independently hydrogen or (Ci -C4)alkyl
  • L 2 is selected from
  • n 2, 3, or 4;
  • Y is O, S, S-S, NH, NCH 3 ;
  • R.21 is hydrogen or (Ci-C4)alkyl
  • R 23 and R 2 4 are independently hydrogen or (C r C6)alkyl
  • R 2 5 is (C C4)alkoxy, hydroxy, or NZ 22 Z 23 ;
  • Z 22 and Z 23 are independently hydrogen or (C r C 4 )alkyl
  • R 2 6 is hydrogen, (C C6)alkyl, or (Ci-C6)alkylcarbonyl.
  • Representative conjugates of Formula (X) include, but are not limited to, the com ounds shown below, in which L is CH 2 CH 2 .
  • the present invention provides pharmaceutical compositions comprised of a compound of Formula (X), as shown above, and at least one pharmaceutically acceptable carrier.
  • the present invention provides compounds of Formula (XI)
  • Ri is OR 2 , NR4R5, or
  • R 2 is (C C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C3-C 8 )cycloalkyl(C,-C6)alkyl, wherein the (C r C6)alkyl, (C 3 -C 8 )cycloalkyl, and (C 3 -C 8 )cycloalkyl(Ci-C6)alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C 6 )alkoxy,
  • Z] and Z 2 are independently H or (Ci-C6)alkyl
  • R 3 is H or C(0)R 6 ;
  • R4 and R 5 are independently H, (Ci-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or
  • (C 3 -C 8 )cycloalkyl(Ci-C6)alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C 6 )alkoxy, (Ci-C 6 )alkoxy(Ci-C6)alkyl, (Ci-C 6 )alkoxycarbonyl,
  • R 6 is H, (C,-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C,-C 6 )alkyl, wherein the (C] -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, and (C 3 -C 8 )cycloalkyl(C r C 6 )alkyl are optionally substituted with 1, 2, 3, or 4 substituents that are independently (Ci-C6)alkoxy,
  • Z 3 and Z 4 are independently H or (C] -C6)alkyl
  • R 7 is OR 2 or NR4R5;
  • L is CH 2 CH 2 .
  • Representative compounds of Formula (XI) include, but are not limited to, the compounds shown below:
  • the present invention provides pharmaceutical compositions comprised of a compound of Formula (XI), as shown above, and at least one pharmaceutically acceptable carrier.
  • the invention provides in separate aspects methods for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, Chronic Obstructive Pulmonary Disease, cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, Latent Autoimmune Diabetes of Adulthood, metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formulae (I- XI), as shown above, or a pharmaceutical composition comprised of a compound of Formulae (I- XI) and at least one pharmaceutically acceptable carrier.
  • the invention provides in separate aspects methods for treating type II diabetes mellitus, metabolic syndrome, dyslipidemia, or insulin resistance in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formulae (I-XI), as shown above, or a pharmaceutical composition comprised of a compound of Formulae (I-XI) and at least one pharmaceutically acceptable carrier.
  • the invention provides in separate aspects provides methods for reducing free fatty acids, triglycerides, advanced glycated end products, ROS, lipid peroxidation, tissue and plasma TNFa and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formulae (I-XI), as shown above, or a pharmaceutical composition comprised of a compound of Formulae (I-XI) and at least one pharmaceutically acceptable carrier.
  • the invention provides in separate aspects provides provides methods for protecting pancreatic beta-cells, preventing their impairment or failure and subsequent lower insulin secretion, in a mammal or human patient comprising administering to the mammal or human patient in need of such treatment a therapeutically effective amount of a compound of Formulae (I-XI), as shown above, or a pharmaceutical composition comprised of a compound of Formulae (I-XI) and at least one pharmaceutically acceptable carrier.
  • the invention provides in separate aspects provides provides uses for compounds of Formulae (I-XI), or pharmaceutical compositions comprised of a compound of Formulae (I-XI) and at least one pharmaceutically acceptable carrier, for preparing, or for the manufacture of, a medicament for treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, COPD, cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, LADA, metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance in a mammal or human patient.
  • the present invention also provides uses for compounds of Formulae (I-XI), or pharmaceutical compositions comprised of a compound of Formulae (I- XI) and at least one pharmaceutically acceptable carrier, for preparing, or for the manufacture of, a medicament for reducing free fatty acids, triglycerides, advanced glycated end products, ROS, lipid peroxidation, tissue and plasma TNFa and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis in a mammal or human patient.
  • the present invention also provides uses for compounds of Formulae (I-XI), or pharmaceutical compositions comprised of a compound of Formulae (I-XI) and at least one pharmaceutically acceptable carrier, for preparing, or for the manufacture of, a medicament for protecting pancreatic b-cells, preventing their impairment or failure and subsequent lower insulin secretion, in a mammal or human patient.
  • the present invention provides methods for treating adipocyte dysfunction related diseases, carbohydrate metabolism related diseases, vascular diseases, neurodegenerative diseases, cancers, arthritis, osteoarthritis, spondylitis, bone resorption diseases, sepsis, septic shock, chronic pulmonary inflammatory disease, fever, periodontal diseases, ulcerative colitis, pyresis, Alzheimer's disease, Parkinson's diseases, cystic fibrosis, dysfunctions of the immune system, stroke, multiple sclerosis, migraine, pain, inflammatory eye conditions including uveitis, glaucoma and conjunctivitis, degenerative bone or joint conditions including osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis ankylosing spondylitis, psoriatic arthritis and other arthritic conditions, as well as inflamed joints, chronic inflammatory skin conditions, including allergic lesions, lichen planus, pityriasis rosea, ec
  • the present invention provides methods for treating adipocyte dysfunction related diseases, carbohydrate metabolism related diseases, vascular diseases, neurodegenerative diseases, cancers, arthritis, osteoarthritis, spondylitis, bone resorption diseases, sepsis, septic shock, chronic pulmonary inflammatory disease, fever, periodontal diseases, ulcerative colitis, pyresis, Alzheimer's disease, Parkinson's diseases, cystic fibrosis, dysfunctions of the immune system, stroke, multiple sclerosis, migraine, pain, inflammatory eye conditions including uveitis, glaucoma and conjunctivitis, degenerative bone or joint conditions including osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis ankylosing spondylitis, psoriatic arthritis and other arthritic conditions, as well as inflamed joints, chronic inflammatory skin conditions, including allergic lesions, lichen planus, pityriasis rosea, ec
  • the present invention provides uses for pharmaceutical compositions for preparing, or for the manufacture of, a medicament for treating the diseases/disorders listed above, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and a conjugate of Formula (I-XI), or a pharmaceutically acceptable salt thereof.
  • (Ci-C6)alkoxy means a (Ci-Ce)alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of (Ci-C6)alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • (Ci-C6)alkoxycarbonyl as used herein, means a (Ci-C6)alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (Ci-C 6 )alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
  • (Ci-C6)alkoxysulfonyl as used herein, means a (Ci-C6)alkoxy group, as defined herein, appended appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of (Ci -Ce)alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.
  • (C] -C6)alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms.
  • Representative examples of (C] -C6)alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, and hexyl.
  • (Ci-C 6 )alkylcarbonyl as used herein, means a (Ci-C6)alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (CpC 6 )alkylcarbonyl include, but are not limited to, acetyl, 1 -oxopropyl, 2,2-dimethyl-l-oxopropyl, 1 -oxobutyl, and 1-oxopentyl.
  • (Ci-C 6 )alkylcarbonyloxy means a (Ci-C 6 )alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of (C]-C 6 )alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
  • (Ci-C6)alkylene means a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 6 carbon atoms.
  • Representative examples of (Ci-C 6 )alkylene include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -C3 ⁇ 4CH(CH 3 )CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • (Ci-C 6 )alkylsulfonyl as used herein, means an (C C6)alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of (Ci-Ce)alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
  • (Ci-C6)alkylthio means a (Ci-C6)alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of (Ci-C6)alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • carbonyl as used herein, means a -C(O)- group.
  • cyano as used herein, means a -CN group.
  • halo or halogen as used herein, means -CI, -Br, -I or -F.
  • halo(Ci-C6)alkoxy means at least one halogen, as defined herein, appended to the parent molecular moiety through a (Ci-Ce)alkoxy group, as defined herein.
  • Representative examples of halo(Ci-C 6 )alkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifiuoromethoxy, and pentafluoroethoxy.
  • halo(Ci-C6)alkyl means at least one halogen, as defined herein, appended to the parent molecular moiety through a (Ci-C6)alkyl group, as defined herein.
  • Representative examples of halo(C)-C 6 )alkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • HTB 2-hydroxy-4-(trifluoromethyl)benzoic acid, a metabolite of triflusal.
  • Conjugates comprised of HTB and one or more antioxidants are specifically contemplated by the present invention.
  • hydroxy as used herein, means an -OH group.
  • hydroxy(Ci-C 6 )alkyl as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through a (C] -C6)alkyl group, as defined herein.
  • Representative examples of hydroxy(Ci-C6)alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and 2,3-dihydroxypentyl.
  • mercapto as used herein, means a -SH group.
  • nitro as used herein, means a -N0 2 group.
  • sulfonyl as used herein, means a -S0 2 - group.
  • Compounds of the present invention include alpha-amino acids, or derivatives thereof such as esters or amides, that can exist as stereoisomers, wherein the asymmetric or chiral center is present at the alpha-carbon.
  • the chiral center is designated (L) or (D) based on the Fischer projections of (L) or (D) aldose. Ernest L. Eliel and Samuel H. Wilen, Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, page 1 12, 1994.
  • compounds of the present invention may contain a stereocenter that is not an alpha-carbon of an alpha-amino acid (or derivative thereof).
  • This center is designated (R) or (S), depending on the configuration of substituents around the chiral carbon atom.
  • the terms (R) and (S) used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45: 13-30.
  • Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution, a technique well-known to those of ordinary skill in the art.
  • the present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-
  • compositions of this invention can be administered to humans
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative agents, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Suspensions in addition to the active compounds, may contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.
  • the compounds of the present invention can be incorporated into slow-release or targeted-delivery systems such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more pharmaceutically acceptable carriers as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of such composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • sterile injectable aqueous or oleaginous suspensions may be fonnulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic, parenterally acceptable diluent or solvent such as a solution in 1 ,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • free fatty acids such as oleic acid are used in the preparation of injectables.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert pharmaceutically acceptable carrier such as sodium citrate or calcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • compositions for rectal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. 8178
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and free fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used.
  • the present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, and the like.
  • the preferred lipids are the natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), p 33 et seq.
  • therapeutically effective amount of the compound of the present invention means a sufficient amount of the compound to treat metabolic disorders, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated.
  • the total daily dose of the compounds of this invention administered to a mammal, and particularly a human from about 0.03 to about 20 mg/kg/day.
  • more preferable doses can be in the range of from about 0.1 to about 10 mg/kg/day.
  • the effective daily dose can be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
  • pharmaceutically acceptable salt means a positively-charged inorganic or organic cation that is generally considered suitable for human consumption.
  • pharmaceutically acceptable cations are alkali metals (lithium, sodium and potassium), magnesium, calcium, ferrous, ferric, ammonium, alkylammonium, dialkylammonium, trialkylammonium, tetraalkylammonium, diethanolammmonium, and choline. Cations may be interchanged by methods known in the art, such as ion exchange.
  • lysine is a preferred free amine for preparing salts of the present invention.
  • the compound of Formula (I) is GMC-299, provided as its lysine salt, as described below in Example lb.
  • the present invention contemplates pharmaceutically active metabolites formed by in vivo biotransformation of conjugates of Formula (I).
  • pharmaceutically active metabolite as used herein, means a compound formed by the in vivo biotransformation of conjugates of Formula (I).
  • the present invention contemplates conjugates of Formula (I) and metabolites thereof. A thorough discussion of biotransformation is provided in (Goodman and Gilman's, The Pharmacological Basis of Therapeutics, seventh edition).
  • Conjugates of Formula (I), wherein Ri, R 2 , R 3 , P , RS, R7, Rs, R , and L are as defined herein, are prepared as described EP 0 080 229, WO 2010/106082, BE 900328 (each of which is incorporated herein by reference in its entirety), or Scheme 1. Acids of formula (1) are treated with an alcohol or mercaptan of formula (2) in an appropriate solvent optionally with heating and optionally with one or more coupling reagents to provide conjugates of Formula (I).
  • Coupling reagents useful for preparing compounds of the present invention include, but are not limited to, dimethylaminopyridine (DMAP), 1 ,3-di-tert-butylcarbodiimide, ⁇ , -carbonyldiimidazole (CDI), ⁇ , ⁇ -thiocarbonyldiimidazole, l, l '-carbonylbis(2- methylimidazole), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), benzotriazol- 1 -yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBOP), bromo- tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop), 0-(-7-azabenzotriazol-l -yl)- ⁇ , ⁇ , ⁇ ', ⁇ ',-tetramethylur
  • conjugates of Formula (I), wherein Ri, R 2 , R3, 4, R5, R7, Rs, R9, and L are as defined in Formula (I) herein, are prepared as described in Scheme 2.
  • Acids of formula (1) are treated with a chlorinating reagent such as thionyl chloride (or PC1 3 ) in an appropriate solvent to provide acid chlorides of formula (3).
  • Conjugates of Formula (3) are treated with a base such as triethylamine (or diisopropylethylamine) and an alcohol or thiol of formula (2) in an appropriate solvent, optionally with heating, to provide conjugates of Formula (I).
  • Conjugates of Formula (II), wherein R 2 , R3, R4, R5, R6, Ria, R2a, 3a, R4a, and R 5a , are as defined in Formula (I) herein, are prepared as described in Scheme 3.
  • Conjugates of Formula (I) are treated with a benzoic acid of formula (4) in the presence of one or more coupling reagents, as disclosed in Scheme 1, in an appropriate solvent to provide conjugates of Formula (II).
  • a conjugate of Formula (4) can be treated with a chlorinating agent (see Scheme 2) and a base including, but not limited to triethylamine or diisopropylethylamine, to provide the corresponding acid chloride.
  • the acid chloride is treated with a conjugate of Formula (I) in an appropriate solvent, optionally with heating, to provide conjugates of Formula (II).
  • R 3b , R4b, and R 5b are as defined in Formula (I) herein, are prepared as described in Scheme 4.
  • Conjugates of Formula (II) are treated with a benzoic acid of formula (5) in the presence of one or more coupling reagents, as disclosed in Scheme 1, in an appropriate solvent to provide conjugates of Formula (III).
  • a conjugate of Formula (5) can be treated with a chlorinating agent (see Scheme 2) and a base including, but not limited to triethylamine or diisopropylethylamine, to provide the corresponding acid chloride.
  • the acid chloride is treated with a conjugate of Formula (II) in an appropriate solvent, optionally with heating, to provide conjugates of Formula (III).
  • mice Male cd-1 mice weighing 25-30 g were purchased from Charles River Laboratories
  • mice were housed in animal quarters at 22°C with a 12-h light / 12-h dark cycle and fed ad libitum. 5-weeks old Male mice C57BL/K.S bearing the db/db mutation (The Jackson Laboratories) were purchased from Charles River Laboratories Spain (Sant Cugat del Valles, Spain).
  • mice Male cd-1 mice weighing 25-30 g are purchased from Charles River Laboratories Spain. The animals are housed in animal quarters at 22°C with a 12-h light / 12-h dark cycle and fed ad libitum. O/N fasted animals are dosed at 9:00 pm with 0.05 mmol/kg of the indicated compound. Mice are sacrificed at the indicated time points, with CO2 euthanasia, and blood is extracted from the inferior cava vein, using heparin as an anticoagulant, and maintained at 4°C until the preparation of plasma. Plasma was separated after centrifugation of blood and kept at -20°C until metabolites determination.
  • Test compounds are incubated with human liver S9 fraction to study its metabolic stability and to profile and identify the forming metabolites.
  • the basic incubation mixture of 500 ⁇ in volume consisted of the following components: 1.5 mg of protein per ml, substrate in DMSO, 1 mM NADPH, 1 mM UDPGA, 1 mM PAPS and 1 mM GSH.
  • the substrate concentration used was 2 ⁇ .
  • the final amount of DMSO in the incubation was 1 % (v/v).
  • Each reaction mixture was preincubated for 2 minutes at +37 °C. The reaction was started by addition of cofactors.
  • mice C57BL/Ks bearing the db/db mutation (The Jackson Laboratories) and 7-weeks old male mice C57BL/6 bearing the ob/ob mutation are purchased from Charles River Laboratories Spain (Sant Cugat del Valles, Spain) are treated with compounds as disclosed herein for a month, administered by single oral injection.
  • Glycemia levels are determined in blood from the Tail Vein, using a rapid glucose analyzer (Accu-Chek Aviva; Roche) 3 times per week, as well as body weight measure. The food and water intake is measured twice a week.
  • mice are sacrificed, in feeding state, with C0 2 euthanasia, and the blood extracted from the Inferior Cave Vein, using heparin as an anticoagulant, and maintained at 4°C until the preparation of plasma.
  • ipITT Intraperitoneal Insulin Tolerance Test
  • an Insulin Tolerance Test is performed as follows. Animals receive an ip injection of Insulin 2 Ul/kg (Humulin®) and glycemia levels are determined at time zero (before the injection of insulin) and at different time points thereafter in blood from the Tail Vein, after the Insulin injection using a rapid glucose analyzer (Accu-Chek Aviva; Roche). Figure 6 shows the insulin tolerance of the subject animals.
  • a Glucose Tolerance Test is performed as follows. Overnight fasted animals receive an ip injection of Glucose 0.5 g/kg (Glucosmon 50 ®). Glycemic levels are determined, at time zero (before the injection of glucose) and at different time points thereafter, in blood from the Tail Vein using a rapid glucose analyzer (Accu-Chek Aviva; Roche). Figure 6 shows the glucose tolerance of the subject animals.
  • the circulating glucose concentration is determined by a rapid glucose analyzer (Accu-Chek Aviva; Roche). Plasma triglycerides and non esterified fatty acids are determined using conventional colorimetric methods (commercially available from Biosystems, Barcelona, Spain, and Wako Chemicals, Neuss, Germany, respectively). Plasma insulin concentration is determined by enzyme-linked immunosorbent assay method (CrystalChem, Downers Grove, IL). Statistical analysis.
  • db/db mice were treated for two weeks with a daily dose of the compound of Example l b, GMC-299, or with vehicle.
  • Figure 7 shows the fasting glycemia of the subject animals. Dosing with the compound of Example l b significantly reduced the fasting glycemia of the animals. A t-test indicated that the value of p was less than 0.01.
  • Diabetic mice or rats generated by streptozotocin administration exhibit an increase in levels of lipid peroxidation and a decrease in activity of antioxidant enzymes in the liver and kidneys as compared to control.
  • Test compounds administered orally and/or intraperitoneally ( ⁇ 250mg/kg) prior to a single dose of streptozotocin (45mg/kg i.p.) in rats followed by 4 additional treatment days can preserve pbeta-cells, reducing the development of hyperglycemia.
  • the blood glucose level in pretreated animals is lower than the control group associated with a preserve capacity of pbeta-cell to secrete insulin measured in the blood.
  • mice challenged by one shot of streptozotocin 45mg/kg i.p.
  • Oral or intraperitoneal administration of a conjugate of the invention, prior and during 5 days following streptozotocin exposure can protect beta-cells from oxidative stress and reduces the development of hyperglycemia over time compared to control.
  • Compounds of the invention can reduce levels of 8-hydroxy-deoxyguanosine (80hdG) and malondialdehyde + 4-hydroxy-2-nonenal (4H E), markers for both oxidative stress and lipid peroxidation in the blood.
  • 80hdG 8-hydroxy-deoxyguanosine
  • H E 4-hydroxy-2-nonenal
  • Diabetic mice induced by streptozotocin injection 120 mg/kg i.p.
  • 250 mg/kg/day oral or i.p.
  • fasting glucose, fructosamine, triglycerides and cholesterol are measured. These biochemical parameters can be reduced in comparison to control group.
  • oxidative stress and lipid peroxidation markers 8-hydroxy-deoxyguanosine (80hdG), malondialdehyde and 4-hydroxy-2-nonenal (4HNE) are also reduced.
  • inflammatory cytokines such as TNFaalpha and IL-6, and glutathione
  • GSH GSH
  • Beta-cell destruction is induced in cd-1 mice after 3 hours of fasting by a single intraperitoneal injection of a freshly prepared solution of alloxan 200mg/kg (Sigma-Aldrich, Saint Louis, MO) that was dissolved in 0.9% NaCl. Test compounds or vehicle control are administered intraperitoneally, 1 hour before alloxan administration. At the end of the treatment, at day 4, animals are killed and the plasma collected and kept at -20°C until used. Conjugates as disclosed herein can beneficially reduce plasma glucose levels in Alloxan- treated animals as compared to control animals.
  • mice 5-8 week old ob/ob and db/db mice are treated for 3 to 4 weeks with a daily dose of 50 to 250mg/kg of a compound of the invention by oral gavage or with drug mix with food or subcutaneously.
  • Glucose tolerance test can detect reduction in glucose level elevation during the test compared to non-treated animals.
  • the capacity of the pbeta-cells to secrete insulin can be improved in the group administered with a compound of the invention compared to control demonstrating the protective effects toward pancreatic beta-cells.
  • compounds of the invention can improve insulin sensitivity as evidenced by a sustained and pronounced glucose lowering effect. Also, the compounds of the invention can provide reduction in oxidative stress and lipid peroxidation as determined by the level of associated biomarkers: 8-hydroxy-deoxyguanosine (80hdG), malondialdehyde and 4- hydroxy-2-nonenal (4HNE). Finally, inflammatory cytokines, TNFa and IL-6, can be reduced while the levels of glutathione (GSH) in the liver and the kidney are restored.
  • GSH glutathione
  • conjugates comprising an antioxidant agent and an inflammatory agent would prevent glucose toxicity and progression of diabetes mellitus associated with ⁇ beta-cell failure overtime.
  • the capacity of conjugates according to certain embodiments of the invention to alter development of disease in this Type 2 diabetic animal model is assessed.
  • pancreas and white adipose tissue were evaluated in in mice orally dosed with the compound described in Example l b (GMC-299).
  • the effect on the pancreas weight (also pancreas weight as a percentage of body weight) is disclosed in Figure 4; the effect on the epididymal (epi) white adipose tissue (WAT) weight is dislcosed in Figure 5.
  • Example lb The compound described in Example lb (GMC-299) was evaluated orally in mice for intraperitoneal insulin tolerance (ipITT) and intraperitoneal glucose tolerance (ipGTT) (Figure 6)
  • Example l b The compound described in Example l b (GMC-299) was evaluated orally in mice for the fasting glycemia at day 15, 20 and 23 (Figure 7), fasting insulinemia at day 15 and 23(Figure 8), and total glycemia and insulinemia at day 27 (Figure 9).
  • Example l b The compound described in Example l b (GMC-299) was evaluated for various markers in plasma.
  • Figure 10 illustrates the level of plasma C-peptide, plasma Adiponectin, plasma triacylglycerol (plasma TAG), and plasma non-esterified fatty acids (plasma NEFA) in treated mice.
  • Figure 1 1 illustrates the level of plasma C-Reactive Protein (plasma CRP) and percent of HblAc in treated mice. Plasma Cholesterol Levels
  • Conjugates of the invention can have beneficial effects in Type 2 diabetic animal models as compared to control animals, including hypolipidemic and anti-diabetic effects as well as antioxidant properties in different animal models of diabetes useful in preventing the development of ⁇ -cell failure and aggravation of the diabetic status leading to cardiovascular complications. Such effects support therapeutic utility of conjugates comprising an antioxidant agent and an anti-inflammatory agent as described hereinl.
  • additive and/or synergism effects of these conjugates allow for the decrease dosing of each independent active ingredient.
  • These additive and/or synergistic effects reduce the liability of side effects associated with a salicylate agent, gastric bleeding, or an antioxidant, tinnitus, given to a patient alone.

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Abstract

La présente invention concerne des conjugués de formule (I), constitués d'un agent anti-inflammatoire et d'un agent antioxydant, comprenant la formule (i), (ii) ou (iii), où L est CH2CH2 et les autres variables sont définies dans les revendications. Dans un autre aspect, la présente invention concerne des méthodes permettant de traiter les troubles métaboliques avec ces conjugués.
PCT/EP2012/068178 2011-09-16 2012-09-14 Conjugués anti-inflammatoires et antioxydants permettant de traiter les troubles métaboliques WO2013037984A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1506934A (en) * 1974-03-28 1978-04-12 Blum J Derivatives of 3-amino-dihydrothiophen-2-one
EP0080229A1 (fr) 1981-11-20 1983-06-01 Pietro Isnardi & C. Spa Dérivés salicyliques de N-acétylcystéine
BE900328A (fr) 1983-08-09 1984-12-03 Guidotti & C Spa Labor Derives de la n-acetylcysteine et de la s-carboxymethylcysteine, leur preparation et compositions en contenant.
EP0301474A2 (fr) 1987-07-30 1989-02-01 Magis Farmaceutici S.P.A. Dérivés de cystéine doués d'une activité expectorante
US20060166901A1 (en) * 2005-01-03 2006-07-27 Yu Ruey J Compositions comprising O-acetylsalicyl derivatives of aminocarbohydrates and amino acids
US20090298923A1 (en) * 2008-05-13 2009-12-03 Genmedica Therapeutics Sl Salicylate Conjugates Useful for Treating Metabolic Disorders
WO2010106082A1 (fr) 2009-03-16 2010-09-23 Genmedica Therapeutics Sl Conjugués anti-inflammatoires et anti-oxydants utiles pour traiter des troubles métaboliques

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1506934A (en) * 1974-03-28 1978-04-12 Blum J Derivatives of 3-amino-dihydrothiophen-2-one
EP0080229A1 (fr) 1981-11-20 1983-06-01 Pietro Isnardi & C. Spa Dérivés salicyliques de N-acétylcystéine
BE900328A (fr) 1983-08-09 1984-12-03 Guidotti & C Spa Labor Derives de la n-acetylcysteine et de la s-carboxymethylcysteine, leur preparation et compositions en contenant.
EP0301474A2 (fr) 1987-07-30 1989-02-01 Magis Farmaceutici S.P.A. Dérivés de cystéine doués d'une activité expectorante
US20060166901A1 (en) * 2005-01-03 2006-07-27 Yu Ruey J Compositions comprising O-acetylsalicyl derivatives of aminocarbohydrates and amino acids
US20090298923A1 (en) * 2008-05-13 2009-12-03 Genmedica Therapeutics Sl Salicylate Conjugates Useful for Treating Metabolic Disorders
WO2010106082A1 (fr) 2009-03-16 2010-09-23 Genmedica Therapeutics Sl Conjugués anti-inflammatoires et anti-oxydants utiles pour traiter des troubles métaboliques

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Title
"IUPAC 1974 Recommendations for Section E", FUNDAMENTAL STEREOCHEMISTRY, PURE APPL. CHEM., vol. 45, 1976, pages 13 - 30
"Methods in Cell Biology", vol. XIV, 1976, ACADEMIC PRESS, pages: 33
ERNEST L. ELIEL; SAMUEL H. WILEN: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS, INC., pages: 112
GOODMAN; GILMAN'S: "The Pharmacological Basis of Therapeutics"

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