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WO2005028488A1 - Composes heteroaryle phosphinyle et thiophosphinyle utiles dans la regulation des taux de glucose, triglycerides et ldl/hdl - Google Patents

Composes heteroaryle phosphinyle et thiophosphinyle utiles dans la regulation des taux de glucose, triglycerides et ldl/hdl Download PDF

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Publication number
WO2005028488A1
WO2005028488A1 PCT/US2004/029701 US2004029701W WO2005028488A1 WO 2005028488 A1 WO2005028488 A1 WO 2005028488A1 US 2004029701 W US2004029701 W US 2004029701W WO 2005028488 A1 WO2005028488 A1 WO 2005028488A1
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Prior art keywords
methyl
oxide
pyrid
bis
fluorophenyl
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PCT/US2004/029701
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English (en)
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Alexander J. Bridges
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Quatrx Pharmaceuticals Co.
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Publication of WO2005028488A1 publication Critical patent/WO2005028488A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
    • C07F9/65392—Five-membered rings containing two nitrogen atoms
    • C07F9/65397—Five-membered rings containing two nitrogen atoms having the two nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4025—Esters of poly(thio)phosphonic acids
    • C07F9/4028—Esters of poly(thio)phosphonic acids containing no further substituents than -PO3H2 groups in free or esterified form
    • C07F9/4031—Acyclic unsaturated derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/653—Five-membered rings
    • C07F9/65306—Five-membered rings containing two nitrogen atoms
    • C07F9/65318—Five-membered rings containing two nitrogen atoms having the two nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65848—Cyclic amide derivatives of acids of phosphorus, in which two nitrogen atoms belong to the ring

Definitions

  • the present invention relates to phosphoms-containing compounds, pharmaceutical formulations comprising phosphoms-containing compounds, and uses thereof. More specifically, the present invention relates to aryl and heteroaryl phosphonates, processes for their preparation, pharmaceutical formulations comprising them, and their use in methods of regulating plasma levels of glucose, triglycerides, and/or HDL/LDL.
  • BACKGROUND OF THE INVENTION Compounds that can bind as ligands for a variety of nuclear hormone receptors, particularly to a sub-family of nuclear hormone receptors that are activated by ligand binding and heterodimerization with retinoid X receptor (RXR) nuclear hormone receptors can be effective in regulating metabolic processes.
  • RXR retinoid X receptor
  • Such receptors include peroxisome proliferator activated receptor (PPAR ⁇ , PPAR ⁇ , PPAR ⁇ ), farnesoid X receptor (FXR), liver X receptor (LXR ⁇ , LXR ⁇ ), vitamin D receptor (VDR), thyroid hormone receptor (TR), and retinoic acid receptor (RAR). These receptors are important regulators of metabolism, and are involved in multiple signal transduction pathways.
  • compounds that modulate these receptors can be useful drags for treatment of a wide range of metabolic disorders, including, for example, hypercholesteremia, hypertriglyceridemia, low HDL-C atherosclerosis, hyperglycemia, syndrome X, hyperinsulinemia, and diabetes.
  • Aralkyl phosphonates have been disclosed with biological activity in a variety of metabolic disease states. For example, some phosphonates reduce total plasma concentrations of cholesterol in many species, [Phan, et al., WO 02/26752]. This effect is caused by major reductions in the plasma Low Density Lipoprotein (LDL-C) fraction.
  • LDL-C Low Density Lipoprotein
  • Lp(a) a LDL-like lipoprotein wherein the major lipoprotein, apo B-100, is covalently linked to an unusual glycoprotein, apoprotien(a), in blood.
  • apo(a) a LDL-like lipoprotein wherein the major lipoprotein, apo B-100
  • apoprotien(a) an unusual glycoprotein, apoprotien(a) in blood.
  • the covalent association between apo(a) and apo B to fonn Lp(a) is a secondary event which is independent of the plasma concentration of apo B. Due to its structural similarity to plasminogen, apo(a) interferes with the normal physiological thrombosis-hemostasis process by preventing thrombolysis, that is clot dissolution.
  • Lp(a) where the LDL lipoprotein is linked to apo(a), is thought to be responsible for its atherogenic and thrombogenic activities. Furthermore, aralkyl phosphonates have been disclosed which raise the amount of the High Density Lipoprotein in serum, [Phan et al. WO 03/070169]. Increases in HDL are strongly co ⁇ elated with decreased cardiovascular disease risk in man, although to date only niacin has been shown to raise HDL in humans by 20% or more.
  • HDL-C Reverse Cholesterol Transport
  • these macrophages ingest lipid residues on the surface of the intima, and then secrete cholesterol which is incorporated into HDL particles, where they are turned into cholesteryl esters, and then absorbed into the liver through SR-B1 scavenger receptors.
  • SR-B1 scavenger receptors Once in the liver, a major route of cholesterol disposal is conversion into bile acids and secretion in bile. In atherosclerotic lesions, this process appears to become highly disregulated, and the macrophages absorb large amounts of lipid, but do not successfully package it into HDL, with the result that they fill up with cholesterol-rich lipids and become foam cells, a major component ofthe atherosclerotic plaque.
  • 03/070179 also cause macrophages to secrete large quantities of Apo E.
  • This apolipoprotein is a minor component of HDL, and may well be involved in RCT from macrophages and the arterial intima.
  • ApoE -/- mice atherosclerotic disease occurs very quickly, and the disease progression can be halted by transfecting Apo E back into the mice, suggesting that Apo E is cardioprotective.
  • Apo E has been shown to have strong antioxidant properties, and may be be useful in neuroprotective indications.
  • cholesterol is secreted from the liver as bile acids, which are derived from cholesterol by a series of oxidative steps.
  • Bile acids When bile acids are secreted from the liver, they also contain cholesterol itself, which can either be excreted or reabsorbed lower in the GI tract. Bile acids turn out to be ligands for the FXR receptor, one of the RXR heterodimerizing nuclear hormone receptors. FXR controls a lot of genes involved in cholesterol homeostasis, and the bile acid/FXR interaction is undoubtedly one of the most important feedback loops in cholesterol homeostasis. Many tissues either do not rely on HDL at all, or only in part for RCT. The other major pathway of cholesterol secretion from tissues is side chain hydroxylation of cholesterol, to give the so-called oxysterols. These compounds have considerably more water solubility than cholesterol itself, and have carrier proteins in plasma.
  • the LXR heterodimeric nuclear hormone receptor is an oxysterol receptor, and controls many genes involved in cholesterol homeostasis, similar to FXR.
  • the PPAR family of RXR-heterodimerizing nuclear hormone receptors is very important in metabolic regulation.
  • PPAR ⁇ is the target of the fibrate drugs, which can raise HDL, and marginally lower LDL, and also strongly reduce triglycerides.
  • PPAR ⁇ agonists have also been revealed to have anti-obesity effects, presumably due to their effects on lipid metabolism [Willson, US Patent 6.028,109].
  • PPAR ⁇ agonists such as Rosiglitazone and Pioglitazone are marketed for lowering blood glucose in diabetics. These compounds can also show effects on semm cholesterol and triglycerides, both of which were lowered by Troglitazone, but raised by Rosiglitazone.
  • PPAR ⁇ is less well characterized than the other PPARs, it also appears to be strongly involved in metabolic regulation and there are claims that using PPAR ⁇ agonists leads to lower total cholesterol levels [Shimokawa et al., US Patent 6,300,364].
  • Retinoids such as Accutane, also have effects on metabolism, with raised triglyceride levels being a major side effect of Accutane treatment.
  • the compounds of the cu ⁇ ent invention are phosphorus- based ligands for several of these receptors, and therefore are useful in treating metabolic disease conditions, and the diseases which arise from metabolic imbalances such as atherosclerosis.
  • the present invention provides aryl and heteroaryl phosphorus-containing compounds, or pharmaceutically acceptable salts thereof, ofthe Formula (I):
  • A is a bond, O, CH 2 , CHF, CF 2 , or NR 6 ;
  • D is a) H or lower alkyl, wherein the L— C bond is a single bond; or b) OH, OCOR 5 , NH 2 , NR 6 R 6a , or NHCOR 5 , wherein the L ⁇ ' C bond is a single bond, with the proviso that A is CH 2 , CHF, CF 2 ;
  • L is a) NR 6 , CR 7 R 8 , -OCR 7 R 8 -, -NR 6 CR 7 R 8 -, or -S(0) m CR 7 R 8 -, wherein the L ⁇ C bond is a single bond; or b) CR 7 , whenin the L— C bond is a double bond, with the proviso that D is absent
  • G is a bond, O, NR 6 , CO, C0 2 , OCO, OC0 2 , S(0) m , CONR 6
  • the present invention also relates to pharmaceutical formulations comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, excipient, solvent, adjuvant or diluent.
  • the present invention further relates to methods of regulating HDL and or LDL cholesterol levels in a subject comprising administering to a subject a compound, or pharmaceutical formulation comprising a compound, of Formula (I) or pharmaceutically acceptable salt thereof.
  • the invention relates to methods of lowering blood triglyceride and/or glucose levels in a subject comprising administering to a subject in need of such treatment an effective amount of a compound, or pharmaceutical formulation comprising a compound, of Formula (I) or pharmaceutically acceptable salt thereof.
  • the invention also relates to methods of treating disease states related to blood levels of HDL/LDL levels, triglycerides, and or glucose in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound, or pharmaceutical formulation comprising a compound, of Formula (I), or pharmaceutically acceptable salt thereof.
  • a “therapeutically effective” amount is defined as an amount effective to reduce or lessen at least one symptom of the disease being treated or to reduce or delay onset of one or more clinical markers or symptoms ofthe disease.
  • the singular forms "a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.
  • reference to a composition containing “a compound” includes a mixture of two or more compounds.
  • the term “or” is generally employed in its sense including “and or” unless the content clearly dictates otherwise.
  • alkyl and “C 1 -G5 alkyl” in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2- hexyl, 3-hexyl, and 3-methylpentyl. It is understood that in cases where an alkyl chain of a substituent (e.g.
  • alkyl, alkoxy or alkenyl group is shorter or longer than 6 carbons, it will be so indicated in the second “C” as, for example, “Cr o indicates a maximum of 10 carbons.
  • halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
  • alkenyl and C 2 -C 6 alkenyl means straight and branched hydrocarbon groups having from 2 to 6 carbon atoms and from one to three double bonds and includes, for example, ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the like.
  • cycloalkyl refers to saturated carbocyclic groups having three to twelve carbon atoms.
  • the cycloalkyl can be monocyclic, or a polycyclic fused system. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the cycloalkyl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • such cycloalkyl groups may be optionally substituted with, for example, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C]-C 6 )alkylamino, di(C ⁇ -C 6 )alkylamino, C 2 -C6alkenyl, C 2 -C6alkynyl, C ⁇ -C 6 haloalkyl, C ⁇ -C 6 haloalkoxy, amino(C ⁇ -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C6)alkyl or di(C 1 -C 6 )alkylamino(C ⁇ -C 6 )alkyl.
  • the present invention relates to phosphoms-containing compounds of Formula (I):
  • A is a bond, O, CH 2 , CHF, CF 2 , or NR 6 ;
  • D is a) H or lower alkyl, wherein the L— C bond is a single bond; or b) OH, OCOR 5 , NH 2 , NR 6 R 6a , or NHCOR 5 , wherein the L ⁇ C bond is a single bond, with the proviso that A is CH 2 , CHF, CF 2 ;
  • L is a) NR 6 , CR 7 R 8 , -OCR 7 R 8 -, -NR 6 CR 7 R 8 -, or -S(0) m CR 7 R 8 -, wherein the L— C bond is a single bond; or b) CR 7 , whenin the L— C bond is a double bond, with the proviso that D is absent when
  • G is a bond, O, NR 6 , CO, C0 2 , OCO, OC0 2 , S(0) m , CONR 6 , NR 6 CO, NR 6 C0 2 , OCONR 6 , NR 6 CONR 6a , or G can optionally be attached to Ar 2 at two contiguous C atoms to form a 5- to 7-membered partially saturated ring, which contains 0, 1, or 2 heteroatoms selected from the group consisting of O, N, and S; X, X 1 are independently O or S
  • Z 2 is nothing, H or Ar 1 optionally substituted with Y 1 and Y 2 ;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from H, -C ⁇ lower alkyl, C 3 -C 6 lower alkenyl, C -C 6 lower alkynyl, C 3 -C 6 lower cycloalkyl, C 4 -C 6 lower cycloalkenyl, or independently R 1 and R 2 or R 3 and R 4 can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group Ci- C 4 lower alkyl, C ⁇ -C 4 lower alkoxy, C ⁇ -C 4 lower alkylamino, C ⁇ -C 4 lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl; U and V are each independently a bond, O or NR ; R 5 R 6 and R 6
  • Z 2 is nothing, H or Ar 1 optionally substituted with Y 1 and Y 2 ;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from H, -C ⁇ lower alkyl, C 3 -C 6 lower alkenyl, C 3 -C 6 lower alkynyl, C 3 -C 6 lower cycloalkyl, C 4 -C 6 lower cycloalkenyl, or independently R 1 and R 2 or R 3 and R 4 can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group Ci- C lower alkyl, C C 4 lower alkoxy, Ci-C 4 lower alkylamino, C ⁇ -C lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl;
  • R 5 R 6 and R 6a are each independently C ⁇ -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -Ce alkenyl, C 3 -C 6 cycloalkenyl, C 3 -C 6 alkynyl, and H;
  • R 7 and R 8 are each independently H, C ⁇ -C 4 lower alkyl, or are taken together to form a saturated C 3 -C ⁇ carbocyclic ring;
  • R f is C ⁇ -C straight or branched lower perfluoroalkyl; all lower alkyl, alkenyl and alkynyl groups including those linked via heteroatoms can be straight chain or branched;
  • m is 0, 1, or 2;
  • n is O, 1, 2, 3, 4, 5, or 6;
  • o is O, 1, 2, 3, 4, 5, or 6;
  • p is 0, 1, 2, 3, 4, 5, or 6; and
  • q is O, 1, 2, 3, 4, 5, or 6; with the provisos that when A is
  • the compound of Formula (I) is selected from: Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2- ⁇ N-methyl-N-pyrid-2-ylamino ⁇ etl ⁇ oxy]-3- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[ ⁇ -(2- ⁇ N-methyl-N-pyrid-2-ylamino ⁇ ethyl)-N- methylaminocarbonyl]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[3 - ⁇ N-methyl-N-pyrid-2-ylamino ⁇ - 1 -oxoprop- 1 - yl]-3-fluorophenyl)methylphosphonate;
  • the compounds of Formula (I) may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers. All isomeric forms are included within the scope ofthe present invention.
  • the invention relates to pharmaceutical formulations comprising a compound, or pharmaceutically acceptable salt thereof, of Formula (I):
  • A is a bond, O, CH 2 , CHF, CF 2 , or ⁇ R 6 ;
  • D is a) H or lower alkyl, wherein the L— C bond is a single bond; or b) OH, OCOR 5 , NH 2 , NR 6 R 6a , or NHCOR 5 , wherein the L " C bond is a single bond, with the proviso that A is CH 2 , CHF, CF 2 ;
  • L is a) NR 6 , CR 7 R 8 , -OCR 7 R 8 -, -NR 6 CR 7 R 8 -, or -S(0) m CR 7 R 8 -, wherein the L ⁇ C bond is a single bond; or b) CR 7 , whenin the L— C bond is a double bond, with the proviso that D is absent
  • the pharmaceutical formulation comprises a compound of Formula (I) selected from: Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2- ⁇ N-methyl-N-pyrid-2-ylamino ⁇ ethoxy]-3- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[ ⁇ -(2- ⁇ N-methyl-N-pyrid-2-ylamino ⁇ ethyl)-N- methylaminocarbonyl] -3 -fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[3 - ⁇ N-methyl-N-pyrid-2-ylamino ⁇ - 1 -oxoprop- 1 - yl]-3-fluorophenyl)methylphosphonate; Diethyl
  • the invention provides methods for treating disease states related to HDL and/or LDL cholesterol levels in blood, comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the invention, or pharmaceutical formulation comprising a compound ofthe invention, or a pharmaceutically acceptable salt thereof.
  • the method can optionally comprise in combination with the compound of Formula (I), pharmaceutical formulation comprising a compound of Formula (I), or pharmaceutically acceptable salts thereof, an effective amount of a compound known to regulate HDL and/or LDL levels in blood.
  • Such known compounds include the non-limiting classes of compounds such as statins, for example, lovastatin, simvastatin, pravastatin, atorvastatin, cerivastatin, and niacin; fibrates, for example, clofibrate, bezafibrate, and gemfibrozil; bile acid sequestrants, for example, cholestyramine; and cholesterol uptake inhibitors, for example, phytosteroids, and ezitimibe.
  • statins for example, lovastatin, simvastatin, pravastatin, atorvastatin, cerivastatin, and niacin
  • fibrates for example, clofibrate, bezafibrate, and gemfibrozil
  • bile acid sequestrants for example, cholestyramine
  • cholesterol uptake inhibitors for example, phytosteroids, and ezitimibe.
  • the invention provides methods for lowering triglyceride levels in blood, comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the invention, or pharmaceutical formulation comprising a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the method can optionally comprise in combination with the compound of Formula (I), pharmaceutical formulation comprising a compound of Formula (I), or pharmaceutically acceptable salts thereof, an effective amount of a compound known to lower triglyceride levels in blood.
  • known compounds include the non-limiting example of fibrates, for example, clofibrate, bezafibrate, and gemfibrozil.
  • the invention provides methods for lowering glucose levels in blood, comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the invention, or pharmaceutical formulation comprising a compound ofthe invention, or a pharmaceutically acceptable salt thereof.
  • the method can optionally comprise in combination with the compound of Formula (I), pharmaceutical formulation comprising a compound of Formula (I), or pharmaceutically acceptable salts thereof, an effective amount of a compound known to lower glucose levels in blood.
  • known compounds include the non-limiting classes glitazones, such as rosiglitazone and pioglitazone; sulfonylureas; insulin; and metformin.
  • the methods of treatment can treat an existing metabolic disease, such as hypercholesteremia, hypertriglyceridemia, low HDL-C atherosclerosis, hyperglycemia, syndrome X, hyperinsulinemia, and diabetes.
  • the methods of freatment can prevent a metabolic disease, such as hypercholesteremia, hypertriglyceridemia, low HDL-C atherosclerosis, hyperglycemia, syndrome X, hyperinsulinemia, and diabetes, from developing or progressing.
  • the subject is a mammal. In a more prefe ⁇ ed embodiment, the mammal is a human.
  • the methods of the invention employ therapeutically effective amounts: for oral, parenteral, sublingual, intranasal, infrathecal, depo, implants, topical, and rectal administration from about 0.1 mg day to about 5,000 mg/day.
  • the therapeutically effective amounts will vary according to various parameters including, for example, the particular therapeutic use and physical characteristics of the subject/patient, and are well within the knowledge of those skilled in the art.
  • the therapeutically effective amounts for oral, parenteral, and depo administration is from about 50 mg/day to about 500 mg/day.
  • the present invention also includes the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in treating a subject who has, or in preventing a subject from developing, a metabolic disease, condition, or disorder, such as, for example, hypercholesteremia, hypertriglyceridemia, low HDL-C atherosclerosis, hyperglycemia, syndrome X, hyperinsulinemia, and diabetes and who is in need of such treatment.
  • a metabolic disease, condition, or disorder such as, for example, hypercholesteremia, hypertriglyceridemia, low HDL-C atherosclerosis, hyperglycemia, syndrome X, hyperinsulinemia, and diabetes and who is in need of such treatment.
  • this use of a compound of formula (I) can be employed where the disease is hypercholesteremia.
  • this use of a compound of formula (I) can be employed where the disease is hypertriglycertidemia.
  • this container kit includes each container adapted for oral delivery and includes a tablet, gel, or capsule. In an embodiment, this container kit includes each container adapted for parenteral delivery and includes a depot product, syringe, ampoule, or vial. In an embodiment, this container kit includes each container adapted for topical delivery and includes a patch, medipad, ointment, or cream.
  • the present invention also includes an agent kit including a compound of formula (I), or a pharmaceutically acceptable salt thereof; and one or more therapeutic agents selected from the group consisting of statins, fibrates, bile acid sequestrants, cholesterol uptake inhibitors, glitazones, sulfonylureas, insulin, and metformin.
  • the compounds of formula (I) can form salts when reacted with appropriate acids or bases.
  • Pharmaceutically acceptable salts are generally prefe ⁇ ed over the corresponding compounds of formula (I) since they frequently produce compounds that are usually more water soluble, stable and/or more crystalline.
  • Pharmaceutically acceptable salts are any salt which retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to whom it is administered and in the context in which it is administered.
  • Pharmaceutically acceptable salts include acid addition salts of both inorganic and organic acids.
  • Prefe ⁇ ed pharmaceutically acceptable salts include salts such as those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such salts may be formed from inorganic and organic acids.
  • Representative examples thereof include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
  • succinic methanesulfonic, ethanedisulfonic
  • acetic propionic
  • tartaric salicylic
  • citric gluconic
  • aspartic aspartic
  • stearic palmitic
  • itaconic glycolic
  • p-aminobenzoic glutamic
  • benzenesulfonic hydrochloric, hydrobromic, sulfuric, cyclo
  • the compounds of the invention are useful for treating mammals suffering from a disease or condition characterized by at least one pathological fo ⁇ n of abnormal HDL and/or LDL levels, triglyceride levels, and/or glucose levels in blood, and are useful for helping to prevent or delay the onset of such a condition.
  • the compounds and formulations of the invention are particularly useful for treating, preventing, or slowing the progression of metabolic disorders, including, for example, hypercholesteremia, hypertriglyceridemia, low HDL-C atherosclerosis, hyperglycemia, syndrome X, hyperinsulinemia, and diabetes.
  • the compounds of the invention can either be used individually or in combination, as is best for the subject.
  • the term “treating” means that compounds of the invention can be used in subjects, preferably human subjects/patients, with existing disease.
  • the compounds ofthe invention will not necessarily cure the subject who has the disease but will delay or slow the progression or prevent further progression of the disease thereby giving the individual a more useful life span.
  • the term “preventing” means that that if the compounds of the invention are administered to those who do not now have the disease but who would normally develop the disease or be at increased risk for the disease, they will not develop the disease.
  • "preventing” also includes delaying the development of the disease in an individual who will ultimately develop the disease or would be at risk for the disease due to age, familial history, genetic or chromosomal abnormalities, and/or due to the presence of one or more biological markers for the disease.
  • compounds ofthe invention can prevent the individual from getting the disease during the period in which the individual would normally have gotten the disease or reduce the rate of development of the disease or some of its effects but for the administration of compounds of the invention up to the time the individual ultimately gets the disease.
  • Preventing also includes administration of the compounds of the invention to those individuals thought to have predisposition for the disease. In a prefe ⁇ ed aspect, the compounds of the invention are useful for slowing the progression of disease symptoms.
  • the compounds of the invention are useful for preventing the further progression of disease symptoms.
  • the compounds of the invention are administered in a therapeutically effective amount.
  • the therapeutically effective amount will vary depending on the particular compound used and the route of administration, as is known to those skilled in the art.
  • a physician may administer a compound of the invention immediately and continue administration indefinitely, as needed.
  • Dosage Forms and Amounts The compounds ofthe invention can be administered orally, parenterally, (IN, IM, depo-IM, SQ, and depo SQ), sublingually, intranasally (inhalation), intrathecally, topically, or rectally.
  • compositions are provided that contain therapeutically effective amounts of the compounds of the invention.
  • the compounds are preferably formulated into suitable pharmaceutical preparations such as tablets, capsules, or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration.
  • suitable pharmaceutical preparations such as tablets, capsules, or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration.
  • the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art.
  • About 1 to 500 mg of a compound or mixture of compounds ofthe invention or a physiologically acceptable salt or ester is compounded with a physiologically acceptable vehicle, ca ⁇ ier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 2 to about 100 mg, more preferably about 10 to about 30 mg of the active ingredient.
  • unit dosage from refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • a suitable phannaceutically acceptable carrier Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion, or the like.
  • Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for lessening or ameliorating at least one symptom of the disease, disorder, or condition treated and may be empirically determined.
  • Pharmaceutical ca ⁇ iers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
  • the active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, or have another action.
  • the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. Where the compounds exhibit insufficient solubility, methods for solubilizing may be used. Such methods are known and include, but are not limited to, using cosolvents such as dimethylsulfoxide (DMSO), using surfactants such as Tween®, and dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts or prodmgs may also be used in formulating effective pharmaceutical compositions. The concentration of the compound is effective for delivery of an amount upon administration that lessens or ameliorates at least one symptom of the disorder for which the compound is administered. Typically, the compositions are formulated for single dosage administration.
  • the compounds of the invention may be prepared with carriers that protect them against rapid elimination from the body, such as time-release formulations or coatings. Such carriers include controlled release formulations, such as, but not limited to, microencapsulated delivery systems.
  • the active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the subject treated.
  • the therapeutically effective concentration may be determined empirically by testing the compounds in known in vitro and in vivo model systems for the treated disorder.
  • the compounds and compositions of the invention can be enclosed in multiple or single dose containers.
  • the enclosed compounds and compositions can be provided in kits, for example, including component parts that can be assembled for use.
  • kits may include a compound inhibitor and a second therapeutic agent for co-administration.
  • the inhibitor and second therapeutic agent may be provided as separate component parts.
  • a kit may include a plurality of containers, each container holding one or more unit dose of the compound of the invention.
  • the containers are preferably adapted for the desired mode of administration, including, but not limited to tablets, gel capsules, sustained-release capsules, and the like for oral administration; depot products, pre-filled syringes, ampoules, vials, and the like for parenteral administration; and patches, medipads, creams, and the like for topical administration.
  • the concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated.
  • the compound should be provided in a composition that protects it from the acidic environment of the stomach.
  • the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
  • the composition may also be fo ⁇ nulated in combination with an antacid or other such ingredient.
  • Oral compositions will generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules.
  • the active compound or compounds can be incorporated with excipients and used in the form of tablets, capsules, or troches.
  • Phannaceutically compatible binding agents and adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches, and the like can contain any of the following ingredients or compounds of a similar nature: a binder such as, but not limited to, gum tragacanth, acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose, starch, or lactose; a disintegrating agent such as, but not limited to, alginic acid and com starch; a lubricant such as, but not limited to, magnesium stearate; a gildant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, or fruit flavoring.
  • a binder such as, but not limited to, gum tragacanth, acacia, corn starch, or gelatin
  • an excipient such as microcrystalline cellulose, starch, or lactose
  • a disintegrating agent such as, but not limited to, al
  • dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can contain various other materials, which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
  • the compounds can also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors.
  • the active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, and the like, or a synthetic fatty vehicle such as ethyl oleate, and the like, polyethylene glycol, glycerine, propylene glycol, or other synthetic solvent; antimicrobial agents such as benzyl alcohol and methyl parabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; and agents for the adjustment of tonicity such as sodium chloride and dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil
  • parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass, plastic, or other suitable material. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
  • suitable carriers include physiological saline, phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, polypropyleneglycol, and mixtures thereof.
  • Liposomal suspensions including tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known for example, as described in U.S. Patent No. 4,522,811.
  • the active compounds may be prepared with ca ⁇ iers that protect the compound against rapid elimination from the body, such as time-release formulations or coatings.
  • ca ⁇ iers include controlled release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers such as collagen, ethylene vinyl acetate, polyarihydrides, polyglycolic acid, polyorthoesters, polylactic acid, and the like. Methods for preparation of such formulations are known to those skilled in the art.
  • the compounds of the invention can be administered orally, parenterally (IV, IM, depo-IM, SQ, and depo-SQ), sublingually, intranasally (inhalation), intrathecally, topically, or rectally.
  • Dosage forms known to those skilled in the art are suitable for delivery of the compounds of the invention.
  • Compounds ofthe invention may be administered enterally or parenterally.
  • compounds of the invention can be administered in usual dosage forms for oral adminisfration as is well known to those skilled in the art.
  • These dosage forms include the usual solid unit dosage forms of tablets and capsules as well as liquid dosage forms such as solutions, suspensions, and elixirs.
  • the solid dosage forms When the solid dosage forms are used, it is prefe ⁇ ed that they be ofthe sustained release type so that the compounds of the invention need to be administered only once or twice daily.
  • the oral dosage forms are administered to the subject 1, 2, 3, or 4 times daily.
  • the compounds of the invention be administered either three or fewer times, more preferably once or twice daily.
  • the compounds of the invention be administered in oral dosage form.
  • whatever oral dosage form is used that it be designed so as to protect the compounds of the invention from the acidic environment of the stomach.
  • Enteric coated tablets are well known to those skilled in the art.
  • capsules filled with small spheres each coated to protect from the acidic stomach are also well known to those skilled in the art.
  • the compounds of the invention can be present as mixtures of isomers, especially as racemates, or in the form of pure isomers, especially optical antipodes.
  • Salts of compounds are preferably the pharmaceutically acceptable or non-toxic salts of compounds of formula I.
  • For isolation and purification purposes it is also possible to use pharmaceutically unacceptable salts.
  • Synthesis of Compounds The compounds useful in the methods of the invention can be synthesized using the procedures set forth in Schemes I- VI below. Those skilled in the art will appreciate that minor modifications may be made to the specific procedures in that article to arrive at compounds useful in the invention. Compounds ofthe present invention can be made by a variety of routes.
  • Phosphite species most of which are known to add across carbonyls, include diesters, cyclic esters, diamides, [Evans et al., Tetrahedron Letters (1977), (29), 2495-8.] cyclic diamides, [Pudovik et al., Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1980), (5), 1183- 5.], and chiral cyclic phosphinamidoates, Sum, V.; Kee, T. P., Journal of the Chemical Society, Perkin Transactions 1 (1993), (22), 2701-11.], as well as thiophosphites [Pudovik, A.
  • 1,1-bisphosphonates may also be made from anions derived from the co ⁇ esponding diphosphonylated methane derivatives, [Vepsalainen et al., Acta Chemica Scandinavica (1997), 51(9), 932-937.] which can be alkylated [Pohjala et al., PCT Int. Appl. (1992), WO 9211269 Al US Patent 5,393,748. Hutchinson, D.
  • 1,2-Bisphosphonates can be made from aldehydes by Horner- Emmons reaction to produce a vinyl phosphonate, [Minami, T.; Motoyoshiya, J., Synthesis (1992), (4), 333-49. Davis et al., Tetrahedron Letters (1998), 39(35), 6263- 6266.], followed by Michael addition of a second phosphite species.

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Abstract

L'invention porte sur des composés contenant du phosphore, sur des formulations pharmaceutiques comprenant ces composés et sur des méthodes d'administration de ces composés à des sujets. Les composés sont de formule (I) dans laquelle A, B, D, L, Ar1, Ar2, Y1, Y2, Z1, Z2, E, F, G, X, U, V, R1 et R2 son tels que définis dans le descriptif.
PCT/US2004/029701 2003-09-12 2004-09-10 Composes heteroaryle phosphinyle et thiophosphinyle utiles dans la regulation des taux de glucose, triglycerides et ldl/hdl WO2005028488A1 (fr)

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WO2008019309A1 (fr) * 2006-08-04 2008-02-14 Metabasis Therapeutics, Inc. Nouveaux inhibiteurs du fructose 1,6-bisphosphatase
US7514419B2 (en) 2003-11-19 2009-04-07 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
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US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
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US11202789B2 (en) 2016-11-21 2021-12-21 Viking Therapeutics, Inc. Method of treating glycogen storage disease
US11707472B2 (en) 2017-06-05 2023-07-25 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis
US11787828B2 (en) 2018-03-22 2023-10-17 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound
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Cited By (17)

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Publication number Priority date Publication date Assignee Title
US7514419B2 (en) 2003-11-19 2009-04-07 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
US7829552B2 (en) 2003-11-19 2010-11-09 Metabasis Therapeutics, Inc. Phosphorus-containing thyromimetics
US10130643B2 (en) 2005-05-26 2018-11-20 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US10925885B2 (en) 2005-05-26 2021-02-23 Metabasis Therapeutics, Inc. Thyromimetics for the treatment of fatty liver diseases
US7910747B2 (en) 2006-07-06 2011-03-22 Bristol-Myers Squibb Company Phosphonate and phosphinate pyrazolylamide glucokinase activators
US8153677B2 (en) 2006-07-06 2012-04-10 Bristol-Myers Squibb Company Substituted pyrazolylamide compounds useful as glucokinase activators
US8614332B2 (en) 2006-07-06 2013-12-24 Bristol-Myers Squibb Company Substituted pyrazolylamides useful as glucokinase activators
WO2008019309A1 (fr) * 2006-08-04 2008-02-14 Metabasis Therapeutics, Inc. Nouveaux inhibiteurs du fructose 1,6-bisphosphatase
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
USRE47193E1 (en) 2013-10-14 2019-01-08 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US11202789B2 (en) 2016-11-21 2021-12-21 Viking Therapeutics, Inc. Method of treating glycogen storage disease
US11707472B2 (en) 2017-06-05 2023-07-25 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis
US11787828B2 (en) 2018-03-22 2023-10-17 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound
US12227533B2 (en) 2018-03-22 2025-02-18 Viking Therapeutics, Inc. Crystalline forms and methods of producing crystalline forms of a compound
US12102646B2 (en) 2018-12-05 2024-10-01 Viking Therapeutics, Inc. Compositions for the treatment of fibrosis and inflammation

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